KR20220151996A - Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides and an anticancer composition comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to an (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide compound and an anticancer agent composition comprising the same as an active ingredient. Specifically, the (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide compound according to the present invention activates procaspase-3 and promotes conversion to caspase-3 so as to be used as a proliferation inhibitor for various cancer cells. The compound according to the present invention is expected to be developed as an active ingredient of a potent anticancer agent.

Description

Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide Compound and anticancer composition containing it as an active ingredient {Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H )-yl)acetohydrazides and an anticancer composition comprising the same as an active ingredient}

The present invention provides novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl) It relates to an acetohydrazide compound and an anticancer agent composition comprising the same as an active ingredient. More specifically, the present invention is a procaspase-3 (procaspase-3) activator (E) -N'-((1- (4-chlorobenzyl) -1H- indol-3-yl) methylene) - It relates to a 2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide compound and an anticancer drug composition comprising the same as an active ingredient.

Cancer is one of the two leading causes of death worldwide. The main cause of cancer development and metastasis is dysregulation of apoptosis. Compounds such as p53 protein and XIAP or Bcl-2 inhibitors act directly on proteins during apoptosis to induce apoptosis and lead to cancer cell death. Caspases are a family of cysteine proteolytic enzymes that are important for maintaining homeostasis through the regulation of apoptosis. A number of studies have demonstrated that direct activation of procaspase-3 by small molecules may have advantages over compounds that induce apoptosis, since procaspase-3 has been shown to be effective in colon, lung, melanoma and liver cancer. This is because it was found to be overexpressed in various tumors, including breast cancer, lymphoma, and neuroblastoma.

Despite the important role of caspases in cancer pathology, few caspase-specific activators have been developed so far. PAC-1 is the first procaspase activating compound reported to show antitumor activity in vivo. Correlation studies on the structure and activity of PAC-1 and other related compounds have revealed that the acylhydrazone moiety plays a very important role in the activity, which is a functional group containing acylhydrazone and zinc. The result was obtained from the formation of a complex between

Prior literature

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[Non-Patent Document 7] Fink D., Schlagbauer-Wadl H., Selzer E., Lucas T., Wolff K., Pehamberger H., Eichler HG, Jansen B. Elevated procaspase levels in human melanoma. Melanoma Res . 2001, 11 , 385-393.

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[Non-Patent Document 9] O'Donovan N., Crown J., Stunell H., Hill AD, McDermott E., O'Higgins N., Duffy MJ Caspase-3 in breast cancer. Clin. Cancer Res. 2003, 9 , 738-742.

[Non-Patent Document 10] Izban KF, Wrone-Smith T., His ED, Schnitzer B., Quevedo ME, Alkan S. Characterization of the interleukin-1β-converting enzyme/Ced-3-family protease, caspase-3/CPP32 , in Hodgkin's disease: lack of Caspase-3 expression in nodular lymphocyte predominance Hodgkin's disease., Am. J. Pathol. 1999, 155 , 1439-1447.

As a result of intensive efforts to develop a novel compound capable of converting or activating procaspase-3 into caspase-3, the present inventors have found that ( E )-N'-((1-( 4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide compounds were synthesized, and their caspase-3 inducing activity and The present invention was completed by experimentally confirming the antiproliferative activity on cancer cells.

Accordingly, the present invention is an activator of procaspase-3 ( E )-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-( An object of the present invention is to provide a 4-oxoquinazolin-3(4H)-yl)acetohydrazide compound or a pharmaceutically acceptable salt thereof.

The present invention also relates to ( E )-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)aceto It is an object of the present invention to provide an anticancer composition comprising a hydrazide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

According to the first embodiment,

the present invention

(E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquina as an activator of procaspase-3 It is intended to provide a zoline-3(4H)-yl)acetohydrazide compound or a pharmaceutically acceptable salt thereof.

As used herein, the term "pharmaceutically acceptable salt" retains the biological efficacy and properties of the compound and is a conventional acid addition salt or base addition salt formed from an appropriate non-toxic organic or inorganic acid or non-toxic organic or inorganic base. means Examples of acid addition salts include acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, Acid addition salts derived from organic acids such as fumaric acid and the like are included. Examples of base addition salts include base addition salts derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. The chemical transformation of pharmaceutical compounds (i.e. drugs) into salts in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds is a technique well known to pharmaceutical chemists, as described in [H . Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457, which are incorporated herein by reference.

As used herein, the term "pharmaceutically acceptable" means, for example, that a pharmaceutically acceptable carrier, excipient, etc. is pharmacologically acceptable to a patient to whom a particular compound is administered and is substantially non-toxic. do.

In the compound or pharmaceutically acceptable salt thereof according to the present invention, the compound or pharmaceutically acceptable salt thereof is characterized by being represented by the following formula (1):

[Formula 1]

(In Formula 1,

R is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy)

In the compound according to the present invention or a pharmaceutically acceptable salt thereof, the halogen is fluorine (F), iodine (I), chlorine (Cl) or bromine (Br).

In the compound according to the present invention or a pharmaceutically acceptable salt thereof, the compound is characterized in that it is any one of the following compounds:

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazine (5a) ;

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-methyl-4-oxoquinazolin-3(4H)-yl)aceto acetoraz (5b);

(E)-N'-(1-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-methyl-4-oxoquinazolin-3(4H)-yl ) acetoacetase (5c);

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-methoxy-4-oxoquinazolin-3(4H)-yl)aceto acetase (5d);

(E)-N'-(1-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(6,7-dimethothoxy-4-oxoquinazoline-3( 4H)-yl)acetohydrazine (5e);

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl) acetoacetase (5f);

(E)-N'-(1-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-fluoro-4-oxoquinazoline-3(4H)- 1) acetoacetorazide (5g);

(E)-2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'(1-(4-chlorobenzyl)-1H-indol-3-yl)methylene(acetylene)aceto hydrazine (5h);

(E) -2- (6-bromo-4-oxoquinazolin-3 (4H) -yl) -N '(1- (4-chlorobenzyl) -1H- indol-3-yl) methylene acetohydrazine ( 5i);

(E)-2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-N'(1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)acetohydrazine (5j);

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-iodo-4-oxoquinazolin-3(4H)-yl) acetoacetase (5k);

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-nitro-4-oxoquinazolin-3(4H)-yl)aceto hydrazine (5l); and

(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-nitro-4-oxoquinazolin-3(4H)-yl)acetohydrazine (5m).

According to the second embodiment,

The present invention is to provide an anticancer composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the term "cancer" includes aggressive characteristics in which cells divide and grow beyond normal growth limits, invasive characteristics infiltrating surrounding tissues, and spreading to other parts of the body. It is a generic term for diseases caused by cells having metastatic characteristics.

In the anticancer agent composition according to the present invention, the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer It is characterized by cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.

In the anticancer drug composition according to the present invention, the compound or a pharmaceutically acceptable salt thereof induces conversion to caspase-3 through activation of procaspase-3.

In the anticancer composition according to the present invention, the anticancer composition comprises (i) a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

Carriers that may be included in the anticancer composition according to the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone , cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.

The anticancer agent composition according to the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, or a preservative. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

A suitable dosage of the anticancer drug composition according to the present invention is determined in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, morbid condition, food, administration time, administration route, excretion rate, and reaction sensitivity. may be prescribed.

The dosage of the anticancer composition according to the present invention may be preferably 0.001-1000 mg/kg (body weight) per day.

The anticancer drug composition according to the present invention may be administered orally or parenterally, and in the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. may be administered.

The concentration of the active ingredient included in the anticancer drug composition according to the present invention is determined in consideration of the treatment purpose, the patient's condition, the required period, and the severity of the disease, and is not limited to a specific range of concentration.

The anticancer drug composition according to the present invention is formulated in unit dosage form by using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by those skilled in the art. It can be prepared or prepared by placing it in a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.

(E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)aceto according to the present invention Hydrazide compounds can activate procaspase-3 to promote conversion to caspase-3, and exhibit antiproliferative activity against various cancer cells. Therefore, it is expected that the compound according to the present invention can be developed as an active ingredient of a potent anticancer agent.

1 is (E) -N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazoline-3 according to an embodiment of the present invention. (4H) -yl) shows a pathway for synthesizing acetohydrazide compounds.
2 is (E) -N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazoline-3 according to an embodiment of the present invention. (4H) -yl) shows the caspase activation effect of the acetohydrazide compound.

Hereinafter, various embodiments are presented to aid understanding of the invention. The following examples are provided to more easily understand the invention, but the protection scope of the invention is not limited to the following examples.

<Experiment materials and methods>

chemical substance

Thin layer chromatography was performed on Whatman® 250 μm Silica Gel GF Uniplates and visualized with UV light at 254 nm to confirm reaction progress and preliminary evaluation of compound homogeneity. Melting points were determined using a Gallenkamp Melting Point Apparatus (LabMerchant, London, United Kingdom) and were uncorrected. Chromatographic purification was performed through open flash silica gel column chromatography using Merck silica gel 60 (240-400 mesh). Nuclear magnetic resonance spectra (1H NMR) were measured on a Bruker 500 MHz spectrometer using tetramethylsilane as an internal standard and dimethyl sulfoxide-d6 (DMSO-d6) as a solvent unless otherwise specified. Chemical shifts were reported in ppm (parts per million) as a downfield from tetramethylsilane, an internal standard. Electron ionization (EI), electrospray ionization (ESI) and high-resolution mass spectra were performed using PE Biosystems API 200 (Perkin Elmer, Palo Alto, CA, USA) and Mariner® (Azco Biotech, Inc. Oceanside, USA), respectively. CA, USA) was measured using a mass spectrometer. Elemental (C, H, N) analysis was performed using a Perkin Elmer model 2400 elemental analyzer. Reagents and solvents are those of Aldrich or Fluka Chemical Corp. unless otherwise specified. (Milwaukee, WI, USA) or purchased from Merck.

<Example>

(E) -N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide compound ( Synthesis of 5) was performed according to the method described in FIG. 1 . Specifically, a mixture of anthranilic acid (1a) or each 5-substituted-2-aminobenzoic acid (1b-m) (2mmol) and formamide (10mmol) was stirred at 120°C for 5-8 hours. The resulting mixture was cooled, poured into an ice bath, filtered when a light gray solid was formed, washed three times with water and dried to give a quinazolin-4(3H)-one derivative (2a-m). This intermediate was used in the next step without further purification.

To a solution of each quinazolin-4(3 H )-one derivative (2a-m) (1 mmol) in acetone (10 mL) was added K ₂ CO ₃ (206.9 mg, 1.5 mmol). The resulting mixture was heated at 80 °C under stirring for 30 min. After adding KI (16.6 mg, 0.1 mmol) and stirring for an additional 15 min, ethyl chloroacetate (0.13 mL, 1.2 mmol) diluted with acetone (1 mL) was added dropwise to the mixture. The reaction mixture was further stirred at 60 °C for 3 hours. After the reaction was complete, the resulting mixture was cooled and poured into a water bath. A brown solid formed, which was filtered and dried to give the corresponding ethyl 2-(4-oxoquinazolin-3-(4 H )-yl)acetate derivatives (3a-m).

Hydrazine monohydrate (2.5 mmol) was slowly added to a solution of each compound 3a-m (0.5 mmol) in ethanol (10 mL). The mixture was stirred at room temperature until complete disappearance of the starting material. A white precipitate formed, which was filtered and washed with cold-ethanol (3 times). The white solids (4a-m) were collected, dried under vacuum and used in the next step without further purification.

The above acetohydrazides (4a-m) were dissolved in ethanol (20 mL) and 2 drops of concentrated acetic acid, onkrasin-1 (0.6 mmol) were added. The mixture was refluxed until the reaction was complete. A precipitate formed and was filtered off and washed with ethanol (three times). The yellow-white solid was washed off, dried in vacuo and re-crystallized from ethanol or column chromatography (DCM/MeOH) to give the following products (5a-m).

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5a )

white solid; Yield: 67%. mp: 194–195 ^o C. R _f = 0.65 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3174 (NH); 3098, 3049 (CH aren); 2943, 2881 (CH, CH ₂ ); 1663 (C=N); 1603 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.57, 11.52 (s, 0.2H, 0.8H, CON H ); 8.42, 8.41 (s, 0.8H, 0.2H, C H =N); 8.40, 8.26 (s, 0.2H, 0.8H, H ₂ ); 8.23, 8.21 (s, 0.2H, 0.8H, H _2' ); 8.18 (d, 1H, J = 7.50 Hz, H ₅ ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.88 (dt, J = 8.50 Hz, J' = 1.25 Hz, 1H, H ₇ ); 7.74 (d, J = 8.00 Hz, 1H, H ₆ ); 7.54 (d, J = 8.00 Hz, 1H, H _7' ); 7.41 (d, J = 8.50 Hz, 2H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.26-7.19 (m, 2H, H _5' , H _6' ); 5.49 (s, 2H, NC H ₂ Ph); 5.30, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.85, 160.83, 149.22, 148.64, 141.58, 137.36, 137.02, 134.90, 134.22, 132.68, 129.56, 129.52 , 123.50, 122.48, 121.99, 121.64, 111.56, 111.23, 49.09, 47.43. HR-MS (ESI) m/z : 470.1381 [M+H] ⁺ , ³⁵ Cl; 472.1351[M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-methyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5b )

white solid; Yield: 69%. mp: 204–205 ^o C. R _f = 0.67 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3171 (NH); 3098, 3059 (CH aren); 2953, 2930 (CH, CH ₂ ); 1682 (C=0); 1663 (C=N); 1611 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.57, 11.52 (s, 0.2H, 0.8H, CON H ); 8.36 (s, 1H, CH =N); 8.33, 8.26 (s, 0.2H, 0.8H, H ₂ ); 8.23, 8.22 (s, 0.2H, 0.8H, H _2' ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.97 (s, 1H, H ₅ ); 7.69 (dd, J = 8.25 Hz, J′ = 1.75 Hz, 1H, H ₇ ); 7.63 (d, J = 8.00 Hz, 1H, H ₈ ); 7.54 (d, J = 8.50 Hz, 1H, H _7' ); 7.41 (d, J = 8.50 Hz, 2H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.21 (m, 2H, H _5' , H _6' ); 5.48 (s, 2H, NC H ₂ Ph); 5.29, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO); 2.48 (s, 3H, C H ₃ ). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.88, 160.78, 148.41, 146.66, 141.54, 137.36, 137.25, 137.02, 136.14, 134.20, 132.69, 129.55 , 122.49, 121.77, 121.65, 111.57, 111.22, 49.10, 47.39, 21.31. HR-MS (ESI) m/z : 484.1536 [M+H] ⁺ , ³⁵ Cl; 486.1507 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(7-methyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5c )

white solid; Yield: 72%. mp: 203–204 ^o C. R _f = 0.67 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3175 (NH); 3105, 3057 (CH aren); 2943 (CH, CH ₂ ); 1684 (C=0); 1657 (C=N); 1614 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.57, 11.52 (s, 0.2H, 0.8H, CON H ); 8.41, 8.38 (s, 0.2H, 0.8H, C H =N); 8.36, 8.26 (s, 0.2H, 0.8H, H ₂ ); 8.23, 8.22 (s, 0.2H, 0.8H, H _2' ); 8.06 (d, J = 8.00 Hz, 1H, H ₅ ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.55 (d, J = 8.50 Hz, 1H, H _7' ); 7.52 (s, 1H, H ₈ ); 7.41-7.40 (m, 3H, H _3” , H _5” , H ₆ ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.26-7.21 (m, 2H, H _5' , H _6' ); 5.48 (s, 2H, NC H ₂ Ph); 5.28, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.92, 160.73, 149.28, 148.78, 145.42, 141.53, 137.36, 137.02, 134.20, 132.69, 129.55, 129.52, 129.11, 128.92 , 122.49, 119.63, 111.58, 111.22, 49.10, 47.30, 21.81. HR-MS (ESI) m/z : 484.1538 [M+H] ⁺ , ³⁵ Cl; 486.1508 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(7-methoxy-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5d )

white solid; Yield: 64%. mp: 209–210 ^o C. R _f = 0.59 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3179 (NH); 3103, 3063 (CH aren); 2926, 2866 (CH, CH ₂ ); 1688 (C=0); 1649 (C=N), 1609 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.57, 11.50 (s, 0.2H, 0.8H, CON H ); 8.38 (s, 1H, CH =N); 8.25 (s, 1H, H ₂ ); 8.22, 8.20 (s, 0.2H, 0.8H, H _2' ); 8.07 (d, J = 8.50 Hz, 1H, H ₅ ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.54 (d, J = 8.50 Hz, 1H, H _7' ); 7.42-7.40 (m, 2H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.28-7.20 (m, 2H, H _5' , H _6' ); 7.17-7.15 (m, 2H, H ₆ , H ₈ ); 5.49 (s, 2H, NC H ₂ Ph); 5.26, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO); 3.93 (s, 3H , OCH ₃ ). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.96, 164.49, 160.37, 150.93, 149.84, 141.51, 137.35, 137.03, 134.20, 132.68, 129.56, 129.52 , 116.99, 115.47, 111.56, 111.22, 108.86, 56.26, 49.09, 47.19. HR-MS (ESI) m/z : 500.1479 [M+H] ⁺ , ³⁵ Cl; 502.1450 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6,7-dimethoxy-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5e )

white solid; Yield: 59%. mp: 214–215 ^o C. R _f = 0.54 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3190 (NH); 3098, 3063 (CH aren); 2988, 2932 (CH, CH ₂ ); 1689 (C=0); 1643 (C=N), 1609 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.58, 11.50 (s, 0.2H, 0.8H, CON H ); 8.41, 8.31 (s, 0.2H, 0.8H, CH =N); 8.28, 8.25 (s, 0.2H, 0.8H, H ₂ ); 8.22, 8.21 (s, 0.2H, 0.8H, H _2' ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.54 (d, J = 8.50 Hz, 1H, H _7' ); 7.48, 7.47 (s, 0.2H, 0.8H, H ₅ ); 7.40 (d, J = 8.50 Hz, 2H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.22 (m, 3H, H _5' , H _6' ); 7.21 (s, 1H, H ₈ ); 5.48 (s, 2H, NC H ₂ Ph); 5.27, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO); 3.94 (s, 3H , 7-OCH ₃ ), 3.89 (s, 3H , 6-OCH ₃ ). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.97, 160.15, 155.03, 149.23, 147.78, 144.82, 141.45, 137.35, 137.03, 134.17, 132.68, 129.56, 129.52, 129.10, 125.22, 123.47, 123.47 , 115.09, 111.58, 111.22, 108.47, 105.59, 56.48, 56.25, 49.09, 47.33. HR-MS (ESI) m/z : 530.1588 [M+H] ⁺ , ³⁵ Cl; 532.1557 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5f )

white solid; Yield: 72%. mp: 200-201 ^o C. R _f = 0.62 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3169 (NH); 3055 (CH aren); 2949, 2899 (CH, CH ₂ ); 1686 (C=0); 1663 (C=N), 1611 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.58, 11.50 (s, 0.2H, 0.8H, CON H ); 8.40, 8.39 (s, 0.2H, 0.8H, CH =N); 8.26 (s, 1H, H ₂ ); 8.22, 8.20 (s, 0.2H, 0.8H, H _2' ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.86-7.86 (m, 3H, H ₅ , H ₇ , H ₈ ); 7.54 (d, J = 8.50 Hz, 1H, H _7' ); 7.41, 7.40 (d, J = 8.50 Hz, 0.4H, 1.6H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.26-7.19 (m, 2H, H _5' , H _6' ); 5.49 (s, 2H, NC H ₂ Ph); 5.30, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.66, 161.69, 160.22, 160.19, 159.74, 148.71, 145.53, 141.64, 137.36, 137.02, 134.26 133.89, 130.71 130.64, 129.53, 129.53, 129.53, 129.53, 129.53 , 123.50, 123.33, 123.24, 123.17, 122.46, 121.64, 111.53, 111.23, 111.07, 49.09, 47.55. HR-MS (ESI) m/z : 488.1282 [M+H] ⁺ , ³⁵ Cl; 490.1252 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5g )

white solid; Yield: 70%. mp: 202–203 ^o C. R _f = 0.62 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3171 (NH); 3101, 3034 (CH aren); 2899 (CH, CH ₂ ); 1686 (C=0); 1661 (C=N); 1616 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.58, 11.50 (s, 0.2H, 0.8H, CON H ); 8.47, 8.44 (s, 0.2H, 0.8H, C H =N); 8.40, 8.26 (s, 0.2H, 0.8H, H ₂ ); 8.23 (dd, J = 8.50, 2.50 Hz, 1H, H ₅ ); 8.22, 8.20 (s, 0.2H, 0.8H, H _2' ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.55-7.52 (m, 2H, H _7′ , H ₈ ); 7.46, 7.45 (dd, J = 8.75 Hz, J′ = 2.50 Hz, 0.2H, 0.8H, H ₆ ); 7.41, 7.40 (d, J = 8.25 Hz, 0.4H, 1.6H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.23 (m, 2H, H _5' , H _6' ); 5.49 (s, 2H, NC H ₂ Ph); 5.29, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.13, 165.13, 162.90, 160.16, 150.86, 150.76, 150.62, 150.51, 141.64, 137.36, 137.02, 134.26, 132.68, 129.78, 129.56, 129.53, 129.53, 129.53 . HR-MS (ESI) m/z : 488.1283 [M+H] ⁺ , ³⁵ Cl; 490.1253 [M+H] ⁺ , ³⁷ Cl.

(E)-2-(6-Chloro-4-oxoquinazolin-3(4H)-yl)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)acetohydrazide ( 5h )

white solid; Yield: 73%. mp: 224–225 ^o C. R _f = 0.64 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3169 (NH); 3096, 3061 (CH aren); 2949 (CH, CH ₂ ); 1688 (C=0); 1661 (C=N); 1609 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.55 (s, 1H, CON H ); 8.46, 8.43 (s, 0.2H, 0.8H, C H =N); 8.41, 8.26 (s, 0.2H, 0.8H, H ₂ ); 8.22, 8.21 (s, 0.2H, 0.8H, H _2' ); 8.12 (d, J = 2.50 Hz, 1H, H ₅ ); 7.91 (dd, J = 8.50 Hz, J' = 2.50 Hz, 1H, H ₇ ); 7.77 (d, J = 8.50 Hz, 1H, H ₈ ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.54 (d, J = 8.00 Hz, 1H, H _7' ); 7.40 (d, J = 8.75 Hz, 2H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.20 (m, 2H, H _5' , H _6' ); 5.48 (s, 2H, NC H 2Ph); 5.30, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.60, 159.87, 149.70, 147.36, 141.68, 137.36, 137.01, 135.08, 134.27, 132.69, 131.86, 130.07 , 123.18, 122.46, 121.64, 111.53, 111.23, 49.10, 47.62. HR-MS (ESI) m/z : 504.0987 [M+H] ⁺ , ³⁵ Cl; 506.0958 [M+H] ⁺ , ³⁷ Cl.

(E)-2-(6-Bromo-4-oxoquinazolin-3(4H)-yl)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)acetohydrazide ( 5i )

white solid; Yield: 69%. mp: 231–232 ^o C. R _f = 0.66 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3175 (NH); 3103, 3061 (CH aren); 2901 (CH, CH ₂ ); 1694 (C=0); 1665 (C=N); 1605 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.55 (s, 1H, CON H ); 8.47 (s, 1H, CH =N); 8.26 (d, J = 2.00 Hz, 1H, H ₅ ); 8.26 (s, 1H, H ₂ ); 8.22, 8.20 (s, 0.2H, 0.8H, H _2' ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 8.03 (dd, J = 8.50 Hz, J' = 2.50 Hz, 1H, H ₇ ); 7.70 (d, J = 8.50 Hz, 1H, H ₈ ); 7.54 (d, J = 8.50 Hz, 1H, H _7' ); 7.41, 7.40 (d, J = 8.50 Hz, 0.4H, 1.6H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.20 (m, 2H, H _5' , H _6' ); 5.49 (s, 2H, NC H ₂ Ph); 5.30, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.59, 159.74, 149.82, 147.63, 141.68, 137.83, 137.36, 137.02, 134.28, 132.68, 130.22, 129.56 , 121.65, 120.02, 111.53, 111.24, 49.09, 47.64. HR-MS (ESI) m/z : 548.0488 [M+H] ⁺ , ⁷⁹ Br; 550.0465 [M+H] ⁺ , ⁸¹ Br.

(E)-2-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)acetohydrazide ( 5j )

white solid; Yield: 65%. mp: 236–237 ^o C. R _f = 0.66 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3173 (NH); 3044 (CH aren); 2980, 2903 (CH, CH ₂ ); 1690 (C=0); 1663 (C=N); 1609 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.54 (s, 1H, CON H ); 8.47 (s, 1H, CH =N); 8.26 (s, 1H, H ₂ ); 8.21 (d, J = 7.50 Hz, 1H, H ₅ ); 8.09 (d, J = 8.50 Hz, 1H, H _4' ); 8.04 (s, 1H, H _2' ); 7.97 (d, J = 1.50 Hz, 1H, H ₈ ); 7.75 (dd, J = 8.75 Hz, J' = 1.75 Hz, 1H, H _7' ); 7.54 (d, J = 8.00 Hz, 1H, H ₆ ); 7.41 (dd, J = 8.50 Hz, J' = 1.50 Hz, 2H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.20 (m, 2H, H _5' , H _6' ); 5.49 (s, 2H, NC H ₂ Ph); 5.29, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.63, 160.39, 160.33, 150.62, 150.50, 150.42, 149.78, 149.72, 141.66, 137.37, 137.02, 134.26, 133.89, 132.68 , 128.66 128.52, 125.21, 123.50, 122.46, 121.64, 121.08, 111.54, 111.23, 49.10, 47.55. HR-MS (ESI) m/z : 548.0490 [M+H] ⁺ , ⁷⁹ Br; 550.0466 [M+H] ⁺ , ⁸¹ Br.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-iodo-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5k )

white solid; Yield: 62%. mp: 240–241 ^o C. R _f = 0.68 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3173 (NH); 3103, 3061 (CH aren); 2984, 2901 (CH, CH ₂ ); 1692 (C=0); 1665 (C=N), 1605 (C=C). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.54 (s, 1H, CON H ); 8.46 (s, 1H, CH =N); 8.44 (d, J = 2.00 Hz, 1H, H ₅ ); 8.25 (s, 1H, H ₂ ); 8.22, 8.20 (s, 0.2H, 0.8H, H _2' ); 8.16 (dd, J = 8.50 Hz, J' = 2.50 Hz, 1H, H ₇ ); 8.04, 8.01 (s, 0.8H, 0.2H, H _4' ); 7.54 (d, J = 8.50 Hz, 2H, H _7′ , H ₈ ); 7.41, 7.40 (d, J = 8.75 Hz, 0.4H, 1.6H, H _3” , H _5” ); 7.29 (d, J = 8.50 Hz, 2H, H _2” , H _6” ); 7.25-7.20 (m, 2H, H _5' , H _6' ); 5.48 (s, 2H, NC H ₂ Ph); 5.29, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.61, 159.54, 149.85, 147.91, 143.31, 141.67, 137.36, 137.01, 134.77, 134.26, 132.69, 129.96 , 122.46, 121.64, 111.53, 111.23, 92.63, 49.10, 47.63. HR-MS (ESI) m/z : 596.0348 [M+H] ⁺ , ³⁵ Cl; 598.0316 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-nitro-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5l )

white solid; Yield: 57%. mp: 196–197 ^o C. R _f = 0.59 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3063 (CH aren); 2972 (CH, CH ₂ ); 1655 (C=N), 1607 (C=C), 1319 (NO ₂ ). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.49 (s, 1H, CH =N); 8.40 (s, 1H, H ₅ ); 8.25-8.15 (m, 3H, H ₂ , H _2′ , H ₇ ); 8.00 (s, 1H, H _4' ); 7.55-7.45 (m, 2H, H _7′ , H ₈ ); 7.45-7.35 (m, 2H, H _3” , H _5” ); 7.30-7.26 (m, 2H, H _2” , H _6” ); 6.90-6.80 (m, 2H, H _5' , H _6' ); 5.47 (s, 2H, NC H ₂ Ph); 5.29, 4.75 (s, 1.6H, 0.4H, NC H ₂ CO). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.40, 161.49, 153.23, 138.31, 137.34, 137.02, 132.68, 129.47, 129.10, 129.03, 125.22, 124.75, 123.45, 121.58, 115.62 , 49.09, 47.26. HR-MS (ESI) m/z : 515.1234 [M+H] ⁺ , ³⁵ Cl; 517.1205 [M+H] ⁺ , ³⁷ Cl.

(E)-N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-(7-nitro-4-oxoquinazolin-3(4H)-yl)acetohydrazide ( 5m )

white solid; Yield: 55%. mp: 194–195 ^o C. R _f = 0.58 (DCM : MeOH = 14 : 1). IR (KBr, cm ⁻¹ ): 3103, 3059 (CH aren); 2972, 2895 (CH, CH ₂ ); 1667 (C=N), 1609 (C=C), 1335 (NO ₂ ). ¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.62, 11.59 (s, 0.2H, 0.8H, CON H ); 8.87, 8.65 (s, 0.5H, 0.5H, CH =N); 8.62-7.94 (m, 5H, H ₂ , H ₅ , H _4′ , H _2′ , H ₈ ); 7.55-7.51 (m, 2H, H _7′ , H ₆ ); 7.41-7.40 (m, 2H, H _3” , H _5” ); 7.30-7.19 (m, 4H, H _5' , H _6' , H _2” , H _6” ); 5.49, 5.48 (s, 1.6H, 0.4H, NC H ₂ Ph); 5.34, 5.11 (s, _1.6H , 0.4H, NCH2CO ). ¹³ C-NMR (125 MHz, DMSO- D ₆ ): δ 167.36, 160.13, 152.68, 152.45, 145.83, 141.84, 137.37, 136.99, 134.33, 132.70, 129.68, 129.53, 129.50 , 122.67, 122.44, 121.95, 121.64, 111.51, 111.25, 49.11, 47.85. HR-MS (ESI) m/z : 515.1233 [M+H] ⁺ , ³⁵ Cl; 517.1205 [M+H] ⁺ , ³⁷ Cl.

<Experimental example>

1. Cytotoxicity assay

The toxicity of the synthesized compound was evaluated using SW620 (colon cancer), PC3 (prostate cancer) and NCI-H23 (lung cancer). The cell line was purchased from a cancer cell bank at the Korea Research Institute of Bioscience and Biotechnology (KRIBB). Media, serum and other reagents used for cell culture were obtained from GIBCO Co. Ltd. (Grand Island, New York, USA). The cells were cultured in DMEM. Then, the cells were suspended at a concentration of 3 × 10 ⁴ cells/mL after trypsinization. On day 0, each well of a 96-well plate was seeded with 180 μL of the cell suspension. Then, the plate was incubated at 37° C. for 24 hours in an incubator containing 5% CO2. Compounds were first dissolved in dimethyl sulfoxide (DMSO) and diluted before use. 20 μL of each compound sample prepared in the above example was added to each well of a 96-well plate seeded with a cell suspension and cultured for 24 hours at different concentrations. The plate was further incubated for 48 hours. The cytotoxicity of the compound was expressed as the average value of three independent measurements (SD≤10%), and 5-fluorouracil was used as a positive control.

Cpd code R
MW
LogP ¹ Cytotoxicity (IC ₅₀ , ² νM)/Cell lines ³ SW620 PC3 NCI-H23 5a H 470.13 4.20 1.01±0.045 1.05±0.087 0.63±0.002 5b 6-CH ₃ 484.15 4.69 3.46±0.082 3.36±0.031 1.79±0.080 5c 7-CH ₃ 484.15 4.69 0.79±0.033 0.51±0.050 0.70±0.057 5d 7-OCH ₃ 500.14 4.08 3.32±0.096 2.76±0.091 1.35±0.026 5e 6,7-(OCH ₃ ) ₂ 530.15 3.95 0.51±0.049 0.81±0.061 0.46±0.007 5f 6-F 488.12 4.36 0.87±0.084 0.44±0.023 0.62±0.050 5g 7-F 488.12 4.36 1.21±0.062 1.16±0.052 0.92±0.048 5h 6-Cl 504.09 4.76 0.49±0.014 0.84±0.030 0.50±0.023 5i 6-Br 548.04 5.03 1.12±0.006 1.18±0.009 1.05±0.070 5j 7-Br 548.04 5.03 2.82±0.019 2.97±0.267 2.26±0.035 5k 6-I 597.03 5.56 1.10±0.051 0.96±0.053 0.79±0.008 5l 6-NO ₂ 515.12 4.24 3.15±0.091 3.71±0.167 2.43±0.198 5m 7-NO ₂ 515.12 4.24 >10 >10 >10 5-FU ⁴ 130.08 -0.81 8.84±1.92 13.61±0.46 13.45±3.92 PAC-1 ⁵ 392.49 3.43 2.63±0.016 2.98±0.139 2.60±0.012 Oncrasin-1 2.69±0.031 2.41±0.021 2.15±0.019

^One Calculated by EPI 320 software; ² The concentration (νM) of compounds that produces a 50% reduction in enzyme activity or cell growth, the numbers represent the averaged results from triplicate experiments with deviation of less than 10%.; ³ Cell lines: SW620, colon cancer; PC3, prostate cancer; NCI-H23, lung cancer; ⁴ 5-FU: 5-Fluorouracil, a positive control; ⁵ PAC-1: a positive control

As can be seen from Table 1, all the compounds according to the present invention exhibited excellent cytotoxicity, and in particular, compounds 5c, 5e and 5h were found to exhibit cytotoxicity more than three times that of PAC-1.

2. Caspase-3 activation assay

U937 cells (5×10 ⁵ cells/well) were plated in 6-well plates and allowed to stabilize overnight. Cells were treated with 5e, 5f and 5l (50 μM in 0.1% dimethyl sulfoxide) in PAC-1 or a compound according to the invention. After 24 hours in incubation, cells were harvested and washed twice with PBS. The cells were lysed with 50 μL of quenched cell lysis buffer at 4° C. for 10 minutes. Cell lysate (100 μg/100 μL/well) was mixed using Ac-DEVD-pNA (200 μM). OD was measured every 30 minutes for 12 hours at 405 nm.

As a result, it was confirmed that the compounds (5c, 5e and 5h) according to the present invention exhibit excellent caspase activity (FIG. 2).

Having described specific parts of the present invention in detail above, it is clear that these specific techniques are merely preferred embodiments for those skilled in the art, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (7)

A compound represented by Formula 1 below as an activator of procaspase-3 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
Wherein R is hydrogen, halogen, NO2, C1-6 alkyl or C1-6 alkoxy).
According to claim 1,
The halogen is a compound or a pharmaceutically acceptable salt thereof, characterized in that the halogen is fluorine (F), iodine (I), chlorine (Cl) or bromine (Br).
According to claim 1,
Characterized in that the compound is any one of the following compounds, or a pharmaceutically acceptable salt thereof:
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazine;
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-methyl-4-oxoquinazolin-3(4H)-yl)aceto acetoraz;
(E)-N'-(1-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-methyl-4-oxoquinazolin-3(4H)-yl ) acetoacetase;
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-methoxy-4-oxoquinazolin-3(4H)-yl)aceto acetase;
(E)-N'-(1-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(6,7-dimethothoxy-4-oxoquinazoline-3( 4H)-yl)acetohydrazine;
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl) acetoacetase;
(E)-N'-(1-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-fluoro-4-oxoquinazoline-3(4H)- 1) acetoacetorazide;
(E)-2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'(1-(4-chlorobenzyl)-1H-indol-3-yl)methylene(acetylene)aceto hydrazine;
(E)-2-(6-bromo-4-oxoquinazolin-3(4H)-yl)-N'(1-(4-chlorobenzyl)-1H-indol-3-yl)methylene acetohydrazine;
(E)-2-(7-bromo-4-oxoquinazolin-3(4H)-yl)-N'(1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)acetohydrazine ;
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-iodo-4-oxoquinazolin-3(4H)-yl) acetoacetase;
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(6-nitro-4-oxoquinazolin-3(4H)-yl)aceto hydrazine; and
(E)-N'-(1-((4-chlorobenzyl)-1H-indol-3-yl)methylene)-2(7-nitro-4-oxoquinazolin-3(4H)-yl)acetohydrazine .
Claims 1 to 3, characterized in that it comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims as an active ingredient, an anticancer composition.
According to claim 4,
The cancer is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer, endometrial cancer, Cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer, characterized in that, the anticancer agent composition.
According to claim 4,
The compound or a pharmaceutically acceptable salt thereof is characterized by inducing conversion to caspase-3 through activation of procaspase-3, anticancer composition.
According to claim 4,
The anticancer composition may include (i) a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (ii) characterized in that provided in the form of a pharmaceutical composition containing a pharmaceutically acceptable carrier, anticancer composition.

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