Application of a compound containing a monoheterocyclic structure in the preparation of drugs for the prevention or treatment of gastric ulcers

Abstract

This invention discloses the application of compounds containing monoheterocyclic structures in the preparation of drugs for the prevention or treatment of gastric ulcers, relating to the field of medicinal chemistry. This invention discovers that compounds D349-3374, S454-0163, and 4593-3993, containing monoheterocyclic structures, exhibit excellent inhibitory effects on gastric ulcers, achieving an ulcer inhibition rate of 46.34% in animal models of gastric ulcers. These compounds can be used to prepare drugs for the prevention or treatment of gastric ulcers, showing broad application prospects. This invention opens up a new application area for compounds D349-3374, S454-0163, and 4593-3993, demonstrating good development and pharmaceutical prospects, and also providing new ideas for the development of drugs for the treatment of gastric ulcers.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to the use of a compound containing a monoheterocyclic structure in the preparation of a drug for the prevention or treatment of gastric ulcers. Background Technology

[0002] With the fast pace of modern life and increased mental stress and work pressure, the incidence of gastric ulcers is on the rise, harming people's physical and mental health. Gastric ulcers refer to damage to the gastric mucosa caused by acidic digestion, commonly occurring in the gastric angle, antrum, and cardia, and are a type of peptic ulcer. Gastric ulcers are a common disease of the digestive system, prone to recurrence. Symptoms are mostly chronic, periodic, and rhythmic upper abdominal pain, which can be dull, distending, burning, or severe, as well as typical dyspeptic symptoms such as belching, acid reflux, bloating, nausea, fullness, vomiting, and heartburn. In severe cases, complications such as bleeding, perforation, or gastric outlet obstruction can occur. Helicobacter pylori infection, the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and abnormal gastric acid secretion are common factors that induce gastric ulcers. Drugs, stress, hormones, and psychological factors, as well as long-term unhealthy lifestyle habits, can all induce gastric ulcers.

[0003] Currently, there are many types of drugs used to treat gastric ulcers, including proton pump inhibitors such as omeprazole and lansoprazole, which can effectively inhibit gastric acid secretion; H2 receptor antagonists such as famotidine and ranitidine, which reduce gastric acid secretion by blocking histamine receptors; gastric mucosal protectants such as bismuth potassium citrate and sucralfate, which can form a protective film on the ulcer surface and promote mucosal repair; and antibacterial drugs such as amoxicillin-clavulanate potassium and clarithromycin. Although these drugs show strong and effective anti-ulcer capabilities, long-term use has adverse effects on organs such as the liver and kidneys, which is not conducive to long-term remission treatment. Therefore, it is still necessary to further develop new drugs with therapeutic effects on gastric ulcers to fill the gaps in existing treatments and improve patients' treatment outcomes and quality of life. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide the application of a compound containing a monoheterocyclic structure in the preparation of a medicament for the prevention or treatment of gastric ulcers.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: the use of compounds containing monoheterocyclic structures as shown in formula (I), (II) or (III) or their pharmaceutically acceptable salts in the preparation of medicaments for the prevention or treatment of gastric ulcers. (I) (II) (III).

[0006] Proton pump inhibitors (PPIs) act on H + -K + -ATPases inhibit basal and induced gastric acid secretion. These drugs have a rapid onset of action, a strong and long-lasting acid-suppressing effect, and good safety and tolerability, making them the first-line drugs for the clinical treatment and prevention of acid-related diseases. Proton pump inhibitors (PPIs) work by specifically and irreversibly inhibiting H2O2 secretion from the secretory membrane of gastric parietal cells. + -K + -ATPase (i.e., "proton pump"), thereby blocking gastric acid secretion. Through extensive compound screening and experimental verification, the inventors of this application discovered that the compounds containing monoheterocyclic structures shown in formulas (I), (II), or (III) above have proton pump inhibitory effects and have a significant inhibitory effect on gastric ulcers.

[0007] As a preferred embodiment of the application described in this invention, the gastric ulcer includes gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis caused by NSAIDs, erosive gastritis, and stress-induced gastric mucosal damage.

[0008] As a preferred embodiment of the application described in this invention, the drug treats gastric ulcers by reducing ulcer foci, alleviating bleeding, and reducing mucosal edema.

[0009] As a preferred embodiment of the application described in this invention, the CAS number of the compound shown in formula (I) is 931338-00-0; the CAS number of the compound shown in formula (II) is 1775457-48-1; and the CAS number of the compound shown in formula (III) is 442564-55-8.

[0010] As a preferred embodiment of the application described in this invention, the pharmaceutically acceptable salts include: hydrochloride, sulfate, bisulfate, and phosphate.

[0011] The present invention also provides a pharmaceutical composition for treating gastric ulcers, comprising an effective therapeutic amount of a compound containing a monoheterocyclic structure as shown in formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical carrier.

[0012] The beneficial effects of this invention are as follows: This invention provides the application of compounds containing monoheterocyclic structures in the preparation of drugs for the prevention or treatment of gastric ulcers. This invention discovers that compounds D349-3374, S454-0163, and 4593-3993 containing monoheterocyclic structures exhibit excellent inhibitory effects on gastric ulcers, with an ulcer inhibition rate of 46.34% in animal models of gastric ulcers. These compounds can be used to prepare drugs for the prevention or treatment of gastric ulcers, showing broad application prospects. This invention opens up a new application field for compounds D349-3374, S454-0163, and 4593-3993, possessing good development and pharmaceutical prospects, and also provides new ideas for the development of drugs for the treatment of gastric ulcers. Attached Figure Description

[0013] Figure 1 The images show the anatomical dissections of the stomachs of mice in the control group, model group, and compound D349-3374 group after administration of compound D349-3374 in Example 1.

[0014] Figure 2 The chart shows the gastric ulcer scores of the control group, model group, and compound D349-3374 group after administration of compound D349-3374 in Example 1.

[0015] Figure 3 The images show the anatomical dissections of the stomachs of mice in the control group, model group, and compound S454-0163 group after administration of compound S454-0163 in Example 2.

[0016] Figure 4 The chart shows the gastric ulcer scores of the control group, model group, and compound S454-0163 group after administration of compound S454-0163 in Example 2.

[0017] Figure 5 The images show the anatomical dissections of the stomachs of mice in the control group, model group, and compound 4593-3993 group after administration of compound 4593-3993 in Example 3.

[0018] Figure 6 The chart shows the gastric ulcer scores of the control group, model group, and compound 4593-3993 group after administration of compound 4593-3993 in Example 3. Detailed Implementation

[0019] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Unless otherwise specified, the various raw materials, reaction equipment, testing equipment, and testing methods used in the following embodiments are all known in the art.

[0020] In this invention, the following experimental methods were used to establish an animal model of gastric ulcer and to evaluate the efficacy of compounds D349-3374, S454-0163, and 4593-3993: 1. Experimental materials: 48 eight-week-old C57 BL / 6J mice weighing 23-25 ​​g (purchased from Beijing Huafukang); compounds D349-3374, S454-0163, 4593-3993, indomethacin, and sodium carboxymethyl cellulose (CMC-Na) were all commercially available; the CAS numbers and structures of compounds D349-3374, S454-0163, and 4593-3993 are shown in Table 1.

[0021] Table 1 2. Experimental steps: (1) Grouping: 18 C57 BL / 6J mice were randomly divided into 3 groups: control group (n=6), model group (n=6), and compound group (n=6). The mice were fasted for 48 h before the experiment and were only allowed to drink water. (2) Administration: The control group was given 1% CMC-Na solution orally, the model group was given indomethacin 40 mg / kg orally, and the compound group was given compound 20 mg / kg orally first, followed by indomethacin 40 mg / kg orally 30 min later. Samples were collected 12 h later.

[0022] (3) Sample collection: After anesthetizing the mice, 0.5 ml of blood was collected through the orbital vein. After standing at room temperature for 10-20 min, the sample was centrifuged at 4000 rpm for 10 min, and the supernatant was collected and stored at -80℃. The intra-abdominal field of view was exposed, and the stomach was cut short at the junction of the cardia and the lower esophagus and the pylorus and the upper duodenum, respectively, and placed in pre-cooled physiological saline. Starting from the cardia, the stomach wall was carefully cut along the greater curvature of the stomach with tissue scissors until it was cut through the pylorus, so that the stomach was in a single-layer sheet. The stomach wall at the edge of the cardia was gently grasped with tissue forceps and repeatedly rinsed back and forth in clean pre-cooled physiological saline for 3-5 times to wash away the stomach contents attached to the stomach wall. The cleaned stomach was laid flat on a sterile drape with the inner wall facing up, the animal number was marked, and a high-definition camera was used to take pictures. Then the gastric mucosa was observed for congestion, edema, erosion, bleeding, etc. and scored.

[0023] (4) Scoring: Examination: Observe the gastric mucosa for congestion, edema, erosion, bleeding, etc., and score: Punctate ulcer: light yellow dots are superficial ulcers, 1 point for each dot; black dots are deep ulcers, 2 points for each dot; Strip-shaped ulcer: 1 point for a yellow stripe of 1 mm, 2 points for a black stripe of 1 mm; Massive ulcer: 1 point for a yellow mass of 1 mm 2 1 point awarded for a 1mm black block. 22 points are awarded for each ulcer perforation (score calculated as S = major axis / 2 × minor axis / 2 × π); 3 points are awarded for each perforation. Each animal is scored according to the above method, and the total ulcer score is calculated. The ulcer inhibition rate of the treatment group can be further calculated based on the ulcer score. Ulcer inhibition rate = (Ulcer score of model group - Ulcer score of treatment group) / Ulcer score of model group.

[0024] Example 1: Pharmacological evaluation of compound D349-3374 This embodiment uses the above method to construct an animal model of gastric ulcer and evaluates the therapeutic effect of compound D349-3374 on gastric ulcer. Experimental results are as follows: Figure 1-2 As shown in Table 2, compared with the model group, the severity of black spot and block ulcers in the compound D349-3374 group was significantly reduced. The scoring results showed that the ulcer inhibition rate of the administered compound D349-3374 reached 46.34%, indicating that compound D349-3374 has the effect of relieving gastric ulcer symptoms and treating gastric ulcers.

[0025] Table 2. Gastric ulcer score in mice after administration of compound D349-3374. Example 2: Pharmacological evaluation of compound S454-0163 This embodiment uses the above method to construct an animal model of gastric ulcer and evaluates the therapeutic effect of compound S454-0163 on gastric ulcer. Experimental results are as follows: Figure 3-4 As shown in Table 3, compared with the model group, the treatment group of compound S454-0163 showed a significant reduction in the severity of black spot and block ulcers. The scoring results showed that the ulcer inhibition rate of compound S454-0163 reached 31.25%, indicating that compound S454-0163 has the effect of alleviating gastric ulcer symptoms and treating gastric ulcers.

[0026] Table 3. Gastric ulcer scoring in mice after administration of compound S454-0163. Example 3: Pharmacological evaluation of compounds 4593-3993 This embodiment uses the above method to construct an animal model of gastric ulcer and evaluates the therapeutic effect of compound 4593-3993 on gastric ulcer. Experimental results are as follows: Figure 5-6 As shown in Table 4, compared with the model group, the severity of yellow spot and block ulcers in the compound 4593-3993 group was significantly reduced, and there was a significant statistical difference. The scoring results showed that the ulcer inhibition rate of compound 4593-3993 was 44.44%, indicating that compound 4593-3993 has the effect of relieving gastric ulcer symptoms and treating gastric ulcers.

[0027] Table 4. Gastric ulcer scoring in mice after administration of compound 4593-3993. Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. The use of compounds containing a monoheterocyclic structure as shown in formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention or treatment of gastric ulcers. (I) (II) (III).

2. The application according to claim 1, characterized in that, The gastric ulcers include gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis caused by NSAIDs, erosive gastritis, and stress-induced gastric mucosal damage.

3. The application according to claim 1, characterized in that, The drug treats gastric ulcers by reducing ulcer foci, alleviating bleeding, and reducing mucosal edema.

4. The application according to claim 1, characterized in that, The CAS number of the compound represented by formula (I) is 931338-00-0; the CAS number of the compound represented by formula (II) is 1775457-48-1; and the CAS number of the compound represented by formula (III) is 442564-55-8.

5. The application according to claim 1, characterized in that, Pharmaceutically acceptable salts include: hydrochloride, sulfate, bisulfate, and phosphate.

6. A pharmaceutical composition for treating gastric ulcers, characterized in that, This includes effective therapeutic amounts of compounds containing a monoheterocyclic structure as shown in formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable pharmaceutical carriers.

7. The pharmaceutical composition according to claim 6, characterized in that, The dosage forms of the pharmaceutical composition include tablets, capsules, granules, and oral liquids.

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