Benzimidazole derivative compounds and their applications

Abstract

The present invention relates to a benzimidazole derivative compound represented by general formula 1 or 2, which exhibits an inhibitory effect on gastric acid secretion, a pharmaceutical composition containing the same as an active ingredient, and uses thereof.

Description

Technical Field

[0001] The present invention relates to benzimidazole derivative compounds and their uses. More specifically, it relates to benzimidazole derivative compounds represented by the following general formula 1 or general formula 2, or pharmaceutically acceptable salts or stereoisomers thereof, and their uses:

[0002] JPEG0007863187000001.jpg62118 e

[0003] JPEG0007863187000002.jpg72136

Background Art

[0004] Gastric acid plays a positive role, such as in protein digestion, absorption of minerals such as calcium and iron powder, and sterilization of harmful microorganisms in ingested food and drink. However, since gastric acid is very strongly acidic at about pH 1 - 2, excessive secretion of gastric acid or reflux into the esophagus may cause gastritis, gastric ulcer, and gastroesophageal reflux disease (GERD).

[0005] The secretion of gastric acid is carried out by the proton pump (H + / K + -ATPase) present in the mucosal cells of the stomach. The proton pump consumes ATP (adenosine triphosphate) by various gastric acid secretion stimulating factors, and discharges hydrogen ions into the gastric lumen by a method of exchanging one hydrogen ion in the cytoplasm with one potassium ion in the gastric lumen on a one-to-one basis.

[0006] H2 receptor antagonists (H2 RAs) and proton pump inhibitors (isoniazid (INH) inhibitors; PPIs) have been the most commonly used gastric acid secretion inhibitors. However, H2 RAs do not directly suppress the proton pump, but only block the histamine pathway that stimulates gastric acid secretion, thus exhibiting only partial effects. Furthermore, PPIs are prodrugs, and only exert their effects after being activated by gastric acid. Therefore, they must be taken before meals, have a slow onset of action, and a short half-life, limiting their effectiveness in suppressing nocturnal acid breakthrough (NAB) symptoms. Consequently, there is a need for the development of novel gastric acid secretion inhibitors with new mechanisms that can overcome these shortcomings.

[0007] Recently, two new types of gastric acid secretion inhibitors, potassium-competitive acid blockers (P-CABs), have entered the market: vonoprazan (Japan, 2015) and tegoprazan (Korea, 2019). Compared to existing PPIs, P-CAB drugs exhibit 5 to 100 times greater proton pump inhibition, resulting in more potent efficacy. Furthermore, from a mechanism of action perspective, existing PPIs are prodrugs requiring activation in acid, whereas P-CABs do not require activation. In particular, while PPIs irreversibly covalently bind to the proton pump, P-CABs bind reversibly, resulting in a very rapid onset time, a long duration of action, and the advantage of being able to be taken regardless of food intake.

[0008] However, among P-CAB drugs, tegoprazan (South Korea, 2019) has pH-dependent water solubility, and is particularly poorly soluble in neutral aqueous solutions. Due to this characteristic, when the pH of the gastric cavity rises to neutral due to food or other factors, the drug's solubility decreases, resulting in reduced bioavailability and making it difficult to formulate into a wide variety of formulations, such as neutral injectable preparations. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Republic of Korea Publication Patent No. 10-2018-0030412 [Patent Document 2] Republic of Korea Publication Patent No. 10-2019-0005674 [Overview of the project] [Problems that the invention aims to solve]

[0010] The object of the present invention is to provide a novel benzimidazole derivative compound represented by general formula 1 or general formula 2 that exhibits gastric acid secretion inhibitory activity.

[0011] Another object of the present invention is to provide a pharmaceutical composition for inhibiting gastric acid secretion, comprising the compound as an active ingredient.

[0012] A further object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases induced by gastric acid secretion disorders, comprising the compound as an active ingredient. [Means for solving the problem]

[0013] According to one aspect of the present invention, a benzimidazole derivative compound represented by the following general formula 1 or general formula 2, or a pharmaceutically acceptable salt or stereoisomer thereof, is provided:

[0014] JPEG0007863187000003.jpg62118

[0015] JPEG0007863187000004.jpg66118

[0016] JPEG0007863187000005.jpg53163

[0017] The benzimidazole derivative compounds of general formula 1 or general formula 2 according to the present invention can form pharmaceutically acceptable salts. These pharmaceutically acceptable salts may include, but are not limited to, alkali metal or alkaline earth metal salts formed from, for example, sodium, lithium, potassium, calcium, magnesium, etc. The benzimidazole derivative compounds of general formula 1 or general formula 2 according to the present invention can be converted to salts thereof by conventional methods.

[0018] On the other hand, since the compounds according to the present invention may have asymmetric carbon centers, they may exist as R or S isomers, racemates, mixtures of partial stereoisomers, and individual partial stereoisomers, and all of these isomers and mixtures are included within the scope of the present invention.

[0019] In this specification, for ease of explanation, unless otherwise specified, the term "benzimidazole derivative compound of general formula 1 or general formula 2" is used to encompass all compounds of general formula 1 or general formula 2, their pharmaceutically acceptable salts, and stereoisomers.

[0020] Throughout this specification, when defining benzimidazole derivative compounds of general formula 1 or general formula 2, the concepts defined for the substituted compounds described below are used.

[0021] Unless otherwise specified, the term "alkyl" in this disclosure means a radical of a straight-chain or branched saturated aliphatic hydrocarbon group having, for example, 1 to 7 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0022] Unless otherwise specified, the term "cycloalkyl" in this disclosure means a radical of a cyclic saturated aliphatic hydrocarbon group having, for example, 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0023] According to one embodiment of the present invention, in the above general formula 1 or general formula 2, R2 and R3 can each independently be hydrogen, C1-C7 alkyl, or C3-C7 cycloalkyl.

[0024] According to another embodiment of the present invention, in the above general formula 1 or general formula 2, R2 and R3 can each independently be hydrogen or C1-C5 alkyl.

[0025] Representative examples of the benzimidazole derivative compounds of the above general formula 1 or general formula 2 according to the present invention may include, but are not limited to only, the following compounds:

[0026] Diisopropyl (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)phosphonate; (S)-di-tert-butyl(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)phosphate; tert-butyl((4-(S)-5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)hydrogen phosphate; (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyldihydrogen phosphate; Sodium (S)-tert-butyl(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)phosphate; and Sodium (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl phosphate.

[0027] According to another aspect of the present invention, a pharmaceutical composition for inhibiting gastric acid secretion is provided, comprising a benzimidazole derivative compound of general formula 1 or general formula 2, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

[0028] According to another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of diseases induced by gastric acid secretion disorders is provided, comprising a benzimidazole derivative compound of general formula 1 or general formula 2, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

[0029] The "pharmaceutical composition" in the present invention may include other chemical components such as carriers, diluents, and excipients in addition to the active compound according to the present invention. Therefore, the pharmaceutical composition may optionally include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof.

[0030] According to other embodiments of the present invention, the diseases induced by impaired gastric acid secretion may include, but are not limited to, gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, gastritis, Helicobacter pylori infection, indigestion, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive gastroesophageal reflux disease (NERD), referred pain (visceral pain sensation, visceral pain), heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, or asthma. [Effects of the Invention]

[0031] The benzimidazole derivative compounds represented by general formula 1 or general formula 2 according to the present invention exhibit an inhibitory effect on gastric acid secretion, and can therefore function as potassium-competitive acid blockers (P-CABs). They can be used as gastric acid secretion inhibitors, or as preventive or therapeutic agents for diseases induced by gastric acid secretion disorders. Furthermore, the benzimidazole derivative compounds represented by general formula 1 or general formula 2 according to the present invention have significantly improved neutral water solubility compared to tegoprazan, which has been developed as an existing gastric acid secretion inhibitor. They are unaffected by in vivo pH such as diet, and are easily formulated into injectable preparations and other formulations. [Modes for carrying out the invention]

[0032] The present invention will be described in more detail below with reference to manufacturing examples and embodiments. However, these embodiments are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0033] The abbreviations used in the following examples are explained below:

[0034] ACN: Acetonitrile DMF: N,N-dimethylformamide alkyl: Ethyl acetate FA: Formic acid MeOH: methanol

[0035] Example 1: Preparation of diisopropyl(S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)phosphonate

[0036] JPEG0007863187000006.jpg8355

[0037] 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl]oxy]-N,N,2-trimethyl-3H-benzimidazole-5-carboxamide (80 mg, 0.21 mmol) was dissolved in dry dimethylformamide (DMF) (2 mL), and then 60% NaH (12.39 mg, 0.31 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Diisopropyl phosphorochloridate (53.85 mg, 0.27 mmol) was added to this reaction mixture at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium 2SO4, and then separated by column chromatography (ethyl acetate:hexane:MeOH = 6:6:1) to obtain the target compound, diisopropyl(S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)phosphonate (43 mg, 37%), which was a white solid.

[0038] NMR(DMSO-d6): 7.13 (1H), 6.93(s, 1H), 6.83(t, 1H), 6.70(d, 1H), 6.03(s, 1H), 4.43~4.37(m, 3H), 4.25(t, 1H), 2.97(s, 6H), 2.45(s, 3H), 2.24(d, 1H), 2.07(t, 1H), 1.24(d, 12H); MS+:552.44

[0039] Example 2: Preparation of (S)-di-tert-butyl(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phosphate ((S)-di-tert-butyl((4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phosphate)

[0040] JPEG0007863187000007.jpg9454

[0041] 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl]oxy]-N,N,2-trimethyl-3H-benzimidazole-5-carboxamide (1,000 mg, 2.58 mmol) was dissolved in dry DMF (25.8 mL), and then 60% NaH (154.89 mg, 3.87 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Diisopropyl phosphorochloridylate (1,336 mg, 5.16 mmol) was added to this reaction mixture at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was extracted with SiO2, washed with brine, dried over anhydrous Na2SO4, and then separated by column chromatography (SiO2:Hexane:MeOH = 6:6:1) to obtain the target compound (S)-di-tert-butyl(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)phosphate (812 mg, 52%), which was a white solid.

[0042] NMR(DMSO-d6): 7.30(s, 1H), 6.94(s, 1H), 6.81(t, 1H), 6.76(d, 1H), 6.14(s, 1H), 6.02(d, 2H), 4.36(d, 1H), 4.22(d, 1H), 2.97(s, 6H), 2.61(s, 3H), 2.22(d, 1H), 2.07(t, 1H), 1.38~1.26(m, 18H); MS+: 610.33

[0043] Example 3: Preparation of tert-butyl((4-(S)-5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)hydrogen phosphate

[0044] JPEG0007863187000008.jpg8354

[0045] (S)-di-tert-butyl(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl) phosphate (295 mg, 0.49 mmol) was dissolved in DMF (4.86 mL), and then 4N HCl (1.4 mL) was added at 0°C and the mixture was stirred at room temperature for 90 minutes. After the reaction was complete, the mixture was separated by reverse-phase column chromatography (0.1% FA) and freeze-dried to obtain the target compound, tert-butyl((4-(S)-5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl) hydrogen phosphate (74.2 mg, 27%), which was a white solid.

[0046] NMR(DMSO-d6): 7.31(s, 1H), 6.94(s, 1H), 6.81(t, 1H), 6.71(d, 1H), 6.15(s, 1H), 5.96(d, 2H), 4.37(d, 1H), 4.23(t, 1H), 2.98(s, 6H), 2.64(s, 3H), 2.24(d, 1H), 2.07(m, 1H), 1.26(s, 9H); MS+:554.47

[0047] Example 4: Preparation of (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyldihydrogen phosphate

[0048] JPEG0007863187000009.jpg6951

[0049] 200 mg, 0.33 mmol of tert-butyl((4-(S)-5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)hydrogen phosphate (200 mg, 0.33 mmol) was dissolved in DMF (6.57 mL), and then 0.5 mL of 4N HCl was added at 0°C. The mixture was stirred at room temperature for 90 minutes. After the reaction was complete, the mixture was separated by reverse-phase column chromatography (0.1% FA) and freeze-dried to obtain the target compound, (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyldihydrogen phosphate (64.1 mg, 35%), which was a white solid.

[0050] NMR(DMSO-d6): 7.31(s, 1H), 6.94(s, 1H), 6.81(t, 1H), 6.71(d, 1H), 6.14(s, 1H), 5.95(d, 2H), 4.37(d, 1H), 4.22(t, 1H), 2.98(s, 6H), 2.64(d, 3H), 2.25(d, 1H), 2.07(m, 1H); MS+:498.29

[0051] Example 5: Preparation of sodium(S)-tert-butyl((4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phosphate

[0052] JPEG0007863187000010.jpg6946

[0053] 52.8 mg, 0.095 mmol of tert-butyl((4-(S)-5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)hydrogen phosphate (9.5 mL) was dissolved in ACN:H2O=1:1, then 4.2 mg, 0.105 mmol of NaOH was added, and the mixture was stirred at room temperature for 1 minute. After the reaction was complete, the mixture was freeze-dried to obtain the target compound, sodium(S)-tert-butyl(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl)phosphate (54 mg, 98%), which was a white solid.

[0054] NMR(D2O): 7.47(s, 1H), 7.13(s, 1H), 6.65~6.56(m, 2H), 5.96~5.93(m, 3H), 4.51~4.45(m, 2H), 3.15(s, 3H), 3.05(s, 3H), 2.72(s, 3H), 2.39(d, 1H), 2.22~2.14(m, 1H), 1.04(s, 9H); MS+: 554.35

[0055] Example 6: Preparation of sodium(S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)methyl phosphate

[0056] JPEG0007863187000011.jpg7148

[0057] (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyldihydrogen phosphate (51.6 mg, 0.104 mmol) was dissolved in ACN:H2O=1:1 (10.4 mL), then NaOH (8.7 mg, 0.218 mmol) was added and the mixture was stirred at room temperature for 1 minute. After the reaction was complete, the mixture was freeze-dried to obtain the target compound, sodium (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl phosphate (52 mg, 93%), which is a white solid.

[0058] NMR(D2O): 7.52(s, 1H), 7.11(s, 1H), 6.65~6.58(m, 2H), 5.95(s, 1H), 5.84(d, 2H), 4.48~4.45(m, 2H), 3.15(s, 3H), 3.06(s, 3H), 2.71(s, 3H), 2.41(d, 1H), 2.22~2.13(m, 1H); MS+: 498.33

[0059] Experimental Example 1: Water Solubility Test (pH 6.8)

[0060] Each test substance was weighed into a glass vial to a concentration of 5.12 mg / ml. 0.5 M Tris-HCl (pH 6.8, T&I Corporation, BTH-9168) was added, and the mixture was vortexed for 1 minute. The solution was then prepared by processing in an ultrasonic shredder (sonicator) for 30 minutes. The solution was observed visually and then photographically recorded. If complete dissolution was not achieved, a buffer solution was added to prepare the solution, and the observation was repeated. Solubility was evaluated by confirming the concentration at which complete dissolution occurred. Tegoprazan was used as a comparison compound. The measured results are shown in Table 1 below.

[0061] JPEG0007863187000012.jpg43119

[0062] As is clear from Table 1 above, the compounds of Example 3 and Example 4 according to the present invention showed a 128-fold improvement in water solubility (pH 6.8) compared to the comparative compound, and the compounds of Example 2, Example 5 and Example 6 showed a 256-fold improvement in water solubility (pH 6.8) compared to the comparative compound. Therefore, the novel benzimidazole derivative compounds of the present invention, which have significantly improved water solubility, are unaffected by the increase in gastric pH associated with diet, and are also easily formulated into formulations including injectable preparations.

[0063] Experimental Example 2: Confirmation Test of Gastric Acid Secretion Inhibitory Efficacy by Oral Administration

[0064] Test animals (rats) were purchased and acclimatized one week prior to the test date. After acclimatization, food was removed the day before the test, and fasting was carried out for 24 hours using a fasting board. The weight of each individual was measured, and weight rankings were assigned sequentially to each group, and the rats were randomly distributed so that the average weights of each group were evenly distributed. The test substances (compounds in the examples and comparative compounds) were dissolved in a 0.5% methylcellulose solution, and tegoprazan was used as the comparative compound. The prepared test drugs were orally administered to the test animals at a dose of 3 mg / 5 mL / kg, and 30 minutes later, inhalation anesthesia (3% isoflurane) was administered for 3 minutes using an inhalation anesthesia machine. After minimal incision was made in the upper abdomen of the anesthetized test animals, approximately 1 cm below the left side of the sternum, the stomach was exposed, and the pyloric ring, the connection between the stomach and duodenum, was ligated. The stomach and duodenum were returned to their original positions, and the abdominal incision was carefully sutured closed with a surgical stapler. Histamine (7.5 mg / 2.5 mL / head) was gradually administered subcutaneously to the back of the neck to stimulate gastric acid secretion. Three hours after the surgery, the experimental animals were anesthetized with isoflurane, and the stomach was removed by laparotomy. The gastric juice obtained from the removed stomach was transferred to a 15 mL cone tube, centrifuged at 5,000 rpm for 10 minutes, and only the supernatant was separated. 0.2 mL of the separated gastric juice was diluted with 24.8 mL of distilled water to prepare a total of 25 mL of diluted solution, which was then titrated with 0.01 N NaOH in small amounts until the pH reached 7. The efficacy was evaluated by calculating the total acidity by adding the amount of gastric juice and the amount of 0.01 N NaOH used in the titration.

[0065] JPEG0007863187000013.jpg21141

[0066] The measured results are shown in Table 2 below.

[0067] JPEG0007863187000014.jpg48164

[0068] As is clear from Table 2 above, it was confirmed that the compounds of Example 1, Example 4, and Example 6 according to the present invention have potent gastric acid secretion inhibitory activity in gastric acid secretion animal models.

[0069] Experimental Example 3: Confirmation test of gastric acid secretion inhibitory effect by administration to the duodenum

[0070] Test animals (rats) were purchased one week prior to the test date and acclimatized. After acclimatization, food was removed the day before the test, and fasting was carried out for 24 hours using a fasting board. The weight of each individual was measured, and weight rankings were assigned sequentially to each group, and the rats were randomly distributed so that the average weights of each group were evenly distributed. The test substances (compounds in the examples and comparative compounds) were dissolved in a 0.5% methylcellulose solution, and tegoprazan was used as the comparative compound. The experimental animals were administered inhalation anesthesia (3% isoflurane) for 3 minutes using an inhalation anesthesia machine. After making a minimal incision in the upper abdomen of the anesthetized test animals, approximately 1 cm below the left side of the sternum, the stomach was exposed, and the pyloric ring, the connection between the stomach and duodenum, was ligated. The prepared drug was administered into the duodenum at a dose of 1 mg / 5 mL / kg, the stomach and duodenum were returned to their original positions, and the abdominal incision was carefully sutured closed with a surgical stapler. Histamine (7.5 mg / 2.5 mL / head) was gradually administered subcutaneously to the back of the neck to stimulate gastric acid secretion. Three hours after the surgery, the experimental animals were anesthetized with isoflurane, and the stomach was removed by laparotomy. The gastric juice obtained from the removed stomach was transferred to a 15 mL cone, centrifuged at 5,000 rpm for 10 minutes, and only the supernatant was separated. 0.2 mL of the separated gastric juice was diluted with 24.8 mL of distilled water to prepare a total of 25 mL of diluted solution, which was then titrated with 0.01 N NaOH in small amounts until the pH reached 7. The efficacy was evaluated by calculating the total acidity by adding the amount of gastric juice and the amount of 0.01 N NaOH used in the titration.

[0071] JPEG0007863187000015.jpg20139

[0072] The measured results are shown in Table 3 below.

[0073] JPEG0007863187000016.jpg24164

[0074] As is clear from Table 3 above, the compound of Example 6 according to the present invention showed improved gastric acid secretion inhibitory ability compared to the comparative compound when the drug was administered to the duodenum, where the pH is neutral. Therefore, it is expected that the compound of Example 6 according to the present invention will exhibit the same efficacy regardless of pH, even after meals or under various biological environments where the pH in the gastric cavity is neutral.

Claims

1. A benzimidazole derivative compound, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized by being sodium (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl phosphate.

2. The sodium (S)-(4-((5,7-difluorochroman-4-yl)oxy)-6-(dimethylcarbamoyl)-2-methyl-1H-benzo[d]imidazole-1-yl)methyl phosphate is

3. The benzimidazole derivative compound according to claim 1, or the pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the pharmaceutically acceptable salt is an alkali metal or alkaline earth metal salt selected from the group consisting of sodium, lithium, potassium, calcium, and magnesium.

4. The benzimidazole derivative compound according to claim 3, or the pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the pharmaceutically acceptable salt is a sodium salt.

5. A pharmaceutical composition for inhibiting gastric acid secretion, comprising, as an active ingredient, a benzimidazole derivative compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for the prevention or treatment of diseases induced by gastric acid secretion disorders, comprising, as an active ingredient, a benzimidazole derivative compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

7. A pharmaceutical composition for the prevention or treatment of a disease induced by impaired gastric acid secretion according to claim 6, characterized in that the disease induced by the impaired gastric acid secretion is selected from the group consisting of gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, gastritis, Helicobacter pylori infection, indigestion, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive gastroesophageal reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, and asthma.

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