A class of piperidine derivatives, their preparation methods and uses

Abstract

This invention provides a class of piperidine derivatives, their preparation methods, and uses, belonging to the field of chemical pharmaceutical technology. The piperidine derivatives are compounds represented by Formula I, their salts, or their optical isomers. The piperidine derivatives of this invention exhibit agonistic activity against μ-opioid receptors and inhibitory activity against σ1 receptors, thus exerting analgesic effects in vivo and reducing the incidence of side effects. These piperidine derivatives can be used to prepare analgesic drugs, which is of great significance for clinical analgesia and has promising application prospects.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a class of piperidine derivatives and their preparation methods and uses. Background Technology

[0002] For a long time, the treatment of moderate to severe pain (intraoperative pain, postoperative pain, late-stage cancer pain, etc.) in clinical practice has mainly relied on opioids. Classic opioids include natural morphine, semi-synthetic oxycodone, and the synthetic fentanyl family. Opioids exert their analgesic effect by stimulating opioid receptors, which mainly include three subtypes: μ, δ, and κ, with the μ subtype exhibiting the strongest analgesic activity. Although opioids have a powerful analgesic effect, their use is accompanied by serious side effects, including nausea, vomiting, constipation, severe respiratory depression, and itching caused by histamine release. Long-term use can also lead to hyperalgesia, tolerance, and a high degree of psychological and physiological dependence resulting in euphoria, posing a significant threat to society. In recent years, many strategies have been proposed to address the side effects of opioids, such as biased ligands that achieve "efficacy" and "side effects separation" in signaling pathways. Currently, there has been a lot of research on the development of biased ligands. In 2013, Chen et al. discovered the first biased small molecule that acts on μ-opioid receptors by screening a compound library. Although this molecule was recently approved by the FDA for clinical use, the incidence of common side effects is still relatively high.

[0003] Meanwhile, the idea of ​​developing multifunctional ligands has also been proposed, which not only have agonistic effects on opioid receptors but also synergistically relieve pain and reduce side effects by acting on other targets. σ1 is a recently emerging new target for pain treatment; it is a class of receptor chaperone proteins that, upon activation, can translocate from its initial location on the endoplasmic reticulum membrane to other plasma membranes and nuclear membranes, mediating the physiological functions of these receptors. Previous studies have shown that σ1 receptor antagonists can enhance the analgesic potency of morphine and reduce side effects such as respiratory depression and constipation.

[0004] Developing a drug that has an agonistic effect on μ-opioid receptors and an inhibitory effect on σ1 receptors, can exert analgesic effects in vivo, and significantly reduces the incidence of common side effects (gastrointestinal depression, respiratory depression, etc.) is of great significance for clinical analgesia. Summary of the Invention

[0005] The purpose of this invention is to provide a class of piperidine derivatives, their preparation methods, and uses. These piperidine derivatives exhibit agonistic activity against μ-opioid receptors and inhibitory activity against σ1 receptors, thus exerting analgesic effects in vivo and reducing the incidence of side effects.

[0006] This invention provides compounds of Formula I, or salts thereof, or optical isomers thereof:

[0007]

[0008] in,

[0009] a is an integer between 0 and 1;

[0010] R1 is selected from substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocycloalkyl groups;

[0011] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0012] b is an integer from 1 to 4;

[0013] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0014] c is the number of R4 elements, which is an integer from 0 to 4;

[0015] Each R4 is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0016] X is N-, CH-, or NC(O)-;

[0017] Ring A is selected from substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups;

[0018] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0019] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0020] Furthermore,

[0021] a is 0 or 1;

[0022] R1 is selected from substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocycloalkyl groups; the heteroatom of the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0023] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0024] b is 1, 2, 3, or 4;

[0025] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0026] c is the number of R4s, which can be 0, 1, 2, 3 or 4;

[0027] Each R4 is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0028] X is N-, CH-, or NC(O)-;

[0029] Ring A is selected from substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; the heteroatom of the heteroaryl or heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0030] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0031] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0032] Furthermore,

[0033] a is 0 or 1;

[0034] R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophene, and substituted or unsubstituted oxazolyl; the substituents of the pyridyl, furanyl, thiophene, and oxazolyl are selected from C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy.

[0035] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, phenyl, furanyl, thiophene, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, C1-C8 alkoxy.

[0036] b is 1, 2, 3, or 4;

[0037] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0038] c is the number of R4s, which can be 0, 1, 2, 3 or 4;

[0039] Each R4 is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups; the substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0040] X is N-, CH-, or NC(O)-;

[0041] Ring A is selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted pyridyl groups; the substituents of the phenyl or pyridyl groups are selected from C1-C8 alkyl groups, halogen groups, trifluoromethyl groups, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, and C1-C8 alkoxy groups.

[0042] Furthermore, the compound is as shown in Formula II:

[0043]

[0044] in,

[0045] a is 0 or 1;

[0046] R1 is selected from substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocycloalkyl groups; the heteroatom of the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0047] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0048] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0049] c is the number of R4s, which can be 0, 1, 2, 3 or 4;

[0050] Each R4 is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0051] Ring A is selected from substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0052] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0053] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0054] Preferably,

[0055] a is 0 or 1;

[0056] R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophene, and substituted or unsubstituted oxazolyl; the substituents of the pyridyl, furanyl, thiophene, and oxazolyl are selected from C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy.

[0057] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, phenyl, furanyl, thiophene, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, C1-C8 alkoxy.

[0058] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0059] c is the number of R4s, which can be 0, 1, 2, 3 or 4;

[0060] Each R4 is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups; the substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0061] Ring A is selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted pyridyl groups; the substituents of the phenyl or pyridyl groups are selected from C1-C8 alkyl groups, halogen groups, trifluoromethyl groups, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, and C1-C8 alkoxy groups.

[0062] Furthermore, the compound is as shown in Formula III:

[0063]

[0064] in,

[0065] a is 0 or 1;

[0066] R1 is selected from substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocycloalkyl groups; the heteroatom of the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0067] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0068] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0069] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0070] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0071] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0072] Preferably,

[0073] a is 0 or 1;

[0074] R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophene, and substituted or unsubstituted oxazolyl; the substituents of the pyridyl, furanyl, thiophene, and oxazolyl are selected from C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy.

[0075] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, phenyl, furanyl, thiophene, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, C1-C8 alkoxy.

[0076] R3 is selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, and C1-C8 alkoxy groups; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, and C1-C8 alkoxy groups.

[0077] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0078] Furthermore, the compound is as shown in Formula IV:

[0079]

[0080] in,

[0081] R 21 R 22 R 23 R 24 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0082] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0083] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0084] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0085] The substituents of the aryl, heteroaryl, and cycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0086] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0087] Preferably,

[0088] R 21 R 22 R 23 R 24 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0089] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, phenyl, furanyl, thiophene, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, C1-C8 alkoxy.

[0090] R3 is selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, and C1-C8 alkoxy groups; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, and C1-C8 alkoxy groups.

[0091] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0092] Furthermore, the compound is as shown in formula V:

[0093]

[0094] in,

[0095] R 21 R 22 R 23 R 24 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0096] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0097] R3 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0098] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0099] The substituents of the aryl, heteroaryl, and cycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0100] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0101] Preferably,

[0102] R 21 R 22 R 23 R 24 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0103] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, phenyl, furanyl, thiophene, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, C1-C8 alkoxy.

[0104] R3 is selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0105] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0106] Furthermore, the compound is as shown in formula VI or formula VII:

[0107]

[0108] in,

[0109] R 21 R 22 R 23 R 24 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0110] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0111] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0112] The substituents of the aryl, heteroaryl, and cycloalkyl groups are selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0113] The substituents of the alkyl group are selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0114] Preferably,

[0115] R 21 R 22 R 23 R 24 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups;

[0116] R2 is selected from substituted or unsubstituted C1-C8 alkyl, ester, carboxyl, C1-C8 alkoxy, phenyl, furanyl, thiophene, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxy, nitro, C1-C8 alkoxy.

[0117] R3 is selected from substituted or unsubstituted C1-C8 alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups; the substituent of the alkyl group is selected from halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0118] R 11 R 12 R 13 R 14 R 15 Each group is independently selected from hydrogen, C1-C8 alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, and C1-C8 alkoxy groups.

[0119] Furthermore, the compound is one of the following compounds:

[0120]

[0121]

[0122] The present invention also provides a method for preparing the aforementioned compound, which includes the following steps:

[0123]

[0124] Step 1: Compound A and compound B react with a base in an organic solvent to obtain compound C;

[0125] Step 2: Compound C and compound D react with a base in an organic solvent to give compound E;

[0126] Step 3: In an organic solvent, compound E reacts with LiAlH4 to give compound F;

[0127] Step 4: Compound F and compound G react with a base in an organic solvent to obtain compound I;

[0128] Among them, rings a, R1, R2, b, R3, c, R4, X, and A are as described above;

[0129] d is an integer selected from 0 to 3;

[0130] Rab is a halogen;

[0131] Preferably,

[0132] In step 1, the organic solvent is dichloromethane; the base is triethylamine;

[0133] And / or, in step 2, the organic solvent is acetonitrile; the base is potassium carbonate or sodium carbonate;

[0134] And / or, in step 3, the organic solvent is anhydrous tetrahydrofuran;

[0135] And / or, in step 4, the organic solvent is dichloromethane; the base is triethylamine.

[0136] The present invention also provides the use of the aforementioned compounds, or salts thereof, or optical isomers thereof, in the preparation of μ-opioid receptor agonists and / or σ1 receptor inhibitors.

[0137] The present invention also provides the use of the aforementioned compounds, or salts thereof, or optical isomers thereof, in the preparation of analgesic drugs.

[0138] The present invention also provides a drug preparation which is prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients to the aforementioned compound, or its salt, or its optical isomer as the active ingredient.

[0139] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0140] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0141] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0142] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C bAlkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1 to C8 alkyl" refers to an alkyl group containing 1 to 8 carbon atoms; "C1 to C8 alkoxy" refers to an alkoxy group containing 1 to 8 carbon atoms.

[0143] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1 to C8 alkyl groups refer to alkyl groups with 1 to 8 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0144] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0145] In this invention, "ester group" includes methyl formate, ethyl formate, methyl acetate, and ethyl acetate.

[0146] In this invention, "amide group" refers to a structure with the following structure: The group, wherein R 1 and R 2 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0147] In this invention, cycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group consisting of a carbon atom, without heteroatoms, and having a single or multiple rings (including fused, bridged, and spirocyclic systems). Heterocyclic refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom; including a single or multiple rings (including fused, bridged, and spirocyclic systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of heterocyclic groups include, for example, piperidinyl, piperazineyl, and morpholinyl.

[0148] In this invention, aryl refers to an aromatic unsaturated group containing a single ring or multiple rings (including fused, bridged, and spirocyclic systems) without a heteroatom, such as phenyl, anthracene, or naphthyl. Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including single rings or multiple rings (including fused, bridged, and spirocyclic systems); wherein the heteroatom refers to a nitrogen atom, oxygen atom, or sulfur atom. Examples include pyridyl, pyrazinyl, pyrazinyl, pyrazolyl, furanyl, thiopheneyl, and oxazolyl.

[0149] In the compound of formula I of this invention, when X is N-, the compound structure is as follows: When X is CH-, the compound structure is: When X is NC(O)-, the compound structure is:

[0150] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0151] This invention provides a class of piperidine derivatives that exhibit agonistic activity against μ-opioid receptors and inhibitory activity against σ1 receptors, thus exerting analgesic effects in vivo and reducing the incidence of side effects. These piperidine derivatives can be used to prepare analgesic drugs, which is of great significance for clinical analgesia and has promising application prospects.

[0152] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0153] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0154] Figure 1 The results show the determination of the function (activation / inhibition) of the σ1 receptor by the representative compound 11 of this invention.

[0155] Figure 2 The figure shows the analgesic effect of the representative compound of this invention on the mouse CFA pain model; in the figure, B is the basic pain threshold for mechanical stimulation (before CFA modeling); C is the pain threshold for mechanical stimulation after CFA modeling.

[0156] Figure 3 Analgesia in a mouse CFA pain model using the representative compound 11 and the positive compound fentanyl of this invention. 50 value.

[0157] Figure 4 The results show the analgesic effect of the mouse formalin pain model of compound 11, a representative compound of this invention.

[0158] Figure 5 Compound 11, a representative compound of this invention, is shown in 1.5×ED. 50 The results of the effect of the dosage on gastrointestinal motility.

[0159] Figure 6 The effect of the representative compound 11 of this invention on gastrointestinal motility at different doses after pre-subcutaneous injection of the σ1 receptor agonist PRE-084.

[0160] Figure 7 Compound 11, a representative compound of this invention, is shown in 1.5×ED. 50 The effect of the dose on respiratory rate. Detailed Implementation

[0161] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0162] The general formula for the synthetic route of the compounds of this invention is:

[0163]

[0164] Example 1: Synthesis of N-(2-(4-phenylpiperazin-1-yl)propyl)-N-(pyridin-2-yl)propionamide oxalate / hydrochloride

[0165]

[0166] Step a: DCM, TEA, 0℃-RT;

[0167] Step b: Acetonitrile, K2CO3, 80℃;

[0168] Step c: THF, LiAlH4, N2, 0℃-50℃;

[0169] Step d: DCM, TEA, 0℃-RT;

[0170] Step e: EA, oxalic acid dihydrate, RT; or dioxane hydrochloride, RT.

[0171] Preparation of Intermediate 1

[0172]

[0173] 2-Aminopyridine (1 g, 1 eq) was dissolved in a suitable amount of dichloromethane (DCM). Triethylamine (TEA, 4.43 mL) was added to the solution under ice bath conditions at 0 °C, followed by the slow dropwise addition of 2-bromopropionyl bromide (2.23 mL, 2 eq). The reaction mixture was then brought to room temperature and stirred. After the reaction was monitored by TLC until complete, the reaction mixture was poured into a separatory funnel and washed successively with saturated sodium bicarbonate solution and water. The organic phases were separated and combined, dried over anhydrous sodium sulfate, and separated by column chromatography under polar PE:EA = 9:1 (v / v) conditions to obtain intermediate 1, a pale yellow viscous oil, with a yield of 66.6% (LC-MS: 229.0). 1H NMR(400MHz, CDCl3)δ8.99(s,1H),8.34(dd,J=4.9,0.9Hz,1H),8.20(d,J=8.4Hz,1H),7.82– 7.71(m,1H),7.10(ddd,J=7.3,5.0,0.8Hz,1H),4.53(q,J=7.0Hz,1H),1.95(d,J=7.0Hz,3H).

[0174] Preparation of intermediate 2

[0175]

[0176] Intermediate 1 (1.613 g, 1 eq) was dissolved in an appropriate amount of acetonitrile, and K2CO3 (2.92 g, 3 eq) and the starting material N-phenylpiperidine (2.16 mL, 2 eq) were added sequentially. The mixture was heated to 80 °C and refluxed. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure. The residue was dissolved in an appropriate amount of DCM, and the organic phase was washed with water to remove inorganic matter. The organic phases were separated and combined and dried over anhydrous sodium sulfate. The crude product was obtained by column chromatography under polar PE:EA = 3:1 (v / v). After washing with a small amount of diethyl ether, the mixture was filtered and dried to obtain intermediate 2, a white solid with a yield of 40.3% and LC-MS: 311.2. 1 H NMR(400MHz, CDCl3)δ9.72(s,1H),8.29(dd,J=4.9,1.0Hz,1H),8.25(d,J=8.4Hz,1H),7.74–7.67(m,1H),7.32–7.24(m,2H),7.04(ddd, J=7.3,4.9,0.9Hz,1H),6.95(d,J=8.1Hz,2H),6.88(t,J=7.3Hz,1H),3.38–3.23(m,5H),2.78(d,J=24.7Hz,4H),1.38(d,J=7.0Hz,3H).

[0177] Preparation of intermediate 3

[0178]

[0179] Intermediate 2 (500 mg, 1 eq) was dissolved in an appropriate amount of anhydrous tetrahydrofuran. Under ice bath (0 °C) and N2 protection, LiAlH4 (1 M in THF, 9.66 mL, 6 eq) was slowly added using a syringe. After the reaction solution cooled to room temperature naturally, it was heated to 50 °C. The reaction was monitored by TLC until complete. Under ice bath conditions, water and 15% NaOH solution were slowly added sequentially using a syringe to quench the reaction. The solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in an appropriate amount of ethyl acetate (EA). The organic phase was washed with water. The organic phases were separated and combined, and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and used directly in the next reaction without further purification. The yield was 100%, LC-MS: 296.

[0180] Preparation of the final product and its soluble salt

[0181]

[0182] Intermediate 3 (478 mg) was dissolved in an appropriate amount of DCM. Under ice bath (0 °C), TEA (0.672 mL, 3 eq) and starting material propionyl chloride (0.282 mL, 2 eq) were added sequentially, and the mixture was stirred at room temperature. After the reaction was complete as monitored by TLC, the reaction mixture was poured into a separatory funnel and washed sequentially with saturated sodium bicarbonate solution and water. The organic phases were separated and combined, and dried over anhydrous sodium sulfate. The target compound was obtained by column chromatography under polar PE:EA = 7:3 (v / v) conditions. The compound was a colorless, transparent oil with a yield of 80.7% (LC-MS: 353.2). 1 H NMR(400MHz, CDCl3)δ8.43(dd,J=4.8,1.4Hz,1H),7.63(td,J=7.8,1.7Hz,1H),7.26–7.09(m,5H),6.77(dd,J=15.4,7.7Hz,3H), 4.02–3.70(m,2H),2.90(d,J=48.9Hz,5H),2.52(d,J=74.3Hz,4H),2.24–2.05(m,2H),1.02(t,J=7.4Hz,3H),0.97–0.84(m,3H).

[0183] The obtained final product was dissolved in an appropriate amount of ethyl acetate, and oxalic acid dihydrate (1 eq) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was dissolved in 6 mL of ultrapure water and lyophilized overnight to obtain a light and fluffy white solid, which was the soluble oxalate of the final product, with a yield of 83.1%.

[0184]

[0185] The hydrochloride salt of the final product can be prepared by dissolving the obtained final product in a dioxane hydrochloride solution (1.05 eq).

[0186]

[0187] All compounds of this invention can be synthesized using a method similar to that in Example 1. The structural and characterization data of the compounds of this invention are shown in Table 1.

[0188] Table 1. Chemical structure and characterization data of the compounds of this invention

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0201] Experimental Example 1: Evaluation of In Vitro Cell Viability

[0202] I. Tests on the agonistic activity of compounds against μ-opioid receptors:

[0203] Opioids exert their analgesic effect primarily by stimulating μ-opioid receptors. Activation of μ-opioid receptors leads to a decrease in intracellular cAMP levels. The following in vitro cell experiments were conducted to test the effect of the compounds of this invention on cAMP levels in CHO cells stably expressing μ-opioid receptors, thus determining the agonistic activity of the compounds on μ-opioid receptors.

[0204] 1. Experimental materials

[0205] Main equipment: Multifunctional microplate reader (BMG), 384-well microplate (Greiner)

[0206] Main reagents: F12K medium (Gibco), fetal bovine serum (Corning), bleomycin (Sigma), hygromycin B (Sigma), cAMP assay kit (Cisbio)

[0207] Cell line: CHO cells stably expressing μ-opioid receptors (Genescript)

[0208] 2. Experimental Methods

[0209] (1) Cell Culture

[0210] CHO cells stably expressing μ-opioid receptors were cultured in F12K medium containing 10% fetal bovine serum, 200 μg / μL bleomycin, and 100 μg / μL hygromycin B, and passaged every other day.

[0211] (2) Detection of the agonistic activity of the compound on μ-opioid receptors

[0212] CHO cells stably expressing μ-opioid receptors were digested and centrifuged, then seeded into 384-well microplates, 3000 cells per well (5 μL). 5 μL of each test compound solution (final concentrations of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM) was added to each well, and the plates were incubated at 37°C in the dark for 45 min. 5 μL of cAMP cytokine solution and 5 μL of cAMP d2 antibody were added to each well, and the plates were incubated at room temperature in the dark for 1 h before detection using a multi-mode microplate reader (fluorescence emission intensity: 665 nm / 620 nm). The half-maximal effector concentration (Cmax) of each compound for μ-opioid receptor activation was fitted using GraphPad Software 8. 50 EC 50 The smaller the value, the lower the concentration required for the compound to take effect, and the better the compound's effect.

[0213] 3. Experimental Results

[0214] EC50 of the compounds on the agonistic activity of μ-opioid receptors 50 The results are shown in Table 2 (fentanyl was used as a positive control).

[0215] Table 2. EC50 of each compound’s agonistic activity against μ-opioid receptors 50

[0216]

[0217]

[0218] Note: "+" indicates that 500nM ≤ EC 50 <1500nM; “++”: 200nM≤EC50 <500nM; "+++": EC 50 <200nM.

[0219] The above experimental results demonstrate that the compounds of this invention can effectively stimulate μ-opioid receptors, thereby exerting analgesic and pain-relieving effects. Compounds 6, 8–13, 15, and 17 show even better effects.

[0220] II. Combination rate test of the compound with σ1 receptor:

[0221] First, it is verified whether the compound of this invention can bind to the σ1 receptor. The binding strength of the compound to the σ1 receptor is determined by a competitive binding experiment: that is, testing the reaction of the test compound with the radioactive positive ligand of the σ1 receptor. 3 The substitution rate of H]Pentazocine is the binding rate of the tested compound to the σ1 receptor.

[0222] 1. Experimental Materials

[0223] Main equipment: GF / C filter (Whatman); liquid scintillation counter (PerkinElmer) Main reagents: sucrose; Tris-HCl; [ 3 [H]Pentazocine; Phenytoin; Sodium hydroxide

[0224] 2. Experimental Methods

[0225] (1) The isolated guinea pig brains were refrigerated in sucrose-Tris buffer (containing 320 mM sucrose, 10 mM Tris-HCl, pH 7.4);

[0226] (2) Homogenize the tissue at 4℃, centrifuge at 700×g for 10min, and collect the suspension;

[0227] (3) Centrifuge the suspension at 4℃ and 48000g for 25 min to separate the membrane and cytoplasm and collect the precipitate;

[0228] (4) Resuspend the membrane particles in 15 mL of sucrose-Tris buffer and repeat the centrifugation steps;

[0229] (5) The binding rate of the compound to the σ1 receptor was determined by a competitive binding experiment: Under the above conditions, 1 μM of the test compound and 4 nM of […] were applied to the σ1 receptor. 3 [H]Pentazocine, 300 μg membrane protein (dissolved in 250 μL 50 mM pH 7.4 Tris buffer) were mixed and incubated;

[0230] (6) Rapid vacuum filtration using a GF / C filter to remove bound / unbound radioactive ligands ([ 3[H]Pentazocine) is isolated to terminate the reaction;

[0231] (7) Determine the effect of the test compound on [ ] using a liquid scintillation counter. 3 The substitution rate of H]Pentazocine is the binding rate of the test compound to the σ1 receptor.

[0232] 3. Experimental Results

[0233] The results of the compound's binding rate to the σ1 receptor are shown in Table 3.

[0234] Table 3. Binding rate (%) of each compound to the σ1 receptor at a concentration of 1 μM

[0235]

[0236]

[0237] Note: "+": 10%-30%; "++": 31%-60%; "+++": 61%-100%.

[0238] The above experimental results show that the compounds of the present invention can effectively bind to σ1 receptors, and the binding rates are all higher than those of the classic opioid fentanyl. Among them, compounds 6, 10, 11, 13, 15 and 17 have high binding rates to σ1 receptors.

[0239] Phenytoin-induced allosteric regulation can increase the binding affinity (Ki) of σ1 receptor agonists while decreasing the binding affinity (Ki) of σ1 receptor antagonists. In binding experiments, phenytoin was added to determine the function of a representative compound 11 on the σ1 receptor; specifically, 1 mM phenytoin was dissolved in 12 mM sodium hydroxide, and the solution was added to the reaction system, with other procedures as previously described. Figure 1 As shown, 1 mM phenytoin reduced the σ1 receptor Ki value of compound 11, causing the curve to shift to the right. Figure 1 The Ki value ranged from 0.419±0.052 μM to 0.877±0.058 μM. Therefore, the representative compound 11 of the present invention binds to and antagonizes the σ1 receptor, thereby synergistically enhancing the analgesic effect in vivo and reducing the side effects of opioids.

[0240] Experimental Example 2: Evaluation of Analgesic Efficacy

[0241] 1. Experimental Method One

[0242] ICR mice (weighing 20–30 g) were acclimatized to the experimental environment for 3 days. The skin in the middle of the left foot sole was stimulated with an electronic von Frey agent, and the withdrawal response was observed as an indicator of pain response. First, the baseline mechanical pain threshold of the mice was measured. Mice meeting the inclusion criteria (mechanical pain threshold: 8–12 g) were injected subcutaneously with 0.02 mL of Frey's complete adjuvant (CFA) into the left foot sole to induce pain. Approximately 16 hours later, the mechanical pain threshold of the left foot was measured. Mice meeting the criteria (mechanical pain threshold reduced to 2.5–3.5 g) were randomly divided into a model group and a test compound group, with 8–10 mice in each group, half male and half female.

[0243] All tested compounds were administered subcutaneously at a concentration of 86 μmol / kg, using physiological saline as the solvent, with an injection volume of 0.1 mL / 10 g. The model group received subcutaneous injection of physiological saline. The mechanical pain threshold of the left hind paw in mice was recorded at 20 min, 40 min, 1 h, 1.5 h, 2 h, and 3 h after administration. Data analysis was performed using GraphPad software after the experiment. An increase in the mechanical pain threshold, with a statistically significant difference compared to the physiological saline group at the corresponding time points, indicates that the tested compounds have an analgesic effect.

[0244] 2. Representative experimental results

[0245] The results of the evaluation of the analgesic effect of the compound of the present invention on the mouse CFA pain model are as follows: Figure 2 As shown in the figure. The results indicate that all compounds increased the pain threshold of mechanical stimulation in the hind paw of mice after injection, with compound 11 showing the most significant analgesic effect and an analgesic duration of not less than 3 hours (***P<0.001 vs saline group; *P<0.05 vs saline group).

[0246] Analgesia in a mouse CFA pain model using compound 11 and the positive compound fentanyl 50 Values ​​such as Figure 3 As shown. ED 50 The half-maximal effective dose (MDD) represents the dose required to achieve 50% analgesia in all mice during analgesia experiments. 50 The maximum analgesic effect was obtained by fitting the curves corresponding to different doses using Graphpad. In the CFA pain model, the maximum analgesic effect of different doses of the compound in each mouse was calculated as follows: Maximum analgesic effect (%) = Maximum mechanical stimulation pain threshold achievable after administration (g) - Model mechanical stimulation pain threshold (g) / Baseline mechanical stimulation pain threshold (g) - Model mechanical stimulation pain threshold (g). After fitting with Graphpad software, the analgesic efficacy of the representative compound 11 and the positive control compound fentanyl in the mouse CFA model was determined. 50The values ​​were 2.4 μmol / kg and 0.28 μmol / kg, respectively.

[0247] 3. Experimental Method Two

[0248] Mice were randomly divided into a model group and a test compound group, with 6-8 mice in each group (half male and half female). Twenty minutes prior to administration, mice were subcutaneously injected with either physiological saline or a solution of the test compound (21.5 μmol / kg, dissolved in physiological saline, injection volume 0.1 mL / 10 g). Twenty minutes after administration, 20 μL of 5% formalin solution was subcutaneously injected into the hind paw to induce acute pain. The total time for grasping, biting, licking, and shaking the hind paw was recorded using a stopwatch to quantify the formalin-induced pain behavior. The recording was divided into two phases: Phase I (0-10 min after formalin injection), representing pain caused by acute noxious stimulation; and Phase II (10-30 min after formalin injection), representing pain caused by central sensitization. Compared to physiological saline, the total time for grasping, biting, licking, and shaking the hind paw was shorter, indicating that the test compound had an analgesic effect.

[0249] 4. Representative Experimental Results II

[0250] The analgesic effect of compound 11 in a mouse formalin pain model was evaluated as follows: Figure 4 As shown. Compound 11 of the present invention can significantly shorten the total time of grasping, biting, licking, and shaking the hind paws of mice after injection of 5% formalin, and has a significant analgesic effect (***P<0.001 vs saline group).

[0251] Experimental Case 3: Side Effect Assessment

[0252] Opioids can induce side effects such as constipation and respiratory depression during their analgesic effects. (The last sentence appears to be incomplete and possibly refers to analgesics.) 50 At the specified dosage (i.e., the analgesic effect can reach 100%), the following experiments demonstrate that the side effects of the compound of the present invention are significantly reduced.

[0253] 1. Experimental Method One

[0254] Before the experiment, ICR mice (weighing 20-30g) were fasted but allowed free access to water overnight. On the day of the experiment, they were randomly divided into three groups: a normal saline group, a positive compound (fentanyl) group, and a test compound group, with six mice in each group, half male and half female.

[0255] 30 minutes prior to administration, a blank saline solution or a solution of the test compound was injected subcutaneously. The concentration of the representative compound 11 was 3.6 μmol / kg (1.5 times the ED). 50 The concentration of the positive compound fentanyl was 0.42 μmol / kg (1.5 times the analgesic ED). 50The dosage was dissolved in physiological saline, and the administration volume was 0.1 mL / 10 g. 30 min later, each mouse was gavaged with 0.3 mL of a gastrointestinal function marker (prepared by repeatedly boiling and cooling an aqueous solution containing 5% gum arabic and 10% activated carbon powder). 30 min after gavage, the mice were euthanized by cervical dislocation, the abdominal cavity was opened, the mesentery was separated, and the portion from the pylorus to the ileocecal junction was cut. The portion was laid flat on a table, and the length from the pylorus to the tip of the ink mark in the small intestine (S / cm) and the total length from the pylorus to the ileocecal junction (L / cm) were measured. The gastrointestinal motility rate can be calculated using the following formula:

[0256] Gastrointestinal motility rate (%) = Ink propulsion rate (%) = S / L × 100%

[0257] The fact that the gastrointestinal motility rate was less than 50% and showed a statistically significant difference compared to the saline group indicates that the tested compound may induce constipation while exerting an analgesic effect.

[0258] 2. Representative experimental results

[0259] Compound 11 of the present invention at 1.5×ED 50 The effect of the dosage on gastrointestinal motility is as follows: Figure 5 As shown. At the point of maximum analgesia, classic opioids (positive control fentanyl) caused strong gastrointestinal motility inhibition (gastrointestinal motility rate <50%), inducing constipation; compound 11 of the present invention did not cause abnormal gastrointestinal motility (gastrointestinal motility rate >50%), and no obvious constipation occurred (**P<0.01 vs saline group).

[0260] The reduction in side effects of the representative compound 11 of this invention was determined to be related to its inhibitory effect on σ1 receptors by subcutaneously injecting the σ1 receptor agonist PRE-084 (40 mg / kg, dissolved in physiological saline) 10 minutes before subcutaneous injection of blank saline or the test compound solution. Figure 6 As shown, the gastrointestinal motility rate of the compound 11+PRE-084 group was lower than that of the compound 11 alone group, indicating that the reduction of opioid side effects of the representative compound 11 of the present invention is due to the inhibitory effect on σ1 receptor (***P<0.001 vs saline group, *P<0.05 vs compound 11 21.5μmol / kg group).

[0261] 3. Experimental Method Two

[0262] Changes in respiratory rate in mice were monitored using a whole-body plethysmography system to reflect whether the drug caused respiratory depression. Baseline respiratory rate was recorded 10 minutes before the experiment. Mice were randomly divided into three groups: a saline (normal) group, a positive compound (fentanyl) group, and a test compound group, with six mice in each group (half male and half female). Blank saline or the test drug solution was injected subcutaneously. The concentration of the representative compound 11 was 3.6 μmol / kg (1.5 times the analgesic ED). 50 The concentration of the positive compound fentanyl was 0.42 μmol / kg (1.5 times the analgesic ED). 50 The drug (dosage) was dissolved in physiological saline, and the administration volume was 0.1 mL / 10 g. Respiratory rate changes were continuously monitored for 40 minutes after administration. A decrease in respiratory rate with a statistically significant difference compared to the physiological saline group demonstrated that the drug caused respiratory depression.

[0263] 4. Representative Experimental Results II

[0264] Compound 11 of the present invention at 1.5×ED 50 The effect of the dose on respiratory rate is as follows: Figure 7 As shown. At the point of maximum analgesia, classic opioids (positive control fentanyl) caused strong and persistent respiratory depression; compound 11 of the present invention did not cause respiratory dysfunction, and there was no statistically significant difference between the control group and the normal saline group at any time monitoring point (***P<0.001 vs saline group; **P<0.01 vs saline group; *P<0.05 vs saline group).

[0265] The above results demonstrate that the compounds of this invention have low side effects and high safety after use.

[0266] In summary, this invention provides a class of piperidine derivatives that exhibit agonistic activity against μ-opioid receptors and inhibitory activity against σ1 receptors, thus exerting analgesic effects in vivo and reducing the incidence of side effects. These piperidine derivatives can be used to prepare analgesic drugs, which is of great significance for clinical analgesia and has promising application prospects.

Claims

1. A compound of formula IV, or a salt thereof: Formula IV R 21 , R 22 , R 23 , R 24 , R 11 , R 13 , R 14 , R 15 is hydrogen; R2 is selected from C1-C8 alkyl; R3 is selected from C1-C8 alkyl; R 12 selected from hydrogen, C1-C8alkyl.

2. A compound of formula V, or a salt thereof: Formula V wherein R 24 , R 11 , R 12 , R 13 , R 14 , R 15 is hydrogen; R 21 , R 22 , R 23 are each independently selected from the group consisting of hydrogen, C1-C8alkyl; R2 is selected from C1-C8 alkyl, furanyl, 3-membered cycloalkyl; R3 is selected from C1-C8 alkyl.

3. A compound, or a salt thereof, characterized by: The compound is of formula VI or formula VII: Formula VI Formula VII R 21 , R 22 , R 23 , R 24 , R 11 , R 12 , R 13 , R 14 , R 15 is hydrogen; R2 is selected from C1-C8 alkyl.

4. A compound, or a salt thereof, characterized by: The compound is one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 5. A method of preparing a compound, characterized by, It comprises the following steps: Step 1: reacting compound A, compound B and a base in an organic solvent to obtain compound C; Step 2: reacting compound C, compound D and a base in an organic solvent to obtain compound E; Step 3: reacting compound E with LiAlH4 in an organic solvent to obtain compound F; Step 4: reacting compound F, compound G and a base in an organic solvent to obtain a compound of formula I; The compound of formula I is the compound of any one of claims 1-4; R ab is halogen.

6. The preparation method of claim 5, wherein: In step 1, the organic solvent is dichloromethane; and the base is triethylamine; and / or, in step 2, the organic solvent is acetonitrile; and the base is potassium carbonate or sodium carbonate; and / or, in step 3, the organic solvent is anhydrous tetrahydrofuran; and / or, in step 4, the organic solvent is dichloromethane; and the base is triethylamine.

7. Use of the compound of any one of claims 1-4, or a salt thereof, in the preparation of a μ opioid receptor agonist.

8. Use of the compound of any one of claims 1-4, or a salt thereof, in the preparation of a μ opioid receptor agonist and σ1 receptor inhibitor.

9. Use of the compound of any one of claims 1-4, or a salt thereof, in the preparation of an analgesic drug.

10. A medicament, characterized by comprising: It is a preparation prepared from the compound of any one of claims 1-4, or a salt thereof, as an active ingredient, plus pharmaceutically acceptable adjuvants or auxiliary ingredients.

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