KR101018791B1 - Composition for prevention or treatment of cancer or cardiovascular disease containing thioxo-thiazolidin-one derivatives or pharmaceutically acceptable salts thereof inhibiting ERK2 as an active ingredient - Google Patents

Abstract

The present invention relates to a composition for the prevention or treatment of cancer or cardiovascular disease containing a thiaoxo-thiazolidin-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient that inhibits the activity of extracellular signal-regulated kinase. In related embodiments, the thioxo-thiazolidin-one derivatives according to the present invention effectively inhibit the activity of extracellular signal-regulating kinases such as ERK2, thereby inducing breast cancer, ovarian cancer, uterine cancer, prostate cancer, Testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocyte tumor, lung cancer epidermal carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer Follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal carcinoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, cholestatic passage, renal carcinoma, hairy cell carcinoma, pharyngeal cancer, It can be usefully used for the prevention or treatment of cardiovascular diseases, such as ischemic stroke, arteriosclerosis, cerebral infarction, or cancer such as carcinoma of cancer, snow cancer, oral cancer, small intestine, colon cancer, colon cancer, rectal cancer, brain and central nervous system cancer and leukemia.

ERK2, extracellular signal-regulated kinase, cancer, ischemic stroke, thioxo-thiazolidin-on derivatives

Description

Composition for the prevention or treatment of cancer or cardiovascular disease containing a thioxo-thiazolidin-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient that inhibits the activity of extracellular signal-regulated kinase or treatment of cancer or cardiovascular disease containing thioxo-thiazolidin-one derivatives or 黄 acceptable salts specifically inhibiting ERK2 as an active ingredient}

The present invention relates to a cancer containing a thioxo-thiazolidin-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient which inhibits the activity of extracellular signal-regulated kinase, preferably extracellular signal-regulated kinase 2. It relates to a composition for preventing or treating cardiovascular diseases.

Many proteins interact with the intracellular signaling system by external stimuli. In particular, changes in the signal transduction cascade due to stimulation of growth factors are known to affect cell transformation and cell proliferation. Stimulation by growth factors occurs in response through a series of signaling systems by receptors on the cell membrane. These signaling systems can be broadly divided into two stages: growth factor receptors present in the cell membrane and intracellular protein kinases. The first step involves GTP-binding protein (Ras protein) through growth factor receptors (GRB2) and guanine nucleotide exchange factor (mSOS) in the cell membrane, and the second step involves the activation and activation of continuous intracellular protein kinases. Protein kinases migrate into the nucleus to increase gene expression. These continuous intracellular protein kinases are called mitogen-activated protein kinase (MAPK) signaling systems.

In vertebrate cells, three independent pathways of MAPK signaling are known: extracellular signal regulated kinase (ERK), JNK / SAPK, and p38. The ERK pathway is primarily activated by growth factors that trigger responses such as cell proliferation, differentiation and survival.

Binding of growth factors to receptor tyrosine kinase (RTK) results in the formation of an active Ras-GTP followed by activation of Raf, MEKK (MAPK kinase), MEK (MAPK kinase), and ERK (MAPK). Activated ERK migrates into the nucleus to phosphorylate ternary complex factor (TCF) or Elk, and phosphorylated TCF / Elk, together with serum-response factor (SRF), is a serum-response element (SRE), a regulatory region of the c-fos gene. Bind to activate c-fos transcription. ERK is also an intermediate mediator that plays a key role in intracellular signaling by regulating the functions of other protein kinases (eg p90rsk), cytoskeleton proteins (eg microtubuleassociated proteins), enzymes (eg cytoplasmic phospholipase A2). It is thought.

ERKs include isomers of ERK-1 (p44MAPK), ERK-2 (p42MAPK), and the heteromorphic MAPK (p40MAPK). ERK-1 and ERK-2 are considered to be functionally identical, with slight differences in substrate specificity.

The activity of the ERK pathway by growth factors is transient, reaching maximum levels in 5 minutes and returning to the original levels in 30-60 minutes. Therefore, the sustained activity of ERK is expected to play an important role in the intracellular signaling system involved in tumorigenesis. The reason for this is first, that the mutation of the ras gene that activates this signaling system and its activation mechanism have been found in many types of carcinomas. Second, gene products belonging to the ERK pathway are gene regulators, and some of these genes are involved in cell division. Recent studies have shown overexpression or activity of ERK in various types of carcinoma (breast carcinoma, kidney carcinoma, etc.).

Extracellular signaling-regulated kinase 2 (ERK2), a type of protein kinase (PK), acts as an important signaling medium in cell growth, differentiation and death ( Oncogene 26). : 3227-3239, 2007; Curr Opin Pharmacol 7 : 77-85, 2007). The activity of ERK2 in cancer, stroke, and immune diseases, in which the biological mechanisms play an important role, is closely related to the development and progression of the disease ( Biochem Biophys Res Commun 336 : 357-363, 2005; Curr Med Chem 14 : 2214-2234, 2007). Therefore, drugs that effectively inhibit ERK2 activity may be used as therapeutic agents for these diseases.

As discussed above, various extracellular signal-regulated kinases are known to cause various disease progression when overexpressed or altered in activity. In particular, ERK2 is breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocyte tumor, lung cancer epidermal carcinoma, large cell carcinoma, small cell carcinoma, Lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal carcinoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, cholestatic passage, renal carcinoma, hair It has been known to be associated with the development and progression of cancer or ischemic cardiovascular diseases such as cell cancer, pharyngeal cancer, carcinoma, snow cancer, oral cancer, small intestine cancer, colon cancer, colon cancer, rectal cancer, brain and central nervous system cancer and leukemia. Therefore, the development of substances that inhibit these extracellular signal-regulating kinases can be usefully used for the prevention or treatment of certain types of diseases such as diabetes, autoimmune diseases, various forms of cancer or cardiovascular diseases.

Accordingly, the present inventors conducted a thorough study to develop a compound that inhibits the activity of the extracellular signal-regulated kinase, a computer including a structure-based virtual screening (docking simulation) using docking simulation, etc. Find a compound that can inhibit extracellular signal-regulated kinase by using the computer-aided drug design protocol, confirm the inhibitory activity of extracellular signal-regulated kinase by in vitro enzyme experiment, and complete the present invention. It was.

It is an object of the present invention for the prevention or treatment of cancer or cardiovascular disease containing a thioxo-thiazolidin-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient that inhibits the activity of extracellular signal-regulated kinase. It is to provide a composition.

In order to achieve the above object, the present invention provides a thioxo-thiazolidin-one derivative or a pharmaceutically acceptable salt thereof that inhibits the activity of extracellular signal-regulated kinase, preferably extracellular signal-regulated kinase 2. It provides a composition for the prevention or treatment of cancer or cardiovascular disease containing as an active ingredient.

Since the thioxo-thiazolidin-one derivative according to the present invention effectively inhibits the activity of extracellular signal-regulated kinases such as ERK2, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, urinary tract caused by their activity Genital cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocytes, lung cancer epidermal carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular Carcinoma, Undifferentiated Carcinoma, Papilloma Carcinoma, Normal Carcinoma, Melanoma, Sarcoma, Bladder Carcinoma, Liver Carcinoma, Bile Passage, Kidney Carcinoma, Hairy Cell Carcinoma, Pharyngeal Cancer, Carcinoma, Sulfur Cancer, Oral Cancer, Small Intestine Cancer, Colon Cancer, It can be usefully used for the prevention or treatment of cancers such as colorectal cancer, rectal cancer, brain and central nervous system cancer and leukemia or cardiovascular diseases such as ischemic stroke, arteriosclerosis and cerebral infarction.

The present invention provides a composition for the prophylaxis or treatment of cancer or cardiovascular diseases comprising a derivative of the general formula (1) which inhibits extracellular signal-regulated kinase activity.

Where

R ¹ is C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ heterocycloaryl,

R ² is C ₅ -C ₁₀ aryl which is unsubstituted or substituted with one or more substituents selected from hydroxy and C ₁ -C ₄ alkoxy; C ₅ ~ C ₁₀ Aryl C ₂ -C ₄ alkenyl; Or C ₅ -C ₁₀ heterocycloaryl.

Preferably, R ¹ is C ₅ ~ C ₈ C ₆ -C ₈ containing one or more aryl or oxygen atoms Heterocycloalkyl aryl, R ² is C ₅ ~ C ₈ aryl, or C ₅ ~ C ₈ of which is substituted with hydroxy and methoxy, or one or two substituents selected from the group consisting of Aryl C ₂ -C ₄ alkenyl.

More preferably, R ¹ is phenyl or 1,3-benzodioxoyl,

R ² is phenyl, 4-hydroxyphenyl, 3-methoxy-4-hydroxyphenyl or phenylethenyl.

In more detail, the compound represented by Formula 1 is as follows:

(1) (5Z) -3-benzyl-5- (4-hydroxybenzylidene) -2-thiaoxo-1,3-thiazolidin-4-one;

(2) (5Z) -3-benzyl-5- (4-hydroxy-3-methoxybenzylidene) -2-thiaoxo-1,3-thiazolidin-4-one; And

(3) (5Z) -3- (1,3-benzodioxo-5-ylmethyl) -5-[(2E) -3-phenylprop-2-ene-1-ylidene] -2-tai Axoxo-1,3-thiazolidin-4-one.

The chemical structural formulas of the compounds are summarized in Table 1.

compound Chemical structure One

2

3

Derivatives of formula (1) according to the invention may also be provided in the form of pharmaceutically acceptable salts. As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfo Nitrate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

The compounds of the invention may also be provided in the form of solvates, in particular hydrates. Hydration may occur during the separation of the compound, or may occur over time due to the hygroscopicity of the compound.

The derivatives of formula 1 of the present invention have the effect of inhibiting the activity of extracellular signal-regulating kinases, in particular ERK2.

Extracellular signaling-regulated kinase 2 (ERK2), a type of protein kinase (PK), acts as an important signaling medium in cell growth, differentiation and death ( Oncogene 26). : 3227-3239, 2007; Curr Opin Pharmacol 7 : 77-85, 2007). The activity of ERK2 in cancer, stroke, and immune diseases, in which the biological mechanisms play an important role, is closely related to the development and progression of the disease ( Biochem Biophys Res Commun 336 : 357-363, 2005; Curr Med Chem 14 : 2214-2234, 2007). Therefore, drugs that effectively inhibit ERK2 activity may be used as therapeutic agents for these diseases.

As discussed above, various extracellular signal-regulated kinases are known to cause various disease progression when overexpressed or altered in activity. In particular, ERK2 is breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocyte tumor, lung cancer epidermal carcinoma, large cell carcinoma, small cell carcinoma, Lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal carcinoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, cholestatic passage, renal carcinoma, hair It has been known to be associated with the development and progression of cancer or ischemic stroke, such as cell cancer, pharyngeal cancer, carcinoma, snow cancer, oral cancer, small intestine cancer, colon cancer, colon cancer, rectal cancer, brain and central nervous system cancer and leukemia. Therefore, the development of substances that inhibit these extracellular signal-regulating kinases can be usefully used for the prevention or treatment of certain types of diseases such as diabetes, autoimmune diseases, various forms of cancer or cardiovascular diseases.

As a result of measuring the inhibitory activity of the derivative of Formula 1 according to the present invention into recombinant ERK2, the inhibitory activity against ERK2 was 5.5-23.7 μM, which is equivalent to the inhibitory activity of the conventional ERK2 inhibitor (SB220025) (19 μM) or It can be seen that it exhibits about 3 times higher inhibitory activity. Therefore, the derivative of Formula 1 according to the present invention exhibits an effective inhibitory activity against extracellular signal-regulated kinase and thus can be effectively used for the prevention or treatment of cardiovascular diseases such as cancer or ischemic stroke, arteriosclerosis, and cerebral infarction caused by ERK2. have.

In the composition of the present invention, the cancer is breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocyte tumor, lung cancer epidermal carcinoma, large Cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal carcinoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, gall bladder , Renal carcinoma, hairy cell carcinoma, pharyngeal cancer, carcinoma, snow cancer, oral cancer, small intestine cancer, colon cancer, colon cancer, rectal cancer, brain and central nervous system cancer, leukemia and the like.

In the composition of the present invention, the cardiovascular disease is preferably ischemic stroke, arteriosclerosis, cerebral infarction and the like.

The compositions can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, capsules, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants ( Eg silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors and sweeteners. The formulations may be prepared by conventional mixing, granulating or coating methods. Also representative of parenteral formulations are injectable formulations, preferably aqueous isotonic solutions or suspensions.

The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure and other therapeutically useful substances and may be formulated according to conventional methods. have.

The pharmaceutical composition of the present invention can be parenterally or orally administered via the intravenous, intramuscular, etc. route as desired, and the derivative of Formula 1 is 0.01-100 mg / kg body weight per day, preferably 0.1 The amount of from 50 mg may be administered in one to several doses. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method and excretion, drug combination and severity of the disease.

Hereinafter, the present invention will be described in more detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Extracellular  Signal control Kinase ( ERK2 Screening of Inhibitory Compounds

Chemical structures recognizing the active site of ERK2 were selected by virtual screening using docking simulation.

First, from the literature (Ohori, M at al., Biochem, Biophys. Res. Comm. 2005, 336, 357) as a receptor model, the three-dimensional structure of the X-ray crystal structure combined with ERK2 and its inhibitor FR180204 (PBD code: 1TVO) ) Was selected. Thereafter, the ligand (FR180204) and the solvent molecule were deleted, and hydrogen atoms were added to each of the protein atoms. Next, the ionizable Asp, Glu, His and Lys residues in the X-ray structure of ERK2 were arranged to be protonated. In general, it is assumed that the side chains of Asp and Glu residues located toward oxygen atoms capable of accepting hydrogen bonds within a distance of 3.5 kPa where hydrogen bonds exist are neutral.

Specifically, it is obtained from an interbioscreen database (http://www.ibscreen.com) containing about 85,000 natural compounds and synthetic compound chemical structures, and the 3D of the ATP binding site of the ERK2 through the AutoDock program. By docking to the structure (binding affinity) was measured in terms of the binding affinity (score) and rank (rank) by measuring the binding energy between the amino acid and the compound at the binding site. As a compound having a high score, a derivative of Formula 1 was obtained.

(1) (5Z) -3-benzyl-5- (4-hydroxybenzylidene) -2-thiaoxo-1,3-thiazolidin-4-one;

(2) (5Z) -3-benzyl-5- (4-hydroxy-3-methoxybenzylidene) -2-thiaoxo-1,3-thiazolidin-4-one; And

(3) (5Z) -3- (1,3-benzodioxol-5-ylmethyl) -5-[(2E) -3-phenylprop-2-ene-1-ylidene] -2-tai Axoxo-1,3-thiazolidin-4-one was obtained. The compound can be obtained from Interbioscreen.

< Example  1> Determination of extracellular signal-regulated kinase inhibitory activity

ERK inhibitory activity assay was performed by the method proposed in Ohori, M at al., Biochem, Biophys. Res. Comm. 2005, 336, 357.

First, a solution of bovine myelin basic protein (MBP) was diluted in phosphate-buffered saline (PBS), and then each well of the Nunc-Immuno 96 microwell plate (MaxiSorpTM) (1 μg / well). The plates were washed with 300 μl PBST (PBS containing 0.05% Tween20) and then 100 μl blocking buffer (PBST containing 3% bovine serum albumin) was added to each well. The plates were then incubated at room temperature for 1 hour.

Experimental compounds were selected by virtual screening (compounds 1-3), and experimental dilution buffer (20 mM 4-morpholine propanesulfonic acid (MOPS), 25 mM β, having a pH of 7.2 for recombinant ERK2 with magnesium / ATP cocktail substrate). -Glycerol phosphate, 5 mM ethylene glycol-bis (2-aminoethylether) -N, N, N ', N'-tetraacetic acid (EGTA), 1 mM Na3VO4, 1 mN thiothritol (DTT) and 0.005% Dilution with bovine serum albumin). This diluted mixture was added to each well of the plate. Kinase-withdrawal group, carrier and positive control SB220055 were used for inter-plate control and background grading.

After 1 hour of incubation at room temperature, the primary antiphospho-MBP antibody was diluted with an appropriate concentration of blocking buffer (1: 20,000 v / v). The diluted antibody was then transferred to each well of the plate, followed by the addition of secondary anti-mouse HRP bound polyclonal antibody diluted with blocking buffer (1: 5,000 v / v). Then o-phenylenediamine dihydrochloride (OPD) substrate mixed solution was added to each well and the plates were incubated for 10 minutes. The enzyme reaction was terminated with 2.5 M sulfuric acid and HRP activity was measured at 490 nm.

The measurement results are shown in Table 2.

division IC ₅₀ (μM) Positive control group (SB220025) 19.0 Compound 1 5.5 Compound 2 14.3 Compound 3 23.7

As shown in Table 2, the derivative of Formula 1 according to the present invention exhibits an inhibitory activity against ERK2 of 5.5-23.7 μM, which is equivalent to or about three times more than that of the conventional ERK2 inhibitor (SB220025). It can be seen that the high inhibitory activity. Therefore, the derivative of Formula 1 according to the present invention exhibits an effective inhibitory activity against extracellular signal-regulated kinase and thus is a cancer or cardiovascular disease caused by ERK2. It can be effectively used for the prevention or treatment of the back.

Examples of formulations for the composition of the present invention are illustrated below.

< Formulation example  1> tablet (direct pressure)

After sieving 5.0 mg of the derivative of Formula 1, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

< Formulation example  2> tablets (wet assembly)

After sifting 5.0 mg of the derivative of Formula 1, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.

< Formulation example  3> with powder Capsule

5.0 mg of the derivative of Formula 1 was sieved, and then mixed together with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

< Formulation 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.

Claims (7)

A pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing a thioxo-thiazolidin-one derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

. (Wherein R ¹ is phenyl or 1,3-benzodioxoyl, R ² is phenyl, 4-hydroxyphenyl, 3-methoxy-4-hydroxyphenyl or phenylethenyl) delete delete The method of claim 1, wherein the derivative (1) (5Z) -3-benzyl-5- (4-hydroxybenzylidene) -2-thiaoxo-1,3-thiazolidin-4-one; (2) (5Z) -3-benzyl-5- (4-hydroxy-3-methoxybenzylidene) -2-thiaoxo-1,3-thiazolidin-4-one; And (3) (5Z) -3- (1,3-benzodioxo-5-ylmethyl) -5-[(2E) -3-phenylprop-2-ene-1-ylidene] -2-tai A pharmaceutical composition for the prevention or treatment of cardiovascular diseases, characterized in that any one selected from the group consisting of aoxo-1,3-thiazolidin-4-one. delete The pharmaceutical composition of claim 1, wherein the cardiovascular disease is an ischemic stroke, arteriosclerosis or cerebral infarction. The pharmaceutical composition for preventing or treating cardiovascular diseases of claim 1, wherein the derivative of Formula 1 inhibits the activity of extracellular neuromodulatory kinase (ERK2).