KR20120031288A - N,n-dimethyl imidodicarbonimidic diamide propionate, method of preparing the same, pharmaceutical composition comprising the same and combined formulation including the same - Google Patents

Abstract

PURPOSE: A N,N-dimethyl imidodicarbonimidic diamide propionate is provided to have excellent solubility, stability, non-hygroscopicity, adhesion preventing properties, processability, and pharmacological effects, and can be manufactured under mild conditions with high yield. CONSTITUTION: The N,N-dimethyl imidodicarbonimidic diamide propionate is in chemical formula 1, and has the melting point of the crystal structure in chemical formula 1 which is 194 - 194.5 °C. The manufacturing method of the N,N-dimethyl imidodicarbonimidic diamide propionate in chemical formula 1 comprises a step of manufacturing the metformin glass base in chemical formula 3 by reacting the metformin hydrochloride in chemical formula 2 with a base under organic solvent, and a step of reacting the metformin glass base with propionic acid.

Description

Propionate of N, N-dimethyl imidodicarbonimidic diamide, preparation method thereof, pharmaceutical composition comprising same and composite preparation comprising same {N, N-dimethyl imidodicarbonimidic diamide propionate, method of preparing the same, pharmaceutical composition comprising the same and combined formulation including the same}

The present invention relates to propionate of N, N-dimethyl imidodicarbonimidic diamide, a method for preparing the same, a pharmaceutical composition comprising the same, and a combination formulation comprising the same.

N, N-dimethyl imidodicarbonimidic diamide, commonly known as metformin, is the most insulin-dependent diabetic medication and has the highest hypoglycemic effect among all oral diabetes medications and the most effective prevention of complications and worsening. It is an excellent biguanide drug.

Among all oral diabetes treatments, metformin is the only first-choice drug that has been shown in several papers. In particular, the fact that metformin activates AMPK (AMP-activated protein kinase) has been justified, demonstrating its clinical effectiveness [Monica Buzzai, et al. Syntemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth, Cancer Res 2007; 67: (14). July 15, 2007].

In addition, metformin has been shown to be effective in treating cancer at normal doses to treat diabetes, such as altering the energy metabolic pathways of cancer cells and increasing anticancer activity in proportion to the dose of metformin when administered to cancer patients lacking the P53 gene.

According to a recently published paper on metformin, Josie M M Evans found that patients with type 2 diabetes had a lower incidence of cancer than those who did not receive metformin treatment [Josie MM, Evans .; Louise A, Donnelly .; Alistair M, Emslie-Smith .; Dario R, Alessi .; Andrew D, Morris. BMJ. 2005, 330, 1304-1305], Samantha L. Bowker reported that type 2 diabetics taking metformin have lower cancer-related mortality than patients taking sulfonylureas or insulin (Samantha L, Bowker .; Sumit R, Majumdar .; Paul, Veugelers .; Jeffrey A, Johnson. Diabetes Care. 2006, 29, 254-258.

Pharmaceutically, metformin is useful in the free base form, but is administered in the form of a pharmaceutically acceptable salt because of the disadvantage of poor stability.

Korean Patent No. 90,479 discloses a pharmaceutically acceptable salt comprising (1) good solubility; (2) good stability; (3) nonhygroscopic; It states that physicochemical criteria such as (4) anti-sticking properties and (5) processability into formulations must be met.

Although studies on metformin addition salts that can satisfy the above properties have been conducted steadily, until now metformin has been approved only as a hydrochloride salt and prescribed as a non-insulin dependent diabetes mellitus treatment. have. However, such metformin hydrochloride has poor physicochemical properties such as solubility, stability, non-hygroscopicity, anti-adhesion properties, and processability as a formulation, which may lower the pharmacological effect when processed into a formulation, and also may cause toxicity due to hydrochloride.

SUMMARY OF THE INVENTION An object of the present invention is to provide a metformin propionate having excellent solubility, stability, non-hygroscopicity and anti-adhesion properties, having excellent processability and good efficacy as a formulation.

It is another object of the present invention to provide a method capable of easily preparing metformin propionate in high yield under mild conditions.

Another object of the present invention is metformin, which is very effective for the prevention or treatment of at least one disease of diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity and rhabdomyolysis It is to provide a pharmaceutical composition comprising a propionate.

Yet another object of the present invention is to provide a combination formulation comprising metformin propionate and a second drug.

The present invention provides metformin propionate represented by the following formula (1).

[Formula 1]

In the present invention, the metformin propionate is interpreted to include all metformin propionate present in crystalline form or in anhydride or hydrate form.

Metformin propionate represented by the formula (1) of the present invention has a superior survival and growth inhibitory effect of cancer cells as compared to metformin hydrochloride, and also has an excellent effect of AMPKα activation. Therefore, it exhibits a better pharmacological effect than metformin hydrochloride for various diseases including diabetes or cancer. In addition, pharmaceutical physicochemical advantages, such as stability, non-hygroscopicity and processability as formulations, have been increased, making them suitable for the preparation of pharmaceutical formulations over merformin hydrochloride.

The present invention also comprises the step of reacting the metformin hydrochloride represented by the formula (2) with a base in an organic solvent to produce a metformin free base represented by the formula (3) and the reaction of the metformin free base with propionic acid It provides a method for producing metformin propionate represented by.

[Formula 1]

[Formula 2]

(3)

In the present invention, the process for manufacturing the metformin free base was established to allow a simple and without special equipment. In order to remove hydrochloric acid of metformin hydrochloride, US Pat. No. 4,080,472 uses an ion exchange resin column, or introduces harsh production conditions such as heating US reflux of a solvent and filtering a hot solution, as in US Pat. No. 4,028,402. However, in the present invention, it is possible to synthesize free base of metformin at a lower cost by increasing the industrial availability by simply improving the process so that the synthesis can be performed under mild conditions using a general production equipment without any special equipment. The synthesis of free bases can be used for the reaction with various acids used to prepare pharmaceutically acceptable salts.

According to the preparation method of the present invention, the metformin propionate represented by Chemical Formula 1 may be prepared by the steps represented by the following Schemes 1 and 2.

Scheme 1

            [Formula 2] [Formula 3]

Scheme 2

            [Formula 3] [Formula 1]

According to the reaction represented by Scheme 1, the metformin free base represented by Chemical Formula 3 may be prepared by reacting metformin hydrochloride represented by Chemical Formula 2 with a base in an organic solvent to remove the hydrochloride.

The metformin free base represented by Formula 3 prepared by the reaction represented by Scheme 1 may be obtained in crystalline form.

In the reaction represented by Scheme 1, the reaction equivalent of the base to the metformin hydrochloride can be appropriately adjusted depending on whether the base is monovalent, divalent or trivalent. For example, when the base is a monovalent base, the base may be used in the amount of 1 to 4 equivalents, preferably 1 to 2 equivalents, based on 1 equivalent of the metformin hydrochloride.

In the reaction represented by Scheme 1, an organic solvent may be used as the solvent, and preferably no water. For example, the solvent is methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (ACN), acetone, dimethylformamide (DMF), N-methylpi Rollidinone (NMP), dimethylacetamide (DMA) or mixtures thereof, preferably isopropanol.

In the reaction represented by Scheme 1, the inorganic base used to form the free base may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. And preferably sodium hydroxide or potassium hydroxide.

According to the reaction represented by Scheme 2, the metformin propionate represented by Formula 1 may be prepared by reacting the metformin free base represented by Formula 3 with propionic acid in a solvent.

In the reaction represented by Scheme 2, the propionic acid is added to the metformin free base represented by Formula 3 under a solvent to prepare a mixture, and the mixture is stirred to filter, wash, and dry the resulting solid to Formula 1 The metformin propionate represented can be prepared. The stirring may be performed at a temperature of about −10 ° C. to 90 ° C., preferably at room temperature.

Metformin propionate prepared by the reaction represented by Scheme 2 may be obtained in crystalline form.

In the preparation of the mixture of the metformin free base and the propionic acid, 1 to 4 equivalents of propionic acid may be used per 1 equivalent of the metformin free base.

In the preparation of the mixture of the metformin free base and the propionic acid, the solvent is water, methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (ACN), acetone, Dimethylformamide (DMF), N-methylpyrrolidinone (NMP), dimethylacetamide (DMA) or mixtures thereof, preferably acetone.

According to the method for producing metformin propionate of the present invention, it is possible to easily prepare metformin propionate without an ion exchange resin column or a high temperature heating step. In addition, the reaction proceeds using a relatively acidic weak propionic acid, such as hydrochloric acid, to produce metformin propionate under mild reaction conditions, thereby producing metformin propionate with economical and high efficiency.

The present invention also relates to diseases of diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity or rhabdomyolysis, including metformin propionate represented by the following formula (1): Prophylactic or therapeutic pharmaceutical compositions are provided.

[Formula 1]

Metformin propionate represented by the formula (1) of the present invention has a superior survival and growth inhibitory effect of cancer cells as compared to metformin hydrochloride, and also has an excellent effect of AMPKα activation. Therefore, while using propionic acid, which is less toxic than hydrochloric acid, it has better blood sugar strengthening effect than metformin hydrochloride, especially on fasting as well as lowering postprandial blood sugar, and can effectively suppress cancer cells, thereby preventing metformin against various diseases including diabetes or cancer. It shows better pharmacological effect than hydrochloride. Therefore, the pharmaceutical composition comprising metformin propionate represented by Chemical Formula 1 may be used as an anticancer agent because it shows an excellent effect not only for treating diabetes but also for treating cancer. More specifically, the cancer may be one selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer, liver cancer, pancreatic cancer, prostate cancer and thyroid cancer, and particularly as an anticancer agent for breast cancer. It can be very useful.

In addition, metformin propionate represented by Chemical Formula 1 has excellent stability, excellent solubility in various solvents, non-hygroscopicity, low adhesion, and excellent physicochemical properties such as processability to formulation. Therefore, when formulated in the form of tablets or capsules, it is possible to produce a tablet or capsule with excellent dispersibility and uniform pharmacological effect, and does not cause a problem that the pharmacological effect is lowered during the formulation process. Therefore, it is possible to produce formulations such as tablets or capsules which have good pharmacological effects and have a uniform pharmacological effect.

Pharmaceutical compositions comprising the metformin propionate of the crystalline form of the present invention may further comprise a pharmaceutically acceptable carrier, diluent, binder, disintegrant, lubricant or other additive.

The pharmaceutically acceptable carrier may be used starch, microcrystalline cellulose, lactose, glucose, mannitol, light silicic anhydride, alkaline earth metal salt, polyethylene glycol and dicalcium phosphate. As a binder, starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, povidone, copovidone and gelatin, etc. Can be used. As lubricants, talc, hard silicic anhydride, stearic acid, magnesium stearate, calcium stearate, zinc stearate, lauryl sulfate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostea Elate, polyethylene glycol 4000 and polyethyleneglycol 6000 may be used, and pharmaceutically acceptable additives may be selected and used as various additives selected from colorants and fragrances.

The pharmaceutical composition comprising the metformin propionate of the present invention may be preferably formulated according to each disease or component by an appropriate method in the art. For example, the pharmaceutical composition may be formulated by additionally adding a pharmaceutically acceptable carrier, diluent, dispersant, surfactant, binder, lubricant and various additives.

In the formulation of the pharmaceutical composition comprising metformin propionate of the present invention, the content of the added carrier, diluent, dispersant, surfactant, binder, lubricant and additive is not particularly limited, and the content range used in conventional formulation It can be adjusted appropriately within.

The pharmaceutical composition comprising metformin propionate may be sustained and rapid release tablets, soft capsules, hard capsules, pills, granules or powders, injections using carriers, diluents, dispersants, surfactants, binders, lubricants and additives. It may be formulated in the form of a liquid, or the like, and used for the prevention or treatment of a pathological condition of diabetes mellitus or its associated accompanying disease.

The pharmaceutical composition comprising the metformin propionate of the present invention may be formulated in a sustained release formulation, wherein an enteric polymer, a water insoluble polymer, a hydrophobic compound, or a hydrophilic polymer may be used as the matrix base.

In the present invention, the enteric polymer is insoluble or stable under acidic conditions of less than pH 5, refers to a polymer that is dissolved or decomposed under conditions of pH 5 or more, and the water-insoluble polymer is a pharmaceutically acceptable to control the release of the drug. Refers to polymers that are not soluble in water, and hydrophobic compounds are substances that are not soluble in pharmaceutically acceptable water that controls the release of the drug, and hydrophilic polymers are soluble in pharmaceutically acceptable water that controls the release of the drug. Refers to a polymer material.

The pharmaceutical composition comprising metformin propionate of the present invention may be orally administered or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) in various forms according to the desired method, preferably It may be a preparation for oral administration.

The pharmaceutical composition of the present invention may be for use in combination with a second drug.

In the present invention, the "second drug" means another pharmaceutically effective ingredient other than metformin propionate of the present invention. Metformin propionate of the present invention can be used for the treatment of various diseases as described above. Thus, the metformin propionate of the present invention can be used in combination with a second drug for more efficient treatment of each disease. For example, the second drug may be an anticancer agent, an antihyperglycemic agent, an antiobesity agent, or the like.

In one embodiment, the second drug may be an anticancer agent. The anticancer agent for use in combination with metformin propionate according to the present invention can be any known anticancer agent.

The anticancer agent may include known chemotherapeutic agents such as alkylating agents, metabolic antagonists, natural agents, hormones and antagonists, and biological agents such as immunotherapy agents and gene therapy agents. For example, the anticancer agent may be nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, zefitinib, vandetanib, nirotinib, semasanib, conservinib, axitinib, Cediranib, restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, biscumalboom, asparaginase, tretinoin, hydride Roxycarbamide, Dasatinib, Estramustine, Gemtuzumab Ozogamycin, Ibritumomab Tucetan, Heptaplatin, Methylaminolevulinic Acid, Amsacrine, Alemtuzumab, Procarbazine, Alprostadil, Holmium nitrate chitosan, gemcitabine, doxyfluidine, pemetrexed, tegapur, capecitabine, gimerasin, otheracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, Enositabine, Plutami , Decitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, tenipo Seed, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temozolomide, busulfan , Phosphamide, cyclophosphamide, melfaran, altretmin, dacarbazine, cheotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemstan, aminoglutesimid, At least one selected from the group consisting of anagrelide, nabelbin, padrazole, tamoxifen, toremifene, testosterone, anastrozole, letrozole, borosol, bicalutamide, romustine and carmustine .

In another aspect, the present invention provides a combination formulation comprising a metformin propionate having a structure of Formula 1 and a second drug.

[Formula 1]

For convenience of medication, metformin propionate may be provided in the form of a combination formulation formulated with a second drug.

In one embodiment, the second drug may be an antihyperglycemic agent. The antihyperglycemic agent may be at least one drug selected from the group consisting of a biguanide drug, a sulfonylurea drug, a thiazolidione drug and an alpha-glucosidase inhibitor. According to other embodiments of the present invention, the second drug may be an anticancer agent, and the types of anticancer agents that can be used are as described above.

The dosage of the pharmaceutical composition or the combination formulation containing metformin propionate of the present invention is in the range according to the weight, age, sex, nationality, health condition, diet, time of administration, method of administration, excretion rate and severity of the patient, etc. There are a variety of, divided administration is possible depending on the judgment of the prescriber. For example, the pharmaceutical composition or co-formulation comprising the metformin propionate of the present invention may be administered orally once to three times daily so that the content of metformin as an active ingredient is 50 mg to 3,000 mg.

Metformin propionate according to the present invention exhibits superior pharmacological effects against various diseases including diabetes and cancer than metformin hydrochloride, which has been used as a conventional diabetes treatment. In addition, the metformin propionate has excellent physicochemical properties such as solubility, stability, non-hygroscopicity and anti-adhesion properties.

In addition, the method for producing metformin propionate according to the present invention can synthesize a new salt of metformin at a lower cost by increasing the industrial availability by simply improving the process to be synthesized in a general production facility without special equipment.

The pharmaceutical composition comprising metformin propionate according to the present invention has excellent pharmacological effects. In addition, the metformin propionate has excellent physicochemical properties, and thus the pharmaceutical composition including the same may be easily formulated into tablets or capsules.

In addition, the combination preparation containing both metformin propionate and the second drug according to the present invention has excellent pharmacological effect and can promote the convenience of the patient's medication.

1 is a view showing the degree of activation of AMPKα of metformin propion hydrochloride according to the present invention.

Hereinafter, preferred preparation examples, examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples and Experimental Examples.

In addition, the reagents and solvents mentioned below were purchased from Aldrich, USA, and Korea's largest purifier, unless otherwise stated. ¹ H-NMR and ¹³ C-NMR data were obtained from Innova 600, Verian, USA. It is a value measured by MHz FT-NMR, and melting point (mp) is No. 18 of Electrothermal, UK. 9201 Melting point measured.

[ Example ]

Example  1: Preparation of Metformin Free Base

16.6 g of metformin hydrochloride and 6.0 g of 93 wt% potassium hydroxide were added to 50 mL of isopropanol and stirred at 50 ° C. for 2 hours. The reaction solution was cooled to 25 ° C., filtered, and washed with 20 mL of isopropanol. Thereafter, after washing once more with 20 mL of acetone, it was concentrated and dried in vacuo to obtain 12.8 g (yield: 98.5%) of white solid metformin freebase.

Melting Point 119.0 ~ 119.5 ℃

¹ H-NMR (600 MHz, D ₂ O) δ (ppm) 3.07 (s, 6H)

¹³ C-NMR (150 MHz, D ₂ O) δ (ppm) 161.05, 158.5, 37.35

Example  2: metformin Propionate  Produce

10.0 g (1.0 equiv) of metformin free base prepared in Example 1 was dissolved in 150 mL of acetone. While stirring the reaction solution, 6.9 mL (1.2 equivalents) of propionic acid was slowly added dropwise, followed by stirring at room temperature for 2 hours. The resulting crystals were filtered and washed sequentially with 20 mL of isopropanol and 50 mL of acetone, followed by hot air drying to give 12.72 g of a white solid metformin propionate (yield: 80.1%).

Melting Point 194.0 ~ 194.5 ℃

¹ H-NMR (600MHz, D ₂ O) δ (ppm) 2.99 (s, CH ₃ , 6H), 2.11 (q, J = 6.6Hz, CH ₂ , 2H), 1.00 (t, J = 7.8Hz, CH ₃ , 3H)

¹³ C-NMR (150 MHz, D ₂ O) δ (ppm) 184.91, 160.13, 158.55, 37.50, 30.82, 10.28

[ Formulation example ]

Formulation example  1: metformin Propionate  Preparation of Containing Tablets

306.79 g of metformin propionate and 62.21 g of microcrystalline cellulose were sieved through a No. 20 sieve, and then mixed in a V-type mixer for 60 minutes. Separately, 15 g of collidone VA64 (BASF, Germany) and 4 g of hard silicic anhydride were sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes. Finally, 2 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.

Subsequently, the final mixture was compressed to prepare a tablet layer containing 306.79 mg of metformin propionate in one tablet, and was coated with Opadry OY-C-7000A as a coating agent as a high coater (SFC-30F, Sejong Machinery, Korea). A 10 mg film coating layer was formed to make tablets containing metformin propionate.

Formulation example  2: metformin Propionate  Preparation of Containing Tablets

613.58 g of metformin propionate and 106.42 g of dicalcium phosphate were sieved through a No. 35 sieve and then mixed in a high speed mixer for 3 minutes. Separately, 20 g of povidone K-30 was added to 100 g of ethanol and dissolved to prepare a binding solution. The binding solution was administered to a high speed mixer and then associated for 3 minutes. The associated union was dried in a steam dryer and formed into a 20 sieve. 5 g of hard silicic anhydride was sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes in a V-type mixer. Finally, 5 g of magnesium stearate was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes. Subsequently, the final mixture was compressed to prepare a tablet layer containing 613.58 mg of metformin propionate in one tablet. A 20 mg film coating layer was formed to make metformin tablets containing metformin propionate.

Formulation example  3: metformin Propionate  Preparation of Contained Sustained-Release Tablets

306.79 g of metformin propionate and 305.21 g of hydroxypropylmethylcellulose 2208 (viscosity 100,000 cps) were sieved through a No. 20 sieve and then mixed in a double cone mixer for 60 minutes. Separately, 20 g of hydroxypropyl cellulose and 4 g of hard silicic anhydride were sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes. Finally, 4 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.

Subsequently, the final mixture was compressed to prepare a sustained-release tablet layer containing 306.58 mg of metformin propionate in one tablet, and was coated with Opadry OY-C-7000A as a high coater (SFC-30F, Sejong Machinery, Korea). A sustained-release tablet containing metformin propionate was prepared by forming a 20 mg film coating layer.

Formulation example  4: metformin Propionate  Preparation of Contained Sustained-Release Tablets

306.79 g of metformin propionate, 45.21 g of microcrystalline cellulose, and 270 g of polyethylene oxide (molecular weight 5 million, Dow Chemical, USA) were sieved through a No. 20 sieve and mixed in a double cone mixer for 60 minutes. Separately, 20 g of collidone VA64 and 4 g of hard silicic anhydride were sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes. Finally, 4 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.

Subsequently, the final mixture was compressed to prepare a sustained-release tablet layer containing 306.58 mg of metformin propionate in one tablet, and was coated with Opadry OY-C-7000A as a high coater (SFC-30F, Sejong Machinery, Korea). A sustained-release tablet containing metformin propionate was prepared by forming a 20 mg film coating layer.

Formulation example  5: metformin Propionate  Preparation of Containing Capsules

153.39 g of metformin propionate and 54.11 g of microcrystalline cellulose were sieved through a No. 20 sieve, respectively, and mixed in a V-type mixer for 60 minutes. 1.5 g of hard silicic anhydride was sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes. Finally, 1 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.

Subsequently, the final mixture was filled into capsules to prepare capsules containing 153.39 mg of metformin propionate in one capsule.

Formulation example  6: metformin With propionate Bicalutamide  Preparation of Containing Tablets

306.79 g of metformin propionate, 50 g of bicalutamide, and 121.21 g of microcrystalline cellulose were sieved through a No. 20 sieve, respectively, and mixed in a V-type mixer for 60 minutes. Separately, 15 g of collidone VA64 (BASF, Germany) and 4 g of hard silicic anhydride were sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes. Finally, 3 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.

Subsequently, the final mixture was compressed to prepare a tablet layer containing 306.79 mg of metformin propionate and 50 mg of bicalutamide in 1 tablet, and Opadry OY-C-7000A was used as a high coater (SFC-30F, Sejong Machinery, Korea). 20 mg of a film coating layer was formed on the basis of the coating to prepare a tablet containing metformin propionate and bicalutamide.

[ Experimental Example ]

Experimental Example  1: metformin Propionate  Confirmation of cancer cell proliferation inhibitory effect

Metformin propionate synthesized in the manner described in Example 2 of the present invention was treated with cancer cells to determine the effect of inhibiting cancer cell proliferation. A brief experimental method is as follows.

MCF7 cells derived from human breast cancer were used as a test system, and the survival rate (%) and cell growth were 50% using MTT (3- (4,5-dimethylthiazole-2-yl) -2,5-ditetrazoliumbromide) assay. The concentration of metformin propionate inhibited by% (cell growth inhibitory concentration, GIC50) was measured to determine the cancer cell proliferation inhibitory effect of metformin propionate.

MCF7 cells were incubated for about 24 hours in a 96 well plate so that each cell number was about 5000 in DMEM medium containing 10% calf serum. Thereafter, 2mM and 10mM of metformin propionate synthesized in Example 2 were treated in the culture solution and cultured for 72 hours. In addition, in order to obtain GIC50, the culture solution was treated with metformin propionate 10 mM, 2 mM, 0.4 mM, 0.08 mM and 0.016 mM, and incubated for 72 hours.

After the metformin propionate treatment, MTT was added to the culture medium to identify living cells and further cultured for 3 hours. The resulting formazan crystal was dissolved using dimethyl sulfoxide (DMSO), and then the absorbance of the solution was measured at 560 nm.

The number of cells surviving in the well plate treated with metformin propionate compared to the number of cells cultured in the well plate not treated with metformin propionate after 72 hours of cultivation is expressed as% cell viability. In addition, the concentration of metformin propionate (GIC 50) in which growth was inhibited to 50% using a cell viability curve was calculated to confirm the effect of inhibiting cancer cell proliferation of metformin propionate, and the results are shown in Table 1 and Table 2, respectively.

In addition, metformin hydrochloride or propionic acid in place of metformin propionate was used to obtain the cell viability (%) and GIC 50 values, and the results are shown in Table 1 and Table 2, respectively.

Table 1 Cell survival rate (%)

TABLE 2 Cell Growth Inhibition Concentration (GIC 50)

As can be seen from the cell viability of Table 1, when MCF7 cells were cultured in the presence of metformin propionate, the cell survival rate was lower than when cultured under metformin hydrochloride, whereby metformin propionate was higher than metformin hydrochloride. It was found to effectively inhibit the survival of cancer cells. In particular, when MCF7 was incubated under 10 mM metformin propionate, the cell survival rate was less than 40%. From this, it was found that metformin propionate could effectively inhibit the survival of breast cancer cells.

On the other hand, as can be seen from the GIC 50 value of Table 2, using 5.3 mM metformin propionate was able to inhibit the growth of MCF7 cells by 50%. In contrast, metformin hydrochloride was able to inhibit the growth of MCF7 cells by using a concentration exceeding 10 mM. From this, it was found that metformin propionate could effectively inhibit the growth of cancer cells derived from breast cancer than metformin hydrochloride.

Experimental Example  2: metformin Propionate AMPK Confirmation of the activation effect of α

The effect of activating AMPKα was measured by treating cells with metformin propionate synthesized in the manner described in Example 2 of the present invention. A brief experimental method is as follows.

MCF 7 cells derived from human breast cancer cells were used as a test system, and the AMPKα (5′-AMP-activated protein kinase alpha) activation effect of metformin propionate was confirmed using an AMPKα immunoassay kit (Invitrogen, catalog No. KHO0651).

MCF 7 cells were cultured in DMEM medium containing 10% calf serum and placed in a 6 well plate such that the number of cells was about 5 × 10 ⁵ , followed by culturing the cells in an incubator supplied with 5% CO _2. . The culture solution was treated with 0.4 mM, 2 mM and 10 mM metformin propionate, respectively, and then cultured for 24 hours.

Phosphorylation of threonine 172 residue (T172) of AMPKα in cells cultured in the presence of metformin propionate and cells cultured without metformin propionate was confirmed using an AMPKα immunoassay kit (Invitrogen, catalog No. KHO0651). After lysing cells in the manner suggested by the AMPKα immunoassay kit (Invitrogen, catalog No. KHO0651), the cell lysate was obtained by protein quantification, and then the method described in the instruction manual of the AMPKα immunoassay kit was used. By confirming the phosphorylated degree of threonine 172 residue of AMPKα from the cell lysate, the results are shown in Table 3 and FIG. The ratio of the degree of phosphorylation of cells cultured in the presence of metformin propionate to the degree of phosphorylation of cells cultured in medium without metformin propionate is shown in Table 3.

In addition, by using metformin hydrochloride instead of metformin propionate, the degree of phosphorylation of threonine 172 residue of AMPKα was confirmed by the same method, and the results are shown in Table 3 below.

[Table 3]

As can be seen in Table 3 and FIG. 1, metformin propionate phosphorylated more threonine 172 residues of AMPKα than metformin hydrochloride at the same concentration. Therefore, metformin propionate activates AMPKα more efficiently than metformin hydrochloride, whereby the pharmaceutical composition comprising metformin propionate is used for diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, It can be seen that it can have an excellent effect on diseases such as cancer, myalgia, myocyte cytotoxicity and rhabdomyolysis.

Claims (18)

Metformin propionate represented by the following formula (1).
[Formula 1]

The metformin propionate of claim 1, wherein the metformin propionate is in crystalline form. 3. The metformin propionate of claim 2, wherein the melting point of the crystalline form is 194 ° C to 194.5 ° C. Preparing a metformin free base represented by Formula 3 by reacting metformin hydrochloride represented by Formula 2 with a base under an organic solvent; And
Method of producing a metformin propionate represented by the formula (1) comprising the step of reacting the metformin free base with propionic acid.
[Formula 1]

(2)

(3)

The method of claim 4, wherein the step of reacting the metformin free base with propionic acid,
Preparing a mixture by adding the propionic acid to a metformin free base represented by Formula 3; And
A method for preparing metformin propionate comprising the step of filtering, washing and drying the resulting solid by stirring the mixture. At least one selected from diabetes mellitus, diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity and rhabdomyolysis, including metformin propionate represented by the following formula (1): Pharmaceutical compositions for the prevention or treatment of diseases.
[Formula 1]

The pharmaceutical composition of claim 6, wherein the cancer is cancer selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer, liver cancer, pancreatic cancer, prostate cancer and thyroid cancer. 8. The pharmaceutical composition of claim 7, wherein the cancer is breast cancer. The pharmaceutical composition of claim 6, which is used as an anticancer agent. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is formulated in the form of tablets, capsules, pills, granules, powders, injections or solutions. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is formulated in the form of a sustained release tablet. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is for use in combination with a second drug. The pharmaceutical composition of claim 12, wherein the second drug is an anticancer agent. The method of claim 13,
The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, zefitinib, vandetanib, nirotinib, semasanib, conservinib, axitinib, cediranib, restab Urtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, biscumalboom, asparaginase, tretinoin, hydroxycarbamide, Dasatinib, estramastin, gemtuzumab ozogamycin, ibritumab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, Gemcitabine, doxyfluridin, pemetrexed, tegapur, capecitabine, gimerasin, oteraceyl, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enositabine, Flutamide, decitabine , Mercaptopurine, thioguanine, cladribine, carmoper, raltitrexed, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin , Idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temozolomide, busulfan, ifospa Mead, cyclophosphamide, melfaran, altretmin, dacarbazine, cheotepa, nimustine, chlorambucil, mitolactol, leukovorin, tretonin, exemestane, aminoglutesimid, anagrely Pharmaceutical composition, which is at least one drug selected from the group consisting of navelbine, padrazole, tamoxifen, toremifene, testosterone, anastrozole, letrozole, borosol, bicalutamide, romusstin and carmustine . The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is for preventing or treating both cancer and diabetes. A combination formulation comprising metformin propionate represented by Formula 1 and a second drug.
[Formula 1]

The combination formulation of claim 16, wherein the second drug is an anticancer agent. The method of claim 17,
The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, zefitinib, vandetanib, nirotinib, semasanib, conservinib, axitinib, cediranib, restab Urtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, biscumalboom, asparaginase, tretinoin, hydroxycarbamide, Dasatinib, estramastin, gemtuzumab ozogamycin, ibritumab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, Gemcitabine, doxyfluridin, pemetrexed, tegapur, capecitabine, gimerasin, oteraceyl, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enositabine, Flutamide, decitabine , Mercaptopurine, thioguanine, cladribine, carmoper, raltitrexed, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin , Idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temozolomide, busulfan, ifospa Mead, cyclophosphamide, melfaran, altretmin, dacarbazine, cheotepa, nimustine, chlorambucil, mitolactol, leukovorin, tretonin, exemestane, aminoglutesimid, anagrely De, Navelvin, Padrazole, Tamoxifen, Torremifen, Testosterone, Anastrozole, Letrozole, Borazole, Bicalutamide, Romustine and Carmustine.

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