Tetrahydrothebaine derivative as well as preparation method and application thereof

Abstract

The invention relates to a tetrahydrothebaine derivative as well as a preparation method and application thereof, in particular to a 7alpha-(2 '-substituted aminophenyl)-6alpha, 14alpha-endo-ethylidene (alkenyl)-tetrahydrothebaine derivative as shown in a general formula (I) or pharmaceutically acceptable salts thereof and a preparation method of the 7alpha-(2'-substituted aminophenyl)-6alpha, 14alpha-endo-ethylidene (alkenyl)-tetrahydrothebaine derivative. The invention further relates to application of the derivatives in preparation of drugs for easing pain, resisting irritable bowel syndrome, resisting itching, resisting addiction and resisting depression. The derivative disclosed by the invention is remarkably improved in the aspects of agonistic activity of a kappa receptor and subtype selectivity of the kappa receptor. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the pharmaceutical field, and relates to a tetrahydrothebaine derivative, a preparation method and use thereof, and specifically relates to a 7α-(2'-substituted aminophenyl)-6α,14α-endo-ethylene(enyl)-tetrahydrothebaine derivative as shown in general formula (I) or a pharmaceutically acceptable salt thereof and a preparation method thereof, and relates to the use of such derivatives in the preparation of analgesic, anti-irritable bowel syndrome, anti-itching, anti-addiction and antidepressant drugs. Background Art

[0002] Although pain is a common clinical symptom, chronic pain such as cancer pain and neuropathic pain can have a serious impact on the patient's quality of life. Active and effective treatment of pain is of great value in ensuring the patient's quality of life, improving the treatment effect of the disease, and improving the utilization of medical resources. At present, the analgesics used in clinical practice can be mainly divided into two categories: non-steroidal anti-inflammatory drugs and narcotic analgesics. Most non-steroidal anti-inflammatory drugs represented by acetylsalicylic acid have antipyretic, analgesic and anti-inflammatory effects, but the analgesic effect is relatively weak, and gastrointestinal irritation is the main problem. Narcotic analgesics represented by morphine have strong analgesic effects and are irreplaceable for the treatment of severe acute and chronic pain such as postoperative pain, cancer pain and neuropathic pain. However, they also bring serious safety issues such as addiction, respiratory depression, constipation and itching that limit their clinical application. Therefore, there is an urgent need for potent and low-toxic analgesics in clinical practice.

[0003] Commonly used narcotic analgesics in clinical practice, such as morphine, pethidine, and fentanyl, mainly exert analgesic effects by stimulating μ opioid receptors. Studies have shown that while μ opioid agonism mediates analgesia, it is also closely related to typical side effects of opioid drugs, such as respiratory depression, physical and mental dependence, and constipation. At present, no effective way has been found to separate analgesia from addiction through μ opioid receptors. κ receptors are a subtype of opioid receptors, and agonizing κ receptors can also produce strong analgesic effects similar to μ receptors. However, unlike μ receptors, κ receptors do not mediate typical opioid-like effects such as addiction and respiratory depression, so κ receptors are an important research target for analgesics. The early discovery of highly selective κ agonists of aromatic acetamides represented by U504886 set off a wave of κ agonist research in the 1980s and 1990s, but with the failure of Phase II clinical trials of representative drugs enadoline and spiradoline, the research on κ agonists fell into a trough. The failure of clinical trials has posed a challenge to the drugability of κ receptors. However, with the successful launch of nalfurafine (TRK-820), a κ agonist of the morphine structure, in Japan and South Korea, κ agonists derived from morphine structures and their use in the preparation of drugs for potential indications such as anti-itching, analgesia, irritable bowel syndrome, addiction, and depression have once again attracted attention. Since many morphine-like agonists have the potential risk of opioid side effects due to their strong opioid μ receptor activity, the search for new morphine-like κ agonists, especially highly selective κ agonists, has practical significance and potential application prospects. Summary of the invention

[0004] The purpose of the present invention is to provide 7α-(2'-substituted aminophenyl)-6α,14α-endo-ethylene(enyl)-tetrahydrothebaine derivatives or pharmaceutically acceptable salts thereof as shown in general formula (I) and a preparation method thereof, and such derivatives have potential uses in the preparation of drugs for analgesia and irritable bowel syndrome, pruritus, addiction, depression and the like.

[0005] According to one aspect of the present invention, there is provided a 7α-(2'-substituted aminophenyl)-6α,14α-endo-ethylene(enyl)-tetrahydrothebaine derivative or a pharmaceutically acceptable salt thereof as shown in the general formula (I),

[0006]

[0007] in

[0008] R1 is selected from H and C1-C6 alkyl, in particular from H and C1-C4 alkyl, more particularly H or CH3;

[0009] R2 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C6 alkyl, C5-C7 cycloalkenylC1-C6 alkyl, C6-C 12 Aryl, 5-7 membered heteroaryl, C6-C 12 Aryl C1-C6 alkyl, 5-7 membered heteroaryl C1-C6 alkyl; in particular, R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl C1-C4 alkyl, C5-C7 cycloalkenyl C1-C4 alkyl, C6-C 12 Aryl, 5-6 membered heteroaryl, C6-C 12 Aryl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl; more particularly, R2 is cyclopropylmethyl, cyclobutylmethyl or phenethyl;

[0010] R3 is selected from H and C1-C6 alkyl, in particular from H and C1-C4 alkyl, more particularly H or CH3;

[0011] R4 is selected from C1-C6 alkylene and C2-C6 alkenylene, in particular C1-C4 alkylene and C2-C4 alkenylene, more particularly -CH=CH- or -CH2-CH2-;

[0012] R5 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C6-C 12 Aryl, 5-9 membered heteroaryl, C3-C6 cycloalkyl unsubstituted or substituted by a substituent selected from Group A C1-C6 alkyl, 5-7 membered heterocycloalkyl unsubstituted or substituted by a substituent selected from Group A C1-C6 alkyl, C6-C 12 Aryl C1-C6 alkyl, 5-9 membered heteroaryl C1-C6 alkyl, unsubstituted or substituted by a substituent selected from Group A C1-C6 alkylacyl, unsubstituted or substituted by a substituent selected from Group A C3-C6 cycloalkyl C1-C6 alkanoyl, unsubstituted or substituted by a substituent selected from Group A C6-C 12 Aryl acyl, 5-9 membered heteroaryl acyl which is unsubstituted or substituted by a substituent selected from Group A, C1-C6 alkoxy acyl which is unsubstituted or substituted by a substituent selected from Group A, C2-C6 alkenyl acyl which is unsubstituted or substituted by a substituent selected from Group A;

[0013] In particular, R5 is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C6-C 12Aryl, 5-9 membered heteroaryl, C3-C6 cycloalkyl, C1-C4 alkyl, 6-membered heterocycloalkyl unsubstituted or substituted by a substituent selected from Group A, C1-C4 alkyl, C6-C 12 Aryl C1-C4 alkyl, 5-9 membered heteroaryl C1-C4 alkyl, unsubstituted or substituted by a substituent selected from Group A; C1-C6 alkylacyl, unsubstituted or substituted by a substituent selected from Group A; C3-C6 cycloalkyl C1-C4 alkanoyl, unsubstituted or substituted by a substituent selected from Group A; C6-C 12 Aryl acyl, 5-9 membered heteroaryl acyl which is unsubstituted or substituted by a substituent selected from Group A, C1-C6 alkoxy acyl which is unsubstituted or substituted by a substituent selected from Group A, C2-C6 alkenyl acyl which is unsubstituted or substituted by a substituent selected from Group A;

[0014] More particularly, R5 is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C4 alkyl, 6-membered azacycloalkylC1-C4 alkyl which is unsubstituted or substituted by C1-C6 alkoxyformyl, C6-C4 alkyl which is unsubstituted or substituted by a substituent selected from C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy 12 Aryl C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkylsulfonylphenyl, phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy naphthyl C1-C6 alkylacyl, unsubstituted or substituted by a substituent selected from amino, amino C1-C4 alkyl C1-C4 cycloalkyl C1-C4 alkanoyl, unsubstituted or substituted by a substituent selected from hydroxy, C1-C4 alkyl, C2-C4 alkanoyloxy, halogen C6-C 12 Aryl acyl, 5-9 membered heteroaryl acyl which is unsubstituted or substituted by a substituent selected from C1-C4 alkyl, C1-C4 alkoxy acyl which is unsubstituted or substituted by a phenyl, C2-C6 alkenyl acyl which is unsubstituted or substituted by a substituent selected from furanyl and dimethylaminophenyl;

[0015] wherein the substituents selected from Group A are each independently selected from C1-C6 alkyl groups which are unsubstituted or substituted with substituents selected from Group B, C1-C6 alkoxy groups which are unsubstituted or substituted with substituents selected from Group B, C1-C6 alkoxy acyl groups, C1-C6 alkanoyloxy groups, C6-C6 alkyl groups which are unsubstituted or substituted with substituents selected from Group B, 12aryl, 5-6 membered heteroaryl which is unsubstituted or substituted by a substituent selected from group B, hydroxyl, halogen, amino, aminoC1-C6 alkyl; in particular, the substituents selected from group A are each independently selected from C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyacyl, C1-C6 alkanoyloxy, C1-C6 alkyl which is unsubstituted or substituted by a substituent selected from C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino 12 Aryl, 5-6 membered heteroaryl, hydroxy, halogen, amino, aminoC1-C6 alkyl; more particularly, the substituents selected from Group A are each independently selected from C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxyacyl, C1-C4 alkanoyloxy, phenyl or naphthyl which is unsubstituted or substituted with substituents selected from C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, furanyl, hydroxy, halogen, amino, aminoC1-C4 alkyl; for example, methoxy, trifluoromethyl, tert-butoxyformyl, propyl, hydroxy, acetyloxy, methyl, Cl, phenyl, methylsulfonylphenyl, naphthyl, methoxynaphthyl, amino, aminomethyl, furan, dimethylaminophenyl;

[0016] The substituents selected from group B are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, di(C1-C6 alkyl)amino; in particular selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, di(C1-C4 alkyl)amino; in particular selected from methyl, methoxy, methanesulfonyl, dimethylamino;

[0017] Most particularly, R5 is selected from H, -COCH3,

[0018] According to one embodiment of the derivative represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein R1 is H or CH3, and the other substituents are as described above.

[0019] According to one embodiment of the derivative represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, R2 is cyclopropylmethyl, cyclobutylmethyl or phenethyl, and the other substituents are as described above.

[0020] According to one embodiment of the derivative represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein R5 is benzyl or benzoyl, and the other substituents are as described above.

[0021] According to the present invention, the derivative represented by general formula (I) is represented by the following formula (I-1):

[0022]

[0023] wherein R5 are as described above respectively.

[0024] Specifically, according to the present invention, there is provided a compound selected from the following or a pharmaceutically acceptable salt thereof:

[0025]

[0026]

[0027]

[0028] According to the present invention, the pharmaceutically acceptable salt can be a salt formed by the derivative represented by general formula (I) and an inorganic acid or an organic acid, such as hydrochloride, hydrobromide, hydroiodide, sulfate or hydrogensulfate, phosphate or hydrogenphosphate, acetate, benzoate, tartrate, succinate, maleate, fumarate, lactate, citrate, gluconate, methanesulfonate, benzenesulfonate or p-toluenesulfonate, preferably hydrochloride.

[0029] According to another aspect of the present invention, there is provided a method for preparing a derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0030] The derivatives wherein R1=H can be prepared by converting the derivatives wherein R1=CH3 in the formula (I) under certain conditions. The conversion conditions are BBr3 / CH2Cl2, different concentrations of H2SO4, different concentrations of HBr, methanesulfonic acid or KOH / diethylene glycol (DEG), sodium propanethiolate / HMPA, preferably BBr3 / CH2Cl2.

[0031] Wherein R2=H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl C1-C6 alkyl, or a derivative of heteroaryl C1-C6 alkyl can be prepared by converting a derivative of formula (I) wherein R2=CH3 under certain conditions. The conversion conditions are: reacting with bromonitrile, ethyl chloroformate, phenyl chloroformate, vinyl chloroformate, diisopropyl azodicarboxylate, ethyl azoformate (Kauer JC, Organic Synthesis, 1963, 4, 411) in an inert solvent, and hydrolyzing with acid to obtain a derivative of formula (I) in which R2=H, wherein the inert solvent is selected from acetonitrile, tetrahydrofuran (THF), ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF) or a mixture of the above solvents, preferably acetonitrile; the conversion conditions are preferably ethyl azoformate; the acidic conditions are selected from H2SO4, HCl or HBr at different concentrations. The intermediate product (II, R2 = H) reacts with monohalogenated hydrocarbons in an inert solvent to obtain the derivative of (I) wherein R2 = C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl C1-C6 alkyl, or heteroaryl C1-C6 alkyl. The monohalogenated hydrocarbon is selected from the chlorine, bromine, and iodide of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl C1-C6 alkyl, and the inert reagent is selected from THF, ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF) or a mixture of the above solvents.

[0032] It is well known in the art that the derivatives of formula (I) wherein R3=H can be obtained by converting the derivatives of formula (I) wherein R3=CH3 under certain conditions, wherein the certain conditions are different concentrations of H2SO4, different concentrations of HBr, methanesulfonic acid or KOH / diethylene glycol (DEG).

[0033] It is also well known in the art that the derivatives of formula (I) wherein R4 is -CH2CH2- can be prepared by converting the derivatives of formula (I) wherein R4 is -CH=CH- under certain reducing conditions, wherein the reducing conditions are selected from reduction under Pd / C catalytic hydrogenation.

[0034] The derivative wherein R5=H can be obtained through a series of conversion reactions of the derivative of formula (III), wherein the conversion conditions are as follows: first, the derivative of formula (III) undergoes a Diels-Alder reaction with 2-nitrostyrene in a high-boiling point inert solvent to obtain a derivative of intermediate (IV), wherein the inert solvent is selected from benzene, toluene, xylene or a mixture of the above solvents, preferably xylene; the derivative of intermediate (IV) can obtain a derivative wherein R5=H of formula (I) under certain reduction conditions, wherein the reduction conditions are selected from reduction under Pd / C catalytic hydrogenation.

[0035] The derivatives of the formula wherein R5=C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, aryl C1-C6 alkyl, heteroaryl C1-C6 alkyl can be obtained by reacting the derivatives of the formula (I) wherein R5=H, R6=H with halogenated hydrocarbons in an inert solvent. The halogenated hydrocarbon is selected from the chlorine, bromine, and iodide of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl C1-C6 alkyl, and the inert reagent is selected from THF, ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF) or a mixture of the above solvents.

[0036] Wherein R5=C1-C6 alkyl substituted acyl, aryl substituted acyl, heteroaryl substituted acyl, heteroaryl C1-C6 alkyl substituted acyl or aryl C1-C6 alkyl substituted acyl derivatives can be obtained by reacting a derivative of formula (I) R5=H, an acyl chloride and a base in an inert solvent. The acyl chloride is selected from C1-C6 alkyl substituted acyl chloride, aryl substituted acyl chloride, heteroaryl substituted acyl chloride, heteroaryl C1-C6 alkyl substituted acyl chloride or aryl C1-C6 alkyl substituted acyl chloride, the base is selected from pyridine, triethylamine, 4-dimethylaminopyridine (DMAP), diisopropylethylamine, potassium carbonate or sodium, potassium hydroxide or sodium, etc., preferably triethylamine; the inert solvent is selected from tetrahydrofuran (THF), ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF) or a mixture of the above solvents, preferably DCM.

[0037]

[0038] According to an embodiment of the present invention, the method comprises:

[0039]

[0040] Reagents and reaction conditions: (a) DIAD, pyridine hydrochloride and acetonitrile; (b) cyclopropyl bromide, Na2CO3 and DMF, room temperature; (c) 2-nitrostyrene and xylene, reflux; (d) Pd / C, H2, 65psi, 25°C; (e) halogenated alkane Na2CO3, DMF, 80°C; (f) carboxylic acid, HATU, DIPEA, or acyl chloride, Et3N, DCM, room temperature;

[0041] Wherein, R5 is defined as above.

[0042] Terminology

[0043] In the present invention, unless otherwise explicitly stated, the terms used in the present invention have the meanings defined below. Terms not explicitly defined in the present invention have the general meanings generally understood by those skilled in the art.

[0044] A dash ("-") not between two letters or symbols indicates the point of attachment of a substituent. For example, -O(C1-C3 alkyl) indicates that the group is attached to the rest of the molecule via an oxygen atom. However, when the point of attachment of a substituent is obvious to one skilled in the art, such as for substituents such as halogen, hydroxyl, etc., the "-" may be omitted.

[0045] When the group has a wavy line , the wavy line shows where the group is attached to the rest of the molecule.

[0046] As used herein, "heteroatom" refers to nitrogen (N), oxygen (O) or sulfur (S) atoms, particularly nitrogen or oxygen, each of which may be substituted or unsubstituted, including oxidized forms thereof. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)- and -S(O)2-, where R is hydrogen, C1-C4 alkyl or nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Any heteroatom with unsatisfied valences is considered to have hydrogen atoms sufficient to satisfy the valences, unless otherwise indicated.

[0047] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. Preferred halogens as substituents are fluorine and chlorine.

[0048] As used herein, "alkyl" refers to a fully saturated straight or branched hydrocarbon group. The number before the alkyl group represents the number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl group having 1-6 carbon atoms, and "C1-C4 alkyl" represents an alkyl group having 1-4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. This definition applies whether the term "alkyl" appears alone or as part of other groups such as haloalkyl, alkoxy, etc.

[0049] As used herein, "alkenyl" refers to a straight or branched hydrocarbon group containing at least one double bond. The number before the alkenyl group represents the number of carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, etc.

[0050] As used herein, "alkoxy" refers to an alkyl group as defined herein connected through an oxygen bridge, i.e., an alkyl-O- group, and the number before the alkoxy group represents the number of carbon atoms. For example, "C1-C6 alkoxy" means an alkoxy group having 1-6 carbon atoms, i.e., -O-C1-6 alkyl. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0051] As used herein, "cycloalkyl" refers to a saturated non-aromatic carbocyclic ring, for example, "C3-C6 cycloalkyl" is intended to include C3, C4, C5 and C6 cycloalkyl groups. Exemplary monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0052] As used herein, "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by halogen, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. For example, "C1-C4 haloalkyl" is intended to include C1, C2, C3 and C4 haloalkyl groups. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl and 1,1,1-trifluoropropyl.

[0053] As used herein, "aryl" is a monocyclic, bicyclic or tricyclic carbocyclic hydrocarbon radical having, for example, 6-12 ring carbon atoms, composed of one ring or multiple rings fused together, wherein at least one ring is aromatic, and the other rings (if present) may be aromatic or non-aromatic, including: a monocyclic aromatic group (e.g., phenyl); or a fused bicyclic system in which one ring is aromatic and the other ring is aromatic (e.g., in naphthalene, biphenyl), etc. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, etc.

[0054] As used herein, "heteroaryl" refers to an aromatic ring system, for example 5-9, 5-7 or 5-6 membered, containing 1 or 2 ring heteroatoms selected from N, O or S, including monocyclic or bicyclic or fused polycyclic rings, with the remaining ring atoms being carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, 1H-benzo[d][1,2,3]triazolyl, and the like.

[0055] As used herein, "heterocycloalkyl" refers to a cycloalkyl group as defined in the present application, provided that one or more ring carbons are replaced by a heteroatom selected from N, O or S, such as -O-, -N=, -NR-, -S-, -S(=O)- and -S(=O)2-, wherein R is hydrogen, C1-4 alkyl or a nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Preferably, the heterocycloalkyl group is a monocyclic, bicyclic or tricyclic saturated non-aromatic ring having, for example, 3-8 ring atoms or 3-6 ring atoms. For example, examples of heterocycloalkyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, azopentyl (pyrrolidinyl), tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidin-2-one, imidazolonyl, piperidinyl (hexahydropyridine), N-methylpiperidinyl, tetrahydropyranyl, oxazinanyl, 1,3-oxazinanyl, hexahydropyrimidinyl, piperazinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]decan-8-yl, morpholino, thiomorpholino, thiomorpholino-S-monooxide (sulfanomorpholino), thiomorpholino-S,S-dioxide (sulfonomorpholino), octahydropyrrolo[3,2-b]pyrrolyl, and the like.

[0056] As used herein, the terms "substituted", "substituted" or "substituted by" mean that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded.

[0057] In the present invention, the composite substituent AB means that it is connected to the parent core through B and is substituted by the group A. For example, "C3-C6 cycloalkyl C1-C6 alkyl" means that it is connected to the parent core through C1-C6 alkyl and the C1-C6 alkyl is substituted by C3-C6 cycloalkyl.

[0058] In the present invention, "substituted or unsubstituted" or "unsubstituted or substituted by..." means that the defined group is not substituted or substituted by...", for example, "C3-C6 cycloalkyl C1-C6 alkyl unsubstituted or substituted by a substituent selected from Group A" in which "unsubstituted or substituted by a substituent selected from Group A" is used to define C3-C6 cycloalkyl.

[0059] According to another aspect of the present invention, a composition is provided, comprising a therapeutically effective amount of a derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, and optional pharmaceutical excipients.

[0060] According to another aspect of the present invention, there is provided a derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, or use of the composition in the preparation of an opioid receptor-mediated therapeutic drug.

[0061] According to another aspect of the present invention, provided is a derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, or use of the composition in the preparation of a drug for treating and / or preventing pain, irritable bowel syndrome, pruritus, addiction, or depression.

[0062] According to the present invention, the pain includes perioperative pain, chronic pain, neuropathic pain, and cancer pain.

[0063] Beneficial Effects

[0064] Compared with the prior art, the derivatives provided by the present invention as shown in the general formula (I) have been significantly improved in terms of agonist activity of κ receptors and subtype selectivity of κ receptors, which is non-obvious; animal studies have shown that some compounds have strong long-acting analgesic activity, and their analgesic effect in vivo can be completely reversed by the selective κ receptor antagonist nor-BNI, and the rotarod fatigue test shows that the sedative central side effect is weak. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 The time curve of the analgesic effect of compound 8 in the hot plate test is shown;

[0066] Figure 2 It is shown that the analgesic effect induced by compound 8 is mediated through the kappa opioid receptor; **p<0.0001;

[0067] Figure 3 Shown is the sedative effect of compound 8 in the rotarod fatigue test, ****p<0.0001, compared with the saline group. DETAILED DESCRIPTION

[0068] The 7α-(2'-substituted aminophenyl)-6α,14α-endo-ethylene(enyl)-tetrahydrothebaine derivatives of the present invention can be used to determine the affinity and selectivity of the ligand for three opioid receptors through radioactive receptor ligand binding experiments. 35 S]GTP γ The S binding assay can be used to determine the receptor agonist activity of the compounds.

[0069] The features, technical solutions and advantages described in the present invention can be more easily understood with reference to the following specific embodiments.

[0070] Unless otherwise specified, the raw materials, reagents, equipment, methods, etc. used in this application are conventional or commercially available raw materials, reagents, equipment, methods in the art.

[0071] The mass spectrometry data of the relevant compounds were measured by Agilent 1100 Series LC / MSD1946D mass spectrometer and expressed as mass-to-nuclear ratio (m / z). High-resolution mass spectrometry (ESI-HRMS) was measured by AB SCIEX TRIPLE TOF 5600+ mass spectrometer. The melting point of the solid was measured by capillary method on a melting point instrument, and the measuring instrument was WRS-1B digital melting point instrument. 1 HNMR was measured on a Varian Mercury plus 400 MHz NMR spectrometer. 13 CNMR was measured on a Bruker 600 MHz NMR spectrometer and was based on the chemical shift of the deuterated solvent CDCl3: 1 The chemical shift value of CDCl3 in HNMR is 7.26ppm. 13 The chemical shift value of CDCl3 in CNMR is 77.0ppm. All chemical shift values ​​are expressed as δ, in ppm, and the coupling constant is expressed as J, in Hz. The peak type s represents a single peak, d represents a doublet, t represents a triplet, q represents a quartet, m represents a multiplet, and br represents a broad peak.

[0072] The solvents used in the reaction were purchased from Sinopharm Shanghai Chemical Reagent Company, analytical grade. Chemical reagents were purchased from reagent companies such as Exploration Chemical, Sinopharm, J&K, McLean, Acros, and Aldrich. Other solvents include petroleum ether, ethyl acetate, dichloromethane, methanol, etc., purchased from Sinopharm, all of synthetic grade. The column chromatography silica gel uses reagent grade zcxII type silica gel from Rushan Sun Desiccant Co., Ltd., with a particle size of 200-300 mesh; the analytical thin layer chromatography silica gel plate uses GF254 type silica gel plate (0.15mm-0.2mm) from Rushan Sun Desiccant Co., Ltd.; the preparative thin layer chromatography plate uses GF254 type silica gel plate (0.5mm) from Rushan Sun Desiccant Co., Ltd. The purity of the compound was measured by Agilent 1260HPLC, and the mobile phase system was methanol: 0.1% trifluoroacetic acid aqueous solution = 40:60 or 95:5, with a flow rate of 1mL / min. The present invention will be illustrated by the following examples.

[0073] Example 1

[0074] Preparation of N-northebaine hydrochloride (1):

[0075]

[0076] Under nitrogen protection, 5.0 g (16.1 mmol) of thebaine and 50 mL of acetonitrile were added to a 250 mL single-necked flask, followed by 3.8 mL (19.3 mmol) of diisopropyl azodicarboxylate. The reaction was refluxed for 4 h, the reaction was stopped, the reaction solution was spin-dried, 5.6 g of pyridine hydrochloride and 50 mL of methanol were added, and the reaction was refluxed for 4 h. The reaction was completed, and a large amount of solid was precipitated. The filter cake was filtered, washed with methanol, and dried to obtain a white solid powder, 3.5 g of N-demethylthebaine hydrochloride, with a yield of 65.3%.

[0077] Example 2

[0078] Preparation of N-cyclopropylmethylnorthebaine (2):

[0079]

[0080] Under nitrogen protection, 3.5 g (10.5 mmol) of N-demethylthebaine hydrochloride, 30 mL of DMF and 3.3 g (31.5 mmol) of sodium carbonate were added to a 50 mL single-necked flask, followed by 1.3 mL (13.6 mmol) of bromocyclopropylmethane. The mixture was heated to 110°C for 2.5 h and the reaction was stopped. The reaction solution was extracted with EA three times, washed with saturated brine, dried overnight, and then spin-dried and subjected to silica gel column chromatography (PE:EA=1:1) to obtain a light yellow oily substance, 2.61 g of N-cyclopropylmethylthebaine, with a yield of 70.0%. [MS] [M+H] + :362.2. 1 H NMR (600MHz, CDCl3) δ6.68(d,J=8.2Hz,1H),6.61(d,J=8.1Hz,1H),5.60(d,J=6.4Hz,1H),5. 06(d,J=6.4Hz,1H),3.98(d,J=6.9Hz,1H),3.86(s,3H),3.61(s,3H),3.31(d,J=17.7Hz,1H) ,3.01-2.80(m,2H),2.75(dd,J=18.0,6.7Hz,1H),2.53(d,J=6.1Hz,2H),2.22(td,J=12.5,5 .3Hz,1H),1.75(d,J=11.9Hz,1H),0.96(s,1H),0.58(d,J=6.9Hz,2H),0.19(d,J=3.9Hz,2H).

[0081] Example 3

[0082] Preparation of N-cyclopropylmethyl-7α-(2'-nitro)phenyl-6α,14α-vinylidene-tetrahydrothebaine (3):

[0083]

[0084] Add 2g (5.69mmol) of N-cyclopropylmethylthebaine, 1.5mL (11.2mmol) of 2-nitrostyrene and 20mL of anhydrous o-xylene to a 50mL three-necked flask equipped with magnetic stirring, reflux condenser and thermometer. Reflux for 30h, concentrate to dryness under reduced pressure, and elute with ethyl acetate / petroleum ether on a silica gel column. Obtain 1.3g of 7α-(2'-nitro)phenyl-6α,14α-endo-vinyl-tetrahydrothebaine as light yellow foam with a yield of 45.7%. [MS] [M+H] + :501.5. 1 H NMR (600MHz, CDCl3) δ8.20-7.96(m,2H),7.56(d,J=7.1Hz,1H),7.40(t,J=7.9Hz,1H),6.65(d,J=7.9Hz,1H),6.5 6(d,J=7.9Hz,1H),5.94(d,J=8.3Hz,1H),5.72(d,J=8.6Hz,1H),4.74(s,1H),3.84(dd,J=5.9,1.7Hz,3H),3.60(s ,1H),3.52-3.39(m,1H),3.39-3.32(m,3H),3.15(d,J=18.5Hz,2H),2.74(s,1H),2.58-2.25(m,4H),2.09(d,J=20 .5Hz,1H),1.95(d,J=12.0Hz,1H),1.44-1.30(m,1H),0.84(d,J=28.5Hz,1H),0.51(d,J=8.7Hz,2H),0.14(s,2H).

[0085] Example 4

[0086] Preparation of N-cyclopropylmethyl-7α-(2'-amino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (4):

[0087]

[0088] Add 1.3 g (2.6 mmol) of N-cyclopropylmethyl-7α-(2'-nitro)phenyl-6α,14α-vinylidene-tetrahydrothebaine, 20 mL of methanol and 0.26 g (2.4 mmol) of 10% palladium on carbon into a pressure bottle, introduce hydrogen, 65 psi, heat at 50°C for 48 h to stop the reaction, filter the reaction solution to remove palladium on carbon, and spin dry the filtrate to obtain 1.0 g of a white foamy solid, yield: 81.3%. [MS] [M+H] + :473.3. 1H NMR (600MHz, CDCl3) δ7.10(t,J=7.4Hz,1H),6.77(d,J=7.6Hz,1H),6.72(d,J=8.1Hz,1H),6.68(s,1H),6.58(t ,J=8.9Hz,2H),4.60(s,1H),3.88(d,J=1.1Hz,3H),3.63(s,2H),3.20(d,J=1.1Hz,3H),3.05(dd,J=20.7,11.6H z,3H),2.64(s,1H),2.31(d,J=21.3Hz,4H),2.15(s,1H),1.73(t,J=11.3Hz,2H),1.64(dd,J=13.3,6.4Hz,1H), 1.52-1.41(m,1H),1.40-1.29(m,1H),0.88(t,J=12.7Hz,1H),0.76(s,1H),0.47(d,J=7.5Hz,2H),0.09(s,2H).

[0089] Example 5

[0090] Preparation of N-cyclopropylmethyl-7α-[2'-(N'-methyl)amino]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (5):

[0091]

[0092] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of ethyl acetate were added to a 10 mL round-bottom flask, followed by 0.8 mL of saturated sodium carbonate aqueous solution. 34 μL of benzyl chloroformate (0.32 mmol, 1.1 eq) was slowly added dropwise under ice bath while stirring. The mixture was reacted at room temperature for 3 h, washed twice with water, dried over anhydrous sodium sulfate, and directly used for the next step after being spun dry. 3 mL of tetrahydrofuran solution of lithium aluminum hydroxide (1 N) was added to a 10 mL three-necked flask under nitrogen protection. The tetrahydrofuran solution of the product of the previous step was slowly added dropwise under ice bath. The mixture was then allowed to stand at room temperature overnight. After the reaction was completed, sodium sulfate decahydrate was added to quench the reaction, followed by 0.5 mL of 2N sodium hydroxide solution. The white solid was filtered off, and the filter cake was washed with DCM:CH3OH=10:1. After concentration under reduced pressure, the mixture was separated on a high-efficiency preparative plate (DCM:CH3OH=50:1) to obtain 24.0 mg of a light yellow oily substance, with a yield of 46.7%. [MS][M+H] + :487.4. 1H NMR (400MHz, CDCl3) δ7.44(d,J=7.2Hz,1H),7.15(dt,J=16.9,7.8Hz,3H),6.73(d,J=7.8Hz,1H),6.59(d, J=7.8Hz,1H),4.70(s,1H),3.88(s,3H),3.22(s,3H),3.12(d,J=5.1Hz,1H),3.03(d,J=18.2Hz,1H),2.91 (d,J=6.1Hz,2H),2.69(s,3H),2.64(d,J=9.7Hz,1H),2.43-2.31(m,3H),2.22(dd,J=13.0,7.0Hz,2H),1. 80(t,J=13.0Hz,2H),1.65(s,1H),1.50(s,2H),1.25(s,1H),0.75(s,1H),0.51-0.39(m,2H),0.09(s,2H). 13 C NMR (151MHz, CDCl3) δ153.30,147.22,141.78,139.13,132.94,128.99,126.56,124.01,121.05,118.83,113.62,92.40,77.69 ,59.64,58.13,56.62,52.59,50.72,46.12,44.13,42.03,37.59,36.55,34.28,30.05,22.64,20.04,13.17,9.40,4.37,3.03.

[0093] Example 6

[0094] Preparation of N-cyclopropylmethyl-7α-[2'-(N'-cyclopropylmethyl)amino]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (6):

[0095]

[0096] 30 mg of compound (4) (0.063 mmol, 1.0 eq) and 2 mL of DMF were added to a 10 mL single-mouth reaction bottle, followed by 30.0 mg of anhydrous sodium carbonate (0.19 mmol, 3.0 eq) and 10.0 μL of bromomethylcyclopropane (0.095 mmol, 1.5 eq), and the mixture was reacted in an oil bath at 80°C for 12 hours. The reaction was stopped by TLC monitoring, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=10 / 1) to obtain 10.0 mg of a light yellow solid, with a yield of 30.2%. [MS] [M+H]+ :527.3. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=7.3Hz,1H),7.15(t,J=7.5Hz,1H),6.81(t,J=7.2Hz,1H),6.74(d,J=8.1Hz,1H),6.67(d,J=7.9 Hz,1H),6.60(d,J=7.9Hz,1H),4.60(s,1H),3.89(d,J=2.7Hz,3H),3.38(d,J=6.3Hz,1H),3.26-3.16(m,2H),3.15(s,4H),3.04( d,J=18.3Hz,1H),2.70(s,1H),2.60(dd,J=11.5,8.2Hz,1H),2.33(s,5H),1.76(d,J=9.8Hz,2H),1.59(d,J=8.5Hz,3H),1.34(s ,1H),1.29(d,J=2.9Hz,1H),0.79(s,1H),0.58(d,J=7.8Hz,2H),0.47(s,2H),0.31(s,1H),0.19(s,1H),0.10(d,J=13.8Hz,2H). 13 C NMR (151MHz, CDCl3) δ148.89,146.33,141.27,127.63,126.35,123.84,123.35,118.40,116.70,113.62,110.91,97.10,77.87,59.11,58 .31,56.29,52.03,48.94,45.70,43.22,37.71,35.34,34.18,31.30,30.81,29.58,29.07,28.66,22.45,15.15,10.29,2.88,2.82,2.63.

[0097] Example 7

[0098] Preparation of N-cyclopropylmethyl-7α-[2'-(N'-cyclopentylmethyl)amino]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (7):

[0099]

[0100] Add 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DMF to a 10 mL single-mouth reaction bottle, then add 35.0 mg of anhydrous sodium carbonate (0.34 mmol, 3.0 eq) and 22 mg of bromomethylcyclopentane (0.13 mmol, 1.2 eq), and react in an oil bath at 95°C for 48 hours. Monitor by TLC, stop the reaction, extract with ethyl acetate (10 mL*3), combine the organic layers, wash the organic phase with water and saturated sodium chloride solution in turn, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE / EA=5 / 1) to obtain 17.5 mg of colorless transparent oil, yield: 29.7%. ESI-MS (M+H) + :555.4. 1 H NMR (400MHz, CDCl3) δ7.34(d,J=7.4Hz,1H),7.15(s,1H),6.80(d,J=7.2Hz,1H),6.71(dd,J=15.1,8.0Hz,2H),6.59(d,J=7.6Hz,1 H),4.55(s,1H),4.31(s,1H),4.10(d,J=27.1Hz,2H),3.88(s,3H),3.42(s,1H),3.35(s,1H),3.30(d,J=5.7Hz,2H),3.13(s,4H), 3.04(d,J=19.8Hz,4H),2.86(t,J=9.4Hz,1H),2.69(s,3H),2.44-2.11(m,7H),1.90(s,2H),1.82(d,J=12.8Hz,3H),1.67(d,J=22 .2Hz,4H),1.46(s,9H),1.40-1.28(m,4H),1.19(d,J=12.0Hz,3H),0.96(t,J=7.4Hz,1H),0.76(s,1H),0.46(s,2H),0.07(s,2H). 13 C NMR (151MHz, CDCl3) δ154.72,149.61,146.89,130.90,128.83,128.19,126.96,118.99,117.09,113.97,111.33,109.01,97.96,79.51,65.56 ,59.74,58.91,56.82,52.65,49.88,39.60,38.80,38.61,35.94,34.81 ,30.88,30.85,29.68,29.27,28.43,25.49,25.36,19.17,15.76,3.43.

[0101] Example 8

[0102] Preparation of N-cyclopropylmethyl-7α-(2'-benzylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (8):

[0103]

[0104] Add 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DMF to a 10 mL single-mouth reaction bottle, then add 35.0 mg of anhydrous sodium carbonate (0.34 mmol, 3.0 eq) and 15 μL of benzyl bromide (0.13 mmol, 1.2 eq), and react in an oil bath at 80°C for 12 hours. Monitor by TLC, stop the reaction, extract with ethyl acetate (10 mL*3), combine the organic layers, wash the organic phase with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE / EA=20 / 1) to obtain 35.0 mg of a colorless transparent oily substance, yield: 56.6%. ESI-MS (M+H) + :562.9. 1 H NMR (400MHz, CDCl3) δ7.40-7.32(m,6H),7.29(s,1H),7.10(t,J=7.5Hz,1H),6.81(t,J=7.4Hz,1H),6.73(d,J=8.0Hz ,1H),6.67(d,J=8.0Hz,1H),6.59(d,J=8.1Hz,1H),4.53(s,1H),4.35(s,2H),3.88(s,3H),3.41(dd,J=11.2,6.4Hz, 1H),3.17(s,3H),3.10(s,1H),3.03(d,J=18.4Hz,1H),2.66(s,1H),2.31(s,5H),1.78(d,J=7.5Hz,1H),1.72(d,J=1 2.6Hz,1H),1.44-1.35(m,2H),1.27(d,J=12.9Hz,2H),0.89(d,J=5.8Hz,1H),0.77(s,1H),0.47(s,2H),0.10(s,2H). 13C NMR (151MHz, CDCl3) δ7.31(s,1H),7.29(s,1H),7.28(s,1H),7.22(t,J=6.9Hz,2H),7.11(t,J=7.9Hz,1H),6. 69(s,2H),6.63(d,J=7.5Hz,2H),6.56(d,J=7.7Hz,1H),4.67(s,2H),4.54(s,1H),3.86(s,3H),3.14(s,1H), 3.05(s,3H),2.96(s,2H),2.60(s,1H),2.28(d,J=11.6Hz,3H),2.10(s,1H),1.68(d,J=12.2Hz,1H),1.60(s, 1H),1.54-1.39(m,2H),1.29(d,J=7.4Hz,1H),1.00(s,1H),0.73(d,J=10.1Hz,1H),0.46(s,2H),0.08(s,2H).

[0105] Example 9

[0106] Preparation of N-cyclopropylmethyl-7α-(2'-p-methoxybenzylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (9):

[0107]

[0108] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DMF were added to a 10 mL single-mouth reaction bottle, followed by 28.0 mg of anhydrous sodium carbonate (0.26 mmol, 3.0 eq) and 18.0 μL of 4-methoxybenzyl chloride (0.12 mmol, 1.4 eq). The mixture was reacted in an oil bath at 80°C for 11 hours. The reaction was stopped by TLC monitoring, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=10 / 1) to obtain 20.0 mg of a transparent oily substance, with a yield of 20.2%. ESI-MS (M+H) + :593.3. 1H NMR (400MHz, CDCl3) δ7.36(d,J=7.6Hz,1H),7.30(d,J=8.4Hz,2H),7.11(t,J=7.6Hz,1H),6.89(d,J=8.5Hz,2H),6.81(t,J =7.4Hz,1H),6.71(dd,J=15.6,8.1Hz,2H),6.59(d,J=8.0Hz,1H),4.51(s,1H),4.26(s,2H),3.88(s,3H),3.80(d,J=13.5H z,3H),3.37(d,J=6.1Hz,1H),3.16(s,3H),3.11(s,1H),3.03(d,J=18.4Hz,2H),2.66(s,1H),2.31(s,5H),1.72(d,J=12.2 Hz,2H),1.38(dd,J=21.4,14.9Hz,2H),1.25(s,1H),0.87(dd,J=10.4,3.5Hz,1H),0.78(s,1H),0.47(s,2H),0.10(s,2H). 13 C NMR (151MHz, CDCl3) δ158.60,148.91,146.93,141.83,131.94,128.53,128.29,126.94,119.02,117.52,114.32,113.98,111.98,97.71,7 8.60,59.74,58.86,56.95,55.27,52.66,47.92,46.34,43.79,38.35 ,35.93,35.12,34.90,29.68,29.27,23.00,15.82,9.45,3.97,3.41.

[0109] Example 10

[0110] Preparation of N-cyclopropylmethyl-7α-(2'-trifluoromethylbenzylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (10):

[0111]

[0112] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DMF were added to a 10 mL single-mouth reaction bottle, followed by 35.0 mg of anhydrous sodium carbonate (0.34 mmol, 3.0 eq) and 30 μL of 4-(trifluoromethyl)benzyl chloride (0.12 mmol, 1.1 eq), and the mixture was reacted in an oil bath at 80°C for 11 hours. The reaction was stopped by TLC monitoring, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 23.0 mg of a white solid, with a yield of 35.0%. ESI-MS (M+H) + :631.4. 1 H NMR (400MHz, CDCl3) δ7.59(d,J=7.7Hz,2H),7.49(d,J=7.6Hz,2H),7.37(d,J=7.3Hz,1H),7.06(t,J=7 .3Hz,1H),6.79(dd,J=19.6,7.6Hz,2H),6.63(d,J=7.8Hz,1H),6.54(d,J=7.9Hz,1H),4.60(s,1H),4.4 5(s,2H),3.89(s,3H),3.47(s,2H),3.19(s,3H),3.08(d,J=18.7Hz,1H),2.93(d,J=6.5Hz,1H),2.53( s,5H),1.92-1.76(m,2H),1.65(s,3H),1.45(d,J=18.6Hz,1H),0.95(s,1H),0.58(s,2H),0.25(s,2H). 13 C NMR(151MHz,CDCl3)13C NMR (151MHz, CDCl3) δ148.01,147.01,144.29,142.26,129.14,128.93,128.2 4,127.31,127.04,126.80,125.43,125.41,125.17,123.36,119.29,117.83,1 14.88,112.07,96.84,78.30,64.34,59.37,58.54,56.94,53.40,52.61,47.72,37.94,36.01,34.75,31.90,29.67,29.35,22.66,15.96,14.09,3.35,0.99.

[0113] Embodiment 11

[0114] Preparation of N-cyclopropylmethyl-7α-{2'-[N'-(N"-Boc-piperidin-4"-)methyl]amino}phenyl-4α,14α-endoethylidene-tetrahydrothebaine (11):

[0115]

[0116] 20 mg of compound (4) (0.043 mmol, 1.0 eq) and 2 mL of DMF were added to a 10 mL single-mouth reaction bottle, followed by 14.0 mg of anhydrous sodium carbonate (0.13 mmol, 3.0 eq) and 19 mg of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.052 mmol, 1.2 eq), and the mixture was reacted in an oil bath at 95°C for 48 hours. The reaction was stopped by TLC monitoring, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated on a preparative plate (PE / EA=5 / 1) to obtain 10.0 mg of a colorless transparent oily substance, with a yield of 34.7%. ESI-MS (M+H) + :670.4. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=7.2Hz,1H),7.15(s,1H),6.81(s,1H),6.73(d,J=7.3Hz,1H),6.6 8(d,J=7.8Hz,1H),6.60(s,1H),4.53(s,1H),4.16(s,2H),3.88(s,4H),3.33(s,1H),3.10(s,4H) ,3.03(d,J=19.7Hz,3H),2.91(s,1H),2.75(s,2H),2.67(s,1H),2.31(m,6H),1.84(s,3H),1.75( d,J=11.6Hz,2H),1.61(s,5H),1.48(s,9H),1.43(s,1H),0.76(s,1H),0.46(s,2H),0.09(s,2H). 13C NMR (151MHz, CDCl3) δ154.88,149.13,146.83,141.84,128.83,128.38,12 6.98,119.04,117.37,114.06,111.35,97.96,79.33,78.65,59.75,58.88 ,56.84,53.41,52.68,50.12,46.37,43.72,38.45,35.97,35.89,35.25,3 4.87,30.53,30.29,29.68,29.21,28.47,22.95,15.71,9.48,3.94,3.42.

[0117] Example 12

[0118] Preparation of N-cyclopropylmethyl-7α-(2'-acetylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (12):

[0119]

[0120] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 33 μL of triethylamine (0.25 mmol, 3.0 eq), and 7.3 μL of acetyl chloride (0.102 mmol, 1.2 eq) was added under ice bath, and the mixture was stirred at room temperature for 2 hours. TLC monitoring was performed, the reaction was stopped, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3), the organic layers were combined, and the organic phases were washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by thick preparative plate (DCM / MeOH=15 / 1) to obtain 15.0 mg of colorless transparent oil, with a yield of 34.3%. ESI-MS (M+H) + :615.2. 1H NMR (400MHz, CDCl3) δ8.59(s,1H),7.68(d,J=7.2Hz,1H),7.45(d,J=6.5Hz,1H),7.20(d,J=6.7Hz,1H),6.7 8-6.68(m,1H),6.61(d,J=7.5Hz,1H),4.52(s,1H),3.89(d,J=2.5Hz,4H),3.30(d,J=4.3Hz,1H),3.21(d,J =2.5Hz,3H),3.15-2.97(m,4H),2.69(s,1H),2.32(d,J=6.9Hz,5H),2.22(d,J=2.6Hz,3H),1.79(dd,J=24. 9,10.5Hz,3H),1.60(d,J=11.5Hz,1H),1.49-1.30(m,3H),0.78(s,2H),0.48(d,J=3.6Hz,2H),0.10(s,2H). 13 C NMR (151MHz, CDCl3) δ168.37,146.73,141.85,137.85,133.70,132.73,128.17,126.70,125.08,124.92,119.26,114.53,98.04,7 8.88,59.86,58.88,56.99,52.87,46.39,43.60,39.34,35.68,35.13,33.87,28.99,24.35,22.99,15.38,14.16,9.37,3.90,3.52.

[0121] Embodiment 13

[0122] Preparation of N-cyclopropylmethyl-7α-(2'-cyclopropylcarboxamido)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (13):

[0123]

[0124] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 48.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 8.4 μL of cyclopropanecarboxylic acid (0.102 mmol, 1.2 eq). The reaction was stirred at room temperature for 6 hours. After TLC monitoring, the reaction was stopped, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 14a as a white solid (16.0 mg). The yield was 34.9%. ESI-MS (M+H) + :541.2. 1 H NMR (400MHz, CDCl3) δ7.70(s,1H),7.54(s,1H),7.24(s,1H),7.08(s,1H),6.73(d,J=8.1Hz,1H), 6.59(d,J=8.1Hz,1H),4.60(s,1H),3.88(s,3H),3.19(s,3H),3.15-3.05(m,2H),3.01(d,J=18.4H z,1H),2.71(s,1H),2.36(dd,J=25.9,7.7Hz,5H),2.19(d,J=8.2Hz,2H),1.82-1.63(m,4H),1.49( d,J=7.4Hz,2H),1.07(s,2H),0.82(d,J=6.7Hz,2H),0.78(s,1H),0.55-0.39(m,2H),0.11(s,2H). 13 C NMR (151MHz, CDCl3) δ176.55,146.65,142.32,138.34,127.92,126.77,124.68,124.39,119.46,114.38,97.61,78.46,77.21,77. 00,76.79,59.48,58.44,56.69,52.94,45.95,39.49,39.11,38.38,35.80,33.71,29.66,29.08,27.77,27.02,15.35,14.16,3.43.

[0125] Embodiment 14

[0126] Preparation of N-cyclopropylmethyl-7α-(2'-trimethylacetylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (14)

[0127]

[0128] Add 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM to a 10 mL single-mouth reaction bottle, then add 45 μL of triethylamine (0.34 mmol, 3.0 eq), place in an ice bath, slowly add 30 μL of trimethylacetyl chloride (0.12 mmol, 1.1 eq) while stirring, and react at room temperature for 6 hours. Monitor by TLC, stop the reaction, remove the solvent under reduced pressure, extract with ethyl acetate (10 mL*3), combine the organic layers, wash the organic phase with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE / EA / Et3N=100 / 20 / 1) to obtain 22.0 mg of a white foamy solid, yield: 35.9%. ESI-MS (M+H) + :557.4. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=7.1Hz,1H),7.43(d,J=7.2Hz,1H),7.24(d,J=7.5Hz,1H),7.17(d,J =7.0Hz,1H),6.78(d,J=7.8Hz,1H),6.65(d,J=7.7Hz,1H),4.55(s,1H),3.90(s,3H),3.39(d,J=31. 6Hz,2H),3.25(s,3H),3.09(d,J=18.3Hz,1H),2.52(s,5H),1.96(s,1H),1.83(d,J=11.0Hz,1H),1. 63(d,J=12.2Hz,1H),1.48(s,2H),1.36(s,9H),1.22(s,2H),0.97(s,2H),0.58(s,2H),0.24(s,2H). 13 C NMR (151MHz, CDCl3) δ176.55,146.65,142.32,138.34,127.92,126.77,124.68,124.39,119.46,114.38,97.61,78.46, 59.48,58.44,56.69,52.94,45.95,39.49,39.11,38.38,35.80,33.71,29.66,29.08,27.77,27.02,15.35,14.16,3.43.

[0129] Embodiment 15

[0130] Preparation of N-cyclopropylmethyl-7α-(2'-valeramido)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (15):

[0131]

[0132] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 20 μL of valproic acid (0.13 mmol, 1.2 eq). The mixture was stirred at room temperature for 48 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 20.0 mg of a colorless transparent oily substance, with a yield of 30.4%. ESI-MS (M+H) + :599.5. 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),7.72(d,J=7.5Hz,1H),7.45(d,J=7.3Hz,1H),7.17(t,J=11.4Hz ,1H),6.75(d,J=7.6Hz,1H),6.65-6.57(m,1H),4.77(s,1H),4.52(s,1H),3.89(s,3H),3.34(s,1H ),3.22(s,3H),3.14(s,1H),3.05(d,J=18.1Hz,2H),2.68(s,1H),2.33(s,5H),1.92-1.72(m,4H), 1.67(s,4H),1.50(d,J=7.4Hz,6H),0.98(d,J=4.1Hz,6H),0.81(s,1H),0.49(s,2H),0.11(s,2H). 13 C NMR (151MHz, CDCl3) δ173.67,146.08,141.36,137.35,132.91,127.48,126 .10,124.43,124.12,118.68,113.55,97.35,78.25,59.16,57.96,56.20,52 .26,47.96,45.79,35.27,35.15,34.94,33.72,33.33,29.69,29.07,28.86,28.52,20.59,20.33,19.89,14.94,13.66,13.58,13.32,12.53,3.56,2.80.

[0133] Example 16

[0134] Preparation of N-cyclopropylmethyl-7α-(2'-benzamido)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (16):

[0135]

[0136] Add 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM to a 10 mL single-mouth reaction bottle, then add 45.0 μL of triethylamine (0.34 mmol, 3.0 eq), add 15 μL of benzoyl chloride (0.13 mmol, 1.2 eq) under ice bath, and react at room temperature for 4 hours. Monitor by TLC, stop the reaction, extract with ethyl acetate (10 mL*3), combine the organic layers, wash the organic phase with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE / EA=20 / 1) to obtain 48.0 mg of white foamy solid, yield: 75.0%. ESI-MS (M+H) + :576.9. 1 H NMR (400MHz, CDCl3) δ8.01(d,J=7.3Hz,2H),7.89(d,J=7.7Hz,1H),7.63-7.46(m,4H),7.31(t,J=7.5Hz,1H),7.23(t,J =7.5Hz,1H),6.75(d,J=8.1Hz,1H),6.62(d,J=8.0Hz,1H),4.54(s,1H),3.90(s,3H),3.41(s,1H),3.34(s,3H),3.13(s, 1H),3.04(d,J=18.3Hz,1H),2.66(s,1H),2.31(s,4H),2.15(s,1H),1.92-1.83(m,1H),1.66(d,J=9.8Hz,3H),1.51(t, J=12.2Hz,1H),1.41(dd,J=14.6,10.2Hz,1H),0.94(t,J=12.4Hz,1H),0.78(s,1H),0.48(d,J=7.1Hz,2H),0.10(s,2H). 13C NMR (151MHz, CDCl3) δ165.75,146.98,143.59,141.79,137.81,135.13,132.85,131.77,128.77,128.60,126.97,125.95,121.20,118.98,118. 07,113.68,93.33,59.85,58.54,56.63,51.16,46.08,43.97,43.86,36 .39,36.11,35.68,29.67,29.64,22.77,18.75,14.10,9.46,4.09,3.36.

[0137] Embodiment 17

[0138] Preparation of N-cyclopropylmethyl-7α-[2'-(2"-hydroxybenzamido)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (17):

[0139]

[0140] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 20.0 mg of salicylic acid (0.13 mmol, 1.2 eq). The mixture was stirred at room temperature for 8 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 11.0 mg of a white solid, with a yield of 17.0%. ESI-MS (M+H) + :593.3. 1H NMR (400MHz, CDCl3) δ7.78(d,J=7.0Hz,1H),7.60(d,J=7.2Hz,1H),7.54(d,J=6.2Hz,1H),7.48(t,J=7.1Hz,1H),7 .32(dd,J=17.3,9.8Hz,2H),7.06(d,J=7.9Hz,1H),6.97(t,J=7.3Hz,1H),6.75(d,J=7.4Hz,1H),6.63(d,J=7.5Hz, 1H),4.56(s,1H),3.89(s,J=10.2Hz,3H),3.37(s,3H),3.18-2.99(m,3H),2.66(s,1H),2.31(s,4H),1.89(d,J=9.8 Hz,1H),1.67(dd,J=24.8,10.5Hz,4H),1.43(s,2H),0.97(d,J=7.3Hz,1H),0.77(s,1H),0.47(s,2H),0.09(s,2H). 13 C NMR (151MHz, CDCl3) δ168.24,162.39,146.42,136.98,134.40,128.50,126 .87,125.51,125.30,125.15,119.31,119.12,118.91,114.65,113.45,98. 23,79.48,65.55,59.80,58.82,56.52,53.24,46.55,43.53,39.56,35.64,33.76,29.68,28.97,22.93,19.17,15.43,14.10,13.71,9.45,3.93,3.48.

[0141] Embodiment 18

[0142] Preparation of N-cyclopropylmethyl-7α-[2'-(2"-acetoxybenzamido)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (18):

[0143]

[0144] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 23.0 mg of o-acetylsalicylic acid (0.13 mmol, 1.2 eq). The mixture was stirred at room temperature for 8 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 17.0 mg of a white solid, with a yield of 24.3%. ESI-MS (M+H) + :635.3. 1 H NMR (400MHz, CDCl3) δ7.74 (s, 2H), 7.50 (d, J = 23.9Hz, 2H), 7.36 (s, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 7.17 (d,J=7.2Hz,1H),6.74(d,J=6.6Hz,1H),6.62(s,1H),4.52(s,1H),3.87(s,3H),3.40(d,J=28.8Hz,1H) ,3.23(s,3H),3.05(d,J=18.0Hz,2H),2.39(s,1H),2.34(s,3H),2.30-2.13(m,2H),1.97(d,J=62.8Hz, 3H),1.72(s,1H),1.59(s,2H),1.43(s,3H),0.93(s,1H),0.84-0.78(m,1H),0.52(s,2H),0.15(s,2H). 13 C NMR (151MHz, CDCl3) δ169.60,167.69,164.25,148.92,146.60,141.85,137.80, 134.39,131.92,130.88,128.81,128.31,128.09,126.85,126.27,125.26,125.0 6,123.68,119.16,114.04,97.76,78.81,65.54,59.74,58.72,56.79,52.95,38.58,35.65,33.89,30.54,30.28,29.66,29.06,19.15,15.47,14.16,13.70,3.42.

[0145] Embodiment 19

[0146] Preparation of N-cyclopropylmethyl-7α-[2'-(3",4"-dimethylbenzamido)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (19):

[0147]

[0148] 100 mg of compound (4) (0.21 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 121.6 mg of HATU (0.32 mmol, 1.5 eq), 70 μL of diisopropylethylamine (0.42 mmol, 2.0 eq), and 37.4 mg of 3,4-dimethylbenzoic acid (0.25 mmol, 1.2 eq). The mixture was stirred at room temperature for 8 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain 46.0 mg of a light yellow solid, with a yield of 35.1%. ESI-MS (M+H) + :605.4. 1 H NMR(400MHz, CDCl3)δ9.51(s,1H),7.88(s,1H),7.84(s,1H),7.68(s,1H),7.50(s,1H),7.32(d, J=24.0Hz,2H),7.22(s,1H),6.68(d,J=47.6Hz,2H),4.54(s,1H),3.90(s,3H),3.40(s,1H),3.35 (s,3H),3.13(s,2H),3.04(d,J=18.8Hz,1H),2.66(s,1H),2.37(s,6H),2.31(s,3H),2.14(s,1H) ,1.87(d,J=12.5Hz,1H),1.54-1.30(m,5H),0.93(s,1H),0.78(s,1H),0.47(s,2H),0.10(s,2H). 13C NMR (151MHz, CDCl3) δ165.00,146.57,141.87,140.82,138.32,137.20,132.34 ,129.97,128.81,128.29,126.79,124.79,124.66,124.02,119.24,113.69,98. 18,79.16,59.78,58.76,56.62,53.12,46.50,43.62,39.44,35.67,33.96,31.90,31.41,30.17,29.67,29.34,29.02,22.67,20.00,19.85,15.45,14.10,3.45.

[0149] Embodiment 20

[0150] Preparation of N-cyclopropylmethyl-7α-[2'-(3",4"-dichlorobenzamido)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (20):

[0151]

[0152] 100 mg of compound (4) (0.21 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 121.6 mg of HATU (0.32 mmol, 1.5 eq), 70 μL of diisopropylethylamine (0.42 mmol, 2.0 eq), and 48.0 mg of 3,4-dichlorobenzoic acid (0.25 mmol, 1.2 eq). The mixture was stirred at room temperature for 8 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain 52.0 mg of a white foamy solid, with a yield of 38.1%. ESI-MS (M+H) + :645.4. 1H NMR (400MHz, CDCl3) δ8.14(s,1H),7.85(d,J=6.8Hz,1H),7.76(d,J=8.0Hz,1H),7.61(d,J=8.3Hz, 1H),7.51(d,J=7.3Hz,1H),7.32(t,J=7.6Hz,1H),7.23(d,J=7.4Hz,1H),6.78(d,J=7.4Hz,1H),6. 66(s,1H),4.53(s,1H),3.91(s,3H),3.40(s,1H),3.35(s,3H),3.07(d,J=18.0Hz,2H),2.81(s,2H ),2.32(s,3H),1.66(d,J=11.7Hz,6H),1.51(s,2H),0.97(s,1H),0.53(s,2H),0.25-0.05(m,2H). 13 C NMR (151MHz, CDCl3) δ162.60,146.58,137.69,136.09,134.74,133.43,130.79,129.90,128.35,127.02,125.55,125.21,124.67,119.4 2,113.99,97.99,79.33,59.66,58.64,56.70,53.40,53.20,39.41,38.59,35.70,33.84,29.68,29.02,22.67,15.47,14.10,3.45,1.00.

[0153] Embodiment 21

[0154] Preparation of N-cyclopropylmethyl-7α-[2'-(indole-5-carboxamido)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (21):

[0155]

[0156] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 20.5 mg of indole-5-carboxylic acid (0.13 mmol, 1.2 eq). The mixture was stirred at room temperature for 48 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 34.0 mg of a white foamy solid, with a yield of 50.2%. ESI-MS (M+H) + :616.4. 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),7.91(d,J=7.4Hz,1H),7.83(d,J=8.3Hz,1H),7.50(t,J=8.4Hz,2H),7.31(s,2H) ,7.22(t,J=7.1Hz,1H),6.75(d,J=7.9Hz,1H),6.70(s,1H),6.62(d,J=7.9Hz,1H),4.55(s,1H),3.90(s,3H),3.44(s ,1H),3.35(s,3H),3.08(dd,J=36.4,22.3Hz,3H),2.66(s,1H),2.31(s,4H),2.12(s,1H),1.87(d,J=9.0Hz,1H),1.6 4-1.60(m,1H),1.58-1.49(m,1H),1.43(s,2H),0.99-0.87(m,1H),0.79(s,1H),0.48(d,J=6.7Hz,2H),0.10(s,2H). 13 C NMR (151MHz, CDCl3) δ166.06,146.56,141.86,138.60,137.72,128.24,12 7.81,126.79,126.51,125.67,125.01,124.54,120.90,120.77,119.23,11 3.55,111.22,103.91,98.13,79.12,59.76,58.74,56.57,53.12,46.43,4 3.66,39.41,38.60,35.70,33.97,29.68,29.05,23.00,15.47,4.07,3.46.

[0157] Embodiment 22

[0158] Preparation of N-cyclopropylmethyl-7α-[2'-(1-methylpyrazole-4-carboxamido)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (22):

[0159]

[0160] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 50.7 mg of HATU (0.128 mmol, 1.5 eq), 28.7 μL of diisopropylethylamine (0.17 mmol, 2.0 eq), and 14.0 mg of 1-methylpyrazole-4-carboxylic acid (0.1 mmol, 1.2 eq). The mixture was stirred at room temperature for 24 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 24.0 mg of a white foamy solid, with a yield of 48.6%. ESI-MS (M+H) + :581.4. 1 H NMR (400MHz, CDCl3) δ7.93(d,J=12.0Hz,2H),7.84(s,1H),7.49(d,J=7.2Hz,1H),7.29(s,1H),7.21(d,J=6.6Hz,1H ),6.75(d,J=7.9Hz,1H),6.61(d,J=7.8Hz,1H),4.53(s,1H),4.05(s,1H),4.00(s,3H),3.91(s,3H),3.39(s,1H),3 .32(s,3H),3.14(s,1H),3.07(s,1H),3.02(s,1H),2.67(s,1H),2.32(s,4H),2.16(s,1H),1.86(d,J=13.2Hz,1H), 1.55-1.46(m,1H),1.41(d,J=10.8Hz,1H),1.25(s,1H),0.98-0.88(m,1H),0.78(s,1H),0.48(s,2H),0.10(s,2H). 13C NMR (151MHz, CDCl3) δ160.23,151.76,146.59,142.40,141.90,138.15,13 7.86,135.02,131.77,129.56,128.33,126.83,124.68,120.87,119.69,1 19.28,114.07,98.21,79.35,59.79,58.78,56.81,53.08,46.42,43.61,3 9.74,39.45,35.66,35.06,33.94,29.00,22.97,15.44,9.35,3.99,3.46.

[0161] Embodiment 23

[0162] Preparation of N-cyclopropylmethyl-7α-(2'-phenylacetylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (23):

[0163]

[0164] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 18 mg of phenylacetic acid (0.13 mmol, 1.2 eq). The mixture was reacted at room temperature for 6 hours. After TLC monitoring, the reaction was stopped, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=20 / 1) to obtain 30.0 mg of a white oily substance, with a yield of 46.0%. ESI-MS (M+H) + :590.9. 1H NMR (400MHz, CDCl3) δ7.70(d,J=7.7Hz,1H),7.52-7.42(m,4H),7.37(dd,J=17.6,7.6Hz,2H),7.22(d,J =7.5Hz,1H),7.14(t,J=7.5Hz,1H),6.72(d,J=8.0Hz,1H),6.57(d,J=7.9Hz,1H),3.90(s,3H),3.81(s, 3H),3.03(s,1H),2.98(s,1H),2.97(s,3H),2.94-2.88(m,1H),2.81(s,1H),2.66(s,1H),2.29(s,4H), 1.93(s,1H),1.65(s,1H),1.45(d,J=13.0Hz,1H),1.25(s,3H),0.80(s,2H),0.47(s,2H),0.09(s,2H). 13 C NMR (151MHz, CDCl3) δ165.75,146.98,143.59,141.79,137.81,135.13,132.85,131.77,128.77,128.60,126.97,125.95,121.20,118.98,118. 07,113.68,93.33,59.85,58.54,56.63,51.16,46.08,43.97,43.86,36 .39,36.11,35.68,29.67,29.64,22.77,18.75,14.10,9.46,4.09,3.36.

[0165] Embodiment 24

[0166] Preparation of N-cyclopropylmethyl-7α-[2'-(4"-methylsulfonylphenylacetylamino)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (24):

[0167]

[0168] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 48.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 22.0 mg of 4-methylsulfonylphenylacetic acid (0.102 mmol, 1.2 eq). The mixture was stirred at room temperature for 12 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=1 / 1) to obtain 32.0 mg of a white solid, with a yield of 56.2%. ESI-MS (M+H) + :669.2. 1 H NMR(400MHz, CDCl3)δ8.47(s,1H),8.05(s,2H),7.67(s,3H),7.36(s,2H),7.19(s, 1H),6.72(s,1H),6.60(s,1H),3.92(s,3H),3.85(d,J=4.6Hz,3H),3.21(d,J=4.6H z,4H),3.02(d,J=21.3Hz,3H),2.91(d,J=3.9Hz,3H),2.81(d,J=4.8Hz,1H),2.73( s,1H),2.35(m,4H),1.71(m,5H),1.40(d,J=25.0Hz,3H),0.51(s,2H),0.12(s,2H). 13 CNMR (151MHz, CDCl3) δ167.82,146.56,142.02,141.20,140.32,137.34,130. 74,128.27,128.14,126.72,125.36,124.95,123.96,119.39,119.14,114.27 ,97.44,78.53,59.90,58.94,56.80,52.67,44.71,44.44,38.60,35.65,31.43,30.22,29.69,28.89,23.13,22.67,15.18,14.19,14.07,4.01,3.59,1.00.

[0169] Embodiment 25

[0170] Preparation of N-cyclopropylmethyl-7α-[2'-(3",4"-dimethylphenylacetylamino)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (25):

[0171]

[0172] 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 21.0 mg of 3,4-dimethylphenylacetic acid (0.13 mmol, 1.2 eq). The mixture was stirred at room temperature for 8 hours. After TLC monitoring, the reaction was stopped, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM / MeOH=50 / 1) to obtain 45.0 mg of a white foamy solid, with a yield of 68.8%. ESI-MS (M+H) + :618.4. 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.65 (s, 1H), 7.22 (d, J = 10.5Hz, 3H), 7.18-7.09 (m, 2H), 6.74 ( d,J=6.8Hz,1H),6.59(s,1H),3.91(s,3H),3.74(d,J=17.0Hz,2H),3.02(d,J=18.3Hz,1H),2.94(s ,3H),2.81(s,3H),2.45(s,3H),2.34(s,3H),2.29(s,3H),2.23(s,1H),1.64(d,J=17.8Hz,5H),1. 43(s,1H),1.29(s,1H),1.21(d,J=12.1Hz,1H),0.83(d,J=12.8Hz,2H),0.57(s,2H),0.17(s,2H).

[0173] Embodiment 26

[0174] Preparation of N-cyclopropylmethyl-7α-{2'-[(6"'-methoxy-naphthyl-2"'-)-α-methyl-acetylamino]}phenyl-4α,14α-endoethylidene-tetrahydrothebaine (26):

[0175]

[0176] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 50.7 mg of HATU (0.128 mmol, 1.5 eq), 28.7 μL of diisopropylethylamine (0.17 mmol, 2.0 eq), and 24.5 mg of (+)-2-methyl-6-methoxy-2-naphthylacetic acid (0.10 mmol, 1.2 eq). The mixture was stirred at room temperature for 12 hours and monitored by TLC. The reaction was stopped and the solvent was removed under reduced pressure. The mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined and washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM / MeOH=50 / 1) to obtain 23.0 mg of a light yellow solid. Yield: 39.5%. ESI-MS (M+H) + :685.4. 1 H NMR (400MHz, CDCl3) δ7.81(d,J=9.4Hz,3H),7.72(d,J=6.7Hz,1H),7.52(d,J=8.1Hz,1H),7.29(d,J=7.3Hz,1 H),7.22(d,J=7.6Hz,1H),7.12(d,J=8.0Hz,3H),6.69(d,J=6.6Hz,1H),6.53(s,1H),3.91(d,J=6.5Hz,1H),3. 85(s,6H),3.32(s,1H),2.97(s,3H),2.90(s,2H),2.54(s,2H),2.22(m,4H),1.67(d,J=6.8Hz,4H),1.44(d,J =9.8Hz,1H),1.38-1.29(m,2H),1.23-1.15(m,2H),1.00-0.92(m,1H),0.72(s,2H),0.47(s,2H),0.07(s,2H). 13 C NMR (151MHz, CDCl3) δ172.32,157.76,146.77,137.74,133.96,130.90,129.39, 129.25,128.82,128.00,126.55,126.39,126.17,124.86,124.62,119.27,119. 00,105.84,96.87,65.55,59.55,58.37,57.11,55.30,52.60,47.77,38.46,35.36,33.56,29.68,28.89,22.67,19.17,18.33,15.14,14.10,13.71,4.06,3.30.

[0177] Embodiment 27

[0178] Preparation of N-cyclopropylmethyl-7α-[2'-(1"-aminomethylcyclohexane-1"acetylamino)]phenyl-4α,14α-endoethylidene-tetrahydrothebaine (27):

[0179]

[0180] Add 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM to a 10 mL single-mouth reaction bottle, then add 65.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 20.5 mg of 1-(Boc-aminomethyl)cyclohexaneacetic acid (0.13 mmol, 1.2 eq), and stir at room temperature for 48 hours. Monitor by TLC, stop the reaction, remove the solvent under reduced pressure, extract with ethyl acetate (10 mL*3), combine the organic layers, wash the organic phases with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and directly proceed to the next step.

[0181] Add 2mL DCM to a 10mL single-mouth reaction bottle, add the reaction concentrate from the previous step, slowly add 1.0mL trifluoroacetic acid while stirring, and stir at room temperature for 4 hours. Monitor by TLC, stop the reaction, remove the solvent under reduced pressure, extract with ethyl acetate (10mL*3), combine the organic layers, wash the organic phase with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate on a thick preparative plate (DCM / MeOH=15 / 1) to obtain 8.0mg of a light yellow solid, yield: 22.0%. ESI-MS (M+H) + :626.4. 1 H NMR (400MHz, CDCl3) δ7.33(d,J=7.3Hz,1H),7.10-6.99(m,1H),6.85(d,J=7.2Hz,1H),6.74(s,2H),6.60(d,J =7.7Hz,1H),4.60(s,1H),3.89(s,3H),3.38(s,1H),3.22(s,2H),3.15(s,3H),3.05(d,J=18.4Hz,1H),2.89( d,J=58.8Hz,2H),2.50(s,2H),2.42(s,4H),2.33(s,2H),2.22(s,1H),2.03(d,J=7.2Hz,1H),1.77(d,J=9.3H z,3H),1.60(s,4H),1.41(d,J=9.0Hz,3H),1.27(s,3H),1.10(s,1H),0.92(s,1H),0.52(s,2H),0.18(s,2H).13 C NMR(151MHz,CDCl3)13C NMR (151MHz, CDCl3) δ146.64,146.42,141.42,127.78,126.20,118.50,118.46,116.54,113.99,96.43,77.71,58.96,58.06, 56.37,52.80,51.90,45.41,43.62,37.65,35.33,33.78,31.31,29.08,28.74,22.73,22.07,15.37,13.50,3.83,2.76,0.40.

[0182] Embodiment 28

[0183] Preparation of N-cyclopropylmethyl-7α-(2'-benzyloxycarbonylamino)phenyl-6α,14α-endoethylidene-tetrahydrothebaine (28):

[0184]

[0185] Add 50 mg of compound (4) (0.11 mmol, 1.0 eq) and 2 mL of DCM to a 10 mL single-mouth reaction bottle, then add 35.0 mg of anhydrous sodium carbonate (0.34 mmol, 3.0 eq), slowly add 34 μL of benzyl chloroformate (0.12 mmol, 1.1 eq) under ice bath while stirring, and react at room temperature for 3 hours. Monitor by TLC, stop the reaction, remove the solvent under reduced pressure, extract with ethyl acetate (10 mL*3), combine the organic layers, wash the organic phase with water and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE / EA=5 / 1) to obtain 17.0 mg of a white solid, yield: 25.5%. ESI-MS (M+H) + :606.3. 1H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 7.65 (s, 1H), 7.44 (d, J = 11.8Hz, 5H), 7.36 (s, 1H), 7.16 (s, 1H), 6.73 (d, J = 6. 9Hz,1H),6.59(d,J=7.1Hz,1H),5.24(s,2H),4.57(s,1H),3.89(s,3H),3.35(s,1H),3.17(s,3H),3.16-3.09(m, 1H),3.04(d,J=18.4Hz,1H),2.73(s,1H),2.34(br,4H),2.23(s,1H),1.82(d,J=9.7Hz,1H),1.74(d,J=12.7Hz,1 H),1.58(s,1H),1.41(d,J=12.7Hz,2H),1.28(s,1H),1.17-1.02(m,1H),0.83(s,2H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ154.32,146.93,138.10,136.55,128.50,128.25,128.06,127.92,126.80,124.37,119.35,115.21,97.03,78.12,66 .77,59.47,58.53,57.09,53.40,52.80,45.81,38.73,35.81,33.87, 31.89,29.66,29.32,29.14,23.69,22.65,15.45,14.09,4.70,3.43.

[0186] Embodiment 29

[0187] Preparation of N-cyclopropylmethyl-7α-[2'-(furan-2"-acrylamide)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (29):

[0188]

[0189] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 48.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 14.0 mg of 2-furanacrylic acid (0.102 mmol, 1.2 eq). The mixture was stirred at room temperature for 12 hours. After TLC monitoring, the reaction was stopped, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE / EA=5 / 1) to obtain 10.0 mg of a white solid, yield: 20.8%. ESI-MS (M+H) + :593.4. 1 H NMR (400MHz, CDCl3) δ7.83(d,J=7.2Hz,1H),7.56(s,1H),7.53(s,1H),7.48(d,J=7.3Hz,1H),7.35(s,1H),7.28(s, 1H),7.21(d,J=6.5Hz,1H),6.75(d,J=7.8Hz,1H),6.62(s,2H),6.50(s,1H),4.60(s,1H),3.91(s,3H),3.36(s,1H) ,3.26(s,3H),3.15(s,1H),3.05(d,J=18.5Hz,1H),2.71(s,1H),2.33(s,5H),1.85(d,J=8.6Hz,1H),1.76(d,J=11. 2Hz,2H),1.68-1.56(m,2H),1.51(s,1H),0.94(d,J=12.5Hz,1H),0.82(d,J=7.2Hz,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ163.88,151.45,146.89,144.12,141.99,138.07,133.56,128.36,128.18,126.78,124.86,124.36,119.49,119.30,114 .74,113.88,112.18,97.97,78.99,59.82,58.86,57.08,52.89,46.42 ,43.74,35.82,34.07,31.50,30.16,29.68,29.15,22.67,14.07,3.49.

[0190] Embodiment 30

[0191] Preparation of N-cyclopropylmethyl-7α-[2'-(4"-dimethylaminophenylacrylamide)]phenyl-6α,14α-endoethylidene-tetrahydrothebaine (30):

[0192]

[0193] 40 mg of compound (4) (0.085 mmol, 1.0 eq) and 2 mL of DCM were added to a 10 mL single-mouth reaction bottle, followed by 48.0 mg of HATU (0.17 mmol, 1.5 eq), 35 μL of diisopropylethylamine (0.22 mmol, 2.0 eq), and 20.0 mg of 4-dimethylaminocinnamic acid (0.102 mmol, 1.2 eq). The mixture was stirred at room temperature for 12 hours. The reaction was stopped by TLC monitoring, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water and a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by a thick preparative plate (DCM / MeOH=15 / 1) to obtain 5.0 mg of a white solid, yield: 9.5%. ESI-MS (M+H) + :646.3. 1 H NMR (400MHz, CDCl3) δ7.83(s,1H),7.69(d,J=15.1Hz,1H),7.53(d,J=29.9Hz,3H),7.36(s,1H),7.19 (s,1H),6.77(d,J=7.7Hz,1H),6.70(s,2H),6.63(d,J=6.8Hz,1H),6.47(s,1H),4.66(d,J=23.6Hz,1H ),3.91(s,3H),3.42(s,1H),3.24(s,3H),3.09(s,1H),3.03(s,3H),2.96(d,J=10.2Hz,2H),2.61-2.1 4(m,5H),2.08(s,1H),1.84(s,2H),1.61(s,3H),1.45(s,1H),0.94(s,1H),0.54(s,2H),0.17(s,2H).

[0194] Performance Test 1: Radioligand binding assay (preliminary screening)

[0195] Compounds used in pharmacological binding screening All are in the form of free base. The experiment is divided into total binding tube and non-specific binding tube, and several groups of sample tubes are set up to add the compounds to be screened. 80uL of cell suspension expressing opioid κ, μ and δ receptors is added to the total binding tube, and [ 3 H]U69593, 3 H]DAMGO,3 H]DPDPE, (final concentration of 0.35nM) 10uL; U50,488H, DAMGO, and DPDPE were added to the corresponding non-specific tubes to make the final concentration of 1uM; 10ul of the same concentration of drug was added to the sample tube (final concentration of 1uM), and the final volume was adjusted to 100uL with 50mM Tris.HCl (pH7.4). Incubate at 37℃ for 30min, and then terminate the reaction in an ice bath. Filter under negative pressure through GF / C (Whatman) glass fiber filter on a Millipore sample collector. Rinse three times with ice-cold 50mM Tris.HCl (pH7.4), 3mL each time. After the filter paper is dried, place it in a 0.5mL Eppendorf tube, add 0.5mL lipophilic scintillation fluid, and measure the radioactivity intensity using a Beckman LS-6500 multifunctional liquid scintillation counter. Each concentration is duplicated (two concentrations in total: 1×10 -5 M, 1×10 -7 M). Inhibition rate = (total binding rate dpm - sample tube dpm) / (total binding tube dpm - non-specific binding tube dpm) × 100%. The experimental results are shown in Table 1. The preliminary screening results showed that compounds 5, 9, 12, 17, 27, and 28 have strong affinity and subtype selectivity for κ receptors.

[0196] Table 1. Inhibition rate of compounds

[0197]

[0198]

[0199] Performance Test 2: Radioligand binding assay (Ki value test)

[0200] Compounds used in pharmacological binding screening All are in the form of free base. The experiment is divided into total binding tube and non-specific binding tube, and several groups of sample tubes are set up to add the compounds to be screened. 80uL of cell suspension expressing opioid κ, μ and δ receptors is added to the total binding tube, and [ 3 H]U69593, 3 H]DAMGO, 3H] DPDPE, (final concentration is 0.35nM) 10uL; U50,488H, DAMGO, DPDPE are added to the corresponding non-specific tubes to make the final concentration 1uM; 10ul of the same concentration of drug is added to the sample tube (final concentration is 1uM), and the final volume is adjusted to 100uL with 50mM Tris.HCl (pH7.4). Incubate at 37℃ for 30min, and then put it in an ice bath to terminate the reaction. Filter it through GF / C (Whatman) glass fiber filter under negative pressure on the Millipore sample collector. Rinse it three times with ice-cold 50mM Tris.HCl (pH7.4), 3mL each time, and after the filter paper is dried, place it in a 0.5mL Eppendorf tube, add 0.5mL lipophilic scintillation fluid, and measure the radioactivity intensity with Beckman LS-6500 multifunctional liquid scintillation counter. Each concentration is duplicated. Inhibition rate = (total binding rate dpm - sample tube dpm) / (total binding tube dpm - non-specific binding tube dpm) × 100%. IC was calculated using Prism 5.0 software 50 Calculate K as follows i Value, K i =IC 50 / (1+[L] / K d ), [L] is the concentration of the added labeled ligand, K d is the equilibrium dissociation parameter of the labeled ligand. The experimental results are shown in Table 2. In the Ki results, compound 8 has a strong nM affinity for κ receptors and a high subtype selectivity.

[0201] Table 2. Binding activity of compounds to receptors

[0202]

[0203]

[0204] Performance Test 3 [ 35 S]GTP γ S binding assay

[0205] Bradford protein concentration assay kit to measure protein concentration: add standard protein BSA at concentrations of 0, 50, 100, 200, 250 μg / ml and the sample to be tested to a 96-well plate, add 20 μl to each well; add 200 μl of G250 staining solution to each well, leave at room temperature for 3-5 minutes, and measure the absorbance at A595 wavelength with an enzyme marker. Calculate the protein concentration based on the standard curve.

[0206] Table 3. 35 S]GTP γ The volume of each component in the nonspecific binding tube, substrate tube, and sample tube in the S binding assay

[0207]

[0208] The prepared membrane receptor was diluted to the required concentration with reaction buffer (RB) and added as shown in Table 3 (unit: μl). The reaction tube was incubated in a 27°C water bath for 1 hour, filtered under reduced pressure with a glass fiber membrane and counted by liquid scintillation. Calculation was performed according to the following formula:

[0209] [ 35 S]GTP γ S binding rate = 100 × (cpm 样品 -cpm 非特异结合 ) / (cpm 基底 -cpm 非特异结合 )

[0210] The experimental results are shown in Table 4. The in vitro functional activity showed that compound 8 exhibited strong complete agonist activity and high subtype selectivity for κ receptors.

[0211] Table 4. Functional activity test data.

[0212]

[0213] a Compound stimulation 35 Efficacy of [S]GTPγS binding to CHO cell membranes stably expressing opioid receptors. Each value represents the mean ± SEM of at least three independent experiments; b Not determined, the compound at 1 μM and 10 μM concentrations has an effect on [ 35 The activation degree of S]GTPγS was low.

[0214] Performance Test 4

[0215] Experimental Animals Male Kunming mice (18-22 g) used in the experiments were obtained from the Laboratory Animal Center of the Chinese Academy of Sciences (Shanghai, China). All mice were randomly grouped and placed in a temperature-controlled environment with a 12-h light / dark cycle (lights on at 8:00 a.m.), and mice were free to eat and drink. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health of the United States and in accordance with standard animal procedures (2019-01-LJG-41).

[0216] The hot plate model (Hot Plate Test) analgesia test placed mice on a heated smooth surface (55°C) and measured the pain latency (latency) from the time they were placed on the surface to the time they licked their hind paws. Before administration, the pain response time of each mouse was measured twice, and the average value was taken as the basal pain latency (basal latency). Mice that did not respond within 30 seconds were no longer used as subsequent test subjects. Mice were removed if there was no pain response within 60 seconds to avoid tissue damage to the mice. Compound 8 (1 mg / kg) was administered to mice by intraperitoneal injection. At different time points, the pain perception of mice was tested in the hot plate test (8-10 mice / group), and the analgesic effect results were calculated as follows: % analgesia (antinociception) = 100×(test latency–basal latency) / (cut-off time–basal latency), analgesia ED 50 The value is the compound dose that produces 50% analgesia. The results are shown in Table 5. Figure 1 Compound 8 has a dose-dependent analgesic effect in the hot plate test, and the analgesic rate is greater than or equal to that of the control compound U50,488H and morphine.

[0217] Abdominal Constriction Test Analgesia test The writhing method in mice refers to the intraperitoneal injection of damaging substances to cause abdominal pain in mice, showing a "writhing reaction" (i.e., the abdomen is concave, the trunk and hind limbs are stretched, and the buttocks are raised). After intraperitoneal injection of different doses of the test compound, 0.6% acetic acid (10ml / kg body weight) is injected into the peritoneum of each mouse, and then the number of writhings of each mouse within 20 minutes is recorded. Calculated by the following formula: % analgesia = 100×(average number of writhings in the control group – number of writhings in the experimental group) / average number of writhings in the control group. Analgesic ED 50 The value is the compound dose that produces 50% analgesia. In vivo mechanism of action studies using the κ receptor selective antagonist nor-BNI: Mice were pretreated with the κ-opioid receptor antagonist nor-BNI (10 mg / kg, ip, -24 h). The antinociceptive effect of compound 8 (1 mg / kg, ip) was then evaluated in the writhing test 8 hours after administration. The data are expressed as the mean ± SEM from 8 mice / data point. The results are shown in Table 5. Figure 2 Compound 8 has analgesic effect in the acetic acid writhing test, and its analgesic effect is higher than or not weaker than that of U50,488H and morphine.

[0218] Table 5 Hot plate and writhing tests to assess the analgesic ED of intraperitoneal injection of compound 8 50

[0219]

[0220] a Analgesic ED of Compound 8 50 Calculated from the data at 8 hours after administration (8-10 mice / group).

[0221] The 95% confidence intervals are in parentheses.

[0222] Rotarod test: Rotarod fatigue test is a classic behavioral experiment to evaluate the anxiety state of mice. The rotating rod system is equipped with an automatic recording system (test time and acceleration time are 240s; minimum speed is 4r / min; maximum speed is 40r / min). Mice were trained three times a day for two days, and mice with a baseline >160 seconds were screened for the following tests. Before dosing on the test day, mice were tested three times, and the average of the results was used as the basal level. Mice were pretreated with saline, U50,488H (5.0mg / kg, -15min) or compound 8 (0.6, 1.9, 3.8, 7.6, 15.2mg / kg, -8h) by intraperitoneal injection. The duration of each mouse falling was recorded, and the latency to fall was calculated. The data are expressed as the mean ± SEM of 10 mice / data point. The results are shown in Figure 3 Compared with saline, compound 8 did not show significant sedation in the entire tested dose range of 0.6 to 15.2 mg / kg.

Claims

1. A 7α-(2'-substituted aminophenyl)-6α,14α-endo-ethylene(enyl)-tetrahydrothebaine derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, in R1 is selected from H and C1-C6 alkyl; R2 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C6 alkyl, C5-C7 cycloalkenylC1-C6 alkyl, C6-C 12 Aryl, 5-7 membered heteroaryl, C6-C 12 Aryl C1-C6 alkyl, 5-7 membered heteroaryl C1-C6 alkyl; R3 is selected from H and C1-C6 alkyl; R4 is selected from C1-C6 alkylene and C2-C6 alkenylene; R5 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C6-C 12 Aryl, 5-9 membered heteroaryl, C3-C6 cycloalkyl unsubstituted or substituted by a substituent selected from Group A C1-C6 alkyl, 5-7 membered heterocycloalkyl unsubstituted or substituted by a substituent selected from Group A C1-C6 alkyl, C6-C 12 Aryl C1-C6 alkyl, 5-9 membered heteroaryl C1-C6 alkyl, unsubstituted or substituted by a substituent selected from Group A C1-C6 alkylacyl, unsubstituted or substituted by a substituent selected from Group A C3-C6 cycloalkyl C1-C6 alkanoyl, unsubstituted or substituted by a substituent selected from Group A C6-C 12 Aryl acyl, 5-9 membered heteroaryl acyl which is unsubstituted or substituted by a substituent selected from Group A, C1-C6 alkoxy acyl which is unsubstituted or substituted by a substituent selected from Group A, C2-C6 alkenyl acyl which is unsubstituted or substituted by a substituent selected from Group A; in, The substituents selected from Group A are each independently selected from C1-C6 alkyl which is unsubstituted or substituted by a substituent selected from Group B, C1-C6 alkoxy which is unsubstituted or substituted by a substituent selected from Group B, C1-C6 alkoxyacyl, C1-C6 alkanoyloxy, C6-C6 alkyl which is unsubstituted or substituted by a substituent selected from Group B 12 Aryl, 5-6 membered heteroaryl which is unsubstituted or substituted by a substituent selected from Group B, hydroxy, halogen, amino, amino C1-C6 alkyl; The substituents selected from Group B are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, di(C1-C6 alkyl)amino.

2. The derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is selected from H and C1-C4 alkyl; and / or R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C4 alkyl, C5-C7 cycloalkenylC1-C4 alkyl, C6-C 12 Aryl, 5-6 membered heteroaryl, C6-C 12 Aryl C1-C6 alkyl, 5-6 membered heteroaryl C1-C6 alkyl; and / or R3 is selected from H and C1-C4 alkyl; and / or R4 is selected from C1-C4 alkylene and C2-C4 alkenylene.

3. The derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is H or CH3; and / or R2 is cyclopropylmethyl, cyclobutylmethyl or phenethyl; and / or R3 is H or CH3; and / or R4 is -CH=CH- or -CH2-CH2-.

4. The derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R5 is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C6-C 12 Aryl, 5-9 membered heteroaryl, C3-C6 cycloalkyl, C1-C4 alkyl, 6-membered heterocycloalkyl unsubstituted or substituted by a substituent selected from Group A, C1-C4 alkyl, C6-C 12 Aryl C1-C4 alkyl, 5-9 membered heteroaryl C1-C4 alkyl, unsubstituted or substituted by a substituent selected from Group A; C1-C6 alkylacyl, unsubstituted or substituted by a substituent selected from Group A; C3-C6 cycloalkyl C1-C4 alkanoyl, unsubstituted or substituted by a substituent selected from Group A; C6-C 12 Aryl acyl, 5-9 membered heteroaryl acyl which is unsubstituted or substituted by a substituent selected from Group A, C1-C6 alkoxy acyl which is unsubstituted or substituted by a substituent selected from Group A, C2-C6 alkenyl acyl which is unsubstituted or substituted by a substituent selected from Group A; and / or The substituents selected from Group A are each independently selected from C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyacyl, C1-C6 alkanoyloxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, unsubstituted or substituted C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, 12 Aryl, 5-6 membered heteroaryl, hydroxy, halogen, amino, amino C1-C6 alkyl; and / or The substituents selected from Group B are each independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, di(C1-C4 alkyl)amino.

5. The derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R5 is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C4 alkyl, 6-membered azacycloalkylC1-C4 alkyl which is unsubstituted or substituted by C1-C6 alkoxycarbonyl, C6-C1-C4 alkyl which is unsubstituted or substituted by a substituent selected from C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy 12 Aryl C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkylsulfonylphenyl, phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy naphthyl C1-C6 alkylacyl, unsubstituted or substituted by a substituent selected from amino, amino C1-C4 alkyl C1-C4 cycloalkyl C1-C4 alkanoyl, unsubstituted or substituted by a substituent selected from hydroxy, C1-C4 alkyl, C2-C4 alkanoyloxy, halogen C6-C 12 Aryl acyl, 5-9 membered heteroaryl acyl which is unsubstituted or substituted with a substituent selected from C1-C4 alkyl, C1-C4 alkoxy acyl which is unsubstituted or substituted with a phenyl, C2-C6 alkenyl acyl which is unsubstituted or substituted with a substituent selected from furanyl and dimethylaminophenyl; and / or The substituents selected from Group A are each independently selected from C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxyacyl, C1-C4 alkanoyloxy, phenyl or naphthyl which is unsubstituted or substituted with a substituent selected from C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, furyl, hydroxy, halogen, amino, aminoC1-C4 alkyl; for example, methoxy, trifluoromethyl, tert-butoxyformyl, propyl, hydroxy, acetyloxy, methyl, Cl, phenyl, methylsulfonylphenyl, naphthyl, methoxynaphthyl, amino, aminomethyl, furan, dimethylaminophenyl; and / or The substituents selected from Group B are each independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, di(C1-C4 alkyl)amino; in particular, selected from methyl, methoxy, methanesulfonyl, dimethylamino.

6. The derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R5 is selected from H, 7. The derivative according to claim 1, 4, 5 or 6 or a pharmaceutically acceptable salt thereof, wherein: The derivative represented by the general formula (I) is represented by the following formula (I-1): Wherein, R5 is as described in claim 1, 4, 5 or 6 respectively.

8. A compound selected from the following or a pharmaceutically acceptable salt thereof:

9. A composition comprising a therapeutically effective amount of the derivative according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient.

10. Use of the derivative according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the composition according to claim 9 in the preparation of an opioid receptor-mediated therapeutic drug, or Use of a derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or a composition according to claim 9, in the preparation of a medicament for treating and / or preventing pain, irritable bowel syndrome, pruritus, addiction, depression; in particular, the pain includes pain during surgery, chronic pain, neuropathic pain, cancer pain.

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