CN-121991158-A - Asiatic acid saponin compound and medical application thereof

Abstract

The invention discloses asiaticoside compounds and medical application thereof, wherein the asiaticoside compounds comprise compounds with a structural formula shown as a formula (I), and pharmaceutically acceptable salts, esters or solvates thereof. The compound of formula (I) of the present invention has anti-inflammatory and anti-ulcer activities, and thus can be used for preparing a medicament for preventing or treating inflammatory diseases or ulcerative diseases.

Inventors

• SUN HONGBIN
• ZHAO DI
• WANG JING
• DAI LIANG
• CHEN YIFAN
• FENG ZHIQI
• XU QINGLONG
• WEN XIAOAN
• YANG XIAOQI

Assignees

• 中国药科大学
• 重庆中国药科大学创新研究院

Dates

Publication Date

20260508

Application Date

20251223

Priority Date

20241107

Claims (9)

1. 1. Asiaticoside compounds represented by the following formula (I) or pharmaceutically acceptable salts, esters or solvates thereof: ; Wherein R 1 is selected from H, beta-D-glucopyranosyl, beta-D-galactopyranosyl, beta-D-xylopyranosyl, alpha-L-arabinopyranosyl, alpha-L-rhamnopyranosyl- (1- > 2) -alpha-L-arabinopyranosyl, alpha-L-rhamnopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl, beta-D-xylopyranosyl- (1- > 2) -alpha-L-arabinopyranosyl, beta-D-xylopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl, beta-D-glucopyranosyl- (1- > 2) -alpha-L-arabinopyranosyl or beta-D-glucopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl; R 2 is selected from H, beta-D-glucopyranosyl, beta-D-galactopyranosyl, beta-D-xylopyranosyl, alpha-L-arabinopyranosyl, alpha-L-rhamnopyranosyl- (1- > 2) -alpha-L-rhamnopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl, beta-D-xylopyranosyl- (1- > 2) -alpha-L-arabinopyranosyl, beta-D-xylopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl, beta-D-glucopyranosyl- (1- > 2) -alpha-L-arabinopyranosyl, beta-D-glucopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl or beta-D-glucopyranosyl- (1- > 3) -alpha-L-arabinopyranosyl; R 1 and R 2 are not simultaneously H.
2. 2. The asiaticoside compound, the pharmaceutically acceptable salt or the ester or the solvate thereof according to claim 1, wherein the compound or the pharmaceutically acceptable salt or the ester or the solvate thereof is selected from any one of the following compounds: 。
3. 3. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, ester or solvate thereof, in the manufacture of a medicament for the prevention or treatment of an inflammatory or ulcerative or neoplastic disease.
4. 4. The use according to claim 3, wherein the inflammatory disease is a metabolic disease, including insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications, nonalcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, hyperuricemia, gout, osteoporosis, stroke, or cerebral infarction.
5. 5. The use according to claim 3, wherein the inflammatory disease is an autoimmune disease, an organ fibrosis disease, a neurodegenerative disease or a disease secondary to infection by a pathogen, including pneumonia, tuberculosis, inflammatory bowel disease, behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloids, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, gangrene-type sepsis, uveitis, idiopathic pulmonary fibrosis, cystic fibrosis, parkinson's disease, alzheimer's disease, α -synucleinopathy, depression, multiple sclerosis, systemic sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, down's syndrome, hartson-Shi Pabing or Huntington's chorea.
6. 6. The method of claim 3, wherein the ulcerative disease is a peptic ulcer, including gastric ulcer, duodenal ulcer, reflux esophagitis, or erosive esophagitis.
7. 7. The method of claim 3, wherein the neoplastic disease comprises bone cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningioma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, fibroneuroma, sarcoma, esophageal carcinoma, gastric carcinoma, pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, renal carcinoma, prostate carcinoma, lymphoma, testicular carcinoma, interstitial cell carcinoma, lung carcinoma, liver carcinoma, skin carcinoma, malignant melanoma or basal cell carcinoma.
8. 8. A pharmaceutical composition for preventing or treating inflammatory or ulcerative diseases, which comprises the compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt or ester or solvent compound thereof as an active ingredient and pharmaceutically acceptable excipients.
9. 9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is preferably a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.

Description

Asiatic acid saponin compound and medical application thereof Technical Field The invention relates to the field of biological medicine, in particular to asiaticoside compounds and medical application thereof. Background Inflammation is a common pathological mechanism of acute and chronic diseases, and can lead to injury of organism tissues, fibrosis and even organ failure to endanger life. In addition, persistent chronic low-grade inflammation can also promote inflammation-cancer transformation, leading to the development of tumors. That is, inflammation is the source of almost all diseases. Traditional anti-inflammatory drugs are mainly steroidal anti-inflammatory drugs (such as dexamethasone, budesonide and the like), non-steroidal anti-inflammatory drugs (such as indomethacin, diclofenac and the like) and immunosuppressants (such as cyclosporine A, hydroxychloroquine and the like), but the above drugs have limited curative effects on inflammatory and autoimmune diseases such as systemic lupus erythematosus and the like, and can cause adverse reactions after long-term administration, for example, the steroidal anti-inflammatory drugs can cause osteoporosis, hyperglycemia, obesity and hypertension, the non-steroidal anti-inflammatory drugs can cause adverse reactions such as gastrointestinal ulcers, bleeding, renal dysfunction and the like, and the immunosuppressants can cause myelosuppression and infection. Emerging therapies for inflammatory and autoimmune diseases include inflammatory cytokine antibodies (e.g., adalimumab, wu Sinu mab, antique You Shan antibody, etc.), cytokine receptor antibodies (e.g., dopen Li Youshan antibody, tolizumab, etc.), and small molecule targeted drugs (Wu Pati ni, clibrol, deuterium-celecoxib, etc.). However, the clinical indications of existing biopharmaceuticals and small molecule targeted drugs for inflammatory and autoimmune diseases are still limited (e.g., limited or even ineffective efficacy for systemic lupus erythematosus), the cost of biopharmaceutical treatment is high and can cause adverse reactions such as infections. Therefore, there is a need in the clinic to develop safer and more effective anti-inflammatory drugs, especially small molecule anti-inflammatory drugs with lower treatment costs. Peptic ulcer (pepticulcer) mainly refers to chronic ulcers occurring in the stomach and duodenum, is a frequently occurring and common disease, seriously affects the life quality of patients, and severe ulcers can lead to upper gastrointestinal bleeding (the death rate of massive hemorrhage is as high as 8% -13.7%). The main causes of peptic ulcer are gastric acid hypersecretion, helicobacter pylori infection, gastric mucosa injury caused by medicines (such as long-term administration of low-dose aspirin), and the like. The most preferred drugs for treating peptic ulcer clinically at present are mainly potassium ion competitive acid blocker (Fu Nuola raw) and proton pump inhibitor (omeprazole and lansoprazole) and the like. However, fu Nuola acid inhibitors such as omeprazole and the like only inhibit gastric acid secretion, but have very limited repairing effect on gastrointestinal mucosa injury, which results in longer treatment course and produces some adverse reactions. For example, a course of treatment such as Vonoprazors fumarate is typically 4-8 weeks, and side effects include diarrhea, constipation, drug hypersensitivity (including anaphylactic shock), drug dermatitis, urticaria, jaundice, polymorphic erythema, and the like. Omeprazole generally has a treatment course of 1 to 2 months, and common adverse reactions are headache, abdominal pain, nausea, diarrhea, constipation and the like, and in addition, the antithrombotic effect (FDA black frame warning) of clopidogrel can be remarkably inhibited by the omeprazole serving as a CYP2C19 inhibitor. As is well known, long-term administration of low dose aspirin (for preventing cardiovascular and cerebrovascular thrombotic events) can cause gastrointestinal ulcers and bleeding, and there is currently a lack of safe and effective gastrointestinal protective drugs that can be administered for long periods of time, neither voronoi nor omeprazole is suitable for long-term use to prevent gastrointestinal damage caused by aspirin due to the safety risks and potential drug-drug interactions of long-term administration. In summary, there is an unmet clinical need for the prevention and treatment of peptic ulcers, and development of novel peptic ulcer drugs is urgently needed. 2 Alpha, 3 beta, 23 alpha-trihydroxy-ursane-12 (13) -ene-28-oic acid (asiatic acid) is an ursane-type pentacyclic triterpene sapogenin, which is mainly present in centella asiatica. Centella asiatica is an internationally recognized herb having an effect of promoting wound healing, and its main active ingredients include asiaticoside, madecassoside, asiatic acid, madecassic acid, etc. Asiaticoside and madecassoside have a wide range of pharmacologica