Dibenzyl tetrahydroisoquinoline derivative, preparation method thereof and application of dibenzyl tetrahydroisoquinoline derivative in treatment of insomnia

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a dibenzyl tetrahydroisoquinoline derivative, a preparation method thereof and application of the dibenzyl tetrahydroisoquinoline derivative in treatment of insomnia. The dibenzyl tetrahydroisoquinoline derivative is a compound as shown in a formula (I), or an optical isomer, a crystal and a pharmaceutically acceptable salt thereof, and in the formula (I), R1 is selected from hydrogen, benzoyl, substituted benzoyl, substituted acylamino, R5-CO-, C1-C6 alkoxy-C1-C6 alkyl, substituted silicon group and-R11OC (= O) OR12. The compound provided by the invention has antagonistic activity on OX1R and OX2R. In an insomnia rat model, the compound provided by the invention significantly prolongs the sleep time, increases the sleep duration of NREM and REM, and has an effect of reducing sleep-awakening conversion times superior to that of a positive drug Darlirasone.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a bisbenzyltetrahydroisoquinoline derivative, its preparation method, and its application in the treatment of insomnia. Background Technology

[0002] Sleep disorder mainly refers to insomnia symptoms such as difficulty falling asleep, frequent awakenings, and reduced sleep caused by various reasons. It is a serious discomfort. Life events that cause insomnia include: (1) Psychological factors: Anxiety, depression, tension, excitement, anger, or excessive thinking caused by various contradictions and difficulties in life and work can all cause insomnia; (2) Insomnia accompanied by neuropsychiatric diseases such as neurosis, emotional disorders, schizophrenia, etc. Patients with neurasthenia often complain of difficulty falling asleep, shallow sleep, and many dreams; insomnia in depression often manifests as early awakening or shallow sleep. EEG recordings show that the awakening time is significantly prolonged, the entire sleep period is shortened, and REM sleep is advanced; mania manifests as difficulty falling asleep or even sleeplessness all night; schizophrenia may manifest as difficulty falling asleep and shallow sleep due to the influence of delusions. (3) Physiological factors: Mental tension, hunger, fatigue, sexual excitement, and some diseases, such as arthritis, peptic ulcer, angina pectoris, migraine, asthma, and arrhythmia, can all cause difficulty falling asleep and shallow sleep; with increasing age, sleep quality can also change, leading to insomnia; those with thalamic lesions may exhibit an inverted sleep rhythm, i.e., sleeping during the day and being awake and sleepless at night. (4) Drug factors: Alcohol consumption, drug abuse, drug dependence, and withdrawal symptoms can all cause insomnia. Common drugs include stimulants, sedatives, thyroid hormones, contraceptives, and antiarrhythmic drugs. Insomnia will disappear after stopping the medication. (5) Unfavorable environment and habits: Unfavorable environment or bad habits can affect sleep for most people. For example, noise, light intensity, and temperature can all cause insomnia; overeating or hunger, strenuous exercise before bedtime, and irregular work and rest can all affect sleep.

[0003] Neferine is a dibenzylisoquinoline alkaloid extracted from the dried young leaves and radicle (i.e., the lotus seed heart) of mature seeds of the lotus plant (Nymphaeaceae family). Its molecular formula is C1. 38 H 44 N₂O₆, with the chemical formula 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenol, and a molecular weight of 624.77 g / mol, has the following chemical structure: .

[0004] Prior art (PMID: 40644919, PMID: 37111298) and Chinese applications (CN2023115460878, CN2018103603808, and CN2025108601160) disclose the chemical preparation method, orexin receptor antagonistic activity, and anti-insomnia effect of methylnephrine. However, although methylnephrine has been found to have orexin receptor antagonistic activity, its activity intensity and duration of action still need further optimization to meet the needs of clinical treatment and promote clinical application. Summary of the Invention

[0005] The purpose of this invention is to provide a bisbenzyltetrahydroisoquinoline derivative, its preparation method, and its application in the treatment of insomnia.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A bisbenzyltetrahydroisoquinoline derivative, which is a compound of formula (I), or an optical isomer, crystal, or pharmaceutically acceptable salt thereof. Equation (Ⅰ); Wherein, R1 is selected from hydrogen, benzoyl, substituted benzoyl, substituted amide, R5-CO-, C1-C6 alkoxy-C1-C6 alkyl, substituted silyl, -R11OC(=O)OR12; The substituents for substituted silicon, substituted benzoyl, and substituted amide are independently selected from halogens, C1-C6 alkyl, nitro, amino, hydroxyl, and C1-C6 alkoxy groups; The number of substituents in the benzoyl group is 1-5; The number of substituents replacing silicon is 1-3; R5 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-substituted carbonate group, C1-C6 alkyl-substituted amino carbonyl group, and piperidinylpiperidine; R2 is selected from: hydrogen, halogen, nitro; R3 and R4 are independently selected from C1-C6 alkyl, benzoyl, substituted benzoyl, -CH2CONR6R7, etc. ; R6, R7, and R8 are independently selected from C1-C6 alkyl groups, benzene rings, -R9-benzene rings, -OC (=O), and OR10, respectively. R9 and R11 are independently selected from C1-C6 alkylene groups; R10 and R12 are independently selected from C1-C6 alkyl groups; When R1 is hydrogen and R2 is hydrogen, R3 is not a C1-C6 alkyl group; When R1 is hydrogen and R3 is a C1-C6 alkyl group, R2 is not hydrogen; When R5 is methyl and R2 is hydrogen, R3 is not a C1-C6 alkyl group.

[0008] According to embodiments of the present invention, the present invention can be further optimized, and the optimized technical solution is as follows:

[0009] In one preferred embodiment, the number of substituents replacing the silicon group is three.

[0010] In one preferred embodiment, the substituents replacing the silicon group are selected from C1-C6 alkyl groups.

[0011] In one preferred embodiment, R5 is selected from C4-C6 alkyl groups.

[0012] In one preferred embodiment, the substituents replacing the benzoyl group are independently selected from fluorine, chlorine, C4-C6 alkyl, and nitro groups.

[0013] In one preferred embodiment, the substituents that replace the amide group are independently selected from C4-C6 alkyl groups.

[0014] In one preferred embodiment, R11 is a C1-C3 alkylene; R12 is a C1-C3 alkyl.

[0015] In one preferred embodiment, R1 is selected from methoxymethyl, acetyl, tert-valeryl, N,N-dicarboxyl, methoxyacetyl, benzoyl, 4-bromobenzoyl, 4-tert-butylbenzoyl, 3-chlorobenzoyl, 4-nitrobenzoyl, 2,3-difluorobenzoyl, n-butylcarbamoyl, 4-ethylsuccinoyl, piperidinylpiperidinyl, triisopropylsilyl, and methylisopropylcarbonate diester.

[0016] In one preferred embodiment, R3 and R4 are selected from methyl, acetyl, benzoyl, , .

[0017] In one preferred embodiment, the bisbenzyltetrahydroisoquinoline derivative is a compound represented by the following formula, or an optical isomer, crystal, or pharmaceutically acceptable salt thereof: F-02 F-03 F-04 F-05 F-07 F-08 F-09 F-10, F-11 F-12 F-13 F-14 F-15 F-16 F-17 F-18 F-19 F-20 F-21.

[0018] Based on the same inventive concept, this invention also claims protection for a method for preparing the bisbenzyltetrahydroisoquinoline derivative, comprising the following steps: A base was added to a methyl lotusine solution, followed by an acyl chloride or acid anhydride, and the mixture was stirred overnight at room temperature. The resulting bisbenzyltetrahydroisoquinoline derivative was then purified.

[0019] In one preferred embodiment, the base is triethylamine.

[0020] In one preferred embodiment, the purification includes extraction and washing.

[0021] Based on the same inventive concept, the present invention also claims protection for the use of the aforementioned bisbenzyltetrahydroisoquinoline derivative in the preparation of anti-insomnia drugs.

[0022] Based on the same inventive concept, the present invention also claims protection for an anti-insomnia drug, wherein the active ingredient of the anti-insomnia drug includes the aforementioned dibenzyltetrahydroisoquinoline derivative.

[0023] In one preferred embodiment, a pharmaceutically acceptable carrier and excipients are used.

[0024] In one preferred embodiment, the pharmaceutically acceptable excipients include solvents, diluents, other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.

[0025] In one preferred embodiment, the dosage form of the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray.

[0026] In one preferred embodiment, the pharmaceutical composition can be administered by any suitable means, such as orally, rectally, parenterally, intracerebrospinal, vaginally, intraperitoneally, or locally, to humans or other animals, depending on the severity of the disease.

[0027] The compounds of the present invention can be in crystalline form as advantageous compounds or as solvates. Methods of solvation are well known in the art, and suitable solvates are pharmaceutical solvates. In a specific embodiment, the solvate is a hydrate.

[0028] The present invention will be further explained below: This invention evaluated the antagonistic activity of all derivatives against orexin receptor 1 (OX1R) / receptor 2 (OX2R) and the anti-insomnia activity of preferred derivatives using well-known methodologies in the art, including the FLIPR Ca²⁺ flow assay, open field assay, sodium pentobarbital-induced sleep assay, and sleep EEG assay. The results showed that, in in vitro activity experiments, the derivatives of this invention, at the same concentration, generally exhibited superior antagonistic activity against both OX1R and OX2R compared to the lead compound methyllimonene (…). Figure 1 Some derivatives showed superior activity compared to the positive control drug daliresen, indicating that bisbenzylisoquinoline derivatives have anti-insomnia potential. In vivo anti-insomnia activity results showed that: in the open field test, the selected derivatives significantly reduced the movement distance of mice, exhibiting sedative activity; in the sodium pentobarbital-induced sleep test, the selected derivatives showed that they shortened sleep latency and prolonged sleep time; in the sleep EEG test, the selected compounds showed sleep-improving effects in an insomnia rat model.

[0029] Compared with the prior art, the beneficial effects of the present invention are: This invention synthesizes several novel derivatives; (1) the compounds of this invention were preliminarily determined to have antagonistic activity against OX1R and OX2R by FLIPR experiment. (2) the compounds of this invention have sedative effects by mouse open field experiment and sodium pentobarbital-induced sleep experiment; in the insomnia rat model, sleep EEG results showed that the compounds of this invention significantly prolonged sleep time, increased NREM and REM sleep duration, and reduced the number of sleep-wake transitions better than the positive control drug dalirazene. (3) the preferred derivatives did not show obvious toxicity at a single dose of 2000 mg / kg, indicating no acute toxicity in animals.

[0030] Therefore, the compounds of the present invention have the potential to become anti-insomnia drugs, providing new candidate drug molecules for the treatment of insomnia. Attached Figure Description

[0031] Figure 1 The fluorescence intensity changes of calcium ion release in Chinese hamster ovary cells (OX1R-CHO) overexpressing orexin receptor 1, as measured by FLIPR under orexin A stimulation, were obtained by treating them with the same concentration of derivative (10⁻⁸ M).

[0032] Figure 2 shows the changes in the fluorescence intensity of calcium ion release in Chinese hamster ovary cells (OX2R-CHO) overexpressing orexin receptor 2, as measured by FLIPR under orexin A stimulation, after treatment with the same concentration of derivative (10⁻⁸ M).

[0033] Figure 3The results of open field experiments for F-01, F-02, F-03, F-04, F-05, F-07, F-08, F-09, F-10, F-13, F-14, F-15, F-16 and F-18 are presented at a dosage of 40 mg / kg.

[0034] Figure 4 The results of open field experiments were used to screen derivatives F-02, F-03, F-07, F-13 and F-14 at a dosage of 20 mg / kg.

[0035] Figure 5 The results of open-field experiments show the optimal derivative F-03 under different dosages.

[0036] Figure 6 The results of a mouse sleep experiment induced by sodium pentobarbital after administration of 20 mg / kg F-03.

[0037] Figure 7 The results of a rat sleep experiment induced by sodium pentobarbital after administration of 20 mg / kg F-03.

[0038] Figure 8 The results of sleep electroencephalogram (EEG) monitoring in rats after administration of 20 mg / kg F-03 are as follows: Figure 8 A shows the electroencephalogram (EEG) and electromyogram (EMG) of the rat. Figure 8 B is a statistical chart showing the percentage of awake, NREM, and REM time in each group of rats. Figure 8 C is a statistical graph showing the sleep-wake transition time of rats in each group.

[0039] Figure 9 The results of the observation on the effect of 20 mg / kg F-03 administration on home behavior activities activating orexin neurons were presented. Figure 9 A is a schematic diagram of stereotactic injection into the brain to activate orexin neurons. Figure 9 B is a behavioral graph of mice within 2 hours after clozapine-induced activation of orexin neurons. Figure 9 C is a statistical graph showing the behavioral changes in mice within 6 hours after F-03 administration. Figure 9 D is a statistical graph showing the sleep, food intake, and water intake of mice 6 hours after drug administration in each group. Detailed Implementation

[0040] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0041] In the following description, the structure and effects of the present invention will be presented in more detail through preparation examples, embodiments, and experimental examples. However, the following preparation examples, embodiments, and experimental examples are provided for illustrative purposes only, and therefore the present invention is not limited thereto.

[0042] The term "unsubstituted" as used in this invention means unsubstituted or substituted only by hydrogen.

[0043] The following are definitions of some of the terms used in this invention:

[0044] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0045] "=O" refers to the oxy group.

[0046] “CF3” refers to trifluoromethyl.

[0047] "-CO-NH-" stands for "-amide-".

[0048] "-NH-CO-" stands for "-aminoacyl-".

[0049] "Carbonyl" refers to " ".

[0050] When "alkyl" is used as a group or part of a group, it refers to a straight-chain or branched aliphatic hydrocarbon group. Preferred alkyl groups are C1-C14 alkyl groups; more preferred are C1-C10 alkyl groups; and most preferred are C1-C6 alkyl groups, unless otherwise specified. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl, etc.

[0051] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, or spirocyclic carbon ring. Rings consisting of 3-9 carbon atoms are preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] "Heteroalkyl" refers to a straight-chain group or a group containing branched alkyl groups, and in the main chain, it contains at least one or more heteroatoms selected from S, O, and N. A chain containing 2-14 atoms is preferred. Heteroalkyl groups include, but are not limited to: ethers, thioethers, alkyl esters, second or third alkylamines, alkyl sulfinic acids, etc.

[0053] "Heterocyclic alkyl" refers to a group formed by replacing one or more (preferably 1, 2, or 3) carbon atoms of the "cycloalkyl" group defined above with oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atoms (preferably oxygen, sulfur, or nitrogen). The terms "heterocyclic alkyl" and "alkyl moiety" are defined herein. Preferably, it contains 1-3 heteroatoms. Preferred rings are 3-14 membered rings (i.e., 3-14 membered heterocyclic alkyl), more preferably 4-7 membered rings (i.e., 4-7 membered heterocyclic alkyl). Heterocyclic alkyl groups include, but are not limited to: pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, dihydropyrazolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, oxocyclopropyl, azirropropyl, or 2-pyrazolinyl, as well as lactams, lactones, cyclic imines, and cyclic anhydrides. Heterocyclic alkyl groups may be substituted with one or more substituents.

[0054] "Acyl" includes (alkyl-CO)- groups and (aryl-CO)- groups, unless otherwise specified. Alkyl or aryl groups are defined herein. Examples of acyl groups include, but are not limited to, acetyl, propionyl, isobutyryl, benzoyl, etc.

[0055] "Amide group" includes (alkyl-CONH)- groups and (aryl-CONH)- groups, unless otherwise specified. Alkyl or aryl groups are defined herein. Examples of amide groups include, but are not limited to, acetamido, propionamido, butyramido, isobutyramido, benzamide, etc.

[0056] "Alkoxy" refers to a (alkyl-O)- group. The "alkyl" portion is defined herein. The alkoxy group is preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexoxy, isohexoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, etc. Additionally, "alkoxycarbonyl" refers to a group in which the "alkoxy" group defined above is bonded to a carbonyl group, such as methoxycarbonyl and ethoxycarbonyl.

[0057] "Aryl" as a group or part of a group refers to: (1) an aromatic monocyclic or fused ring; preferably an aromatic carbocyclic ring with 5-12 carbon atoms (a cyclic structure in which all ring atoms are carbon). Examples of aryl groups include, but are not limited to: phenyl, naphthyl; (2) a group that can be connected to a partially saturated carbocyclic ring, for example: a phenyl group and a C5-7 cycloalkyl or C5-7 cycloalkenyl group fused together to form a cyclic structure. Examples include, but are not limited to: tetrahydronaphthyl, indenyl, or hydroindenyl. An aryl group may be substituted by one or more substituents.

[0058] "Heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic group, preferably an aromatic group having one or more (preferably 3 to 14, more preferably 5 to 10, especially preferably 5 or 6) carbon atoms and one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N) as cyclic atoms. Preferably, the aromatic group is a 4-15 membered heteroaryl, more preferably a 5-7 membered heteroaryl. Examples of the heteroaryl groups include, for example: furanyl, thiopheneyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, 3-phenylpyrrolyl, thiazolyl-oxazolyl, tetrazolyl, isoxazolyl, inzolyl, pyridazinyl, quinolinyl, purinyl, carbazoleyl, acridineyl, pyrimidinyl, 2,3'-bifuranyl, and isoquinolinyl.

[0059] "Carbonate group" is a class of functional groups or substituents containing the structural characteristics of carbonic acid (carbonyl + ester). Its core structural unit is -OC(=O)-O-, that is, one carbon atom is connected to two oxygen atoms by double bonds and single bonds (carbonyl C=O), and the carbon atom is also connected to two other oxygen atoms (forming two CO bonds), thus forming a cyclic or chain-like carbonate structure. Examples of carbonate groups include: dimethyl carbonate group, diethyl carbonate group, and ethylene carbonate group.

[0060] "Aminocarbonyl" means that a molecule contains both an amino group (-NH2 or -NHR or -NR2) and a carbonyl group (C=O, such as the carbonyl group in aldehydes, ketones, carboxylic acids, esters and amides).

[0061] Unless otherwise stated, the subunits of this invention refer to divalent groups, that is, groups in which one hydrogen atom in a monovalent group is replaced by a chemical valence. For example, "heteroalkylene" refers to a heteroalkyl group in which one hydrogen atom is replaced by a chemical valence; "heterocyclicene" refers to a heterocyclic group in which one hydrogen atom is replaced by a chemical valence; "arylene" refers to an aryl group in which one hydrogen atom is replaced by a chemical valence; "alkylene" refers to an alkyl group in which one hydrogen atom is replaced by a chemical valence; "alkenylene" refers to an alkenyl group in which one hydrogen atom is replaced by a chemical valence; "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is replaced by a chemical valence; "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is replaced by a chemical valence; "heterocyclic alkylene" refers to a heterocyclic alkyl group in which one hydrogen atom is replaced by a chemical valence; "heterocyclic alkenylene" refers to a heterocyclic alkenyl group in which one hydrogen atom is replaced by a chemical valence; "alkoxyene" refers to an alkoxyene group in which one hydrogen atom is replaced by a chemical valence; "alkenyloxyene" refers to an alkenyloxyene group in which one hydrogen atom is replaced by a chemical valence; "alkynyloxyene" refers to an alynyloxyene group in which one hydrogen atom is replaced by a chemical valence, etc. The definitions of heterocyclic groups, aryl groups, alkyl groups, alkenyl groups, cycloalkyl groups, heteroaryl groups, heterocyclic alkyl groups, heterocyclic alkenyl groups, alkoxy groups, alkenyloxy groups, and alkynyloxy groups mentioned above are provided in the relevant definitions in this article.

[0062] This invention includes compounds represented by general formula (I) and their various possible isomers. These include: non-mirror image isomers, mirror image isomers, tautomers, and geometric isomers of "E" or "Z" configuration isomers. Any chemist with a basic understanding can isolate the above-mentioned optically pure or stereoisomerically pure compounds.

[0063] The term "pharmaceutically acceptable salt" refers to certain salts of the aforementioned compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of compounds represented by general formula (I) can be formed in two forms: one is a salt formed with an acid; the other is a salt formed with a base or alkali metal. Acids that form pharmaceutically acceptable salts with compounds represented by general formula (I) include inorganic acids and organic acids. Suitable inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids, and sulfonic acids; examples include, but are not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acids, and aromatic sulfonic acids. Alkali metals that form pharmaceutically acceptable salts with compounds represented by general formula (I) include lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases that form pharmaceutically acceptable salts with compounds represented by general formula (I) include choline, diethanolamine, morpholine, etc.

[0064] The compounds of this invention can be used alone or in combination with one or more other drugs; or in combination with surgery or radiotherapy; or formulated into a specific dosage form with pharmaceutically acceptable carriers, diluents, or excipients for administration. The specific dosage form depends on the route of administration.

[0065] The non-enteric injectable drug formulations of the present invention include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersants, suspending agents or emulsifiers, and powder injections that are prepared into injectable sterile aqueous solutions only before use.

[0066] If desired, and for more efficient distribution, the compounds of the present invention can be incorporated into slow-release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres.

[0067] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. These solid dosage forms contain an active compound represented by general formula (I) mixed with at least one inert and pharmaceutically acceptable excipient or carrier. These excipients or carriers include sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) disintegrants, such as agar gum, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; d) dissolution delayers, such as paraffin wax; e) absorption accelerators, such as quaternary ammonium compounds; f) wetting agents, such as cetyl alcohol and glyceryl monostearate; g) adsorbents, such as kaolin and bentonite; and h) lubricants, such as talc, calcium stearate, magnesium stearate, and solid polyethylene glycol.

[0068] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with a coating or shell.

[0069] The active compound can also be administered in microcapsule form. If desired, one or more of the excipients mentioned above may be included.

[0070] Orally administered liquid dosage forms include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, etc. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in this art, such as water or other solvents, stabilizers, and emulsifiers, such as ethyl alcohol, ethyl carbonate, ethyl acetate, benzoic acid alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, etc.

[0071] In addition to inert diluents, oral compositions may also include excipients such as humectants, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0072] In addition to the active compounds, the suspension may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan anhydride esters.

[0073] Compositions for rectal or vaginal administration are preferably suppositories. Preparation can be achieved by mixing the compounds of the invention with suitable non-irritating excipients or carriers.

[0074] The dosage forms for topical administration of the compounds of this invention include powders, patches, sprays, ointments, and inhalers. The active compounds are prepared under sterile conditions by mixing with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0075] Example 1

[0076] Preparation of methyl lotus seed base acylated derivatives

[0077] Triethylamine TEA (3.0 equiv) was added to a 0.1 M solution of methylnepenone (1.0 equiv) in dichloromethane. The corresponding acyl chloride or anhydride (1.2 equiv) was then added to the reaction mixture, which was stirred overnight at room temperature. The reaction mixture was subsequently extracted with dichloromethane, washed once with saturated sodium bicarbonate solution, and twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding acylated derivatives of methylnepenone.

[0078] The general formula for methyl lotus seed base acylated derivatives is: .

[0079] Eleven methyl lotus seed base acylated derivatives were obtained (F-01~F-05, F-08~F-10, F-13, F-14 and F-17, with yields ranging from 15% to 90%). The structures and corresponding structural characterizations of each compound are as follows:

[0080] F-01

[0081] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl acetate (F-01)

[0082] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of acetic anhydride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow viscous liquid in 23% yield. 1 H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 8.1 Hz, 1H), 6.86 (d,J = 8.6 Hz, 2H), 6.78 (dd, J = 8.2, 1.9 Hz, 1H), 6.69 – 6.63 (m, 3H), 6.50(s, 1H), 6.44 (d, J = 1.8 Hz, 1H), 6.20 (s, 1H), 5.76 (s, 1H), 3.89 (dd, J =9.7, 3.7 Hz, 1H), 3.86 – 3.81 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.71 (s,3H), 3.51 (s, 3H), 3.40 (dd, J = 13.4, 4.0 Hz, 1H), 3.35 – 3.29 (m, 1H), 3.28– 3.19 (m, 1H), 3.14 (dd, J = 13.7, 4.8 Hz, 1H), 3.06 – 2.99 (m, 1H), 2.97 –2.88 (m, 3H), 2.80 (dd, J = 13.7, 7.4 Hz, 1H), 2.75 – 2.66 (m, 3H), 2.59 (s,3H), 2.57 (s, 3H), 2.21 (s, 3H), 2.02 (s, 6H). 13C NMR (100 MHz, CDCl3) δ175.9, 168.9, 158.2, 150.0, 149.1, 148.1, 146.9, 142.6, 139.4, 130.7, 124.5,123.4, 120.4, 119.5, 113.7, 112.6, 111.2, 77.5, 77.2, 76.8, 64.5, 64.1, 56.0,55.9, 55.8, 55.3, 46.2, 45.3, 41.6, 41.0, 40.8, 39.9, 31.6, 29.8, 24.9, 23.7,22.8, 21.9, 20.7. ESI-HRMS m / z calcd C40H47N2O7 [M+H] + 667.3378, found 667.3391.

[0083] F-02

[0084] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)benzoate (F-02)

[0085] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of benzoyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the corresponding dibenzylisoquinoline compound as a viscous liquid in 75% yield. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz, 4H), 8.01 (d, J =7.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.3 Hz, 2H), 7.41 (dt, J= 14.9, 7.6 Hz, 6H), 7.11 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.9 Hz,1H), 6.85 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 1.8 Hz, 1H), 6.61 (d, J = 8.6 Hz,2H), 6.56 (s, 1H), 6.53 (s, 1H), 6.14 (s, 1H), 5.86 (s, 1H), 4.12 (dd, J =9.7, 3.4 Hz, 1H), 3.97 (dd, J = 7.8, 4.5 Hz, 1H), 3.82 (s, 3H), 3.65 (s, 3H),3.61 (s, 3H), 3.58 (s, 3H), 3.48 (ddd, J = 12.8, 11.4, 5.5 Hz, 1H), 3.32(ddd, J = 13.0, 10.2, 5.7 Hz, 1H), 3.26 (dd, J = 13.8, 4.5 Hz, 1H), 3.23 –3.18 (m, 1H), 3.10 (ddd, J = 12.9, 6.0, 3.6 Hz, 1H), 3.01 (ddd, J = 17.3,11.0, 6.6 Hz, 1H), 2.89 (ddd, J = 16.5, 9.9, 6.4 Hz, 1H), 2.84 – 2.76 (m,3H), 2.76 – 2.69 (m, 1H), 2.73 (s, 3H), 2.62 (s, 3H). 13C NMR (125 MHz, CDCl3)δ 171.7, 164.5, 158.4, 149.9, 148.8, 148.5, 147.2, 143.6, 140.1, 137.0,133.9, 133.6, 131.8, 130.8, 130.4, 129.9, 129.6, 129.5, 128.5, 128.2, 128.1,126.5, 125.3, 125.0, 123.8, 123.0, 121.1, 119.5, 113.9, 112.6, 111.4, 111.3,64.5, 64.0, 56.0, 56.0, 55.9, 55.3, 45.5, 44.9, 40.9, 40.7, 40.5, 40.0, 23.9,23.2. ESI-HRMS m / z calcd C45H49N2O7 [M+H] + 729.3534, found 729.3582.

[0086] F-03

[0087] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl neopentanoate (F-03)

[0088] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of pentanoic anhydride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow solid powder, with a yield of 83%. 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.76 (dd, J = 8.2, 1.9 Hz, 1H), 6.70 – 6.66 (m, 2H),6.66 (d, J = 1.9 Hz, 1H), 6.60 (s, 1H), 6.49 (s, 1H), 6.34 (s, 1H), 6.04 (s,1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H), 3.69 – 3.62 (m, 2H), 3.61 (s,3H), 3.17 – 3.09 (m, 3H), 2.94 (dd, J = 14.1, 5.8 Hz, 1H), 2.85 – 2.69 (m,6H), 2.62 – 2.51 (m, 2H), 2.47 (s, 3H), 2.46 (s, 3H), 1.23 (s, 9H). 13 C NMR(100 MHz, CDCl3) δ 176.2, 158.6, 150.2, 148.9, 148.2, 147.4, 143.8, 140.8,135.4, 130.8, 128.3, 126.6, 125.5, 123.8, 121.6, 120.7, 118.7, 114.0, 112.7,111.2, 111.2, 64.5, 64.0, 56.1, 56.0, 55.9, 55.3, 45.1, 44.5, 40.7, 40.1,39.9, 39.7, 39.1, 27.2, 23.1, 22.3. ESI-HRMS m / z calcd C43H53N2O7 [M+H] + 709.3847, found 709.3821.

[0089] F-04

[0090] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl-4-bromobenzoate (F-04)

[0091] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of 4-bromobenzoyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow oily liquid in 50% yield. 1 H NMR (400 MHz, CDCl3) δ 7.93 – 7.83 (m, 2H), 7.59 – 7.53(m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.84 (dd, J =8.2, 1.9 Hz, 1H), 6.71 (d, J = 1.8 Hz, 1H), 6.68 – 6.62 (m, 2H), 6.51 (d, J =3.6 Hz, 2H), 6.38 (s, 1H), 3.80 (s, 3H), 3.75 – 3.68 (m, 4H), 3.64 (s, 3H),3.63 (s, 3H), 3.62-3.60 (m, 1H), 3.23 – 3.08 (m, 3H), 2.95 (dd, J = 14.1, 5.6Hz, 1H), 2.84 – 2.75 (m, 4H), 2.74 – 2.66 (m, 2H), 2.61 – 2.53 (m, 2H), 2.51(s, 3H), 2.46(s, 3H). 13 C NMR (125 MHz, CDCl3) δ 163.9, 158.1, 149.3, 148.9,147.8, 146.9, 143.4, 139.5, 131.9, 131.9, 131.1, 130.7, 129.0, 128.7, 128.5,124.9, 123.3, 120.7, 119.3, 113.6, 112.6, 111.4, 111.1, 68.4, 64.8, 64.5,56.0, 55.3, 47.2, 46.5, 42.5, 42.2, 41.0, 40.0, 38.9, 31.8, 31.6, 30.6, 29.9,29.9, 29.6, 29.1, 25.7, 24.0, 23.2. ESI-HRMS m / z calcd C45H48BrN2O7 [M+H] + 807.2639, found 807.2653.

[0092] F-05

[0093] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl-4-(tert-butyl)benzoate (F-05)

[0094] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of 4-tert-butylbenzoyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the corresponding dibenzylisoquinoline compound as a white solid in 48% yield. 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.3 Hz, 2H), 7.44(d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.83(dd, J = 8.2, 1.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 3H), 6.54 (s, 2H), 6.23 (s,1H), 5.86 (s, 1H), 4.01 – 3.88 (m, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.62 (s,3H), 3.56 (s, 3H), 3.49 – 3.40 (m, 1H), 3.34 – 3.23 (m, 2H), 3.05 – 2.75 (m,9H), 2.70 (s, 3H), 2.62 (s, 3H), 1.32 (s, 9H). 13C NMR (125 MHz, CDCl3) δ164.24, 158.64, 157.47, 149.13, 147.48, 140.45, 134.84, 130.91, 130.11,126.32, 125.43, 123.95, 123.45, 119.75, 114.03, 112.64, 111.16, 110.95,55.98, 55.84, 55.82, 55.24, 40.17, 36.50, 35.50, 35.19, 31.89, 31.49, 31.42,31.14, 31.10, 30.18, 29.68, 29.64, 22.67, 14.10. 13 C NMR (125 MHz, CDCl3) δ164.2, 158.6, 157.5, 149.1, 147.5, 140.4, 134.8, 130.9, 130.1, 126.3, 125.4,124.0, 123.5, 119.7, 114.0, 112.6, 111.2, 111.0, 56.0, 55.8, 55.8, 55.2,40.2, 36.5, 35.5, 35.2, 31.9, 31.5, 31.4, 31.1, 31.1, 30.2, 29.7, 29.6, 22.7,14.1. ESI-HRMS m / z calcd C49H57N2O7 [M+H] + 785.4160, found 785.4133.

[0095] F-08

[0096] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl-3-chlorobenzoate (F-08)

[0097] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of 3-chlorobenzoyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow oily liquid, with a yield of 29%. 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.90 (m, 1H), 7.89 (t, J =1.7 Hz, 1H), 7.54 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H),7.10 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.85 (dd, J = 8.2, 1.9Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.66 (d, J = 8.6 Hz, 2H), 6.51 (d, J = 8.1Hz, 2H), 6.34 (s, 1H), 6.07 (s, 1H), 3.81 (s, 3H), 3.77 – 3.72 (m, 1H), 3.71(s, 3H), 3.68 (d, J = 10.0 Hz, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 3.27 – 3.18(m, 2H), 3.18 – 3.11 (m, 1H), 2.99 (dd, J = 13.6, 5.2 Hz, 1H), 2.90 – 2.77(m, 5H), 2.73 (dd, J = 8.8, 4.5 Hz, 2H), 2.60 (dd, J = 16.5, 8.2 Hz, 2H),2.54 (s, 3H), 2.48 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 163.4, 158.1, 149.1,148.7, 147.8, 146.9, 143.6, 139.5, 134.6, 133.5, 131.3, 130.7, 130.4, 129.8,128.6, 125.1, 123.3, 121.1, 118.9, 113.6, 112.6, 111.5, 111.1, 64.9, 64.5,56.0, 56.0, 55.9, 55.3, 47.4, 46.8, 42.6, 42.5, 41.0, 40.2, 31.7, 30.4, 29.9.ESI-HRMS m / z calcd C45H48ClN2O7 [M+H] + 763.3145, found 763.3172.

[0098] F-09

[0099] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl-2-methoxyacetic acid ester (F-09)

[0100] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of methoxyacetic anhydride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow oily liquid with a yield of 75%. 1 H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.76 (dd, J = 8.1, 1.6 Hz, 1H), 6.67 (d, J = 8.5 Hz, 2H), 6.61 (s, 1H), 6.55 (d, J = 1.5 Hz, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.96(s, 1H), 4.21 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H), 3.69 – 3.62(m, 2H), 3.59 (s, 3H), 3.46 (s, 3H), 3.21 – 3.09 (m, 3H), 2.96 (q, J = 5.8Hz, 1H), 2.85 – 2.68 (m, 6H), 2.64 – 2.51 (m, 2H), 2.48 (s, 3H), 2.48 (s,3H). 13C NMR (125 MHz, CDCl3) δ 168.5, 158.0, 149.6, 149.1, 147.7, 146.8,142.5, 138.9, 138.5, 130.7, 124.3, 123.0, 120.2, 119.3, 113.6, 112.8, 111.4,111.1, 69.7, 64.8, 64.5, 59.6, 56.1, 55.9, 55.3, 47.4, 46.6, 42.8, 42.4,41.1, 40.1, 29.9, 26.1, 25.0. ESI-HRMS m / z calcd C41H49N2O8 [M+H] + 697.3483, found 697.3527.

[0101] F-10

[0102] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl[1,4'-bipiperidine]-1'-carboxylic acid ester (F-10)

[0103] Triethylamine was added to a dichloromethane solution of methyl lotusine, followed by the addition of ethylpiperidinylpiperidincarnate chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow viscous liquid, with a yield of 81%. 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.2 Hz,1H), 6.93 (d, J = 8.4 Hz, 2H), 6.78 (dd, J = 8.2, 1.9 Hz, 1H), 6.68 (d, J =8.6 Hz, 3H), 6.60 (s, 1H), 6.46 (d, J = 18.9 Hz, 2H), 6.10 (s, 1H), 4.26 –4.11 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.67 – 3.58 (m, 5H),3.16 – 3.06 (m, 3H), 2.90 (dd, J = 14.1, 6.0 Hz, 1H), 2.81 (t, J = 4.7 Hz,2H), 2.77 – 2.66 (m, 6H), 2.60 – 2.46 (m, 9H), 2.45 (s, 3H), 2.43 (s, 3H),1.85 – 1.71 (m, 2H), 1.61 (d, J = 4.8 Hz, 4H), 1.48 – 1.40 (m, 4H). 13 C NMR(125 MHz, CDCl3) δ 157.9, 153.3, 148.9, 148.6, 147.5, 146.8, 143.9, 140.5,138.4, 131.8, 130.6, 130.3, 129.1, 125.9, 124.9, 123.6, 120.5, 118.6, 113.5,112.6, 111.4, 111.0, 64.9, 64.5, 62.8, 56.2, 56.0, 55.9, 55.3, 50.1, 46.9,42.9, 42.7, 41.1, 40.3, 32.1, 31.7, 31.6, 30.4, 30.3, 29.9, 29.6, 25.9, 25.4,24.6, 23.2. ESI-HRMS m / z calcd C49H63N4O7 [M+H] + 819.4691, found 819.4513.

[0104] F-13

[0105] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl-4-nitrobenzene ester (F-13)

[0106] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of p-nitrobenzoyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a yellow viscous liquid, with a yield of 31%. 1 H NMR (400 MHz, CDCl3) δ 8.24 – 8.20 (m, 2H), 8.17 – 8.13(m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 6.83-6.79 (m, 3H), 6.58 (d, J = 8.8 Hz, 3H), 6.47 (d, J = 5.9 Hz, 2H), 6.24 (s, 1H), 5.90 (s, 1H), 3.83 – 3.77 (m,1H), 3.75 (s, 3H), 3.73 – 3.69 (m, 1H), 3.64 (s, 3H), 3.56 (s, 3H), 3.55 (s, 3H), 3.42 – 3.33 (m, 1H), 3.31 – 3.21 (m, 1H), 3.18 – 3.10 (m, 1H), 3.08 –3.00 (m, 2H), 2.90 – 2.83 (m, 1H), 2.80 – 2.71 (m, 4H), 2.67 – 2.59 (m, 2H), 2.55 (s, 3H), 2.49 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.9, 158.0, 150.9,149.2, 148.9, 147.8, 146.9, 142.9, 139.3, 139.1, 135.1, 131.6, 131.4, 130.8,130.7, 124.8, 123.6, 123.0, 120.4, 119.6, 113.6, 112.6, 111.4, 111.1, 64.8,64.5, 56.0, 55.3, 47.3, 46.6, 42.7, 42.4, 41.0, 39.9, 29.9, 29.6, 26.1, 25.1.ESI-HRMS m / z calcd C45H48N3O9 [M+H] + 774.3385, found 774.3352.

[0107] F-14

[0108] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl 2,3-difluorobenzoate (F-14)

[0109] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of 2,3-difluorobenzoyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a yellow viscous liquid, with a yield of 27%. 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 7.7, 6.2 Hz,1H), 7.45 – 7.33 (m, 3H), 7.19 – 7.05 (m, 3H), 6.90 (d, J = 8.5 Hz, 2H), 6.84(d, J = 7.4 Hz, 1H), 6.69 – 6.58 (m, 3H), 6.54 (d, J = 13.7 Hz, 2H), 6.36 (s,1H), 5.97 (s, 1H), 3.87 – 3.76 (m, 5H), 3.72 (s, 3H), 3.67 (s, 3H), 3.61 (s,3H), 3.36 – 3.16 (m, 3H), 3.16 – 3.05 (m, 1H), 2.95-2.76 (m, 6H), 2.73-2.64(m, 2H), 2.58 (s, 3H), 2.55 (s, 3H). ESI-HRMS m / z calcd C45H47F2N2O7 [M+H] + 765.3346, found 765.3373.

[0110] F-17

[0111] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl dimethylcarbamate (F-17)

[0112] Triethylamine was added to a dichloromethane solution of methylnephrine, followed by the addition of N,N-dimethylformyl chloride to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a pale yellow oily liquid, with a yield of 27%. 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.79 (dd, J = 8.2, 1.8 Hz, 1H), 6.67 (d, J = 8.6Hz, 2H), 6.65 – 6.60 (m, 2H), 6.50 (s, 1H), 6.41 (s, 1H), 6.03 (s, 1H), 3.80(s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.72 – 3.62 (m, 2H), 3.61 (s, 3H), 3.25– 3.11 (m, 3H), 2.96 (dd, J = 14.1, 5.8 Hz, 1H), 2.90 (s, 6H), 2.87 – 2.71(m, 6H), 2.63 – 2.55 (m, 2H), 2.51 (s, 3H), 2.48 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.2, 154.4, 149.6, 148.9, 147.1, 143.9, 140.7, 130.7, 130.5, 126.6, 124.9, 124.6, 124.0, 120.5, 119.1, 113.7, 112.6, 111.3, 111.1, 64.9,64.5, 56.2, 56.0, 56.0, 55.3, 42.2, 41.0, 40.1, 36.9, 36.6, 32.1, 31.7, 30.5,30.3, 29.6. ESI-HRMS m / z calcd C41H50N3O7 [M+H] + 696.3643, found 696.3679.

[0113] Example 2

[0114] Preparation of methylated derivatives of methylnephrine

[0115]

[0116] Experimental procedure: Under nitrogen protection, methyl lotusine (20 mg, 0.032 mmol, 1.0 equiv), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN) (6.2 mg, 0.048 mmol, 1.5 equiv) and 0.4 mL of dimethyl carbonate were heated at 120 °C for 14 h. The mixture was then extracted with dichloromethane, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain F-06 (6.1 mg, 30%), a light yellow oily liquid.

[0117] The full name of F-06 is (R)-7-(5-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-methoxyphenoxy)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline. Characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 8.6 Hz, 2H), 6.81 (d, J =8.3 Hz, 1H), 6.69 (dd, J = 8.3, 1.9 Hz, 1H), 6.67 (s, 1H), 6.63 (d, J = 10.7Hz, 2H), 6.56 (d, J = 1.9 Hz, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.97 (s, 1H), 3.80 (s, 6H), 3.78 (s, 3H), 3.70 (s, 3H), 3.70 – 3.64 (m, 2H), 3.56 (s, 3H),3.21 – 3.10 (m, 3H), 3.00 (dd, J = 13.8, 5.1 Hz, 1H), 2.87 – 2.75 (m, 5H), 2.71 (dd, J = 13.6, 8.1 Hz, 1H), 2.65 – 2.56 (m, 2H), 2.50 (s, 3H), 2.49 (s,3H). 13C NMR (100 MHz, CDCl3) δ 158.0, 149.2, 148.8, 147.7, 146.7, 146.2,143.5, 130.6, 124.9, 119.6, 118.7, 113.6, 112.4, 112.3, 111.3, 111.1, 64.8,64.5, 56.2, 56.0, 55.9, 55.7, 55.2, 47.2, 46.5, 42.5, 42.2, 40.7, 40.0, 32.1,29.8. ESI-HRMS m / z calcd C39H47N2O6 [M+H] + 639.3429, found 639.3457.

[0118] Example 3

[0119] Preparation of methylnephrine butyl carbamate derivatives

[0120]

[0121] Experimental procedure: Methylnephrine (20 mg, 0.032 mmol, 1.0 equiv), triethylamine (6.4 mg, 0.064 mmol, 2.0 equiv), n-butyl isocyanate (3.2 mg, 0.032 mmol, 1.0 equiv), and 0.3 mL of acetonitrile were added to a reaction flask. After stirring at room temperature for 2 hours, the reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain F-07 (12.7 mg, 55%), a pale yellow oily liquid.

[0122] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl butylcarbamate (F-07): 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.5Hz, 2H), 6.77 (dd, J = 8.2, 1.6 Hz, 1H), 6.67 (d, J = 8.6 Hz, 2H), 6.61 (s,1H), 6.52 (s, 1H), 6.48 (s, 1H), 6.42 (s, 1H), 5.93 (s, 1H), 5.02 (t, J = 5.8Hz, 1H), 3.78 (d, J = 6.6 Hz, 3H), 3.75 (s, 3H), 3.74 – 3.68 (m, 5H), 3.58(s, 3H), 3.28 – 3.10 (m, 5H), 2.98 (dd, J = 13.8, 5.2 Hz, 1H), 2.89 – 2.75(m, 5H), 2.70 (dd, J = 13.4, 8.5 Hz, 1H), 2.65 – 2.55 (m, 2H), 2.52 (s, 3H), 2.50 (s, 3H), 1.52 – 1.43 (m, 2H), 1.38 – 1.32 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.0, 154.3, 149.5, 149.4, 147.8, 146.8,143.1, 139.8, 130.7, 124.4, 123.7, 119.9, 119.6, 113.6, 112.6, 111.3, 111.1,64.7, 64.4, 56.1, 55.9, 55.3, 47.2, 46.2, 42.4, 41.9, 41.1, 40.9, 39.9, 32.0,29.8, 22.8, 20.0, 14.2, 13.8. ESI-HRMS m / z calcd C43H54N3O7 [M+H] + 724.3956, found 724.3992.

[0123] Example 4

[0124] Preparation of methylnepenone silicified derivatives

[0125]

[0126] Experimental procedure: Triethylamine (48.6 mg, 0.48 mmol) was added to a dichloromethane solution (1.6 mL) of methyllimonin (100 mg, 0.16 mmol), followed by the addition of triisopropylchlorosilane (46.3 mg, 0.24 mmol). The mixture was stirred overnight at room temperature. The reaction was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding dibenzylisoquinoline compound as a yellow viscous liquid, with a yield of 50%.

[0127] (R)-7-(5-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-((triisopropylsilyl)oxy)phenoxy)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,2,3,4-tetrahydroxyisoquinoline (F-11) spectral data: 1 H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.68 – 6.63 (m, 3H), 6.59 (dd, J = 7.2, 3.0 Hz,2H), 6.18 (s, 1H), 6.06 (s, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 3.65 (dd, J = 7.4, 4.7 Hz, 1H), 3.59 (t, J = 5.8 Hz, 1H), 3.56 (s, 3H), 3.20– 3.08 (m, 3H), 2.96 (dd, J = 14.1, 5.6 Hz, 1H), 2.82 – 2.72 (m, 5H), 2.71 –2.66 (m, 1H), 2.63 – 2.55 (m, 2H), 2.48 (s, 3H), 2.46 (s, 3H), 1.21 – 1.11(m, 3H), 0.99 (s, 6H), 0.98 (s, 6H), 0.97 (s, 3H), 0.96 (s, 3H). 13C NMR (100MHz, CDCl3) δ 130.3, 130.3, 125.3, 125.3, 121.1, 121.1, 119.9, 119.9, 116.9,116.9, 113.4, 113.4, 112.2, 112.2, 111.2, 111.2, 110.9, 110.9, 64.9, 64.6,47.0, 46.8, 40.7, 40.5, 29.7, 25.2, 17.9, 12.8. ESI-HRMS m / z calcdC47H65N2O6Si [M+H] + 781.4606, found 781.4654.

[0128] Example 5

[0129] Preparation of methyl isopropyl carbonate derivatives of methyl lotusine

[0130]

[0131] Experimental procedure: A solution of N,N-dimethylformamide containing methyl lotusine (50 mg, 0.08 mmol, 1.0 equiv) and K₂CO₃ (27.6 mg, 0.2 mmol, 2.5 equiv) in methyl isopropyl carbonate (97.6 mg, 0.4 mmol, 5.0 equiv) in methyl isopropyl carbonate (0.4 mL) was added dropwise to a solution of N,N-dimethylformamide containing methyl isopropyl carbonate (97.6 mg, 0.4 mmol, 5.0 equiv). The reaction mixture was stirred overnight at room temperature, extracted with dichloromethane, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain F-15 (a pale yellow viscous liquid, 47%).

[0132] (4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenoxy)methyl isopropyl carbonate (F-15): This compound exists as a 50:50 mixture of rotational isomers. The corresponding signals are: 1H NMR (400MHz, CDCl3) δ 7.07 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.90 (dd, J= 8.5, 5.1 Hz, 4H), 6.75 (dd, J = 8.2, 1.9 Hz, 1H), 6.71 (dd, J = 8.3, 1.9Hz, 1H), 6.67 (d, J = 8.6 Hz, 4H), 6.62 (d, J = 4.1 Hz, 2H), 6.54 (d, J = 1.8Hz, 1H), 6.51 (d, J = 1.9 Hz, 1H), 6.48 (s, 2H), 6.47 (s, 1H), 6.31 (s, 1H),5.96 (d, J = 5.2 Hz, 2H), 5.71 (q, J = 6.2 Hz, 2H), 5.29 (s, 1H), 4.90 (dtd,J = 12.5, 6.2, 3.2 Hz, 2H), 3.79 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.73(s, 3H), 3.71 (s, 3H), 3.71 (s, 3H), 3.69 – 3.62 (m, 4H), 3.57 (s, 3H), 3.57(s, 3H), 3.22 – 3.08 (m, 6H), 3.04 – 2.93 (m, 2H), 2.88 – 2.67 (m, 14H), 2.67– 2.52 (m, 6H), 2.50 (s, 3H), 2.48 (s, 3H), 2.47 (d, J = 2.2 Hz, 6H). 13C NMR(100 MHz, CDCl3) δ 158.1, 153.8, 152.9, 149.8, 149.5, 149.4, 148.1, 147.7,146.8, 145.7, 145.3, 142.8, 142.7, 130.7, 125.0, 124.6, 122.8, 120.3, 119.8,119.5, 119.4, 119.2, 113.7, 113.6, 112.9, 112.6, 111.4, 111.1, 90.3, 73.2,72.7, 64.7, 64.5, 56.1, 56.0, 55.9, 55.9, 55.8, 55.3, 47.3, 47.1, 46.4, 46.3,42.7, 42.5, 42.2, 41.0, 40.8, 40.1, 40.0, 32.1, 31.7, 31.6, 30.5, 30.3, 29.6,21.9, 21.9. ESI-HRMS m / z calcd C43H53N2O9 [M+H] + 741.3746, found 741.3708.

[0133] Example 6

[0134] Preparation of nitrated derivatives of methylnephrine

[0135]

[0136] Experimental procedure: Methylnephrine (100 mg, 0.16 mmol) was dissolved in acetic anhydride (0.5 mL) and nitric acid (0.5 mL) solution. After stirring at -40℃ for 5 hours, the reaction solution was quenched with cold ammonia water, the reaction was diluted with dichloromethane, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to obtain F-12 (16 mg, 15%), an orange-red solid.

[0137] 4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)-6-nitrophenol (F-12): 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.67 (s, 1H), 6.65 (d, J = 8.6 Hz, 2H), 6.49 (s,1H), 6.35 (s, 1H), 6.14 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H),3.72-3.71 (m, 1H), 3.69 (s, 3H), 3.62 (t, J = 5.7 Hz, 1H), 3.24 – 3.17 (m,1H), 3.14 – 3.04 (m, 2H), 2.95 (dd, J = 14.3, 6.4 Hz, 1H), 2.89 (dd, J =14.1, 5.2 Hz, 2H), 2.86 – 2.81 (m, 1H), 2.77 – 2.64 (m, 5H), 2.55 (s, 3H), 2.41 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 158.2, 158.2, 149.1, 147.8, 147.4,146.6, 145.6, 145.6, 142.8, 134.1, 134.1, 131.0, 130.7, 130.7, 127.3, 126.9,126.9, 119.5, 118.9, 118.9, 113.7, 113.7, 112.8, 112.8, 111.7, 111.7, 110.6,110.6, 64.6, 64.2, 56.2, 56.0, 55.3, 47.4, 46.9, 42.7, 42.4, 40.4, 39.9,32.1, 31.6, 30.4, 29.9, 25.3, 22.9. ESI-HRMS m / z calcd C38H44N3O8 [M+H] + 670.3123, found 670.3157.

[0138] Example 7

[0139] Preparation of brominated derivatives of methylnephrine

[0140]

[0141] Experimental Procedure: Methyllimonin (100 mg, 0.16 mmol, 1.0 equiv) was dissolved in glacial acetic acid (3.2 mL), and tribromopyridinium salt (77 mg, 0.24 mmol, 1.5 equiv) was added. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was adjusted to alkali with ammonia and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 63.9 mg of a light brown solid, with a yield of 51%. TEA (8.6 mg, 0.085 mmol, 3.0 equiv) was added to a dichloromethane solution (0.57 mL) of the previous step product (20 mg, 0.028 mmol, 1.0 equiv), followed by the addition of pentanoic anhydride (10.6 mg, 0.057 mmol, 1.2 equiv). The mixture was stirred overnight at room temperature. Extraction reaction with dichloromethane, washing with saturated sodium bicarbonate solution, washing twice with water, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and then purifying by column chromatography to obtain F-16 (17 mg, 76%), a light yellow oily liquid.

[0142] 5-Bromo-4-(((R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(((R)-6-methoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3-4-tetrahydroisoquinoline-7-yl)oxy)phenyl neopentanoate (F-16): 1 H NMR (500 MHz, CDCl3) δ 7.01 (s, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 6.61 (s, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.04 (s,1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.71 (s, 4H), 3.69-3.65 (m, 2H), 3.63 (s,3H), 3.18 – 3.06 (m, 3H), 2.99 (dd, J = 13.9, 5.5 Hz, 1H), 2.83 – 2.73 (m,5H), 2.69 (dd, J = 13.7, 7.7 Hz, 1H), 2.65 – 2.58 (m, 1H), 2.55-2.51 (m, 1H), 2.47 (s, 3H), 2.44 (s, 3H), 1.30 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 183.2,175.2, 167.9, 158.0, 150.2, 149.3, 147.7, 146.9, 142.7, 139.3, 137.8, 131.4,130.7, 130.7, 130.6, 130.0, 128.1, 127.9, 125.5, 119.6, 118.6, 117.1, 113.6,112.9, 111.5, 111.0, 64.5, 64.4, 56.1, 56.0, 56.0, 55.3, 47.0, 46.4, 42.4,42.2, 40.9, 40.1, 39.3, 29.8, 27.7, 27.3, 25.7, 24.8. ESI-HRMS m / z calcdC43H52BrN2O7 [M+H] + 787.2952, found 787.2978.

[0143] Example 8

[0144] Preparation of acetaminated derivatives of methylnephrine

[0145]

[0146] Experimental steps: (1) Add the corresponding bromoacetamide group (1.2 equiv) and DIPEA (3.0 equiv) to a tetrahydrofuran solution (0.1 M) of compound A or B (1.0 equiv). Stir the reaction mixture overnight at room temperature. Extract the reaction mixture with dichloromethane, wash twice with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the corresponding tetrahydroisoquinoline derivatives C and D. (2) Add NaH (1.0 equiv) and MOMBr (1.0 equiv) to a tetrahydrofuran solution (0.1 M) of compound C (1.0 equiv) at 0 °C. After reacting the reaction mixture at room temperature for 1 hour, add methanol to terminate the reaction. Extract the reaction mixture with dichloromethane, wash twice with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain E. (3) Compound E (1.0 equiv), D (1.2 equiv), a mixture of cuprous bromide and dimethyl sulfide (20 mol%), 2-pyridinecarboxylic acid (0.4 equiv), and potassium phosphate (3.0 equiv) were added to a Schlenk flask. Pyridine (0.05 M) was added under anhydrous and oxygen-free conditions, and the reaction was then heated at 110 °C for 3 days. After the reaction was complete, the pyridine was removed by vacuum concentration, the reaction was extracted with dichloromethane, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by column chromatography to obtain the target compound.

[0147]

[0148] (R) -N-benzyl-2-(1-(3-bromo-4-hydroxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylacetamide (C-1): foamy solid, 74% yield. This compound exists as a mixture of 53:47 amide rotational isomers. The spectral signal of the compound is as follows: 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.35 – 7.27(m, 6H), 7.24 (dd, J = 10.1, 4.4 Hz, 2H), 7.20 (d, J = 7.1 Hz, 2H), 7.03 (dd,J = 8.3, 1.8 Hz, 1H), 7.01 – 6.97 (m, 3H), 6.93 (d, J = 8.2 Hz, 1H), 6.90 (d,J = 8.2 Hz, 1H), 6.57 (s, 1H), 6.56 (s, 1H), 6.37 (s, 1H), 6.24 (s, 1H), 4.71(d, J = 14.6 Hz, 1H), 4.52 (d, J = 16.9 Hz, 1H), 4.20 (d, J = 14.6 Hz, 1H),4.00 (d, J = 17.0 Hz, 1H), 3.84 (s, 3H), 3.84 (s, 3H), 3.83 – 3.80 (m, 1H),3.75 (s, 4H), 3.70 (s, 3H), 3.48 – 3.44 (m, 1H), 3.40 – 3.30 (m, 4H), 3.29(d, J = 12.8 Hz, 1H), 3.03 – 2.96 (m, 3H), 2.95 (s, 3H), 2.92 (dd, J = 14.2,9.6 Hz, 3H), 2.88 (s, 3H), 2.82 – 2.78 (m, 2H), 2.77 (s, 3H), 2.71 (s, 3H),2.52 – 2.45 (m, 1H), 2.42 (dd, J = 16.0, 4.6 Hz, 1H). 13C NMR (150 MHz, CDCl3)δ 170.76, 170.36, 162.82, 151.00, 150.97, 147.87, 147.83, 147.32, 147.06,137.46, 137.29, 134.12, 133.91, 133.11, 133.04, 130.50, 130.37, 128.97,128.74, 128.56, 128.43, 128.27, 127.50, 127.45, 126.44, 125.72, 125.68,115.92, 115.86, 111.68, 111.65, 111.22, 111.09, 109.80, 109.72, 63.13, 57.34,57.26, 56.02, 55.91, 52.78, 51.25, 43.45, 43.22, 41.57, 41.27, 36.73, 34.64,34.09, 31.82, 31.68, 29.89, 29.82, 23.59, 22.91. ESI-HRMS m / z calcdC28H32BrN2O4 [M+H]+ 539.1540, found 539.1542.

[0149]

[0150] (R)-4-(2-(1-(3-bromo-4-hydroxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)acetyl)piperazine-1-carboxylic acid tert-butyl ester (C-2): pale yellow liquid, yield 71%. 1H NMR (500 MHz, CDCl3) δ8.01 (s, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.94 (d, J= 8.2 Hz, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.74 –3.69 (m, 1H), 3.69 – 3.59 (m, 1H), 3.41 (d, J = 12.8 Hz, 2H), 3.34 – 3.15 (m,6H), 3.08 – 2.97 (m, 3H), 2.91 (dd, J = 14.3, 9.5 Hz, 1H), 2.87 – 2.78 (m,2H), 2.45 (dd, J = 16.8, 4.2 Hz, 1H), 1.47 (s, 9H). 13 C NMR (125 MHz, CDCl3) δ168.97, 162.83, 154.81, 151.21, 148.00, 147.39, 133.94, 132.87, 130.16,128.32, 125.65, 111.83, 111.09,80.51,63.65,57.46,56.06,56.04,45.39,42.58,41.72,41.56,36.71,31.83,31.68,29.89,28.62,22.92. ESI-HRMS m / zcalcd C29H39BrN3O6 [M+H]+ 604.2017, found 604.2034.

[0151]

[0152] (R)-N-benzyl-2-(1-(3-bromo-4-(methoxymethoxy)benzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylacetamide (E-1): 68% yield, foamy solid. This compound exists as a mixture of 62:38 amide rotational isomers. Signals corresponding to the major rotational isomer: 1H NMR (400 MHz, CDCl3) δ 7.40(d, J = 1.6 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.26 – 7.19 (m, 2H), 7.08 (dd, J =8.4, 1.9 Hz, 1H), 7.04 – 6.98 (m, 2H), 6.56 (s, 1H), 6.39 (s, 1H), 5.24 –5.17 (m, 2H), 4.55 (d, J = 17.0 Hz, 1H), 3.96 (d, J = 17.0 Hz, 1H), 3.85 (s,3H), 3.77 (s, 3H), 3.50 (s, 3H), 3.47 – 3.41 (m, 1H), 3.41 – 3.33 (m, 2H), 3.28 (d, J = 12.7 Hz, 1H), 3.08 – 2.86 (m, 3H), 2.84 – 2.79 (m, 1H), 2.77 (s,3H), 2.46 – 2.38 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 152.21, 147.99, 147.43,147.17, 137.58, 137.46, 134.50, 129.85, 129.67, 128.98, 128.76, 128.29,127.51, 127.45, 126.48, 125.68, 116.40, 116.28, 112.69, 111.77, 111.32,111.21, 95.40, 63.12, 63.04, 60.27, 56.57, 56.53, 56.07, 55.95, 52.76, 51.24,43.44, 43.27, 41.66, 34.57, 34.06, 29.91, 23.54, 22.89. ESI-HRMS m / z calcdC30H36BrN2O5 [M+H]+ 583.1802, found 583.1837.

[0153]

[0154] (R)-4-(2-(1-(3-bromo-4-(methoxymethoxy)benzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)acetyl)piperazine-1-carboxylic acid tert-butyl ester (E-2): Yield 61%, pale yellow liquid. 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4Hz, 1H), 6.57 (s, 1H), 6.31 (s, 1H), 5.24 – 5.17 (m, 2H), 3.85 (s, 3H), 3.82– 3.75 (m, 1H), 3.74 (s, 3H), 3.70 – 3.63 (m, 1H), 3.51 (s, 3H), 3.42 (d, J =13.0 Hz, 2H), 3.30 (ddd, J = 30.3, 21.9, 10.9 Hz, 6H), 3.15 – 2.86 (m, 5H), 2.82 (dd, J = 14.0, 5.7 Hz, 1H), 2.48 (dd, J = 16.4, 4.0 Hz, 1H), 1.46 (s,9H). 13 C NMR (125 MHz, CDCl3) δ 154.72, 152.35, 148.03, 147.36, 135.45,134.18, 129.64, 125.57, 116.35, 112.78, 111.81, 111.20, 95.46, 80.34, 56.51,56.07, 56.01, 45.47, 41.78, 41.51, 32.13, 29.90, 28.61, 23.19, 22.90. ESI-HRMS m / z calcd C31H43BrN3O7 [M+H]+ 648.2279, found 648.2298.

[0155]

[0156] (R)-N-Benzyl-2-(7-hydroxy-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylacetamide (D-1): White solid powder, 52% yield. This compound exists as a mixture of 54:46 amide rotational isomers. Signals corresponding to the major rotational isomer: 1H NMR (600 MHz, CDCl3) δ 7.32 – 7.27(m, 3H), 7.26 – 7.21 (m, 1H), 7.09 (t, J = 8.0 Hz, 3H), 6.78 (d, J = 8.5 Hz,2H), 6.60 (s, 1H), 6.55 (s, 1H), 4.33 (d, J = 16.9 Hz, 1H), 3.95 (d, J = 16.9Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.74 – 3.69 (m, 1H), 3.40 – 3.31 (m,2H), 3.24 (d, J = 12.7 Hz, 1H), 3.04 – 2.93 (m, 2H), 2.90 (dd, J = 14.1, 9.9Hz, 1H), 2.84 (dt, J = 14.2, 4.0 Hz, 1H), 2.41 (dd, J = 16.7, 4.1 Hz, 1H). 13 CNMR (150 MHz, CDCl3) δ 170.70, 170.32, 161.69, 158.08, 145.52, 143.97,143.84, 137.59, 130.53, 130.46, 128.84, 128.70, 128.25, 127.44, 127.33,126.57, 114.43, 113.92, 113.89, 113.70, 113.69, 111.05, 63.84, 63.71, 59.40,57.59, 57.40, 56.10, 55.48, 55.45, ESI-HRMS m / z calcd C28H33N2O4 [M+H]+ 461.2435, found 461.2440.

[0157]

[0158] (R)-4-(2-(7-hydroxy-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)acetyl)piperazine-1-carboxylic acid tert-butyl ester (D-2): pale yellow liquid, yield 78%.1 H NMR (500 MHz, CDCl3) δ 8.18(s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.60 (s, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.74 – 3.55 (m, 3H), 3.46 (dd, J =16.9, 3.1 Hz, 2H), 3.37 (d, J = 12.6 Hz, 1H), 3.34 – 3.27 (m, 1H), 3.23-3.12(m, 4H), 3.04 – 2.91 (m, 2H), 2.89 – 2.82 (m, 3H), 2.41 (dd, J = 16.7, 3.8Hz, 1H), 1.47 (s, 9H). 13 C NMR (125 MHz, CDCl3) δ 168.99, 164.52, 160.35,158.25, 154.74, 145.57, 144.02, 132.58, 130.25, 129.75, 125.18, 113.85,111.13, 80.78, 80.24, 63.98, 60.77, 57.69, 56.13, 55.54, 45.28, 42.10, 41.68,29.88, 28.58, 28.55, 22.76. m / z calcd C29H40N3O6 [M+H]+ 526.2912, found 526.2956.

[0159]

[0160] N-Benzyl-2-((R)-7-(5-(((R”-2-(2-(benzyl(methyl)amino)-2-oxoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(methoxymethoxy)phenoxy)-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylacetamide (F-20): White solid, 35% yield. 1H NMR(500 MHz, CDCl3) δ 7.31 – 7.27 (mii, 8H), 7.24 – 7.20 (m, 6H), 7.16 (d, J =6.8 Hz, 2H), 7.09 – 7.02 (m, 5H), 7.00 – 6.92 (m, 7H), 6.83 – 6.76 (m, 3H),6.73 – 6.61 (m, 9H), 6.60 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 6.47 (d, J =1.7 Hz, 1H), 6.43 (s, 1H), 6.25 (s, 1H), 6.16 (s, 1H), 5.21 – 5.13 (m, 4H),4.62 (dd, J = 14.0, 9.6 Hz, 1H), 4.54 (d, J = 16.9 Hz, 1H), 4.38 – 4.30 (m,2H), 4.22 – 4.16 (m, 1H), 4.10 (d, J = 17.3 Hz, 1H), 3.96 – 3.90 (m, 2H),3.85 – 3.82 (m, 2H), 3.80 (s, 6H), 3.78 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H),3.71 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 3.51 – 3.43 (m, 8H),3.39 – 3.23 (m, 9H), 3.02 – 2.89 (m, 9H), 2.82 (s, 3H), 2.73 (s, 3H), 2.68(s, 3H), 2.56 (s, 3H), 2.49 – 2.38 (m, 3H). ESI-HRMS m / z calcd C58H67N4O9 [M+H] + 963.4903, found 963.4896.

[0161]

[0162] 4-(2-(((R)-7-(5-((((R)-2-(2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-oxyethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(methoxymethoxy)phenoxy)-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)acetyl)piperazin-1-carboxylic acid tert-butyl ester (F-21): pale yellow liquid, yield 29%. 1 H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 8.1 Hz, 1H), 7.07 – 6.99 (m,2H), 6.78 (dd, J = 19.9, 10.4 Hz, 3H), 6.67 (s, 1H), 6.63 – 6.50 (m, 3H),6.14 (s, 1H), 5.17 (s, 2H), 3.86 – 3.82 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H),3.74 (s, 3H), 3.74 – 3.69 (m, 2H), 3.65 (s, 6H), 3.45 (s, 2H), 3.43-3.39 (m,3H), 3.38 – 3.29 (m, 6H), 3.24 – 3.14 (m, 6H), 3.04 – 2.96 (m, 3H), 2.93 –2.87 (m, 3H), 2.85 – 2.75 (m, 3H), 2.62 (s, 2H), 2.55 – 2.44 (m, 2H). 13C NMR(125 MHz, CDCl3) δ 162.42, 161.24, 155.53, 154.76, 154.73, 153.06, 152.52,152.21, 150.07, 149.50, 139.12, 138.24, 135.40, 132.06, 130.24, 129.52,124.23, 123.69, 116.12, 114.28, 113.87, 113.03, 113.00, 111.67, 111.24,95.97, 80.36, 80.31, 63.44, 63.35, 56.33, 56.18, 56.03, 55.94, 55.50, 45.43,45.28, 41.80, 41.71, 41.18, 34.94, 34.66, 34.47, 32.13, 31.84, 29.88, 28.59,22.89. ESI-HRMS m / z calcd C60H81N6O13 [M+H] + 1093.5856, found 1093.5904.

[0163] Example 9

[0164] Preparation of N-benzoylated derivatives of methylnephrine

[0165] .

[0166] Experimental steps: (1) Add the corresponding acid anhydride (1.2 equiv) and TEA (3.0 equiv) to a dichloromethane solution (0.1 M) of compound A or B (1.0 equiv). Stir the reaction mixture overnight at room temperature. Extract the reaction with dichloromethane, wash twice with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the corresponding tetrahydroisoquinoline derivatives F and G. (2) Add NaH (2.5 mg, 0.1 mmol, 1.0 equiv) and MOMBr (12.5 mg, 0.1 mmol, 1.0 equiv) to a tetrahydrofuran solution (0.1 M) of compound F (50 mg, 0.1 mmol, 1.0 equiv) at 0 °C. After reacting the reaction mixture at room temperature for 1 hour, add methanol to terminate the reaction. The reaction was extracted with dichloromethane, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain H (48.3 mg, 87%), a colorless liquid. (3) Compound H (1.0 equiv), G (1.2 equiv), a mixture of cuprous bromide and dimethyl sulfide (20 mol%), 2-pyridinecarboxylic acid (0.4 equiv), and potassium phosphate (3.0 equiv) were added to a Schlenk flask. Pyridine (0.05 M) was added under anhydrous and oxygen-free conditions, and then the reaction was heated at 110 °C for 3 days. After the reaction was complete, pyridine was removed by concentration under reduced pressure, the reaction was extracted with dichloromethane, washed twice with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound FJ-07. (4) F-18 (18.5 mg, 0.022 mmol) was dissolved in methanol (0.4 mL), and 1.0 M HCl solution (0.2 mL) was added. The reaction was carried out at room temperature for 1 day. The reaction was terminated by adding saturated sodium bicarbonate solution, extracted with dichloromethane, washed twice with water, dried the organic phase, filtered, and diluted under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography to obtain F-19 (9.0 mg, 51%), a white solid.

[0167]

[0168] (R)-(1-(3-bromo-4-hydroxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)(phenyl)methyl ketone (F): white solid, 47% yield. This compound exists as a mixture of 62:38 amide rotational isomers. Signals corresponding to the major rotational isomers: 1H NMR (600 MHz, CDCl3) δ 7.40 – 7.37 (m, 2H), 7.29 (d, J= 1.7 Hz, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.10 (dd, J = 8.3, 1.8 Hz, 1H), 6.91(d, J = 8.3 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.56 (s, 1H), 6.40 (s, 1H),5.81 (t, J = 6.9 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.71 – 3.67 (m, 1H),3.38 – 3.30 (m, 2H), 3.12 – 3.07 (m, 2H), 2.79 (ddd, J = 13.9, 9.7, 4.9 Hz,2H), 2.57 – 2.51 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ 171.56, 170.87, 151.99,151.58, 148.48, 148.13, 147.63, 147.52, 136.49, 135.92, 133.35, 133.17,131.66, 130.92, 130.69, 130.47, 129.76, 129.59, 128.82, 128.51, 128.10,127.76, 126.69, 126.61, 126.30, 125.42, 116.25, 111.88, 111.44, 110.52,110.35, 109.83, 109.79, 60.06, 56.16, 56.11, 56.05, 53.65, 42.16, 42.01,41.33, 35.80, 29.90, 29.85, 29.53, 29.13, 28.14. ESI-HRMS m / z calcdC25H25BrNO4 [M+H]+ 482.0889, found 482.0985.

[0169]

[0170] (R)-(1-(3-bromo-4-(methoxymethoxy)benzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)(phenyl)methyl ketone (H): 87% yield, colorless liquid. This compound exists as a mixture of 61:39 amide rotational isomers. Signals corresponding to the major rotational isomer: 1 H NMR (600 MHz, CDCl3) δ 7.40 (d, J =6.3 Hz, 3H), 7.30 – 7.26 (m, 2H), 7.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.58 (s, 1H), 6.37 (s, 1H), 5.82 (t,J = 6.9 Hz, 1H), 5.23 (ddd, J = 21.7, 15.8, 6.8 Hz, 3H), 3.85 (s, 3H), 3.73(s, 3H), 3.50 (s, 3H), 3.36 – 3.31 (m, 1H), 3.14 (dq, J = 13.4, 6.7 Hz, 2H), 2.85 – 2.77 (m, 2H), 2.56 (dd, J = 12.9, 2.9 Hz, 1H). 13 C NMR (150 MHz, CDCl3)δ 171.26, 170.74, 152.84, 152.70, 148.45, 148.11, 147.54, 147.41, 136.67,136.20, 134.74, 134.43, 133.36, 132.86, 130.07, 129.89, 129.69, 129.49,128.78, 128.52, 128.07, 127.80, 126.72, 126.55, 125.49, 116.50, 116.35,113.23, 112.69, 111.88, 111.44, 110.61, 109.87, 95.40, 95.28, 59.83, 56.56,56.10, 55.99, 53.52, 42.23, 42.03, 41.25, 35.70, 29.90, 29.14, 28.08. ESI-HRMS m / z calcd C27H29BrNO5 [M+H] + 526.1224 was found; 526.1254 was also found.

[0171]

[0172] (R)-(7-hydroxy-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)(phenyl)methyl ketone (G): white solid, yield 39%. The compound exists as a mixture of 52:48 amide rotational isomers. 1 H NMR(600 MHz, CDCl3) δ 7.39 – 7.34 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 – 7.18(m, 2H), 7.16 (t, J = 7.7 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.81 (dt, J =16.9, 8.3 Hz, 6H), 6.72 (s, 1H), 6.67 (d, J = 7.4 Hz, 2H), 6.53 (s, 1H), 5.88(t, J = 6.6 Hz, 1H), 4.87 (dd, J = 13.0, 6.1 Hz, 1H), 4.77 (dd, J = 9.8, 4.3Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.64 – 3.57(m, 1H), 3.36 (td, J = 12.5, 4.5 Hz, 1H), 3.27 (dd, J = 13.9, 6.0 Hz, 1H), 3.16 (td, J = 13.2, 4.0 Hz, 1H), 3.12 – 3.06 (m, 2H), 3.02 (dd, J = 14.2, 9.9Hz, 1H), 2.82 – 2.76 (m, 2H), 2.75 – 2.68 (m, 1H), 2.44 (d, J = 15.7 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 171.43, 170.61, 158.81, 158.56, 145.96, 145.65,144.33, 144.06, 136.96, 136.19, 130.87, 130.76, 130.28, 130.03, 129.82,129.44, 129.38, 129.25, 129.18, 128.67, 128.59, 128.23, 126.64, 126.60,125.77, 125.08, 114.26, 113.81, 113.40, 112.70, 111.20, 110.74, 59.97, 56.16,56.13, 55.58, 55.43, 53.07, 42.32, 42.05, 41.33, 35.59, 29.29, 28.21. ESI-HRMS m / z calcd C25H26NO4 [M+H] + 404.1856 was found; 404.1882 was also found.

[0173]

[0174] (R)-7-(5-((R)-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-(methoxymethoxy)phenoxy)-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)(phenyl)methyl ketone (F-18): a colorless viscous liquid in 71% yield. This compound exists as a mixture of four amide rotational isomers. Signals corresponding to the rotational isomers: 1H NMR (600 MHz, CDCl3) δ 7.39 – 7.30 (m, 11H), 7.27(d, J = 2.3 Hz, 1H), 7.23 – 7.11 (m, 10H), 7.10 – 6.99 (m, 5H), 6.98 – 6.94(m, 2H), 6.93 – 6.84 (m, 3H), 6.78 – 6.69 (m, 8H), 6.69 – 6.55 (m, 10H), 6.49(dd, J = 24.2, 7.6 Hz, 3H), 6.41 (d, J = 6.8 Hz, 1H), 6.34 (s, 1H), 6.28 (s,1H), 5.99 (d, J = 24.3 Hz, 1H), 5.84 (dt, J = 14.0, 6.8 Hz, 2H), 5.77 – 5.69(m, 2H), 5.25 – 5.16 (m, 4H), 5.11 (d, J = 6.6 Hz, 1H), 4.97 (s, 1H), 4.89 –4.74 (m, 2H), 4.73 – 4.63 (m, 2H), 3.80 (s, 2H), 3.79 (s, 8H), 3.74 (s, 6H),3.73 (s, 4H), 3.71 (s, 2H), 3.70 (s, 6H), 3.66 (s, 2H), 3.60 (s, 2H), 3.56(s, 1H), 3.51 (s, 2H), 3.46 (s, 4H), 3.38 (s, 2H), 3.34 – 3.24 (m, 3H), 3.18– 3.02 (m, 9H), 2.95 (ddd, J = 17.8, 13.8, 8.9 Hz, 3H), 2.85 – 2.70 (m, 7H),2.54 – 2.43 (m, 3H). 13C NMR (150 MHz, CDCl3) δ 170.6, 170.5, 170.4, 170.3,158.6, 158.4, 152.1, 149.7, 149.4, 147.9, 147.9, 147.4, 147.1, 146.9, 146.6,146.4, 144.3, 143.9, 143.6, 142.9, 136.8, 136.4, 136.1, 135.3, 132.7, 130.7,129.9, 129.8, 129.5, 129.5, 129.4, 129.1, 129.0 128.9, 128.9, 128.7, 128.6, 128.5, 128.4, 128.1, 126.6, 126.6, 125.3, 124.2, 123.6, 120.3, 119.1, 118.9, 118.1, 117.7, 117.6, 117.3, 116.0, 114.1, 114.0, 113.7, 113.7, 113.0, 112.6, 111.7, 111.3, 110.5, 95.8, 95.6, 59.7, 59.7, 56.3, 56.2, 56.1, 56.0, 56.0,55.9, 55.9, 55.4, 55.3, 53.3, 53.1, 52.7, 42.7, 41.8, 41.7, 41.6, 41.5, 41.2,41.0, 35.7, 35.4, 34.9, 34.4, 32.1, 31.8, 30.4, 29.8, 29.8, 29.5, 29.4, 29.1,28.4, 27.9, 22.8. ESI-HRMS m / z calcd C52H53N2O9 [M+H] + 849.3746, found 849.3733.

[0175]

[0176] (R)-7-(5-((R)-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)-6-methoxy-1-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-yl)(phenyl)methyl ketone (F-19): 51% yield, white solid. This compound exists as a mixture of four amide rotational isomers. Signals corresponding to the rotational isomers: 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 6.5 Hz, 8H), 7.24 – 7.10(m, 8H), 7.08 – 6.99 (m, 2H), 6.95 – 6.82 (m, 4H), 6.80 – 6.71 (m, 8H), 6.71– 6.58 (m, 5H), 6.52 (m, 2H), 6.38 (m, 1H), 6.29 (m, 1H), 6.06 (m, 1H), 5.93– 5.68 (m, 3H), 4.97-4.79 (m, 2H), 4.78 – 4.59 (m, 1H), 3.83 (s, 3H), 3.81(s, 6H), 3.78 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H), 3.65 (s,3H), 3.64 (s, 3H), 3.60 – 3.48 (m, 2H), 3.33 – 3.15 (m, 5H), 3.12 (d, J = 6.7Hz, 2H), 3.10 – 2.90 (m, 5H), 2.89 – 2.68 (m, 6H), 2.60 – 2.46 (m, 3H). 13 CNMR (125 MHz, CDCl3) δ 172.27, 170.63, 164.69, 156.67, 146.11, 144.92,141.88, 141.00, 140.78, 139.51, 138.52, 138.21, 135.46, 133.82, 130.84,129.58, 128.74, 126.74, 126.67, 124.27, 123.72, 113.87, 112.81, 109.40,107.60, 105.34, 102.24, 102.07, 99.06, 56.24, 56.10, 56.05, 55.41, 52.93,52.66, 46.78, 41.97, 41.71, 41.30, 32.14, 31.84, 31.10, 29.91, 29.81, 29.57,29.18, 28.59, 22.91, 14.32. ESI-HRMS m / z calcd C50H49N2O8 [M+H] + 805.3483,found 805.3497.

[0177] Example 10

[0178] Evaluation of in vitro orexin receptor antagonistic activity of bisbenzyltetrahydroisoquinoline derivatives

[0179] Experimental principle: After orexin A stimulates OX1R and OX2R, it can promote the activation of phospholipase C, thereby increasing intracellular calcium levels. 2+ The concentration increases. Therefore, when different derivatives antagonize OX1R / OX2R, intracellular Ca2+ increases under the stimulation of the agonist appetite A. 2+ The concentration will increase to varying degrees, which can be detected by testing intracellular Ca. 2+ The degree of concentration increase is used to evaluate the strength of a compound's antagonistic effect on orexin receptors. Calcium-sensitive indicator dyes are used to measure changes in intracellular calcium levels; compounds with strong antagonistic activity show higher calcium concentrations. 2+ With reduced influx, the fluorescence signal intensity changes little.

[0180] Experimental Procedure: Chinese hamster ovary cells overexpressing OX1R and OX2R (OX1R-CHO and OX2R-CHO) were seeded into 96-well cell culture plates (black clear bottom), approximately 30,000 cells per well, and cultured overnight. The culture medium was discarded, and the Fluo-4 probe was prepared using buffer and added to the wells. The plates were then incubated at 37 °C for 1 h in the dark. The Fluo-4 probe was discarded, and the cells were washed once with buffer (150 μL / well). 50 μL of buffer was added for testing. The test compound (10...) was prepared... -8 M), add to the corresponding compound in a 96-well plate, and pre-incubate for 15-30 min; prepare the agonist orexin A (10 -6 M) was added to a 96-well plate containing the drug; FLIPR (high-throughput real-time fluorescence signal detection and analysis system) was used for detection, with excitation light in the wavelength range of 470-495 nm and emission light in the wavelength range of 515-575 nm. The change in fluorescence intensity (ΔF) before and after the addition of the agonist was measured and calculated; the values ​​were processed and analyzed, and plotted using GraphPad Prism 8.

[0181] Experimental results: such as Figure 1 and 2 As shown, compared with the control group, the derivatives F-02~F-21 of the present invention can effectively antagonize the agonistic effect of orexin A on OX1R and OX2R, inhibit the Ca2+ influx induced by orexin A, and have antagonistic activity against orexin receptors 1 and 2. At the same concentration, the derivatives F-02~F-21 have stronger inhibitory activity against OX1R and OX2R than methylnephrine.

[0182] Example 11

[0183] Evaluation of the sedative activity of bisbenzyltetrahydroisoquinoline derivatives

[0184] Experimental Principle: In the open field test, the total distance traveled by an animal is a core indicator of its overall locomotor activity. One of the core manifestations of sedation is the reduction of central nervous system excitability, leading to a decrease in spontaneous activity. Therefore, this invention uses the open field test to preliminarily evaluate the sedative effects of preferred derivatives F-02, F-03, F-04, F-05, F-07, F-08, F-09, F-10, F-13, F-14, F-15, F-16, and F-18, which exhibit good orexin receptor antagonistic activity in vitro.

[0185] Experimental results: such as Figure 3 As shown, the sedative effect was evaluated by measuring the total distance traveled by mice 25 minutes after oral administration of a 40 mg / kg dose of the derivative. Initial screening revealed that derivatives F-02, F-03, F-05, F-07, F-08, F-13, F-14, F-15, and F-16 significantly reduced the distance traveled by mice compared to the control group, with statistically significant differences. Subsequently, we selected F-02, F-03, F-07, F-13, and F-14 at reduced doses for further activity validation. Figure 4 As shown, using daliresen as a positive control, reducing the dosage of derivatives to 20 mg / kg, derivatives F-03 and F-13 significantly reduced the movement distance of mice within 25 minutes, with F-03 exhibiting a more significant sedative effect. Based on this, the present invention further screened the effect of the preferred derivative F-03 at different dosages on the spontaneous activity of mice, finding that 5 mg / kg, 10 mg / kg, and 20 mg / kg of F-03 all effectively reduced the spontaneous activity of mice. Compared with the positive control, the effect of 10 mg / kg of F-03 was superior to that of 20 mg / kg of daliresen. Figure 5 ).

[0186] Example 12

[0187] Pentobarbital sodium-induced sleep experiment with dibenzyltetrahydroisoquinoline derivatives

[0188] Experimental Methods: The sodium pentobarbital-induced sleep experiment is a preliminary, rapid, and economical in vivo model for screening compounds with sedative, hypnotic, and anxiolytic activities. Thirty minutes after administration of the test drug, animals were intraperitoneally injected with a subthreshold hypnotic dose of sodium pentobarbital (50 mg / kg). Sleep latency and sleep duration were observed and recorded. Sleep latency was defined as the time from sodium pentobarbital injection to the disappearance of the righting reflex. Sleep duration was defined as the time from the disappearance of the righting reflex to its recovery. This study evaluated the hypnotic activity of compounds using the sodium pentobarbital-induced sleep experiment. Sodium pentobarbital-induced sleep experiments were conducted in C57BL / 6 mice and SD rats to assess the effect of the preferred compound F-03 on sleep latency and sleep duration.

[0189] Experimental results: such as Figure 6 As shown, after injection of a hypnotic dose of sodium pentobarbital (50 mg / kg), compared with the normal group, F-03 at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg significantly prolonged sleep time and shortened sleep latency in mice. In rats, F-03 at 10 mg / kg and 20 mg / kg showed similar hypnotic effects to those in mice, and the hypnotic effect of 10 mg / kg F-03 was comparable to that of the positive control drug daliresen in rats. Figure 7 ).

[0190] Example 13

[0191] Animal electroencephalogram monitoring experiment of bisbenzyltetrahydroisoquinoline derivatives

[0192] Electroencephalography (EEG) is a non-invasive technique that records the spontaneous, rhythmic electrical activity of numerous neurons in the brain using electrodes placed on the scalp. By recording the electrical activity of the cerebral cortex, it is used to accurately distinguish sleep stages (wakefulness, N1, N2, N3 slow-wave sleep, and REM sleep). In this experiment, we used EEG to monitor changes in the brain waves of selected compounds in animals to assess the effects of these compounds on sleep duration and structure, representing the "gold standard" method for accurately analyzing sleep structure and diagnosing sleep disorders.

[0193] Experimental Results: Sleep deprivation mice are an ideal model for studying the efficacy of insomnia drugs. This invention used chronic unpredictable stimulation to establish a rat model of sleep deprivation. Rats were divided into a control group, an insomnia model group, a drug F-03 group, and a positive control drug dalirazene group. After drug administration, the electroencephalogram (EEG) of the rats was observed to evaluate the drug's effect on sleep improvement in insomnia-stricken rats. The EEG monitoring results of rats after administration of 20 mg / kg F-03 are as follows: Figure 8 As shown, where, Figure 8 A shows the electroencephalogram (EEG) and electromyogram (EMG) of the rat. Figure 8B is a statistical chart showing the percentage of awake, NREM, and REM time in each group of rats. Figure 8 C shows the statistical graph of sleep-wake transition time in each group of rats. The results showed that, compared to insomnia-prone rats, administration of 20 mg / kg F-03 significantly increased non-rapid eye movement (MREM) sleep, and the wakefulness time of the rats was significantly reduced compared to insomnia-prone rats, which was statistically significant. While administration of 20 mg / kg methylcaproic acid under the same conditions reduced the wakefulness time compared to insomnia-prone rats, it did not increase MREM sleep. There was no significant difference in nighttime activity time in rats after F-03 administration, indicating that F-03 did not affect normal activity time. Analysis of the rats' sleep quality was performed, such as... Figure 8 As shown, insomniac rats exhibited a significantly increased sleep-wake transition time compared to normal rats. Administration of 20 mg / kg F-03 significantly reduced non-rapid eye movement (NREM) sleep-wake (NW) transition time compared to insomniac rats, demonstrating a significant improvement in sleep disruption and showing superior improvement in sleep quality compared to the positive control drug daliridane. However, under the same conditions, administration of 20 mg / kg methylnephrine had no significant effect on NW transition time.

[0194] Example 14 Home Behavior Activity Observation Box Experiment To further explore the relationship between the efficacy of F-03 and orexin neurons, this invention, following the existing technology (Liu D, Zheng X, Hui Y, et al. Lateral hypothalamus orexinergic projection to the medial prefrontal cortex modulates chronic stress-induced anhedonia but not anxiety and despair[J]. Translational Psychiatry, 2024, 14(1).DOI:10.1038 / s41398-024-02860-9.), studied the effect of F-03 on sleep behavior in mice. Spontaneous activities such as sleep, eating, drinking, and running were recorded in a rodent home behavior observation box for 24 hours after drug administration. The duration of behaviors such as sleep, eating, drinking, walking, jumping, and standing on hind limbs were statistically analyzed. The results are as follows: Figure 9 As shown, where, Figure 9 A is a schematic diagram of stereotactic injection into the brain to activate orexin neurons. Figure 9 B is a behavioral graph of mice within 2 hours after clozapine-induced activation of orexin neurons. Figure 9C is a statistical graph showing the behavioral changes in mice within 6 hours after F-03 administration. Figure 9 D shows the statistical graphs of sleep, food intake, and water intake of mice 6 hours after drug administration in each group. Three weeks after stereotactic lentiviral injection into the brain, clozapine was administered to induce the activation of orexin neurons. Behavioral tests of mice within 2 hours after activation revealed that, compared to the normal group, activated orexin neurons significantly reduced sleep duration and promoted food and water intake, indicating that the stereotactic injection model for activating orexin neurons was successfully established. Figure 9 B). The behavioral performance of mice in the normal group, F-03 administration group (20 mg / kg), methylcaproic acid administration group (20 mg / kg), orexin neuron activation group, and F-03 administration followed by orexin neuron activation group were then tested. The results showed that compared to the normal group, F-03 administration prolonged sleep time and significantly suppressed appetite in mice. Figure 9 C and Figure 9 (D) After administration of F-03, the activation of orexin neurons induced by clozapine showed that the sleep-inducing and appetite-suppressing effects were weaker than those of the F-03 direct administration group, but stronger than those of the orexin neuron activation group, further indicating that F-03 has sleep-inducing and appetite-suppressing activities. At this dose, the prolongation of sleep time and appetite suppression in mice were not significant after administration of methylnephrine.

[0195] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all possible implementations here. All obvious variations or modifications derived from the technical solutions of this invention are still within the scope of protection of this invention.

Claims

1. A bisbenzyltetrahydroisoquinoline derivative, characterized in that, It is a compound as shown in formula (I), or an optical isomer, crystal, or pharmaceutically acceptable salt thereof. Equation (Ⅰ); Wherein, R1 is selected from hydrogen, benzoyl, substituted benzoyl, substituted amide, R5-CO-, C1-C6 alkoxy-C1-C6 alkyl, substituted silyl, -R11OC(=O)OR12; The substituents for substituted silicon, substituted benzoyl, and substituted amide are independently selected from halogens, C1-C6 alkyl, nitro, amino, hydroxyl, and C1-C6 alkoxy groups; The number of substituents in the benzoyl group is 1-5; The number of substituents replacing silicon is 1-3; R5 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-substituted carbonate group, C1-C6 alkyl-substituted amino carbonyl group, and piperidinylpiperidine; R2 is selected from: hydrogen, halogen, nitro; R3 and R4 are independently selected from C1-C6 alkyl, benzoyl, substituted benzoyl, -CH2CONR6R7, etc. ; R6, R7, and R8 are independently selected from C1-C6 alkyl groups, benzene rings, -R9-benzene rings, -OC (=O), and OR10, respectively. R9 and R11 are independently selected from C1-C6 alkylene groups; R10 and R12 are independently selected from C1-C6 alkyl groups; When R1 is hydrogen and R2 is hydrogen, R3 is not a C1-C6 alkyl group; When R1 is hydrogen and R3 is a C1-C6 alkyl group, R2 is not hydrogen; When R5 is methyl and R2 is hydrogen, R3 is not a C1-C6 alkyl group.

2. The bisbenzyltetrahydroisoquinoline derivative according to claim 1, characterized in that, The number of substituents in the substituted silicon group is 3; the substituents in the substituted silicon group are selected from C1-C6 alkyl groups.

3. The bisbenzyltetrahydroisoquinoline derivative according to claim 1, characterized in that, R5 is selected from C4-C6 alkyl; the substituents of the benzoyl group are independently selected from fluorine, chlorine, C4-C6 alkyl, nitro; the substituents of the amide group are independently selected from C4-C6 alkyl; R11 is C1-C3 alkylene; R12 is C1-C3 alkyl.

4. The bisbenzyltetrahydroisoquinoline derivative according to claim 1, characterized in that, R1 is selected from methoxymethyl, acetyl, pivaloyl, N,N-dicarboxyl, methoxyacetyl, benzoyl, 4-bromobenzoyl, 4-tert-butylbenzoyl, 3-chlorobenzoyl, 4-nitrobenzoyl, 2,3-difluorobenzoyl, n-butylcarbamoyl, 4-ethylsuccinoyl, piperidinylpiperidincarbamoyl, triisopropylsilyl, and methylisopropylcarbonate diester.

5. The bisbenzyltetrahydroisoquinoline derivative according to claim 1, characterized in that, R3 and R4 are selected from methyl, acetyl, and benzoyl groups. , .

6. The bisbenzyltetrahydroisoquinoline derivative according to any one of claims 1-5, characterized in that, It is a compound represented by the following formula, or an optical isomer, crystal, or pharmaceutically acceptable salt thereof: F-02 F-03 F-04 F-05 F-07 F-08 F-09 F-10、 F-11 F-12 F-13 F-14 F-15 F-16 F-17 F-18 F-19 F-20 F-21。 7. The method for preparing the bisbenzyltetrahydroisoquinoline derivative according to any one of claims 1-6, characterized in that, Includes the following steps: A base was added to a methyl lotusine solution, followed by an acyl chloride or acid anhydride, and the mixture was stirred overnight at room temperature. The resulting bisbenzyltetrahydroisoquinoline derivative was then purified.

8. The preparation method according to claim 7, characterized in that, The alkali is triethylamine; the purification includes extraction and washing.

9. The use of the bisbenzyltetrahydroisoquinoline derivative according to any one of claims 1-6 in the preparation of an anti-insomnia drug.

10. An anti-insomnia drug, characterized in that, The active ingredient of the anti-insomnia drug includes the bisbenzyltetrahydroisoquinoline derivative according to any one of claims 1-6.

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