WO2023274095A1 - Application d'un composé kaurane dans la préparation d'un médicament pour la prévention et le traitement d'une maladie intestinale inflammatoire - Google Patents

Application d'un composé kaurane dans la préparation d'un médicament pour la prévention et le traitement d'une maladie intestinale inflammatoire Download PDF

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WO2023274095A1
WO2023274095A1 PCT/CN2022/101349 CN2022101349W WO2023274095A1 WO 2023274095 A1 WO2023274095 A1 WO 2023274095A1 CN 2022101349 W CN2022101349 W CN 2022101349W WO 2023274095 A1 WO2023274095 A1 WO 2023274095A1
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compound
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bowel disease
inflammatory bowel
inflammatory
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PCT/CN2022/101349
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王善平
谭文
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东莞市凯法生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • the invention discloses a kauritanes compound for alleviating and treating inflammatory bowel disease.
  • the invention discloses that the kauritanes compound can obviously reduce the body weight of enteritis model mice induced by dextran sodium sulfate (DSS), improve the shortening of the colon length of the colitis model mice, and reduce the infiltration of inflammatory cells in the colon tissue of the colitis model , reduce the increase of white blood cells, neutrophils, lymphocytes and monocytes in colitis model mice, and reduce the expression of inflammatory factors.
  • the invention discloses the regulating effect of the kauritanes on macrophages and T cells when inflammatory bowel disease occurs.
  • Inflammatory bowel disease is a chronic intestinal inflammatory disease with unclear pathogenesis, mainly including ulcerative colitis (Ulcerative Colitis, UC) and Crohn's disease (Crohn's disease, CD).
  • UC ulcerative colitis
  • Crohn's disease Crohn's disease
  • CD Crohn's disease
  • CD is a kind of chronic granulomatous inflammation, and the lesions can involve all parts of the gastrointestinal tract, but it is more likely to occur in the terminal ileum and right colon; the main clinical manifestations are abdominal pain, diarrhea, and intestinal obstruction (Peixoto Armando, ACG Case Reports Journal, 2017, 4(1):e46).
  • IBD is common in western countries, and the prevalence rate in European and North American countries is as high as 120-200/100,000. It is a common disease in the digestive field. According to statistics, the incidence of IBD has been increasing rapidly in Africa, Asia and South America since 1990.
  • IBD In Brazil, the annual growth rate of the incidence of UC and CD is as high as 15% and 11% respectively; in my country, the incidence of IBD is also showing an increasing trend year by year, and the annual growth rate of the incidence of UC and CD in Taiwan is 5% and 4% respectively (Kamm Michael A, The Lancet, 2017, 390(10114):2741-2742), IBD has become a common disease of the digestive system in my country and the main cause of chronic diarrhea and blood in the stool. Its etiology and pathogenesis are unknown, but it is generally believed to be related to heredity, abnormal intestinal mucosal immune regulation, persistent intestinal infection, and intestinal mucosal barrier defect.
  • the main method of IBD treatment is to restore the balance between pro-inflammatory factors and anti-inflammatory factors and regulate intestinal mucosal immune abnormalities.
  • the immune response includes intestinal mucosal adaptation.
  • Sexual immune response such as T cells
  • innate immune response such as macrophages
  • T cells including Th1, Th2 and Th17 cells, are involved in the pathogenesis of DSS-induced enteritis.
  • CD4+ T cells in which CD was considered to be dominated by Th1-type mucosal inflammation; UC was dominated by Th2-type.
  • Th17 cell subsets are a type of CD4+T cell subsets discovered in recent years. In recent studies, it has been found that IBD patients have a large number of Th17 cell infiltration, which opens up a new field of research on inflammatory bowel disease.
  • Th17 cells include clearing specific extracellular pathogens, thereby playing a protective role; also including causing inflammation and autoimmune diseases.
  • the main function of Th17 cells is to secrete cytokines, including IL-17A, IL-21, etc., which play an important role in the occurrence of various autoimmune diseases and induce inflammatory responses in IBD immune regulation.
  • Macrophages are a group of highly heterogeneous cells, which can be divided into two subpopulations: classically activated macrophages (M1 type) and alternatively activated macrophages (M2 type) according to their activation status (Besedovsky H, Clinical and experimental immunology, 1977; 27(1):1-12).
  • M1 type classically activated macrophages
  • M2 type alternatively activated macrophages
  • the polarization of macrophages is influenced by various cytokines in the microenvironment and has considerable plasticity.
  • M1 macrophages are mainly activated by IFN- ⁇ , TNF- ⁇ , LPS and other stimuli, and can secrete a large number of inflammatory cytokines, such as IL-1 ⁇ , IL-13, TNF- ⁇ , etc., as well as reactive oxygen products.
  • Th1 and Th17 cells can promote the activation of Th1 and Th17 cells, promote local inflammatory responses, and accelerate the clearance of intracellular pathogens. If the activity of M1 macrophages is not controlled, it will lead to excessive inflammatory response and cause tissue damage (Knobloch HS, Frontiers in behavioral neuroscience, 2014; 8:31). Under the action of IL-4 and IL-13 produced by granulocytes or Th2 cells, macrophages are polarized into M2 macrophages, which are insensitive to LPS stimulation and secrete growth factors, IL-10, TGF- ⁇ , etc. recruit Th2 and regulatory T cells (Treg), downregulate local inflammatory response, promote tissue repair and clearance of parasites.
  • Th2 and regulatory T cells Treg
  • Therapeutic drugs include aminosalicylic acid preparations, glucocorticoids, immunosuppressants and various biological agents (such as TNF- ⁇ monoclonal antibody, etc.).
  • aminosalicylic acid drugs are likely to cause drug resistance in patients, and glucocorticoids will relapse after drug withdrawal.
  • the cost of TNF antibody production and treatment is high, and it is prone to failure after long-term use, and it is easy to cause patients infection (Paolo Gionchetti, Dig Liver Dis, 2017, 49(6):604-17). Therefore, finding safer and more effective anti-colitis drugs is one of the hotspots in current IBD research, and it is an urgent clinical need that has not been met.
  • Compound A is a bayonene terpenoid isolated from stevioside.
  • Stevia is a well-known traditional plant in South America and is a widely used sweetener worldwide.
  • the effect of stevia on metabolism and cardiovascular system (Geuns JMC.Stevioside.Phytochemistry.2003; 64(5):913-21) has also been reported.
  • kaurane-like compounds represented by compound A have protective effects on heart and brain tissue, and can be used to treat myocardial ischemia and cerebral infarction (patent 1: CN100508962 C).
  • compound A and related kaurane-type compounds can also inhibit tissue damage leading to inflammation, and inhibit fibrosis of myocardial and lung tissue (patent 2: CN108348481 A).
  • Compound A may also be used for metabolic diseases and diabetic myocarditis.
  • Studies have also proved that compound A also has inhibitory effect on some cytokines such as TNF- ⁇ , interleukin IL-6 and so on.
  • compound A and related kauritanes have not been reported in the treatment of inflammatory bowel disease. It is now known that immune dysfunction is the main cause of inflammatory bowel disease, and the imbalance of macrophages and T cells plays a key role in the initiation and development of the above-mentioned cytokine storm. However, compound A and related kaurane compounds have no reports on the immune regulation effects of the above-mentioned immune dysfunction and macrophages and T cells.
  • compound A and related kauritanes can be used to treat inflammatory bowel disease; they can improve inflammatory bowel disease.
  • Compound A and related kauritanes can also regulate the abnormal immune inflammatory response by inhibiting the polarization of macrophages and the differentiation of T cells caused by inflammatory bowel disease, and inhibiting the expression of various cytokines and chemical toxic substances. To achieve the effect of treating inflammatory bowel disease.
  • the object of the present invention is to provide the application of a kauritanes compound in the preparation of medicaments for the treatment and prevention of inflammatory bowel disease.
  • the invention discloses a novel medicine for treating and/or preventing inflammatory bowel disease.
  • the invention discloses kaurane compounds, such as compound A (structural formula (I)), which are used for treating sepsis and multiple organ failure.
  • Structural formula (I) represents a class of natural, synthetic or semi-synthetic compounds. Many of these compounds are already known to the public (Kinghorn AD, 2002, p86-137; Sinder BB et al., 1998; Chang FR et al., 1998; Hsu FL et al., 2002).
  • Compounds of formula (I) may have one or more asymmetric centers and may exist as different stereoisomers.
  • R1 hydrogen, hydroxyl or alkoxy.
  • R2 carboxyl group, carboxylate, acid halide, aldehyde group, methylol group, and ester group, acrylamide group, acyl group or ether bond group that can generate carboxyl group.
  • R3, R4, R5, R6, R8 Oxygen, hydroxyl, hydroxymethyl, and ester groups or alkoxymethyl groups that can be hydrolyzed to form hydroxymethyl.
  • v. R7 methyl group, hydroxyl group, and ester group or alkoxymethyl group that can be hydrolyzed to form hydroxymethyl group.
  • the structure of a group of preferred compounds is shown in formula (I').
  • the compound has a kaurane structure, which is substituted at C13 and derivatized at C17 and C18.
  • the compounds may possess multiple asymmetric centers and exist as different stereoisomers or diastereomers.
  • the absolute configurations of positions 8 and 13 are (8R, 13S) or (8S, 13R).
  • R2 Carboxyl, carboxylate, aldehyde, hydroxymethyl, methyl ester, acylmethyl, acid halide.
  • R7 methyl, hydroxymethyl or methyl ether.
  • Compound A can be obtained after natural stevioside hydrolysis.
  • Compound B is the aglycone of stevioside, and stevioside is the glycoside of compound B.
  • Compounds A and B are isomers.
  • Compound B can be obtained by hydrolysis and oxidation of stevioside, or by catalyzed reaction of intestinal bacteria in animals.
  • the molecular formula of compound A is C 20 H 30 O 3 , and the chemical name is (4 ⁇ , 8 ⁇ , 13 ⁇ )-13-methyl-16-oxo-17-norkauran-18-oic acid.
  • Compound A is also known as ent-16-ketobeyran-18-oic acid.
  • the compound is a tetracyclic diterpenoid compound containing a kaurane structure, wherein the absolute configuration of the asymmetric carbon atom is: (4R, 5S, 8R, 9R, 10s, 13s), and the carbon 13 position is substituted with a methyl group group, a carbonyl group at carbon 16, and a carboxyl group at carbon 18 (Rodrigues et al., 1988).
  • the molecular formula of compound B is C 20 H 30 O 3 , and the chemical name is ent-13-hyrdoxykaur-16-en-18-oicacid, which is also known as steviol.
  • This compound is also a tetracyclic diterpenoid containing a kaurane structure.
  • the absolute configuration of the chiral carbon atom is (4R, 5S, 8R, 9R, 10S, 13S), the hydroxyl group is connected to the carbon 13, the methylene is connected to the double bond adjacent to the carbon 16, and the carboxyl group is connected to the carbon 18 (Rodrigues et al., 1993).
  • Compound A or B can also exist in the form of carboxylate at carbon 18, wherein the carboxylate is sodium and alkali metal or chloride and halogen. Both compounds A and B are kaurane compounds containing a kaurene structure.
  • Compound A is a preferred compound of the invention.
  • the present invention discloses that compound A or B has similar therapeutic effects in the treatment and prevention of cardiac hypertrophy and pulmonary hypertension. It can be concluded that all other compounds of formula (I) also have the same therapeutic effect as compound A. It is reported that Compound B is mutagenic under certain conditions in vitro. Therefore, compared with compound B, compound A is more suitable as a therapeutic drug.
  • Compound A used in the present invention is the sodium salt of Compound A with better solubility.
  • the invention discloses the application of compound A structural formula (I) in the treatment and prevention of inflammatory bowel disease.
  • DSS induced inflammatory bowel disease in mice
  • the mice lost weight and had hematochezia After administration of DSS, compound A was administered intraperitoneally, the body weight of the mice recovered, and the blood in the stool was significantly reduced.
  • DSS was added in free drinking water.
  • the mice lost weight significantly, had blood in the stool, diarrhea, and histopathological scores increased; /kg), the body weight of the mice recovered, and the hematochezia and diarrhea were relieved in a dose-dependent manner.
  • the present invention also discloses that in mice with inflammatory bowel disease induced by DSS, the results of routine blood test show that the values of white blood cells, neutrophils and monocytes in the mice are significantly higher than those in the normal group, showing that the DSS model group The mice had an inflammatory response; after administration of compound A, the white blood cells, neutrophils and monocytes of the mice were significantly lower than those of the DSS model group, and at the same time approached the normal level.
  • the effect is better than or equivalent to the commercially available drugs 5-aminosalicylic acid (5-ASA), dexamethasone (Dex) and infest interest (IFX). It shows that compound A has obvious regulating effect on immune dysfunction caused by inflammatory bowel disease, and makes it return to normal.
  • compound B in structural formula (I) also has similar effects to compound A.
  • the above disclosed content has not been reported in the past, nor can it be predicted and deduced by industry insiders, and should be regarded as novel and creative.
  • this study also disclosed a surprising finding: in the DSS-induced inflammatory bowel disease mice, after administration of Dex, the neutrophils increased further compared with the inflammatory bowel disease mice. It shows that immune dysfunction not only did not return to normal, but aggravated the disorder of immune function.
  • the spleen is an important organ for regulating immune antibodies, and the various immunoglobulins it produces are crucial for the body to fight against pathogens.
  • the spleen/body weight ratio of mice with inflammatory bowel disease increased significantly. However, with hormone therapy, this proportion decreased significantly. and lower than normal control levels. The body's ability to fight pathogens is reduced.
  • the present invention discloses for the first time that the use of compound A to treat inflammatory bowel disease can avoid the toxic and side effects of clinical use of corticosteroids to treat inflammatory bowel disease.
  • compound B in structural formula (I) also has similar effects to compound A.
  • the above disclosed content has not been reported in the past, nor can it be predicted and deduced by industry insiders, and should be regarded as novel and creative.
  • the systemic massive production of cytokines in the body is an important reason for the occurrence and development of inflammatory bowel disease.
  • the levels of TNF- ⁇ , IL-1 ⁇ and IFN- ⁇ in the serum of the detected mice were significantly increased compared with the normal group, and different doses of compound A were given
  • the TNF- ⁇ , IL-1 ⁇ and IFN- ⁇ in the post-treatment serum decreased significantly.
  • the present invention discloses for the first time that compound A can inhibit the increase of cytokines caused by inflammatory bowel disease.
  • the present invention also discloses that the spleen macrophages M1 and M2 increase significantly during the inflammatory bowel disease.
  • the above-mentioned biomarkers of M1 and M2 macrophages and the number of macrophages were significantly decreased after compound A was administered.
  • Compound A can regulate the inflammatory response caused by macrophages by inhibiting M1 and M2 macrophages.
  • the invention also discloses the influence of the inflammatory bowel disease on spleen T cells.
  • Th17 cells increased significantly, while Treg cells decreased.
  • Treg cells decreased.
  • Compound A can slow down the inflammatory response by regulating T cells.
  • Figure 1 is the effect of Compound A in Example 1 of the present invention on blood in the stool of mice with inflammatory bowel disease.
  • Figure 2 is the effect of intraperitoneal injection of Compound A of different doses on the body weight of DSS-induced inflammatory bowel disease mice in Example 1 of the present invention
  • Fig. 3 is the effect of Compound A in Example 1 of the present invention on the colon length of mice with inflammatory bowel disease.
  • Fig. 4 is the effect of Compound A in Example 1 of the present invention on the spleen weight of mice with inflammatory bowel disease.
  • Fig. 5 is HE staining of compound A in Example 1 of the present invention on mouse tissue with inflammatory bowel disease.
  • Fig. 6 is the effect of Compound A in Example 1 of the present invention on the histopathological score of mice with inflammatory bowel disease.
  • Fig. 7 is the effect of Compound A in Example 2 of the present invention on the intestinal permeability of mice with inflammatory bowel disease.
  • Fig. 8 is the effect of Compound A in Example 3 of the present invention on the blood routine of mice with inflammatory bowel disease.
  • Figure 9 is the effect of Compound A in Example 4 of the present invention on inflammatory factors in mice with inflammatory bowel disease
  • Figure 10 is the effect of Compound A in Example 5 of the present invention on Th7 cells in mice with inflammatory bowel disease
  • Figure 11 is the effect of Compound A in Example 5 of the present invention on FoxP3 cells in mice with inflammatory bowel disease
  • Figure 12 is the effect of Compound A in Example 5 of the present invention on macrophage M1 of mice with inflammatory bowel disease
  • Fig. 13 is the effect of Compound A in Example 5 of the present invention on macrophage M2 in mice with inflammatory bowel disease.
  • the case provides the experimental methods and results used to support and validate the animal models used in the present invention. Appropriate control group experiments and statistical analysis methods were used for the cases involved. The following cases are used to describe rather than limit the application of the present invention. The methods and techniques involved in these cases can be used to screen and determine the therapeutic effect of such compound preparations. The same method can be used to evaluate the therapeutic effect of other such compound preparations.
  • mice adult male Balb/c mice, weighing 20g ⁇ 5g, aged 6-8 weeks.
  • the rearing environment included constant temperature, humidity, and strict dark-to-light cycles, with ad libitum feeding.
  • Chemical reagent Compound A (ent-17-norkaurane-16-oxo-18-oic acid, molecular formula, C 20 H 40 O 3 , molecular weight: 318.5) is obtained from stevioside through acid hydrolysis and crystallization purification.
  • the sodium salt of compound A can be obtained by adding NaOH or other sodium-containing bases; the purity of the sodium salt of compound A measured by high performance liquid chromatography is greater than 99%.
  • the administration mode of the test compound intravenous injection or intraperitoneal injection or oral administration. Dosage: compound A (or its sodium salt), 10 mg/kg to 15 mg/kg.
  • mice in the experimental group were intraperitoneally injected with compound A, Dex and IFX, and 5-ASA, and the mice in the control group were injected with normal saline intraperitoneally.
  • the experimental group was administered for 2 consecutive days. From the third day, both the experimental group and the control group began to drink 3.5% DSS aqueous solution freely, and the daily drinking volume of each mouse was calculated as 7 mL, and fresh DSS solution was changed every two days. DSS was given for 7 days in total, and the mice were observed every day. Weight changes, blood in the stool and stool consistency. On the 10th day, the mice were blood-collected and killed, and the colorectal tissues of the mice were taken and measured for length. Part of the tissues were formalin-fixed and the remaining tissues were frozen at -80°C for subsequent histology. Analytical and molecular biology experiments.
  • mice in the model group of the DSS group had severe hematochezia, and after compound A was administered, the hematochezia of the mice was alleviated.
  • Increased spleen weights in animals may correlate with the degree of inflammation. It can be seen from Figure 4 that after administration of DSS, the spleen weight of the mice will increase, showing splenomegaly. After being sacrificed on the 9th day, the weight of the spleen was weighed and recorded, and continued to be corrected by the weight of each animal before sacrifice. It can be found that the spleen size and weight of the mice in the model group are significantly different from those in the normal control group. Different degrees of splenomegaly were relieved in each administration group. Compared with the model group, whether the compound A, 5-ASA, Dex and infliximab groups decreased or not, there were significant differences compared with the model group.
  • This case mainly observes the permeability of the colon of experimental mice in each group.
  • mice Take several normal mice, collect hemolysis-free serum, weigh 200 ⁇ g of FITC-dextran powder, dissolve it in 5ml serum, and dilute it in multiples, and then use a microplate reader to detect the fluorescence intensity to obtain the standard curve.
  • Serum was added to a 96-well plate, and 100 ⁇ l per well was used to detect the fluorescence intensity with a microplate reader (excitation light 488 nm, emission light 520 nm).
  • FITC-dextran fluorescein-labeled dextran
  • FITC-dextran is a fluorescent dye. After exogenous administration of FITC-dextran to mice, the level of intestinal permeability can be reflected by detecting the fluorescence intensity of FITC-dextran in serum. A novel index for evaluating intestinal inflammation. Therefore, on the day of sacrificing the animals, the mice were fasted for more than 6 hours, and then given FITC-dextran by intragastric administration, and after 6 hours, the fluorescence content of FITC-dextran in the serum was detected. As shown in Figure 7, the FITC content in the serum of the mice in the normal control group was very low, indicating that the intestinal permeability was normal.
  • the FITC content increased significantly, indicating that the intestinal permeability increased and the intestinal wall was damaged.
  • the content of FITCF in the compound A, 5-ASA, Dex and Infliximab groups was significantly reduced, indicating that compound A has a certain effect on protecting the intestinal tract.
  • This case mainly illustrates the effect of compound A on the blood routine of inflammatory bowel disease.
  • RBC red blood cell count
  • MONO monocytes
  • LYMPH neutrophils
  • PPT platelets
  • HGB hemoglobin
  • HCT hematocrit
  • WBC white blood cell count
  • This case mainly illustrates the effect of Compound A on inflammatory factors.
  • Serum TNF- ⁇ , IFN- ⁇ and IL-1 ⁇ levels were determined according to the instructions provided by the ELISA kit.
  • This example illustrates the effect of Compound A on the polarization of T cells and macrophages.
  • mice 70 6-8 week-old Balb/c male mice were adaptively fed for one week, and randomly divided into 8 groups with 10 mice in each group, which were normal group, compound A normal control group, DSS model group, Compound A group, 5-ASA group, Dex group and infliximab group. Drink DSS freely for seven consecutive days.
  • mice were killed by necking on the eighth day, and spleen T cells and macrophages were extracted.
  • Th17 cells were significantly reduced after compound A, 5-ASA group, Dex group and infliximab intervention, and Treg cells were significantly increased, indicating that compound A plays an important role in the regulation of T cells important.

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Abstract

L'invention concerne une application d'un composé kaurane dans la préparation d'un médicament pour le traitement d'une maladie intestinale inflammatoire. Le composé kaurane peut atténuer la réaction inflammatoire des souris modèles de maladie intestinale inflammatoire induite par le dextran sodium sulfate (DSS) et améliorer la gravité de la maladie intestinale inflammatoire, et peut être utilisé pour préparer un médicament ou un produit de soins de santé pour traiter la maladie intestinale inflammatoire.
PCT/CN2022/101349 2021-06-27 2022-06-26 Application d'un composé kaurane dans la préparation d'un médicament pour la prévention et le traitement d'une maladie intestinale inflammatoire WO2023274095A1 (fr)

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WAN HUIDA: "Enzymatic Transglycosylation and Hydrolysis of Stevioside", CHINESE DOCTORAL DISSERTATIONS FULL-TEXT DATABASE, UNIVERSITY OF CHINESE ACADEMY OF SCIENCES, CN, no. 4, 15 April 2013 (2013-04-15), CN , XP093017993, ISSN: 1674-022X *
WANG SHANPING, HUANG JIANDONG, LIU FEI, SINN TAN KEAI, DENG LIANGJUN, LIN YUE, TAN WEN: "Isosteviol Sodium Exerts Anti-Colitic Effects on BALB/c Mice with Dextran Sodium Sulfate-Induced Colitis Through Metabolic Reprogramming and Immune Response Modulation", JOURNAL OF INFLAMMATION RESEARCH, vol. 14, 20 December 2021 (2021-12-20), pages 7107 - 7130, XP093017987, DOI: 10.2147/JIR.S344990 *

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