KR101932347B1 - Novel Ajoene derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel azo derivative, a process for its production, and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient. The novel azo derivative according to the present invention is useful as a renal cancer cell line (ACHN) Which can inhibit the proliferation of cancer cells (MDA-MB-231), colon cancer cell line (HCT-15), prostate cancer cell line (PC-3), gastric cancer cell line (NUGC- And it can be usefully used as a pharmaceutical composition for preventing or treating cancer containing it as an active ingredient.

Description

TECHNICAL FIELD The present invention relates to a novel azo derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. ingredient}

The present invention relates to a novel azo derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Ajoene is a natural product formed from garlic-derived organosulfur compound Allicin, which contains allyl sulfoxide and vinyl disulfide and exists as an E / Z isomer.

It has been reported that azoin exhibits anti-cancer, antibacterial, antifungal, anti-hypertrophic activity and platelet aggregation inhibitory activity and induces apoptosis in human promyeloleukemic cells.

On the other hand, studies on the inhibition of cancer cell proliferation of various organosulfur compounds including azoenes and the development of anticancer drugs based on the studies have been made in the past, but they remain at a level that confirms the mechanism of inhibiting cancer cell proliferation (Non-Patent Document 1 ), Cancer growth inhibiting activity and physical properties that are required as effective ingredients of anticancer agents are not ensured, and new anticancer active substances based on the structure of organic sulfur compounds derived from garlic are required to be discovered.

Accordingly, the inventors of the present invention have uncovered novel organic sulfur compounds based on the structure of azoenes, which are relatively stable, in order to develop organic sulfur compounds having improved drug efficacy and selectivity for the purpose of anti-cancer. The novel azo-type derivatives proposed in the present invention exhibit cancer-inhibiting activity at an intended level, from which a pharmaceutical composition for the prevention or treatment of cancer or a health functional food composition for preventing or ameliorating cancer The present invention has been completed.

The garlic compound ajoene targets protein folding in the endoplasmic reticulum of cancer cells, KASCHULA et al., Molecular Carcinogenesis, 55 (8): 1213-28 (2016).

It is an object of the present invention to provide a compound represented by the following general formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R < ¹ > is allyl, or unsubstituted or substituted benzyl,

Wherein said substituted benzyl is selected from the group consisting of hydroxy, amine, nitro, cyano, halogen, allyl, unsubstituted or substituted C _1-5 straight or branched chain alkyl, and unsubstituted or substituted C _1-5 Linear or branched alkoxy, may be substituted with one or more substituents selected from the group consisting of halogen,

Wherein said substituted alkyl and substituted alkoxy can be independently substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, an amine, a nitro, and a cyano;

R ² is an unsubstituted or substituted C _2-6 straight or branched chain alkenyl, unsubstituted or substituted C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _1-5 straight or branched Alkoxy, or unsubstituted or substituted C _1-3 alkyl C _6-10 aryl,

Wherein said substituted alkenyl, substituted alkyl, substituted alkoxy and substituted alkylaryl are independently selected from the group consisting of hydroxy, halogen, amine, nitro, cyano, unsubstituted or substituted C _1-3 straight or branched Alkyl and unsubstituted or substituted C < 1 > ₃ straight or branched alkoxy.

Another object of the present invention is to provide a process for the preparation of

A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1);

Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2);

Reacting the compound represented by the formula (4) prepared in the step 2 with p-TolSO ₂ SR ² (para-toluenesulfonyl-SR ² ) to prepare a compound represented by the formula (5) (step 3); And

And a step (step 4) of preparing a compound represented by the formula (1) from the compound represented by the formula (5) prepared in the step (3).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

Wherein R ¹ and R ² are the same as defined in the above formula (1). .

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer containing the above-mentioned Ajoene derivative as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or ameliorating cancer containing the above-mentioned Ajoene derivative as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R < ¹ > is allyl, or unsubstituted or substituted benzyl,

Wherein said substituted benzyl is selected from the group consisting of hydroxy, amine, nitro, cyano, halogen, allyl, unsubstituted or substituted C _1-5 straight or branched chain alkyl, and unsubstituted or substituted C _1-5 Linear or branched alkoxy, may be substituted with one or more substituents selected from the group consisting of halogen,

Wherein said substituted alkyl and substituted alkoxy can be independently substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, an amine, a nitro, and a cyano;

R ² is an unsubstituted or substituted C _2-6 straight or branched chain alkenyl, unsubstituted or substituted C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _1-5 straight or branched Alkoxy, or unsubstituted or substituted C _1-3 alkyl C _6-10 aryl,

Wherein said substituted alkenyl, substituted alkyl, substituted alkoxy and substituted alkylaryl are independently selected from the group consisting of hydroxy, halogen, amine, nitro, cyano, unsubstituted or substituted C _1-3 straight or branched Alkyl and unsubstituted or substituted C < 1 > ₃ straight or branched alkoxy.

The present invention also relates to a process for producing a compound represented by the formula (1)

A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1);

Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2);

Reacting the compound represented by the formula (4) prepared in the step 2 with p-TolSO ₂ SR ² (para-toluenesulfonyl-SR ² ) to prepare a compound represented by the formula (5) (step 3); And

And a step of preparing a compound represented by the formula (1) from the compound represented by the formula (5) prepared in the above step (3).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

Wherein R ¹ and R ² are independently as defined in the above formula (1).

Further, the present invention provides a health functional food composition for preventing or ameliorating cancer, which comprises a compound represented by the above-mentioned formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel azo derivatives according to the present invention are useful for the treatment and prophylaxis of kidney cancer cell lines (ACHN), breast cancer cell lines (MDA-MB-231), colon cancer cell lines (HCT-15), prostate cancer cell lines (PC- 3), and lung cancer cell line (NCI-H23), and can be effectively used as a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Hereinafter, the present invention will be described in detail.

The following description is provided to assist the understanding of the invention, and the present invention is not limited to the following description.

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R < ¹ > is allyl, or unsubstituted or substituted benzyl,

Wherein said substituted benzyl is selected from the group consisting of hydroxy, amine, nitro, cyano, halogen, allyl, unsubstituted or substituted C _1-5 straight or branched chain alkyl, and unsubstituted or substituted C _1-5 Linear or branched alkoxy, may be substituted with one or more substituents selected from the group consisting of halogen,

Wherein said substituted alkyl and substituted alkoxy can be independently substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, an amine, a nitro, and a cyano;

R ² is an unsubstituted or substituted C _2-6 straight or branched chain alkenyl, unsubstituted or substituted C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _1-5 straight or branched Alkoxy, or unsubstituted or substituted C _1-3 alkyl C _6-10 aryl,

Wherein said substituted alkenyl, substituted alkyl, substituted alkoxy and substituted alkylaryl are independently selected from the group consisting of hydroxy, halogen, amine, nitro, cyano, unsubstituted or substituted C _1-3 straight or branched Alkyl and unsubstituted or substituted C < 1 > ₃ straight or branched alkoxy.

Preferably,

Wherein R < ¹ > is allyl, or unsubstituted or substituted benzyl,

Wherein said substituted benzyl is selected from the group consisting of hydroxy, halogen, unsubstituted or substituted C _1-3 straight or branched chain alkyl, and unsubstituted or substituted C _1-3 straight or branched chain alkoxy. Lt; RTI ID = 0.0 > 1, < / RTI >

Wherein said substituted alkyl and substituted alkoxy may be independently substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, an amine, a nitro, and a cyano.

Preferably,

Wherein R ² is an allyl, unsubstituted or substituted C _1-3 linear or branched alkyl, or unsubstituted or substituted benzyl,

Wherein said substituted alkyl, substituted benzyl is independently selected from the group consisting of a hydroxy group, a halogen, an amine, a nitro, a cyano, an unsubstituted or substituted C _1-3 linear or branched alkyl and an unsubstituted or substituted C _1- with one or more substituents selected from the group consisting of the ₃ straight or branched alkoxy which may be substituted.

More preferably,

Wherein R ¹ is allyl, unsubstituted benzyl, or benzyl substituted with one or more methoxy;

,

,

,

,

,

또는

일 수 있다.Wherein R < ^{2 &}

,

,

,

,

,

or

Lt; / RTI >

Most preferably,

The compound represented by Formula 1 is any compound selected from the following group of compounds:

(1) (E) -1- (3- (Allylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(2) (Z) -1- (3- (allylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(3) (E) -1- (3- (Allylsulfinyl) prop-1-enyl) -2-benzyldisulfane;

(4) (Z) -1- (3- (Allylsulfinyl) prop-1-enyl) -2-benzyldisulfane;

(5) (E) -1- (3- (Allylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl) dicyclene;

(6) (Z) -1- (3- (Allylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl) dicarbonate;

(7) (E) -1- (3- (Allylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl) dicyclene;

(8) (Z) -1- (3- (Allylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl) dicarbonate;

(9) (E) -1-Allyl-2- (3- (benzylsulfinyl) prop-1-enyl) dicyclene;

(10) (Z) -1-allyl-2- (3- (benzylsulfinyl) prop-1-enyl) dicyclene;

(11) (E) -1- (3- (Benzylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(12) (Z) -1- (3- (Benzylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(13) (E) -1-Benzyl-2- (3- (benzylsulfinyl) prop-1-enyl) dicyclene;

(14) (Z) -1-benzyl-2- (3- (benzylsulfinyl) prop-1-enyl)

(15) (E) -1- (3- (Benzylsulfinyl) prop-1-enyl) -2- (4- fluorobenzyl)

(16) (Z) -1- (3- (Benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl) dicyclene;

(17) (E) -1- (3- (Phenylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl) dicyclene; And

(18) (Z) -1- (3- (Phenylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl) dicarbonate.

The present invention was carried out to develop a novel anticancer drug by synthesizing isosteric compounds of garlic-derived Ajoene on the basis of its antiproliferative activity against cancer.

Specifically, at the initial stage of the study, the present inventors focused attention on inhibiting the proliferative activity of azoin cancer, and in order to prepare a compound capable of exhibiting a better cancer proliferation inhibitory activity, Respectively.

First, the structure of the equimolar compound considered to be possible is selected. As a candidate group of the equimolar electron compound of azoene, a benzyl group which is equivalent to an allyl group of azoene at the R ¹ position of the representative formula (1) Benzyl substituted with a small methoxynaldazine was sieved to synthesize a compound.

The synthesized allyl or benzyl-based azo compound of equine was first introduced into a variety of human cancer cell lines (kidney cancer cell line (ACHN), breast cancer cell line (MDA-MB-231), colon cancer cell line (HCT-15), prostate cancer cell line (GI ₅₀ ) was evaluated by examining the cancer growth inhibitory activity of the cancer cell line (PC-3), the gastric cancer cell line (NUGC-3) and the lung cancer cell line (NCI-H23) Which is superior to azoene in electron donating ability.

Thus, the present inventors have confirmed that a compound in which azo enantiomeric compound, R ¹ is allyl, benzyl, or substituted benzyl is suitable as a novel anti-cancer agent candidate group.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

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

Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by Formula 1 and pharmaceutically acceptable salts thereof.

The present invention also relates to a process for producing a compound represented by the formula (1)

A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1);

Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2);

Reacting the compound represented by the formula (4) prepared in the step 2 with p-TolSO ₂ SR ² (para-toluenesulfonyl-SR ² ) to prepare a compound represented by the formula (5) (step 3); And

And a step of preparing a compound represented by the formula (1) from the compound represented by the formula (5) prepared in the above step (3).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

Wherein R ¹ and R ² are independently as defined in the above formula (1).

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In the process for preparing a compound represented by the formula (1) according to the present invention, the step (1) is a step for preparing a compound represented by the formula (3) from a compound represented by the formula (2).

At this time, It can be understood as a propargylation reaction. Useful for but not limited to, but conducted the iodonium salt _{^{(R 1 SC (¼NH 2)}} NH 2 þ Br) from the reaction by the addition of propargyl halo fluoride with thiol R ¹ SH or iso Im OY equivalent, in the reaction , The reaction temperature may be 10-40 캜, preferably 20-30 캜, and room temperature. However, the reaction time may be 0.5-20 hours, preferably 1-10 hours, It does not. In addition, the conditions such as the above-mentioned temperature and reaction time may be varied according to the object to be performed, and the present invention includes the scope of performing the object of the present invention or changing the object according to the object.

In the process for preparing the compound represented by the formula (1) according to the present invention represented by the above Reaction Scheme 1, the above Step 2 is a step for preparing the compound represented by the formula (4) from the compound represented by the formula (3) .

In this case, the step 2 may be understood as a radical addition reaction, but it is not limited thereto. Alternatively, the compound prepared in the step 1 may be reacted with a radical initiator and thioacetic acid in the form of a stereoisomeric mixture, O acetate. In the above reaction, the reaction temperature may be 60-100 ° C., preferably 70-90 ° C. However, the reaction time is not limited thereto. And is not particularly limited. In addition, the conditions such as the above-mentioned temperature and reaction time may be varied according to the object to be performed, and the present invention includes the scope of performing the object of the present invention or changing the object according to the object.

In step (3), the compound of formula (4) and p-TolSO ₂ SR ² (para-toluenesulfonyl- SR < ² >) to prepare a compound represented by the formula (5).

In this case, step 3 can be understood as a sulfenylation reaction with vinyl disulfide. However, the compound prepared in step 2 is not limited to S-allyl p-toluenesulfonyl thioate or a compound equivalent thereto To thereby prepare a target compound which is a vinyl disulfide. In the above reaction, the reaction temperature may be -20 to 10 ° C, preferably -10 to 0 ° C, but it is the temperature in the progress of the reaction, and when adding each compound, liquefied nitrogen, liquefied nitrogen / acetone nitrile The reaction time may be adjusted according to the present invention as long as the reaction proceeds completely and the reaction product can be maximally converted. And is preferably carried out for 0.5 to 10 hours, more preferably for 1 to 5 hours, but is not particularly limited. In addition, the conditions such as the above-mentioned temperature and reaction time may be varied according to the object to be performed, and the present invention includes the scope of performing the object of the present invention or changing the object according to the object.

In the process for preparing a compound represented by the general formula (1) of the present invention represented by the above-mentioned Reaction Scheme 1, the above Step 4 is a step for preparing a compound represented by the general formula (1) from a compound represented by the general formula (5) .

In this case, step 4 may be understood as an oxidation reaction. But are not limited to, the step of obtaining the final desired compound as an E / Z mixture or a single stereoisomer by adding the compound prepared in step 3 above with m-CPBA or a compound equivalent thereto. In the above reaction, the reaction temperature may be 0 to 30 ° C, preferably 10 to 20 ° C, and preferably, liquefied nitrogen, liquefied nitrogen / acetone nitrile or liquefied nitrogen / acetone is added The reaction may be carried out at room temperature over a period of several hours, but not limited thereto, the reaction time may be a time during which the reaction proceeds completely and the reaction product can be maximally converted Is included in the present invention, and is not particularly limited. In addition, the conditions such as the above-mentioned temperature and reaction time may be varied according to the object to be performed, and the present invention includes the scope of performing the object of the present invention or changing the object according to the object.

The manufacturing method of the present invention described above can be carried out in the most preferred form as in the production examples and the embodiments of the present invention. However, the present invention is not limited thereto.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the above-mentioned formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The cancer may be at least one selected from the group consisting of caustic myxoma, intrahepatic biliary cancer, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, oral cancer, oral cancer, bacterial sarcoma, acute myelogenous leukemia, acute lymphoblastic leukemia, Cholangiocarcinoma, chronic lymphocytic leukemia, choroidal melanoma, diffuse large B cell lymphoma, bladder cancer, bladder cancer, peritoneal cancer, metastatic breast cancer, breast cancer, Pancreatic cancer, pancreatic cancer, kidney cancer, kidney cancer, cardiac cancer, duodenal cancer, pancreatic cancer, pancreatic cancer, pancreatic cancer, pancreatic cancer, pancreatic cancer, pancreatic cancer, Malignant soft tissue tumor, malignant osteoma, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovary, vulvar cancer, urethral cancer, urethral cancer, unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms' tumor, breast The present invention provides a method of treating cancer, cancer, sarcoma, penile cancer, pharyngitis, pregnancy chorioamnion, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, A cancer selected from the group consisting of Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell cancer, lung cancer, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, Or more, and may preferably be at least one kind of cancer selected from the group consisting of kidney cancer, breast cancer, colon cancer, prostate cancer, stomach cancer, lung cancer, and childhood cancer.

The present invention also provides a health functional food composition for preventing or ameliorating cancer, which comprises a compound represented by the above-mentioned formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The following experiment was conducted to evaluate the cancer growth inhibitory activity of the novel azo derivative according to the present invention.

(Kidney cancer cell line (ACHN), breast cancer cell line (MDA-MB-231), colorectal cancer cell line (HCT-15), and colon cancer cell line) as the allyl or benzyl- (GI ₅₀ ) of prostate cancer cell line (PC-3), gastric cancer cell line (NUGC-3) and lung cancer cell line (NCI-H23) (AJOENE), which is known to have a cancer-suppressing activity in the past (see Experimental Example 1 below).

Hereinafter, the present invention is described in detail by way of Production Examples, Examples and Experimental Examples.

However, the following Production Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Production Examples, Examples and Experimental Examples.

≪ Preparation method > Para-toluenesulfonyl-SR ² Manufacturing

To a solution of DMF (1 M) in which potassium p-toluene thiosulfonate (1 eq) was dissolved, R ² X (X = ¼Cl or Br; 1.0 eq.) Was dissolved in DMF without solvent or slowly added via syringe . Then, it was stirred at room temperature for 3 hours or heated while confirming the conversion of R ² C by TLC, after which the reaction was terminated with saturated aqueous NaHCO ₃ . The resulting mixture was extracted with dichloromethane, and the obtained organic extract was dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using a hexane / ethyl acetate mixture to give the desired compound.

PREPARATION EXAMPLE 1 Synthesis of toluene-4-thiosulfonic acid, S-2-propen-1-yl ester

Obtained form: pale yellow oil (90.7%); R _f = 0.34 (n-hexane / Ethyl acetate 10: 1); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.48 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 5.57-5.67 (1H, m), 5.09-5.14 (1H, m), 4.99-5.03 (2H, m), 3.57-3.59 (2H, m), 2.36 (3H, s); ¹³ C NMR (100 MHz, CDCl 3)? 144.4, 141.4, 130.1, 129.3, 126.5, 119.6, 38.3, 21.3.

PREPARATION EXAMPLE 2 Preparation of toluene-4-thiosulfonic acid, S-propyl ester

Obtained form: pale yellow oil (80.5%)%); R _f = 0.29 (n-hexane / Ethyl acetate 10: 1); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.81 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 2.96 (2H, t, J = 7.2 Hz), 2.45 (3H , s), 1.58-1.68 (2H, m), 0.92 (3H, t, J = 7.2 Hz); ¹³ C NMR (100 MHz, CDCl ₃ )? 144.7, 142.0, 129.8, 126.9, 37.9, 22.1, 21.6, 13.1.

PREPARATION EXAMPLE 3 Toluene-4-thiosulfonic acid, S-benzyl ester

Obtained form: white solid (96.4%); R _f = 0.36 (n-hexane / ethyl acetate 10: 1); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.72 (2H, d J = 8.4 Hz), 7.26 (2H, d J = 8.4 Hz), 7.20-7.23 (3H, m), 7.16-7.18 (2H, m) , 4.24 (2 H, s), 2.42 (3 H, s); ¹³ C NMR (100 MHz, CDCl ₃ )? 144.6, 141.9, 133.7, 129.7, 129.1, 128.8, 127.9, 126.9, 40.3, 21.6.

PREPARATION EXAMPLE 4 Toluene-4-thiosulfonic acid, S- (4-fluoro-benzyl) ester

Obtained form: white solid (89.5%); R _f = 0.31 (n-hexane / ethyl acetate 8: 1); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.69 (2H, dd, J = 1.6, 6.8 Hz), 7.27 (2H, dd, J = 1.6, 6.8 Hz), 7.13-7.17 (2H, m), 6.88- 6.92 (2H, m), 4.22 (2H, s), 2.43 (3H, s); ¹³ C NMR (100 MHz, CDCl 3)? 144.8, 141.9, 130.8, 130.7, 1209.7, 126.9, 115.8, 115.5, 39.5, 21.6

PREPARATION EXAMPLE 5 Synthesis of toluene-4-thiosulfonic acid, S- (4-methoxy-benzyl) ester

Obtained form: white solid (63.0%); R _f = 0.24 (n-hexane / Ethyl acetate 8: 1); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.69 (2H, dd, J = 1.6, 8.4 Hz), 7.27 (2H, dd, J = 1.6, 8.4 Hz), 7.13-7.17 (2H, m), 6.88- 6.92 (2H, m), 4.22 (2H, s), 2.43 (3H, s); ¹³ C NMR (100 MHz, CDCl 3)? 130.4, 129.7, 126.9, 114.2, 55.3, 39.9, 21.6.

PREPARATION EXAMPLE 6 Toluene-4-thiosulfonic acid, S- (4-chloro-benzyl) ester

Obtained form: pale yellow oil (68.7%); R _f = 0.24 (n-hexane / Ethyl acetate 8: 1); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.67 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8 Hz), 7.17 (1H, dd, J = 2, 6.4 Hz), 7.10 (2H, d, J = 8.8Hz), 4.21 (2H, s), 2.43 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ )? 144.9, 142.1, 133.9, 132.6, 130.5, 129.8, 128.9, 127.0, 39.7, 21.7.

PREPARATION EXAMPLE 7 Synthesis of toluene-4-thiosulfonic acid, S- (3,4-dichloro-benzyl) ester

Obtained form: pale yellow oil (78.9%); R _f = 0.46 (n-hexane / Ethyl acetate 4: 1); ¹ H NMR (400 MHz, CDCl ₃ )? 7.62 (2H, dd, J = 2, 6.8 Hz), 7.21? 7.26 (3H, m), 7.14 dd, J = 2.4, 8.4 Hz), 4.19 (2H, s), 2.42 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ )? 145.0, 141.9, 134.3, 132.5, 131.9, 130.8, 130.4, 129.6, 128.3, 126.9, 39.0, 21.6.

Example 1 Preparation of (E) -1- (3- (allylsulfinyl) prop-1-enyl) -2-propyldisulfane

Step 1: Propargylation reaction

Prop- ₂ -en-1-thiol or the corresponding isothiouronium salt (pro-2-phen-1-SC (NNH ₂ ) NH ₂ Br Br) was dissolved in degassed methanol (0.5 M) And KOH (1.2 equivalents to ethenthiol or 2.5 equivalents to the salt) of solid was added. After 5 min, propargyl bromide (1.5 eq., 80% in toluene) was added and the resulting mixture was allowed to warm to room temperature. After several hours, the propanation reaction was confirmed to be complete by TLC, the methanol was removed under reduced pressure, and the residue was extracted with water and ethyl acetate or dichloromethane (3 times). Subsequently, the solution was dried and the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography with a toluene / hexane mixture to obtain the desired compound as a sulfamide sulfide.

Step 2: Radical addition reaction

Degassed toluene (0.5 M) and AIBN or its equivalent radical initiator (5 mol%) were added to the compound prepared in step 1 above. The resulting mixture was heated to 85 캜 and thioacetic acid (1.1 eq) dissolved in toluene (1 M) was added dropwise over 1 hour. Thereafter, the reaction was stirred to maximize the reaction while confirming by TLC. In some cases, the reaction was allowed to proceed fully by addition of thioacetic acid, with care being taken to avoid formation of adducts. After the reaction was completed, the solvent was removed and the residue was purified by silica gel column chromatography using toluene or an ethyl acetate / petroleum ether mixture to give the title compound Z: E isomer as a mixture of vinyl thioacetate in a weight ratio of 2: 1 Respectively.

Step 3: Sulfonation of vinyl disulfide

The compound prepared in the above step 2 was dissolved in methanol (1 M) and cooled to -40 캜 using a cooling bath of acetone nitrile / liquefied nitrogen. KOH (1.05 eq., 1 M) dissolved in methanol was slowly added by syringe and the resulting mixture was stirred for 20 min and then cooled to -78 [deg.] C using a cooling bath of acetone / liquefied nitrogen. Methanol (1.1 eq., 1 M) in which the compound prepared in Preparative Example 2 was dissolved was added to the above solution with a syringe to make the temperature at 0 ° C, followed by stirring for 2 hours and the reaction was terminated with NH ₄ Cl aqueous solution. The organic product was then extracted with ethyl acetate or dichloromethane (3 times), dried, the solvent was removed, and the residue was purified by column chromatography to give the desired compound as a vinyl disulfide.

Step 4: Oxidation reaction

The compound prepared in step 3 was dissolved in dichloromethane (0.2 M), cooled to -78 ° C under a nitrogen gas, and m-CPBA (1.1 eq.) Was added in one portion. The reaction was allowed to proceed to room temperature over several hours until TLC (40% ethyl acetate / petroleum ether) showed that the reaction had run out. The reaction was quenched with saturated aqueous NaHCO ₃ and the product was extracted with ethyl acetate or dichloromethane (3 times). The obtained organic layer was dried under reduced pressure and concentrated to give a residue. This was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixture to give the final desired compound as an E / Z mixture. In some cases, the stereoisomers could be separated by gravity chromatography using low flow rates, the yield varied from 60 to 90%, and the reaction temperature for optimal conversion was different for each substrate.

2: 1 cis: trans (11.7%, removable)

Obtained form: colorless oil

Rf = 0.36 (n-hexane / ethyl acetate = 1: 2); (E) IR (neat, cm-1) 3082, 2961, 1635, 1610, 1034, 934, 795; (2H, m), 3.69-3.71 (1H, m), 3.59-7.30 (2H, m) 3.61 (2H, m), 3.48-3.50 (1H, m), 2.73 (2H, t, J = 7.2 Hz), 1.69-1.75 (2H, m), 1.01 (3H, t, J = 7.2 Hz); 13 C NMR (100 MHz, CD 3 OD)? 134.6, 125.9, 122.9, 116.0, 53.9, 52.4, 39.6, 21.9, 11.8.

Example 2 Preparation of (Z) -1- (3- (allylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 1 was repeated except that the stereoisomer was obtained as the target compound.

2: 1 cis: trans (11.7%, removable)

Obtained form: colorless oil

Rf = 0.36 (n-hexane / ethyl acetate = 1: 2); (Z) IR (neat, cm-1) 3082, 2961, 2925, 1634, 1612, 1030, 934, 797; (1H, m), 5.44-5.48 (2H, m), 3.63-2.30 (1H, m) 3.75 (3H, m), 3.49-3.53 (1H, m), 2.75 (2H, t, J = 7.2 Hz), 1.70-1.75 (2H, m), 1.01 (3H, t, J = 7.2 Hz); ≪ 13 > C NMR (100 MHz, CD3OD) [delta] 138.9, 125.8, 123.0, 117.7, 63.2, 54.2, 40.5, 21.8, 11.8.

Example 3 Preparation of (E) -1- (3- (allylsulfinyl) prop-1-enyl) -2-benzyldisulfane

The procedure of Example 1 was repeated, except that the compound of Preparation Example 3 was used instead of the compound of Preparation Example 2 used in Step 3 of Example 1 to obtain the target compound.

2: 1 cis: trans (34.0%, removable)

Obtained form: yellow oil

Rf = 0.36 (n-hexane / ethyl acetate = 1: 2); (E) IR (neat, cm-1) 3027, 2962, 2923, 1634, 1602, 1494, 1454, 1030, 935, 796; (2H, m), 3.86 (2H, m), 3.86 (2H, m), 2.50 , s), 3.44-3.53 (2H, m), 3.29-3.39 (2H, m); 13 C NMR (100 MHz, CD 3 OD)? 134.1, 129.1, 128.1, 127.2, 125.8, 122.9, 116.4, 53.8, 52.3, 41.8.

Example 4 Preparation of (Z) -1- (3- (allylsulfinyl) prop-1-enyl) -2-benzyldisulfane

The procedure of Example 3 was repeated except that the stereoisomer was obtained as the target compound.

2: 1 cis: trans (34.0%, removable)

Obtained form: yellow oil

Rf = 0.36 (n-hexane / ethyl acetate = 1: 2); (Z) IR (neat, cm-1) 33028, 2962, 2924, 2360, 2341, 1634, 1600, 1030, 795; (1H, m), 5.32 (1H, d, J = 9.6 Hz) 5.39 (2H, m), 3.88 (2H, s), 3.46 ~ 3.58 (3H, m), 3.33 ~ 3.38 (1H, m); 13 C NMR (100 MHz, CD 3 OD)? 139.4, 130.3, 129.2, 128.2, 126.9, 124.1, 118.7, 55.2, 50.1, 43.6.

Example 5 Preparation of (E) -1- (3- (allylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl)

The procedure of Example 1 was repeated except that the compound of Preparation Example 4 was used in place of the compound of Preparation Example 2 used in Step 3 of Example 1 to obtain the target compound.

5: 3 cis: trans (17.7%, removable)

Obtained form: yellow oil

Rf = 0.33 (n-hexane / ethyl acetate = 1: 2); (E) IR (neat, cm-1) 2962, 2920, 1689, 1599, 1508, 1037, 936, 800; (1H, d, J = 14.4 Hz), 5.84-5.89 (2H, m), 5.41-7.30 (2H, m) 5.48 (2H, m), 3.96 (2H, s), 3.55-3.64 (2H, m), 3.41-3.49 (2H, m); 13 C NMR (100 MHz, CD 3 OD)? 137.3, 130.8, 124.8, 123.1, 118.8, 114.7, 114.1, 105.1, 54.8, 49.6, 41.7.

Example 6 Preparation of (Z) -1- (3- (allylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl)

The procedure of Example 5 was repeated except that the stereoisomer was obtained as the target compound.

5: 3 cis: trans (17.7%, removable)

Obtained form: yellow oil

Rf = 0.33 (n-hexane / ethyl acetate = 2: 1); (Z) IR (neat, cm-1) 2923, 2854, 1731, 1689, 1599, 1508, 1042, 931, 837; (2H, m), 6.33 (1H, d, J = 9.6Hz), 5.89-5.94 (1H, m), 5.63-7.30 (2H, m) 5.69 (1H, m), 5.43-5.48 (2H, m), 3.98 (2H, s), 3.58-3.69 (3H, m), 3.44-3.49 (1H, m); 13 C NMR (100 MHz, CD 3 OD)? 138.3, 131.0, 125.8, 123.0, 117.8, 114.9, 114.7, 105.0, 54.2, 49.1, 41.5.

Example 7 Preparation of (E) -1- (3- (allylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl)

The procedure of Example 1 was repeated, except that the compound of Preparation Example 5 was used instead of the compound of Preparation Example 2 used in Step 3 of Example 1 to obtain the target compound.

2: 1 cis: trans (25.9%, removable)

Obtained form: yellow oil

Rf = 0.36 (n-hexane / ethyl acetate = 1: 2); (E) IR (neat, cm-1) 3002, 2958, 2930, 1608, 1583, 1510, 1032, 933, 833; D, J = 8.4 Hz), 6.87 (2H, d, J = 8.4 Hz), 6.31 m), 5.41-5.48 (2H, m), 3.92 (2H, s), 3.78 (3H, s), 3.58-3.60 (2H, m), 3.47-3.49 (2H, m); 13 C NMR (100 MHz, CD 3 OD)? 135.7, 131.8, 127.2, 124.4, 117.6, 114.9, 55.7, 55.2, 53.8, 42.8.

Example 8 Preparation of (Z) -1- (3- (allylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl)

The procedure of Example 7 was repeated except that the stereoisomer thereof was obtained as a target compound.

2: 1 cis: trans (25.9%, removable)

Obtained form: yellow oil

Rf = 0.36 (n-hexane / ethyl acetate = 1: 2); (Z) IR (neat, cm-1) 2959, 2835, 1607, 1509, 1462, 1030, 795; (1H, d, J = 9.6 Hz), 5.90 (2H, dd, J = (2H, m), 3.94 (2H, s), 3.78 (2H, s), 5.96 ~ 3.49 (1H, m); 13 C NMR (100 MHz, CD 3 OD)? 160.7, 140.0, 131.8, 130.1, 127.2, 124.8, 118.8, 114.9, 55.7, 55.5, 50.5, 43.5.

Example 9 Preparation of (E) -1-allyl-2- (3- (benzylsulfinyl) prop-1-enyl)

Example 1 Step 1 pro-2-pen-l-thiol or the corresponding iodonium salts isobutyronitrile Im OY that used in the (pro-2-pen _{-1-SC (¼NH 2) NH} 2 þ Br,) of the (Benzyl-SC (¼NH ₂ ) NH ₂ þ Br) instead of benzyl-thiol or the corresponding isothioururonium salt (benzyl-SC (¼NH ₂ ) NH ₂ þ Br) To give the desired compound.

2: 1 cis: trans (64.4%, removable)

Obtained form: yellow oil

Rf = 0.22 (n-hexane / ethyl acetate = 2: 1); (2H, m), 5.16-5.22 (2H, m), 6.36 (1H, d, J = , 3.98 (2H, s), 3.44-3.49 (2H, m), 3.29-3.37 (2H, m).

Example 10 Preparation of (Z) -1-allyl-2- (3- (benzylsulfinyl) prop-1-enyl)

The procedure of Example 9 was repeated except that the stereoisomer was obtained as the target compound.

2: 1 cis: trans (64.4%, removable)

Obtained form: yellow oil

Rf = 0.22 (n-hexane / ethyl acetate = 2: 1); M), 5.15-5.20 (2H, m), 6.59 (1H, d, J = 9.6 Hz) , 3.98 (2H, s), 3.53 ~ 3.58 (2H, m), 3.43 ~ 3.49 (2H, m).

Example 11 Preparation of (E) -1- (3- (benzylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 9 was repeated, except that the compound of Preparation Example 2 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 9 to obtain the target compound.

1: 1 cis: trans (60.7%, removable)

Obtained form: yellow oil

Rf = 0.21 (n-hexane / ethyl acetate = 2: 1); (1H, m), 3.98 (2H, s), 3.45 (2H, s), 4.05 (1H, (2H, m), 3.50 (1H, m), 3.29-3.35 (1H, m), 2.72 (2H, t, J = 7.2 Hz), 1.67-1.76 (2H, m), 1.01 (3H, t, J = 7.2 Hz); 13 C NMR (100 MHz, CDCl 3)? 134.9, 130.1, 129.1, 128.5, 116.3, 56.9, 52.9, 40.4, 22.5, 13.1.

Example 12 Preparation of (Z) -1- (3- (benzylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 11 was repeated except that the stereoisomer was obtained as the target compound.

1: 1 cis: trans (60.7%, removable)

Obtained form: yellow oil

Rf = 0.21 (n-hexane / ethyl acetate = 2: 1); (1H, m), 3.97 (2H, s), 3.33 (2H, s), 2.54 (1H, (1H, m), 3.49 (1H, m), 3.28-3.35 (1H, m), 2.69 (2H, t, J = 7.2 Hz).

Example 13 Preparation of (E) -1-benzyl-2- (3- (benzylsulfinyl) prop-1-enyl)

The procedure of Example 9 was repeated, except that the compound of Preparation Example 3 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 9 to obtain the target compound.

2: 1 cis: trans (57.9%, removable)

Obtained form: white solid

Rf = 0.34 (n-hexane / ethyl acetate = 2: 1); (1H, m), 3.92 (2H, s), 3.92 (2H, s), 3.92 (2H, s), 3.33-3.38 (1H, m), 3.19-3.24 (1H, m).

Example 14 Preparation of (Z) -1-benzyl-2- (3- (benzylsulfinyl) prop-1-enyl)

The procedure of Example 13 was repeated except that the stereoisomer was obtained as the target compound.

2: 1 cis: trans (57.9%, removable)

Obtained form: white solid

Rf = 0.34 (n-hexane / ethyl acetate = 2: 1); (1H, m), 3.94 (4H, s), 3.47 (4H, s), 2.50 ~ 3.52 (1H, m), 3.37-3.43 (1H, m); 13 C NMR (100 MHz, CDCl 3)? 138.0, 130.1, 129.4, 129.0, 128.6, 128.4, 127.7, 117.9, 57.4, 49.6, 43.5.

Example 15 Preparation of (E) -1- (3- (benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl)

The procedure of Example 9 was repeated, except that the compound of Preparation Example 4 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 9 to obtain the target compound.

2: 1 cis: trans (63.4%, removable)

Obtained form: Yellow solid

Rf = 0.34 (n-hexane / ethyl acetate = 1: 1); M), 6.98-7.26 (2H, m), 6.15 (1H, d, J = 14.8 Hz), 5.81-5.89 (1H, m) , 3.95 (2H, s), 3.90 (2H, s), 3.34 ~ 3.39 (1H, m), 3.19 ~ 3.25 (1H, m); 13 C NMR (100 MHz, CDCl 3)? 133.9, 131.1, 130.9, 129.9, 129.0, 128.4, 117.1, 115.6, 115.4, 56.9, 52.7, 41.7.

Example 16 Preparation of (Z) -1- (3- (benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl)

The procedure of Example 15 was repeated except that the stereoisomer was obtained as the target compound.

2: 1 cis: trans (63.4%, removable)

Obtained form: Yellow solid

Rf = 0.34 (n-hexane / ethyl acetate = 1: 1); (2H, m), 6.26 (1H, d, J = 9.2Hz), 5.63-5.69 (1H, m) , 3.95 (2H, s), 3.90 (2H, s), 3.37-3.51 (1H, m), 3.65-3.71 (1H, m); 13C NMR (100 MHz, CDCl3) [delta] 137.7, 130.7, 129.7, 128.7, 128.1, 117.9, 115.1, 57.2, 49.3, 42.3.

Example 17 Preparation of (E) -1- (3- (phenylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl)

The procedure of Example 9 was repeated, except that the compound of Preparation Example 5 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 9 to obtain the desired compound.

1: 2 cis: trans (37.9%, removable)

Obtained form: white solid

Rf = 0.34 (n-hexane / ethyl acetate = 2: 1); (2H, d, J = 8.4 Hz), 6.17 (1H, d, J = 8.3 Hz) (2H, s), 3.77 (3H, s), 3.35-3.40 (1H, m), 3.21-3.26 ); 13 C NMR (100 MHz, CDCl 3)? 159.6, 134.8, 131.0, 130.5, 129.4, 128.9, 117.1, 114.4, 57.2, 55.7, 53.3, 42.6.

Example 18 Preparation of (Z) -1- (3- (phenylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl)

Following the procedure of Example 17, the stereoisomer was obtained as the target compound.

1: 2 cis: trans (37.9%, removable)

Obtained form: white solid

Rf = 0.34 (n-hexane / ethyl acetate = 2: 1); (2H, d, J = 8.4Hz), 6.29 (1H, d, J = 8.4Hz) (2H, s), 3.79 (2H, s), 3.79 (3H, s), 3.47-3.53 (2H, m), 3.39-3.43 2H, m); 13 C NMR (100 MHz, CDCl 3)? 138.2, 130.5, 130.1, 129.9, 128.9, 128.5, 128.4, 117.8, 113.9, 57.5, 55.3, 49.7, 43.0.

≪ Comparative Example 1 > Preparation of E-Ajoene

Was carried out in a similar manner to the above Example compound to give the desired compound.

Colorless 2: 1 Z: E mixture (48.5%, removable); R _f = 0.36 (n-hexane / Ethyl acetate 1: 2); ^{(E) 1 H NMR (400} MHz, CDCl 3) δ 6.39 (1H, d, J = 14.8 Hz), 5.78 ~ 5.98 (3H, m), 5.39 ~ 5.49 (2H, m), 5.17 ~ 5.22 (2H, m), 3.48 ~ 3.65 (3H, m), 3.36 ~ 3.45 (3H, m); ¹³ C NMR (100 MHz, CDCl ₃ )? 134.7, 132.5, 125.5, 123.8, 119.2, 116.7, 54.3, 52.9, 41.3.

≪ Comparative Example 2 > Preparation of Z-azoene (Z-Ajoene)

Was carried out in a similar manner to the above Example compound to give the desired compound.

^{(Z) 1 H NMR (400} MHz, CDCl 3) δ 6.53 (1H, d, J = 9.2 Hz), 5.69 ~ 5.89 (3H, m), 5.37 ~ 5.45 (2H, m), 5.13 ~ 5.18 (2H, m), 3.46-3.65 (4H, m), 3.34-3.40 (2H, m). ^{13 C NMR (100 MHz, CDCl} 3) δ 138.9, 132.9, 125.9, 124.2, 119.6, 118.3, 55.2, 49.9, 42.4.

The chemical structures of the compounds prepared in Examples 1 to 18 are summarized in Table 1 below.

Example constitutional formula One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

≪ Experimental Example 1 > Evaluation of Cancer Proliferation Inhibitory Activity

In order to evaluate the cancer growth inhibitory activity of the compound according to the present invention, the following experiment was conducted.

Specifically, compounds in which R ¹ is allyl (Comparative Examples 1 and 2 and Example 1-8) and azo isosteric compounds of Examples 1 to 18 are compounds in which R ¹ is benzyl (MDC-MB-231), colorectal cancer cell line (HCT-15), prostate cancer cell line (PC-3), gastric cancer cell line (NUGC -3) and lung cancer cell line (NCI-H23)).

The human cancer cell lines (ACHN, breast cancer cell line (MDA-MB-231), colorectal cancer cell line (HCT-15), prostate cancer cell line (PC-3), gastric cancer cell line (NUGC- lung cancer cell line (NCI-H23)) is American Type culture Collection (Manassas, VA, was purchased from the USA), and cultured in RPMI 1640 with 10% fetal bovine serum supplemented with 5% of CO 37 under ₂ wet atmosphere ≪ / RTI > Cells were injected into 96-well plates and treated with either no treatment (0.1% DMSO) or increasing the concentration of the compound of Example (0.1 μM to 10 μM). After 48 hours, the cells were fixed with 50% trichloroacetic acid and stained with 1% acetic acid in which 0.4% of sulforodamine B was dissolved. Unbound dye was removed by washing with 1% acetic acid and the protein binding dye was extracted with 10 mM Tris base (pH 10.5). Absorbance was measured at 540 nm using a VersaMax microplate reader (Molecular devices, Sunnyvale, Calif., USA). GI ₅₀ values were calculated using GraphPad Prism software (GraphPad Software, Inc., San Diego, Calif., USA) and the results are shown in Table 2.

Isomer R ¹ R ² GI ₅₀ ([mu] M) ACHN MDA-MB-231 PC-3 NUGC-3 HCT-15 NCI-H23 Comparative Example 1 E Ally Ally 3.35 1.44 1.72 2.37 2.34 2.18 Comparative Example 2 Z Ally Ally > 10 > 10 > 10 > 10 > 10 > 10 Example 1 E Ally profile 3.29 2.94 1.78 3.48 5.59 3.45 Example 2 Z Ally profile 3.53 2.05 2.73 2.69 2.96 0.86 Example 3 E Ally benzyl > 10 > 10 > 10 > 10 > 10 > 10 Example 4 Z Ally benzyl 3.26 4.64 2.31 2.05 4.96 3.59 Example 5 E Ally 4-FB > 10 > 10 > 10 > 10 > 10 > 10 Example 6 Z Ally 4-FB > 10 > 10 > 10 > 10 > 10 > 10 Example 7 E Ally 4-MB > 10 > 10 > 10 > 10 > 10 > 10 Example 8 Z Ally 4-MB > 10 > 10 > 10 > 10 > 10 > 10 Example 9 E benzyl Ally 5.32 2.42 3.28 8.07 5.93 5.98 Example 10 Z benzyl Ally 4.43 5.45 6.85 10.30 9.10 4.41 Example 11 E benzyl profile 3.79 2.19 2.29 3.27 3.03 2.93 Example 12 Z benzyl profile 4.03 3.11 3.49 3.69 3.56 3.43 Example 13 E benzyl benzyl 4.22 2.11 3.88 3.30 3.63 6.41 Example 14 Z benzyl benzyl 1.45 1.51 1.89 2.37 1.79 2.42 Example 15 E benzyl 4-FB 4.10 1.66 2.04 1.88 2.27 2.83 Example 16 Z benzyl 4-FB 2.32 3.24 3.59 2.09 2.63 2.89 Example 17 E benzyl 4-MB 1.13 1.95 1.06 1.14 1.29 1.90 Example 18 Z benzyl 4-MB 1.11 1.19 0.78 0.58 0.93 1.75

(In Table 2,

4-FB: 4-fluorobenzyl; And

4-MB: 4-methoxybenzyl.)

As can be seen from Table 2, the novel azine derivative according to the present invention was found to be superior to the compound of Comparative Example 2 in inhibiting cancer growth.

Therefore, it has been confirmed that the novel azo derivative of the present invention has an excellent cancer proliferation inhibitory activity over that of azo, so that the active ingredient of the pharmaceutical composition for the prevention or treatment of cancer, or the health functional food composition for prevention or improvement of cancer It can be seen that there is a useful effect as an active ingredient.

Claims (9)

A compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
(15) (E) -1- (3- (Benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl) dicyclene; And
(16) (Z) -1- (3- (Benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl) dibutane.
delete delete delete delete delete A pharmaceutical composition for preventing or treating cancer comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient,
Wherein said cancer is at least one selected from the group consisting of renal cancer, breast cancer, colon cancer, prostate cancer, gastric cancer, and lung cancer.
delete A health functional food composition for preventing or ameliorating cancer comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient,
Wherein the cancer is at least one selected from the group consisting of renal cancer, breast cancer, colon cancer, prostate cancer, gastric cancer, and lung cancer.