Cannabidiol aminoquinone derivative as well as preparation method and application thereof

Abstract

The invention discloses a cannabidiol aminoquinone derivative as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The cannabidiol aminoquinone derivative is a compound with a structure as shown in a formula I, a stereoisomer, a solvate, a hydrate or a pharmaceutically acceptable salt. Tests show that the cannabidiol aminoquinone derivative disclosed by the invention has excellent anti-neuroinflammation activity and anti-Alzheimer's disease activity, and shows huge application potential in the field of treatment of Alzheimer's disease.

Description

Technical Field

[0001] This invention relates to the field of organic pharmaceutical technology, specifically to cannabidiol aminoquinone derivatives, their preparation methods, and applications. Background Technology

[0002] Cannabidiol (CBD) is a non-psychoaddictive cannabinoid derived from the medicinal plant cannabis. CBD and its structural analogues regulate a variety of pharmacological targets, including multiple orphan receptors, G protein-coupled receptors (GPCRs), serotonin 1A receptor (5-HT1A), peroxisome proliferator-activated receptor gamma (PPARγ), and transient receptor potential vanillin subfamily 1 (also known as capsaicin receptor, TRPV1). Therefore, CBD exhibits a variety of potential therapeutic effects, such as neuroprotection, anti-epileptic activity, anti-inflammatory effects, and antioxidant effects. More importantly, CBD can treat various neurodegenerative diseases through multiple mechanisms, including Alzheimer's disease, multiple sclerosis, epilepsy, and Parkinson's disease. Currently, CBD has been approved as an orphan drug by the U.S. Food and Drug Administration (FDA) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome.

[0003] Because cannabidiol (CBD) does not activate central cannabinoid receptors, it does not have the side effect of psychological dependence. CBD's favorable safety profile and non-psychodependent nature demonstrate superior potential in the treatment of neurodegenerative diseases. Natural CBD and synthetic CBD derivatives exhibit different functional characteristics. Among these active CBD derivatives, CBD aminoquinone derivatives have shown outstanding therapeutic potential, exhibiting potent anti-inflammatory effects in peripheral diseases such as systemic sclerosis and cardiac fibrosis, as well as in models of central nervous system diseases such as multiple sclerosis, Parkinson's disease, and traumatic brain injury. Summary of the Invention

[0004] The purpose of this invention is to provide cannabidiol aminoquinone derivatives with novel structures, their preparation methods, and their applications in anti-neuroinflammatory and anti-Alzheimer's disease treatments.

[0005] In a first aspect, the present invention provides compounds, stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts having the structure described in general formula I: ; R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl, C6-12 Aryl, fused ring, or R1 and R2 together with the atoms attached to them and the N atom to form a 5-6 membered heterocyclic group; Optionally, the C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl and C 6-12 Aryl groups are independently and optionally bonded by 0, 1, 2 or 3 R groups. a Replace; where R a Each is independently selected from hydrogen, halogen, and C. 1-8 Alkyl, halogen-substituted C 1-8 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, 5-12-membered heteroaryl, C 6-12 Aryl; Optionally, when R a Selected from 5-12 heteroaryl groups, C 6-12 When aryl, R a Choose any 0, 1, 2 or 3 Rs b Replace; where R b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino; The 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, 5-12-membered heteroaryl, and 5-6-membered heterocyclic groups each independently contain at least one atom or group selected independently from N, O, S, and NH.

[0006] Preferably, R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl, Ra-substituted C 1-8 alkyl, Ra and other variables are defined as described above.

[0007] Preferably, Ra is independently selected from hydrogen, halogen, and C. 1-8 Alkyl, halogen-substituted C 1-8 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, Rb and other variables are defined as described above.

[0008] Preferably, R1 and R2 are independently selected from H, .

[0009] Preferably, the compound is selected from: .

[0010] Secondly, the present invention provides a method for synthesizing compounds, stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts having the structure described in general formula I. The general formula for the synthetic method is as follows: ; R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl, C 6-12 Aryl, fused ring, or R1 and R2 together with the atoms attached to them and the N atom to form a 5-6 membered heterocyclic (alkane) group; Optionally, the C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl and C 6-12 Aryl groups are independently and optionally bonded by 0, 1, 2 or 3 R groups. a Replace; where R a Each is independently selected from hydrogen, halogen, and C. 1-8 Alkyl, halogen-substituted C 1-8 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, 5-12-membered heteroaryl, C 6-12 Aryl; Optionally, when R a Selected from 5-12 heteroaryl groups, C 6-12 When aryl, R a Choose any 0, 1, 2 or 3 Rs b Replace; where R b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino; The 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, 5-12-membered heteroaryl, and 5-6-membered heterocyclic groups each independently contain at least one atom or group selected independently from N, O, S, and NH.

[0011] Preferably, the synthesis method includes: dissolving cannabidiol in a solvent, adding an oxidant under inert gas protection, reacting, separating and purifying to obtain a cannabidiol oxyquinone intermediate; reacting the obtained cannabidiol oxyquinone intermediate with the corresponding amine R1R2NH under alkaline conditions to obtain a compound having the structure of general formula I.

[0012] Thirdly, the present invention provides compositions. The compositions comprise at least one compound having the structure of general formula I, a stereoisomer, a solvate, a hydrate, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0013] Fourthly, the present invention provides the use of compounds, stereoisomers, solvates, hydrates, pharmaceutically acceptable salts, or compositions having the structure of general formula I in the preparation of anti-neuroinflammatory drugs.

[0014] Fifthly, the present invention provides the use of the compound, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, or composition having the structure of general formula I in the preparation of an anti-Alzheimer's disease medicament.

[0015] In a sixth aspect, the present invention provides the use of the compound, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, or composition having the structure of general formula I in the preparation of non-therapeutic care products. Attached Figure Description

[0016] Figure 1 The daily body weight of mice in different groups during the treatment period was characterized.

[0017] Figure 2 A behavioral experiment characterizing the open field (OFT). The components are: (A) a representative trajectory in the OFT; (B) the total dynamic distance in the OFT; (C) the average velocity over the total distance traveled in the OFT; and (D) the distance traveled in the central region of the OFT.

[0018] Figure 3 Behavioral experiments characterizing the Morris Water Maze (MWM). Among them, (A) the average trajectory of mice in the MWM on the last day, (B) the learning curve of the escape delay during the data acquisition phase, (C) the number of times the mice crossed the platform during the data acquisition phase, and (D) the time spent in the target quadrant during the data acquisition phase.

[0019] Figure 4 Characterize the neuroprotective effects of cannabidiol aminoquinone derivatives on Alzheimer's disease.

[0020] Figure 5 Characterizing the therapeutic effects of cannabidiol aminoquinone derivatives on Alzheimer's disease. Among them, (A) used mouse Aβ... 1-42 ELISA kits quantify Aβ in the whole brain and hippocampus of different groups of mice. 1-42 The total amount (P < 0.05), (B) Standard curve of a given compound as determined by the ELISA kit.

[0021] In the above figures, mean ± standard deviation (n=10); letters indicate significant differences (P < 0.05). Detailed Implementation

[0022] The present invention is further illustrated by the following embodiments. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the present invention.

[0023] Compounds, stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts having the structure described in Formula I: .

[0024] R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl (e.g., C) 1-6 Alkyl, preferably C 1-3 Alkyl), C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl (e.g., 5-6-membered heteroaryl), C 6-12 Aryl, fused ring. Alternatively, R1 and R2, together with the atoms attached to them and the N atom, form a 5-6 membered heterocyclic (alkane) group.

[0025] Optionally, the C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl (e.g., 3-6-membered heterocycloalkyl), 5-12-membered heteroaryl (e.g., 5-6-membered heteroaryl), and C 6-12 Aryl groups are independently and optionally bonded by 0, 1, 2 or 3 R groups. a Replace; where R a Each is independently selected from hydrogen, halogens (e.g., F, Cl, Br, I), and C. 1-8 Alkyl (e.g., C) 1-6 Alkyl, preferably C 1-3 Alkyl), halogen-substituted C 1-8 Alkyl groups (e.g., halogen-substituted C4 groups) 1-6 Alkyl groups, preferably halogen-substituted, especially trifluoromethyl groups, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, 5-12-membered heteroaryl (e.g., 5-6-membered heteroaryl), C 6-12 Aryl (e.g., phenyl).

[0026] Optionally, when R a Selected from 5-12 heteroaryl groups, C 6-12 When aryl, R a Choose any 0, 1, 2 or 3 Rs b Replace; where R b Each is independently selected from hydrogen, halogen, and C.1-6 Alkyl (e.g., C) 1-3 Alkyl), halogen-substituted C 1-6 Alkyl groups (e.g., halogen-substituted C4 groups) 1-3 Alkyl), C 1-3 Alkoxy, C 1-3 Alkylamino.

[0027] The heterocyclic alkyl, heterocyclic alkenyl, heteroaryl, and heterocyclic groups each independently contain at least one (e.g., 1, 2, 3, 4) atom or group of atoms independently selected from N, O, S, and NH.

[0028] In an optional implementation, R1 and R2 are independently selected from H and C, respectively. 1-3 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 0, 1, 2, or 3 R groups. a Replace; R a Selected independently from H, halogens (e.g., F, Cl, Br, I), -CF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12 membered heterocyclic alkyl (e.g., 3-6 membered heterocyclic alkyl), C 6-12 Aryl and 5-6-membered heteroaryl; the heterocyclic alkyl (e.g., 3-12-membered heterocyclic alkyl), heterocyclic alkenyl and heteroaryl (e.g., 5-6-membered heteroaryl) each independently comprises at least one (e.g., 1, 2, 3 or 4) atoms or groups independently selected from N, O, S and NH.

[0029] In an optional implementation, R1 and R2 are independently selected from H and C, respectively. 1-3 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 0, 1, 2, or 3 R groups. a Replace, R a Other variables are as defined in this invention.

[0030] In an optional embodiment, R1 and R2 are independently selected from H, -CH2-CH2-OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridylethyl, piperazine, piperidinyl, and 2-(1H-indol-2-yl)ethyl, wherein the phenyl, benzyl, phenethyl, piperazine, piperidinyl, and 2-(1H-indol-2-yl)ethyl are independently optionally substituted by 0, 1, 2, or 3 Ra, and Ra and other variables are as defined in this invention.

[0031] Ideally, R a Selected from H, halogens (e.g., F, Cl, Br, I), -CF3, C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12 membered heterocyclic alkyl (e.g., 3-6 membered heterocyclic alkyl), C 6-12 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, C 6-12 Mixed aromatic compounds.

[0032] Ideally, R b Selected from H, halogens (e.g., F, Cl, Br, I), -CF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino.

[0033] In an optional implementation, R1 and R2 are independently selected from H, .

[0034] In some embodiments, the compound is selected from: .

[0035] Synthesis of compounds of general formula I This invention uses cannabidiol as the main component to synthesize its aminoquinone derivatives. The synthetic method for cannabidiol aminoquinone derivatives is as follows: .

[0036] This invention provides an exemplary method for synthesizing the above-mentioned cannabidiol aminoquinone derivatives, comprising the following steps: Cannabidiol was dissolved in an organic solvent, and an oxidizing agent was added under inert gas protection. The intermediate, cannabidiol oxyquinone, was obtained through reaction, separation, and purification. Reagents and reaction conditions: the oxidizing agent was 2-iodooxybenzoic acid (IBX), the solvent was ethyl acetate, the reaction temperature was room temperature, and the reaction time was 3–5 hours.

[0037] The obtained intermediate was reacted with the corresponding amine under alkaline conditions to generate a cannabidiol aminoquinone derivative of formula I. Reagents and conditions: R1R2NH, EtOH, alkaline conditions, room temperature, overnight.

[0038] In addition to the active ingredient, the compounds of the present invention can be formulated into various dosage forms such as tablets, capsules, lozenges, injections, suspensions, suppositories, or ointments by adding pharmaceutically acceptable excipients (e.g., pharmaceutically acceptable carriers, excipients, etc.). Such excipients allow the pharmaceutical compositions of the present invention to be appropriately selected based on the availability of one or more formulations suitable for use in selecting the present invention.

[0039] The excipients include, but are not limited to, one or more combinations of calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. The carriers include, but are not limited to, one or more combinations of diluents, disintegrants, binders, and lubricants. The excipient formulation can be appropriately selected based on the available substances. For example, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose hydrochloride, sodium alginate, polyvinylpyrrolidone, etc., can be used as suspending agents or dispersants.

[0040] This invention also provides the application of the above-mentioned cannabidiol derivatives in neuroinflammation and anti-Alzheimer's disease. The results of anti-Alzheimer's activity assays show that the cannabidiol derivatives of this invention possess good anti-neuroinflammation and anti-Alzheimer's disease activities, demonstrating promising application prospects in the treatment of Alzheimer's disease.

[0041] Abbreviations: ICV (intraventricular injection); PO (oral administration).

[0042] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0043] Example 1: Preparation of compound G-1 Synthesis of (1'S,6'R)-6-hydroxy-3-((2-methoxyethyl)amino)-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Compound 1 (cannabidiol) (629 mg, 2 mmol) was dissolved in ethyl acetate (30 mL), and 2-iodobenzoic acid (1120 mg, 4 mmol) was added under argon atmosphere at room temperature, and the mixture was stirred for 3 h. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, the organic phase was washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate, gradient elution) to give compound 2 (518 mg, 79% yield).

[0044] Compound 2 from the above steps was dissolved in ethanol (20 mL), and the corresponding amine (6 mmol) and Cs₂CO₃ (4 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until compound 2 disappeared. Ethyl acetate (20 mL) was added, and the mixture was washed twice with water and saturated brine. The organic phase was then dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate, gradient elution) to give the corresponding compound G-1.

[0045] 1 H NMR (600 MHz, DMSO- d 6) : d 10.28 (s, 1H, OH), 6.79 (t, J = 6.0 Hz,1H, NH), 5.06 (s, 1H, CH =C), 4.49 (d, J = 6.5 Hz, 2H, CH 2=C), 3.59 – 3.56 (m,2H, NCH2), 3.52 (t, J = 5.3 Hz, 2H, OCH2), 3.28 (s, 3H, OCH3), 2.75 – 2.69 (m,1H), 2.41 (t, J = 7.8 Hz, 2H), 2.07 (m, 1H), 1.92 (dd, J = 17.5, 5.3 Hz, 1H), 1.68 – 1.65 (m, 1H), 1.58 (d, J = 13.9 Hz, 8H), 1.33 – 1.25 (m, 6H), 0.85 (t,J = 6.9 Hz, 3H). 13 C NMR (151 MHz, DMSO) d182.86 (C=O), 179.30 (C=O), 155.88(C-OH), 148.20 (C=CH2), 144.70, 131.88, 124.04, 116.12, 110.28, 106.56 (C=CH2), 70.52 (OCH2), 58.10 (OCH3), 43.73, 43.55 (NCH2), 39.52, 35.34, 31.20,30.11, 29.61, 28.60, 23.17, 22.95, 21.96, 18.65, 13.88. TOF-HRMS (ESI) m / z: [M+H] + calcd for C 24 H 36 NO4: 402.2639; found: 402.2636.

[0046] Example 2: Preparation of compound G-2 Synthesis of (1'S,6'R)-3-(cyclopropylamino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (400 MHz, CDCl3): d 8.31 (s, 1H, OH), 6.45 (s, 1H, NH), 5.10 (s, 1H), 4.54 (d, J = 4.9 Hz, 2H), 3.60 (d, J = 9.8Hz, 1H), 2.89 – 2.81 (m, 1H, NCH, cyclopropyl), 2.76 – 2.66 (m, 3H), 2.17 (s,1H), 1.94 (d, J = 17.2 Hz, 1H), 1.77 – 1.71 (m, 1H), 1.63 (d, J = 14.8 Hz, 7H), 1.45 (s, 2H), 1.33 – 1.28 (m, 4H), 0.86 (d, J = 6.0 Hz, 5H), 0.72 (s, 2H, cyclopropyl). 13 C NMR (101 MHz, CDCl3) d183.04 (C=O), 180.18 (C=O),154.57, 148.49, 146.00, 133.55, 123.18, 116.42, 110.62, 108.24, 44.56, 36.03,32.14, 30.87, 30.54, 29.04, 27.11 (NCH, cyclopropyl), 23.85, 23.49, 22.66,18.86, 14.15, 9.89 (cyclopropyl), 9.86 (cyclopropyl). TOF-HRMS (ESI) m / z: [M+H] + calcd for C 24 H 34 NO3: 384.2533; found: 384.2538.

[0047] Example 3: Preparation of compound G-3 Synthesis of (1'S,6'R)-3-(cyclobutylamino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (400 MHz, CDCl3) : d 8.39 (s, 1H, OH), 6.45 (s, 1H, NH), 5.12 (s, 1H, CH =C), 4.61 – 4.52 (m, 2H, CH 2=C), 3.62 (dd, J = 4.2, 2.2 Hz, 1H, NCH), 3.42 (q, J = 6.6 Hz, 2H), 2.77 – 2.66 (m, 1H), 2.51 – 2.44 (m, 2H), 2.25 – 2.13 (m, 1H), 1.96 (dd, J = 17.3, 4.5 Hz, 1H), 1.77 –1.72 (m, 1H), 1.64 (d, J = 15.9 Hz, 9H), 1.44 – 1.37 (m, 2H), 1.35 – 1.26 (m,4H), 0.99 (t, J= 7.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 183.05 (C=O), 179.63 (C=O), 154.93 (C-OH), 148.59, 145.65, 133.57,123.31, 116.16, 110.64, 106.49, 46.52 (NCH), 44.62, 36.14, 31.87, 30.58 (2C,cyclobutyl), 29.73, 29.08, 23.91, 23.76, 23.53, 22.61, 18.90, 14.15, 11.31. TOF-HRMS (ESI) m / z: [M+H] + calcd for C 25 H 36 NO3: 398.2690; found: 398.2691.

[0048] Example 4: Preparation of compound G-4 Synthesis of (1'S,6'R)-3-(cyclopentylamino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (400 MHz, CDCl3): d 8.39 (s, 1H, OH), 6.51 (d, J = 8.4 Hz, 1H, NH), 5.12 (s, 1H), 4.55 (s, 2H), 4.10 (s, 1H), 3.61(d, J = 9.6 Hz, 1H, NCH, cyclopentyl), 2.75 – 2.68 (m, 1H), 2.47 (s, 1H), 2.42 – 2.38 (m, 1H), 2.18 (s, 1H), 1.97 (s, 2H), 1.75 (d, J = 9.7 Hz, 5H), 1.64 (d, J = 13.8 Hz, 11H), 1.40 (s, 1H), 1.32 – 1.28 (m, 4H), 0.87 (d,J =6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 183.01 (C=O), 179.35 (C=O), 155.03 (C-OH), 148.49, 144.72, 133.46, 123.28, 116.06, 110.58, 106.08, 55.18 (NCH,cyclopentyl), 44.55, 36.15, 35.25 (cyclopentyl), 35.20 (cyclopentyl), 31.80,30.52, 30.03, 29.03, 24.00, 23.97 (cyclopentyl), 23.91 (cyclopentyl), 23.47,22.53, 18.86, 14.11. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 26 H 38 NO3: 412.2846; found: 412.2852.

[0049] Example 5: Preparation of compound G-5 Synthesis of (1'S,6'R)-3-(cyclohexylamino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 7.33 (d, J = 9.6Hz, 1H), 5.14 (s, 1H, CH =C), 4.51 (d, J = 9.5 Hz, 2H, CH 2=C), 3.63 (s, 1H), 3.38 (s, 1H, NCH), 2.86 (d, J = 14.2 Hz, 2H), 2.46 (s, 1H), 2.32 (d, J = 9.0Hz, 1H), 2.22 (s, 1H), 1.94 (d, J= 11.3 Hz, 4H, cyclohexyl), 1.79 – 1.76 (m,3H), 1.66 (s, 4H, cyclohexyl), 1.52 (s, 2H, cyclohexyl), 1.42 (d, J = 4.6 Hz,1H), 1.32 – 1.29 (m, 7H), 1.25 (s, 2H), 1.23 (s, 1H), 0.91 (d, J = 7.5 Hz, 1H), 0.86 (t, J = 6.8 Hz, 3H). TOF-HRMS (ESI) m / z: [M + H] + , calcd forC 27 H 40 NO3: 426.3003; found: 426.2999.

[0050] Example 6: Preparation of compound G-6 Synthesis of (1'S,6'R)-6-hydroxy-3'-methyl-4-pentyl-3-(phenylamino)-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d8.10 (s, 1H, OH),7.80 (s, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.08 (d, J= 7.8 Hz, 2H), 5.20 (s, 1H), 4.61 (d, J = 3.6 Hz, 2H), 3.74 – 3.67 (m, 1H), 2.80 – 2.74 (m, 1H), 2.43 (d, J = 4.0 Hz, 1H), 2.24 – 2.20 (m, 1H), 2.07 –2.03 (m, 2H), 1.79 (t, J = 2.1 Hz, 2H), 1.70 (s, 2H), 1.67 (m, 3H), 1.41 (s,1H), 1.30 – 1.28 (m, 2H), 1.09 (s, 2H), 0.87 (s, 2H), 0.73 (t, J = 7.3 Hz,3H). TOF-HRMS (ESI) m / z: [M + H] + calcd for C 27 H 34 NO3:420.2533; found:420.2534.

[0051] Example 7: Preparation of compound G-7 Synthesis of (1'S,6'R)-3-((4-chlorophenyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 8.09 (s, 1H, OH),7.70 (s, 1H, NH), 7.10 – 7.00 (m, 4H, benzene), 5.18 (s, 1H, CH =C), 4.63 –4.56 (m, 2H, CH 2=C), 3.73 – 3.68 (m, 1H), 2.79 – 2.73 (m, 1H), 2.27 – 2.18(m, 1H), 2.02 – 1.99 (m, 2H), 1.81 – 1.76 (m, 1H), 1.68 (d, J= 15.9 Hz, 7H), 1.27 (d, J = 14.4 Hz, 1H), 1.11 – 1.02 (m, 4H), 0.89 – 0.82 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H). TOF-HRMS (ESI) m / z: [M + H] + calcd for C 27 H 33 ClNO3: 454.2144; found: 454.2150.

[0052] Example 8: Preparation of compound G-8 Synthesis of (1'S,6'R)-3-((4-fluorophenyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (600 MHz, DMSO- d 6) : d 10.37 (s, 1H,OH), 8.61 (d, J = 3.2 Hz, 1H, NH), 7.12 (m, 4H, benzene), 5.13 (s, 1H, CH =C), 4.54 (d, J = 9.4 Hz, 2H, CH 2=C), 3.61 (d, J = 10.4 Hz, 1H), 2.78 – 2.71 (m,1H), 2.10 (m, 1H), 2.00 – 1.95 (m, 2H), 1.68 (d, J = 5.5 Hz, 1H), 1.60 (d, J= 6.7 Hz, 7H), 1.31 – 1.21 (m, 1H), 1.05 – 0.99 (m, 4H), 0.86 – 0.81 (m, 2H), 0.71 (td, J = 7.2, 2.6 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) d183.31 (C=O),181.01 (C=O), 159.10 (d, J = 241.9 Hz, CF), 155.02, 148.26, 142.60, 136.43,131.92, 125.87, 125.82, 123.96, 117.27, 115.15, 115.00, 112.21, 110.39,43.84, 35.35, 30.98, 30.09, 28.51, 26.78, 23.57, 23.20, 21.63, 18.74, 13.79. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 27 H 33 FNO3: 438.2439; found: 438.2446.

[0053] Example 9: Preparation of compound G-9 Synthesis of (1'S,6'R)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3) : d 7.93 (s, 1H, OH),7.71 (s, 1H, NH), 7.59 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 5.19(s, 1H), 4.59 (d, J = 7.6 Hz, 2H), 3.72 (d, J = 8.9 Hz, 1H), 2.79 – 2.73 (m,1H), 2.22 (s, 1H), 2.14 – 2.10 (m, 2H), 2.00 (d, J = 17.2 Hz, 1H), 1.81 –1.77 (m, 1H), 1.68 (d, J = 19.4 Hz, 6H), 1.27 (d, J = 14.2 Hz, 1H), 1.13 (q, J= 7.7 Hz, 2H), 1.03 (q, J = 7.3 Hz, 2H), 0.92 – 0.88 (m, 2H), 0.73 (t, J =7.3 Hz, 3H). 13 C NMR (126 MHz, CDCl3) d 183.65 (C=O), 181.94 (C=O), 153.58 (C-OH), 148.50, 142.32, 141.60, 134.14, 127.05 (d, J = 33.1 Hz, CF3), 126.26,126.23, 125.86 (C-CF3), 125.28, 123.12, 122.71, 118.10, 114.50, 110.85,44.87, 36.19, 31.52, 30.61, 28.97, 27.12, 25.10, 23.60, 22.29, 18.89, 13.98. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 28 H 33 F3NO3:488.2407; found: 488.2410.

[0054] Example 10: Preparation of compound G-10 Synthesis of (1'S,6'R)-3-((3,4-difluorophenyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 7.99 (s, 1H, OH),7.60 (s, 1H, NH), 7.14 (d, J = 9.6 Hz, 1H), 6.91 (d, J = 3.4 Hz, 1H), 6.83(d, J = 8.8 Hz, 1H), 5.18 (s, 1H), 4.61 – 4.57 (m, 2H), 3.73 – 3.67 (m, 1H), 2.79 – 2.72 (m, 1H), 2.42 (d,J = 7.8 Hz, 1H), 2.22 (s, 1H), 2.05 (s, 1H), 1.79 (s, 1H), 1.70 (s, 3H), 1.66 (s, 3H), 1.61 (m, 1H), 1.33 (m, 1H), 1.29(d, J = 4.6 Hz, 1H), 1.25 (m, 1H), 1.13 – 1.09 (m, 2H), 0.93 – 0.89 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H). TOF-HRMS (ESI) m / z: [M + H] + calcd for C 27 H 32 F2NO3:456.2345; found: 456.2348.

[0055] Example 11: Preparation of compound G-11 Synthesis of (1'S,6'R)-3-((3-ethylphenyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (600 MHz, DMSO- d 6) : d 8.80 (s, 1H,OH), 7.56 (d, J = 8.3 Hz, 1H, NH), 7.29 (d, J = 8.5 Hz, 2H, benzene), 7.10 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H, benzene), 5.16 (s, 1H, CH =C), 4.58 (d, J = 8.8 Hz, 2H, CH2=C), 3.66 (dd, J = 10.7, 2.0 Hz, 1H), 2.86 – 2.70(m, 1H), 2.20 (q, J = 7.7 Hz, 2H), 2.10 (d, J = 5.0 Hz, 1H), 1.98 – 1.87 (m,2H), 1.69 (d, J = 4.3 Hz, 1H), 1.61 (d, J = 5.7 Hz, 8H), 1.18 – 1.14 (m, 4H), 1.06 – 1.02 (m, 2H), 0.95 (d, J = 7.0 Hz, 2H), 0.70 (t, J = 7.3 Hz, 3H). TOF-HRMS (ESI) m / z: [M + H] + calcd for C 29 H 38 NO3:448.2846; found: 448.2650.

[0056] Example 12: Preparation of compound G-12 Synthesis of (1'S,6'R)-3-((2-fluorobenzyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (600 MHz, CDCl3): d 7.31 (d, J = 7.0Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 9.1Hz, 1H), 6.60 (t, J = 6.2 Hz, 1H, NH), 5.15 (s, 1H, CH =C), 4.70 (d, J = 6.3Hz, 2H, CH2=C), 4.61 – 4.55 (m, 2H, NCH2), 3.67 – 3.61 (m, 1H), 2.76 – 2.70(m, 1H), 2.46 – 2.41 (m, 2H), 2.18 (m, 1H), 1.97 (dd, J = 17.4, 5.2 Hz, 1H), 1.75 (d, J = 3.3 Hz, 1H), 1.65 (d, J = 19.8 Hz, 7H), 1.44 (m, 2H), 1.31 –1.26 (m, 5H), 0.87 (t, J = 6.7 Hz, 3H). 13 C NMR (151 MHz, CDCl3) d 182.97 (C=O), 180.28 (C=O), 160.44 (d, J = 247.3 Hz, CF), 154.50 (C-OH), 148.55,145.26, 133.63, 130.01 (d, J = 8.0 Hz), 129.13 (d, J = 3.4 Hz), 124.72 (d, J= 4.2 Hz), 124.59, 123.15, 116.65, 115.84 (d, J = 20.8 Hz), 110.68, 107.72,44.65, 42.68 (d, J = 4.4 Hz, NCH2), 36.15, 31.85, 30.66, 30.55, 29.01, 23.95,23.52, 22.57, 18.88, 14.11. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 28 H 35 FNO3: 452.2596; found: 452.2606.

[0057] Example 13: Preparation of compound G-13 Synthesis of (1'S,6'R)-3-((2-chlorobenzyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (400 MHz, CDCl3): d7.25 (s, 1H), 7.12 (s, 3H), 6.52 (d, J = 5.4 Hz, 1H, NH), 5.14 (s, 1H), 5.02 (s, 1H), 4.58 (d, J = 6.3 Hz, 2H, CH 2=C), 4.45 (d, J = 5.8 Hz, 2H, NCH2), 3.51 (d, J = 9.8 Hz,1H), 2.63 – 2.55 (m, 1H), 2.23 – 2.17 (m, 2H), 2.05 (s, 1H), 1.87 – 1.78 (m,1H), 1.65 – 1.60 (m, 1H), 1.52 (d, J = 12.3 Hz, 7H), 1.28 (m, 2H), 1.16 –1.10 (m, 4H), 0.72 (t, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 183.04 (C=O), 180.34 (C=O), 154.48 (C-OH), 148.57, 145.38, 135.15 (C-Cl), 133.63,133.01, 130.00, 129.41, 128.67, 127.43, 123.14, 116.72, 110.69, 107.89,46.64, 44.67 (NCH2), 36.15, 31.91, 30.82, 30.55, 29.01, 24.01, 23.53, 22.60,18.88, 14.12. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 28 H 35 ClNO3: 468.2300; found: 468.2309.

[0058] Example 14: Preparation of compound G-14 Synthesis of (1'S,6'R)-3-((4-chlorobenzyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 8.17 (s, 1H, OH), 7.35 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 6.60 (s, 1H), 5.15 (s,1H), 4.60 (dd, J = 18.5, 8.2 Hz, 4H, CH 2=C, NCH2), 3.65 (s, 1H), 2.73 (s, 1H),2.44 – 2.40 (m, 2H), 2.19 (s, 1H), 1.99 (s, 1H), 1.76 (s, 1H), 1.66 (m, 6H),1.42 (m, 2H), 1.30 – 1.26 (m, 5H), 0.88 (t, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl3) d 182.90 (C=O), 180.26 (C=O), 154.35 (C-OH), 148.54, 145.06, 135.99,134.00, 133.67 (C-Cl), 129.27 (2C), 128.51 (2C), 122.98, 116.62, 110.57,107.62, 48.09 (NCH2), 44.59, 36.07, 31.78, 30.69, 30.48, 28.94, 23.85, 23.47,22.53, 18.82, 14.05. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 28 H 35 ClNO3:468.2300; found: 468.2305.

[0059] Example 15: Preparation of compound G-15 Synthesis of (1'S,6'R)-6-hydroxy-3-((4-methoxybenzyl)amino)-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 8.25 (s, 1H,OH),7.19 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.55 (s, 1H, NH), 5.14(s, 1H), 4.61 – 4.55 (m, 4H), 3.82 (s, 3H, OCH3), 3.63 (d, J = 10.8 Hz, 1H), 2.75 – 2.69 (m, 1H), 2.52 – 2.46 (m, 2H), 2.18 (s, 1H), 1.98 (d, J = 16.8 Hz, 1H), 1.78 – 1.74 (m, 1H), 1.67 (m, 4H), 1.64 (s, 3H), 1.45 (d, J = 9.7 Hz,2H), 1.34 – 1.26 (m, 4H), 0.91 – 0.86 (m, 3H). 13 C NMR (126 MHz, CDCl3) d 182.88 (C=O), 179.97 (C=O), 159.52 (CO, benzene), 154.57 (C-OH), 148.54,145.26, 133.57, 129.27, 128.82 (2C), 123.12, 116.34, 114.48 (2C), 110.58,107.10, 55.37 (methoxyl), 48.44 (NCH2), 44.58, 36.08, 31.82, 30.81, 30.49,28.97, 23.94, 23.47, 22.58, 18.83, 14.08. TOF-HRMS (ESI) m / z: [M + H] + , calcdfor C 29 H 38 NO4: 464.2796; found: 464.2804.

[0060] Example 16: Preparation of compound G-16 Synthesis of (1'R,6'R)-3-((3-fluorophenylethyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1H NMR (400 MHz, CDCl3) : d 8.33 (s, 1H, OH),7.32 – 7.27 (m, 1H), 6.94 (m, 3H), 6.44 (t, J = 5.8 Hz, 1H, NH), 5.13 (s,1H), 4.58 – 4.55 (m, 2H, CH 2=C), 3.74 – 3.69 (m, 2H, NCH2), 3.65 – 3.60 (m,1H), 2.92 (t, J = 7.1 Hz, 2H, CH2-Ph), 2.76 – 2.68 (m, 1H), 2.51 – 2.46 (m,2H), 2.19 (s, 1H), 1.97 (dd, J = 17.3, 4.5 Hz, 1H), 1.78 – 1.74 (m, 1H), 1.65(d, J = 15.9 Hz, 8H), 1.41 (d, J = 6.2 Hz, 2H), 1.32 – 1.29 (m, 3H), 0.87 (d, J = 6.8 Hz, 3H)。 13 C NMR (101 MHz, CDCl3) d 182.93 (C=O), 179.95 (C=O), 163.12(d, J = 246.7 Hz, C-F), 154.56 (C-OH), 148.56, 145.23, 140.12 (d, J = 7.2Hz), 133.60, 130.44 (d, J = 8.3 Hz), 124.38 (d, J = 2.7 Hz), 123.18, 116.49,115.59 (d, J = 21.2 Hz), 114.05 (d, J= 21.0 Hz), 110.64, 107.12, 45.677(NCH2), 44.57, 36.46, 36.08, 31.80, 30.55, 30.29, 29.04, 23.90, 23.49, 22.60,18.8, 14.10. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 29 H 37 FNO3: 466.2752; found: 466.2756.

[0061] Example 17: Preparation of compound G-17 Synthesis of (1'S,6'R)-3-((3-chlorophenylethyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (600 MHz, CDCl3): d 8.27 (s, 1H,OH),7.26 (d, J = 6.9 Hz, 2H), 7.19 (s, 1H), 7.07 (d, J = 6.7 Hz, 1H), 6.40 (t, J= 6.1 Hz, 1H, NH), 5.13 (s, 1H), 4.60 – 4.51 (m, 2H, CH 2=C), 3.72 (q, J = 6.9Hz, 2H, NCH2), 3.65 – 3.59 (m, 1H), 2.90 (t, J = 7.2 Hz, 2H), 2.72 (td, J =11.8, 11.0, 2.6 Hz, 1H), 2.51 – 2.45 (m, 2H), 2.20 (td, J = 13.0, 12.2, 5.7Hz, 1H), 1.98 (dd, J = 17.6, 5.1 Hz, 1H), 1.80 – 1.74 (m, 1H), 1.65 (d, J =27.0 Hz, 7H), 1.40 (t, J = 7.8 Hz, 2H), 1.31 (dq, J = 11.4, 7.0, 5.3 Hz, 4H), 0.90 – 0.87 (m, 3H). 13C NMR (151 MHz, CDCl3) d 182.96 (C=O), 180.01 (C=O),154.55 (C-OH), 148.64, 145.24, 139.66, 134.83, 133.73, 130.24, 128.87,127.39, 126.95, 123.19, 116.54, 110.69, 107.20, 45.74 (NCH2), 44.64, 36.46,36.15, 31.87, 30.61, 30.37, 29.09, 23.97, 23.57, 22.67, 18.95, 14.19. TOF-HRMS(ESI) m / z: [M + H] + calcd for C 29 H 37 ClNO3:482.2457; found: 482.2460.

[0062] Example 18: Preparation of compound G-18 Synthesis of (1'S,6'R)-3-((4-fluorophenylethyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (400 MHz, CDCl3): d 8.30 (d, J = 22.6Hz, 1H, OH), 7.32 – 7.25 (m, 1H, benzene), 6.98 – 6.86 (m, 3H, benzene), 6.44(s, 1H, NH), 5.13 (s, 1H, CH =C), 4.60 – 4.52 (m, 2H, CH 2=C), 3.73 (q, J = 6.9Hz, 2H, NCH2), 3.66 – 3.57 (m, 1H), 2.92 (t, J = 7.1 Hz, 2H, Ph-CH2), 2.78 –2.67 (m, 1H), 2.53 – 2.45 (m, 2H), 2.26 – 2.14 (m, 1H), 1.97 (dd, J= 17.3,4.5 Hz, 1H), 1.80 – 1.73 (m, 1H), 1.65 (d, J = 15.9 Hz, 7H), 1.40 (s, 2H), 1.30 (dt, J = 7.0, 3.7 Hz, 4H), 0.87 (t, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, CDCl3) d 183.61 (C=O), 181.38 (C=O), 153.90 (C-OH), 148.43, 142.34, 137.48,133.76, 131.18, 128.94 (2C, benzene), 125.61 (2C, benzene), 117.45, 112.03,110.73, 53.50 (NCH2), 44.60, 35.97, 31.45, 30.48, 29.72, 28.88, 27.31, 24.36,23.49, 22.25, 18.78, 13.97. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 29 H 37 FNO3: 466.2752; found: 466.2744.

[0063] Example 19: Preparation of compound G-19 Synthesis of (1'S,6'R)-3-((4-chlorophenylethyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 7.30 (d, J = 8.3Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 6.39 (s, 1H, NH), 5.12 (s, 1H), 4.56 (d, J= 12.8 Hz, 2H, CH2=C), 3.70 (d, J = 6.5 Hz, 2H, NCH2), 3.62 (d, J = 8.8 Hz,1H), 2.89 (t, J = 7.0 Hz, 2H, CH2-Ph), 2.70 (d, J = 10.6 Hz, 1H), 2.50 – 2.46(m, 2H), 2.17 (d, J = 30.5 Hz, 2H), 1.98 (d, J = 21.8 Hz, 2H), 1.68 (s, 3H), 1.63 (s, 2H), 1.43 – 1.41 (m, 1H), 1.30 – 1.28 (m, 4H), 1.26 (s, 2H), 0.88(t, J = 6.6 Hz, 4H). TOF-HRMS (ESI) m / z: [M + H] + calcd for C 29 H 37 ClNO3: 482.2457; found: 482.2462.

[0064] Example 20: Preparation of compound G-20 Synthesis of (1'S,6'R)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-3-((pyridin-4-ylmethyl)amino)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 8.63 (d, J = 4.6Hz, 1H, NH), 8.32 (s, 1H, OH), 7.76 (t, J = 4.7 Hz, 1H), 7.70 (td, J = 7.7,1.6 Hz, 1H), 7.26 – 7.21 (m, 2H, pyridine), 5.15 (s, 1H, CH =C), 4.82 (d, J =5.4 Hz, 2H, CH2=C), 4.57 (s, 2H, NCH2), 3.70 – 3.63 (m, 1H), 2.80 – 2.72 (m,1H), 2.55 – 2.47 (m, 2H), 2.25 – 2.16 (m, 1H), 1.98 (dd, J = 17.4, 4.5 Hz,1H), 1.79 – 1.74 (m, 1H), 1.67 (s, 4H), 1.64 (s, 3H), 1.48 – 1.41 (m, 2H),1.36 – 1.30 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl3) d 183.16 (C=O), 179.78 (C=O), 155.41, 154.37 (C-OH), 149.37 (NCH, pyridine), 148.59 (NCH, pyridine), 145.65, 136.98, 133.46, 123.27, 122.78, 121.53,116.50, 110.56, 107.61, 48.85, 44.48, 36.05, 31.80, 30.49, 30.46, 29.02,23.70, 23.46, 22.55, 18.86, 14.09. TOF-HRMS (ESI) m / z: [M + H] + , calcd forC 27 H 35 N2O3:435.2642; found: 435.2639.

[0065] Example 21: Preparation of compound G-21 Synthesis of (1'S,6'R)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-3-((pyridin-3-ylmethyl)amino)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (600 MHz, DMSO- d 6) : d10.24 (s, 1H,OH), 8.46 (s, 1H, NH), 7.61 – 7.55 (m, 3H, pyridine), 7.35 (d, J = 3.0 Hz,1H, pyridine), 5.09 (s, 1H, CH =C), 4.67 (d, J = 7.2 Hz, 2H, CH 2=C), 4.52 (s,1H), 4.45 (d, J = 2.7 Hz, 1H), 3.60 – 3.56 (m, 1H), 2.72 (t, J = 11.4 Hz,1H), 2.24 (t, J = 7.9 Hz, 2H), 2.06 (dd, J = 12.2, 5.6 Hz, 1H), 1.92 (dd, J =17.6, 5.3 Hz, 1H), 1.66 (s, 1H), 1.57 (d, J = 18.3 Hz, 8H), 1.25 (s, 2H),1.18 (m, 3H), 0.80 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, DMSO) d 183.26 (C=O),179.65 (C=O), 155.42 (C-OH), 148.24 (NCH, pyridine), 147.87 (NCH, pyridine),145.00, 135.16, 134.09, 131.81, 124.08, 123.70, 123.56, 116.63, 110.31,107.71, 45.02, 43.85 (NCH2), 35.37, 31.19, 30.12, 29.32, 28.55, 23.19, 23.04,21.98, 18.63, 13.87. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 27 H 35 N2O3: 435.2642; found: 435.2646.

[0066] Example 22: Preparation of compound G-22 Synthesis of (1'S,6'R)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-3-((pyridin-2-ylmethyl)amino)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 8.56 (dd, J =18.0, 2.6 Hz, 2H, pyridine), 8.39 (s, 1H, OH), 7.58 (d, J = 7.8 Hz, 1H), 7.31(dd, J = 7.8, 4.9 Hz, 1H), 6.57 (t, J = 6.1 Hz, 1H, NH), 5.13 (s, 1H, CH =C),4.66 (d, J = 6.3 Hz, 2H, CH 2=C), 4.56 (d, J = 10.9 Hz, 2H, NCH2), 3.66 – 3.59(m, 1H), 2.74 – 2.67 (m, 1H), 2.45 – 2.38 (m, 2H), 2.21 – 2.13 (m, 1H), 1.96(dd, J = 17.3, 4.5 Hz, 1H), 1.77 – 1.71 (m, 1H), 1.64 (d, J = 17.9 Hz, 7H), 1.41 (d, J = 6.2 Hz, 2H), 1.30 – 1.24 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H). 13CNMR (126 MHz, CDCl3) δ 182.95 (C=O), 180.55 (C=O), 154.47 (C-OH), 149.60,148.82 (NCH, pyridine), 148.56 (NCH, pyridine), 144.95, 134.97, 133.72,133.32, 123.96, 123.05, 116.90, 110.69, 108.07, 46.35 (NCH2), 44.66, 36.12,31.84, 30.68, 30.53, 28.98, 23.93, 23.52, 22.59, 18.85, 14.11. TOF-HRMS (ESI)m / z: [M + H] + calcd for C 27 H 35 N2O3: 435.2642; found: 435.2645.

[0067] Example 23: Preparation of compound G-23 Synthesis of (1'S,6'R)-6-hydroxy-3'-methyl-4-pentyl-3-(piperazin-1-yl)-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 5.30 (s, 1H), 5.16 (s, 1H), CH =C), 4.56 – 4.53 (m, 2H, CH 2=C), 3.68 – 3.65 (m, 1H), 3.42 (m, 2H, piperazine), 3.33 – 3.29 (m, 2H, piperazine), 3.03 (m, 2H, piperazine), 2.77– 2.68 (m, 2H, piperazine), 2.39 (dd, J = 5.4, 2.6 Hz, 3H), 2.25 – 2.16 (m,2H), 2.00 (s, 1H, NH), 1.75 (d, J = 5.2 Hz, 1H), 1.68 (s, 3H), 1.62 (d, J=4.5 Hz, 3H), 1.44 (d, J = 8.3 Hz, 2H), 1.32 (d, J = 2.3 Hz, 3H), 1.25 (s,2H), 0.89 (d, J = 4.5 Hz, 3H). 13 C NMR (126 MHz, CDCl3) d 184.93 (C=O), 183.05(C=O), 152.48, 151.60, 149.00, 133.61, 123.64, 123.19, 120.06, 110.61, 52.73(2C, piperazine), 46.43, 44.82 (2C, piperazine), 36.54, 32.24, 30.58, 29.83, 29.04, 25.94, 23.60, 22.57, 18.95, 14.17. TOF-HRMS (ESI) m / z: [M + H] + , calcdfor C 25 H 37 N2O3:413.2799; found: 413.2807.

[0068] Example 24: Preparation of compound G-24 Synthesis of (1'R,6'R)-6-hydroxy-3'-methyl-4-pentyl-3-((2-(piperazin-1-yl)ethyl)amino)-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3) : d 6.97 (s, 1H,),5.30 (s, 1H, NH), 5.12 (s, 1H, CH =C), 4.55 (s, 2H, CH2=C), 3.64 – 3.60 (m,1H), 3.56 (d, J = 5.4 Hz, 1H), 3.14 (s, 2H, NCH2), 2.78 – 2.73 (m, 1H,pyridazinyl), 2.69 – 2.65 (m, 5H, pyridazinyl), 2.49 – 2.45 (m, 2H,pyridazinyl), 2.21 (d, J = 3.7 Hz, 1H), 2.00 – 1.95 (m, 1H), 1.78 – 1.74 (m,1H), 1.65 (d, J = 20.3 Hz, 8H), 1.41 (s, 1H), 1.32 (dd, J = 6.9, 2.7 Hz, 4H), 1.28 (d, J = 3.3 Hz, 2H), 1.25 (s, 3H), 0.88 (d, J = 5.2 Hz, 3H). TOF-HRMS(ESI) m / z: [M + H] + calcd for C 27 H 42 N3O3:456.3221; found: 456.3227.

[0069] Example 25: Preparation of compound G-25 Synthesis of (1'S,6'R)-3-(4-benzylpiperidin-1-yl)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (500 MHz, CDCl3): d 7.27 (t, J = 7.5Hz, 2H, benzene), 7.19 – 7.12 (m, 3H, benzene), 5.24 (s, 1H, OH), 5.18 (s,1H, CH =C), 4.59 – 4.53 (m, 2H, CH 2=C), 3.71 – 3.64 (m, 1H), 3.46 – 3.37 (m,2H, NCH2, piperidine), 3.13 – 3.03 (m, 2H, NCH2, piperidine), 2.77 – 2.69 (m,1H), 2.57 (d,J = 7.1 Hz, 2H, CH2, benzyl), 2.40 – 2.32 (m, 2H), 2.20 (s,1H), 1.97 (d, J = 13.1 Hz, 1H), 1.75 (d, J = 8.1 Hz, 2H), 1.64 (d, J = 23.8Hz, 9H), 1.48 – 1.40 (m, 3H), 1.34 – 1.24 (m, 5H), 0.88 (t, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl3) d 184.91 (C=O), 182.34 (C=O), 153.62 (C-OH), 151.48,148.78, 140.08, 132.99, 129.07 (2C), 128.24 (2C), 125.96, 123.42, 121.65,119.41, 110.46, 53.44, 52.74 (CN, piperidine), 52.69 (CN, piperidine),44.68, 43.14 (CH2, benzyl), 37.78, 36.46, 33.01, 32.13, 30.47, 29.08, 28.96,25.86, 23.41, 22.42, 18.79, 14.03. TOF-HRMS (ESI) m / z: [M + H] + , calcd forC 33 H 44 NO3: 502.3316; found: 502.3321.

[0070] Example 26: Preparation of compound G-26 Synthesis of (1'S, 6'R)-3-((2-(5-chloro-1H-indol-2-yl)ethyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (400 MHz, CDCl3): d8.33 (s, 1H, OH),7.53 (s, 1H, NH, indole), 7.27 (s, 1H, CH =C, indole), 7.12 (d, J = 33.1 Hz,3H), 6.51 (s, 1H, NH), 5.12 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H, CH 2=C), 3.78(d, J = 5.9 Hz, 2H), 3.62 (d, J = 9.8 Hz, 1H), 3.05 (t, J = 6.0 Hz, 2H), 2.72(t, J = 10.8 Hz, 1H), 2.52 – 2.45 (m, 2H), 2.16 (d, J = 10.8 Hz, 1H), 1.96(d, J = 17.1 Hz, 1H), 1.74 (s, 1H), 1.64 (d, J = 13.5 Hz, 7H), 1.41 – 1.36(m, 2H), 1.29 (m , 4H), 0.87 (s, 3H)。 13 C NMR (101 MHz, CDCl3) d 183.09 (C=O),179.73 (C=O), 154.83 (C-OH), 148.66, 145.50, 134.97 (NC, indole), 133.67,128.11 (C-Cl), 125.61, 123.96, 123.26, 122.88, 118.10, 116.31, 112.60,111.48, 110.66, 106.87, 44.56, 44.51 (NCH2), 36.13, 31.88, 30.59, 30.54,29.11, 26.23, 23.98, 23.55, 22.67, 18.99, 14.18。TOF-HRMS (ESI) m / z: [M + H] + ,calcd for C 31 H 38 ClN2O3:521.2566; found: 522.2573。

[0071] Example 27: Preparation of compound G-27 Synthesis of (1'R, 6'R)-6-hydroxy-3-((2-(5-methoxy-1H-indol-2-yl)ethyl)amino)-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl)-[1,1'-bis(cyclohexane)]-2',3,6-trien-2,5-dione Refer to the synthesis steps of general formula structure I. 1 H NMR (600 MHz, DMSO- d 6) : d 10.75 – 10.68(m, 1H, OH), 7.24 (d, J = 8.7 Hz, 1H, benzene), 7.12 (dd, J = 15.3, 2.4 Hz,2H, benzene), 7.02 (t, J = 6.4 Hz, 1H, NH), 6.73 (dd, J = 8.7, 2.4 Hz, 1H,NH), 5.07 (s, 1H, CH =C), 4.54 – 4.46 (m, 2H, CH 2=C), 3.77 (s, 3H, OCH3), 3.70 (d, J = 7.0 Hz, 2H), 3.56 (d, J = 10.6 Hz, 1H), 2.97 (t, J = 7.2 Hz, 2H), 2.78 – 2.70 (m, 1H), 2.43 (t, J = 7.8 Hz, 2H), 2.07 (dd, J = 12.4, 5.7 Hz,1H), 1.93 (dd, J = 17.4, 5.2 Hz, 1H), 1.68 (dd, J = 12.0, 5.7 Hz, 1H), 1.71 –1.48 (m, 7H), 1.34 – 1.13 (m, 7H), 0.81 (t, J = 6.7 Hz, 3H). 13 C NMR (151 MHz, DMSO) d182.95 (C=O), 179.02 (C=O), 156.06(CO, benzene), 153.14 (C-OH),148.25, 144.75, 131.88, 131.48, 127.35, 124.14, 123.62, 116.02, 112.12,111.35, 110.46, 110.35, 105.99, 100.11, 55.28 (OCH3), 44.46, 43.73 (NCH2),35.34, 31.21, 30.12, 29.62, 28.62, 26.08, 23.19, 23.13, 21.95, 18.71, 13.90. TOF-HRMS (ESI) m / z: [M + H] + calcd for C 32 H 41 N2O4:517.3061; found: 517.3060.

[0072] Bioactivity assay (cellular level)

[0073] Verification of the anti-neuroinflammatory and Alzheimer's disease activities of cannabidiol aminoquinone derivatives.

[0074] To verify that the cannabidiol aminoquinone derivatives of the present invention have anti-neuroinflammatory and Alzheimer's disease activities, the cannabidiol aminoquinone derivatives prepared in the above examples were selected for activity experiments.

[0075] Experimental Principle: Lipopolysaccharide (LPS) is a component of the cell wall of Gram-negative bacteria. LPS is a pathogen found in nature, and its toxic component is mainly lipid A, which is the main pathogenic part that triggers inflammatory responses. The aim is to inhibit nitric oxide production in LPS-stimulated BV2 cells. As a signaling molecule, nitric oxide plays a crucial role in the pathogenesis of inflammation. In the inflamed brain, astrocytes and microglia produce large amounts of nitric oxide during inflammation; excessive nitric oxide can lead to neurotoxicity and death. Therefore, drugs that reduce nitric oxide production can limit neuronal damage caused by neuroinflammation. To evaluate the anti-inflammatory effects of cannabidiol aminoquinone compounds, the level of nitric oxide release induced by LPS in BV2 cells was detected using Griess' reagent. The results showed that LPS treatment significantly increased nitric oxide release compared to the blank control. Pretreatment with a 5 μmol concentration of cannabidiol aminoquinone derivative (PBS + 0.5% DMSO) reduced LPS-induced nitric oxide production in the supernatant.

[0076] Experimental Procedure: The production of nitric oxide by activated BV2 cells was determined by measuring the content of nitrite (a relatively stable NO oxidation product). BV2 cells were cultured in 48-well plates at a rate of 5 × 10⁻⁶ cells / well. 4 Cells were cultured overnight at a density of [number] cells / mL. One hour after adding different concentrations of cannabidiol aminoquinone derivatives, cells were stimulated with LPS for 24 hours. Testing was performed according to the kit instructions (Griess reagent, Beyotime, China). NO inhibition rate was calculated using the following formula: NO inhibition rate (%) = (A (刺激孔) -A ( 给药孔） ) ÷ (A (刺激孔) -A （对照孔） )×100.

[0077] The results of the anti-inflammatory activity verification of cannabidiol aminoquinone derivatives are shown in Table 1. The values ​​measured at 5 μM represent the NO inhibition rates at the corresponding concentrations.

[0078] Table 1

[0079] Experimental results: Cannabidiol aminoquinone analogues exhibited potent anti-inflammatory activity, among which compounds G-5, G-6, G-8, G-9, G-14, G-15, and G-19 significantly reduced the LPS-induced increase in nitric oxide release (IC50). 50 = 1.60, 1.93, 1.39, 0.41, 0.34, 0.37 and 1.59 μM).

[0080] Bioactivity testing (animal level)

[0081] Behavioral tests on the anti-Alzheimer's disease effects of cannabidiol aminoquinone derivatives.

[0082] To verify the anti-Alzheimer's disease effect of the cannabidiol aminoquinone derivative of the present invention, animal experiments were conducted using the cannabidiol aminoquinone derivative prepared in the above examples.

[0083] Principle: In vivo anti-Alzheimer's activity study. One of the main goals of Alzheimer's drug development is to improve cognitive function. To gain a deeper understanding of the anti-Alzheimer's properties of the cannabidiol aminoquinone derivative (G-8), Aβ was studied. 1-42 A peptide-induced cognitive impairment model. To investigate the effects of cannabidiol aminoquinone derivatives (G-8) on Aβ. 1-42 The effects of peptide-induced cognitive impairment were investigated using open field and water maze experiments.

[0084] Materials: ICR male mice, 18-25 g, 6-8 weeks old.

[0085] Experimental groups: control group; sham operation group (intracerebral injection of saline); model group (intracerebral injection of Aβ). 1-42 Peptide); donepezil (positive control group, 15 mg / kg of donepezil administered by gavage); G-8-L (low-dose group of compound G-8, 2.5 mg / kg of compound G-8 administered by gavage); G-8-H (high-dose group of compound G-8, 10 mg / kg of compound G-8 administered by gavage).

[0086] Experimental procedure: On the first day, mice were administered Aβ via injection. 1-42 Peptides. The same procedure was repeated on the second day. An advanced absenteeism test was performed on day 10 to observe the mice, followed by a water maze study, which included 5 days of learning and memory training (days 11-15) and an exploratory test on day 6.

[0087] Experimental results: Figure 1 Daily body weight was characterized in different groups of mice during treatment. There was no significant difference in body weight gain between the model group and the saline group, confirming the safety and rationale for the surgical procedure. Furthermore, there was no significant difference in body weight gain between the treatment group and the control group, indicating that these compounds are highly safe in vivo.

[0088] Figure 2 Behavioral experiments characterizing the open field (OFT). (A) Representative trajectory in the OFT. (B) Total dynamic distance in the OFT. (C) Average velocity over the total distance traveled in the OFT. (D) Distance traveled in the central region of the OFT. The open field test (OFT) evaluates exploratory behavior and general activity in rodents. The results show the open field behavior of mice in the study. There was no significant difference in the total distance traveled between the normal and sham-operated groups. Nevertheless, Aβ... 1-42 The duration of movement in mice modeled by intracerebral injection was shorter. (Injection of Aβ) 1-42 Mice exhibited lower movement speeds and shorter distances to the center. These changes were reversed and enhanced in the cannabidiol aminoquinone derivative (G-8) and donepezil groups, Aβ 1-42 The resulting behavioral disorders in mice were improved.

[0089] Figure 3Behavioral experiments characterizing the Morris water maze (MWM). (A) Average trajectory of mice in the final day of the MWM. (B) Learning curve of evacuation delay during the data collection phase. (C) Number of times the platform was traversed during the data collection phase. (D) Time spent in the target quadrant during the data collection phase. The Morris water maze task is a hippocampal-dependent memory and spatial learning task, commonly used to study the effects of reducing the time required to reach an escape platform on long-term memory. The results of the Morris water maze experiment showed that the effect of injecting saline into the lateral ventricle (sham surgery) was negligible, and the trajectory and time to reach the platform in the saline group were almost indistinguishable from those in the control group. The figure shows that the mice in the model group exhibited significant deterioration in learning and memory abilities, especially during platform search and subsequent spatial exploration. In contrast, the donepezil and cannabidiol aminoquinone derivative (G-8) group showed remarkable abilities in learning and recognizing the platform. Furthermore, the donepezil and cannabidiol aminoquinone derivative (G-8) group navigated the platform location and corresponding quadrant multiple times during the evacuation maneuver.

[0090] Neuroprotective and therapeutic effects of cannabidiol aminoquinone derivatives on Alzheimer's disease Background: Neurological damage is a pathological feature throughout the entire course of Alzheimer's disease (AD). Although the degree of damage varies at different stages, it has attracted widespread attention and become a recognized core pathological feature of AD. Furthermore, neurological damage interacts with almost all pathways in AD. Microglia and astrocytes are the main inflammatory immune cells in the brain. In the brains of AD patients, the reactivity of microglia and astrocytes is enhanced, leading to the release of large amounts of pro-inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), thereby triggering neuroinflammation. The inflammatory environment created by neuroinflammation affects the clearance of Aβ by microglia. In addition, the activation of glial cells (astrocytes and microglia) leads to the expression of β-secretase (BACE1), producing more Aβ protein. Simultaneously, Aβ deposition further activates glial cells, releasing more pro-inflammatory factors, exacerbating neuroinflammation and creating a vicious cycle. This ultimately leads to neuronal death. On the other hand, Aβ-induced neuroinflammation increases intracellular calcium ion concentration, activating certain signaling pathways, such as the glycogen synthase kinase 3β pathway (GSK-3β), and promoting tau protein phosphorylation. Phosphorylated tau protein disrupts the neuronal microtubule system, and tau protein aggregation leads to the formation of neurofibrillary tangles, affecting neuronal function and survival, exacerbating nerve damage, and accelerating neuronal death. Neuroinflammation, Aβ aggregation, and tau protein phosphorylation—the three core pathological features of Alzheimer's disease (AD)—are intertwined and mutually reinforcing, forming a vicious cycle that snowballs, accelerating neuronal functional loss and death, worsening the disease, and ultimately leading to the complete loss of memory and cognitive abilities.

[0091] Materials: PC12 cell line Groups: (1) control group; (2) H2O2 group (H2O2 added only); (3) donepezil group (H2O2 added after dopapizil was added); (4) G-5 group (H2O2 added after G-5 was added); (5) G-6 group (H2O2 added after G-6 was added); (6) G-8 ​​group (H2O2 added after G-8 was added); (7) G-9 group (H2O2 added after G-9 was added); (8) G-14 group (H2O2 added after G-14 was added); (9) G-15 group (H2O2 added after G-15 was added); (10) G-19 group (H2O2 added after G-19 was added).

[0092] Evaluation of Neuroprotective Effects: Neuroprotective Effect of Cannabidiol Aminoquinone on Hydrogen Peroxide (H2O2)-Induced Cell Death. To investigate the neuroprotective potential of cannabidiol aminoquinone derivatives, the PC12 cell line, a commonly used cell line in neurobiology research, was used, and its viability was assessed using the MTT assay. In this experiment, the effect of the compounds on hydrogen peroxide-induced cytotoxicity was determined using the MTT assay. First, PC12 cells were seeded into 96-well plates and cultured in a cell culture incubator for 24 hours. After incubating the cells with different concentrations of the compound for 3 hours, 300 mM H2O2 was added to the 96-well plates and incubated for 24 hours. Then, 20 μL of 0.5 mg / mL MTT solution was added and incubated for 4 hours. Absorbance was measured at 492 nm. After shaking on a plate shaker for 10 minutes, absorbance was measured at 492 nm using a multi-reader.

[0093] Evaluation results of neuroprotective effect: Figure 4 This study demonstrates the neuroprotective effect of H2O2-induced PC12 cell damage. Results are shown as mean ± standard deviation (n = 3) from at least three independent experiments, P < 0.05. The results indicate that cannabidiol oxide partially reverses hydrogen peroxide-stimulated PC12 cell death. The survival rate of hydrogen peroxide-treated PC12 cells was only 50.66%, and 10 μM donepezil showed weak protective effect with almost no reversal. G-5 and G-8 (2.5, 5, 10 μM) had good reversal effects. G-5 significantly increased survival (IC50). 50 =1.08 ± 0.27 μM). Similarly, G-12 increased cell viability from 50.66% to 73.85%, 86.92%, and 94.16%, respectively (IC50, 1.08 ± 0.27 μM). 50=1.29 ± 0.02 μM). In the initial screening for anti-inflammatory activity and neuroprotective effects against hydrogen peroxide-induced PC12 cell death, two compounds (G-5 and G-8) with outstanding overall performance were identified. Notably, G-5 and G-8 showed strong protective effects even at 2.5 μM. Therefore, G-5 and G-8 were further evaluated.

[0094] Materials: ICR male mice, 18-25 g, 6-8 weeks old.

[0095] Experimental groups: control group; sham operation group (intracerebral injection of saline); model group (intracerebral injection of Aβ). 1-42 Peptide); donepezil (positive control group, 15 mg / kg of donepezil administered by gavage); G-8-L (low-dose group of compound G-8, 2.5 mg / kg of compound G-8 administered by gavage); G-8-H (high-dose group of compound G-8, 10 mg / kg of compound G-8 administered by gavage).

[0096] Immunohistochemical results: Figure 5 Aβ in the mouse brain 1-42 Changes in Aβ levels in brain tissue of each group. Quantitative analysis of Aβ levels in each group. 1-42 Protein concentrations, showing Aβ levels throughout the brain and hippocampus in the model group. 1-42 The average level of Aβ was significantly elevated, thus confirming the effectiveness of our model. Meanwhile, Aβ levels in the drug treatment group were significantly higher. 1-42 Protein concentration decreased significantly. 1-42 Aβ levels were significantly reduced in mice treated with donepezil and G-8. Analysis of Aβ levels in the whole brain and hippocampus showed that the concentration of Aβ in the hippocampus exceeded that in the whole brain, confirming the increased Aβ expression in the hippocampus and further demonstrating that G-8 can significantly reduce Aβ accumulation in this region.

[0097] In summary, the cannabidiol aminoquinone derivatives of the present invention exhibit effective activity in anti-inflammatory, neuroprotective, and anti-Alzheimer's disease aspects. In particular, the cannabidiol aminoquinone derivative G-8 not only possesses good anti-inflammatory activity (IC50, 100 mg / kg / day), but also... 50 = 1.39 ± 0.11 mM) and neuroprotective capacity (IC) 50= 1.29 ± 0.02 mM). This compound exhibits good anti-inflammatory and anti-Alzheimer's activity, demonstrating exceptionally outstanding performance in behavioral experiments. It shows comparable or even superior effects compared to the classic anti-Alzheimer's drug donepezil, and significantly enhances memory and Aβ. 1-42 Cognitive abilities in mice with induced cognitive impairment.

[0098] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail, those skilled in the art should have a certain understanding and be able to modify or make equivalent substitutions to the present solution without departing from the spirit and scope of the technical solutions of the present invention, but all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. Compounds, stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts having the structure described in Formula I: ； R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl, C 6-12 Aryl groups, or R1 and R2 together with the atoms attached to them and the N atom, form 5-6 membered heterocyclic groups; Optionally, the C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl and C 6-12 Aryl groups are independently and optionally bonded by 0, 1, 2 or 3 R groups. a Replace; among them, R a Each is independently selected from hydrogen, halogen, and C. 1-8 Alkyl, halogen-substituted C 1-8 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, 5-12-membered heteroaryl, C 6-12 Aryl; Optionally, when R a Selected from 5-12 heteroaryl groups, C 6-12 When aryl, R a Choose any 0, 1, 2 or 3 Rs b Replace; where R b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino; The 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, 5-12-membered heteroaryl, and 5-6-membered heterocyclic groups each independently contain at least one atom or group selected independently from N, O, S, and NH.

2. The compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt having the structure of general formula I according to claim 1, characterized in that, R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl, Ra-substituted C 1-8 alkyl, Ra and other variables are defined as described in claim 1.

3. The compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt having the structure of general formula I according to claim 1 or 2, characterized in that, Ra is independently selected from hydrogen, halogen, and C. 1-8 Alkyl, halogen-substituted C 1-8 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, Rb and other variables are defined as described in claim 1.

4. A compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt having the structure of general formula I according to any one of claims 1 to 3, characterized in that, R1 and R2 are independently selected from H, .

5. A compound, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt having the structure of general formula I according to any one of claims 1 to 4, characterized in that, The compound is selected from: 。 6. A method for synthesizing compounds, stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts having the structure described in Formula I, characterized in that, The general formula for the synthesis method is as follows: ； R1 and R2 are independently selected from H and C, respectively. 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl, C 6-12 Aryl groups, or R1 and R2 together with the atoms attached to them and the N atom, form 5-6 membered heterocyclic groups; Optionally, the C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 5-12-membered heteroaryl and C 6-12 Aryl groups are independently and optionally bonded by 0, 1, 2 or 3 R groups. a Replace; where R a Each is independently selected from hydrogen, halogen, and C. 1-8 Alkyl, halogen-substituted C 1-8 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, 5-12-membered heteroaryl, C 6-12 Aryl; Optionally, when R a Selected from 5-12 heteroaryl groups, C 6-12 When aryl, R a Choose any 0, 1, 2 or 3 Rs b Replace; where R b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino; The 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, 5-12-membered heteroaryl, and 5-6-membered heterocyclic groups each independently contain at least one atom or group selected independently from N, O, S, and NH.

7. The synthesis method according to claim 6, characterized in that, The synthesis method includes: dissolving cannabidiol in a solvent, adding an oxidant under inert gas protection, reacting, separating and purifying to obtain a cannabidiol oxyquinone intermediate; reacting the obtained cannabidiol oxyquinone intermediate with the corresponding amine R1R2NH under alkaline conditions to obtain a compound having the structure described in general formula I.

8. A composition comprising at least one compound having the structure of general formula I according to claim 1, a stereoisomer, a solvate, a hydrate, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

9. Use of the compound, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt having the structure of general formula I according to claim 1, or the composition according to claim 8, in the preparation of an anti-neuroinflammatory drug.

10. Use of the compound, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt having the structure of general formula I according to claim 1, or the composition according to claim 8, in the preparation of an anti-Alzheimer's disease medicament.

11. Use of the compound, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt having the structure of general formula I according to claim 1, or the composition according to claim 8, in the preparation of a non-therapeutic care product.

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