WO2014175623A1 - Novel tubulin polymerization inhibitor and method for synthesizing same - Google Patents

Abstract

The present invention relates to (E)-ethyl 2-(2-methyl-3-((2-(naphtho[2,1-b]furan-2-carbonyl)hydrazono)methyl)-1H-indol-1-yl)acetate as a novel tubulin polymerization inhibitor and a method for synthesizing the same. The compound of the present invention can inhibit mitosis and induce apoptosis and thus be used as an anticancer agent, by binding to tubulin to inhibit microtube polymerization. According to the synthesis method of the present invention, the reaction is simplified and the efficiency is 60% or higher, leading to a very high yield, thereby providing an effective synthesis method.

Description

Novel tubulin polymerization inhibitor and its synthesis method

The present invention relates to novel tubulin polymerization inhibitors and methods for their synthesis. More specifically, the present invention provides (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) -1H -Indol-1-yl) acetate ((e) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) -1h-indol -1-yl) acetate) and its synthesis method.

The microtubule is a major component of the cytoskeleton and consists of a tubulin heteropolymer composed of α and β subunits. Microtubules perform a variety of cellular functions, including intracellular transport, polarity maintenance, intracellular signal transduction, cell migration and proliferation. During mitosis of cells, spinal cords are formed so that the chromosomes are arranged at the center of the cell and then separated into an anode. If the spindle does not function properly, cell division is inhibited, resulting in apoptosis (apoptosis), which is attracting attention as a target of anticancer drugs.

Drugs targeting microtubules are largely divided into two groups: drugs that stabilize microtubules and drugs that destabilize microtubules. First, microtubule stabilizers include taxane, paclitaxel (Taxol), decetaxel, etc., to prevent depolymerization of microtubules and to enhance polymerization. Most microtubule stabilizers bind to the taxane-binding site or the overlapping site of β tubulin. Second, microtubule destabilizers include colchicine and vinca alkaloid, which bind to colchicine binding sites or vinca binding sites. The same is true for drugs targeting these microtubules themselves at lower concentrations than drugs affecting microtubule polymers, resulting in inhibition of cell mitosis.

Most tubulin inhibitors show drug resistance, which is a major obstacle to long-term reactions and to improve the survival of cancer patients. Therefore, there is a lot of interest in the development of novel tubulin inhibitors that can overcome the multi-drug resistance, many active compounds have been found. In addition, neurotoxicity as well as resistance is one of the major side effects of tubulin inhibitors derived from complex natural products, which affects the quality of life of cancer patients. Moreover, low oral-bioavailability is a constraint for comfortable oral administration. Therefore, there is an increasing demand for the development of novel tubulin inhibitors that have low neurotoxicity, no side effects, excellent oral-bioavailability, and are not affected by anticancer drug resistance mechanisms.

Accordingly, the present inventors screened a substance that inhibits cell proliferation from a small molecule library, and as a result, the compound "(E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan)" -2-carbonyl) hydrazono) methyl) -1H-indol-1-yl) acetate "was first confirmed that the activity of inhibiting cell mitosis was completed and the present invention was completed.

The present invention provides a novel tubulin polymerization inhibitor (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) It is an object to provide methyl) -1H-indol-1-yl) acetate.

The present invention provides a novel tubulin polymerization inhibitor (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) It is an object to provide an effective synthetic route for the synthesis of methyl) -1H-indol-1-yl) acetate.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention provides (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) represented by the following general formula (I): -1H-indol-1-yl) acetate.

[Formula I]

In one embodiment of the invention, the compound is characterized in that the tubulin polymerization inhibitor.

The present invention, the first step of condensation reaction of 2-hydroxy-1-naphthaldehyde and ethyl bromoacetate; A second step of esterifying naphtho [2,1-b] furan-2-carboxylic acid in the product obtained in the first step; A third step of hydrating the product obtained in the second step; A fourth step of formylating 2-methyl-1H-indole; A fifth step of nucleophilic substitution reaction of the product obtained in the fourth step; And a sixth step of condensing the product obtained in the third step with the product obtained in the fifth step, (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2 , 1-b] furan-2-carbonyl) hydrazono) methyl) -1H-indol-1-yl) acetate.

In one embodiment of the present invention, the condensation reaction of the first step is characterized by using anhydrous K ₂ CO ₃ as a base and dimethylformamide (DMF) as a solvent.

In another embodiment of the present invention, the second step of the esterification reaction is characterized in using ethanol and SOCl ₂ .

In another embodiment of the present invention, the hydrazine reaction of the third step is characterized by using hydrazine hydrate.

In another embodiment of the present invention, the fourth step of the formylation reaction is carried out by reacting dimethylformamide (DMF) with POCl ₃ as a solvent and further reacting 2-methyl-1H-indole thereto. do.

In another embodiment of the present invention, the nucleophilic substitution reaction of the fifth step is characterized by using NaH and ethyl bromoacetate as a base.

In another embodiment of the present invention, the condensation reaction of the sixth step is characterized by using acetic acid as a catalyst.

According to the compound of the present invention, it can be used as an excellent anticancer agent because it can inhibit cell mitosis and induce cell death by binding to tubulin and inhibiting microtubule polymerization.

According to the synthesis method of the present invention, since the reaction is simple and the yield is very high, with an efficiency of 60% or more, an effective synthesis method can be provided.

Figure 1 shows the ¹ H NMR and ¹³ C NMR Spectrum results for compound (2a).

2 shows the Mass Spectrum results for compound (2a).

Figure 3 shows the ¹ H NMR Spectrum results for compound (2b).

Figure 4 shows the Mass Spectrum results for compound (2b).

5 shows the ¹ H NMR Spectrum results for compound (3).

Figure 6 shows the Mass Spectrum results for compound (3).

Figure 7 shows the ¹ H NMR Spectrum results for compound (5).

8 shows the Mass Spectrum results for compound (5).

9 shows the ¹ H NMR Spectrum results for compound (6).

10 shows the Mass Spectrum results for compound (6).

11 shows the ¹ H NMR Spectrum results for compound (7).

12 shows the ¹³ C NMR Spectrum results for compound (7).

13 shows the DEPT NMR Spectrum results for compound (7).

14 shows the Mass Spectrum results for compound (7).

Tubulin Inhibitor Compound of the Invention "(E) -Ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl)- 1H-indol-1-yl) acetate " The compound is in the form of a bioactive heterocyclic scaffold naphthofuran, wherein the N -substituted indole is linked via an N -acyl hydrazone structural motif.

[Formula I]

The tubulin inhibitor compounds of the present invention can be used as anticancer agents because they can inhibit cell mitosis and induce cell death by binding to tubulin and inhibiting microtubule polymerization.

Tubulin Inhibitor Compound of the Invention "(E) -Ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl)- The schematic diagram of the synthesis method of "1H-indol-1-yl) acetate" is as follows.

As can be seen from the above schematic diagram, the synthesis method of the present invention comprises six reaction steps, namely condensation and cyclization reaction, esterification reaction, hydrazinolysis of ester, Vilsmeier-Haack formylation reaction, and nucleophilic substitution reaction. (nucleophillic substitution) and condensation reaction of hydrazide with aldehyde.

As a first step in the reaction of the pathway for preparing the final product compound (7), the starting material is 2-hydroxy-1-naphthaldehyde compound (1), which is reacted with ethyl bromoacetate or ethylchloroacetate to produce naphtha. The to [2,1-b] furan-2-carboxylic acid compound (2a) can be obtained. In this reaction, both cyclization and condensation occur in a single step with a yield of 90%.

At this time, anhydrous K ₂ CO ₃ , Cs ₂ CO _3, etc. may be used as a base, and dimethylformamide (DMF), N, N -dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), etc. may be used as a solvent. Can be. The reaction temperature of 2-hydroxy-1-naphthaldehyde compound (1), DMF, and anhydrous K ₂ CO ₃ is preferably 10 to 40 ° C., and the reaction time is about 10 to 60 minutes. The resulting mixture and ethyl bromoacetate The reaction temperature is preferably 100 to 200, and the reaction time is 10 to 30 hours.

The chemical structure of naphtho [2,1-b] furan-2-carboxylic acid compound (2a) can be determined by ¹ H NMR and ESIMS analysis. Seven aromatic proton-specific signals appear at δ8.269-7.460 ppm in ¹ H NMR analysis and 13 carbon signals at δ161.293-105.238 ppm in ¹³ C NMR (see FIG. 1). In addition, the mass spectrum showed a molecular ion peak at m / z 211.4 [MH] ⁻ , which corresponds to the molecular formula C ₁₃ H ₈ O ₃ (see FIG. 2).

In the second step of the reaction, the naphtho [2,1-b] furan-2-carboxylic acid compound (2a) is prepared by esterification reaction using ethanol and SOCl ₂ . b] converted to furan-2-carboxylic acid compound (2b), yielding 60%.

At this time, dimethylformamide (DMF), ethanol, or the like may be used as the solvent, and the reaction conditions are preferably stirred for 10 to 60 minutes at -10 to 10 ° C, followed by further stirring at 10 to 80 for 1 to 6 hours.

The chemical structure of the ester ethylnaphtho [2,1-b] furan-2-carboxylic acid compound (2b) can be determined by ¹ H NMR and ESIMS analysis. ^With seven aromatic proton signals in the ¹ H NMR spectrum, the new peak quartet -CH ₂ appears at δ4.424-4.370 ppm ( J = 7.2 Hz), and triplet -CH ₃ has δ1.388-1.353 ppm ( J = 7.2 Hz) (see FIG. 3). In addition, the molecular spectral peak was found in m / z 241.4 [M + H] ⁺ , and ESIMS analysis showed 263.4 [M + Na] ⁺ , which corresponds to the molecular formula C ₁₅ H ₁₂ O ₃ (FIG. 4).

In the third step of the reaction, esterethylnaphtho [2,1-b] furan-2-carboxylic acid compound (2b) is reacted with hydrazine hydrate to give an intermediate compound naphtho [2,1- b ] furan 2-Carbohydrazide Compound (3) can be obtained, with a yield of 72%.

At this time, ethanol, methanol or the like can be used as the solvent, and the reaction conditions are preferably heated at 50 to 90 ° C, stirred for 1 to 6 hours, and then cooled.

The ¹ H NMR spectrum of the naphtho [2,1- b ] furan-2-carbohydrazide compound (3) shows that since the peak is not observed, it corresponds to the ester. A signal of δ10.049 ppm for amide O = C-NH and a signal of δ4.597 ppm for -NH ₂ (substitutable for D ₂ O) of hydrazide (see FIG. 5). In addition, the mass spectrum showed a molecular ion peak of m / z 225.4 [MH] ^- , 227.4 [M + H] ⁺ , and 249.4 [M + Na] ^{+, corresponding to} the molecular formula C ₁₃ H ₁₀ N ₂ O ₂ . (See FIG. 6).

In the fourth step of the reaction, Vilsmeier-Haack formylation of 2-methyl-1H-indole (4) afforded 2-methyl-1H-indole-3-carbaldehyde compound (5), the yield being 87%. All. This can be obtained by first reacting POCl ₃ with a solvent at low temperature to obtain an electrophilic substance, and then slowly adding 2-methyl-1H-indole (4) and sodium hydroxide or potassium hydroxide.

At this time, the solvent may be DMF and the like, the reaction is preferably stirred for 10 to 60 minutes at -10 ~ 10 ℃.

The chemical structure of 2-methyl-1H-indole-3-carbaldehyde compound (5) can be confirmed by the ¹ H NMR spectrum, showing a new peak of δ10.058 ppm for -CHO instead of one aromatic proton (FIG. 7). ESIMS analysis showed molecular ion peaks of m / z 158 .4 [MH] ^- , 160.4 [M + H] ⁺ , and 182.3 [M + Na] ⁺ , corresponding to the molecular formula C ₁₀ H ₉ NO (FIG. 8). Reference).

In the fifth step of the reaction, an intermediate compound ethyl 2- (3-formyl-2-methyl-1H-indol-1-yl) acetate compound (6) can be obtained, which is 2-methyl-1H-indole-. This is the result of N -substitution of 2-methyl-1H-indole-3-carbaldehyde compound (5) by adding a base and ethyl bromoacetate or ethylchloroacetate to 3-carbaldehyde compound (5). The yield is 86%.

In this case, tetrahydrofuran (THF), DMF, acetone, and the like may be used as the solvent, and NaH, K ₂ CO ₃ , or the like may be used as the base. It is preferable to stir reaction conditions for 10 to 60 minutes at -10-10 degreeC.

The chemical structure of the ethyl 2- (3-formyl-2-methyl-1H-indol-1-yl) acetate compound (6) can be confirmed by the ¹ H NMR spectral results, and a new compound instead of the indole-NH signal at δ 11.962 ppm was obtained. The signal is observed. That is, quartet -CH ₂ is represented as δ 4.208-4.155 ppm, triplet -CH 3 This is represented by δ 1.241-1.205 ppm (see FIG. 9). ESIMS analysis showed the molecular ion peak of m / z 244.4 [MH] ^- , 246.4 [M + H] ⁺ , 268.4 [M + Na] ⁺ , corresponding to the molecular formula C ₁₄ H ₁₅ NO ₃ (see FIG. 10). ).

Finally, in the sixth step of the reaction, the final product is "(E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl)" Hydrazono) methyl) -1H-indol-1-yl) acetate ", which is a condensation of the hydrazide product (3) and aldehyde product (6) obtained in the previous step with a catalyst in a solvent. The result is. Yield 75%.

In this case, ethanol, methanol, and the like may be used as the solvent, and acetic acid, sulfur phase, hydrochloric acid and the like may be used as the catalyst. It is preferable to stir reaction conditions at 50-100 degreeC for 1 to 10 hours.

The chemical structure of the final product compound (7) can be confirmed by ¹ H NMR, ¹³ C NMR, mass analysis. ¹ H NMR showed a single δ11.838 ppm for amide proton O = C-NH- and a single δ8.862 ppm for azomethine proton-CH = N-, with 11 aromatic protons δ8.438- Observed between 7.198 ppm, δ5.192 ppm for -N-CH ₂ , δ4.211-4.158 ppm for -O-CH ₂ , δ1.249-1.214 ppm for -CH ₃ , and bound to an aromatic ring is observed as δ2.505 ppm with respect to the -CH ₃ (see Fig. 11). ¹³ C NMR spectra of the final product (7) show only a total of 27 carbon signals (see Fig. 12), mass spectrum analysis m / zm / z 452.6 [MH ] -, 454.6 [M + H] +, 476.5 [M A molecular ion peak of + Na] ⁺ appears, corresponding to the molecular formula C ₂₇ H ₂₃ N ₃ O ₄ (see FIGS. 13 and 14).

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

EXAMPLE

Unless otherwise specified in this experiment, all reactions were carried out in an oven-dried glass container and nitrogen (N ₂ ) environment, and the mixing reaction was stirred with a Teflon-coated magnetic bar. In addition, the reaction was monitored using fluorescent labeling (Merck) on thin silica gel chromatography (TLC) silica gel (Kieselgel 60 F254) plates. Plates were checked with slow heating with UV, acidic p- anisaldehyde, phosphomolybdic acid and 10% ethanol H ₂ SO ₄ dye. Solvent was removed under reduced pressure with a standard rotary evaporator. The products of each reaction step were purified by silica gel (particle size 40-63 μM, Merck) flashcolumn chromatography using the solvent system described in the instructions.

It demonstrates concretely below.

Example 1 Synthesis of Naphtho [2,1-b] furan-2-carboxylic Acid Compound (2a)

Under nitrogen atmosphere, anhydrous potassium carbonate (K ₂ CO ₃ ) (64.13 g, 290 mmol) in a solution of 2-hydroxy-1-naphthaldehyde (1) (10 g, 58 mmol) in anhydrous dimethylformamide (DMF) (150 mL). ) Was added. The mixture was stirred at rt for 30 min and then ethyl bromoacetate (8.36 mL, 75 mmol) was added. Thereafter, the obtained reaction mixture was heated to 140 ° C., stirred for 22 hours, cooled at room temperature, and poured with cold water. The resultant was filtered, washed with water and dried, recrystallized from diethyl ether to give a light brown solid compound naphtho [2,1-b] furan-2-carboxylic acid compound (2a) (11.3 g, yield 92%) ( R _f = 0.14) and ethyl naphtho [2,1-b] furan-2-carboxylic acid compound (2b) (0.7 g, yield 5%) as a yellow solid compound (R _{f =} 0.87) (hexane: ethyl acetate = 1: 1) to give a purified product.

The ¹ H NMR and ¹³ C NMR Spectrum results for the obtained naphtho [2,1-b] furan-2-carboxylic acid compound (2a) are shown in FIG. 1, and the Mass Spectrum results are shown in FIG. 2.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 8.269-8.250 (1H, d, J = 7.6, Ar-H), 8.000-7.980 (1H, d, J = 8, Ar-H), 7.788- 7.765 (1H, d, J = 9.2, Ar-H), 7.727-7.704 (1H, d, J = 9.2, Ar-H), 7.558-7.599 (1H, t, J = 7.6, Ar-H), 7.541 (1H, s, Ar-H), 7.498-7.460 (1H, t, J = 7.6, Ar-H); ¹³ C NMR (100 MHz, DMSO- d ₆ ): δ ppm: 161.293, 156.558, 150.965, 129.704, 128.491, 127.679, 126.142, 124.875, 124.263, 123.6, 123.465, 112.824, 105.238; ESIMS found: m / z 211.4 [M ⁻ H] ⁻ .

Example 2: Synthesis of Esterethylnaphtho [2,1-b] furan-2-carboxylic Acid Compound (2b)

Dichloromethane was obtained in a round-bottomed flask in which the naphtho [2,1-b] furan-2-carboxylic acid compound (2a) (10.0 g, 47 mmol) obtained in Example 1 was dried in an oven-dried flask under nitrogen atmosphere. (CH ₂ Cl ₂ ) (100 mL) and absolute ethanol (EtOH) (150 mL). The solution was cooled to 0 ° C. in an ice bath, and thionyl chloride (SOCl ₂ ) (5.1 mL, 70.5 mmol) was slowly added in the form of droplets with a syringe. The resulting reaction was stirred at 0 ° C. for 30 minutes, at 50 ° C. for 6 hours, and the solvent was removed and diluted with H ₂ O and ethyl acetate. The layers were separated, the aqueous layer was removed with ethyl acetate (3 × 250 mL), the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The concentrate was recrystallized from diethyl ether and hexane to obtain a purified product of ethyl naphtho [2,1-b] furan-2-carboxylic acid compound (2b) (6.8 g, yield 60%) as a yellow solid compound. .

The ¹ H NMR Spectrum results for the obtained ethylnaphtho [2,1-b] furan-2-carboxylic acid compound (2b) are shown in FIG. 3, and the Mass Spectrum results are shown in FIG. 4.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 8.466-8.448 (1H, d, J = 7.2, Ar-H), 8.464 (1H, s, Ar-H), 8.091-8.071 (1H, d, J = 8, Ar-H), 8.049-8.027 (1H, d, J = 8.8, Ar-H), 7.892-7.868 (1H, d, J = 8.8, Ar-H), 7.714-7.673 (1H, t , J = 8.2, Ar-H), 7.614-7.573 (1H, t, J = 8.2, Ar-H), 4.424-4.370 (2H, q, J = 7.2, -O-CH ₂ ), 1.388-1.353 ( 3H, t, J = 7.2, -CH ₃ ); ESIMS found: m / z 241.4 [M + H] ⁺ , 263.4 [M + Na] ⁺ ; R _{f =} 0.87 (hexane: ethyl acetate = 1: 1).

Example 3: Naphtho [2,1- b ] Synthesis of furan-2-carbohydrazide compound (3)

Hydrazine hydrate (NH ₂ NH ₂ ) in ethanol (EtOH) (100 mL) solution of ethylnaphtho [2,1-b] furan-2-carboxylic acid (2b) (5 g, 20.8 mmmol) obtained in Example ₂ H ₂ O) 5 mL was added. The reaction mixture was heated at 70 ° C. and stirred for 4 hours, then cooled to room temperature and poured cold water. This was filtered, washed with water and dried, and then recrystallized from diethyl ether and hexane to give a pale yellow solid compound naphtho [2,1- b ] furan-2-carbohydrazide compound (3) (3.4 g, yield 72%). The purified product of) was obtained.

The ¹ H NMR Spectrum results for the obtained naphtho [2,1- b ] furan-2-carbohydrazide compound (3) are shown in FIG. 5, and the Mass Spectrum results are shown in FIG. 6.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 10.049 (1H, s, O = C-NH-), 8.340-8.320 (1H, d, J = 8.0, Ar-H), 8.175 (1H, s , Ar-H), 8.080-8.060 (1H, d, J = 8.0, Ar-H), 7.978-7.954 (1H, d, J = 9.6, Ar-H), 7.816-7.794 (1H, d, J = 8.8, Ar-H), 7.697-7.657 (1H, t, J = 8, Ar-H), 7.591-7.550 (1H, t, J = 8.2, Ar-H), 4.597 (2H, s, -NH ₂ ); ESIMS found: m / z 225.4 [M−H] ⁻ , 227.4 [M + H] ⁺ , 249.4 [M + Na] ⁺ ; R _f = 0.17 (hexane: ethyl acetate = 1: 1).

Example 4: Synthesis of 2-methyl-1H-indole-3-carbaldehyde compound (5)

Anhydrous N, N- dimethylformamide (DMF) (12.6 mL, 163.4 mmol) was added to a 250 mL three-necked round bottom flask with N ₂ -purge and cooled to 0 ° C. in an ice bath. This is in phosphorus oxychloride _{(POCl 3) (phosphorus oxychloride)} (3.9 mL, 41.84 mmol) and then slowly added and the mixture was stirred at 0 ℃ for 40 minutes. To this, a solution of 2-methyl-1H-indole (4) (4.8 g, 36.5 mmol) in DMF (7.5 mL) was added slowly, maintaining the temperature below 5 ° C. The resulting solution was stirred at 0 ° C. for 40 minutes, then warmed at room temperature and further stirred for 40 minutes. Ice cubes were then added to the flask and sodium hydroxide (NaOH) solution (16.5 g, 412.5 mmol dissolved in 50 mL of water) was added dropwise using a dropping funnel with vigorous stirring. The obtained solution was heated to 100 ° C, stirred for 30 minutes, and then cooled at room temperature. The pale yellow precipitate obtained was filtered, washed with water and dried, and then recrystallized from diethyl ether and hexane to purify 2-methyl-1H-indole-3-carbaldehyde compound (5) (5.0 g, 87%) as a pale yellow solid. The product was obtained.

The ¹ H NMR Spectrum results for the obtained 2-methyl-1H-indole-3-carbaldehyde compound (5) are shown in FIG. 7, and the Mass Spectrum results are shown in FIG. 8.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 11.962 (1H, s, -NH), 10.058 (1H, s, -CHO), 8.054-80.33 (1H, dd, J = 8.4, 2.0, Ar- H), 7.396-7.373 (1H, doublet of doublets, J = 6.6, 2.4, Ar-H), 7.188-7.130 (2H, m, Ar-H), 2.681 (3H, s, -CH ₃ ); ESIMS found: m / z 158.4 [M−H] ⁻ , 160.4 [M + H] ⁺ , 182.3 [M + Na] ⁺ ; R f = 0.29 (hexane: ethyl acetate = 1: 1).

Example 5: Synthesis of Ethyl 2- (3-formyl-2-methyl-1H-indol-1-yl) acetate Compound (6)

2-Methyl-1H-indole-3-carbaldehyde (5) (3 g, 18.8 mmol) in tetrahydrofuran (THF) (50 mL) was cooled to 0 ° C. in an ice bath and then sodium hydride (NaH) (sodium) hydride) (60% dispersion in mineral oil) (1.5 g, 37.6 mmol). The mixture was stirred at 0 ° C. for 30 minutes and then ethyl bromoacetate (2.5 mL, 28.6 mmol) was added. The mixture was stirred at 0 ° C. for 30 minutes and then warmed at room temperature (rt) and stirred for 3 hours. TLC at this time showed exhaustion of the starting material. The reaction mixture was cooled and cooled with ice water. The THF solvent was removed under vacuum and the remainder diluted with H ₂ O and ethyl acetate. The layers were separated, the aqueous layer was extracted with ethyl acetate (3 × 200 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The concentrate was recrystallized from diethyl ether and hexane to give a pale yellow solid compound of ethyl 2- (3-formyl-2-methyl-1H-indol-1-yl) acetate compound (6) (4.0 g, yield 86%). Purified product was obtained.

The ¹ H NMR Spectrum results for the obtained ethyl 2- (3-formyl-2-methyl-1H-indol-1-yl) acetate compound (6) are shown in FIG. 9, and the Mass Spectrum results are shown in FIG. 10.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 10.125 (1H, s, -CHO), 8.125-8.103 (1H, dd, J = 7.6, 2.8, Ar-H), 7.530-7.508 (1H, dd) , J = 6.8, 2, Ar-H), 7.255-7.200 (2H, m, Ar-H), 5.236 (2H, s, -N-CH ₂ ), 4.208-4.155 (2H, q, J = 7.2, -O-CH ₂ ), 2.652 (3H, s, -CH ₃ ), 1.241-1.205 (3H, t, J = 7.2, -CH ₃ ); ESIMS found: m / z 244.4 [M−H] ⁻ , 246.4 [M + H] ⁺ , 268.4 [M + Na] ⁺ _; R f = 0.53 (hexane: ethyl acetate = 2: 1).

Example 6: (E) -Ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) -1H-indole- 1-yl) acetate compound (7)

Naphtho [2,1- b ] furan-2-carbohydrazide compound (3) solution (2 g, 8.8 mmol), ethyl 2- (3-formyl-2-methyl-1H-indol-1-yl) acetate 200 ml of a solution of compound 6 (2.16 g, 8.8 mmol) and a catalytic amount of acetic acid (AcOH) (10 ml) of ethanol (EtOH) was stirred at 90 ° C for 4 hours. TLC analysis showed that the starting material was exhausted. After cooling the reaction mixture at room temperature, ice water was added, and the separated solid mass was filtered, washed with water and dried. The remainder was purified by silica gel flash column chromatography using a hexane: ethyl acetate (1: 1) mobile phase, and finally (E) -ethyl 2- (2-methyl-3-((2- ( Naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) -1H-indol-1-yl) acetate compound 7 (3 g, yield 75%) was obtained.

Obtained (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) -1H-indol-1-yl ) in the ¹ H NMR Spectrum Figure 11 the results for the acetate compound (7), ¹³ C NMR Spectrum Figure 12 the result, the result of DEPT NMR Spectrum Figure 13 a, Mass Spectrum results are shown in Fig.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 11.838 (1H, s,), 8.862 (1H, s,), 8.438-8.418 (1H, d, J = 8, Ar-H), 8.355-8.307 (2H, dd, J = 8.8, 3.6, Ar-H), 8.114-8.094 (1H, d, J = 8.0, Ar-H), 8.041-8.018 (1H, d, J = 8.0, Ar-H), 7.891-7.869 (1H, d, J = 8.8, Ar-H), 7.731-7.694 (1H, t, J = 7.2, Ar-H), 7.622-7.585 (1H, t, J = 8.0, Ar-H) , 7.483-7.461 (1H, t, J = 8.8, Ar-H), 7.217-7.198 (2H, m, Ar-H), 5.192 (2H, s, -N-CH ₂ ), 4.211-4.158 (2H, q, J = 7.2, -O-CH ₂ ), 2.505 (3H, s, -CH ₃ ), 1.249-1.214 (3H, t, J = 7.2, -CH ₃ ); ¹³ C NMR (100 MHz, DMSO- d ₆ ): δ ppm: 168.602, 153.88, 152.217, 148.131, 145.138, 141.430, 137.031, 130.101, 128.833, 128.178, 127.482, 127.271, 125.388, 124.674, 123.720, 122.755, 122.242, 122.242 , 120.985, 112.485, 109.656, 109.539, 108.235, 61.201, 44.431, 14.026, 9.961. ESIMS found: m / z 452.6 [M−H] ⁻ , 454.6 [M + H] ⁺ , 476.5 [M + Na] ⁺ _; R _{f =} 0.50 (hexane: ethyl acetate = 1: 2).

According to the compound of the present invention, it can be used as an excellent anticancer agent because it can inhibit cell mitosis and induce cell death by binding to tubulin and inhibiting microtubule polymerization.

According to the method for synthesizing the compound of the present invention, since the reaction is simple and the yield is very high with efficiency of 60% or more, an effective synthesis method can be provided.

Claims (9)

1. (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) methyl) -1H-indole represented by the formula -1-yl) acetate compound.

   [Formula I]

   
2. The compound of claim 1, wherein the compound is a tubulin polymerization inhibitor.
3. (E) -ethyl 2- (2-methyl-3-((2- (naphtho [2,1-b] furan-2-carbonyl) hydrazono) according to claim 1, comprising the following steps: Synthesis method of methyl) -1H-indol-1-yl) acetate.

   (a) a first step of condensation reaction between 2-hydroxy-1-naphthaldehyde and ethyl bromoacetate;

   (b) a second step of esterifying naphtho [2,1-b] furan-2-carboxylic acid in the product obtained in the first step;

   (c) a third step of hydrazineing the product obtained in the second step;

   (d) a fourth step of formylating 2-methyl-1H-indole;

   (e) a fifth step of nucleophilic substitution reaction of the product obtained in the fourth step; And

   (f) a sixth step of condensing the product obtained in the third step with the product obtained in the fifth step.
4. 4. The method of claim 3, wherein the condensation reaction of the first step uses anhydrous K ₂ CO ₃ as a base and dimethylformamide (DMF) as a solvent.
5. The method of claim 3, wherein the second esterification reaction comprises using ethanol and SOCl ₂ .
6. 4. The method according to claim 3, wherein the hydrazine reaction of the third step uses hydrazine hydrate.
7. The method of claim 3, wherein the formylation reaction of the fourth step is carried out by reacting dimethylformamide (DMF) with POCl ₃ as a solvent and further reacting 2-methyl-1H-indole thereto. .
8. 4. The method according to claim 3, wherein the nucleophilic substitution reaction of the fifth step uses NaH and ethyl bromoacetate as bases.
9. 4. The synthesis method according to claim 3, wherein the condensation reaction of the sixth step uses acetic acid as a catalyst.

Images