Use of tetrahydronaphthylidine derivatives in the preparation of drugs for the prevention and treatment of 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 priority over the prior applications filed with the China National Intellectual Property Administration on May 30, 2022, patent application number 202210596510.4, titled "Use of Tetrahydronaphthirizine Derivatives in the Preparation of Drugs for the Prevention and Treatment of Adhesion-Related Diseases," and filed with the China National Intellectual Property Administration on October 20, 2022, patent application number 202211286168.4, titled "Use of Tetrahydronaphthirizine Derivatives in the Preparation of Drugs for the Prevention and Treatment of Adhesion-Related Diseases." All the contents of the aforementioned prior applications are applied to this invention by reference.

[0002] This invention relates to the field of pharmaceuticals, and more specifically to the use of tetrahydronaphthylidine derivatives in the preparation of drugs for preventing and treating adhesion-related diseases. [Background technology]

[0003] Adhesions are a result of tissue damage, and their causes include sharp instruments, mechanical or thermal injury, infection, radiation, ischemia, dehydration, abrasion, foreign body reactions, and tumors. Regardless of the trigger, 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 suffers biological, physical, or chemical damage, an acute inflammatory response occurs. Tissue ischemia, tissue factor and cytokines, increased vascular permeability, and the release of inflammatory factors cause intestinal and intraperitoneal adhesions. Simultaneously, a large amount of exudate containing fibrinogen and fibrin can deposit, coagulate, and form a fibrous network that concentrates on the surface of the irritated tissue organ and adheres to the surrounding tissue. Under normal circumstances, peritoneal mesothelial cell exudate releases fibrinogen and has a fibrinolytic effect, dissolving and absorbing the cellulose network and reducing adhesion formation. The balance between fibrin deposition and degradation plays a crucial role in normal repair, healing, or adhesion formation, and key factors that cause an imbalance between these two are the degree of local injury and inflammatory response.

[0004] Postoperative adhesions (e.g., intestinal or peritoneal adhesions) can lead to infertility, pain, or ileus, and can increase the difficulty of subsequent abdominal or pelvic surgery. All surgeons must be familiar with the risks and consequences of postoperative adhesions and employ measures to minimize their occurrence as much as possible. Theoretically, adhesion formation can be reduced by decreasing peritoneal damage during surgery, preventing the introduction of reactive foreign bodies, reducing local inflammatory responses, inhibiting coagulation cascades, promoting fibrinolysis, or creating barriers between damaged tissues. However, studies show that regardless of the surgical method chosen, surgeries such as uterine myomectomy typically result in adhesions. The incidence of adhesions after open myomectomy was greater than 90%, but even after laparoscopic myomectomy, the incidence was at least 70%. Using bioabsorbable adhesion-preventing membranes to physically isolate the surgical site from nearby peritoneum or adjacent organs to prevent mutual adhesion is considered one viable approach. The FDA has approved various adhesion prevention membrane products, including membranes made of hyaluronic acid and carboxymethylcellulose (Seprafilm). Clinical studies have shown that patients in a test group who received absorbable medical membranes on wound sites after abdominal surgery had significantly shorter postoperative bowel sound recovery times and expulsion times than patients in a control group who did not receive postoperative intervention. These membranes also exhibited superior postoperative signs and good biocompatibility and safety. These bioabsorbable membranes effectively prevent postoperative adhesions, reduce the risk of secondary surgery, and significantly improve compliance. However, the action of bioabsorbable membranes is limited to the implantation site, requiring surgeons to identify areas prone to adhesion. Adhesion formation may occur slightly away from the surgical site, and the implantation procedure for adhesion prevention membranes is difficult, making their use in laparoscopic surgery challenging.

[0005] Currently, there are many studies evaluating the effectiveness of drugs including recombinant tPA, streptokinase, heparin, low molecular weight heparin, nonsteroidal anti-inflammatory drugs, gonadotropin-releasing hormone agonists, phosphatidylcholine, vitamin E antioxidant molecules, and corticosteroids in preventing adhesions. These drugs were originally developed to treat conditions other than postoperative adhesions, and the mechanism of adhesion prevention is unclear, and their effects need further investigation. Recent studies have shown that intestinal wounds (incisions, surgical procedures, and hypoperfusion) lead to the disruption of the intestinal mucosal barrier, after which peptic proteases are introduced into the intestinal tissue and visceral lumen. These proteases cause protein hydrolysis damage to the mesothelial surface of the viscera, leading to adhesion formation during the healing of damaged tissue as part of the biological repair process. In long-term research, the inventors have found that certain tetrahydronaphthirizine derivatives, acting as broad-spectrum serine protease inhibitors, can neutralize the activity of digestive proteases excessively released due to damage to the intestinal mucosal barrier during surgery, thereby reducing damage to gastrointestinal tissue, accelerating the recovery of gastrointestinal function, and thus preventing postoperative intestinal adhesions. [Overview of the Initiative]

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

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

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

[0009] In one specific embodiment, the gastrointestinal injury-related disease refers to adhesions, and in particular includes various adhesions resulting from postoperative abdominal gastrointestinal injury, infection, etc., such as postoperative intestinal adhesions, abdominal adhesions, intercostal adhesions, peritoneal adhesions, uterine adhesions, etc.

[0010] In one specific embodiment, gastrointestinal injury-related disorders may further include complications resulting from postoperative adhesions, such as one or more of female infertility, postoperative ileus, and pain.

[0011] The present invention further provides the use of tetrahydronaphthirizine derivatives in the preparation of drugs that inhibit gastrointestinal protein kinases.

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

[0013] In the present invention, "prevention and treatment" means "prevention" and / or "treatment," where "prevention" means avoiding, mitigating, or reducing the risk of the occurrence and development of a disease, and "treatment" means eliminating, blocking, mitigating, attenuating, limiting, suppressing, or inhibiting the symptoms of a disease or the onset, progression, or development of the symptoms of a disease through artificial intervention. [Effects of the Invention]

[0014] In this invention, through research, we have discovered that the tetrahydronaphthirizine derivative has a good effect in preventing and treating gastrointestinal injury-related diseases, and can be used in the preparation of drugs that prevent and treat gastrointestinal injury or drugs that inhibit gastrointestinal protein kinases. In particular, we have found that it has a good preventive and therapeutic effect against symptoms and complications of gastrointestinal adhesions, abdominal adhesions, intercostal adhesions, peritoneal adhesions, uterine adhesions, etc. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 is a photograph of the abdominal cavity of rats in the sham surgery group in Experiment Example 3, taken 7 days post-surgery before sacrifice. [Figure 2] Figure 2 is a photograph of the abdominal intestine of the rat in the model group after sacrifice on the 7th day after surgery in Test Example 3. [Figure 3] Figure 3 is a photograph of the abdominal intestine of the rat in the drug group after sacrifice on the 7th day after surgery in Test Example 3. [Figure 4] Figure 4 is a bar graph of the scores for the adhesion status of the rat intestine in Test Example 4 using the Phillips classification method.

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 only 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] 1.12 g of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate was weighed and dissolved in 20 mL of N,N-dimethylformamide. 2.44 g of zinc cyanide and 483 mg of tetrakis(triphenylphosphine)palladium were added, and the mixture was substituted three times with argon. The mixture was reacted at 120°C for 3 hours. TLC indicated that the starting materials had been completely consumed. The mixture was diluted with ethyl acetate, 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). [ka]

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

[0025] Step 3: Preparation of 5,6,7,8-tetrahydro-1,6-naphthyrizine-2-carboxylate hydrochloride

[0026] 1.1 g of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate was weighed and dissolved in 25 mL of 6 M hydrochloric acid solution, and reacted overnight at 120 °C. LC-MS indicated that the starting material had been completely consumed, and the reaction was concentrated until dry. The title compound (726 mg) was separated by pre-HPLC to obtain the compound. [ka]

[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] [ka]

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

[0031] 0.9 g of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthirizine hydrochloride was suspended in 15 mL of dichloromethane, 1.4 g of N,N-diisopropylethylamine was added, followed by 1.15 g of di-tert-butyl dicarbonate, and the mixture was reacted at room temperature for 1 hour. TLC showed that the starting materials had been completely consumed. The reaction mixture was diluted with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting 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 [ka]

[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(dibenzalacetone)dipalladium (34 mg), 1,1'-bis(diphenylphosphine)ferrocene (41 mg), and triethylamine (75 mg) were added. The system was reacted overnight at 120 °C. TLC showed that the starting materials were completely consumed, so ethyl acetate was added to dilute the mixture, filtered through diatomaceous earth, the filtrate was collected and concentrated, and the resulting crude product was purified by Prepared 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-naphthyridine-2-yl)phosphonate [ka]

[0037] 70 mg of tert-butyl 2-(diethoxyphosphoryl)-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate was dissolved in 5 mL of concentrated hydrochloric acid and reacted overnight at 100°C. LC-MS indicated that the starting material had been completely consumed. The reaction mixture was concentrated, and the crude product was purified by Prepared HPLC to obtain 30 mg of the target compound.

[0038] MS(ESI)m / z(M+H) + =215.0. 1H 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] Biology experiment Test Example 1 1. Experimental Objectives The inhibitory activity of the compound of the present invention against total proteases in a homogenate solution 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 quantification of protein i. Tissue collection: Experimental animals were anesthetized, bled, and then sacrificed. The small intestine was folded in half from the ileocecal region towards the lower end of the stomach and the duodenum, and the middle 4 cm of the jejunum was taken. After washing with a 0.9% sodium chloride solution, it was rapidly frozen in liquid nitrogen and then stored at -80°C. ii. Intestinal tissue homogenate: Intestinal tissue was cut into small pieces using sterile surgical scissors on ice and transferred to 2 mL EP tubes. 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 at 4°C using a high-throughput cryopolis. Homogenization was performed twice, each time at 3600 rpm for 30 seconds; iii. After centrifuging 12,000 g of tissue homogenate at 4°C for 10 minutes, the homogenate supernatant (intestinal homogenate solution) was carefully removed, transferred to a new EP tube, aliquoted, and stored at -80°C. iv. Total protein quantification was performed on the intestinal homogenate solution, referring to the instructions for the BCA protein concentration measurement kit.

[0042] b) Compound inhibitory activity test i. Compound storage solution: The compound was dissolved in Assay Buffer to prepare a 400 mM stock solution, which was then dispensed and stored at -20°C. ii. 4× Compound Working Solution: The compound stock solution was gradient diluted threefold, resulting in 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. 4x Intestinal Protease Agent Solution: Dilute the intestinal homogenate solution to the specified concentration with Assay Buffer; iv. The following table shows an example of preparing a 200 μL Reaction Mix solution according to the table below; [Table 4] v. 10 μL of 4× compound activator, 10 μL of 4× enteroprotease activator, and 20 μL of Reaction Mix solution were sequentially added to a black flat-bottomed 384-well reaction plate. The plate was rapidly centrifuged at 3000 rpm for 10 seconds, and then immediately detected. vi. In dynamic mode, a fluorescence signal with FI=Ex485 / Em 520nm was continuously detected within 30 minutes (once every 5 minutes).

[0043] c) Data analysis The difference in fluorescence signals over 30 minutes was recorded as ΔRFU and calculated. 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 intestinal homogenate was measured by the above test, and the measured IC 50 values are as follows.

Table 5

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

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

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

Table 6

Table 7

[0049] Reaction Buffer Trypsin: 100mM Tris-HCl, 75mM NaCl, 2.5mM CaCl2, 10mM Cysteine, pH 7.5 MMP9: 50mM Tris, 10mM CaCl2, 150mM NaCl, 0.05% Brij-35(w / v), pH7.5 TACE: 25 mM Tris, 2.5 μM ZnCl2, 0.005% Brij-35 (w / v), pH 9.0

[0050] 3. Experiment Steps a) The compound was dissolved in PBS or an equimolar volume aqueous solution of NaOH to prepare a 100 mM stock solution. b) The compound is diluted threefold using a gradient, resulting in a total of 10 concentration points, and the diluent is PBS. c) 5 μL of the gradient-diluted compound solution was taken and added to the experimental plate. d) 4× enzyme activators of Trypsin, MMP9, and TACE were prepared separately, and 5 μL of each was added to a plate to achieve final concentrations of 75 nM, 0.2 μg / mL, and 0.2 μg / mL, respectively. e) Prepare a 2× substrate solution and add 10 μL to Trypsin, MMP9, and TACE plates so that the final concentrations are 120, 10, and 20 μM, respectively. f) After incubation at room temperature (MMP9 and TACE) or 37°C (Trypsin) for 30 minutes (MMP9 and TACE) or 60 minutes (Trypsin), fluorescence values ​​were read using a multifunction microplate reader. g) The signal from the well containing protein and substrate but not the compound was designated as High Control, and the signal from the well containing substrate but not protein or compound was designated as Low Control. The inhibition rate for each test well was calculated using the following formula. Inhibition rate % = 100 - 100 × (Testwell - Low Control) / (High Control - Low Control) h) Using the logarithm of the concentration as the X-axis and the inhibition rate percentage as the Y-axis, the IC205 model fitting effect curve of the analysis software IDBS_XLFit was used to calculate the IC205 for the enzyme activity of each compound. 50 The value was obtained. Fitting formula: fit=(A+((BA) / (1+((C / x)^D)))); A: Bottom; B: Top; C: IC 50 ; D: Hillslope

[0051] The inhibitory effect of the compound of the present invention on the three proteases described above was measured by the above tests. 50 The values ​​were as follows: [Table 8]

[0052] Experimental data show that the compound of the present invention has a certain inhibitory effect on all three proteases.

[0053] Test Example 3 3.1 Experimental Animals: SPF-grade male 220g SD rats were purchased from the Experimental Animal Center of Hangzhou Medical College and inspected and approved by the Zhejiang Provincial Laboratory Animal Quality Supervision and Inspection Station. Thirty SD rats were adaptively reared in the laboratory for 10 days after arrival, and then randomly divided into three groups of 10 rats each, using their ear tag numbers.

[0054] 3.2 Test Substances: The active compound of Test Substance 1 is 5,6,7,8-tetrahydro-1,6-naphthiridine-2-carboxylic acid, and the active compound of Test Substance 2 is (5,6,7,8-tetrahydro-1,6-naphthiridine-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: Take 68.56 g of compound polyethylene glycol electrolyte solution from one bag, dissolve it in 1 L of pure water, and then add 44 g of glucose (hydrated) so that the glucose content of the solvent becomes 4% (w / v). After preparation, store at 2-8°C and use within one week.

[0056] 3.4 Preparation of intragastric solution: A fixed amount of the test substance was weighed, and an appropriate amount of sterile ultrapure water was added to prepare a 20% (w / v) mother liquor. An equivalent amount of NaOH was added to adjust the pH to neutral, and the substance was found to be completely dissolved (pH value measured). One part of the mother liquor was taken, and nine parts of electrolyte solution (1:9, v:v) were added to prepare a 2% (w / v) intragastric solution (pH range measured).

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

[0058] 3.6 Molding: An abdominal adhesion model was created using the filing method. Animals were fasted preoperatively but not watered (>12h). Under inhalation anesthesia, the abdomen was locally dehaired and disinfected with iodine solution. A 3cm incision was made in the midline region of the abdomen of the experimental animals using a scalpel, the cecum was removed, and the serosal layer was repeatedly rubbed with a file on the right side of the ileocecal region until a pinpoint hemorrhage appeared on the surface, creating a wound surface of approximately 0.5cm × 0.5cm. This was returned to the abdominal cavity, and after lavage and administration were completed, the abdominal cavity was closed by suturing one layer at a time with surgical sutures. Three animals from each group were crossed over. A sham surgery control group was set up with only abdominal surgery and no cecal damage.

[0059] 3.7 Administration: A single oral intragastric dose of 12 mL / kg was administered 2 hours before laparotomy. After cecal injury, a single intraperitoneal lavage was performed with 2 mL / animal before abdominal suturing. [Table 9]

[0060] 3.8 Adhesion Score: Postoperative intra-abdominal adhesions were scored using the Phillips classification criteria. The results are shown in the table below. [Table 10]

[0061] 3.9 Result Detection On postoperative day 7, the dissected animals were sacrificed, and the condition of intestinal adhesions was scored using the Phillips classification method. As shown in Figures 1 (sham surgery group), 2 (model group), and 3 (test substance 2), no abdominal and cecal adhesions were observed in the sham surgery group 7 days after molding; in the model group rats, large-area intestinal adhesions were observed in multiple locations 7 days after cecal friction molding; after administering 2% test substance 2 solution intragastricly and lavaging the abdominal cavity with 1% solution, the quantity and extent of intestinal adhesions in over 80% of the animals were clearly improved compared to the model group.

[0062] Test Example 4 4.1 Laboratory Animals Seventy SPF-grade male SD rats, weighing 220±20g each, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. After adaptive rearing in the laboratory for two weeks, the rats were randomly divided into seven groups of eight rats each, using their ear tag numbers.

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

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

[0065] Solutions for intragastric administration of test substance: A fixed amount of test substance 1 was weighed, and 64 mM and 21 mM solutions were prepared by adding an electrolyte solution. An appropriate amount of NaOH was added to adjust the pH to approximately 7.5, and the mixture was allowed to stand. No precipitation was observed. A fixed amount of test substance 2 was weighed, and a 64 mM clear solution was prepared. An appropriate amount of NaOH was added to adjust the pH to neutral. A fixed 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 dose of 12 mL / kg was administered to both the sham surgery group and the model group. [Table 11]

[0067] 4.4 Molding Before surgery, the animals were fasted but not deprived of water (>12 hours). Under inhalation anesthesia, the abdomen was locally depilated and disinfected with iodine solution. A 3 cm incision was made in the midline region of the abdomen of the experimental animals using a scalpel, the cecum was removed, and the serosal layer on both sides of the ileocecal region was repeatedly rubbed with sterile gauze until pinpoint hemorrhages appeared on the surface to form damaged wounds on the inside and outside of the cecum. The cecum was then returned to the abdominal cavity, and the abdominal cavity was closed by suturing each layer with surgical sutures, disinfecting the area. Sterility was maintained throughout the entire surgical procedure. Four animals from each group were crossed over. The sham surgery group only underwent laparotomy and did not damage the cecum.

[0068] 4.5 Adhesion score Anatomical observations were performed during the 7th postoperative period, and the status of postoperative intra-abdominal adhesions was scored using the Phillips classification criteria. The results are shown in the table below. [Table 12]

[0069] 4.6 Results On the 7th postoperative day, surviving animals from each group were dissected, and the condition of intestinal adhesions was scored using the Phillips classification method. As shown in Figure 4, no abdominal-cecal adhesions were observed in the sham surgery group; in the model rats, large-area intestinal adhesions were observed in multiple locations 7 days after cecal friction molding; compared to the model group, one animal in each tranexamic acid group died postoperatively, the degree of intra-abdominal adhesions was clearly reduced in the 64mM group, and tended to be reduced in the 21mM group; in rats administered with 64mM test substance 1, the site and degree of intra-abdominal adhesions were significantly reduced; in rats administered with 21mM test substance 1, the site and degree of adhesions were reduced; and in rats administered with 64mM test substance 2, the site and degree of intra-abdominal adhesions improved to some extent.

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

Claims

1. The use of tetrahydronaphthirizine derivatives in the preparation of drugs for the prevention and treatment of gastrointestinal injury-related diseases, The tetrahydronaphthiridine derivative is selected from 5,6,7,8-tetrahydro-1,6-naphthiridine-2-carboxylic acid, 5,6,7,8-tetrahydro-1,6-naphthiridine-2-phosphonic acid, and hydrates, pharmaceutically acceptable salts, or mixtures of the said compounds, and the said gastrointestinal injury-related disease refers to adhesions, and is used.

2. The adhesion is characterized in that it is postoperative adhesion or a complication resulting from postoperative adhesion. The use described in claim 1.

3. The postoperative adhesions are characterized by being one or more types selected from intestinal adhesions, abdominal adhesions, intercostal adhesions, peritoneal adhesions, and uterine adhesions. The use described in claim 2.

4. The complications resulting from the postoperative adhesions are characterized by being one or more selected from female infertility, postoperative ileus, and pain. The use described in claim 2.

5. The pharmaceutically acceptable salt is characterized by being the hydrochloride salt of the tetrahydronaphthirizine derivative. The use according to any one of claims 1 to 4.

Images