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WO2024216818A1 - Composé diterpénoïde de type isopimarane, son procédé de préparation et son utilisation - Google Patents

Composé diterpénoïde de type isopimarane, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024216818A1
WO2024216818A1 PCT/CN2023/117274 CN2023117274W WO2024216818A1 WO 2024216818 A1 WO2024216818 A1 WO 2024216818A1 CN 2023117274 W CN2023117274 W CN 2023117274W WO 2024216818 A1 WO2024216818 A1 WO 2024216818A1
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Prior art keywords
isopimarane
formula
compound
rheumatoid arthritis
present
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PCT/CN2023/117274
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English (en)
Chinese (zh)
Inventor
甘礼社
罗咏欣
龚旭
赵春林
蔡宏芳
李志宣
莫金凤
李冬利
吴日辉
金静维
Original Assignee
五邑大学
江门市大健康国际创新研究院
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Publication of WO2024216818A1 publication Critical patent/WO2024216818A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/80—Phthalic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the invention relates to the technical field of organic synthesis, and in particular to an isopimarane-type diterpenoid compound and a preparation method and application thereof.
  • Rheumatoid arthritis is a chronic systemic autoimmune disease with an unknown etiology. It often occurs in small joints such as the proximal interphalangeal joints and metacarpophalangeal joints. The basic pathological changes are synovitis, pannus formation, and gradual destruction of articular cartilage and bone tissue, which may eventually lead to joint deformity and loss of function. Many anti-inflammatory drugs used clinically have developed drug resistance, and the continuous discovery of new anti-inflammatory drugs, especially anti-rheumatoid arthritis drugs, remains an important task for pharmacists.
  • immune disorder is the main pathogenesis of rheumatoid arthritis.
  • Activated CD4 + T cells and antigen-presenting cells (APCs) infiltrate the synovial membrane of the joints.
  • APCs antigen-presenting cells
  • Certain special components or endogenous substances in the synovium may be presented as antigens by APCs to activated CD4 + T cells, initiating specific immune responses and producing corresponding inflammatory symptoms.
  • Different T cells proliferate to varying degrees due to the stimulation of different antigens inside and outside the body.
  • Macrophages in the synovium are also activated by antigens and produce more proinflammatory factors such as IL-6 and IL-1, which cause the synovium to be in a state of chronic inflammation.
  • Tumor necrosis factor ⁇ (TNF- ⁇ ) further destroys articular cartilage and bone tissue, resulting in joint deformities.
  • TNF- ⁇ Tumor necrosis factor ⁇
  • B cells differentiate into plasma cells through activation, secrete large amounts of immunoglobulins, and form immune complexes with antibodies in the body, which can induce inflammation after complement activation.
  • First-line drugs for the treatment of rheumatoid arthritis are mainly divided into non-steroidal anti-inflammatory drugs, immunosuppressants, glucocorticoids, biological agents and herbal medicines according to their properties.
  • rheumatoid arthritis cannot be cured, and the disease activity can only be alleviated or reduced through drugs and specific surgical treatments. Therefore, seeking highly effective and low-toxic drugs for the treatment of rheumatoid arthritis in order to improve the quality of life of patients and save their lives has become an urgent issue to be solved.
  • the present invention aims to solve at least one of the technical problems existing in the prior art.
  • the first aspect of the present invention provides an isopimarane-type diterpenoid compound, which can be effectively used for anti-rheumatoid arthritis.
  • the second aspect of the present invention also provides a method for preparing an isopimarane-type diterpenoid compound.
  • the third aspect of the present invention also provides a pharmaceutical composition.
  • the fourth aspect of the present invention also provides an application of an isopimarane-type diterpenoid compound.
  • an isopimarane-type diterpenoid compound which has a compound represented by formula (I) or formula (II);
  • R 1 is selected from H, C 1-6 alkyl
  • R2 and R3 are H, hydroxyl or both of them form a carbonyl group with the carbon atom to which they are connected.
  • the new isopimarane-type diterpenoid compounds provided by the present invention have novel structures and no obvious cytotoxicity, and can be prepared into drugs for reducing the release of IL-1 ⁇ and IL-6. By inhibiting the release of the anti-inflammatory factor IL-1 ⁇ , the proliferation of synovial cells and the infiltration of inflammatory cells are reduced. Drugs for alleviating rheumatoid arthritis can also be further prepared, which has clear scientific value and practical significance for the research and development of innovative anti-rheumatoid arthritis drugs with controllable quality, low toxicity and high efficiency.
  • the isopimarane-type diterpenoid compound is selected from one of the following structural formulas:
  • a method for preparing an isopimarane-type diterpenoid compound comprising the following steps:
  • solvents I and IV are respectively alcohol-water mixed solutions, and the alcohols in the solvents I and IV are the same or different;
  • the alcohol is methanol, ethanol or isopropanol
  • orthosiphol K is reacted with a halogenated alkane to obtain a compound of formula (II); or orthosiphol K is reacted with a Jones reagent to obtain a compound of formula (II).
  • orthosiphol K is as follows:
  • the soaking extraction in step S1 is performed at room temperature.
  • the normal temperature is 0°C to 35°C.
  • the normal temperature is 15°C to 30°C.
  • the soaking and extraction operation in step S1 is performed three times, each time for seven days.
  • the macroporous resin chromatographic column is a D101 macroporous resin chromatographic column or an AB-8 macroporous resin chromatographic column.
  • the volume proportion of alcohol in the solvent I is 95%.
  • the solvent IV used in the gradient elution process is an alcohol-water mixed solution with an alcohol volume percentage of 5% to 75%, preferably 60% to 70%.
  • the volume proportion of petroleum ether in the eluent in step S4 is 10% to 20%.
  • the compound of formula (II-1) is prepared by the following method:
  • Orthosiphol K was dissolved in anhydrous dimethylformamide (DMF), Cs 2 CO 3 was added, stirred, placed in an ice bath, ethyl bromide was slowly added dropwise, and refluxed for reaction. After the reaction was completed, the reaction system was diffused with ethyl acetate, extracted three times with pure water, sodium chloride solution and saturated sodium chloride solution respectively, the organic phase was retained, dried with anhydrous sodium sulfate, concentrated by vacuum distillation, and purified to obtain the compound of formula (II-1).
  • DMF dimethylformamide
  • the compound of formula (II-2) is prepared by the following method:
  • the compound of formula (II-3) is prepared by the following method:
  • Orthosiphol K was dissolved in anhydrous acetone, stirred, placed in an ice bath, Jones reagent was added dropwise, and the reaction was allowed to react at room temperature. After the reaction was completed, Jones reagent was quenched with a large amount of methanol. The reaction system changed from dark brown to dark green. The reaction system was concentrated and diffused with ethyl acetate. The reaction system was extracted three times each with pure water, sodium chloride solution and saturated sodium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and purified to obtain a compound of formula (II-3).
  • the third aspect of the present invention provides a pharmaceutical composition, comprising the above-mentioned isopimarane-type diterpenoid compound and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipient includes at least one of a disintegrant, a diluent, a lubricant, a binder, a flavoring agent, a suspending agent, a surfactant or a preservative.
  • the disintegrant is selected from at least one of corn starch, potato starch, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or alginic acid.
  • the diluent is selected from at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate or crystalline cellulose.
  • the lubricant is selected from at least one of micro-powder silica gel, magnesium stearate, calcium stearate, stearic acid, talc or anhydrous silica gel.
  • the binder is selected from at least one of gum arabic, gelatin, dextrin, hydroxypropyl cellulose, methyl cellulose or polyvinyl pyrrolidone.
  • the flavoring agent is selected from at least one of aspartame, stevioside, sucrose, maltitol or citric acid.
  • the suspending agent is selected from at least one of gum arabic, gelatin, methyl cellulose, sodium carboxymethyl cellulose, hydroxymethyl cellulose or aluminum stearate gel.
  • the surfactant is selected from at least one of lecithin, sorbitan monooleate or glyceryl monostearate.
  • the preservative is selected from at least one of methylparaben or propylparaben.
  • the dosage form of the pharmaceutical composition is tablets, capsules, granules, pills, oral liquids, emulsions, dry suspensions, dry extracts or injections.
  • the fourth aspect of the present invention also provides the use of the above-mentioned isopimarane-type diterpenoid compound or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and/or preventing rheumatoid arthritis.
  • the rheumatoid arthritis comprises a joint swelling stage.
  • the joint swelling is acute synovitis caused by rheumatoid arthritis.
  • the fifth aspect of the present invention also provides a method for treating and/or preventing rheumatoid arthritis, comprising administering a therapeutically effective amount of the above-mentioned isopimarane-type diterpenoid compound or the above-mentioned pharmaceutical composition to a subject in need thereof.
  • the rheumatoid arthritis comprises a joint swelling stage.
  • the joint swelling is acute synovitis caused by rheumatoid arthritis.
  • FIG1 is a hydrogen nuclear magnetic resonance spectrum of the compound represented by formula (I) prepared in Example 1 of the present invention.
  • FIG2 is a carbon NMR spectrum of the compound represented by formula (I) prepared in Example 1 of the present invention.
  • FIG3 is a hydrogen nuclear magnetic resonance spectrum of the compound represented by formula (II-1) prepared in Example 1 of the present invention.
  • FIG4 is a carbon NMR spectrum of the compound represented by formula (II-1) prepared in Example 1 of the present invention.
  • FIG5 is a hydrogen nuclear magnetic resonance spectrum of the compound represented by formula (II-2) prepared in Example 2 of the present invention.
  • FIG6 is a carbon NMR spectrum of the compound represented by formula (II-2) prepared in Example 2 of the present invention.
  • FIG7 is a hydrogen nuclear magnetic resonance spectrum of the compound represented by formula (II-3) prepared in Example 3 of the present invention.
  • FIG8 is a carbon NMR spectrum of the compound represented by formula (II-3) prepared in Example 3 of the present invention.
  • FIG9 is a theoretically calculated absolute configuration spectrum of the compound represented by formula (I) prepared in Example 1 of the present invention.
  • Figure 10A is a graph showing the toxicity test results of the compounds in the examples of the present invention at a concentration of 5 ⁇ M
  • Figure 10B is a graph showing the toxicity test results of the compounds in the examples of the present invention at a concentration of 10 ⁇ M
  • Figure 10C is a graph showing the toxicity test results of the compounds in the examples of the present invention at a concentration of 15 ⁇ M
  • Figure 10D is a graph showing the toxicity test results of the compounds in the examples of the present invention at a concentration of 20 ⁇ M
  • Figure 10E is a graph showing the toxicity test results of the compounds in the examples of the present invention at a concentration of 50 ⁇ M.
  • Figure 11A is a comparison chart of the cytokine IL-1 ⁇ release rates of the compounds in the examples of the present invention
  • Figure 11B is a comparison chart of the cytokine IL-6 release rates of the compounds in the examples of the present invention
  • ## represents p ⁇ 0.01 compared with the control group
  • #### represents p ⁇ 0.0001 compared with the control group
  • * represents p ⁇ 0.05 compared with the model group
  • ** represents p ⁇ 0.01 compared with the model group
  • *** represents p ⁇ 0.001 compared with the model group
  • **** represents p ⁇ 0.0001 compared with the model group.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.
  • This embodiment provides an isopimarane-type diterpenoid compound, which is a compound represented by formula (I) and a compound represented by formula (II-1), and the steps are as follows:
  • the crude extract was suspended in 2 L of water, and extracted three times with petroleum ether, ethyl acetate, and n-butanol in sequence, with 2 L of solvent used each time, to obtain 223.7 g of the combined layer of petroleum ether and ethyl acetate layers;
  • the combined layer was separated by D101 macroporous resin, eluted with gradient methanol, the volume percentage of methanol was from 30% to 90%, and then eluted with 30%, 50%, 60%, 70%, 80%, and 90% methanol aqueous solution, discarding 30% of the components, combining 80-90% of the components, and obtaining 5 effective components (B1-B5);
  • the S4 and B4 components were subjected to normal phase silica gel column chromatography and eluted with a dichloromethane-petroleum ether solvent system with the volume percentage of petroleum ether ranging from 10% to 20%.
  • the dichloromethane-petroleum ether solvent system was used for elution with the volume percentage of dichloromethane being 10%, 15%, and 20% in sequence to obtain 28 mg of the compound represented by formula (I) and 839.3 mg of the compound Orthosiphol K.
  • Orthosiphol K 10mg (2 ⁇ 10 -2 mmol) was weighed and placed in a dry 10mL reaction tube at room temperature, and dissolved in 1mL of anhydrous dimethylformamide. After dissolution, 2.0 equivalents of Cs 2 CO 3 were added, and the mixture was stirred on a magnetic stirrer for 5 minutes. 4.0 equivalents of bromoethane compound were slowly added dropwise, and the mixture was refluxed at 80°C for 1.5 hours. The reaction process was monitored by TLC until the reaction was completed. After the reaction was completed, the reaction system was diffused with ethyl acetate, and extracted three times with pure water, 5% sodium chloride solution and saturated sodium chloride solution respectively.
  • Tables 1 to 2 The specific detection data are shown in Tables 1 to 2 below, wherein Table 1 is the attribution of 1 HNMR chemical signals of the compound represented by formula (I) and the compound represented by formula (II-1), Table 2 is the attribution of 13 CNMR chemical signals of the compound represented by formula (I) and the compound represented by formula (II-1), and Figure 9 is the absolute configuration determined by theoretical calculation of the compound represented by formula (II-1).
  • Example 2 provides a compound represented by formula (II-2), and its reaction equation and preparation method are as follows:
  • Orthosiphol K (10 mg, 4 ⁇ 10 -2 mmol) was weighed into a dry 10 mL reaction tube at room temperature, dissolved with 1 mL of anhydrous DMF, and then 2.0 equivalents of Cs 2 CO 3 were added after dissolution, placed in an ice bath, stirred with a magnetic stirrer for 5 min, and 4.0 equivalents of MeI were slowly added dropwise, and then the temperature was raised to 80°C and refluxed for 24 h. The reaction process was monitored by TLC until the reaction was completed. After the reaction was completed, the reaction system was diffused with ethyl acetate, extracted three times with pure water, 5% sodium chloride solution and saturated sodium chloride solution respectively, and the organic phase was retained.
  • Example 3 provides a compound represented by formula (II-3), and its reaction equation and preparation method are as follows:
  • orthosiphol K (10 mg, 2 ⁇ 10 -2 mmol) was weighed at room temperature in a dry 10 mL reaction tube, dissolved in 0.6 mL of anhydrous acetone in a 10 mL reaction tube, placed in an ice bath, and slowly added 0.3 mL of Jones reagent. After 5 minutes of dropwise addition, the ice bath was removed and gradually restored to room temperature. The reaction time was 1.5 hours. TLC monitored the reaction progress. During the reaction, the reaction system changed from dark orange-red after the dropwise addition to dark brown-red. After the reaction was completed, the Jones reagent was quenched with a large amount of methanol, and the reaction system changed from dark brown to dark green.
  • Comparative Examples 1 to 4 provide a series of isopimarane-type diterpenoid compounds, as shown in Table 3 for details.
  • MH7A cells (commercially purchased) in the logarithmic growth phase were adjusted to a cell density of 5*10 ⁇ 3 cells/well, inoculated into 96-well plates at 100 ⁇ L/well, and cultured in a cell culture incubator at 37°C overnight.
  • the drug was diluted five times in a concentration gradient using DMEM medium containing 10% fetal bovine serum in total volume.
  • MH7A cells The initial concentration was set to 50 ⁇ M (with a concentration gradient of 50, 20, 15, 10, and 5 ⁇ M). After discarding the old supernatant in the well plate, 100 ⁇ L of the diluted drug was taken from each well and added to the MH7A cells in the 96-well plate in 1). Five replicate wells were set for each drug concentration. The culture medium without sample was used as the blank control, and dexamethasone was added as the positive control drug.
  • the isopimarane-type diterpene compounds of the present invention have significant therapeutic effects and can significantly inhibit the release of inflammatory factors such as IL-1 ⁇ and IL-6.
  • the specific test method is as follows:
  • MH7A cells (commercially purchased) in the logarithmic growth phase were adjusted to a cell density of 2*10 ⁇ 4 cells/well, inoculated into 96-well plates at 100 ⁇ L/well, and cultured in a cell culture incubator at 37°C overnight.
  • the drug concentration was diluted to 15 ⁇ M using DMEM medium containing 10% fetal bovine serum in total volume.
  • MH7A cells After discarding the old supernatant in the well plate, take 100 ⁇ L of the diluted drug per well and add it to the MH7A cells in the 96-well plate in 1), and set up 3 replicate wells for each drug concentration.
  • the medium with the addition of inducer but no sample is used as the model control (Model), the medium without the addition of sample is used as the blank control (Control), and dexamethasone is used as the positive control drug (Dex).
  • TNF- ⁇ inducer with a total concentration of 10ng/mL to induce inflammation in the model and release cytokines.
  • the ELISA kit was operated according to the instructions, and the absorbance (OD) at 450 nm was measured with a microplate reader.
  • the compounds prepared in Examples 1 to 3 of the present invention can significantly reduce the levels of IL-1 ⁇ and IL-6 inflammatory factors. Release, which shows that the compounds in each embodiment of the present invention have the effect of improving rheumatoid arthritis, and have good application prospects in the preparation of corresponding drugs, especially the compound represented by compound formula (II-1) has comprehensive and significant effects. Specific values are shown in Table 4 (taking the pro-inflammatory factor IL-1 ⁇ as an example).
  • the test example of the present invention uses TNF- ⁇ to induce MH7A cells as a cell model of rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the source material human rheumatic pannus
  • the MH7A cell line is immortalized by transfecting RA patient FLSs with SV40 large T antigen. Therefore, MH7A has been used as a cell model in the art to conduct relevant research on drug screening and mechanism of action of RA.
  • the inflammatory response in the body is simulated by TNF- ⁇ , and then the oxidative damage in the cell is stimulated, so as to verify the drug effect, the verification process is scientific and reasonable, and the verification result is accurate and reliable. It can be seen from Figures 10A to 10E and Figures 11A and 11B that the isopimarine diterpenoid compounds in the embodiments of the present invention have good application prospects in the preparation of drugs for preventing and treating rheumatoid arthritis.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Rheumatology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé diterpénoïde de type isopimarane, son procédé de préparation et son utilisation. Le composé est un composé tel que représenté par la formule (I) ou la formule (II). Le composé peut être préparé en un médicament pour réduire la libération d'IL-1β et d'IL-6, ce qui permet de réduire l'hyperplasie des cellules synoviales et l'infiltration de cellules inflammatoires au moyen de l'inhibition de la libération du facteur anti-inflammatoire IL-1β, et peut en outre être préparé dans un médicament pour soulager la polyarthrite rhumatoïde, ayant une valeur scientifique définie et une signification pratique pour la recherche et le développement de médicaments anti-polyarthrite rhumatoïde innovants avec une qualité contrôlable, une faible toxicité et une efficacité élevée.
PCT/CN2023/117274 2023-04-19 2023-09-06 Composé diterpénoïde de type isopimarane, son procédé de préparation et son utilisation WO2024216818A1 (fr)

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