Double-target compound based on multi-mode analgesia, composition and application

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a dual-target compound based on multimode analgesia, a composition and application. According to the invention, active metabolite M1, loxoprofen sodium active metabolite (trans-OH body) and amino-acid ester hydrochloride which are generated by CYP2D6 enzyme metabolism of tramadol in the liver are used as raw materials, and esterification, hydrolysis and condensation reactions are carried out to finally prepare the twin drug compound of M1 and loxoprofen sodium active metabolite. The compound overcomes the problem of gastrointestinal irritation after loxoprofen sodium is orally taken and absorbed, and can reduce the problem of inaccurate M1 dosage caused by different CYP2D6 enzyme activity due to individual difference, so as to ensure a good analgesic effect and tolerability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a dual-target compound based on multi-modal analgesia, a composition and use. BACKGROUND

[0002] Pain is a sensation of discomfort or emotional expression produced by stimulation, which can be divided into two categories: chronic pain and acute pain. Chronic pain usually does not cause sympathetic excitation, but may be accompanied by some reactions of the autonomic nervous system, such as fatigue, decreased libido and decreased appetite, and may also cause emotional depression. Unlike chronic pain, acute pain is generally associated with damage to non-neural tissue, which may be due to inflammation after surgery or other forms of tissue damage, or conditions such as migraine.

[0003] Multi-modal analgesia strategy as an effective pain management method has been widely used in perioperative pain control. Multi-modal analgesia can achieve synergistic or additive effects of analgesia by combining different analgesic drugs and methods with different mechanisms of action, and can maximize the reduction of pain in patients. The American Society of Anesthesiologists (ASA) clearly recommends the use of multi-modal analgesia strategy in the guidelines released in 2012. Through multi-modal analgesia, the use of opioid drugs can be reduced, and moderate to severe pain can be effectively managed.

[0004] In the field of multi-modal analgesia, the combination of opioid drugs and non-steroidal anti-inflammatory drugs (NSAIDs) has been widely accepted. Tramadol, as a central-acting synthetic analgesic drug, is different from traditional opioid drugs and mainly exerts analgesic effect through two mechanisms. Tramadol has two isomers: (+) tramadol and (-) tramadol, the former is a μ opioid receptor agonist, and (+) tramadol and (-) tramadol inhibit the reuptake of central 5-hydroxytryptamine (5-HT) and norepinephrine (NE), respectively, and improve the inhibition of spinal pain transmission. The synergistic effect of the two isomers enhances the regulation of the central nervous system to pain, but may also cause 5-hydroxytryptamine syndrome, including changes in mental status (such as anxiety, hallucinations), autonomic nervous dysfunction (such as tachycardia, hypertension), neuromuscular abnormalities (such as tremor, hyperreflexia) and other adverse reactions.

[0005] In order to further optimize the analgesic effect of tramadol and reduce its adverse reactions, in recent years, there have been compound drug forms combining tramadol with NSAIDs. Patent CN105007907A discloses a pharmaceutical composition containing dexketoprofen and tramadol. Patent CN1086133A discloses a composition of acecarbromal and acetylamino benzene, and confirms that its analgesic activity has a synergistic effect. Such compound preparations have simple process, can reduce single drug dose, and reduce potential toxic side effects. However, compound drugs cannot change the physical and chemical properties of drugs, which limits the absorption, dissolution and other aspects of the drugs, affecting the full play of the efficacy of the drugs. To solve these problems, in 2021, FDA approved the listing of celecoxib hydrochloride tramadol tablets, which are in the form of co-crystals. Compared with the above-mentioned compound preparations, such co-crystal drugs change the pharmacokinetic properties of the drugs, reduce some of the side effects of tramadol, and provide a new method of safe and efficient pain management. Patent CN102946871A discloses a pharmaceutical composition of co-crystals of tramadol and celecoxib, which reduces the secondary effects (secondary effects) of tramadol while ensuring efficacy, thereby improving over the marketed form. Regarding celecoxib, both the absorption rate and extent are increased, but the number of drug-drug co-crystals is small, the preparation process is complex, and the quality control is difficult, which limits its large-scale production and application.

[0006] Currently marketed tramadol multimodal analgesic drugs are all combinations of NSAIDs and tramadol. Tramadol is mainly metabolized in the liver by the CYP2D6 enzyme system into the more active metabolite O-desmethyl tramadol M1. Metabolite M1 mainly produces analgesic effect by agonizing μ opioid receptors, with 200 times the affinity for μ opioid receptors than tramadol itself, and a longer half-life (about 9 hours, 6 hours for tramadol) but weaker inhibition of 5-HT reuptake. Therefore, selecting M1 can appropriately increase the analgesic effect while reducing adverse reactions caused by inhibition of 5-HT and NE reuptake.

[0007] However, the study on the influencing factors of CYP2D6 genotyping (Inspection Medicine, 2024, 39(03): 291-297.) reported that the genetic polymorphism of CYP2D6 brings about metabolic differences among individuals, leading to too fast or too slow metabolism of tramadol in some populations, affecting the rate and dose of O-desmethyl tramadol generation, and thus affecting drug efficacy and tolerance. For example, individuals with low metabolic activity may not achieve the desired analgesic effect due to insufficient drug metabolism, while individuals with high metabolic activity may increase the risk of side effects due to excessive production of metabolites.

[0008] Therefore, how to overcome the influence of CYP2D6 genetic polymorphism on the efficacy and safety of tramadol, and develop an analgesic drug that can adapt to patients of different genetic types, has low preparation and quality control difficulty, and is suitable for large-scale production, has become a problem to be solved. SUMMARY

[0009] To solve these problems, M1 is selected as a part of the components in the combination drug, which can effectively avoid the metabolic difference caused by CYP2D6 genetic polymorphism, thereby reducing the difference in drug response among individuals. In addition, the interaction of drugs (CYP2D6 enzyme substrates) can be reduced, and the incidence of adverse reactions caused by the inhibition of 5-HT and NE reuptake can be reduced. The reaction formula of tramadol hydrochloride metabolized into M1 is as follows:

[0010]

[0011] Loxoprofen is a liver metabolism type prodrug, which can be biotransformed into a hydroxyl metabolite with 3 chiral centers in vivo, theoretically generating 8 stereoisomers, of which (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl) methyl) phenyl) propanoic acid (trans-OH body) plays a major biological activity. The clearance rate of loxoprofen and its trans-hydroxyl active metabolite in the body is very fast after oral administration. From the perspective of efficacy and safety, direct use of the trans-hydroxyl active metabolite can effectively reduce the problem of gastrointestinal irritation after oral administration of sodium loxoprofen, improve the efficacy, and reduce related side effects.

[0012]

[0013] The purpose of the present application is to provide a new method for improving the performance of tramadol, and in particular, to treat pain by providing a new compound drug form in which M1 is chemically linked to the active metabolite (trans-OH body) of sodium loxoprofen, so as to achieve the best synergistic analgesic effect and reduce the adverse reactions of tramadol.

[0014] The present application aims to provide a compound, composition and use having synergistic analgesic effect. The compound exhibits high stability and high bioavailability in the treatment of pain, especially acute pain and neuropathic pain.

[0015] To achieve the above-mentioned purpose, the technical scheme of the present application is:

[0016] One of the purposes of the present application is to provide a compound represented by structural formula (I), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate,

[0017]

[0018] n = 0 or 1;

[0019] wherein linker is selected from the following structures:

[0020]

[0021] wherein R1and R2are the same or different and independently of each other selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5- to 8-membered heterocyclyl, C 6-8 aryl and 5- to 8-membered heteroaryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, 5- to 8-membered heterocyclyl, C 6-8 aryl and 5- to 8-membered heteroaryl can optionally be substituted with one, two or more halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl, C 6-8 aryl or 5- to 8-membered heteroaryl optionally substituted with C 1-6 alkyl.

[0022] According to embodiments of the present application, wherein R1and R2are the same or different and independently of each other selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 alkoxy can optionally be substituted with one, two or more fluorine, chlorine, bromine, iodine, hydroxy, amino or C 1-6 alkyl substituted phenyl.

[0023] According to embodiments of the present application, wherein R1and R2are the same or different and independently of each other selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl.

[0024] According to embodiments of the present application, wherein n = 0 the compounds of formula (I) are selected from the following structures:

[0025]

[0026] According to embodiments of the present application, wherein n = 1 the compounds of formula (I) are selected from the following structures:

[0027]

[0028]

[0029] The second object of the present application provides the use of the compound shown in formula (I), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate in the preparation of non-steroidal anti-inflammatory drugs.

[0030] According to the present application, the drug is used for treating acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe pain reduction, hyperalgesia, pain associated with central sensitization, allodynia, cancer pain, diabetic neuropathy or diabetic peripheral neuropathy, osteoarthritis, fibromyalgia, rheumatoid arthritis, ankylosing spondylitis, shoulder stiffness or sciatica.

[0031] The third object of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds shown in structural formula (I), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate.

[0032] The pharmaceutical composition is a tablet, capsule, granule, injection, eye drop, gel, cream, ointment or cataplasm.

[0033] According to the present application, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0034] According to the present application, the pharmaceutical composition is in the form of a preparation. Further, the pharmaceutical composition is a tablet, capsule, granule, injection, eye drop, gel, cream, ointment or cataplasm.

[0035] According to the present application, the pharmaceutical composition can further contain one or more additional therapeutic agents.

[0036] The present application also provides a preparation method of compounds 1-6, characterized by comprising the following steps: condensing (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl) methyl) phenyl) propionic acid with amino acid ester hydrochloride to form an amide, then hydrolyzing the ester group into an acid, and then condensing with O-desmethyl tramadol (M1) to form an ester, and finally obtaining the final product after purification treatment;

[0037] The present application also provides a preparation method of compounds 7-8, comprising the following steps: esterifying (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl) methyl) phenyl) propionic acid with 2-bromocarboxylic acid benzyl ester under alkaline conditions, then hydrogenating and debenzylizing to form a carboxylic acid, and finally condensing with O-desmethyl tramadol (M1) to form an ester, and finally obtaining the final product after purification treatment;

[0038] The present application also provides a preparation method of compound 9-12, comprising the following steps: O-desmethyl tramadol (M1) is subjected to esterification reaction with 2-bromine carboxylic acid, and then subjected to reaction with (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl) methyl) phenyl) propionic acid, and finally the end product is obtained through purification treatment.

[0039] According to the embodiments of the present application, the condensing agent in the condensation reaction is selected from at least one of the following: 1,3-dicyclohexyl carbodiimide (DCC); N,N'-carbonyldiimidazole (CDI); 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); 1-hydroxybenzotriazole (HOBT); 2-(7-azobenzotriazol)-tetramethyluronium hexafluorophosphate (HATU); O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU); 6-chlorobenzotriazol-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU),

[0040] According to the embodiments of the present application, under the basic condition, the base is selected from at least one of the following: alkali metal or alkaline earth metal hydride, hydroxide, alkoxide, acetate, fluoride, phosphate, carbonate and bicarbonate. The preferred base is sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate; the organic base can be selected from at least one of the following: tertiary amine, substituted or unsubstituted pyridine and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-tetramethylethylenediamine, N,N-dimethyl-1,4-diazabicyclohexane, N,N-diethyl-1,4-diazabicyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole and methylimidazole.

[0041] The composition of the present application can be formulated as a unit dosage form, each dosage containing about 5-1000 mg, more usually about 100-500 mg, of the active ingredient. The term "unit dosage form" means physically discrete unitary dosages suitable for single administration of a predetermined dosage of an active ingredient which is calculated to produce the desired therapeutic effect.

[0042] The amount of compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered; the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0043] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present application. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed essentially uniformly in the composition so that there is substantially no variation in the active ingredient level from particle to particle within the composition. When such solid preformulation compositions are subjected to various compressive forces, or placed in a container containing a liquid, there can be a change in the amount of active ingredient per unit of the composition. The solid preformulation compositions can be subjected to various manipulations such as mixing, granulating, compressing, tabletting, or mixing with a liquid, to form tablets, or other dosage forms. These manipulations result in the formation of a heterogeneous mixture, i.e., a mixture that is not homogeneous. The dosage forms formed from the solid preformulation compositions can be divided into unit dosages of, for example, about 0.1 to 1000 mg of the active ingredient of the present application.

[0044] Tablets or pills of the application can be coated or otherwise compounded to provide a dosage form affording a long period of action. For example, a tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in turn compressed, enteric-coated, or otherwise taken into a form which only after, or not until, the latter has been released, the former is released. A wide variety of material can be used for this outer dosage layer or coating.

[0045] The amount of compound or composition administered to a subject will vary depending upon what is being administered, the purpose to be served by the administration, e.g., prophylactic or therapeutic; the state of the subject, the manner of administration, etc. In therapeutic applications, e.g., an amount adequate to cure or at least partially arrest symptoms of a disease and its complications is administered to a subject already suffering from the disease. Effective dosages should be determined by the treating physician, considering factors which modify the action of drugs e.g., the disorder up be treated, the age, body weight, general health condition, sex, and diet of the subject.

[0046] The therapeutic dosage of the compounds of the present application can be determined, for example, by the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present application in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compositions for parenteral administration can comprise from about 0.1 to 10% w / v of the compound. Certain typical dosages are in the range of about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage will likely depend on such variables as the kind and extent of the disease or disorder, the general health and age of the particular patient, the relative biological efficacy of the compound selected, the excipient formulation employed, and the route of administration. Effective dosages can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0047] The present application has the following advantages:

[0048] The present application selects tramadol active metabolite M1 and active metabolite of loxoprofen sodium (trans-OH body) as starting materials through structural optimization design, and finally prepares a class of compounds connected by different connecting arms, which enhances the chemical stability and efficacy of the compounds, enables stable absorption in the stomach, and degrades into therapeutic drugs in the blood.

[0049] In addition, the oral absorption and bioavailability of M1 can be improved, the drug can reach the ideal concentration in the body, the frequency of administration can be reduced, and the quality of life of patients can be improved. The individual differences in therapeutic effect caused by CYP2D6 genetic polymorphism are effectively reduced, thereby achieving more uniform and predictable analgesic effect. At the same time, the compound can reduce the use amount of M1 and avoid the stimulation of the original drug to the digestive tract, reduce the side effects of the gastrointestinal tract, improve the tolerance of the drug, and improve the compliance of patients.

[0050] Compared with the combination of complex preparations and co-crystals, the compound designed in the present application not only can change the pharmacokinetic properties of the drug, reduce the single drug dose and the possible toxic side effects, enhance the therapeutic effect, but also has lower preparation and quality control difficulty compared with co-crystals, is convenient for large-scale production and clinical application, and has broad development prospects. DETAILED DESCRIPTION

[0051] The present application will be further described in detail below in conjunction with specific embodiments. The following examples are only descriptive and not limiting, and the protection scope of the present application cannot be limited by the following examples. If not otherwise specified, the raw materials used can be obtained by market or self-made.

[0052] Synthesis of compound 1 of example 1

[0053] (1) Step one

[0054]

[0055] trans-OH body (2.5g), alanine methyl ester hydrochloride (1.39g), pyridine 40ml were added to the reaction bottle, then DCC (3g), DMAP (0.5g) were added. Nitrogen protection, stirring at room temperature overnight. The insoluble was removed by filtration, the filtrate was concentrated, 50ml ethyl acetate was added to dissolve, then 2M hydrochloric acid 30ml was added to wash twice, the ethyl acetate phase was concentrated to obtain an oil (1-M01).

[0056] (2) Step two

[0057]

[0058] 1-M01 (2g), tetrahydrofuran 20ml, methanol 10ml, water 10ml were added to the reaction bottle, then lithium hydroxide (0.75g) was added, and the reaction was stirred at 45-50℃. After the reaction was completed, the reaction system was cooled to room temperature, then 6M hydrochloric acid was added to adjust pH = 2-3, 50ml ethyl acetate was added to stir and extract, the liquid was separated, concentrated, and column chromatography (PE / EA) was used to obtain 1-M02.

[0059] (3) Step three

[0060]

[0061] 1-M02 (0.21g), M1 (0.0.2g), dichloromethane 20ml, DCC (0.21g), DMAP (0.1g), nitrogen protection, stirring at room temperature overnight. After the reaction was completed, the insoluble was removed by filtration, the filtrate was concentrated, and the compound 1 was purified.

[0062] Synthesis of compound 2 in Example 2

[0063] (1) Step one

[0064]

[0065] trans-OH body (4.5g), glycine methyl ester hydrochloride (2.3g), pyridine 60ml were added to the reaction bottle, then DCC (5.4g), DMAP (0.9g) were added. Nitrogen protection, stirring at room temperature overnight. The insoluble was removed by filtration, the filtrate was concentrated, 100ml ethyl acetate was added to dissolve, then 2M hydrochloric acid 50ml was added to wash twice, the ethyl acetate phase was concentrated to obtain an oil (2-M01).

[0066] (2) Step two

[0067]

[0068] Into a reaction flask was placed 2-M01 (4 g), water 20 ml, THF 40 ml, methanol 20 ml, lithium hydroxide 1.3 g, and the reaction was stirred at 45-50°C. After the reaction was completed, the temperature was lowered to room temperature, and 6M hydrochloric acid was added to adjust the pH to 2-3. Ethyl acetate 100 ml was added and stirred to extract, and the liquid was separated. The product was concentrated and purified by column chromatography (PE / EA). A foamy solid (2-M02) 1.9 g was obtained.

[0069] (3) Step three

[0070]

[0071] Into a reaction flask was placed 2-M02 (0.5 g), M1 (0.49 g), dichloromethane 30 ml, and the reaction was stirred at 0-5°C under nitrogen protection. HATU (0.75 g) and N,N-diisopropyl ethylamine (3 ml) were added, and the reaction was stirred at room temperature for 2 h and then overnight. The product was concentrated and purified to obtain compound 2.

[0072] Synthesis of compound 3 of Example 3

[0073] (1) Step one

[0074]

[0075] Into a reaction flask was placed trans-OH (1.5 g), tetrahydrofuran 30 ml, and CDI (0.98 g) was added. The reaction was stirred for 1 h, and L-valine tert-butyl ester (1 g) was added. The reaction was stirred at 45-50°C for 2-3 h. The product was concentrated and purified by column chromatography to obtain white solid (3-M01) 1.2 g.

[0076] (2) Step two

[0077]

[0078] Into a reaction flask was placed 3-M01 (0.67 g), methanol 20 ml, water 10 ml, and lithium hydroxide 0.3 g. The reaction was stirred at 45-50°C, and after the reaction was completed, the temperature was lowered to room temperature. 6M hydrochloric acid was added to adjust the pH to 2-3. Ethyl acetate 100 ml was added and stirred to extract, and the liquid was separated. The product was concentrated and purified by column chromatography (PE / EA) to obtain foamy solid (3-M02) 0.4 g.

[0079] (3) Step three

[0080]

[0081] Into a reaction flask was placed 3-M02 (0.13 g), M1 (0.11 g), dichloromethane 10 ml, nitrogen protection, temperature was lowered to 0-5 °C, stirring for 15-30 min, 1 ml of N,N-diisopropyl ethylamine, HATU (0.2 g) was added, and the reaction was kept at temperature for 1 h, and then stirred at room temperature overnight. Concentration and column chromatography purification gave compound 3.

[0082] Synthesis of compound 4 in Example 4

[0083] (1) Step one

[0084]

[0085] Into a reaction flask was placed trans-OH (1 g), dichloromethane 30 ml, CDI (1.14 g) was added, and the reaction was stirred for 1 h, then L-proline tert-butyl ester (1 g) was added, and the reaction was stirred at room temperature overnight. Concentration and column chromatography purification (PE / EA) gave oil (4-M01) 0.8 g.

[0086] (2) Step two

[0087]

[0088] Into a reaction flask was placed 4-M01 (0.24 g), tetrahydrofuran 20 ml, methanol 10 ml, water 10 ml, lithium hydroxide 0.2 g, and the reaction was stirred at 45-50 °C. After the reaction was completed, the temperature was lowered to room temperature, 6 M hydrochloric acid was added to adjust pH to 2-3, 100 ml of ethyl acetate was added and stirred for extraction, and then the liquid was separated, concentrated, and column chromatography purification (DCM / MeOH) gave 0.16 g of 4-M02.

[0089] (3) Step three

[0090]

[0091] Into a reaction flask was placed 4-M02 (0.15 g), M1 (0.13 g), dichloromethane 30 ml, and the reaction was stirred at room temperature, nitrogen protection, temperature was lowered to 0-5 °C, 1 ml of N,N-diisopropyl ethylamine, HATU (0.2 g) was added, and the reaction was kept at temperature for 30 min, and then stirred at room temperature overnight. Concentration and column chromatography purification gave compound 4.

[0092] Synthesis of compound 5 in Example 5

[0093] (1) Step one

[0094]

[0095] trans-OH body (3 g), 2-amino butyric acid methyl ester hydrochloride (1.98 g), pyridine 40 ml, DCC (3.8 g), DMAP (1 g) were added to the reaction bottle, nitrogen protection, stirring at room temperature overnight. After the reaction was completed, the insoluble matter was removed by filtration, concentrated, dissolved in 120 ml of ethyl acetate, then washed twice with 2M hydrochloric acid 60 ml, concentrated the ethyl acetate phase to obtain an oil (5-M01).

[0096] (2) Step two

[0097]

[0098] The above concentrate was added to the reaction bottle, tetrahydrofuran 50 ml, methanol 15 ml, water 15 ml, lithium hydroxide 1 g were added to the reaction bottle, and the reaction was stirred at 45-50°C. After the reaction was completed, the temperature was lowered to room temperature, 6M hydrochloric acid was added to adjust pH = 2-3, 100 ml of ethyl acetate was added and stirred to extract, the liquid was separated, concentrated, and column chromatography was used for purification (PE / EA) to obtain a foamy solid (5-M02) 1.7 g.

[0099] (3) Step three

[0100]

[0101] 5-M02 (0.33 g), M1 (0.27 g), dichloromethane 30 ml were added to the reaction bottle, nitrogen protection, the temperature was lowered to 0-5°C, 3 ml of N, N-diisopropyl ethylamine, HATU (0.42 g) were added, and the reaction was kept for 30 min, and stirred at room temperature overnight. Concentration, column chromatography purification to obtain compound 5.

[0102] Synthesis of compound 6 of example 6

[0103] (1) Step one

[0104]

[0105] trans-OH body (3 g), 2-amino butyric acid methyl ester hydrochloride (1.98 g), pyridine 40 ml, DCC (3.8 g), DMAP (1 g) were added to the reaction bottle, nitrogen protection, stirring at room temperature overnight. After the reaction was completed, the insoluble matter was removed by filtration, concentrated, dissolved in 120 ml of ethyl acetate, then washed twice with 2M hydrochloric acid 60 ml, concentrated the ethyl acetate phase to obtain an oil (5-M01).

[0106] (2) Step two

[0107]

[0108] The above concentrate was added to a reaction flask, and tetrahydrofuran 50 ml, methanol 15 ml, water 15 ml, lithium hydroxide 1 g were added to the reaction flask, and the reaction was stirred at 45-50°C. After the reaction was completed, the temperature was lowered to room temperature, 6M hydrochloric acid was used to adjust the pH to 2-3, 100 ml of ethyl acetate was added and stirred for extraction, and the liquid was separated. The concentrate was purified by column chromatography (PE / EA) to obtain a foam solid (6-M02) 1.5 g.

[0109] (3) Step three

[0110]

[0111] 6-M02 (0.35 g), M1 (0.27 g), dichloromethane 30 ml were added to a reaction flask, and the temperature was lowered to 0-5°C under nitrogen protection. N, N-diisopropyl ethylamine 3 ml, HATU (0.42 g) were added, and the reaction was kept at room temperature for 30 min and stirred overnight. The concentrate was purified by column chromatography to obtain compound 6.

[0112] Example 7 Synthesis of compound 7

[0113] (1) Step one

[0114]

[0115] trans-OH (2.48 g), tetrahydrofuran 50 ml, sodium hydroxide 0.4 g were added to a reaction flask, and the mixture was stirred at room temperature for 1-2 h. KI was added as a catalyst, and benzyl bromoacetate 1.5 ml / 5 ml THF solution was added dropwise. After the addition was completed, the reaction was stirred at 45-50°C for 1 h. After the reaction was completed, the concentrate was purified by column chromatography (PE / EA) to obtain an oil (7-M01) 3.7 g.

[0116] (2) Step two

[0117]

[0118] 7-M01 (2 g), ethyl acetate 30 ml, and palladium carbon 0.5 g were added to a reaction flask, and the reaction was hydrogenated under normal pressure. After the reaction was completed, the filtrate was concentrated. The concentrate was purified by column chromatography (PE / EA) to obtain 7-M02.

[0119] (3) Step three

[0120]

[0121] 7-M02 (0.5 g), M1 (0.5 g), dichloromethane 25 ml were added to a reaction flask, and the temperature was lowered to 0-5°C under nitrogen protection. HOBT (0.22 g), EDCI (0.35 g) were added, and the mixture was stirred at room temperature for 2 h and overnight. The concentrate was purified by column chromatography to obtain compound 7.

[0122] Synthesis of compound 8

[0123] (1) Step one

[0124]

[0125] trans-OH (2.48g), THF 50ml, NaOH 0.4g were added into a reaction flask, stirred at room temperature for 1-2h, KI was added as catalyst, and benzyl 3-bromo-2-propenoate 2.4g / 5ml THF solution was added dropwise. After the addition, the reaction was stirred at 45-50°C for 1h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (PE / EA) to obtain an oil (8-M01) 2.7g.

[0126] (2) Step two

[0127]

[0128] 8-M01 (2g), ethyl acetate 30ml, Pd-C 0.5g were added into a reaction flask, and the reaction was carried out under normal pressure hydrogenation. After the reaction was completed, the reaction mixture was filtered and concentrated. The product was purified by column chromatography (PE / EA) to obtain 8-M02.

[0129] (3) Step three

[0130]

[0131] 8-M02 (0.61g), M1 (0.53g), dichloromethane 25ml were added into a reaction flask, and the reaction was carried out under nitrogen protection at 0-5°C. HOBT (0.22g), EDCI (0.35g) were added, and the reaction was stirred at room temperature for 2h and overnight. The reaction mixture was concentrated and purified by column chromatography to obtain compound 8.

[0132] Synthesis of compound 9

[0133] (1) Step one

[0134]

[0135] 2-bromobutyric acid (0.34g) was added into dry THF, and CDI (0.4g) was added. The reaction was stirred at room temperature for 1h to obtain reaction liquid 1. M1 (0.5g) was added into another reaction flask, and the reaction was carried out under nitrogen protection at 0-5°C. NaH (0.05g) was added, and the reaction was stirred for 1h. Then, the reaction liquid was added into reaction liquid 1, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (PE / EA) to obtain 9-M01.

[0136] (2) Step two

[0137]

[0138] Into a flask was placed trans-OH (0.5 g), dry THF 20 ml, under nitrogen protection, cooling to 0-5 °C, NaH (0.08 g) was added, then stirring at room temperature for 1 h, 9-M01 (0.82 g) was added, stirring at room temperature for 1 h, then warming to 30-40 °C, stirring. After completion of the reaction, concentration, column chromatography purification to give compound 9.

[0139] Example 10 Synthesis of compound 10

[0140] (1) Step one

[0141]

[0142] Into a flask was placed M1 (0.5 g), 2-bromovaleric acid (0.4 g), pyridine 20 ml, under nitrogen protection, DCC (0.6 g), DMAP (0.1 g) was added, stirring at room temperature. After completion of the reaction, filtration to remove insoluble matter, column chromatography purification to give 10-M01.

[0143] (2) Step two

[0144]

[0145] Into a flask was placed trans-OH (0.5 g), dry THF 20 ml, under nitrogen protection, cooling to 0-5 °C, NaH (0.08 g) was added, then stirring at room temperature for 1 h, 10-M01 (0.82 g) was added, catalytic amount of KI, stirring at room temperature for 1 h, then warming to 30-40 °C, stirring. After completion of the reaction, concentration, column chromatography purification to give compound 10.

[0146] Example 11 Synthesis of compound 11

[0147] (1) Step one

[0148]

[0149] Into a flask was placed M1 (0.5 g), 2-bromovaleric acid (0.4 g), pyridine 20 ml, under nitrogen protection, DCC (0.6 g), DMAP (0.1 g) was added, stirring at room temperature. After completion of the reaction, filtration to remove insoluble matter, column chromatography purification to give 10-M01.

[0150] (2) Step two

[0151]

[0152] Into a reaction flask was placed trans-OH (0.4 g), dry tetrahydrofuran 20 ml, nitrogen protection, cooling to 0-5 °C, NaH (0.06 g) was added, then stirred at room temperature for 1 h, then 11-M01 (0.65 g) was added, a catalytic amount of KI was added, and the reaction was stirred at room temperature for 1 h. The reaction was warmed to 30-40 °C and stirred. After the reaction was completed, it was concentrated and purified by column chromatography to obtain compound 11.

[0153] Example 12 Synthesis of compound 12

[0154] (1) Step one

[0155]

[0156] Into a reaction flask was placed M1 (0.8 g), 2-bromo-2-cyclopropylacetic acid (0.6 g), pyridine 30 ml, nitrogen protection, DCC (1 g) and DMAP (0.15 g) were added, and the reaction was stirred at room temperature. After the reaction was completed, the insoluble matter was removed by filtration, and the product was purified by column chromatography to obtain 12-M01.

[0157]

[0158] Into a reaction flask was placed trans-OH (0.3 g), dry tetrahydrofuran 20 ml, nitrogen protection, cooling to 0-5 °C, NaH (0.05 g) was added, then stirred at room temperature for 1 h, then 12-M01 (0.5 g) was added, a catalytic amount of KI was added, and the reaction was stirred at room temperature for 1 h. The reaction was warmed to 30-40 °C and stirred. After the reaction was completed, it was concentrated and purified by column chromatography to obtain compound 12.

[0159] Example 13

[0160]

[0161] Into a reaction flask was placed M1 (300 mg, 1.21 mmol, 1.0 eq), trans-OH (328 mg, 1.33 mmol, 1.1 eq), N,N-diisopropyl ethylamine (466 mg, 3.62 mmol, 3.0 eq) and dichloromethane (10 ml), and stirred at 0 °C for 30 min. HATU (550 mg, 1.57 mmol, 1.2 eq) was added, and the reaction was allowed to warm to room temperature and stirred for 15 h. After the reaction was completed, it was directly concentrated under reduced pressure, and purified by column chromatography to obtain 500 mg of colorless oil, with a yield of 86%.

Claims

1. A compound represented by structural formula (I), a racemate, stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof, n = 0 or 1; in, The linker is selected from the following structures: Wherein, R1 and R2 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, 5-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl groups may be optionally substituted by one, two or more halogen, hydroxy, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, optionally C 1-6 Alkyl substituted C 6-8 Aryl or optionally C 1-6 Alkyl-substituted 5- to 8-membered heteroaryl.

2. The compound according to claim 1, wherein R1 and R2 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 The alkoxy group may be optionally replaced by one, two or more fluorine, chlorine, bromine, iodine, hydroxyl, amino or optionally C 1-6 Alkyl substituted phenyl substituted.

3. The compound according to claim 1, wherein R1 and R2 are the same or different and are independently selected from one of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and cyclopropyl.

4. The compound according to claim 1, wherein n=0 The compound represented by structural formula (I) is selected from the following structures: Wherein, n=1, the compound represented by structural formula (I) is selected from the following structures:

5. Use of the compound according to any one of claims 1 to 4, its racemate, stereoisomer, pharmaceutically acceptable salt or solvate in the preparation of non-steroidal anti-inflammatory drugs.

6. The use according to claim 5, characterized in that The medicament is used to treat acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe hypoalgesia, hyperalgesia, pain associated with central sensitization, allodynia, cancer pain, diabetic neuropathy or diabetic peripheral neuropathy, osteoarthritis, fibromyalgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 4, or its racemate, stereoisomer, pharmaceutically acceptable salt or solvate.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition is in the form of tablets, capsules, granules, injections, eye drops, gels, creams, ointments or papules.

9. A method for preparing compound 1-6 according to claim 4, characterized in that: The following steps are involved: (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl)methyl)phenyl)propionic acid is condensed with amino acid ester hydrochloride to form an amide, the ester group is hydrolyzed into an acid, and then condensed with O-desmethyltramadol (M1) to form an ester, which is purified to obtain the final product; A method for preparing compound 7-8 in claim 4, characterized in that: The following steps are involved: (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl)methyl)phenyl)propionic acid is esterified with 2-bromocarboxylic acid benzyl ester under alkaline conditions, followed by hydrogenation and debenzylation to form a carboxylic acid, and finally condensed with O-desmethyltramadol (M1) to form an ester, which is then purified to obtain the final product; A method for preparing compounds 9-12 in claim 4, characterized in that: The following steps are involved: O-desmethyl tramadol (M1) is subjected to an esterification reaction with 2-bromocarboxylic acid, and then reacted with (S)-2-(4-(((1R,2S)-2-hydroxycyclopentyl)methyl)phenyl)propionic acid, and the final product is obtained after purification.

10. The preparation method according to claim 9, characterized in that The condensing agent in the condensation reaction is selected from at least one of the following: DCC, CDI, EDCI, HOBt, HATU, HBTU, HCTU, Under the alkaline conditions, the base is selected from at least one of the following: hydrides, hydroxides, alcoholates, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals. Preferred bases are sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate; the organic base can be selected from at least one of the following: tertiary amines, substituted or unsubstituted pyridines and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N- Dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-tetramethylethylenediamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, and methylimidazole.

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