Novel salt of tegoprazan and method for preparing same

Abstract

The present invention relates to a novel salt compound of tegoprazan, which is a potassium-competitive acid blocker (P-CAB)-based drug, and a method for preparing same. The method according to the present invention can provide a novel tegoprazan orotate salt by using orotic acid, which is not harmful to the human body. In addition, through the preparation method of the present invention, it is possible to prepare a novel tegoprazan orotate salt with high purity (99.95% or greater) and properties similar to or superior to those of tegoprazan (e.g., the solubility of a tegoprazan orotate salt is 24 mg / mL whereas the solubility of tegoprazan is 3 mg / mL).

Description

Novel salt of tegoprazan and method for preparing the same

[0001] The present invention relates to a novel salt form of tegoprazan, tegoprazan orotate salt, and a method for producing the same.

[0002] Tegoprazan is a benzimidazole derivative having acid pump inhibitory activity (H+ K+ ATPase inhibitor) for the treatment of gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders and asthma, and is a compound named 4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benz[d]imidazole-6-carboxamide represented by the chemical formula 1. HKINNOEN (CJ Healthcare) developed and marketed K-CAP after acquiring the initial material from LaQualia Pharma Inc. (International Patent Publication No. 2007 / 072146).

[0003] [Chemical Formula 1]

[0004]

[0005] Korean Patent No. 10-1829706 introduces amorphous salts of the compound represented by Chemical Formula 1, which have excellent liquid stability, solid stability, water solubility, precipitation stability, and hygroscopicity, as the free base of the compound represented by Chemical Formula 1 has very low water solubility.

[0006] However, in the case of the pidolate salt and maleate salt of the compound represented by Chemical Formula 1, the amount of total flexible substances and the amount of residual solvent were measured to be higher than expected at the initial stage of synthesis and when stored under specific conditions, and in particular, the amount of residual solvent was much higher than the standard of the ICH guideline.

[0007] Therefore, a new salt of tegoprazan that is easy to formulate and has improved physicochemical stability, moisture absorption, etc., while remaining below the residual solvent standards recommended by the ICH guidelines has not yet been discovered.

[0008] [Prior Art Literature]

[0009] [Patent Document]

[0010] (Patent Document 1) International Patent Publication No. 2007 / 072146

[0011] (Patent Document 2) Republic of Korea Patent No. 10-1829706

[0012] The purpose of the present invention is to solve the above problem, and the solution is to provide a novel tegoprazan orotate salt that improves physicochemical stability and moisture absorption by using orotic acid that is not harmful to the human body and has a residual solvent level below the standard recommended by the ICH guideline.

[0013] Another object of the present invention is to provide a novel high-purity (99.95% or more) tegoprazan orotate salt having similar or superior properties to tegoprazan (e.g., the solubility of tegoprazan orotate salt is 24 mg / mL, while the solubility of tegoprazan is 3 mg / mL) through the manufacturing method of the present invention.

[0014] In order to solve the above problem, the present invention discloses the following means.

[0015] In one aspect, the present invention discloses a tegoprazan orotate salt represented by the following chemical formula 2.

[0016] [Chemical Formula 2]

[0017]

[0018] In another aspect, the present invention discloses a method for preparing tegoprazan orotate salt represented by the chemical formula 2, comprising the step of (a) reacting tegoprazan and orotic acid in an organic solvent.

[0019] According to the present invention, a novel tegoprazan orotate salt and a method for preparing the same can be provided using orotic acid that is not harmful to the human body, and further, through the preparation method of the present invention, a high-purity (99.95% or more) tegoprazan orotate salt can be prepared that has similar or superior properties to tegoprazan (e.g., the solubility of tegoprazan orotate salt is 24 mg / mL, while the solubility of tegoprazan is 3 mg / mL).

[0020] Specifically, the present invention provides a novel tegoprazan orotate salt having excellent stability when considering the total amount of flexible substances and moisture absorbency, and having a residual solvent level below the standard recommended by the ICH guideline.

[0021] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0022] Figure 1 is a diagram of the tegoprazan orotate salt according to the present invention. 1 It shows the H-nuclear magnetic resonance (NMR) spectrum.

[0023] Hereinafter, the present specification will be described in more detail.

[0024] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0025] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0026] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0027] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0028] Expressions such as “comprising” as used herein should be understood as open-ended terms that imply the possibility of including other embodiments.

[0029] The inventors of the present invention, while conducting research to develop a new salt of tegoprazan, confirmed that tegoprazan orotate salt, which is in the form of an orotic acid addition salt, can improve stability by minimizing the generation of volatile substances at the initial stage of synthesis and under conditions of 40°C and RH75% compared to other acid addition salts, and has low moisture absorption and residual solvents that meet the standards of the ICH guideline, thereby completing the present invention.

[0030] Hereinafter, the present invention will be described in detail.

[0031] New salt of Tegoprazan

[0032] To solve the above problem, the present invention provides a tegoprazan orotate salt. The tegoprazan orotate salt of the present invention is a compound represented by the following chemical formula 2.

[0033] [Chemical Formula 2]

[0034]

[0035] Specifically, the tegoprazan orotate salt represented by the above chemical formula 2 is named 4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide orotic acid [[(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide] orotic acid].

[0036] The tegoprazan orotate salt of the present invention comprises stereoisomers.

[0037] In the present invention, the term “stereoisomer” means a compound having one or more chiral centers (*), each of which can exist in the R or S form. Stereoisomers include not only diastereoisomers, enantiomers, and epimers, but also racemates and mixtures thereof.

[0038] Although it is known that preparing a salt form can improve the physical or pharmacological properties of a pharmaceutically active compound, it is impossible to predict which salt form will be effective for a specific purpose before it is actually prepared and characterized. Because salt formation can alter the physicochemical properties of a drug without altering its chemical structure, selecting an appropriate salt is a crucial consideration for solubility and stability. Solubility, in particular, is a critical property that can influence its suitability for use as a drug.

[0039] The tegoprazan orotate salt according to the present invention has superior physicochemical properties compared to tegoprazan or other salts of tegoprazan.

[0040] Specifically, the tegoprazan orotate salt of the present invention can minimize the generation of related substances in the initial stage of synthesis and under the conditions of 40°C and RH75%, thereby improving stability. In particular, the total amount of related substances measured in the initial stage of synthesis is at least three times less than that of the conventionally known tegoprazan pidolate salt and tegoprazan malate salt, and in the case of residual solvent, it is at least 72 times less than that of the tegoprazan pidolate salt and tegoprazan malate salt, so it can be considered to have stable characteristics of the salt itself. Therefore, even when the formulation is manufactured and stored for a long period of time, the same state is maintained, so the content uniformity of the formulation can be stably maintained, and thus it can be easily applied to mass production.

[0041] The tegoprazan orotate salt according to the present invention can be usefully applied as a medicine for diseases mediated by acid pump antagonism activity by using orotic acid, which is not harmful to the human body.

[0042] In one embodiment of the present invention, the tegoprazan orotate salt may be a combination of tegoprazan and orotic acid in a molar ratio of 1:1.

[0043] Method for preparing a novel salt of tegoprazan

[0044] In order to solve the above problem, the present invention provides a method for preparing tegoprazan orotate salt represented by the following chemical formula 2.

[0045] [Chemical Formula 2]

[0046]

[0047] The manufacturing method of the present invention comprises the step of (a) reacting tegoprazan and orotic acid in an organic solvent.

[0048] In the present invention, the manufacturing method may further include the following steps, but is not limited thereto.

[0049] (b) a step of precipitating a solid by concentrating the solution in step (a) under reduced pressure, and then adding a co-solvent and stirring; and

[0050] (c) A step of filtering and drying the precipitated solid.

[0051] In the present invention, the organic solvent of step (a) may be methanol or a mixed solution of methanol and water, but is not limited thereto.

[0052] In the present invention, the organic solvent of step (a) may be added 10 to 30 times (volume / weight) relative to tegoprazan, but is not limited thereto.

[0053] Specifically, the organic solvent of the above step (a) may be a mixed solution of methanol and water, and at this time, the mixed solution of methanol and water may be added with 20 (volume / weight) times the amount of methanol and 5 to 15 (volume / weight) times the amount of water, preferably 10 (volume / weight) times the amount of water, relative to tegoprazan, but is not limited thereto.

[0054] In the present invention, the orotic acid of step (a) may be added in a molar ratio of 0.8 to 1.5 equivalents per 1.0 equivalent of tegoprazan free base, but is not limited thereto.

[0055] In the present invention, the co-solvent of step (b) may be selected from the group consisting of methanol, ethanol, acetone, isopropanol, and mixed solvents thereof, but is not limited thereto.

[0056] In the present invention, the co-solvent of step (b) may be added 3 to 8 times (volume / weight) relative to the tegoprazan free base, but is not limited thereto.

[0057] In the present invention, the step (c) may be a step of washing the precipitated solid with any one solvent selected from the group consisting of methanol, ethanol, acetone, isopropanol, and a mixed solvent thereof, but is not limited thereto.

[0058] In the present invention, the drying in step (c) may be performed at 30 to 80°C for 10 to 30 hours, but is not limited thereto.

[0059] The tegoprazan orotate salt prepared according to the present invention is applied in the same manner as the above tegoprazan orotate salt, as long as they are not contradictory to each other.

[0060] Pharmaceutical composition for preventing or treating diseases mediated by acid pump antagonist activity, comprising tegoprazan orotate salt as an active ingredient

[0061] To solve the above problem, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by acid pump antagonism activity, containing tegoprazan orotate salt as an active ingredient.

[0062] In the present invention, the term “active ingredient” means a substance or group of substances that are expected to directly or indirectly exhibit the efficacy and effect of the composition through inherent pharmacological action, including the main ingredient.

[0063] In one embodiment of the present invention, the pharmaceutical composition of the present invention may be manufactured in a unit dose form or may be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains.

[0064] In the present invention, the term “pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not typically cause allergic reactions or similar reactions such as gastrointestinal disorders or dizziness when administered to humans.

[0065] In the present invention, the term "pharmaceutically acceptable carrier" typically includes a liquid or non-liquid basis of the pharmaceutical composition. If the pharmaceutical composition is provided in liquid form, the carrier is typically pyrogen-free water; an isotonic saline solution or a buffered (aqueous) solution, e.g., a buffered solution of phosphate, citric acid, etc. The injection buffer may be a hypertonic, isotonic, or hypotonic reference medium, i.e., the buffer may have a salt content higher than, equal to, or lower than that of the reference medium, and preferably, such concentrations of the aforementioned salts may be used that do not induce cell damage due to osmotic or other concentration effects. The reference medium is a liquid occurring in, e.g., an "in vivo" method, such as blood, lymph, interstitial fluid, or other body fluid, or a body fluid that can be used as a reference medium in, e.g., an "in vitro" method as a general buffer or liquid. Such general buffers or liquids are known to those skilled in the art.

[0066] In the present invention, the pharmaceutically acceptable carrier includes, but is not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0067] In the present invention, the pharmaceutical composition may include a diluent or excipient such as a filler, a bulking agent, a binder, a wetting agent, a disintegrating agent, a surfactant, and other pharmaceutically acceptable additives.

[0068] In the present invention, the pharmaceutical composition can be prepared in the form of a liquid, suspension, powder, granule, tablet, capsule, pill or extract.

[0069] In the present invention, the pharmaceutical composition can be administered orally or parenterally (e.g., by application or intravenous, subcutaneous, or intraperitoneal injection).

[0070] In the present invention, the term “oral administration” refers to a method of administering a drug for improving pathological symptoms through the mouth, and in the present invention, the term “parenteral administration” refers to a method of administering subcutaneously, intramuscularly, intravenously, or intraperitoneally using a tube, excluding oral administration.

[0071] Solid preparations for oral administration include powders, granules, tablets, capsules, soft capsules, and pills. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, and aerosols. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included.

[0072] Preparations for parenteral administration may be formulated and used in the form of external preparations such as sterilized aqueous solutions, liquids, non-aqueous solvents, suspensions, emulsions, eye drops, eye ointments, syrups, suppositories, aerosols, etc., and sterilized injection preparations according to conventional methods, and preferably, pharmaceutical compositions such as creams, gels, patches, sprays, ointments, warnings, lotions, liniments, eye ointments, eye drops, pastes, or cataplasmas may be prepared and used, but are not limited thereto. Compositions for topical administration may be anhydrous or aqueous depending on clinical prescriptions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases that can be used include witepsol, macrogol, tween 61, cocoa butter, laurin butter, and glycerogelatin.

[0073] The pharmaceutically acceptable additive according to the present invention may be included in an amount of 0.1 to 99.9 parts by weight relative to the pharmaceutical composition, specifically, 0.1 to 50 parts by weight, but is not limited thereto.

[0074] In the present invention, the term “treatment” means partially or completely alleviating, improving, alleviating, inhibiting or delaying the onset of a specific disease, disorder and / or condition, reducing the severity or reducing the occurrence of one or more symptoms or characteristics.

[0075] In the present invention, the term "prevention" refers to the delay of the onset of a disease, disorder, or condition. Prevention may be considered complete if the onset of a disease, disorder, or condition is delayed for a predetermined period of time.

[0076] In one embodiment of the present invention, the disease mediated by acid pump antagonist activity may be any one selected from the group including, but not limited to, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by NSAID, gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway obstruction and asthma.

[0077] The present invention provides a pharmaceutical composition for preventing or treating a disease mediated by acid pump antagonism by containing 25 mg or 50 mg of tegoprazan orotate salt as tegoprazan and administering the composition once a day.

[0078] Methods for preventing or treating diseases mediated by acid pump antagonist activity

[0079] To solve the above problem, the present invention provides a method for preventing or treating a disease mediated by acid pump antagonist activity by administering a therapeutically effective amount of tegoprazan orotate salt to a subject in need of treatment.

[0080] In the present invention, the term "therapeutically effective amount" means the amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue, animal, or human, as conceived by a researcher, veterinarian, physician, or other clinician, including an amount that induces alleviation of symptoms of a disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration of the active ingredient of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be readily determined by those skilled in the art, and can be adjusted according to various factors, including the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of formulation, and the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, and the excretion rate of the composition, the treatment period, and concurrently used drugs.

[0081] Specifically, the therapeutically effective amount is an amount of the tegoprazan orotate salt of the present invention that is effective in preventing or treating a disease mediated by acid pump antagonist activity, preferably 25 mg or 50 mg of tegoprazan orotate salt may be administered once a day, but the therapeutically effective amount may be interpreted to encompass all doses at which the symptoms of the disease mediated by acid pump antagonist activity are improved or completely cured by the pharmaceutical composition.

[0082] The preventive or therapeutic method of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering a pharmaceutical composition.

[0083] In the present invention, the term “subject requiring treatment” means mammals such as monkeys, cows, horses, dogs, cats, rabbits, rats, and mice, and particularly includes humans.

[0084] In the present invention, the term "administration" means providing a predetermined substance to a patient by any suitable method. In the treatment method of the present invention, a pharmaceutical composition for the prevention or treatment of a disease mediated by acid pump antagonist activity, containing the tegoprazan orotate salt of the present invention as an active ingredient, may be administered in a conventional manner via oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular, or intradermal routes.

[0085] Additionally, the preventive or therapeutic method of the present invention may further include administration of a therapeutically effective amount of an additional active agent helpful in treating a disease together with the pharmaceutical composition, wherein the additional active agent may exhibit a synergistic or additive effect together with the pharmaceutical composition.

[0086] Use of a pharmaceutical composition comprising tegoprazan orotate salt for the manufacture of a medicament for the prevention or treatment of diseases mediated by acid pump antagonist activity

[0087] The present invention provides the use of a pharmaceutical composition comprising tegoprazan orotate salt for the manufacture of a medicament for the prevention or treatment of a disease mediated by acid pump antagonist activity.

[0088] In the present invention, the pharmaceutical composition comprising the tegoprazan orotate salt of the present invention for the manufacture of a drug may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers, etc., and may be manufactured into a complex preparation together with other active agents to have a synergistic effect.

[0089] Use of a pharmaceutical composition comprising tegoprazan orotate salt for the prevention or treatment of diseases mediated by acid pump antagonist activity

[0090] The present invention provides a use of a pharmaceutical composition comprising tegoprazan orotate salt for the prevention or treatment of diseases mediated by acid pump antagonist activity.

[0091] The matters mentioned in the pharmaceutical composition, treatment method and use of the present invention apply equally unless they are contradictory to each other.

[0092] Hereinafter, the present invention will be described in detail based on examples, comparative examples, and experimental examples. However, the following examples, comparative examples, and experimental examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0093] Exploration of pyogenic cystitis

[0094] Tegoprazan acid addition salts were prepared using various acids listed in Table 1 below. Each acid was prepared using the most appropriate method among the preparation methods 1 to 3 below.

[0095] Specifically, the acid addition salt was not obtained by manufacturing method 1, which is the manufacturing method described in the registered patent no. 10-1829706, and only orotate and phosphate could be obtained by manufacturing method 3, and in most cases, it could be obtained by using manufacturing method 2.

[0096] No. Type of acid Addition amount Manufacturing method Solvent ratio 1 Orotic acid 1.05 equivalent 3 Methanol solution 86.0% 2 L-pyroglutamic acid 1.05 equivalent 2 Methanol 87.2% 3 L-malic acid 1.05 equivalent 2 Methanol 87.5% 4 phosphoric acid 1.05 equivalent 3 Methanol 82.4% 5 Lactobionic acid 1.05 equivalent Not available for production Methanol-6 Isethionic acid 1.05 equivalent Decomposition during production Methanol-7 Hippuric acid 1.05 equivalent Not available for production Methanol-8 D-glucuronic acid 1.05 equivalent 2 Methanol 83.5% 9 Gluconic acid 1.05 equivalent Not available for production Methanol-10 1,2-ethane disulfonic acid 0.52 equivalent Decomposition during production Methanol-11(+)-10-camphorsulfonic acid acid 1.05 equivalent Decomposition during production Methanol-12 glycolic acid 1.05 equivalent Not produced Methanol-13 pamoic acid 1.05 equivalent 2 Methanol 84.3% 14 lactic acid 1.05 equivalent Not produced Methanol-15 benzoic acid 1.05 equivalent Not produced Methanol-16 propionic acid 1.05 equivalent Not produced Methanol-17 acetic acid 1.05 equivalent Not produced Methanol-18 naphthalene-2-sulfonic acid 1.05 equivalent Decomposition during production Methanol-19 ethansulfonic acid 1.05 equivalent Decomposition during production Methanol-20 4-hydroxybenzoic acid 1.05 equivalent Not produced Methanol-21 2,4-Dihydroxybenzoic acid 1.05 equivalent 2 Methanol 78.6% 22 3,4-Dihydroxybenzoic acid 1.05 Equivalent production impossible methanol-23 glutaric acid 1.05 Equivalent production impossible methanol-24 gallic acid 1.05 Equivalent production impossible methanol-25 Methanesulfonic acid 1.05 Equivalent production decomposition methanol-26 Salicylic acid 1.05 Equivalent production impossible methanol-27 Maleic acid 1.05 Equivalent production impossible methanol-28 L-tartaric acid 1.05 Equivalent production impossible methanol-29 Salicylic ...2%292,5-dihydroxybenzoic acid1.05 equivalent2Methanol84.9%30Nicotinic acid1.05 equivalent2Methanol75.3%31P-toluenesulfonic acid1.05 equivalentDecomposition during productionMethanol-321,5-naphthalene disulfonic acid0.52 equivalentDecomposition during productionMethanol-33Citric acid1.05 equivalent2Methanol81.5%34Oxalic acid1.05 equivalent2Methanol84.7%35Fumaric acid1.05 equivalent2Methanol83.4%36Succinic acid1.05 equivalentUnmanufacturedMethanol-37Malonic acid1.05 equivalent2Methanol78.6%.

[0097] (In the above Table 1, No. 1 is an example of synthesizing the tegoprazan orotate salt of the present invention, using a methanol aqueous solution. In this case, the methanol aqueous solution means adding 10 (volume / weight) times the amount of water to 20 (volume / weight) times the amount of methanol relative to tegoprazan.)

[0098] Manufacturing method 1) (Manufacturing method listed in Patent No. 10-1829706)

[0099] At 25°C, 100 g of tegoprazan and an acid (1.05 equivalents per 1.0 equivalent of tegoprazan free base) were completely dissolved in 1000 mL of methanol, and the solution was concentrated under reduced pressure at 50°C while stirring until a solid precipitated. To the concentrate, a co-solvent of acetone / ethyl acetate = 1 / 4 (500 mL, 5 (vol / weight) times relative to tegoprazan free base, 1 time acetone, 4 times ethyl acetate) was added at 25°C, and the mixture was stirred vigorously for 30 minutes. The solid was filtered under reduced pressure, washed with ethyl acetate (100 mL, 1 (vol / weight) times relative to tegoprazan free base), and then dried under vacuum at 40°C for 16 hours to obtain the acid addition salt of tegoprazan.

[0100] Manufacturing method 2)

[0101] At 25°C, 100 g of tegoprazan and an acid (1.05 equivalents per 1.0 equivalent of tegoprazan free base) were completely dissolved in 1000 mL of methanol, and the solution was concentrated under reduced pressure at 50°C while stirring until a solid precipitated. The concentrate was dissolved in methanol (200 mL, 2 (volume / weight) times relative to tegoprazan free base) at 25°C, and then a co-solvent of diisopropyl ether (2000 mL, 20 (volume / weight) times relative to tegoprazan free base) was added, and the mixture was stirred for 1 hour to precipitate crystals. The solid was filtered under reduced pressure, washed with diisopropyl ether (100 mL, 1 (volume / weight) times relative to tegoprazan free base), and dried under vacuum at 40°C for 16 hours to obtain tegoprazan acid addition salt.

[0102] Manufacturing method 3) - Manufacturing example of the present invention

[0103] At 25°C, 100 g of tegoprazan and an acid (1.05 equivalents per 1.0 equivalent of tegoprazan free base) were completely dissolved in 1000 mL of methanol (phosphoric acid) or 3000 mL of methanol aqueous solution (2000 mL of methanol and 1000 mL of water mixed), and the solution was concentrated under reduced pressure at 50°C until a solid precipitated. A co-solvent of acetone (500 mL, 5 (vol / weight) times relative to tegoprazan free base) was added to the concentrate, stirred, and then stirred for 1 hour to precipitate crystals. The solid was filtered under reduced pressure, washed with acetone (100 mL, 1 (vol / weight) times relative to tegoprazan free base), and dried under vacuum at 40°C for 16 hours to obtain tegoprazan acid addition salt.

[0104] (In the case of the tegoprazan orotate salt according to the present invention, it is manufactured through manufacturing method 3, and at this time, for elucidating the structure 1 For H-NMR, it is shown in Figure 1.)

[0105] Stability test

[0106] Test method

[0107] Method for measuring total flexible substances, moisture, and residual solvents in initial synthetic acid addition salts

[0108] -Method for measuring total flexible substances (HPLC analysis)

[0109] Purity was measured using liquid chromatography. The specific methods and conditions are as follows.

[0110] Test solution: Weigh approximately 40 mg of the initially synthesized tegoprazan acid addition salt, place it in a 100 mL volumetric flask, dissolve it in a small amount of dilution solvent (50% ACN), and then dilute it with the dilution solvent (50% ACN) to make 100 mL.

[0111] DetectorExternal spectrophotometer (220 nm)ColumnZORBAX Eclipse Plus 5 μm, 4.6 × 250 mm, Agilent (P / N: 959990-902)Column temperatureConstant temperature around 40℃Mobile phaseA0.1% phosphoric acid containing waterMobile phase BAcetonitrileInjection amount10 μLFlow rate1.0 mL / minConcentration gradientConditionTime (min)Mobile phase AMobile phase B0901059010401090501090519010609010

[0112] - Moisture measurement method (Karl Fischer analysis)

[0113] A test was conducted using a moisture measurement solution using approximately 0.5 g of the initial synthetic tegoprazan acid addition salt according to the Karl Fischer method (direct titration method of volumetric titration) of the General Test Methods of the Korean Pharmacopoeia.

[0114] - Residual solvent measurement method (GC analysis)

[0115] Residual solvent was tested using the headspace method of gas chromatography. The specific measurement method and conditions are as follows.

[0116] Test solution: Approximately 0.2 g of the initial synthetic tegoprazan acid addition salt and 10 mL of DMSO were placed in a headspace vial and sealed.

[0117] Standard stock solution: Accurately weigh 0.3 g of methanol, place it in a 100 mL volumetric flask containing a small amount of 60 mL of DMSO, dissolve it, and then dilute it to 100 mL with DMSO to make a standard stock solution.

[0118] Standard solution: Exactly 5 mL of the standard solution was placed in a 100 mL volumetric flask, diluted to 100 mL with DMSO, and used as the standard solution. 5 mL of the standard solution was placed in headspace vials and sealed.

[0119] Detector FID Column DB-624 (30 m x 0.32 mm, 1.8 um) Column Temperature 40℃ (3 min) -> 10℃ / min -> 200℃ (0 min) Mobile Phase Gas Helium (He)

[0120] Accelerated stability test method

[0121] The above synthesized tegoprazan acid addition salts were stored in PE bags in a stability chamber at 40°C and RH75% for one month. Thereafter, the degree of moisture generation using the Karl Fischer method and the degree of flexible substances generation using the HPLC analysis method are shown in Table 4.

[0122] Test results

[0123] Referring to Table 4 below, it was confirmed that acid addition salts other than orthoic acid salts had increased total flexible substances and high moisture absorption as a result of stability.

[0124] In addition, it was confirmed that the acid addition salts had residual solvent levels much higher than the standards of the ICH guideline (methanol 3000 ppm (0.3%) or less, acetone 5000 ppm (0.5%) or less, diisopropyl ether 5000 ppm (0.5%)).

[0125] No. Type of acid Initial synthesis results Stability results (40℃, RH75%, 1 month) Manufacturing method Total flexible substance Moisture Residual solvent Total flexible substance Moisture 1 Orotic acid 0.06 % 1.21 % 0.06 % 0.06 % 1.19 % Method 3 2 L-pyroglutamic acid 0.19 % 0.97 % 6.34 % 0.26 % 3.24 % Method 2 3 L-malic acid 0.18 % 0.95 % 4.32 % 0.25 % 2.79 % Method 2 4 phosphoric acid 0.24 % 1.49 % 5.44 % 0.61 % 5.52 % Method 3 5 Lactobionic acid Acid addition salt not produced 6 Isethionic acid Acid addition salt decomposed during production, producing approximately 6% of flexible substances 7 Hippuric acid Acid addition salt not produced 8 D-glucuronic acid 0.22 % 1.25 %7.07%0.33%3.45%Method 2 9Gluconic acidAcid addition salt not produced 101,2-ethane disulfonic acidAcid addition salt decomposed during production, producing approximately 29% of related substances 11(+)-10-camphorsulfonic acidAcid addition salt decomposed during production, producing approximately 7% of related substances 12Glycolic acidAcid addition salt not produced 13Pamoic acid0.21%1.56%3.91%0.35%4.72%Method 2 14Lactic acidAcid addition salt not produced 15Benzoic acidAcid addition salt not produced 16Propionic acidAcid addition salt not produced 17Acetic acidAcid addition salt not produced 18Naphthalene-2-sulfonic acidAcid addition salt decomposed during production, producing approximately 41% of related substances 19Ethansulfonic acidAcid addition salt decomposed during production, producing approximately 34% of related substances 204-hydroxybenzoic acidAcid addition salt produced No212,4-Dihydroxybenzoic acid0.22 %1.43 %6.13%0.31 %5.64 %Method 2 223,4-Dihydroxybenzoic acid acid addition salt not produced 23glutaric acid acid addition salt not produced 24gallic acid acid addition salt not produced 25methanesulfonic acid acid addition salt decomposed during production, producing about 40% of related substances 26Salicylic acid 0.19 %1.13 %4.42%0.33 %5.21 %Method 2 27Maleic acid 0.21 %1.21 %3.91%0.39 %4.32 %Method 2 28L-tartaric acid 0.22 %1.08 %7.13%0.34 %3.95 %Method 2 2925-dihydroxybenzoic acid 0.18 %1.01 %5.76%0.29 %5.12 %Method 2 30nicotinic acid 0.21 %1.38 %3.67%0.39 %4.65 %Method 2 31p-toluenesulfonic acid Decomposition during the production of acid addition salt, producing approximately 42% of related substances 321,5-naphthalene disulfonic acid Decomposition during the production of acid addition salt, producing approximately 14% of related substances 33Citric acid0.19 %1.19 %5.76%0.31 %3.76 %Method 2 34Oxalic acid0.24 %1.42 %6.29%0.42 %6.12 %Method 2 35Fumaric acid0.20 %1.12 %6.41%0.33 %3.94 %Method 2 36Succinic acid Acid addition salt not produced 37Malonic acid0.19 %1.02 %8.23%0.28 %4.73 %Method 2.

[0126] Solubility

[0127] Solubility measurement method

[0128] 2 g of each of tegoprazan free base and tegoprazan orotate salt of the present invention obtained in Preparation Method 3 were added to 50 mL of purified water and stirred at room temperature (20-25°C) for 1 hour to prepare a saturated solution. Approximately 2 mL of the solution was taken from the saturated solution using a 5 mL syringe and a syringe filter (0.45 μm, Whatman), and the solubility was measured using HPLC (High Performance Liquid Chromatography) under the conditions shown in Table 2 above.

[0129] The results are summarized in Table 5 below.

[0130] Solubility measurement results

[0131] Referring to Table 5, it was confirmed that the tegoprazan orotate salt of the present invention obtained by manufacturing method 3 exhibited superior properties in terms of solubility compared to the tegoprazan free base.

[0132] Solubility in water1 Tegoprazan free base3 mg / ml2 Tegoprazan orotate salt24 mg / ml

[0133] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. Tegoprazan orotate salt represented by the following chemical formula 2: [Chemical Formula 2] 2.(a) A method for producing a tegoprazan orotate salt of claim 1, represented by the following chemical formula 2, comprising a step of reacting tegoprazan and orotic acid in an organic solvent: [Chemical Formula 2] .

3. In paragraph 2, (b) a step of precipitating a solid by concentrating the solution in step (a) under reduced pressure, and then adding a co-solvent and stirring; and (c) a step of filtering and drying the precipitated solid; A method for producing tegoprazan orotate salt, further comprising:

4. A method for producing tegoprazan orotate salt in the second paragraph, wherein the organic solvent of step (a) is methanol or a mixed solution of methanol and water.

5. A method for producing tegoprazan orotate salt, wherein the organic solvent of step (a) is added in an amount of 10 to 30 (volume / weight) times that of tegoprazan in the second paragraph.

6. A method for producing tegoprazan orotate salt, wherein in the second paragraph, the orotic acid of step (a) is added in a molar ratio of 0.8 to 1.5 equivalents with respect to 1.0 equivalent of tegoprazan free base.

7. A method for producing tegoprazan orotate salt in the third paragraph, wherein the co-solvent of step (b) is selected from the group consisting of methanol, ethanol, acetone, isopropanol, and a mixed solvent thereof.

8. A method for producing tegoprazan orotate salt, wherein the co-solvent of step (b) is added in an amount of 3 to 8 (volume / weight) times that of tegoprazan free base in the third paragraph.

Images