WO2020177744A1 - Composé d'ammonium quaternaire alcaloïde de type berbérine d'acide salicylique et son utilisation pour la préparation de médicaments - Google Patents

Composé d'ammonium quaternaire alcaloïde de type berbérine d'acide salicylique et son utilisation pour la préparation de médicaments Download PDF

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WO2020177744A1
WO2020177744A1 PCT/CN2020/078049 CN2020078049W WO2020177744A1 WO 2020177744 A1 WO2020177744 A1 WO 2020177744A1 CN 2020078049 W CN2020078049 W CN 2020078049W WO 2020177744 A1 WO2020177744 A1 WO 2020177744A1
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quaternary ammonium
ammonium salt
compound
group
present
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Chinese (zh)
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秦海林
吴练秋
李景
张海婧
邓安珺
唐晓楠
李想
王与菲
李志宏
王文杰
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中国医学科学院药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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

Definitions

  • the invention relates to a salicylic acid berberine alkaloid quaternary ammonium synthesized by using salicylic acid aromatic organic acids and various berberine alkaloid quaternary ammonium compounds whose acid radicals are not salicylic acid radicals as substrates
  • the compound of the present invention has shown remarkable effectiveness in the pharmacodynamic experiment for the treatment of ulcerative colitis; the compound of the present invention has shown remarkable safety in the toxicology experiment; the compound of the present invention is excellent in a 60% ethanol-water mixed solvent The solubility.
  • the compound of the present invention has significant creativity and practical value in pharmaceutical applications, and can be made into various pharmaceutical dosage forms including ordinary tablet oral and gastric administration forms. It is used to treat ulcerative colitis.
  • the specific structure of the compound of the present invention is based on 5-aminohydrochloride or 4-aminosalicylate or salicylic acid radicals such as salicylic acid radical as the acid radical balance anion unit, with 5,6-dihydrodibenzo[a, g] Quinazine-7-cationic quaternary ammonium salts are base-balanced cation units, and the two form salicylic acid berberine-type alkaloid quaternary ammonium salt compounds.
  • the compound of the present invention can be used to prepare pharmaceutical products for preventing, relieving and/or treating ulcerative colitis, and belongs to the technical field of medicine.
  • Ulcerative colitis is a chronic, non-specific, recurrent, intestinal mucosal inflammatory bowel disease, and also an autoimmune disease; its focus is mainly located in the sigmoid colon and rectum, and it can also extend to descending The colon or even the entire colon; based on these characteristics, they are called rectal ulcerative colitis, left colon ulcerative colitis, and total colonic ulcerative colitis. Ulcerative colitis lesions are mainly confined to the mucosa and submucosa. Pathological examination or microscopy shows that the basic structures of the intestinal mucosa and submucosa are destroyed, including the exfoliation of the intestinal mucosa with congestion, hemorrhage, and edema.
  • Inflammatory cells invade the muscle layer.
  • abdominal pain, bloody diarrhea with pus and mucus are the most common early symptoms.
  • Other symptoms include paroxysmal colonic spasm pain, pale complexion, weight loss, tenesmus, vomiting, etc.; therefore, ulcerative colon Inflammation is mainly characterized by abdominal pain, diarrhea and mucus pus and blood in the stool.
  • Patients with diarrhea less than 5 times a day are considered as mild patients, and severe patients with diarrhea more than 5 times a day, even up to 30 times per day, or water Diarrhea or bloody stools, severe abdominal pain, fever, and body temperature can exceed 38.5°C.
  • Ulcerative colitis can also have some serious complications, including toxic colon dilation, intestinal perforation, hemorrhage, polyps, cancer, enteritis, arthritis, skin and mucosal lesions (multiple abscesses, localized abscesses, pustular gangrene , Erythema multiforme, etc.), a variety of eye diseases (iritis, iridocyclitis, uveitis, corneal ulcers, etc.).
  • ulcerative colitis has common symptoms such as prolonged onset, difficult to cure, and malignant transformation. Although it is chronic and low-malignant in some patient groups, it is acute and catastrophic in another group (about 15%); these patients have frequent bloody stools, high fever, abdominal pain, etc.
  • Statistical investigations show that the incidence of ulcerative colitis has been increasing in recent years worldwide [Russel MG. Changes in the incidence of inflammatory bowel disease: what does it mean? .Eur J Inter Med,2000,11:191.;Jiang XI,et al.An analysis of 10218 ulcerative colitis cases in China.World J Gastroenterol,2002,1:158]. Therefore, ulcerative colitis is a recognized malignant disease that seriously affects the quality of life of patients and even threatens survival, and is listed as a difficult disease by the WHO.
  • Acute severe ulcerative colitis refers to bloody stool frequency ⁇ 6 times/day, accompanied by pulse rate>90 beats/min or body temperature>37.8°C or hemoglobin level ⁇ 105g/l or red blood cell sedimentation rate >30mm/h. 15% to 25% of patients with ulcerative colitis will have an episode of ASUC.
  • the first-line treatment for ASUC is intravenous corticosteroids, but if the patient does not respond after 3-5 days, cyclosporine or infliximab treatment is salvage therapy, and the patient’s symptoms and serum C- Reactive protein and albumin levels; when the response to these treatments is poor, the patient needs to undergo colon resection.
  • xbp1 downstream key transcription factor X-box-binding protein 1
  • the clinical treatment strategy adopted is mainly palliative therapy similar to tumor treatment, that is, although most patients with ulcerative colitis cannot obtain curative treatment, they still need active treatment and care to control the symptoms. Attention is paid to psychological, social and spiritual issues; special emphasis is placed on various strategies such as symptom control, patient support, and improvement of quality of life, to maintain long-term relief and minimize drug-related adverse reactions; the purpose is to win the best for patients and their families. Probably the best quality of life.
  • NF- ⁇ B nuclear factor kappa-B
  • scavenging mechanism of free radicals in the sense of conventional anti-inflammatory, and single-line treatment for tumor necrosis factor-alpha (TNF ⁇ ).
  • Cloned antibodies anti-TNF ⁇ antibodies
  • tyrosine kinases Janus kinases, JAK
  • the present invention has discovered a class of compounds with significant anti-ulcerative colitis activity, safe use, and excellent physical and chemical properties.
  • Using various salicylic acid and substituted salicylic acid type aromatic organic acid compounds and various berberine chloride type alkaloid quaternary ammonium salt compounds as substrates to prepare the compound of the present invention it includes two steps: (1) Under neutral conditions, 8-acetone dihydroberberine-type alkaloid intermediates can be obtained through the nucleophilic addition of the enol ion of acetone to the berberine chloride-type alkaloid quaternary ammonium salt substrate; (2) Dissolve 5-aminosalicylic acid in DMSO or dissolve 4-aminosalicylic acid or salicylic acid in THF, add the intermediates already obtained in step (1) and stir to react until the product precipitates, thereby obtaining the present invention Compound salicylic acid berberine type alkaloid quaternary ammonium compound.
  • the structure of the compound of the present invention has been confirmed by various structural confirmation methods and combined with synthetic routes (see the experimental example part). Further through extensive screening of pharmacological activity, evidence of the pharmacological characteristics of the compound of the present invention having significant anti-ulcerative colitis activity was obtained, and a comparative test showed that the anti-ulcerative colitis pharmacological strength of the compound of the present invention was significantly better than that of The pharmacological effects of the berberine chloride type alkaloid quaternary ammonium salt and the salicylic acid aromatic acid, which are the synthetic raw materials of the compound of the present invention, and the two are mixed in the principle of equal molar ratio.
  • the cytotoxicity evaluation and the acute toxicity evaluation results of animal experiments show that the compound of the present invention does not show obvious toxic effects on normal cells (line), experimental cells and experimental animals, and belongs to a non-toxic or low-toxic molecular entity.
  • the solubility test experiment proved that the compound of the present invention has excellent solubility in alcohol-water mixed solvents; it is precisely because the compound of the present invention has excellent physical and chemical properties of solubility in alcohol-water mixed solvents, it is a large-scale preparation in line with general pharmaceutical technology. Standardization of salicylic acid berberine alkaloid quaternary ammonium salt active compounds and the search for new pharmacological activities have laid the foundation for improving the strength of the drug.
  • the test results of the stability of physical and chemical properties show that the compound of the present invention is stable in physical and chemical properties, and the structure of the compound of the present invention is extremely stable even if it is placed in a solution. Therefore, the compound of the present invention has significant application value in the preparation of anti-ulcerative colitis products, and can be used to prepare products for preventing, alleviating and/or treating ulcerative colitis.
  • the technical problem solved by the present invention is to provide a class of aromatic salicylic acid radicals as acid radical counter anions and berberine alkaloid quaternary ammonium cations as base counter cations by means of chemical synthesis.
  • the present invention provides the following technical solutions:
  • the first aspect of the present invention provides a salicylic acid berberine type alkaloid quaternary ammonium salt compound represented by general formula I as the compound of the present invention.
  • the second aspect of the present invention provides a method for preparing the salicylic acid berberine type alkaloid quaternary ammonium salt compound represented by general formula I.
  • the third aspect of the present invention provides a product composition of a salicylic acid berberine type alkaloid quaternary ammonium salt compound represented by general formula I; the product is selected from drugs.
  • the fourth aspect of the present invention provides the use of the salicylic acid berberine type alkaloid quaternary ammonium salt compound represented by general formula I in the prevention, alleviation and/or treatment of ulcerative colitis.
  • R is independently selected from H, NH 2 , OH, halogen, C2-C4 alkanoyloxy, C2-C4 alkanoyloxy, C1-C4 alkyl or C1-C4 alkoxy, R is a single Substitution or multi-substitution, when R is mono-substituted, the substitution position is 3-position or 4-position or 5-position or 6-position; when R is poly-substituted, it is selected from NH 2 , OH, halogen, C2-C4 alkamido group, C2-C4 Alkanoyloxy, C1-C4 alkyl, or C1-C4 alkoxy of any combination of 2- or 3- or 4-substituted; further, the halogen is selected from fluorine, chlorine, bromine, and iodine; The C2-C4 alkanoyl group is selected from acetamido, propionamido, butyramido, and isobutyramido; the C
  • R 1 is independently selected from H, C2-C4 alkanoyl or C1-C4 alkyl; further, said C2-C4 alkanoyl is selected from acetyl, propionyl, butyryl, isobutyryl; said C1 -C4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl;
  • R 2 and R 3 are each independently selected from H, OH, C2-C4 alkanoyloxy, C1-C4 alkyl or C1-C4 alkoxy, or R 2 and R 3 are connected to form a hydrocarbylene dioxy group; further
  • the C2-C4 alkanoyloxy groups described in R 2 and R 3 are each independently selected from acetoxy, propionyloxy, butyryloxy, isobutyryloxy;
  • the C1-C4 alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, and butyl;
  • the C1-C4 alkoxy groups described in R 2 and R 3 are each independently selected from methoxy Group, ethoxy group, propoxy group, isopropoxy group, butoxy group;
  • the alkylene dioxy group in R 2 and R 3 is independently selected from methylene dioxy group, ethylene dioxy group, Propylenedioxy, butylened
  • R 9 , R 10 , R 11 , and R 12 are each independently selected from H, OH, C1-C4 alkyl, C2-C4 alkanoyloxy or C1-C4 alkoxy, or R 9 and R 10 are connected to form a sub Hydrocarbyl dioxy and R 11 and R 12 are each independently selected from H, OH, C1-C4 alkyl, C2-C4 alkanoyloxy, C1-C4 alkoxy, or R 9 and R 12 are each independently selected From H, OH, C1-C4 alkyl, C2-C4 alkanoyloxy, C1-C4 alkoxy and R 10 and R 11 are connected to form a hydrocarbylene dioxy group, or R 9 and R 10 are each independently selected from H, OH, C1-C4 alkyl, C2-C4 alkanoyloxy, C1-C4 alkoxy and R 11 and R 12 are connected to form a hydrocarbylene dioxy group; further, R 9 , R 10
  • the most preferred salicylic acid berberine alkaloid quaternary ammonium salt compound of the present invention is selected from compounds 1-21 in the following compound groups:
  • the second aspect of the present invention provides a preparation method of the salicylic acid berberine alkaloid quaternary ammonium salt compound of the present invention.
  • the salicylic acid berberine-type alkaloid quaternary ammonium salt compound can be synthesized by the general formula of the following synthetic route (route 1; see experimental examples for specific synthetic conditions):
  • Synthesis steps (a) Various berberine alkaloid quaternary ammonium compounds whose acid radicals are not salicylic acid radicals react with acetone under alkaline conditions to obtain 8-acetonyl dihydroberberine intermediates; b) The 8-acetonyl dihydroberberine intermediates are subjected to quaternary ammonium salting in the presence of salicylic aromatic organic acids to obtain various compounds of the present invention.
  • the synthesis method of 5-aminosalicylic acid berberine-type alkaloid quaternary ammonium salt compound is as follows: Weigh various berberine-type alkaloid quaternary ammonium salt compounds whose acid roots are not 5-aminosalicylic acid roots into the reaction flask Add sodium hydroxide aqueous solution, then add acetone dropwise, and stir the reaction until the raw material reaction is complete. The reaction mixture was filtered with suction, and the filter cake was washed with water to neutrality to obtain a solid 8-acetone dihydroberberine type alkaloid.
  • the synthesis method of 4-aminosalicylic acid or salicylic acid berberine type alkaloid quaternary ammonium salt compound is as follows: Weigh 8-acetone dihydroberberine type alkaloid into a reaction flask, add tetrahydrofuran to make it completely dissolved Add 4-aminosalicylic acid or salicylic acid under stirring. After the addition, reflux the reaction to completion, let stand and cool to room temperature, and filter the reaction mixture. The filter cake is the compound 4-aminosalicylic acid of the present invention. Berberine type alkaloid quaternary ammonium compound or salicylic acid berberine type quaternary ammonium compound.
  • the third aspect of the present invention also relates to a pharmaceutical composition using the salicylic acid berberine alkaloid quaternary ammonium salt compound as the active ingredient of the first aspect of the present invention.
  • These pharmaceutical compositions can be prepared according to their well-known methods.
  • the compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to prepare any dosage form suitable for human or animal use.
  • the content of the compound of the present invention in its pharmaceutical composition is usually 0.1-99.9% (W/W).
  • the compound of the present invention or the pharmaceutical composition containing the compound of the present invention can be administered in a unit dosage form, and the route of administration can be mainly the digestive tract, such as oral administration, enteral administration, and the like.
  • parenteral administration is also acceptable, such as intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract, vagina, application to the skin, and so on.
  • intravenous injection intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract, vagina, application to the skin, and so on.
  • its outstanding advantage is that it can be made into ordinary oral preparations such as ordinary tablets and ordinary capsules for direct oral administration without special treatment, and is very convenient to use.
  • Various other routes and methods of administration such as suppositories, can also be used.
  • Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including O/W type, W/O type and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops Tablets, nasal drops, lotions and liniments; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, air (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Cream type, gel, paste, etc.
  • the compounds of the present invention can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various particle delivery systems.
  • diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent can be water, ethanol, Isopropanol, etc.
  • the binder can be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia syrup, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrant can be dry starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, Isopropanol, etc.
  • the binder can be starch syrup,
  • the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multilayer tablets.
  • the compound of the present invention can be mixed with a diluent, glidant, and the mixture can be directly placed in a hard or soft capsule; or the compound of the present invention can be mixed with a diluent, a binder,
  • the disintegrant is made into granules or pellets, and then placed in hard or soft capsules.
  • the various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the compound tablets of the present invention can also be used to prepare the compound capsules of the present invention.
  • water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvents and appropriate solubilizers, cosolvents, pH regulators, and osmotic pressure regulators commonly used in the pharmaceutical field can be added.
  • the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.;
  • the pH regulator can be phosphate, acetate, hydrochloride, sodium hydroxide, etc.; osmotic pressure adjustment
  • the agent can be sodium chloride, mannitol, glucose, phosphate, acetate and the like.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents if necessary, coloring agents, preservatives, perfumes, flavoring agents or other additives can also be added to the pharmaceutical preparations.
  • the drug (compound) or pharmaceutical composition of the present invention can be administered and used by any known administration method and application mode.
  • the administration (application) or dosage (use) of the compound pharmaceutical composition of the present invention depends on the severity of the prevention or treatment of ulcerative colitis, the individual condition of the patient or animal, the administration (application) route and dosage form, etc. Changes in scope. Generally speaking, the appropriate daily dose range of the compound of the present invention is 0.001-500 mg/kg body weight, preferably 0.1-100 mg/kg body weight, more preferably 1-60 mg/kg body weight, and most preferably 2-40 mg/kg body weight.
  • the above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience, the progress of treatment, and the administration (use) plan including the use of other treatment (application) means.
  • the compound or product composition of the present invention can be taken alone or combined with other therapeutic drugs or symptomatic drugs.
  • the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
  • the fourth aspect of the present invention provides the use of the salicylic acid berberine-type alkaloid quaternary ammonium salt compound represented by general formula I in the preparation of products for the prevention, relief and/or treatment of ulcerative colitis.
  • the product includes medicine. See the experimental example of the present invention for the remarkable pharmacodynamic effect of the compound of the present invention in treating ulcerative colitis.
  • the solubility test experiment proved that the compound of the present invention has significantly improved solubility in alcohol-water mixed solvents compared with the corresponding berberine chloride alkaloid quaternary ammonium salts and 5-aminosalicylic acid aromatic acid compounds Therefore, it has significant practical value for the large-scale preparation of active molecular entities of salicylic acid berberine alkaloid quaternary ammonium salt that meets the general technical specifications of pharmaceuticals, and for finding new pharmacological activities and improving the strength of the drug; stability test results It shows that the compound of the present invention is not only stable in physical and chemical properties in the solid state, but its structure is extremely stable even when placed in a solution.
  • the compound of the present invention exists in the form of ion pairs or ion clusters in a solution, and has a specific arrangement rather than a mixture. Therefore, the compound of the present invention has significant medicinal effectiveness, safety and quality controllability, and its application prospects in the pharmaceutical field are very significant.
  • the compound of the present invention has significant application value in the preparation of anti-ulcerative colitis products, and can be used to prepare products for preventing, alleviating and/or treating ulcerative colitis.
  • the compound of the present invention can significantly improve the symptoms of weight loss, loose stools, blood in the stool, colon contracture and other symptoms of ulcerative colitis model animals, and is significantly better than the current clinically commonly used anti-ulcerative colitis treatment drug sulfasalazine, and better than other related compounds.
  • the compound of the present invention 5-aminosalicylic acid berberine quaternary ammonium salt (1), 5-aminosalicylic acid isocberine quaternary ammonium salt (2), 5-aminosalicylic acid
  • the therapeutic effects of palmatine quaternary ammonium salt (3) and 5-aminosalicylic acid berberine quaternary ammonium salt (4) against acute ulcerative colitis are significantly higher than the positive control drug sulfasalazine given 500 mg/kg.
  • the therapeutic effect of the drug dosage, and parallel experiments show that the anti-ulcerative colitis of the compound of the present invention is also significantly better than the berberine-type alkaloid quaternary ammonium salt (including the quaternary berberine chloride Ammonium salt, quaternary ammonium salt of isoxarine chloride, quaternary ammonium salt of palmatine chloride and quaternary berberine chloride) and 5-aminosalicylic acid monomer compounds; especially 5-aminosalicylic acid in
  • the percentage of body weight change of model animals, the percentage of colon contracture, the dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis animal model mouse disease activity composite index score and disease activity composite index inhibition rate In terms of the influence, the data are only -15.09%, 39.78% (colon length 4.80 ⁇ 0.28cm), 2.97 ⁇ 0.11 and 7.76%, which are significantly lower than the data of all the detected compounds of the present invention (see experimental
  • the above treatment data of the compound of the present invention is compared with the corresponding data when the dose of the positive control drug sulfasalazine in the parallel experiment is 500 mg/kg, including the percentage change (decrease) of animal weight in the sulfasalazine administration group- 13.47% (no significant difference compared with the model group), animal colon contracture percentage 32.23% (no significant difference compared with the model group), disease activity comprehensive index score 2.12 ⁇ 0.28 # and disease activity comprehensive index inhibition rate experimental data 31.39 % And the results of colonic histopathological examination, the curative effect is very significant.
  • the compound of the invention can significantly improve the symptoms of chronic ulcerative colitis model animals such as weight loss, loose stools, blood in the stool, colonic contracture, etc., and is significantly better than the current clinically commonly used anti-ulcerative colitis treatment drug sulfasalazine.
  • 5-aminosalicylic acid berberine quaternary ammonium salt (1) was used as a representative compound to investigate the effect of the compound of the present invention against oxazolone-induced chronic ulcerative colitis in BALB/c mice and the dose-effect relationship. The results show that 5-aminosalicylic acid berberine quaternary ammonium salt (1) not only has a strong anti-chronic ulcerative colitis, but also has a significant dose-effect relationship.
  • the above treatment data of the compound of the present invention is compared with the corresponding data when the dose of the positive control drug sulfasalazine in the parallel experiment is 500 mg/kg, including the percentage change (decrease) of animal weight in the sulfasalazine administration group- 22.82% (no significant difference compared with the model group), animal colon contracture percentage 24.64% (no significant difference compared with the model group), and disease activity comprehensive index inhibition rate value experimental data 14.29% (no significant difference compared with the model group) ) Comparison, the effect is very significant.
  • the compound of the present invention has a significant therapeutic effect on chronic ulcerative colitis model animals The effect is significantly better than that of sulfasalazine, a commonly used clinical treatment for anti-ulcerative colitis.
  • the disease activity comprehensive index inhibition rate values were 94.44% ## ⁇ 58.33% # and 38.89% # ( # p ⁇ 0.05, ## p ⁇ 0.01, compared with the model group), compared with the experimental data of 50.00% of the inhibitory rate of the disease activity composite index when the dose of the positive control drug sulfasalazine in the parallel experiment is 500mg/kg, Especially in the high-dose and middle-dose administration groups, the curative effect is very significant, and the dose-effect relationship is clear.
  • 5-aminosalicylic acid is used as the acid radical to balance the anion unit, and the berberine type organism Alkaline quaternary ammonium cations are base-balanced cation units, and the two form salicylic acid berberine-type alkaloid quaternary ammonium salt compounds, but they show exceptional antiulcerative colitis activity in direct oral administration experiments. Therefore, The effective mechanism of the compound of the present invention in the treatment of ulcerative colitis remains to be further studied.
  • 5-aminosalicylic acid, berberine chloride quaternary ammonium salt, palmatine chloride quaternary ammonium salt, berberine chloride quaternary ammonium salt, and berberine chloride quaternary ammonium salt, and berberine chloride are formulated according to the principle of equal
  • a mixture of quaternary ammonium salt and 5-aminosalicylic acid, a mixture of palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid, and a mixture of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid The effect comparison test also shows that the compound of the present invention is significantly different from the mixture of berberine chloride type quaternary ammonium salt and 5-aminosalicylic acid prepared simply by the principle of equal moles.
  • the compound of the present invention is based on 5-aminohydrochloride (or 4-aminosalicylate or salicylate) as the acid-balanced anion unit, and 5,6-dihydrodibenzo[a,g]quinazine-7-
  • the cationic quaternary ammonium structure is a base-balanced cationic unit. The two match through a specific intermolecular attraction to form a salicylic acid berberine alkaloid quaternary ammonium salt compound. Each structural unit is arranged regularly in the substance.
  • the cloth, the structure is stable, and the mixture of berberine-type alkaloid quaternary ammonium salt and salicylic acid formulated on the principle of simply equaling the number of moles has essential differences; the compound of the present invention has significant anti-ulcerative colitis efficacy.
  • the compound of the present invention has significant anti-ulcerative colitis efficacy.
  • 5-aminosalicylic acid, berberine chloride type quaternary ammonium salt substrate and a mixture of berberine chloride type quaternary ammonium salt substrate and 5-aminosalicylic acid prepared on the principle of equal moles specifically For the data, see pharmacodynamic experiment examples 1, 4, 6 and 7).
  • the pharmacological effects of the compounds of the present invention related to anti-ulcerative colitis are also significantly better than those of tartrate, citrate, oxalate, maleate, malate, fumarate and
  • organic acid radicals such as benzenesulfonate are acid radical counter-anion
  • other organic acid berberine-type alkaloid quaternary ammonium salt compounds are prepared with berberine-type alkaloid quaternary ammonium cation as base counter-cation.
  • Acid root is the acid root balancing anion
  • the organic acid berberine alkaloid quaternary ammonium salt compound prepared with the berberine alkaloid quaternary ammonium cation as the base balancing cation has the transcriptional activation effect of the xbp1 promoter of these other types of organic acids
  • the berberine-type alkaloid quaternary ammonium salt compound has a positive or ineffective activation factor for xbp1 promoter transcription within the range of 1.02-1.31, while the activation factor of dihydroberberine in parallel experiments is 1.64, which has obvious activation Effect (see pharmacodynamic experiment example for specific data).
  • another outstanding feature of the compound of the present invention is that it also has the advantages of non-toxicity or low toxicity.
  • the inhibition rates of compounds 1, 2, 3 and 4 on normal cell growth were 12.35, respectively. %, 14.94%, 3.96% and 14.68%.
  • the compound of the present invention 5-aminosalicylic acid berberine quaternary ammonium salt (1), 5-aminosalicylic acid isoberberine
  • both the quaternary ammonium salt (2) and the 5-aminosalicylic acid palmatine quaternary ammonium salt (3) were administered at a dose of 5.0 g/kg, the animals were not dead and were in good general condition.
  • the 5-aminosalicylic acid berberine quaternary ammonium salt (4) has an LD 50 value of 3.0 g/kg. Therefore, the compounds of the present invention are all non-toxic or low-toxic specific anti-ulcerative colitis compounds.
  • the solubility of the compound of the present invention in a mixed solvent of ethanol and water is significantly improved; at an ambient temperature of 25°C ⁇ 2°C
  • the amount of 60% ethanol-water mixed solvent needed to dissolve each gram of the compound of the present invention is 5-aminosalicylic acid berberine quaternary ammonium salt (1) 300ml, 5-aminosalicylic acid isocberine quaternary ammonium salt (2) 200ml, 5-aminosalicylic acid palmatine quaternary ammonium salt (3) 400ml, 5-aminosalicylic acid berberine quaternary ammonium salt (4) 350ml.
  • the alcohol-water mixed solvent of the compound of the present invention has higher solubility, and the amount of 60% ethanol-water mixed solvent required to dissolve the compound of the present invention is 5-aminosalicylic acid berberine quaternary ammonium salt (1) 38ml, 5-aminosalicylic acid isoberberine quaternary ammonium salt (2) 26ml, 5-aminosalicylic acid palmatine quaternary ammonium salt (3) 47ml, 5-aminosalicylic acid berberine quaternary ammonium salt (4) ) 73ml; these physical and chemical properties are very suitable for large-scale preparation of compounds.
  • Figure 1 Positive drugs sulfasalazine, berberine chloride quaternary ammonium salt, dihydroberberine, and different doses of the compound 1 administration group of the present invention on weight loss in mice with acute ulcerative colitis induced by sodium dextran sulfate Improvement effect (**p ⁇ 0.01, compared with the normal control group; ## p ⁇ 0.01, compared with the model group).
  • Figure 2 The positive drug sulfasalazine, berberine chloride quaternary ammonium salt, dihydroberberine, compound 1 of the present invention, high, medium, and low dose administration groups in the acute ulcerative colitis model induced by sodium dextran sulfate The percentage of mouse colonic contracture during the treatment of mice (Note: ** p ⁇ 0.01, compared with the normal control group; # p ⁇ 0.05, ## p ⁇ 0.01, compared with the model group).
  • Figure 3 The positive drug sulfasalazine, berberine chloride quaternary ammonium salt, dihydroberberine, compound 1 of the present invention in high, medium and low dose administration groups in the acute ulcerative colitis model induced by sodium dextran sulfate Mouse Disease Activity Comprehensive Index (DAI) score during treatment of mice (Note: ** p ⁇ 0.01, compared with normal control group; # p ⁇ 0.05, ## p ⁇ 0.01, compared with model group).
  • DAI Mouse Disease Activity Comprehensive Index
  • Figure 4 The therapeutic effect of compound 1 of the present invention on pathological damage of colon tissue in mice with acute ulcerative colitis induced by sodium dextran sulfate (HE, 40 times).
  • Figure 5 The improvement effect of the positive drug sulfasalazine and different doses of compound 1 of the present invention on the weight loss of oxazolone-induced chronic ulcerative colitis model mice (**p ⁇ 0.01, compared with the normal control group; # p ⁇ 0.05, compared with the model group).
  • Figure 6 The improving effect of compound 1 of the present invention on oxazolone-induced colonic contracture in mice with chronic ulcerative colitis.
  • Figure 7 The composite index score of disease activity of mice in the treatment of oxazolone-induced chronic ulcerative colitis model mice in the low, medium and high dose administration groups of positive drug sulfasalazine and compound 1 of the present invention (Note: ** p ⁇ 0.01, compared with the normal control group; ## p ⁇ 0.01, compared with the model group).
  • the obtained filter cake was put into 0.17L NaHCO 3 solution with a concentration of 0.5mol/l, stirred and placed in a water bath at 80°C for 2h, filtered while hot, added 9ml concentrated hydrochloric acid to the filtrate, cooled to room temperature, crystals were precipitated, filtered and dried 137 mg of 2,3-methylenedioxy-9,10-ethylenedioxy-5,6-dihydrodibenzo[a,g]quinazine quaternary ammonium chloride was obtained with a yield of 24.90%.
  • the obtained filter cake was put into 0.17l NaHCO 3 solution with a concentration of 0.5mol/l and stirred and placed in a water bath at 80°C for 2h, filtered while hot, and 9ml concentrated hydrochloric acid was added to the filtrate, cooled to room temperature, crystals precipitated, filtered and dried 331 mg of 2,3:10,11-bisethylenedioxy-5,6-dihydrodibenzo[a,g]quinazine quaternary ammonium chloride was obtained, with a yield of 60.00%.
  • the synthesis method of 8-acetone dihydroberberine is the same as compound 1 of the present invention.
  • the reaction mixture was filtered off by suction and the filter cake was washed with tetrahydrofuran three times to obtain 79 mg of compound 14 as a yellow solid with a yield of 63.00%.
  • the synthesis method of 8-acetone dihydroisoberine is the same as compound 2 of the present invention.
  • the reaction solution was filtered and the filter cake was washed with tetrahydrofuran three times to obtain 118 mg of compound 15 as a yellow solid with a yield of 94.10%.
  • the synthesis method of 8-acetone dihydropalmatine is the same as that of compound 3 of the present invention.
  • the synthesis method of 8-acetone dihydroberberine is the same as compound 4 of the present invention.
  • the reaction mixture was filtered off by suction and the filter cake was washed with tetrahydrofuran three times to obtain 93 mg of compound 17 as a yellow solid with a yield of 74.37%.
  • the solubility was measured at a temperature of 25°C ⁇ 2°C.
  • the amount of 60% ethanol-water mixed solvent required to dissolve the compound of the present invention was 5-aminosalicylic acid berberine quaternary ammonium salt (1) 300ml, 5 -Aminosalicylic acid isoberberine quaternary ammonium salt (2) 200ml, 5-aminosalicylic acid palmatine quaternary ammonium salt (3) 400ml, 5-aminosalicylic acid berberine quaternary ammonium salt (4) 350ml; In parallel determinations, it takes 60 per gram of berberine-type alkaloid quaternary ammonium salt substrates to dissolve berberine-type alkaloid quaternary ammonium salt and isberberine chloride quaternary ammonium salt and 5-aminosalicylic acid.
  • the amount of% ethanol water mixed solvent is 1200ml, 680ml and 800ml respectively. Measured under reflux conditions, the amount of 60% ethanol-water mixed solvent required to dissolve each gram of the compound of the present invention is 5-aminosalicylic acid berberine quaternary ammonium salt (1) 38ml, 5-aminosalicylic acid isocericine quaternary Ammonium salt (2) 26ml, 5-aminosalicylic acid palmatine quaternary ammonium salt (3) 47ml, 5-aminosalicylic acid berberine quaternary ammonium salt (4) 73ml.
  • Experimental example 1 The anti-ulcerative colitis activity (therapeutic effect) of the compounds 1, 2, 3, and 4 of the present invention on the acute C57BL/6J mouse ulcerative colitis model induced by sodium dextran sulfate and the study with berberine chloride Examples of comparative study on the curative effect of quaternary ammonium salt, isoflavine chloride quaternary ammonium salt, palmatine chloride quaternary ammonium salt, berberine chloride quaternary ammonium salt and 5-aminosalicylic acid
  • Dosage and frequency of administration The dose of the positive drug sulfasalazine administration group is 500 mg/kg; the compounds 1, 2, 3 and 4 of the present invention, 5-aminosalicylic acid, berberine chloride quaternary ammonium salt The dosage of the quaternary ammonium salt of isberberine chloride, the quaternary ammonium salt of palmatine chloride, and the quaternary berberine chloride group were all 100mg/kg; once a day for 7 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • Mice in the model group and each compound administration group were given dextran sodium sulfate (MP, CA9011-18-1, US) every day to model ulcerative colitis model established in the laboratory [Zhang ZH, et al. Synthesis] and structure-activity relationships of quaternary coptisine derivatives as potential anti-ulcerative Colitis agents.J.Med.Chem.,2015,58,7557-7571].
  • the normal control group and the model group were given 0.5% sodium carboxymethylcellulose aqueous solution by gavage once a day.
  • the ammonium salt administration group was administered intragastrically according to the experimental design plan, once a day.
  • Sulfasalazine, each compound of the present invention and comparative compounds were all prepared with 0.5% sodium carboxymethyl cellulose aqueous solution according to the dosage of the experimental plan.
  • the compounds 1, 2, 3, and 4 of the present invention have significant therapeutic effects in vivo on the acute C57BL/6J mouse ulcerative colitis model induced by sodium dextran sulfate, which is better than other comparative compounds; the results of each evaluation index are as follows.
  • the compounds 1, 2, 3 and 4 of the present invention can effectively reduce the weight loss of acute C57BL/6J mouse ulcerative colitis model animal induced by sodium dextran sulfate (see Table 1).
  • the animal weight change rate of the compound 1, 2, 3, and 4 administration groups of the present invention at a dosage of 100 mg/kg was -0.87% ## ( ## p ⁇ 0.01, compared with the model group), -5.48 % # ( # p ⁇ 0.05, compared with the model group), -4.42% # ( # p ⁇ 0.05, compared with the model group) and -6.54% # ( # p ⁇ 0.05, compared with the model group). Therefore, the compounds 1, 2, 3, and 4 of the present invention can slow down or significantly slow down the weight loss of model animals, which is statistically significantly different from the model group.
  • the improvement effect of the compound 1, 2, 3, and 4 administration group of the present invention is significantly better than that of the 5-aminosalicylic acid administration group in parallel experiments (the animal body weight change rate is -15.09, compared with the model group There is no significant difference), and they are also superior to the corresponding berberine chloride alkaloid quaternary ammonium salt.
  • the compound 1, 2, 3 and 4 of the present invention improve the effect of dextran sodium sulfate on the colonic contracture induced by acute C57BL/6J mouse ulcerative colitis model animals (see Table 2)
  • Table 2 shows the colon length value and colon contracture percentage of each group of animals after the experiment. The results showed that compared with the normal control group, the mouse colon in the model group was significantly shorter, with a length of 4.87 ⁇ 0.15 cm, and the colon contracture ratio reached 38.91% ** ( ** p ⁇ 0.01, compared with the normal control group).
  • mice in the compound 1, 2, 3, and 4 administration groups of the present invention had significantly increased colon lengths compared with the model mice; the colon length of the mice in the compound 1 group was 6.08 ⁇ 0.12cm, the colonic contracture ratio was 23.64% ## ( ## p ⁇ 0.01, compared with the model group), the colon length of mice in the compound 2 group was 5.90 ⁇ 0.13cm, and the colonic contracture ratio was 25.94% ## ( # # p ⁇ 0.01, compared with the model group), the length of the mouse colon in the compound 3 group was 5.97 ⁇ 0.14cm, and the colon contracture ratio was 25.11% ## ( ## p ⁇ 0.01, compared with the model group), the compound 4 group The length of the mouse colon was 5.80 ⁇ 0.27cm, and the colon contracture ratio was 27.20% # ( # p ⁇ 0.05, compared with the model group).
  • the colonic contracture ratio of the positive drug sulfasalazine 500 mg/kg dose group was 37.45% (compared to the model group). Therefore, the compounds 1, 2, 3 and 4 of the present invention have a very significant improvement effect on dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal colon contracture; and the improvement effect is significantly better than the 5 in parallel experiments.
  • the comprehensive disease activity index score evaluates the effect of active compound treatment from indicators such as the percentage of animal weight loss, stool characteristics and blood in the stool that are closely related to the clinical symptoms of ulcerative colitis; the lower the comprehensive disease activity index score, the greater the inhibition rate of the comprehensive disease activity index , Indicating that the model animals are closer to the normal physiological state of the animals after treatment.
  • Table 3 The effects of the compound 1, 2, 3 and 4 administration groups of the present invention on the dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal disease activity comprehensive index score and disease activity comprehensive index inhibition rate
  • Experimental example 2 The therapeutic effect of compound 1 of the present invention on the acute C57BL/6J mouse ulcerative colitis model animal induced by sodium dextran sulfate, the dose-effect relationship and the comparative study with related compounds
  • Dosage and frequency of administration The dosage of the sulfasalazine administration group is 500 mg/kg; the dosage of the berberine chloride quaternary ammonium salt and the dihydroberberine administration group are both 100 mg/kg; the compound of the present invention 1.
  • the dosages of the high-dose, medium-dose and low-dose administration groups were 200, 100 and 50 mg/kg respectively; once a day, the administration was administered for 7 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • Mice in the model group and each compound administration group were given dextran sodium sulfate (MP, CA9011-18-1, US) every day to model ulcerative colitis model established in the laboratory [Zhang ZH, et al. Synthesis] and structure-activity relationships of quaternary coptisine derivatives as potential anti-ulcerative Colitis agents.J.Med.Chem.,2015,58,7557-7571].
  • the normal control group and the model group were given 0.5% sodium carboxymethylcellulose aqueous solution by gavage once a day.
  • the sulfasalazine administration group, the berberine chloride quaternary ammonium salt administration group, the dihydroberberine administration group, and the compound 1 high-dose, middle-dose and low-dose administration groups of the present invention were administered intragastrically according to the experimental protocol. Once a day.
  • the positive drug, berberine chloride quaternary ammonium salt, dihydroberberine and compound 1 of the present invention were all prepared with 0.5% sodium carboxymethyl cellulose aqueous solution according to the experimental protocol.
  • the compound 1 of the present invention can effectively reduce the weight loss of acute C57BL/6J mouse ulcerative colitis model animals induced by sodium dextran sulfate (see Table 4 and Figure 1), and the effect intensity is significantly better than the positive drug sulfasalazine , Coptisine Chloride Quaternary Ammonium Salt and Dihydro Coptisine.
  • the dose-effect relationship is clear.
  • the positive drug sulfasalazine at a dosage of 500 mg/kg has an improvement effect on the weight loss of mice even not as good as the compound 1 low-dose administration group of the present invention.
  • the positive drug sulfasalazine, berberine chloride quaternary ammonium salt, dihydroberberine, compound 1 of the present invention can induce acute ulcerative colitis in mice with dextran sodium sulfate See Table 6 and Figure 3 for the influence of the comprehensive activity index score and the inhibition rate of the comprehensive disease activity index.
  • Comparison 1 Coptisine chloride quaternary ammonium salt
  • Comparison 2 Dihydro berberine.
  • the berberine chloride quaternary ammonium salt and dihydroberberine at the same dosage as the compound 1 of the present invention are used to induce acute C57BL/6J mouse ulcerative colitis model animal disease activity comprehensive index scores and The effect of improving the inhibition rate of the comprehensive index of disease activity is significantly lower than that of the parallel experiment of the compound of the present invention.
  • the comprehensive disease activity index score is evaluated from the animal's weight loss, stool characteristics, blood in the stool and other indicators. The lower the disease activity comprehensive index score, the closer the animal is to the normal physiological state, see Table 7.
  • a normal stool formed stool
  • b loose stool mushy, semi-formed stool that does not adhere to the anus
  • c loose stool watery stool.
  • the positive drug sulfasalazine group only slightly improved the colon tissue damage of the acute ulcerative colitis model mice induced by sodium dextran sulfate, which showed symptoms of ulcerative colitis (destruction of the basic structure of the intestinal mucosa, disorder and loss of the arrangement of epithelial cells) Polarity phenomenon) No significant improvement (although there is improvement), there is mild edema and inflammatory cell infiltration in the submucosa and muscle layer.
  • Experimental example 3 The therapeutic effect of compound 1 of the present invention on oxazolone-induced chronic BALB/c mouse ulcerative colitis model animal and the research implementation example of the dose-effect relationship
  • the dosage of the positive drug sulfasalazine administration group is 500 mg/kg, and the dosage of the compound 1 of the present invention is 50, 100 and 200 mg for the low-dose, middle-dose and high-dose administration groups, respectively /kg; once a day for 6 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • Mice in the model group, positive drug and compound 1 administration group of the present invention were modeled with oxazolone (Sigma, E0753, 15646-46-5, USA) according to the literature oxazolone-induced animal ulcerative colitis model [Heller F,et al. Oxazolone Colitis,a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-proding NK-T cells.Immunity,2002,17,629-638].
  • the normal control group and the model group were given 0.5% sodium carboxymethylcellulose aqueous solution by gavage once a day.
  • the sulfasalazine administration group, the compound 1 low-dose, middle-dose and high-dose administration groups of the present invention were administered intragastrically according to the experimental protocol, once a day.
  • Both the positive drug and the compound 1 of the present invention were prepared with 0.5% sodium carboxymethyl cellulose aqueous solution according to the experimental protocol.
  • the compound 1 of the present invention can effectively reduce the weight loss of oxazolone-induced chronic BALB/c mouse ulcerative colitis model animals (see Table 8 and Figure 5), and the effect intensity is significantly better than the positive drug sulfasalazine. The effective relationship is clear.
  • Table 8 The improvement effect of each administration group of the positive drug sulfasalazine and the compound 1 of the present invention on the weight loss of oxazolone-induced chronic ulcerative colitis model mice
  • the low-dose group and the middle-dose group of the compound 1 of the present invention did not show statistical differences in effectively alleviating the weight loss of oxazolone-induced chronic ulcerative colitis model mice, the trend of the compound 1 of the present invention to alleviate the weight loss effect Obviously, and has a good dose-effect relationship.
  • Table 9 The improvement effect of each administration group of the positive drug sulfasalazine and the compound 1 of the present invention on the colon contracture of mice with chronic ulcerative colitis induced by oxazolone
  • the compound 1 low-dose group of the present invention did not show a statistical difference in the effective alleviation of oxazolone-induced chronic ulcerative colitis model mice disease activity comprehensive index score, the trend of the remission effect of the compound 1 of the present invention is obvious.
  • Experimental Example 4 Comparison of the effect (therapeutic effect) of a mixture of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid prepared by the principle of equal mole number of compound 1 of the present invention against acute ulcerative colitis induced by sodium dextran sulfate Experimental implementation examples
  • the administration dose of the positive drug sulfasalazine administration group is 500 mg/kg
  • the administration dose of the compound 1 administration group of the present invention is 100 mg/kg
  • the number of moles is equal.
  • the dosage of the mixture administration group of alkali quaternary ammonium salt and 5-aminosalicylic acid was 107 mg/kg; once a day, the administration was administered for 7 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • Mice in the model group and each compound administration group were given dextran sodium sulfate (MP, CA9011-18-1, US) every day to model ulcerative colitis model established in the laboratory [Zhang ZH, et al. Synthesis] and structure-activity relationships of quaternary coptisine derivatives as potential anti-ulcerative Colitis agents.J.Med.Chem.,2015,58,7557-7571].
  • the normal control group and the model group were given 0.5% sodium carboxymethylcellulose aqueous solution by gavage once a day.
  • the sulfasalazine administration group, the compound 1 administration group of the present invention, and the mixture of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid (c1+A) administration group prepared by the principle of equal moles were designed according to the experiment The regimen was administered by gavage, once a day, all were prepared with 0.5% sodium carboxymethyl cellulose aqueous solution according to the experimental regimen.
  • the compound 1 of the present invention has a significant therapeutic effect in vivo on the acute C57BL/6J mouse ulcerative colitis animal model induced by dextran sodium sulfate, which is significantly better than the quaternary ammonium chloride and berberine chloride formulated on the principle of equal moles Each evaluation index of 5-aminosalicylic acid mixture (c1+A) administration group.
  • the compound 1 of the present invention effectively reduces the weight loss of dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal, which is significantly better than the berberine chloride quaternary ammonium salt formulated on the principle of equal moles and 5- The aminosalicylic acid mixture (c1+A) administration group (see Table 11).
  • the compound 1 administration group of the present invention has an animal body weight change rate of -2.47% at a dose of 100 mg/kg ## ( ## p ⁇ 0.01, compared with the model group), which is significantly better than the principle of equal number of moles.
  • the corresponding value of the berberine chloride quaternary ammonium salt and 5-aminosalicylic acid mixture administration group is -13.11% (compared with the model group, there is no significant difference).
  • the compound 1 of the present invention has a significantly better effect of improving colonic contracture in the acute C57BL/6J mouse ulcerative colitis model animal induced by dextran sodium sulfate than the berberine chloride quaternary ammonium salt and 5- A mixture of aminosalicylic acid (see Table 12).
  • Table 12 shows the colon length value and colon contracture percentage of each group of animals after the experiment.
  • the results showed that compared with the normal control group’s colon length value of 8.08 ⁇ 0.22cm, the model group’s colon was significantly shorter to 5.58 ⁇ 0.12cm, and the colon contracture ratio reached 30.94% ( ** p ⁇ 0.01, compared with the normal control group ).
  • the mice in the compound 1 administration group of the present invention had significantly increased colon length compared with the model group mice; the colon length of the mice in the compound 1 group was 7.12 ⁇ 0.12 cm, and the colon contracture The ratio is 11.88% ## ( ## p ⁇ 0.01, compared with the model group).
  • the colonic contracture ratio of the group administered with the mixture of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid prepared on the principle of equal moles reached 30.20% (no significant difference compared with the model group). Therefore, the compound 1 of the present invention has a very significant improvement effect on the colonic contracture induced by dextran sodium sulfate in the acute C57BL/6J mouse ulcerative colitis model animal, which is significantly better than the quaternary ammonium chloride of berberine prepared by the principle of equal mole number And 5-aminosalicylic acid mixture.
  • the investigation of the influence of the comprehensive index score and the inhibition rate of the disease activity comprehensive index showed that the compound 1 of the present invention has a significant anti-ulcerative colitis effect at a dosage of 100 mg/kg, which is significantly better than the number of moles in the parallel experiment
  • the animal disease activity comprehensive index score of the model group was significantly increased, which was 3.00 ⁇ 0.42**, which was statistically significant, indicating that the model was successful.
  • the 100 mg/kg administration group of compound 1 of the present invention can significantly reduce the comprehensive index score of experimental animal disease activity (score of 0.80 ⁇ 0.37 ## ), and the difference is statistically significant.
  • a mixture of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid prepared according to the principle of equal mole number on dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal disease activity comprehensive index score and disease activity
  • the improvement effect values of the comprehensive index inhibition rate were 2.87 ⁇ 0.33 and 4.44%, respectively, and there was no statistically significant difference, which was significantly lower than the compound of the present invention.
  • Table 13 The compound 1 administration group of the present invention and the molar number are equal to the mixture administration group of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid induced acute ulcer in C57BL/6J mice with sodium dextran sulfate Of disease activity index score and disease activity index inhibition rate of animal model of colitis
  • Experimental example 5 The therapeutic effect of compound 1 of the present invention on the chronic C57BL/6J mouse ulcerative colitis model animal induced by sodium dextran sulfate and the implementation example of the dose-effect relationship
  • Dosage and frequency of administration The dosage of the positive drug sulfasalazine administration group is 500 mg/kg, and the dosage of compound 1 of the present invention is 50, 100 and 200 mg for the low-dose, middle-dose and high-dose administration groups, respectively /kg; once a day for 40 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • the mice in the model group, the positive drug group and each administration group of compound 1 of the present invention were given 2% dextran sodium sulfate (MP, CA9011-18-1, US) on day 1-6 and normal drinking on day 7-20
  • the normal control group and the model group were given 0.5% sodium carboxymethyl cellulose aqueous solution by gavage, once a day after the start of administration.
  • the sulfasalazine administration group, the compound 1 low-dose, middle-dose and high-dose administration groups of the present invention were administered intragastrically from day 7 according to the experimental protocol, once a day. The experiment was terminated on the 46th day for a total of 40 days of administration.
  • Both the positive drug and the compound 1 of the present invention were prepared with 0.5% sodium carboxymethyl cellulose aqueous solution according to the experimental protocol.
  • Table 14 Note: In an animal experiment for evaluating anti-chronic ulcerative colitis activity in an animal model of chronic ulcerative colitis in C57BL/6J mice induced by sodium dextran sulfate, the compound of the present invention has an effect on chronic ulcerative colitis model animals. It has a significant therapeutic effect and is significantly better than the current first-line treatment drug sulfasalazine for anti-ulcerative colitis.
  • the disease activity comprehensive index inhibition rate values were 94.44% ## ⁇ 58.33% # and 38.89% # ( # p ⁇ 0.05, ## p ⁇ 0.01, compared with the model group), compared with the positive control drug sulfasalazine in the parallel experiment, when the dose of sulfasalazine is 500 mg/kg, the comprehensive index of disease activity inhibition rate value is 50.00% (with Compared with the model group, there is no significant difference), the curative effect is very significant, and the dose-effect relationship is clear.
  • the dosage of the positive drug dexamethasone in single administration group is 0.5 mg/kg
  • the dosage of compound 3 of the present invention in the low, middle and high dose single administration groups is 50 mg/kg, respectively , 100mg/kg and 200mg/kg
  • the dosage of palmatine chloride quaternary ammonium salt single-administration group and 5-aminosalicylic acid single-administration group are both 100mg/kg
  • the chlorinated chlorination is prepared based on the principle of equal number of moles
  • the dosage of the combined administration group of the mixture of palmatine quaternary ammonium salt and 5-aminosalicylic acid was 100 mg/kg; once a day, the administration was administered for 7 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • Mice in the model group and each compound administration group were given dextran sodium sulfate (MP, CA9011-18-1, US) every day to model ulcerative colitis model established in the laboratory [Zhang ZH, et al. Synthesis] and structure-activity relationships of quaternary coptisine derivatives as potential anti-ulcerative Colitis agents.J.Med.Chem.,2015,58,7557-7571].
  • the normal control group and the model group were given 0.5% sodium carboxymethylcellulose aqueous solution by gavage once a day.
  • Positive drug dexamethasone single-administration group, compound 3 of the present invention low-dose single-administration group, medium-dose single-administration group and high-dose single-administration group, palmatine chloride single-administration group, 5-
  • the aminosalicylic acid single administration group and the palmatine quaternary ammonium chloride and 5-aminosalicylic acid homogenous mixture (c3+A) prepared by the principle of equal moles were administered by gavage according to the experimental design plan , Once a day, are prepared with 0.5% sodium carboxymethyl cellulose aqueous solution according to the experimental protocol.
  • the compound 3 of the present invention shows a significant therapeutic effect in vivo on the acute C57BL/6J mouse ulcerative colitis animal model induced by dextran sodium sulfate, which is significantly better than palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid And a homogeneous mixture of palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid (c3+A) prepared on the principle of equal moles.
  • the compound 3 of the present invention effectively reduces the pharmacological effects of dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal weight loss significantly better than palmatine chloride quaternary ammonium salt, 5-aminosalicylic acid and A homogeneous mixture of palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid (c3+A) prepared according to the principle of equal mole number (see Table 15).
  • the compound 3 single-administration group of the present invention effectively reduces the pharmacological effect of the weight loss of model animals significantly better than the single-administration palmatine chloride quaternary ammonium salt group and 5-aminosalicylic acid
  • the single administration group and the combined administration group of palmatine quaternary ammonium chloride and 5-aminosalicylic acid homogeneous mixture (c3+A) prepared on the principle of equal moles the corresponding values of the latter three are -19.80% respectively , -14.68% and -23.94% (there are no significant differences compared with the model group).
  • Single administration of the positive drug dexamethasone showed significant pharmacological effects in the experiment.
  • the compound 3 of the present invention is significantly better than palmatine quaternary ammonium chloride, 5-aminosalicylic acid and massage in improving the effect of dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal colon contracture
  • a homogeneous mixture of palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid (c3+A) prepared by the principle of equal number of mols (see Table 16).
  • Table 16 shows the colon length value and colon contracture percentage of each group of animals after the experiment. The results showed that compared with the normal control group’s colon length value of 7.32 ⁇ 0.29cm, the model group’s colon was significantly shorter to 4.48 ⁇ 0.76cm, and the colon contracture ratio reached 38.75% ** ( ** p ⁇ 0.01, compared with the normal control group compared to). Compared with the mice in the model group, the length of the colon of the mice in the low-dose, medium-dose and high-dose single administration group of compound 3 of the present invention was significantly increased, which were 5.60 ⁇ 0.40cm, 6.03 ⁇ 0.76cm and 7.03 ⁇ 0.80cm, respectively.
  • the contracture ratios were 23.50% # , 17.58% ## and 3.92% ## ( # p ⁇ 0.05, ## p ⁇ 0.01, compared with the model group).
  • the palmatine chloride quaternary ammonium salt single-administration group, the 5-aminosalicylic acid single-administration group, and the homogeneous mixture of palmatine chloride quaternary ammonium chloride and 5-aminosalicylic acid prepared on the principle of equal moles ( c3+A)
  • the colonic contracture rate of the combined administration group at a dose of 100 mg/kg reached 32.38%, 25.77% and 33.61% respectively (compared with the model group, there is no significant difference).
  • the compound 3 of the present invention has a very significant improvement effect on dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal colon contracture, and the dose-effect relationship is prominent. In the experiment, the same dosage is used.
  • Inventive compound 3 is significantly better than palmatine quaternary ammonium chloride, 5-aminosalicylic acid and equal moles in improving colonic contracture induced by dextran sodium sulfate in acute C57BL/6J mouse ulcerative colitis model animals
  • a homogeneous mixture of palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid (c3+A) prepared in principle.
  • the compound 3 of the present invention palmatine chloride quaternary ammonium salt, 5-aminosalicylic acid, and the principle of equal molar number of palmatine chloride and 5-amino water prepared by using the same batch of whole animal experiments
  • the effect of the homogeneous mixture of salicylic acid (c3+A) on the dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal disease activity comprehensive index score and disease activity comprehensive index inhibition rate the results show that the compound 3 of the present invention Not only has significant anti-ulcerative colitis activity and a clear dose-effect relationship, it is significantly better than the palmatine chloride quaternary ammonium salt administration group and 5-aminosalicylic acid administration in parallel experiments at the same dosage Group and the administration group of homogeneous mixture of palmatine chloride quaternary ammonium salt and 5-aminosalicylic acid (c3+A) prepared on the principle of equal moles.
  • the low-dose (50mg/kg), medium-dose (100mg/kg) and high-dose (200mg/kg) administration groups of Compound 3 of the present invention significantly reduced the comprehensive index scores of the disease activity of experimental animals to 2.56 ⁇ 0.40 ## , 2.06 ⁇ 0.98 ## and 1.33 ⁇ 1.05 ## , both have statistically significant differences compared with the model group.
  • the values of the improvement effect of the comprehensive disease activity index score and the inhibition rate of the comprehensive disease activity index inhibition rate of the acute C57BL/6J mouse ulcerative colitis model induced by dextran sodium sulfate are respectively 3.00 ⁇ 0.92, 2.61 ⁇ 0.74 # and 2.78 ⁇ 1.50
  • 5-aminosalicylic acid administration groups have statistically significant differences, but they are significantly lower than the compound 3 of the present invention; the other two administration groups are not statistically significant The sex difference is significantly lower than that of compound 3 of the present invention.
  • Experimental Example 7 The compound 4 of the present invention is single-administered with berberine chloride quaternary ammonium salt, 5-aminosalicylic acid is single-administered, and berberine chloride quaternary ammonium salt and The pharmacological effect of the homogeneous mixture of 5-aminosalicylic acid combined with dextran sodium sulfate-induced acute ulcerative colitis in mice is comparative experimental example
  • Dosage and frequency of administration the dosage of the positive drug dexamethasone single administration group is 0.5 mg/kg, and the dosage of compound 4 of the present invention is 25 mg/kg for the low, middle and high dose single administration groups, respectively , 50mg/kg and 100mg/kg, the dosage of berberine chloride quaternary ammonium salt single-administration group and 5-aminosalicylic acid single-administration group is 100mg/kg, and the number of moles is equal.
  • the dosage of the combined administration group of the uniform mixture of berberine quaternary ammonium salt and 5-aminosalicylic acid was 100 mg/kg; once a day, the administration was administered for 7 days.
  • mice were adaptively reared in an SPF animal room (experimental animal license number: SYXK ( ⁇ )2014-0023) for one week, and then randomly grouped according to the experimental design.
  • Mice in the model group and each compound administration group were given dextran sodium sulfate (MP, CA9011-18-1, US) every day to model ulcerative colitis model established in the laboratory [Zhang ZH, et al. Synthesis] and structure-activity relationships of quaternary coptisine derivatives as potential anti-ulcerative Colitis agents.J.Med.Chem.,2015,58,7557-7571].
  • the normal control group and the model group were given 0.5% sodium carboxymethylcellulose aqueous solution by gavage once a day.
  • Positive drug dexamethasone single administration group, compound 4 of the present invention low-dose, middle-dose and high-dose single administration group, berberine chloride quaternary ammonium salt single administration group, 5-aminosalicylic acid single administration group
  • the combined administration group of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid homogenous mixture (c4+A) prepared on the principle of equal moles was administered by gavage according to the experimental design plan, once a day, both at 0.5 % Sodium carboxymethyl cellulose aqueous solution was prepared according to the experimental dosage.
  • the drug was continuously administered for 7 days, until the model group animals showed obvious symptoms of ulcerative colitis such as malaise, reduced activity, weight loss, loose stools, blood in the stool, etc., the experiment was terminated in due course, the animals in each group were killed, and the relevant evaluation indicators were tested. (See the experimental results part), comprehensively evaluate the anti-ulcerative colitis pharmacodynamic effect of the compound 4 of the present invention through the mouse disease activity comprehensive index score and the disease activity comprehensive index inhibition rate.
  • the compound 4 of the present invention has a significant therapeutic effect in vivo on the acute C57BL/6J mouse ulcerative colitis animal model induced by dextran sodium sulfate, and its pharmacological effect is significantly better than berberine chloride quaternary ammonium salt and 5-amino water
  • berberine chloride quaternary ammonium salt and 5-aminosalicylic acid c4+A prepared on the principle that salicylic acid and moles are equal.
  • the compound of the present invention 4 single administration group, berberine chloride quaternary ammonium salt single administration group, 5-aminosalicylic acid single administration group, and berberine chloride quaternary ammonium salt and 5 -Aminosalicylic acid homogenous mixture (c4+A) combined administration group on the dextran sodium sulfate-induced acute ulcerative colitis model mice disease activity comprehensive index score and disease activity comprehensive index inhibition rate, see Table 18 .
  • the low-dose (25mg/kg) single-administered compound 4 of the present invention has no obvious pharmacological effect in reducing the comprehensive index score of experimental animal disease activity, but both the middle-dose (50mg/kg) and high-dose (100mg/kg) single-administered groups Significantly reduce the comprehensive index scores of laboratory animal disease activity to 1.78 ⁇ 0.89 # and 1.56 ⁇ 0.66 ## , both of which are statistically significantly different from the model group.
  • Berberine chloride quaternary ammonium salt for single administration group 5-aminosalicylic acid single administration group, and a homogeneous mixture of berberine chloride quaternary ammonium salt and 5-aminosalicylic acid prepared on the principle of equal moles ( c4+A)
  • the combined administration group improves the dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal disease activity comprehensive index score and disease activity comprehensive index inhibition rate at a dose of 100 mg/kg
  • the effect values were 2.72 ⁇ 0.98, 2.11 ⁇ 0.54 # and 2.17 ⁇ 0.69.
  • the compound of the present invention 4 single administration, single administration of berberine chloride quaternary ammonium salt, 5-aminosalicylic acid single administration and the principle of equal molar number of berberine chloride and 5 -Aminosalicylic acid homogenous mixture (c4+A) combined administration on dextran sodium sulfate-induced acute C57BL/6J mouse ulcerative colitis model animal disease activity composite index score and disease activity composite index inhibition rate
  • Experimental example 8 Experimental example of the transcriptional activation effect of related compounds on pGL3-pxbp1
  • mice weight range of 18-22g into groups, each group of 10, male and female, a total of 8 dose groups, according to the Bliss method from the highest dose (5g/kg) in descending proportions to set each The dose of the administration group (1:0.8).
  • Mice were given intragastric administration. The animals were fasted and watered the night before the administration. The mice were given a normal diet 4h after administration. After a single dose, continuous observation of the animals 14 days mental state, weight, diet, behavior, secretions, excretions, and the reaction poisoning death and IC50 values are calculated index LD.
  • the results of the acute toxicity test in animals of the compounds 1, 2, 3 and 4 of the present invention are as follows: Compounds 1, 2, and 3 have no animal death and abnormal changes in physiological indicators at a dose of 5.0 g/kg.
  • the LD 50 value is 3.0 g/kg. Therefore, the compounds of the present invention are all non-toxic or low-toxic specific anti-ulcerative colitis compounds.

Abstract

La présente invention concerne un composé d'ammonium quaternaire d'alcaloïde de type berbérine d'acide salicylique tel que représenté dans la formule générale (I), un procédé de préparation associé, des caractéristiques de solubilité, une composition pharmaceutique et une utilisation associée dans la préparation de produits médicamenteux. Le composé d'ammonium quaternaire alcaloïde de type berbérine d'acide salicylique tel que représenté dans la formule générale (I) peut être préparé par un procédé de synthèse organique, et présente une solubilité évidente de solvants mixtes alcool-eau. Le composé peut être préparé de façon pratique à grande échelle, et présente une activité anti-colite ulcéreuse significative, avec des caractéristiques non toxiques ou à faible toxicité. Le composé peut être utilisé pour préparer des produits destinés à prévenir, soulager et/ou traiter la colite ulcéreuse.
PCT/CN2020/078049 2019-03-05 2020-03-05 Composé d'ammonium quaternaire alcaloïde de type berbérine d'acide salicylique et son utilisation pour la préparation de médicaments WO2020177744A1 (fr)

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CN114790204A (zh) * 2021-01-26 2022-07-26 成都贝诺科成生物科技有限公司 一种防治肠道疾病的化合物及其药用组合物
WO2024080768A1 (fr) * 2022-10-14 2024-04-18 주식회사 알트메디칼 Composition de prévention ou de traitement d'une neuropathie périphérique, contenant un dérivé d'isoquinoléine en tant que principe actif
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CN114790204B (zh) * 2021-01-26 2024-05-03 成都贝诺科成生物科技有限公司 一种防治肠道疾病的化合物及其药用组合物
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WO2024080768A1 (fr) * 2022-10-14 2024-04-18 주식회사 알트메디칼 Composition de prévention ou de traitement d'une neuropathie périphérique, contenant un dérivé d'isoquinoléine en tant que principe actif
WO2024085618A1 (fr) * 2022-10-19 2024-04-25 주식회사 알트메디칼 Composition pour la prévention ou le traitement du syndrome de melas, contenant un dérivé d'isopquinoline en tant que principe actif

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