Imidazolo[1,2-a]pyridine compounds, their preparation methods and applications

Abstract

This invention belongs to the field of biomedical technology, specifically relating to an imidazo[1,2-a]pyridine compound, its preparation method, and its applications. The imidazo[1,2-a]pyridine compound has the following structural formula: [Formula omitted for brevity]. Wherein, R is selected from sodium ions, potassium ions, calcium ions, magnesium ions, lithium ions, or ammonium ions; when R is a sodium ion, potassium ion, ammonium ion, or lithium ion, n=2; when R is a calcium ion or magnesium ion, n=1. The imidazo[1,2-a]pyridine compound provided by this invention exhibits high solubility, high dissolution rate, and excellent bioactivity in inhibiting gastric acid secretion, providing a new option for treating gastric acid-related diseases such as peptic ulcers.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to an imidazo[1,2-a]pyridine compound, its preparation method, and its application. Background Technology

[0002] Peptic ulcer, primarily referring to chronic ulcers occurring in the stomach and duodenum, is a common disease worldwide. It is characterized by high incidence, long course, and high recurrence rate, and can occur at any age. Common complications of peptic ulcers include upper gastrointestinal bleeding, perforation, pyloric obstruction, and malignant transformation. Upper gastrointestinal bleeding is the most common complication, more prevalent in duodenal ulcers than gastric ulcers, and is the leading cause of non-variceal rupture bleeding.

[0003] The main pathogenic factors of peptic ulcers include hyperacidity, weakened mucosal protection, and Helicobacter pylori infection. Therefore, common clinical treatment regimens include anti-Hp therapy, inhibition of gastric acid secretion, and protection of the gastric mucosa. Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole, and ilaprazole, are among the first-line drugs for treating peptic ulcers (PUD). They strongly inhibit gastric acid secretion, creating a low-acid environment for ulcer healing. Traditional PPIs, after reaching the secretory tubules of gastric parietal cells, require an acidic environment to be activated and covalently bind to H+ / K+-ATPase in stimulated parietal cells. P-CABs, however, can be activated without an acidic environment. They bind non-covalently to phosphorylated E2-type H+ / K+-ATPase in a K+-competitive and reversible manner, thereby inhibiting H+-K+-ATPase, blocking H+ and K+ exchange, and thus inhibiting gastric acid secretion.

[0004] Current proton pump inhibitors (PPIs) have several drawbacks. For example: 1) They carry the risk of fractures and mineral deficiencies. High-dose PPIs used for more than one year can inhibit the absorption of calcium, magnesium, and iron in the intestines, increasing the risk of hip, wrist, and spinal fractures; 2) They can cause intestinal infections and dysbiosis. PPIs can weaken the gastric acid barrier, potentially increasing the incidence of intestinal infections such as Clostridium difficile, Salmonella, and norovirus; 3) Long-term use of PPIs may lead to small intestinal bacterial overgrowth (SIBO); 4) Long-term use of PPIs may be associated with acute interstitial nephritis and the progression of chronic kidney disease, and creatinine monitoring is required in some high-risk individuals; 5) Rebound gastric acid increase may occur within 1-2 weeks after abrupt discontinuation of the drug, causing heartburn and upper abdominal pain, which can easily be mistaken for a relapse of the original disease, leading to re-administration and long-term dependence.

[0005] Potassium-competitive acid blockers (P-CABs) are novel acid-suppressing agents, including vonoprazan, tigorazan, and kelprazan. Compared to traditional PPIs, P-CABs have significant clinical advantages: 1) Faster onset of action: Gastric pH can be significantly increased within 2-4 hours after the first dose, while PPIs require 3-5 days to reach maximum acid-suppressing effect; 2) Longer acid-suppressing intensity and duration: The maintenance time ratio (HTR) of P-CABs maintaining pH > 6 reaches 75%, rising to 97% by day 7, significantly higher than PPIs (≈40%-50%); 3) Better nocturnal acid suppression: Due to the dual inhibition of the resting and active pumps, nocturnal acid breakthrough (NAB) is significantly reduced, which is beneficial for nocturnal mucosal protection in patients with duodenal bulb ulcers and high risk of bleeding. Therefore, P-CABs have broad clinical development prospects.

[0006] Imidazo[1,2-a]pyridine is a key chemical backbone that forms the core of first-generation P-CAB drugs. Currently, substituted imidazo[1,2-a]pyridines are used to treat peptic ulcer disease. These are documented in patents such as EP0033094A1, US4450164A, EP0204285A1, US4725601A, WO1999055706A1, WO1999055705A1, WO2003018582A1, and WO2006100119A1, as well as in JJ Kaminski et al.'s publication in J. Med. Chem., "Antiulcer agents. 1. Gastric antisecretory and cytoprotective properties of substituted imidazo[1,2-a]pyridines" (1985, vol. 28, i7, p876–892) and "Antiulcer agents. 5. Inhibition of gastric H+ / K+-ATPase by substituted...". This has been disclosed in publications such as *Imidazo[1,2-a]pyridines and related analogs and its implication in modeling the high affinity potassiumion binding site of the gastric proton pump enzyme* (1991, vol. 34, i2, pp. 533-541). However, existing imidazo[1,2-a]pyridine compounds have drawbacks such as poor solubility, limited dosage forms, and a relatively long onset time after administration. This remains inconvenient for patients with peptic ulcers, especially those with acute bleeding.

[0007] Therefore, there is an urgent need to provide a P-CAB with higher solubility and faster onset of action. Summary of the Invention

[0008] In view of this, one of the objectives of the present invention is to provide a compound with high solubility, which supports the development of novel potassium ion competitive acid blockers.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A highly soluble compound, said compound being an imidazo[1,2-a]pyridine derivative or a pharmaceutically acceptable salt thereof, having the structural formula shown in Formula I;

[0011]

[0012] Ⅰ;

[0013] Wherein, R is selected from sodium ion, potassium ion, calcium ion, magnesium ion, lithium ion or ammonium ion; when R is sodium ion, potassium ion, ammonium ion or lithium ion, n=2; when R is calcium ion or magnesium ion, n=1.

[0014] Preferably, the compound is any one of compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13; the structural formulas of each compound are as follows:

[0015] .

[0016] A second objective of this invention is to provide a method for preparing compounds 8, 9, 10, or 11.

[0017] To achieve the above objectives, the present invention adopts the following technical solution:

[0018] The preparation method of compounds 8, 9, 10 or 11 includes the following steps:

[0019] (1) Add 1H-tetrazole and starting material 2 to the mixture of acetonitrile and DCM. After the reaction solution is cooled to 0~5℃, add dibenzyl N,N-diisopropylphosphamide to react. After the reaction is completed, add m-chloroperoxybenzoic acid to continue the reaction to obtain compound 4.

[0020] (2) Using compound 4 obtained in step (1) as a raw material and palladium on carbon as a catalyst, compound 6 was obtained by reaction;

[0021] (3) React the compound 6 obtained in step (2) with NaOH, KOH, concentrated ammonia or lithium hydroxide to obtain the target compound;

[0022] The structural formulas of starting material 2, compound 4, and compound 6 are as follows:

[0023] .

[0024] Preferably, in step (1), the molar ratio of the starting material 2, the 1H-tetrazole, the dibenzyl N,N-diisopropylphosphamide, and the m-chloroperoxybenzoic acid is 0.08~0.15:0.15~0.2:0.14~0.18:0.14~0.18, more preferably 0.11:0.176:0.165:0.165.

[0025] Preferably, step (1) includes: adding 1H-tetrazole and the starting material 2 to a mixture of acetonitrile and DCM; cooling the resulting reaction solution to 0-5°C; adding dibenzyl N,N-diisopropylphosphite; and reacting at 0-5°C for 3.5-6 hours; after the reaction is complete, adding m-chloroperoxybenzoic acid; and reacting at 0-5°C for 0.3-1 hours to obtain compound 4. More preferably, the reaction is carried out for 4.5 hours after adding dibenzyl N,N-diisopropylphosphite, and then for 0.5 hours after adding m-chloroperoxybenzoic acid.

[0026] Preferably, in step (1), the volume ratio of acetonitrile to DCM is 1:0.5~2, more preferably 1:1.

[0027] As a preferred embodiment, the post-processing steps of step (1) include: adding DCM to the obtained reaction solution, washing twice with 5% sodium thiosulfate solution, separating the liquid, and washing with water and saline solution in sequence; drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound 4.

[0028] As a preferred option, step (2) is as follows:

[0029] Method 1: Dissolve compound 4 obtained in step (1) in formic acid, add palladium on carbon, and react to obtain compound 6;

[0030] Or method 2: 1) Dissolve compound 4 obtained in step (1) in methanol, add palladium on carbon, and react to obtain compound 5; 2) Dissolve compound 5 obtained in step 1) in a mixed solvent of formic acid and methanol, add palladium on carbon, and react to obtain compound 6;

[0031] The structural formula of compound 5 is as follows:

[0032]

[0033] Compound 5.

[0034] Preferably, in Method 1, the mass ratio of compound 4, formic acid, and palladium on carbon is 80~110:1000~2000:5~15; in step 1) of Method 2, the amount ratio of compound 4, methanol, and palladium on carbon is 40~60g:0.8~1.2L:3.5~5.5g; in step 2) of Method 2, the amount ratio of compound 5, formic acid, methanol, and palladium on carbon is 0.3~1.0g:10~20g:4~10mL:5~15mg.

[0035] Preferably, in method one, the mass ratio of compound 4, formic acid, and palladium on carbon is 94.8:1520:9.12.

[0036] Preferably, in step 1) of method 2, the ratio of compound 4, methanol and palladium on carbon is 49.8g:1.03L:4.56g.

[0037] Preferably, in step 2) of method 2, the ratio of compound 5, formic acid, methanol and palladium on carbon is 0.5g:13.8g:6mL:10mg.

[0038] As a preferred method, in method one, the reaction temperature is from room temperature to 35°C, and the reaction time is from 4 hours to overnight.

[0039] As a preferred embodiment, in step 1) of method 2, the reaction temperature is from room temperature to 35°C, and the reaction time is from 4 hours to overnight;

[0040] As a preferred option, in step 2) of method 2, the reaction temperature is from room temperature to 35°C, and the reaction time is from 4 hours to overnight.

[0041] Preferably, in step (2), the palladium on carbon is 3% to 20%, and more preferably 10%.

[0042] As a preferred method, in method one, the reaction conditions are overnight at room temperature; TLC (DCM:MeOH = 15:1, 1 drop of acetic acid) is used to monitor the disappearance of the starting material.

[0043] As a preferred method, after the reaction is completed, the resulting reaction solution is filtered and concentrated under reduced pressure; the concentrate is added to methanol, dispersed in a water bath at 45-50°C, water is added dropwise, crystallized in an ice bath, filtered, and dried under reduced pressure to obtain compound 6.

[0044] As a preferred option, in step 1) of method 2, the reaction conditions are room temperature reaction for 4.5 hours.

[0045] As a preferred embodiment, the reaction solution obtained in step 1) of method two is filtered, washed with methanol, dispersed in a methanol / water mixture, and 1N NaOH solution is added dropwise to adjust the pH to 8-9; the mixture is then filtered, and the filtrate is placed in an ice bath, where 1N hydrochloric acid solution is added dropwise to adjust the pH to 5-6; crystallization occurs, followed by filtration and drying under reduced pressure to obtain compound 5. Preferably, the volume ratio of methanol to water in the methanol / water mixture is 1:1.

[0046] As a preferred option, in step 2) of method 2, the reaction conditions are overnight at room temperature.

[0047] As a preferred option, in step 2) of method two, after the reaction is completed, the resulting reaction solution is filtered, the filter cake is dispersed in water, the pH is adjusted to 13 with 1 NaOH, and then filtered; the pH of the filtrate is adjusted to 2 with 1N hydrochloric acid; crystals are precipitated, filtered, and dried under reduced pressure to obtain compound 6.

[0048] Preferably, in step (3), the pH is controlled to be 7-11; the reaction solvent is any one or more of methanol, ethanol, isopropanol, and a mixture of methanol and chloroform, more preferably methanol.

[0049] Preferably, in step (3), the pH is controlled to be 9-11.

[0050] As a preferred embodiment, in step (3), when the target compound is compound 7, 1N NaOH solution is added dropwise to adjust the pH to 7; when the target compound is compound 8, 1N NaOH solution is added dropwise to adjust the pH to 10-11; when the target compound is compound 9, 1N KOH solution is added dropwise to adjust the pH to 9; when the target compound is compound 10, concentrated ammonia is added dropwise to adjust the pH to 9; and when the target compound is compound 11, 1N lithium hydroxide solution is added dropwise to adjust the pH to 9-10.

[0051] Preferably, in step (3), the ratio of compound 6 to solvent is 1g:5~15mL, more preferably 1g:7.5~15mL, and most preferably 1g:7.5mL.

[0052] Preferably, in step (3), the post-processing steps include: the obtained reaction solution is concentrated under reduced pressure, crystallized in an ice bath, filtered, and dried under reduced pressure to obtain the target compound; the crystallization solvent is acetone.

[0053] Preferably, the starting material 2 is prepared by the following method:

[0054] S1: Starting material 1 is obtained by reacting methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate and 2,6-dimethylbenzyl chloride in the presence of sodium iodide and potassium carbonate.

[0055] S2: The starting material 1 obtained from S1 is mixed with ethanolamine and DBU, and the mixture is heated to reflux to react and obtain the starting material 2.

[0056] The structural formula of the starting material 1 is as follows:

[0057]

[0058] Starting material 1.

[0059] Preferably, in S1, the molar ratio of methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate, sodium iodide, potassium carbonate, and 2,6-dimethylbenzyl chloride is 0.01~0.03:0.008~0.015:0.03~0.07:0.01~0.03, more preferably 0.02:0.012:0.05:0.022.

[0060] Preferably, in S1, the reaction temperature is 50-80°C and the reaction time is 1.5-4 hours, more preferably 60°C for 2 hours.

[0061] Preferably, in S1, the reaction solvent is any one or more of isopropanol, methanol, and ethanol, and more preferably isopropanol.

[0062] Preferably, in S1, the ratio of methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid to isopropanol is 4.4 g: 15~50 mL, more preferably 4.4 g: 27 mL.

[0063] As a preferred embodiment, S1 specifically includes: adding methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate, sodium iodide, and potassium carbonate to isopropanol, heating to 60-80°C, and then adding a solution of 2,6-dimethylbenzylchloroisopropanol to react. More preferably, the temperature is raised to 70°C.

[0064] As a preferred embodiment, the post-processing step S1 includes: cooling the obtained reaction solution to 30-50°C, adding water dropwise, cooling again, filtering, washing the filter cake sequentially with water and ice-cold isopropanol, and vacuum drying to obtain starting material 1. More preferably, the obtained reaction solution is cooled to 40°C.

[0065] Preferably, in S2, the molar ratio of the starting material 1, the ethanolamine, and the DBU is 0.05~0.1:0.2~0.5:0.04~0.09; the reaction solvent is any one or more of methanol, ethanol, and isopropanol; and the reaction condition is reflux reaction for 3.5~6 hours.

[0066] More preferably, in S2, the molar ratio of the starting material 1, the ethanolamine, and the DBU is 0.07:0.36:0.074.

[0067] Preferably, in S2, the reaction solvent is one or more of methanol, ethanol, and isopropanol, more preferably methanol.

[0068] As a better option, in S2, the reaction time is 4.5 hours.

[0069] Preferably, in S2, the ratio of the starting material 1 to methanol is 1g:3~10mL, more preferably 1g:5mL.

[0070] As a preferred embodiment, in S2, the resulting reaction solution is cooled, subjected to an ice bath, filtered, the filter cake is washed with ice methanol, and then vacuum dried to obtain starting material 2.

[0071] A third objective of this invention is to provide a method for preparing compound 12 or 13.

[0072] To achieve the above objectives, the present invention adopts the following technical solution:

[0073] The preparation method of compound 12 or 13 involves preparing compound 8 using the aforementioned method; compound 8 is then reacted with calcium chloride or magnesium chloride to obtain the target compound.

[0074] Preferably, the mass ratio of compound 8 to calcium chloride or magnesium chloride is 5:0.5~2.5, more preferably 5:1.07~1.25.

[0075] Preferably, the reaction solvent is methanol or water.

[0076] Preferably, the mass-to-volume ratio of compound 8 to solvent is 1g:20~50mL, more preferably 1g:30mL.

[0077] As a preferred embodiment, the method specifically includes: dissolving compound 8, then adding an aqueous solution of calcium chloride or a methanol solution of magnesium chloride; crystallizing in an ice bath, filtering, and drying under reduced pressure to obtain compound 12 or 13.

[0078] The fourth objective of this invention is to provide an application of the aforementioned compound in the preparation of an inhibitor for suppressing gastric acid secretion.

[0079] The fifth objective of this invention is to provide an application of the aforementioned compound in the preparation of potassium ion competitive acid blockers.

[0080] The sixth objective of this invention is to provide the use of the aforementioned compound in the preparation of a medicament for treating and / or preventing gastroesophageal reflux disease, peptic ulcers, Zollinger-Ellison syndrome, functional dyspepsia, Helicobacter pylori infection, nonsteroidal anti-inflammatory drug-associated ulcers, postoperative stress-induced hyperacidity or stress ulcers and / or upper gastrointestinal bleeding caused by peptic ulcers or acute stress-induced gastric mucosal injury.

[0081] To achieve the above objectives, the present invention adopts the following technical solution:

[0082] The aforementioned compounds are used in the preparation of drugs for the treatment and / or prevention of gastroesophageal reflux disease, peptic ulcers, Zollinger-Ellison syndrome, functional dyspepsia, Helicobacter pylori infection, nonsteroidal anti-inflammatory drug-associated ulcers, postoperative stress-induced hyperacidity or stress ulcers and / or upper gastrointestinal bleeding caused by peptic ulcers or acute stress-induced gastric mucosal injury.

[0083] Preferably, the peptic ulcer includes gastric ulcer, duodenal ulcer, or anastomotic ulcer; the gastroesophageal reflux disease includes non-erosive reflux disease, erosive esophagitis, reflux esophagitis, laryngopharyngeal reflux disease, Barrett's esophagus, or asymptomatic gastroesophageal reflux disease; the upper gastrointestinal bleeding caused by acute stress gastric mucosal injury includes upper gastrointestinal bleeding caused by acute stress ulcer, upper gastrointestinal bleeding caused by hemorrhagic gastritis, or upper gastrointestinal bleeding caused by invasive stress factors.

[0084] Preferably, the peptic ulcer is a peptic ulcer caused by excessive gastric acid; the drug treats the peptic ulcer by inhibiting gastric acid secretion.

[0085] The seventh objective of this invention is to provide a pharmaceutical composition for inhibiting gastric acid secretion.

[0086] To achieve the above objectives, the present invention adopts the following technical solution:

[0087] A pharmaceutical composition for inhibiting gastric acid secretion, the pharmaceutical composition comprising the aforementioned compound and a pharmaceutically acceptable carrier or excipient.

[0088] The beneficial effects of this invention are as follows:

[0089] 1. The imidazo[1,2-a]pyridine derivatives or pharmaceutically acceptable salts thereof provided by this invention exhibit significantly improved solubility compared to control compounds and key starting materials. For example, in water, the solubilities of compounds 8-10 reach 33.88 mg / mL, 43.66 mg / mL, and 25.81 mg / mL, respectively; and in pH 7.4 phosphate buffer, the solubilities of compounds 8-10 are 6.73 mg / mL, 8.26 mg / mL, and 6.95 mg / mL, respectively. In contrast, the solubilities of control compounds 3 and 4, obtained by direct salt formation from starting material 2, are only 6.28 mg / mL and 6.42 mg / mL in water, respectively, and further reduced to 0.61 mg / mL and 0.42 mg / mL in pH 7.4 phosphate buffer. This significantly improves drug usability and patient compliance.

[0090] 2. The imidazo[1,2-a]pyridine derivative or its pharmaceutically acceptable salt provided by this invention possesses excellent biological activity. Experimental results show that compound 8, administered orally at 9 μmol / kg and intravenously at 5 μmol / kg, inhibited histamine-stimulated gastric acid secretion in rats by more than 70% and 90%, respectively. This indicates that compound 8 of this invention can effectively inhibit gastric acid secretion. This invention provides a new treatment option for peptic ulcers and other diseases related to excessive gastric acid. Attached Figure Description

[0091] Figure 1 The hydrogen spectrum of compound 1 prepared in Example 1;

[0092] Figure 2 The mass spectrum of compound 1 prepared in Example 1;

[0093] Figure 3 The proton NMR spectrum of compound 2 prepared in Example 2;

[0094] Figure 4 The mass spectrum of compound 2 prepared in Example 2;

[0095] Figure 5 The proton NMR spectrum of compound 3 prepared in Example 3;

[0096] Figure 6 The mass spectrum of compound 3 prepared in Example 3;

[0097] Figure 7 The proton NMR spectrum of compound 4 prepared in Example 4;

[0098] Figure 8 The mass spectrum of compound 4 prepared in Example 4;

[0099] Figure 9The hydrogen spectrum of compound 5 prepared in Example 5;

[0100] Figure 10 The mass spectrum of compound 5 prepared in Example 5;

[0101] Figure 11 The mass spectrum POS chromatogram of compound 6 prepared in Example 6;

[0102] Figure 12 The NEG mass spectrum of compound 6 prepared in Example 6;

[0103] Figure 13 The proton NMR spectrum of compound 8 prepared in Example 9;

[0104] Figure 14 The mass spectrum of compound 8 prepared in Example 9;

[0105] Figure 15 The mass spectrum of compound 9 prepared in Example 10;

[0106] Figure 16 The mass spectrum POS chromatogram of compound 10 prepared in Example 11;

[0107] Figure 17 The NEG mass spectrum of compound 10 prepared in Example 11;

[0108] Figure 18 The mass spectrum of compound 11 prepared in Example 12;

[0109] Figure 19 The mass spectrum of compound 12 prepared in Example 13;

[0110] Figure 20 The mass spectrum of compound 13 prepared in Example 14;

[0111] Figure 21 The proton spectrum of starting material 1 prepared in Example 15;

[0112] Figure 22 The mass spectrum of starting material 1 prepared in Example 15;

[0113] Figure 23 The proton spectrum of starting material 2 prepared in Example 16;

[0114] Figure 24 The mass spectrum of starting material 2 prepared in Example 16;

[0115] Figure 25 The proton NMR spectrum of control compound 1 prepared for Comparative Example 1;

[0116] Figure 26The mass spectrum of control compound 1 prepared for Comparative Example 1;

[0117] Figure 27 The proton NMR spectrum of control compound 2 prepared for Comparative Example 2;

[0118] Figure 28 The mass spectrum of control compound 2 prepared for Comparative Example 2;

[0119] Figure 29 The graph shows the results of detecting the effect of compound 8 administered by gavage on gastric acid secretion in rats in Example 17;

[0120] Figure 30 The graph shows the results of detecting the effect of intravenous injection of compound 8 in Example 17 on gastric acid secretion in rats. Detailed Implementation

[0121] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0122] In this embodiment of the invention, the chemical name of compound 1 is ethyl acetate 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}.

[0123] In this embodiment of the invention, the chemical name of compound 2 is 2-[(2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carbamate}ethoxy)carbonyl]benzoic acid.

[0124] In this embodiment of the invention, the chemical name of compound 3 is ethyl 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carbamoyl}propionate.

[0125] In this embodiment of the invention, compound 4 is chemically named dibenzyl phosphate [2-(8-{[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl] ester.

[0126] In this embodiment of the invention, compound 5 is chemically named benzyl phosphate [2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl]hydrogen ester.

[0127] In this embodiment of the invention, the chemical name of compound 6 is 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl phosphate.

[0128] In this embodiment of the invention, the chemical name of compound 7 is 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl sodium hydrogen phosphate.

[0129] In this embodiment of the invention, compound 8 is chemically named sodium 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl phosphate.

[0130] In this embodiment of the invention, compound 9 is chemically named 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl phosphate potassium.

[0131] In this embodiment of the invention, the chemical name of compound 10 is 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethylammonium phosphate.

[0132] In this embodiment of the invention, the chemical name of compound 11 is 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl lithium phosphate.

[0133] In this embodiment of the invention, the chemical name of compound 12 is 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl calcium phosphate.

[0134] In this embodiment of the invention, the chemical name of compound 13 is 2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamido}ethyl magnesium phosphate.

[0135] In this embodiment of the invention, the chemical name of starting material 1 is methyl 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0136] In this embodiment of the invention, the chemical name of starting material 2 is 8-[(2,6-dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide.

[0137] In this embodiment of the invention, the chemical name of control compound 1 is 4-[2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carbamate}ethoxy]-4-oxobutyric acid.

[0138] In this embodiment of the invention, the chemical name of control compound 2 is 5-[2-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carbamate}ethoxy]-5-oxovalerate.

[0139] Example 1. Preparation method of compound 1

[0140]

[0141] Starting material 2 (2 g, 5.46 mmol), acetic anhydride (2.86 g, 28.01 mmol), pyridine (2.3 g, 29.08 mmol), and DMAP (0.15 g, 1.23 mmol) were added to DMF (16 mL). The reaction mixture was heated to 70 °C and stirred for 10 hours. 50 mL of ethyl acetate was added, and the mixture was washed with 50 mL of water twice. The aqueous layer was then extracted with 30 mL of acetate twice. The organic layers were combined, washed successively with 50 mL of water and 50 mL of saturated brine, and 40 mL of methanol was added. The mixture was dried, filtered, and concentrated to obtain an oily substance. 60 mL of ethyl acetate was added, and the mixture was refluxed for 0.5 h. After cooling and filtration, the mixture was dried under vacuum to obtain 0.89 g of compound 1, with a yield of 39.9%.

[0142] The proton NMR spectrum of compound 1 is as follows: Figure 1 As shown, 1 H-NMR (400MHz, d6-DMSO): δ2.04(s, 3H), 2.26(s,3H), 2.35(s, 6H), 2.40(s, 3H), 3.51-3.56(q, 2H), 4.15-4.18(t, 2H), 4.38-4.40(d,2H), 5.19(s, 1H), 6.79(s, 1H), 7.07-7.17(m, 3H), 8.13(s, 1H), 8.66-8.69(t, 1H).

[0143] The mass spectrum of compound 1 is as follows: Figure 2 As shown, MS(ESI) m / z: [M+H] + =409.6; [M+Na] + =431.7; [2M+2H] + =818.0; [2M+H+Na] + =840.0.

[0144] Example 2. Preparation method of compound 2

[0145]

[0146] Starting material 2 (2 g, 5.46 mmol) and phthalic anhydride (2.2 g, 14.85 mmol) were added to DMF (16 mL). The reaction mixture was heated to 75 °C and stirred for 3 hours. Acetone (56 mL) was added, the mixture was cooled, filtered, and dried under vacuum to obtain 2.65 g of compound 2, with a yield of 94.3%.

[0147] The proton NMR spectrum of compound 2 is as follows: Figure 3 As shown, 1 H-NMR (400MHz, d6-DMSO): δ2.22(s, 3H), 2.34-2.38(m, 9H), 3.63-3.67(q, 2H), 4.37-4.40(t, 4H), 5.13-5.15(t, 1H), 6.75(s, 1H), 7.07-7.17(m, 3H), 7.58-7.64(s, 2H), 7.67-7.70(s, 2H), 8.11(s, 1H), 8.66-8.69(t, 1H).

[0148] The mass spectrum of compound 2 is as follows Figure 4 As shown, MS(ESI) m / z: [M+H] + =515.7; [M+Na] + =537.7.

[0149] Example 3. Preparation method of compound 3

[0150]

[0151] Add starting material 2 (2 g, 5.46 mmol), propionic anhydride (1.56 g, 12.00 mmol), triethylamine (1.27 g, 12.55 mmol), and DMAP (0.05 g, 0.41 mmol) to DMF (16 mL). Stir the mixture at 80 °C for 2.5 hours. Add 50 mL of ethyl acetate, wash with 50 mL × 2 times of water, then extract the aqueous layer with 30 mL × 2 times of ethyl acetate. Combine the organic layers, wash successively with 50 mL of water and 50 mL of saturated brine, dry, filter, and concentrate to obtain an oily substance. Add 20 mL of ethyl acetate, heat to reflux, add 60 mL of n-hexane dropwise, cool, filter, and dry under vacuum to obtain 1.96 g of compound 3, with a yield of 84.8%.

[0152] The proton NMR spectrum of compound 3 is as follows: Figure 5 As shown, 1H-NMR (400MHz, d6-DMSO): δ0.97-1.05(ddd, 3H), 2.18-2.39(m, 14H), 3.51-3.55(q, 2H), 4.17-4.19(t, 2H), 4.38-4.39(d, 2H), 5.06(s, 1H), 6.71(s, 1H), 7.07-7.16(m, 3H), 8.07-8.08(s, 1H), 8.58-8.61(t, 1H).

[0153] The mass spectrum of compound 3 is as follows: Figure 6 As shown, MS(ESI) m / z: [M+H] + =423.5; [M+Na] + =445.5; [2M+H] + =845.9.

[0154] Example 4. Preparation method of compound 4

[0155]

[0156] Add starting material 2 (40 g, 0.11 mol) and 1H-tetrazole (12.3 g, 0.176 mol) to a mixture of acetonitrile (560 mL) and DCM (560 mL). Cool the reaction solution to 0–5 °C and slowly add dibenzyl N,N-diisopropylphosphonamide (57.0 g, 0.165 mol). Maintain the reaction temperature at 0–5 °C for 4.5 hours. Slowly add m-chloroperoxybenzoic acid (33.5 g, 0.165 mol) and maintain the reaction temperature at 0–5 °C for 0.5 hours. Add DCM (700 mL) to the reaction solution and wash with 5% sodium thiosulfate solution (400 mL × 2). After separation, wash successively with drinking water (400 mL) and saline (400 mL). Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 94.8 g (theoretical value 68.4 g) of compound 4. A small amount of the concentrate was purified by column chromatography (DCM:MeOH=100:1) to obtain approximately 0.61g.

[0157] The proton NMR spectrum of compound 4 is shown below. Figure 7 As shown, 1H-NMR (400MHz, d6-DMSO): δ2.25(s, 3H), 2.32(s,6H), 2.35(s, 3H), 3.56-3.57(d, 2H), 4.13-4.18(dd, 2H), 4.34-4.35(d, 2H), 4.69-4.71(d, 1H), 5.02-5.04(d, 4H), 6.76(s, 1H), 7.06-7.16(m, 3H), 7.30-7.33(m, 10H), 8.10(s, 1H), 8.70-8.82(t, 1H).

[0158] The mass spectrum of compound 4 is as follows Figure 8 As shown, MS(ESI) m / z: [M+H] + =627.8; [M+Na] + =649.8.

[0159] Example 5. Preparation method of compound 5

[0160]

[0161] Compound 4 (49.8 g) prepared in Example 4 was dissolved in methanol (1.03 L), and 10% palladium on carbon (4.56 g) was added. The reaction was carried out at room temperature for 4.5 hours. The mixture was filtered, and the filter cake was washed with methanol. It was dispersed in a methanol / water mixture (methanol / water = 1 / 1, 600 mL), and 1N NaOH solution was added dropwise to adjust the pH to 8-9. The mixture was filtered, and the filtrate was placed in an ice bath. 1N hydrochloric acid solution was added dropwise to adjust the pH to 5-6. Crystallization was performed, and the mixture was filtered and dried under reduced pressure to give 16.16 g of compound 5, with a yield of 55.2%.

[0162] The proton NMR spectrum of compound 5 is as follows: Figure 9 As shown, 1 H-NMR (400MHz, d6-DMSO): δ2.28(s, 3H), 2.30(s,3H), 2.34(s, 6H), 2.50-2.51(d, 2H), 3.89-3.92(dd, 2H), 4.38-4.39(d, 2H), 4.63-4.64(d, 2H), 6.20(s, 1H), 7.00-7.09(m, 3H), 7.14(s, 1H), 7.21-7.30(m, 5H), 8.23(s, 1H), 9.33(s, 1H).

[0163] The mass spectrum of compound 5 is as follows: Figure 10 As shown, MS(ESI) m / z: [M+H] + =537.6; [M+Na] +=559.6.

[0164] Example 6. Preparation method of compound 6

[0165]

[0166] Compound 5 (0.5 g) prepared in Example 5 was dissolved in formic acid (13.8 g) and methanol (6 mL), and 10% palladium on carbon (10 mg) was added. The reaction was carried out overnight at room temperature. The mixture was filtered, the filter cake was dispersed in water, and the pH was adjusted to 13 with 1 N NaOH. The filtrate was then adjusted to pH 2 with 1 N hydrochloric acid. Crystallization was performed, filtered, and dried under reduced pressure to give 0.15 g of compound 6, with a yield of 35.7%.

[0167] The POS mass spectrum of compound 6 is shown below. Figure 11 As shown, the NEG mass spectrum is as follows: Figure 12 As shown. MS (ESI) m / z: POS: [(M-2H)+3Na] +- =513.6. NEG: [MH] - =445.5.

[0168] Example 7. Preparation method of compound 6

[0169]

[0170] Compound 4 (94.8 g) prepared in Example 4 was dissolved in formic acid (1520 g), and 10% palladium on carbon (9.12 g) was added. The reaction was carried out overnight at room temperature, and the disappearance of the starting material was monitored by TLC (DCM:MeOH = 15:1, 1 drop of acetic acid). The mixture was filtered and concentrated under reduced pressure. The concentrate was added to methanol (365 mL), dispersed in a water bath at 45-50 °C, and then drinking water (365 mL) was added dropwise. Crystallization was carried out in an ice bath, filtered, and dried under reduced pressure to obtain 47.1 g of compound 6, with a yield of 96.7%.

[0171] Example 8. Preparation method of compound 7

[0172]

[0173] Compound 6 (1.2 g) prepared in Example 7 was dispersed in methanol (9 mL), and 1N NaOH solution was added dropwise to adjust the pH to approximately 7. After removing methanol by vacuum concentration, acetone (36 mL) was added, and crystals were precipitated in an ice bath. The crystals were filtered and dried under reduced pressure to obtain 0.75 g of compound 7, with a yield of 59.5%.

[0174] Example 9. Preparation method of compound 8

[0175]

[0176] Compound 6 (20 g) prepared in Example 7 was dispersed in methanol (150 mL), and 1 N NaOH solution was added dropwise to adjust the pH to approximately 10-11. After removing methanol by vacuum concentration, acetone (200 mL) was added, and crystals were precipitated in an ice bath. After filtration and drying under vacuum, 21.8 g of compound 8 was obtained, with a yield of 99.2%.

[0177] The proton NMR spectrum of compound 8 is as follows: Figure 13 As shown, 1 H-NMR (400MHz, CD3OD): δ2.29(s, 3H), 2.40(s, 6H), 2.44(s, 3H), 3.64-3.65(t, 2H), 4.04-4.09(ddd, 2H), 4.47(s, 2H), 6.86(s, 1H), 7.06-7.14(m, 3H), 8.16(d, 1H), 8.55(s, 1H).

[0178] The mass spectrum of compound 8 is as follows: Figure 14 As shown, MS(ESI) m / z: [M+H] + =491.6; [M+Na] + =513.6; [2M+H] + =981.9.

[0179] Example 10. Preparation method of compound 9

[0180]

[0181] Compound 6 (5 g) prepared in Example 7 was dispersed in methanol (37.5 mL), and 1 N potassium hydroxide solution was added dropwise to adjust the pH to approximately 9. After removing methanol by vacuum concentration, acetone (50 mL) was added, and crystals were precipitated in an ice bath. The crystals were filtered and dried under reduced pressure to obtain 5.1 g of compound 9, with a yield of 87.5%.

[0182] The mass spectrum of compound 9 is as follows: Figure 15 As shown, MS(ESI) m / z: [M+H] + =523.5; [M+Na] + =545.5; [M+K] + =561.5.

[0183] Example 11. Preparation method of compound 10

[0184]

[0185] Compound 6 (5 g) prepared in Example 7 was dispersed in methanol (37.5 mL), and concentrated ammonia was added dropwise to adjust the pH to approximately 9. After removing methanol by vacuum concentration, acetone (50 mL) was added, and crystals were precipitated in an ice bath. The crystals were filtered and dried under reduced pressure to obtain 4.1 g of compound 10, with a yield of 76.6%.

[0186] The POS mass spectrum of compound 10 is shown below. Figure 16 As shown, the NEG mass spectrum is as follows: Figure 17 As shown. MS (ESI) m / z: POS: [(M-2NH4+2H)+H] + =447.6; [2(M-2NH4+2H)+H] + =893.8. NEG: [(M-2NH4+2H)-H] - =445.5; [2(M-2NH4+2H)-H] - =891.9.

[0187] Example 12. Preparation method of compound 11

[0188]

[0189] Compound 6 (5 g) prepared in Example 7 was dispersed in methanol (75 mL), and 1 N lithium hydroxide solution was added dropwise to adjust the pH to approximately 9-10. After removing methanol by vacuum concentration, acetone (50 mL) was added, and crystals were precipitated in an ice bath. After filtration and drying under vacuum, 4.4 g of compound 11 was obtained, with a yield of 80.4%.

[0190] The mass spectrum of compound 11 is as follows: Figure 18 As shown, MS(ESI) m / z: [M+H] + =459.6; [2M+H] + =917.9.

[0191] Example 13 Preparation method of compound 12

[0192]

[0193] Compound 8 (5 g) prepared in Example 9 was dissolved in purified water (150 mL), and an aqueous solution of calcium chloride (1.25 g) was added dropwise. Crystallization was carried out in an ice bath. After filtration and drying under reduced pressure, 3.87 g of compound 12 was obtained, with a yield of 71.3%.

[0194] The mass spectrum of compound 12 is as follows: Figure 19 As shown, MS(ESI) m / z: [(M-Ca)+H] + =445.3; [M+Na] + =507.3; [(M-Ca)+2H+DIPEA]+ =575.5; [2(M-Ca)+Na+DMSO] + =989.0.

[0195] Example 14: Preparation method of compound 13

[0196]

[0197] Compound 8 (5 g) prepared in Example 9 was dissolved in methanol (150 mL), and a methanol solution of magnesium chloride (1.07 g) was added dropwise. Crystallization was carried out in an ice bath. After filtration and drying under reduced pressure, 3.87 g of compound 13 was obtained, with a yield of 71.3%.

[0198] The mass spectrum of compound 13 is as follows: Figure 20 As shown, MS (ESI) m / z: [(M-Mg+2H)+H] + =447.6; [(M-Mg+2H)+Na] + =469.6; [2(M-Mg+2H)+Na] + =915.8.

[0199] Example 15. Preparation method of starting material 1

[0200]

[0201] Methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (4.4 g, 0.02 mol), sodium iodide (1.8 g, 0.012 mol), and potassium carbonate (6.9 g, 0.05 mol) were added to isopropanol (27 mL). The reaction solution was heated to approximately 70 °C. 2,6-Dimethylbenzyl chloride (3.4 g, 0.022 mol) was dissolved in isopropanol (26.4 mL) and slowly added to the reaction solution. The reaction solution was cooled to approximately 60 °C and reacted for about 2 hours. The reaction solution was cooled to approximately 40 °C, and drinking water (55 mL) was added dropwise. The mixture was cooled, filtered, and the filter cake was washed successively with drinking water and ice-cold isopropanol. Vacuum drying yielded 4.59 g of starting material 1, with a yield of 68%.

[0202] The proton spectrum of starting material 1 is as follows: Figure 21 As shown, 1 H-NMR (400MHz, d6-DMSO): δ2.25(s, 3H), 2.35(s, 6H), 2.39(s, 3H), 3.87(s, 3H), 4.38-4.40(d, 2H), 5.22-5.24(t, 1H), 6.62(s,1H), 7.06-7.15(m, 3H), 8.12(s, 1H).

[0203] The mass spectrum of starting material 1 is as follows: Figure 22 As shown, MS(ESI) m / z: [M+H] + =338.4; [M+Na] + =360.2; [M+K] + =376.4; [2M+H] + =675.6; [2M+K] + =713.7.

[0204] Example 16. Preparation method of starting material 2

[0205]

[0206] To methanol (120 mL), 24.0 g (0.07 mol) of starting material 1 prepared in Example 15, 22.2 g (0.36 mol), and 11.3 g (0.074 mol) of DBU were added. The mixture was heated to reflux and reacted for approximately 4.5 hours. The reaction solution was cooled, placed in an ice bath, filtered, and the filter cake was washed with ice-cold methanol. Vacuum drying yielded 21.9 g of starting material 2, with a yield of 84.0%.

[0207] The proton spectrum of starting material 2 is as follows Figure 23 As shown, 1 H-NMR (400MHz, d6-DMSO): δ2.24(s, 3H), 2.35(s, 6H), 2.38(s, 3H), 3.36-3.39(t, 2H), 3.53-3.57(dd, 2H), 4.38-4.39(d, 2H), 4.78-4.81(t, 1H), 4.97-5.00(t, 1H), 6.73(s, 1H), 7.07-7.16(m, 3H), 8.10 (s, 1H), 8.45-8.48(t, 1H).

[0208] The mass spectrum of starting material 2 is as follows Figure 24 As shown, MS(ESI) m / z: [M+H] + =367.1; [M+Na] + =389.4.

[0209] Comparative Example 1. Preparation method of control compound 1

[0210]

[0211] Add starting material 2 (2 g, 5.46 mmol) and succinic anhydride (1.2 g, 12.01 mmol) to DMF (16 mL). Heat the reaction mixture to 70 °C and stir for 2 hours. Add acetone (56 mL), cool, filter, and dry under vacuum to obtain 2.63 g of control compound 1, with a yield of 100%.

[0212] The proton spectrum of compound 1 is shown below. Figure 25 As shown, 1 H-NMR (400MHz, d6-DMSO): δ2.24(s, 3H), 2.35(s, 6H), 2.38(s, 3H), 2.53-2.55(s, 2H), 2.73(s, 1H), 2.89(s, 1H), 3.51-3.55(q, 2H), 4.17-4.20(t, 2H), 4.38-4.39(d, 2H), 5.01-5.03(t, 1H), 6.69(s, 1H), 7.07-7.16(m, 3H), 8.07(s, 1H), 8.57-8.60(t, 1H), 12.26(s, 1H).

[0213] The mass spectrum of compound 1 is shown below. Figure 26 As shown, MS(ESI) m / z: [M+H] + =467.5; [M+Na] + =489.4; [M+K] + =505.4; [2M+H] + =933.8.

[0214] Comparative Example 2. Preparation method of control compound 2

[0215]

[0216] Add starting material 2 (2 g, 5.46 mmol) and glutaric anhydride (1.37 g, 12.01 mmol) to DMF (10 mL). Heat the reaction mixture to 80 °C and stir for 2.5 hours. Add acetone (56 mL), cool, filter, and dry under vacuum to obtain control compound 2 at 2.44 g, with a yield of 93.1%.

[0217] The proton spectrum of compound 2 is shown below. Figure 27 As shown, 1H-NMR (400MHz, d6-DMSO): δ1.72-1.79(m,2H), 2.24-2.38(m, 16H), 3.51-3.56(dd, 2H), 4.17-4.20(t, 2H), 4.38-4.39(d, 2H), 5.01-5.03(t, 1H), 6.70(s, 1H), 7.07-7.16(m, 3H), 8.06-8.07(d, 1H), 8.57-8.60(t, 1H), 12.12(s, 1H).

[0218] The mass spectrum of compound 2 is shown below. Figure 28 As shown, MS(ESI) m / z: [M+H] + =481.7; [M+H+DMSO] + =559.7; [2M+2H] + =962.0.

[0219] Comparative Example 3: Preparation method of control compound 3

[0220]

[0221] Starting material 2 (5 g, 13.64 mmol) was dissolved in a mixture of methanol (200 mL) and dichloromethane (200 mL). 1 mol / L hydrochloric acid (25 mL) was added dropwise at 0–15 °C to adjust the pH to ≈3. The solvent was removed by concentration under reduced pressure, and acetone (75 mL) was added. Crystallization was carried out in an ice bath, filtered, and dried under vacuum to obtain control compound 3 with a yield of 5.20 g, which was 94.5%.

[0222] Comparative Example 4: Preparation method of control compound 4

[0223]

[0224] Starting material 2 (5 g, 13.64 mmol) was dissolved in a mixture of methanol (200 mL) and dichloromethane (200 mL). 1 mol / L phosphoric acid (64 mL) was added dropwise at 0–15 °C to adjust the pH to ≈ 4. The solvent was removed by concentration under reduced pressure, acetone (75 mL) was added, crystallization was carried out in an ice bath, and the mixture was filtered and dried under vacuum to obtain control compound 4 with a yield of 5.69 g, which was 89.7%.

[0225] Example 17. Solubility test of imidazo[1,2-a]pyridine derivatives in water

[0226] The solubility of compounds 1, 2, 3, 5, and 6 prepared in the above examples, as well as control compounds 1 and 2 in the comparative examples, was tested in aqueous solution. Appropriate amounts of the test compounds were weighed and added to test tubes, followed by the addition of an appropriate amount of aqueous solution. The tubes were then vigorously shaken for 30 seconds every 5 minutes at room temperature. The dissolution was observed over 30 minutes; complete dissolution was considered achieved when no visible solute particles or droplets were observed. The solubility was calculated by measuring the amount of solvent used to dissolve the sample. The test results are shown in Table 1. These results indicate that the solubility of starting material 2, compounds 1, 2, 3, 5, and 6, as well as control compounds 2 and 1, is all below 1 mg / ml.

[0227] Table 1

[0228]

[0229] Example 18. Solubility Comparison Test

[0230] This embodiment further compares the solubility of the salts of imidazo[1,2-a]pyridine derivatives with starting material 2, control compound 2, the hydrochloride salt of starting material 2 (control compound 3) and its phosphate salt (control compound 4) in water and pH 7.4 phosphate buffer.

[0231] The specific steps include: adding excess amounts of the salt of imidazo[1,2-a]pyridine derivative, starting material 2, control compound 2, control compound 3 and control compound 4 to aqueous solution and pH 7.4 phosphate buffer solution respectively to prepare saturated solutions, shaking at 25°C for more than 12 hours, and determining the content of the sample in the saturated solution by HPLC.

[0232] HPLC test conditions included: wavelength 220 nm; column temperature 30 ℃; volume 10 μL; flow rate 1.0 mL / min; column: Shim-Pack Scepter C18-120 4.6 mm * 150 mm; mobile phase A: 0.01 mol / L dipotassium hydrogen phosphate aqueous solution; mobile phase B: 90% acetonitrile; mobile phase ratio: mobile phase B: mobile phase A between 25% and 50%.

[0233] The experimental results are shown in Table 2. These results indicate that the solubility of the salts of imidazo[1,2-a]pyridine derivatives of the present invention, compounds 8, 9, and 10, is significantly improved compared to control compounds 2, 3, 4, and starting material 2. Furthermore, the solubility of the salts of imidazo[1,2-a]pyridine derivatives is also significantly improved compared to other compounds 1, 2, 3, 5, and 6 in the present invention.

[0234] Table 2

[0235]

[0236] Example 19. Biological effects of compound 8

[0237] This embodiment further investigated the inhibitory effect of histamine on gastric acid secretion in rats. Sprague-Dawly rats were fasted for 18-24 hours but allowed free access to water, and then anesthetized with an intraperitoneal injection of urethane (1.25 g / kg). After anesthesia, the animals were shaved and the abdominal skin was disinfected. The skin was incised along the midline of the upper abdomen, and the pyloric portion of the stomach was gently lifted. A suture was passed through the avascular area of ​​the duodenal mesentery and the pyloric ring was ligated with forceps. The stomach was repeatedly lavaged with raw saline (37°C) through a gastric tube. After suturing the abdominal incision for 30 minutes, 2 mg of diphenhydramine hydrochloride was injected intramuscularly to reduce the side effects of histamine. 30 minutes later, 30 mg / kg of histamine phosphate was injected intramuscularly. Three hours after histamine administration, the rats were sacrificed with CO2, and the stomach was removed to collect the retained gastric fluid. The volume and acidity of the gastric fluid were measured. For the collected gastric juice samples, using 1% phenolphthalein as an indicator, titration with 0.01 mol / L NaOH resulted in a phenolphthalein color (pink). The total amount of NaOH consumed is the total acidity. Based on the total acidity and the gastric juice volume, the amount of gastric acid secretion was calculated.

[0238] The drug was administered orally 2 hours before histamine stimulation (1, 3, and 9 µmol / kg) or intravenously 30 minutes after modeling (1, 2.5, and 5 µmol / kg). The mean response was calculated for groups of 8 rats. When administration was given after histamine stimulation, acid production during the 30-minute period before administration was defined as 1.0, and acid production during the same period after administration of the test substance or solvent was expressed as a fractional response. The percentage inhibition rate was calculated from the fractional responses induced by the test compound and solvent. When administration was given before histamine stimulation, the percentage inhibition was calculated directly from the acid production recorded after administration of the test compound and solvent. Results showed that the compound 8 of this invention, administered orally at 9 µmol / kg and intravenously at 5 µmol / kg, inhibited histamine-stimulated gastric acid secretion in rats by more than 70% and 90%, respectively. See details... Figure 29 and Figure 30 .

Claims

1. A compound, characterized in that, The compound is an imidazo[1,2-a]pyridine derivative or a pharmaceutically acceptable salt thereof, and a structural formula is shown as Formula I. ； Wherein, R is selected from sodium ion, potassium ion, calcium ion, magnesium ion, lithium ion or ammonium ion; when R is sodium ion, potassium ion, ammonium ion or lithium ion, n=2; when R is calcium ion or magnesium ion, n=1.

2. The compound of claim 1, wherein The compound is any one of compound 8, compound 9, compound 10, compound 11, compound 12 or compound 13; and the structural formula of each compound is as follows: 。 3. Process for the preparation of compound 8, 9, 10 or 11, characterized in that, The method comprises the following steps: (1) adding 1H-tetrazole and starting material 2 into a mixed solution of acetonitrile and DCM, cooling the obtained reaction solution to 0-5℃, then adding dibenzyl N,N-diisopropyl phosphoramidite for reaction, adding m-chloroperbenzoic acid for continuous reaction after the reaction is completed, and preparing compound 4; (2) taking compound 4 obtained in step (1) as a raw material, and taking palladium-carbon as a catalyst to react and obtain compound 6; (3) reacting compound 6 obtained in step (2) with NaOH, KOH, concentrated ammonia or lithium hydroxide to obtain the target compound; The structural formula of each compound is as follows: 。 4. The production method according to claim 3, characterized by, Step (2) is specifically as follows: Method one: dissolving compound 4 obtained in step (1) in formic acid, adding palladium-carbon, and reacting to obtain compound 6; Or method two: 1) dissolving compound 4 obtained in step (1) in methanol, adding palladium-carbon, and reacting to obtain compound 5; 2) dissolving compound 5 obtained in step 1) in a mixed solvent of formic acid and methanol, adding palladium-carbon, and reacting to obtain compound 6; The structural formula of compound 5 is as follows: 。 5. The preparation method according to claim 3, characterized in that, In step (3), the pH is controlled to be 7-11; and the reaction solvent is any one or more of methanol, ethanol, isopropyl alcohol, a mixed solvent of methanol and chloroform.

6. Process for the preparation of compound 12 or 13, characterized in that, The compound 8 is prepared by the method in any one of claims 3-5; and the compound 8 is reacted with calcium chloride or magnesium chloride to obtain the target compound; The structural formula of compound 12 or compound 13 is as follows: 。 7. Use of the compound in any one of claims 1-2 in the preparation of an inhibitor for inhibiting gastric acid secretion.

8. Use of the compound in any one of claims 1-2 in the preparation of a potassium ion competitive acid blocker.

9. Use of the compound in any one of claims 1-2 in the preparation of a drug for treating and / or preventing gastroesophageal reflux disease, peptic ulcer, Zollinger-Ellison syndrome, functional dyspepsia, Helicobacter pylori infection, non-steroidal anti-inflammatory drug related ulcer, postoperative stress gastric acid hypersecretion or stress ulcer, and upper gastrointestinal bleeding caused by peptic ulcer, acute stress gastric mucosal injury.

10. Use according to claim 9, characterized in that, The peptic ulcer is selected from gastric ulcer, duodenal ulcer or anastomotic ulcer; the gastroesophageal reflux disease is selected from non-erosive reflux disease, erosive esophagitis, reflux esophagitis, laryngopharyngeal reflux disease, Barrett's esophagus or asymptomatic gastroesophageal reflux disease; and the upper gastrointestinal bleeding caused by acute stress gastric mucosal injury is selected from upper gastrointestinal bleeding caused by acute stress ulcer, upper gastrointestinal bleeding caused by hemorrhagic gastritis or upper gastrointestinal bleeding caused by invasive stress factors.

11. A pharmaceutical composition for inhibiting gastric acid secretion, characterized by comprising a compound of the formula (I) as an active ingredient. The pharmaceutical composition contains the compound according to any one of claims 1 to 2, and a pharmaceutically acceptable adjuvant.

Images