KR100598133B1 - Aziridinecarbonylguanidine derivatives, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to aziridinecarbonylguanidine derivatives, a preparation method thereof and a pharmaceutical composition comprising the same. The aziridinecarbonylguanidine derivative of the present invention protects cardiomyocytes by enhancing cardiac function recovery and reducing myocardial infarction against ischemia / reperfusion injury through a potent inhibitory action on sodium / hydrogen exchange pathway NHE-1. It is useful for the prevention and treatment of ischemic heart disease such as myocardial infarction, arrhythmia and angina pectoris.It can also be used as a cardioprotective agent during reperfusion therapy such as surgical therapy such as coronary artery bypass surgery, coronary percutaneous plastic surgery, or drug therapy using thrombolytics. have.

Description

AZIRIDINECARBONYLGUANIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM}

The present invention relates to aziridinecarbonylguanidine derivatives, methods for their preparation, and pharmaceutical compositions comprising the same.

Myocardial ischemia is a phenomenon in which the blood supply to the heart is blocked and the oxygen supply of the myocardium is markedly short of the required amount. Such myocardial ischemia ultimately leads to irreversible damage of the myocardium, that is, necrosis of cells and tissues. . In the early stages of reversible damage, irreversible damage can be prevented by surgical treatments such as coronary percutaneous grafting and coronary artery bypass surgery, or by reperfusion therapy such as drug therapy using thrombolytics. It is known that reperfusion injury occurs at a high rate such as deterioration, arrhythmia and neurocognitive decline [Robert, M. (2003) Ann. Thorac. Surg. 75: S700-708. 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. Ischemia / reperfusion injury involves various physiological mechanisms such as metabolism, immune response and ionic constant change, oxygen free radicals, and so on. DJ. (1998) Prog. Cariovasc. Dis. 30: 381-402. In addition to the mechanism research, the development of therapeutic agents and surgical procedures by the new point of action has been actively conducted, but the technology for protecting cardiomyocytes from ischemia / reperfusion has not been commercialized clinically. 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.

Meanwhile, intracellular pH changes play an important role in the pathophysiology of essential hypertension, ischemic myocardial disease, dysfunction due to ischemia / reperfusion and cell death. Cells have a mechanism for regulating intracellular pH, which is activated to correct intracellular acidification by ischemia and reperfusion. One of the major ion channels present in cardiomyocytes and alkalizing acidified intracellular pH is the sodium-hydrogen exchanger (NHE), which is essential for normalizing intracellular pH. However, overloading of sodium can cause cell damage.

NHE is expressed in a variety of cell species as a membrane protein that plays an important role in regulating intracellular pH while maintaining neutrality electrostatically by sending one hydrogen ion out of the cell and bringing one Na ⁺ into the cell. To date, seven subtypes have been identified and NHE-1, the main subtype of cardiomyocytes, is known to play a major role in ischemia / reperfusion injury [Avkiran, M. et . al ., (2002) J. Am. Coll. Cardiol. 39 : 747-753. At normal physiological pH (≒ 7.2), NHE-1 hardly works. In the ischemic state lacking oxygen, energy production depends on glycolysis, which increases the concentration of hydrogen ions in the cell, which leads to acidification (pH 6.4), which activates NHE-1 with a proton sensor. The concentration of sodium ions in the cells increases because of the release of sodium ions into 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, under normal conditions, NCX (Na _⁺ / Ca ⁺⁺ exchanger), which is a sodium / calcium channel that exports calcium and imports sodium, works in the reverse direction to control elevated sodium concentrations, which releases sodium ions and imports calcium ions into intracellular calcium ions. The concentration of becomes high. Increasing intracellular calcium concentration activates enzymes such as protease, phospholipase, and endonuclease, which leads to the breakdown of various proteins, increased free radicals due to fat metabolism, and DNA modification. Will cause cell damage.

Therefore, by inhibiting the activity of NHE-1 to inhibit the increase of intracellular sodium ion concentration, it is possible to suppress the reverse operation of NCX, and to suppress the increase of intracellular calcium ion concentration to prevent cell damage by ischemia / reperfusion. have. Increased hydrogen ions are regulated by other ion channels, so that it is reported that intracellular acidification by inhibition of NHE-1 does not occur.

The diuretic pyrazine derivative amylolide was first known as an NHE inhibitor [Benos, DJ. (1982) AJ Physiol. 242 : C131]. Amylolide has an inhibitory effect on NHE-1, and rat extraction cardiac experiments have been shown to enhance the recovery of cardiac function after ischemia / reperfusion, but in addition to NHE-1, it inhibits NHE-2 and sodium channels. There was a problem as a protective agent. Subsequently, studies on drug development with selectivity for NHE-1 were carried out, and cariporide, a benzoylguanidine derivative having high selectivity for NHE-1, by Hoechst Marion Roussel (now Aventis). HOE-694) has been developed [Scholz, W. et . al ., (1993) Br. J. Pharmacol. 109 : 562]. Carriporide showed an excellent cardioprotective effect in animal models and clinically showed significant protective effect when administered to patients with coronary artery bypass surgery. Most of the NHE-1 inhibitors known to date are acylguanidine derivatives, and many drugs such as eniporide, zoniporide, SM-20220, and BMS-284640 are being developed as selective NHE-1 inhibitors. They 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 overloading sodium and calcium ions [Karmazyn, M ( 2002) Science & Medicine : 18-26 ].

Accordingly, the present inventors found that aziridinecarbonylguanidine derivatives have an excellent selective inhibitory effect on NHE-1 during efforts to develop a safe and effective drug that can slow the progression of cardiomyocyte damage caused by ischemia and alleviate reperfusion injury. Discovered and completed the present invention.

The present invention seeks to provide aziridinecarbonylguanidine derivatives and pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide a method for preparing aziridinecarbonylguanidine derivative.

It is another object of the present invention to provide a pharmaceutical composition comprising aziridinecarbonylguanidine derivatives and pharmaceutically acceptable salts thereof as an active ingredient.

The present invention provides a novel aziridinecarbonylguanidine derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention provides aziridinecarbonylguanidine derivatives represented by the following Formula 1 and pharmaceutically acceptable salts thereof.

(Wherein

R ¹ and R ² are each independently H, F, Cl, Br, I, NO ₂ , CF ₃ , CN, OCH ₃ , C ₁ -C ₅ linear or ground alkyl; R ³ is H, acetyl, benzoyl, C ₁ -C ₅ straight or branched alkyl.)

Preferred compounds among the aziridinecarbonylguanidine derivatives of Formula 1 are specifically as follows.

1) [3- (4-chlorophenyl) aziridine-2-carbonyl] guanidine

2) [3- (2,4-dichlorophenyl) aziridine-2-carbonyl] guanidine

3) [3- (3-nitrophenyl) aziridine-2-carbonyl] guanidine

4) [3- (3-bromo-4-fluorophenyl) aziridine-2-carbonyl] guanidine

5) [3- (3-trifluoromethyl-4-chlorophenyl) aziridine-2-carbonyl] guanidine

6) [1-acetyl-3- (4-chlorophenyl) aziridine-2-carbonyl] guanidine

7) [1-acetyl-3- (3-bromo-4-fluorophenyl) aziridine-2-carbonyl] guanidine

The aziridinecarbonylguanidine derivative represented by Formula 1 of the present invention includes not only a pharmaceutically acceptable salt thereof, but also all possible solvates and hydrates that can be prepared therefrom, and also includes all possible stereoisomers.

As the pharmaceutically acceptable salt of the compound of formula 1 , acid addition salts formed by pharmaceutically acceptable free acid are useful. Organic acids and inorganic acids 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, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid may be used as the organic acid. , Acetic acid, glycolic 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 methanesulfonic acid, hydrochloric acid or the like is used.

Addition salt according to the present invention is a conventional method, that is, after 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 aqueous acid solution of an inorganic acid It can be prepared by precipitation or crystallization. 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.

The present invention also provides a method for preparing the aziridinecarbonylguanidine derivative of the formula (1 ).

Specifically, the present invention provides a method for preparing the aziridine carbonyl guanidine compound of Formula 1 by reacting aziridine carboxylic acid derivative (II) with guanidine in the presence of a base or an excess of guanidine, as represented by Scheme 1 below . (Method 1).

(Wherein

R ¹ , R ² , and R ³ are as defined in Formula 1 ;

L is a leaving group which can be easily released by guanidine, and a C ₁ to C ₃ alkoxy group, a halide group, an alkanecarbonyloxy group, a hydroxy group, p-nitrophenoxy group, N-hydroxysuccinimide group, penta Fluorophenoxy group.)

Examples of the carboxylic acid derivative (II) include esters, acyl halides, and carboxylic acid anhydride derivatives. The ester derivative is preferably a general C ₁ ~ C ₃ alkyl ester (eg methyl ester, ethyl ester), but active ester derivative (eg p-nitrophenyl ester, N-hydroxysuccinimide ester, Pentafluorophenyl ester) can be used. Such carboxylic acid derivatives can be readily prepared from carboxylic acids by conventional known methods.

The invention the aziridine in the presence condensing a carboxylic acid of claim (condensing agent) is reacted with guanidine aziridine carbonyl guanidine compound of the compound (III) as described below, as another method for producing a compound of formula (1) shown in Scheme 2 It provides a method of manufacture (Manufacturing Method 2).

Wherein R ¹ , R ² , and R ³ are as defined in Formula 1 .

Hereinafter, the preparation method of the aziridinecarbonylguanidine derivative of the formula 1 according to the present invention will be described in detail.

(1) Manufacturing Method 1

If there is that needs to be protected by protecting groups are substituents that are affected by the reaction in the substituents R ¹ and R ² in the carboxylic acid derivative (II) in the production method of the compound of formula (1) shown by the reaction formula 1 is a reaction scheme and then protected with a suitable protecting group Compound 1 is prepared by removing the protecting group after reaction of 1 .

When the carboxylic acid derivative (II) of Scheme 1 is an alkyl ester or an active ester, compound I is prepared by reaction with quantitative or excess guanidine using an appropriate solvent.

The reaction solvent may be an alcohol solvent such as methanol, ethanol or isopropanol, an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dimethylformamide (DMF), or a solvent such as this. Use a mixed solvent of these. The reaction temperature is from room temperature to the boiling point of the solvent.

When the carboxylic acid derivative (II) of Scheme 1 is an acyl halide or an acid anhydride, compound (I) is prepared by reacting with an excess of guanidine in a suitable solvent or with guanidine in the presence of a base. Examples of the base that can be used include inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate or organic bases such as triethylamine and pyridine.

The reaction solvent may be an aromatic hydrocarbon solvent such as benzene or toluene, an ether solvent such as tetrahydrofuran, a halogenated hydrocarbon solvent such as dichloromethane or chloroform, or DMF, or a mixed solvent thereof. .

(2) Manufacturing Method 2

In the preparation of the compound of Formula 1 represented by Scheme 2 , if there are substituents affected by the reaction in the substituent R ¹ or R ² of the carboxylic acid (III), the reaction of Scheme 1 is performed by protecting with a suitable protecting group Compound I is then prepared by removing the protecting group.

Compound (I) is prepared by reacting the carboxylic acid compound in Scheme 2 with an equivalent or excess of guanidine in the presence of a condensing agent in a suitable reaction solvent. The reaction temperature is from room temperature to the boiling point of the solvent.

At this time, condensing agents that can be used are N, N-carbonyldiimidazole, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC)), diphenylphosphonylazide (DPPA) and the like.

Solvents that can be used include ether solvents such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene and toluene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, DMF or These are mixed solvents.

(3) Preparation of starting material

When the aziridinecarboxylic acid derivative (II) used in Scheme 1 is methyl or ethyl ester (L = OCH ₃ or OCH ₂ CH ₃ ) and R ³ is H, substituted cinnamic acid ester compound (IV) Was prepared as a starting material and reacted as in Scheme 3 below to prepare an aziridinecarboxylic acid ester compound (II ₁ ).

( Wherein R ¹ and R ² are as defined in formula 1 and R ^a is a methyl or ethyl group.)

Oxylane compound (V) is prepared by epoxidation of substituted cinnamic acid methyl or ethyl ester compound (IV). In this case, m-chloroperbenzoic acid, hydrogen peroxide, or monoperoxy phthalate magnesium salt may be used as the oxidizing agent, and dichloromethane or chloroform is preferably used as the solvent. Alternatively, an oxirane compound may be prepared using oxone as an oxidant in a mixed solvent of an acetone solvent and a saturated aqueous NaHCO ₃ solution.

In order to stereoselectively prepare the oxylane compound (V), a known method such as Sharpless epoxidation, Jacobsen epoxidation, or the like can be used.

The preparation of the azido alcohol compound in the oxylane compound (V) uses NaN ₃ . It is preferable to use 1 to 3 equivalents of NaN ₃ , and NH ₄ Cl can be used as an 1 to 3 equivalent adduct. As the reaction solvent, a mixed solvent of acetone and water is used, or a mixed solvent of alcohol solvent such as methanol, ethanol, propanol, ethylene glycol and water is used. The reaction temperature is selected between the boiling point of the solvent at room temperature.

The preparation of the aziridine compound (II ₁ ) from the azido alcohol compound (VI) uses 1 to 3 equivalents of triphenylphosphine (PPh ₃ ). The reaction solvent is selected from acetonitrile, benzene, toluene, ether and the like, and the reaction temperature is from room temperature to the boiling point of the solvent.

When the aziridinecarboxylic acid derivative (II) used in Scheme 1 is methyl or ethyl ester (L = OCH ₃ or OCH ₂ CH ₃ ), and R ³ is acetyl, benzoyl, C ₁ to C ₅ linear or ground alkyl, It is prepared from the compound (II ₁ ) prepared in Scheme 3 as in Scheme 4 below.

Compound (II ₁ ) is prepared by alkylation using an alkyl halide using conventionally known methods or by conventional acylation using an acyl halide or an acid anhydride.

( Wherein R ¹ and R ² are as defined in Formula 1 , R ^a is as defined in Scheme 3 , and R ³ is excluded from H in the definition of Formula 1).

Carboxylic acid compound (III), which is a starting material of Scheme 2 , may be prepared by hydrolyzing ester compound (II ₁ ) or (II ₂ ) prepared in Scheme 3 and Scheme 4 by using a base.

Compounds other than methyl or ethyl ester compounds in the starting material (II) of Scheme 1 may be prepared by the same method as in Scheme 3 or Scheme 4 or prepared by the conventional method from the carboxylic acid compound (III).

In addition, the present invention is a pharmaceutical composition for the prevention and treatment of ischemic heart disease, comprising aziridinecarbonylguanidine derivative represented by the formula (1 ) and a pharmaceutically acceptable salt thereof as an active ingredient, and for protecting the heart used in reperfusion therapy It provides a pharmaceutical composition.

The derivatives and salts thereof of the present invention have a potent inhibitory effect on NHE-1 in cells expressing human NHE-1, promote recovery of myocardial damage by ischemia / reperfusion in the isolated ischemic heart model, and in vivo ischemia. In animal models, myocardial infarction was significantly reduced in size and showed excellent cardioprotective effect. Therefore, it can be used as a prophylactic and therapeutic agent for ischemic heart disease such as myocardial infarction, heart failure, angina pectoris, and can be used as a cardioprotective agent during reperfusion therapy procedures such as coronary artery bypass surgery, coronary percutaneous plastic surgery, or drug therapy using thrombolytic drugs. .

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, pills, powders, granules, capsules, troches and the like, which solid preparations contain at least one excipient such as starch, calcium carbonate, water, or the like. Prepared with a mixture of 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 may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. 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 the judgment of a doctor or a pharmacist.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are illustrative of the present invention and the contents of the present invention are not limited by the examples.

In the present invention, the molecular structure was confirmed by comparing infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement and elemental analysis calculations and actual measurements of representative compounds.

Preparation Example 1 Preparation of 2,3-Epoxy-3-phenylpropionate Compound

Methyl 2,3-epoxy-3- (4-chlorophenyl) propionate

1.28 g (6.48 mmol) of 4-chlorocinnamic acid methyl ester was dissolved in 30 mL of dichloromethane, and 30 mL of saturated NaHCO ₃ aqueous solution was added thereto. 3.2 g (13 mmol) of 70% m-chloroperbenzoic acid was slowly added thereto, followed by stirring at room temperature for 24 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane and the organic layer was dehydrated with anhydrous sodium sulfate. Purification by silica gel column chromatography (hexane: ethyl acetate = 10: 1) gave 700 mg (yield 51%) of the compound in oil form.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.46 (d, 1H), 3.83 (s, 3H), 4.08 (d, 1H), 7.22 (d, 2H), 7.35 (d, 2H)

Methyl 2,3-epoxy-3- (2,4-dichlorophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.37 (d, 1H), 3.86 (s, 3H), 4.39 (d, 1H), 7.17 (d, 1H), 7.27 (m, 1H), 7.41 (d, 1H)

Methyl 2,3-epoxy-3- (3-nitrophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.52 (d, 1H), 3.86 (s, 3H), 4.23 (d, 1H), 7.55 (t, 1H), 7.64 (d, 1H), 8.18 (m, 2H)

Ethyl 2,3-epoxy-3- (3-bromo-4-fluorophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (t, 3H), 3.44 (d, 1H), 4.06 (d, 1H), 4.27 (m, 2H), 7.12 (t, 2H), 7.22 (m, 1H), 7.48 (m, 1H)

Ethyl 2,3-epoxy-3- (3-trifluoromethyl-4-chlorophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (t, 3H), 3.45 (d, 1H), 4.13 (d, 1H), 4.32 (m, 2H), 7.40 (dd, 1H), 7.51 (d, 1H), 7.62 (d, 1H)

Preparation Example 2 Preparation of 3-azido-2-hydroxy-3-phenylpropionate compound

Methyl 3-azido-2-hydroxy-3- (4-chlorophenyl) propionate

700 mg (3.29 mmol) of methyl 2,3-epoxy-3- (4-chlorophenyl) propionate was dissolved in 17 ml of 80% ethanol, followed by 321 mg (4.94 mmol) of NaN ₃ and 264 mg (4.94 mmol) of NH ₄ Cl. ) Was heated to reflux for 1 hour. The reaction mixture was cooled and then extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 531 mg (yield 63%) of the compound in oil form.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.00 (d, 1H), 3.72 (s, 3H), 4.53 (q, 1H), 4.86 (d, 1H), 7.26 (d, 2H), 7.35 (d, 2H)

Methyl 3-azido-2-hydroxy-3- (2,4-dichlorophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.34 (br, 1H), 3.70 (s, 3H), 4.58 (d, 1H), 5.32 (d, 1H), 7.28 (dd, 1H), 7.43 (m, 1H)

Methyl 3-azido-2-hydroxy-3- (3-nitrophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.13 (d, 1H), 3.76 (s, 3H), 4.60 (t, 1H), 5.02 (d, 1H), 7.58 (t, 1H), 7.71 (d, 1H), 8.21 (d, 2H)

Ethyl 3-azido-2-hydroxy-3- (3-bromo-4-fluorophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.23 (t, 3H), 3.09 (d, 1H), 4.23 (m, 2H), 4.50 (m, 1H), 4.85 (d, 1H), 7.12 (t, 1H), 7.30 (m, 1H), 7.57 (m, 1H)

Ethyl 3-azido-2-hydroxy-3- (3-trifluoromethyl-4-chlorophenyl) propionate

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (t, 3H), 3.10 (d, 1H), 4.13 (q, 2H), 4.50 (m, 1H), 4.85 (d, 1H), 7.40 (dd, 1H), 7.49 (d, 1H), 7.58 (d, 1H)

Preparation Example 3 Preparation of 3-phenylaziridine-2-carboxylic Acid Ester Compound

3- (4-chlorophenyl) aziridine-2-carboxylic acid methyl ester

530 mg (2.07 mmol) of methyl 3-azido-2-hydroxy-3- (4-chlorophenyl) propionate was dissolved in 8 ml of acetonitrile and then 651 mg (2.48 mmol) of triphenyl phosphine. The mixture was heated to reflux for 24 hours. The reaction mixture was cooled and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 193 mg (yield 44%) of the compound in oil form.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60 (br, NH), 2.54 (s, 1H), 3.24 (d, 1H), 3.81 (s, 3H), 7.30 (m, 4H)

3- (2,4-Dichlorophenyl) aziridine-2-carboxylic acid methyl ester

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.87 (t, 1H), 2.45 (dd, 1H), 3.49 (dd, 1H), 3.84 (s, 3H), 7.36 (m, 3H)

3- (3-nitrophenyl) aziridine-2-carboxylic acid methyl ester

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.03 (t, 1H), 2.58 (dd, 1H), 3.36 (dd, 1H), 3.84 (s, 3H), 7.50 (t, 1H), 7.62 (d, 1H), 8.12 (m, 2H)

3- (3-Bromo-4-fluorophenyl) aziridine-2-carboxylic acid ethyl ester

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (t, 3H), 1.91 (t, 1H), 2.49 (dd, 1H), 3.20 (dd, 1H), 4.26 (m, 2H), 7.06 (t, 1H), 7.21 (m, 1H), 7.48 (dd, 1H)

3- (3-Trifluoromethyl-4-chlorophenyl) aziridine-2-carboxylic acid ethyl ester

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (t, 3H), 1.96 (dd, 1H), 2.51 (dd, 1H), 3.28 (dd, 1H), 4.27 (q, 2H), 7.38 to 7.47 ( m, 2H), 7.62 (s, 1H)

1-acetyl-3- (4-chlorophenyl) aziridine-2-carboxylic acid methyl ester

100 mg (0.47 mmol) of 3- (4-chlorophenyl) aziridine-2-carboxylic acid methyl ester were dissolved in 3 mL of dichloromethane, and 0.13 mL (0.94 mmol) of triethylamine was added thereto. 0.05 ml (0.71 mmol) of acetyl chloride was slowly added thereto at 0 ° C., and the temperature was raised to room temperature, followed by stirring for 30 minutes. After the reaction, the mixture was extracted with dichloromethane and the organic layer was dehydrated with anhydrous sodium sulfate and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 75 mg (yield 63%) of the compound in oil form.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.14 (s, 3H), 3.16 (d, 1H), 3.81 (d, 4H), 7.23 (d, 2H), 7.32 (d, 2H)

1-acetyl-3- (3-bromo-4-fluorophenyl) aziridine-2-carboxylic acid ethyl ester

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (t, 3H), 2.16 (s, 3H), 3.12 (dd, 1H), 3.79 (dd, 1H), 4.27 (q, 2H), 7.11 (t, 1H), 7.22 (m, 1H), 7.50 (dd, 1H)

Example 1 Preparation of [3- (4-chlorophenyl) aziridine-2-carbonyl] guanidine

150 mg (0.71 mmol) of 3- (4-chlorophenyl) aziridine-2-carboxylic acid methyl ester was dissolved in 5 ml of N, N-dimethylformamide, followed by 1.8 ml of 2.0 M guanidine methanol solution. Stirred. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and purified by silica gel column chromatography (20% MeOH / CH ₂ Cl ₂ ) to give 148 mg (87% yield) of the compound in the form of a white solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.06 (m, 1H), 2.22 (m, 1H), 2.96 (m, 1H), 6.70 (br, 2H), 7.32 (m, 4H), 7.80 (br) , 2H)

MASS: 238 (M ⁺ -1), 223 (M ⁺ -NH ₂ )

Example 2 Preparation of [3- (2,4-Dichlorophenyl) aziridine-2-carbonyl] guanidine

Dissolve 85 mg (0.35 mmol) of 3- (2,4-dichlorophenyl) aziridine-2-carboxylic acid methyl ester in 3 ml of N, N-dimethylformamide, and add 0.35 ml of 2.0 M guanidine methanol solution at room temperature for 3 hours. Stirred. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 60 mg (yield 63%) of the compound in the form of a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 2.34 (d, 1H), 3.30 (d, 1H), 7.26 (m, 2H), 7.39 (s, 1H)

MASS: 272 (M ⁺ -1)

Example 3 Preparation of [3- (3-nitrophenyl) aziridine-2-carbonyl] guanidine

Using 60 mg (0.27 mmol) of 3- (3-nitrophenyl) aziridine-2-carboxylic acid methyl ester in the same manner as in Example 2, 27 mg (yield 40%) of the title compound was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.24 (m, 2H), 3.16 (m, 1H), 6.79 (br, 1H), 7.61 (t, 1H), 7.73 (d, 1H), 7.96 (d , 2H)

MASS: 233 (M ⁺ -NH ₂ )

Example 4 Preparation of [3- (3-bromo-4-fluorophenyl) aziridine-2-carbonyl] guanidine

Reaction was carried out in the same manner as in Example 1 using 122 mg (0.42 mmol) of 3- (3-bromo-4-fluorophenyl) aziridine-2-carboxylic acid ethyl ester to yield 119 mg of the target compound (yield 95%). Got.

¹ H NMR (300MHz, DMSO- d ₆ ) δ 2.35 (d, 1H), 2.76 (s, 1H), 2.89 (s, 1H), 3.00 (d, 1H), 7.01 (m, 1H), 7.18 (m , 1H), 7.21 (dd, 1H)

MASS: 301 (M ⁺ ), 285 (M ⁺ -NH ₂ )

Example 5 Preparation of [3- (3-trifluoromethyl-4-chlorophenyl) aziridine-2-carbonyl] guanidine

100 mg (0.34 mmol) of 3- (3-trifluoromethyl-4-chlorophenyl) aziridine-2-carboxylic acid ethyl ester were reacted in the same manner as in Example 1 to obtain 102 mg of the target compound (yield 98%). )

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.21 (d, 1H), 2.25 (d, 1H), 3.12 (d, 1H), 6.73 (br-s, 2H), 7.55 to 7.75 (m, 2H) , 7.76 (s, 1 H)

MS ( m / z ) M ⁺ = 305, 287, 250, 208

Example 6 Preparation of [1-acetyl-3- (4-chlorophenyl) aziridine-2-carbonyl] guanidine

Reaction was carried out in the same manner as in Example 1 using 70 mg (0.28 mmol) of 1-acetyl-3- (4-chlorophenyl) aziridine-2-carboxylic acid methyl ester to obtain 63 mg (yield 80%) of the title compound. .

¹ H NMR (300 MHz, CD ₃ OD) δ 2.01 (s, 3H), 3.02 (d, 1H), 3.59 (d, 1H), 7.22 (m, 4H)

MS ( m / z ) M ⁺ = 281,265

Example 7 Preparation of [1-acetyl-3- (3-bromo-4-fluorophenyl) aziridine-2-carbonyl] guanidine

70 mg (0.21 mmol) of 1-acetyl-3- (3-bromo-4-fluorophenyl) aziridine-2-carboxylic acid ethyl ester was reacted in the same manner as in Example 1 to obtain 50 mg of the target compound (yield) 70%).

¹ H NMR (300 MHz, CD ₃ OD) δ 2.13 (s, 3H), 3.14 (d, 1H), 3.71 (d, 1H), 7.18 (t, 1H), 7.35 (m, 1H), 7.57 (dd, 1H)

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

Experimental Example 1 NHE-1 Inhibitory Effect

In order to determine the NHE-1 inhibitory effect of the compound of Formula 1 according to the present invention at the cellular stage, the following experiment was performed.

Human NHE-1 was expressed in PS120 cells derived from CCL39. DMEM (100X solution) and 1% L-glutamine (200 mM aqueous solution) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin (100 mM solution) The cells were cultured in Dulbecco's modified Eagle's medium). Trypsin treated PS120 / NHE-1 cells grown about 80-90% in a 100 mm diameter dish, then once with PBS (phosphate buffer saline), Na-free buffer (38.2 mM) Choline chloride, 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, at pH 7.4) It was. 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). After incubation for 30 minutes in a 37 ℃ CO ₂ incubator. In order to remove NH ₄ Cl and simultaneously wash the remaining BCECF-AM, 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. 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 in a 96-well plate, 20 Dispense 10 μl of mM HEPES, at pH 7.4) and DMSO or DMSO-dissolved compound (0.03-10 uM), mix well, and finally add 10 μl of PS120 / NHE-1 cells with intracellular acidification. Stirred. 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 the High-K ⁺ / nigericin technique. Cells induced intracellular acidification with NH ₄ Cl prepulse will restore intracellular acidification back to normal by the operation of NHE-1, with a concentration of compounds that inhibit the recovery of intracellular acidification by 50%. Was determined (IC ₅₀ value) to determine the inhibitory effect on NHE-1. Experiments were carried out using cariporide as a control.

The experimental results are shown in Table 1 below.

compound IC ₅₀ (μM) Cariporide 1.0 Example 1 13.2 Example 2 6.9 Example 3 5.8 Example 4 1.1 Example 5 2.4 Example 6 > 30 Example 7 2.1

As shown in Table 1 , the control material, Carporide, showed an IC ₅₀ of 1.0 μM, showing an excellent inhibitory effect on NHE-1. The compounds of Examples 2, 4, 5 and 7 showed IC ₅₀ of 10 μM or less, which showed a significant NHE-1 inhibitory effect. In particular, the compounds of Examples 4, 5, and 7 showed IC ₅₀ of 1.1, 2.4, and 2.1 μM, respectively, and were excellent in inhibiting NHE-1.

Therefore, the compound of formula 1 according to the present invention exhibits a strong inhibitory effect on NHE-1, and can be used as a protective agent against ischemia / reperfusion injury through NHE-1 inhibition.

Experimental Example 2 Cardioprotective Effect on Extracted Ischemic Heart in Rats

In order to find out whether the compounds of Formula 1 according to the present invention exhibit a cardioprotective effect by promoting the recovery of the function of the ischemic heart in the extraction heart, the following extraction heart experiment was conducted in rats.

Male rats (300-450 g, Korea Research Institute of Chemical Technology) were anesthetized by intraperitoneal injection of 100 mg / kg of sodium pentobarbital, and then heparin 1000 U / kg was administered intravenously and the heart was extracted. It was. Specifically, a cannula (PE 240) is inserted into the trachea, and artificial respiration is performed using a rodent ventilator. In this state, the aortic cannula is inserted into the aorta, and the heart is extracted under retrograde perfusion, and the Langendorf instrument (Modified Krebs-Henseleit bicarbonate buffer; composition at 37 ° C. saturated with 95% O ₂ /5% CO ₂ under constant pressure perfusion (85 mmHg) after quickly hanging up in Langendorff Apparatus and removing unnecessary tissue attached to the heart <mM / L>: 116 NaCl, 4.7 KCl, 1.1 MgSO ₄ , 1.17 KH ₂ PO ₄ , 24.9 NaHCO ₃ , 2.52 CaCl ₂ , 8.32 glucose, 2.0 pyruvate). A metal cannula connected with a rubber balloon (latex balloon) filled with a mixture of ethanol and distilled water (1: 1 vol / vol) is inserted through the pulmonary vein into the left ventricle and the left ventricular pressure delivered to the balloon is equilibrated through a pressure transducer. (isovolumetric) magnifier (Plugsys bridge amplifier) was processed and recorded on a recorder (Linearcorder mark 8 WR 3500). After the heart had stabilized for 15 minutes, left ventricular enddiastolic pressure (LVEDP) was 5 mmHg and the balloon volume was maintained for the entire experimental period.

Baseline heart contractile function and heart rate (HR) were measured. Left ventricular developed pressure (LVDP), an indicator of cardiac contractile function, is the difference between left ventricular peak systolic pressure (LVSP) and left ventricular end diastolic pressure (LVEDP). Calculated. Unlike the in vivo heart, the heart rate-pressure product (Double product RPP) is an important indicator of cardiac performance indirectly in Langendorff heart, where cardiac output cannot be measured. rate-pressure product) was calculated by multiplying the heart rate (HR) by the left ventricular development pressure (LVDP). The temperature of the heart is 95% O ₂ /5% CO ₂ It was kept constant by soaking in a continuously supplied physiological fluid at 37 ℃. After stabilization, the perfusion fluid is perfused for 10 minutes to the heart, the heart contraction function and heart rate (HR, heart rate) are measured, and the supply of perfusion fluid is completely blocked to induce global ischemia for 30 minutes. It was. After perfusion for 30 minutes, each indicator (LVDP, HR, LVEDP) was measured again. At this time, the perfusion solution was prepared by dissolving the compound prepared in Example in DMSO (dimethylsulfoxide) at a predetermined concentration and diluting it with HBS buffer. At this time, the concentration of DMSO was 0.04%, and 0.04% of the negative control group. HBS buffer containing DMSO was used as perfusate. The experimental results are shown in Table 2 below.

compound Concentration (μM) LVDP ¹ × HR ² (%) LVEDP ³ (mmHg) Negative Control - 15.5 55.3 Example 2 10 5.3 33.7 Example 3 10 17.1 48.0 Example 4 10 45.9 29.0 Example 5 10 35.8 52.7 Example 7 10 39.2 35.0 ¹ ; left ventricular developing pressure ² ; heart rate ³ ; left vetricualr end diastolic pressure

As shown in Table 2, in the negative control group, the value after reperfusion of the left ventricular development pressure (LVDP) and the heart rate (LVDP × HR) reflecting the contractile function of the heart was 15.5% before the drug administration. As a result, the cardiac contractile function sharply decreased. When ATP energy is insufficient due to ischemia / reperfusion, myocardial contracture occurs and left ventricular diastolic pressure rises, so reperfusion left ventricular end pressure, another indicator of cardiac protection, is 5 mmHg. Then increased significantly to 55.3 mmHg.

In the group administered with 10 μM of Examples 4, 5, and 7 compounds, the cardiac contractile function (LVDP x HR) after reperfusion was 45.9, 35.8, and 39.2% before ischemia induction, respectively, and was significantly higher than the negative control group. Left ventricular diastolic pressure (LVEDP) of the 7 compound-treated group was 29.0 mmHg and 35.0 mmHg, which was significantly lower than that of the negative control group, indicating a protective effect of the ischemic heart.

As such, the compound of Formula 1 according to the present invention has an excellent protective effect on the ischemic heart by promoting recovery of heart function by ischemia / reperfusion injury, and thus may be used as an agent for preventing and treating diseases related to ischemic cardiovascular disease.

Experimental Example 3 In Vivo of Rats in vivo) Cardioprotection against ischemic heart model

In order to find out whether the compound of Formula 1 according to the present invention has a protective effect on the ischemic heart in vivo, the anti-ischemic effects on rats were investigated through the following experiment.

Male rats (350-450 g, Korea Research Institute of Chemistry) were anesthetized by intraperitoneal injection of pentobarbital at 75 mg / kg. After tracheotomy, artificial respiration was performed at a stroke volume of 10 ml / kg and 60 heart rate per minute. Cannula was inserted into the femoral vein and the femoral artery and used for drug administration and blood pressure measurement, respectively. On the other hand, in the ischemic myocardial injury model, the body temperature has a significant effect on the results, so that the temperature of the rat is constant at 37 ° C. by using a probe inserted into the rectum and a homeothermic blanket control unit. Maintained. Afterwards, mean arterial blood pressure and heart rate (HR) were continuously measured in the rat. Statham P23XL pressure transducer (Statham P23XL pressure transducer, Grass Ins., MA, USA) was used to measure blood pressure, and ECG / RATE Coupler, Hugo Sachs Electronic (Germany) was used to measure heart rate. . In addition, all changes were recorded continuously using a Graphtec Linearcorder WR 3310, Hugo Sachs Electronic.

The left coronary artery was occluded by the method of Selye H. as follows. In other words, a part of the chest of the rat is opened by left thoracotomy, the pressure is applied to the right chest of the rat anesthetized with the left hand of the anesthesia, and the heart is pushed outwards to lightly press the heart with the thumb and index finger of the left hand. Fixed. After that, the surgeon (5-0 silk ligature) attached suture needle carefully lifted the part containing the left anterior desending coronary artery (LAD) and then quickly opened the heart to the thoracic repositioned in the cavity and both ends of the surgeon were positioned externally. Both ends of the surgeon were stabilized by passing through a PE tube (PE100, 2.5 cm) and left for 20 minutes. Thereafter, 2 mL of the compound prepared in Example was dissolved in 50% PEG 400 through a cannula inserted into the femoral vein, and left for 30 minutes to sufficiently exhibit the effect of the drug. The negative control group received only 50% PEG 400.

Afterwards, the PE tube inserted into the thread was pushed into the heart, and the end of the tube was pulled with hemostatic tweezers, and the PE tube was pressed vertically to the coronary artery. Then, the coronary artery was ligated for 45 minutes. Posterior hemostatic tweezers was removed and reperfused for 90 minutes.

The coronary artery was religated by this method and 2 ml of 1% Evans blue solution was administered intravenously. Pentobarbital was then intravenously administered to slaughter rats and the heart was removed to remove the right ventricle and both atria. The left ventricle was horizontally cut into 5-6 slices from the apex and the weight of each section was measured. The surface of each cardiac segment is input to a computer using a high-scope, compact micro vision system, and an image pro plus, from which the blue Areas of normal blood flow tissue colored and uncolored areas were measured. The area ratio of the uncolored area to the total area of each section was calculated and multiplied by the weight of each section to calculate the area at risk (AAR). The AARs for each of the sections thus obtained were summed and divided by the total left ventricular weight, and the AAR (%) was calculated by the following equation .

AAR (%) = [(sum of AAR for each section) / (total left ventricular weight)] × 100

In addition, the heart sections were incubated for 15 minutes in 1% 2,3,5-triphenyltetrazolium chloride phosphate buffer solution (2,3,5-triphenyltetrazolium chloride (TTC) phosphate buffer, 37 ° C, pH 7.4) and 10% It was fixed in formalin solution for 20 to 24 hours. In this way, 2,3,5-triphenyltetrazolium chloride is reduced to formazan dye by dehydrogenase and cofactor NADH of myocardium. (brick-red color). On the other hand, since there are no dehydrogenases and cofactors in the infarcts of tissues, 2,3,5-triphenyltetrazolium chloride is not reduced and thus does not have a red brick color.

As described above, the normal area and the infarct zone of each section were determined by the same method as in the AAR measurement, depending on whether the tissue site was stained with 2,3,5-triphenyltetrazolium chloride . The infarct regions for each section thus obtained were summed and divided by the total AAR weight or the total left ventricular weight, and IZ (%) was obtained by the following equation (2 ). In this experimental model, it was determined that the lower the IZ (%), the smaller the infarct area, the stronger the anti-ischemic effect of the test substance. The results are shown in Table 3 below.

IZ (%) = [(sum of infarct area for each section) / (weight of total left ventricle or total AAR)] × 100

compound Myocardial infarction rate (IZ / AAR ¹ ,%) 0.3 mg / kg Negative Control 58.6 Example 3 45.9 Example 4 49.2 Example 5 44.1 Example 7 45.7 ¹ ; IZ / AAR (infacrt zone / area at risk)

As shown in Table 3 , the compound of the present invention showed a significantly reduced myocardial infarction rate in the risk area in vivo in ischemic myocardial injury model using rats. Specifically, the solvent-administered group (negative control group) had a myocardial infarction rate (IZ / AAR,%) of 58.6% for the dangerous area (AAR), indicating that the myocardial damage caused by ischemia is very severe. Examples 3, 5, and 7 The compounds of showed 45.9, 44.1 and 45.7% infarction, respectively, and myocardial infarction was reduced by more than 20% compared to the control group, which showed significant ischemic heart protection effect. As described above, the compounds of the present invention have excellent protection against ischemic heart by reducing myocardial infarction rate in the ischemic heart model in vivo, and thus can be used as an agent for preventing and treating ischemic heart disease such as myocardial infarction, arrhythmia and angina pectoris. It can be used as a cardioprotective agent during cardiac procedures such as coronary percutaneous plastic surgery, or during thrombolytic procedures.

Experimental Example 4 Acute Toxicity in Rats

In order to determine the acute toxicity of the compound of Formula 1 of the present invention, the following experiment was performed.

Acute toxicity test was performed using SPF SD rats at 6 weeks of age. Two animals per group were suspended orally administered at a dose of 10 mg / kg / 15 ml, each of the compounds obtained in Examples 1-7, suspended in 0.5% methylcellulose solution.

After administration of the test substance, mortality, clinical symptoms, and changes in body weight were examined. Hematological and hematological examinations were performed. Necropsy was performed to visually observe abdominal and thoracic organ abnormalities.

As a result, all animals treated with test substance showed no clinical symptoms and no dead animals, and no toxic changes were observed in weight change, blood test, blood biochemical test, autopsy findings. As a result, all of the tested compounds did not show toxic changes up to 10 mg / kg in rats, and the minimum oral dose (LD ₅₀ ) was determined to be a safe substance of 100 mg / kg or more.

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.

Preparation Example 1 Tablet (Direct Pressurization)

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.

Preparation Example 2 Tablet (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.

Preparation Example 3 Powder and 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 treated with a hard No. Filled in 5 gelatin capsules.

<Example 4> Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

As described above, the aziridinecarbonylguanidine derivative of Formula 1 according to the present invention exhibits a strong inhibitory effect on NHE-1, enhances the recovery of myocardial damage by ischemia / reperfusion in the isolated ischemic heart model, and in vivo Significantly reduces the size of myocardial infarction in the ischemic animal model, showing excellent cardioprotective effect Therefore, the pharmaceutical composition of the present invention can be used as a prophylactic and therapeutic agent for ischemic heart disease such as myocardial infarction, arrhythmia, angina pectoris and as a cardioprotective agent for reperfusion therapy such as coronary artery bypass surgery, coronary percutaneous plastic surgery or thrombolytic therapy. Can be used.

Claims (10)

Aziridinecarbonylguanidine derivative represented by the following formula (1 ) and a pharmaceutically acceptable salt thereof. <Formula 1>

(Wherein R ¹ and R ² are each independently H, F, Cl, Br, NO ₂ or CF ₃ , and R ³ is H or acetyl.) According to claim 1, wherein the compound of Formula 1 1) [3- (4-chlorophenyl) aziridine-2-carbonyl] guanidine 2) [3- (2,4-dichlorophenyl) aziridine-2-carbonyl] guanidine 3) [3- (3-nitrophenyl) aziridine-2-carbonyl] guanidine 4) [3- (3-bromo-4-fluorophenyl) aziridine-2-carbonyl] guanidine 5) [3- (3-trifluoromethyl-4-chlorophenyl) aziridine-2-carbonyl] guanidine 6) [1-acetyl-3- (4-chlorophenyl) aziridine-2-carbonyl] guanidine 7) Aziridinecarbonylguanidine derivatives and pharmaceutically acceptable salts thereof, which are [1-acetyl-3- (3-bromo-4-fluorophenyl) aziridine-2-carbonyl] guanidine. A method for producing an aziridinecarbonylguanidine compound represented by the following Scheme 1 , wherein the carboxylic acid derivative compound (II) is reacted with guanidine in the presence of a base or with an excess guanidine to obtain compound (I). <Scheme 1>

(Wherein R ¹ , R ² , and R ³ are as defined in Formula 1, and L is a leaving group that can be easily released by guanidine.) The leaving group L is a C ₁ to C ₃ alkoxy group, a halide group, an alkanecarbonyloxy group, a hydroxy group, p-nitrophenoxy group, N-hydroxysuccinimide group, pentafluoro A method for producing an aziridine carbonylguanidine compound, characterized in that selected from the group consisting of phenoxy group. delete delete A pharmaceutical composition for the prevention and treatment of ischemic heart disease, comprising the aziridinecarbonylguanidine derivative of claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient. 8. The pharmaceutical composition of claim 7, wherein the ischemic heart disease is myocardial infarction, arrhythmia or angina pectoris. Claim 1 aziridine carbonyl guanidine derivatives and a pharmaceutical composition for the protection of ischemia / reperfusion injury during reperfusion therapy comprising a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 9, wherein the reperfusion therapy is a surgical therapy of coronary artery bypass surgery or coronary percutaneous plastic surgery, or a drug therapy using thrombolytics.