WO2023213279A1 - Piperidine derivative, preparation method therefor, and use thereof - Google Patents

Abstract

Provided in the present invention are a piperidine derivative, a preparation method therefor, and a use thereof, relating to the chemical and pharmaceutical technical fields. The piperidine derivative is a compound represented by formula I, or a salt thereof, or an optical isomer thereof. The piperidine derivative of the present invention has an agonistic effect on μ opioid receptors and also an inhibitory effect on σ1 receptors, and can exert an analgesic effect in vivo and reduce the incidence of side effects. The piperidine derivative can be used for preparing analgesic drugs, has important significance for clinical analgesia, and has good prospects for use.

Description

A class of piperidine derivatives and preparation methods and uses thereof Technical field

The invention belongs to the technical field of chemical drugs, and specifically relates to a class of piperidine derivatives and their preparation methods and uses.

Background technique

For a long time, clinical treatment of moderate to severe pain (intraoperative pain, postoperative pain, late-stage cancer pain, etc.) has mainly relied on opioids. Classic opioids include natural morphine, semi-synthetic oxycodone, Synthetic fentanyl family, etc. Opioids exert analgesic effects by stimulating opioid receptors, which mainly include three subtypes: μ, δ, and κ, among which the μ subtype mediates the strongest analgesic activity. Although opioids have powerful analgesic effects, their use is accompanied by serious side effects, including nausea, vomiting, constipation, strong respiratory depression, itching caused by histamine release, etc.; long-term use can also cause hyperalgesia. The high degree of psychological and physiological dependence caused by , tolerance and euphoria has brought huge hidden dangers to society. In recent years, in order to solve the side effects of opioids, many strategies have been proposed, such as biased ligands to achieve "separation of drug efficacy" and "side effects" on signaling pathways; currently, many studies have been conducted on the development of biased ligands. In 2013, Chen et al. discovered the first biased small molecule that acts on the μ-opioid receptor by screening a compound library. Although this molecule was recently approved for clinical use by the FDA, the incidence of common side effects is still high.

At the same time, the idea of developing multifunctional ligands has also been proposed, that is, it not only has an agonistic effect on opioid receptors, but also synergistically relieves pain and reduces side effects by acting on other targets. σ ₁ is a new target for pain treatment that has emerged recently. It is a type of receptor chaperone protein. After activation, it can be transferred from the endoplasmic reticulum membrane where it initially resides to other plasma membranes and nuclear membranes to mediate the physiological functions of these receptors. Preliminary studies have shown that σ ₁ receptor antagonists can enhance the analgesic intensity of morphine and reduce side effects such as respiratory depression and constipation.

Developing a drug that has an agonistic effect on μ opioid receptors and an inhibitory effect on σ1 receptors can exert an analgesic effect in the body and significantly reduce the incidence of common side effects (inhibition of gastrointestinal function, respiratory depression, etc.) for clinical use. Analgesia is of great importance.

Contents of the invention

The object of the present invention is to provide a class of piperidine derivatives and their preparation methods and uses. This type of piperidine derivative has an agonistic effect on μ opioid receptors and an inhibitory effect on σ1 receptors. It can exert an analgesic effect in the body and reduce the incidence of side effects.

The present invention provides a compound represented by formula I, or a salt thereof, or an optical isomer thereof:

in,

a is an integer from 0 to 1;

R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl;

b is an integer from 1 to 4;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group;

c is the number of R ₄ , which is an integer from 0 to 4;

Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ;

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

Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, and C ₁ to C ₈ alkoxy group.

further,

a is 0 or 1;

R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroatom of the heteroaryl or heterocycloalkyl is N, O or S, the number of heteroatoms is 1, 2 or 3;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

b is 1, 2, 3 or 4;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group;

c is the number of R ₄ , which is 0, 1, 2, 3 or 4;

Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ;

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

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

The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, and C ₁ to C ₈ alkoxy group.

further,

a is 0 or 1;

_R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl; the pyridyl, furyl, thienyl, oxazole The substituents of the base are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

b is 1, 2, 3 or 4;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide group, cyano group, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; the The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

c is the number of R ₄ , which is 0, 1, 2, 3 or 4;

Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

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

Ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group.

Further, the compound is represented by formula II:

in,

a is 0 or 1;

R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroatom of the heteroaryl or heterocycloalkyl is N, O or S, the number of heteroatoms is 1, 2 or 3;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group;

c is the number of R ₄ , which is 0, 1, 2, 3 or 4;

Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ;

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

The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

Preferably,

a is 0 or 1;

_R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl; the pyridyl, furyl, thienyl, oxazole The substituents of the base are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide group, cyano group, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; the The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

c is the number of R ₄ , which is 0, 1, 2, 3 or 4;

Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

Ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group.

Further, the compound is represented by formula III:

in,

a is 0 or 1;

R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroatom of the heteroaryl or heterocycloalkyl is N, O or S, the number of heteroatoms is 1, 2 or 3;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group;

The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

Preferably,

a is 0 or 1;

_R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl; the pyridyl, furyl, thienyl, oxazole The substituents of the base are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group.

Further, the compound is represented by formula IV:

in,

R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the hetero The heteroatom of the aryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group;

The substituents of the aryl group, heteroaryl group, and cycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

Preferably,

R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group.

Further, the compound is represented by formula V:

in,

R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ 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 the heteroatoms is 1, 2 or 3;

R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group;

The substituents of the aryl group, heteroaryl group, and cycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

Preferably,

R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group.

Further, the compound is represented by formula VI or formula VII:

in,

R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group;

The substituents of the aryl group, heteroaryl group, and cycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, C ₁ ~ C ₈ alkoxy;

The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

Preferably,

R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy;

R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group;

R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group;

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group.

Further, the compound is one of the following compounds:

The present invention also provides a preparation method of the aforementioned compound, which includes the following steps:

Step 1: react compound A, compound B and a base in an organic solvent to obtain compound C;

Step 2: react compound C, compound D and a base in an organic solvent to obtain compound E;

Step 3: React compound E with LiAlH ₄ in an organic solvent to obtain compound F;

Step 4: react compound F, compound G and a base in an organic solvent to obtain the compound of formula I;

Among them, a, R ₁ , R ₂ , b, R ₃ , c, R ₄ , X and A ring are as described above;

d is selected from an integer from 0 to 3;

Rab is halogen;

Preferably,

In step 1, the organic solvent is methylene chloride; the base is triethylamine;

And/or, in step 2, the organic solvent is acetonitrile; 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 methylene chloride; the base is triethylamine.

The present invention also provides the use of the aforementioned compound, or its salt, or its optical isomer in the preparation of μ opioid receptor agonists and/or σ1 receptor inhibitors.

The present invention also provides the use of the aforementioned compound, or its salt, or its optical isomer in the preparation of analgesic drugs.

The present invention also provides a medicine, which is a preparation prepared from the aforementioned compound, or its salt, or its optical isomer as an active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.

Compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems.

Definitions of terms used in the present invention: Unless otherwise stated, the initial definition provided for a group or term in this article applies to the group or term throughout the entire specification; there is no specific definition for this article. The terms shall be given the meanings that those skilled in the art can give them based on the disclosure and context.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum content of carbon atoms in a hydrocarbon group is indicated by a prefix, for example, the prefix C _a to C _b alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C ₁ -C ₈ alkyl" refers to an alkyl group containing 1 to 8 carbon atoms; "C ₁ -C ₈ alkoxy" refers to an alkoxy group containing 1 to 8 carbon atoms.

"Alkyl" refers to a saturated hydrocarbon chain having the specified number of carbon atoms. For example, C ₁ -C ₈ alkyl refers to an alkyl group having 1 to 8 carbon atoms, that is, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Alkyl groups can be straight 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). base) and hexyl group, etc.

"Halogen" is fluorine, chlorine, bromine or iodine.

In the present invention, "ester group" includes methyl formate, ethyl formate, methyl acetate, and ethyl acetate.

In the present invention, "amide group" means that the structure is A group, wherein R ¹ and R ² are independently selected from hydrogen and C ₁ to C ₈ alkyl groups.

In the present invention, cycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group composed of carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems) . Heterocycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom; including a single ring or multiple rings (including fused, bridged and spiro ring systems); where the heteroatom refers to nitrogen atoms, oxygen atoms, sulfur atoms. Examples of heterocyclyl groups include, for example, piperidinyl, piperazinyl, morpholinyl.

In the present invention, aryl refers to an aromatic unsaturated group that has no ring heteroatoms and has a single ring or multiple rings (including fused, bridged and spiro ring systems), such as phenyl, anthracenyl, naphthalene base. Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including a single ring or multiple rings (including fused, bridged and spiro ring systems); where the heteroatoms refer to nitrogen atoms, oxygen atoms, and sulfur atoms. Such as pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, oxazolyl, etc.

In the compound of formula I of the present invention, when X is N-, the compound structure is when When X is CH-, the compound structure is When X is NC(O)-, the compound structure is

Compared with the prior art, the beneficial effects of the present invention are:

The invention provides a type of piperidine derivative, which has an agonistic effect on μ opioid receptors and an inhibitory effect on σ1 receptors, and can exert an analgesic effect in the body and reduce the incidence of side effects. This type of piperidine derivatives can be used to prepare analgesic drugs, which is of great significance for clinical analgesia and has good application prospects.

Obviously, according to the above content of the present invention, according to the common technical knowledge and common means in the field, without departing from the above basic technical idea of the present invention, various other forms of modifications, replacements or changes can also be made.

The above contents of the present invention will be further described in detail below through specific implementation methods in the form of examples. However, this should not be understood to mean that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

Description of the drawings

Figure 1 shows the results of determining the function (agonism/inhibition) of the representative compound 11 of the present invention on the σ1 receptor.

Figure 2 shows the evaluation results of the analgesic effect of the representative compounds of the present invention on the mouse CFA pain model; in the figure, B is the basic pain threshold of mechanical stimulation (before CFA modeling); C is the pain threshold of mechanical stimulation after CFA modeling.

Figure 3 shows the analgesic ED ₅₀ values of the mouse CFA pain model of the representative compound 11 of the present invention and the positive compound fentanyl.

Figure 4 shows the evaluation results of the analgesic effect of the representative compound 11 of the present invention in the mouse formalin pain model.

Figure 5 shows the effect of representative compound 11 of the present invention on gastrointestinal motility rate at a dose of 1.5×ED ₅₀ affect the result.

Figure 6 shows the effect of representative compound 11 of the present invention on gastrointestinal motility rate at different doses after early subcutaneous injection of σ1 receptor agonist PRE-084.

Figure 7 shows the effect of representative compound 11 of the present invention on respiratory frequency at a dose of 1.5×ED ₅₀ .

Detailed ways

The raw materials and equipment used in the specific embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

The general formula of the synthesis route of the compound of the present invention is:

Example 1. Synthesis of N-(2-(4-phenylpiperazin-1-yl)propyl)-N-(pyridin-2-yl)propionamide oxalate/hydrochloride

Step a: DCM, TEA, 0℃-RT;

Step b: acetonitrile, K ₂ CO ₃ , 80°C;

Step c: THF, LiAlH ₄ , N ₂ , 0℃-50℃;

Step d: DCM, TEA, 0℃-RT;

Step e: EA, oxalic acid dihydrate (Oxalic acid dihydrate), RT; or dioxane hydrochloride, RT.

Preparation of intermediate 1

Dissolve the raw material 2-aminopyridine (1g, 1eq) in an appropriate amount of dichloromethane (DCM), add triethylamine (TEA, 4.43mL) under ice bath conditions at 0°C, and then slowly add the raw material 2-bromopropyl Acid bromide (2.23 mL, 2 eq), the reaction solution was moved to room temperature and stirred. After TLC monitors that the reaction is complete, pour the reaction solution into a separatory funnel, wash the organic phase with saturated sodium bicarbonate solution and water in sequence; separate and combine the organic phases, add anhydrous sodium sulfate to dry; use column chromatography, Intermediate 1 was isolated under the conditions of PE:EA=9:1 (v/v), a light yellow viscous oil, yield 66.6%, LC-MS: 229.0. ¹ H NMR (400MHz, CDCl ₃ ) 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).

Preparation of intermediate 2

Dissolve Intermediate 1 (1.613g, 1eq) in an appropriate amount of acetonitrile, add K ₂ CO ₃ (2.92g, 3eq) and raw material N-phenylpiperidine (2.16mL, 2eq) to it in sequence, and heat to 80°C to reflux reaction. After TLC monitors that the reaction is complete, concentrate the reaction solution under reduced pressure; dissolve the residue in an appropriate amount of DCM, wash the organic phase with water to remove inorganic matter, separate and combine the organic phases, and dry over anhydrous sodium sulfate; use column chromatography, in polar PE : The crude product was separated under the conditions of EA=3:1 (v/v); stirred and washed with a small amount of diethyl ether, filtered and dried to obtain intermediate 2, a white solid, yield 40.3%, LC-MS: 311.2. ¹ H NMR (400MHz, CDCl ₃ ) 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).

Preparation of intermediate 3

Dissolve intermediate 2 (500mg, 1eq) in an appropriate amount of anhydrous tetrahydrofuran, slowly add LiAlH ₄ (1M in THF, 9.66mL, 6eq) using a syringe under ice bath (0°C) and _N2 protection, and wait for the reaction After the liquid temperature naturally returns to room temperature, it is heated to 50°C for reaction. TLC monitors that the reaction is complete. Use a syringe to slowly add water and 15% NaOH solution to the reaction solution under ice bath conditions to quench the reaction. Filter the solid; concentrate the filtrate under reduced pressure and dissolve the residue in an appropriate amount of ethyl acetate (EA). , wash the organic phase with water; separate and combine the organic phases, and dry using anhydrous sodium sulfate; concentrate under reduced pressure to obtain a crude product, which is directly used in the next step of the reaction without further purification. The yield is 100%, LC-MS: 296 .

Preparation of final products and their soluble salts

Dissolve intermediate 3 (478 mg) in an appropriate amount of DCM, add TEA (0.672 mL, 3 eq) and raw material propionyl chloride (0.282 mL, 2 eq) to it in an ice bath (0°C) in sequence, and move to room temperature to stir the reaction. After TLC monitors that the reaction is complete, pour the reaction solution into a separatory funnel, and wash the organic phase with saturated sodium bicarbonate solution and water in sequence; separate and combine the organic phases, and dry with anhydrous sodium sulfate; use column chromatography, and Under the conditions of PE:EA=7:3 (v/v), the target compound was isolated as a colorless and transparent oil, with a yield of 80.7% and LC-MS: 353.2. ¹ H NMR (400MHz, CDCl ₃ ) 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).

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

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

All compounds of the present invention can be synthesized by methods similar to Example 1. The structure and characterization data of the compounds of the present invention are shown in Table 1.

Table 1. Chemical structure and characterization data of the compounds of the present invention

The beneficial effects of the present invention are demonstrated below through specific test examples.

Test Example 1. In vitro cell activity evaluation

1. Test of the agonistic activity of compounds on μ opioid receptors:

Opioids mainly exert analgesic effects by stimulating μ-opioid receptors. When μ-opioid receptors are stimulated, intracellular cAMP content decreases. The following in vitro cell experiments were conducted to test the effects of the compounds of the present invention on the cAMP content of CHO cells stably expressing μ-opioid receptors, and to determine the agonistic activity of the compounds on μ-opioid receptors.

1. Experimental materials

Main equipment: multifunctional microplate reader (BMG), micro-volume 384-well plate (Greiner)

Main reagents: F12K medium (Gibco), fetal calf serum (Corning), bleomycin (Sigma), hygromycin B (Sigma), cAMP detection kit (Cisbio)

Cell line: CHO cells stably expressing mu opioid receptors (Genescript)

2. Experimental methods

(1) Cell culture

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

(2) Detect the agonistic activity of compounds on μ opioid receptors

The CHO cells stably expressing μ opioid receptors were digested and centrifuged, and then spread into a micro-well 384-well plate at 3,000 cells per well (5 μL). Add 5 μL of test compound solution of each concentration (final concentration: 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM) to each well, and incubate at 37°C in the dark for 45 min. Add 5 μL cAMP Cryptate solution and 5 μL cAMP d2 antibody to each well, incubate for 1 hour at room temperature in the dark, and then detect on a multifunctional microplate reader (fluorescence emission intensity: 665nm/620nm). Use GraphPad Software 8 to fit the half-maximum effect concentration (EC ₅₀ ) of each compound on μ-opioid receptor agonism. The smaller the EC ₅₀ value, the lower the concentration required for onset of action, and the better the effect of the compound.

3. Experimental results

The EC ₅₀ results of each compound's agonistic activity on μ-type opioid receptors are shown in Table 2 (fentanyl is a positive control).

Table 2. EC ₅₀ of each compound on μ-opioid receptor agonist activity


Note: “+”: 500nM≤EC ₅₀ <1500nM; “++”: 200nM≤EC ₅₀ <500nM;
“+++”: _EC50 <200nM.

The above test results show that the compound of the present invention can effectively stimulate the mu opioid receptor, thereby exerting analgesic and analgesic effects. Among them, compounds 6, 8-13, 15 and 17 have better effects.

2. Test of the binding rate of compounds to σ ₁ receptor:

Firstly, it is verified whether the compound of the present invention can bind to the σ ₁ receptor. The binding strength of the compound to the σ ₁ receptor is determined through a competitive binding experiment: that is, the test compound’s binding strength to the σ ₁ receptor radioactive positive ligand [ ^3H ]Pentazocine is tested. The substitution rate is the binding rate of the tested compound to the σ ₁ receptor.

1. Experimental materials

Main equipment: GF/C filter (Whatman); liquid scintillation counter (PerkinElmer)

Main reagents: sucrose; Tris-HCl; [ ³ H]Pentazocine; phenytoin; sodium hydroxide

2. Experimental methods

(1) Freeze the isolated guinea pig brain in sucrose-Tris buffer (containing 320mM sucrose, 10mM Tris-HCl, pH 7.4);

(2) Homogenize the tissue at 4°C, centrifuge at 700×g for 10 minutes, and collect the suspension;

(3) Centrifuge the suspension at high speed at 4°C and 48,000g for 25 minutes to separate the membrane and cytoplasm, and collect the precipitate;

(4) Resuspend the membrane pellet in 15mL sucrose-Tris buffer and repeat the centrifugation step;

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

(6) Use GF/C filter to quickly vacuum filtrate to separate the bound/unbound radioligand ([ ³ H]Pentazocine) to terminate the reaction;

(7) Use a liquid scintillation counter to determine the substitution rate of [ ³ H]Pentazocine by the compound to be tested, which is the binding rate of the compound to be tested to the σ ₁ receptor.

3. Experimental results

The test results of the binding rate of the compound to the σ ₁ receptor are shown in Table 3.

Table 3. Binding rate (%) of each compound to σ ₁ receptor at 1 μM concentration


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

The above test results show that the compounds of the present invention can effectively bind to σ ₁ receptors, and the binding rates are higher than the classic opioid fentanyl. Among them, compounds 6, 10, 11, 13, 15 and 17 have binding rates to σ ₁ receptors. high.

Phenytoin-induced allosteric modulation can increase the binding affinity (Ki) of sigma ₁ receptor agonists while decreasing the binding affinity (Ki) of sigma ₁ receptor antagonists. Phenytoin was added in the binding experiment to determine the function of representative compound 11 on the σ ₁ receptor. That is, 1mM phenytoin was dissolved in 12mM sodium hydroxide, and the solution was added to the reaction system. Other operations were as described above. . As shown in Figure 1, 1mM phenytoin reduced the _σ1 receptor Ki value of compound 11, causing the curve to shift to the right (Ki value from 0.419±0.052μM to 0.877±0.058μM in Figure 1). Therefore, the representative compound 11 of the present invention binds to and acts as an antagonist to the σ ₁ receptor, and can synergistically enhance the analgesic effect in vivo and reduce opioid side effects.

Test Example 2. Evaluation of analgesic efficacy

1. Experimental method one

ICR mice (body weight 20-30g) were adapted to the experimental environment for 3 days. Electron von Frey was used to stimulate the skin of the middle part of the left foot of mice, and its paw withdrawal reaction was observed as an indicator of pain response. First, the basal pain threshold of mechanical stimulation of mice was measured. Each mouse that met the inclusion criteria (mechanical stimulation pain threshold: 8-12g) was subcutaneously injected with 0.02 mL Freund's complete adjuvant (CFA) in the sole of the left foot to induce pain. After about 16 hours, the mechanical stimulation pain threshold of the left foot was measured, and the mice that met the conditions (the mechanical stimulation pain threshold was reduced to 2.5-3.5g) were randomly divided into a model group and a test compound group, with 8-10 mice in each group, male and female. Half and half.

All tested compound groups were administered by subcutaneous injection, the compound concentration was 86 μmol/kg, the solvent was physiological saline, and the injection volume was 0.1 mL/10g; the model group was injected subcutaneously with physiological saline. After administration, the mechanical stimulation pain threshold of the mouse's left hind paw was recorded at 20 min, 40 min, 1 h, 1.5 h, 2 h, and 3 h respectively. After the experiment, GraphPad software was used for data analysis. The mechanical stimulation pain threshold increased, and there was a statistical difference with the mechanical stimulation pain threshold of the normal saline group at the corresponding time point, which means that the tested compound has an analgesic effect.

2. Representative experimental results 1

The evaluation results of the analgesic effect of the compounds of the present invention on the mouse CFA pain model are shown in Figure 2. The results show that all compounds can increase the pain threshold of mechanical stimulation of the hind paws of mice after injection. Among them, compound 11 has the most significant analgesic effect, and the analgesic duration is not less than 3 hours (***P<0.001 vs. normal saline group ; *P<0.05 vs normal saline group).

The analgesic ED ₅₀ values of compound 11 and the positive compound fentanyl in the mouse CFA pain model are shown in Figure 3. ED ₅₀ is the half effective dose, which represents the dose required to achieve 50% analgesia in all mice in analgesic experiments. ED ₅₀ is obtained by Graphpad fitting the maximum analgesic effect curve corresponding to different doses. In the CFA pain model, the maximum analgesic effect of different doses of compounds in each mouse is calculated as follows: maximum analgesic effect (%) = maximum mechanical stimulation pain threshold that can be achieved after administration (g) - model mechanical stimulation Pain threshold (g)/mechanical stimulation basic pain threshold (g) - model mechanical stimulation pain threshold (g). After fitting with Graphpad software, the analgesic ED ₅₀ values of the representative compound 11 of the present invention and the positive compound fentanyl on the mouse CFA model were 2.4 μmol/kg and 0.28 μmol/kg respectively.

3. Experimental method two

Mice were randomly divided into model group and test compound group, with 6-8 mice in each group, half male and half male. They were injected subcutaneously with physiological saline or test compound solution 20 minutes in advance (compound concentration was 21.5 μmol/kg, dissolved in physiological saline). (injection volume: 0.1 mL/10 g); 20 min after administration, 20 μL of 5% formalin solution was subcutaneously injected into the hind paws of mice to cause stimulation and induce acute pain. The total time of scratching, biting, licking, and shaking the hind paw was recorded with a stopwatch to quantify the nociceptive behavior induced by formalin injection. The records are divided into two periods. The first stage is 0-10 minutes after the injection of formalin (Phase I), which represents the pain caused by acute noxious stimulation; the second stage is 10-30 minutes after the injection of formalin (Phase II), which represents the pain caused by central sensitization. of pain. Compared with physiological saline, the total time for scratching, biting, licking, and shaking the hind paw was shortened, indicating that the tested compound had an analgesic effect.

4. Representative experimental results 2

The evaluation results of the analgesic effect of Compound 11 of the present invention in the mouse formalin pain model are shown in Figure 4. Compound 11 of the present invention can significantly shorten the total time for mice to scratch, bite, lick and shake their hind paws after injection of 5% formalin, and has a significant analgesic effect (***P<0.001 vs. physiological saline group).

Test example 3, side effect evaluation

Opioids can also induce side effects during their analgesic effects, such as constipation and respiratory depression. At a dose of 1.5 times the analgesic ED ₅₀ (that is, the analgesic effect can reach 100%), the following experiments prove that the side effects of the compound of the present invention are significantly reduced.

1. Experimental method one

Before the start of the experiment, ICR mice (weighing 20 to 30 g) were kept without food and water overnight. On the day of the experiment, they were randomly divided into a normal saline (normal) group, a positive compound (fentanyl) group, and a tested compound group. There were 6 animals in each group, half male and half female.

Blank physiological saline or test compound solution was injected subcutaneously 30 minutes in advance. The concentration of representative compound 11 was 3.6 μmol/kg (1.5 times the analgesic ED ₅₀ dose), and the concentration of the positive compound fentanyl was 0.42 μmol/kg (1.5 times the analgesic ED 50 dose). ED ₅₀ dose), were dissolved in normal saline, and the administration volume was 0.1mL/10g. After 30 minutes, each mouse was orally administered 0.3 mL of gastrointestinal function markers (made by repeatedly boiling an aqueous solution containing 5% gum arabic and 10% activated carbon powder and then cooling); The mice were sacrificed by cervical dislocation, the abdominal cavity was opened to separate the mesentery, the mouse pylorus to the ileocecal part was cut, and the length from the pylorus to the ileocecal part of the mouse small intestine was measured (S/cm). Total length (L/cm). The gastrointestinal motility rate can be calculated by the following formula:

Gastrointestinal motility rate (%) = ink propulsion rate (%) = S/L × 100%

The gastrointestinal motility rate was less than 50% and was statistically different from the normal saline group, indicating that the tested compound may induce constipation while exerting analgesic effects.

2. Representative experimental results 1

The effect of compound 11 of the present invention on the gastrointestinal motility rate at a dose of 1.5×ED ₅₀ is shown in Figure 5. When reaching the maximum analgesic effect, classic opioids (positive control fentanyl) caused strong inhibition of gastrointestinal motility (gastrointestinal motility rate <50%) and induced constipation; Compound 11 of the present invention did not cause gastrointestinal motility. The peristalsis rate was abnormal (gastrointestinal peristalsis rate >50%), and no obvious constipation occurred (**P<0.01 vs. normal saline group).

By subcutaneously injecting the σ1 receptor agonist PRE-084 (40 mg/kg, dissolved in physiological saline) 10 minutes before the subcutaneous injection of blank physiological saline or test compound solution, the reduction of side effects of the representative compound 11 of the present invention and its Related to the inhibitory effect on σ1 receptors. As shown in Figure 6, 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 comes from the inhibition of σ1 receptors. (***P<0.001 vs. normal saline group, *P<0.05 vs. compound 11 21.5 μmol/kg group).

3. Experimental method two

Changes in the mouse's respiratory rate were monitored using a whole-body tracing system to reflect whether the drug caused respiratory depression. The respiratory frequency baseline of the mice was recorded 10 min before the start of the experiment; the mice were randomly divided into physiological Saline (normal) group, positive compound (fentanyl) group, test compound group, each group has 6 animals, half male and half female. Blank physiological saline or tested drug solution was injected subcutaneously. The concentration of representative compound 11 was 3.6 μmol/kg (1.5 times the analgesic ED ₅₀ doses), and the concentration of the positive compound fentanyl was 0.42 μmol/kg (1.5 times the analgesic ED ₅₀ doses), all dissolved in physiological saline, and the administration volume is 0.1mL/10g. The changes in respiratory frequency within 40 minutes after administration were continuously monitored. The respiratory frequency decreased and was statistically different from the normal saline group, proving that the drug caused respiratory depression.

4. Representative experimental results 2

The effect of compound 11 of the present invention on respiratory frequency at a dose of 1.5× _ED50 is shown in Figure 7. When reaching the maximum analgesic effect, classic opioids (positive control fentanyl) caused strong and sustained respiratory depression; compound 11 of the present invention did not cause abnormal respiratory function, and there was no difference between the monitoring point at any time and the normal saline injection group. There was no statistical difference (***P<0.001 vs normal saline group; **P<0.01 vs normal saline group; *P<0.05 vs normal saline group).

The above results show that the compound of the present invention has low side effects and high safety after use.

In summary, the present invention provides a type of piperidine derivative, which has an agonistic effect on μ opioid receptors and an inhibitory effect on σ1 receptors, and can exert an analgesic effect in the body and reduce the incidence of side effects. This type of piperidine derivatives can be used to prepare analgesic drugs, which is of great significance for clinical analgesia and has good application prospects.

Claims (13)

The compound represented by formula I, or its salt, or its optical isomer:
in, a is an integer from 0 to 1; R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; b is an integer from 1 to 4; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group; c is the number of R ₄ , which is an integer from 0 to 4; Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; X is N-, CH- or NC(O)-; Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, and C ₁ to C ₈ alkoxy group. The compound according to claim 1, or a salt thereof, or an optical isomer thereof, characterized in that: a is 0 or 1; R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroatom of the heteroaryl or heterocycloalkyl is N, O or S, the number of heteroatoms The number is 1, 2 or 3; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; b is 1, 2, 3 or 4; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group; c is the number of R ₄ , which is 0, 1, 2, 3 or 4; Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; X is N-, CH- or NC(O)-; Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the heteroatom of the heteroaryl or heterocyclyl is N, O or S, and the number of heteroatoms is 1 or 2 or 3; The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, and C ₁ to C ₈ alkoxy group. The compound according to claim 2, or a salt thereof, or an optical isomer thereof, characterized in that: a is 0 or 1; _R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl; the pyridyl, furyl, thienyl, oxazole The substituents of the base are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; b is 1, 2, 3 or 4; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide group, cyano group, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; the The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; c is the number of R ₄ , which is 0, 1, 2, 3 or 4; Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; The substituent of the alkyl group is selected from Halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; X is N-, CH- or NC(O)-; Ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group. The compound according to any one of claims 1 to 3, or its salt, or its optical isomer, is characterized in that: the compound is represented by formula II:
in, a is 0 or 1; R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroatom of the heteroaryl or heterocycloalkyl is N, O or S, the number of heteroatoms is 1, 2 or 3; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group; c is the number of R ₄ , which is 0, 1, 2, 3 or 4; Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the heteroatom of the heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3; The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; Preferably, a is 0 or 1; _R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl; the pyridyl, furyl, thienyl, oxazole The substituents of the base are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide group, cyano group, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; the The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; c is the number of R ₄ , which is 0, 1, 2, 3 or 4; Each R ₄ is independently selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester group, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy ; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; Ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group. The compound according to any one of claims 1 to 3, or its salt, or its optical isomer, is characterized in that: the compound is represented by formula III:
in, a is 0 or 1; R ₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroatom of the heteroaryl or heterocycloalkyl is N, O or S, the number of heteroatoms is 1, 2 or 3; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group; The substituents of the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, Hydroxy, nitro, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; Preferably, a is 0 or 1; _R1 is selected from substituted or unsubstituted pyridyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl; the pyridyl, furyl, thienyl, oxazole The substituents of the base are selected from C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group. The compound according to any one of claims 1 to 3, or its salt, or its optical isomer, is characterized in that: the compound is represented by formula IV:
in, R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group; The substituents of the aryl group, heteroaryl group, and cycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; Preferably, R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group. The compound according to any one of claims 1 to 3, or its salt, or its optical isomer, is characterized in that: the compound is represented by formula V:
in, R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; R ₃ is selected from hydrogen, substituted or unsubstituted C ₁ to C ₈ alkyl group, halogen, amino group, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group; The substituents of the aryl group, heteroaryl group, and cycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; Preferably, R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group. The compound according to any one of claims 1 to 3, or its salt, or its optical isomer, is characterized in that: the compound is represented by formula VI or formula VII:
in, R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl; the heteroatom of the heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group; The substituents of the aryl group, heteroaryl group, and cycloalkyl group are selected from substituted or unsubstituted C ₁ to C ₈ alkyl groups, halogens, amino groups, ester groups, amide groups, cyano groups, carboxyl groups, hydroxyl groups, nitro groups, C ₁ ~ C ₈ alkoxy; The substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; Preferably, R ₂₁ , R ₂₂ , R ₂₃ , and R ₂₄ are each independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ ~ C ₈ alkoxy; R ₂ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, ester group, carboxyl, C ₁ to C ₈ alkoxy, phenyl, furyl, thienyl, oxazolyl, 3 to 6-membered cycloalkyl base; the substituent of the alkyl group is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl, nitro, C ₁ to C ₈ alkoxy group; R ₃ is selected from substituted or unsubstituted C ₁ to C ₈ alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C ₁ to C ₈ alkoxy; the alkyl The substituent is selected from halogen, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, nitro group, C ₁ to C ₈ alkoxy group; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from hydrogen, C ₁ to C ₈ alkyl, halogen, trifluoromethyl, amino, ester group, amide group, cyano group, carboxyl group, hydroxyl group, Nitro group, C ₁ ~ C ₈ alkoxy group. The compound according to any one of claims 1 to 3, or its salt, or its optical isomer, is characterized in that: the compound is one of the following compounds:

The preparation method of the compound according to any one of claims 1 to 9, characterized in that: it includes the following steps:
Step 1: react compound A, compound B and a base in an organic solvent to obtain compound C; Step 2: react compound C, compound D and a base in an organic solvent to obtain compound E; Step 3: React compound E with LiAlH ₄ in an organic solvent to obtain compound F; Step 4: react compound F, compound G and a base in an organic solvent to obtain the compound of formula I; Wherein, a, R ₁ , R ₂ , b, R ₃ , c, R ₄ , X and A ring are as described in any one of claims 1 to 9; d is selected from an integer from 0 to 3; Rab is halogen; Preferably, In step 1, the organic solvent is methylene chloride; the base is triethylamine; And/or, in step 2, the organic solvent is acetonitrile; 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 methylene chloride; the base is triethylamine. Use of the compound according to any one of claims 1 to 9, or a salt thereof, or an optical isomer thereof, in the preparation of a μ opioid receptor agonist and/or a σ1 receptor inhibitor. The use of the compound according to any one of claims 1 to 9, or its salt, or its optical isomer in the preparation of analgesic drugs. A medicine, characterized in that: it is composed of the compound described in any one of claims 1 to 9, or its salt, or its optical isomer as an active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients preparations prepared.