WO2025236860A1 - Bufotenine derivative and use thereof in analgesic and antidepressant drugs - Google Patents

Abstract

The present invention provides a bufotenine derivative and a use thereof in analgesic and antidepressant drugs. The bufotenine derivative has a structure as represented by formula (I). The bufotenine derivative has excellent analgesic activity, and especially has a remarkably outstanding antineuralgic effect. In addition, the bufotenine derivative has excellent antidepressant activity, and can be used for treating symptoms related to pain and depression comorbidity.

Description

Toad tryptamine derivatives and their application in analgesics and antidepressants Technical Field

This invention relates to the pharmaceutical field, and more specifically, to a toad tryptophan derivative and its application in analgesic and antidepressant drugs.

Background Technology

Chronic pain typically lasts or recurs for more than 3 months, and the prolonged unpleasant sensations and emotional torment can lead to depression. Statistics show that 85% of patients with chronic pain also suffer from depression. Conversely, over 60% of patients with anxiety and depression experience somatic symptoms primarily characterized by pain. There is a positive correlation between pain severity and depressive symptoms, exhibiting a comorbid pain-depression pattern.

Cancer pain is a common chronic pain symptom. It is a mixed pain, encompassing both inflammatory nociceptive pain and neuropathic pain. Many refractory cancer pain cases are closely related to neuropathic pain. Clinically, drug treatment for cancer pain involves not only analgesics but also adjunctive analgesics such as anticonvulsants, antidepressants, and antisedatives. Even so, current drug interventions fall far short of satisfactory control, and patients continue to suffer from cancer-related pain and depression.

Toad venom, a traditional and precious animal-based medicine in my country, possesses the effects of clearing heat and detoxifying, reducing swelling and relieving pain, and refreshing the mind. Pharmacological studies have shown that it exhibits anti-inflammatory, analgesic, cardiotonic, and antitumor activities. Its chemical components mainly include bufotoxins, bufageins, and bufoteinines. Among these, bufoteinines are indole alkaloids with certain biological activity. More than ten indole derivatives have been isolated and identified, including N-methylserotonin, bufotenine, 5-methoxybufotenine, bufotenine inner salt, bufotenine, bufobutamoic acid, bufopyramide, bufoviridine, and dehydrobufotenine. In addition, there are a large number of artificially synthesized bufotenine analogues.

These substances possess analgesic and antidepressant pharmacological activities. However, the pharmacological activity of existing bufotenoids is still insufficient, and there is an urgent need to provide bufotenoid derivatives with superior activity.

Summary of the Invention

Therefore, the present invention provides a toad tryptamine derivative, which has excellent analgesic and antidepressant activities.

In one aspect of the invention, a compound of formula I, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer is provided:

Wherein, _R1 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, _-SO2Ra , _-CORa , _{-COORa ;}

_R2 , _R5 , and _R6 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C2-12 alkenyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted 3-25 heterocyclic alkyl, substituted or unsubstituted C6-25 aryl, substituted or unsubstituted 5-25 heteroaryl, _-ORa , _-CORa , _-COORa , _-OCORa , _-NRaRb , _-CONRaRb , _-SO2Ra , _{-SO2NRaR , and} -C= _N - _{ORa .}

_Ra and _Rb are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted C6-25 aryl, and substituted or unsubstituted 5-25 heteroaryl.

_R3 and _R4 are independently selected from hydrogen, substituted or unsubstituted C1-12 alkyl, -OR _x , and one of _R3 and _R4 is -OR _x ;

R _x is selected from substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted C6-25 aryl, and substituted or unsubstituted 5-25 heteroaryl.

L is selected from substituted or unsubstituted C1-12 alkylene groups;

_R11 , _R12 , and _R13 are independently selected from substituted or unsubstituted C1-12 alkyl groups, substituted or unsubstituted C3-25 cycloalkyl groups, substituted or unsubstituted C6-25 aryl groups, substituted or unsubstituted 5-25 heteroaryl groups, or _R11 and _R12 are linked together to form a ring.

^X- is a pharmaceutically acceptable anion.

In another aspect, the present invention provides a pharmaceutical composition comprising the compounds of the present invention.

In another aspect of the invention, the invention provides the use of the compound of the invention in the preparation of analgesic or antidepressant medicaments.

In another aspect, the present invention provides a method for relieving pain or depression.

In another aspect of the invention, a method for preparing the compounds of the invention is provided.

The beneficial effects of this invention are:

This invention provides a bufotenine derivative and its application in analgesic and antidepressant drugs. Experimental results show that the compound of this invention has excellent analgesic activity, particularly a very prominent anti-neuralgia effect. In addition, the compound of this invention also exhibits excellent antidepressant activity.

Detailed Implementation

definition

Unless otherwise defined, the terminology used herein has the same meaning as commonly understood by one of ordinary skill in the art to which it belongs. The terminology used in this specification is for describing particular embodiments only and is not intended to limit the invention.

In this article, This indicates the connection point of the connected part.

In this invention, the term "alkyl" refers to a straight-chain, branched, fully saturated hydrocarbon group, preferably C1-15, more preferably C1-12, C1-6, or C1-4 alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl (e.g., n-pentyl), hexyl (e.g., n-hexyl), heptyl (e.g., n-heptyl), octyl (e.g., n-octyl), nonyl (e.g., n-nonyl), decyl (e.g., n-decyl), and so on. Alkyl groups may optionally be substituted.

In this invention, the term "alkenyl" refers to a straight-chain, branched hydrocarbon group containing one or more carbon-carbon double bonds, preferably C2-15, more preferably C2-12, C2-6, or C2-4 alkenyl. Examples of alkenyl groups include vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl, etc. Alkenyl groups may optionally be substituted.

In this invention, the term "alkynyl" refers to a straight-chain, branched hydrocarbon group containing one or more carbon-carbon triple bonds, preferably C2-15, more preferably C2-12, C2-6, or C2-4 alkynyl. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexenyl, 2-heptynyl, 2-octyne, etc. The alkynyl group may optionally be substituted.

In this invention, the term "cycloalkyl" refers to a C3-20 monocyclic or polycyclic alkyl group, preferably a C3-15 monocyclic or polycyclic alkyl group, and most preferably a C3-10 or C3-6 monocyclic or polycyclic alkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The cycloalkyl group may optionally be substituted.

In this invention, the term "heterocyclic alkyl" refers to a 3-25 member monocyclic or polycyclic alkyl, preferably a 3-15 member monocyclic or polycyclic alkyl, most preferably a 3-10 member, 3-7 member, or 3-6 member monocyclic or polycyclic alkyl, wherein at least one (e.g., 1, 2, 3, 4, or 5) cyclic carbon atom in its cyclic structure is replaced by a heteroatom selected from N, O, S, or P. Examples of heterocyclic alkyl groups include: azahexacyclic butyl, oxacyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxacyclopentyl (e.g., 1,3-dioxacyclopentyl), dithiohexacyclopentyl, oxothiohexacyclopentyl, oxalyl (e.g., 1,3-dioxalyl, 1,4-dioxalyl), thiaalkyl (e.g., 1,3-dithiaalkyl, 1,4-dithiaalkyl), piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dithiaalkyl, hexahydropyridinyl, hexahydropyrimidinyl, homopiperidinyl, homopiperazinyl, etc. Heterocyclic alkyl groups may optionally be substituted.

In this invention, the term "aryl" refers to a C6-C25 aromatic group having a monocyclic (e.g., phenyl) or fused ring (e.g., naphthyl, anthracene, phenanthrene, etc.) shape that can be optionally substituted, preferably a C6-14, more preferably a C6-10 aromatic group. The aryl group can be optionally substituted.

In this invention, the term "heteroaryl" refers to a 5-25 member monocyclic or fused-ring aromatic group containing at least one (e.g., 1, 2, 3, 4 or 5) heteroatom (e.g., N, O, S or P), preferably a 5-10 member, more preferably a 5-7 member or a 5-6 member aromatic group. Examples of heteroaryl groups include furanyl, thiopheneyl, pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, or 5-pyrimidinyl), pyrazinyl, pyrazinyl, triazinyl, indolyl, isindolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothiopheneyl, benzooxazolyl, benzothiazolyl, carbazoleyl (including carbazole-9-yl), quinolinyl, isoquinolinyl, indolazinyl, dibenzofuranyl, dibenzothiopheneyl, and naphridinyl; furthermore, cases where the ring carbon atom in the above groups is replaced by nitrogen are also included. Heteroaryl groups may optionally be substituted.

The term "alkylene" refers to the collective divalent group remaining after removing one more hydrogen atom from the stated group. For example, "alkylene" refers to the collective divalent group remaining after removing one more hydrogen atom from an alkyl group, and so on.

The term "halogen" refers to F, Cl, Br, and I.

The term "substituted or unsubstituted" includes both "substituted" and "unsubstituted". "Unsubstituted" refers to substitution only by hydrogen atoms. The term "substituted" refers to the independent presence of one or more substituents at any carbon (or nitrogen) position in a molecule/group, preferably 1, 2, 3, 4, or 5 substituents, most preferably 1, 2, or 3 substituents. Substituents can be: deuterium, halogen, hydroxyl, mercapto, carboxyl, cyano, nitro, amino, aminocarbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylcarbonyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, substituted or unsubstituted ester, etc. Preferably, the substituents can be: deuterium, halogen (preferably 1, 2 or 3 halogens), hydroxyl, hydroxyl, carboxyl, cyano, nitro, amino, aminocarbonyl, C1-10 alkyl (preferably C1-6 alkyl), halo-C1-6 alkyl (preferably _CH2F , _CHF2 , _CF3 ), C3-7 cycloalkyl, C1-6 alkoxy (preferably methoxy, ethoxy), haloalkoxy (preferably _CF3O- ), C6-10 aryloxy, C1-6 alkyl-S-, C6-10 aryl (especially phenyl, and substituted phenyl such as tolyl, trimethylphenyl, pentadeuterated phenyl), 5-7 heteroaryl, 5-7 heterocycloalkyl, C1-6 alkylcarbonyl, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 ester, etc. More preferably, the substituents can be: halogen, hydroxyl, carboxyl, cyano, nitro, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, _CH₂F , _CHF₂ , _CF₃ , methoxy, ethoxy, _CF₃O- , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, -COOMe, -COOEt, -COMe, -COEt, methylamino, dimethylamino, ethylamino, diethylamino, -CONH₂, -CONHMe, -CONHEt, -CON(Me) _₂ , -CON(Et) _{₂ ,} etc.

The term "pharmaceuticalally acceptable excipient" refers to an excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, and is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to: excipients, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmolarity regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and anti-flocculators, antioxidants, adsorbents, filter aids, and release inhibitors.

In this invention, the term "pharmaceutically acceptable salt" refers to a salt of a compound of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, fumaric acid, succinic acid, fumaric acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also include salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

In this invention, the term "prodrug" will refer to a functional derivative of the compound that is readily converted in vivo into the desired compound. Therefore, in the treatment methods of this invention, the term "administration" will encompass treating the described various conditions with a specifically disclosed compound or with a compound that may not be specifically disclosed but is convertible in vivo into a specific compound after administration to a patient. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," H. Bundgaard, Elsevier, eds., 1985.

In this invention, the term "solvent" refers to an association or complex of one or more solvent molecules with the compounds of this invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, acetonitrile, acetone, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecules are water.

In this invention, the term "stereoisomer" refers to a compound having the same chemical composition and connectivity, but whose atoms have different spatial orientations that cannot be interchanged by single bond rotation. "Stereoisomer" includes both "diastereomers" and "enantiomers." A "diastereomer" is a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as crystallization, electrophoresis, and chromatography. An "enantiomer" is a stereoisomer of a compound that is a non-overlapping mirror image of each other.

In this invention, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) active atoms, such as keto-enol tautomers.

In one aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof:

Wherein, _R1 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, _-SO2Ra , _-CORa , _{-COORa ;}

_R2 , _R5 , and _R6 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C2-12 alkenyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted 3-25 heterocyclic alkyl, substituted or unsubstituted C6-25 aryl, substituted or unsubstituted 5-25 heteroaryl, _-ORa , _-CORa , _-COORa , _-OCORa , _-NRaRb , _-CONRaRb , _-SO2Ra , _{-SO2NRaR , and} -C= _N - _{ORa .}

_Ra and _Rb are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted C6-25 aryl, and substituted or unsubstituted 5-25 heteroaryl.

_R3 and _R4 are independently selected from hydrogen, substituted or unsubstituted C1-12 alkyl, -OR _x , and one of _R3 and _R4 is -OR _x ;

R _x is selected from substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted C6-25 aryl, and substituted or unsubstituted 5-25 heteroaryl.

L is selected from substituted or unsubstituted C1-12 alkylene groups;

_R11 , _R12 , and _R13 are independently selected from substituted or unsubstituted C1-12 alkyl groups, substituted or unsubstituted C3-25 cycloalkyl groups, substituted or unsubstituted C6-25 aryl groups, substituted or unsubstituted 5-25 heteroaryl groups, or _R11 and _R12 are linked together to form a ring.

^X- is a pharmaceutically acceptable anion.

In a preferred embodiment, _R1 is selected from hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, _-SO2 C1-6 alkyl, -COC1-6 alkyl, and -COOC1-6 alkyl.

Preferably, _R1 is selected from _hydrogen , _-SO2CH3 , _-SO2C2H5 , _{-SO2C3H7 , -SO2C4H9} , _-COOCH3 , _{-COOC2H5 , -COOC3H7 , and -COOC4H9 . Wherein} , _{-C4H9 includes} -C _{( CH3 ) 3 .}

The preferred choice is _R1 , which is selected from hydrogen and -COOC( _CH3 ) ₃ .

In a preferred embodiment, _R2 , _R5 , and _R6 are independently selected from hydrogen, C1-6 alkyl, and halogenated C1-6 alkyl.

Preferably, _R2 , _R5 , and _R6 are independently selected from hydrogen.

In a preferred embodiment, R _x is selected from C1-6 alkyl, C1-6 alkyl substituted with one or more of the following groups: halogen, hydroxyl, cyano, nitro, carboxyl, amino, -OC1-6 alkyl, -OC1-6 alkylene-OH, -OC1-6 alkylene-OC1-6 alkyl, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl, -NHC1-6 alkyl, -NH(C1-6 alkyl) ₂ , -SO2 _C1-6 alkyl, -OC1-6 alkyl, -OC1-6 alkylene-OH, -OC1-6 alkylene-OC1-6 alkyl, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl, -NHC1-6 alkyl, -NH(C1-6 alkyl) ₂ , _-SO2 C1-6 alkyl, where the C1-6 alkyl is optionally substituted with a halogen.

Preferably, _Rx is selected from C1-6 alkyl, halogenated C1-6 alkyl, -( _CH2 ) _nCOOC1-6 alkyl, -( _CH2 ) _nOCOC1-6 alkyl, and n is selected from 1, 2, 3, 4, 5 or 6.

More preferably, _Rx is selected from _-CH3 , _-C2H5 , _-C3H7 , -C4H9, _-C5H11 , _-C6H13 , _-CF3 , _-CF2CH3 , -CH2CF3, _-C2F5 , _{- (} CH2 ₎ nCOOCH3, - _{( CH2} ) _nCOOC2H5 , -( _{CH2 ) nCOOC3H7} , -( _{CH2 ) nOCOCH3} , -( _{CH2 ) nOCOC2H5} , -( _{CH2 ) nOCOC3H7} , _{and n} is selected _{from 1 , 2 , 3 , 4 , 5} or _{6 .}

Most preferably, _Rx is selected _{from -CH3} , _-C2H5 , _{-CF3 , and -CH2COOC2H5} .

In a preferred embodiment, _R3 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, _{and R4} is selected from -OR _x , or _R4 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, and _R3 is selected from -OR _x .

In a preferred embodiment, L is selected from substituted or unsubstituted C1-6 alkylene groups.

Preferably, L is selected from -( _CRcRd ) _m- , _Rc and _Rd are independently selected from halogens and C1-4 alkyl groups, and m is selected from 1, 2, 3 _, 4, 5 or 6.

Preferably, L is selected from -( _CH2 ) _m- , and m is selected from 1, 2, 3, 4, 5 or 6.

In a preferred embodiment, _R11 , _R12 , and _R13 are independently selected from substituted or unsubstituted C1-6 alkyl groups, or two of _R11 , _R12 , and _R13 are interconnected to form a ring.

In one embodiment, _R11 , _R12 , and _R13 are independently selected from C1-6 alkyl and halogenated C1-C6 alkyl.

Preferably _{, R11} , _R12 , and _R13 are independently selected _{from -CH3 , -C2H5} , _-C3H7 , _-C4H9 , _-C5H11 , _{-C6H13 , -CF3 , -CF2CH3 , -CH2CF3} , _{and -C2F5 .}

More preferably, _R11 , _R12 , and _R13 are independently _selected from _-CH3 , _-C2H5 , _{-C3H7 , and -C4H9} .

More preferably, _R11 and _R12 are selected from _-CH3 , _{and R13} is selected from _-CH3 , _-C2H5 , _{-C3H7 , and -C4H9} .

In one embodiment, _R11 and _R12 are interconnected to form a ring, and _R13 is selected from C1-6 alkyl or halogenated C1-C6 alkyl.

Preferred, Selected from R ₁₃ is selected from -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₅ H ₁₁ , -C ₆ H ₁₃ , -CF ₃ , -CF ₂ CH ₃ , -CH ₂ CF ₃ , -C ₂ F ₅ .

In a preferred embodiment, X is selected from chlorine, bromine, iodine, phosphate, sulfate, hydrobromide, succinate, citrate, acetate, fumarate, maleate, tartrate, methanesulfonate, malate, fumarate, toluenesulfonate, lactate, oxalate, glutamate, and fatty acid radicals.

Preferably, X is selected from chlorine.

In a preferred embodiment, the compound of formula I is selected from:

X is selected from chlorine, bromine, iodine, succinate, and fumarate.

Preferably, the compound of formula I is selected from:

In another aspect of the invention, the invention provides a pharmaceutical composition comprising a compound of Formula I, a pharmaceutically acceptable salt thereof, a hydrate, a solvate, a prodrug, a stereoisomer, or a tautomer thereof.

In a preferred embodiment, the pharmaceutical composition comprises pharmaceutically acceptable excipients.

In another aspect of the invention, the invention provides the use of a compound of formula I, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, or a pharmaceutical composition of the invention in the preparation of analgesic or antidepressant medicaments.

In another aspect of the invention, the invention provides a method of analgesia or antidepressant, comprising providing to an individual in need a compound of Formula I of the invention, a pharmaceutically acceptable salt thereof, a hydrate, a solvate, a prodrug, a stereoisomer or tautomer thereof, or a pharmaceutical composition of the invention.

In a preferred embodiment, the drug or method is used to treat various acute and chronic pains and to treat depression.

In a preferred embodiment, the drug or method is used for treating neuralgia, postoperative pain, joint pain, herpes pain, headache, bone pain, and cancer pain.

Preferably, the neuralgia includes neuralgia present in cancer, neuralgia caused by chemotherapy drugs, neuralgia caused by viral infections (e.g., herpes zoster), neuralgia caused by diabetic complications, and trigeminal neuralgia.

In a preferred embodiment, the drug or method is used to treat pain-depression comorbidity. Pain-depression comorbidity includes syndromes of emotional distress such as pain-induced depression or chronic pain symptoms induced by depression.

In this invention, the pharmaceutical composition or the dosage form of the drug is a conventional pharmaceutical preparation, including but not limited to tablets, powders, solutions, sprays, drops, capsules, pills, granules, powders, and injectable preparations.

In this invention, the pharmaceutical composition or drug can be administered orally, by injection, by nasal administration, by inhalation, by transdermal administration, by topical administration, by intestinal administration, etc.

In another aspect of the present invention, a method for preparing a compound of formula I is provided, the method comprising the following steps:

This transforms compound II into compound I.

In a preferred embodiment, the method comprises: reacting a compound of formula II with a methylating agent in an organic solvent to obtain a compound of formula I in which _R13 is methyl.

Preferably, the methylating agent is selected from iodomethane, bromomethane, chloromethane, methyl trifluoromethanesulfonate, and dimethyl sulfate; more preferably from iodomethane and bromomethane; and more preferably from iodomethane. The molar ratio of the methylating agent to the compound of formula II is 1-30:1, preferably 5-25:1, and more preferably 10-15:1.

Preferably, the organic solvent is selected from one or more of C1-6 alcohols, C1-6 esters, C1-6 ketones, C1-6 ethers or cyclic ethers, C1-6 alkyl nitriles, DMF or DMSO, and more preferably from one or more of methanol, ethanol, ethyl acetate, acetone, methyl tert-butyl ether, diethyl ether, acetonitrile or tetrahydrofuran, and more preferably from methanol or ethanol.

Preferably, the reaction temperature is 0-60℃, more preferably 10-50℃, and even more preferably 20-40℃.

Preferably, the reaction is carried out under light-protected conditions.

Preferably, silver chloride is added after the compound of formula II has completely reacted with the methylating agent to perform a substitution, thereby obtaining the compound of formula I where X is chlorine. Optionally, this step is carried out under light-protected conditions.

In a preferred embodiment, the method further includes dissolving a compound of formula I, where X is chlorine, in an organic solvent, adding silver oxide and silver nitrate, removing the precipitate, and then adding acid HX to obtain a compound of formula I, where X is a pharmaceutically acceptable anion other than chlorine (such as bromine, iodine, phosphate, sulfate, hydrobromide, succinate, citrate, acetate, fumarate, maleate, tartrate, methanesulfonate, malate, fumarate, toluenesulfonate, lactate, oxalate, glutamate, or fatty acid anion).

The invention is described in more detail below to aid in understanding it.

Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. Where specific techniques or conditions are not specified in the embodiments, they should be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions.

Example 1: 2-(5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride (ID: 1)

Synthesis of 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine

Weigh 1.0303 g (5.90 mmol) of 4-methoxyphenylhydrazine hydrochloride into an appropriate amount of water and stir at room temperature for 10 min to ensure complete dissolution. Slowly add 400 μL of concentrated sulfuric acid to the system. Dissolve 1.516 mL (7.08 mmol) of 4-dimethylaminobutyraldehyde diethanolate in acetonitrile and add the mixed solution dropwise to a flask. React under _N2 conditions for 20 h. Monitor the starting material using TLC during the reaction. After the starting material has reacted completely, add excess 10% NaOH solution to the reaction system, extract the organic phase with ethyl acetate, and dry with anhydrous sodium sulfate. Distill under reduced pressure, mix with silica gel, and separate by column chromatography using dichloromethane:methanol = 30:1 to obtain 1.1334 g of compound 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethyl-1-amine as a brownish-red oil, with a yield of 88%.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.70-10.66(m,1H),7.26(d,J＝8.7Hz,1H),7.11(d,J＝2.4Hz,1H),7.01(d,J＝2.5Hz,1H),6.74 (dd,J＝8.7,2.4Hz,1H),3.77(s,3H),2.85-2.78(m,2H),2.55(dd,J＝9.0,6.8Hz,2H),2.25(s,6H).

Synthesis of 2-(5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride

Weigh 592.5 mg (2.714 mmol) of 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine into an appropriate amount of methanol. Add 1.690 mL (27.141 mmol) of iodomethane to the system and mix thoroughly. Incubate in the dark for 48 h. After the reaction of the starting material is complete as monitored by TLC, evaporate the solution to dryness, add excess AgCl and methanol, and incubate in the dark for 24 h. Filter out impurities. Distill under reduced pressure, mix with silica gel, and separate by column chromatography using dichloromethane:methanol = 10:1 as the eluent to obtain 402.92 mg of 2-(5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride as a pale yellow solid, with a yield of 55%.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.98(d,J＝2.6Hz,1H),7.27(d,J＝8.7Hz,1H),7.22(d,J＝2.4Hz,1H),7.11(d,J＝2.4Hz,1H) ,6.76(dd,J=8.7,2.4Hz,1H),3.80(s,3H),3.62-3.57(m,2H),3.21(s,9H),3.16-3.11(m,2H).

Example 2: 2-(5-ethoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride (ID: 2)

Synthesis of 2-(5-ethoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine

3-(2-(dimethylamino)ethyl)-1H-indole-5-ol (157.3 mg, 0.77 mmol) and benzyltrimethylammonium chloride (50 mg, 0.27 mmol) were dissolved in 10 mL of ethanol, and 5 mL of 30% sodium hydroxide aqueous solution was added to the system. The mixture was thoroughly mixed and reacted at room temperature for 10 min. Diethyl sulfate (300 μl, 2.28 mmol) was added, and the reaction was carried out at room temperature for 10 h under a nitrogen atmosphere. After the reaction of the starting materials was completed by TLC, the reaction system was diluted with water to 50 mL, and the reaction solution was extracted with dichloromethane. The organic layer was collected, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The mixture was then distilled under reduced pressure, mixed with silica gel, and separated by column chromatography with dichloromethane:methanol = 15:1 as the eluent to give 140.9 mg of compound 2-(5-ethoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine as a pale yellow oil with a yield of 79%.

¹ H NMR(500MHz,Chloroform-d)δ9.28(s,1H),7.29(d,J＝8.9Hz,1H),7.00(d,J＝2.4Hz,1H),6.90(s,1H) ,6.79(dd,J＝8.8,2.3Hz,1H),4.05(q,J＝7.0Hz,2H),3.01(s,4H),2.65(s,6H),1.40(t,J＝6.9Hz,3H).

Synthesis of 2-(5-ethoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride

2-(5-ethoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine (132.3 mg, 0.57 mmol) was dissolved in 20 mL of methanol, and 355 μl (5.7 mmol) of iodomethane was added. The mixture was reacted in the dark for 48 h. Then, 20 mL of methanol and excess AgCl were added, and the mixture was reacted in the dark for 24 h. After the reaction was complete, the mixture was filtered, and the filtrate was collected. The solution was distilled under reduced pressure, mixed with neutral alumina, and separated by column chromatography using dichloromethane:methanol as the eluent (5:1). 96.4 mg of 2-(5-ethoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride was obtained as a brownish-brown oil, with a yield of 62%.

¹ H NMR (500MHz, DMSO-d ₆ )δ9.06(d,J＝7.0Hz,1H),7.29(d,J＝7.3Hz,1H),7.23(d,J＝7.1Hz,1H),6.99(d,J＝2.9Hz,1H),6.85(dd,J＝7.3,2. 7Hz, 1H), 4.03 (q, J = 6.7Hz, 2H), 3.67 (t, J = 8.3Hz, 2H), 3.29 (t, J = 8.4Hz, 2H), 3.23 (s, 9H), 1.43 (t, J = 6.6Hz, 3H).

Example 3: N,N,N-Trimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethane-1-ammonium chloride (ID: 3)

Synthesis of N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethane-1-amine

Weigh 2.0 g (8.74 mmol) of 4-trifluoromethoxyphenylhydrazine hydrochloride into an appropriate amount of water and stir at room temperature for 10 min to ensure complete dissolution. Slowly add 600 μl of concentrated sulfuric acid to the system. Dissolve 2.81 ml (13.1 mmol) of 4-dimethylaminobutyraldehyde diethanolate in acetonitrile and add the mixed solution dropwise to a flask. React under _N2 conditions for 20 h. Monitor the starting material using TLC during the reaction. After the starting material has reacted completely, add excess 10% NaOH solution to the reaction system, extract the organic phase with ethyl acetate, and dry with anhydrous sodium sulfate. Distill under reduced pressure, mix with silica gel, and separate by column chromatography using dichloromethane:methanol = 20:1 to obtain 1.38 g of N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethane-1-amine as a brownish-red oil, with a yield of 58%.

¹ H NMR(500MHz,Chloroform-d)δ9.06(d,J＝7.0Hz,1H),7.30-7.23(m,2H),7.10(dd,J＝6.5 ,2.8Hz,1H),7.04(d,J=7.1Hz,1H),2.98-2.94(m,2H),2.94-2.90(m,2H),2.39(s,6H).

Synthesis of N,N,N-trimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethane-1-ammonium chloride

Weigh 544.5 mg (2.0 mmol) of N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethane-1-amine into an appropriate amount of methanol. Add 1.245 ml (20.0 mmol) of iodomethane to the system and mix thoroughly. Incubate in the dark for 48 h. After the reaction of the starting material is complete as monitored by TLC, evaporate the solution to dryness, add AgCl and methanol, and incubate in the dark for 24 h. Filter out impurities. Distill under reduced pressure, mix with silica gel, and separate by column chromatography using dichloromethane:methanol = 10:1 as the eluent to obtain 471.4 mg of N,N,N-trimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethane-1-ammonium chloride, as a yellow-brown solid, with a yield of 73%.

¹ H NMR(500MHz,Chloroform-d)δ9.06(d,J＝7.0Hz,1H),7.28(d,J＝6.4Hz,1H),7.25(d,J＝2.7Hz,1H),7.23( d,J＝7.0Hz,1H),7.10(dd,J＝6.5,2.8Hz,1H),3.67(t,J＝8.3Hz,2H),3.29(t,J＝8.4Hz,2H),3.23(s,9H).

Example 4: 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride (ID: 4)

Synthesis of 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine

Weigh 220.0 mg (1.0 mmol) of 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine into a round-bottom flask, add 20 mL of dichloromethane, and mix thoroughly. Add triethylamine (167 μl, 1.2 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) to the system and react at room temperature for 10 min. Then add an appropriate amount of di-tert-butyl dicarbonate dissolved in dichloromethane (575 μl, 2.5 mmol) and react at room temperature for 19 h. Distill under reduced pressure, mix with silica gel, and separate by column chromatography with dichloromethane:methanol = 40:1 as the eluent to give 206.82 mg of 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine as a deep yellow oil, with a yield of 65%.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.90(d,J＝9.0Hz,1H),7.44(s,1H),7.09(d,J＝2.5Hz,1H),6.92(dd,J＝9.0,2.5Hz,1H ),3.81(s,3H),2.77(t,J＝7.5Hz,2H),2.53(t,J＝7.5Hz,2H),2.22(s,6H),1.61(s,9H).

Synthesis of 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride

Weigh 796.0 mg (2.5 mmol) of 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-3-yl)-N,N,dimethylethane-1-amine into an appropriate amount of methanol. Add 623 μl (10.0 mmol) of iodomethane to the system and mix thoroughly. React in the dark for 48 h. After the reaction of the starting material is complete as monitored by TLC, evaporate the system solution to dryness, add excess AgCl and methanol, and react in the dark for 24 h. Filter out impurities. Distill under reduced pressure, mix with silica gel, and separate by column chromatography using dichloromethane:methanol = 10:1 as the eluent to give 424.9 mg of compound 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride, as a yellow-green solid, with a yield of 46%.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.90(d,J＝9.0Hz,1H),7.44(s,1H),7.09(d,J＝2.5Hz,1H),6.92(dd,J＝9.0,2.5Hz,1H ),3.81(s,3H),2.77(t,J＝7.5Hz,2H),2.53(t,J＝7.5Hz,2H),2.22(s,9H),1.61(s,9H).

Example 5: 2-(5-(2-ethoxy-2-oxoethoxy)-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride (ID: 5)

Synthesis of 2-(5-(2-ethoxy-2-oxoethoxy)-1H-indol-3-yl)-N,N-dimethylethane-1-amine

3-(2-(dimethylamino)ethyl)-1H-indol-5-ol (53.0 mg, 0.26 mmol) was dissolved in 20 mL of acetone solution and mixed thoroughly. Potassium carbonate (75.4 mg, 0.55 mmol) and ethyl bromoacetate solution (45.4 μl, 0.43 mmol) were added, and the mixture was reacted at room temperature for 60 h under a nitrogen atmosphere. After the reaction was complete as monitored by TLC, the filtrate was collected, distilled under reduced pressure, mixed with silica gel, and separated by column chromatography using dichloromethane:methanol = 20:1 as the eluent. This yielded 24.7 mg of compound 2-(5-(2-ethoxy-2-oxoethoxy)-1H-indol-3-yl)-N,N-dimethylethane-1-amine, a brown oily substance, with a yield of 33%.

¹ H NMR (500MHz, DMSO-d ₆ )δ9.06(d,J＝7.0Hz,1H),7.29(d,J＝7.4Hz,1H),7.07-7.02(m,2H),6.92(dd,J＝7.3,2.7Hz,1H ),4.69(s,1H),4.25(q,J＝6.6Hz,2H),2.99-2.89(m,4H),2.39(s,6H),1.27(t,J＝6.6Hz,3H).

Synthesis of 2-(5-(2-ethoxy-2-oxoethoxy)-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride

49.4 mg (0.17 mmol) of 2-(5-(2-ethoxy-2-oxoethoxy)-1H-indol-3-yl)-N,N,dimethylethane-1-amine was dissolved in 10 mL of methanol, and 106 μl (1.7 mmol) of iodomethane was added. The mixture was reacted in the dark for 48 h. Then, 10 mL of methanol and excess AgCl were added, and the mixture was reacted in the dark for 24 h. After the reaction was complete, the mixture was filtered, and the filtrate was collected. The solution was distilled under reduced pressure, mixed with neutral alumina, and separated by column chromatography using dichloromethane:methanol as the eluent (4:1). The result was 27.2 mg of 2-(5-(2-ethoxy-2-oxoethoxy)-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium chloride, a brown oily substance with a yield of 47%.

¹ H NMR (500MHz, DMSO-d ₆ )δ9.06(d,J＝7.0Hz,1H),7.29(d,J＝7.4Hz,1H),7.23(d,J＝7.1Hz,1H),7.08(d,J＝2.6Hz,1H),6.92(dd,J＝7.3,2.7Hz,1H ),4.69(s,2H),4.25(q,J＝6.6Hz,2H),3.67(t,J＝8.3Hz,2H),3.29(t,J＝8.4Hz,2H),3.23(s,9H),1.27(t,J＝6.6Hz,3H).

Example 6: 2-(5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium fumarate

Compound 1 (61.5 mg, 0.23 mmol) was dissolved in dilute methanol solution, and silver oxide (79.2 mg, 0.34 mmol) was added and stirred for 10-15 min. After centrifugation, a small amount of the supernatant was added to silver nitrate solution. If no precipitate was formed, the reaction was complete. After centrifugation, the precipitate was discarded, and the supernatant was evaporated to dryness. The remaining product was dissolved in methanol, and fumaric acid (53.4 mg, 0.46 mmol) was added. The mixture was stirred thoroughly, evaporated to dryness, washed several times with anhydrous ethanol, and evaporated to dryness to obtain 2-(5-methoxy-1H-indol-3-yl)-N,N,N-trimethylethane-1-ammonium fumarate.

Salts of compounds 1-5 can be prepared in various forms using the same method.

Example 7: Evaluation of the anti-neuralgia activity of toad venom tryptamine derivatives

Neuropathic pain is a common pathological component in various clinical pain responses, and neuropathic pain is involved in the occurrence of pain in many cancers. This example evaluates the antineuralgic activity of several bufotenine derivatives.

1. Experimental Methods

Paclitaxel-induced neuralgia in rats: Adult male SD rats, SPF grade, weighing 180–220 g, license number: SCXK(浙)2019-0002. Rats were randomly divided into a blank control group, a paclitaxel model group, control group 1 and control group 2, and treatment groups with different toad tryptamine derivatives. Before the animal experiment, all groups were acclimatized for one week under the following conditions: temperature 23±3℃; relative humidity 55±5%, with free access to food and water. Paclitaxel was dissolved in a mixture of polypropylene castor oil and ethanol at a volume ratio of [volume ratio missing], and then diluted with physiological saline to the final concentration at a volume ratio of [volume ratio missing]. Except for the blank control group, the paclitaxel solution in the other groups was injected intraperitoneally at 9–10 am on days 1, 3, and 5 of the experiment to induce neuralgia, with a cumulative total dose of 8 mg/kg. Physiological saline and the drug were administered intraperitoneally daily for 3 consecutive days from day 4 to 6. The blank control group and the model group were given physiological saline. Control group 1 was given bufotenine (10 mg/kg at a constant dose), control group 2 was given bufotenine quaternary ammonium salt 2-(5-hydroxy-1H-indol-3-yl)-N,N,N-trimethylethyl-1-ammonium chloride (10 mg/kg at a constant dose), and the other groups were given five bufotenine analogues (10 mg/kg at a constant dose). Changes in thermal pain threshold and mechanical stimulation paw withdrawal pain threshold were measured 1 hour after the last administration on day 6.

Determination of the paw mechanical withdrawal threshold (PMWT). The paw withdrawal threshold of the right hind paw in rats was determined using an "up-and-down" method with Von Frey fibers: In a quiet environment, rats were placed in a glass beaker with a metal mesh bottom and allowed to acclimatize for 3–5 minutes. During the test, different g values of Von Frey fibers were used sequentially to vertically stimulate the middle of the paw pad of the rat's right hind paw, causing the fibers to bend into an "S" shape for approximately 3–5 seconds. If escape behaviors such as rapid paw lifting or licking occurred, it was considered a positive response, and the corresponding g value on the fiber was recorded as the PMWT value. Each stimulation was spaced at least 30 seconds apart until a fiber that elicited a 50% paw lifting response was found. The paw withdrawal threshold was measured on day 0 and after the last dose on day 6.

The thermal pain threshold was measured in a hot plate analgesia device at 48±0.1℃. The thermal pain threshold of each rat was measured twice in parallel with an interval of ≥5 min. The appearance of jumping, licking paws or avoiding behavior in the animals was used as a positive reaction indicator. The thermal pain threshold was measured on day 0 and day 6 after the last administration.

All experimental data were analyzed and processed using Excel software. Measurement data were presented in the format of "...". The results were statistically analyzed using the Student's T-test, with P < 0.05 indicating a significant difference and P < 0.01 indicating a highly significant difference. The inhibition rate of analgesic activity was calculated as: [(Pain threshold _{model group 0d} - Pain threshold _{model group 6d} ) - (Pain threshold _{test drug group 0d} - Pain threshold _{test drug group 6d} )] ÷ (Pain threshold _{model group 0d} - Pain threshold _{model group 6d} ) × 100%.

2. Experimental Results: Inhibitory Effect of Toad Tryptamine Derivatives on Neuralgia in Rats

This embodiment selected paclitaxel, a commonly used chemotherapy drug, to induce neuropathic pain in rats. During the experiment, there were no abnormalities in the diet, mental state, hair luster, or secretions of rats in each group before and after drug administration and modeling. Compared with the control group, the pain threshold of the paclitaxel neuropathic pain model group decreased significantly on the 4th day after modeling, and the model could maintain a neuropathic pain response for several days. To facilitate drug screening, pain threshold evaluation was uniformly performed on the 6th day after modeling. The results are shown in Tables 1-2 below.

The mechanical pain threshold in the model group was significantly lower than that in the normal group (P<0.01). However, the thermal pain threshold in each treatment group was significantly prolonged to varying degrees. This indicates that bufotenoids can increase the mechanical pain threshold induced by paclitaxel chemotherapy and inhibit the occurrence of neuromechanical pain. The five bufotenoid analogues have better antineuralgia activity than natural bufotenoids and their quaternary ammonium salts, in the following order: compound 5 > compound 1 ≈ compound 3 > compound 4 ≈ compound 2 > bufotenoid quaternary ammonium salt > bufotenoids.

Table 2 shows that bufotenoids can increase the thermal pain threshold induced by paclitaxel chemotherapy and inhibit the occurrence of central pain. Furthermore, the thermal pain threshold increased significantly to varying degrees in all treatment groups, in the following order: compound 5 > compound 1 ≈ compound 3 ≈ compound 4 > compound 2 > bufotenoid quaternary ammonium salt > bufotenoid.

Table 1. Effects of toad tryptamine derivatives on the mechanical pain threshold in rats with neuralgia (n = 6-8)

Note:

^# P<0.05, the model group is significantly different from the normal group; ^## P<0.01, the model group is extremely significantly different from the normal group.

*P<0.05, indicating a significant difference compared to the paclitaxel pain model group; **P<0.01, indicating a highly significant difference compared to the paclitaxel pain model group.

^△ P < 0.05, indicating a significant difference compared to control group 2; ^△△ P < 0.01, indicating a highly significant difference compared to control group 2.

Table 2. Effects of bufotenine derivatives on the thermal pain threshold in rats with neuralgia (n = 6-8)

Note:

^# P<0.05, the model group is significantly different from the normal group; ^## P<0.01, the model group is extremely significantly different from the normal group.

*P<0.05, indicating a significant difference compared to the paclitaxel pain model group; **P<0.01, indicating a highly significant difference compared to the paclitaxel pain model group.

^△ P < 0.05, indicating a significant difference compared to control group 2; ^△△ P < 0.01, indicating a highly significant difference compared to control group 2.

Example 8: Evaluation of the antidepressant activity of toad venom tryptamine derivatives

1. Experimental Methods

Healthy adult ICR mice, half male and half female, were randomly divided into groups according to body weight: a blank control group, a model group (corticosterone), control group 1, control group 2, and treatment groups for various bufotenine derivatives. Mice outside the blank control group received subcutaneous injections of 40 mg/kg corticosterone daily, while the blank control group received subcutaneous injections of saline for 21 consecutive days to establish a depression model. Control group 1 received bufotenine (10 mg/kg at a constant dose), control group 2 received bufotenine quaternary ammonium salt 2-(5-hydroxy-1H-indol-3-yl)-N,N,N-trimethylethyl-1-ammonium chloride (10 mg/kg at a constant dose), and the other groups received five different bufotenine analogues (10 mg/kg at a constant dose) for 3 consecutive days.

Following the method established by Lucien Steru, mice were placed in a black, enclosed tail-suspension box half an hour after drug treatment. The top center was connected to a frame with a rope, and medical tape was attached to the tail of the mouse 2 cm from the end. The tape was then clamped, so that the mouse was suspended upside down in the black, enclosed tail-suspension box. The cumulative time the mouse remained motionless in the tail-suspension box was recorded within the first 6 minutes and then for the last 4 minutes. The criterion for motionlessness was that the mouse stopped struggling and its body was in a static upside-down position.

Following the method established by Porsolt RD et al., mice were placed in a swimming pool with a water depth of 10 cm half an hour after drug treatment. The cumulative time the mice remained still during swimming was recorded within 6 minutes and 4 minutes after that. The criterion for determining stillness was that the mice stopped struggling and their bodies were floating.

All experimental data were analyzed and processed using Excel software. Measurement data were presented in the format of "...". The results were statistically analyzed using the Student's T-test, with P < 0.05 indicating a significant difference and P < 0.01 indicating a highly significant difference. The results are shown in Tables 3-4 below. The inhibition rate of antidepressant activity = (immobile time _{model group} - immobile time _{test drug group} ) ÷ (immobile time _{model group} - immobile time _{blank group} ) × 100%

2. Experimental Results

The cumulative immobility time of the suspended tail in the model group was significantly prolonged compared to the normal group (P<0.01). However, the immobility time of the suspended tail decreased to varying degrees in all drug-treated groups. This indicates that bufotenoids can significantly improve depressive-like behavior in model mice. Five bufotenoid analogues exhibited superior antidepressant activity compared to natural bufotenoid and its quaternary ammonium salt, in the following order: compound 3 > compound 1 > compound 4 > compound 5 ≈ compound 2 > bufotenoid quaternary ammonium salt > bufotenoid.

The forced swimming immobility time in the model group was significantly prolonged compared to the normal group (P<0.01). However, the forced swimming immobility time decreased to varying degrees in all drug-treated groups. This indicates that bufotenoids can improve depressive-like behavior in this model mouse. Five bufotenoid analogues exhibited superior antidepressant activity compared to natural bufotenoids and their quaternary ammonium salts, in the following order: compound 3 > compound 1 > compound 4 > compound 5 > compound 2 > bufotenoid quaternary ammonium salt > bufotenoids.

Table 3. Effects of toad tryptamine derivatives on tail suspension immobility time in depressed mice (n = 8-10)

Note: *P<0.05 indicates a significant difference compared to the model group; **P<0.01 indicates a highly significant difference compared to the model group.

^## P<0.01, indicating a highly significant difference between the model group and the normal group.

^△ P<0.05, which is significantly different from control group 2; ^△△ P<0.01, which is extremely significantly different from control group 2.

Table 4. Effects of toad tryptamine derivatives on immobility time during swimming in depressed mice (n = 8-10)

Note: *P<0.05 indicates a significant difference compared to the model group; **P<0.01 indicates a highly significant difference compared to the model group; ^## P<0.01 indicates a highly significant difference between the model group and the normal group.

^△ P<0.05, which is significantly different from control group 2; ^△△ P<0.01, which is extremely significantly different from control group 2.

The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims (10)

A compound of formula I, and its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer:
Wherein, _R1 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, _-SO2Ra , _-CORa , _{-COORa ; R2} , _R5 , and _R6 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C2-12 alkenyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted 3-25 heterocyclic alkyl, substituted or unsubstituted C6-25 aryl, substituted or unsubstituted 5-25 heteroaryl, _-ORa , _-CORa , _-COORa , _-OCORa , _-NRaRb , _-CONRaRb , _-SO2Ra , _{-SO2NRaR , and} -C= _N - _{ORa . Ra} and _Rb are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted C6-25 aryl, and substituted or unsubstituted 5-25 heteroaryl. _R3 and _R4 are independently selected from hydrogen, substituted or unsubstituted C1-12 alkyl, -OR _x , and one of _R3 and _R4 is -OR _x ; R _x is selected from substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C3-25 cycloalkyl, substituted or unsubstituted C6-25 aryl, and substituted or unsubstituted 5-25 heteroaryl. L is selected from substituted or unsubstituted C1-12 alkylene groups; _R11 , _R12 , and _R13 are independently selected from substituted or unsubstituted C1-12 alkyl groups, substituted or unsubstituted C3-25 cycloalkyl groups, substituted or unsubstituted C6-25 aryl groups, substituted or unsubstituted 5-25 heteroaryl groups, or _R11 and _R12 are linked together to form a ring. ^X- is a pharmaceutically acceptable anion. The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is characterized in that _R1 is selected from hydrogen, C1-6 alkyl, _halo- C1-6 alkyl, -SO2C1-6 alkyl, -COC1-6 alkyl, and -COOC1-6 alkyl; _preferably , _R1 is selected from _hydrogen , _-SO2CH3 , _-SO2C2H5 , _-SO2C3H7 , _-SO2C4H9 , _{-COOCH3 , -COOC2H5 , -COOC3H7} , _{and -COOC4H9} . _Wherein , _-C4H9 includes -C( _{CH3 ) 3 ;} more preferably _{, R1 is} selected from hydrogen and -COOC( _CH3 ) _{3 .} The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is characterized in that R _x is selected from C1-6 alkyl, C1-6 alkyl substituted with one or more of the following groups: halogen, hydroxyl, cyano, nitro, carboxyl, amino, -OC1-6 alkyl, -OC1-6 alkylene-OH, -OC1-6 alkylene-OC1-6 alkyl, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl, -NHC1-6 alkyl, -NH(C1-6 alkyl) ₂ , _-SO2 C1-6 alkyl, and -OC1-6 alkyl, -OC1-6 alkyl-OH, -OC1-6 alkylene-OC1-6 alkyl, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl, -NHC1-6 alkyl, -NH(C1-6 alkyl) ₂ , _-SO2 The C1-6 alkyl group is optionally substituted with a halogen; preferably, _Rx is selected from C1-6 alkyl, halogenated C1-6 alkyl, -( _CH2 ) _nCOOC1-6 alkyl, -( _CH2 ) _nOCOC1-6 alkyl, and n is selected from 1, 2, ₃ , 4, ₅ , or 6; more preferably, _Rx is selected from _-CH3 , _-C2H5 , _-C3H7 , _{-C4H9 , -C5H11} , _-C6H13 , _-CF3 , _-CF2CH3 , -CH2CF3, _-C2F5 , _{- ( CH2 ) nCOOCH3} , -( _{CH2 ) nCOOC2H5} , -( _CH2 ) _nCOOC3H7 , -( _CH2 ) _nOCOCH3 , _- ( _CH2 ) _nCOOC3H7 , -( _CH2 ) _nOCOCH3 , -(CH2 _{) nCOOC1-6 alkyl ...} -( _CH2 ) _nOCOC2H5 , -( _CH2 ) _nOCOC3H7 , _where n is selected from 1 _{, 2 ,} 3 _{, 4} , 5 or 6; most preferably, _Rx is selected from _-CH3 , _-C2H5 , _-CF3 , _-CH2COOC2H5 . The compound according to claim 1 or 3, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer, is characterized in that _R3 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, and _R4 is selected from -OR _x , or _R4 is selected from hydrogen, substituted or unsubstituted C1-12 alkyl, and _R3 is selected from -OR _x . The compound according to claim 1, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer, is characterized in that L is selected from substituted or unsubstituted C1-6 alkylene groups; preferably, L is selected from -( _CRcRd ) _m- , where _Rc and _Rd are independently selected from halogens or C1-4 alkyl groups, and m is selected from 1 _, 2, 3, 4, 5 or 6; more preferably, L is selected from -( _CH2 ) _m- , where m is selected from 1, 2, 3, 4, 5 or 6; _R11 , _R12 , and _R13 are independently selected from substituted or unsubstituted C1-6 alkyl groups, or two of _R11 , _R12 , and _R13 are interconnected to form a ring; preferably, _R11 , _R12 , and _R13 are independently selected from C1-6 alkyl groups and halogenated C1-C6 alkyl groups; more preferably, _R11 , _R12 , _{and R13} are independently selected from _{-CH3 , -C2H5} , _-C3H7 , _-C4H9 , _-C5H11 , _-C6H13 , _{-CF3 , -CF2CH3 , -CH2CF3 , and -C2F5} ; _{or ,} Alternatively, _R11 and _R12 may be interconnected to form a ring, _{and R13} may be selected from C1-6 alkyl or halogenated C1-C6 alkyl; preferably, Selected from R ₁₃ is selected from -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₅ H ₁₁ , -C ₆ H ₁₃ , -CF ₃ , -CF ₂ CH ₃ , -CH ₂ CF ₃ , -C ₂ F ₅ . According to claim 1, the compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is characterized in that the compound of formula I is selected from:
X is selected from chloride, bromine, iodine, succinate, and fumarate. Preferably, the compound of formula I is selected from:
A pharmaceutical composition comprising a compound of Formula I as described in any one of claims 1-6, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The use of the compound of formula I according to any one of claims 1-6, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer, or the pharmaceutical composition according to claim 7 in the preparation of analgesic or antidepressant medicaments. According to claim 8, the drug or method is used to treat various acute and chronic pains; preferably, the drug is used to treat neuralgia, postoperative pain, joint pain, herpes pain, headache, bone pain, and cancer pain; more preferably, the neuralgia includes neuralgia present in cancer, neuralgia caused by chemotherapy drugs, neuralgia caused by viral infections (e.g., herpes zoster), neuralgia caused by diabetic complications, and trigeminal neuralgia; and even more preferably, the drug is used to treat pain-depression comorbidity. The method for preparing the compound of formula I according to claim 1, the method comprising the following steps:
This converts compound II into compound I.