Medicine for improving chronic atrophic gastritis and its application

Abstract

The present invention relates to the field of small molecule drug technology, and more specifically to a drug for ameliorating chronic atrophic gastritis and its use. One object of the present invention is to provide a compound, a pharmaceutical composition comprising the compound, and its use. The 9- and 13-substituted berberine derivatives of the present invention have a significant ameliorative effect on CAG. Further studies and observations have shown that the compounds inhibit CAG symptoms, such as atrophy of gastric mucosal glandular epithelial cells, thinning of the gastric mucosa, infiltration and adhesion of large numbers of neutrophils and lymphocytes, and inflammatory factors. It was found that the 9- and 13-substituted berberine derivatives of the present invention can be used to prevent and / or treat CAG.

Description

Technical Field

[0001] The present invention relates to the technical field of small molecule drugs, and in particular to a drug for improving chronic atrophic gastritis and application thereof. Background Art

[0002] Chronic atrophic gastritis (CAG) is a chronic digestive disease caused by multiple pathogenic factors. Long-term chronic inflammation leads to atrophy (reduction in number and function) of the gastric mucosal glands, resulting in reduced secretion of gastric juice and pepsin, which in turn affects the stomach's normal physiological function. Most patients experience varying degrees of abdominal pain, loss of appetite, and belching. CAG is characterized by a long course and difficulty in recovery, significantly impacting patients' standard of living and quality of life. CAG is classified by the World Health Organization as a precancerous condition of the stomach. Patients with intestinal metaplasia and dysplasia are particularly likely to develop cancer, making timely and effective treatment crucial.

[0003] Helicobacter pylori infection is one of the most important causes of CAG, and almost all patients currently infected have chronic active gastritis. It is also the most important risk factor for peptic ulcers, dyspepsia, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. Dietary and environmental factors are associated with the development of CAG. Unhealthy dietary habits, such as consuming excessively cold or hot foods, as well as rough or irritating foods, can damage the gastric mucosa. Epidemiological studies have shown that a high salt diet and a lack of fresh fruits and vegetables are closely associated with gastric mucosal atrophy, intestinal metaplasia, and gastric cancer. Autoimmune gastritis is a form of CAG caused by an autoimmune mechanism. Patients develop autoantibodies against various components of gastric tissue, such as anti-intrinsic factor and anti-parietal cell antibodies, leading to tissue damage and dysfunction. Other autoimmune diseases may also coexist, such as thyroid disease and type 1 diabetes. Bile reflux is also a common cause of chronic atrophic gastritis. The surface of the normal gastric mucosa is covered by a mucus-bicarbonate barrier that prevents gastric acid from penetrating the mucosa. Gastrointestinal motility disorders, liver and biliary tract diseases, and distal gastrointestinal obstruction caused by various factors can cause bile reflux. Bile, pancreatic juice, and duodenal fluid refluxed into the stomach can disrupt the gastric mucosal barrier, causing gastric mucosal damage. Long-term, repeated irritation can lead to CAG. Drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, can directly damage the gastric mucosa. They can also inhibit prostaglandin synthesis through metabolic pathways, reducing the gastric mucosal defense and repair capacity, making them a clear risk factor for CAG. Alcohol consumption can also cause gastric mucosal damage and bleeding. The combined use of alcohol and NSAIDs can further damage the gastric mucosa. Furthermore, degenerative changes can occur in the elderly, impairing the gastric mucosal repair and regeneration function and causing glandular atrophy in the epithelium. Therefore, CAG is more common in the elderly.

[0004] Currently, treatment for CAG focuses on relieving symptoms, improving gastric mucosal conditions, and preventing cancer. For CAG caused by Helicobacter pylori (Hp), eradication of Hp is key to treatment, as it can slow or reverse gastric mucosal atrophy and intestinal metaplasia. Antacids, gastric mucosal protectants, and prokinetics can effectively alleviate symptoms such as bloating, abdominal pain, and indigestion. Traditional Chinese medicine (TCM) treatments have shown some effectiveness in improving symptoms and gastric mucosal conditions. Traditional Chinese medicines such as Morodan and Weifuchun, for example, promote blood circulation, remove blood stasis, strengthen the spleen and regulate the stomach, and thus aid in gastric mucosal repair. Improving dietary habits and lifestyles, such as reducing the intake of spicy and irritating foods, quitting smoking and limiting alcohol consumption, and maintaining a regular sleep and rest schedule, can have a positive effect on improving patients' overall health and symptoms.

[0005] However, current treatments for CAG still have some limitations. Although treatment can effectively relieve symptoms, it often cannot completely cure CAG, especially the atrophy and intestinal metaplasia of the gastric mucosa. In addition, different patients may respond very differently to treatment, which may affect the prediction and adjustment of treatment effects. Long-term use of certain medications may cause side effects, such as long-term damage to the gastric mucosa caused by non-steroidal anti-inflammatory drugs (NSAIDs). Patients need to maintain long-term treatment, but some patients may stop taking the medication on their own due to side effects or after symptom relief, affecting the treatment effect. In short, the treatment of CAG is a comprehensive process that requires an individualized treatment plan based on the patient's specific situation. Although current treatments can relieve symptoms and improve the condition of the gastric mucosa to a certain extent, achieving a complete cure remains challenging. Summary of the Invention

[0006] The present invention aims to at least partially address one of the technical problems in the related art. To this end, one object of the present invention is to provide a compound, a pharmaceutical composition comprising the compound, and uses thereof. The 9-, 13-substituted berberine derivatives of the present invention, represented by general formula (I), exhibit significant ameliorative effects on CAG. Further studies and observations revealed that the compounds inhibited CAG symptoms, such as atrophy of gastric mucosal glandular epithelial cells, thinning of the gastric mucosa, extensive neutrophil and lymphocyte infiltration and adhesion, and inflammatory factors. The findings indicate that the 9-, 13-substituted berberine derivatives of the present invention are useful for preventing and / or treating CAG.

[0007] To this end, the first aspect of the present invention provides a compound, which is a compound represented by general formula (I) or a stereoisomer, tautomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by general formula (I):

[0008]

[0009] R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl;

[0010] m=1~10, n=1~10,

[0011] R3 is unsubstituted or substituted with at least one R b Substituted 3-10 membered heterocyclic group, C6-C 20 Aryl, 5-20 membered heteroaryl;

[0012] Ra 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 20 Alkoxy, C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl.

[0013] The inventors improved the structure of berberine to obtain 9- and 13-substituted berberine derivatives represented by the general formula (I) of the present invention. They unexpectedly discovered that these compounds have inhibitory effects on CAG, including atrophy of gastric mucosal glandular epithelial cells, thinning of the gastric mucosa, infiltration and adhesion of large numbers of neutrophils and lymphocytes, and inflammatory factors. Therefore, the 9- and 13-substituted berberine derivatives of the present invention can be used to prevent and / or treat CAG and can be used to prepare drugs for the treatment of CAG.

[0014] According to an embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl;

[0015] m=1~10, n=1~10,

[0016] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 Aryl, 5-20 membered heteroaryl;

[0017] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 15 Alkoxy, C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl.

[0018] According to an embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl;

[0019] m=1~5, n=1~10,

[0020] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 aryl;

[0021] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0022] According to an embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl;

[0023] m=1~5, n=1~10,

[0024] R3 is unsubstituted or substituted with at least one R b substituted phenyl;

[0025] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0026] According to an embodiment of the present invention, R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 alkyl.

[0027] According to an embodiment of the present invention, R a is -NH2;

[0028] R b Selected from -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 alkyl.

[0029] According to an embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10 Alkynyl, unsubstituted or substituted with at least one R a Substituted C1-C 10 alkyl;

[0030] m=1~5, n=1~10,

[0031] R3 is unsubstituted or substituted with at least one R b substituted phenyl;

[0032] R a is -NH2;

[0033] R b Selected from -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 alkyl.

[0034] According to an embodiment of the present invention, the compound is selected from one of the following structures:

[0035]

[0036]

[0037]

[0038] The second aspect of the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the compound described in the first aspect.

[0039] According to an embodiment of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier, diluent or excipient.

[0040] The compounds provided by the present invention are used to prepare medicines in various dosage forms, which are administered to subjects in a therapeutically effective amount. After being absorbed by the subjects, the medicines can treat or improve chronic atrophic gastritis.

[0041] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more other therapeutic agents, wherein the other therapeutic agents have similar functions to the compounds of the present invention and can be used to treat or improve chronic atrophic gastritis.

[0042] The present invention relates to suitable pharmaceutically acceptable salts of the compounds represented by general formula (I) or (I), including but not limited to hydrochloride, hydrobromide, sulfate or hydrogensulfate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate or p-toluenesulfonate. As mentioned above, any compound of the present invention mentioned herein includes its pharmaceutically acceptable salt, solvate or combination thereof.

[0043] In addition to the pharmaceutically acceptable salts of the compounds of the present invention, the present invention also includes other salts that may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used for the identification, characterization or purification of the compounds of the present invention.

[0044] The third aspect of the present invention provides use of the compound described in the first aspect in the preparation of a medicament for treating chronic atrophic gastritis.

[0045] The inventors conducted a series of in vitro and in vivo experiments to demonstrate the inhibitory and therapeutic effects of the 9- and 13-substituted berberine derivatives of the present invention on CAG. Specifically, they discovered that the 9- and 13-substituted berberine derivatives provided herein can alleviate the progression of CAG in mice by inhibiting the expression of inflammatory factors; their efficacy in treating CAG in mice is superior to that of berberine. The inventors also discovered that the berberine derivatives of the present invention treat CAG in mice by improving the extent of gastric mucosal lesions at a pathological level and inhibiting the expression of inflammatory factors at the cellular and protein levels. In summary, the inventors have discovered a compound represented by general formula (I) that can ameliorate and treat CAG and can be used to prepare a medicament for the treatment of CAG.

[0046] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0048] Figure 1 The effects of BBR and the berberine derivatives of the present invention on the IL-1β content in the supernatant of MNNG-induced GES-1 cells are shown;

[0049] Figure 2 The effects of BBR and the berberine derivatives of the present invention on GES-1 cell viability are shown;

[0050] Figure 3 The effects of BBR and the berberine derivatives of the present invention on the gastric mucosa of CAG model mice are shown;

[0051] Figure 4 The HE staining results of gastric mucosa of mice in the normal group, CAG group, BBR group, and BBR-5 group are shown;

[0052] Figure 5 The results of IHC test of gastric mucosa of mice in the normal group, CAG group, BBR group, and BBR-5 group are shown;

[0053] Figure 6 The protein expressions of inflammatory mediators TNF-α, IL-6, and IL-1β in the gastric tissues of mice in the normal group, CAG group, BBR group, and BBR-5 group are shown. DETAILED DESCRIPTION

[0054] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0055] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0056] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0057] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present invention belongs.

[0058] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0059] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0060] Definitions and Explanations of Terms

[0061] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0062] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed with Al, Ca, Li, Mg, K, Na, and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary, or tertiary amines, including naturally occurring substituted or unsubstituted amines, cyclic amines, and basic ion exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzylpenicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, or polyamine resins. Salts derived from inorganic and organic acids include, but are not limited to, organic salts formed from sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid.

[0063] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0064] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0065] The term "drug" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a drug is to facilitate administration of the compound to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0066] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0067] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying functional groups in the compound, and the modification can be removed by conventional manipulation or in vivo to obtain the parent compound.

[0068] The term "C1-C 10 The term "alkyl" is understood to mean a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Such alkyl radicals are, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylbutyl, "C1-C6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0069] The term "C2-C 20“Alkynyl” is understood as preferably meaning a linear or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0070] The term "C2-C 20 “Alkenyl” is understood as preferably meaning a linear or branched, monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0071] The term "3-10 membered heterocyclyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O and S. In particular, the heterocyclyl may include, but is not limited to: a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic.

[0072] The term "C6-C 20 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0073] The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S, which in each case may additionally be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0074] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Non-limiting examples of the term "excipient" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling characteristics of a pharmaceutical formulation, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression. Examples of typical "pharmaceutically acceptable carriers" suitable for the above-mentioned preparations are: sugars, such as lactose, sucrose, mannitol and sorbitol, or corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants and the like excipients commonly used in pharmaceutical preparations.

[0075] For the discovery and development of contemporary drugs, natural products provide a variety of lead structures and new drugs. Derivatives of natural products are regarded as privileged molecular entities for drug discovery activities, highlighting new potential therapeutic benefits outside of their original biological space. The present invention involves derivatives of berberine, which have been structurally remodeled and modified to have significantly better activity than berberine. The derivatives of the present invention can alleviate and treat MNNG-induced CAG, improve inflammatory cytokines, and have no side effects on liver and kidney function. The analysis results show that the derivatives have a very significant therapeutic effect on CAG at the mouse level, indicating that berberine derivatives may be used as potential drugs for the treatment of CAG. This study provides a new research idea for clarifying the role of berberine derivatives in improving CAG.

[0076] Chronic gastritis includes chronic superficial gastritis and chronic atrophic gastritis (CAG). Atrophic gastritis is a fertile ground for cancer development and is listed by the World Health Organization as a pre-cancerous condition for gastric cancer. In recent years, with the widespread use of gastroscopy, the detection rates of chronic superficial gastritis and CAG have been increasing. The etiology of CAG is complex and is associated with genetic factors, metal exposure, bile or duodenal fluid reflux, immune factors, and Helicobacter pylori infection. Pathological manifestations include varying degrees of glandular atrophy and disappearance, replaced by pyloric or intestinal glandular metaplasia, and significant interstitial inflammatory infiltration.

[0077] CAG is a chronic gastric disease characterized by atrophy, decreased number, or disappearance of gastric mucosal glands, often accompanied by mucosal thinning, intestinal metaplasia, or dysplasia. While the disease is more common in middle-aged and elderly individuals, its incidence has been increasing in younger individuals in recent years. It is closely associated with Helicobacter pylori (Hp) infection and unhealthy lifestyle habits. CAG is a precancerous lesion of gastric cancer, and the risk of cancer is significantly increased when combined with intestinal metaplasia or dysplasia. Therefore, early diagnosis and treatment are crucial.

[0078] Currently, there is no specifically effective treatment for chronic atrophic gastritis. Symptomatic treatment is primarily symptomatic, but reversing the atrophic condition is often difficult. Western medicine treatment focuses on eliminating the underlying cause, selecting commonly used medications based on the severity of the condition, avoiding medications that damage the gastric mucosa, such as glucocorticoids, and actively treating related diseases and infections.

[0079] Berberine, also known as berberine, is a common isoquinoline alkaloid. Modern pharmacological studies have shown that berberine has multiple biological activities, including anti-inflammatory effects. Berberine inhibits inflammatory responses through multiple mechanisms and has significant anti-inflammatory effects. Berberine can enhance human immunity and regulate immune system function, and is indispensable for solving certain autoimmune and related health problems. The berberine derivatives of the present invention are novel small molecule drug derivatives synthesized by rationally modifying and altering the molecular structure of berberine. Combined with the superior anti-inflammatory activity of berberine itself, this study aims to verify whether berberine derivatives have better effects in improving CAG, whether they can be rationally developed and applied as potential drugs for the treatment of CAG, and provide more options for the clinical use of CAG.

[0080] Based on this, the purpose of the present invention is to provide a class of 9,13-substituted berberine derivatives and their preparation methods and applications. Through the rational design and modification of BBR, candidate drugs with improved activity, new mechanisms and good safety are obtained.

[0081] According to a specific embodiment of the present invention, the present invention provides a compound, which is a compound represented by general formula (I) or a stereoisomer, tautomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by general formula (I):

[0082]

[0083] R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl;

[0084] m=1~10, n=1~10,

[0085] R3 is unsubstituted or substituted with at least one R b Substituted 3-10 membered heterocyclic group, C6-C 20 Aryl, 5-20 membered heteroaryl;

[0086] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 20 Alkoxy, C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl.

[0087] It should be noted that m can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For example, m is 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, or 1-10, and n is 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, or 1-10.

[0088] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl;

[0089] m=1~10, n=1~10,

[0090] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 Aryl, 5-20 membered heteroaryl;

[0091] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 15 Alkoxy, C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl.

[0092] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl;

[0093] m=1~5, n=1~10,

[0094] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 aryl;

[0095] R a 、R bEach independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0096] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl;

[0097] m=1~5, n=1~10,

[0098] R3 is unsubstituted or substituted with at least one R b substituted phenyl;

[0099] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0100] According to a specific embodiment of the present invention, R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 alkyl.

[0101] According to a specific embodiment of the present invention, R a is -NH2;

[0102] R b Selected from -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 alkyl.

[0103] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10Alkynyl, unsubstituted or substituted with at least one R a Substituted C1-C 10 alkyl;

[0104] m=1~5, n=1~10,

[0105] R3 is unsubstituted or substituted with at least one R b substituted phenyl;

[0106] R a is -NH2;

[0107] R b Selected from -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 wherein halogen is fluorine, chlorine, bromine or iodine.

[0108] According to a specific embodiment of the present invention, the present invention provides a method for preparing a 9-, 13-substituted berberine derivative, comprising the following steps:

[0109]

[0110] (S-1), anhydrous acetonitrile, potassium carbonate, and the first raw material were reacted at 60-70°C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was cooled until the solid was completely precipitated, filtered, and the filtrate was mixed with silica gel and purified by flash column chromatography using dichloromethane and methanol as the mobile phase to obtain the yellow intermediate (S-2). The intermediate obtained above was reacted with anhydrous acetonitrile, sodium hydroxide, and the second raw material at 70-90°C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was neutralized with methanolic hydrochloric acid solution, mixed with silica gel, and purified by flash column chromatography using dichloromethane and methanol as the mobile phase to obtain the yellow final product.

[0111] According to a specific embodiment of the present invention, the present invention provides the use of the aforementioned 9, 13-substituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation, prevention and / or treatment of products for chronic atrophic gastritis.

[0112] According to a specific embodiment of the present invention, the present invention provides the use of the aforementioned 9, 13-substituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation, prevention and / or treatment of chronic atrophic gastritis.

[0113] The scheme of the present disclosure will be explained below in conjunction with the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. Where specific techniques or conditions are not specified in the examples, they are carried out according to the techniques or conditions described in the literature in this area or according to the product instructions. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0114] Example 1 Synthesis of 13-allyl-9-(allyloxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-1)

[0115]

[0116] S-1, anhydrous acetonitrile, potassium carbonate, and 3-bromopropene (first raw material) were reacted at 60-70°C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was cooled until the solid was completely precipitated, filtered, and the filtrate was mixed with silica gel and purified by flash column chromatography using dichloromethane and methanol as the mobile phase to obtain a yellow intermediate. The intermediate obtained above was reacted with anhydrous acetonitrile, sodium hydroxide, and 3-bromopropene (second raw material) at 70-90°C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was neutralized with methanolic hydrochloric acid solution, mixed with silica gel, and purified by flash column chromatography using dichloromethane and methanol as the mobile phase to obtain the yellow final product BBR-1. The NMR results of the final product are as follows:

[0117] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.06 (tt, J = 11.2,5.6 Hz, 1H), 6.04 (s, 2H), 5.89 (tt, J = 16.4, 8.1 Hz, 1H), 5.40 – 5.32 (m,2H), 5.17 (ddt, J = 16.4, 2.1, 1.0 Hz, 1H), 5.07 (ddt, J = 16.4, 2.1, 1.0 Hz,1H), 4.69 (dt, J= 5.6, 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 3.90(s, 3H), 3.40 (dt, J = 8.1, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H).

[0118] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.81, 147.54, 147.35, 141.53,137.27, 136.35, 132.43, 130.25, 130.17, 128.45, 122.35, 122.02, 121.02,118.45, 117.90, 116.29, 108.80, 108.41, 101.51, 71.77, 58.15, 56.16, 34.24,27.89.

[0119] ESI + :402.47.

[0120] Example 2 Synthesis of 13-allyl-9-(hex-5-en-1-yloxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-2)

[0121]

[0122] The experimental steps were the same as in Example 1, except that the first raw material was m-6-bromohexene and the second raw material was 3-bromopropene; the NMR results of the final product were as follows:

[0123] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.41 – 7.36(m, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.96 –5.73 (m, 2H), 5.21 – 5.03 (m, 3H), 4.97 (ddt, J= 17.1, 2.1, 1.0 Hz, 1H), 4.64(ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.06 (t, J = 5.5 Hz, 2H), 3.89 (s, 3H), 3.40(dt, J = 8.1, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.06(tdt, J = 7.9, 6.9, 1.1 Hz, 2H), 1.77 (tt, J = 8.1, 5.5 Hz, 2H), 1.58 – 1.48 (m,2H).

[0124] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.89, 148.44, 147.54, 141.72,138.27, 137.27, 136.35, 130.25, 130.17, 128.45, 122.35, 122.04, 121.24,118.39, 116.29, 114.91, 108.80, 108.41, 101.51, 71.86, 58.15, 56.16, 34.24,33.27, 28.87, 27.89, 25.76.

[0125] ESI + :444.22.

[0126] Example 3 Synthesis of 13-((E)-but-2-en-1-yl)-9-((E)-but-2-en-1-yl)oxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-3)

[0127]

[0128] The experimental steps were the same as in Example 1, except that the first raw material was crotonyl bromide and the second raw material was crotonyl bromide; the NMR results of the final product were as follows:

[0129] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d,J = 8.8Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.88 –5.78 (m, 1H), 5.74 – 5.56 (m, 3H), 4.69 (dt, J = 4.3, 1.0 Hz, 2H), 4.64 (ddd, J =7.3, 4.6, 1.7 Hz, 2H), 3.90 (s, 3H), 3.43 (dp, J = 7.0, 1.1 Hz, 2H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 1.67 (ddt, J = 5.4, 1.8, 1.0 Hz, 3H),1.62 (dq, J = 5.3, 1.1 Hz, 3H).

[0130] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.81, 147.54, 141.52, 136.71,130.37, 130.25, 129.74, 128.40, 128.26, 127.61, 126.35, 122.33, 122.02,121.05, 118.45, 108.80, 108.41, 101.51, 71.64, 58.15, 56.16, 33.10, 27.89,17.90, 17.70.

[0131] ESI + :430.52.

[0132] Example 4 Synthesis of (E)-13-(but-2-en-1-yl)-10-methoxy-9-((3-methylbut-2-en-2-yl)oxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-4)

[0133]

[0134] The experimental steps were the same as in Example 1, except that the first raw material was 3,3-dimethylallyl bromide and the second raw material was crotonyl bromide; the NMR results of the final product were as follows:

[0135] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.88 –5.78 (m, 1H), 5.72 – 5.62 (m, 1H), 5.30 (dtq, J = 4.8, 3.2, 1.7 Hz, 1H), 4.67 –4.61 (m, 4H), 3.90 (s, 3H), 3.43 (dp, J = 7.0, 1.1 Hz, 2H), 3.16 (dddd, J = 19.3,7.6, 4.6, 1.0 Hz, 2H), 1.75 (q, J = 1.1 Hz, 6H), 1.64 – 1.59 (m, 3H).

[0136] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.81, 147.72, 147.54, 141.52,136.71, 136.42, 130.37, 130.25, 128.40, 128.26, 127.61, 122.33, 122.02,121.05, 119.36, 118.45, 108.80, 108.41, 101.51, 68.79, 58.15, 56.16, 33.10,27.89, 24.62, 19.90, 17.90.

[0137] ESI + :444.55.

[0138] Example 5 Synthesis of (E)-9-(but-2-en-1-yloxy)-10-methoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-5)

[0139]

[0140] The experimental steps were the same as in Example 1, except that the first raw material was crotonyl bromide and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows:

[0141] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.74 –5.56 (m, 2H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 4.69 (dt, J = 4.2, 1.0Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 3.90 (s, 3H), 3.46 (dp, J = 7.5,1.1 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 1.70 – 1.64 (m, 9H).

[0142] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.81, 147.54, 141.50, 136.77,130.34, 130.25, 129.75, 129.74, 128.30, 126.35, 123.77, 122.33, 122.02,121.02, 118.45, 108.80, 108.41, 101.51, 71.64, 58.15, 56.16, 28.68, 27.89,24.49, 19.28, 17.70.

[0143] ESI + :444.55.

[0144] Example 6 Synthesis of 10-methoxy-13-(3-methylbut-2-en-1-yl)-9-((3-methylbut-2-en-1-yloxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-6)

[0145]

[0146] The experimental steps were the same as in Example 1, except that the first raw material was 3,3-dimethylallyl bromide and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows:

[0147] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 0H), 7.32 (d, J = 8.8 Hz, 0H), 6.04(s, 1H), 5.30 (dtp, J = 8.3, 5.1, 1.6 Hz, 1H), 4.64 (ddt, J = 6.9, 3.1, 1.7 Hz,2H), 3.90 (s, 1H), 3.46 (dp, J = 7.4, 1.1 Hz, 1H), 3.16 (dddd, J = 19.3, 7.6,4.6, 1.0 Hz, 1H), 1.75 (q, J = 1.1 Hz, 3H), 1.68 (q, J = 1.2 Hz, 3H).

[0148] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.81, 147.72, 147.54, 141.50,136.77, 136.42, 130.34, 130.25, 129.75, 128.30, 123.77, 122.33, 122.02,121.02, 119.36, 118.45, 108.80, 108.41, 101.51, 68.79, 58.15, 56.16, 28.68,27.89, 24.62, 24.50, 19.90, 19.28.

[0149] ESI + :458.58.

[0150] Example 7 Synthesis of 10-methoxy-13-(4-methylbenzyl)-9-((4-nitrobenzyl)oxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-7)

[0151]

[0152] The experimental steps were the same as in Example 1, except that the first raw material was p-nitrobenzyl bromide and the second raw material was p-methylbenzyl bromide; the NMR results of the final product were as follows:

[0153] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 0H), 8.14 – 8.08 (m, 1H), 7.61(dt, J = 8.2, 1.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 0H), 7.18 – 7.06 (m, 2H), 6.04(s, 1H), 5.16 (t, J = 1.0 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 1H), 4.19 (t, J = 1.0 Hz, 1H), 3.90 (s, 1H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 1H), 2.33(d, J = 1.1 Hz, 1H).

[0154] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.97, 148.25, 147.54, 147.13,141.49, 140.63, 138.17, 137.14, 136.95, 131.12, 130.81, 129.27, 128.72,128.45, 128.18, 123.76, 123.65, 122.54, 120.58, 118.47, 108.80, 108.18,101.51, 73.04, 57.39, 56.16, 36.00, 27.89, 21.04.

[0155] ESI + :561.2.

[0156] Example 8 Synthesis of 13-(3,5-dimethylbenzyl)-10-methoxy-9-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-8)

[0157]

[0158] The experimental steps were the same as in Example 1, except that the first raw material was 3,3-dimethylallyl bromide and the second raw material was 3,5-dimethylbenzyl bromide. The NMR results of the final product were as follows:

[0159] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.49 (s, 1H), 7.30 (d, J = 8.5Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.89 (dt, J = 2.3, 1.1Hz, 2H), 6.75 (t, J = 2.3 Hz, 1H), 6.04 (s, 2H), 5.30 (ddp, J = 6.5, 3.2, 1.6 Hz,1H), 4.67 – 4.61 (m, 4H), 4.45 (t, J = 1.0 Hz, 2H), 3.90 (s, 3H), 3.16 (dddd, J =19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.26 (s, 6H), 1.75 (q, J = 1.1 Hz, 6H).

[0160] 13C NMR (125 MHz, DMSO-d6) δ 149.57, 148.84, 147.87, 147.54, 141.46,138.42, 137.48, 137.05, 136.42, 131.12, 130.84, 129.90, 128.45, 128.11,123.78, 122.54, 120.25, 119.36, 118.41, 108.80, 108.18, 101.51, 68.79, 57.39,56.16, 36.40, 27.89, 24.62, 21.09, 19.90.

[0161] ESI + :508.64.

[0162] Example 9 Synthesis of 13-(3,5-dimethoxybenzyl)-9-(hex-5-yn-1-yloxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-9)

[0163]

[0164] The experimental steps were the same as in Example 1, except that the first raw material was 6-bromohexyne and the second raw material was 3,5-dimethoxybenzyl bromide; the NMR results of the final product were as follows:

[0165] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 0H), 7.49 (s, 0H), 7.37 (d, J = 8.8Hz, 0H), 7.15 (d, J = 8.8 Hz, 0H), 6.99 (t, J = 1.0 Hz, 0H), 6.46 (dt, J = 2.2, 1.0Hz, 1H), 6.36 (t, J = 2.4 Hz, 1H), 6.04 (s, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz,1H), 4.11 (t, J = 5.0 Hz, 1H), 4.08 (dt, J = 9.5, 1.0 Hz, 1H), 4.00 (dt, J= 9.3,1.0 Hz, 1H), 3.89 (s, 1H), 3.79 (s, 3H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0Hz, 1H), 2.47 (td, J = 5.9, 3.0 Hz, 1H), 1.80 (tt, J = 7.4, 5.0 Hz, 1H), 1.58(tt, J = 7.5, 5.6 Hz, 1H).

[0166] 13 C NMR (125 MHz, DMSO-d6) δ 160.81, 149.57, 148.92, 148.54, 147.54,141.64, 139.48, 137.03, 131.14, 130.64, 128.45, 123.79, 122.55, 120.36,118.35, 108.80, 108.24, 108.18, 101.51, 98.82, 83.76, 71.89, 69.15, 57.39,56.16, 55.33, 36.36, 28.59, 27.89, 25.28, 18.09.

[0167] ESI + :552.65.

[0168] Example 10 Synthesis of 9-(hept-6-en-1-yloxy)-10-methoxy-13-(4-nitrobenzyl)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-10)

[0169]

[0170] The experimental steps were the same as in Example 1, except that the first raw material was 7-bromoheptene and the second raw material was p-nitrobenzyl bromide; the NMR results of the final product were as follows:

[0171] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.21 – 8.15 (m, 2H), 7.55 –7.47 (m, 3H), 7.37 (d, J = 8.8 Hz, 1H), 7.15 (d, J<h2 style=";text-align:left;direction:ltr">= 8.8 Hz, 1H), 6.99 (t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 1.0Hz, 1H), 6.04 (s, 2H), 5.77 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 10.3, 6.8 Hz, 1H), 5.10 (ddt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 10.3, 2.0,1.0 Hz, 1H), 4.98 (ddt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 10.2, 2.1, 1.0 Hz, 1H), 4.64 (ddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.3, 4.6, 1.7Hz, 2H), 4.20 (t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 1.1 Hz, 2H), 4.07 (t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 6.0 Hz, 2H), 3.89(s, 2H), 3.16(dddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.03 (tdt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.0, 6.9, 1.1 Hz, 2H),1.70 (qd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 6.8, 5.9 Hz, 2H), 1.43 (qd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 6.6, 5.6 Hz, 2H), 1.39 – 1.30 (m,2H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0172] <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR (125 MHz,DMSO-d6) δ 149.57, 149.54, 148.92, 148.54, 147.54,143.96, 141.64, 138.86, 137.13, 131.12, 130.87, 128.79, 128.45, 123.81,123.79, 122.54, 120.36, 118.35, 114.60, 108.80, 108.18, 101.51, 72.63, 57.39,56.16, 36.04, 33.67, 29.05, 28.63, 27.89, 25.86.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0173] <h2 style=";text-align:left;direction:ltr"> ESI<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> :553.63.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0174] Example 11 Synthesis of 9-(3-aminopropyloxy)-13-(3-aminopropyl)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-11)

[0175]

[0176] The experimental steps were the same as in Example 1, except that the first raw material was 3-bromopropylamine and the second raw material was 3-bromopropylamine; the NMR results of the final product were as follows:

[0177] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.5Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.93 (pd, J = 5.8, 0.7 Hz, 2H), 2.87 –2.77 (m, 6H), 2.03 (p, J = 5.6 Hz, 2H), 1.87 (tt, J = 8.1, 5.3 Hz, 2H), 1.74 (t, J = 6.3 Hz, 2H).

[0178] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.86, 148.31, 147.55, 141.65, 137.11, 134.45, 132.34, 131.24, 121.92, 121.89, 120.78, 118.39, 109.19,108.80, 101.51, 70.41, 58.81, 56.16, 40.83, 37.04, 29.70, 29.09, 28.76,27.89.

[0179] ESI + :436.53.

[0180] Example 12 Synthesis of 10-methoxy-9-(pent-4-en-1-yloxy)-13-pentyl-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-12)

[0181]

[0182] The experimental steps were the same as in Example 1, except that the first raw material was 5-bromopentene and the second raw material was 5-bromopentane; the NMR results of the final product were as follows:

[0183] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.5Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.01 – 6.97 (m, 1H), 6.04 (s, 2H), 5.74 (tt, J = 10.3, 6.8 Hz, 1H), 5.10 (ddt, J = 10.3, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J = 10.2,2.1, 1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.04 (t, J = 6.8 Hz, 2H), 3.89 (s, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.86 – 2.76 (m, 1H), 2.76 – 2.67 (m, 1H), 2.14 (tdt, J = 8.0, 6.8, 1.2 Hz, 2H), 1.78 (tt, J = 8.4, 6.8Hz, 2H), 1.68 (tt, J = 8.2, 7.3 Hz, 2H), 1.35 (dddd, J= 8.8, 7.4, 6.2, 3.5 Hz, 4H), 0.92 – 0.86 (m, 3H).

[0184] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.86, 148.34, 147.55, 141.65,137.60, 137.36, 134.67, 134.45, 131.22, 121.89, 120.78, 118.39, 115.13,109.19, 108.80, 101.51, 71.51, 58.81, 56.16, 32.42, 30.44, 30.17, 28.68,28.24, 27.89, 23.18, 14.04.

[0185] ESI + :460.59.

[0186] Example 13 Synthesis of 9-(cyanomethoxy)-13-(hept-6-en-1-yl)-10-methoxy-5,6-dihydro-[1,3]dioxacyclo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-13)

[0187]

[0188] The experimental steps were the same as in Example 1, except that the first raw material was bromoacetylene and the second raw material was 7-bromoheptene; the NMR results of the final product were as follows:

[0189] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.77(tt, J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 5.01 – 4.94(m, 1H), 4.95 (s, 3H), 4.63 (ddd, J= 7.6, 4.9, 1.2 Hz, 2H), 3.89 (s, 3H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t, J = 8.5 Hz, 2H), 2.03 (tdt, J =7.8, 6.7, 1.1 Hz, 2H), 1.69 (tt, J = 8.5, 6.8 Hz, 2H), 1.39 – 1.30 (m, 4H).

[0190] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.68, 147.55, 146.68, 141.53,139.08, 137.37, 134.69, 134.45, 131.06, 121.89, 121.84, 120.85, 118.58,115.38, 114.41, 109.19, 108.80, 101.51, 58.81, 57.53, 56.16, 33.79, 30.56,28.72, 28.49, 28.44, 27.89.

[0191] ESI + :457.55.

[0192] Example 14 Synthesis of 9-(allyloxy)-13-(hex-5-en-1-yl)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-14)

[0193]

[0194] The experimental steps were the same as in Example 1, except that the first raw material was 3-bromopropene and the second raw material was 6-bromohexene; the NMR results of the final product were as follows:

[0195] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.25 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J<h2 style=";text-align:left;direction:ltr">= 1.1 Hz, 1H), 6.06 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 11.2, 5.6 Hz, 1H), 6.04 (s, 2H), 5.77 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 10.1, 6.9 Hz, 1H), 5.40 – 5.32 (m,2H), 5.10 (ddt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 10.3, 2.0, 1.0 Hz, 1H), 4.98 (ddt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 10.2, 2.1, 1.0 Hz,1H), 4.69 (dt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 5.6, 1.0 Hz, 2H), 4.63 (ddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.6, 4.9, 1.2 Hz, 2H), 3.90(s, 3H), 3.16(dddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.83 (dt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 16.1, 8.0 Hz,1H), 2.75 (dt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 15.9, 8.0 Hz, 1H), 2.09 – 2.01 (m, 2H), 1.66 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.1, 6.0Hz, 2H), 1.41 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.8, 6.1 Hz, 2H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0196] <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR (125 MHz, DMSO-d6) δ 149.57, 148.78, 147.55, 147.09, 141.47,138.29, 137.37, 134.69, 134.45, 132.43, 131.24, 121.89, 121.87, 120.90,118.47, 117.90, 114.90, 109.19, 108.80, 101.51, 71.77, 58.81, 56.16, 33.39,30.38, 28.12, 27.98, 27.89.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0197] <h2 style=";text-align:left;direction:ltr"> ESI<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> :444.55.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0198] Example 15 Synthesis of 10-methoxy-13-(pent-4-en-1-yl)-9-(pentyloxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-15)

[0199]

[0200] The experimental steps were the same as in Example 1, except that the first raw material was 1-bromopentane and the second raw material was 5-bromopentene; the NMR results of the final product were as follows:

[0201] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.5Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.71(tt, J = 17.2, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J =17.1, 2.1, 1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.07 (t, J = 5.7Hz, 2H), 3.89 (s, 3H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.87 (t, J =9.2 Hz, 2H), 2.14 (tdt, J = 8.0, 6.9, 1.1 Hz, 2H), 1.76 (tt, J = 7.4, 5.7 Hz,2H), 1.65 (tt, J = 9.3, 7.9 Hz, 2H), 1.46 – 1.31 (m, 4H), 0.90 (t, J = 6.8 Hz,3H).

[0202] 13C NMR (125 MHz, DMSO-d6) δ 149.57, 148.86, 148.32, 147.55, 141.65,138.25, 137.10, 134.45, 133.08, 131.24, 121.91, 121.89, 120.78, 118.39,114.91, 109.19, 108.80, 101.51, 71.86, 58.81, 56.16, 33.02, 30.13, 28.87,28.46, 27.89, 27.85, 22.46, 13.97.

[0203] ESI + :460.59.

[0204] Example 16 Synthesis of 0-methoxy-9-((4-methylbenzyl)oxy)-13-(oct-7-yl-1-yl)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-16)

[0205]

[0206] The experimental steps were the same as in Example 1, except that the first raw material was p-methylbenzyl bromide and the second raw material was 8-bromoheptyne; the NMR results of the final product were as follows:

[0207] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.35 – 7.27 (m,3H), 7.15 (dd, J = 8.3, 2.7 Hz, 3H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.16(t, J = 1.0 Hz, 2H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 3.90 (s, 2H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t, J = 8.5 Hz, 2H), 2.34 (d, J = 1.0Hz, 2H), 2.12 (td, J= 5.9, 3.0 Hz, 2H), 2.06 (t, J = 2.9 Hz, 1H), 1.68 (tt, J =8.4, 7.2 Hz, 2H), 1.47 (dq, J = 6.8, 5.8, 5.3 Hz, 2H), 1.44 – 1.34 (m, 4H).

[0208] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.91, 147.55, 146.87, 141.47,138.34, 137.37, 134.68, 134.45, 133.72, 131.24, 129.09, 128.12, 121.89,121.84, 120.81, 118.58, 109.19, 108.80, 101.51, 83.81, 73.04, 69.15, 58.81,56.16, 30.56, 28.81, 28.59, 28.38, 28.04, 27.89, 21.05, 17.91.

[0209] ESI + :534.68.

[0210] Example 17 Synthesis of 13-(hept-6-yn-1-yl)-9-(hept-6-yn-1-yloxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-17)

[0211]

[0212] The experimental steps were the same as in Example 1, except that the first raw material was 7-bromoheptyne and the second raw material was 7-bromoheptyne; the NMR results of the final product were as follows:

[0213] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 0H), 7.32 (d, J = 8.5 Hz, 0H), 6.04(s, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.06 (t, J = 6.1 Hz, 1H), 3.89 (s,1H), 3.16 (dddd,J = 19.3, 7.6, 4.6, 1.0 Hz, 1H), 2.78 (t, J = 8.5 Hz, 1H), 2.11(td, J = 5.9, 3.0 Hz, 2H), 2.06 (t, J = 2.9 Hz, 1H), 1.81 – 1.71 (m, 2H), 1.59 –1.46 (m, 3H), 1.43 – 1.35 (m, 1H).

[0214] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.86, 148.32, 147.55, 141.65,137.36, 134.68, 134.45, 131.22, 121.89, 120.76, 118.39, 109.19, 108.80,101.51, 83.82, 83.79, 72.63, 69.16, 69.15, 58.81, 56.16, 30.59, 29.03, 28.64,28.07, 28.01, 27.89, 27.85, 25.70, 17.92.

[0215] ESI + :510.65.

[0216] Example 18 Synthesis of 9-(hept-6-en-1-yloxy)-13-(hex-5-yn-1-yl)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-18)

[0217]

[0218] The experimental steps were the same as in Example 1, except that the first raw material was 6-bromohexene and the second raw material was 6-bromohexyne; the NMR results of the final product were as follows:

[0219] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.5Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.99 (t, J= 1.0 Hz, 1H), 6.04 (s, 2H), 5.80(tt, J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J =17.1, 2.1, 1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.06 (t, J = 5.5Hz, 2H), 3.89 (s, 3H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.83 (dt, J =15.8, 7.3 Hz, 1H), 2.74 (dt, J = 15.6, 7.3 Hz, 1H), 2.46 (td, J = 5.7, 3.0 Hz,2H), 2.11 – 2.02 (m, 3H), 1.84 – 1.72 (m, 4H), 1.63 – 1.48 (m, 4H).

[0220] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.86, 148.32, 147.55, 141.65, 138.27, 137.36, 134.67, 134.45, 131.22, 121.89, 120.74, 118.39, 114.91,109.19, 108.80, 101.51, 83.79, 71.86, 69.15, 58.81, 56.16, 33.27, 30.57,28.87, 27.89, 27.61, 27.50, 25.76, 18.24.

[0221] ESI + :484.62.

[0222] Example 19 Synthesis of 9-(3-aminopropoxy)-13-(but-3-yn-1-yl)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-19)

[0223]

[0224] The experimental steps were the same as in Example 1, except that the first raw material was 3-bromopropylamine and the second raw material was 4-bromobutyne; the NMR results of the final product were as follows:

[0225] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.5Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.97 – 2.85 (m, 4H), 2.85 – 2.78 (m,4H), 2.47 (t, J = 3.0 Hz, 1H), 2.03 (p, J = 5.6 Hz, 2H).

[0226] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.86, 148.31, 147.55, 141.59,136.37, 134.50, 131.26, 130.54, 122.13, 121.90, 120.86, 118.39, 109.19,108.80, 101.51, 83.35, 70.41, 69.74, 58.81, 56.16, 37.04, 30.41, 28.76,27.89, 18.02.

[0227] ESI + :431.51.

[0228] Example 20 Synthesis of 13-(hex-5-yn-1-yl)-10-methoxy-9-(prop-2-yn-1-yloxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-20)

[0229]

[0230] The experimental steps were the same as in Example 1, except that the first raw material was 3-bromopropyne and the second raw material was 6-bromohexyne; the NMR results of the final product were as follows:

[0231] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 4.85(d, J = 2.9 Hz, 2H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 3.89 (s, 2H), 3.35 (s,0H), 3.35 (d, J = 6.1 Hz, 0H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.83(dt, J = 15.8, 7.3 Hz, 1H), 2.74 (dt, J = 15.6, 7.3 Hz, 1H), 2.46 (td, J = 5.7, 3.0Hz, 2H), 2.06 (t, J = 3.1 Hz, 1H), 1.79 (tt, J = 7.4, 6.1 Hz, 2H), 1.59 (p, J = 5.9Hz, 2H).

[0232] 13C NMR (125 MHz, DMSO-d6) δ 149.57, 148.63, 147.64, 147.55, 141.59,137.37, 134.68, 134.45, 131.16, 121.89, 121.84, 120.77, 118.58, 109.19,108.80, 101.51, 83.79, 78.88, 76.69, 69.15, 61.36, 58.81, 56.16, 30.57,27.89, 27.61, 27.50, 18.24.

[0233] ESI + :440.52.

[0234] Example 21 Synthesis of (E)-9-(but-2-en-1-yloxy)-13-(cyanomethyl)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium (BBR-21)

[0235]

[0236] The experimental steps were the same as in Example 1, except that the first raw material was crotonyl bromide and the second raw material was bromoacetonitrile; the NMR results of the final product were as follows:

[0237] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.73 –5.64 (m, 1H), 5.64 – 5.56 (m, 1H), 4.69 (dt, J = 4.4, 1.1 Hz, 2H), 4.63 (ddd, J =7.3, 4.6, 1.1 Hz, 2H), 4.20 (s, 2H), 3.90 (s, 2H), 3.16 (dddd, J = 17.3, 7.3,4.6, 1.0 Hz, 2H), 1.67 (ddt, J = 5.4, 1.7, 1.0 Hz, 3H).

[0238] 13 C NMR (125 MHz, DMSO-d6) δ 149.57, 148.84, 147.79, 147.51, 141.44,136.11, 130.26, 129.74, 128.89, 127.92, 126.35, 122.75, 121.96, 121.08,118.41, 117.11, 108.80, 108.36, 101.51, 71.64, 58.16, 56.16, 27.89, 18.88,17.70.

[0239] ESI + :415.47.

[0240] Example 22 Berberine derivatives improve chronic atrophic gastritis

[0241] (I) In vitro experiments

[0242] Cells used: human gastric epithelial GES-1;

[0243] Drugs used: ELISA kit, MNNG, 21 small molecule compounds synthesized based on BBR;

[0244] Experimental plan: ELISA was used to screen drugs that were sensitive to N-methyl-N-nitro-nitrosoguanidine (MNNG)-induced human gastric epithelial GES-1 cells.

[0245] (1) MNNG was used to induce GES-1 to establish a precancerous inflammatory cell model;

[0246] (2) GES-1 cells were set as the blank group, and the successfully modeled cells were divided into the control group and the drug-containing group (grouped according to the 21 compounds screened by the previous chemical synthesis, labeled as berberine-1, berberine-2, berberine-3... and so on);

[0247] (3) ELISA was used to determine the changes in IL-1β levels in the supernatant compared to the blank and control groups after adding the same concentrations of 21 compounds. The cells were cultured in DMEM medium containing 10% fetal bovine serum for 24 hours. Statistical analysis was performed to determine the inhibitory rates of the drugs on MNNG-induced inflammation in human gastric epithelial GES-1 cells.

[0248] To investigate the anti-inflammatory, particularly CAG, activity of 21 berberine-based compounds (compounds synthesized in Examples 1-21), this study used MNNG-induced GES-1 cells. Wild-type GES-1 cells served as the blank control group, while MNNG-induced GES-1 cells were treated with the blank, berberine, berberine-1, berberine-2, and so on up to berberine-21. The corresponding drugs were added at the same concentration (20 µmol / L) and cultured under the same conditions for 24 hours. IL-1β levels in the cell supernatants were measured using an ELISA kit for statistical analysis.

[0249] The results are as follows Figure 1 As shown, the effects of BBR and the berberine derivatives of the present invention on the IL-1β content in the supernatant of MNNG-induced GES-1 cells are demonstrated. The results show that compared with the control group BBR, the berberine derivatives of the present invention have a better inhibition rate on inflammatory factors.

[0250] The drug toxicity of 21 compounds was also determined by CCK8 assay. GES-1 cells were treated with berberine and the berberine derivative of the present invention, and cell viability was detected. The results were as follows: Figure 2 , indicating that the berberine derivatives of the present invention have low drug toxicity to cells, just like berberine.

[0251] To verify the anti-inflammatory effect of berberine-5 in vitro, GES-1 cells were induced to produce inflammation using MNNG (70 nmol / mL), and the induced cells were then treated with berberine and the above-mentioned 21 compounds. The experimental results are shown in Table 1. Compared with the control group, the levels of inflammatory factors IL-6 and TNF-α secreted by cells in each group after administration decreased to varying degrees.

[0252] Table 1

[0253]

[0254] (II) In vivo experiments

[0255] Experimental animals: 6-8 week old C57BL / 6 female mice

[0256] Reagent preparation (1) Normal saline, purchased medical 0.9% NaCl aqueous solution;

[0257] (2) MNNG: weigh 50 mg of MNNG and prepare a 50 mg / mL drug solution using 0.9% NaCl aqueous solution;

[0258] (3) Ranitidine: weigh 75 mg and prepare a 75 mg / mL drug solution using 0.9% NaCl aqueous solution;

[0259] (4) CMC: weigh 500 mg of CMC and add it to 50 mL of pure water to prepare a 10 mg / mL drug solution;

[0260] (5) Berberine: weigh 3 g and use 10 mg / mL CMC solution to prepare a 3 mg / mL drug solution;

[0261] (6) Berberine-5, weigh 3 g, use 10 mg / mL CMC solution to prepare a 3 mg / mL drug solution.

[0262] Modeling plan (1) 40 6-8 week old C57BL / 6 mice were purchased and bred in an SPF animal room for one week, and then divided into 4 groups: blank, model, berberine, and berberine-5;

[0263] (2) The control group was given 0.2 ml of 0.9% NaCl aqueous solution by gavage. The blank, model, berberine, and berberine-5 groups were each intraperitoneally injected with 400 μl of 75 mg / mL Ranitidine. Half an hour later, each group was given 0.2 ml of 50 mg / mL MNNG by gavage. The administration was continued daily for 2 weeks.

[0264] (3) One mouse was euthanized from each of the four groups: blank, model, berberine, and berberine-5. The stomach tissue was fixed and pathological examination was performed to analyze whether the CAG model was successfully constructed.

[0265] (4) After the CAG model was successfully constructed, the mice were gavaged with 0.2 ml of a blank 0.9% NaCl solution. The model group was gavaged with 0.2 ml of 10 mg / mL CMC. The berberine group and the berberine-5 group were gavaged with 0.2 ml of a 3 mg / mL berberine solution and 0.2 ml of a 3 mg / mL berberine-5 solution. The administration was continued daily for 4 weeks.

[0266] (5) After the administration, blood was collected from the eyeballs of the mice. The stomach tissue of the mice was collected and the contents were emptied. Half of the stomach tissue was used for Western blotting experiments, and the other half was fixed for pathological examination.

[0267] The surface of the gastric mucosa becomes rough and uneven due to chronic inflammation, which causes cell atrophy, decrease in number, and proliferation of epithelial cells and glands, and sometimes presents a nodular or scaly appearance. Figure 3 The results showed that the gastric mucosa of the mice in the model group showed the same situation as above (the gastric mucosa was not smooth or had exfoliation-like changes, and the intrinsic glands were atrophied), while the berberine and berberine-5 groups, especially the berberine-5 group, turned red and the mucosal shape changed to smooth after drug treatment, and the gastric mucosal state tended to be normal. Among them, the gastric mucosal state of the berberine derivative treatment group was better than that of the berberine treatment group.

[0268] HE staining was performed on the gastric mucosa of mice in the normal group, model group, berberine group and berberine-5 group. Figure 4 , indicating that compared with the control group, the model group can be seen to have a reduced number of glands, a smaller glandular volume, and in some areas, almost no obvious glandular structure can be seen. As the glands atrophy, the gastric mucosa becomes thinner. Under HE staining, the thickness of the mucosal layer is significantly thinner than that of normal gastric mucosa. Chronic atrophic gastritis is usually accompanied by chronic inflammation. In HE staining, infiltration of lymphocytes and plasma cells can be seen in the mucosal layer and submucosal layer. These results indicate that the model was successfully established. The presence of these inflammatory cells is the response of the gastric mucosa to long-term inflammatory stimulation. In some cases of chronic atrophic gastritis, the gastric mucosal epithelium can be seen to be replaced by intestinal epithelial cells. This phenomenon is called intestinal metaplasia. In the berberine and berberine-5 groups, especially the berberine-5 group, after drug treatment, the atrophy of gastric mucosal epithelial cells was alleviated, glandular loss was reduced, the glands tended to be normal, and the infiltration of lymphocytes and plasma cells was alleviated. That is, berberine-5, one of the berberine derivatives of the present invention, has an effect on the treatment of CAG, among which the effect of reducing inflammatory infiltration in the berberine derivative treatment group is better than that in the berberine treatment group.

[0269] IHC tests were performed on the gastric mucosa of mice in the blank group, model group, berberine group and berberine-5 group. The results are shown in Figure 2. Figure 5 , indicating that inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) also increased significantly in the model group. These inflammatory mediators promote inflammatory responses by activating nuclear factor-κB (NF-κB), further exacerbating gastric mucosal damage and atrophy. However, in the berberine and berberine derivative groups, the expression of inflammatory factors such as TNF-α, IL-6, and IL-1β decreased, and the berberine derivative treatment group showed a greater decrease in inflammatory factor expression than the berberine treatment group.

[0270] WB test results are as follows Figure 6 , indicating that the protein expression of inflammatory mediators such as TNF-α, IL-6 and IL-1β in the model group was significantly increased, but in the berberine and berberine-5 groups, the protein expression of TNF-α, IL-6 and IL-1β decreased, among which the protein expression of inflammatory factors in the berberine derivative treatment group decreased more than that in the berberine treatment group.

[0271] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", "some implementation plans" or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0272] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, characterized in that The compound is a compound represented by general formula (I) or a pharmaceutically acceptable salt of the compound represented by general formula (I): R1 is selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10 Alkynyl, through at least one R a Substituted C1-C 10 alkyl; R2 is selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10 Alkynyl, unsubstituted or substituted with at least one R a Substituted C1-C 10 Alkyl; m=1, n=1~5, R3 is substituted by at least one R b substituted phenyl; R a is -NH2; R b Selected from -NO2, halogen, C1 alkoxy, C1 alkyl, Wherein, the compound is not the following structure:

2. The compound according to claim 1, wherein The compound is selected from one of the following structures:

3. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to claim 1 or 2.

4. Use of the compound in the preparation of a medicament for treating chronic atrophic gastritis, The compound is a compound represented by general formula (I) or a pharmaceutically acceptable salt of the compound represented by general formula (I): R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10 Alkynyl, unsubstituted or substituted with at least one R a Substituted C1-C 10 alkyl; m=1, n=1~5, R3 is unsubstituted or substituted with at least one R b substituted phenyl; R a is -NH2; R b Selected from -NO2, halogen, C1 alkoxy, C1 alkyl, And R1 is not a methyl group.

5. The use according to claim 4, characterized in that The compound is selected from one of the following structures:

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