4-Aminopiperidine derivatives and preparation method and application thereof

Abstract

The present invention relates to 4-amide piperidine derivatives having dual-target activity of Sigma-1 (σ1) receptor and Mu (μ) opioid receptor, which are used for preparing drugs for preventing and treating pain-related diseases. The compounds are compounds having the general formula I, pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, wherein the definitions of the substituents of the general formula I are the same as those in the specification. The experimental results show that the compounds of the general formula I provided by the present invention have a high affinity for σ1 receptors and μ receptors. At the same time, the animal test results also show that the compounds provided by the present invention can not only significantly improve the I and II phase pain induced by formalin, but also show good analgesic activity in the acetic acid writhing test. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of organic drug synthesis, and relates to a 4-amidopiperidine derivative, a preparation method thereof, and its application in medicine. In particular, the present invention relates to a 4-amidopiperidine derivative shown in general formula I, a preparation method thereof, a pharmaceutical composition containing the derivative, and its application in preparing a drug for treating pain diseases. Background Art

[0002] Pain is a complex physiological and psychological activity of the human body, including unpleasant sensations and emotional experiences related to actual or potential tissue damage, or similar experiences. "Pain" is accompanied by the existence of human birth, aging, illness and death, and more than 40% of patients who go to the hospital for medical help are "driven" by pain. Currently, the most common analgesics for moderate and severe pain in clinical practice are still opioids that act on μ opioid receptors (MOR), such as fentanyl, alfentanil, sufentanil, remifentanil, morphine, oxycodone, buprenorphine, etc. However, although these drugs have very significant analgesic effects, they all have relatively serious central nervous system and gastrointestinal side effects, including: addiction, respiratory depression, nausea, vomiting, constipation, excessive sedation, etc. Therefore, the research and development of painkillers without side effects is particularly important and urgent.

[0003] In view of the serious side effects caused by single-target analgesics acting on μ opioid receptors, and the bottleneck of research and development for many single pain targets, the concept of multi-target therapeutics provides a new idea. Compared with single-target drugs, multi-target drugs can act on multiple related targets that are intrinsically linked in the disease. Even if their activity against a single target may be lower than that of single-target drugs, the synergistic effect of multi-target regulation improves the overall effect, resulting in better efficacy and fewer adverse reactions.

[0004] Sigma-1 (σ1) receptor was first discovered in 1976. It has attracted the attention of academia and the pharmaceutical industry for its wide range of biological activities and unique molecular chaperone mechanisms. It is one of the emerging hot drug targets in recent years. σ1 receptors are widely distributed in the central nervous system and peripheral organs, and are involved in regulating a variety of biological processes in the intracellular nervous system. In the 1990s, the regulatory effect of σ1 receptors on μ receptors in analgesia has been reported. Studies have found that σ1 receptor antagonists can enhance the analgesic activity of opioids, while σ1 receptor agonists have the opposite effect. Subsequent studies have found that in σ1 receptor gene knockout mice, the pain response of the model group in the formalin pain model, capsaicin-induced neuralgia hypersensitivity model, paclitaxel-induced neuralgia model, and sciatica model disappeared or was significantly reduced. In the pain model of normal mice, σ1 receptor antagonists can increase the effect of classic opioids by 2 to 3.3 times and can be used as an adjuvant drug for opioid pain treatment. Further experiments have shown that σ1 receptors synergistically regulate the analgesic effect of μ receptor agonists by directly interacting with μ receptors. At the same time, in the inflammatory pain model, σ1 receptor antagonists can weaken the inhibitory effect of σ1 receptors on the μ receptor signaling pathway, allowing endogenous opioid peptides secreted by immune cells in the inflammatory site to produce analgesic effects. Therefore, the synergistic effect of σ1 receptors and μ receptors in analgesia has been confirmed and supported by a large number of studies.

[0005] Based on the synergistic effect of σ1 receptor / μ receptor in analgesia, the possible advantages of drugs with dual σ1 receptor / μ receptor activity are: a) while improving the analgesic effect of μ receptor agonists, reducing side effects such as respiratory depression, addiction, drug resistance, and constipation; b) improving the therapeutic effect of μ receptor agonists in chronic pain or neuropathic pain. Therefore, the study of compound ligands with dual σ1 receptor / μ receptor activity for pain treatment has important scientific value and social significance for the prevention and treatment of clinical pain. Summary of the invention

[0006] The present invention provides a 4-amide piperidine derivative, which can be used to prepare a drug for treating pain diseases, especially for moderate to severe pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, acute pain, hyperalgesia and visceral pain.

[0007] The present invention provides a compound represented by Formula I, a pharmaceutically acceptable salt thereof, a tautomer, a mesomer, a racemate, an enantiomer or a diastereomer thereof:

[0008]

[0009] wherein R1 is independently selected from substituted or unsubstituted C 1-5Alkyl, substituted or unsubstituted C 1-5 Alkoxy, substituted or unsubstituted aromatic, substituted or unsubstituted heterocyclic aromatic substituents, substituted or unsubstituted C 3-8 wherein the substituent is selected from the group consisting of a deuterium atom, an amino group, a hydroxyl group, a thiol group, a cyano group, a sulfonamide group, a carboxyl group, a halogen group, a C 1-5 Alkyl, C 1-5 One or more of the alkoxy groups;

[0010] R2 is independently selected from a hydrogen atom, a deuterium atom, an amino group, a hydroxyl group, a thiol group, a cyano group, a sulfonamide group, a carboxyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heterocyclic aromatic group, a substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 wherein the substituent is selected from the group consisting of deuterium atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, sulfonamide groups, carboxyl groups, halogen groups, C 1-5 Alkyl, C 1-5 One or more of the alkoxy groups;

[0011] R3 is independently selected from substituted or unsubstituted aromatic groups, substituted or unsubstituted heterocyclic aromatic substituents, substituted or unsubstituted C 3-8 wherein the substituent is selected from the group consisting of a deuterium atom, an amino group, a hydroxyl group, a thiol group, a cyano group, a sulfonamide group, a carboxyl group, a halogen group, a C 1-5 Alkyl, C 1-5 One or more of the alkoxy groups;

[0012] R4 is independently selected from a hydrogen atom, a deuterium atom, a substituted or unsubstituted amino group, a hydroxyl group, a thiol group, a cyano group, a sulfonamide group, a carboxyl group, a halogen group, a C 1-5 Alkyl or C 1-5 Alkoxy; wherein the substituent is selected from C 1-5 Alkyl, C 1-5 One or more of the alkoxy groups;

[0013] R5 is a hydrogen atom, a methoxymethylene group, a methoxymethylester group, a methoxyformyl group or a methylthioformamide group;

[0014] R6 is independently selected from a hydrogen atom, a deuterium atom, an amino group, a hydroxyl group, a thiol group, a cyano group, a sulfonamide group, a carboxyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heterocyclic aromatic group, a substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 wherein the substituent is selected from the group consisting of deuterium atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, sulfonamide groups, carboxyl groups, halogen groups, C 1-5 Alkyl, C1-5 One or more of the alkoxy groups;

[0015] n is 0, 1 or 2;

[0016] m is 0, 1 or 2;

[0017] X is independently selected from methylene or a nitrogen atom, an oxygen atom, a sulfur atom or a heteroatom.

[0018] In some embodiments, in Formula I, the unsubstituted C 1-5 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl or isopentyl, and the substituted C 1-5 The alkyl group is selected from methoxymethylene, methylthiomethylene or halogen-substituted C 1-5 The halogen is fluorine, chlorine, bromine or iodine.

[0019] In some embodiments, in Formula I, the unsubstituted aromatic group is selected from phenyl, naphthyl, and the substituted aromatic group is selected from halogen, C 1-5 Alkyl, C 1-5 Alkoxy, hydroxy, cyano mono- or poly-substituted phenyl or naphthyl; wherein the halogen is fluorine, chlorine, bromine or iodine.

[0020] In some embodiments, in Formula I, the unsubstituted heterocyclic aromatic substituent is furan, thiophene, pyridine or pyrimidine, and the substituted heterocyclic aromatic substituent is selected from halogen, C 1-5 Alkyl, C 1-5 Alkoxy, hydroxy, cyano mono- or poly-substituted furan, thiophene, pyridine or pyrimidine; wherein the halogen is fluorine, chlorine, bromine or iodine.

[0021] In some embodiments, in Formula I, the unsubstituted C 3-8 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and the substituted C 3-8 Cycloalkyl is halogen, C 1-5 Alkyl, C 1-5 Alkoxy, hydroxy, cyano mono- or poly-substituted C 3-8 Cycloalkyl; wherein the halogen is fluorine, chlorine, bromine or iodine.

[0022] In some embodiments, in Formula I, the compound or its pharmaceutically acceptable salt is selected from the following compounds or their pharmaceutically acceptable salts:

[0023] (1) N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide

[0024] (2) N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)acetamide

[0025] (3) N-(4-fluorobenzyl)-2-methoxy-N-(1-phenethylpiperidin-4-yl)acetamide

[0026] (4) N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide

[0027] (5) N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0028] (6) N-Benzyl-N-(1-phenylethylpiperidin-4-yl)-2-furamide

[0029] (7) N-Phenethyl-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0030] (8) N-(2-Fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide

[0031] (9) N-(2-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0032] (10) N-(2-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide

[0033] (11) N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide

[0034] (12) N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0035] (13) N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide

[0036] (14) N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide

[0037] (15) N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0038] (16) N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide

[0039] (17) N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0040] (18) N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide

[0041] (19) N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide

[0042] (20) N-(2,4-difluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide

[0043] (21) N-(2,4-difluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide

[0044] (22) N-(4-methylbenzyl)-N-(1-phenylethylpiperidin-4-yl)-2-furamide

[0045] (23) N-(1-phenethylpiperidin-4-yl)-N-(1-phenethyl)-2-furamide

[0046] (24) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)propionamide

[0047] (25) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)acetamide

[0048] (26) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)butyramide

[0049] (27) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)-2-furamide

[0050] (28) N-(1-Benzylpiperidin-4-yl)-N-(4-chlorophenyl)-2-furamide

[0051] (29) N-(1-Benzylpiperidin-4-yl)-N-(4-bromophenyl)-2-furamide

[0052] (30) N-(1-Benzylpiperidin-4-yl)-N-(4-methylphenyl)-2-furamide

[0053] (31) N-(1-Benzylpiperidin-4-yl)-N-(4-methoxyphenyl)-2-furamide

[0054] (32) N-(1-Benzylpiperidin-4-yl)-N-(4-methoxyphenyl)butyramide

[0055] (33) N-(1-Benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)-2-furamide

[0056] (34) N-(1-Benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)butyramide

[0057] (35) N-(1-Benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)propionamide

[0058] (36) N-(1-Benzylpiperidin-4-yl)-N-(2,6-dimethylphenyl)-2-furamide

[0059] (37) N-(1-Benzylpiperidin-4-yl)-N-(2-fluorophenyl)-2-furamide

[0060] (38) N-(1-Benzylpiperidin-4-yl)-N-(3-fluorophenyl)-2-furamide.

[0061] In some embodiments, in Formula I, the pharmaceutically acceptable salt is a salt containing a pharmaceutically acceptable anion, and the anion salt is hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, oxalate, acetate, propionate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, ethanesulfonate, propanesulfonate, gluconate, glucarate, benzoate, p-toluate, benzenesulfonate or p-toluenesulfonate.

[0062] The present invention also provides a method for preparing a compound of formula I, a pharmaceutically acceptable salt thereof, a tautomer, a mesomer, a racemate, an enantiomer or a diastereomer thereof, comprising the following steps:

[0063]

[0064] The compound of formula IA undergoes a substitution reaction with the compound of formula IB to obtain a compound of formula I;

[0065] Wherein, Y is fluorine, chlorine, bromine or iodine, hydroxyl,

[0066] X, R1, R2, R3, R4, R5, R6, m and n are as described above.

[0067] The present invention also provides a method for preparing a compound of formula I, a pharmaceutically acceptable salt thereof, a tautomer, a mesomer, a racemate, an enantiomer or a diastereomer thereof, comprising the following steps:

[0068]

[0069] The compound of general formula IC undergoes a substitution reaction with the compound of general formula ID to obtain a compound of general formula I;

[0070] Wherein, Y is fluorine, chlorine, bromine or iodine, hydroxyl,

[0071] X, R1, R2, R3, R4, R5, R6, m and n are as defined above.

[0072] The present invention also provides a pharmaceutical composition, comprising an effective therapeutic dose of a compound of formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, the composition can be used to prepare a drug for the prevention and treatment of pain-related diseases. The pain-related diseases include acute pain, such as acute injury pain of soft tissue and joints, postoperative pain, obstetric pain, acute herpes zoster pain, gout, etc. The pain-related diseases include chronic pain, such as strain or degeneration pain of soft tissue and joints, intervertebral disc-derived pain, neurogenic pain, etc. The pain-related diseases include intractable pain, such as trigeminal neuralgia, postherpetic neuralgia, intractable headache, etc. The pain-related diseases include cancer pain, such as advanced tumor pain, tumor metastasis pain, etc. The pain-related diseases include special pain, such as thromboangiitis, intractable angina pectoris, idiopathic chest and abdominal pain, etc.

[0073] The compound of formula I of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients are prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer a single dose. The unit dose of the compound or composition provided by the present invention can be expressed in the form of tablets, capsules, injections, granules, tinctures, lozenges, suppositories, regeneration powders or liquid preparations.

[0074] The dosage of the compound or composition used in the method of use thereof will generally vary with the severity of the pain, the patient's weight and the relative efficacy of the compound. As a general guide, a suitable unit dosage may be 0.01 to 1000 mg.

[0075] The pharmaceutical composition provided by the present invention may contain one or more auxiliary materials in addition to the active compound, and the auxiliary materials are selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99 weight percent of the active compound.

[0076] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, injection or transdermal administration in the form of a drug delivery system such as a patch, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, injections, lyophilized powders, or syrups or tinctures. Oral or injectable compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents, pH regulators and preservatives.

[0077] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Aqueous suspensions may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents and one or more sweetening agents.

[0078] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil and may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added.

[0079] The pharmaceutical composition can be in the form of a sterile injection aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. The sterile injection can be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin, and then the oil solution is added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion can be injected into the patient's blood by local injection. Alternatively, the solution and microemulsion can be given in a manner that can maintain a constant circulating concentration of the compound provided by the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used.

[0080] The pharmaceutical composition can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents as described above. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable five-toxic diluents or solvents. In addition, sterile fixed oils can be used as solvents or suspension media.

[0081] The pharmaceutical compositions disclosed herein can be in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum. Such excipients can include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various degrees of polymerization, and mixtures of fatty esters of polyethylene glycol.

[0082] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the general formula compound I or the type of salt to be used can be verified according to traditional treatment plans.

[0083] The compounds provided herein may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure disclosed herein, except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-Fluorine (18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. Deuterated compounds can generally retain activity comparable to that of undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages (such as increased half-life in vivo or reduced dosage requirements).

[0084] The compounds provided by the present invention also include various deuterated forms of compounds of formula I. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula I with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds of formula I, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

[0085] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the subject, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0086] Beneficial technical effects of the present invention:

[0087] In vitro isotope receptor ligand binding tests show that the compounds of general formula I provided by the present invention have high affinity for σ1 receptors and μ receptors. At the same time, animal test results also show that the compounds of the present invention can not only significantly improve formalin-induced phase I and phase II pain, but also show good analgesic activity in acetic acid writhing experiments. Since these in vitro action targets and in vivo pharmacological models are closely related to pain, the compounds provided by the present invention have the potential to prepare drugs for treating pain-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 Schematic diagram of the results of the acetic acid writhing test on mice for the preferred compound 4.

[0089] Figure 2 Schematic diagram of the experimental results of the rat formalin-induced pain model of the preferred compound 4.

[0090] Figure 3 Schematic diagram of the results of the acetic acid writhing test on mice for the preferred compound 6.

[0091] Figure 4 Schematic diagram of the results of the acetic acid writhing test on mice for the preferred compound 17. DETAILED DESCRIPTION

[0092] The technical solutions of various embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0093] Test method:

[0094] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR measurement uses a Bruker AV-500 nuclear magnetic spectrometer, the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The chemical shift (δ) unit is ppm.

[0095] Aglient 1260-1956A Quadrupole (manufacturer: Aglient, MS model: 1956A Quadrupole) was used for MS measurement; Aglient LC-MS / MS QTOF 6530 (manufacturer: Aglient, MS model: QTOF6530) was used for HR-MS measurement.

[0096] The following examples are for illustrative purposes only and are not intended to limit the present invention.

[0097] All temperatures are in degrees Celsius (°C).

[0098] A. Compound Synthesis Examples

[0099] Example 1 Synthesis of N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (1)

[0100] Reaction formula 1

[0101]

[0102] Phenethyl piperidone (IE) is synthesized by reacting piperidone with β-ethyl bromide, and phenethyl piperidone is further reacted with a benzylamine derivative to generate an intermediate IF, and finally reacted with an acyl chloride or a carboxylic acid to obtain the target product.

[0103] S1) Synthesis of phenethylpiperidone

[0104] Take 6.1g of piperidone hydrochloride monohydrate and 8.9g of β-bromoethane and dissolve them in 80ml of acetonitrile, then add 10.2g of sodium carbonate and 0.6g of sodium iodide. Heat and reflux for 12h. After the reaction is complete, cool to room temperature, filter to remove the lower layer of solid in the reaction solution, remove acetonitrile by vacuum distillation, then add 60ml of ethyl acetate and purified water, separate the ethyl acetate layer, extract the water layer with ethyl acetate twice (60ml*2), combine the ethyl acetate layers, remove the solvent by vacuum distillation, and obtain a brown oily substance. After silica gel column chromatography (200-300 mesh silica gel, dichloromethane: methanol = 25:1), 6.2g of light yellow solid was obtained, with a yield of 76.4%.

[0105] S2) Synthesis of N-(4-fluorobenzyl)-1-phenethylpiperidin-4-amine

[0106] Take 2.1g of the reaction product of step S1 and 1.5g of p-fluorobenzylamine, dissolve them in 50ml of dichloromethane, add 4.4g of sodium triacetylborohydride several times, and stir at room temperature for 8h. After the reaction is completed, add 50ml of 10% sodium hydroxide aqueous solution, stir for 5min, and then use a separatory funnel to separate the dichloromethane layer. The water layer is extracted twice with dichloromethane and then the dichloromethane layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain 2.6g of yellow oil, with a yield of 80.0%.

[0107] S3) Synthesis of N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide

[0108] Take 0.5g of the reaction product of step S2 and 0.3g of propionyl chloride, dissolve in 30ml of dichloromethane, react at room temperature for 1h, add 0.4g of triethylamine, and continue to react for 6h. After the reaction is completed, add 30ml of purified aqueous solution, stir for 5min, and separate the dichloromethane layer with a separatory funnel. Extract the water layer twice with dichloromethane, combine the dichloromethane layers, wash with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 0.6g of yellow oil, with a yield of 100.0%.

[0109] 1H NMR(500MHz,DMSO-d6)δ7.33(dd,J=7.5,7.5Hz,2H),7.26(m,5H),7.19 / 7.10(dd ,J=8.7,8.7Hz,2H),4.56 / 4.14(tt,J=9.6,4.2Hz,1H),4.55 / 4.48(s,2H),3.48( d,J=11.9Hz,2H),3.15(dd,J=11.2,6.0Hz,2H),3.05–2.84(m,4H),2.55 / 2.23(q ,J=7.3Hz,2H),2.01(m,2H),1.70(t,J=15.3Hz,2H),1.07 / 0.97(t,J=7.3Hz,3H).

[0110] HR-MS (ESI) m / z369.2330 ([M+H]+, calculated369.2337).

[0111] Example 2 Synthesis of N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)acetamide (2)

[0112] The only difference from Example 1 is that the propionyl chloride in step S3 is replaced by acetyl chloride, and the other steps are basically the same and will not be repeated here.

[0113] 1 H NMR(500MHz,DMSO-d6)δ7.37–7.22(m,7H),7.20 / 7.10(dd,J=8.9,8.9Hz,2H),4.55 / 4.47(s,2H),4.52 / 4.08(tt,J=12.1,4.0Hz,1H) ,3.48(d,J=12.0Hz,2H),3.18–3.10(m,2H),2.96(m,4H),2.22 / 1.98(s,3H),2.05-1.94(m,2H),1.74 / 1.67(dd,J=13.9,3.9Hz,2H).

[0114] MS (ESI) m / z 355.4 [M+H] + .

[0115] Example 3 Synthesis of N-(4-fluorobenzyl)-2-methoxy-N-(1-phenethylpiperidin-4-yl)acetamide (3)

[0116] The only difference from Example 1 is that the propionyl chloride in step S3 is replaced by methoxycarbonyl chloride, and the other steps are basically the same and will not be repeated here.

[0117] 1H NMR(500MHz,DMSO-d6)δ7.38–7.23(m,7H),7.20 / 7.11(t,J=8.7Hz,2H),4.50 / 4.49(s,2H),4.42 / 3.98(t,J=10.9Hz,1H),4.31 / 4.01(s,2H) ),3.49(d,J=11.9Hz,2H),3.36 / 3.26(s,3H),3.16(dd,J=10.8,6.1Hz,2H),2.97(m,4H),2.13–1.96(m,2H),1.74 / 1.69(d,J=12.9Hz,2H).

[0118] MS (ESI) m / z 385.4 [M+H] + .

[0119] Example 4 Synthesis of N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (4)

[0120] The only difference from Example 1 is that the propionyl chloride in step S3 is replaced by butyryl chloride, and the other steps are basically the same and will not be repeated here.

[0121] 1 H NMR (500MHz, DMSO-d6) δ7.33 (td, J=7.4, 1.9Hz, 2H), 7.24 (m, 5H), 7.20 / 7.10 (dd, J=8. 7,8.7Hz,2H),4.55 / 4.48(s,2H),4.58 / 4.13(tt,J=12.2,4.0Hz,1H),3.47(d,J=11.9H z,2H),3.14(dd,J=11.1,6.0Hz,2H),2.96(m,4H),2.51 / 2.20(t,J=7.2Hz,2H),2.00(m ,2H),1.69(t,J=15.5Hz,2H),1.60 / 1.52(h,J=7.3Hz,2H),0.95 / 0.82(t,J=7.4Hz,3H).

[0122] HR-MS (ESI) m / z 383.2487 ([M+H] + , calculated383.2497).

[0123] Example 5 Synthesis of N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (5)

[0124] The only difference from Example 1 is that the propionyl chloride in step S3 is replaced by furoyl chloride, and the other steps are basically the same and will not be repeated here.

[0125] 1H NMR(500MHz,DMSO-d6)δ7.82(s,1H),7.40–7.28(m,4H),7.28–7.19(m,3H),7.16dd,J=8.8,8.8Hz,2H),7.06–6.91(m,1H),6.62(br.s,1H),4.72(s,2 H),4.44(tt,J=12.0,3.9Hz,1H),3.49(d,J=12.0Hz,2H),3.20–3.09(m,2H ),3.03–2.87(m,4H),2.14(qd,J=13.1,3.8Hz,2H),1.81(d,J=12.9Hz,2H).

[0126] HR-MS (ESI) m / z 407.2127 ([M+H] + , calculated407.2129).

[0127] Example 6 N-Benzyl-N-(1-phenethylpiperidin-4-yl)-2-furamide (6)

[0128] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by benzylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0129] 1 H NMR(500MHz,DMSO-d6)δ7.82(br.s,1H),7.45–7.16(m,10H),6.98(br.s,1H),6.61(br.s,1H),4.75(s,2H),4.46(tt,J=12.0,3 .9Hz,1H),3.49(d,J=11.9Hz,2H),3.22–3.02(m,2H),3.03–2.79(m,4H),2.14(qd,J=13.2,3.9Hz,2H),1.82(d,J=13.0Hz,2H).

[0130] MS (ESI) m / z 389.2 [M+H] + .

[0131] Example 7 N-phenethyl-N-(1-phenethylpiperidin-4-yl)-2-furamide (7)

[0132] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by phenethylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0133] 1H NMR(500MHz,DMSO-d6)δ7.92(br.s,1H),7.44–7.17(m,10H),7.05(d,J=3.4Hz,1H),6.67(dd,J=3.5,1.8Hz,1H),4.37(br .s,1H),3.56(d,J=11.2Hz,4H),3.19(m,2H),3.09–2.94(m,4H),2.94–2.73(m,2H),2.28(m,2H),1.89(d,J=12.9Hz,2H).

[0134] MS (ESI) m / z 403.3 [M+H] + .

[0135] Example 8 N-(2-Fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (8)

[0136] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by 2-fluorobenzylamine, and the other steps are basically the same and will not be repeated here.

[0137] 1 H NMR (500MHz, DMSO-d6) δ7.46–7.04(m,9H),4.59 / 4.48(s,2H),4.54 / 4.18(m,1H),3.47(d,J=12.0Hz,2H),3.14(dd,J=10.9,6.1Hz, 2H),3.06–2.83(m,4H),2.59 / 2.24(q,J=7.3Hz,2H),2.03–3.89(m,2H),1.82 / 1.71(d,J=13.2Hz,2H),1.07 / 0.97(t,J=7.3Hz,3H).

[0138] MS (ESI) m / z 369.2 [M+H] + .

[0139] Example 9 N-(2-Fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (9)

[0140] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by 2-fluorobenzylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0141] 1H NMR(500MHz,DMSO-d6)δ7.82(s,1H),7.39–7.13(m,9H),7.01(s,1H),6.62(s,1H),4.75(s,2H),4.47(tt,J=12.3,3.8Hz, 1H),3.50(d,J=11.9Hz,2H),3.24–3.08(m,2H),3.05–2.82(m,4H),2.11(qd,J=13.1,3.8Hz,2H),1.90(d,J=13.0Hz,2H).

[0142] MS (ESI) m / z 407.2 [M+H] + .

[0143] Example 10 N-(2-Fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (10)

[0144] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by 2-fluorobenzylamine, and the propionyl chloride in step S3 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0145] 1 H NMR(500MHz,DMSO-d6)δ7.43–7.01(m,9H),4.59 / 4.48(s,2H),4.54 / 4.19(tt, J=12.0,4.0Hz,1H),3.47(d,J=11.9Hz,2H),3.22–3.09(m,2H),3.06–2.96(m,2 H),2.96–2.85(m,2H),2.54 / 2.20(t,J=7.2Hz,2H),2.04–1.90(m,2H),1.81 / 1. 71(d,J=13.2Hz,2H),1.60 / 1.53(h,J=7.6Hz,2H),0.95 / 0.82(t,J=7.3Hz,3H).

[0146] MS (ESI) m / z 483.4 [M+H] + .

[0147] Example 11 N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (11)

[0148] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by p-chlorobenzylamine, and the other steps are basically the same and will not be repeated here.

[0149] 1H NMR(500MHz,DMSO-d6)δ7.42(d,J=8.1Hz,1H),7.33(dd,J=7.8,7.8Hz,3H),7 .29–7.17(m,5H),4.56 / 4.48(s,2H),4.58 / 4.13(tt,J=12.0,4.0Hz,1H),3.4 7(d,J=11.8Hz,2H),3.22–3.08(m,2H),2.99–2.93(m,4H),2.55 / 2.22(q,J=7 .3Hz,2H),2.05–1.93(m,2H),1.82–1.57(m,2H),1.07 / 0.97(t,J=7.3Hz,3H).

[0150] MS (ESI) m / z 485.4 [M+H] + .

[0151] Example 12 N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (12)

[0152] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by p-chlorobenzylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0153] 1 H NMR (500MHz, DMSO-d6) δ7.82(br.s,1H),7.39(d,J=8.4Hz,2H),7.36–7.29(m,4H),7.25(d,J=7.1Hz,3H),7.01(br.s,1H),6.62(br.s,1H),4.73(s,2 H),4.46(tt,J=12.0,3.9Hz,1H),3.49(d,J=11.9Hz,2H),3.22–3.07(m,2H ),3.00–2.90(m,4H),2.13(qd,J=13.0,3.8Hz,2H),1.82(d,J=13.0Hz,2H).

[0154] MS (ESI) m / z 423.2 [M+H] + .

[0155] Example 13 N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)butanamide (13)

[0156] The difference from Example 1 is that p-fluorobenzylamine in step S2 is replaced by p-chlorobenzylamine, and propionyl chloride in step S3 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0157] 1H NMR(500MHz,DMSO-d6)δ7.43(d,J=8.3Hz,1H),7.37–7.29(m,3H),7.29–7.19(m,5H) ,4.59 / 4.14(tt,J=11.9,3.9Hz,1H),4.57 / 4.48(s,2H),3.46(d,J=12.0Hz,2H),3.19 –3.07(m,2H),3.02–2.90(m,4H),2.51 / 2.19(t,J=7.2Hz,2H),2.08–1.87(m,2H),1.6 9(dd,J=21.7,13.6Hz,2H),1.60 / 1.52(h,J=7.3Hz,2H),0.95 / 0.82(t,J=7.4Hz,3H).

[0158] MS (ESI) m / z 399.2 [M+H] + .

[0159] Example 14 N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (14)

[0160] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by p-methoxybenzylamine, and the other steps are basically the same and will not be repeated here.

[0161] 1 H NMR(500MHz,DMSO-d6)δ7.37–7.30(m,2H),7.25(dd,J=7.4,3.2Hz,3H),7.18–7.10(m,2H ),6.93 / 6.84(d,J=8.3Hz,2H),4.54 / 4.09(tt,J=12.0,3.9Hz,1H),4.48 / 4.43(s,2H),3. 75 / 3.72(s,3H),3.47(d,J=9.0Hz,2H),3.23–3.08(m,2H),3.04–2.89(m,4H),2.54 / 2.25 (q,J=7.3Hz,2H),2.09–1.93(m,2H),1.67(d,J=11.6Hz,2H),1.06 / 0.97(t,J=7.3Hz,3H).

[0162] MS (ESI) m / z 381.3 [M+H] + .

[0163] Example 15 N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (15)

[0164] The difference from Example 1 is that p-fluorobenzylamine in step S2 is replaced by p-methoxybenzylamine, and propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0165] 1 H NMR(500MHz,DMSO-d6)δ7.82(s,1H),7.39–7.30(m,2H),7.29–7.23(m,3H),7.21( d,J=8.4Hz,2H),6.98(s,1H),6.90(d,J=8.6Hz,2H),6.61(s,1H),4.68(s,2H),4.4 2(tt,J=11.5,3.6Hz,1H),3.74(s,3H),3.52(d,J=11.9Hz,2H),3.25–3.12(m,2H) ,3.06–2.98(m,2H),2.98–2.91(m,2H),2.24–2.10(m,2H),1.80(d,J=13.1Hz,2H).

[0166] HR-MS(ESI)m / z419.2324([M+H] + , calculated419.2329).

[0167] Example 16 N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (16)

[0168] The difference from Example 1 is that p-fluorobenzylamine in step S2 is replaced by p-methoxybenzylamine, and propionyl chloride in step S3 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0169] 1 H NMR(500MHz,DMSO-d6)δ7.40–7.29(m,2H),7.28–7.20(m,3H),7.14(dd,J=8.6,4.0Hz,2H),6. 93 / 6.84(d,J=8.3Hz,2H),4.56 / 4.11(tt,J=8.8,3.6Hz,1H),4.49 / 4.43(s,2H),3.75 / 3.72(s ,3H),3.54–3.38(m,2H),3.21–3.08(m,2H),3.04–2.86(m,4H),2.48 / 2.22(t,J=7.2Hz,2H),2 .10–2.92(m,2H),1.75–1.63(m,2H),1.61 / 1.52(h,J=7.3Hz,2H),0.96 / 0.82(t,J=7.4Hz,3H).

[0170] HR-MS (ESI) m / z 395.2689 ([M+H] + , calculated395.2693).

[0171] Example 17 N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (17)

[0172] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by m-fluorobenzylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0173] 1 H NMR(500MHz,DMSO-d6)δ7.83(br.s,1H),7.45–7.29(m,3H),7.25(d,J=7.3Hz,3H),7.18–7.05(m,3H),7.02(br.s,1H),6.63(br.s,1H),4.75(s,2H) ,4.48(tt,J=12.0,3.9Hz,1H),3.50(d,J=11.9Hz,2H),3.22–3.08(m,2H) ,3.05–2.87(m,4H),2.15(dd,J=12.5,3.8Hz,2H),1.85(d,J=12.9Hz,2H).

[0174] HR-MS (ESI) m / z 407.2130 ([M+H] + , calculated407.2129).

[0175] Example 18 N-(3-Fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butanamide (18)

[0176] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by m-fluorobenzylamine, and the propionyl chloride in step S3 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0177] 1 H NMR(500MHz,DMSO-d6)δ7.48–7.29(m,3H),7.28–7.22(t,J=6.1Hz,3H),7.16–6.94(m,3H) ,4.60 / 4.51(s,2H),4.58 / 4.16(tt,J=12.0,7.9Hz,1H),3.47(d,J=11.9Hz,2H),3.15 / 3.1 4(d,J=11.1Hz,2H),3.04–2.88(m,4H),2.54 / 2.19(t,J=7.2Hz,2H),2.00(h,J=12.6Hz,2H ), 1.74 / 1.69 (d, J = 12.2Hz, 2H), 1.61 / 1.52 (h, J = 7.3Hz, 2H), 0.96 / 0.82 (t, J = 7.4Hz, 3H).

[0178] HR-MS (ESI) m / z 383.2494 ([M+H] +, calculated383.2493).

[0179] Example 19 N-(3-Fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (19)

[0180] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by m-fluorobenzylamine, and the other steps are basically the same and will not be repeated here.

[0181] 1 H NMR(500MHz,DMSO-d6)δ7.46–7.29(m,3H),7.28–7.21(m,3H),7.15–6.94(m ,3H),4.59 / 4.50(s,2H),4.56 / 4.16(tt,J=13.1,4.3Hz,1H),3.48(d,J=11.9 Hz,2H),3.21–3.07(m,2H),3.04–2.87(m,4H),2.57 / 2.22(q,J=7.3Hz,2H),2 .07–1.93(m,2H),1.75 / 1.70(d,J=13.2Hz,2H),1.08 / 0.97(t,J=7.3Hz,3H).

[0182] HR-MS (ESI) m / z 369.2334 ([M+H] + , calculated369.2337).

[0183] Example 20 N-(2,4-difluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (20)

[0184] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by 2,4-difluorobenzylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0185] 1 H NMR(500MHz,DMSO-d6)δ7.82(br.s,1H),7.37–7.29(m,3H),7.28–7.21(m,4H ),7.06(ddd,J=8.5,8.5,2.5Hz,1H),7.04–7.01(m,1H),6.63(br.s,1H),4.70 (s,2H),4.45(tt,J=12.1,3.8Hz,1H),3.50(d,J=12.0Hz,2H),3.21–3.06(m, 2H), 3.01–2.91 (m, 4H), 2.10 (dq, J=13.0, 3.8Hz, 2H), 1.89 (d, J=13.0Hz, 2H).

[0186] HR-MS (ESI) m / z 425.2036 ([M+H]+ ,calculated425.2035).

[0187] Example 21 N-(2,4-difluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butanamide (21)

[0188] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by 2,4-difluorobenzylamine, and the propionyl chloride in step S3 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0189] 1 H NMR(500MHz,DMSO-d6)δ7.36–7.31(m,2H),7.30–7.22(m,4H),7.22–6.95(m,2H),4.56 / 4.4 4(s,2H),4.51 / 4.22(tt,J=12.0,5.7Hz,1H),3.53(d,J=12.0Hz,2H),3.25–3.18(m,2H),3. 11 / 3.03(t,J=12.3Hz,2H),2.99–2.92(m,2H),2.54 / 2.22(t,J=7.2Hz,2H),2.08–1.91(m,2 H), 1.83 / 1.71 (d, J = 13.2Hz, 2H), 1.60 / 1.54 (h, J = 7.5Hz, 2H), 0.95 / 0.83 (t, J = 7.4Hz, 3H).

[0190] HR-MS (ESI) m / z 401.2399 ([M+H] + , calculated401.2399).

[0191] Example 22 N-(4-methylbenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (22)

[0192] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by 4-methylbenzylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0193] 1H NMR(500MHz,DMSO-d6)δ7.81(br.s,1H),7.36–7.30(m,2H),7.28–7.22(m,3H),7.19–7.12(m,4H),6.97(br.s,1H),6.61(br.s,1H),4.71(s,2H),4 .44(tt,J=12.0,3.8Hz,1H),3.50(d,J=12.0Hz,2H),3.22–3.10(m,2H),3 .03–2.88(m,4H),2.28(s,3H),2.21–2.06(m,2H),1.81(d,J=13.1Hz,2H).

[0194] HR-MS (ESI) m / z 403.2378 ([M+H] + , calculated403.2380).

[0195] Example 23 N-(1-phenethylpiperidin-4-yl)-N-(1-phenethyl)-2-furamide (23)

[0196] The difference from Example 1 is that the p-fluorobenzylamine in step S2 is replaced by α-phenylethylamine, and the propionyl chloride in step S3 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0197] 1 H NMR(500MHz,Methanol-d4)δ7.74(s,1H),7.50–7.37(m,4H),7.36–7.29(m,3H) ,7.29–7.20(m,3H),7.08(d,J=3.2Hz,1H),6.64(d,J=3.2Hz,1H),5.57(s,1H),3 .71(br.s,1H),3.47(br.s,2H),3.33–3.20(m,2H),3.20–3.08(m,2H),3.01(br .s,2H),2.79(m,2H),1.97(br.s,1H),1.80(d,J=6.3Hz,3H),1.30–0.88(m,1H).

[0198] HR-MS (ESI) m / z 403.2378 ([M+H] + , calculated403.2380).

[0199] Example 24 N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)propionamide (24)

[0200] Reaction formula 2

[0201]

[0202] Benzylpiperidone is used as a raw material and reacts with an aniline derivative to obtain an intermediate IG, which is further reacted with an acyl chloride or a carboxylic acid to obtain the target product.

[0203] P1) Synthesis of 1-Benzyl-N-(2,4,6-trimethylphenyl)piperidin-4-amine

[0204] Take 9.6g of N-benzylpiperidone and 8.1g of 2,4,6-trimethylaniline and dissolve them in 100ml of dichloromethane. Add 8.0g of sodium cyanoborohydride several times and stir at room temperature for 8h. After the reaction is completed, add 60ml of 10% sodium hydroxide aqueous solution, stir for 5min, and then separate the dichloromethane layer with a separatory funnel. Extract the water layer with dichloromethane twice and combine the dichloromethane layers, wash with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain a brown oil. After silica gel column chromatography (200-300 mesh silica gel, dichloromethane: methanol = 20: 1), 10.1g of light yellow solid was obtained, with a yield of 64.1%.

[0205] P2) Synthesis of N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)propionamide

[0206] Take 0.5g of the reaction product of step P1 and 0.4g of propionyl chloride, dissolve them in 40ml of dichloromethane, react at room temperature for 1h, then add 0.4g of triethylamine and continue to react for 6h. After the reaction is completed, add 30ml of purified aqueous solution, stir for 5min, and separate the dichloromethane layer with a separatory funnel. Extract the water layer twice with dichloromethane, combine the dichloromethane layers, wash with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 0.5g of yellow oil with a yield of 84.6%.

[0207] 1 H NMR (500MHz, DMSO-d6) δ7.52–7.29(m,5H),6.97(s,2H),4.13(tt,J=11.9,3.9Hz,1H),4.09(s,2H),3.21(d,J=12.1Hz,2H),2.86(td,J=1 2.8,2.5Hz,2H),2.24(s,3H),2.09(s,6H),2.00–1.92(m,2H),1.69(q,J=7.4Hz,2H),1.56(qd,J=13.0,3.7Hz,2H),0.87(t,J=7.4Hz,3H).

[0208] MS (ESI) m / z 365.4 ([M+H] + ).

[0209] Example 25 N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)acetamide (25)

[0210] The difference from Example 24 is that the propionyl chloride in step P2 is replaced by acetyl chloride, and the other steps are basically the same and will not be repeated here.

[0211] 1 H NMR (500MHz, DMSO-d6) δ7.56(dd,J=6.7,3.0Hz,2H),7.42(m,3H),6.98(s,2H),4.20(s,2H),4.16(tt,J=12.6,4.1Hz,1H),3.25(d,J= 12.2Hz,2H),3.01(dd,J=11.8,11.7Hz,2H),2.24(s,3H),2.13(s,6H),2.01–1.87(m,2H),1.75(dh,J=16.2,3.7Hz,2H),1.54(s,3H).

[0212] MS (ESI) m / z 351.4 ([M+H] + ).

[0213] Example 26 N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)butyramide (26)

[0214] The difference from Example 24 is that the propionyl chloride in step P2 is replaced by butyryl chloride, and the other steps are basically the same and will not be repeated here.

[0215] 1 H NMR (500MHz, DMSO-d6) δ7.41(m,5H),6.97(s,2H),4.14(tt,J=11.8,3.8Hz,1H),4.08(s,2H),3.20(d,J=11.9Hz,2H),2.94–2.77(m,2H),2.24(s ,3H),2.09(s,6H),1.99–1.89(m,2H),1.67(t,J=7.1Hz,2H),1.58(ddd,J=12.9,12.9,3.6Hz,2H),1.42(q,J=7.2Hz,2H),0.73(t,J=7.4Hz,3H).

[0216] MS (ESI) m / z 379.4 ([M+H] + ).

[0217] Example 27 N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)-2-furamide (27)

[0218] The difference from Example 24 is that the propionyl chloride in step P2 is replaced by furoyl chloride, and the other steps are basically the same and will not be repeated here.

[0219] 1H NMR(500MHz,DMSO-d6)δ7.68(d,J=1.6Hz,1H),7.46–7.33(m,5H),7.00(s,2 H), 6.32 (dd, J = 3.6, 1.7Hz, 1H), 5.33 (d, J = 3.5Hz, 1H), 4.25 (tt, J = 11.9, 3. 8Hz,1H),4.08(s,2H),3.24(d,J=12.0Hz,2H),2.87(t,J=12.3Hz,2H),2.28 (s,3H),2.08(s,6H),2.00(d,J=13.2Hz,2H),1.75(dd,J=12.5,3.6Hz,2H).

[0220] MS (ESI) m / z 403.2 ([M+H] + ).

[0221] Example 28 N-(1-Benzylpiperidin-4-yl)-N-(4-chlorophenyl)-2-furamide (28)

[0222] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 4-chloroaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0223] 1 H NMR(500MHz,DMSO-d6)δ7.66(d,J=1.6Hz,1H),7.56–7.48(m,2H),7.40(s,5H ),7.34–7.25(m,2H),6.38(dd,J=3.5,1.7Hz,1H),5.78(d,J=3.6Hz,1H),4.72 (tt,J=12.1,3.8Hz,1H),4.03(s,2H),3.22(d,J=11.7Hz,2H),2.88(dd,J=12 .3,12.3Hz,2H),1.96(d,J=12.3Hz,2H),1.58(ddd,J=13.0,13.0,3.8Hz,2H).

[0224] HR-MS (ESI) m / z 395.1517 ([M+H] + , calculated395.1521).

[0225] Example 29 N-(1-Benzylpiperidin-4-yl)-N-(4-bromophenyl)-2-furamide (29)

[0226] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 4-bromoaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0227] 1 H NMR(500MHz,DMSO-d6)δ7.69–7.66(m,2H),7.65(m,1H),7.40(s,5H),7.26 –7.21(m,2H),6.39(dd,J=3.6,1.7Hz,1H),5.79(d,J=3.6Hz,1H),4.71(tt, J=12.2,3.9Hz,1H),4.02(s,2H),3.21(d,J=12.1Hz,2H),2.87(dd,J=12.3 ,12.3Hz,2H),1.95(d,J=13.1Hz,2H),1.57(ddd,J=13.0,13.0,3.9Hz,2H).

[0228] HR-MS (ESI) m / z 439.1015 ([M+H] + , calculated439.1016).

[0229] Example 30 N-(1-Benzylpiperidin-4-yl)-N-(4-methylphenyl)-2-furamide (30)

[0230] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 4-methylaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0231] 1 H NMR(500MHz,DMSO-d6)δ7.67(d,J=1.6Hz,1H),7.41(s,5H),7.28(d,J=7.9Hz,2 H),7.13(d,J=8.1Hz,2H),6.33(dd,J=3.6,1.7Hz,1H),5.43(br.s,1H),4.74(t t,J=12.2,3.8Hz,1H),4.10(s,2H),3.26(d,J=12.0Hz,2H),2.98(dd,J=12.0,1 2.0Hz,2H),2.37(s,3H),1.96(d,J=12.5Hz,2H),1.60(dd,J=12.8,3.8Hz,2H).

[0232] HR-MS (ESI) m / z 375.2063 ([M+H] + , calculated375.2067).

[0233] Example 31 N-(1-benzylpiperidin-4-yl)-N-(4-methoxyphenyl)-2-furamide (31)

[0234] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 4-methoxyaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0235] 1 H NMR(500MHz,DMSO-d6)δ7.68(d,J=1.7Hz,1H),7.40(s,5H),7.17(d,J=8.8Hz,2H ),7.01(d,J=8.8Hz,2H),6.34(dd,J=3.6,1.7Hz,1H),5.42(br.s,1H),4.71(tt,J =12.2,3.8Hz,1H),4.03(s,2H),3.80(s,3H),3.22(d,J=11.8Hz,2H),2.88(dd,J =12.6,12.6Hz,2H),1.94(d,J=12.8Hz,2H),1.57(ddd,J=13.0,13.0,3.8Hz,2H).

[0236] HR-MS(ESI)m / z391.2020([M+H] + , calculated391.2016).

[0237] Example 32 N-(1-Benzylpiperidin-4-yl)-N-(4-methoxyphenyl)butyramide (32)

[0238] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 4-methoxyaniline, and the propionyl chloride in step P2 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0239] 1 H NMR(500MHz,DMSO-d6)δ7.39(s,5H),7.14–7.02(m,2H),7.03–6.88(m,2H),4.61(tt,J=12.1,3.9Hz,1H),4.03(s,2H),3.7 8(s,3H),3.30–3.10(m,2H),2.85(td,J=12.7,2.7Hz,2H),1.82(t,J=7.3Hz,4H),1.55–1.29(m,4H),0.73(t,J=7.4Hz,3H).

[0240] HR-MS(ESI)m / z367.2382([M+H] + , calculated367.2380).

[0241] Example 33 N-(1-benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)-2-furamide (33)

[0242] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 2,4-dimethylaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0243] 1 H NMR(500MHz,DMSO-d6)δ7.69(d,J=1.6Hz,1H),7.47–7.35(m,5H),7.15(d,J=1.8Hz,1H),7.14–7.06(m,2H) ,6.32(dd,J=3.5,1.7Hz,1H),5.33(br.s,1H),4.63(tt,J=12.1,3.8Hz,1H),4.08(s,2H),3.27(d,J=11.9Hz ,1H),3.20(d,J=12.3Hz,1H),2.91(tdd,J=12.3,8.5,2.8Hz,2H),2.32(s,3H),2.11(dt,J=13.4,3.1Hz,1H) ,2.02(s,3H),1.88(ddd,J=12.8,12.8,3.8Hz,1H),1.85–1.79(m,1H),1.52(ddd,J=12.9,12.9,4.0Hz,1H).

[0244] HR-MS (ESI) m / z 389.2215 ([M+H] + , calculated389.2224).

[0245] Example 34 N-(1-benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)butyramide (34)

[0246] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 2,4-dimethylaniline, and the propionyl chloride in step P2 is replaced by butyryl chloride. The other steps are basically the same and will not be repeated here.

[0247] 1H NMR (500MHz, DMSO-d6) δ7.40(s,5H),7.17(d,J=2.0Hz,1H),7.07(dd,J=8.0,2.0Hz,1H),6.97(d,J= 7.9Hz,1H),4.51(tt,J=12.1,3.9Hz,1H),4.05(s,2H),3.22(d,J=11.5Hz,1H),3.15(d,J=12.1Hz,1H ),2.85(dddd,J=15.2,11.7,7.1,2.5Hz,2H),2.30(s,3H),2.11(s,3H),2.04–1.97(m,1H),1.81–1. 73(m,2H),1.73–1.63(m,2H),1.42(qd,J=7.3,1.8Hz,2H),1.38–1.27(m,1H),0.72(t,J=7.4Hz,3H).

[0248] HR-MS (ESI) m / z 365.2584 ([M+H] + , calculated365.2587).

[0249] Example 35 N-(1-benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)propionamide (35)

[0250] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 2,4-dimethylaniline, and the other steps are basically the same and will not be repeated here.

[0251] 1 H NMR(500MHz,DMSO-d6)δ7.39(s,5H),7.17(d,J=2.3Hz,1H),7.07(dd,J=8.0,2.0Hz,1H), 6.98(d,J=7.9Hz,1H),4.50(tt,J=12.1,3.9Hz,1H),4.03(s,2H),3.20(d,J=12.1Hz,1H), 3.14(d,J=12.5Hz,1H),2.91–2.73(m,2H),2.30(s,3H),2.11(s,3H),2.00(dt,J=13.6,3 .2Hz,1H),1.85–1.61(m,4H),1.34(ddd,J=12.9,12.9,4.1Hz,1H),0.87(t,J=7.4Hz,3H).

[0252] HR-MS (ESI) m / z 351.2435 ([M+H] + , calculated351.2431).

[0253] Example 36 N-(1-benzylpiperidin-4-yl)-N-(2,6-dimethylphenyl)-2-furamide (36)

[0254] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 2,6-dimethylaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0255] 1 H NMR(500MHz,Chloroform-d)δ7.37(d,J=1.6Hz,1H),7.35–7.27(m,4H),7.27–7.19(m,2H), 7.13(d,J=7.6Hz,2H),7.04–6.90(m,1H),6.14(dd,J=3.6,1.7Hz,1H),5.29(d,J=3.5Hz,1H) ,4.31(ddd,J=12.0,8.1,3.9Hz,1H),3.51(s,2H),2.92(dt,J=13.0,3.2Hz,2H),2.21(s,6H ), 2.14(td,J=12.1,2.2Hz,2H), 2.02(dq,J=12.7,2.9Hz,2H), 1.63(qd,J=12.2,3.7Hz,2H).

[0256] HR-MS (ESI) m / z 389.2214 ([M+H] + , calculated389.2224).

[0257] Example 37 N-(1-Benzylpiperidin-4-yl)-N-(2-fluorophenyl)-2-furamide (37)

[0258] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 2-fluoroaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0259] 1H NMR(500MHz,DMSO-d6)δ7.65(d,J=1.6Hz,1H),7.54(dddd,J=8.5,7.1,5.0,1.7Hz,1H),7.44 (td,J=7.9,1.8Hz,1H),7.40(s,5H),7.38–7.27(m,3H),6.38(dd,J=3.5,1.7Hz,1H),5.84(b r.s,1H),4.74(ddd,J=12.2,8.3,3.9Hz,1H),4.02(s,2H),3.22(m,2H),2.88(dd,J=11.7,11 .7Hz,2H),2.11–1.97(m,1H),1.98–1.82(m,1H),1.77–1.60(m,1H),1.51(d,J=12.7Hz,1H).

[0260] HR-MS (ESI) m / z 378.1815 ([M+H] + , calculated378.1816).

[0261] Example 38 N-(1-Benzylpiperidin-4-yl)-N-(3-fluorophenyl)-2-furamide (38)

[0262] The difference from Example 24 is that the 2,4,6-trimethylaniline in step P1 is replaced by 3-fluoroaniline, and the propionyl chloride in step P2 is replaced by furoyl chloride. The other steps are basically the same and will not be repeated here.

[0263] 1 H NMR(500MHz,DMSO-d6)δ7.65(d,J=1.5Hz,1H),7.50(td,J=8.2,6.6Hz,1H),7.40(s,5H),7.34 (td,J=8.7,2.6Hz,1H),7.26(dt,J=9.8,2.2Hz,1H),7.15–7.08(m,1H),6.38(dd,J=3.6,1.7H z,1H),5.76(d,J=3.8Hz,1H),4.71(tt,J=12.2,3.8Hz,1H),4.03(s,2H),3.22(d,J=12.0Hz,2 H), 2.88 (dd, J=12.4, 12.4Hz, 2H), 1.98 (dt, J=13.9, 2.7Hz, 2H), 1.61 (qd, J=13.0, 3.9Hz, 2H).

[0264] HR-MS (ESI) m / z 378.1809 ([M+H] + , calculated378.1816).

[0265] Table 1 Numbers and structural formulas of compounds prepared in Examples 1-38

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274] B. Pharmacological Examples

[0275] Example 39 Preparation of σ1 receptor membrane and determination of ligand affinity

[0276] Preparation of σ1 receptor membranes

[0277] The guinea pig was decapitated and operated on ice. The whole brain of the guinea pig was quickly taken out. The tissues were put into a centrifuge tube, and buffer A (10mM Tris-HCl buffer containing 320mM sucrose solution, pH=7.4) was added. The mixture was mixed with a homogenizer, and centrifuged at 50000g, 4℃ for 25min, and the supernatant was discarded. The centrifugation was repeated once, and the precipitate was taken out and stored at -80℃ for later use.

[0278] σ1 receptor competition binding assay

[0279] Step 1: Add 50 μl Tris-HCl buffer to the total binding tube (TB) and 10 μM Haloperidol (final concentration 1.0×10 -5 M) 50 μl, and 50 μl of the test compound was added to each test compound specific binding tube (CB).

[0280] Step 2: Add 100 μl of Tris-HCl buffer to each reaction tube.

[0281] Step 3: First, prepare the prepared membrane into a 500 mg / ml membrane suspension using Tris-HCl buffer for later use.

[0282] Step 4: Add 50 μl of membrane preparation to each reaction tube.

[0283] Step 5: Add radioligand to each reaction tube3 H] (+)-pentazocine 50 μl (final concentration 4 nM).

[0284] Step 6: Incubate each reaction tube at 25°C for 135 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. The Whatman test paper GF / B is saturated with 0.5% PEI solution 1 h in advance and washed thoroughly with ice-cold Tris buffer. The filter is taken out and placed in a 4 mL scintillation tube, 1 mL of toluene scintillation fluid is added, and it is left to stand at room temperature for more than 10 h.

[0285] Step 7: Place the scintillation vial into a liquid scintillation counter for counting.

[0286] Data processing and statistical analysis

[0287]

[0288] Where, TB: total binding constant

[0289] NB: nonspecific binding constant

[0290] CB: compound-specific binding constant

[0291] Example 4 Preparation of 0μ receptor membrane and determination of ligand affinity

[0292] Preparation of μ receptor membrane

[0293] CHO-μ was taken out of the -80℃ freezer and thawed naturally. It was centrifuged at 2000g for 10 min, and buffer B (50mM Tris-HCl, 10mM MgCl2, 0.1mM EDTA, pH 7.4) was added to the precipitate. The precipitate was mixed with a vortex mixer and centrifuged at 50000g, 4℃ for 25 min. The supernatant was discarded, the precipitate was taken, and the centrifugation was repeated once. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80℃ for later use.

[0294] μ opioid receptor competition binding assay

[0295] Step 1: First, prepare the prepared membrane into a 10 mg / ml membrane suspension using a standard binding buffer for later use.

[0296] Step 2: Add 100ul of membrane preparation to each reaction tube.

[0297] Step 3: Add 100 μl of standard binding buffer to the total binding tube (TB) and 10 μM DAMGO (final concentration 1.0×10 -5 M) 100 μl, and 100 μl of the test compound was added to each test compound specific binding tube (CB).

[0298] Step 4: Add 3 nM of radioligand to each reaction tube 3 H]-DAMGO 10 μl.

[0299] Step 5: Incubate each reaction tube at 25°C for 90 min. After the reaction is completed, the bound ligand is quickly filtered through reduced pressure. The Whatman test paper GF / B is saturated with 0.5% PEI solution 1 hour in advance, and washed thoroughly with ice-cold Tris buffer. After filtration, the filter membrane is dried at 60°C, and 40μl scintillation fluid is added after the base membrane is attached. The upper membrane is sealed and allowed to stand.

[0300] Step 6: Place the scintillation vial into a liquid scintillation counter for counting.

[0301] Data processing and statistical analysis

[0302]

[0303] Where, TB: total binding constant

[0304] NB: nonspecific binding constant

[0305] CB: compound-specific binding constant.

[0306] Example 41 Formalin-induced pain model experiment in rats

[0307] SD rats, male, 200–260 g, were randomly divided into negative control group, model group, positive drug group (pregabalin and fentanyl) and compound dose groups, 8 rats in each group. The negative control group and model group were subcutaneously administered with the corresponding solvent saline, the positive drug group was subcutaneously administered with the corresponding positive drug, and the compound dose groups were subcutaneously administered with the corresponding dose of compound, and the administration volume was 5 ml / kg. 5 min after subcutaneous administration, 75 ul of 5% formalin was injected into the sole of the left hind foot of the rat to establish the model, and the formation of a skin mound was the standard for successful modeling. The software automatically recorded the number of foot liftings in the 1-min time period between 0-60 min after modeling, and then analyzed and calculated the total number of foot liftings of rats in phase I (1-10 min) and phase II (10-60 min) according to the results of the software. The results of compound phase II were compared with those of model phase II, and the foot lifting inhibition rate was used as an objective standard for judging whether there was analgesia.

[0308] Example 42: Acetic acid writhing test in mice

[0309] ICR mice, female, 22–30 g, were randomly divided into negative control group, model group, positive drug group (pregabalin and fentanyl) and compound dose groups, 8 mice in each group. The negative control group and model group were subcutaneously administered with the corresponding solvent saline, the positive drug group was subcutaneously administered with the corresponding positive drug, and the compound dose groups were subcutaneously administered with the corresponding dose of compound, and the administration volume was 10 ml / kg. 5 minutes after subcutaneous administration, 1% acetic acid was intraperitoneally administered to the mice, and the number of twisting of the mice within 30 minutes was recorded. The compound test results were compared with the model test results, and the twisting inhibition rate was used as an objective criterion for judging whether there was analgesia. The results are shown in Table 3 below.

[0310] Table 2 In vitro experimental results of compounds on μ and σ1

[0311]

[0312]

[0313] Note: The concentration of each test compound is 10 μM.

[0314] Table 3 In vivo experimental results of preferred compounds

[0315]

[0316] The results showed that compounds 1-38 showed high affinity for σ1 receptor and μ receptor in the in vitro activity screening process, that is, they had σ1 / μ dual-target activity. At the same time, the preferred compounds 1, 4, 5, 6, 7, 9, 17, 20, and 23 showed excellent analgesic activity in the acetic acid writhing test in mice, and their half effective dose (ED50) 50 ) were all below 5 mg / kg. In addition, the preferred compounds 1, 4, and 5 also showed good analgesic effects in the rat formalin-induced pain model, and their ED 50 The values ​​were 6.5, 6.4 and 4.7 mg / kg respectively.

[0317] The results of the acetic acid writhing test on mice of the preferred compound 4 are as follows Figure 1 As shown, the experimental results of the rat formalin-induced pain model of preferred compound 4 are as follows Figure 2 shown.

[0318] The results of the acetic acid writhing test on mice of the preferred compound 6 are as follows Figure 3 shown.

[0319] The results of the mouse acetic acid writhing test of the preferred compound 17 are as follows Figure 4 shown.

[0320] C. Composition Examples

[0321] Example 43, Tablet

[0322] Components Dosage Active ingredient (compound of the present invention) 10mg Microcrystalline Cellulose 40mg lactose 100mg Povidone K30 10mg Sodium carboxymethyl starch 10mg Silicon dioxide 2mg Magnesium Stearate 1mg

[0323] The raw and auxiliary materials are sieved through an 80-mesh sieve for later use. The prescribed amount of active ingredients, microcrystalline cellulose, lactose, and povidone K30 are weighed and added to a high-speed mixer. The mixture is stirred at a low speed and mixed evenly. An appropriate amount of purified water is added. The mixture is stirred at a low speed and granulated at a high speed. The wet granules are dried at 65°C for 2.5 h, sieved through a 24-mesh sieve, and the prescribed amount of sodium carboxymethyl starch, silicon dioxide, and magnesium stearate are added. The mixture is mixed and the tablets are compressed on a rotary tablet press.

[0324] Example 44, injection

[0325]

[0326]

[0327] According to the above prescription, the production process is sequentially carried out through (1) bottle sorting, bottle washing and sterilization steps; (2) preparation step; (3) filtration step; (4) filling step; (5) sterilization and leak detection step; (6) light inspection step; and (7) packaging step to obtain an injection solution containing the active ingredient of the compound of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof having dual-target activity of σ1 receptor / μ receptor, wherein: The compound or its pharmaceutically acceptable salt is selected from the following compounds or their pharmaceutically acceptable salts: (1) N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (2) N-(4-fluorobenzyl)-N-(1-phenylethylpiperidin-4-yl)acetamide (3) N-(4-fluorobenzyl)-2-methoxy-N-(1-phenethylpiperidin-4-yl)acetamide (4) N-(4-fluorobenzyl)-N-(1-phenylethylpiperidin-4-yl)butyramide (5) N-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (6) N-Benzyl-N-(1-phenylethylpiperidin-4-yl)-2-furamide (7) N-Phenethyl-N-(1-phenethylpiperidin-4-yl)-2-furamide (8) N-(2-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (9) N-(2-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (10) N-(2-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (11) N-(4-chlorobenzyl)-N-(1-phenylethylpiperidin-4-yl)propionamide (12) N-(4-chlorobenzyl)-N-(1-phenylethylpiperidin-4-yl)-2-furamide (13) N-(4-chlorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (14) N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (15) N-(4-methoxybenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (16) N-(4-methoxybenzyl)-N-(1-phenylethylpiperidin-4-yl)butyramide (17) N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-2-furamide (18) N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (19) N-(3-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)propionamide (20) N-(2,4-difluorobenzyl)-N-(1-phenylethylpiperidin-4-yl)-2-furamide (21) N-(2,4-difluorobenzyl)-N-(1-phenethylpiperidin-4-yl)butyramide (22) N-(4-methylbenzyl)-N-(1-phenylethylpiperidin-4-yl)-2-furamide (23) N-(1-phenethylpiperidin-4-yl)-N-(1-phenethyl)-2-furamide (24) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)propionamide (25) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)acetamide (26) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)butyramide (27) N-(1-Benzylpiperidin-4-yl)-N-(2,4,6-trimethylphenyl)-2-furamide (28) N-(1-Benzylpiperidin-4-yl)-N-(4-chlorophenyl)-2-furamide (29) N-(1-Benzylpiperidin-4-yl)-N-(4-bromophenyl)-2-furamide (33) N-(1-Benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)-2-furamide (34) N-(1-Benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)butyramide (35) N-(1-Benzylpiperidin-4-yl)-N-(2,4-dimethylphenyl)propionamide (36) N-(1-Benzylpiperidin-4-yl)-N-(2,6-dimethylphenyl)-2-furamide (37) N-(1-Benzylpiperidin-4-yl)-N-(2-fluorophenyl)-2-furamide.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The pharmaceutically acceptable salt is a salt containing a pharmaceutically acceptable anion, wherein the anion salt is hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate, oxalate, acetate, propionate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, ethanesulfonate, propanesulfonate, gluconate, glucarate, benzoate, p-toluate, benzenesulfonate or p-toluenesulfonate.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, excipient, binder, disintegrant, lubricant or sweetener.

4. Use of the compound according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claim 3 in the preparation of a medicament for preventing or treating pain.

5. The use according to claim 4, wherein: The pain includes moderate to severe pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, acute pain, hyperalgesia, and visceral pain.

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