Novel salt of GLP-1R receptor agonist compound, its preparation method and pharmaceutical composition containing the same

Abstract

The present invention relates to a GLP-1 receptor agonist compound, and to a novel salt thereof having excellent in vivo solubility, stability, bioavailability, etc., a preparation method thereof, and a pharmaceutical composition containing the same.

Description

[Technical field]

[0001] The present invention relates to a novel salt of a GLP-1R agonist compound which exhibits improved physical properties such as stability and solubility and excellent bioavailability, a method for preparing the same, and a pharmaceutical composition containing the same. [Background technology]

[0002] It is already well known from large-scale clinical studies that in the treatment of diabetes, strict blood glucose regulation close to normal blood glucose is important for preventing various complications caused by diabetes. One candidate compound that can strongly stimulate insulin secretion and lower blood glucose is a hormone called glucagon-like peptide-1 (GLP-1). GLP-1 was first discovered in 1985 as an incretin hormone secreted from L-cells in the ileum and large intestine. GLP-1 acts on a receptor called GLP-1R (Glucagon-like peptide-1 receptor) to increase insulin secretion. GLP-1 is secreted in response to stimulation from absorbed nutrients or blood glucose concentration. Treatment of diabetes using GLP-1 has the advantage of not causing hypoglycemia, since insulin secretion is performed according to the glucose concentration. This hormone is also known to have effects such as reducing the motility of the upper digestive organs and suppressing appetite, and to proliferate existing pancreatic beta cells.

[0003] Currently, various GLP-1 analogs that are resistant to DPP-4 enzyme that destroys GLP-1 in blood have been developed and are used as treatments for type 2 diabetes. These GLP-1 analogs have a considerably longer half-life than GLP-1, so they have the advantage of being able to maintain the effect of lowering blood sugar for a long period of time, but they cannot be administered orally and must be administered in the form of an injection, which makes them less convenient to take. Therefore, some research has been conducted recently to find small molecule GLP-1R agonists that can be administered orally and develop them as treatments for diabetes.

[0004] Accordingly, there is a demand for small molecule GLP-1R agonists to have improved bioavailability, as well as improved physicochemical properties such as solubility, stability, and non-hygroscopicity, and reduced toxicity.

[0005] Under these circumstances, the present inventors have discovered that, as a GLP-1 receptor agonist compound, the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid has superior physicochemical properties, high purity, and superior bioavailability compared to other commonly used pharma- ceutical acceptable salt compounds, and have thus completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006] The problem to be solved by the present invention is to provide a novel salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0007] In particular, the objective of the present invention is to provide a novel salt which has excellent physicochemical and / or pharmaceutical properties such as hygroscopicity, thermal stability, and solubility, and therefore has excellent formulation processability, storage stability, and bioavailability, a method for producing such a salt, and a pharmaceutical composition containing the same. [Means for solving the problem]

[0008] In order to solve the above problems, the present invention provides a novel salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, a method for preparing the salt, and a pharmaceutical composition containing the salt as an active ingredient.

[0009] Each of these will be explained in detail below.

[0010] Novel salts of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid For the above purposes, the present invention provides the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0011] The tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid can be represented by the following chemical formula I.

[0012] [Chemical formula I] [ka]

[0013] The novel salts according to the present invention exhibit excellent physicochemical and pharmacokinetic properties in various aspects such as thermal stability, in vivo solubility and bioavailability.

[0014] The tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid of the present invention can exhibit a thermogravimetric analysis (TGA) pattern of less than 1.0 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, or 0.2 wt% weight loss at or below 170° C. Specifically, the thermogravimetric analysis (TGA) pattern of FIG. 2 can be exhibited.

[0015] The tromethamine salt of the present invention (specifically, its crystalline form) is characterized in that, when the heating rate is 10°C / min in a differential scanning calorimetry (DSC) graph, it has an endothermic transition peak value at 174 to 204°C, preferably 179 to 199°C, more preferably 184 to 194°C, and even more preferably 189±2°C.

[0016] In addition, the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid of the present invention can show the differential scanning calorimetry (DSC) of FIG. 2.

[0017] Additionally, the novel tromethamine salts of the present invention are preferably in crystalline form.

[0018] The crystalline form of the tromethamine salt of the present invention may comprise, in an X-ray powder diffraction analysis (XRPD) graph, three or more diffraction peaks selected from the group consisting of the following 2θ (theta) angles: 4.03±0.2, 8.09±0.2, 10.04±0.2, 15.07±0.2, 15.71±0.2, 17.90±0.2, 19.60±0.2, 22.07±0.2, 24.92±0.2 and 25.39±0.2.

[0019] More specifically, the crystalline form of the tromethamine salt of the present invention may include, in an X-ray powder diffraction analysis (XRPD) graph, diffraction peaks having values ​​of 2θ (theta) angles of 4.03±0.2, 8.09±0.2, 10.04±0.2, 15.07±0.2, 15.71±0.2, 17.90±0.2, 19.60±0.2, 22.07±0.2, 24.92±0.2 and 25.39±0.2.

[0020] More specifically, the crystalline form of the tromethamine salt of the present invention may further include any one or more diffraction peaks in an X-ray powder diffraction analysis (XRPD) graph having 2θ (theta) angles of 12.17±0.2, 14.39±0.2, 17.02±0.2, 20.18±0.2, and 21.81±0.2.

[0021] In the present invention, the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid having the above-mentioned characteristics can be referred to as crystalline Form 1.

[0022] In addition, the crystalline form of the tromethamine salt of the present invention may further include one or more diffraction peaks selected from the group consisting of 2θ (theta) angles of 19.80±0.2 and 24.53±0.2 in an X-ray powder diffraction analysis (XRPD) graph.

[0023] In the present invention, the crystalline form of the tromethamine salt further includes diffraction peaks having 2θ (theta) angles of 19.80±0.2 and 24.53±0.2 in an X-ray powder diffraction analysis (XRPD) graph, and may be crystalline Form 1A.

[0024] In addition, the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid of the present invention can exhibit the powder X-ray diffraction spectroscopic pattern shown in FIG. 1.

[0025] The present invention has produced a novel salt that has never been used in the prior art. Specifically, the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid has excellent thermal stability, stability against temperature and humidity, and can be stably maintained without any change in content for a long period of time. In particular, it has excellent thermal stability against high temperatures and the like, and therefore has excellent storage stability. Therefore, the raw material of the novel salt of the present invention can be obtained with high yield and high purity, and even during long-term storage, the increase in lamp smoke substances is significantly low, and high purity can be maintained for a long period of time.

[0026] In addition, the novel salt of the present invention exhibits excellent solubility under various pH conditions, particularly under bio-relevant media conditions, and therefore has high bioavailability and excellent pharmacological effects, and can be usefully used as a novel active ingredient of pharmaceutical compositions capable of treating various indications.

[0027] According to one embodiment of the present invention, when simulated gastric fluid (SGF), fasting simulated intestinal fluid (FaSSIF), and fed simulated intestinal fluid (FeSSIF) were prepared and tested to measure solubility and dissolution rate under conditions similar to the in vivo environment, excellent solubility was observed. In particular, the tromethamine salt had excellent solubility in FaSSIF. This confirmed that the novel salt according to the present invention has excellent in vivo solubility and can exhibit high bioavailability. In addition, the novel salt according to the present invention has a remarkable effect of having high bioavailability by maintaining a high blood concentration due to its high in vivo solubility and high exposure in the body.

[0028] Furthermore, since the novel salt of the present invention exhibits high bioavailability when orally administered, it can exhibit excellent therapeutic effects even when taken in small doses, and can significantly improve convenience of administration for patients.

[0029] In addition, the novel salt of the present invention has a rapid onset of action and a thermodynamically stable form, which is very advantageous in pharmaceutical processing and storage, and therefore can be easily formulated. Furthermore, since the same state is maintained even after preparation, the content uniformity of the preparation can be stably maintained for a long period of time, and the salt can be easily applied to mass production.

[0030] In the present invention, the crystalline form 1 (Form 1) of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid can change to the crystalline form 1A (Form 1A) when exposed to moisture in the air under specific relative humidity conditions, specifically, conditions of 20°C and 55% RH or more.

[0031] The Form 1A can revert to the crystalline state of the Form 1 when desorbed under changing relative humidity conditions such as 20° C. and less than 55% RH, preferably 20° C. and 50% RH or less, and more preferably 20° C. and 45% RH or less.

[0032] The crystalline form 1 of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid according to the present invention is a non-stoichiometric hydrate, and when exposed to a wide range of moisture in the air up to 90% RH, only the lattice expands and contracts due to water molecules, and the lattice structure does not collapse or a crystal phase transition does not occur upon adsorption and desorption. Therefore, the crystalline form of the tromethamine salt according to the present invention can return to the existing crystalline form, crystalline form 1, upon desorption, even if moisture is adsorbed when exposed to a wide range of humidity.

[0033] Method for preparing the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0034] The present invention provides a method for preparing the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, represented by the following chemical formula I:

[0035] [Chemical formula I] [ka]

[0036] Specifically, the manufacturing method of the present invention can be carried out in the following steps.

[0037] (1) mixing a compound represented by the following chemical formula II with a single organic solvent or a mixture of organic solvents, and reacting the resulting mixture with tromethamine represented by the following chemical formula III;

[0038] [Chemical formula II] [ka]

[0039] [Chemical formula III] [ka]

[0040] (2) a step of heating and stirring the reaction solution in the step (1);

[0041] (3) cooling and stirring the reaction solution in step (2); and

[0042] (4) filtering and drying the product of step (3);

[0043] In the preparation method of the present invention, the compound represented by the chemical formula II is (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, which may be a free base prepared according to Comparative Example 1 of the present invention.

[0044] In the production method of the present invention, the organic solvent used in the reaction in step (1) can be a single organic solvent or a mixture of organic solvents. The organic solvent can be one or a combination of two or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, normal propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran. Preferably, the organic solvent can be one or a combination of two or more organic solvents consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and ethyl acetate.

[0045] The mixing ratio of the mixed solvent may be 1:1 to 1:20 by volume.

[0046] In the present invention, tromethamine represented by the above chemical formula III is called tris(hydroxymethyl)aminomethane, and may also be called Tris. That is, in the present specification, Tris means tromethamine.

[0047] In the step (1), tromethamine is preferably used in an amount of 0.6 to 1.5 equivalents, more preferably 0.7 to 1.3 equivalents, and even more preferably 0.9 to 1.1 equivalents, relative to 1.0 equivalent of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0048] In the production method of the present invention, the reaction in step (1) can be carried out at a temperature of 20 to 80°C, preferably 40 to 70°C, and more preferably 55 to 60°C.

[0049] The step (2) is a step of precipitating a solid precipitate, and the step (3) can be a step of separating the solid precipitate produced in the step (2). The separation of the solid precipitate can be performed using a process commonly performed in the relevant field, such as a centrifugation method.

[0050] In the novel method for producing a salt of the present invention, the reaction temperature and time can be adjusted depending on the types and amounts of the sample and solvent used in the reaction, and are not limited to the above ranges.

[0051] Pharmaceutical Compositions The present invention provides a pharmaceutical composition for preventing or treating a metabolic disease, comprising the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid represented by the following chemical formula I:

[0052] [Chemical formula I] [ka]

[0053] The novel tromethamine salt according to the present invention has excellent stability, thermal stability and pH stability, and exhibits excellent in vivo solubility under biorelevant media conditions close to the in vivo environment, and therefore can exhibit excellent pharmacological effects.

[0054] Specifically, metabolic diseases include, for example, diabetes (T1D and / or T2DM, e.g., prediabetes), idiopathic type 1 diabetes (T1D (type 1b)), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (T2DM (EOD)), atypical diabetes mellitus of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney injury, renal tubular dysfunction, infectious changes to the proximal tubules), diabetes Retinopathy, adipocyte dysfunction, visceral adiposity, sleep apnea, obesity (e.g., hypothalamic and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (e.g., bulimia nervosa, hyperorexia nervosa, and syndromic obesity, e.g., Prader-Willi syndrome and Bardet-Biedl syndrome), weight gain due to the use of other medications (e.g., due to the use of steroids and antipsychotics), excessive sugar cravings, dyslipidemia (hyperlipidemia, hypertriglyceridemia, total cholesterol) increased cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, nonalcoholic fatty liver disease (NAFLD) (including associated diseases, e.g., steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and spontaneous cell death), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication , postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, vision loss, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, transient ischemic attack, vascular restenosis, glucose metabolic disorders, symptoms of fasting glucose disorder, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome,It may be for the prevention or treatment of polycystic ovary syndrome and for the treatment of addiction (e.g., alcohol and / or drug abuse).

[0055] Specifically, the metabolic disease includes diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, and pulmonary hypertension. The condition may be any one or more selected from the group consisting of hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, decreased vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, transient ischemic attack, vascular restenosis, glucose metabolic disorder, symptoms of fasting glucose disorder, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcer, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

[0056] Specifically, the non-alcoholic fatty liver disease can be, for example, any one or more selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma.The above-mentioned exemplary non-alcoholic fatty liver disease includes the category of metabolic disease that has significant association with various medical diseases other than the category of alcoholic liver disease.

[0057] In one aspect, the present invention provides a pharmaceutical composition comprising the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, represented by the following chemical formula I: and a pharma- ceutically acceptable carrier.

[0058] [Chemical formula I] [ka]

[0059] In the present invention, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0060] The compositions of the present invention can be in a variety of forms, including, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories, depending on the intended mode of administration and therapeutic application.

[0061] Typical compositions are in the form of compositions similar to injectable and infusible solutions.One mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular).

[0062] The solid dosage form for oral administration can be provided, for example, as a hard or soft capsule, pill, sachet, lozenge or tablet, each containing a predetermined amount of one or more compounds of the invention, hi yet another embodiment, the oral administration can be in powder or granular form.

[0063] In yet another embodiment, oral administration can be in liquid dosage forms, including, for example, pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).

[0064] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention may be prepared by any of the well-known pharmaceutical techniques, including effective formulation and administration procedures.

[0065] These preparations can be manufactured by conventional methods used in the art for formulation or methods disclosed in Remington's Pharmaceutical Sciences (latest edition), Mack Publishing Company, Easton PA, and can be formulated into various preparations depending on each disease or ingredient.

[0066] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dosage ranges depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of disease, etc. The daily dosage of the novel salt of the present invention is about 0.01 to 500 mg / kg, preferably 0.1 to 100 mg / kg, and can be administered once a day or in divided doses.

[0067] The pharmaceutical compositions of the present invention may contain, in addition to the novel salts, one or more additional active ingredients exhibiting the same or similar pharmacological activity.

[0068] Uses and methods for treating metabolic disorders and their use in the manufacture of therapeutic agents The present invention provides a pharmaceutical composition for preventing or treating a metabolic disease, comprising the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid represented by the following chemical formula I:

[0069] [Chemical formula I] [ka]

[0070] The present invention provides a method of treating a metabolic disease, comprising administering to a subject in need thereof a therapeutically effective amount of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0071] Subjects in need thereof are mammals, including humans, including mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, mice, and the like.

[0072] The term "therapeutically effective amount" used in the present invention refers to the amount of the novel salt or pharmaceutical composition containing the same that is effective for preventing or treating a metabolic disease, and for example, the amount of the novel salt administered to a subject to be treated may include all amounts of pharmaceutical compositions containing the aforementioned salts that prevent the onset or recurrence of a metabolic disease, alleviate symptoms, inhibit direct or indirect pathological consequences, prevent metastasis, reduce the rate of progression, alleviate or temporarily alleviate a condition, or improve prognosis. That is, the therapeutically effective amount may be interpreted as including all doses that improve or completely cure the symptoms of a metabolic disease by the pharmaceutical composition.

[0073] The method for preventing or treating a metabolic disease of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms by administering the salt or pharmaceutical composition containing the salt. In managing a disease, the prophylactic or therapeutic dose of a particular active ingredient varies depending on the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The dose and frequency of dose vary depending on the age, weight, and response of an individual patient. A suitable dose and method of administration can be easily selected by a person of ordinary skill in the art who will naturally take such factors into consideration. In addition, the pharmaceutical composition of the present invention and the method for treating a metabolic disease may further include administration of a therapeutically effective amount of an additional active agent useful for treating the disease together with the salt, and the additional active agent may exhibit a synergistic or complementary effect with the salt, which is the active ingredient according to the present invention.

[0074] The present invention also provides a use of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid for the manufacture of a medicament for treating a metabolic disease. The above-mentioned salt for the manufacture of a medicament can be mixed with an acceptable auxiliary, diluent, carrier, etc., and can be manufactured as a composite preparation together with other active ingredients to have a synergistic effect of the active ingredients.

[0075] All references to uses, compositions, and methods of treatment of the present invention apply equally unless they contradict each other. Effect of the Invention

[0076] The novel salt according to the present invention has excellent stability, and therefore can enhance the stability of formulations. Furthermore, due to the improved solubility (particularly, solubility in vivo) and bioavailability, the salt can be usefully used as an active ingredient in pharmaceutical compositions. [Brief description of the drawings]

[0077] The following drawings attached to this specification illustrate preferred embodiments of the present invention and, together with the above-mentioned content of the invention, serve to further understand the technical concept of the present invention. The present invention should not be interpreted as being limited only to the matters shown in such drawings.

[0078] [Figure 1] 1 is an XRPD (X-ray powder diffraction) graph of the tromethamine salt compound (crystal type 1) represented by chemical formula I prepared in Example 3 of the present invention. [Diagram 2] 2 is a thermogravimetric analysis (TGA) pattern analysis graph and a differential scanning calorimetry (DSC) pattern graph of the tromethamine salt compound (crystal type 1) represented by chemical formula I prepared in Example 3 of the present invention. [Diagram 3] 1 is a thermogravimetric analysis (TGA) pattern analysis graph of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base prepared in Comparative Example 1. [Figure 4] 1 is a differential scanning calorimetry (DSC) pattern analysis graph of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base prepared in Comparative Example 1. [Diagram 5] 1 is an XRPD (X-ray powder diffraction analysis) graph of the L-arginine salt compound of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 2. [Figure 6]1 is a thermogravimetric analysis (TGA) pattern analysis graph of the L-arginine salt compound of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 2. [Figure 7] 1 is a differential scanning calorimetry (DSC) pattern analysis graph of the L-arginine salt compound of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 2. [Figure 8] FIG. 1 is an XRPD (X-ray powder diffraction analysis) graph of the meglumine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 3. [Figure 9] 1 is a thermogravimetric analysis (TGA) pattern analysis graph of the meglumine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 3. [Figure 10] 1 is a differential scanning calorimetry (DSC) pattern analysis graph of the meglumine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 3. [Figure 11] FIG. 1 is an XRPD (X-ray powder diffraction) graph of the potassium salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 4. [Figure 12] 1 is a thermogravimetric analysis (TGA) pattern analysis graph of the potassium salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 4. [Figure 13] 1 is a differential scanning calorimetry (DSC) pattern analysis graph of the potassium salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 4. [Figure 14] 1 is a graph showing the results of DVS measurement of the tromethamine salt compound (crystal type 1) represented by chemical formula I prepared in Example 3 of the present invention. [Figure 15] 1 is a graph showing the results of DVS measurement of the L-arginine salt compound of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 2. [Figure 16] 1 is a graph showing the results of DVS measurement of the meglumine salt compound of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 3. [Figure 17] 1 is a graph showing the results of DVS measurement of the potassium salt compound of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared in Comparative Example 4. [Figure 18]A graph showing the XRPD pattern of crystalline form 1A of the tromethamine salt compound represented by Chemical Formula I produced in Example 3 of the present invention and analyzed under the conditions of 20 °C and a relative humidity of 55% RH or more.

Mode for Carrying Out the Invention

[0079] Hereinafter, for the purpose of facilitating the understanding of the present invention, examples and the like will be given for detailed description. However, the examples according to the present invention can be deformed into various other forms, and it should not be construed that the scope of the present invention is limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those having average knowledge in the art.

[0080] <XRPD, DVS and NMR Analysis Conditions> 1) XRPD (X-ray Powder Diffractometer) Using DYY884-AERIS-300 manufactured by PANALYTICAL, the powder X-ray diffraction (XRPD) pattern was measured, and the analysis was carried out at a 2θ angle in the range of about 2° to 45° with a step size of about 0.02°. The operating conditions were set as shown in Table 1 below.

[0081]

Table 1

[0082] 2) DVS (Dynamic Vapor Sorption) Using DVS Intrinsic 1 manufactured by Surface Measurement System Ltd., a sample of about 5 to 25 mg was tested for the adsorption / desorption profile of moisture at 25 °C under a relative humidity (RH) cycle of 0% to 90% using the parameters shown in Table 2 below.

[0083]

Table 2

[0084] 3) 1 H-NMR(Nuclear Magnetic Resonance) Approximately 3 mg of compound was weighed into a nuclear magnetic tube, and 0.5 mL of deuterated dimethyl sulfoxide was added to completely dissolve the sample. The tube was placed in the rotor, placed in the open position of the autosampler, and scanned with a BRUKER AVANCE III (400 MHz).

[0085] Example 1: Preparation of tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 500 mg of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base prepared according to Comparative Example 1 was added with 5 mL of acetone and mixed at room temperature. 1.1 equivalents of tromethamine was added to the mixture and reacted by stirring under reflux for 1 hour. The reaction solution was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with acetone, and then dried to obtain 0.4 g of tromethamine salt (yield 65.6%).

[0086] The NMR analysis results of the tromethamine salt prepared in Example 1 are as follows:

[0087] 1 H NMR (400 MHz, DMSO-d 6):δ 8.99 (dd, Ja = 2.0 Hz, Jb = 0.4 Hz, 1H), 8.30 (dd, Ja = 8.0 Hz, Jb = 2.0 Hz, 1H), 8.19 (d, J = 0.8 Hz, 1H), 7.82 (dd, Ja = 8.4 Hz, Jb = 1.2 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.51 (t, Ja = 16.0 Hz, Jb = 8.0 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.42 (s, 2H), 5.09 - 5.07 (m, 1H), 4.78 - 4.72 (m, 1H), 4.63 - 4.59 (m, 1H), 4.51 - 4.46 (m, 1H), 4.40 - 4.35 (m, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.77 (d, J = 13.6 Hz, 1H), 3.40 (s, 6H), 3.33 - 3.32 (m, 4H), 2.73 - 2.65 (m, 1H), 2.48 - 2.41 (m, 5H).

[0088] Example 2: Preparation of tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 3 mL of methanol and 15 mL of ethanol were added to 16 g of the free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared by Comparative Example 1, and then mixed at room temperature. 1.05 equivalents of tromethamine were added to the mixture, and the mixture was reacted by stirring at a temperature of 70° C. for 1 hour. The reaction solution was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with ethanol, and dried to obtain 17.64 g of tromethamine salt (yield 90.0%).

[0089] <Example 3> Preparation of tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (crystal type 1) 17 L of methanol and 34 L of ethyl acetate were added to 3.4 kg of the free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid prepared by Comparative Example 1, and then mixed at room temperature. 1.05 equivalents of tromethamine were added to the mixture, and the mixture was reacted by stirring at a temperature of 55 to 60° C. for 1 hour. The reaction solution was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with ethyl acetate, and then dried to obtain 3.84 kg of tromethamine salt (yield 92.31%).

[0090] As a result of measuring the XRPD of the tromethamine salt prepared in Example 3, the 2θ diffraction pattern as shown in FIG. 1 and the following Table 3 was confirmed, and it was confirmed that the substance had the same crystal form as the tromethamine salts of Examples 1 and 2. In addition, only one crystal form was confirmed from the above results.

[0091] [Table 3]

[0092] Comparative Example 1: Preparation of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base can be prepared by the same method as disclosed in Korean Patent Publication No. 10-2021-0059653, and the specific method is as follows.

[0093] (1) Step: Synthesis of methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile (233 mg), methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (232 mg), and potassium carbonate (436 mg) were placed in a round-bottom flask and dissolved in acetonitrile (10 mL) and stirred at 60° C. for 1 day. After confirming the completion of the reaction by TLC, the solution was diluted with ethyl acetate and the organic layer was extracted with NaHCO 3 Saturated aqueous solution, NH 4 The mixture was washed with a saturated aqueous solution of Cl and brine. The organic layer was then dried over anhydrous magnesium sulfate and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the target compound methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate as a clear syrup (390 mg, 89% yield).

[0094] (2) Step: Synthesis of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound (387 mg) obtained in step (1) was placed in a round-bottom flask, dissolved in acetonitrile (10 mL), and stirred. 1.0 M TBD aqueous solution (1.4 mL) was added dropwise while stirring. Purified water (0.6 mL) was added to the mixture, and the mixture was stirred at 60° C. for 1 day. After confirming the completion of the reaction by TLC, the mixture was neutralized to pH 7 with 1N HCl aqueous solution, extracted with DCM / meOH 10% solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to obtain the filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / meOH) to obtain the final compound as a pale green solid (225 mg, yield 60%).

[0095] <Comparative Example 2> Preparation of L-arginine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of 1 mL of acetonitrile added to a 2 mL vial filled with 20 mg of the free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid was mixed at room temperature for 5 seconds. 1.1 equivalents of L-arginine was added to the mixture, and a ThermoMixer C (Eppendorf) was used for a heating-cooling cycle. After the temperature cycle, the suspension was centrifuged, and the resulting precipitate was dried under vacuum at room temperature to obtain the L-arginine salt. XRPD analysis of the L-arginine salt was performed, and the results are shown in FIG. 5.

[0096] Comparative Example 3: Preparation of meglumine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A 2 mL vial filled with 20 mg of the free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid was mixed with 1 mL of acetonitrile for 5 seconds at room temperature. 1.1 equivalents of meglumine were added to the mixture, and a ThermoMixer C (Eppendorf) was used for a heating-cooling cycle. After the temperature cycle, the suspension was centrifuged, and the resulting precipitate was dried under vacuum at room temperature to obtain the meglumine salt. XRPD analysis of the meglumine salt was performed, and the results are shown in FIG. 8.

[0097] <Comparative Example 4> Preparation of potassium salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of 1 mL of acetonitrile added to a 2 mL vial filled with 20 mg of the free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid was mixed at room temperature for 5 seconds. 1.1 equivalents of potassium hydroxide (KOH) was added to the mixture, and a ThermoMixer C (Eppendorf) was used for a heating-cooling cycle. After the temperature cycle, the suspension was centrifuged, and the resulting precipitate was dried under vacuum at room temperature to obtain the potassium salt. XRPD analysis of the potassium salt was performed, and the results are shown in FIG. 11.

[0098] <Experimental Example 1> Thermogravimetric (TGA) analysis Thermogravimetric (TGA) analysis was performed on the tromethamine salt prepared in Example 3, the free base prepared in Comparative Example 1, the L-arginine salt prepared in Comparative Example 2, the meglumine salt prepared in Comparative Example 3, and the potassium salt prepared in Comparative Example 4. The thermogravimetric analysis was performed using a TA Instruments TGA Q50 under nitrogen conditions, with a heating rate of 10°C / min in the range of 20°C to 350°C. The weight loss results at about 170°C or less were measured, and the results are shown in Figure 2 (tromethamine salt), Figure 3 (free base), Figure 6 (L-arginine salt), Figure 9 (meglumine salt), and Figure 12 (potassium salt), which are shown in Table 4 below.

[0099] [Table 4]

[0100] As can be seen from the above results, the free base of Comparative Example 1 and the other salts of Comparative Examples 2 to 4 showed weight loss due to the inclusion of moisture or organic solvents, but the tromethamine salt of the present invention showed almost no weight loss. Therefore, it was confirmed that the tromethamine salt of the present invention has excellent physicochemical properties without containing moisture or organic solvents.

[0101] <Experimental Example 2> Differential Scanning Calorimetry (DSC) Analysis Differential scanning calorimetry (DSC) analysis was carried out on the tromethamine salt prepared in Example 3, the free base prepared in Comparative Example 1, and the other salts prepared in Comparative Examples 2 to 4. Specifically, DSC was measured in a sealed pan at a scan rate of 10°C / min over a range of 30°C to 300°C under nitrogen purification using a DSC analyzer. The DSC result of the tromethamine salt prepared in Example 3 is shown in FIG. 2, the DSC result of the free base of Comparative Example 1 is shown in FIG. 4, and the DSC results of the other salts obtained in Comparative Examples 2 to 4 are shown in FIG. 7, FIG. 10, and FIG. 13, respectively, and are shown in Table 5 below.

[0102] [Table 5]

[0103] As can be seen from Table 5, (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base has the disadvantage of having a low melting point and poor thermodynamic stability. On the other hand, the tromethamine salt of the present invention has a much higher melting point than the other salts and free bases obtained in Comparative Examples 2 to 4, confirming its excellent thermodynamic stability.

[0104] <Experimental Example 3> Hygroscopicity test (1) 25°C, 90% RH conditions The hygroscopicity was measured for the tromethamine salt prepared in Example 3, the L-arginine salt prepared in Comparative Example 2, the meglumine salt prepared in Comparative Example 3, and the potassium salt prepared in Comparative Example 4. The results are shown in Figures 14 to 17, respectively, and the weight increase rate due to water absorption is shown in Table 6 below.

[0105] [Table 6]

[0106] 14 to 17 and Table 6, when the hygroscopicity of the tromethamine salt was measured by DVS at 25° C. and 90% humidity, the weight change was about 1.44%, which was significantly lower than that of the L-arginine salt, meglumine salt, and potassium salt. Therefore, it was confirmed that the novel tromethamine salt of the present invention has excellent storage stability.

[0107] (2) 25°C, 80% RH According to the hygroscopicity test conditions of the European Pharmacopoeia (EP), the tromethamine salt prepared in Example 3 and the free base prepared in Comparative Example 1 were stored at a temperature of 25° C. and a relative humidity of 80% for 24 hours, and the change in mass of the samples due to moisture absorption was measured.

[0108] The results are shown in Table 7 below.

[0109] [Table 7]

[0110] As can be seen from Table 7 above, the tromethamine salt of the present invention had a moisture absorption rate of 0.22%, which showed significantly better non-hygroscopicity than the (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid free base.

[0111] Therefore, it was confirmed that the tromethamine salt of the present invention has significantly superior storage stability compared to the free base, and is suitable for formulation.

[0112] <Experimental Example 4> Evaluation of solubility in biorelevant media The solubility of the tromethamine salt and free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid was confirmed in water and the biologically relevant media SGF (Stimulated Gastric Fluid), FeSSIF (Fasted State Simulated Intestinal Fluid), and FaSSIF (Fed State Simulated Intestinal Fluid).

[0113] Biorelevant medium buffer solutions were prepared as follows.

[0114] Water: Laboratory Milli-Q purified water.

[0115] SGF (Stimulated Gastric Fluid): Dissolve 2.0g of sodium chloride and 7mL of hydrochloric acid in 1000mL of water.

[0116] FaSSIF (Fasted State Simulated Intestinal Fluid): A commercial product was used, purchased from Biorelevant Company and manufactured according to the manual.

[0117] FeSSIF (Fed State Simulated Intestinal Fluid): A commercial product was purchased from Biorelevant Company and prepared according to the manual.

[0118] For the experiment, approximately 2 mg of compound (2 mg as free base form) was weighed into each glass vial, followed by the addition of 1 mL of medium (final concentration 2 mg / mL). The samples were then stirred continuously for 24 hours at room temperature with a magnetic stirrer at a speed of 5000 rpm. The pH was then measured and the results were analyzed using a MultiScreen HTS The mixture was filtered using a -HV 96-well plate (Merck; 0.45 μm hydrophilic, low protein binding Durapore membrane). The solubility was analyzed using HPLC. The experimental results are shown in Table 8.

[0119] [Table 8]

[0120] As can be seen from Table 8, the tromethamine salt exhibits excellent solubility in SGF, FaSSIF and FeSSIF, which regulate pH similar to that of the stomach and intestine in vivo, the small intestine before a meal and the small intestine after a meal, and in particular, it exhibits very good solubility under FaSSIF (Fasted State Simulated Intestinal Fluid) conditions, which mimic the small intestine where most drug absorption occurs. This behavior indicates that the tromethamine salt can exhibit high solubility regardless of meals, and that it has higher absorption and better bioavailability than the free base.

[0121] <Experimental Example 5> Evaluation of drug stability The tromethamine salt and free base of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid were weighed into individual vials and stored under stressed conditions to study the stability.

[0122] The stress conditions are as follows:

[0123] -High temperature open condition: 80℃; Samples were analyzed by XRPD and HPLC at the start (day 0) and after the first week of storage. The HPLC results are shown in Table 9 below.

[0124] [Table 9]

[0125] As can be seen from Table 9, the tromethamine salt according to the present invention exhibited a purity change rate of less than 1% under harsh conditions, and was found to have significantly superior stability compared to the free base. In addition, the XRPD pattern did not show any change under harsh conditions, and it was confirmed that the salt was a very stable substance with no change in appearance.

[0126] <Experimental Example 6> Analysis of crystal morphology according to relative humidity (reversible adsorption / desorption) For the crystal form 1 of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, the relative humidity was changed in the range of 15 to 90% RH under the temperature condition of 20°C in the XRPD analysis environment, and the change in the crystal form due to the change was confirmed. The results are shown in FIG. 18 and Tables 10 and 11. Table 10 shows the results of the crystal form while changing the relative humidity from 15% RH to 60% RH, and Table 11 shows the results of the crystal form while desorption is performed from 50% RH to 15% RH.

[0127] [Table 10]

[0128] [Table 11]

[0129] With reference to FIG. 18, crystalline Form 1A was observed to have the diffraction pattern set forth in Table 3 above, 2θ±0.2 degrees 2θ, and further including peaks at 19.8019±0.2 degrees 2θ and 24.5314±0.2 degrees 2θ.

[0130] As can be seen from Tables 10 and 11, the tromethamine salt of the present invention was found to maintain the crystalline form 1 under conditions of 20° C. and a relative humidity of 15% RH or more and less than 55% RH. However, a change in the XRPD peak appeared under conditions of 20° C. and a relative humidity of 55% RH or more (crystalline form 1A formation), and it was also found that the crystalline form returned to the crystalline form 1 upon desorption under conditions of 20° C. and a relative humidity of 15% RH or more and less than 55% RH.

[0131] The above results indicate that the crystal form of the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid is a non-stoichiometric hydrate, and that upon adsorption and desorption of water, only lattice expansion and contraction occurs, but the lattice does not collapse.

Claims

1. Tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid represented by the following chemical formula I: [Chemical formula I] 【Chemistry 8】

2. 2. The tromethamine salt of claim 1, wherein the tromethamine salt has a thermogravimetric analysis (TGA) pattern exhibiting a weight loss of less than 0.2 wt % at or below 170°C.

3. 2. The tromethamine salt of claim 1, wherein the tromethamine salt has an endothermic transition peak value at 174 to 204° C. in a differential scanning calorimetry (DSC) graph.

4. 2. The tromethamine salt of claim 1, wherein the tromethamine salt has an endothermic transition peak value at 189±2° C. in a differential scanning calorimetry (DSC) graph.

5. The tromethamine salt of claim 1 , wherein the tromethamine salt is in a crystalline form.

6. 6. The tromethamine salt of claim 5, wherein the crystalline form comprises three or more diffraction peaks in an X-ray powder diffraction analysis (XRPD) graph selected from the group consisting of the following 2θ (theta) angles: 4.03±0.2, 8.09±0.2, 10.04±0.2, 15.07±0.2, 15.71±0.2, 17.90±0.2, 19.60±0.2, 22.07±0.2, 24.92±0.2 and 25.39±0.

2.

7. 7. The tromethamine salt of claim 6, wherein the crystalline form comprises diffraction peaks in an X-ray powder diffraction analysis (XRPD) graph at 2θ (theta) angles of 4.03±0.2, 8.09±0.2, 10.04±0.2, 15.07±0.2, 15.71±0.2, 17.90±0.2, 19.60±0.2, 22.07±0.2, 24.92±0.2 and 25.39±0.

2.

8. 7. The tromethamine salt of claim 6, wherein the crystalline form further comprises one or more diffraction peaks in an X-ray powder diffraction (XRPD) graph at 2θ (theta) angles selected from the group consisting of 12.17±0.2, 14.39±0.2, 17.02±0.2, 20.18±0.2 and 21.81±0.

2.

9. A pharmaceutical composition comprising a tromethamine salt according to any one of claims 1 to 8 and a pharma- ceutically acceptable carrier.

10. (1) mixing a compound represented by the following chemical formula II with a single organic solvent or a mixture of organic solvents, and reacting the resulting mixture with tromethamine represented by the following chemical formula III; (2) a step of increasing the temperature of the reaction solution in the step (1) and stirring the solution while heating; (3) cooling and stirring the reaction solution in step (2); (4) filtering and drying the product of step (3). A method for producing the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid represented by the following chemical formula I: [Chemical formula I] 【Chemistry 9】 [Chemical formula II] 【Chemistry 10】 [Chemical formula III] 【Chemistry 11】

11. The method for producing the tromethamine salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid according to claim 10, characterized in that the organic solvent in the step (1) is one or a combination of two or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, acetone and ethyl acetate.

12. A pharmaceutical composition for preventing or treating a metabolic disease, comprising a tromethamine salt according to any one of claims 1 to 8.

13. The metabolic diseases include diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, angiogenesis. A pharmaceutical composition for preventing or treating a metabolic disease, which is any one or more selected from the group consisting of postoperative restenosis, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, decreased vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, transient ischemic attack, vascular restenosis, glucose metabolic disorder, symptoms of fasting glucose disorder, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcer, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome and polycystic ovary syndrome.

14. The pharmaceutical composition for preventing or treating a metabolic disease according to claim 13, wherein the non-alcoholic fatty liver disease is at least one selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.

15. A GLP-1R agonist comprising a tromethamine salt according to any one of claims 1 to 8.

16. 9. A method of treating a metabolic disease comprising administering to a subject in need thereof a therapeutically effective amount of a tromethamine salt according to any one of claims 1 to 8.

17. The metabolic diseases include diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), atypical diabetes mellitus of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, The method according to claim 16, wherein the condition is any one or more selected from the group consisting of restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, decreased vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, transient ischemic attack, vascular restenosis, glucose metabolic disorders, symptoms of fasting glucose disorder, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcer, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome and polycystic ovary syndrome.

18. 18. The method of claim 17, wherein the non-alcoholic fatty liver disease is any one or more selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.

19. 10. Use of a tromethamine salt according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of a metabolic disease.

20. The metabolic diseases include diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), atypical diabetes mellitus of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, The use according to claim 19, which is any one or more selected from the group consisting of restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, decreased vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, transient ischemic attack, vascular restenosis, glucose metabolic disorders, symptoms of fasting glucose disorder, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcer, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome and polycystic ovary syndrome.

21. The use according to claim 20, wherein the non-alcoholic fatty liver disease is any one or more selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.

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