CN114539217B - A kind of dimeric isoquinoline alkaloid compound and its preparation and use - Google Patents

Abstract

The invention relates to a preparation method and application of a dimeric isoquinoline alkaloid compound from radix puerariae hepiali, and a test of a part of compound dopamine D1 receptor targets shows that the dimeric isoquinoline alkaloid compound has certain pharmacological activity and can be used for preparing medicaments for preventing or treating diseases related to the receptor.

Description

A kind of dimeric isoquinoline alkaloid compound and its preparation and use

Technical field

The invention belongs to the field of natural medicinal chemistry and relates to a preparation method of a dimeric isoquinoline alkaloid compound and its related applications in the prevention or treatment of neurological diseases.

Background technique

Isoquinoline alkaloids are an important class of nitrogen heterocyclic bioactive natural products that are common in the plant kingdom. They are most likely derived from tyrosine or phenylalanine and exhibit wide structural diversity. Since the first biologically active isoquinoline alkaloid, morphine, was isolated from the opium plant in the early 19th century, this class of compounds has attracted widespread attention in the scientific community. More and more isoquinoline alkaloids have been isolated and identified from natural resources, and various studies have reported their anti-tumor, anti-malarial, antibacterial, antifungal, antiparasitic and insecticidal, antiviral, anti-inflammatory, and anti-inflammatory properties. Platelet and other activities. As lead compounds in the drug discovery and development process, isoquinoline alkaloids have a high probability of success, and some revolutionary drugs such as: the analgesic morphine, the antibacterial drug berberine, the antitussive codeine, the treatment Sinomenine for rheumatism and the acetylcholinesterase inhibitor galantamine, etc. Therefore, the search for structurally novel bioactive isoquinoline alkaloids as promising drug leads remains an active research direction in the field of natural product chemistry. Dopamine receptors are receptors located in organisms that act through their corresponding membrane receptors.

Dopamine receptors are a family of G protein-coupled receptors composed of seven transmembrane regions, and five dopamine receptors (D1-D5) have been isolated. According to their biochemical and pharmacological properties, they can be divided into D1 category (D1-like) and D2 category (D2-like). D1 receptors include D1 and D5 receptors (also called D1A and D1B receptors in rats, D1A receptor is D1 receptor, D1B receptor is D5 receptor). The D2 class includes D2, D3 and D4 receptors. D1 receptors are most expressed in the dorsal and ventral striatum, followed by the frontal cortex, amygdala, olfactory tubercle, and thalamus. Hypothalamus and hypothalamic nuclei. Some important pharmacological studies have shown that D1 antagonists have antipsychotic and preventive and therapeutic effects on drug addiction. Therefore, targeted drug discovery for D1 receptors is very important.

Pueraria lobata is the rhizome of Pueraria genus in the Fangjiaceae family. It was first recorded in "Chinese Medicinal Plants" and is also known as Beidou root. As a commonly used traditional Chinese medicine, it was included in the Pharmacopoeia in 2010. Modern pharmacological research shows that it has anti-arrhythmic and antihypertensive effects, and mainly contains a large amount of isoquinoline alkaloids. In previous work, some new alkaloid components have been isolated and discovered. Therefore, in order to continue to find more valuable components of this type, more in-depth material research was conducted on this plant.

Contents of the invention

The invention provides the use of a dimeric isoquinoline alkaloid compound in preparing drugs for preventing or treating dopamine D1 receptor and other related diseases, wherein the compound has the following structural formula:

in:

R1 to R8 are independently selected from hydrogen, halogen (one of F, Cl, Br, and I), hydroxyl, carboxyl, C1 to C6 alkoxy, sugar, C1 to C6 alkyl, C2 to C6 One of the alkenyl groups.

Further, R1 is selected from methyl, R2 and R5 are selected from hydrogen, R3, R4, R6, R7 and R8 are hydroxyl groups, and the compound of formula (A) is as shown in formula (I)

Further, the stereoconfiguration of the compound I is selected from one of (1R, 1′R), (1R, 1′S), (1S, 1′R), (1R, 1′S) or Two or more types.

Furthermore, the preferred stereoconfiguration of compound I is (1R, 1′R).

The present invention also provides a method for preparing the above compound I, which is characterized by comprising the following steps:

(1) Extraction of medicinal materials: 1 kg to 100 kg of dried medicinal materials from Beanroot. Add 6 to 10L of ethanol with a volume fraction of 50% to 90% to each kilogram of medicinal materials and soak for 1 to 24 hours. Heat to 50°C to 90°C and reflux for extraction. 1 to 5 times, combine the extracts and concentrate to obtain the northern bean root extract;

(2) Preparation of total base: Add 0.1% to 3% sulfuric acid to the above extraction solution to adjust the pH to 1 to 4, then add ethyl acetate that is 1 to 3 times the volume of the acid-adjusted solution and extract 1 to 5 times. After each extraction, 0.1% to 3% sulfuric acid is added to the acid aqueous layer to adjust the pH to 1 to 4, and finally the acid aqueous layer is obtained. Then add a weak base to the acidic water layer to adjust the pH to 8-10, then add n-butanol 1 to 3 times the volume of the alkali-adjusted solution, extract 1-5 times, and combine the n-butanol obtained 1-5 times. layer and concentrate to obtain the crude alkali of Beanroot, which is then passed through an ion exchange chromatography column to decolorize and remove impurities to obtain the refined total alkali;

(3) Prepare the total base obtained in step (2) using reversed-phase preparative HPLC. The stationary phase of the chromatographic column is C18HCE (5~60 μm, 20×250~100×250mm), the flow rate is 10mL/min~350mL/min, and the volume Elute with (0.01%~5%) formic acid-methanol/(0.01%~5%) formic acid-water solution with a ratio of 0:100~100:0, and collect fractions F1~F8 according to time;

(4) Prepare the subfraction F6 obtained in step (3) through reversed-phase preparative HPLC. The chromatographic column is C18CE stationary phase (5~60μm, 20×250~100×250mm), and the flow rate is 10mL/min~350mL/min. The mobile phase is methanol (A) and water (B, containing ammonia water with a volume fraction of 0.01% to 2% and a mass concentration of 25% to 28%). The elution gradient is 0 to 80 min, 0% A to 95% A. A total of 8 subfractions were collected according to time, namely F6-1 ~ F6-8;

(5) Prepare subfraction F6-7 obtained in step (4) through preparative HPLC. The chromatographic column adopts conventional C18 stationary phase (5~60μm, 4.6×250~50×250mm), and the flow rate is 0.5mL/min~100mL/min. , the mobile phase is acetonitrile and water (each containing trifluoroacetic acid with a volume fraction of 0.01 to 1%), the elution gradient is 0 to 60 min, 5% A to 95% A, and the obtained fraction is then passed through C18CE (5 to 60 μm, 4.6× 250～20×250mm), the mobile phase is methanol (A) and water (B) (each containing triethylamine acetate with a volume fraction of 0.1% to 10% (the volume ratio of acetic acid to triethylamine is 1:1～1: 5)), the elution gradient is 0~60min, 0%A~90%A, and the obtained fraction continues to pass through the C18HCE stationary phase (5~60μm, 4.6×250~20×250mm), the flow rate is 0.5mL/min~50mL /min, mobile phase A is the volume fraction (0.01~1%) formic acid-methanol, B is the volume fraction (0.01~1%) formic acid-water, and the elution gradient is 0~40min, 0%A~90%A, to obtain Compound I;

In the present invention: the glycosyl includes but is not limited to glucose, glucuronic acid, mannosyl, galactosyl, allosyl, fructosyl, sorbosyl, fructosyl, and rhamnosyl. , gallinosyl, arabinosyl, lyxosyl, xylosyl, ribosyl, and various disaccharide and polysaccharide groups formed by the above monosaccharides; the C ₁ to C ₆ alkyl group is Refers to the alkyl group of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ , that is, a straight-chain or branched alkyl group with 1 to 6 carbon atoms; the alkenyl group of C ₁ to C ₆ refers to A linear or branched alkenyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 1 to 6 double bonds.

Another object of the present invention is to provide a new isoquinoline alkaloid dimer derivative, or its crystal form, or its isomer, or its pharmaceutically acceptable salt, or its solvate, or Its prodrugs, or its metabolites are used as active ingredients, or any one or more of the above are used as dopamine D1 receptor ligands, in the preparation of prevention and/or treatment of neurological disorders related to analgesia, schizophrenia, etc. Disease drug development research.

The diseases include, but are not limited to, analgesia, schizophrenia, etc. The mental diseases related to dopamine receptors include but are not limited to pain, drug abuse, Parkinson's disease, Huntington's disease, schizophrenia, Alzheimer's disease, depression, etc.

The pharmaceutical composition means that one or more compounds of the present invention can be used in combination with each other, or optionally in combination with any other active agent. If a panel of compounds is used, the compounds can be administered to the subject simultaneously, separately, or sequentially. The amount of active ingredients (i.e. compounds of the present invention) in the pharmaceutical composition of the present invention can be specifically applied according to the patient's condition and the diagnosis of the doctor. The dosage or concentration of the active compound can be adjusted within a wide range. The content ranges from 1% to 90% of the pharmaceutical composition.

Obviously, based on the above content of the present invention, various other modifications, substitutions or changes can be made according to the common technical knowledge and common methods in the field without departing from the above basic technical ideas of the present invention.

Description of the drawings

Figure 1 Preparation flow chart of compound I

Figure 2 ESI ⁺ primary mass spectrum of compound I

Figure 3 ¹ HNMR spectrum and ¹³ CNMR spectrum of compound I

Figure 4 Correlation between H, H-COSY and HMBC of compound I

Figure 5 Determination of D1 receptor antagonistic activity of compound I: dose response curve on HEK-293-D1 cells

Detailed ways

The following examples are intended to illustrate the present invention but not to further limit the present invention. The present invention can be implemented in any manner described in the summary of the invention.

Preparation examples of compounds of formula (I) of the present invention:

Compound preparation

100 kilograms of northern bean root medicinal materials,

(1) Extraction of medicinal materials: Weigh 100kg of northern bean root medicinal materials, add 1000L of ethanol with a volume concentration of 70%, soak for 24 hours, heat and reflux at 60°C for extraction for 2 hours, obtain extract 1 after suction filtration, and add 1000L of filtered residue Ethanol with a volume concentration of 70% was heated and refluxed at 60°C for 2 hours. After filtration, extract 2 was obtained. Continue to add 1000L ethanol with a volume concentration of 70% to the filtered residue. Heat and reflux at 60°C for 2 hours. After filtration, the extraction solution was obtained. Liquid 3, combine the extracts 1 to 3, and concentrate to 50L to obtain the northern bean root extract.

(2) Preparation of total alkali: Add dilute sulfuric acid with a volume concentration of 1% to the northern bean root extract to adjust the pH to between 2 and 3, then add the same volume of ethyl acetate as the acid-adjusted extract to extract the third Once, let stand and separate the layers to obtain the ethyl acetate extraction layer 1 and the acid water layer 1. Then continue to add dilute sulfuric acid with a volume concentration of 0.2% to the acid water layer 1 to adjust the pH to between 2 and 3, and then add the Extract the acid-adjusted extract for the second time with the same volume of ethyl acetate to obtain the ethyl acetate layer 2 and the acid water layer 2. Then add dilute sulfuric acid with a volume concentration of 1% to the acid water layer 2 to adjust the pH to 2~ 3, then add the same volume of ethyl acetate as the acid-adjusted extract and extract for a third time, thereby obtaining an ethyl acetate layer 3 and an acid water layer 3. Add ammonia water with a mass concentration of 25% to 28% in the acid water layer 3 to adjust the pH to between 9 and 10. Add the same volume of n-butanol as the alkali-adjusted sample for extraction, and let it stand for layering to obtain n-butyl alcohol. Alcohol layer 1 and alkali water layer 1, then add ammonia water with a mass concentration of 25% to 28% in the alkali water layer 1 to adjust the pH to between 9 and 10, and then add normal volume of the same volume of the alkali-adjusted extract. Butanol is extracted for the second time to obtain n-butanol layer 2 and alkaline water layer 2. Then add ammonia water with a mass concentration of 25% to 28% in the alkali aqueous layer 2 to adjust the pH to between 9 and 10, and then add the same volume of n-butanol as the alkali-adjusted extract for the third extraction, to obtain n-butanol layer 3 and alkaline water layer 3, combine n-butanol layer 1 to 3 and concentrate into an extract, redissolve with methanol to 12L, take 10ml of concentrated liquid and measure the solid content to be about 500g/L. Calculate and obtain Beidou root The crude alkali is about 6.0kg, accounting for 6.0% of the quality of the medicinal materials. Based on this calculation, take about 1L of crude alkali sample reconstituted with methanol, add 1L of pure water to dilute and dissolve, centrifuge and filter to obtain the supernatant, and then pass the supernatant through an ion exchange Q column with agarose gel matrix to decolorize and remove impurities, that is About 500g of refined total alkali was obtained, and the recovery rate was about 97%.

(3) The total base obtained in step (2) is prepared by reversed-phase preparative HPLC. The stationary phase of the chromatographic column is C18HCE (particle size 10 μm, diameter and height 100×250mm) for separation and purification. The flow rate is 300mL/min. The mobile phase is methanol (A) and water (B) (each containing formic acid with a volume concentration of 0.1%). The elution gradient is 0-10min, 0%B (volume ratio); 10-20min, 10%B; 20-35min , 20% B; 35-45min, 25%B; 45-60min, 30%B; 60-75min, 90%B elutes, collected according to peaks, and obtained 8 fractions respectively as F1 (RT: 0~17min), F2 (RT: 17～24min), F3 (RT: 24～28min), F4 (RT: 28～32.5min), F5 (RT: 32.5～38.5min), F6 (RT: 38.5～52min), F7 (RT :52～62min), F8(RT: 62～74min);

(4) Prepare the sub-fraction F6 obtained in step (3) through reversed-phase preparative HPLC. The chromatographic column is C8GE stationary phase (particle size 10 μm, diameter and height 100×250 mm), flow rate 300 mL/min, and the mobile phase is methanol (A ) and water (B, containing ammonia with a volume fraction of 0.03% and a mass concentration of 25% to 28%), the elution gradient is 0 to 30min, 10% to 95% A (linear gradient), 30 to 40min, 95% A (volume ratio), collected according to peaks, a total of 8 subfractions were obtained, namely F6-1 (RT: 2~7min), F6-2 (RT: 7~11min), F6-3 (RT: 11~13min) , F6-4 (RT: 13～17min), F6-5 (RT: 17～22min), F6-6 (RT: 22～27min), F6-7 (RT: 27～31min), F6-8 (RT :31～35min);

(5) The subfraction F6-7 obtained in step (4) is prepared by preparative HPLC. The chromatographic column uses a conventional C18 stationary phase (particle size 7 μm, diameter and height 30×250 mm). The flow rate is 30mL/min, the mobile phase is acetonitrile (A) and water (B) (each containing trifluoroacetic acid with a volume fraction of 0.01-1%), the elution gradient is 0-15min, 10%-20%A (linear gradient) , 15-50min, 20%-40%A, 50-60min, 95%A (volume ratio). The obtained fraction F6-7-7 (RT: 28~32min) is then passed through C18CE (particle size 7 μm, diameter and height 10×250mm), flow rate 3mL/min, mobile phase is methanol (A) and water (B) (each containing Triethylamine acetate with a volume fraction of 0.05% (the volume ratio of acetic acid:triethylamine is 1:3), pH 10.5), elution gradient is 0-20min, 10%-90%A (linear gradient), 20- 30min, 90%A (volume ratio). The obtained fraction F6-7-7-7 (RT: 27~28.5min) continues to pass through the C18HCE stationary phase (particle size 7 μm, diameter and height 10×250mm), and the mobile phases A and B are methanol and water respectively (each contains volume Fraction 0.01～1% formic acid), elution gradient is 0～40min, 0%A～90%A (linear gradient), collect the main peak to obtain compound 1;

(6) The structure of the compound I was determined by ultraviolet, mass spectrometry and nuclear magnetic characterization. The information is as follows:

Compound I: 4 mg, C ₄₄ H ₄₆ N ₂ O ₇ , MW: 714, white powder, soluble in methanol.

¹ H NMR (CD3OD, 600MHz) δ7.16 (2H,dd,J＝10.0,2.9Hz,H-15′),7.08(2H,dd,J＝8.5,2.0Hz,H-15′),7.02( 2H,d,J＝8.5Hz,H-10),7.01(1H,m,H-11′),6.96(1H,d,J＝2.0Hz,H-17),6.99(1H,m,H- 14),6.93(1H,d,J＝8.5Hz,H-20),6.84(1H,d,J＝8.5Hz,H-11,13),6.35(1H,dd,J＝9.5,2.0Hz, H-12′),6.22(2H,dd,J＝10.0,2.0Hz,H-14′),6.76(1H,s,H-5),6.73(1H,s,H-5′),5.84( 1H,s,H-8),5.84(1H,s,H-8),3.83-3.41(2H,m,H-15),_3.47-3.21(2H,m,H-3′),_3 .61-3.21(2H,m,H-3),3.34-2.92(2H,m,H-9),3.11-3.05(2H,m,H-4),2.82(2H,m,H-4′ ),2.28-2.21(2H,m,H-9′),3.80(1H,m,H-1′),4.28(1H,dd,J＝10.5,4.0Hz,H-1),3.83-3.41( 2H,m,H-15),3.78(3H,s,OCH3-6),3.42(3H,s,OCH3-7),3.76(3H,s,OCH3-6′),3.57(3H,s,OCH3 -7′),2.85(3H,s,NCH3-2).

¹³ C NMR (CD3OD, 600MHz) δ65.9(CH,C-1),46.7(CH2,C-3),24.2(CH2,C-4),124.2(C,C-4a),112.8(CH, C-5),150.2(C,C-6),148.3(C,C-7),112.8(CH,C-8),125.0(C,C-8a),40.0(C-9),131.8( C,C-9a),132.3(C,C-10,14),158.9(C,C-12),118.0(C,C-11,13),65.6(CH,C-1′),52.7( CH2,C-3′),28.2(CH2,C-4′),129.5(C,C-4′a),113.0(CH,C-5′),154.8(C,C-6′),145.5 (C,C-7′),133.4(C,C-8′),48.6(CH2,C-9′),52.8(CH2,C-10′),156.7(C,C-11′),128.7 (C,C-12′),188.5(C,C-13′),127.8(C,C-14′),153.1(C,C C-15′),60.6(CH2,C-15),130.2 (C,C-16),123.8(CH,C-17),144.3(C,C-18),150.0(C,C-19),118.0(CH,C-20),127.9(CH,C- 21),41.2(CH3,NCH3-2),56.7(CH3,OCH3-6),56.2(CH3,OCH3-7),56.3(OCH3-6′),61.3(OCH3-7′).

Activity test examples:

Sample preparation of new compounds; HEK-293-D1 stably transfected cells to construct references (Xu, F.F.; Zhou, H.; Liu, X.M.; Zhang, X.L.; Wang, Z.W.; Hou, T.; Wang, J.X.; Qu ,L.L.; Zhang, P.Y.; Piao, H.L.; Liang, D1 is the dopamine D1 receptor); dopamine (Product No.: KB712097) was purchased from Shanghai Civic Chemical Technology Co., Ltd.; Calcium-6 fluorescent dye kit (Product No.: 3221567) was purchased from Molecular Devices, and the masking dye Amaranth (Product No.: A1016- 50G) was purchased from Sigma, DMEM high-glucose culture medium (Cat. No.: C11995500BT) was purchased from ThermoFisher Company, fetal bovine serum (Cat. No.: 04000101A) was purchased from Shenyang Huibai Biotechnology Co., Ltd.; polylysine (Cat. No.: P2100) Purchased from Beijing Solebao Technology Co., Ltd.; Balanced salt solution HBSS (Product No.: 14065-056) and HEPES (Product No.: 15630-080) were purchased from Gibco; FLIPR special 96-well cell culture plate (Product No.: 655090) was purchased from Greiner Company; The detection platform high-throughput real-time fluorescence detection system (FLIPRTetra) was purchased from Molecular Devices.

HEK-293-D1 cells in the logarithmic growth phase were inoculated into a FLIPR-specific 96 cell culture plate coated with poly-D-lysine (PDL), and the culture medium in each well (composition : DMEM+10% fetal bovine serum (FBS) (v/v)) volume is 100 μL, cell seeding density is 8.0×10 ⁴ cells/well, place the seeded 96-well cell plate in a cell culture incubator and culture at 37°C After 20 to 24 hours, until the cell confluence reaches about 95%, the activity is detected. Remove the culture medium from the cultured cells and add 100 μL of fluorescent dye solution (Calcium-6) to each well and incubate at 37°C for 1 hour; remove the dye solution and add 100 μL of Amaranth (0.5 mg/mL) to each well and incubate at room temperature. 5min;

Add compound I to the microwell plate inoculated with HEK293-D1 cells. Compound I is configured at 8 concentrations: 100 μM, 25 μM, 6.25 μM, 1.56 μM, 0.39 μM, 0.097 μM, 0.024 μM, and 0.006 μM, three times in parallel. The solvent is HBSS buffer containing 20mM HEPES, placed in a 96-well drug plate, recorded as drug plate A; the D1 agonist dopamine is placed at a fixed final concentration of 50nM (the solvent is HBSS buffer containing 20mM HEPES) in a 96-well drug plate , recorded as drug plate B; on HEK-293-D1 cells, FLIPR was used to characterize the antagonistic activity of compound I. The samples in drug plates A and B were automatically added to the FLIPR cell plate, and 2 samples were added to each well. The volume is 50 μL each, and calcium flow fluorescence signal detection is performed at 520 nm and 488 nm wavelengths. The test results are shown in Figure 5. Compound I can antagonize the fluorescence signal of dopamine in a dose-dependent manner, and the curve is a single-phase "S" shape. Its IC ₅₀ value is 8.400 ± 2.006 μM, indicating that compound I has the antagonistic activity of D1.

Current research shows that dopamine D1 receptors are associated with schizophrenia, pain, depression, anxiety, and Alzheimer's disease. The compounds of the present invention have important clinical applications in diseases such as schizophrenia, pain, depression, anxiety, constipation, irritable bowel syndrome and Alzheimer's disease.

Claims (8)

1. A dimeric isoquinoline alkaloid compound has a structural formula shown in a formula (I):

。

2. the compound according to claim 1, wherein the steric configuration of compound I is selected from one or more of (1R, 1 ʹ R), (1R, 1 ʹ S), (1S, 1 ʹ R), (1R, 1 ʹ S), respectively.

3. The compound according to claim 2, wherein the stereochemistry at compound I is (1R, 1 ʹ R), respectively.

4. A process for the preparation of a compound as claimed in any one of claims 1 to 3 comprising the steps of:

(1) Extracting medicinal materials: 1 kg-100 kg of asiatic moonseed rhizome, adding 6-10L of ethanol with the volume fraction of 50% -90% into each kg of medicinal materials, soaking for 1-24 h, heating to 50-90 ℃ to extract for 1-3 h, and filtering to obtain an extract; adding 6-10L of ethanol with the volume fraction of 50% -90% into each kilogram of medicinal materials in the solid materials, repeating the extraction and filtration process for 0-4 times, carrying out the extraction and filtration operation process for 1-5 times, combining the extracting solutions, and concentrating the obtained extracting solution to 0.3-0.6L of the extracting solution per kilogram of medicinal materials to obtain rhizoma Menispermi extracting solution;

(2) Preparing total alkali: adding sulfuric acid with the volume concentration of 0.1% -3% into the rhizoma Menispermi extract to adjust the pH to 1-4, adding ethyl acetate with the volume being 1-3 times of the volume of the acid-adjusted extract to extract, layering to obtain an ethyl acetate extract layer and an acid water layer, adding ethyl acetate again to re-extract and layering process for 0-4 times, extracting for 1-5 times, adding weak base into the acid water layer, adding ammonia water with the mass concentration of 25-28% to adjust the pH to 8-10, adding n-butanol with the volume being 1-3 times of the volume of the alkali-adjusted sample to extract, layering to obtain n-butanol and an alkali water layer, adding n-butanol again to re-extract and layering process for 0-4 times to co-extract for 1-5 times, combining n-butanol organic layers, concentrating the n-butanol to obtain rhizoma Menispermi crude alkali, decolorizing and removing impurities through an ion exchange chromatographic column to obtain refined total alkali;

(3) Separating and purifying the total alkali obtained in the step (2) by adopting a reversed phase column filled with C18HCE, wherein the volume ratio is 0: 100-100: 0, 0.01-5% formic acid-methanol/0.01-5% formic acid-water solution, and collecting according to peaks to obtain fractions F1-F8; the particle size of the filler is 5-60 mu m;

(4) Preparing the subfraction F6 obtained in the step (3) by reversed phase preparative HPLC, wherein a chromatographic column is C18CE stationary phase 5-60 mu m, 20X 250-100X 250mm, mobile phase A is ammonia water-methanol with the volume fraction of 0.01-10%, B is ammonia water-water with the volume fraction of 0.01-10% and the mass concentration of 25-28%, the elution gradient is 0-80 minutes, 0-95% A (V/V) is collected according to peaks, and 8 subfractions are obtained, wherein F6-1-F6-8 are respectively;

(5) Preparing the subfraction F6-7 obtained in the step (4) by preparative HPLC, wherein a chromatographic column adopts a conventional C18 stationary phase of 5-60 mu m, 4.6X1250-20X 250mm, a mobile phase of acetonitrile and water, each containing 0.01-1% of trifluoroacetic acid by volume fraction, the elution gradient is 0-60min, 5% A-95% A, the obtained fraction is subjected to C18CE of 5-60 mu m, 4.6X1250-20X 250mm, the elution gradient is 0-60min, 0% A-90% A, the obtained fraction is subjected to C18HCE stationary phase of 5-60 mu m, 4.6X1250-20X 250mm, the mobile phase A is 0.01-1% formic acid-methanol by volume fraction, the B is 0.01-1% formic acid-water by volume fraction, the elution gradient is 0-40 min,0% A-90% A (V/V) is collected according to peaks, and the compound I is obtained.

5. A process for producing a compound according to claim 4,

in the step (1), when reflux extraction is carried out for 2-5 times, filtering materials in the last reflux extraction process, adding 6-10L of ethanol with the volume fraction of 50% -90% into each kilogram of medicinal materials into the filtered filter residues, heating to 50-90 ℃ and reflux extracting for 1-3 hours, and filtering to obtain an extracting solution; mixing the extractive solutions;

when ethyl acetate is extracted for 2-5 times in the step (2), firstly, adjusting the pH of an acid water layer layered last time to 1-4 by adopting sulfuric acid with the volume concentration of 0.1% -3%, adding ethyl acetate with the volume of 1-3 times of the volume of the acid water layer into the acid water layer for extraction, and layering to obtain an ethyl acetate extraction layer and an acid water layer;

the weak base is ammonia water with the mass concentration of 10-25%;

when n-butanol is extracted for 2-5 times, firstly, weak base is adopted to adjust the pH value of an alkaline water layer which is layered last time to 8-10, and n-butanol with the volume being 1-3 times of the volume of the alkaline water layer is added into the alkaline water layer for extraction and layering, so that n-butanol and an alkaline water layer are obtained.

6. Use of one or more of the compounds I according to any one of claims 1 to 3 for the preparation of a medicament for the prophylaxis and/or treatment of one or more diseases of pain, substance abuse, parkinson, huntington, schizophrenia, alzheimer, depression, anxiety.

7. A pharmaceutical composition characterized by: comprising one or more of the compounds according to any one of claims 1 to 3.

8. The pharmaceutical composition according to claim 7, wherein a pharmaceutically acceptable adjuvant or carrier or solvent is added to prepare a formulation.