Application of tetrahydronaphthyridine derivative in preparation of medicine for preventing and treating adhesion-related diseases

Abstract

The invention provides application of a tetrahydronaphthyridine derivative in preparation of drugs for preventing and treating gastrointestinal injury related diseases or inhibiting gastrointestinal protein kinase. The tetrahydronaphthyridine derivative has a good effect of preventing and treating gastrointestinal injury related diseases.

Description

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

[0001] This application claims priority to prior applications No. 202210596510.4, filed with the State Intellectual Property Office of China on May 30, 2022, entitled "Application of Tetrahydronaphthyridine Derivatives in the Preparation of Medicaments for Preventing and Treating Adhesion-Related Diseases," and No. 202211286168.4, filed with the State Intellectual Property Office of China on October 20, 2022, entitled "Application of Tetrahydronaphthyridine Derivatives in the Preparation of Medicaments for Preventing and Treating Adhesion-Related Diseases." The entire contents of both prior applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to the use of tetrahydronaphthyridine derivatives in preparing medicines for preventing and treating adhesion-related diseases. Background Art

[0003] Adhesions are the result of tissue damage, triggered by factors including sharp, mechanical, or thermal injury, infection, radiation, ischemia, desiccation, abrasion, foreign body reactions, and tumors. Regardless of the triggering factor, adhesions are formed by the interaction of three intertwined processes in the body: the fibrinolytic system, extracellular matrix deposition and remodeling, and the inflammatory system. When the gastrointestinal tract is damaged by biological, physical, or chemical insults, an acute inflammatory response occurs. Tissue ischemia, the release of tissue factors and cytokines, increased vascular permeability, and the release of inflammatory factors trigger intestinal and intraperitoneal adhesions. Simultaneously, large amounts of exudate containing fibrinogen and fibrin can deposit and coagulate into a fibrous network, converging on the surfaces of irritated tissues and organs and adhering to surrounding tissues. Under normal circumstances, peritoneal mesothelial cell exudate, in addition to releasing fibrinogen, also has a fibrinolytic effect, dissolving and resorbing the cellulose network and reducing adhesion formation. The balance between fibrin deposition and degradation plays a key role in normal repair and healing, as well as adhesion formation. Key factors contributing to an imbalance between these two processes are local injury and the degree of inflammatory response.

[0004] Postoperative adhesions, such as intestinal adhesions or peritoneal adhesions, can lead to infertility, pain, or intestinal obstruction and may increase the difficulty of subsequent abdominal or pelvic surgery. All surgeons must be familiar with the risks and consequences of postoperative adhesions and take measures to minimize their occurrence. Theoretically, adhesion formation can be reduced by minimizing peritoneal injury during surgery, preventing the introduction of reactive foreign bodies, reducing local inflammatory responses, inhibiting the coagulation cascade, promoting fibrinolysis, or creating a barrier between damaged tissues. However, studies have shown that procedures such as myomectomy often result in adhesions, regardless of the surgical approach. The incidence of adhesions after open myomectomy is greater than 90%, but it remains at least 70% after laparoscopic myomectomy. The use of bioresorbable anti-adhesion membranes to physically isolate the surgical site from the adjacent peritoneum or adjacent organs and prevent adhesions is considered a viable approach. The FDA has approved several anti-adhesion membrane products, such as a film composed of hyaluronic acid and carboxymethylcellulose (Seprafilm). Clinical studies have shown that patients in the experimental group who had absorbable medical membranes placed on the wound surface after abdominal surgery had significantly shorter bowel sound recovery and flatus time than those in the control group who received no intervention. Their postoperative physical signs were also better than those in the control group, and they demonstrated good biocompatibility and safety. This bioabsorbable membrane can effectively prevent postoperative adhesions, reduce the risk of secondary surgery, and significantly improve compliance. However, the bioabsorbable membrane's site of action is limited to the placement site, requiring surgeons to identify potential adhesion sites, which may be some distance from the surgical site. Furthermore, the placement of anti-adhesion membranes is difficult, making them difficult to use in laparoscopic surgery.

[0005] Currently, several studies have evaluated the efficacy of drugs for preventing adhesions, including recombinant tPA, streptokinase, heparin, low molecular weight heparin, nonsteroidal anti-inflammatory drugs, gonadotropin-releasing hormone agonists, phosphatidylcholine, vitamin E antioxidant molecules, and corticosteroids. These drugs were originally developed to treat conditions other than postoperative adhesions. Their mechanisms of adhesion prevention and treatment remain unclear, and their effectiveness requires further verification. Recent studies have shown that intestinal trauma (incision, surgical manipulation, and hypoperfusion) can lead to a breakdown of the intestinal mucosal barrier, subsequently allowing digestive proteases to enter the intestinal tissue and visceral cavity. These proteases can cause proteolytic damage to the mesothelial surface of the viscera, and as part of the biological repair process, they can trigger adhesion formation during the healing of damaged tissue. The present inventors have discovered through long-term research that certain specific tetrahydronaphthyridine derivatives can act as broad-spectrum serine protease inhibitors, neutralizing the activity of digestive proteases excessively released during surgery due to intestinal mucosal barrier damage, thereby reducing damage to gastrointestinal tissue and accelerating the recovery of gastrointestinal function, thereby achieving the purpose of preventing and treating postoperative intestinal adhesions.

[0006] Summary of the Invention

[0007] One of the purposes of the present invention is to provide a use of a tetrahydronaphthyridine derivative for preparing a drug for preventing and treating diseases related to gastrointestinal damage.

[0008] In certain specific embodiments, 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, or pharmaceutically acceptable salts, or prodrugs, or mixtures thereof.

[0009] In certain specific embodiments, the pharmaceutically acceptable salt is the hydrochloride of the tetrahydronaphthyridine derivative.

[0010] In certain specific embodiments, the gastrointestinal injury-related disease refers to adhesion, particularly including various adhesions caused by abdominal gastrointestinal injury, infection, etc. after surgery, such as postoperative intestinal adhesions, abdominal adhesions, intercostal adhesions, peritoneal adhesions, uterine adhesions, etc.

[0011] In certain specific embodiments, the gastrointestinal injury-related disease further includes complications caused by postoperative adhesions, such as one or more of female infertility, postoperative intestinal obstruction, and pain.

[0012] The present invention further provides the use of the tetrahydronaphthyridine derivative in preparing a drug for inhibiting gastrointestinal protein kinase.

[0013] In certain specific embodiments, the gastrointestinal protein kinase is selected from at least one of Trypsin, MMP9 and TACE.

[0014] In the sense of the present invention, "prevention" refers to "prevention" and / or "treatment", wherein "prevention" refers to avoiding, alleviating, or reducing the risk of occurrence and development of a disease; "treatment" refers to the use of artificial intervention to eliminate, hinder, alleviate, weaken, limit, inhibit or curb the symptoms of a disease or the development, process or progression of disease symptoms. Beneficial effects

[0015] The present invention has found that the tetrahydronaphthyridine derivative has a good effect in preventing and treating diseases related to gastrointestinal injury, and can be used to prepare drugs for preventing and treating gastrointestinal injury or drugs for inhibiting gastrointestinal protein kinase, especially for gastrointestinal adhesions, abdominal adhesions, intercostal adhesions, peritoneal adhesions, uterine adhesions and other diseases and their complications. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a photo of the abdominal intestinal area of ​​rats in the sham operation group in Experimental Example 3 after being sacrificed on the 7th day after surgery.

[0017] Figure 2 is a photo of the abdominal intestinal area of ​​the model group rats in Experimental Example 3 after being sacrificed on the 7th day after surgery

[0018] Figure 3 is a photo of the abdominal intestinal area of ​​rats in the drug group in Experimental Example 3 after being killed on the 7th day after surgery

[0019] Figure 4 is a bar graph showing the scoring of intestinal adhesions in rats in Experiment 4 using the Phillips grading method. DETAILED DESCRIPTION

[0020] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0021] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0022] Preparation Example 1

[0023] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0024] 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 to dissociate the mixture. Di-tert-butyl dicarbonate (1.15 g) was then added and the mixture was allowed to react at room temperature for 1 h. TLC indicated complete consumption of the starting material. Purification by column chromatography afforded the title compound (1.12 g).

[0025] MS (ESI) m / z (M+H) + =269.0.

[0026] Step 2: Preparation of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0027] Weigh tert-Butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.12 g) and dissolve it in N,N-dimethylformamide (20 mL). Add zinc cyanide (2.44 g) and tetrakis(triphenylphosphine)palladium (483 mg). Replace the atmosphere with argon three times and react at 120°C for 3 h. TLC shows complete consumption of the starting material. Dilute with ethyl acetate, filter through celite, extract twice with ethyl acetate, wash once with saturated brine, dry over anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound (1.1 g).

[0028] MS (ESI) m / z (M+H) + =260.0.

[0029] Step 3: Preparation of 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid hydrochloride

[0030] 1.1 g of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate was dissolved in 25 mL of 6 M aqueous hydrochloric acid and reacted at 120°C overnight. LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated to dryness and separated by pre-HPLC to obtain the title compound (726 mg).

[0031] MS (ESI) m / z (M+H) + =179.0.

[0032] 1 H NMR (400MHz, Methanol-d4) δ8.21(d,J=8.1Hz,1H),8.12(d,J=8.0Hz,1H),4.60(s,2H),3.71(t,J=6.4Hz,2H),3.42(t,J=6.4Hz,2H).

[0033] Preparation Example 2

[0034] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0035] 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, followed by di-tert-butyl dicarbonate (1.15 g). The mixture was allowed to react at room temperature for 1 h. TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to yield 1.12 g of the title compound.

[0036] MS (ESI) m / z (M+H) + =269.0.

[0037] Step 2: Preparation of tert-butyl 2-(diethoxyphosphoryl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0038] 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). Diethyl phosphite (102 mg), tris(dibenzylideneacetone)dipalladium (34 mg), 1,1'-bis(diphenylphosphino)ferrocene (41 mg), and triethylamine (75 mg) were added, and the system was reacted at 120°C overnight. TLC indicated complete consumption of the starting material. The mixture was diluted with ethyl acetate and filtered through celite. The filtrate was collected and concentrated. The crude product was purified by preparative TLC to yield 70 mg of the title compound.

[0039] MS (ESI) m / z (M+H) + =371.1.

[0040] Step 3: Preparation of (5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phosphonic acid hydrochloride

[0041] Dissolve tert-butyl 2-(diethoxyphosphoryl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (70 mg) in concentrated hydrochloric acid (5 mL) and react overnight at 100°C. LCMS showed complete consumption of the starting material. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC to obtain 30 mg of the title compound.

[0042] MS (ESI) m / z (M+H) + =215.0.

[0043] 1 H NMR (400MHz, D2O) δ8.35(dd,J=8.0,2.4Hz,1H),8.06(t,J=7.7Hz,1H),4.59(s,2H),3.67(t,J=6.0Hz,2H),3.49(t,J=6.4Hz,2H).

[0044] Biological tests

[0045] Test Example 1

[0046] 1. Purpose of the experiment

[0047] The inhibitory activity of the compounds of the present invention on total proteases in the homogenate of rat small intestine jejunum was determined.

[0048] 2. Experimental Materials and Instruments

[0049] experimental animals

[0050] Main reagents and consumables

[0051] instrument

[0052] 3. Experimental Procedure

[0053] a) Preparation of rat intestinal homogenate and protein quantification

[0054] i. Tissue Collection: Experimental animals were anesthetized and exsanguinated. The small intestine was folded in half from the ileocecal region toward the duodenum at the lower end of the stomach. The central 4 cm of jejunum was removed. After washing with 0.9% sodium chloride solution, the sample was quickly frozen in liquid nitrogen and stored at -80°C.

[0055] ii. Intestinal tissue homogenate: Cut the intestinal tissue into small pieces with sterile surgical scissors on ice and transfer them to a 2 mL EP tube. Add 4 μL of Assay Buffer (Protease Activity Assay Kit,

[0056] Two small steel beads were added to each EP tube, and the tissue was homogenized using a high-throughput cryo-grinder at 4°C, at 3600 rpm for 30 s each time, for a total of two homogenizations.

[0057] iii. After centrifugation of the tissue homogenate at 12,000 g and 4°C for 10 min, carefully remove the homogenate supernatant (intestinal homogenate) into a new EP tube, aliquot and store at -80°C.

[0058] iv. Quantify the total protein in the intestinal homogenate according to the instructions of the BCA protein concentration assay kit.

[0059] b) Compound inhibitory activity test

[0060] i. Compound stock solution: Dissolve the compound in Assay Buffer to prepare a 400 mM stock solution, aliquot and store at -20°C.

[0061] ii. 4× compound working solution: dilute the compound stock solution 3-fold to a total of 10 concentration points using assay buffer. Set wells without compound as negative controls and wells without protease homogenate as blank controls.

[0062] iii. 4× Intestinal Protease Working Solution: Dilute the intestinal homogenate to the specified concentration with Assay Buffer;

[0063] iv. Prepare the Reaction Mix solution according to the table below, using 200 μL of Reaction Mix solution as an example.

[0064] v. To a black flat-bottom 384-well reaction plate, add 10 μL of 4× compound working solution, 10 μL of 4× enteropeptide working solution, and 20 μL of reaction mix solution. Centrifuge at 3000 rpm for 10 seconds and immediately assay.

[0065] vi. In kinetic mode, the fluorescence signal at FI = Ex 485 / Em 520 nm was continuously detected within 30 min (once every 5 min).

[0066] c) Data analysis.

[0067] The difference in fluorescence signal within the 30-min interval was calculated and recorded as ΔRFU.

[0068] The logarithmic value of the compound concentration was used as the X-axis and the fluorescence signal difference (ΔRFU) was used as the Y-axis. The four-parameter model (log (inhibitor) vs. response-variable slope) of the analysis software GraphPad 7 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 value.

[0069] Fitting formula: Y = min + (max - min) / (1 + 10^((LogIC 50 -X)×Hillslope)).

[0070] The inhibitory effect of the compounds of the present invention on the total protease in the above rat small intestine homogenate was determined by the above test. The measured IC 50 The values ​​are as follows.

[0071] Experimental data show that the compound of the present invention has a certain inhibitory activity on total proteases in rat small intestine.

[0072] Test Example 2

[0073] 1. Experimental Purpose

[0074] The inhibitory activities of the compounds of the present invention against recombinant human proteases Trypsin, MMP9 and TACE were determined.

[0075] 2. Experimental materials and instruments

[0076] Main reagents and consumables

[0077] instrument

[0078] Reaction buffer

[0079] Trypsin: 100mM Tris-HCl, 75mM NaCl, 2.5mM CaCl2, 10mM Cysteine, pH 7.5

[0080] MMP9: 50mM Tris, 10mM CaCl2, 150mM NaCl, 0.05% Brij-35 (w / v), pH7.5

[0081] TACE: 25mM Tris, 2.5μM ZnCl2, 0.005% Brij-35 (w / v), pH 9.0

[0082] 3. Experimental steps

[0083] a) Dissolve the compound in PBS or an equimolar NaOH aqueous solution to a 100 mM stock solution.

[0084] b) The compound was diluted 3-fold in a series, with a total of 10 concentration points, and the diluent was PBS.

[0085] c) Take 5 μL of the serially diluted compound solution and add it to the experimental plate.

[0086] d) Prepare 4× enzyme working solutions of Trypsin, MMP9, and TACE, respectively, and add 5 μL to the experimental plate to achieve final concentrations of 75 nM, 0.2 μg / mL, and 0.2 μg / mL, respectively.

[0087] e) Prepare 2× substrate solution and add 10 μL to the Trypsin, MMP9, and TACE assay plates to final concentrations of 120, 10, and 20 μM, respectively.

[0088] f) After incubation at room temperature (MMP9 and TACE) or 37°C (Trypsin) for 30 min (MMP9 and TACE) or 60 min (Trypsin), the fluorescence value was read using a multifunctional microplate reader.

[0089] g) The signal from the well containing protein and substrate but no compound is designated as the High Control; the signal from the well containing substrate but no protein or compound is designated as the Low Control. Calculate the inhibition rate for each test well according to the following formula:

[0090] Inhibition rate % = 100 - 100 × (test well - Low Control) / (High Control - Low Control)

[0091] h) The logarithmic value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis to fit the dose-effect curve using the Mode 205 model of the analysis software IDBS_XLFit to obtain the IC value of each compound on the enzyme activity. 50 value.

[0092] Fitting formula: fit = (A + ((BA) / (1 + ((C / x)^D))));

[0093] A:Bottom; B:Top; C:IC 50 ;D:Hillslope

[0094] The inhibitory effects of the compounds of the present invention on the above three proteases were determined by the above test, and the measured IC 50 The values ​​are as follows.

[0095] Experimental data show that the compounds of the present invention have a certain inhibitory effect on the three proteases.

[0096] Test Example 3

[0097] 3.1 Experimental Animals: SPF-grade male 220 g Sprague-Dawley rats were purchased from the Laboratory Animal Center of Hangzhou Medical College and inspected by the Zhejiang Provincial Laboratory Animal Quality Supervision and Inspection Station. Thirty Sprague-Dawley rats were housed for 10 days after entering the laboratory and then numbered using ear tags and randomly divided into three groups of 10 rats each.

[0098] 3.2 Test Samples: The active compound to be tested for Test Sample 1 is 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, and the active compound to be tested for Test Sample 2 is (5,6,7,8-tetrahydro-1,6-naphthyridine-2-yl)phosphonic acid. The solvent for oral administration is a polyethylene glycol electrolyte solution; the solvent for lavage administration is sterile saline solution.

[0099] 3.3 Solvent Preparation: Dissolve one bag of compound polyethylene glycol electrolyte solution (68.56 g) in 1 L of pure water. Add 44 g of glucose (water-containing) to a glucose content of 4% (w / v). Store at 2-8°C and use within one week.

[0100] 3.4 Preparation of intragastric solution: Weigh a certain amount of test sample and add an appropriate amount of sterile ultrapure water to prepare a 20% (w / v) stock solution. Add an equivalent amount of NaOH to adjust the pH to neutral and completely dissolve the sample (measure the pH value). Take 1 part of the stock solution and add 9 parts of electrolyte solution (1:9, v:v) to prepare a 2% (w / v) intragastric solution (measure the pH range).

[0101] 3.5 Preparation of lavage solution: Weigh a certain amount of test sample and prepare a 1% (w / v) peritoneal lavage solution using normal saline (adjust the pH to neutral).

[0102] 3.6 Modeling: A peritoneal adhesion model was established using a file technique. Animals were fasted for >12 hours prior to surgery. Under inhalation anesthesia, the abdomen was locally hairless and disinfected with iodine solution. A 3 cm incision was made in the midline of the abdomen with a scalpel. The cecum was removed. The serosa was repeatedly abraded on the right side of the ileocecal region until a pinpoint bleeding point formed, creating a wound approximately 0.5 cm × 0.5 cm in size. The cecum was then placed back into the peritoneal cavity. After lavage and drug administration, the peritoneal cavity was closed with surgical sutures layer by layer. Three animals were included in each group. A sham-operated control group was established: only the cecum was opened without injury.

[0103] 3.7 Administration: Administer a single dose of 12 mL / kg via oral gavage 2 hours before laparotomy. After cecal injury, administer an intraperitoneal lavage of 2 mL / animal before abdominal suturing.

[0104] 3.8 Adhesion score: The Phillips grading standard was used to score the postoperative intra-abdominal adhesions, as shown in the following table

[0105] 3.9 Result Testing

[0106] The animals were killed and dissected on the 7th day after surgery, and the intestinal adhesions were scored using the Phillips grading method. The results are shown in Figure 1 (sham operation group), Figure 2 (model group) and Figure 3 (test product 2). 7 days after modeling, no adhesions were observed in the abdominal cavity and cecum of the sham operation group; 7 days after modeling by cecal friction, multiple and large-area intestinal adhesions were observed in the model group rats; after oral gavage with 2% test product 2 solution + peritoneal lavage with 1% solution, the number and degree of intestinal adhesions were significantly improved in more than 80% of the animals compared with the model group.

[0107] Test Example 4

[0108] 4.1 Experimental Animals

[0109] Seventy SPF male Sprague-Dawley rats (220 ± 20 g) were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. After two weeks of adaptive feeding in the laboratory, they were numbered using ear tags and randomly divided into seven groups, with eight rats in each group.

[0110] 4.2 Preparation of test sample and solvent

[0111] Test Samples: The active compound to be tested for Test Sample 1 is 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid hydrochloride, and the active compound to be tested for Test Sample 2 is (5,6,7,8-tetrahydro-1,6-naphthyridine-2-yl)phosphonic acid hydrochloride. The positive drug is tranexamic acid (TXA).

[0112] Solvent: Dissolve one bag of compound polyethylene glycol electrolyte solution powder (68.56g) in 1L of pure water. Add 44g of glucose (water) to a glucose content of 4% (w / v). Store at 2-8°C and use within one week.

[0113] Test sample gavage solution: Weigh a certain amount of test sample 1 and add electrolyte solution to prepare 64mM and 21mM solutions. Add appropriate amount of NaOH to adjust the pH to approximately 7.5. Allow to stand and observe for precipitation. Weigh a certain amount of test sample 2 to prepare a 64mM clear solution and add appropriate amount of NaOH to adjust the pH to neutral. Weigh a certain amount of the positive drug tranexamic acid (TXA) and add electrolyte solution to prepare 64mM and 21mM solutions, respectively.

[0114] 4.3 Grouping and Dosing

[0115] Two hours before laparotomy, the drug was given a single dose of 12 mL / kg by oral gavage, while the sham operation group and the model group were given the vehicle.

[0116] 4.4 Modeling

[0117] Before surgery, animals were fasted but not watered (>12 hours). Under inhalation anesthesia, the abdomen was partially hairless and disinfected with iodine solution. A 3 cm incision was made in the midline of the abdomen with a scalpel, and the cecum was removed. Sterile gauze was used to repeatedly rub the serosal layer on both sides of the ileocecal region until pinpoint bleeding was observed on the surface, creating a wound surface on the inner and outer sides of the cecum. The cecum was then placed back into the abdominal cavity, closed with surgical sutures layer by layer, and disinfected. The entire surgical procedure was performed under sterile conditions. Four animals were included in each group. The sham-operated group underwent only laparotomy without damaging the cecum.

[0118] 4.5 Adhesion score

[0119] The anatomical observation was performed 7 days after surgery, and the Phillips grading standard was used to score the postoperative intra-abdominal adhesions, as shown in the following table.

[0120] 4.6 Results

[0121] Seven days after surgery, surviving animals in each group were dissected and intestinal adhesions were scored using the Phillips scale. The results are shown in Figure 4. No adhesions were observed in the sham-operated group in the peritoneal cavity or cecum. Seven days after cecal friction modeling, multiple, large-area intestinal adhesions were observed in the model group. Compared with the model group, one animal died in each of the tranexamic acid groups after surgery. The degree of intra-abdominal adhesions in the 64 mM group was significantly reduced, and there was a trend of reduction in the 21 mM group. The location and degree of intra-abdominal adhesions in rats given 64 mM test product 1 were significantly reduced. The location and degree of adhesions in rats given 21 mM test product 1 were reduced. The location and degree of intra-abdominal adhesions in rats given 64 mM test product 2 were somewhat improved.

[0122] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the claims of this application.

Claims

1. The use of tetrahydronaphthyridine derivatives in the preparation of drugs for preventing and treating diseases related to gastrointestinal damage; 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, or pharmaceutically acceptable salts, or prodrugs, or mixtures thereof.

2. The use according to claim 1, characterized in that The gastrointestinal tract injury-related disease refers to adhesion.

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

4. The use according to claim 3, characterized in that The postoperative adhesion is selected from one or more of intestinal adhesion, abdominal adhesion, intercostal adhesion, peritoneal adhesion, and uterine adhesion.

5. The use according to claim 3, wherein the complications caused by postoperative adhesions are selected from one or more of female infertility, postoperative intestinal obstruction, and pain.

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

7. Use of tetrahydronaphthyridine derivatives in the preparation of drugs for inhibiting gastrointestinal protein kinases; 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, or pharmaceutically acceptable salts, or prodrugs, or mixtures thereof.

8. The use according to claim 7, characterized in that The gastrointestinal protein kinase is at least one selected from Trypsin, MMP9 and TACE.

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