KR100564354B1 - Alkoxybenzylcyanoguanidine derivatives, method for preparation thereof and pharmaceutical compositions containing the said derivatives - Google Patents

Abstract

The present invention relates to an alkoxybenzylcyanoguanidine derivative represented by the following formula (1), a method for preparing the same, and a pharmaceutical composition containing the active ingredient, wherein the alkoxybenzylcyanoguanidine derivative or a pharmaceutically acceptable salt thereof of the present invention The pharmaceutical composition containing as an active ingredient can be usefully used for the prevention or treatment of coronary vessel restenosis showing high recurrence rate after surgical procedures for angina pectoris, myocardial infarction and atherosclerosis due to coronary vessel stenosis.

Formula 1

(Wherein R ¹ , R ² , R ³ and n are as described in the specification)

Alkoxybenzylcyanoguanidine derivatives, coronary vessel restenosis

Description

Alkoxybenzyl cyanoguanidine derivatives, a method for preparing the same, and a pharmaceutical composition comprising the same.

The present invention relates to alkoxybenzylcyanoguanidine derivatives, methods for their preparation and pharmaceutical compositions comprising them. More specifically, the pharmaceutical composition containing the alkoxybenzylcyanoguanidine derivative of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient shows an excellent effect of inhibiting vascular restenosis.

Angina, myocardial infarction and atherosclerosis, which are representative diseases of coronary vascular stenosis, are caused by an increase in plaque in the intima of blood vessels and eventually narrowing of the vascular diameter. Since the introduction of percutaneous transluminal coronary angioplasty in 1977, the success rate has been more than 95%, with more than 15 million procedures annually worldwide. Coronary angioplasty is a surgical procedure for coronary stenosis. It is the most widely used method [Blindt, R., Cardiovascular Res . 2002 , 54 , 630.

However, despite the continuous improvement of technical equipment and medical technology, 20-50% of patients who underwent coronary angioplasty are known to develop restenosis that narrows the endoscopic diameter within 6 months after the procedure. Bult, H., Tips 2000 , 21 , 279].

The cause of restenosis has not been elucidated. However, the causes of the restenosis are known to be caused by a combination of the formation of blood clots caused by intima damage, migration and proliferation of coronary smooth muscle cells, and remodeling of arterial vessel walls.

Therefore, the problem of restenosis after the procedure is accompanied by damage to the intima causing the restenosis by using a method of expanding the endoscopic diameter by scraping the arteries during the surgical procedure (percutaneous coronary interventions), It has been reported that the treatment of restenosis provides the cause of recurrence.

For example, balloon surgery, a surgical procedure for atherosclerotic deposits, is a method of scraping arteries to widen the vessel diameter. At this time, the damaged intima is exposed to the endothelial layer and the subcutaneous layer, causing blood clots and inflammation. The initial reaction consists of protein and platelet layers followed by mononuclear inflammatory cells. After several weeks, smooth muscle cell proliferation, migration and matrix are deposited to form neointima and proceed to the growth of intima.

Another method of surgery is to insert a stent into the coronary vessel, in addition to balloon surgery. However, stents cause vascular trauma and the duration of cell proliferation and the proportion of monocytes is greater than balloon damage. Balloon plastic surgery stimulates smooth muscle cells by transient stimulation of the vessel wall, and regulates gene expression that amplifies the proliferative phase of vascular damage repair, whereas stent implantation provides continuous mechanical stimulation that can lead to increased blood vessel damage resulting in chronic inflammation. Orford, JL, Am. J. Cardiol . 2000 , 86 (suppl), 6H]. Therefore, about 30% of patients with stenting are observed with restenosis within 6 months after the procedure, and stent implantation still suffers from problems [Blindt, R., Cardiovascular Res . 2002 , 54 , 630.

Arterial remodeling is a technique that changes the size of the artery, which may be beneficial by compensating for reduced lumens due to thickening of the intima as the artery expands, but due to collagen formed of myofibroblasts, many wound tissues around it can expand the artery. It may not be possible or rather the size of the artery may be reduced after injury. Animal and clinical studies show that restenosis is more dependent on chronic contraction of blood vessels than enlargement of intima (Bult, H., Tips 2000 , 21 , 279).

The exact cause of the onset of restenosis has not yet been identified and no suitable animal disease model has been established. However, in order to reduce the incidence of restenosis, research on new material stents and development of gene therapy are in progress, and among them, research on various classes of drugs is active.

In general, the final pathway of platelet aggregation is a process in which fibrinogen binds to glycoprotein IIb / IIIa and connects platelets. From this, a glycoprotein IIb / IIIa antagonist that inhibits platelet aggregation has been developed for the purpose of suppressing restenosis, and for example, aspirin, ticlopidine, antagonists of thromboxane receptors, etc. have been steadily studied as antiplatelet agents. have. In addition, as an anti-stenosis inhibitor, an anticoagulant including heparin, a phosphodiesterase V inhibitor such as dipyridamole, HMG-coA reductase inhibitors such as lovastatin, fluvastatin, nifedipine, verapamil, etc. Calcium antagonists, ACE (angiotensin converting enzyme) inhibitors such as silazapril, immunosuppressants such as prednisolone, platelet-derived growth factor antagonists such as trappy, and somatostatin such as angiopeptin. There are antioxidants such as derivatives, nitric oxide (NO) donors such as molarjimin, and probucol. Some of them have reported positive results in the clinic [Bult, H, Tips 2000 , 21 , 279].

Therefore, the present inventors have been trying to develop a compound exhibiting a pharmacological effect having an inhibitory effect of restenosis, while restoring stenosis containing an alkoxybenzyl cyanoguanidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient. The present invention has been completed by revealing the effect on the prevention or treatment of Restenosis.

An object of the present invention is to provide a novel alkoxybenzylcyanoguanidine derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing an alkoxybenzylcyanoguanidine derivative represented by the formula (1).

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of restenosis (Restenosis) containing an alkoxybenzyl cyanoguanidine derivative represented by Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient. .

In order to achieve the above object, the present invention provides an alkoxybenzyl cyanoguanidine derivative represented by the following general formula (1) and a pharmaceutically acceptable salt thereof.

(Wherein

R ¹ is —NO ₂ or —NH ₂ ;

R ² is —CO ₂ R ⁴ , —CH ₂ OH, or —CH (OCH ₃ ) ₂ , wherein R ⁴ is H, or C ₁ -C ₂ alkyl;

R ³ is —H, halogen, C ₁ -C ₃ alkyl, —OCH ₃ , —NO ₂ , or —NH ₂ ;

n represents 0 or 1)

The present invention includes all of the alkoxybenzylcyanoguanidine derivatives represented by Formula 1, pharmaceutically acceptable salts thereof, as well as possible solvates and hydrates that can be prepared therefrom.

Preferred compounds among the compounds of Formula 1 are as follows.

1) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine;

2) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-methoxyphenyl) guanidine;

3) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-methylphenyl) guanidine;

4) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-nitrophenyl) guanidine;

5) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N'-benzylguanidine;

6) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine;

7) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N '-(4-nitrophenyl) guanidine;

8) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N'-benzylguanidine;

9) N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine;

10) N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-nitrophenyl) guanidine;

11) N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N'-benzylguanidine; and

12) N "-cyano-N- [5-amino-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-aminophenyl) guanidine.

In the present invention, the compound of formula 1 may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.

The pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid and phosphoric acid; And organic acids such as citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic 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 prepared.

Acid addition salts according to the invention are prepared by conventional methods, for example by dissolving a compound of formula 1 in an excess aqueous solution of an acid and precipitating by addition of a water miscible organic solvent selected from methanol, ethanol, acetone or acetonitrile. can do.

In another method, an acid is added to the same amount of the compound of Formula 1 and a solvent selected from water or glycol monomethyl ether, followed by heating, followed by evaporation or drying of the mixed solution or suction filtration of the precipitated salt. can do.

In addition, the form of the pharmaceutically acceptable salt of the present invention may be a pharmaceutically acceptable metal salt. The metal salt is an alkali metal salt or alkaline earth metal salt comprising the compound of formula 1, preferably the metal is selected from sodium, potassium or calcium.

The metal salt of the present invention may be prepared by dissolving a compound of Formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, and filtering the undissolved material in the above step and then evaporating or drying the filtrate. Corresponding silver salts can also be obtained by reacting alkali metal or alkaline earth metal salts with silver nitrate.

The present invention also provides a method for preparing an alkoxybenzylcyanoguanidine derivative represented by the formula (1).

Specifically, the present invention provides a method for preparing a compound of Formula 1a, wherein R ¹ is -NO ₂ in the alkoxybenzylcyanoguanidine derivative represented by Scheme 1 below.

Wherein R ² , R ³ and n are as defined above.

The present invention also provides another method for preparing a compound of Formula 1a, wherein R ¹ is -NO ₂ in the alkoxybenzylcyanoguanidine derivative represented by Scheme 2 below.

Wherein R ² , R ³ and n are as defined above.

In another aspect, the present invention provides a method for preparing a compound of Formula 1b, wherein R ¹ is -NH ₂ in the compound of Formula 1 according to Scheme 3 from the compound of Formula 1a prepared by Scheme 1 or Scheme 2 (Preparation Method) 3).

Wherein R ² , R ³ and n are as defined above.

Hereinafter, the preparation method of the alkoxybenzylcyanoguanidine derivative of the formula (1) of the present invention will be described in detail.

I. Preparation of Starting Material (Compound of Formula 2)

The compound of Formula 2 used as a starting material in Scheme 1 or Scheme 2 may be prepared by the following Scheme 4.

(Wherein R ² is as defined above)

The reduction reaction is hydrogenation in the presence of lithium aluminum hydride, triethyl phosphate, palladium catalyst or reduction using triphenylphosphine and H ₂ O. More preferably, it is reduced using triphenylphosphine and H ₂ O in a tetrahydrofuran solvent.

More specifically, the azide compound which is the compound of Formula 2a may be prepared by the following Scheme 5.

When the Scheme 5 is described in detail, 1) replacing 2-hydroxy-5-nitrobenzyl bromide 7 with sodium azide to obtain an azide compound of Formula 8; 2) alkylating the compound of Formula 8 with ethyl 2-bromopropionate to obtain a compound wherein R ² is —CO ₂ Et in Formula 2a-1; 3) hydrolyzing the compound of Formula 2a-1 with sodium hydroxide to obtain a compound wherein R ² is -COOH in Formula 2a-2; 4) reducing the compound of Formula 2a-2 using a reducing agent to obtain a compound of Formula 2a-3 wherein R ² is —CH ₂ OH; 5) oxidizing the compound of Chemical Formula 2a-3 to obtain a compound of R ² aldehyde group in Chemical Formula 2a-4; And 6) acetalization of the compound of Chemical Formula 2a-4 to prepare a compound wherein R ² is -CH (OCH ₃ ) ₂ in Chemical Formula 2a.

II. Manufacturing Method 1

In the method for preparing the compound of Formula 1a represented by Scheme 1, the amine compound of Formula 2 and the thiourea compound of Formula 3 are condensed with an appropriate condensing agent in the presence of a suitable solvent.

A condensing agent uses a carbodiimide type compound. More preferably, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide condensation agent is N, N'-dicyclohexylcarbodiimide or water-soluble carbodiimide, and most preferably Is a 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide condensing agent which is a water-soluble carbodiimide.

At this time, the preferable usage-amount of a condensing agent is 1-3 equivalents with respect to an amine compound (Formula 2), and a thiourea compound (Formula 3) is added with 1-2 equivalents with respect to an amine compound (Formula 2). .

The reaction solvent is preferably selected from the group consisting of methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,2-dichloroethane and dioxane, and the preferred reaction temperature is 5 to 40. It is carried out at ℃.

On the other hand, the thiourea compound (Chemical Formula 3) used in Scheme 1 may be prepared by reacting an isocyanate compound (Chemical Formula 3a) with sodium cyanide (NaNHCN) in an ethanol solvent as in Scheme 6 [KS Atwal et. al., Tetrahedron Lett . 30, 7317 (1989). At this time, it is preferable to make reaction temperature into the boiling point vicinity of a solvent.

Wherein R ³ and n are as defined above.

III. Manufacturing Method 2

Method for preparing a compound of Formula 1a represented by Scheme 2

1) preparing a compound of formula 4 by reacting an amine compound (Formula 2) with diphenylcyanocarbonimidate (Formula 5) in the presence of a base in a suitable solvent (Step 1); And

2) reacting the compound of Formula 4 with an amine compound (Formula 6) to prepare a compound of Formula 1a (step 2).

From the above reaction, a compound of Formula 1a, in which R ¹ is NO ₂ , may be prepared.

In step 1, an inorganic base and an organic base may be used. That is, inorganic bases such as calcium carbonate (CaCO ₃ ), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium carbonate (Na ₂ CO ₃ ), sodium bicarbonate (NaHCO ₃ ), sodium methoxide (CH ₃ ONa), Metal salts of alcohols such as sodium ethoxide (CH ₃ CH ₂ ONa), sodium acetate (CH ₃ COONa), metal salts of ammonia, 1,8-diazabicyclo [5.4.0] undec-7-ene (1, 8-diazabicyclo [5.4.0] undec-7-ene, DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (1,5-diazabicyclo [4.3.0] non-5-ene Bicyclic amidine, triethylamine, N, N-diisopropylethylamine, pyridine, lutidine, N, N-dimethylaniline, 4- (dimethylamino) pyridine, Organic bases, such as 4, diazabicyclo [2.2.2] octane (DABCO), can be used. More preferably triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene or 4- (dimethylamino) pyridine It is.

At this time, it is preferable to add 1-3 equivalents with respect to an amine compound (Formula 2), and, as for diphenyl cyano carbonimidate (Formula 5), it is 1-2 equivalents with respect to an amine compound (Formula 2). It is preferable to add.

The reaction solvent is preferably selected from an organic solvent consisting of alcohol solvents such as ethanol and isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and chloroform. The reaction temperature is preferably performed at a boiling point of 5 ° C. to the solvent used.

A preferred amount of the amine compound (Formula 6) in step 2 is to add 1 to 5 equivalents to the amine compound of formula (2).

In this case, the reaction solvent is preferably selected from an organic solvent consisting of an alcohol solvent such as ethanol and isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and chloroform. The reaction temperature is preferably performed at a boiling point of 5 ° C. to the solvent used.

It is also possible to add by adding a base in the above step. As the base, those mentioned above are used.

Ⅳ. Manufacturing Method 3

The compound of Formula 1b, wherein R ¹ is -NH ₂ in Formula 1 represented by Scheme 3, may be prepared by reduction of the compound of Formula 1a, wherein R ¹ is -NO ₂ .

In this case, the reduction reaction may be carried out through a hydrogenation reaction using a metal catalyst such as platinum, palladium attached charcoal (Pd / C; palladium on carbon) or Raney-nickel in a suitable solvent. The reaction solvent uses an alcohol solvent such as methanol or ethanol or ethyl acetate.

Another method of the reduction reaction may be reduced by using a reducing agent such as NaBH _{4 in} the presence of CuSO ₄ , Cu (OAc) ₂ , CoCl ₂ , SnCl ₂ , NiCl ₂ , and the like. At this time, the reaction solvent is preferably a mixed solvent of water and methanol, the reaction temperature is preferably carried out at room temperature.

In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of restenosis (Restenosis) comprising the alkoxybenzyl cyanoguanidine derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof.

As a result of testing the inhibitory effect on the proliferation of smooth muscle cells, the compound of formula 1 effectively inhibits DNA synthesis by showing a binding rate of [ ³ H] -Thymidine of 50% or less.

In addition, after the procedure of balloon injury (balloon injury) shows a high recurrence rate, the compound of formula 1 of the present invention observed the thickness of the intima after injury of balloon injury (balloon injury), the carotid intima thickening Inhibition, wherein the inhibition rate is dose dependent.

The compound of formula 1 may be administered orally or parenterally during clinical administration and may be used in the form of a general pharmaceutical preparation.

The compound of formula 1 of the present invention can be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, diluents such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. that are commonly used, or It can be formulated using excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, sucrose or lactose in one or more compounds of formula (I). , Gelatin, etc. can be mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, 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 pharmaceutical compositions of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection. In order to formulate into a parenteral formulation, the alkoxybenzylcyanoguanidine derivative and the pharmaceutically acceptable salt thereof are mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is a unit dosage form of ampoules or vials. Formulated as

The dosage of the active ingredient according to the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the disease to be treated, but in general 1 It may be administered in divided doses of 3 to 3 times, preferably 0.1 to 100 mg / kg, more preferably may be formulated to be administered at a concentration of 1 to 30 mg / kg. The exact amount, route of administration, and frequency of the agent can be readily determined according to the nature of the agent, the weight and condition of the subject to be administered, and the nature of the particular derivative to be used.

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 content of the present invention is not limited by the examples.

Example 1 N ''-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N'-

Preparation of (4-chlorophenyl) guanidine

Step 1: Preparation of 2-azidomethyl-4-nitrophenol

1 g (4.3 mmol) of 2-hydroxy-5-nitrobenzyl bromide was dissolved in 12 mL of DMF, followed by addition of 0.56 g (8.6 mmol) of sodium azide (NaN ₃ ). After addition, the reaction solution was stirred at room temperature for 2 hours. 14 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (14 mL × 2). After washing with 20 ml of aqueous NaCl solution, dehydrated with MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain 0.8 g of the target compound (yield 96%). Got it.

¹ H NMR (200 MHz, CDCl ₃ ); δ 4.53 (s, 2H), 6.88 (s, 1H), 6.98 (d, 1H), 8.14 (d, 1H), 8.18 (d, 1H)

Step 2: Preparation of 2- (2-azidomethyl-4-nitrophenoxy) propionic acid ethyl ester

7.1 g (36.7 mmol) of the compound obtained in step 1 was dissolved in 100 mL of DMF, and then 1.76 g (44.04 mmol) of 60% NaH was slowly added at 0 ° C. After addition, 5.71 mL (44.04 mmol) of ethyl 2-bromopropionate was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized with 1 N HCl and then extracted with ethyl acetate (150 mL × 2). After dehydrating with MgSO ₄ and concentrated under reduced pressure, the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain 9.1 g (yield 90%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.28 (t, 3H), 1.75 (d, 3H), 4.25 (q, 2H), 4.48 (d, 1H), 4.61 (d, 1H), 4.95 (q, 1H), 6.83 (d, 1H), 8.18-8.26 (m, 2H)

Step 3; Preparation of 2- (2-aminomethyl-4-nitrophenoxy) propionic acid ethyl ester

500 mg (1.7 mmol) of the compound obtained in step 2 was dissolved in 8 ml of THF, and 535 mg (2.04 mmol) of triphenylphosphine and 35.7 µl (2.04 mmol) of water were added thereto. After addition, the reaction solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (20% methanol: ethyl acetate) to obtain 290.7 mg (yield 64%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.26 (t, 3H), 1.70 (d, 3H), 1.82 (s, 2H), 3.87 (d, 1H), 4.02 (d, 1H), 4.22 (q, 2H), 4.93 (q, 1H), 6.76 (d, 1H), 8.11 (dd, 1H), 8.22 (d, 1H)

Step 4: Preparation of N "-Cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine

66.9 mg (0.25 mmol) of the compound obtained in step 3 was dissolved in 1 ml of DMF, and then 75.5 mg (0.32 mmol) of N-cyano-N '-(4-chlorophenyl) thiourea and 1- [3- (di Methylamino) propyl] -2-ethylcarbodiimide hydrochloride (hereinafter referred to as "WSC") 62.2 mg (0.324 mmol) was added. After addition, the reaction solution was stirred at room temperature for 3 hours, extracted with water and ethyl acetate (2 mL × 2). After dehydration with MgSO ₄ and concentration under reduced pressure, the residue was purified by column chromatography (hexane: ethyl acetate = 1: 2) to give 25.5 mg (yield 23%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.23 (t, 3H), 1.55 (d, 3H), 1.70 (s, 1H), 4.11 (q, 2H), 4.53 (dd, 1H), 4.59 (dd, 1H), 4.87 (q, 1H), 6.02 (t, 1H), 6.77 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 8.13 (dd, 1H), 8.21 (d, 1H)

Example 2 N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl]-

Preparation of N '-(4-methoxyphenyl) guanidine

The same method as Example 4, using 68 mg of the compound obtained in Step 3 of Example 1 and 75 mg of N-cyano-N '-(4-methoxyphenyl) thiourea sodium salt, 63 mg of WSC. To give, 30 mg (yield 27%) of the title compound were obtained.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.24 (t, 3H), 1.54 (d, 3H), 3.81 (s, 3H), 4.14 (q, 2H), 4.56 (m, 2H), 4.85 (q, 1H), 5.50 (s, 1H), 6.74 (d, 1H), 6.93 (d, 2H), 7.19 (d, 2H), 8.12 (d, 1H), 8.17 (s, 1H).

Example 3 N "-Cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl]-

Preparation of N '-(4-methylphenyl) guanidine

Example 4, except that 80 mg of the compound obtained in Step 3 of Example 1 and 83 mg of N-cyano-N '-(4-methylphenyl) thiourea sodium salt and 74 mg of WSC were used. The same procedure was followed to obtain 40.9 mg (yield 32%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.23 (t, 3H), 1.52 (d, 3H), 1.71 (s, 1H), 4.14 (q, 2H), 4.54 (m, 2H), 4.84 (q, 1H), 5.67 (t, 1H), 6.74 (d, 1H), 7.13 (d, 2H), 7.20 (d, 2H), 8.09 (d, 1H), 8.15 (dd, 1H).

Example 4 N ''-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl]-

Preparation of N '-(4-nitrophenyl) guanidine

Example 1, except that 80 mg of the compound obtained in step 3 of Example 1 and 95 mg of N-cyano-N '-(4-nitrophenyl) thiourea sodium salt and 74 mg of WSC were used. 46.2 mg (yield 34%) of the title compound was obtained by the same method as the procedure above.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.24 (t, 3H), 1.59 (d, 3H), 1.63 (s, 1H), 4.14 (q, 2H), 4.60 (m, 2H), 4.91 (q, 1H), 6.81 (d, 2H), 7.24 (d, 2H), 8.15-8.20 (m, 2H), 8.25 (d, 1H).

Example 5 N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl]-

Preparation of N'-benzylguanidine

In the same manner as in Step 4 of Example 1, except that 87 mg of the compound obtained in Step 3 of Example 1 and 90 mg of N-cyano-N'-benzyl thiourea sodium salt and 81 mg of WSC were used. The target compound was obtained 32 mg (yield 23%).

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.26 (t, 3H), 1.59 (d, 3H), 4.25 (q, 2H), 4.40-4.98 (m, 4H), 5.18 (q, 1H), 5.40 (s, 1H), 5.81 (s, 1H ), 6.81 (d, 1 H), 7.04 (d, 1 H), 7.13- 7.30 (m, 3 H), 8.00-8.17 (m, 3H).

Example 6 N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl]-

Preparation of N '-(4-chlorophenyl) guanidine

Step 1; Preparation of 2- (2-aminomethyl-4-nitrophenoxy) propan-1-ol

310 mg (1.02 mmol) of the compound obtained in step 2 of Example 1 was dissolved in 8 mL of THF, cooled at 0 ° C., and 77.4 mg (2.04 mmol) of LAH was slowly added thereto, and the reaction solution was stirred at 0 ° C. for 20 minutes. 1N HCl aqueous solution was added to the reaction solution until the pH was 3-4, and the aqueous layer extracted with 10 ml of dichloromethane was adjusted to pH 8-9 with 2N NaOH. The aqueous layer was extracted with ethyl acetate (15 mL × 2), dehydrated with MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (10% methanol: dichloromethane) to give 80 mg of the target compound (yield 35%). )

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.41 (d, 3H), 2.75 (s, 3H), 3.68 (d, 2H), 3.75 (d, 1H), 4.10 (d, 1H), 4.55 (m, 1H), 6.99 (d, 1H), 8.08 (d, 1 H), 8.15 (dd, 1 H).

Step 2; Preparation of N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine

Same as step 4 of Example 1, except that 77 mg of the compound obtained in step 1, 103 mg of N-cyano-N '-(4-chlorophenyl) thiourea sodium salt, and 85 mg of WSC were used. 87.4 mg (yield 64%) of the title compound was obtained by the method.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.24 (d, 3H), 3.64 (m, H), 4.47-4.57 (m, 3H), 6.17 (t, 1H), 6.91 (d, 1H), 7.15 (d, 2H), 7.28 (d, 2H ), 8.05 (d, 1H), 8.11 (d, 1H).

Example 7 N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl]-

Preparation of N '-(4-nitrophenyl) guanidine

Step 1 of Example 1, except that 118 mg of the compound obtained in step 1 of Example 6, 165 mg of N-cyano-N '-(4-nitrophenyl) thiourea sodium salt and 130 mg of WSC were used. By the same method as in 4, 96.1 mg (yield 45%) of the title compound was obtained.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.36 (d, 3H), 4.74 (d, 2H), 4.62 (s, 2H), 4.75 (q, 1H), 7.25 (d, 1H), 7.46 (d, 2H), 8.19-8.25 (m, 5H ).

Example 8 N ″ -cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl]-

Preparation of N'-benzylguanidine

Was carried out in the same manner as in Step 1 of Example 1, except that 240 mg of the compound obtained in Step 1 of Example 6, 294 mg of N-cyano-N'-benzyl thiourea sodium salt and 265 mg of WSC were used. It was. At this time, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain 125.3 mg (yield 30%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.29 (d, 3H), 3.40 (s, 1H), 3.71 (d, 2H), 4.26-4.44 (m, 4H), 4.59 (m, 1H), 6.06 (t, 1H), 6.33 (s, 1H ), 6.92 (d, 1H), 7.18-7.32 (m, 4H), 8.04-8.13 (m, 3H).

Example 9 of N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine Produce

Step 1; Preparation of 2- (2-azidomethyl-4-nitrophenoxy) propionic acid

90 mg (0.31 mmol) of the compound obtained in Step 2 of Example 1 was dissolved in 2 ml of ethanol, and 1 ml of 2N NaOH aqueous solution was added thereto. After addition, the reaction solution was heated to reflux at 90 ° C. for 2 hours. Ethanol was evaporated under reduced pressure, neutralized with 1N HCl and extracted with ethyl acetate (5 mL × 2). The resultant was dehydrated with MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (10% methanol: ethyl acetate) to obtain 70.9 mg (yield 78%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.78 (d, 3H), 4.45 (d, 1H), 4.56 (d, 1H), 5.00 (q, 1H), 6.85 (d, 1H), 8.17 (d, 1H), 8.23 (d, 1H).

Step 2; Preparation of 2- (2-azidomethyl-4-nitrophenoxy) propan-1-ol

1 g (3.76 mmol) of the compound obtained in step 1 was dissolved in 3 mL of THF, 11.3 mL (11.3 mmol) of 1 M BH ₃ / THF was slowly added at 0 ° C., and the reaction solution was stirred at room temperature for 4 hours. Na ₂ HCO ₃ aqueous solution (4 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL × 2), dehydrated with MgSO ₄ , and concentrated under reduced pressure. The residue obtained above was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 592.8 mg of the target compound (yield 62.6%).

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.38 (d, 3H), 2.36 (s, 1H), 3.82 (d, 2H), 4.38 (d, 1H), 4.49 (d, 1H), 4.72 (m, 1H), 7.05 (d, 1H), 8.20 (dd, 1 H), 8.25 (d, 1 H).

Step 3; Preparation of 2- (2-azidomethyl-4-nitrophenoxy) propionaldehyde

1.356 g (5.38 mmol) of the compound obtained in step 2 was dissolved in 20 mL of dichloromethane, cooled to −50 ° C., 0.7 mL (8.06 mmol) of oxalin chloride was added thereto, the reaction solution was stirred for 10 minutes, and DMSO 0.91 mL (12.9). mmol) was added. The reaction solution was stirred at −50 ° C. for 2 hours, and then 3.75 mL (26.9 mmol) of triethylamine was added. The temperature was slowly raised to 0 ° C. and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with water and ethyl acetate (30 mL × 2), dehydrated with MgSO ₄ , and concentrated under reduced pressure. The residue obtained above was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 965.8 mg (yield 72%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.63 (d, 1H), 4.52 (s, 2H), 4.89 (m, 1H), 6.83 (d, 1H), 8.18-8.26 (m, 2H), 9.72 (s, 1H)

Step 4; Preparation of 2-azidomethyl-1- (2,2-dimethoxy-1-methylethoxy) -4-nitrobenzene

965.8 mg 3.9 mmol) of the compound obtained in step 3 was dissolved in 16 ml of methanol, and then a catalytic amount of p -toluenesulfonic acid ( p -TsOH) was added thereto, followed by heating to reflux for 17 hours. Methanol was evaporated under reduced pressure, 10 ml of Na ₂ HCO ₃ aqueous solution was added, extracted with ethyl acetate (10 ml × 2), dehydrated with MgSO ₄ , and concentrated under reduced pressure. The residue obtained above was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 1.1158 g (yield 97.6%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.40 (d, 3H), 3.42 (s, 3H), 3.49 (s, 3H), 4.35-4.44 (m, 3H), 4.57 (m, 1H), 7.04 (dd, 1H), 8.10 (dd, 1H ), 8.24 (d, 1 H).

Step 5; Preparation of 2- (2,2-dimethoxy-1-methylethoxy) -5-nitrobenzylamine

8 g (27 mmol) of the compound obtained in step 4 was dissolved in 100 mL of THF, and 8.4 g (32.4 mmol) of triphenylphosphine and 0.59 mL (32.4 mmol) of water were added thereto. After addition, the reaction solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (20% methanol: ethyl acetate) to obtain 6.2 g (yield 85%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.41 (d, 3H), 3.42 (s, 3H), 3.49 (s, 3H), 3.88 (d, 1H), 3.92 (d, 1H), 4.44 (d, 1H), 4.55 (m, 1H), 6.96 (d, 1 H), 8.14 (dd, 1 H), 8.20 (d, 1 H).

Step 6; Preparation of N "-Cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine

In the same manner as in Step 4 of Example 1, except that 107 mg of the compound obtained in Step 5, 120 mg of N-cyano-N '-(4-chlorophenyl) thiourea sodium salt and 98 mg of WSC were used. This resulted in 77 mg (yield 44%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.28 (d, 3H), 3.19 (s, 3H), 3.35 (s, 3H), 4.20 (d, 1H), 4.48 (m, 3H), 5.69 (s, 1H), 6.95 (d, 1H), 7.19 (d, 2H), 7.38 (d, 2H), 7.92 (s, 1H), 8.16 (d, 1H), 8.18 (s, 1H).

Example 10 N ″ -cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl]-

Preparation of N '-(4-nitrophenyl) guanidine

Step 1 of Example 1, except that 107 mg of compound obtained in step 5 of Example 9, 126 mg of N-cyano-N '-(4-nitrophenyl) thiourea sodium salt and 99 mg of WSC were used By the same method as in 4, 73.2 mg (yield 40%) of the title compound was obtained.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.35 (d, 3H), 3.13 (s, 3H), 3.27 (s, 3H), 4.13 (d, 1H), 4.45-4.60 (m, 3H), 6.67 (s, 1H), 6.97 (d, 1H ), 7.43 (d, 2H), 8.13-8.25 (m, 4H), 8.95 (s, 1H).

Example 11 N ″ -cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl]-

Preparation of N'-benzylguanidine

126 mg of the compound obtained in step 5 of Example 9 was dissolved in 3 ml of DMF, and 122 mg of diphenylcyanocarbonimidate and 78 µl of triethylamine were added. After the addition, the reaction solution was stirred at room temperature for 12 hours, and 149 mg of benzylamine was added thereto. Stirred again at room temperature for 12 hours, added 20 ml of water and extracted with 30 ml of ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and the solvent was concentrated under reduced pressure. The residue obtained above was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give 144 mg (yield 70%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.32 (d, 3H), 3.33 (s, 3H), 3.41 (s, 3H), 4.32-4.52 (m, 6H), 6.27 (s, 1H), 6.94 (d, 1H), 7.20-7.61 (m , 5H), 8.09 (d, 1H), 8.13 (s, 1H).

Example 12 N ''-Cyano-N- [5-amino-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl]-

Preparation of N '-(4-aminophenyl) guanidine

50 mg of the compound obtained in Example 10 was dissolved in 2 ml of methanol, and 5 mg of Pd / C was added. The hydrogenation was carried out for 9 hours in the presence of hydrogen gas. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain 29 mg (yield 66%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ); δ 1.14 (d, 3H), 3.20 (s, 3H), 3.31 (s, 3H), 3.40-3.90 (br-s, 4H, NH ₂ ), 4.11 (m, 2H), 4.32 (d, 2H), 6.51-6.72 (m, 4H), 6.91 (d, 2H), 7.81 (s, 1H).

The following experiments were conducted on the compounds of Formula 1 according to the present invention to investigate the pharmacological effect on the restenosis inhibition effect.

Experimental Example 1 Inhibition of Vascular Smooth Muscle Cell Proliferation (DNA Synthesis Inhibitory Effect)

In order to determine whether the compounds of Formula 1 prepared in the above example inhibit the proliferation of smooth muscle cells, the following experiment was performed.

Rat aortic smooth muscle cells were incubated for 3 days using Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS) on 24 well flights. When the cultured cells were fused, DMEM-10% FBS was removed and incubated for 48 hours in serum-free DMEM medium to quiescent. 1 μM each of the compounds prepared in Examples 2, 3, 4, 6, 7, 8, 9 and 10 were pretreated and treated after 15 minutes with angiotensin II, 10 ⁻⁷ M to promote cell proliferation. Incubated for hours. To measure DNA synthesis, 1 μCi / ml of [ ³ H] -Thymidine was treated in each well and incubated for 4 hours. DMEM cells were washed three times (2 × 1 mL) to remove unbound isotopes, and then cells were removed by treatment with 0.1 mL of 0.25% trypsin-EDTA (ethylenediamine tetraacetate) for 30 minutes. After treatment with 0.25 ml of 0.2 N NaOH for 90 minutes, 1 ml of 15% TCA (trichloroacetic acid) was added and left again at 37 ° C. and 5% CO _{2 for} at least 2 hours. All samples were filtered under a vacuum (GF / B Whatman glass microfiber filter), washed three times with 2 ml of 5% TCA, and the filter paper was placed in a vial to monitor the activity of the radioisotope (Liquid Scintillation Analyzer, Packard, TRI-CARB 2100TR). [ ³ H] -Thymidine bound to the synthesized DNA is shown in Table 1 below.

Inhibitory effect of vascular smooth muscle cell proliferation compound Binding rate of [ ³ H] -Thymidine (%) Angiotensin II 100 Example 2 86.1 Example 3 49.6 Example 4 49.6 Example 6 79.6 Example 7 80.9 Example 8 82.6 Example 9 67.7 Example 10 38.0

As shown in Table 1, the compounds of Examples 3, 4 and 10 exhibited a binding rate of [ ³ H] -Thymidine of 50% or less, significantly inhibiting DNA synthesis, and in particular, the compound of Example 10 was 38% Showed a low binding rate.

Experimental Example 2 Inhibitory Effect of Compounds on Intima Proliferation after Balloon Injury in Rats

Rats of the compound of Formula 1 according to the present invention were subjected to the following experiment in order to see the effect on the thickness of intima after the procedure of balloon surgery.

Male rats (Sprague-Dawley-based, 400-450 g, Biogenomics, Seoul, Korea) were anesthetized with intravenous injection of 35 mg / Kg of phenobarbital sodium salt under intramuscular injection and left carotid artery (angioplasty). After dissection of the central site, the outer left carotid artery was identified and the surrounding tissue removed. An incision was made in the left carotid artery wall, through which an embolectomy catheter (2 Fr, Baxter Healthcare, Santa Ana, CA, USA) was inserted into the left carotid artery. The catheter fixed the distance from the carotid artery to the coronary inlet and inflated with a volume of solution and pulled back into the insertion site to completely diminish. After swelling and shrinking three times artificially wounding, the balloon catheter was removed from the vessel and the incision of the vessel wall was closed. The animals were reared under constant control of temperature and sunshine time (12-hour contrast cycle) from the time of recovery from the surgery, and the feed and water were freely eaten.

Test substance (1, 3, 10 mg / Kg / day, twice a day) was orally administered for 21 days from 6 days before balloon injury to 14 days after the procedure. At 14 days after balloonplasty, rats received heparin 100 IU / rat and were killed by blood death under phenobarbital anesthesia. The left carotid artery was removed and fixed with 10% formaldehyde neutral solution for morphological analysis. Formaldehyde was fixed, surrounded by paraffin, cut into pieces (500 μm each) and stained with hemotoxylin-eosin. Areas of the intima, media, and lumina portions were measured by a computer image analyzer (Image Pro PlusR, Media Cybernetics, Silver Spring, MD, USA) and are shown in Table 2 below. Inhibition rate (%) was calculated by the following equation .

Inhibitory Effect of Compounds on Intima Proliferation after Balloon Surgery compound Intima area (mm ² ) Inhibition Rate (%) Normal 0.0031 - Control 0.17 - Example 10 (Oral) 3 mg / Kg / day 0.13 24 10 mg / Kg / day 0.11 36

As shown in Table 2, the compound of Example 10 was orally administered at 3 and 10 mg / Kg / day dose, and significantly inhibited carotid intima thickening due to balloon injury. , Dose dependent.

Therefore, the compounds of the present invention not only show the effect of inhibiting the proliferation of vascular smooth muscle cells, but also significantly inhibit the carotid intima thickening after a procedure such as balloon injury, thereby preventing angina, myocardial infarction and After surgery following coronary stenosis, including atherosclerosis, restenosis, which develops with high relapse rate, can be prevented and treated.

As described above, the present invention

The compounds of formula (I) of the present invention was effectively suppressed from being integrated village layer is thickened by the damage was effectively inhibit the proliferation of vascular smooth muscle cells, in in vivo models, balloon angioplasty (balloon injury).

Therefore, the pharmaceutical composition containing the alkoxybenzyl cyanoguanidine derivative represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a surgical treatment for angina pectoris, myocardial infarction and atherosclerosis caused by coronary vascular stenosis. After the procedure, it can be usefully used for the prevention or treatment of coronary restenosis with high recurrence rate.

Claims (10)

An alkoxybenzylcyanoguanidine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. Formula 1

(Wherein R ¹ is —NO ₂ or —NH ₂ ; R ² is —CO ₂ R ⁴ , —CH ₂ OH, or —CH (OCH ₃ ) ₂ , wherein R ⁴ is H or C ₁ -C ₂ alkyl; R ³ is —H, halogen, C ₁ -C ₃ alkyl, —OCH ₃ , —NO ₂ , or —NH ₂ ; n represents 0 or 1) The compound of claim 1 wherein 1) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine; 2) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-methoxyphenyl) guanidine; 3) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-methylphenyl) guanidine; 4) N "-cyano-N- [5-nitro-2-[(1-ethoxycarbonyl) ethoxy] benzyl] -N '-(4-nitrophenyl) guanidine; 5) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N'-benzylguanidine; 6) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine; 7) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N '-(4-nitrophenyl) guanidine; 8) N "-cyano-N- [5-nitro-2-[(2-hydroxy-1-methyl) ethoxy] benzyl] -N'-benzylguanidine; 9) N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-chlorophenyl) guanidine; 10) N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-nitrophenyl) guanidine; 11) N "-cyano-N- [5-nitro-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N'-benzylguanidine; and 12) N "-cyano-N- [5-amino-2-[(2-dimethoxy-1-methyl) ethoxy] benzyl] -N '-(4-aminophenyl) guanidine selected from the group consisting of Either alkoxybenzylcyanoguanidine derivatives or pharmaceutically acceptable salts thereof. A process for producing an alkoxybenzylcyanoguanidine derivative characterized in that the compound of formula 1a is obtained by reacting an amine compound (2) with a thiourea compound (3) in the presence of a condensing agent as in Scheme 1 below. Scheme 1

Wherein R ² , R ³ and n are as defined above. The method of claim 3, further comprising reducing the compound of Formula 1a to obtain a compound of Formula 1b. Scheme 3

Wherein R ² , R ³ and n are as defined above. 4. The condensation agent according to claim 3, wherein the condensing agent is any one selected from the group consisting of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide and N, N'-dicyclohexylcarbodiimide. The manufacturing method to make. The manufacturing method of Claim 3 which adds 1-3 equivalents with respect to an amine compound (2). 1) preparing a compound of formula 4 by reacting an amine compound (2) with diphenylcyanocarbonimidate (5) in the presence of a base; And 2) A process for producing a compound of formula 1a by reacting a compound of formula 4 with an amine compound (6). Scheme 2

Wherein R ² , R ³ and n are as defined above. The method of claim 7, further comprising the step of reducing the compound of Formula 1a to obtain a compound of Formula 1b. Scheme 3

Wherein R ² , R ³ and n are as defined above. 8. The method of claim 7, wherein the base in step 1 is triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene or 4- (dimethyl Amino) pyridine. A pharmaceutical composition for preventing or treating restenosis comprising the alkoxybenzyl cyanoguanidine derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.