KR101713027B1 - Composition for preventing or treating cancer comprising phenyloxazol derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising a phenyloxazole derivative represented by chemical formula 1, as active ingredient, a composition for promoting an anticancer therapeutic effect, or a health functional food for preventing or alleviating cancer. Phosphorylation of FLT3 and STAT5, substrate protein thereof, is inhibited, when the derivative is treated to various cancer cell lines comprising lung cancer, breast cancer, colorectal cancer and acute leukemia, apoptosis-induced cell death is increased, and cell proliferation inhibition or the apoptosis-induced cell death is increased, when both a known anticancer drug and radiation are applied to the derivative.

Description

[0001] The present invention relates to a composition for preventing or treating cancer comprising a phenyloxazole-based derivative,

The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a phenyloxazole-based derivative, a composition for enhancing an anti-cancer effect, or a health functional food for cancer prevention or improvement.

Receptor tyrosine kinases (RTKs) are transmembrane proteins that penetrate cell membranes and are one of the most important receptor groups responsible for cell signaling systems that regulate cell proliferation, cell migration, cell cycle and cell differentiation Human RTKs are classified into about 20. Platelet Derived Growth Factor Receptor (PDGFR) can be activated by ligand platelet-derived growth factor (PDGF), mitogen-activated protein kinases (MAPK), phosphatidyl Inositol 3-kinase (PI3K) and STAT3 (signal transducer and activator of transcription 3) can activate the downstream signaling pathway. Activation of PDGFR, including mutations, is observed in GISTs, Glioblastoma multiforme, and chronic myeloid leukemia. An internal tandem duplication (IDT) mutation in the juxtamembrane domain of FLT3 (FMS-like tyrosine kinase 3) gene in approximately 30% of patients with acute myeloid leukemia (AML) About 3% of patients with acute lymphoblastic leukemia (ALL) have mutations, and patients with these mutations are known to have poor prognosis. Thus, FLT3 inhibition may be helpful in the treatment of acute myelogenous leukemia and acute lymphoblastic leukemia. c-Kit can be activated by ligand stem cell factor (SCF), and point mutants such as D816V or V560G are constantly activated without ligand to resist cell proliferation, cell survival and apoptosis Lt; / RTI > In particular, c-Kit activates mastocytosis and induces mastocytosis to increase expression in various organs (skin, liver, gastrointestinal tract, genitalia, etc.) gastrointestinal stromal tumor (GIST), small cell lung cancer, testicular cancer, and polymorphic glioblastoma. Patients with about 70-80% GISTs have a gain-of-function mutation in c-Kit. In addition, we have reported the possibility of rapid growth and metastasis of non-small cell lung cancer due to the activation of c-Kit of non-small cell lung cancer by increasing SCF by nicotine.

Cyclin-depenedent kinase (CDK) is a serine / threonine protein kinase that is crucial to the cell cycle. These complexes consist of two catalytic small molecules, cyclin-dependent kinase (CDK) and regulatory small molecule, cyclin. Each CDK is complexed with a specific cyclin to activate it. The progression of each cell cycle can be controlled by specific CDK / cyclin complexes. CDK1 / cyclin B1, CDK2 / cycle E, and CDK2 / cyclin A are important factors in cell cycle progression.

A number of RTK inhibitors have been tried in clinical trials and have shown initial clinical response, but they are transient and have a problem that resistance may develop rapidly. The RTK inhibitor may cause a D816V mutation in the KIT, a D842V mutation in the PDGFR, and a D835V mutation in the FLT3, interfering with the binding of the RTK inhibitor to the target by various mutations.

Therefore, RTK activation and rapid cell cycle progression are involved in the regulation of abnormal cells in various cancer species. Therefore, the development of inhibitors targeting RTK activity and CDK1 / cyclin B and CDK2 / cyclin A and CDK5 / p35 complex kinase activity Is required.

1. Korean Patent Publication No. 10-2003-0031998.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating cancer that inhibits a specific kinase.

The present invention also provides a composition for enhancing the effect of an anticancer therapy inhibiting a specific kinase.

The present invention also provides a health functional food for cancer prevention or improvement which inhibits a specific kinase.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

R ₁ is halogen.

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According to another aspect of the present invention, there is provided a composition for enhancing an anticancer therapeutic effect, comprising the phenyloxazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, there is provided a health functional food for preventing or ameliorating cancer comprising the phenyloxazole-based derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

According to the present invention, there is provided a pharmaceutical composition comprising 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazole-2- Amine treatment inhibits the phosphorylation of FLT3 and its substrate protein, STAT5, leading to an increase in apoptosis-induced apoptosis, as well as inhibition of cell proliferation or apoptosis in combination with known anticancer agents or radiation irradiation The present invention can be effectively utilized as a pharmaceutical composition for preventing or treating cancer, a composition for enhancing the effect of chemotherapy or a health functional food for cancer prevention or improvement. .

Figure 1 shows that MV4-11 leukemia cells were treated with the derivative 1 [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine] And the phosphorylation of FLT3 and the phosphorylation of STAT5 (signal transducer and activator of transcription 5), a substrate protein of FLT3,
FIG. 2 shows the results of apoptosis-induced apoptosis when the derivative 1 according to the present invention was treated with the breast cancer cell line MDA-MB231, the human lung cancer cell line H1299, or the human colorectal cancer cell line HCT116,
FIG. 3 shows the results of confirming the production of lactate dehydrogenase (LDH) when H1299, a human lung cancer cell line, was treated with derivative 1 according to the present invention.
FIG. 4 shows the result of confirming inhibition of cell proliferation when H1299 was used in combination with the derivative 1 according to the present invention and the anticancer agent 5-FU,
FIG. 4 shows the results of confirming that cell death was increased when H1299 was used in combination with derivative 1 according to the present invention and irradiation with radiation.

Hereinafter, the present invention will be described in detail.

The inventors of the present invention found that Abl, AMP-activated protein kinase alpha 1 (AMP-activated protein kinase alpha 1), ARK5 (AMPK-related protein kinase 5), Aurora-A, cyclin-dependent kinase (CDK1) / cyclin B, CDK2 / cyclin A, CDK5 / p35, (Casein Kinase? 1, CK1? 1), cKit, cKit (D816H), cKit (V560G), cSRC, Discoidin Domain Receptor 2, DDR2, FLT1, FLT3, FLT3 (D835Y), FLT4, PDGFR? , PDGFRα (D842V), PDGFRβ, Pim-1, protein kinase Bα (protein kinase Bα, PKBα) and TrkA (Tropomyosin receptor kinase A) were synthesized.

According to one embodiment of the present invention, a process for producing 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol- - (naphthalen-1-yl) oxazol-2-amine] was treated with leukemia cells, the degree of phosphorylation of FLT3 protein and the level of STAT5 phosphorylation of FLT3 kinase were inhibited in a concentration-dependent manner.

According to another embodiment of the present invention, there is provided a method for producing 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol- Apoptosis induced apoptosis occurred when treated with cancer cells.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

R < ₁ > may be halogen.

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The phenyloxazole-based derivative represented by the above-mentioned formula (1) can be produced by reacting 5- (4-bromophenyl) -N- (naphthalen- 1 -yl) oxazol- 1-yl) oxazol-2-amine] or 5- (4-fluorophenyl) -N- (naphthalen- 1 -yl) oxazol- -1-yl) oxazol-2-amine], and more preferably 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine.

Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, renal cancer, blood cancer, and rectal cancer.

The pharmaceutical compositions according to the present invention may further comprise suitable carriers, excipients or diluents conventionally used in the production of pharmaceutical compositions.

Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The amount of the phenyloxazole-based derivative which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, body weight and disease of the patient, but it is preferably 0.001 to 100 mg / kg, more preferably 0.01 to 10 mg / It can be administered once to several times a day.

The dose of the phenyloxazole-based derivative according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.

In another embodiment of the present invention, an anticancer agent or radiation known as 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol- The effect of the combination therapy on cell proliferation and apoptosis was confirmed.

Accordingly, the present invention provides a composition for enhancing an anticancer therapeutic effect comprising a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

R < ₁ > may be halogen.

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The phenyloxazole-based derivative represented by the above-mentioned formula (1) can be produced by reacting 5- (4-bromophenyl) -N- (naphthalen- 1 -yl) oxazol- 1-yl) oxazol-2-amine] or 5- (4-fluorophenyl) -N- (naphthalen- 1 -yl) oxazol- -1-yl) oxazol-2-amine], and more preferably 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine.

The chemotherapy is chemotherapy or radiotherapy.

The anticancer agent may be selected from the group consisting of 5-fluorouracil, 5-FU, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, and mitomycin- C (mitomycin-C), but is not limited thereto.

The composition may comprise 1 to 99% by weight of an anti-cancer agent and 1 to 99% by weight of a phenyloxazole-based derivative.

The chemotherapy may be used for the treatment of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, renal cancer, blood cancer and rectal cancer, but the cancer is not limited thereto.

In addition, the present invention provides a health functional food for preventing or ameliorating cancer, comprising a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

R < ₁ > may be halogen.

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The phenyloxazole-based derivative represented by the above-mentioned formula (1) can be produced by reacting 5- (4-bromophenyl) -N- (naphthalen- 1 -yl) oxazol- 1-yl) oxazol-2-amine] or 5- (4-fluorophenyl) -N- (naphthalen- 1 -yl) oxazol- -1-yl) oxazol-2-amine], and more preferably 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine.

Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, renal cancer, blood cancer, and rectal cancer.

The health functional food according to the present invention may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health functional food may contain other food or food additives other than the phenyloxazole derivatives according to the present invention, And can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.

The effective dose of the phenyloxazole-based derivative contained in the health functional food may be used in accordance with the effective dose of the pharmaceutical composition. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, And the active ingredient can be used in an amount of more than the above range because there is no problem in terms of safety.

There is no particular limitation on the kind of the above health functional food and examples thereof include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, , Drinks, alcoholic beverages and vitamin complexes.

The phenyloxazole derivative of the present invention can be used in the form of a pharmaceutically acceptable salt, and the acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. As the free acid, an inorganic acid and an organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

In addition, the phenyloxazole derivatives of the present invention include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

R₁은 할로겐이며,
R₂는 나프틸 또는

이고,
상기 R₃ 내지 R₅는 각각 서로 동일하거나 다르며, H, -OCH₃ 및 -SO₂Et로 이루어진 군에서 선택된 어느 하나일 수 있다.
상기 화학식 2로 표시되는 페닐옥사졸계 유도체는 5-(4-브로모페닐)-N-(나프탈렌-1-일)옥사졸-2-아민[5-(4-bromophenyl)-N-(naphthalen-1-yl)oxazol-2-amine], 5-(4-브로모페닐)-N-(2,5-디메톡시페닐)옥사졸-2-아민[5-(4-bromophenyl)-N-(2,5-dimethoxyphenyl)oxazol-2-amine], 5-(4-브로모페닐)-N-(4-메톡시페닐)옥사졸-2-아민[5-(4-bromophenyl)-N-(4-methoxyphenyl)oxazol-2-amine], 5-(4-브로모페닐)-N-페닐옥사졸-2-아민[5-(4-bromophenyl)-N-phenyloxazol-2-amine], 5-(4-브로모페닐)-N-(5-(에틸설포닐)-2-메톡시페닐)옥사졸-2-아민[5-(4-bromophenyl)-N-(5-(ethylsulfonyl)-2-methoxyphenyl)oxazol-2-amine], 5-(4-플루오로페닐)-N-(나프탈렌-1-일)옥사졸-2-아민[5-(4-fluorophenyl)-N-(naphthalen-1-yl)oxazol-2-amine], 5-(4-플루오로페닐)-N-페닐옥사졸-2-아민[5-(4-fluorophenyl)-N-phenyloxazol-2-amine], 5-(4-플루오로페닐)-N-(4-메톡시페닐)옥사졸-2-아민[5-(4-fluorophenyl)-N-(4-methoxyphenyl)oxazol-2-amine, N-(2,5-디메톡시페닐)-5-(4-플루오로페닐)옥사졸-2-아민[N-(2,5-dimethoxyphenyl)-5-(4-fluorophenyl)oxazol-2-amine] 및 N-(5-(에틸설포닐)-2-메톡시페닐)-5-(4-플루오로페닐)옥사졸-2-아민[N-(5-(ethylsulfonyl)-2-methoxyphenyl)-5-(4-fluorophenyl)oxazol-2-amine]으로 이루어진 군에서 선택된 어느 하나일 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

The present invention also relates to a phenyloxazole derivative represented by the following formula (2) or a pharmaceutically acceptable salt thereof, wherein the phenyloxazole derivative or a pharmaceutically acceptable salt thereof is in the form of a living body The present invention provides a reagent composition for inhibiting FLT3, which inhibits FLT3 (FMS-like tyrosine kinase 3) in vitro.
(2)

R < ₁ > is halogen,
R ₂ is naphthyl or

ego,
The R ₃ to R ₅ may be the same or different from each other and may be any one selected from the group consisting of H, -OCH _3, and -SO ₂ Et.
The phenyloxazole-based derivative represented by the above-mentioned general formula (2) can be obtained by reacting 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol- 1-yl) oxazol-2-amine, 5- (4-bromophenyl) -N- (2,5-dimethoxyphenyl) oxazol- 2,5-dimethoxyphenyl) oxazol-2-amine, 5- (4-bromophenyl) -N- (4-methoxyphenyl) oxazole- 4-methoxyphenyl) oxazol-2-amine], 5- (4-bromophenyl) -N-phenyloxazol- 5- (4-bromophenyl) -N- (5- (ethylsulfonyl) -2-methoxyphenyl) -methoxyphenyl) oxazol-2-amine, 5- (4-fluorophenyl) -N- (naphthalen-1-yl) oxazol- -yl) oxazol-2-amine, 5- (4-fluorophenyl) -N-phenyloxazol- 4- (4-fluorophenyl) -N- (4-methoxyphenyl) oxazol-2- amine, N- (2,5-dimethoxyphenyl) -5- (4-fluorophenyl) oxazol-2- N- (5- (ethylsulfonyl) -2-methoxyphenyl) -5- (4-fluorophenyl) oxazole- ) -5- (4-fluorophenyl) oxazol-2-amine].

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Reference example  1>

The melting point of the synthesized compound was determined using a Kruess M5000 Melting Point apparatus and the value was not corrected. Proton NMR spectra were recorded on an Avance-300 (Bruker) at 300 MHz. Chemical shifts were recorded in ppm and Me4Si was used as a reference standard.

The mass spectra were recorded on a JEOL, JMS-600W VG Trio-2 GC-MS.

The reaction products were purified using clean column chromatography on silica gel 60 (230-400 mesh, Merck), precoated silica gel 60 F254 (precoated silica gel 60 F254, E. Merch, Mumbai, India ) Using thin layer chromatography. The spots were stained with phosphomolybdic acid (PMA) or Hanessian's solution and visualized with UV light (254 nm).

< Example  1> Phenyloxazol series  Derivative synthesis

The phenyloxazole derivative according to the present invention was synthesized by the reaction shown in Reaction Scheme 1 below.

[Reaction Scheme 1]

One. Azide ( Azide ) formation

Bromo-4'-fluoroacetophenone was added to a solution of 4'-bromophenacyl bromide (1.0 eq) in 0.2M acetone or azide Sodium azide (3.0 eq) was added. After stirring and reaction at room temperature for 16 hours, the mixture was filtered and concentrated in vacuo to afford the azide compound (1a-b) (93% yield).

2. Isothiocyanate ( Isothiocyanate ) formation

Dichloromethane (dichloromethane, DCM) in aniline (Aniline) within the amine solution, p - anisidine (p -Anisidine), 2,5- dimethoxy aniline (2,5-Dimethoxyaniline), 1- naphthylamine (1 Thiophosgene (1.2 eq) was treated with 3-amino-4-methoxyphenyl ethyl sulfone (1.0 eq each) and stirred for 4 hours. After the reaction was complete, the mixture was diluted with K ₂ CO ₃ saturated solution and extracted with DCM at each time.

The combined organic layers were dried under anhydrous MgSO ₄ , filtered and concentrated in vacuo to afford the isothiocyanate compound (2a-l).

2. Isoxazole ( Isooxazole ) formation

To a solution of the azide compound (1a-b) (1.0 eq) prepared above and stirring the isothiocyanate compound (2a-1) (1.0 eq) in dioxane (0.2M) was added triphenylphosphine (triphenylphosphine, PPh ₃ ) (1.0 eq).

The mixture was stirred for 4 hours while heating to 90 &lt; 0 &gt; C. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by applying pressure. The residue was purified by column chromatography on a silica gel column using ethyl acetate (EtOAc) / hexane (1:10) Purification by chromatography yielded the eluant (3a-j, 32% yield).

R ₁ and R ₂ of the phenyloxazole derivative represented by the following formula (1) are shown in Table 1 below.

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(2)

derivative R ₁
R ₂
Vehicle = DMSO One Br

2 Br

3 Br

4 Br

5 Br

6 F

7 F

8 F

9 F

10 F

* DMSO: dimethyl sulfoxide

The results of nuclear magnetic resonance (NMR) of each derivative are as follows.

derivative 1: 5 -(4- Bromophenyl ) -N- (naphthalen-1-yl) Oxazole -2- Amine [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-

Yellow ^{solid, mp = 183-185 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.19 (s, 1H), 8.30-8.34 (m, 1H), 8.10-8.12 (d, J = 7.32 Hz, 1H), 7.92-7.95 (m, 1H), 7.64-7.67 (m, 3H), 7.48-7.56 (m, 6H); MS (FAB) m / z 365 (M ^&lt; ^{+ &} gt ^; ).

derivative 2: 5 -(4- Bromophenyl ) -N- (2,5- Dimethoxyphenyl ) Oxazole -2- Amine [5- (4-bromophenyl) -N- (2,5-dimethoxyphenyl) oxazol-2-amine]

Yellow ^{solid, mp = 133-135 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.37 (s, 1H), 7.62-7.65 (m, 4H), 7.52-7.54 (m, 3H), 7.29- 7.34 (m, 2 H), 6.94-6.98 (t, J = 8.99 Hz, 1H); MS (FAB) m / z 316 (MH ^&lt; ⁺ & gt ^; ).

derivative 3: 5 -(4- Bromophenyl ) -N- (4- Methoxyphenyl ) Oxazole -2- Amine [5- (4-bromophenyl) -N- (4-methoxyphenyl) oxazol-2-amine]

White ^{solid, mp = 213-215 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.19 (s, 1H), 7.88-7.95 (m, 2H), 7.72-7.76 (d, J = 2.20 Hz, 2H), 7.64-7.67 (dd, J = 5.41, 8.71 Hz, 1H), 7.47-7.50 (m, 2H), 6.91-6.94 (m, 2H), 3.74 (s, 3H); MS (FAB) m / z 346 (MH ^&lt; ⁺ & gt ^; ).

derivative 4: 5 -(4- Bromophenyl ) -N- Phenyloxazole -2- Amine [5- (4- bromophenyl ) -N-phenyloxazol-2-amine &lt; / RTI &gt;

White ^{solid, mp = 214-216 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 9.30 (br s, 1H), 7.86 (q, J = 2.20 Hz, 1H), 7.52-7.85 (m, 5H ), 6.93-6.96 (m, IH), 6.51-6.55 (m, IH), 3.80 (s, 3H), 3.71 (s, 3H); MS (FAB) m / z 376 (MH &lt; ⁺ & gt ^; ).

Derivative 5: 5- (4-bromophenyl) -N- (5- (ethylsulfonyl) -2-methoxyphenyl) oxazol-2-amine [(5- (4-bromophenyl) -N- (5 - (ethylsulfonyl) -2-methoxyphenyl) oxazol-2-amine]

White ^{solid, mp = 188-190 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.24 (s, 1H), 8.76-8.77 (dd, J = 2.20 Hz, 1H), 7.76 (dd, J = J = 7.15 Hz, 2H), 1.11 (t, J &lt; RTI ID = 0.0 &gt; = 7.43 Hz, 3H); MS (FAB) m / z 437 (M ^&lt; ^{+ &} gt ^; ).

derivative 6: 5 -(4- Fluorophenyl ) -N- (naphthalen-1-yl) Oxazole -2- Amine [5- (4- fluorophenyl ) -N- (naphthalen-1-yl) oxazol-2-amine]

Yellow ^{solid, mp = 165-167 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.14 (s, 1H), 8.29-8.37 (m, 1H), 8.12 (d, J = 7.32 Hz, 1H) , 7.81-7.99 (m, 1H), 7.43-7.71 (m, 7H), 7.33-7.27 (t, J = 8.99 Hz, 2H); MS (FAB) m / z 305 (MH ^&lt; ⁺ & gt ^; ).

derivative 7: 5 -(4- Fluorophenyl ) -N- Phenyloxazole -2- Amine [5- (4- fluorophenyl ) -N- henyloxazole -2-amine]

Light yellow ^{solid, mp = 160-162 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.31 (s, 1H), 7.57-7.68 (m, 5H), 7.26-7.35 (m, 4H), 6.89 -7. 03 (m, 1H); MS (FAB) m / z 254 (M ^&lt; ^{+ &} gt ^; ).

derivative 8: 5 -(4- Fluorophenyl ) -N- (4- Methoxyphenyl ) Oxazole -2- Amine [5- (4-fluorophenyl) -N- (4-methoxyphenyl) oxazol-2-amine

Pale Brown, mp = 198.6-198.8 ℃, 1 H NMR (300 MHz, DMSO-d 6) δ 10.19 (s, 1H), 8.37 (dd, 2H), 7.53-7.55 (t, J = 8.99 Hz, 2H) 7.30-7.35 (d, J = 2.20 Hz, 2H), 7.24-7.27 (m, 2H), 6.91-6.94 (m, 1H), 3.69 (s, 3H); MS (FAB) m / z 346 (MH ^&lt; ⁺ & gt ^; ).

Derivative 9: N- (2,5- Dimethoxyphenyl ) -5- (4- Fluorophenyl ) Oxazole -2- Amine [N- (2,5- dimethoxyphenyl ) -5- (4-fluorophenyl) oxazol-2-amine]

Yellow ^{solid, mp = 214-216 ℃,, 1} H NMR (300 MHz, DMSO-d 6) δ 9.33 (br s, 1H), 7.51-7.72 (m, 6H), 6.91-6.94 (m, 1H), 6.51-6.54 (m, 1 H), 3.87 (s, 3 H), 3.74 (s, 3 H); MS (FAB) m / z 315 (MH ^&lt; ⁺ & gt ^; ).

2-methoxyphenyl) -5- (4-fluorophenyl) oxazole- 2-amine [N- (5- (ethylsulfonyl) -2- methoxyphenyl) -5- (4-fluorophenyl) oxazol-2-amine]

Yellow ^{solid, mp = 191-193 ℃, 1 H} NMR (300 MHz, DMSO-d 6) δ 10.14 (s, 1H), 8.78 (d, J = 2.20 Hz, 1H), 7.65 (dd, J = 5.41, (M, 3H), 3.98 (s, 3H), 3.20 (q, J = 7.15 Hz, 2H), 1.11 (t, J = 7.43 Hz, 3H); MS (FAB) m / z 377 (MH ^&lt; ⁺ & gt ^; ).

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< Example  2> Confirmation of inhibition of kinase activity

1. Identification of Inhibitory Effect of Derivative 1

It was confirmed whether the derivative 1 [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine] among the phenyloxazole derivatives synthesized in Example 1 suppressed the kinase activity of RTK Respectively.

Various kinase activity inhibitory effects of the derivative 1 at a concentration of 10 μM were measured using the kinase profiling service of Eurofins. The results are shown in Table 2 below.

Kinase Derivative 1 ( 10 μM  ) Abl 49 AMPKα1 75 ARK5 38 Aurora-A 72 CDK1 / cyclinB 62 CDK2 / cyclin A 61 CDK5 / p35 42 CK1? 1 63 cKit 30 cKit (D816H) 52 cKit (V560G) 9 cSRC 78 DDR2 45 FLT1 56 FLT3 10 Flt3 (D835Y) 25 FLT4 22 PDGFRα 52 PDGFR? (D842V) 77 PDGFR? 49 Pim-1 63 PKBα 76 TrkA 60

As a result, as shown in Table 2, the derivative 1 showed 23 kinds of inhibition of kinase activity, and showed an excellent inhibitory effect especially against cKit (V560G), FLT3, ARK5, Flt4 or cKit kinase.

In addition, the half-maximal inhibitory concentration (IC50) of the derivative 1 was determined for the kinase exhibiting the above-mentioned significant inhibitory effect, and it is shown in Table 3 below.

Kinase Derivative 1 (IC50- μM ) ARK4 1.48 cKit 0.20 cKit (V560G) 0.03 FLT3 0.16 FLT4 0.89

As a result, as shown in Table 3, the derivative 1 showed excellent inhibitory effect even at a low concentration of kinase except ARK4 and FLT4.

2. Confirmation of inhibitory effect of phenyloxazole derivatives (derivatives 2 to 10)

Based on the results of the inhibitory effect on the kinase activity of the derivative 1 identified in Example 1 above, the inhibitory effects of derivatives 2 to 12 on cKit and FLT3 kinase activity were confirmed and are shown in Table 4 below.

derivative c-Kit FLT3 DMSO 100 100 2 4 One 3 32 9 4 66 19 5 13 One 6 One 5 7 0 0 8 0 One 9 81 80 10 85 81

As a result, as shown in Table 4, both derivatives 2 to 10 showed inhibitory effects on c-Kit and FLT3 kinase activity, and in particular, derivatives 2, 3, 5, 6, 7 and 8 showed excellent effects on c-Kit and FLT3 kinase Inhibitory effect.

< Example  3> Various human body Cancer cell  About Phenyloxazole  Identification of the effect of derivatives

The inhibitory effect of the derivatives 1 to 10 synthesized in Example 1 on the cell growth rate of various cancer cell lines was confirmed. For this, human lung cancer cell lines A549 and H1299, human breast cancer cell line MDA-MB231, human colorectal cancer cell lines HCT116 and HT29, human acute leukemia cell line MV4-11, and human normal colon cell line purchased from the American Type Culture Collection (ATCC) CCD18-Co or human normal lung epithelial cell line BEAS2B were cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 100 μg / ml streptomycin and 100 unit / The cells were cultured in RPMI or MEM (MV4-11) medium at 5% CO ₂ and 37 ° C, respectively.

1. Derivative 1 FLT3  or STAT5  Inhibit phosphorylation  effect  Confirm

MV4-11 leukemia cells cultured in the above were treated with the derivative 1 synthesized in Example 1 and confirmed by FLAP3 and STAT5 phosphorylation inhibition using Western blot. After treating the derivative 1 at a concentration of 0.1, 1, 2, 5 or 10 μM for 1 hour, cells were obtained and a cell lysate was obtained by a method commonly used in the art. The cell lysate was separated by performing electrophoresis using 9% gradient SDS-PAGE, and transferred to a nitrocellulose membrane (BioRad, Hercules, CA, USA). The membranes were blocked with 5% skim milk and then incubated with primary anti-phospho-FLT3 (Cell signaling, USA), anti-phospho-STAT5 antibody (Santa Cruz Biotechnology (GAPDH, Anti-GAPDH, Santa Cruz Biotechnology) was reacted for 1 hour with a control group (Glyceraldehyde-3-phosphate dehydrogenase, GAPDH, Then, horseradish peroxidase-conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology) was incubated and visualized using an ECL system (GE, USA).

As a result, as shown in Fig. 1, it was confirmed that treatment of derivative 1 in MV4-11 leukemia cells inhibited the phosphorylation of FLT3 and the phosphorylation of STAT5, a substrate protein of FLT3 kinase, in a concentration-dependent manner.

2. Cancer cell Inhibitory effect on survival  Confirm

Various cell lines cultured in the above were dispensed into 96-well plates in the number of 3 × 10 ³ , and cultured for 24 hours. Then, 10 μM derivative 1 synthesized in Example 1 was treated and cultured for 48 hours. 0.5 mg / mL MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution was then added to each well and further incubated at 37 ° C for 3 hours. After the incubation, the supernatant was removed and the formazan crystals formed were dissolved in DMSO and then measured at 590 nm using a spectrophotometer (Lap Systems, USA). Controls were treated with DMSO and the results are shown in Table 5 as relative growth rates relative to 100% survival.

Human cell line Control group ( DMSO ; % ) Derivative 1 ( % ) A549 100 ± 9.03 32.45 + - 6.28 H1299 100 ± 1.45 27.53 + - 0.55 MDA-MB231 100 ± 2.14 28.52 + - 1.27 HCT116 100 ± 5.03 21.85 ± 0.77 HT29 100 ± 7.01 24.42 + 0.48 MV4-11 100 ± 4.48 20.14 ± 2.96 CCD18-Co 100 ± 6.07 20.14 ± 2.96 BEAS2B 100 ± 2.01 67.23 + - 3.47

As shown in Table 5, the derivative 1 [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol- 2 -amine] according to the present invention was found to be useful in lung cancer, breast cancer, The cell survival rate of CCD18-co and BEAS2B normal cells was inhibited by only about 30% at the same concentration, indicating that they had a selective inhibitory effect on cancer cell proliferation.

The human breast cancer cell line MDA-MB231, human lung cancer cell line H1299, or human colorectal cancer cell line HCT116 cultured as described above was treated with 10 μM derivative 1 and cultured for 48 hours. Then, annexin V and propidium iodide (propidium iodide, PI) double staining. This was analyzed using a FACSort flow cytometer (Becton dickinson, USA). Total apoptosis was determined by summing up early and late apoptotic cells.

As a result, apoptosis-induced apoptosis was induced in MDA-MB201 breast cancer, H1299 human lung cancer, and HCT116 human colorectal cancer cell lines by 6.6-fold, 4.9-fold, and 3.6-fold, respectively.

In addition, MV4-11, which is an acute leukemia cell, was treated with the derivatives 2 to 10 synthesized in Example 1, and the inhibitory effect on cell survival was confirmed.

Cells were seeded in 96-well plates at a number of 3 × 10 ³ , and cultured for 24 hours. Then, 10 μM of each of the derivatives 2 to 10 synthesized in Example 1 was treated and cultured for 48 hours. A 0.5 mg / mL MTT solution was then added to each well and further incubated at 37 [deg.] C for 3 hours. After incubation, the supernatant was removed and the formazan crystals formed were dissolved in DMSO and measured at 590 nm using a spectrophotometer. Controls were treated with DMSO and the results are shown in Table 6 as relative growth rates relative to 100% survival.

Experimental group Cell survival rate (%) DMSO 100 ± 4.34 Derivative 2 32.43 ± 1.77 Derivative 3 59.25 + 2.09 Derivative 4 44.16 ± 1.49 Derivative 5 29.30 ± 1.34 Derivative 6 30.89 ± 1.00 Derivative 7 34.30 + - 0.80 Derivative 8 34.58 ± 1.19 Derivative 9 65.75 ± 2.11 Derivative 10 79.53 + - 4.04

As a result, as shown in Table 6, it was confirmed that the derivatives 2 to 10 synthesized in Example 1 excellently suppressed the survival rate of leukemia cells.

3. Lactate dehydrogenase (Lactate Dehydrogenase , LDH ) analysis

In normal cells, the LDH enzyme does not pass through the cell membrane but is released by cell membrane destruction during cell death. Therefore, LDH enzyme can be measured in cell culture to measure apoptosis. First, 10 μM of the derivative 1 was treated for 1, 3, 8, 24, or 48 hours with human lung cancer cell line H1299, and then the cell supernatant was collected and dispensed into a 96-well plate. This was analyzed by spectrophotometric analysis at 450 nm using an LDH assay kit (LDH assay kit, Dojindo, Japan).

As a result, as shown in Fig. 3, LDH enzyme was increased 1.6 times as compared with the control group after 48 hours of treatment with the derivative 1. Thus, it has been confirmed that the derivative 1 [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine] has apoptotic effect on human lung cancer cells.

< Example  4> Confirmation of anticancer effect by combination treatment with anticancer agent

H1299 lung cancer cells cultured in the same manner as in Example 3 were treated with 5 μM of derivative 1 and 1 μM of known anticancer agent 5-FU (10 μM) for 48 hours, and cell viability was analyzed by MTT assay.

As a result, as shown in Fig. 4, when the 5-FU and the derivative 1 were co-administered, the cell proliferation inhibitory effect was increased by 60% or more as compared with the case of 5-FU alone. Accordingly, it has been found that the derivative 1 [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2-amine] as the phenyloxazole derivative according to the present invention can increase the effect It was confirmed that it could be used as an anticancer adjuvant.

< Example  5> Confirmation of anticancer effect by combination treatment with irradiation

H1299 lung cancer cells cultured in the same manner as in Example 3 were dispensed into 6 cm cell culture plates, and the derivative 1 synthesized in Example 1 was treated with 3 or more times of 1 or 5 μM concentration. Then, gamma radiation was irradiated at 2, 4, 6 or 8 Gy and cultured at 5% CO ₂ and 37 ° C for 7 days. The cultured cells were recovered, stained with a 1% methylene blue mixed solution in 100% methanol, and the viable cells in which the colonies were formed were counted. The results are shown in Fig. 5A.

As a result, it was confirmed that the surviving fraction was remarkably decreased when 5 μM concentration of the derivative 1 according to the present invention was treated with irradiation.

In addition, cleavage of caspase-3 (caspase-3) involved in apoptosis and PARP (poly-ADP ribose polymerase) involved in DNA repair was confirmed by Western blotting in the same manner as in 1. of Example 3 above. At this time, proteins and cleaved PARP proteins were detected with caspase-3 antibody (Cell signaling technology, Inc. USA) and PARP-1 antibody (PARP-1, Cell signaling technology, Inc. USA).

As a result, it was confirmed that the expression of PARP and truncated caspase-3 protein cleaved when the derivative 1 according to the present invention at a concentration of 5 μM and 1 Gy of radiation were treated together as shown in FIG. 5B.

5, it can be seen that the derivative 1 [5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol-2- amine], which is a phenyloxazole derivative, It is possible to use it as a radiotherapy adjuvant which can increase the effect.

Hereinafter, formulation examples of the derivative 1 of the phenyloxazole derivative according to the present invention will be described, but the present invention is not intended to be limited thereto but will be specifically described.

< Prescription example  1 > Prescription example

One. Sanje  Produce

1, 20 mg of the derivative, 100 mg of lactose, and 10 mg of talc were mixed and filled in an airtight container to prepare a powder.

2. Preparation of tablets

1, 20 mg of corn starch, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed and tableted according to a conventional preparation method.

3. Preparation of capsules

1, 10 mg of corn starch, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed, and the above components were mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

4. Preparation of injections

1, 10 mg of the derivative, the sterile distilled water suitable amount for injection, and the pH adjuster were mixed, and the contents were adjusted to the above contents in the amount of 2 ml per ampoule according to the usual injection preparation method.

5. Manufacture of Ointment

The mixture of the derivative 1, 10 mg, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg of white petrolatum, 1.44 mg of methyl p-hydroxybenzoate, 0.18 mg of propyl p- To prepare an ointment agent.

< Prescription example  2> Health functional foods

1. Manufacture of health food

(Vitamin A acetate: 70 ㎍, vitamin E: 1.0 mg, vitamin B 1: 0.13 mg, vitamin B 2: 0.15 mg, vitamin B 6: 0.5 mg, vitamin B 12: 0.2 쨉 g, vitamin C 10 mg, 10 mg of biotin, 1.7 mg of nicotinic acid amide, 50 엽 of folic acid and 0.5 mg of calcium pantothenate) and an appropriate amount of mineral mixture (1.75 mg of ferrous sulfate, 0.82 mg of zinc oxide, 25.3 mg of magnesium carbonate, 15 mg of potassium phosphate, 55 mg of calcium, 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride) were mixed to prepare a granule, and a health food was prepared according to a conventional method.

2. Manufacture of health drinks

1 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine and purified water to make a total of 900 ml, and the above components were mixed according to a conventional health drink manufacturing method, After stirring for 1 hour at 85 ° C, the solution was filtered and sterilized in a sterilized 2 L container, and then refrigerated.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. It is to be understood that various modifications and changes may be made without departing from the scope of the appended claims.

Claims (14)

1. A pharmaceutical composition for preventing or treating cancer, comprising a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]

R ₁ is halogen. The method according to claim 1,
The phenyloxazole-based derivative represented by the above-mentioned formula (1) can be produced by reacting 5- (4-bromophenyl) -N- (naphthalen- 1 -yl) oxazol- 1-yl) oxazol-2-amine] or 5- (4-fluorophenyl) -N- (naphthalen- 1 -yl) oxazol- -1-yl) oxazol-2-amine]. &Lt; / RTI &gt; The method according to claim 1,
Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Wherein the cancer is any one selected from the group consisting of cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, renal cancer, blood cancer, and rectal cancer. 1. A composition for enhancing an anticancer therapeutic effect comprising a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]

R ₁ is halogen. 5. The method of claim 4,
The phenyloxazole-based derivative represented by the above-mentioned formula (1) can be produced by reacting 5- (4-bromophenyl) -N- (naphthalen- 1 -yl) oxazol- 1-yl) oxazol-2-amine] or 5- (4-fluorophenyl) -N- (naphthalen- 1 -yl) oxazol- -1-yl) oxazol-2-amine]. &Lt; / RTI &gt; 5. The method of claim 4,
Wherein the anticancer therapy is an anticancer therapy or a radiation therapy. The method according to claim 6,
The anticancer agent is selected from the group consisting of 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, D), teniposide, etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, and mitomycin-C. C). &Lt; RTI ID = 0.0 &gt; 21. &lt; / RTI &gt; 8. The method of claim 7,
Wherein the composition comprises 1 to 99% by weight of an anticancer agent and 1 to 99% by weight of a phenyloxazole-based derivative. 5. The method of claim 4,
The chemotherapy may be used for the treatment of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer. A health functional food for preventing or ameliorating cancer, comprising a phenyloxazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]

R ₁ is halogen. 11. The method of claim 10,
The phenyloxazole-based derivative represented by the above-mentioned formula (1) can be produced by reacting 5- (4-bromophenyl) -N- (naphthalen- 1 -yl) oxazol- 1-yl) oxazol-2-amine] or 5- (4-fluorophenyl) -N- (naphthalen- 1 -yl) oxazol- -1-yl) oxazol-2-amine]. &Lt; / RTI &gt; 11. The method of claim 10,
Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.


A phenyloxazole derivative represented by the following formula (2) or a pharmaceutically acceptable salt thereof, wherein the phenyloxazole derivative or a pharmaceutically acceptable salt thereof is in vitro, Inhibits FLT3 (FMS-like tyrosine kinase 3).
(2)

R &lt; ₁ &gt; is halogen,
R ₂ is naphthyl or

ego,
R ₃ to R ₅ are the same or different from each other, and are selected from the group consisting of H, -OCH _3, and -SO ₂ Et. 14. The method of claim 13,
The phenyloxazole-based derivative represented by the above-mentioned general formula (2) can be obtained by reacting 5- (4-bromophenyl) -N- (naphthalen-1-yl) oxazol- 1-yl) oxazol-2-amine, 5- (4-bromophenyl) -N- (2,5-dimethoxyphenyl) oxazol- 2,5-dimethoxyphenyl) oxazol-2-amine, 5- (4-bromophenyl) -N- (4-methoxyphenyl) oxazole- 4-methoxyphenyl) oxazol-2-amine], 5- (4-bromophenyl) -N-phenyloxazol- 5- (4-bromophenyl) -N- (5- (ethylsulfonyl) -2-methoxyphenyl) -methoxyphenyl) oxazol-2-amine, 5- (4-fluorophenyl) -N- (naphthalen-1-yl) oxazol- -yl) oxazol-2-amine, 5- (4-fluorophenyl) -N-phenyloxazol- 4- (4-fluorophenyl) -N- (4-methoxyphenyl) oxazol-2- amine, N- (2,5-dimethoxyphenyl) -5- (4-fluorophenyl) oxazol-2- N- (5- (ethylsulfonyl) -2-methoxyphenyl) -5- (4-fluorophenyl) oxazole- ) -5- (4-fluorophenyl) oxazol-2-amine].

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