Rebamipivonoprazan salt as well as preparation method and application of rebamipivonoprazan salt

Abstract

The invention belongs to the field of medicines, and discloses a rebamipivonoprazan salt, which has a structure as shown in a formula (I), or an optical isomer or a deuterated compound of the structure as shown in the formula (I), and the structure of the formula (I) is as shown in the specification. The invention discloses a preparation method of the rebamipivonoprazine salt and application of the rebamipivonoprazine salt in preparation of drugs for treating and / or preventing gastric acid related diseases and helicobacter pylori infection diseases.

Description

Technical Field

[0001] This application belongs to the pharmaceutical field and relates to a drug for the preparation of a treatment and / or prevention of gastric acid-related diseases and Helicobacter pylori infection, and particularly to a rebamipide vonoprazan salt, its preparation method and application. Background Technology

[0002] Acid-related diseases (ARDs) are caused by excessive gastric acid secretion or increased mucosal sensitivity to gastric acid, including erosive esophagitis, gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), and gastric mucosal damage associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Currently, the most effective drugs for suppressing acid in clinical practice are proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, and esomeprazole. However, traditional PPIs have the following inherent defects: (1) They need to be activated in an acidic environment to generate sulfenic acid / sulfinamide before they can covalently inhibit H⁺ / K⁺-ATPase, resulting in delayed onset of action; (2) Their metabolism is significantly affected by CYP2C19 gene polymorphism, leading to large individual differences in blood drug concentration; (3) Their plasma half-life is short (0.5–2 h), resulting in insufficient acid suppression intensity and short duration, with significant nocturnal acid rebound, affecting the quality of healing.

[0003] Potassium-competitive acid blockers (P-CABs) directly inhibit H⁺ / K⁺-ATPase by reversibly competing for K⁺ binding sites, without acid activation, thus overcoming the defects of PPIs and are considered potential alternatives to PPIs. Vonoprazan (chemical name: 1-[5-(2-fluorophenyl)-1-(pyridin-3-sulfonyl)-1H-pyrrolo-3-yl]-N-methylamine, structure shown in formula (II)) is the world's first marketed reversible P-CAB. Its fumarate tablets were developed by Takeda Pharmaceutical Company Ltd. of Japan. In December 2014, it was first approved in Japan for the treatment of erosive esophagitis, peptic ulcers, and Helicobacter pylori (H. pylori) infection eradication. It was subsequently approved in China in 2019 and in the United States in 2023. In vitro experiments showed that vonoprazan inhibits the IC50 of H⁺ / K⁺-ATPase. 50 It is approximately 1 / 400th the size of lansoprazole, has a selectivity for Na⁺ / K⁺-ATPase greater than 1000 times, and exhibits significantly superior acid-suppressing activity compared to traditional PPIs.

[0004] Although vonoprazan has shown superior acid-suppressing effects compared to PPIs, its standard clinical treatment course still requires 4–8 weeks, which does not yet meet the clinical demand for "shorter treatment courses and faster healing." Furthermore, the oral absolute bioavailability of vonoprazan fumarate in rats is only about 10%, and its water solubility is poor (<0.1 mg / mL), which is unfavorable for developing non-oral formulations such as injections, thus limiting its clinical application.

[0005] To improve the solubility, bioavailability, and acid-suppressing efficacy of vonoprazan, researchers have attempted to modify its structure or employ salt-forming strategies. For example: Jiangsu Kefeiping Pharmaceutical Co., Ltd. introduced an ether chain benzene ring onto the pyridine ring of vonoprazan to obtain Keverprazan, which significantly improved its water solubility and gastric wall targeting. After animal administration, the drug concentration in gastric tissue was approximately 12.6 times that of vonoprazan. Multiple patent documents (CN105693693A, CN107759568A, KR102222443B1, KR102756118B1, CN103951652B, CN117597338A, CN116262738A, CN1086899) 91B et al. disclosed vonoprazan acetate, mesylate, phosphate, L-malate, citrate, dihydrochloride, orotate, octanoate, pyroglutamate, hydrobromide, L-tartrate, etc., and preliminarily characterized the physicochemical properties of the above salts, such as solubility, hygroscopicity, and solid stability. CN114989138B, CN112839934B, and CN116462659A further formed vonoprazan with flurbiprofen, citrate-tartrate-bismuth complex or ferulic acid to form complex salts / complexes, and investigated the feasibility of intravenous administration.

[0006] However, the aforementioned existing technologies only focus on physicochemical properties or evaluation of local irritation after injection, without providing pharmacokinetic (e.g., Cmax, AUC, F) or in vivo acid-suppressing pharmacodynamics (e.g., duration of pH>4, AUEC) data after oral administration. Since changes in salt form can significantly affect drug dissolution, membrane permeability, and first-pass metabolism in the gastrointestinal tract, thus determining its oral bioavailability and clinical efficacy, the development of a novel vonoprazan salt that can significantly improve oral bioavailability and shorten the treatment course remains a pressing clinical need and an unmet technological requirement. Summary of the Invention

[0007] The technical problem to be solved by this application is to overcome the shortcomings of the prior art and provide a novel vonoprazan salt that can improve oral bioavailability and shorten the course of treatment, as well as its preparation method and application.

[0008] To solve the above-mentioned technical problems, the technical solution proposed in this application is as follows: A rebapetevoranose salt having the structure shown in formula (I), or an optical isomer or deuterated compound of the structure shown in formula (I), wherein the structure of formula (I) is as follows:

[0009] This rebapate vonoprazan salt exhibits better pharmacokinetic properties and in vivo efficacy compared to existing vonoprazan salts.

[0010] The concept of this invention is as follows: Rebamipide [structure shown in formula (III)] can increase the secretion of gastric mucosal fluid, gastric mucosal blood flow, gastric mucosal prostaglandins, and gastric alkaline substances. It has the effects of eliminating hydroxyl free radicals, inhibiting the infiltration of inflammatory cells in the gastric mucosa, and inhibiting the increase in interleukin-8 production in human gastric mucosal epithelial cells caused by Helicobacter pylori. It promotes the regeneration of gastric mucosal cells and repairs damaged gastric mucosa, thus having a promoting healing effect on gastric ulcers and gastritis in clinical practice. Vonoprazan and rebamipide form a salt, which can fully exert the drug compatibility effect through different mechanisms. It can shorten the treatment time of existing vonoprazan [structure shown in formula (II)] in the treatment of gastric acid-related diseases, increase the treatment effect of related diseases, and provide doctors and patients with more clinical drug options.

[0011] Wherein, equation (II) is Equation (III) is .

[0012] It can be understood that salts formed from optical isomers or deuterated compounds of formulas (II) and (III) can be used.

[0013] According to one alternative embodiment, the melting point of the rebapete vonopate salt is 238-243°C, and in some embodiments the melting point of the vonopate vonopate salt is 240.67°C.

[0014] Optionally, the XRD pattern of this rebapai tevonola salt has diffraction peaks at 2θ values ​​of: 7.171±0.2°, 7.737±0.2°, 12.954±0.2°, 14.372±0.2°, 18.571±0.2°, 18.848±0.2°, 19.698±0.2°, 20.404±0.2°, 21.141±0.2°, 21.592±0.2°, and 25.485±0.2°.

[0015] Optionally, the XRD pattern of this rebapai tevonola salt has diffraction peaks at 2θ values ​​of 9.302±0.2°, 10.371±0.2°, 15.341±0.2°, 17.468±0.2°, 18.268±0.2°, 22.050±0.2°, 24.510±0.2°, 25.165±0.2°, 26.152±0.2°, 26.482±0.2°, 26.772±0.2°, and 28.421±0.2°.

[0016] Optionally, in the XRD pattern of this rebapai tevonola salt, at 6.510±0.2°, 11.685±0.2°, 12.092±0.2°, 16.418±0.2°, 22.382±0.2°, 22.882±0.2°, 23.085±0.2°, 27.438±0.2°, 28.029±0.2°, 28.813±0.2°, 29.216±0.2°, 29.831±0.2°, 30.833±0.2°, 31.157±0.2°, 31.722±0.2°, 32.492±0.2°, 33.048±0.2°, 35.934±0.2°, 37 A diffraction peak is present at 0.552±0.2°.

[0017] This application also provides a method for preparing the rebapate vonoprazan salt, comprising the following steps: mixing rebapate and vonoprazan in an organic solvent, heating to react, and collecting the solid precipitated in the reaction mixture to obtain the rebapate vonoprazan salt.

[0018] Rebamipide contains a carboxyl group and is a Lewis acid; vonoprazan contains an amino group and is a Lewis base. They can combine to form an ionic salt. Utilizing the difference in solubility between this ionic salt and the reactants, the ionic salt can precipitate from the reaction mixture, thus easily separating the rebamipide vonoprazan salt.

[0019] Optionally, the organic solvent is one or a mixture of several of the following: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, dioxane, ethylene glycol dimethyl ether, dichloromethane, N,N-dimethylformamide, methyl tert-butyl ether, 1,2-dichloroethane, and chloroform.

[0020] Optionally, during the heating process, the temperature of the reaction mixture is controlled to be above 70°C, or the organic solvent in the reaction mixture is placed in a reflux state.

[0021] Optionally, rebamipide is added to an organic solvent, heated to dissolve, then vonoprazan is added, and the mixture is heated for 0.5-3 hours, then cooled to room temperature. The precipitated solid is then separated to obtain the rebamipide vonoprazan salt.

[0022] Optionally, the molar amount of vonoprazan added to the reaction mixture is 1.1-1.8 times that of rebapamide.

[0023] Based on the same inventive concept, this application also provides a pharmaceutical composition comprising the aforementioned rebamipide vonoprazan salt. For example, the pharmaceutical composition may also contain a drug carrier to load the rebamipide vonoprazan salt.

[0024] Based on the same inventive concept, this application also provides the use of the above-mentioned rebamipide vonoprazan salt in the preparation of medicaments for the treatment and / or prevention of gastric acid-related diseases and Helicobacter pylori infection.

[0025] Compared with the prior art, the advantages of the present invention are as follows: This application involves reacting rebamipide with vonoprazan to form a salt, resulting in a novel vonoprazan salt that can improve oral bioavailability, increase the healing rate of gastric ulcers, and potentially shorten the course of treatment. This salt can be used in the preparation of drugs for the treatment and / or prevention of acid-related diseases and Helicobacter pylori infection, and is particularly suitable for the preparation of drugs for the treatment of gastric ulcers, exhibiting very good efficacy. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 The chemical formula for rebapete vonoprene is 1.

[0028] Figure 2 The nuclear magnetic resonance spectrum of the rebapiprofen salt prepared for Experiment 1.

[0029] Figure 3 The X-ray powder diffraction pattern of the rebapiperazine prepared in Experiment 1.

[0030] Figure 4 DSC diagram of the rebapi tevoranopyr prepared for Experiment 1.

[0031] Figure 5 TGA image of the rebapiprofen prepared in Experiment 1.

[0032] Figure 6 X-ray powder diffraction patterns of rebapiperazine after treatment under different conditions. Detailed Implementation

[0033] To facilitate understanding of this application, the following description will be more comprehensive and detailed in conjunction with the accompanying drawings and preferred embodiments, but the scope of protection of this application is not limited to the specific embodiments described below.

[0034] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of this application.

[0035] Unless otherwise specified, all reagents and raw materials used in this application are commercially available products or products that can be prepared by known methods.

[0036] Example 1: Preparation of Rebapai Tevonolatum Salt (1) Experiment 1 Rebamipide (1 g, 2.7 mmol) was added to 20 ml of methanol solvent and stirred under reflux for 1 hour. Then, 1.5 equivalents (1.4 g, 4.1 mmol) of vonoprazan (free base, in an oily state) were added and briefly dissolved. Stirring was continued at the same temperature until a solid gradually precipitated. This process was continued for 1 hour, followed by slow cooling to room temperature and stirring for 5 hours. A white solid continued to precipitate. The solution was filtered to obtain vonoprazan-rebamipide salt (chemical structure shown below). Figure 1 It was named crystal form A.

[0037] Rebapapa vonoporogenous salt crystal form A nuclear magnetic resonance spectral data (see NMR spectrum) Figure 2 ): 1 H NMR (400MHz, DMSO- d 6) delta 11.58 (s, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.95 – 7.86 (m, 2H), 7.83 – 7.77 (m, 2H), 7.73(s, 1H), 7.65 – 7.58 (m, 1H), 7.56 – 7.43 (m, 4H), 7.30 (d, J = 8.0 Hz, 1H),7.25 – 7.14 (m, 3H), 7.10 (t, J= 7.6 Hz, 1H), 6.50 (s, 1H), 6.41 (s, 1H), 4.62 – 4.48 (m, 1H), 3.84 (s, 2H), 3.52 (dd, J = 13.6, 4.0 Hz, 1H), 3.10 (dd, J = 14.0, 10.0 Hz, 1H), 2.42 (s, 3H). The spectrum shows that rebappetite and vonoprene form an equisional salt.

[0038] The X-ray powder diffraction pattern of the rebapapa tevonola salt crystal form A obtained in this embodiment is shown below. Figure 3 When the 2θ values ​​are 6.510±0.2°, 7.171±0.2°, 7.737±0.2°, 9.302±0.2°, 10.371±0.2°, 11.685±0.2°, 12.092±0.2°, 12.954±0.2°, 14.372±0.2°, 15.341±0.2°, and 16... 0.418±0.2°, 17.468±0.2°, 18.268±0.2°, 18.571±0.2°, 18.848±0.2°, 19.698±0.2°, 20.404±0.2°, 21.141±0.2°, 21.592±0.2°, 22.050±0.2°, 22 0.382±0.2°, 22.882±0.2°, 23.085±0.2°, 24.510±0.2°, 25.165±0.2°, 25.485±0.2°, 26.152±0.2°, 26.482±0.2°, 26.772±0.2°, 27.438±0.2°, 28.029±0.2°, 28.421±0.2°, 28.813±0.2°, 29.216±0.2°, 29.831±0.2°, 30.833±0.2°, 31.157±0.2°, 31.722±0.2°, 32.492±0.2°, 33.048±0.2°, 35 Diffraction peaks are observed at 0.934±0.2° and 37.552±0.2°.

[0039] The DSC image of the rebapapa tevonola salt crystal form A obtained in the embodiments of this application is shown below. Figure 4Differential thermal analysis (DTA) results showed a distinct endothermic peak near 132.34°C, with an initial temperature of 124.54°C and a peak temperature of 132.34°C. The calculated enthalpy of fusion was 4.1681 J / g. During heating, the sample exhibited a sharp endothermic peak with an extrapolated onset temperature of 240.67°C and a peak temperature of 241.60°C. The calculated enthalpy of fusion was 105.26 J / g, indicating a melting point of 240.67°C. The TGA chromatogram of the rebapiperazine vonoporogen salt crystal form A obtained in the embodiments of this application is shown below. Figure 5 The results showed that the compound had a weight loss plateau at 105.00℃, with a weight loss of 0.005 mg (weight loss rate of 0.072%), indicating that it has good thermal stability.

[0040] Similarly, using ethanol and isopropanol under the same operating conditions, the rebamipide vonoprazan salt was also prepared in crystal form A. The specific solvents and operations are shown in Table 1 below, where the solvent volume represents the concentration of 1g of raw material rebamipide in the solvent (similar expressions are used below, with the same meaning).

[0041] Table 1 Solvents and Operations

[0042] (2) Experiment 2 Rebamipide (1 g, 2.7 mmol) was added to 100 ml of acetone solvent and stirred under reflux for 1 hour. Then, vonoprazan (1.4 g, 4.1 mmol) was added, but it did not dissolve completely. Stirring continued at the same temperature for another hour, followed by slow cooling to room temperature and stirring for 5 hours. A slight increase in solids was observed. The solid was obtained by filtration. Nuclear magnetic resonance spectroscopy and powder X-ray diffraction confirmed it to be vonoprazan-rebamipide salt, crystal form A.

[0043] Similarly, using tetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether, dioxane, ethylene glycol dimethyl ether, dichloromethane, and isopropanol under the same operating conditions, crystal form A can also be prepared. The specific solvents and operations are shown in Table 2 below.

[0044] Table 2 Solvents and Operations

[0045] (3) Experiment 3 Rebamipide (1 g, 2.7 mmol) was added to 15 ml of N,N-dimethylformamide solvent and stirred at 80 °C for 1 hour. Then, vonoprazan (1.4 g, 4.1 mmol) was added and dissolved. Stirring continued at the same temperature for another hour without any solid precipitation. After adding 150 ml of water, solid gradually precipitated. The mixture was then slowly cooled to room temperature and stirred for 5 hours, resulting in a slight increase in solid concentration. The solid was obtained by filtration. Nuclear magnetic resonance spectroscopy and X-ray powder diffraction confirmed it to be vonoprazan-rebamipide salt, crystal form A.

[0046] Similarly, using N,N-dimethylacetamide under the same operating conditions, crystal form A was also prepared. The specific solvent and operation are shown in Table 3 below.

[0047] Table 3 Solvents and Operations

[0048] (4) Experiment 4 Rebamipide (1 g, 2.7 mmol) was added to solvent A and stirred for half an hour at the specified temperature (as shown in Table 4). Vonoprazan (1.4 g, 4.1 mmol) was then added to the solution, and the mixture dissolved and clarified. Stirring continued for 5–10 minutes, followed by addition to solvent B. The mixture was then stirred for another hour at the same temperature, followed by slow cooling to room temperature and stirring for 5 hours. The solid was obtained by filtration. Nuclear magnetic resonance spectroscopy and powder X-ray diffraction confirmed it to be vonoprazan-rebamipide salt crystal form A.

[0049] Similarly, the same effect was obtained by using the solvents listed in Table 4 below.

[0050] Table 4 Solvents and Operations

[0051] Example 2: Experiment on factors affecting the crystal form A of rebapiperazine vonoporogen. Rebapai vonoprazan salt crystal form A was placed in an open, clean weighing bottle. The stability of the sample was investigated under the conditions of high temperature 60℃±2℃, light irradiation (visible light: 4500lux±500lux), and high humidity 90%±5% RH. The sampling period was 30 days. The results are shown in Table 5 below.

[0052] Table 5. Stability of samples under high temperature, light, and high humidity conditions

[0053] Experimental results show that rebamectin vonoprazan salt of formula I exhibits good chemical stability under conditions of 60℃ and 92.5%RH. Under light irradiation, the chemical stability of rebamectin vonoprazan salt of formula I is slightly worse.

[0054] X-ray powder diffraction pattern ( Figure 6 The results show that the crystal form A of rebapapait vonoprazan is relatively stable under high temperature (60℃), high humidity (92.5%RH), and light (5000Lux) conditions.

[0055] In this application, the high-performance liquid chromatography (HPLC) purity data are obtained from a Shimadzu LC-2050, and the detector used is a diode array detector (PDA). The HPLC method parameters for testing purity in this application are as follows: Using octadecylsilane-bonded silica gel as the packing material, the mobile phase A was 0.02 mol / L dipotassium hydrogen phosphate solution (adjusted to pH 11.0 with 3M potassium hydroxide solution), the mobile phase B was acetonitrile, and the mobile phase C was methanol. Gradient elution was performed according to Table 6 below. The flow rate was 1.0 mL per minute, the detection wavelength was 254 nm, the column temperature was 30 °C, and the injection volume was 2 μL.

[0056] Table 6 Gradient elution conditions

[0057] Example 3: Pharmacokinetic Study of Rebamipide-Vonoprazan Salt in Rats After Single Intravenous Injection Experimental Methods: Nine male SD rats (6-8 weeks old; 180g-240g) were randomly divided into 3 groups (n=3). Equimolar amounts of vonoprazan fumarate, rebamipide (vonoprazan salt A), and rebamipide (calculated as 18.2×10⁻³ mmol / kg based on vonoprazan fumarate 8.4 mg / kg, solvent: 10% DMSO + 40% PEG-400 + 50% physiological saline) were slowly injected intravenously. Blood samples were collected before administration and at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 4 h, and 8 h after administration. Approximately 120 μL of blood was collected via the jugular or tail vein into EDTA-K2 anticoagulant tubes and placed on moist ice. The tubes were then centrifuged (2000g, 10 min, 4℃) to separate the plasma. The plasma was then transferred to individual test tubes and immediately frozen (at -70℃) until analysis. The concentrations of free vonoprazan and rebamipide in rat plasma were measured. The results are shown in Table 7 below.

[0058] Table 7. Pharmacokinetic parameters of vonoprazan and rebamipide in plasma of SD rats after a single intravenous administration (Mean±SD, n=3)

[0059] Experimental results showed that the AUC of free vonoprazan molecules in plasma after injection of vonoprazan fumarate was... 0-last The mean value was 1323 h·ng / mL, and the AUC of free vonoprazan molecules in salt crystal form A was...0-last The mean value was 1299 h·ng / mL. Rebamipide AUC 0-last The mean value was 6785 h·ng / mL, and the AUC of rebamipide in salt crystal form A was... 0-last The mean value was 6443 h·ng / mL. The plasma exposure of each drug in vonoprazan salt form A of rebamipide was essentially consistent with the exposure of each drug administered alone, and the plasma drug-time curves in rats were also essentially consistent. The half-life (t) of rebamipide after injection... 1 / 2 The time to rebamipide concentration in injected salt crystal form A plasma was 0.52 h. 1 / 2 The time to rebamipide concentration in plasma of salt crystal form A was 1.44 h. 1 / 2 It has been extended.

[0060] Example 4: Pharmacokinetic Study of Rebamipide Vonoprazan Salt in Rats After Single Oral Administration Experimental Methods: Nine male SD rats (6-8 weeks old; 180g-240g) were randomly divided into 3 groups (n=3). Each group was orally administered equimolar amounts of vonoprazan fumarate, rebamipide (vonoprazan salt crystal form A), and rebamipide (calculated at vonoprazan fumarate 8.4mg / kg, each equivalent to 18.2×10⁻⁶ mg / kg). -3 Blood was collected at 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 24 hours after administration (mmol / kg, solvent: 0.5% methylcellulose). Approximately 120 μL of blood was collected via the jugular or tail vein into EDTA-K2 anticoagulant tubes and placed on wet ice. The tubes were centrifuged (2000g, 10 min, 4℃) over 30 min to separate the plasma. The plasma was then transferred to separate test tubes and immediately frozen (at -70℃) until analysis. The concentrations of free vonoprazan and rebamipide in the plasma were measured. The experimental results are shown in Table 8 below.

[0061] Table 8. Pharmacokinetic parameters of vonoprazan and rebamipide in plasma of SD rats after a single oral administration (Mean±SD, n=3)

[0062] Experimental results showed that the AUC of free vonoprazan in plasma after oral administration of vonoprazan fumarate was... 0-last The mean value was 210 h.ng / mL, and the AUC of free vonoprazan in plasma in oral saline crystal form A was... 0-last The mean value was 331 h·ng / mL, which was 1.58 times that of oral vonoprazan fumarate; the AUC of free molecules in plasma after oral rebamipide was... 0-last The mean value was 159 h·ng / mL, and the AUC of rebamipide free molecules in oral saline crystalline A plasma was... 0-lastThe concentration was 295 h·ng / mL, which is 1.86 times that of oral rebamipide. The exposure levels of all drugs in rebamipide vonoprazan salt form A were higher than those administered alone. (Rebamipide t) 1 / 2 For 2.04 h, rebappetite T in salt crystal form A 1 / 2 The time was 2.88 h, and the comparison showed that the t of rebamipide in salt crystal form A was 2.88 h. 1 / 2 It has been extended.

[0063] Based on data from intravenous administration, and according to the formula: Bioavailability F = Oral plasma exposure at the same dose / Intravenous plasma exposure × 100%, the bioavailability of oral vonoprazan fumarate was 15.87%, while the bioavailability of oral vonoprazan salt form A in plasma was 25.48%, indicating that oral vonoprazan salt form A improves the bioavailability of vonoprazan. In this experiment, the bioavailability F of oral rebamipide was 2.34%, while the bioavailability F of oral rebamipide vonoprazan salt form A was 4.58%, indicating that oral vonoprazan salt form A also improves the bioavailability of rebamipide.

[0064] In summary, compared with oral administration of vonoprazan fumarate and rebamipide alone, oral administration of rebamipide to vonoprazan salt crystal form A in rats improved the bioavailability and exposure of both vonoprazan and rebamipide, suggesting that they may exhibit stronger in vivo pharmacodynamic effects than either drug alone.

[0065] Example 5: Study on the anti-gastric ulcer efficacy of rebamipide vonoprazan salt crystal form A Experimental Methods: Male SD rats were randomly divided into 5 groups according to their body weight (sham-operated control group, model control group, vonoprazan fumarate 2.67 mg / kg group, rebamipide vonoprazan salt crystal form A group 4.14 mg / kg group, and rebamipide 2.15 mg / kg group). Except for the sham-operated control group (n=5), each of the other groups had 8 animals. All animals were administered the drug at an equimolar dose (equivalent to 20 mg of human clinical dose based on vonoprazan), and the solvent was 0.5% methylcellulose. The drug was administered orally once. After fasting for 24 hours but with unlimited water, the animals were given the solvent or compound orally. One hour after administration, the animals were anesthetized with isoflurane and, except for the sham-operated group, the pylorus was ligated with 5-0 silk suture. After pyloric ligation, the animals were fasted and deprived of water for 18 hours. After 18 hours of fasting and deprivation of water, the animals were euthanized. After ligation of the pylorus and cardia, the stomach was harvested, cut open along the greater curvature, and flattened. The length and width of the gastric ulcer were measured, the ulcer area was calculated, and the ulcer index was evaluated. The ulcer scoring criteria are shown in Tables 9 and 10 below.

[0066] Table 9 Macroscopic Scoring Criteria for Gastric Tissue

[0067] Table 10 Okabe Gastric Ulcer Score

[0068] The ulcer scores of each group of rats are shown in Table 11 below.

[0069] Table 11 Ulcer scores of rats in each group (Mean±SEM, n=8)

[0070] Notes: ①1. Ulcer total score inhibition rate = (total ulcer score in model control group - total ulcer score in drug-treated group) / total ulcer score in model control group × 100%; ②Compared with the sham-operated control group, ### express P <0.001; compared with the model group, * indicates P <0.05 Experimental results: From a macroscopic scoring perspective, except for the rebamipide group, compared with the model control group, the total ulcer score of the oral rebamipide vonoprazan salt crystal form A group and the vonoprazan fumarate group was significantly reduced. P <0.05%, both showed significant anti-gastric ulcer effects, and rebamipide vonoprazan salt crystal form A showed a stronger trend in anti-gastric ulcer activity compared to vonoprazan fumarate. From the Okabe score, compared to the model control group, rebamipide vonoprazan salt crystal form A was significantly reduced ( P The concentration of rebamipide (<0.05) also indicates a stronger anti-gastric ulcer effect compared to vonoprazan fumarate. In terms of the overall ulcer score inhibition rate, oral rebamipide vonoprazan salt crystal form A showed a higher inhibition rate compared to vonoprazan fumarate. These data indicate that oral administration of rebamipide vonoprazan salt crystal form A to rats has a stronger anti-gastric ulcer effect than oral administration of vonoprazan fumarate.

[0071] In summary, rebamipide vonoprazan salt crystal form A exhibits better pharmacokinetic properties and stronger anti-gastric ulcer effects in rats compared to vonoprazan fumarate and rebamipide monotherapy. It is expected to improve the clinical efficacy in treating and / or preventing gastric acid-related diseases such as gastric ulcers and Helicobacter pylori infection.

Claims

1. A type of rebapiperazine, characterized in that, The rebapete vonoprazan salt has the structure shown in formula (I), or an optical isomer or deuterated compound of the structure shown in formula (I), wherein the structure of formula (I) is as follows: .

2. The rebapete vonoprazan salt according to claim 1, characterized in that, The melting point of the rebapaite vonoran salt is 238-243℃.

3. The rebapete vonoprazan salt according to claim 1, characterized in that, The XRD pattern of the rebapaite vonoporane salt shows diffraction peaks at 2θ values ​​of 7.171±0.2°, 7.737±0.2°, 12.954±0.2°, 14.372±0.2°, 18.571±0.2°, 18.848±0.2°, 19.698±0.2°, 20.404±0.2°, 21.141±0.2°, 21.592±0.2°, and 25.485±0.2°.

4. A method for preparing the rebapete vonoprazan salt of claim 1, characterized in that, Includes the following steps: Rebapate and vonoprazan are mixed in an organic solvent and heated to react. The solid precipitated in the reaction mixture is collected to obtain the rebapate-vonoprazan salt.

5. The method according to claim 4, characterized in that, The organic solvent is one or a mixture of several of the following: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, dioxane, ethylene glycol dimethyl ether, dichloromethane, N,N-dimethylformamide, methyl tert-butyl ether, 1,2-dichloroethane, and chloroform.

6. The method according to claim 4, characterized in that, During the heating process, the temperature of the reaction mixture is controlled to be above 70°C, or the organic solvent in the reaction mixture is kept in a reflux state.

7. The method according to claim 4, characterized in that, Rebamipide is added to an organic solvent and heated to dissolve. Then vonoprazan is added, and the mixture is heated for 0.5-3 hours. The mixture is then cooled to room temperature, and the precipitated solid is separated to obtain the rebamipide-vonoprazan salt.

8. The method according to claim 4, characterized in that, The molar amount of vonoprazan added to the reaction mixture is 1.1-1.8 times that of rebamipide.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises rebamipide vonoprazan salt as described in any one of claims 1-3.

10. The use of rebamipide vonoprazan salt according to any one of claims 1-3 in the preparation of a medicament for treating and / or preventing gastric acid-related diseases and Helicobacter pylori infection.

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