CN117003693A - Piperidine derivatives, preparation method and application thereof - Google Patents

Piperidine derivatives, preparation method and application thereof Download PDF

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CN117003693A
CN117003693A CN202310481412.0A CN202310481412A CN117003693A CN 117003693 A CN117003693 A CN 117003693A CN 202310481412 A CN202310481412 A CN 202310481412A CN 117003693 A CN117003693 A CN 117003693A
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substituted
unsubstituted
alkyl
ester
carboxyl
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柯博文
刘进
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West China Hospital of Sichuan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The invention provides piperidine derivatives, a preparation method and application thereof, and belongs to the technical field of chemical medicines. The piperidine derivative is a compound shown in a formula I, or a salt or an optical isomer thereof. The piperidine derivative has an agonism effect on mu opioid receptors and an inhibition effect on sigma 1 receptors, can play an analgesic effect in vivo, and reduces the incidence rate of side effects. The piperidine derivative can be used for preparing analgesic drugs, has important significance for clinical analgesia, and has the following characteristics ofGood application prospect.

Description

Piperidine derivatives, preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to piperidine derivatives, a preparation method and application thereof.
Background
For a long time, the treatment of clinically moderate to severe pain (intra-operative pain, post-operative pain, late cancer pain, etc.) has been largely dependent on opioids, classical opioids including natural morphine, semisynthetic oxycodone, synthetic fentanyl family, etc. Opioid drugs exert analgesic effects by agonizing opioid receptors, which mainly comprise three subtypes of μ, δ, κ, with the μ subtype mediated having the strongest analgesic activity. Although opioids have strong analgesic effect, serious side effects including nausea, vomiting, constipation, strong respiratory depression, itching caused by histamine release, etc. are accompanied with the use; the long-term use of the traditional Chinese medicine composition also causes high psychological and physiological dependence caused by hyperalgesia, tolerance and euphoria, and brings great hidden trouble to society. In recent years, in order to solve the side effects of opioids, various strategies have been proposed, such as a biasing ligand that achieves "drug effect" and "side effect separation" on the signal pathway; at present, more researches are conducted on developing biased ligands, and Chen et al in 2013 find that a first biased small molecule acts on mu opioid receptors by screening a compound library; despite recent approval of the molecule by the FDA for clinical use, the incidence of common side effects is still high.
Meanwhile, the thought of developing the multifunctional ligand is also provided, namely, the multifunctional ligand has an agonizing effect on opioid receptors, and can also act on other targets to synergistically ease pain and reduce side effects. Sigma (sigma) 1 Is a new target for pain treatment which is recently developed, is a receptor chaperone protein and can be activated byThe plasma membrane, where it was initially located, is transferred to other plasma and nuclear membranes, mediating the physiological functions of these receptors. Early studies showed sigma 1 The receptor antagonist can enhance analgesic strength of morphine, and reduce side effects such as respiratory depression and constipation.
The development of a drug which has an agonism effect on mu opioid receptors and an inhibition effect on sigma 1 receptors, can play an analgesic effect in vivo and has remarkably reduced incidence rate of common side effects (gastrointestinal tract function inhibition, respiratory inhibition and the like) has important significance for clinical analgesia.
Disclosure of Invention
The invention aims to provide piperidine derivatives, and a preparation method and application thereof. The piperidine derivatives have an agonizing effect on mu opioid receptors and an inhibiting effect on sigma 1 receptors, can play an analgesic effect in vivo, and reduce the incidence rate of side effects.
The present invention provides a compound represented by formula I:
Wherein,
a is an integer of 0 to 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl;
b is an integer of 1 to 4;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is an integer of 0 to 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
x is N-, CH-, or NC (O) -;
the A ring is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the method comprises the steps of,
a is 0 or 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the hetero atom of the heteroaryl or the heterocycloalkyl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
b is 1, 2, 3 or 4;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
x is N-, CH-, or NC (O) -;
the A ring is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the hetero atom of the heteroaryl or the heterocyclic group is N, O or S, and the number of the hetero atom is 1, 2 or 3;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the method comprises the steps of,
a is 0 or 1;
R 1 selected from the group consisting of a substituted or unsubstituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, and a substituted or unsubstituted oxazolyl group; the substituents of the pyridyl, furyl, thienyl and oxazolyl are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
b is 1, 2, 3 or 4;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
x is N-, CH-, or NC (O) -;
the A ring is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the compound is represented by formula II:
wherein,
a is 0 or 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the hetero atom of the heteroaryl or the heterocycloalkyl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 Selected from hydrogenSubstituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the A ring is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
a is 0 or 1;
R 1 selected from the group consisting of a substituted or unsubstituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, and a substituted or unsubstituted oxazolyl group; the substituents of the pyridyl, furyl, thienyl and oxazolyl are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the A ring is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the compound is represented by formula III:
wherein,
a is 0 or 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the hetero atom of the heteroaryl or the heterocycloalkyl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstitutedHeteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
a is 0 or 1;
R 1 selected from the group consisting of a substituted or unsubstituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, and a substituted or unsubstituted oxazolyl group; the substituents of the pyridyl, furyl, thienyl and oxazolyl are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the compound is represented by formula IV:
Wherein,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl groupHalogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl and cycloalkyl are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the compound is represented by formula V:
wherein,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 Selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl and cycloalkyl are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the compound is represented by formula VI or formula VII:
wherein,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl and cycloalkyl are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
Further, the compound is one of the following compounds:
the invention also provides a preparation method of the compound, which comprises the following steps:
Step 1: in an organic solvent, the compound A, the compound B and alkali react to obtain a compound C;
step 2: in an organic solvent, the compound C, the compound D and alkali react to obtain a compound E;
step 3: in an organic solvent, the compound E and LiAlH 4 Reacting to obtain a compound F;
step 4: in an organic solvent, reacting a compound F, a compound G and a base to obtain a compound shown in a formula I;
wherein a, R 1 、R 2 、b、R 3 、c、R 4 The X and A rings are as previously described;
d is an integer from 0 to 3;
rab is halogen;
preferably, the method comprises the steps of,
in the step 1, the organic solvent is dichloromethane; the base is triethylamine;
and/or, in the step 2, the organic solvent is acetonitrile; the alkali is potassium carbonate or sodium carbonate;
and/or, in the step 3, the organic solvent is anhydrous tetrahydrofuran;
and/or, in the step 4, the organic solvent is dichloromethane; the base is triethylamine.
The invention also provides application of the compound, or salt or optical isomer thereof in preparing mu opioid receptor agonist and/or sigma 1 receptor inhibition inhibitor.
The invention also provides application of the compound, or salt or optical isomer thereof in preparing analgesic drugs.
The invention also provides a medicine which is a preparation prepared by taking the compound, or the salt or the optical isomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a ～C b Alkyl indicates any alkyl group containing from "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 indicated number of carbon atoms. For example, C 1 ～C 8 Alkyl groupRefers to alkyl groups having 1 to 8 carbon atoms, i.e., having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The alkyl group may be linear 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), hexyl and the like.
"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 a structure ofWherein R is a group of 1 And R is 2 Are independently selected from hydrogen, C 1 ～C 8 An alkyl group.
Cycloalkyl in the present invention refers to a saturated or partially saturated non-aromatic cyclic group consisting of carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems). Heterocycloalkyl means a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein the hetero atom refers to nitrogen atom, oxygen atom and sulfur atom. Examples of heterocyclyl groups include, for example, piperidinyl, piperazinyl, morpholinyl.
Aryl in the present invention refers to aromatic unsaturated containing groups such as phenyl, anthracyl, naphthyl, having no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems). Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein the hetero atom refers to nitrogen atom, oxygen atom and sulfur atom. Such as pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, furyl, thienyl, oxazolyl, and the like.
In the compounds of formula I of the present invention, when X is N-, the compound structure isWhen X is CH-, the compound structure is +.>When X is NC (O) -, the compound structure is +.>/>
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a piperidine derivative which has an agonism effect on mu opioid receptors and an inhibition effect on sigma 1 receptors, can play an analgesic effect in vivo and reduce the incidence rate of side effects. The piperidine derivative can be used for preparing analgesic drugs, has important significance for clinical analgesia, and has good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 shows the results of determining the function (agonism/inhibition) of the sigma 1 receptor by representative compound 11 of the present invention.
FIG. 2 is a graph showing the evaluation of analgesic effect of representative compounds of the present invention on a mouse CFA pain model; in the figure, B is the basic pain threshold of mechanical stimulation (before CFA modeling); c is the mechanical stimulus pain threshold after CFA modeling.
FIG. 3 is a graph showing the model of pain ED in mice CFA pain of representative Compound 11 and the positive Compound fentanyl of the present invention 50 Values.
Fig. 4 is a graph showing the evaluation result of the analgesic effect of the representative compound 11 of the present invention in the formalin pain model of mice.
FIG. 5 shows a 1.5XED of a representative compound 11 according to the invention 50 The effect on gastrointestinal motility at doses.
Fig. 6 is a graph showing the effect of representative compound 11 of the present invention on gastrointestinal motility at various doses following advanced subcutaneous injection of sigma 1 receptor agonist PRE-084.
FIG. 7 shows a 1.5XED of a representative compound 11 according to the invention 50 The effect on respiratory rate at the dose.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
The synthetic route of the compound of the invention has the general formula:
EXAMPLE 1 Synthesis of N- (2- (4-phenylpiperazin-1-yl) propyl) -N- (pyridin-2-yl) propanamide oxalate/hydrochloride
Step a: DCM, TEA, 0-RT;
step b: acetonitrile, K 2 CO 3 ，80℃；
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
Raw material 2-aminopyridine (1 g,1 eq) was dissolved in an appropriate amount of Dichloromethane (DCM), triethylamine (TEA, 4.43 mL) was added thereto under ice-bath conditions of 0 ℃, followed by slowly dropwise addition of raw material 2-bromopropionyl bromide (2.23 mL,2 eq), and the reaction solution was moved to room temperature and stirred. After the completion of the reaction, the reaction solution was poured into a separating funnel, and the organic phase was washed with saturated sodium bicarbonate solution and water in this order; separating and combining the organic phases, adding anhydrous sodium sulfate and drying; using column chromatography, in polar PE: ea=9: 1 (v/v) to give intermediate 1 as a pale yellow viscous oil in 66.6% yield, 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
Intermediate 1 (1.613 g,1 eq) was dissolved in a suitable amount of acetonitrile to which K was added in sequence 2 CO 3 (2.92 g,3 eq) and raw N-phenylpiperidine (2.16 mL,2 eq) were heated to 80℃and reacted under reflux. After the TLC monitoring reaction is completed, the reaction solution is concentrated under reduced pressure; the residue was dissolved in an appropriate amount of DCM, the organic phase was washed with water to remove inorganic materials, the organic phases were separated, combined and dried over anhydrous sodium sulfate; using column chromatography, in polar PE: ea=3: 1 (v/v) to obtain a crude product; stirring and washing with a small amount of diethyl ether, filtering, and drying to obtain intermediate 2 as a white solid with a yield of 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
Intermediate 2 (500 mg,1 eq) was dissolved in an appropriate amount of anhydrous tetrahydrofuran and the mixture was cooled in an ice bath (0 ℃ C.) in N 2 LiAlH was slowly added thereto using a syringe under protection 4 (1M in THF,9.66mL,6eq) after the temperature of the reaction solution naturally returns to room temperature, heating to 50 ℃ for reaction. TLC monitoring reaction is complete, water and 15% NaOH solution are slowly added into the reaction liquid by using a syringe under ice bath condition to quench the reaction, and the solid is filtered by suction; concentrating the filtrate under reduced pressure, dissolving the residue in an appropriate amount of Ethyl Acetate (EA), and washing the organic phase with water; the organic phases were separated and combined and dried over anhydrous sodium sulfate; the crude product was obtained after concentration under reduced pressure and was used directly in the next reaction without further purification in 100% yield, LC-MS:296.
preparation of the end product and its soluble salts
Intermediate 3 (478 mg) was dissolved in an appropriate amount of DCM, to which TEA (0.672 mL,3 eq) and propionyl chloride (0.282 mL,2 eq) were added in this order under ice bath (0deg.C), and the reaction was stirred at room temperature. After the completion of the reaction, the reaction solution was poured into a separating funnel, and the organic phase was washed with saturated sodium bicarbonate solution and water in this order; the organic phases were separated and combined and dried over anhydrous sodium sulfate; using column chromatography, in polar PE: ea=7: 3 (v/v) to give the title compound as a colorless transparent oil in 80.7% yield by 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 a proper amount of ethyl acetate, oxalic acid dihydrate (1 eq) was added thereto, and stirred at room temperature for 3 hours. After the reaction, the reaction solution was suction-filtered, and the filter cake was dissolved in 6mL of ultrapure water, and freeze-dried overnight to obtain a light and fluffy white solid, i.e., the soluble oxalate as the final product, with a yield of 83.1%.
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The hydrochloride of the final product was prepared by dissolving the final product obtained above in dioxane hydrochloride solution (1.05 eq).
All compounds of the present invention can be synthesized by a similar method to example 1. The structure and characterization data of the compounds of the present invention are shown in table 1.
TABLE 1 chemical structures and characterization data for the compounds of the invention
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The beneficial effects of the present invention are demonstrated by specific test examples below.
Test example 1, evaluation of in vitro cell Activity
1. Test of agonistic activity of compounds at mu opioid receptors:
opioid drugs exert analgesic effects mainly by agonizing mu opioid receptors, which, when agonized, cause a decrease in intracellular cAMP levels. The effect of the compounds of the present invention on cAMP content of CHO cells stably expressing mu opioid receptor was tested by the following in vitro cell experiments, and the agonistic activity of the compounds on mu opioid receptor was determined.
1. Experimental materials
The main equipment is as follows: multifunctional enzyme-labeled instrument (BMG), micro 384 well plate (Greiner)
The main reagent comprises: F12K Medium (Gibco), fetal bovine serum (Corning), bleomycin (Sigma), hygromycin B (Sigma), cAMP detection kit (Cisbio)
Cell line: CHO cells stably expressing mu opioid receptor (Genescript)
2. Experimental method
(1) Cell culture
CHO cells stably expressing mu opioid receptor were cultured in F12K medium containing 10% fetal bovine serum, 200 μg/μl bleomycin, 100 μg/μl hygromycin B and passaged once a day.
(2) Detection of agonistic Activity of Compounds on mu opioid receptors
CHO cells stably expressing mu opioid receptors were digested and centrifuged, plated into a micro 384-well plate, 3000 (5 μl) per well. mu.L of each concentration (final concentration of 10. Mu.M, 1. Mu.M, 100nM, 10nM, 1nM, 100pM, 10pM, 1 pM) of test compound solution was added to each well and incubated at 37℃for 45min in the absence of light. mu.L of cAMP Cryptate solution and 5. Mu.L of cAMP d2 antibody were added to each well, and after incubation at room temperature for 1 hour in a dark place, detection was performed on a multifunctional microplate reader (fluorescence emission intensity: 665nm/620 nm). Half maximal Effect Concentration (EC) of each compound on mu opioid receptor agonism was fitted using GraphPad Software 8 50 )，EC 50 The smaller the value of (c) indicates the lower the concentration required to act, the better the effect of the compound.
3. Experimental results
EC of Compounds for agonistic Activity of mu opioid receptors 50 The results are shown in Table 2 (fentanyl is a positive control).
TABLE 2 EC of agonistic activity of the compounds on mu opioid receptors 50
Note that: "+": EC of 500nM or less 50 <1500nM；“++”：200nM≤EC 50 ＜500nM；“+++”：EC 50 <200nM。
The test results above demonstrate that: the compound of the invention can effectively excite mu opioid receptor, thereby playing the analgesic effect. Of these, compounds 6, 8 to 13, 15 and 17 are more effective.
2. Compound pair sigma 1 Binding rate test of receptor:
it was first verified whether the compounds of the invention bind sigma 1 Receptor, compound pair sigma 1 The binding strength of the receptor is determined by competitive binding experiments: i.e. testing the tested compound against sigma 1 Receptor radioactive positive ligand [ 3 H]The replacement rate of Pentazocine is the sigma of the tested compound 1 Binding rate of the receptor.
1. Experimental materials
The main equipment is as follows: GF/C filter (Whatman); liquid scintillation counter (PerkinElmer) primary reagents: sucrose; tris-HCl; [ 3 H]Pentazocine; phenytoin; sodium hydroxide
2. Experimental method
(1) The isolated guinea pig brain was chilled in sucrose-Tris buffer (containing 320mM sucrose, 10mM Tris-HCl, pH 7.4);
(2) Homogenizing at 4deg.C, centrifuging at 700 Xg for 10min, and collecting suspension;
(3) Centrifuging the suspension at 4deg.C and 48000g for 25min at high speed, separating membrane and cytoplasm, and collecting precipitate;
(4) Resuspending the membrane particles in 15mL sucrose-Tris buffer, repeating the centrifugation step;
(5) Compound pair sigma 1 The binding rate of the receptor is determined by competitive binding experiments: under the above conditions, 1. Mu.M of the test compound, 4nM [ 3 H]Pentazocine, 300. Mu.g membrane protein (dissolved in 250. Mu.L 50mM Tris buffer pH 7.4) were mixed and incubated;
(6) Rapid vacuum filtration Using GF/C filters, bound/unbound radioligand(s) ([ A ] were filtered 3 H]Pentazocine) to terminate the reaction;
(7) Determination of test Compound pair by liquid scintillation counter 3 H]The replacement rate of Pentazocine is the sigma of the compound to be tested 1 Binding rate of the receptor.
3. Experimental results
Compound pair sigma 1 The results of the receptor binding rate test are shown in table 3.
TABLE 3 Sigma for each compound at a concentration of 1. Mu.M 1 Binding Rate of receptor (%)
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Note that: "+":10% -30%; "++":31% -60%; "+++":61% -100%.
The test results above demonstrate that: the compound of the invention can effectively bind sigma 1 Receptors, all with higher binding rates than the classical opioid fentanyl, wherein compounds 6, 10, 11, 13, 15 and 17 and sigma 1 The receptor binding rate is high.
Phenytoin-induced allosteric modulation can increase σ 1 Binding affinity (Ki) of receptor agonists with simultaneous sigma reduction 1 Binding affinity (Ki) of receptor antagonists. Phenytoin was added to the binding experiments to determine the sigma of representative compound 11 1 The function on the receptor, i.e., 1mM phenytoin was dissolved in 12mM sodium hydroxide, and the solution was added to the reaction system, and the other procedures were as described above. As shown in FIG. 1, 1mM phenytoin reduced sigma for Compound 11 1 Receptor Ki values, resulting in a shift of the curve to the right (Ki values from 0.419±0.052 μm to 0.877±0.058 μm in fig. 1). Thus, representative Compound 11 of the present invention binds to and pair σ 1 The receptor has antagonism, and can synergistically enhance the in vivo analgesic effect and reduce the side effects of opioid medicines.
Test example 2 evaluation of analgesic efficacy
1. Experimental method one
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 of the mouse was stimulated with electronic von frey, and the depsipelas were observed as an index of pain response. First, the basal pain threshold of mechanical stimulation of mice was measured, and mice meeting the criteria of inclusion group (mechanical stimulation pain threshold: 8-12 g) were subcutaneously injected with 0.02mL Freund's complete adjuvant (CFA) to induce pain each at the bottom of the left foot. After about 16 hours, the mechanical stimulus pain threshold of the left foot was measured and mice meeting the conditions (mechanical stimulus pain threshold reduced to 2.5-3.5 g) were randomly divided into model groups, test compound groups of 8-10, male and female halves.
All tested compound groups were administered subcutaneously with a compound concentration of 86. Mu. Mol/kg, solvent saline, injection volume of 0.1mL/10 g; the model group is subcutaneous injection of physiological saline. The mechanical stimulus pain threshold of the left hind foot of the mice at 20min, 40min, 1h, 1.5h, 2h and 3h are recorded after administration. After the experiment was completed, data analysis was performed using GraphPad software. The mechanical stimulus pain threshold is increased, and the statistical difference between the mechanical stimulus pain threshold and the physiological saline group at the corresponding time point represents that the tested compound has analgesic effect.
2. Representative Experimental results 1
The evaluation results of the analgesic effect of the compound of the present invention on the CFA pain model of the mice are shown in fig. 2. The results show that: the pain threshold of the hind paw mechanical stimulation of the mice can be improved after all the compounds are injected, wherein the analgesic effect of the compound 11 is most remarkable, and the duration of the analgesia is not less than 3 hours (P <0.001 vs. physiological saline group; P <0.05 vs. physiological saline group).
Mouse CFA pain model analgesic ED of compound 11 and positive compound fentanyl 50 The values are shown in figure 3. ED (ED) and method for producing the same 50 I.e., half the effective dose, represents the dose required to achieve 50% analgesic effect in all mice in the analgesic experiments. ED (ED) and method for producing the same 50 Is obtained by graph pad according to curve fitting of maximum analgesic effect corresponding to different doses. In the CFA pain model, the maximum analgesic effect of different doses of compound in each mouse was calculated as follows: maximum analgesic effect (%) = maximum mechanical stimulus pain threshold (g) -model mechanical stimulus pain threshold (g)/mechanical stimulus basal pain threshold (g) -model mechanical stimulus pain threshold (g) that can be reached after administration. Analgesic ED of representative Compound 11 and the Positive Compound fentanyl on the mouse CFA model of the invention was fitted by Graphpad software 50 The values were 2.4. Mu. Mol/kg and 0.28. Mu. Mol/kg, respectively.
3. Experimental method two
The mice are randomly divided into a model group and a tested compound group, 6-8 mice in each group are respectively injected with physiological saline or tested compound solution (the compound concentration is 21.5 mu mol/kg, the compound is dissolved in the physiological saline, and the injection volume is 0.1mL/10 g) by subcutaneous injection respectively in advance for 20 min; after 20min of administration, 20 μl of 5% formalin solution was subcutaneously injected into the hind legs of mice to cause irritation, which induced acute pain. The total time of grasping, biting, licking, throwing hind feet was recorded by a stopwatch and formalin injection-induced pain behavior was quantified. The recording is divided into two periods. The first stage is 0-10min (phase I) after formalin injection, representing pain caused by acute nociceptive stimulation; the second phase was 10-30min (phase II) after formalin injection, representing pain caused by central sensitization. Compared with normal saline, the total time of grabbing, biting, licking and throwing the hind legs is shortened, which indicates that the tested compound has analgesic effect.
4. Representative experiment results two
The evaluation result of the analgesic effect of the formalin pain model of the compound 11 of the present invention is shown in fig. 4. The compound 11 can obviously shorten the total time of mice grasping, biting, licking and throwing hind feet after 5% formalin injection, and has obvious analgesic effect (P <0.001vs physiological saline group).
Test example 3, evaluation of side effects
Opioids also induce side effects during the course of analgesic effects, such as constipation, respiratory depression. Analgesic ED at 1.5 times 50 The following experiments prove that the side effects of the compound of the invention are obviously reduced at the dosage (i.e. the analgesic effect can reach 100%).
1. Experimental method one
ICR mice (weighing 20-30 g) were fasted without water withdrawal overnight before the start of the experiment. On the day of the experiment, the animals were randomized into normal saline (normal) and positive compounds (fentanyl) groups, 6 tested compounds each, and male and female halves.
A blank physiological saline or test compound solution was injected subcutaneously 30min ahead of time, and the concentration of representative compound 11 was 3.6. Mu. Mol/kg (1.5-fold analgesic ED 50 Dosage), the concentration of the positive compound fentanyl was 0.42. Mu. Mol/kg (1.5-fold analgesic ED) 50 Dose), all dissolved in physiological saline, and the administration volume was 0.1mL/10g. After 30min, every time Only mice were perfused with 0.3mL of gastrointestinal function marker (prepared by repeatedly boiling an aqueous solution containing 5% gum arabic and 10% activated carbon powder and cooling the same); after the gastrointestinal function marker is irrigated for 30min, the mice are killed by cervical dislocation, the celiac separation mesentery is dissected, the pylorus of the mice is sheared to the ileocecum, and the length (S/cm) from the pylorus to the front end of ink and the total length (L/cm) from the pylorus to the ileocecum of the mice are measured by spreading on a table. The gastrointestinal motility can be determined by the following formula:
gastrointestinal tract creep rate (%) =ink thrust rate (%) =s/l×100%
The gastrointestinal motility was less than 50% and the statistical difference from the saline group suggests that the tested compounds may induce constipation while exerting analgesic effects.
2. Representative Experimental results 1
Compound 11 of the present invention was found to be present in 1.5 XED 50 The effect on gastrointestinal motility at doses of (2) is shown in figure 5. Upon reaching maximum analgesic effect, classical opioids (positive control fentanyl) cause strong inhibition of gastrointestinal motility (gastrointestinal motility rate)<50%), induced constipation; compound 11 of the present invention does not cause abnormal gastrointestinal motility (gastrointestinal motility rate>50%) no apparent constipation (P) <0.01vs saline group).
The reduction of side effects of representative compound 11 of the present invention was determined to be associated with its inhibition of sigma 1 receptor by subcutaneous injection of sigma 1 receptor agonist PRE-084 (40 mg/kg, dissolved in physiological saline) 10min in advance of the subcutaneous injection of blank physiological saline or test compound solution. As shown in fig. 6, the gastrointestinal motility rates of compound 11+pre-084 were lower than that of compound 11 alone, indicating that the reduction in opioid side effects of representative compound 11 of the present invention resulted from inhibition of sigma 1 receptor (P <0.001 vs. saline group, P <0.05 vs. 11.5 μmol/kg group).
3. Experimental method two
Whether or not the drug causes respiratory depression is reflected by monitoring changes in the respiratory rate of the mice using a whole body electrogram system. The respiratory rate baseline of the mice was recorded 10min before the start of the experiment; will be smallThe mice were randomly divided into normal saline (normal), positive compound (fentanyl) and test compound groups of 6 animals each, male and female halves. A blank physiological saline or test drug solution was subcutaneously injected, and the concentration of representative compound 11 was 3.6. Mu. Mol/kg (1.5-fold analgesic ED 50 Dosage), the concentration of the positive compound fentanyl was 0.42. Mu. Mol/kg (1.5-fold analgesic ED) 50 Dose), all dissolved in physiological saline, and the administration volume was 0.1mL/10g. The respiratory rate change within 40min after administration was continuously monitored, respiratory rate was decreased and statistical differences from the saline group demonstrated that the drug induced respiratory depression.
4. Representative experiment results two
Compound 11 of the present invention was found to be present in 1.5 XED 50 The effect on respiratory rate at the dose of (2) is shown in figure 7. Upon reaching maximum analgesic effect, classical opioids (positive control fentanyl) cause strong and sustained respiratory depression; compound 11 of the present invention did not cause respiratory dysfunction, and there was no statistical difference between the monitoring points at any time and normal group of injected physiological saline (/ P)<0.001vs physiological saline group; * P<0.01vs physiological saline group; * P (P)<0.05vs saline group).
The results show that the compound of the invention has low side effect and high safety after being used.
In summary, the invention provides piperidine derivatives which have an agonistic effect on mu opioid receptors and an inhibitory effect on sigma 1 receptors, and can exert 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 application prospect.

Claims (13)

1. A compound represented by formula I:
wherein,
a is an integer of 0 to 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl;
b is an integer of 1 to 4;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is an integer of 0 to 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
x is N-, CH-, or NC (O) -;
the A ring is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
2. The compound of claim 1, or a salt thereof, or an optical isomer thereof, wherein:
a is 0 or 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the heteroaryl or heterocycloalkyl groupThe heteroatom of the group is N, O or S, and the number of the heteroatom is 1, 2 or 3;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
b is 1, 2, 3 or 4;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
x is N-, CH-, or NC (O) -;
the A ring is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the hetero atom of the heteroaryl or the heterocyclic group is N, O or S, and the number of the hetero atom is 1, 2 or 3;
The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
3. A compound according to claim 2, or a salt thereof, or an optical isomer thereof, characterized in that:
a is 0 or 1;
R 1 selected from substituted or unsubstituted pioglitazoneA pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted oxazolyl group; the substituents of the pyridyl, furyl, thienyl and oxazolyl are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
b is 1, 2, 3 or 4;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
x is N-, CH-, or NC (O) -;
the A ring is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl and pyridyl groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
4. A compound according to any one of claims 1 to 3, or a salt thereof, or an optical isomer thereof, wherein: the compound is shown in a formula II:
wherein,
a is 0 or 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the hetero atom of the heteroaryl or the heterocycloalkyl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 2 Selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the A ring is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, and carboxylRadicals, hydroxy, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
Preferably, the method comprises the steps of,
a is 0 or 1;
R 1 selected from the group consisting of a substituted or unsubstituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, and a substituted or unsubstituted oxazolyl group; the substituents of the pyridyl, furyl, thienyl and oxazolyl are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
c is R 4 Is 0, 1, 2, 3 or 4;
each R 4 Independently selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
ring A is selected from the group consisting of substitutionOr unsubstituted phenyl, substituted or unsubstituted pyridinyl; the substituents of the phenyl and pyridyl groups are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
5. A compound according to any one of claims 1 to 3, or a salt thereof, or an optical isomer thereof, wherein: the compound is shown in a formula III:
wherein,
a is 0 or 1;
R 1 selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the hetero atom of the heteroaryl or the heterocycloalkyl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from substituted or unsubstitutedC of (2) 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
a is 0 or 1;
R 1 selected from the group consisting of a substituted or unsubstituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, and a substituted or unsubstituted oxazolyl group; the substituents of the pyridyl, furyl, thienyl and oxazolyl are selected from C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
6. A compound according to any one of claims 1 to 3, or a salt thereof, or an optical isomer thereof, wherein: the compound is shown in a formula IV:
wherein,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl and cycloalkyl are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
7. A compound according to any one of claims 1 to 3, or a salt thereof, or an optical isomer thereof, wherein: the compound is shown in a formula V:
wherein,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro,C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 3 selected from hydrogen, substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl and cycloalkyl are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl and nitro、C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
8. A compound according to any one of claims 1 to 3, or a salt thereof, or an optical isomer thereof, wherein: the compound is shown in a formula VI or a formula VII:
Wherein,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl; the hetero atom of the heteroaryl is N, O or S, and the number of the hetero atom is 1, 2 or 3;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethylAmino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituents of the aryl, heteroaryl and cycloalkyl are selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
preferably, the method comprises the steps of,
R 21 、R 22 、R 23 、R 24 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 2 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, ester, carboxyl, C 1 ～C 8 Alkoxy, phenyl, furyl, thienyl, oxazolyl, 3-6 membered cycloalkyl; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 3 selected from substituted or unsubstituted C 1 ～C 8 Alkyl, halogen, amino, ester, amide, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group; the substituent of the alkyl is selected from halogen, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group;
R 11 、R 12 、R 13 、R 14 、R 15 are independently selected from hydrogen, C 1 ～C 8 Alkyl, halogen, trifluoromethyl, amino, ester, amido, cyano, carboxyl, hydroxyl, nitro, C 1 ～C 8 An alkoxy group.
9. A compound according to any one of claims 1 to 3, or a salt thereof, or an optical isomer thereof, wherein: the compound is one of the following compounds:
10. a process for the preparation of a compound as claimed in any one of claims 1 to 9, characterized in that: it comprises the following steps:
step 1: in an organic solvent, the compound A, the compound B and alkali react to obtain a compound C;
step 2: in an organic solvent, the compound C, the compound D and alkali react to obtain a compound E;
step 3: in an organic solvent, the compound E and LiAlH 4 Reacting to obtain a compound F;
step 4: in an organic solvent, reacting a compound F, a compound G and a base to obtain a compound shown in a formula I;
wherein a, R 1 、R 2 、b、R 3 、c、R 4 The X and a rings as claimed in any one of claims 1 to 9;
d is an integer from 0 to 3;
rab is halogen;
preferably, the method comprises the steps of,
in the step 1, the organic solvent is dichloromethane; the base is triethylamine;
and/or, in the step 2, the organic solvent is acetonitrile; the alkali is potassium carbonate or sodium carbonate;
and/or, in the step 3, the organic solvent is anhydrous tetrahydrofuran;
and/or, in the step 4, the organic solvent is dichloromethane; the base is triethylamine.
11. Use of a compound according to any one of claims 1 to 9, or a salt thereof, or an optical isomer thereof, for the preparation of a mu opioid receptor agonist and/or a sigma 1 receptor inhibitor.
12. Use of a compound according to any one of claims 1 to 9, or a salt thereof, or an optical isomer thereof, for the preparation of an analgesic drug.
13. A medicament, characterized in that: a preparation prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into the compound, or the salt or the optical isomer thereof as an active ingredient of any one of claims 1 to 9.
CN202310481412.0A 2022-05-05 2023-04-28 Piperidine derivatives, preparation method and application thereof Pending CN117003693A (en)

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MX9201991A (en) * 1991-05-02 1992-11-01 Jonh Wyeth & Brother Limited DERIVATIVES OF PIPERAZINE AND PROCEDURE FOR ITS PREPARATION.
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