CN113750088A - Application of heterocyclic compound in preparation of medicine for treating ulcerative colitis - Google Patents
Application of heterocyclic compound in preparation of medicine for treating ulcerative colitis Download PDFInfo
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- CN113750088A CN113750088A CN202111088303.XA CN202111088303A CN113750088A CN 113750088 A CN113750088 A CN 113750088A CN 202111088303 A CN202111088303 A CN 202111088303A CN 113750088 A CN113750088 A CN 113750088A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- 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
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- 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
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- 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]
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Abstract
The invention discloses an application of a heterocyclic compound in preparing a medicine for treating ulcerative colitis. The heterocyclic compound can effectively treat and relieve symptoms of ulcerative colitis such as weight reduction, diarrhea, hematochezia and the like, can inhibit the generation of inflammatory mediators such as TNF-alpha, IL-6 or IL-1 beta and the like, can regulate the composition of intestinal flora and promote the restoration of the flora, and can further protect mucosal barrier and improve DSS-induced colonic injury. Therefore, the heterocyclic compound can be used as an effective therapeutic drug for ulcerative colitis, and can be prepared into various dosage forms or pharmaceutical compositions for treating ulcerative colitis.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of a heterocyclic compound in preparation of a medicine for treating ulcerative colitis.
Background
Ulcerative Colitis (UC) is the main type of Inflammatory Bowel Disease (IBD), one of the refractory diseases in the digestive system, with a high incidence worldwide, especially in the middle and young ages of 30-40 years and with brainworkers as the main group of people. The clinical manifestations of UC include hematochezia, diarrhea, abdominal pain, tenesmus, fever, difficult to cure, and long recurrence and course of disease, which finally results in an increased risk of colorectal cancer, seriously affects the work and life of patients, and reduces the quality of life of patients.
At present, the pathogenesis of UC is not clear, and it is mainly considered that its occurrence and development are caused by various factors and interactions, such as inducible nitric oxide synthase, COX2, apoptosis, cytokines, diet, and the like. The inflammatory immune factors play a key role in the development of ulcerative colitis, and are mainly reflected in infiltration of a large number of inflammatory cells to colon tissues, increase of abnormal IgM and IgG in humoral immunity and imbalance of proinflammatory cytokines and anti-inflammatory cytokines, so that an organism develops towards the direction of proinflammatory action, and further serious pathological manifestations are caused.
The cure of the UC is very difficult, the current main treatment measures for the UC comprise two aspects of drug treatment and surgical treatment, but the existing treatment methods still have a plurality of defects. UC is generally regarded as an incurable chronic disease, and at present, only a few patients who undergo surgery and have a lesion colorectal resection may be cured, but the quality of life after the cure is seriously affected. Therefore, the main goal of clinical treatment is to induce and maintain remission, while preventing the occurrence of adverse consequences such as colorectal resection and carcinogenesis due to ulcerative colitis. The current therapeutic drugs mainly comprise: 5-aminosalicylic acids such as mesalamine, steroid hormones, azathioprine, biologicals (infliximab, vedolizumab, etc.), tacrolimus, and the like. In terms of induced remission, the primary drug for mild UC is mesalazine; for mild ulcerative colitis with moderate and severe UC or no response to mesalazine, glucocorticoid can be adopted for inducing remission treatment; thiopurines are generally used for severe UC and mild to moderate UC that is hormone-unresponsive, as well as anti-TNF- α preparations and tacrolimus, among others.
However, no drug capable of effectively curing the ulcerative colon exists in clinic so far, and the main problems are that treatment fails due to partial patients having no response or no continuous response to the drug, and therefore, the patients need to be treated by colorectal resection, patients with large side effects cannot tolerate the drug, patients with poor compliance have heavy economic burden, and the treatment cannot be maintained. Therefore, there is a need to develop new drugs for treating ulcerative colitis to meet the urgent clinical needs.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides an application of a heterocyclic compound in preparing a medicament for treating ulcerative colitis, wherein the structural formula of the heterocyclic compound is shown as the formula (I):
according to a specific embodiment of the invention, at least the following advantages are achieved: the heterocyclic compound can effectively treat and relieve the symptoms of ulcerative colitis: including weight loss, diarrhea, and hematochezia; can inhibit the production of inflammatory mediators: inflammatory molecules such as TNF-alpha, IL-6 or IL-1 beta are included to relieve inflammatory symptoms and alleviate intestinal symptoms; can regulate the composition of intestinal flora, promote flora recovery, and regulate intestinal health; and to further protect mucosal barriers and repair colon damage; therefore, the heterocyclic compound can be used as an effective therapeutic agent for ulcerative colitis.
In some embodiments of the invention, the treatment of ulcerative colitis comprises alleviating at least one of the symptoms of ulcerative colitis including weight loss, diarrhea, and hematochezia.
In some embodiments of the invention, the heterocyclic compound is capable of inhibiting inflammatory mediators.
In some preferred embodiments of the invention, the inflammatory mediator comprises at least one of TNF- α, IL-6, or IL-1 β.
In some embodiments of the invention, the heterocyclic compound is capable of protecting the colonic mucosal barrier and/or repairing DSS-induced colonic injury.
In some embodiments of the invention, the heterocyclic compound is capable of modulating gut flora composition and/or promoting flora restoration.
In some embodiments of the present invention, the pharmaceutical formulation is a capsule, a tablet, a pill, a granule, an oral liquid, or an injection.
In some embodiments of the invention, the medicament further comprises a pharmaceutically acceptable carrier.
In some preferred embodiments of the present invention, the pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as: diluents, excipients such as water, etc., fillers such as starch, sucrose, etc.; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and bentonite clay; lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol, and the like. Other adjuvants such as sweetener, flavoring agent, etc. can also be added into the composition.
In some embodiments of the invention, the heterocyclic compound is administered in an amount of 10mg to 20mg per kilogram of the individual's body weight.
By "pharmaceutically acceptable carrier" herein is meant a diluent, adjuvant, excipient, or vehicle that is administered with the active ingredient and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, complication, or other problem, commensurate with a reasonable benefit/risk ratio.
In the present invention, the term "treating" includes alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the generation of complications: ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom. As used herein, administration can result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay in onset, slow progression, or decrease in duration of a condition.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is a graph showing the effect of BE-7-131 on the body weight of mice induced with DSS in the examples of the present invention;
FIG. 2 is a graph showing the effect of BE-7-131 on the score of fecal traits in DSS-induced mice in examples of the present invention;
FIG. 3 is a graph showing the effect of BE-7-131 on the mean fecal blood fraction of DSS-induced mice in an example of the present invention;
FIG. 4 is a graph showing the effect of BE-7-131 on DAI values in DSS-induced mice in examples of the present invention;
FIG. 5 is a graph showing the effect of BE-7-131 on the length of the colon of DSS-induced mice in examples of the present invention;
FIG. 6 is a graph showing the staining of HE and AB-PAS on DSS-induced mouse colon by BE-7-131 in the examples of the present invention;
FIG. 7 is a graph showing the effect of BE-7-131 on the histopathological score of DSS-induced mouse colon in an example of the present invention;
FIG. 8 is a graph showing the effect of BE-7-131 on TNF- α, IL-6, and IL-1 β in DSS-induced colon tissue in mice according to an embodiment of the present invention;
FIG. 9 is a schematic diagram showing the effect of BE-7-131 on the structure of DSS-induced intestinal flora in mice according to an embodiment of the present invention;
FIG. 10 is a schematic diagram of the analysis of the diversity of BE-7-131 on DSS-induced intestinal flora alpha in mice in the example of the present invention;
FIG. 11 is a schematic diagram of the analysis of BE-7-131 on DSS-induced intestinal flora PCoA (2D) in mice in the example of the present invention;
FIG. 12 is a schematic diagram of the BE-7-131 in the example of the present invention in analyzing the species difference of DSS-induced intestinal flora in mice.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention. The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available reagents and materials unless otherwise specified.
In the examples below, the heterocyclic compound used is BE-7-131, which has the formula: c16H23N3O2S, the structural formula is as follows:
example (b): research on effect of BE-7-131 on mouse ulcerative colitis
1. Animal grouping and dosing regimens
C57BL/6 mice, male, 6 weeks old, body mass 20 + -2 g, SPF grade, purchased from the center of navy specialty medicine center. After the mice are adaptively raised for 5 days, the mice are randomly divided into 4 groups by SPSS software, wherein each group comprises 10 mice, and the groups comprise a control group, a model group, a BE-7-131 treatment group (500mg/kg) and a positive drug group (600 mg/kg) respectively. Adopting a DSS induction method to establish a ulceration model: except for the control group, mice were free to drink 3% DSS solution for seven consecutive days. Continuously feeding the medicines once a day for nine consecutive days from the first day of model building, feeding 10mg/kg BE-7-131 to a BE-7-131 treatment group by intragastric administration every day, feeding 600mg/kg mesalazine to a positive medicine group by intragastric administration, and feeding equal volume of distilled water to a control group and a model group by intragastric administration.
For the construction of colitis model, Dextran Sulfate Sodium Salt (DSS) colitis (UC) model is most widely used.
2. Experimental methods and data processing
2.1 Disease Activity Index (DAI) score
The body weight, diet and water intake, sticky feces and bloody stool of the mice were observed and recorded every day. And (4) scoring according to DAI scoring standard, wherein the scoring standard of the fecal character score is as follows: the normal is 0 minutes, the normal and loose state is 1 minute, the loose state is 2 minutes, the loose state is 3 minutes, and the loose state is 4 minutes; the scoring criteria for the occult blood degree score were: the index of non-hematochezia is 0 point, 1 point between non-hematochezia and occult blood, 2 points for occult blood positive, 3 points between occult blood and macroscopic hematochezia, 4 points for macroscopic hematochezia, and DAI ═ 3 (body mass loss rate score + stool character score + occult blood degree score).
2.2 Colon Length
On the 9 th day of the experiment, each group of mice was sacrificed by cervical dislocation, the entire colon tissue was isolated, and the length of the colon was measured with a ruler for statistical analysis.
2.3 Colon histopathological Observation and Scoring
The lesion colon tissues of each group of mice are taken and embedded by normal paraffin, sliced and stained by HE and AB-PAS. Referring to the blind scoring of Boirivant and other standard lines, according to the shapes of epithelial cells, the infiltration condition of inflammatory cells and the like, 2 pathologists respectively read the film in a double-blind way, and the results are averaged to score.
2.4 colonic tissue inflammatory factor detection
Taking 200mg of colon tissue, adding 2mL of physiological saline for homogenization, centrifuging at 4000r/min for 10min, taking supernatant, and determining the content of IL-1 beta, IL-6 and TNF-alpha according to the steps of the kit specification.
2.5 fecal sample Collection and processing
The mice are sacrificed on the 9 th day of the experiment, the abdominal cavity is cut open, the complete colon tissue from the anus to the tail end of the cecum is taken out and placed on an ice tray, the colon tissue is longitudinally cut open along the mesentery, the feces particles (2-3 particles) in the colon are taken out and collected in a freezing tube, and the feces particles are immediately placed in liquid nitrogen for storage until the DNA of bacteria in the feces is extracted.
2.6 extraction and sequencing of bacterial DNA in feces
2.6.1 extraction and detection of DNA
Total DNA in the feces was extracted using a DNA extraction kit, DNA concentration and purity were checked using NanoDrop2000, and DNA extraction quality was checked using 1% agarose gel electrophoresis.
2.6.2 PCR amplification and product recovery
The variable region sequences of V3-V4 of 16S rRNA genes of bacteria are taken as targets, 338F-806R with barcode sequences is taken as a primer, PCR amplification is carried out, PCR products are obtained, 2% agarose Gel is used for recovering the PCR products, AxyPrep DNA Gel Extraction Kit (Axygen Biosciences, USA) is used for purification, Tris-HCl elution is carried out, and 2% agarose electrophoresis is used for detection.
2.6.3 quantitation of fluorescence
Referring to the preliminary quantitative results of electrophoresis, quantitative detection was performed using QuantiFluorTM-ST (Promega, USA). And then mixing according to the corresponding proportion according to the sequencing quantity requirement of each sample.
2.6.4 sequencing analysis
Samples were sequenced on the Illumina NovaSeq platform according to the manufacturer's recommendations, supplied by LC-Bio. The paired end sequences were assigned to the samples according to their unique barcodes, and the barcode and primer sequences introduced by the pooling were removed. And using FLASH to merge the reading of the matching end. The raw read data is quality filtered under specific filtering conditions to obtain a high quality clean label according to fqtrm (v 0.94). The chimeric sequence was filtered using Vsearch software (v2.3.4). Demodulation is performed using DADA2 to obtain a feature table and a feature sequence. Diversity and diversity were calculated by normalizing to the same random sequence. The feature abundances are then normalized by the relative abundance of each sample according to the SILVA (release132) classifier. Alpha diversity is used to analyze the complexity of sample species diversity by 5 indices including Chao1, observedspeces, Goodscoverage, Shannon, Simpson (these indices are calculated by qime 2). Beta diversity was calculated by QIIME2, plotted in R-package. Sequence alignment was performed using Blast, and each representative sequence was annotated with the SILVA database for the signature sequences. Results were plotted and sequence analysis was performed by using the R package (v3.5.2).
2.7 statistical processing of data
Data analysis was performed using the SPSS 22.0 statistical software package, with continuity data for normal distribution, multiple sample means comparisons and uniform variance analysis using ANOVA.
3. Results and discussion
3.1 mouse general Condition and disease Activity index changes
The body quality, food intake and water intake of each group of mice were recorded and analyzed. As a result, as shown in FIG. 1, the change of body weight per day was recorded in each of the control group, model group, positive control group and BE-7-131 treatment group, and the abscissa in the figure represents the number of days and the ordinate represents the weight change (%)). The food intake and water intake of the control group mice are normal, and the physique and the quality are in an ascending trend; after the model group mice started to model, the food intake and the water intake were both reduced, and the body weight tended to decrease from the 4 th day of model making, and was statistically significant compared with the control group. The mice in the BE-7-131 treatment group also have reduced body mass, but have obvious difference compared with the model group from the 6 th day, and the effect is equivalent to that of the positive medicine group.
3.2 stool consistency and hematochezia
The results of stool consistency and hematochezia are shown in fig. 2-4, wherein fig. 2 shows the stool character scores of different groups of mice, fig. 3 shows the average stool blood score (mean stool blood score) on the right of different groups of mice, and fig. 4 shows the DAI values of different groups of mice. The defecation times of the model group mice are increased after the third day, and the situations of soft stools, water-sample stools and the like occur; the occult blood and bloody stool appear after the fourth day; after the fifth day, the conditions of water sampling excrement and bloody excrement are aggravated, and the excrement discharging is difficult. After the positive medicine group and the BE-7-131 treatment group are subjected to dry prognosis, the activity of the mice is increased, the hair condition is improved, and on the 8 th day, compared with the model group, the stool consistency and the hematochezia condition are improved after the BE-7-131 intervention is performed.
3.3 general Colon and pathological observations
The entire colon tissue was isolated and the length of the colon was measured with a ruler for each group of mice and analyzed for relevant statistics. The results are shown in fig. 5, the colon length of the control group mouse is the longest, the colon length of the model group mouse is the shortest, and the difference between the positive medicine group and the BE-7-131 treatment group is significant (P is less than 0.001) compared with the control group in the model group; the colon length of the BE-7-131 treatment group was significantly longer than that of the model group.
The colon lesion tissues were HE stained and AB-PAS stained and histopathologically scored. . The staining results are shown in fig. 6, the arrangement of the intestinal glands in the mucosal layer of the control mice is tight, the shape of the epithelial cells of the intestinal glands is normal, and the structure is normal without defects; the colon of the mouse in the model group can be seen to lose intestinal glands and epithelial cells, and has obvious defect, and is accompanied with a large amount of inflammatory cell infiltration, and inflammation invades submucosa and muscularis; after the intervention administration of the positive medicine group and the BE-7-131 treatment group, the infiltration of inflammatory cells is reduced, and the integrity of epithelial cells of intestinal mucosa is improved. Pathological tissue score results figure 7 shows that the lesion score in the model group was significantly higher (P < 0.001) compared to the control group. Compared with the model group, the pathological score of the mice in the BE-7-131 treatment group is obviously reduced (P is less than 0.01). The result shows that BE-7-131 can improve the DSS-induced colon inflammation of mice and has the effect of reducing the lesion of local colon lesions of ulcerated and knotted mice.
3.4 colonic tissue inflammatory factor assay results
The colon tissues of each group of mice are tested for the levels of inflammatory factors IL-1 beta, IL-6 and TNF-alpha. The results are shown in FIG. 8, where the colon tissue of the control mice had the lowest IL-1 β, IL-6, TNF- α levels; the levels of IL-1 beta, IL-6 and TNF-alpha in colon tissues of the model group are the highest and are obviously increased compared with the control group (P is less than 0.001); the levels of IL-1 beta, IL-6 and TNF-alpha in colon tissues of the positive drug group and the BE-7-131 treatment group are also obviously reduced compared with the model group (P is less than 0.001). The result shows that BE-7-131 can inhibit the expression of IL-1 beta, IL-6 and TNF-alpha in local colon tissues of mice with ulcerative colitis.
3.5 colonic intestinal flora species Annotation
Based on the absolute abundance of OUT and the annotation information, the ratio of the number of sequences in each sample at the phylum level and the genus level to the total number of sequences was statistically analyzed, and the species composition differences of each group at the phylum level and the genus level were determined. FIG. 9 shows a structural diagram of the intestinal flora of different groups of mice. In the control group, the flora profile reflects the composition of normal mouse intestinal flora, with bacteroides (79.26%), Firmicutes (16.40%), Proteobacteria (1.01%), epsilon bacteraeota (0.63%) being the 4 major phyla of bacteria. Murebacteriaceae _ unclassified, Alloprovella, Mureballum, Alisiples are the constituents at the level of the main genus of the control group. In the model group, the flora profile reflects the composition of the mouse intestinal flora in case of disease, with Firmicutes (60.23%), epsilon bacteraeota (15.55%), bacteriodes (13.91%), Proteobacteria (8.44%) being the 4 major phyla of bacteria. The Firmicutes, Epsilonbacterota and Proteobacteria ratios were increased and the bacterioides ratios were decreased compared to the control group. In the BE-7-131 treatment group, Bacteroides (56.64%), Firmictites (36.23%), Proteobacteria (2.28%) and EpsilonBacaeota (2.18%) are 4 major phyla of bacteria, wherein the proportion of the Bacteroides and Firmictites is similar to that of the blank control group, and the Patescibacteria appears in the main bacteria for the first time, which suggests that the bacteria may participate in the action of the BE-7-131 treatment group in alleviating ulcerative colitis.
3.6 colonic intestinal flora species diversity analysis
Species abundance and diversity of microbial communities can be reflected by diversity analysis (alpha analysis) of individual samples, we use two indexes for evaluation, Chao1 reflects species abundance in samples, regardless of the proportion (uniformity) of each species; simpson reflects the abundance and uniformity of species, and the results are shown in FIG. 10. It was found that the intervention of the BE-7-131 treatment group did not improve the species abundance and diversity of the microflora in the intestinal flora. The beta diversity is an index for measuring the similarity of the flora composition between different samples, and the species distance between the samples can be reflected by weighted PCoA analysis, and the analysis result is shown in FIG. 11. The model group was farther apart than the control group, and the positive drug group and the BE-7-131 treatment group were closer to the control group than the model group. Therefore, after the treatment of the BE-7-131 treatment group, the content of the intestinal flora is changed and is more similar to the structure of the normal intestinal flora.
3.7 colonic intestinal flora species differential analysis
The difference in gut flora abundance at the class level of each species caused by 3% DSS induction treatment was further compared using LeFSe analysis. LeFSe analysis is the combination of non-parametric test and linear discriminant analysis, is suitable for the flora abundance difference test, and determines the differential microorganisms in each group by taking LDA more than 4 and P less than 0.5 as the screening standard. The experimental result shows that p _ bacteroides, f _ muribacteriaceae and g _ Alloprevotella are the main significant difference bacteria of the control group; f _ helicobacter, p _ epsilon bactereota, c _ campylobacter and f _ Ruminococcaceae are main differential bacteria of the model group; f _ Prevotelleceae, g _ Alloprovella _ unclassified and g _ Akkermansia are the main differential bacteria of the BE-7-131 treatment group. As shown in FIG. 12, the results of the experiment show that, after BE-7-131 administration, the proportion of bacteriodes is increased remarkably, the proportion of Firmicutes and Proteobacteria is reduced remarkably, and the proportion of probiotics such as bacteriodes and Alloprovella is increased, so that the change of flora structure and components can play a role in the development of ulcerative colitis.
The effect of the invention is evaluated by establishing a DSS-induced acute mouse colitis model. The animal model is commonly used for researching the pathological mechanism of the ulcerative colitis and evaluating the curative effect of the medicine. We tested mice general physical and qualitative characteristics, DAI score, colon length, colon histopathological score by DSS-induced colitis mouse model. The experimental results show that the heterocyclic compound can effectively treat and relieve the symptoms of ulcerative colitis: including weight loss, diarrhea, and hematochezia; can inhibit the production of inflammatory mediators: inflammatory molecules such as TNF-alpha, IL-6 or IL-1 beta are included to relieve inflammatory symptoms; can regulate the composition of intestinal flora, promote flora recovery, and regulate intestinal health; and can further protect mucosal barriers and repair colonic lesions. Therefore, the heterocyclic compound can be used as an effective therapeutic drug for ulcerative colitis, and can be prepared into various dosage forms or pharmaceutical compositions for treating ulcerative colitis.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (8)
1. The application of a heterocyclic compound in preparing a medicament for treating ulcerative colitis is characterized in that the structural formula of the heterocyclic compound is shown as the formula (I):
2. the use of claim 1, wherein the treatment of ulcerative colitis comprises alleviating symptoms of ulcerative colitis including at least one of weight loss, diarrhea, and hematochezia.
3. Use according to claim 1, characterized in that the heterocyclic compound is capable of inhibiting inflammatory mediators.
4. The use of claim 3, wherein the inflammatory mediator comprises at least one of TNF-a, IL-6 or IL-1 β.
5. The use according to claim 1, wherein the heterocyclic compound is capable of protecting the colonic mucosal barrier and/or repairing DSS-induced colonic damage.
6. Use according to claim 1, wherein the heterocyclic compound is capable of modulating the gut flora composition and/or promoting flora restoration.
7. The use of claim 1, wherein the medicament is in the form of capsules, tablets, pills, granules, oral liquid or injections.
8. The use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier.
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