Salt form of pyrrole sulfonamide acid inhibitor as well as preparation method and application of salt form

Abstract

The invention relates to a salt form of a pyrrole sulfonamide acid inhibitor as well as a preparation method and application of the salt form. Specifically, the invention discloses a compound shown as a formula (I), n = 0.1-2.0, and HA is an organic acid or an inorganic acid. The compound has the characteristics of convenience in storage, long-term stability of the product and simple preparation method, meets the industrial production requirements, and meets the development requirements of clinical pharmaceutical preparations. The compound disclosed by the invention can be used for preparing a potassium ion competitive acid blocker and preparing a medicine for treating gastric acid related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of compounds, and particularly relates to a salt form of a pyrrole sulfonamide antacid and its preparation method and application field. Background Art

[0002] Acid-related diseases (ARDs) are a class of diseases induced or caused by gastric acid attacks, mainly including peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), etc. In the drug treatment of these diseases, clinically, antacid drugs are the most effective means for treating acid-related diseases. Although proton pump inhibitors (PPIs) dominate the antacid field, there are problems such as slow onset, unstable acid suppression, large individual differences in drug efficacy, and many drug interactions.

[0003] Potassium competitive acid blockers (P-CABs) competitively bind to H + / K + / K + -ATPase non-covalently (hydrogen bonds and ionic bonds), thereby inhibiting the activity of H + / K + -ATPase, and have a strong and lasting effect on inhibiting gastric acid secretion. Vonoprazan, a new generation of antacid drug of the potassium competitive acid blocker (P-CAB) class developed by Takeda in Japan, has a brand-new mechanism of action and features such as full efficacy with the first dose and strong acid suppression. It has been approved successively for the treatment of acid-related diseases, including reflux esophagitis, gastric ulcer, duodenal ulcer, and combined with antibiotics to eradicate Helicobacter pylori. The latest version of the Chinese Guidelines for the Diagnosis and Treatment of Gastroesophageal Reflux Disease (GERD) has listed P-CAB and PPI together as the first-choice drugs for treatment.

[0004] Patent CN113620930B discloses the structures of a series of compounds containing a sulfonamide structure (specifically, in Preparation Example 9), and at the same time, this structure exhibits better biological activity. However, when this patent CN113620930B was applied for, no further research was carried out to develop a salt form suitable for industrial production, nor a process method suitable for industrial application was developed, nor was the salt form of the compound of formula (I) deeply studied to improve the physical and chemical properties of the compound and meet the requirements of pharmaceutical or clinical applications.

[0005] Therefore, in order to seek suitable characteristics such as convenient storage and long-term stability of the product, the present invention has conducted a comprehensive study on the salts of the above-mentioned substances and is committed to obtaining the most suitable salt. Summary of the Invention

[0006] The object of the present invention is to provide a salt of a compound of formula (I) that is convenient for storage and has long-term stability of the product.

[0007] In the first aspect of the present invention, there is provided a compound having the structure shown by the general formula (I),

[0008]

[0009] wherein,

[0010] n = 0.1 - 2.0;

[0011] HA is an organic acid or an inorganic acid.

[0012] In another preferred embodiment, the organic acid is selected from the group consisting of: fumaric acid, malic acid, oxalic acid, tartaric acid.

[0013] In another preferred embodiment, the inorganic acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid.

[0014] In another preferred embodiment, the inorganic acid is hydrochloric acid.

[0015] In another preferred embodiment, the HA is fumaric acid, hydrochloric acid, malic acid, oxalic acid, tartaric acid.

[0016] In another preferred embodiment, n = 0.5, 1.0, 1.5, 2.0.

[0017] In another preferred embodiment, n = 0.5, 1.0, 1.5, 2.0; HA is fumaric acid, hydrochloric acid, malic acid, oxalic acid, tartaric acid.

[0018] In the second aspect of the present invention, there is provided a preparation method of the compound as described in the first aspect of the present invention, comprising the following steps:

[0019] (s1) Provide a first substance, which is 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;

[0020] (s2) Mix the first substance with an organic solvent and an acid, and react fully to obtain the compound shown by the general formula (I).

[0021] In another preferred embodiment, the organic solvent is selected from the group consisting of: ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, toluene, acetone.

[0022] In another preferred example, the acid is selected from the group consisting of: fumaric acid, malic acid, oxalic acid, tartaric acid, sulfuric acid, hydrobromic acid, phosphoric acid.

[0023] In another preferred example, the mass-volume ratio of the first substance to the organic solvent is 0.01 - 0.5 g / ml, preferably 0.1 - 0.3 g / ml, more preferably 0.15 - 0.2 g / ml.

[0024] In another preferred example, the mass ratio of the first substance to the acid is 1:5 - 10:1, preferably 1:1 - 5:1.

[0025] In another preferred example, the reaction is carried out at 0 - 40 °C, preferably 10 - 30 °C, more preferably 15 - 25 °C.

[0026] In another preferred example, the organic solvent is selected from: ethyl acetate, methanol.

[0027] In another preferred example, the preparation method further includes a post-treatment step.

[0028] In another preferred example, the post-treatment step includes filtration, washing, and vacuum drying.

[0029] In another preferred example, the washing solution is selected from the group consisting of: ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, toluene, acetone.

[0030] In another preferred example, the washing solution is selected from the group consisting of: ethyl acetate, methanol.

[0031] In another preferred example, the vacuum drying is carried out at 40 - 80 °C, preferably 40 - 60 °C, more preferably 45 - 55 °C, for example 50 °C.

[0032] In another preferred example, the time for vacuum drying is 1 - 10 h, preferably 4 - 8 h, more preferably 5 - 7 h, for example 6 h.

[0033] In another preferred example, the preparation method includes the following steps:

[0034] (a1) Providing a second substance, which is the hydrochloride of 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine;

[0035] (a2) Mixing the second substance with an organic solvent, adjusting the pH to alkaline with sodium hydroxide solution, extracting, and concentrating the organic phase to obtain the free base;

[0036] (a3) Adding an acid to the free base for reaction to obtain the compound represented by the general formula (I).

[0037] In another preferred example, in step (a2), the molar ratio of sodium hydroxide solution to the second substance is: 2.2 to 3.0:1.0, preferably 2.2 to 2.5:1.0.

[0038] In another preferred example, the molar ratio of free base to acid is 5:3 to 2:7, preferably 10:9 to 5:6.

[0039] In another preferred example, the temperature of the reaction is 0 to 40 °C.

[0040] In another preferred example, the reaction time is 0.5 to 3 h, preferably 0.5 to 2 h, more preferably 0.5 to 1.5 h, for example 1 h.

[0041] In the third aspect of the present invention, there is provided a pharmaceutical composition comprising (a) a compound represented by formula (I) and (b) a pharmaceutically acceptable carrier.

[0042] In the fourth aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention for preparing a potassium ion competitive acid blocker, for preparing a drug or pharmaceutical composition for treating gastric acid-related diseases.

[0043] In another preferred example, the gastric acid-related diseases are selected from the group consisting of: reflux esophagitis, gastric ulcer, duodenal ulcer.

[0044] In another preferred example, it is used for preparing a drug or pharmaceutical composition for eradicating Helicobacter pylori in combination with an antibiotic.

[0045] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed implementation manners

[0046] Through extensive and in-depth research, and through a large number of screenings and tests, the present inventors have provided a 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine salt, which is convenient for storage, the product is stable for a long time, and the production process is simple, and is suitable for large-scale industrial production. The present invention has been completed on this basis.

[0047] Terms

[0048] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains.

[0049] As used herein, the terms "comprising" or "including" can be open-ended, semi-closed, and closed-ended. In other words, these terms also include "consisting essentially of" or "consisting of".

[0050] As used herein, the terms "salt form of pyrrolosulfonamide antacids", "1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine salt", "compounds of the present invention", "active ingredients of the present invention", and "compounds of formula (I)" are used interchangeably and all refer to the compounds having the structure shown in general formula (I).

[0051] Biological activity of the active ingredient of the present invention

[0052] As used herein, the terms "salt form of pyrrolosulfonamide antacids", "1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine salt", "compounds of the present invention", "active ingredients of the present invention", and "compounds of formula (I)" are used interchangeably and all refer to the compounds having the structure shown in general formula (I).

[0053] The compounds involved in the present invention have potassium ion competitive inhibition and are gastric acid secretion inhibitors. The compounds of the present invention competitively bind to H + / K + / K + -ATPase non-covalently (hydrogen bonds and ionic bonds), inhibiting the activity of H + / K + -ATPase, thereby inhibiting gastric acid secretion.

[0054] The compounds of the present invention have the characteristics of being easy to store and having long-term stability of the product. Compared with the structure of a series of compounds containing a sulfonamide structure disclosed in Patent CN113620930B (specifically, Preparation Example 9), they have better biological activity.

[0055] Compositions containing the active ingredient of the present invention

[0056] In the present invention, "pharmaceutical composition" refers to a preparation of the compounds of the present invention and a medium commonly accepted in the art for delivering bioactive compounds to mammals (such as humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the administration to organisms, facilitate the absorption of the active ingredient, and thereby exert biological activity.

[0057] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any of the components contained in the composition.

[0058] In the present invention, "pharmaceutically acceptable carriers" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifying agents that are permitted by the relevant government regulatory authorities for use in humans or livestock.

[0059] There is no particular limitation on the mode of administration of the compounds or pharmaceutical compositions of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0060] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate, or with the following components: (a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropylmethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0061] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric materials and waxes. If necessary, the active compound can also be in the form of microcapsules formed with one or more of the above excipients.

[0062] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0063] In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and perfumes.

[0064] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide and agar or mixtures of these substances, etc.

[0065] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non - aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non - aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and their suitable mixtures.

[0066] As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to an amount of at least one agent or compound that, when administered, is sufficient to, to some extent, alleviate one or more symptoms of the disease or disorder being treated. The result can be a reduction and / or alleviation of the sign, symptom or cause, or any other desired change in the biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of the disorder. Techniques such as dose - escalation trials can be used to determine the effective amount suitable for any individual case.

[0067] As used herein, the terms "administering", "applying", "dosing", etc. refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the administration techniques applicable to the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0068] As used herein, the terms "drug combination", "drug combination therapy", "combination drug therapy", "administering additional therapy", "administering additional therapeutic agent", etc. refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, co-administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0069] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dosage unit, more preferably, it contains 10 - 1000 mg of the compound of the present invention per dosage unit. Preferably, the "dosage unit" is a capsule, a tablet, or a preparation.

[0070] Preparation method of the compound of the present invention

[0071] The hydrochloride salt of 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine was prepared with reference to the literature (CN113620930B; Research, 2022, 2022(4):582 - 593).

[0072] An organic solvent is added to the hydrochloride of 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine. After adjusting the pH to alkaline with sodium hydroxide solution at room temperature, the mixture is separated into layers, extracted, and the organic phase is concentrated to obtain the free base. The free base is dissolved in an organic solvent, and the corresponding acid is added respectively. The reaction is carried out for 0.5 - 3 h, followed by filtration, washing, and vacuum drying at 50 °C for 5 - 8 h to obtain the corresponding salt.

[0073] The organic solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, toluene, and acetone.

[0074] The main advantages of the present invention include:

[0075] (1) The compounds of the present invention have the characteristics of being convenient for storage and long-term stability of the product;

[0076] (2) The compounds of the present invention have excellent potassium ion competitive inhibitory effects and can be used for preparing potassium ion competitive acid blockers and drugs for treating gastric acid-related diseases, such as reflux esophagitis, gastric ulcer, duodenal ulcer, and eradicating Helicobacter pylori in combination with antibiotics, etc.;

[0077] (3) The preparation method of the compounds of the present invention is simple.

[0078] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0079] Example 1: 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine mono-fumarate

[0080] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), ethyl acetate (30 ml), and fumaric acid (1.47 g) are added to a 100 ml single-necked flask. The mixture is stirred at room temperature for 1 h, filtered, washed with ethyl acetate (10 ml), and vacuum dried at 50 °C for 6 h to obtain 5.57 g of a white solid with a yield of 87.0%.

[0081] Example 2: 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine oxalate

[0082] Add 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), ethyl acetate (30 ml), and oxalic acid (1.14 g) to a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with ethyl acetate (10 ml), and dry under vacuum at 50 °C for 6 h to obtain 5.15 g of a white solid with a yield of 84.7%.

[0083] Example 3: 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine tartrate

[0084] Add 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), ethyl acetate (30 ml), and DL-tartaric acid (1.90 g) to a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with ethyl acetate (10 ml), and dry under vacuum at 50 °C for 6 h to obtain 5.85 g of a white solid with a yield of 85.9%.

[0085] Example 4: 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine malate

[0086] Add 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), ethyl acetate (30 ml), and DL-malic acid (1.69 g) to a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with ethyl acetate (10 ml), and dry under vacuum at 50 °C for 6 h to obtain 5.75 g of a white solid with a yield of 87.0%.

[0087] Example 5: 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine sulfate

[0088] Add 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), methanol (30 ml), and sulfuric acid (1.24 g) to a 100 ml single-necked flask. Stir at room temperature for 1 h, filter, wash with ethyl acetate (10 ml), and dry under vacuum at 50 °C for 6 h to obtain 4.45 g of a white solid with a yield of 72.0%.

[0089] Example 6: 1-[5-[4-(Cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine hydrobromide

[0090] 1-[5-[4-(Cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), methanol (30 ml), and hydrobromic acid (3.40 g) were added to a 100 ml single-necked flask, stirred at room temperature for 1 h, filtered, washed with methanol (10 ml), and dried in vacuo at 50 °C for 6 h to obtain 2.56 g of a white solid with a yield of 42.9%.

[0091] Example 7 (comparative example): 1-[5-[4-(Cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine nitrate

[0092] 1-[5-[4-(Cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (5.00 g), ethyl acetate (30 ml), and nitric acid (1.69 g) were added to a 100 ml single-necked flask, stirred at room temperature for 1 h, and no solid precipitated.

[0093] Example 8: Stability investigation experiment of the compounds of the present invention

[0094] Stress testing: The various salt forms of 1-[5-[4-(Cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine were subjected to stress testing (naked exposure): high temperature (60 °C), high humidity (92.5% RH), and light (4500 lx). Samples were taken for detection on the 5th, 10th, and 30th days respectively.

[0095] Table 1 Data table of stability experiments of various salt forms

[0096]

[0097]

[0098]

[0099] Through the stress testing of the compounds of various salt forms, the comparative results showed that:

[0100] Under light conditions, the various salt forms of fumaric acid, malic acid, oxalic acid, tartaric acid, sulfuric acid, hydrobromic acid, and hydrochloric acid all degraded to varying degrees. Among them, the degradation of sulfuric acid, hydrobromic acid, and hydrochloric acid was relatively strong, while the degradation of fumaric acid, malic acid, oxalic acid, and tartaric acid was relatively weak.

[0101] Under high temperature conditions, fumaric acid, malic acid, oxalic acid, tartaric acid, sulfuric acid, hydrobromic acid, and hydrochloric acid are all relatively stable.

[0102] Under high humidity conditions, sulfuric acid, hydrobromic acid, and hydrochloric acid are hygroscopic, and the related substances increase slightly. Fumaric acid, malic acid, oxalic acid, and tartrate salts are almost non-hygroscopic, and the related substances show no obvious change.

[0103] The stability study of each salt form provides support for the selection of the salt form of this compound.

[0104] All the documents mentioned in the present invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound having the structure shown in general formula (I), characterized in that, wherein, n＝0.1～2.0； HA is an organic acid or an inorganic acid.

2. The compound according to claim 1, wherein The organic acid is selected from the following group: fumaric acid, malic acid, oxalic acid, tartaric acid.

3. The compound according to claim 1, wherein The inorganic acid is selected from the following group: hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid.

4. A method for preparing a compound according to any one of claims 1 to 3, characterized in that, Comprising the following steps: (s1) Providing a first substance, the first substance being 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridine-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine; (s2) Mixing the first substance with an organic solvent and an acid, and reacting fully to obtain the compound shown in general formula (I).

5. The preparation method according to claim 4, characterized in that, The organic solvent is selected from the following group: ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, toluene, acetone.

6. The preparation method according to claim 4, characterized in that, The acid is selected from the following group: fumaric acid, malic acid, oxalic acid, tartaric acid, sulfuric acid, hydrobromic acid, phosphoric acid.

7. The preparation method according to claim 4, characterized in that, The mass-volume ratio of the first substance to the organic solvent is 0.01 - 0.5 g / ml.

8. The preparation method according to claim 4, characterized in that, The mass ratio of the first substance to the acid is 1:5 - 10:

1.

9. A pharmaceutical composition, characterized in that, Comprising (a) the compound shown in formula (I) and (b) a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 3, characterized in that, For preparing a potassium ion competitive acid blocker, preparing a drug or a pharmaceutical composition for treating gastric acid-related diseases.

Images