KR100991397B1 - 4-substituted 2-amino-5-methylimidazole derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and a pharmaceutical composition for the prevention and treatment of ischemic heart diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention provides 2-amino-5-methylimidazole derivatives substituted with 4-positions represented by the following Chemical Formula 1, or pharmaceutically acceptable salts thereof, preparation methods thereof, and prevention of ischemic heart disease containing the same as an active ingredient. And a therapeutic pharmaceutical composition, wherein 4-amino-substituted 2-amino-5-methylimidazole derivative according to the present invention exhibits a strong inhibitory effect on sodium / hydrogen exchange channel NHE-1. It may be useful for the prevention and treatment of ischemic heart disease such as infarction, arrhythmia and angina pectoris, and may be useful as a cardioprotective agent for reperfusion therapy such as coronary artery bypass surgery or coronary artery percutaneous surgery.

[Formula 1]

(Wherein R is as defined herein)

2-amino-5-methylimidazole, sodium / hydrogen, ischemia, heart protectant

Description

2-Amino-5-methylimidazole derivative substituted with 4-position or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing and treating ischemic heart disease containing the same as an active ingredient substituted 2-amino-5-methylimidazole derivatives or pharmaceutically acceptable salts, preparation method according to the formula and the pharmaceutical composition for the prevention and treatment of ischemic heart diseases containing the same as an active ingredient

The present invention provides a 2-position substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for preventing and treating ischemic heart disease containing the same as an active ingredient. It is about.

Ischemic heart diseases such as myocardial infarction, arrhythmia, and heart failure caused by myocardial cell damage and cardiac function during ischemia / reperfusion are high in morbidity, mortality, and hard to cure. Wang, QD. et al., (2002) Cardiovasc. Res. 55: 25-37.

Ischemic heart disease is a phenomenon in which the blood supply to the heart is blocked and the oxygen supply of the myocardium is significantly short of the required amount. This ischemic heart disease ultimately leads to irreversible myocardial damage, ie necrosis of cells and tissues. In the early stages of reversible damage, irreversible damage can be prevented by reperfusion therapy, such as pharmacotherapy using thrombolytics or surgery such as coronary percutaneous plastic surgery and coronary artery bypass surgery. It is known that reperfusion injury occurs at a high rate such as dysfunction, arrhythmia, and neurocognitive decline [Robert, M. (2003) Ann. Thorac. Surg. 75: S700-708.

Ischemia / reperfusion injury involves various physiological mechanisms such as metabolic changes, immune response and ionic constant, and oxygen free radicals. Therefore, various mechanism studies and development of therapeutic agents and surgical procedures have been actively carried out. Technology to protect cardiomyocytes from reperfusion has not yet been clinically commercialized. Therefore, there is a need for development of a prophylactic or therapeutic agent for ischemic heart disease or a cardioprotective agent that can slow the progression of cardiomyocyte damage due to ischemia and alleviate reperfusion injury.

On the other hand, NHE (sodium-hydrogen exchanger) is an ion channel that is expressed in various cell species. It is electrostatically neutral and plays an important role in regulating intracellular pH by letting out one hydrogen ion inside the cell and bringing one Na ⁺ into the cell. It is a membrane protein. To date, seven subtypes have been identified and NHE-1, which is a subtype of cardiomyocytes and plays an important role in maintaining intracellular pH, sodium ion concentration and cell size, is known to play a major role in ischemia-reperfusion injury [Avkiran, M. et . al ., (2002) J. Am . Coll. Cardiol . 39 : 747-753. The NHE-1 hardly operates at normal physiological pH (= 7.2), but in oxygen-ischemic state, it is acidified (pH = 6.4) by increasing the concentration of hydrogen ions in cells by relying on glycolysis for energy generation. As a result, NHE-1 detects and activates hydrogen ions to release hydrogen ions and bring sodium ions into the cell, thereby increasing the concentration of sodium ions in the cells. In ischemia, Na ⁺ / K ⁺ ATPase is inhibited due to the reduction of ATP energy production, so sodium ions accumulated in cells by the sodium pump cannot be exported. Therefore, in normal state, NCX (Na ⁺ / Ca ⁺⁺ exchanger), which is a sodium / calcium channel that exports calcium and imports sodium, works in reverse direction to release sodium ions and bring calcium ions into cells The concentration of becomes high. Increasing the calcium ion concentration in the cell activates enzymes such as proteases, phospholipases, endonucleases, and the like, causing cell damage by causing various protein breakdowns, an increase in free radicals due to fat metabolism disorders, and DNA deformation.

Therefore, the inhibition of NHE-1 prevents the increase of intracellular sodium ion concentration, thereby inhibiting the reverse operation of NCX, and inhibits the increase of intracellular calcium ion concentration to protect cell damage by ischemia / reperfusion. . Increased hydrogen ions are regulated by other ion channels, so it has been reported that intracellular acidification by inhibition of NHE-1 does not occur.

NHE-1 inhibitors have been shown to have protective effects against ischemia / reperfusion injury by improving myocardial contractility, reducing arrhythmia, reducing apoptosis and necrosis, improving metabolic status, and reducing overloading of sodium and calcium ions [Karmazyn , M (2002) Science & Medicine : 18-26. Therefore, the selective NHE-1 inhibitor may be applied as a cardioprotective agent for ischemia / reperfusion injury such as surgical procedures such as acute myocardial infarction, coronary artery bypass surgery and coronary angioplasty, and thrombolytic therapy. Treatment and prevention of the disease is expected.

The diuretic pyrazine derivative amylolide is the first known NHE inhibitor [Benos, DJ. (1982) AJ Physiol . 242 : C131], rat extraction cardiac experiments have been shown to enhance the recovery of cardiac function after ischemia / reperfusion, but lacking selectivity, such as inhibiting NHE-2 and sodium channels, in addition to NHE-1, has had problems with cardioprotectants. Accordingly, research on drug development with selectivity for NHE-1 was conducted, and benzoylguanidine derivative cariporide (HOE-694) having high selectivity for NHE-1 was developed by Hoechst Marion Roussel (now Aventis). Scholz, W. et . al ., (1993) Br . J. Pharmacol . 109 : 562]. The califoride showed an excellent cardioprotective effect in an animal model and also showed a significant protective effect when administered to patients with coronary artery bypass surgery. However, compared with the superior cardioprotective effect in animal models, the results of clinical phase 2/3 phases were unsatisfactory [Karmazyn, M. (2000) Expert Opin . Investig . Drugs 9 : 1099], the clinical results of eniporide, a successor substance with better NHE-1 inhibitory effect than carporide, have not been successful [Zeymer, U. et . al ., (2001) J. Am . Coll . Cardiol . 38 : 1644].

For this reason, it was suggested that acylguanidine, which plays an important role in the NHE-1 inhibitory effect, is likely to be metabolized and toxic by guanidine is the main cause of failure [Atwal, KS et . al ., (2006) Bioorg . med. Chem . Lett . 16 : 4796]. Therefore, studies on the structure that can eliminate the problem while maintaining the drug efficacy of acylguanidine continues.

Accordingly, the present inventors made efforts to develop a selective NHE-1 inhibitor that does not contain an acylguanidine group, and produced 2-amino-5-methylimidazole derivatives substituted with 4-positions, and these derivatives selectively contained NHE. The present invention was completed by demonstrating an excellent inhibitory effect by showing -1 inhibitory effect, enhancing recovery of cardiac function damage by ischemia / reperfusion, and significantly reducing the size of myocardial infarction.

It is an object of the present invention to provide a 4-position substituted 2-amino-5-methylimidazole derivative having excellent selective inhibitory effect on NHE-1 or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the 2-amino-5-methylimidazole derivative substituted with the 4-position.

Still another object of the present invention is to provide a pharmaceutical composition for preventing and treating ischemic heart disease, wherein the 4-position is substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. There is.

Still another object of the present invention is to provide a cardioprotective agent for surgery or pharmacotherapy with the 4-position substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.

In order to achieve the above object, the present invention provides a 2-amino-5-methylimidazole derivative substituted with 4-position or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preparing the 2-amino-5-methylimidazole derivative substituted with the 4-position.

Furthermore, the present invention provides a pharmaceutical composition for preventing and treating ischemic heart disease, wherein the 4-position is substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a cardioprotective agent for surgery or pharmacotherapy procedures using the 4-position substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. There is.

4-amino-substituted 2-amino-5-methylimidazole derivatives according to the present invention exhibit a potent inhibitory effect on NHE-1, a sodium / hydrogen exchange pathway, to restore cardiac function impairment by ischemia / reperfusion, It can be used for the prevention and treatment of ischemic heart disease such as myocardial infarction, arrhythmia and angina due to its cardioprotective effect, low toxicity and high stability, and during cardiac procedures such as coronary artery bypass surgery and coronary percutaneous plastic surgery. It may be usefully used as a cardioprotectant against reperfusion therapy such as a solubilizer.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention provides 2-amino-5-methylimidazole derivatives substituted with the 4-position.

In Chemical Formula 1,

또는

이고,R is

or

ego,

Wherein R ¹ and R ² are each independently hydrogen, a halogen atom or an alkoxy group of C _{1 to} C ₅ ,

R ³ is hydrogen, an amino group or a C ₁ to C ₅ straight or branched alkyl group,

R ⁴ is hydrogen, a halogen atom, a C ₁ to C ₅ straight or branched alkyl group, a C ₁ to C ₅ alkoxy group, a halogen substituted C ₁ to C ₅ straight or branched alkyl group, an amino group, a nitro group, a cyano group And C ₅ -C ₈ aryl groups.

Preferably,

R ¹ and R ² are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methoxy group and ethoxy group,

R ³ is hydrogen,

R ⁴ is a chlorine, bromine or cyano group.

Preferred compounds among the 2-amino-5-methylimidazole derivatives substituted with the 4-position of the present invention are specifically as follows:

1) 4- [5- (3-fluorophenyl) furan-2-yl] -2-amino-5-methylimidazole methanesulfonate;

2) 4- [5- (3,5-difluorophenyl) furan-2-yl] -2-amino-5-methylimidazole;

3) 4- [5- (2-methoxy-5-chlorophenyl) furan-2-yl] -2-amino-5-methylimidazole methanesulfonate;

4) 4- (4-bromobenzothiophen-2-yl) -2-amino-5-methylimidazole; And

5) 4- (4-cyanobenzothiophen-2-yl) -2-amino-5-methylimidazole methanesulfonate.

4-amino-substituted 2-amino-5-methylimidazole derivative of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and as a salt, a pharmaceutically acceptable free acid ( Acid addition salts formed by free acid are useful. The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. may be used as the inorganic acid. Phonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid and the like can be used. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid.

In addition, 4-amino-substituted 2-amino-5-methylimidazole derivative represented by Formula 1 of the present invention is not only a pharmaceutically acceptable salt, but also any salt that can be prepared by a conventional method, Includes both hydrates and solvates.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

In another aspect, the present invention provides a method for producing a novel 4-position substituted 2-amino-5-methylimidazole derivative represented by the formula (1).

This will be described in detail below.

Preparation method 1

A method for preparing a derivative of Formula 1 according to the present invention is to react the carboxylic acid compound (2) with 1-5 equivalents of N, O-dimethylhydroxylamine in the presence of a condensing agent in a reaction solvent, as shown in Scheme 1 below. To prepare methoxymethylamide (Weinreb amide) compound (3) (step 1);

Reacting the methoxymethylamide compound (3) prepared in step 1 with 1-10 equivalents of ethylmagnesium bromide under a reaction solvent to prepare a 1-position substituted propion compound (4) (step 2);

Preparing a 2-bromopropanone compound (5) by α-bromination of the 1-position substituted propion compound (4) prepared in step 2;

2-Bromopropanone Compound (5) prepared in Step 3 was reacted with 1-10 equivalents of 1-acetylguanidine to 2- (N-acetyl) amino-5-methylimidazole having 4-position substituted. Preparing compound (6) (step 4); And

Deacetylating the 4-position substituted 2- (N-acetyl) amino-5-methylimidazole compound (6) prepared in Step 4 to prepare a compound of Formula 1 (Step 5) do.

(In Scheme 1, R is as defined in Formula 1)

First, step 1 is to react carboxylic acid compound (2) with 1-5 equivalents of N, O-dimethylhydroxylamine in the presence of a condensing agent in a reaction solvent to produce methoxymethylamide (Weinreb amide) compound (3). Step.

In the production method according to the present invention, the reaction solvent is an ether solvent such as tetrahydrofuran, 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene and toluene; Halogenated hydrocarbon solvents such as dichloromethane and chloroform; DMF or a mixed solvent thereof can be used.

In the production method according to the present invention, the condensing agent is N, N-carbonyldiimidazole (N, N-carbonyldiimidazole), dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (diisopropylcarbodiimide) , DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), diphenylphosphonylazide (DPPA), etc. Can be used.

Next, step 2 is a step of preparing a 1-position substituted propion compound (4) by reacting the methoxymethylamide compound (3) prepared in Step 1 with 1-10 equivalents of ethylmagnesium bromide under a reaction solvent. to be.

In the production method according to the present invention, the reaction solvent is an ether solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane; DMF or a mixed solvent thereof can be used. In this case, the reaction may be carried out in a temperature range from -78 ℃ to room temperature.

Next, step 3 is a step of preparing 2-bromopropanone compound (5) by α-bromination of the 1-position substituted propion compound (4) prepared in step 2.

As the nucleophile in the α-bromination reaction, Br ₂ , CuBr ₂ , NBS, etc. may be used, and as a solvent, a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride; Ether solvents such as tetrahydrofuran and 1,4-dioic acid; Or ethyl acetate, acetonitrile and the like can be used. In this case, the reaction may be carried out in the temperature range from 0 ℃ to the boiling point of the solvent.

Next, step 4 is a 2- (N-acetyl substituted 4-position by reacting the 2-bromopropane compound (5) prepared in Step 3 with 1 to 10 equivalents of 1-acetylguanidine under a reaction solvent. ) A step of preparing amino-5-methylimidazole compound (6).

At this time, the reaction solvent is an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane; Dimethylformamide (DMF), dimethylsulfoxide (DMSO) or a mixed solvent thereof can be used. In addition, the reaction may be carried out in a temperature range from room temperature to the boiling point of the solvent.

Next, step 5 deacetylated 4- (substituted 2- (N-acetyl) amino-5-methylimidazole compound (6) prepared in Step 4 to substitute 4-position of Formula 1 To prepare a 2-amino-5-methylimidazole derivative.

Deacetylation in this step is an acid such as hydrochloric acid; Or hydrazine. It can be carried out by using bases such as sodium methoxide (NaOMe) and sodium t-butoxide.

As a reaction solvent, Alcohol solvents, such as methanol and t-butanol; Ether solvents such as tetrahydrofuran; Halogenated hydrocarbon solvents such as dichloromethane and chloroform; Or DMF or the like, or a mixed solvent thereof may be used. In this case, the reaction may be carried out in the temperature range from 0 ℃ to the boiling point of the solvent.

Preparation method 2

In addition, a method for preparing a derivative of Formula 1 according to the present invention, as shown in Scheme 2 below, reacts the carboxylic acid ester compound (7) with ethylmagnesium bromide under a metal catalyst to displace the 1-position propion compound (4) Preparing a step (step a);

Preparing a 2-bromopropanone compound (5) by α-bromination of the 1-position substituted propion compound (4) prepared in step a;

2-Bromopropanone Compound (5) prepared in step b was reacted with 1-10 equivalents of 1-acetylguanidine to 4- (substituted 2- (N-acetyl) amino-5-methylimidazole Preparing compound (6) (step c); And

Deacetylating the 4-position substituted 2- (N-acetyl) amino-5-methylimidazole compound (6) prepared in step b to prepare a compound of formula 1 (step d) do.

(In Scheme 2, R is as defined in Formula 1, Q is an ester group)

Step a is a step of reacting the carboxylic ester compound (7) with ethylmagnesium bromide under a metal catalyst to prepare a 1-position substituted propion compound (4).

In the production method according to the present invention, the metal catalyst may be used alone or mixed with palladium, copper, silver, and the like, wherein the palladium catalyst Pd (PPh ₃ ), Pd-C, PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ , PdCl ₂ (dppf), [PdCl (allyl)] ₂ , Pd (OAc) ₂ , PdCl _2, etc. may be used, and CuI, CuBr, CuOTf, etc. may be used as the copper catalyst. have.

Examples of the solvent include ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene and xylene; Alcohol solvents such as methanol and ethanol; DMF, acetonitrile and the like may be used alone or in combination. In this case, the reaction may be carried out in a temperature range from room temperature to the boiling point of the solvent.

Thereafter, the steps b to d are the same as described above in steps 3 to 5 of Scheme 1.

The 4-position substituted 2-amino-5-methylimidazole derivative prepared according to the present invention as described above is prepared after the infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure The molecular structure can be confirmed by the determination method, the photoluminescence measurement method, and the comparison of the elemental analysis calculations and actual measurements of representative compounds.

In addition, the present invention is a pharmaceutical composition for the prevention and treatment of ischemic heart disease, or coronary artery, wherein the 4-position is substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Provide cardiac protection for cardiac procedures such as bypass surgery, coronary percutaneous plastic surgery, or reperfusion therapy such as thrombolytics.

Derivatives of formula (1) and pharmaceutically acceptable salts thereof according to the present invention exhibit cardioprotective activity by selectively inhibiting NHE-1. Specifically, it showed a strong inhibitory effect on NHE-1 in cells expressing human NHE-1 (see Table 1). Therefore, the compounds of the present invention exhibit a strong inhibitory effect on NHE-1, can be useful for the prevention and treatment of ischemic heart disease such as myocardial infarction, heart failure, angina pectoris, cardiovascular surgery, coronary percutaneous plastic surgery, etc. Or as a cardioprotectant against reperfusion therapy such as thrombolytics.

The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

Hereinafter, preferred 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.

< Example  1> 4- [5- (3- Fluorophenyl ) Furan -2-yl] -2-amino-5- Methylimidazole Methanesulfonate  Produce

1-1. 5- (3- Fluorophenyl ) Furan -2- Carboxylic acid Of methoxymethylamide  Produce

Dissolve 5- (3-fluorophenyl) furan-2-carboxylic acid (1.71 g) in THF (25 mL), add 1,1-carbonyldiimidazole (1.62 g, 9.95 mmol), and add 1 at room temperature. After reacting for an hour, N, O-dimethylhydroxylamine hydrochloride (1.21 g, 12.4 mmol) was added thereto and reacted at room temperature for 12 hours. After completion of the reaction, water (30 mL) was added and extracted twice with ethyl acetate (60 mL). The organic layer was washed with saturated NaCl solution, dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 1.80 g (yield 87%) of the title compound as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.38 (s, 3H), 3.82 (s, 3H), 6.77 (d, 1H, J = 3.6 Hz), 7.02 (m, 1H), 7.23 (d, 1H, J = 3.6 Hz), 7.37 (m, 1H), 7.47 (d, 1H, J = 9.9 Hz), 7.56 (dd, 1H, J = 0.9, 7.5 Hz)

1-2. 1- [5- (3- Fluorophenyl ) Furan Preparation of 2-yl] -propan-1-one

The amide compound (1.7 g, 6.9 mmol) prepared in 1-1 above was dissolved in THF (18 mL), cooled to -78 ° C, and then ethyl magnesium bromide 2M solution (in THF) (17.3 mL, 34.6 mmol) was added thereto. Slowly added and stirred for 1 hour. After completion of the reaction, water (20 mL) was added and extracted twice with ethyl acetate (60 mL). The organic layer was washed with saturated NaCl solution, dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 1.030 g (yield 68%) of the target compound in the form of an oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.25 (t, 3H, J = 7.4 Hz), 2.92 (q, 2H, J = 7.4 Hz), 6.79 (d, 1H, J = 3.7 Hz), 7.06 (m, 1H), 7.25 (d, 1H, J = 3.7 Hz), 7.39-7.49 (m, 2H), 7.55 (d, 1H)

1-3. 1- [5- (3- Fluorophenyl ) Furan -2- day] -2- Bromopropane Preparation of -1-one

The propanone compound (1.03 g, 4.7 mmol) prepared in 1-2 was dissolved in CH ₂ Cl ₂ (15 mL), Br ₂ (0.26 mL, 5.2 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. I was. After the reaction was completed, water (20 mL) was added and extracted twice with CH ₂ Cl ₂ (50 mL). The organic layer was washed with saturated NaHCO ₃ and NaCl solution, dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 904 mg (yield 65%) of the title compound as a yellow sec solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.91 (d, 3H, J = 6.9 Hz), 5.20 (q, 1H, J = 6.9 Hz), 6.84 (d, 1H, J = 3.7 Hz), 7.09 (m, 1H), 7.41-7.51 (m, 3H), 7.58 (dd, 1H, J = 1.2, 6.6 Hz)

1-4. 4- [5- (3- Fluorophenyl ) Furan -2-yl] -2- (N-acetyl) amino-5- Methylimidazole  Produce

2-bromopropanone compound (500 mg, 1.68 mmol) prepared in 1-3 was dissolved in DMF (7 mL), and 1-acetylguanidine (510.4 mg, 5.05 mmol) was added and reacted at 60 ° C. for 12 hours. . Thereafter, water (5 mL) was added to terminate the reaction, followed by extraction twice with ethyl acetate (50 mL), and the organic layers were washed with NaHCO ₃ and saturated NaCl solution, respectively. Thereafter, the mixture was dried over MgSO ₄ , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1-&gt; 1: 9) to give 196.5 mg of the target compound as a yellow solid ( Yield 39%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.14 (s, 3H), 2.50 (s, 3H), 6.51 (d, 1H, J = 3.5 Hz), 6.74 (d, 1H, J = 3.5 Hz), 6.95 ( m, 1H), 7.30-7.38 (m, 1H), 7.42-7.47 (m, 2H)

1-5. 4- [5- (3- Fluorophenyl ) Furan -2-yl] -2-amino-5- Methylimidazole Methanesulfonate  Produce

2- (N-acetyl) amino-5-methylimidazole compound (160.1 mg, 0.53 mmol) prepared in 1-4 was dissolved in methanol (3 mL), and then 8 N HCl (1.5 mL) was added thereto. Heated to reflux for hours. The pH was adjusted to about 10 with 6 N NaOH and extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% methanol / dichloromethane) to dissolve the compound in acetone (4 mL) and methanesulfonic acid (0.2 mL) was added to precipitate a solid. The resulting solid was filtered to give 38.5 mg (yield 21%) of the title compound as a brown solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 2.44 (s, 3H), 2.73 (s, 3H), 6.71 (d, 1H, J = 3.6 Hz), 7.00 (d, 1H, J = 3.6 Hz), 7.02 -7.08 (m, 1H), 7.41-7.51 (m, 2H), 7.58 (d, 1H, J = 7.9 Hz)

< Example  2> 4- [5- (3,5- Difluorophenyl ) Furan -2-yl] -2-amino-5- Methylimidazole  Produce

 2-1. 5- (3,5- Difluorophenyl ) Furan -2- Carboxylic acid Of methoxymethylamide  Produce

5 (3,5-Difluorophenyl) furan-2-carboxylic acid (775.7 mg, 3.46 mmol) was reacted in the same manner as in Example 1-1 using the starting material 693.2 mg (yield 75%) were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.38 (s, 3H), 3.82 (s, 3H), 6.77 (m, 1H), 6.79 (d, 1H, J = 3.7 Hz), 7.23 (d, 1H, J = 3.7 Hz), 7.26-7.32 (m, 2H)

2-2. 1- [5- (3,5- Difluorophenyl ) Furan Preparation of 2-yl] -propan-1-one

The amide compound (667.2 mg, 2.5 mmol) prepared in 2-1 was used as a starting material and reacted in the same manner as in Example 1-2, to obtain 500.7 mg (yield 85%) of the title compound as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.25 (t, 3H, J = 7.2 Hz), 2.92 (q, 2H, J = 7.2 Hz), 6.77-6.85 (m, 2H), 7.24-7.32 (m, 3H )

2-3. 1- [5- (3,5- Difluorophenyl ) Furan -2- day] -2- Bromopropane Preparation of -1-one

Using the propane compound (450 mg, 1.91 mmol) prepared in 2-2 as a starting material, the reaction was carried out in the same manner as in Example 1-3, to obtain 480 mg (yield 80%) of the title compound as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.91 (d, 3H, J = 6.9 Hz), 5.18 (q, 1H, J = 6.9 Hz), 6.80-6.88 (m, 2H), 7.30 (dd, 2H, J) = 2.1, 8.1 Hz), 7.41 (d, 1H, J = 3.9 Hz)

2-4. 4- [5- (3,5- Difluorophenyl ) Furan -2-yl] -2- (N-acetyl) amino-5- Methylimidazole  Produce

Using the 2-bromopropanone compound (460 mg, 1.46 mmol) prepared in 2-3 as a starting material, the reaction was carried out in the same manner as in Example 1-4, to obtain 181.2 mg of the target compound as a yellow solid (yield 39%). )

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.13 (s, 3H), 2.51 (s, 3H), 6.50 (d, 1H, J = 3.6 Hz), 6.68 (m, 1H), 6.76 (d, 1H, J = 3.6 Hz), 7.17 (dd, 2H, J = 2.1, 8.7 Hz)

2-5. 4- [5- (2,5- Fluorophenyl ) Furan -2-yl] -2-amino-5- Methylimidazole  Produce

2- (N-acetyl) amino-5-methylimidazole compound prepared in 2-4 (139.6 mg, 0.44 mmol) was dissolved in methanol (4 mL), and 8 N HCl (2 mL) was added thereto to give 12 Heated to reflux for hours. The pH was adjusted to about 10 with 6 N NaOH and extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol / dichloromethane) to give 63.9 mg (yield 53%) of the title compound as a brown solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33 (s, 3H), 4.68-4.74 (brm, 3H), 6.36 (d, 1H, J = 3.3 Hz), 6.58 (m, 1H), 6.62 (d, 1H , J = 3,3 Hz), 6.99 (d, 2H, J = 6.6 Hz)

< Example  3> 4- [5- (2- Methoxy -5- Chlorophenyl ) Furan -2-yl] -2-amino-5- Methylimidazole Methanesulfonate  Produce

3-1. 5- (2- Methoxy -5- Chlorophenyl ) Furan -2- Carboxylic acid Of methoxymethylamide  Produce

5- (2-methoxy-5-chlorophenyl) furan-2-carboxylic acid (2.4 g, 9.5 mmol) was used as a starting material and reacted in the same manner as in Example 1-1. 2.50 g (89% yield) were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.38 (s, 3H), 3.82 (s, 3H), 3.94 (s, 3H), 6.89 (d, 1H, J = 8.7 Hz), 7.05 (d, 1H, J = 3.6 Hz), 7.22-7.26 (m, 2H), 7.98 (d, 1H, J = 2.7 Hz)

3-2. 1- [5- (2- Methoxy -5- Chlorophenyl ) Furan Preparation of 2-yl] -propan-1-one

Using the amide compound (2.5 g, 8.5 mmol) prepared in 3-1 as a starting material, the reaction was carried out in the same manner as in Example 1-2, to obtain 1.75 g (yield 78%) of the title compound as a green solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.25 (t, 3H, J = 7.3 Hz), 2.93 (q, 2H, J = 7.3 Hz), 3.94 (s, 3H), 6.90 (d, 1H, J = 5.6 Hz), 7.07 (d, 1H, J = 3.7 Hz), 7.23- 7.33 (m, 2H), 7.94 (d, 1H, J = 2.6 Hz)

3-3. 1- [5- (2- Methoxy -5- Chlorophenyl ) Furan -2- day] -2- Bromopropane Preparation of -1-one

Using the propanone compound (1.03 g, 3.9 mmol) prepared in 3-2 as a starting material, the reaction was carried out in the same manner as in Example 1-3, to obtain 803 mg (yield 60%) of the title compound as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.91 (d, 3H, J = 6.8 Hz), 3.96 (s, 3H), 5.22 (q, 1H, J = 6.8 Hz), 6.93 (d, 1H, J = 8.9 Hz), 7.12 (d, 1H, J = 3.8 Hz), 7.30 (dd, 2H, J = 2.6, 8.9 Hz), 7.41 (d, 1H, J = 3.8 Hz), 7.94 (d, 1H, J = 2.6 Hz)

3-4. 4- [5- (2- Methoxy -5- Chlorophenyl ) Furan -2-yl] -2- (N-acetyl) amino-5- Methylimidazole  Produce

Using the 2-bromopropanone compound (150 mg, 0.44 mmol) prepared in 3-3 as a starting material, the reaction was carried out in the same manner as in Example 1-4, to obtain 61.5 mg of the target compound as a yellow solid (yield 41%). )

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.24 (s, 3H), 2.48 (s, 3H), 3.94 (s, 3H), 6.50 (d, 1H, J = 3.5 Hz), 6.87 (d, 1H, J = 8.8 Hz), 7.04 (d, 1H, J = 3.5 Hz), 7.16 (dd, 2H, J = 2.6, 8.8 Hz), 7.95 (brs, 1H)

3-5. 4- [5- (2- Methoxy -5- Chlorophenyl ) Furan -2-yl] -2-amino-5- Methylimidazole Methanesulfonate  Produce

The white solid was reacted in the same manner as in Example 1-5 using 2- (N-acetyl) amino-5-methylimidazole compound (146 mg, 0.42 mmol) prepared in 3-4 as a starting material. 26 mg (yield 16%) of the title compound were obtained.

¹ H NMR (300 MHz, CD ₃ OD) δ 2.43 (s, 3H), 2.73 (s, 3H0, 3.99) s, 3H), 6.70 (d, 1H, J = 3.6 Hz), 6.70 (d, 1H, J = 3.6 Hz), 7.07-7.12 (m, 2H), 7.28 (dd, 1H, J = 2.6, 8.8 Hz), 7.86 (d, 1H, J = 2.6 Hz)

< Example  4> 4- (4- Bromobenzothiophene -2-yl) -2-amino-5- Methylimidazole  Produce

4-1. 4- Bromobenzothiophene -2- Carboxylic acid Of methoxymethylamide  Produce

Reaction was carried out in the same manner as in Example 1-1, using 4-bromobenzothiophene-2-carboxylic acid (847 mg, 3.29 mmol) as a starting material. 296 mg of a target compound as a yellow solid (yield 28%) Got.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.45 (s, 3H), 3.85 (s, 3H), 7.30 (m, 1H), 7.59 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 8.0 Hz), 8.34 (s, 1H)

4-2. 1- (4- Bromobenzothiophene Preparation of 2-yl) -propan-1-one

Using the amide compound (539 mg, 1.80 mmol) prepared in 4-1 as a starting material, the reaction was carried out in the same manner as in Example 1-2, to obtain 361 mg (yield 75%) of the title compound as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.31 (t, 3H), 3.09 (q, 2H), 7.33 (d, 1H, J = 8.2 Hz), 7.58 (dd, 1H, J = 7.6, 8.2 Hz), 7.79 (d, 1 H, J = 7.6 Hz), 8.07 (s, 1 H)

4-3. 1- (4- Bromobenzothiophene -2- days) -2- Bromopropane Preparation of -1-one

Using the propanone compound (275 mg, 1.02 mmol) prepared in 4-2 as a starting material, the reaction was carried out in the same manner as in Example 1-3, to obtain 286 mg (yield 86%) of the target compound as a yellow solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.97 (d, 3H), 5.33 (q, 1H), 7.35 (m, 1H), 7.62 (d, 1H, J = 7.2 Hz), 7.82 (d, 1H, J = 8.4 Hz), 8.21 (s, 1H)

4-4. 4- (4- Bromobenzothiophene -2-yl) -2- (N-acetyl) amino-5- Methylimidazole  Produce

The reaction mixture was prepared in the same manner as in Example 1-4, using the 2-bromopropanone compound (260 mg, 0.804 mmol) prepared in 4-3 as a starting material. 100 mg of the target compound of a brown solid (yield 36) %) Was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.14 (s, 3H), 2.55 (s, 3H), 7.15 (m, 1H), 7.46 (s, 1H), 7.52 (d, 1H, J = 8.0 Hz), 7.75 (d, 1 H, J = 8.4 Hz)

4-5. 4- (4- Bromobenzothiophene -2-yl) -2-amino-5- Methylimidazole  Produce

The brown solid was reacted in the same manner as in Example 2-5 using 2- (N-acetyl) amino-5-methylimidazole compound (90 mg, 0.257 mmol) prepared in 4-4 as a starting material. 63 mg (yield 80%) of the title compound were obtained.

¹ H NMR (300 MHz, CD ₃ OD) δ 2.43 (s, 3H), 7.18 (dd, 1H, J = 7.8, 7.8 Hz), 7.40 (s, 1H), 7.55 (d, 1H, J = 7.8 Hz) , 7.83 (d, 1H, J = 7.8 Hz)

< Example  5> 4- (4- Cyanobenzothiophene -2-yl) -2-amino-5- Methylimidazole Methanesulfonate  Produce

4-1. 4- Cyanobenzothiophene -2- Carboxylic acid Of methoxymethylamide  Produce

4-Cyanobenzothiophene-2-carboxylic acid (460 mg, 2.26 mmol) was used as a starting material and reacted in the same manner as in Example 1-1, to yield 327 mg of a target compound as a white solid (yield 59%). Got.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.47 (s, 3H), 3.87 (s, 3H), 7.53 (dd, 1H, J = 7.6, 8.0 Hz), 7.81 (d, 1H, J = 7.6 Hz), 8.01 (d, 1 H, J = 8.0 Hz), 8.43 (s, 1 H)

5-2. 1- (4- Cyanobenzothiophene Preparation of 2-yl) -propan-1-one

Using the amide compound (325 mg, 1.32 mmol) prepared in 5-1 as a starting material, the reaction was carried out in the same manner as in Example 1-2, to obtain 185 mg (yield 65%) of the title compound as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.30 (t, 3H), 3.13 (q, 2H), 7.35 (dd, 1H, J = 7.2, 8.4 Hz), 7.79 (dd, 1H, J = 7.2 Hz), 8.11 (d, 1 H, J = 8.4 Hz), 8.14 (s, 1 H)

5-3. 1- (4- Cyanobenzothiophene -2- days) -2- Bromopropane Preparation of -1-one

Using the propanone compound (166 mg, 0.77 mmol) prepared in 5-2 as a starting material, the reaction was carried out in the same manner as in Example 1-3, to obtain 223 mg (yield 98%) of the target compound as a light yellow solid. .

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.98 (d, 3H), 5.28 (q, 1H), 7.56 (dd, 1H, J = 7.8, 8.0 Hz), 7.82 (d, 1H, J = 7.8 Hz), 8.12 (d, 1 H, J = 8.0 Hz), 8.26 (s, 1 H)

5-4. 4- (4- Cyanobenzothiophene -2-yl) -2- (N-acetyl) amino-5- Methylimidazole  Produce

Using the 2-bromopropanone compound (220 mg, 0.748 mmol) prepared in 5-3 as a starting material was reacted in the same manner as in Example 1-4, 64 mg of the target compound as a yellow solid (yield 29% )

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.14 (s, 3H), 2.57 (s, 3H), 7.34 (dd, 1H, J = 7.6, 8.2 Hz), 7.55 (s, 1H), 7.68 (d, 1H , J = 7.6 Hz), 7.99 (d, 1H, J = 8.2 Hz), 8.04 (s, 1H0, 10.76 (brs, 1H)

5-5. 4- (4- Cyanobenzothiophene -2-yl) -2-amino-5- Methylimidazole Methanesulfonei Manufacturing

2- (N-acetyl) amino-5-methylimidazole compound prepared in 5-4 (60 mg, 0.202 mmol) was used as a starting material, and reacted in the same manner as in Example 1-5, to light yellow. 30 mg (yield 42%) of the title compound was obtained as a solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 2.33 (s, 3H), 7.58 (dd, 1H, J = 6.0, 9.0 Hz), 7.72 (s, 2H), 7.85 (s, 1H), 7.96 (d, 1H, J = 6.0 Hz), 8.39 (d, 1H, J = 9.0 Hz), 12.64 (brs, 1H)

The pharmacological action of the compounds of formula 1 according to the present invention was investigated by performing the following experiment.

< Experimental Example  1> NHE -1 inhibitory effect

In order to measure the NHE-1 inhibitory effect of 4-position substituted 2-amino-5-methylimidazole derivatives according to the present invention at the cellular stage, the following experiment was performed.

<1-1> PS120 Of NHE -1 cell preparation

Human NHE-1 was expressed in PS120 cells derived from CCL39, and DMEM (Dulbecco's modified) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin (100X solution) and 1% L-glutamine (200 mM aqueous solution) The cells were cultured in Eagle's medium). After treatment with trypsin PS120 / NHE-1 cells grown about 80-90% in a 100 mm diameter dish, and once with PBS (phosphate buffer saline), Na-free buffer (138.2 mM choline chloride) ), and washed once with _{4.9 mM KCl, 1.5 mM CaCl 2} · 2H 2 O, 1.2 mM MgSO 4 · 7H 2 O, 1.2 mM KH 2 PO 4, 15 mM D- glucose, 20 mM HEPES, pH 7.4). This was centrifuged to precipitate the precipitate in sodium free buffer containing 20 mM NH ₄ Cl and 10 μM BCECF-AM [2 ', 7'-bis (2-carboxyethyl) -5,6-carboxy-fluorescein acetoxymethyl ester]. Then, incubated for 30 minutes at 37 ℃, CO ₂ incubator. In order to remove NH ₄ Cl and simultaneously wash BCECF-AM remaining outside the cells, PS120 / NHE-1 cells were centrifuged and washed once with sodium free buffer, so that the number of cells was 2.5 × 10 ⁴ cells / 10 μl. A suspension was made and stored in the dark at 4 ° C.

<1-2> NHE -1 inhibitory effect measurement

180 μl HBS buffer (137 mM NaCl, 4.9 mM KCl, 1.5 mM CaCl _{2 ·} 2H ₂ O, 1.2 mM MgSO ₄ · 7H ₂ O, 1.2 mM KH ₂ PO ₄ , 15 mM D-glucose, 20 mM in 96 well plates) HEPES, pH 7.4) and 10 μl each of the compounds of Examples 1-5 (0.03-10 μM) dissolved in DMSO or DMSO were aliquoted and mixed well. Finally, the PS120 / NHE-1 cells in which the intracellular acidification was induced were mixed. Add μl and stir. Four minutes after the addition of the cells, fluorescence (excitation: 485/444 nm, emission: 535 nm) was measured using a fluorescence spectrophotometer (XEMINI-XS; Molecular Device) for 96 well plates. The measured fluorescence value was converted to pH using potassium cation / nigericin technique (high-K + / nigericin technique). Cells that induced intracellular acidification with NH ₄ Cl prepulse are able to restore intracellular acidification back to normal by the operation of NHE-1, wherein a concentration of a compound that inhibits the recovery of intracellular acidification by 50% is reduced. Obtained (IC ₅₀ value) the inhibitory effect on NHE-1 was measured. As a control material, experiment was carried out using a cariporide (cariporide), and as a comparative example, a carbonylguanidine compound was used. The compound structures of the Examples and Comparative Examples are shown in Table 1, and the experimental results are shown in Table 2.

division rescue Example 1

Example 2

Example 3

Example 4

Example 5

Comparative Example 1

Comparative Example 2

Comparative Example 3

Comparative Example 4

Comparative Example 5

division IC ₅₀ (μM) Cariporide 1.0 Example 1 0.2 Example 2 0.5 Example 3 0.07 Example 4 0.9 Example 5 1.0 Comparative Example 1 1.9 Comparative Example 2 0.6 Comparative Example 3 0.06 Comparative Example 4 0.3 Comparative Example 5 3.0

As shown in Table 2, the compounds of Examples 4-5 exhibited IC ₅₀ of 0.9 and 1.0 μM, respectively, thereby inhibiting NHE-1 similar to the above-mentioned carporide (IC ₅₀ = 1.0 μM), which is used as one of the conventional cardioprotectants. The effect was shown. In addition, the compounds of Examples 1 to 3 exhibited an IC ₅₀ of 0.07 to 0.5 μM, which showed an effect of inhibiting NHE-1 superior to the carporide. In particular, it can be seen that the compound of Example 3 exhibits an NHE-1 inhibitory effect that is at least 10-fold higher than that of carrieporide (IC ₅₀ = 1.0 μM). From this, it can be seen that the 4-position substituted 2-amino-5-methylimidazole derivative according to the present invention can be usefully used as a protective agent against ischemia / reperfusion injury through NHE-1 inhibition.

As a result of comparing the 4-amino-substituted 2-amino-5-methylimidazole derivative according to the present invention with the compound where 2-amino-5-methylimidazole is substituted with carbonyl guanidine, NHE-1 inhibitory effect Although the acylguanidine is reported to be a possible cause of toxicity by liberating guanidine by the body metabolism, it is considered that the compounds of the present invention are superior in terms of safety.

On the other hand, the compound according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> tablet (direct pressure)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

< Formulation example  2> tablets (wet assembly)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.

< Formulation example  3> with powder Capsule

After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Capsules were prepared in 5 gelatin capsules.

< Formulation example  4> Injection

100 mg of active ingredient, mannitol 180 mg, 26 mg of Na ₂ HPO ₄ 12H ₂ O and 2974 mg of distilled water were mixed. The mixed solution was filled into an ampoule of transparent glass, filled under dissolution by dissolving the glass, and autoclaved at 120 ° C. for at least 15 minutes to prepare an injection.

Claims (13)

4-Amino-substituted 2-amino-5-methylimidazole derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

. (In the formula 1, R is

or

ego, Wherein R ¹ and R ² are each independently hydrogen, a halogen atom or an alkoxy group of C _{1 to} C ₅ , R ³ is hydrogen, an amino group or a C ₁ to C ₅ straight or branched alkyl group, R ⁴ is hydrogen, a halogen atom, a C ₁ to C ₅ straight or branched alkyl group, a C ₁ to C ₅ alkoxy group, a halogen substituted C ₁ to C ₅ straight or branched alkyl group, an amino group, a nitro group, a cyano group And it is any one selected from the group consisting of C ₅ ~ C ₈ aryl group) According to claim 1, R ¹ and R ² of Formula 1 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methoxy group and ethoxy group, R ³ is hydrogen, R ⁴ is a chlorine, bromine or cyano group Characterized by 4-position substituted 2-amino-5-methylimidazole derivative or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the 2-amino-5-methylimidazole derivative of Formula 1 is 1) 4- [5- (3-fluorophenyl) furan-2-yl] -2-amino-5-methylimidazole methanesulfonate; 2) 4- [5- (3,5-difluorophenyl) furan-2-yl] -2-amino-5-methylimidazole; 3) 4- [5- (2-methoxy-5-chlorophenyl) furan-2-yl] -2-amino-5-methylimidazole methanesulfonate; 4) 4- (4-bromobenzothiophen-2-yl) -2-amino-5-methylimidazole; And 5) 4- (4-cyanobenzothiophen-2-yl) -2-amino-5-methylimidazole methanesulfonate, any one selected from the group consisting of 2-amino-5-methylimidazole derivatives or pharmaceutically acceptable salts thereof. As shown in Scheme 1 below, the carboxylic acid compound (2) is reacted with 1-5 equivalents of N, O-dimethylhydroxylamine in the presence of a condensing agent in a reaction solvent to yield a methoxymethylamide (Weinreb amide) compound (3 ) (Step 1); Reacting the methoxymethylamide compound (3) prepared in step 1 with 1-10 equivalents of ethylmagnesium bromide under a reaction solvent to prepare a 1-position substituted propion compound (4) (step 2); Preparing a 2-bromopropanone compound (5) by α-bromination of the 1-position substituted propion compound (4) prepared in step 2; 2-Bromopropanone Compound (5) prepared in Step 3 was reacted with 1-10 equivalents of 1-acetylguanidine to 2- (N-acetyl) amino-5-methylimidazole having 4-position substituted. Preparing compound (6) (step 4); And Deacetylating the 4-position substituted 2- (N-acetyl) amino-5-methylimidazole compound (6) prepared in step 4 to prepare compound (1) (step 5) A method for preparing the 2-amino-5-methylimidazole derivative substituted with the 4-position of claim 1 Scheme 1

. (In Scheme 1, R is

or

ego, Wherein R ¹ and R ² are each independently hydrogen, a halogen atom or an alkoxy group of C _{1 to} C ₅ , R ³ is hydrogen, an amino group or a C ₁ to C ₅ straight or branched alkyl group, R ⁴ is hydrogen, a halogen atom, a C ₁ to C ₅ straight or branched alkyl group, a C ₁ to C ₅ alkoxy group, a halogen substituted C ₁ to C ₅ straight or branched alkyl group, an amino group, a nitro group, a cyano group And it is any one selected from the group consisting of C ₅ ~ C ₈ aryl group) As shown by Scheme 2 below, reacting the carboxylic acid ester compound (7) with ethylmagnesium bromide under a metal catalyst to prepare a 1-position substituted propion compound (4) (step a); Preparing a 2-bromopropanone compound (5) by α-bromination of the 1-position substituted propion compound (4) prepared in step a; 2-Bromopropanone Compound (5) prepared in step b was reacted with 1 to 10 equivalents of 1-acetylguanidine to 2- (N-acetyl) amino-5-methylimidazole having 4-position substituted. Preparing compound (6) (step c); And Deacetylating 4- (2-substituted 2- (N-acetyl) amino-5-methylimidazole compound (6) prepared in step b to prepare compound (1) (step d) A method for preparing the 2-amino-5-methylimidazole derivative substituted with the 4-position of claim 1 Scheme 2

. (In Scheme 2, Q is an ester group, R is

or

ego, Wherein R ¹ and R ² are each independently hydrogen, a halogen atom or an alkoxy group of C _{1 to} C ₅ , R ³ is hydrogen, an amino group or a C ₁ to C ₅ straight or branched alkyl group, R ⁴ is hydrogen, a halogen atom, a C ₁ to C ₅ straight or branched alkyl group, a C ₁ to C ₅ alkoxy group, a halogen substituted C ₁ to C ₅ straight or branched alkyl group, an amino group, a nitro group, a cyano group And it is any one selected from the group consisting of C ₅ ~ C ₈ aryl group) The method of claim 4, wherein the condensation agent of step 1 is N, N-carbonyldiimidazole, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (diisopropylcarbodiimide, DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) and diphenylphosphonylazide (DPPA) Method for producing a 4-position substituted 2-amino-5-methylimidazole derivative, characterized in that it is selected from the group. 6. The method of claim 5, wherein the metal catalyst of step a is used alone or in combination with palladium, copper, or silver. 7. Pharmaceutical composition for the prevention and treatment of ischemic heart disease containing 2-amino-5-methylimidazole derivative substituted with 4-position represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient . The pharmaceutical composition for preventing and treating ischemic heart disease of claim 8, wherein the ischemic heart disease is myocardial infarction, heart failure, or angina pectoris. The pharmaceutical composition for preventing and treating ischemic heart disease of claim 8, wherein the composition selectively inhibits NHE-1. A cardioprotective agent for a surgical or pharmacotherapy procedure containing a 2-amino-5-methylimidazole derivative substituted with a 4-position represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The cardiac protective agent according to claim 11, wherein the surgery is coronary artery bypass surgery or coronary percutaneous plastic surgery, and the drug therapy is reperfusion therapy using a thrombolytic agent. 12. The cardioprotective agent according to claim 11, wherein the composition selectively inhibits NHE-1.