Use of tetrahydronaphthyridine derivatives in the preparation of drugs for preventing and treating adhesion-related diseases

Abstract

The present invention provides the use of a tetrahydronaphthyridine derivative in the preparation of a drug for preventing and treating gastrointestinal tract injury-related diseases or a drug for inhibiting gastrointestinal protein kinases. The said compound has a good effect of preventing and treating gastrointestinal tract injury-related diseases.

Description

Technical Field

[0001] This invention claims the priority of the prior applications, which were filed with the China National Intellectual Property Administration on May 30, 2022, with the patent application number 202210596510.4 and the invention title "Use of Tetrahydronaphthyridine Derivatives in the Preparation of Drugs for Preventing and Treating Adhesion-Related Diseases", and on October 20, 2022, with the patent application number 202211286168.4 and the invention title "Use of Tetrahydronaphthyridine Derivatives in the Preparation of Drugs for Preventing and Treating Adhesion-Related Diseases". All the contents of the prior applications are incorporated herein by reference.

[0002] This invention relates to the field of medicine, and specifically to the use of tetrahydronaphthyridine derivatives in the preparation of drugs for preventing and treating adhesion-related diseases.

Background Art

[0003] Adhesions are the result of tissue damage, and the causes include sharp instruments, mechanical or thermal injury, infection, radiation, ischemia, dryness, abrasion, foreign body reaction, tumors, etc. Whatever the inducing factor, adhesions are formed by the interaction of three interconnected processes in the body, namely, the fibrinolytic system, extracellular matrix deposition and remodeling, and the inflammatory system. When the gastrointestinal tract is damaged biologically, physically or chemically, an acute inflammatory reaction appears. Tissue ischemia, tissue factors and cytokines, increased vascular permeability, release of inflammatory factors, etc. cause intestinal adhesions and intra-abdominal adhesions. At the same time, a large amount of exudate containing fibrinogen and fibrin deposits, coagulates to form a fibrous network, concentrates on the surface of the stimulated tissue organs, and can adhere to the surrounding tissues. Under normal circumstances, peritoneal mesothelial cell exudate not only releases fibrinogen but also has fibrinolytic activity, dissolving and absorbing the cellulose network and reducing adhesion formation. The balance between fibrin deposition and degradation plays an important role in normal repair and healing or adhesion formation, and the important factors causing the imbalance of these two balances are the degree of local damage and inflammatory reaction.

[0004] Postoperative adhesions (e.g., intestinal adhesions or peritoneal adhesions) can cause infertility, pain, or ileus, and may increase the difficulty of subsequent abdominal or pelvic surgeries. All surgeons should be familiar with the risks and consequences of postoperative adhesions and adopt measures to minimize their occurrence. Theoretically, adhesion formation can be reduced by decreasing peritoneal injury during surgery, preventing the introduction of reactive foreign bodies, reducing the local inflammatory response, inhibiting the coagulation cascade reaction, promoting fibrinolysis, or providing a barrier between damaged tissues. However, studies have shown that no matter which surgical method is chosen, surgeries such as myomectomy usually result in adhesions. The adhesion incidence after open myomectomy was greater than 90%, but the adhesion incidence was at least 70% even after laparoscopic myomectomy. Using an adhesion prevention bioabsorbable membrane to physically isolate the surgical site from the nearby peritoneum or adjacent organs to prevent mutual adhesions is considered one of the feasible methods. The FDA has approved various adhesion prevention membrane products such as the membrane (Seprafilm) composed of hyaluronic acid and carboxymethyl cellulose. According to clinical studies, patients in the test group where an absorbable medical membrane was placed at sites such as the wound surface after abdominal surgery had significantly shorter recovery times of bowel sounds and exhaust times after surgery compared to patients in the control group who did not undergo intervention after surgery. The symptoms of each item after surgery were superior to those of patients in the control group and had good biocompatibility and safety. This bioabsorbable membrane can well prevent postoperative adhesions, reduce the risk of secondary surgery, and can clearly improve compliance. However, the action site of the bioabsorbable membrane is limited to the indwelling site. Surgeons need to determine the sites where adhesions may occur, and the adhesion occurrence location may be slightly away from the surgical site. At the same time, since the indwelling operation of the adhesion prevention membrane is difficult, it is difficult to be used in laparoscopic surgery.

[0005] There are many studies evaluating the effectiveness of drugs for adhesion prevention, including recombinant tPA, streptokinase, heparin, low molecular weight heparin, non-steroidal anti-inflammatory drugs, gonadotropin-releasing hormone agonists, phosphatidylcholine, vitamin E antioxidant molecules, and corticosteroids. These agents were initially developed for the treatment of diseases other than postoperative adhesions. The mechanism of adhesion prevention is not clear, and their effects need to be further verified. Recent studies have shown that intestinal trauma (incision, surgical manipulation, and hypoperfusion) leads to disruption of the intestinal mucosal barrier, followed by the introduction of digestive proteases into the intestinal tissue and visceral cavity. These proteases cause proteolytic damage to the mesothelial surface of the viscera and trigger adhesion formation during the healing of damaged tissues as part of the body's repair process. The inventors have found in long-term studies that certain tetrahydronaphthyridine derivatives, as broad-spectrum serine protease inhibitors, can neutralize the activity of digestive proteases excessively released due to intestinal mucosal barrier damage during surgery, thereby reducing damage to gastrointestinal tissues, accelerating the recovery of gastrointestinal function, and thus achieving the goal of preventing postoperative intestinal adhesions.

Summary of the Invention

[0006] One object of the present invention is to provide the use of tetrahydronaphthyridine derivatives in the preparation of drugs for preventing and treating gastrointestinal damage-related diseases.

[0007] In a specific embodiment, the tetrahydronaphthyridine derivative is selected from 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, 5,6,7,8-tetrahydro-1,6-naphthyridine-2-phosphonic acid, and hydrates of said compounds, or pharmaceutically acceptable salts, or prodrugs, or mixtures.

[0008] In a specific embodiment, the pharmaceutically acceptable salt is the hydrochloride salt of the tetrahydronaphthyridine derivative.

[0009] In a specific embodiment, the gastrointestinal tract injury-related disease refers to adhesion, particularly various adhesions caused by postoperative abdominal gastrointestinal tract injury, infection, etc., such as postoperative intestinal adhesion, abdominal adhesion, intercostal adhesion, peritoneal adhesion, uterine adhesion, etc.

[0010] In a specific embodiment, the gastrointestinal tract injury-related disease further includes one or more of the complications caused by postoperative adhesion, such as female infertility, postoperative ileus, and pain.

[0011] The present invention further provides the use of a tetrahydronaphthyridine derivative in the preparation of a drug for inhibiting gastrointestinal protein kinase.

[0012] In a specific embodiment, the gastrointestinal protein kinase is at least one selected from Trypsin, MMP9, and TACE.

[0013] In the present invention, "prevention and treatment" refers to "prevention" and / or "treatment", where "prevention" refers to avoiding, reducing, or decreasing the risk of the occurrence and onset of a disease, and "treatment" refers to artificially intervening to eliminate, prevent, reduce, weaken, limit, suppress, or inhibit the symptoms of a disease or the occurrence, progression, or development of the symptoms of a disease.

Effects of the Invention

[0014] In the present invention, through research, it has been found that the tetrahydronaphthyridine derivative has a good effect on preventing and treating gastrointestinal tract injury-related diseases, and is used in the preparation of a drug for preventing and treating gastrointestinal tract injury or a drug for inhibiting gastrointestinal protein kinase, and particularly has a good preventive and therapeutic effect on symptoms such as gastrointestinal adhesion, abdominal adhesion, intercostal adhesion, peritoneal adhesion, uterine adhesion, etc. and their complications.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0016] Hereinafter, the technical solution of the present disclosure will be described in more detail by combining specific examples. It should be understood that the following examples are merely illustrative of the present disclosure and do not limit the scope of the present disclosure. The technology realized based on the above content of the present disclosure is included within the protection scope of the present disclosure.

[0017] Unless otherwise specified, all raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

[0018]

Chemical Formula

[0019] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0020] Weigh 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (0.9 g) and suspend it in dichloromethane (15 mL). After liberating N,N-diisopropylethylamine (1.4 g), add di-tert-butyl dicarbonate (1.15 g) and react at room temperature for 1 hour. TLC indicated that the raw material was completely consumed, and it was purified by column chromatography to obtain the title compound (1.12 g).

Chemical Formula

[0021] MS(ESI) m / z (M+H) + = 269.0

[0022] Step 2: Preparation of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0023] tert-Butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.12 g) was weighed and dissolved in N,N-dimethylformamide (20 mL), zinc cyanide (2.44 g) and tetrakis(triphenylphosphine)palladium (483 mg) were added, the mixture was purged with argon three times, and reacted at 120 °C for 3 hours. TLC indicated that the raw material was completely consumed. Ethyl acetate was added for dilution, filtered through diatomaceous earth, extracted twice with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound (1.1 g).

Chemical formula

[0024] MS(ESI) m / z (M+H) + = 260.0

[0025] Step 3: Preparation of 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid hydrochloride

[0026] tert-Butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate (1.1 g) was weighed and dissolved in 6M hydrochloric acid aqueous solution (25 mL), and reacted at 120 °C overnight. LCMS indicated that the raw material was completely consumed. The reaction mixture was concentrated until dry, and the title compound (726 mg) was obtained by separation by pre-HPLC.

Chemical formula

[0027] MS(ESI) m / z (M+H) + = 179.0

[0028] 1 H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 4.60 (s, 2H), 3.71 (t, J = 6.4 Hz, 2H), 3.42 (t, J = 6.4 Hz, 2H).

[0029]

Chem.

[0030] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

Chem.

[0031] 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (0.9 g) was suspended in dichloromethane (15 mL), N,N-diisopropylethylamine (1.4 g) was added, and then di-tert-butyl dicarbonate (1.15 g) was added. The mixture was reacted at room temperature for 1 hour. TLC showed that the raw material was completely consumed. Water was added to dilute the reaction solution, and the solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was purified by column chromatography to obtain 1.12 g of the target compound.

[0032] MS(ESI) m / z (M+H) + = 269.0

[0033] Step 2: Preparation of tert-butyl 2-(diethoxyphosphoryl)-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

Chem.

[0034] Under an argon atmosphere, tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (100 mg) was dissolved in toluene (20 mL), and diethyl phosphite (102 mg), tris(dibenzylideneacetone)dipalladium (34 mg), 1,1'-bis(diphenylphosphino)ferrocene (41 mg) and triethylamine (75 mg) were added. The system was reacted at 120 °C overnight. TLC showed that the raw materials were completely consumed. Ethyl acetate was added for dilution, and the mixture was filtered through diatomaceous earth. The filtrate was collected and concentrated. The obtained crude product was purified by preparative TLC to obtain 70 mg of the target compound.

[0035] MS(ESI) m / z (M+H)+ = 371.1.

[0036] Step 3: Preparation of (5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phosphonic acid hydrochloride

Chem.

[0037] tert-Butyl 2-(diethoxyphosphoryl)-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate (70 mg) was dissolved in concentrated hydrochloric acid (5 mL) and reacted at 100 °C overnight. LCMS showed that the raw materials were completely consumed. The reaction solution was concentrated, and the crude product was purified by preparative HPLC to obtain 30 mg of the target compound.

[0038] MS(ESI) m / z (M+H) + = 215.0. 11H NMR (400 MHz, D2O) δ 8.35 (dd, J = 8.0, 2.4 Hz, 1H), 8.06 (t, J = 7.7 Hz, 1H), 4.59 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.49 (t, J = 6.4 Hz, 2H).

[0039] Biological experiment Test Example 1 1. Experimental purpose The inhibitory activity of the compound of the present invention against total proteases in the homogenate of rat small intestine jejunum segments was measured.

[0040] 2. Experimental materials and equipment [Table 1] [Table 2] [Table 3]

[0041] 3. Experimental steps a) Preparation of rat intestinal homogenate and protein quantification i. Tissue collection: After anesthetizing the experimental animals, they were bled and sacrificed. The small intestine was folded in half from the ileocecal junction towards the lower end of the stomach and duodenum, and approximately 4 cm of jejunum in the middle was taken. After washing with 0.9% sodium chloride solution, it was placed in liquid nitrogen for rapid freezing, and then transferred to a -80 °C condition for storage. ii. Intestinal tissue homogenate: Using sterile surgical scissors on ice, the intestinal tissue was cut into small pieces and transferred to a 2 mL EP tube. 4 μL of Assay Buffer (Protease Activity Assay Kit, Abcam, ab111750) was added for every 1 mg of tissue; Two small steel balls were added to each EP tube, and the tissue was homogenized using a high-throughput cryogenic grinder under 4 °C conditions, homogenizing at 3600 rpm for 30 seconds each time, and a total of 2 times of homogenization was performed; iii. After centrifuging the tissue homogenate at 12,000 g for 10 minutes at 4°C, the homogenate supernatant (intestinal homogenate solution) was carefully taken, transferred to a new EP tube, dispensed, and then stored at -80°C. iv. Referring to the instructions of the BCA protein concentration measurement kit, total protein quantification was performed on the intestinal homogenate solution.

[0042] b) Compound inhibition activity test i. Compound stock solution: The compound was dissolved in Assay Buffer to prepare a 400 mM stock solution, dispensed, and then stored at -20°C. ii. 4× compound working solution: The compound stock solution was diluted in a 3-fold gradient, with a total of 10 concentration points. The diluent was Assay buffer. Wells without the compound were set as negative controls, and wells without the protease homogenate solution were set as blank controls. iii. 4× intestinal protease working solution: Dilute the intestinal homogenate solution to the specified concentration with Assay Buffer. iv. Prepare the Reaction Mix solution according to the following table. Taking the preparation of 200 μL of the Reaction Mix solution as an example.

Table 4

[0043] c) Data analysis The difference value of the fluorescence signal within 30 minutes was recorded and calculated as ΔRFU. Using the log value of the compound concentration as the X-axis and the fluorescence signal difference value (ΔRFU) as the Y-axis, and fitting the dose-response curve with the 4-parameter model (log(inhibitor) vs. response - variable slope) of the analysis software GraphPad 7, the IC 50 value for the enzyme activity of each compound was determined.

[0044] Fitting formula: Y = min+(max-min) / (1+10^((LogIC 50 -X)×Hillslope)).

[0045] The inhibitory effect of the compound of the present invention on the total proteases in the above rat small intestine homogenate was measured by the above test, and the measured IC 50 value is as follows.

Table 5

[0046] The experimental data shows that the compound of the present invention has a certain inhibitory activity against the total proteases in the rat small intestine.

[0047] Test Example 2 1. Experimental Purpose The inhibitory activity of the compound of the present invention against the recombinant human proteases trypsin, MMP9 and TACE was measured.

[0048] 2. Experimental Materials and Equipment Main Reagents and Consumables

Table 6

Table 7

[0049] Reaction Buffer Trypsin: 100 mM Tris-HCl, 75 mM NaCl, 2.5 mM CaCl2, 10 mM Cysteine, pH 7.5 MMP9: 50 mM Tris, 10 mM CaCl2, 150 mM NaCl, 0.05 % Brij-35 (w / v), pH 7.5 TACE: 25 mM Tris, 2.5 μM ZnCl2, 0.005 % Brij-35 (w / v), pH 9.0

[0050] 3. Experimental steps a) The compound was dissolved in PBS or an aqueous NaOH solution with an equimolar volume concentration to prepare a 100 mM stock solution. b) The compound was serially diluted three-fold, with a total of 10 concentration points, and the diluent was PBS. c) 5 μL of the serially diluted compound solution was taken and added to the experimental plate. d) 4× enzyme working solutions of Trypsin, MMP9, and TACE were prepared respectively, and 5 μL of the plate was added so that the final concentrations were 75 nM, 0.2 μg / mL, and 0.2 μg / mL respectively. e) 2× substrate solutions were prepared, and 10 μL was added to the Trypsin, MMP9, and TACE plates so that the final concentrations were 120, 10, and 20 μM respectively. f) After incubating at room temperature (for MMP9 and TACE) or 37 °C (for Trypsin) for 30 minutes (for MMP9 and TACE) or 60 minutes (for Trypsin), the fluorescence values were read using a multifunctional microplate reader. g) The signal of the wells containing protein, substrate, and no compound was used as High Control, and the signal of the wells containing substrate and no protein and compound was used as Low Control. The inhibition rate of each test well was calculated using the following formula. Inhibition rate % = 100 - 100 × (test well - Low Control) / (High Control - Low Control) h) Using the log value of the concentration as the X-axis and the inhibition rate percentage as the Y-axis, the IC of each compound against the enzyme activity was obtained using the Mode205 model fitting dose-response curve of the analysis software IDBS_XLFit. 50 value. Fitting formula: fit=(A+((B-A) / (1+((C / x)^D)))); A: Bottom; B: Top; C: IC 50 ; D: Hillslope

[0051] The inhibitory effects of the compounds of the present invention on the above three proteases were measured by the above tests. The measured IC 50 values were as follows.

Table 8

[0052] The experimental data show that the compounds of the present invention all have a certain inhibitory effect on the three proteases.

[0053] Test Example 3 3.1 Experimental animals: SPF-grade male 220 g SD rats, purchased from the Experimental Animal Center of Hangzhou Medical College and inspected and qualified by the Zhejiang Experimental Animal Quality Supervision and Inspection Station. Thirty SD rats were adaptively bred for 10 days after entering the laboratory and randomly divided into 3 groups with 10 rats in each group using ear tag numbers.

[0054] 3.2 Test substances: The test active compound of test substance 1 is 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, and the test active compound of test substance 2 is (5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phosphonic acid. The solvent for intragastric administration is a compound polyethylene glycol electrolyte solution, and the solvent for lavage administration is sterile physiological saline.

[0055] 3.3 Solvent Preparation: One bag of compound polyethylene glycol electrolyte solution (68.56 g) was taken, dissolved in 1 L of pure water, and 44 g of glucose (hydrous) was added to make the glucose content of the solvent 4% (w / v). It was stored at 2 - 8 °C after preparation and used within one week.

[0056] 3.4 Preparation of Gastric Administration Solution: A certain amount of the test substance was weighed, an appropriate amount of sterile ultrapure water was added to prepare a 20% (w / v) stock solution, an equivalent amount of NaOH was added to adjust the pH to neutral, and it presented a completely dissolved state (pH value was measured). One part of the stock solution was taken, 9 parts of electrolyte solution (1:9, v:v) was added, and a 2% (w / v) gastric administration solution (pH range was measured) was prepared.

[0057] 3.5 Preparation of Washing Solution: A certain amount of the test substance was weighed, and a 1% (w / v) peritoneal washing solution was prepared using physiological saline (pH was adjusted to neutral).

[0058] 3.6 Modeling: An abdominal adhesion model was created using the rasp method. Before the operation, the animals fasted but did not abstain from water (>12 h). Under inhalation anesthesia, the abdomen was locally depilated, disinfected with iodophor solution, and a 3 - cm incision was made in the midline area of the abdomen of the experimental animals using a scalpel. The cecum was taken out, and on the right side of the ileocecal junction, the serosa layer was repeatedly rubbed with a rasp until needle - tip - like bleeding points appeared on the surface, forming a damaged wound surface of about 0.5 cm × 0.5 cm. This was returned to the abdominal cavity. After completing the washing and administration, it was sutured layer by layer with surgical suture to close the abdominal cavity. The animals in each group were crossed with 3 animals in each group. A sham - operation group control without cecal injury was set up with only laparotomy.

[0059] 3.7 Administration: It was administered orally once at 12 mL / kg 2 hours before laparotomy. After damaging the cecum, peritoneal lavage was performed once at 2 mL per animal before abdominal suture.

Table 9

[0060] 3.8 Adhesion Scoring: The postoperative intra - abdominal adhesion condition was scored using the Phillips classification criteria. It is as shown in the following table.

Table 10

[0061] 3.9 Result Detection On the 7th day after the operation, the dissected animals were sacrificed, and the condition of intestinal adhesion was scored using the Phillips classification method. The results are shown in Figure 1 (sham operation group), Figure 2 (model group), and Figure 3 (test substance 2). In the sham operation group, no adhesion between the peritoneum and the cecum was observed 7 days after molding; in the model group rats, extensive intestinal adhesions were observed at multiple sites 7 days after cecal friction molding; after adopting intragastric administration of 2% test substance 2 solution + peritoneal lavage with 1% solution, the quantity and degree of intestinal adhesions in more than 80% of the animals in the model group were significantly improved.

[0062] Test Example 4 4.1 Experimental Animals 70 SPF-grade male SD rats weighing 220 ± 20 g were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. After adaptively breeding for 2 weeks after entering the laboratory, they were randomly divided into 7 groups using ear tag numbers, with 8 rats in each group.

[0063] 4.2 Preparation of Test Substances and Solvents Test substances: The test active compound of test substance 1 is 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid hydrochloride, and the test active compound of test substance 2 is (5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phosphonic acid hydrochloride. The positive drug is Tranexamic Acid (TXA).

[0064] Solvent: One bag of compound polyethylene glycol electrolyte solution powder (68.56 g) was taken, dissolved in 1 L of pure water, and 44 g of glucose (hydrous) was added to make the glucose content of the solvent 4% (w / v). After preparation, it was stored at 2 - 8°C and used within 1 week.

[0065] Solution for intragastric administration of the test substance: A certain amount of test substance 1 was weighed, an electrolyte solution was added to prepare 64 mM and 21 mM solutions, appropriate NaOH was added to adjust the pH to about 7.5, and the mixture was left standing without any precipitation observed. A certain amount of test substance 2 was weighed to prepare a 64 mM clear solution, and appropriate NaOH was added to adjust the pH to neutral. A certain amount of the positive drug tranexamic acid (TXA) was weighed and added to the electrolyte solution to prepare 64 mM and 21 mM solutions respectively.

[0066] 4.3 Grouping and administration Two hours before laparotomy, a single oral intragastric administration was performed at 12 mL / kg, and the solvent was administered to the sham operation group and the model group.

Table 11

[0067] 4.4 Modeling Before the operation, the animals were fasted but not water-deprived (>12 h). Under inhalation anesthesia, the abdomen of the animals was locally depilated, disinfected with iodophor solution, and the abdomen of the experimental animals was incised 3 cm in the midline region using a scalpel. The cecum was taken out, and on both sides of the ileocecal junction, the serosa layer was repeatedly rubbed with sterile gauze until needle tip-like bleeding points appeared on the surface to form damaged wound surfaces on the inner and outer sides of the cecum. Then it was returned to the abdominal cavity and sutured layer by layer with surgical suture to close the abdominal cavity, disinfected, and the entire surgical operation process maintained sterility. Four animals in each group were crossed. The sham operation group only underwent laparotomy without damaging the cecum.

[0068] 4.5 Adhesion scoring Anatomical observation was performed 7 days after the operation, and the intraperitoneal adhesion condition after the operation was scored using the Phillips classification criteria. The results are as shown in the following table.

Table 12

[0069] 4.6 Results On the 7th day after the operation, the surviving animals in each group were dissected, and the condition of intestinal adhesion was scored using the Phillips classification method. As shown in Fig. 4, no adhesion between the abdominal cavity and the cecum was observed in the sham operation group; in the model group rats, extensive intestinal adhesions were observed at multiple sites 7 days after cecal abrasion molding; compared with the model group, in the tranexamic acid group, one animal died after the operation in each group. The degree of intraperitoneal adhesion in the 64 mM group was significantly reduced, and there was a tendency to reduce in the 21 mM group; in the rats administered with 64 mM test substance 1, the intraperitoneal adhesion site and degree were significantly reduced; in the rats administered with 21 mM test substance 1, the adhesion site and degree were reduced; in the rats administered with 64 mM test substance 2, the intraperitoneal adhesion site and degree were improved to some extent.

[0070] As described above, the embodiments of the technical solution of the present invention have been exemplarily described. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the scope of the spirit and principle of the present disclosure should be included within the protection scope of the claims of this application.

Claims

1. Use of a tetrahydronaphthyridine derivative in the preparation of a drug for preventing and treating gastrointestinal tract injury-related diseases, wherein the tetrahydronaphthyridine derivative is selected from 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, 5,6,7,8-tetrahydro-1,6-naphthyridine-2-phosphonic acid, hydrates of the above compounds, pharmaceutically acceptable salts, prodrugs, or mixtures, the use.

2. The gastrointestinal tract injury-related disease is adhesion, characterized by, the use according to claim 1.

3. The adhesion is postoperative adhesion or a complication caused by postoperative adhesion, characterized by, the use according to claim 2.

4. The postoperative adhesion is one or more selected from intestinal adhesion, peritoneal adhesion, intercostal adhesion, peritoneal adhesion, and uterine adhesion, characterized by, the use according to claim 3.

5. The complication caused by the postoperative adhesion is one or more selected from female infertility, postoperative ileus, and pain, characterized by, the use according to claim 3.

6. The pharmaceutically acceptable salt is the hydrochloride salt of the tetrahydronaphthyridine derivative, characterized by, the use according to any one of claims 1 to 5.

7. Use of a tetrahydronaphthyridine derivative in the preparation of a drug for inhibiting gastrointestinal protein kinase, wherein the tetrahydronaphthyridine derivative is selected from 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, 5,6,7,8-tetrahydro-1,6-naphthyridine-2-phosphonic acid, hydrates of the above compounds, pharmaceutically acceptable salts, prodrugs, or mixtures, the use.

8. The gastrointestinal protein kinase is at least one selected from trypsin, MMP9, and TACE, characterized by, the use according to claim 7.

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