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WO2018068769A1 - Utilisation de composés de type dihydroberbérine dans la préparation d'un produit destiné au traitement de maladies tumorales associées à la voie de signalisation stat3 - Google Patents

Utilisation de composés de type dihydroberbérine dans la préparation d'un produit destiné au traitement de maladies tumorales associées à la voie de signalisation stat3 Download PDF

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WO2018068769A1
WO2018068769A1 PCT/CN2017/106227 CN2017106227W WO2018068769A1 WO 2018068769 A1 WO2018068769 A1 WO 2018068769A1 CN 2017106227 W CN2017106227 W CN 2017106227W WO 2018068769 A1 WO2018068769 A1 WO 2018068769A1
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compound
compounds
colorectal cancer
group
present
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Chinese (zh)
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秦海林
吴练秋
张志辉
张海婧
邓安珺
王文杰
李志宏
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Institute of Materia Medica of CAMS and PUMC
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Institute of Materia Medica of CAMS and PUMC
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Priority to CN201780063266.2A priority Critical patent/CN110062624B/zh
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a series of medicinal chemistry and new pharmacological effects of a dihydroberberine-type compound having the same parent skeleton structure and a ( ⁇ )-8-acetonyldihydroberberine-type compound. Specifically, it relates to dihydroisoxanthine, dihydroclavine, dihydropalmatine, ( ⁇ )-8-acetonyl dihydroisoxanthine, ( ⁇ )-8-acetonyl dihydroclavinine and ( ⁇ )- The use of 8-acetonyl dihydropalmatine as a STAT3 inhibitor in the preparation of products for the prevention, alleviation and/or treatment of STAT3 signaling pathway-associated tumor diseases. It belongs to the field of medical technology.
  • cancers malignant tumors
  • cancers are all serious diseases that seriously endanger human health, causing tremendous physical and mental pain and economic pressure on patients and their families.
  • cancers malignant tumors
  • it is often clinically forced to combine the methods of surgery, radiation therapy and chemotherapy as a first-line clinical treatment to treat patients.
  • the prevention, alleviation and treatment of various human cancers is still a very difficult scientific research work in the field of medical science research. It is a systematic project that requires huge investment in capital and manpower.
  • Berberine-type compounds are generally referred to as the following three different types of compounds in the field of natural organic chemistry: (1) having 6,8-dihydro-5H-isoquino[3,2-a]isoquinoline ( 6,8-dihydro-5H-isoquinolino[3,2-a]isoquinoline) Basic structure of 7,8-imine salt type structure of berberine quaternary ammonium salt type compound (I), (2) having 6,8 - Dihydro-5H-isoquino[3,2-a]isoquinoline basic parent structure of dihydroberberine-type compounds (II) and (3) having 6,8,13,13a-tetrahydro- 5H-isoquinoline[3,2-a]isoquinoline (6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-a]isoquinoline) basic parent structure of tetrahydroberberine ( The protoberberine-type compound and its various salts (III), the chemical formula of the three parent forms are shown in
  • the berberine quaternary ammonium salt type compound (I) and the dihydroberberine type compound (II) have a plurality of different resonance forms as shown in Formulas 2 and 3, respectively, but due to the difference in structure, The resonance structure and number of the two are not the same; their structural features and basic carbon framework structure with 6,8,13,13a-tetrahydro-5H-isoquino[3,2-a]isoquinoline type There is also a significant difference between the benzylisoquinoline type compound (i.e., the protoberberine type or the tetrahydroberberine type compound) and its various salts (III), that is, in the III, in addition to the asymmetric center of 13a.
  • the benzylisoquinoline type compound i.e., the protoberberine type or the tetrahydroberberine type compound
  • its various salts (III) that is, in the III, in addition to the asymmetric center of 13a.
  • the berberine quaternary ammonium salt type compound and the dihydroberberine type compound belong to different structural type compounds.
  • some berberine quaternary ammonium salt type compounds and tetrahydroberberine type compounds have relatively abundant natural resources, according to current research reports, the structure of the dihydroberberine type compound has only a specific environment. Stability (in the above three types of berberine-type compounds, the structure of the dihydro-type berberine compound is the most unique), so the existence in nature is greatly limited, or the raw material obtained from the scale of nature has Quite difficult.
  • the dihydroberberine type compound and the ( ⁇ )-8-acetonyldihydroberberine type compound are all synthesized by an organic chemical method.
  • berberine and palmatine have certain anti-colon cancer activity.
  • berberine can inhibit colon cancer cells by inactivating the Wnt/ ⁇ -catenin signaling pathway. Proliferation (see literature: Wu K, et. al.
  • Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/ ⁇ -catenin signaling, International Journal of Oncology, 2012, 41, 292-298), and has the effect of inhibiting human colon cancer cells
  • Pharmacological activity of growth in nude mice see patent document: CN1313093C
  • palmatine chloride is a photosensitizer and is phototoxic to colonic adenocarcinoma cell line HT-29 (see literature: Wu J, et al. Photodynamic action) Of palmatine hydrochloride on colon adenocarcinoma HT-29cells, Photodiagnosis and Photodynamic Therapy, 2016, 15, 53-58); we also evaluated the activity of copperine quaternary ammonium salt against colon cancer cell lines in vitro.
  • dihydroberberine-type compounds are known to be limited to the specific compound dihydroberberine showing synergistic anti-tumor effects in pharmaceutical compositions consisting of sunitinib, including colon, lung and liver cancer. Role (see patent document: CN 105434435 A), and so on.
  • the berberine-type compounds have structural diversity; from the perspective of the relationship between organic structure and properties, the three types of berberine-type compounds are not only structurally inconsistent, but also have significant physical and chemical properties.
  • the berberine quaternary ammonium salt type compound not only causes a poor solubility in various solvents due to the unique presence of a passivating functional group in the 7,8-imine salt type aromatic electrophilic substitution reaction, but also a conjugated system.
  • the isoproterenium quaternary ammonium salt, the berberine quaternary ammonium salt, the palmatine quaternary ammonium salt and the berberine quaternary ammonium salt in the berberine quaternary ammonium salt type compound are transformed into a series of fat-soluble dihydrogen by functional group change.
  • Berberine-type compounds including dihydroisoxanthine (1), dihydroclavidine (2), dihydropalmatine (3) and dihydroberberine, for solubility, bioavailability, activity and toxicity Evaluation, the results showed that these dihydroberberine-type compounds were significantly improved in solubility in various organic solvents such as dioxane, acetone or tetrahydrofuran, compared with the berberine quaternary ammonium salt type compound.
  • both compounds 1 and 2 are more than 5g / Kg, is a non-toxic compound;
  • Compound 3 has an LD 50 value of 800mg / Kg, is a low toxicity compound;
  • the LD 50 value of the tumor-acting dihydroberberine is only 160 mg/Kg, which is the most toxic compound in this series of compounds. This was confirmed in our animal experiments, that is, dihydroberberine was used in 50 mg. /Kg dose after experimental administration of experimental animals The phenomenon of rapid death, and 1, 2 and 3 did not appear the death of experimental animals, even 1 and 2 did not appear in the death of experimental animals when the dose was large.
  • the result of the inhibitory activity does not indicate its anticancer activity.
  • Compound 2 does not exhibit cytostatic activity against HCT cell lines, and the IC 50 value is greater than 5 ⁇ g/mL (data are described in Zhi-Hui Zhang, et al. Syntheses and structure – Activity relationships in cytotoxicities of 13-substituted quaternary coptisine derivatives, European Journal of Medicinal Chemistry, 2014, 86, 542-549; IC 50 values greater than 5 ⁇ g/mL, ie greater than 15.56 ⁇ M, considered to be inactive compounds; The results of the study showing anti-tumor activity gave us the opposite technical inspiration and led us to abandon the idea of this type of compound research.
  • the present invention synthesizes a ( ⁇ )-8-acetonyl substituted derivative of a dihydroberberine-type compound, including ( ⁇ )-8-acetonyldihydroisoxanthine, starting from a quaternary ammonium type berberine-type compound.
  • ( ⁇ )-8-acetonyl dihydroclavinine (5), ( ⁇ )-8-acetonyl dihydropalmatine (6) and ( ⁇ )-8-acetonyl dihydroberberine
  • the toxicity and antitumor activity were evaluated.
  • the results of the compound 5 showing no obvious cytotoxicity to IEC-6 intestinal epithelial cells also indicate that it is a low toxicity compound (the IEC-6 cytotoxicity experimental data of Compound 5 is shown in the literature: Zhi-Hui Zhang, et al., Synthesis and Structure-activity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents.Journal of Medicinal Chemistry.2015,58,7557-7571;Zhi-Hui Zhang,et al.Syntheses and structure-activity relationships in cytotoxicities of13-substituted Quaternary coptisine derivatives, European Journal of Medicinal Chemistry, 2014, 86, 542-549).
  • compounds 1, 2, 3 and 5 are used as examples to treat Azoxymethane (AOM)/Dextran sulfate sodium.
  • DSS Azoxymethane
  • STAT3 signal transduction and activator of transcription 3
  • STAT3 is closely related to the occurrence and development of various tumors.
  • STAT3 is over-activated and expressed at high levels in cells of various tumors.
  • Inhibition of overexpression of STAT3 is one of the means of treating tumors.
  • the results of the present study indicate that Compounds 1, 2, 3 and 5 all have significant STAT3 inhibition, further illustrating that the series of compounds of the present invention can prevent or treat STAT3 signaling pathway-associated tumor diseases by inhibiting STAT3.
  • the technical problem solved by the present invention is to provide a class of dihydroberberine-type compounds and ( ⁇ )-8-acetonyldihydroberberine-type compounds in the preparation of STAT3 inhibitors and preparation of products for preventing or treating STAT3 signaling pathway-related tumor diseases.
  • the application further, provides its use in the preparation of a product for the prevention or treatment of malignant colorectal cancer.
  • the present invention provides the following technical solutions:
  • a first aspect of the technical solution of the present invention provides a use of a dihydroberberine-type compound and a ( ⁇ )-8-acetonyldihydroberberine-type compound in the preparation of a STAT3 inhibitor, and a preparation thereof for prevention or For use in the treatment of STAT3 signaling pathway-associated tumor disease products
  • the dihydroberberine-type compounds include dihydroisoxantine, dihydroclavine, and dihydropalmatine, ( ⁇ )-8-acetonyl dihydrogen
  • the berberine-type compound includes ( ⁇ )-8-acetonyldihydroisoxanthine, ( ⁇ )-8-acetonyl dihydroclavinate, and ( ⁇ )-8-acetonyl dihydropalmatine.
  • Specific compounds are dihydroisoxanthine, dihydroclavonic base, dihydropalmatine, ( ⁇ )-8-acetonyldihydroisoxanthine, ( ⁇ )-8-acetone, as shown in Formulas 1-6, respectively.
  • the products include medicines and health care products.
  • the STAT3 signaling pathway-associated tumor disease is selected from the group consisting of colorectal cancer, and various types of malignant tumors, including colorectal cancer associated with ulcerative colitis and other types of colorectal cancer.
  • the colorectal cancer includes colon cancer and rectal cancer.
  • a second aspect of the present invention provides a dihydroisoxanthine, dihydropyrazine, dihydropalmatine, ( ⁇ )-8-acetonyldihydroisoxanthine as shown in Formula 1-6. , ( ⁇ )-8-acetonyl dihydroclavinine and Use of a pharmaceutical composition of a specific compound of one or more of ( ⁇ )-8-acetonyl dihydropalmatine for the preparation of a product for preventing or treating a STAT3 signaling pathway-associated tumor disease.
  • the STAT3 signaling pathway-associated tumor disease is selected from the group consisting of colorectal cancer, and various types of malignant tumors, and the products include medicines and health care products.
  • the colorectal cancer includes ulcerative colitis-associated colorectal cancer and other types of colorectal cancer.
  • the colorectal cancer includes colon cancer and rectal cancer.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the preferred dosage form is ordinary or enteric. solid preparations.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 99.9% (w/w).
  • the compound of the present invention or a pharmaceutical composition containing the compound of the present invention can be administered in a unit dosage form, which can be enterally or parenterally, such as orally.
  • a unit dosage form which can be enterally or parenterally, such as orally.
  • intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory, skin, vaginal, rectal administration, and the like can also be administered.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including O/W type, W/O type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc. Preferred dosage forms of the dihydroberberine-type compound and the ( ⁇ )-8-acetonyldihydrober
  • the compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • the diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.;
  • the wetting agent may be water, ethanol, Isopropanol, etc.;
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linking Polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate, polyoxyethylene
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets, preferably coated tablets are common or enteric coated sheet.
  • the active ingredient (the compound of the present invention) may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient (the compound of the present invention) may also be granulated or pelletized with a diluent, a binder or a disintegrating agent, and then placed in a hard capsule or a soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizer, a solubilizer, a pH adjuster, an osmotic pressure adjusting agent which is commonly used in the art may be added and appropriately added.
  • a solubilizer e.g., a solubilizer, a solubilizer, a pH adjuster, an osmotic pressure adjusting agent which is commonly used in the art may be added and appropriately added.
  • the solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.;
  • the pH adjusting agent may be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.;
  • the stabilizer may be Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.;
  • the osmotic pressure adjusting agent may be sodium chloride, mannitol, glucose, phosphate, acetate or the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the therapeutic effect can be enhanced, and the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method, and the preferred administration method is oral administration of a common or enteric preparation.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the colorectal cancer to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of a compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably 0.1-100 mg/Kg body weight, more preferably 1-60 mg/Kg body weight, and most preferably 2-30 mg/Kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or pharmaceutical compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the present invention uses a PEG as a dispersing agent to prepare a dihydroberberine-type compound and a ( ⁇ )-8-acetonyldihydroberberine-type compound dispersant entity.
  • Oral administration or oral administration in the form of dispersion of CMC-Na/Tween-80 aqueous solution lays a foundation for subsequent formulation studies; the compound of the present invention can achieve therapeutic effects for colorectal cancer with remarkable effects.
  • the calculated tumor burden of coptisine (1), dihydroclavidine (2), dihydropalmatine (3) and ( ⁇ )-8-acetonyl dihydroisoxaine (4) at a dose of 50 mg /Kg reached 0.06, 0.13, 0.01, 0.08, respectively, even close to the value of 0.00 in the normal control group; compared with the 1.25 of the tumor control load of the positive control drug, the effect was very significant.
  • the calculated tumor burden of ( ⁇ )-8-acetonyl dihydroclavinine (5) and ( ⁇ )-8-acetonyl dihydropalmatine (6) reached 2.75 at a dose of 50 mg/kg, respectively. 0.40, compared with the same batch of positive control drug tumor load calculated value of 8.33, the effect is very significant.
  • the compound of the present invention has the advantages of no toxicity or low toxicity, and the LD 50 values of dihydroisoxantine and dihydroclavidine are all above 5.0 g/Kg, and dihydropalmatine
  • the LD 50 value is 0.8 g/Kg, ( ⁇ )-8-acetonyl dihydroisoxanthine, ( ⁇ )-8-acetonyl dihydroclavinine and ( ⁇ )-8-acetonyl dihydropalmatine
  • the LD 50 values were 5.0 g/Kg, 3.9 g/Kg, and 1.6 g/Kg, respectively, and were non-toxic or low-toxic specific anti-tumor compounds.
  • the compound of the present invention is STAT3 inhibitor; by pharmacodynamic experiments, it has been confirmed that the compound of the present invention has significant anti-colorectal cancer activity in vivo, and the activity is significantly higher than that of the positive control drug; the compound of the present invention is Non-toxic or low toxicity specific anti-tumor compounds, in prevention, slow It is a highly medicinal compound for the prevention, alleviation and/or treatment of colorectal cancer diseases by and/or treatment of STAT3 signaling pathway-associated tumor diseases.
  • FIG. 4 Histopathological examination of colorectal tumors of colorectal cancer model mice by compound 1-4 of the present invention (HE staining, 100-fold).
  • A is a normal control group
  • B is a colorectal cancer model group
  • C is a positive drug capecitabine administration group
  • D is a compound 1 administration group
  • E is a compound 2 administration group
  • F is a compound 3 administration group.
  • G is a compound 4 administration group.
  • FIG. 8 Histopathological examination of colorectal tumors of colorectal cancer model mice by compound 5 and 6 of the present invention (HE staining, 100-fold).
  • A is a normal control group
  • B is a colorectal cancer model group
  • C is a positive drug capecitabine administration group
  • D is a compound 5 administration group
  • E is a compound 6 administration group.
  • the compounds 1, 2, 3 and 4 of the present invention were each prepared as a PEG dispersing agent as a form of administration. When administered, The compound of the present invention is suspended by intragastric administration using water as a solvent.
  • C57BL/6J mice female were subjected to adaptive normal feeding for one week in a clean animal room, and then a single dose of AOM was administered to the experimental animals at a dose of 10 mg/Kg as the first day of the experiment, followed by normal feeding for 6 days. As the first week of the experiment.
  • the experimental animals were allowed to drink 2% of the DSS aqueous solution freely. After 7 days of induction, the normal drinking water was allowed to continue to allow the experimental animals to drink freely for two weeks (third week and fourth week) as the first induction.
  • the experimental animals were allowed to drink 2% of the DSS aqueous solution freely. After 7 days of induction, the normal drinking water was allowed to continue to allow the experimental animals to drink freely for two weeks (sixth and seventh weeks) as the second induction.
  • the experimental animals were allowed to drink 2% of the DSS aqueous solution freely. After 7 days of induction, the normal drinking water was allowed to continue to allow the experimental animals to drink freely for one week (ninth week) as the third induction.
  • each compound of the present invention was administered to each group of animals at a dose of 50 mg/kg according to the experimental design, once a day, once a day, the positive drug capecitabine was administered at a dose of 500 mg/Kg per day. once.
  • each group of animals was treated as usual, and the percentage change of body weight, spleen weight, colon length, colon tumor burden calculation, colon tumor histopathology, etc. after treatment were observed. Changes in indicators.
  • the experimental results show that the compounds of the present invention show significant anti-tumor activity in the experiments of treating colorectal cancer in vivo, and the curative effect is significantly better than that of the positive control drugs.
  • Figure 1 and Table 2 show that the model group is compared with the normal control spleen weight value (0.085 g). The spleen weight of the mice was significantly increased (0.131 g) (**, p ⁇ 0.01). The spleen weight of the mice in each administration group was reduced to different degrees compared with the mice in the model group.
  • the positive drug was 0.112 g, the compound 1 was 0.090 g, the compound 2 was 0.100 g, the compound 3 was 0.080 g, and the compound 4 was 0.100.
  • Figure 2 and Table 3 show that the model group mice were compared with the normal control group (6.84 cm). Colon length was significantly reduced (5.52 cm) (**, p ⁇ 0.01).
  • the mice in the compound administration group of the present invention have different degrees of improvement in colonic contracture, and the colon length is increased compared with the model group, and the compound 1 colon
  • the length was 6.35 cm
  • the compound 2 was 6.30 cm
  • the compound 3 was 5.97 cm
  • the compound 4 was 5.90 cm (##, p ⁇ 0.01; #, p ⁇ 0.05).
  • the positive drug capecitabine had a statistically significant difference in the improvement of colonic contracture (5.80 cm) in mice compared with the model group.
  • Figure 3 and Table 4 show the effect of Compound 1-4 of the present invention on colorectal tumor burden in colorectal cancer model mice.
  • Figure 3 and Table 4 show that compared with the normal control group, the tumor load is calculated as a relative value of 0.00, colorectal cancer.
  • the tumor burden of the model group was significantly increased, and the relative calculated value was about 22.64 (**, p ⁇ 0.01).
  • the tumor burden of each group after continuous administration for 8 weeks, the tumor burden of each group showed a very significant improvement, which was manifested by a decrease in the number of tumors in the whole colon range and a decrease in tumor volume (including gland). Tumor and adenocarcinoma).
  • the tumor load was calculated to be 0.06 for compound 1, 0.13 for compound 2, 0.00 for compound 3, 0.08 for compound 4, and 1.25 for the positive drug group.
  • the statistical difference was significant between the drug-administered group and the colorectal cancer model group. (##, p ⁇ 0.01).
  • the compounds of the present invention have a very remarkable effect compared with the positive control drug.
  • the calculation method of tumor load calculation value is as follows:
  • Figure 4 is a histopathological examination (HE staining, 100-fold) of colorectal tumors of colorectal cancer model mice of each compound 1-4 of the present invention.
  • a normal control group normal structure of the colon, showing a clear layer of intestinal tissue, intact structure, no inflammatory changes.
  • Inflammatory lesions of intestinal tissue were significant; inflammation involved the entire mucosal epithelium and submucosal lamina intestinal (transmural inflammation), almost all crypts were destroyed, part of the mucosal epidermis was missing; a large number of inflammatory cells were infiltrated in the inflammatory lesions, and inflammatory cells were Lymphocytes, neutrophils, and a small number of monocytes; inflammatory ulcers can be seen in the area of local inflammation, and inflammatory fibrous tissue hyperplasia can be seen at the bottom of the ulcer, which is a moderately differentiated adenocarcinoma (++++).
  • C positive drug capecitabine group intestinal tissue inflammation lesions, inflammation involving 2 / 3 intestinal mucosa interstitial, local visible transmural inflammatory lesions, local crypt destruction, intestinal mucosa epidermis relatively intact; inflammatory lesions visible interstitial Infiltrated by inflammatory cells, inflammatory cells are mainly lymphocytes, neutrophils, with a small number of monocytes; local lamina basement inflammation is obvious, non-cancerous inflammation becomes the main (+++).
  • D compound 1 administration group local intestinal tissue interstitial showed scattered inflammatory cell infiltration, inflammation was confined to the mucosal layer, no obvious lamina basement membrane was observed, no obvious crypt destruction, intestinal mucosal epithelium intact; inflammatory cells were mainly lymphocytes With a small amount of neutrophils and monocytes, non-cancerous (+).
  • E compound 2 administration group local intestinal tissue interstitial showed scattered inflammatory cell infiltration, inflammation was confined to the mucosal layer, no obvious lamina basement membrane was observed, no obvious crypt destruction, intestinal mucosal epithelial integrity; inflammatory cells were mainly lymphocytes With a small amount of neutrophils and monocytes, non-cancerous (+).
  • F compound 3 administration group local intestinal tissue interstitial showed scattered inflammatory cell infiltration, inflammation was confined to the mucosal layer, no obvious lamina basement membrane was observed, no obvious crypt destruction, intestinal mucosal epithelium intact; inflammatory cells were drenched Ba cells are predominant, with a small number of neutrophils and monocytes, non-cancerous (+).
  • G compound 4 administration group local intestinal tissue interstitial showed scattered inflammatory cell infiltration, inflammation was mainly confined to the mucosal layer, local lamina basement membrane was slightly affected, no obvious crypt destruction, intestinal mucosal epithelium intact; inflammatory cells with lymphocytes Primary, with a small amount of neutrophils and monocytes, non-cancerous (+).
  • Compounds 5 and 6 of the present invention were each prepared as a PEG dispersant as a form of administration. At the time of administration, the compound of the present invention is suspended by using water as a solvent, followed by intragastric administration.
  • C57BL/6J mice female were subjected to adaptive normal feeding for one week in a clean animal room, and then a single dose of AOM was administered to the experimental animals at a dose of 10 mg/Kg as the first day of the experiment, followed by normal feeding for 6 days. As the first week of the experiment.
  • the experimental animals were allowed to drink 2% of the DSS aqueous solution freely. After 7 days of induction, the normal drinking water was allowed to continue to allow the experimental animals to drink freely for two weeks (third week and fourth week) as the first induction.
  • the experimental animals were allowed to drink 2% of the DSS aqueous solution freely. After 7 days of induction, the normal drinking water was allowed to continue to allow the experimental animals to drink freely for two weeks (sixth and seventh weeks) as the second induction.
  • the experimental animals were allowed to drink 2% of the DSS aqueous solution freely. After 7 days of induction, the normal drinking water was allowed to continue to allow the experimental animals to drink freely for one week (ninth week) as the third induction.
  • each compound of the present invention was administered to each group of animals at a dose of 50 mg/kg according to the experimental design, once a day, once a day, the positive drug capecitabine was administered at a dose of 500 mg/Kg per day. once.
  • each group of animals was treated as usual, and the percentage change of body weight, spleen weight, colon length, colon tumor burden calculation, colon tumor histopathology, etc. after treatment were observed. Changes in indicators.
  • the experimental results show that the compounds of the present invention show significant anti-tumor activity in the experiments of treating colorectal cancer in vivo, and the curative effect is significantly better than that of the positive control drugs.
  • the specific data are shown in Table 5, Figure 5, Table 6, Figure 6, respectively. Table 7, Figure 7, Table 8, and Figure 8.
  • Figure 5 and Table 6 show: model group compared with normal control spleen weight value (0.088 g) The spleen weight of the mice was significantly increased (0.106 g) (**, p ⁇ 0.01). The spleen weight of the mice in each administration group was reduced to some extent compared with the mice in the model group, the positive drug was 0.086 g, the compound 5 was 0.068 g, and the compound 6 was 0.060 g (##, p ⁇ 0.01). The results suggest that the compounds of the present invention have a significant improvement in the increase in spleen weight caused by model mice.
  • Figure 6 and Table 7 show that the model group has a significantly longer colon length than the normal control group (7.283 cm). Lower (6.000 cm) (**, p ⁇ 0.01).
  • the mice in the 5 and 6 administration groups of the present invention had different degrees of improvement in colonic contracture, which showed that the colon length was increased compared with the model group, and the compound 5 colon length was 6.333 cm. 6 is 6.517 cm (#, p ⁇ 0.05).
  • the positive drug capecitabine had a statistically significant difference in the improvement of colonic contracture (6.03 cm) in mice compared with the model group.
  • Figure 7 and Table 8 show the effect of compounds 5 and 6 of the present invention on colorectal tumor burden in colorectal cancer model mice.
  • Figure 7 and Table 8 show that colorectal cancer is compared with the normal control group tumor tumor relative to the calculated value of 0.00.
  • the tumor burden of the model group was significantly increased, and the relative calculated value was about 28.33 (**, p ⁇ 0.01).
  • the tumor burden of each group showed a very significant improvement effect, which was manifested by a decrease in the number of tumors in the whole colon range and a decrease in tumor volume. Small (including adenoma and adenocarcinoma).
  • the tumor load was calculated to be 2.75 for Compound 5, 0.40 for Compound 6, and 8.33 for the positive drug group.
  • the statistical difference was significant between the drug-administered group and the colorectal cancer model group (#, p ⁇ 0.05,##, p ⁇ 0.01).
  • the compounds 5 and 6 of the present invention are very effective in comparison with the positive control drug.
  • the calculation method of tumor load calculation value is as follows:
  • Figure 8 is a histopathological examination (HE staining, 100-fold) of colorectal tumors of colorectal cancer model mice of the present invention.
  • a normal control group normal structure of the colon, showing a clear layer of intestinal tissue, intact structure, no inflammatory changes.
  • Inflammatory lesions of intestinal tissue were significant; inflammation involved the entire mucosal epithelium and submucosal lamina intestinal (transmural inflammation), almost all crypts were destroyed, part of the mucosal epidermis was missing; a large number of inflammatory cells were infiltrated in the inflammatory lesions, and inflammatory cells were Lymphocytes, neutrophils, and a small number of monocytes; inflammatory ulcers can be seen in the area of local inflammation, and inflammatory fibrous tissue hyperplasia can be seen at the bottom of the ulcer, which is a moderately differentiated adenocarcinoma (++++).
  • C positive drug capecitabine group intestinal tissue inflammation lesions, inflammation involving 2 / 3 intestinal mucosa interstitial, local visible transmural inflammatory lesions, local crypt destruction, intestinal mucosa epidermis relatively intact; inflammatory lesions visible interstitial Infiltrated by inflammatory cells, inflammatory cells are mainly lymphocytes, neutrophils, with a small number of monocytes; local lamina basement inflammation is obvious, non-cancerous inflammation becomes the main (+++).
  • D compound 5 administration group local intestinal tissue interstitial showed scattered inflammatory cell infiltration, inflammation was confined to the mucosal layer, no obvious lamina basement membrane was observed, no obvious crypt destruction, intestinal mucosal epithelium intact; inflammatory cells were mainly lymphocytes With a small amount of neutrophils and monocytes, non-cancerous (+).
  • E compound 6 administration group local intestinal tissue interstitial showed scattered inflammatory cell infiltration, inflammation was confined to the mucosal layer, no obvious lamina basement membrane was observed, no obvious crypt destruction, intestinal mucosal epithelium intact; inflammatory cells were mainly lymphocytes With a small amount of neutrophils and monocytes, non-cancerous (+).
  • mice Eight weeks after administration of each group of animals, the mice were sacrificed in a conventional manner at the end of the experiment. Select 2 cm of colon tissue from the anus of the mouse. Weighed colon tissue was weighed and thawed twice in liquid nitrogen, and sonicated in RIPA lysate, then lysed at 4 degrees for 30 min, centrifuged at 13,000 rpm for 10 min. The supernatant was taken and the protein concentration was determined by the Brandford method. Western-blot (WB) detection was performed by taking the same amount of protein according to the protein concentration.
  • WB Western-blot
  • 5% concentrated gel and 10% separating gel were prepared according to standard SDS-PAGE method.
  • Cell lysate supernatants containing the same protein concentration were mixed with 5 x SDS loading buffer and boiled for 5 min. Load after cooling.
  • the wet transfer method was transferred to the PVDF membrane.
  • Non-specific binding sites were blocked overnight at 4 °C with TBST (0.1% Tween-20; 10 mmol/L Tris-Cl, pH 7.5; 3% BSA; 150 mmol/L NaCl). The membrane was washed with TBST solution, 10 min/time x 3 times.
  • the membrane was incubated with diluted primary antibody (1:500) for 3 h at room temperature, and the membrane was washed with TBST solution for 10 min/time x 3 times.
  • the membrane was transferred to a secondary antibody (1:1000 dilution) and allowed to react at room temperature for 2 h.
  • the membrane was washed with TBST, 10 min/time ⁇ 3 times.
  • the film was placed flat, the luminescent liquid was added dropwise, and the chemiluminescence was imaged.
  • the results indicate that the compounds 1, 2, 3 and 5 of the present invention have a significant inhibitory effect on the signal molecule STAT3 which is closely related to the pathogenesis of colorectal cancer at the protein level.
  • the specific data is shown in Figure 9 and Figure 10.
  • the upper part is the WB hybrid development map, and the lower is the relative quantitative detection result of the protein.
  • Figure 9 is a graph showing the effects of compounds 1 and 2 on the expression of target STAT3 protein in colorectal tissues of mice with colorectal cancer.
  • the lanes are lane 1: normal control group; lane 2: AOM/DSS model group; lane 3: Compound 1 administration group; lane 4: Compound 2 administration group.
  • the semi-quantitative results of WB protein showed that compared with the relative quantitative calculation value of stat3/actin in the colon tissue of normal control mice, the expression of STAT3 in the intestinal tissue of the colorectal cancer model group was significantly increased, and the relative value was 1.82. The difference was very significant (**, p ⁇ 0.01).
  • the compounds 1 and 2 of the present invention all have a very significant improvement effect, and the expression of STAT3 protein is significantly decreased.
  • the relative ratio of stat3/actin is 0.25 for compound 1 and 0.33 for compound 2, statistics. The difference is very significant (##, p ⁇ 0.01).
  • Figure 10 is a graph showing the effects of compounds 1, 2, 3 and 5 of the present invention on the expression of target STAT3 protein in colorectal tissues of mice with colorectal cancer.
  • the lanes are lane 1: normal control group; lane 2: AOM/DSS Model group; lane 4: Compound 2 administration group; lane 5: Compound 5 administration group; lane 7: Compound 1 administration group; lane 8: Compound 3 administration group.
  • the semi-quantitative results of WB protein showed that compared with the normal quantitative calculation of stat3/actin in the colon tissue of normal control mice, the expression of STAT3 in the intestinal tissue of the colorectal cancer model group was significantly increased, the relative value was 0.43, statistically. The difference was very significant (**, p ⁇ 0.01).
  • the compounds of the present invention 1, 2, 3 and 5 all have a very significant inhibitory effect, showing a significant decrease in the expression of STAT3 protein, and the relative ratio of stat3/actin is 0.13, and compound 2 is 0.23, compound 3 was 0.19, and compound 5 was 0.20.
  • the statistical difference was very significant (p ⁇ 0.01).
  • the test results of the compounds 1-6 of the present invention showed LD 50 values of 5.0 g/kg, 5.0 g/kg, 0.8 g/kg, 5.0 g/kg, 3.9 g/kg and 1.6 g/kg, respectively. Further, the LD 50 value of dihydroberberine was 160 mg/Kg.

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Abstract

L'invention concerne l'utilisation de composés de type dihydroberbérine et de composés de type (±)-8-acétonyldihydroberbérine dans la préparation de produits pour la prévention, le soulagement et/ou le traitement de maladies tumorales associées à la voie de signalisation STAT3, les composés de type dihydroberbérine comprenant de la dihydroisocoptisine, de la dihydrocoptisine et de la dihydropalmatine, et les composés de type (±)-8-acétonyldihydroberbérine comprenant de la (±)-8-acétonyldihydroisocoptisine, de la (±)-8-acétonyldihydrocoptisine et de la (±)-8-acétonyldihydropalmatine. Les maladies tumorales associées à la voie de signalisation STAT3 sont choisies parmi diverses tumeurs, en particulier le cancer colorectal.
PCT/CN2017/106227 2016-10-14 2017-10-14 Utilisation de composés de type dihydroberbérine dans la préparation d'un produit destiné au traitement de maladies tumorales associées à la voie de signalisation stat3 Ceased WO2018068769A1 (fr)

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