KR101930638B1 - Novel Organosulfur 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 organic sulfur compound, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. The novel organic sulfur compound according to the present invention is useful as a histone deacetylation (HDAC) (MDA-MB-231), colorectal cancer cell line (HCT-15), prostate cancer (HDL), and the like. (NCI-H23), and it is confirmed that it is possible to inhibit the proliferation of cancer cells (PC-3), gastric cancer cell line (NUGC-3) and lung cancer cell line Can be usefully used.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel organic sulfur compound, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. }

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

Organosulfur compounds are organic compounds containing sulfur and exist in various forms in nature. Particularly, plants such as garlic and onion include various kinds of organic sulfur compounds, and they exhibit various physiological activities such as anti-cancer, anti-inflammation, antibacterial activity (Non-Patent Document 1). Garlic contains alliin, a precursor of organic sulfur compounds. During the cooking process, allicin is produced by the action of alliinase, and through continuous conversion, allyl sulfide, polysulfide a variety of organic sulfur compounds such as polysulfides and azoenes.

Of these, azoenes are relatively stable among the organic sulfur compounds formed from garlic and contain allyl sulfoxide and vinyl disulfide.

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.

Studies on the inhibition of cancer cell proliferation of various organosulfur compounds including azoenes and development of anticancer drugs based on them have been made in the past, but they remain at a level that confirms the action of cancer cell proliferation inhibition (Non-Patent Document 2) It is impossible to secure the cancer growth inhibitory activity and physical properties required for use as an active ingredient of anticancer drugs, and therefore it is required to find new anticancer active substances based on the structure of organic sulfur compounds derived from garlic.

On the other hand, it has been reported that diallyl disulfide (DADS), which is one of the organic sulfur compounds of garlic, and allyl mercaptan (AM), which is a metabolite thereof, inhibit histone deacetylation (HDAC) enzyme and inhibit the proliferation of cancer cells. Therefore, it was decided to use the basic framework of organic sulfur compounds to discover new anticancer substances with histone deacetylase inhibiting activity.

Histone deacetylase is an enzyme that regulates the balance of acetylation and deacetylation of histone and non-histone proteins by promoting the hydrolysis of the ε-amide bond of lysine residues. It is involved in gene expression and differentiation, And plays an important role in maintenance of homeostasis (Non-Patent Document 3). Overexpression of HDAC in various cancer cells leads to the inhibition of important growth inhibitory genes and has a mechanism to promote cancer cell proliferation. Therefore, HDAC has been actively developed as an important drug target for development of an anticancer drug.

Currently, many HDAC inhibitors have been reported for anticancer purposes and are under clinical development. Up to now, four HDAC inhibitors (Vorinostat, Belinostat, Panobinostat and Romidepsin) have been approved by the FDA for use in skin T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL) Inhibitors are in clinical or preclinical stages for a variety of cancers, but most HDAC inhibitors have been shown to cause many side effects, including fatigue, nausea, vomiting and cardiac toxicity. It is reported that this is due to the lack of HDAC isozyme selectivity, and it is required to develop a selective inhibitor to solve this problem. However, the development of HDAC selective inhibitors is at an early stage, and the development of HDAC 8 selective inhibitors has not been reported.

Accordingly, the inventors of the present invention have developed a new HDAC inhibitor having improved pharmacological activity and selectivity for the purpose of anti-cancer, and the novel HDAC inhibitor according to the present invention selectively targets HDAC 8, And it can be used as a pharmaceutical composition for prevention or treatment of cancer, thereby completing the present invention.

WO / 2009/065926

Organosulfur compounds and cancer, Lee MA, Advances in Experimental Medicine and Biology, 1996, 401, 147-54 (1996). The garlic compound ajoene targets protein folding in the endoplasmic reticulum of cancer cells, KASCHULA et al., Molecular Carcinogenesis, 55 (8): 1213-28 (2016). Genes Dev, 2000, 14, 55; Expert Rev. Anticancer Ther. 2010, 10, 935; Am. J. Trans. Res, 2011, 3, 166

It is an object of the present invention to provide novel organic sulfur compounds.

Another object of the present invention is to provide a method for producing the organic sulfur compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer containing the above organic sulfur compound 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 organic sulfur compound 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 unsubstituted or substituted phenyl,

Wherein said substituted phenyl 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).

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 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 novel organic sulfur compounds according to the present invention are capable of selectively inhibiting histone deacetylated (HDAC) enzymes, in particular HDAC 8, in concentrations of nanomolar or micromolar units, and are useful in the treatment of renal cancer cell lines (ACHN) (MDA-MB-231), colon cancer cell line (HCT-15), prostate cancer cell line (PC-3), gastric cancer cell line (NUGC-3) and lung cancer cell line (NCI-H23) And can be usefully used as a pharmaceutical composition for preventing or treating cancer containing it as an active ingredient.

Figure 1 shows the course of the administration of SAHA (Vorinostat, 100 mg / kg), Comparative Examples 1 and 2 (Ajoene, 50 mg / kg), Examples 17 and 31 (50 mg / kg) 2 days to 14 days).
2 shows the course of the administration of SAHA (Vorinostat, 100 mg / kg), Comparative Examples 1 and 2 (Ajoene, 50 mg / kg), Examples 17 and 31 (50 mg / kg) (Mm < ³ > SE) according to the number of days (2 to 14 days).
FIG. 3 shows the results of the administration of SAHA (Vorinostat, 100 mg / kg), Comparative Examples 1 and 2 (Ajoene, 50 mg / kg) and Examples 17 and 31 (50 mg / It is a photograph of a cancer extracted from a mouse.
FIG. 4 shows the results of the administration of SAHA (Vorinostat, 100 mg / kg), Comparative Examples 1 and 2 (Ajoene, 50 mg / kg) and Examples 17 and 31 (50 mg / (Mg) of the cancer removed from the mouse.

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 unsubstituted or substituted phenyl,

Wherein said substituted phenyl 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 unsubstituted or substituted phenyl,

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

More preferably,

,

또는

이고;Wherein R < ^{1 &}

,

or

ego;

,

,

,

,

,

또는

일 수 있다.Wherein R < ^{2 &}

,

,

,

,

,

or

Lt; / RTI >

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

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

(2) (Z) -1-allyl-2- (3- (phenylsulfinyl) prop-1-enyl) diesulfan;

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

(4) (Z) -1- (3- (Phenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(5) (E) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(6) (Z) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(7) (E) -1- (4-fluorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(8) (Z) -1- (4-fluorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(9) (E) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(10) (Z) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(11) (E) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(12) (Z) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(13) (E) -1- (3,4-Dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(14) (Z) -1- (3,4-Dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;

(15) (E) -1-Allyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(16) (Z) -1-Allyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(17) (E) -1- (3- (3-Methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(18) (Z) -1- (3- (3-Methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(19) (E) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(20) (Z) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(21) (E) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(22) (Z) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(23) (E) -1- (4-Chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(24) (Z) -1- (4-Chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(25) (E) -1- (3,4-Dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(26) (Z) -1- (3,4-Dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(27) (E) -1-Allyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(28) (Z) -1-Allyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(29) (E) -1- (3- (4-Methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(30) (Z) -1- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

(31) (E) -1-Benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(32) (Z) -1-Benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(33) (E) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(34) (Z) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(35) (E) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclopentane;

(36) (Z) -1- (4-Chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

(37) (E) -1- (3,4-Dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene; And

(38) (Z) -1- (3,4-Dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) diesulfan.

The present invention was completed by confirming the cancer-suppressing activity of the organic sulfur compounds of the present invention based on the cancer-inhibiting activity of garlic-derived azoenes (Ajoene).

Specifically, at the beginning of the study, the present inventors noticed that diallyl disulfide (DADS), one of the organic sulfur compounds of garlic, and its metabolism allyl mercaptan (AM) inhibit histone deacetylation (HDAC) , Azoenes were evaluated through molecular modeling and activity evaluation to determine whether they could inhibit HDAC. In order to prepare a compound capable of better inhibition of HDAC enzyme, a compound in equilibrium electron relationship of Ajoene was synthesized Respectively.

As a candidate group of the isosteric compound of Ajoene, benzyl which is isosteric with allyl of azoene at the R ¹ position (zinc bonding part) of the representative formula 1 of the present invention or Benzyl substituted with methoxy naphthalene having a small size was sieved to synthesize a compound.

On the other hand, in consideration of the spatial characteristics of the HDAC binding site and the conversion of physicochemical properties, attempts were made to introduce phenyl, which is a relatively boiling electrophile, instead of benzyl, which can be directly used as an eutectic with allyl of azoenes. In the case of phenyl, a considerable difference in stereoselective and electronic differences from allyl was expected. The effect of introduction of the methoxy nhalogen substituent in the phenyl ring is expected to have a more direct effect on sulfoxides, The synthesis of the compound was proceeded.

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.

At this time, the compound represented by the formula (1) inhibits HDAC (Histone deacetylase) to prevent or treat cancer, and inhibits the action mechanism of histone deacetylase, thereby inhibiting cancer proliferation.

Specifically, histone deacetylase (Histone deacetylase) is an enzyme that regulates the balance between acetylation and deacetylation of histone and non-histone proteins by promoting the hydrolysis of the ε-amide bond of lysine residues. , Plays an important role in the maintenance of the homeostasis of cells. Overexpression of HDAC in various cancer cells causes inhibition of important growth inhibitory genes, thereby promoting cancer cell proliferation. The compound represented by the formula (I) according to the present invention, its stereoisomer or its pharmaceutically acceptable salt can inhibit the above-mentioned action mechanism and is capable of inhibiting cancer cell proliferation.

On the other hand, the cancer can be diagnosed as a malignant myxoma, an intrahepatic bile duct cancer, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a myelodysplastic syndrome, a oral cancer, a laryngeal cancer, a bacterial sarcoma, an 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.

At this time, the compound represented by the formula (1) inhibits HDAC (Histone deacetylase) to prevent or treat cancer, and inhibits the action mechanism of histone deacetylase, thereby inhibiting cancer proliferation.

Specifically, histone deacetylase (Histone deacetylase) is an enzyme that regulates the balance between acetylation and deacetylation of histone and non-histone proteins by promoting the hydrolysis of the ε-amide bond of lysine residues. , Plays an important role in the maintenance of the homeostasis of cells. Overexpression of HDAC in various cancer cells causes inhibition of important growth inhibitory genes, thereby promoting cancer cell proliferation. The compound represented by the formula (I) according to the present invention, its stereoisomer or its pharmaceutically acceptable salt can inhibit the above-mentioned action mechanism and is capable of inhibiting cancer cell proliferation.

In order to evaluate the cancer growth inhibitory activity of the compound represented by the formula (1) according to the present invention, its stereoisomer or its pharmaceutically acceptable salt, the following experiment was conducted.

First, 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- The cancer growth inhibitory activity (GI ₅₀ ) of the lung cancer cell line (NCI-H23) was evaluated. As a result, the cancer growth inhibitory activity was superior to that of Ajoene. In particular, In the compound where R ¹ is phenyl, it was confirmed that not only azoene but also R ¹ exhibited better cancer proliferation inhibitory activity than benzyl or allyl compound (see Experimental Example 1-1 below).

The present inventors, by combining additionally a derivative from the R ¹ represents the general formula (I) of the present invention, the phenyl compound, was carried out the same cancer growth inhibition activity test, the result, the phenyl than the case of R ¹ is phenyl In the case where methoxy was substituted for the 3 rd or 4 rd position, more excellent cancer proliferation inhibitory activity was confirmed (see Experimental Example 1-2 below).

After the experiments described above, the present inventors evaluated the inhibitory activity (IC ₅₀ ) against HDAC 1, 6, and 8 in order to confirm HDAC enzyme inhibitory activity of phenyl-based derivatives.

At this time, the inhibitory activity was compared in terms of percentage by using HDAC target anticancer agent SAOR (Vorinostat), which was conventionally known as a control group. As a result, it was confirmed that the phenyl-based derivatives according to the present invention exhibited better HDAC inhibitory activity than azoenes and SAHA I could.

In particular, the novel organic sulfur compound according to the present invention has an inhibitory activity of about 30 to 100-fold in HDAC 8 compared to HDAC 1 and 6, and has an HDAC inhibitory activity equivalent to 161.9% (See Experimental Example 2 below).

As a result of an in vivo experiment, an experiment was conducted to evaluate the cancer proliferation inhibitory activity of a mouse xenografted with prostate cancer. As a result, the novel organosulfur compound according to the present invention was found to have an inhibitory activity against cancer cell proliferation (See Experimental Example 3, 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-allyl-2- (3- (phenylsulfinyl) prop-1-enyl)

Step 1: Propargylation reaction

Benzene thiol or iso Im OY the corresponding iodonium salts _{(Ph-SC (¼NH 2)} NH 2 þ Br,) for the addition to 0 ℃ degassed methanol (0.5 M) and, KOH (ethene thiol of solid 1.2 equiv. Or 2.5 equiv with respect to the salt). 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 Preparation Example 1 was dissolved was added to the solution with a syringe, and the mixture was allowed to stand at 0 ° C. The mixture was stirred 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.

1: 2 cis: trans (46.5%, removable)

Obtained form: yellow oil

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (2H, m), 5.10-5.14 (1 H, m), 7.21 (1H, d, J = m), 5.10-5.14 (2H, m), 3.81-3.87 (1H, m), 3.65-3.70 (1H, m), 3.25-3.30 (2H, m).

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

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

1: 2 cis: trans (46.5%, removable)

Obtained form: yellow oil

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (1H, m), 5.55-5.62 (1H, m), 6.55 (1H, d, J = m), 5.13-5.20 (2H, m), 3.87-3.93 (1H, m), 3.75-3.81 (1H, m), 3.26-3.34 (2H, m).

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

The procedure of Example 1 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 1 to obtain the target compound.

2.5: 1 cis: trans (56.6%, removable)

Obtained form: yellow oil

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (1H, m), 5.30-5.37 (2H, m), 7.22 (1H, d, J = , 3.81-3.87 (2H, m), 3.65-3.71 (2H, m), 2.60 (2H, t, J = 7.2 Hz), 1.59-1.69 ); ≪ 13 > C NMR (100 MHz, CD3OD) [delta] 136.1, 132.6, 130.4, 125.7, 59.3, 48.4, 40.8, 13.3.

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

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

2.5: 1 cis: trans (56.6%, removable)

Obtained form: yellow oil

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (1H, m), 3.86-3.91 (1 H, m), 6.54 (1H, d, J = m), 3.73-3.79 (1H, m), 2.62 (2H, t, J = 7.2 Hz), 1.58-1.66 (2H, m), 0.96 (3H, t, J = 7.2 Hz).

Example 5 Preparation of (E) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 1 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 1 to obtain the desired compound.

1: 1 cis: trans (51.3%, removable)

Obtained form: yellow oil

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (5H, m), 6.09 (1H, d, J = 14.4Hz), 5.56-5.64 (5H, m) 1H, m), 3.84 (2H, s), 3.73-3.79 (1H, m), 3.58-3.63 (1H, m); 13 C NMR (100 MHz, CD 3 OD + CDCl 3)? 136.1, 133.6, 131.3, 129.7, 128.9, 128.5, 127.3, 119.2, 41.4, 36.5.

Example 6 Preparation of (Z) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl)

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

1: 1 cis: trans (51.3%, removable)

Obtained form: yellow oil

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (5H, m), 6.21 (1H, d, J = 9.6Hz), 5.38-5.45 (5H, m) 1H, m), 3.86 (2H, s), 3.78-3.84 (1H, m), 3.67-3.72 (1H, m).

Example 7 Preparation of (E) -1- (4-fluorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 1 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 1 to obtain the target compound.

1: 2 cis: trans (48.4%, removable)

Obtained form: yellow oil

Rf = 0.24 (n-hexane / ethyl acetate = 2: 1); (2H, m), 6.98 (1H, m), 5.98 (1H, d, J = 14.4 Hz) , 5.58-5.66 (1H, m), 3.81 (2H, s), 3.56-3.62 (1H, m), 3.44-3.49 (1H, m); 13 C NMR (100 MHz, CDCl 3)? 134.3, 131.5, 131.4, 131.3, 129.4, 124.6, 116.6, 115.9, 115.7, 59.6, 41.7.

Example 8 Preparation of (Z) -1- (4-fluorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

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

1: 2 cis: trans (48.4%, removable)

Obtained form: yellow oil

Rf = 0.24 (n-hexane / ethyl acetate = 2: 1); (2H, m), 6.23 (1H, d, J = 9.2 Hz), 7.26-7.29 (2H, m) , 5.40-5.47 (1H, m), 3.87 (2H, s), 3.79-3.84 (1H, m), 3.69-3.73 (1H, m).

Example 9 Preparation of (E) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 1 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 1 to obtain the target compound.

1: 2 cis: trans (46.6%, removable)

Obtained form: white solid

Rf = 0.24 (n-hexane / ethyl acetate = 2: 1); (2H, d, J = 8.8Hz), 6.09 (1H, d, J = 8.8Hz) , J = 14.8 Hz), 5.56-5.63 (1H, m), 3.79 (2H, s), 3.78 (3H, s), 3.72-3.76 (1H, m), 3.58-3.66 (1H, m).

Example 10 Preparation of (Z) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

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

1: 2 cis: trans (46.6%, removable)

Obtained form: white solid

Rf = 0.24 (n-hexane / ethyl acetate = 2: 1); (2H, d, J 8.8 Hz), 7.17 (2H, d, J = 8.8Hz) ), 6.20 (1H, d, J = 9.6 Hz), 5.43-5.49 (1H, m), 3.82 (2H, s), 3.80 1H, m); 13 C NMR (100 MHz, CDCl 3)? 143.2, 138.8, 131.5, 130.8, 129.4, 128.8, 124.6, 118.3, 114.3, 56.4, 55.6, 43.2.

Example 11 Preparation of (E) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 1 was repeated, except that the compound of Preparation Example 6 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 1 to obtain the target compound.

2: 1 cis: trans (35%, removable)

Obtained form: yellow oil

Rf = 0.25 (n-hexane / ethyl acetate = 2: 1); (2H, m), 7.16 (2H, d, J = 8.4Hz), 5.94 (1H, d, J = 8.4Hz). 1H NMR (400MHz, CDCl3)? 7.45-7.57 14.8 Hz), 5.53-5.61 (1H, m), 3.79 (2H, s), 3.53-3.58 (1H, m), 3.41-3.46 (1H, m).

Example 12 Preparation of (Z) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

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

2: 1 cis: trans (35%, removable)

Obtained form: colorless oil

Rf = 0.33 (n-hexane / ethyl acetate = 2: 1); (2H, d, J = 8.2 Hz), 7.17 (2H, d, J = 8.2 Hz) J = 8.3 Hz), 6.16 (1H, d, J = 9.4Hz), 5.39-5.45 (1H, m), 3.79 (2H, s), 3.66-3.72 (1H, m). 3.57-3.64 (1H, m).

Example 13 Preparation of (E) -1- (3,4-dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 1 was repeated, except that the compound of Preparation Example 7 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 1 to obtain the desired compound.

1: 2 cis: trans (37%, removable)

Obtained form: colorless oil

Rf = 0.23 (n-hexane / ethyl acetate = 2: 1); D, J = 8.2, 1.4 Hz), 7.33 (1H, s), 7.09 (1H, d, J = M), 3.42-3.49 (IH, m), 3.76 (2H, s), 5.8-3.61 .

Example 14 Preparation of (Z) -1- (3,4-dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

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

1: 2 cis: trans (37%, removable)

Obtained form: colorless oil

Rf = 0.31 (n-hexane / ethyl acetate = 2: 1); (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 1.8 Hz), 7.10 (1H, dd (1H, m, J = 8.2, 1.9 Hz), 6.20 (1H, d, J = 9.4 Hz), 5.43-5.50 (1H, m), 3.77 1H, m).

Example 15 Preparation of (E) -1-allyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Isobutyronitrile Im OY corresponding to the embodiment of benzene thiol used in step 1 of the first or in the place of the iodonium salt _{(Ph-SC (¼NH 2)} NH 2 þ Br,) 3- methoxybenzene thiol or equivalent (3-methoxyphenyl-SC (NNH ₂ ) NH ₂ Br Br,) was used instead of the isothiourone salt of Example 1 to obtain the target compound.

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (1H, d, J = 7.5 Hz), 7.01-7.04 (1H, m), 7.71 (2H, m), 6.14 (1H, d, J = 14.8Hz), 5.64-5.84 (2H, m), 5.13-5.18 , 7.9, 0.9 Hz), 3.53 (1H, ddd, J = 12.9, 7.9, 0.9 Hz), 3.27 (2H, d, J = 7.4 Hz); 13 C NMR (100 MHz, CDCl 3)? 160.5, 144.3, 134.6, 132.6, 130.2, 119.4, 117.8, 116.4, 116.3, 108.9, 59.5, 55.8, 41.1.

Example 16 Preparation of (Z) -1-allyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

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

Rf = 0.35 (n-hexane / ethyl acetate = 2: 1); (1H, m), 7.02 (1H, dd, J = 7.9 Hz), 7.21-7.20 (1H, m), 7.13-7.10 (1H, m, J = 8.2, 2.1 Hz), 6.48 (1H, d, J = 9.4 Hz), 5.78-5.83 (1H, m), 5.54-5.61 , 3.72-3.83 (1H, m), 3.60-3.70 (1H, m), 3.29 (2H, d, J = 7.4 Hz); 13 C NMR (100 MHz, CDCl 3)? 160.5, 144.3, 138.8, 133.2, 132.7, 130.2, 129.8, 128.2, 119.3, 118.4, 117.9, 116.6, 108.8, 56.2, 55.7, 42.1.

Example 17 Preparation of (E) -1- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 15 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 15 to obtain the target compound.

Rf = 0.27 (n-hexane / ethyl acetate = 2: 1); (1H, m), 7.07 (1H, dd, J = 7.6, 1.2 Hz), 7.02 (1H, (d, J = 7.6, 2.4 Hz), 6.15 (1H, d, J = 14.8 Hz), 5.72-5.75 (1H, m), 3.87 (3H, s), 3.62-3.67 3.65 (1H, m), 2.62 (2H, t, J = 7.2 Hz), 1.63-1.71 (2H, m), 0.98 (3H, t, J = 7.2 Hz).

EXAMPLE 18 Preparation of (Z) -1- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

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

Rf = 0.35 (n-hexane / ethyl acetate = 2: 1); (1H, m), 7.13-7.11 (1H, m), 7.03-7.02 (1H, m) ), 6.50 (1H, d, J = 9.6 Hz), 5.53-5.59 (1H, m), 3.87 (3H, s), 3.79-3.74 2H, t, J = 7.2 Hz), 1.63-1.69 (2H, m), 0.98 (3H, t, J = 7.2 Hz).

Example 19 Preparation of (E) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 15 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 15 to obtain the target compound.

Rf = 0.23 (n-hexane / ethyl acetate = 2: 1); (1H, m), 7.06 (1H, d, J = 8 Hz), 7.30 (1H, ), 7.02 (1H, dd, J = 8.2,2.5Hz), 5.98 (1H, d, J = 14.8 Hz), 5.55-5.64 (1H, m), 3.83 m), 3.49-3.43 (2H, m); 13 C NMR (100 MHz, CDCl 3)? 160.4, 144.2, 136.6, 134.2, 130.1, 129.5, 128.7, 127.7, 117.8, 116.4, 116.2, 108.9, 59.5, 55.7, 42.5.

Example 20 Preparation of (Z) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 19, the stereoisomer was obtained as the target compound.

1: 1.5 cis: trans (40%, removable)

Obtained form: yellow oil

Rf = 0.31 (n-hexane / ethyl acetate = 2: 1); (1H, s), 7.08 (1H, d, J = 8 Hz), 7.28 (1H, ), 7.01 (1H, dd, J = 8.2,2.5 Hz), 6.17 (1H, d, J = 9.4 Hz), 5.40-5.48 m), 3.63 ~ 3.57 (1H, m); 13 C NMR (100 MHz, CDCl 3)? 160.5, 144.5, 138.3, 136.8, 130.2, 129.5, 128.7, 127.7, 118.3, 117.8, 116.5, 108.8, 56.2, 55.7, 43.5.

Example 21 Preparation of (E) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1 -enyl)

The procedure of Example 15 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 15 to obtain the target compound.

1: 2 cis: trans (38%, removable)

Obtained form: Yellow solid

Rf = 0.23 (n-hexane / ethyl acetate = 2: 1); (2H, m), 7.15-7.17 (1H, m), 7.07 (1H, dd, J) (1H, s), 3.81 (2H, s), 3.91 (2H, s) , 3.61-3.56 (1H, m), 3.48-3.43 (1H, m).

Example 22 Preparation of (Z) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1 -enyl)

Following the procedure of Example 21, the stereoisomer was obtained as the target compound.

1: 2 cis: trans (38%, removable)

Obtained form: Yellow solid

Rf = 0.31 (n-hexane / ethyl acetate = 2: 1); (2H, m), 7.18-7.19 (1H, m), 7.09 (1H, d, J = 7.9 Hz) (1H, s), 3.73 (3H, s), 3.73 (1H, s) 3.67 (1H, m), 3.59-3.63 (1H, m).

Example 23 Preparation of (E) -1- (4-chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1 -enyl)

The procedure of Example 15 was repeated except that the compound of Preparation Example 6 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 15 to obtain the target compound.

2: 1 cis: trans (38%, removable)

Obtained form: colorless oil

Rf = 0.23 (n-hexane / ethyl acetate = 2: 1); (2H, m), 7.18-7.16 (3H, m), 7.07 (1H, d, J = 8 Hz, (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 8.2, 2.1 Hz), 5.98 (100 MHz, CDCl 3) 隆 160.5, 144.1, 135.3, 133.9, 133.6, 130.8, 130.2, 128.8, 117.8, 116.5, 1H), 3.57-3.52 (1H, m), 3.44-3.39 116.4, 108.9, 59.3, 55.7, 41.6.

Example 24 Preparation of (Z) -1- (4-chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1 -enyl)

Following the procedure of Example 23, the stereoisomer was obtained as the target compound.

2: 1 cis: trans (38%, removable)

Obtained form: colorless oil

Rf = 0.31 (n-hexane / ethyl acetate = 2: 1); (2H, m), 7.20-7.18 (3H, m), 7.08 (1H, d, J = (1H, d, J = 9.4 Hz), 7.01 (1H, dd, J = 8.2, 2.6 Hz), 6.18 s), 3.73 ~ 3.69 (1H, m), 3.63 ~ 3.59 (1H, m); 13 C NMR (100 MHz, CDCl 3)? 160.5, 144.3, 138.1, 135.4, 133.6, 133.0, 130.9, 130.8, 130.2, 130.2, 129.7, 128.8, 128.2, 118.6, 117.8, 116.5, 108.8, 56.1, 55.7, 42.6.

Example 25 Preparation of (E) -1- (3,4-dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1- enyl)

The procedure of Example 15 was repeated except that the compound of Preparation Example 7 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 15 to obtain the target compound.

1: 2 cis: trans (47%, removable)

Obtained form: colorless oil

Rf = 0.23 (n-hexane / ethyl acetate = 2: 1); (1H, d, J = 8.2 Hz), 7.16-7.15 (1H, d, J = (1H, m), 7.10-7.06 (2H, m), 7.02 (1H, dd, J = 8.2, 2.5 Hz), 6.00 (1H, d, J = 14.8 Hz), 5.65-5.57 3H, s), 3.76 (2H, s), 3.62 ~ 3.56 (1H, m), 3.47 ~ 3.42 (1H, m); 13 C NMR (100 MHz, CDCl 3) 隆 160.5, 144.2, 137.1, 133.6, 132.6, 131.9, 131.3, 130.6, 130.2, 128.9, 117.7, 117.0, 116.4, 108.9, 76.8, 59.2, 55.8, 41.1.

Example 26 Preparation of (Z) -1- (3,4-dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1- enyl)

The procedure of Example 25 was repeated except that the stereoisomer was obtained as the target compound.

1: 2 cis: trans (47%, removable)

Obtained form: colorless oil

Rf = 0.31 (n-hexane / ethyl acetate 2: 1); (2H, m), 7.34 (1H, d, J = 2.0 Hz), 7.19-7.17 (1H, m), 7.11-7. (2H, s), 3.72 (2H, s), 7.01 (1H, dd, J = 8.2,2.5 Hz), 6.21 3.67 (1H, m), 3.60-3.54 (1H, m); 13 C NMR (100 MHz, CDCl 3)? 160.5, 144.4, 137.9, 137.3, 132.6, 131.9, 131.4, 130.7, 130.3, 128.9, 119.0, 117.8, 116.5, 108.8, 56.1, 55.8, 42.1.

Example 27 Preparation of (E) -1-allyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Isobutyronitrile Im OY corresponding to the embodiment of benzene thiol used in step 1 of the first or in the place of the iodonium salt _{(Ph-SC (¼NH 2)} NH 2 þ Br,) 4- methoxybenzene thiol or equivalent The objective compound was obtained in a similar manner to Example 1, except that the isothiourone salt (4-methoxyphenyl-SC (NNH ₂ ) NH ₂ þ Br) was used.

2: 1 cis: trans (16.3%, removable)

Obtained form: colorless oil

Rf = 0.20 (n-hexane / ethyl acetate = 2: 1); (E) IR (neat, cm-1) 2916, 2848, 2358, 1733, 1593, 1496, 1462, 1258, 1086, 1018, 893, 797; D, J = 8.8 Hz), 6.11 (1H, d, J = 14.8Hz), 5.63-5.82 (2H, m ), 5.17 (2H, s), 5.14 (2H, d J = 4.8 Hz), 3.86 (3H, s), 3.50-3.52 (2H, m), 3.27 (2H, d, J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3)? 134.6, 132.6, 130.9, 126.4, 119.4, 116.5, 114.8, 92.6, 59.6, 55.7, 41.1, 38.1.

Example 28 Preparation of (Z) -1-allyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 27, the stereoisomer was obtained as the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: colorless oil

Rf = 0.20 (n-hexane / ethyl acetate = 2: 1); (Z) IR (neat, cm-1) 2916, 2848, 2358, 1592, 1494, 1455, 1303, 1251, 1172, 1129, 1085, 1046, 926, 830; (2H, d J = 8.8 Hz), 6.45 (1H, d J = 9.2 Hz), 5.72-5.83 (1H, m) , 5.51-5.58 (1H, m), 5.12-5.17 (2H, m), 3.85 (3H, s), 3.62-3.72 (2H, m), 3.34 (2H, d, J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3)? 138.57, 133.88, 132.74, 126.38, 119.25, 118.59, 115.00, 114.83, 56.45, 55.67, 42.11, 34.79.

Example 29: Preparation of (E) -1- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 27 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 27 to obtain the desired compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: colorless oil

(E) IR (neat, cm-1) 2961, 1715, 1592, 1494, 1302, 1251, 1086, 1027, 829; (2H, d, J = 8.8 Hz), 6.12 (1H, d, J = 14.8Hz), 5.63-5.71 (1H, (m, 2H), 3.87 (3H, s), 3.58 (2H, dd, J = 1.6, 6.8 Hz), 2.62 (3H, t, J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3)? 135.01, 133.29, 130.11, 118.92, 117.88, 116.47, 115.52, 108.83, 59.59, 55.74, 40.26, 35.34, 22.48, 13.17.

Example 30 Preparation of (Z) -1- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

Following the procedure of Example 29, the stereoisomer was obtained as the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: yellow oil

Rf = 0.20 (n-hexane / ethyl acetate = 2: 1); (Z) IR (neat, cm-1) 2961, 1716, 1591, 1494, 1302, 1250, 1086, 1027, 829; (2H, d, J = 8.8 Hz), 6.48 (1H, d, J = 9.6 Hz), 5.50-5.56 (1H, , 3.96 (3H, s), 3.74-3.64 (2H, m), 2.63 (2H, t, J = 6.8 Hz), 1.64 (2H, q, J = 7.2 Hz), 0.97 J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3)? 160.48, 144.52, 139.42, 130.21, 117.89, 117.84, 116.55, 108.75, 56.29, 55.75, 41.25, 22.34, 13.11.

Example 31 Preparation of (Z) -1-benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 27 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 27 to obtain the target compound.

2: 1 cis: trans (32.3%, removable)

Obtained form: yellow oil

Rf = 0.24 (n-hexane / ethyl acetate = 2/1); (E) IR (neat, cm-1) 2919, 1590, 1490, 1455, 1288, 1247, 1171, 1087, 1028, 822; D, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.23-7.31 (5H, m), 5.96 14.8 Hz), 5.54-5.61 (1H, m), 4.83 (3H, s), 3.49-3.52 (2H, m); 13 C NMR (100 MHz, CDCl 3)? 134.1, 133.3, 129.5, 128.7, 127.8, 126.4, 116.6, 114.8, 59.7, 55.7, 42.6, 38.1.

Example 32 Preparation of (Z) -1-benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 31, the stereoisomer was obtained as the target compound.

2: 1 cis: trans (32.3%, removable)

Obtained form: colorless oil

Rf = 0.24 (n-hexane / ethyl acetate = 2/1); (Z) IR (neat, cm-1) 2914, 1733, 1591, 1492, 1454, 1301, 1247, 1170, 1085, 1025, 826; (2H, d, J = 8.8 Hz), 7.24-7.33 (5H, m), 6.16 (1H, d, J = 8.8 Hz) 9.2 Hz), 5.39-5.45 (1H, m), 3.84 (3H, s), 3.59-3.68 (2H, m); 13 C NMR (100 MHz, CDCl 3)? 138.2, 129.5, 129.1, 128.7, 127.7, 126.4, 118.4, 114.8, 114.6, 56.4, 55.6, 43.6.

Example 33 Preparation of (E) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1 -enyl)

The procedure of Example 27 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 27 to obtain the target compound.

2: 1 cis: trans (32.3%, removable)

Obtained form: colorless oil

Rf = 0.18 (n-hexane / ethyl acetate = 2: 1); (E) IR (neat, cm-1) 2962, 2837, 1593, 1508, 1495, 1457, 1408, 1303, 1252, 1222, 1156, 1086, 1027, 942, 830; D, J = 5.6, 8.4 Hz), 6.97-7.04 (4H, m), 5.97 (1H, d, J = 8.8 Hz) J = 14.8 Hz), 5.57-5.65 (1H, m), 4.84 (3H, s), 3.81 (2H, s), 3.45-3.56 (2H, m); 13 C NMR (100 MHz, CDCl 3) δ 162.2, 133.9, 131.2, 131.1, 130.8, 126.4, 116.8, 116.1, 115.7, 115.5, 114.8, 59.6, 55.7, 41.6, 38.1.

Example 34 Preparation of (Z) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1 -enyl)

The procedure of Example 33 was repeated except that the stereoisomer was obtained as the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: colorless oil

Rf = 0.18 (n-hexane / ethyl acetate = 2/1); (Z) IR (neat, cm-1) 2961, 2837, 1593, 1577, 1508, 1303, 1252, 1221, 1171, 1157, 1087, 1047, 829; (2H, d, J = 5.6,8.4 Hz), 6.97-7.02 (4H, m), 6.16 (1H, d, J = 8.8 Hz) J = 9.6 Hz), 5.39-5.46 (1H, m), 3.84 (3H, s), 3.82 (2H, s), 3.61-3.65 (2H, m); 13C NMR (100 MHz, CDCl3) δ 163.6, 138.1, 133.8, 131.2, 131.1, 126.4, 118.6, 115.7, 115, 5, 114.8, 56.4, 55.7, 42.6.

Example 35 Preparation of (E) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1 -enyl)

The procedure of Example 27 was repeated, except that the compound of Preparation Example 6 was used instead of the compound of Preparation Example 1 used in Step 3 of Example 27 to obtain the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: yellow oil

Rf = 0.19 (n-hexane / ethyl acetate = 2: 1); (E) IR (neat, cm-1) 2963, 2837, 1593, 1494, 1461, 1440, 1406, 1319, 1256, 1179, 1147, 1087, 1026, 940, 831; (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz) M), 3.84 (2H, s), 3.44 (2H, s), 3.44 (2H, m) ; 13 C NMR (100 MHz, CDCl 3) δ 162.2, 135.3, 133.8, 130.9, 128.9, 127.6, 126.4, 116.9, 114.8, 59.6, 55.7, 41.7, 37.9.

Example 36 Preparation of (Z) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1 -enyl)

Following the procedure of Example 35, the stereoisomer was obtained as the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: yellow oil

Rf = 0.19 (n-hexane / ethyl acetate = 2: 1); (Z) IR (neat, cm-1) 2960, 2835, 1592, 1491, 1405, 1302, 1250, 1170, 1145, 1087, 1046, 829; D, J = 8.8 Hz), 7.18-7.29 (4H, m), 7.01 (2H, d, J = 8.8 Hz), 6.16 9.2 Hz), 5.39-5.46 (1H, m), 3.84 (3H, s), 3.81 (2H, s), 3.58-3.67 (2H, m); 13C NMR (100 MHz, CDCl3) δ 162.3, 137.9, 132.5, 130.9, 128.9, 126.4, 118.8, 114.8, 56.5, 56.4, 55.7, 46.1, 42.7.

Example 37 Preparation of (E) -1- (3,4-dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1- enyl)

The procedure of Example 27 was repeated except that the compound of Preparation 7 was used instead of the compound of Preparation 1 used in Step 3 of Example 27 to obtain the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: Yellow solid

Rf = 0.20 (n-hexane / ethyl acetate = 2/1); (E) IR (neat, cm-1) 2962, 1714, 1592, 1495, 1470, 1395, 1303, 1254, 1171, 1133, 1086, 1030, 827; (2H, d, J = 8 Hz), 7.34 (1H, d, J = 2 Hz), 7.10 (1H, d, J = 8.8 Hz) (1H, m), 3.85 (3H, s), 3.76 (2H, d, J = 8.8 Hz) (2H, s), 3.44-3.57 (2H, m); 13 C NMR (100 MHz, CDCl 3)? 137.09, 133.59, 131.4, 130.6, 128.9, 126.3, 117.4, 114.9, 59.46, 55.68, 41.09.

Example 38 Preparation of (Z) -1- (3,4-dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1- enyl)

Following the procedure of Example 37, the stereoisomer was obtained as the target compound.

2: 1 cis: trans (16.3%, removable)

Obtained form: Yellow solid

Rf = 0.20 (n-hexane / ethyl acetate = 2/1); (Z) IR (neat, cm-1) 2963, 1592, 1494, 1469, 1440, 1408, 1303, 1260, 1171, 1087, 1029, 798; D, J = 8 Hz), 7.38 (1H, d, J = 8 Hz), 7.10 (1H, d, J = (1H, m), 3.77 (2H, d, J = 8.8 Hz), 7.02 (2H, s), 3.57-3.69 (2H, m); 13 C NMR (100 MHz, CDCl 3) δ 162.2, 137.5, 137.1, 133.6, 132.4, 131.7, 131.2, 130.5, 128.7, 126.2, 118.9, 114.7, 56.1, 55.5, 41.9.

≪ Comparative Example 1 > Preparation of E-azoene (Ajoene)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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 (Ajoene)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

^{(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.

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

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

2: 1 cis: trans (34%, removable)

_Rf = 0.36 (n-hexane / ethyl acetate = 1/2); ^{1 H NMR (400 MHz, CD} 3 OD) (E) δ 7.16 ~ 7.26 (5H, m), 6.21 (1H, d, J = 14.8 Hz), 5.71 ~ 5.85 (2H, m), 5.30 ~ 5.37 (2H m), 3.86 (2H, s), 3.44 ~ 3.53 (2H, m), 3.29 ~ 3.39 (2H, m); ^{13 C NMR (100 MHz, CD} 3 OD) δ (Z) (400 MHz, CD 3 OD + CDCl 3) δ 7.16 ~ 7.22 (5H, m), 6.21 (1H, d, J = 9.6 Hz), 5.77 ~ 5.88 (1H, m), 5.49-5.56 (1H, m), 5.32-5.39 (2H, m), 3.88 (2H, s), 3.46-3.58 (3H, m), 3.33-3.38 (1H, m); ¹³ C NMR (100 MHz, CDCl ₃ )? 139.4, 130.3, 129.2, 128.2, 126.9, 124.1, 118.7, 55.2, 50.1, 43.6.

Comparative Example 4 Preparation of (Z) -1-allyl-2- (3- (benzylsulfinyl) prop-1-enyl)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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).

Comparative Example 5 Preparation of (E) -1-allyl-2- (3- (benzylsulfinyl) prop-1-enyl)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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

Obtained form: yellow oil

_Rf = 0.22 (n-hexane / ethyl acetate = 2: 1); ^{(E) 1 H NMR (400} MHz, CDCl 3)? (2H, m), 3.98 (2H, s), 3.44-3.49 (2H, m), 7.26-7.41 (5H, m), 6.36 (1H, d, J = 2H, m), 3.29-3.37 (2H, m).

Comparative Example 6 Preparation of (E) -1- (3- (benzylsulfinyl) prop-1-enyl) -2-propyldisulfane

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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.

Comparative Example 7 Preparation of (E) -1-benzyl-2- (3- (benzylsulfinyl) prop-1-enyl)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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).

COMPARATIVE EXAMPLE 8 Preparation of (E) -1- (3- (benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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.

Comparative Example 9 Preparation of (Z) -1- (3- (benzylsulfinyl) prop-1-enyl) -2- (4-fluorobenzyl)

The objective compound was prepared in a similar manner to the preparation of the compound of Example.

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.

The chemical structures of the compounds prepared in Examples 1 to 38 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

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

≪ Experimental Example 1 > Evaluation of Cancer Proliferation Inhibitory Activity

<Experimental Example 1-1> 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, the compound of the present invention (azo and azo isosteric compound wherein R ¹ is allyl and R ¹ is benzyl) and the compound of the present invention (azo yen (Ajoene) and the like is not R ¹ is a human cancer cell lines (kidney cancer cell line (ACHN), breast cancer cell line (MDA-MB-231), colon cancer cell line (HCT-15) a compound phenyl) e-relationship, prostate (PC-3), gastric cancer cell line (NUGC-3) and lung cancer cell line (NCI-H23)).

The 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- 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, under 37 ℃ 5% of CO ₂ wet atmosphere Respectively. 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, CA, USA) and the results are shown in Table 2 below.

Isomer R ¹ R ² GI ₅₀ ([mu] M) ACHN MDA-MB-231 PC-3 NUGC-3 HCT-15 NCI-H23 Comparative Example 2 Z Ally Ally > 10 > 10 > 10 > 10 > 10 > 10 Comparative Example 3 Z Ally benzyl 3.26 4.64 2.31 2.05 4.96 3.59 Comparative Example 4 E benzyl Ally 5.32 3.28 8.07 5.93 5.98 Comparative Example 5 Z benzyl Ally 4.43 5.45 6.85 10.30 9.10 4.41 Comparative Example 6 E benzyl profile 2.19 3.27 3.03 2.93 Comparative Example 7 E benzyl benzyl 4.22 3.88 6.41 Comparative Example 8 E benzyl 4-FB 4.10 2.04 2.27 2.83 Comparative Example 9 Z benzyl 4-FB 2.32 3.24 Example 3 E Phenyl profile 2.15 2.93 2.64 2.80 Example 5 E Phenyl benzyl 3.19 3.71 3.97 2.98 Example 9 E Phenyl 4-MB 2.94 1.54 2.72 1.43 3.03 1.45 Example 10 Z Phenyl 4-MB 2.72 3.58 4.24 1.66 2.33 2.03

(In Table 2,

4-FB: 4-fluorobenzyl; And

4-MB: 4-methoxybenzyl.)

As can be seen in Table 2, the compounds of Examples 3, 5, 9, and 10 according to the present invention, that is, compounds wherein R ¹ is phenyl, exhibit the cancer growth inhibitory activity of Comparative Compound 2-9, that is, R ¹ is allyl or benzyl It has been confirmed that it has superior cancer proliferation inhibitory activity than phosphorus compounds and azoenes (Ajoene).

EXPERIMENTAL EXAMPLE 1-2 Evaluation of antiproliferative activity against cancer of Ajoene boiling electron compound

On the basis of the results confirmed in Experimental Example 1-1, a derivative in which R ¹ is phenyl was further synthesized, and the cancer proliferation inhibiting activity was evaluated in the same manner as in Experimental Example 1-1, Table 3 shows the results.

Isomer R ¹ R ² GI ₅₀ ([mu] M) ACHN MDA-MB-231 PC-3 NUGC-3 HCT-15 NCI-H23 Comparative Example 2 Z Ally Ally > 10 > 10 > 10 > 10 > 10 > 10 Example 3 E Phenyl profile 3.90 2.15 4.74 2.93 2.64 2.80 Example 5 E Phenyl benzyl 5.75 6.27 3.19 3.71 3.97 2.98 Example 6 Z Phenyl benzyl 5.42 3.96 5.35 3.25 6.48 4.91 Example 7 E Phenyl 4-FB 7.11 3.24 3.89 6.84 10.44 7.69 Example 9 E Phenyl 4-MB 2.94 1.54 2.720 1.43 3.03 1.45 Example 10 Z Phenyl 4-MB 2.72 3.58 4.24 1.66 2.33 2.03 Example 11 E Phenyl 4-CB 1.22 1.56 1.30 1.16 1.67 2.00 Example 12 Z Phenyl 4-CB 2.95 2.26 4.99 3.24 5.48 3.51 Example 13 Z Phenyl 3,4-DCB 1.97 7.50 2.30 1.77 2.78 2.92 Example 14 E 3-MP Ally 7.68 4.78 4.55 8.51 > 10 7.35 Example 15 Z 3-MP Ally 2.56 4.51 3.02 2.95 2.58 3.42 Example 17 E 3-MP profile 1.57 1.38 1.99 1.59 2.17 1.58 Example 18 Z 3-MP profile 2.06 2.43 1.92 1.71 1.34 1.59 Example 19 E 3-MP benzyl 2.50 1.77 1.44 2.34 2.08 2.12 Example 20 Z 3-MP benzyl 3.72 4.34 2.96 3.78 2.60 3.46 Example 21 E 3-MP 4-FB 2.46 2.02 1.97 1.56 1.75 2.12 Example 22 Z 3-MP 4-FB 3.85 4.41 3.04 3.67 3.01 2.71 Example 23 E 3-MP 4-CB 5.47 3.12 3.76 5.92 4.37 4.85 Example 24 Z 3-MP 4-CB 5.82 3.57 5.97 5.80 3.65 5.27 Example 26 Z 3-MP 3,4-DCB > 10 > 10 6.67 3.22 7.25 > 10 Example 27 E 4-MP Ally 3.86 5.62 4.38 4.62 6.61 3.91 Example 28 Z 4-MP Ally 5.06 7.28 4.47 3.77 3.94 4.24 Example 29 E 4-MP profile 1.65 2.20 2.41 2.04 1.48 1.41 Example 30 Z 4-MP profile 3.23 2.14 3.02 2.363 2.43 3.58 Example 32 Z 4-MP benzyl 3.12 5.88 3.19 3.82 1.55 4.37 Example 33 E 4-MP 4-FB 0.17 0.16 0.29 0.24 0.25 0.27 Example 34 Z 4-MP 4-FB 1.34 1.09 1.35 2.65 1.45 1.49 Example 35 E 4-MP 4-CB 0.88 1.16 1.05 1.08 0.88 0.97 Example 36 Z 4-MP 4-CB 2.41 1.78 2.28 2.84 1.62 2.19 Example 37 E 4-MP 3,4-DCB 3.75 4.19 5.17 5.48 3.32 3.09 Example 38 Z 4-MP 3,4-DCB 5.19 2.07 4.36 4.61 7.18 3.33

(In Table 3,

4-FB: 4-fluorobenzyl;

4-MB: 4-methoxybenzyl;

4-CB: 4-chlorobenzyl;

3,4-DCB: 3,4-dichlorobenzyl;

3-MP: 3-methoxyphenyl; And

4-MP: 4-methoxyphenyl).

As can be seen in Table 3, the derivatives of the example compounds according to the present invention, wherein R ¹ is phenyl, exhibit better cancer proliferation inhibitory activity than the benzene or allyl derivatives of Azone, R ¹ , It was confirmed that it was released. In particular, it was confirmed that when R ¹ is substituted phenyl (Examples 15-38), the cancer growth inhibitory activity is superior to that of unsubstituted phenyl.

Therefore, as is apparent from Experimental Examples 1-1 and 1-2, the novel organosulfur compounds of the present invention exhibit excellent proliferation inhibitory activity against cancer and are useful as pharmaceuticals for the prevention or treatment of cancer, It can be seen that it can be usefully used as a composition.

<Experimental Example 2> Evaluation of HDAC inhibitory activity

In order to evaluate the inhibitory activity against the histone deacetylation (HDAC) enzyme of the compound according to the present invention, the following experiment was conducted.

Specifically, HDAC enzyme assay as was based on a uniform fluorescence emission analysis, first, the analysis buffer containing 25 mM HEPES (pH 8.0), 137 mM NaCl, 1 mM MgCl 2, and 2.7 mM KCL, various concentrations The diluted compound of the Example according to the present invention or Comparative Example 1 was treated to cultivate the recombinant HDAC enzyme. After 10 minutes, the fluorescence inducing substrate Boc-Lys (acetyl) -AMC was added and further incubated at 37 [deg.] C. At this time, the concentration and the incubation time of the fluorogenic substrate were controlled according to the isotypes of the HDAC enzyme. Thereafter, the reaction was terminated by trypsinization at room temperature for 20 minutes so that the glare signal could be amplified. Fluorescence intensity measurements were made using a fluorescence analyzer at an excitation wavelength of 380 nm and an emission wavelength of 460 nm, respectively. The inhibition rate was calculated from the measured fluorescence intensity of the test well for the control wells, and the IC ₅₀ value of the compound was determined by analyzing the dose-response inhibition curve, and the results are shown in Table 4.

The inhibitory activity against HDAC 8 was expressed as a percentage relative to the inhibitory activity of SAHA using SAHA (Vorinostat) as a reference compound, and the results are shown in Table 4.

Isomer R ¹ R ² IC ₅₀ ([mu] M) Inhibitory activity (%) HDAC 1 HDAC 6 HDAC 8 HDAC 8 Comparative Example 1 E Ally Ally 73.4 Comparative Example 2 Z Ally Ally 52.5 Example 1 E Phenyl Ally 32.1 Example 2 Z Phenyl Ally 37.5 Example 3 E Phenyl profile 43.8 Example 4 Z Phenyl profile 115.2 Example 5 E Phenyl benzyl 88.6 Example 6 Z Phenyl benzyl 3.89 49.15 0.043 129.1 Example 7 E Phenyl 4-FB 37.1 Example 8 Z Phenyl 4-FB 24.9 Example 9 E Phenyl 4-MB 48.7 Example 10 Z Phenyl 4-MB 73.8 Example 11 E Phenyl 4-CB 74.4 Example 12 Z Phenyl 4-CB 105.4 Example 13 E Phenyl 3,4-DCB 76.6 Example 14 Z Phenyl 3,4-DCB 146.4 Example 15 E 3-MP Ally 84.6 Example 16 Z 3-MP Ally 105.3 Example 17 E 3-MP profile 78.4 Example 18 Z 3-MP profile 3.52 1.10 0.035 147.2 Example 19 E 3-MP benzyl 88.1 Example 20 Z 3-MP benzyl 114.3 Example 21 E 3-MP 4-FB 109.2 Example 22 Z 3-MP 4-FB 122.9 Example 23 E 3-MP 4-CB 72.6 Example 24 Z 3-MP 4-CB 1.27 140.4 Example 25 E 3-MP 3,4-DCB 138.9 Example 26 Z 3-MP 3,4-DCB 161.9 Example 27 E 4-MP Ally 39.8 Example 28 Z 4-MP Ally 73.5 Example 29 E 4-MP profile 69.9 Example 30 Z 4-MP profile 0.29 52.9 Example 31 E 4-MP benzyl 74.6 Example 32 Z 4-MP benzyl 4.55 0.55 0.037 150.4 Example 33 E 4-MP 4-FB 111.7 Example 34 Z 4-MP 4-FB 68.1 Example 35 E 4-MP 4-CB 107.2 Example 36 Z 4-MP 4-CB 98.7 Example 37 E 4-MP 3,4-DCB 106.1 Example 38 Z 4-MP 3,4-DCB 55.5

(In Table 4,

Inhibitory activity (%): (HDAC inhibitory activity of Example compound / HDAC inhibitory activity of SAHA) × 100;

4-FB: 4-fluorobenzyl;

4-MB: 4-methoxybenzyl;

4-CB: 4-chlorobenzyl;

3,4-DCB: 3,4-dichlorobenzyl;

3-MP: 3-methoxyphenyl; And

4-MP: 4-methoxyphenyl).

As can be seen in Table 4, the inventive compounds according to the present invention were found to have better inhibitory activity against HDACs 1, 6 and 8 than the comparative compounds, It is confirmed that it has a selective inhibitory activity of up to 100 times. For Example 18, the IC ₅₀ value for HDAC 8 is found to be 35 nM.

Accordingly, the compound of the present invention exhibits superior HDAC enzyme inhibitory activity and can selectively inhibit the HDAC 8 enzyme, thereby reducing the adverse effects that can be induced from the non-arterial HDAC inhibitor, 8, and the effect of inhibiting cancer proliferation preferably can be enhanced.

< Experimental Example 3> Evaluation of anticancer activity in a prostate cancer xenograft model

In order to evaluate the anticancer activity against the prostate cancer (PC-3) xenograft model of the compound according to the present invention, the following experiment was conducted.

Specifically, PC-3 cells (9 × 10 ⁶ cells), human prostate cancer cells, were inoculated subcutaneously to the right side of 5-week-old female BALB / c nu / nu mice (Nara Biotech, Seoul, Republic of Korea) when the size is 40-60 mm ^3, randomly divided the mouse (one per group 4) no treatment (10% dimethyl acetamide, 10% tween 80 and 80% distilled water), Comparative examples 1 and 2 (azo yen (Ajoene (50 mg / kg), Examples 18 and 32 (50 mg / kg), and SAHA (Vorinostat, 100 mg / kg) as a positive control were administered once a day for a total of 16 days. During the administration, the size of the cancer was measured with a vernier caliper and evaluated according to the following formula: length (mm) × width (mm) × height (mm) / 2, and body weight were measured periodically.

The mice were sacrificed at the end of the administration (after 16 days) and the weights of the cancers were measured. All experiments were carried out using an experimental protocol approved by the Institutional Animal Care and Use Committee (IACUC) Lt; / RTI &gt; The results obtained from the above experiment are shown in Figs. 1, 2, 3 and 4.

1, the administration of SAHA (Vorinostat, 100 mg / kg), Comparative Examples 1 and 2 (Ajoene, 50 mg / kg) and Examples 18 and 32 (50 mg / kg) It was confirmed that only normal body weight gain was observed with the passage of time, and it was considered that there was no visible toxicity.

As shown in Figure 2, SAHA (Vorinostat, 100 mg / kg), Comparative Examples 1 and 2 (Ajoene, 50 mg / kg), Examples 18 and 32 (50 mg / kg) In particular, it was confirmed that Example 18 inhibited the proliferation of cancer at a level similar to that of the positive control group, SAHA. This may be considered very encouraging in view of the fact that the dose of SAHA is twice that of Example 18.

As can be seen in FIG. 3, the compound of the example of the present invention showed small cancer size compared to the untreated group after administration and showed a comparable level of cancer proliferation inhibitory effect as compared with the positive control group SAHA . It may also be considered very encouraging, given that the dose of SAHA is twice the dose of the example compound.

As can be seen in FIG. 4, the weight of the cancer treated with the compound of Example 18 according to the present invention was found to be small relative to the weight of the untreated group, Comparative Examples 1 and 2 (Ajoene) And that the positive control, SAHA, is similar to the weight of the treated cancer. This may be considered very encouraging in view of the fact that the dose of SAHA is twice that of Example 18.

Therefore, the compound according to the present invention has a visible effect on cancer proliferation inhibition, as seen in Experimental Example 3, and shows a similar or better effect as compared with the positive control group, SAHA, Or a therapeutic pharmaceutical composition or a health functional food composition for preventing or ameliorating cancer.

Claims (10)

A compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
(4) (Z) -1- (3- (Phenylsulfinyl) prop-1-enyl) -2-propyldisulfane;
(6) (Z) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;
(9) (E) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;
(10) (Z) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;
(11) (E) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;
(12) (Z) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;
(14) (Z) -1- (3,4-Dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl) dicyclene;
(16) (Z) -1-Allyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(17) (E) -1- (3- (3-Methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;
(18) (Z) -1- (3- (3-Methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;
(19) (E) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(20) (Z) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(21) (E) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(22) (Z) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(24) (Z) -1- (4-Chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(25) (E) -1- (3,4-Dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(26) (Z) -1- (3,4-Dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(29) (E) -1- (3- (4-Methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane;
(32) (Z) -1-Benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(33) (E) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(34) (Z) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;
(35) (E) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclopentane;
(36) (Z) -1- (4-Chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene; And
(37) (E) -1- (3,4-Dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) diesulfan.
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.
8. The method of claim 7,
Wherein said compound inhibits HDAC (Histone deacetylase) to prevent or treat 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.

Images