WO2019143142A1 - Novel pharmaceutical composition for preventing or treating glioblastoma - Google Patents

Abstract

The present invention relates to a novel pharmaceutical composition for preventing or treating glioblastoma. An active ingredient compound, according to the present invention, may excellently inhibit histone deacetylase (HDAC), especially HDAC 8, selectively to a nanomole- or micromole-level concentration, and the compound has been confirmed to exhibit glioblastoma proliferation inhibition and cell death effects, and thus a useful effect may be achieved whereby a pharmaceutical composition for preventing or treating glioblastoma, containing the compound as an active ingredient may be provided.

Description

Novel pharmaceutical composition for the prevention or treatment of glioblastoma

The present invention relates to a novel pharmaceutical composition for the prophylaxis or treatment of glioblastoma.

Cancer is one of the most common causes of death worldwide. Approximately 10 million new cases occur every year, accounting for about 12% of all deaths and are reported as the third most common cause of death.

Among various types of cancer, brain cancer, especially in children, occurs more frequently than other cancers. Brain cancer refers to brain cancer, secondary brain cancer that has spread from cancer of the brain and other parts of the body, such as brain cancer that occurs in the brain surrounding the brain. Such brain cancer is often distinguished from cancer that occurs in other organs. First, the cancer that develops in the lungs, stomach, and breast is limited to one or two kinds of organs, and their properties are the same or similar. However, there are many different types of cancer in the brain. For example, polymorphous glioblastoma, malignant glioma, lymphadenoma, germ cell tumor, and metastatic tumor.

Among them, glioma, especially glioblastoma multiforme (GBM), is the most malignant and aggressive disease with very poor prognosis and a very fatal disease with an average survival of less than 1 year after diagnosis. Since the boundary between brain cells and tumor cells is not clear, it is almost impossible to surgically remove GBM.

Despite advances in the field of cancer therapy, currently the leading treatment is surgery, radiation and chemotherapy. The chemotherapeutic approach is mainly used to treat metastatic or particularly aggressive cancers. Most of the currently used cancer chemotherapeutic agents are cytotoxins. Cytotoxic agents work by damaging or killing fast-growing cells.

Ideal cytotoxic agents should have specificity for cancer and tumor cells, but not for normal cells. However, these ideal cytotoxic agents have not been found to date, and instead, only agents that specifically target rapidly differentiating cells (both tumor cells and normal cells) are being used.

Accordingly, substances which are cytotoxic to cancer cells are preferred, while only a mild effect is given to normal cells. Thus, many recent studies have suggested that an alternative anticancer substance, which can specifically inhibit the proliferation of tumor cells The focus is on developing.

Meanwhile, 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. And plays an important role in maintaining homeostasis of cells. 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 developing anticancer drugs. In particular, inhibitors targeting HDAC have been actively developed for the treatment of glioblastomas, and a number of documents have been reported that show the possibility and usefulness (Oncoimmunology. 2013 Aug 1; 2 (8): e25219.) .

However, there has been no prospective drug development for the treatment of glioblastoma, and currently 20 promising HDAC inhibitors are in clinical or preclinical stages for a variety of carcinomas, but most HDAC inhibitors show fatigue, nausea, vomiting, , Which is still under development and research.

Accordingly, the inventors of the present invention have developed a new HDAC inhibitor having improved drug efficacy and selectivity for the purpose of providing a therapeutic agent for a glioblastoma, and the novel HDAC inhibitor according to the present invention has a desired level of drug efficacy, The present invention can be used as a pharmaceutical composition for the prophylactic or therapeutic treatment of osteoblastoma.

It is an object of the present invention to provide a novel pharmaceutical composition for the prevention or treatment of glioblastoma.

Another object of the present invention is to provide a novel health functional food composition for preventing or improving glioblastoma.

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, unsubstituted or substituted benzyl, or unsubstituted or substituted phenyl,

Wherein said substituted phenyl and substituted benzyl are independently 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 and the C is one or more substituents selected from the group consisting of a straight or branched chain alkoxy of _{1 to 5} may be substituted,

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 pharmaceutical composition for preventing or treating a glioblastoma comprising the compound represented by the 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 a glioblastoma comprising the compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The active ingredient compound according to the present invention was found to be able to inhibit histone deacetylated (HDAC) enzyme at a nanomolar or micromole unit concentration, and to inhibit proliferation and cell death of glioblastoma. There is a useful effect that can be provided by a pharmaceutical composition for the prevention or treatment of glioblastoma containing the active ingredient.

Figures 1 a and b show cell survival rates of the glioblastoma TS cells (TS 13-64) treated with the compounds of the Examples of the present invention at concentrations of 1 μM, 5 μM, 10 μM, 20 μM and 50 μM, respectively The graph shows the change.

FIG. 2 shows the results obtained by treating the cells of Example 49, Example 51, SAHA, and PCI34051 with 5 uM for 72 hours in a glioblastoma TS cell (TS 13-64, TS 14-15, TS 15-88) Lt; RTI ID = 0.0 > proliferation < / RTI >

FIG. 3 shows the results obtained by treating the glioblastoma TS cells (TS 13-64, TS 14-15, TS 15-88) of Example 49, Example 51, SAHA and PCI 34051 with 5 uM for 72 hours, It is a graphical representation of changes in ATP production of blastoma.

FIG. 4 shows the results obtained by treating the glioma cell line TS cells (TS 13-64, TS 14-15, TS 15-88) of Example 49, Example 51, SAHA and PCI34051 for 72 hours at 5 uM, The photographs were observed after 3-week culture of tumor cells.

FIG. 5 shows the results obtained by treating the glioma cell line TS cells (TS 13-64, TS 14-15, TS 15-88) with the compound of Example 49, Example 51, SAHA and PCI34051 for 72 hours at 5 uM, The cells were cultured for 3 weeks, and then the ratio of the radius of the tumor to the proportion of the tumor forming well was calculated and shown in a graph.

FIG. 6 shows the results obtained by treating the glioma cells TS cells (TS 13-64, TS 14-15, TS 15-88) with the compound of Example 49, Example 51, SAHA and PCI34051, Expression of the gene related to the Stemness is observed.

FIG. 7 shows the results obtained by treating the glioma cell line TS cells (TS 13-64, TS 14-15, TS 15-88) with the compound of Example 49, Example 51, SAHA and PCI34051 for 72 hours at 5 uM, Fig. 2 is a photograph showing the infiltration ability of the tumor sphere by using the infiltration analysis method (the inset photograph is a photograph taken immediately after the cell transplant).

FIG. 8 is a graph showing the extent of infiltration of a tumor of a glioblastoma TS cell (TS 13-64, TS 14-15, TS 15-88) according to the treatment of Example 49, Example 51, SAHA and PCI 34051 Respectively.

Fig. 9 shows the results obtained by treating the glioma cell line TS cells (TS 13-64, TS 14-15, TS 15-88) with the compounds of Example 49 and Example 51, SAHA and PCI34051, The expression of the gene is observed and shown.

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, unsubstituted or substituted benzyl, or unsubstituted or substituted phenyl,

Wherein said substituted phenyl and substituted benzyl are independently 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 and the C is one or more substituents selected from the group consisting of a straight or branched chain alkoxy of _{1 to 5} may be substituted,

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, unsubstituted or substituted benzyl, or unsubstituted or substituted phenyl,

Wherein said substituted phenyl and substituted benzyl are independently 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 Lt; / RTI > may be substituted with one or more substituents selected from the group consisting of < RTI ID = 0.0 >

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 < ^{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- (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;

(18) (Z) -1- (3- (Phenylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl) dicyclene;

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

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

(21) (E) -1- (3- (phenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(50) (Z) -1-benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

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

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

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

(54) (Z) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

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

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

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, but the reaction time is not limited thereto. If the reaction time is such that the reaction proceeds completely and the reaction product can be maximally converted, 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 a temperature of -30 to -90 캜 for several hours, followed by cooling to room temperature for several hours. However, the reaction time is not limited to the time 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.

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

The compound represented by the above formula (1) inhibits HDAC (histone deacetylase) to prevent or treat glioblastoma. It inhibits the action mechanism of histone deacetylase, thereby inhibiting the proliferation of glioblastoma .

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 homeostasis of cells. Overexpression of HDAC in glioblastoma cells causes inhibition of important growth inhibitory genes and promotes glioblastoma cell proliferation. The compound represented by the formula (1), its stereoisomer or pharmaceutically acceptable salt thereof according to the present invention can inhibit the above-mentioned action mechanism and is capable of inhibiting the proliferation of glioblastoma cells.

However, the present invention is not limited to the above-described effects of the pharmacological mechanism, and the cell proliferation inhibitory activity and cell death effect of the glioblastoma cell line are confirmed as in the following Experimental Example, Based on this, it can be seen that the compound represented by the formula (1) of the present invention can be provided as an active ingredient of a pharmaceutical composition for the prevention or treatment of glioblastoma.

On the other hand, the glioblastoma is based on the effect of the present invention proved by the following experimental examples, and it is easy for a general practitioner to know that the glioblastoma can be effective for a similar tumor disease, for example, subspecies of glioblastoma, mutant species, You will understand.

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

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

As a result, excellent proliferation inhibitory activity was confirmed in glioblastoma. In particular, when R ^{1 in} the representative formula 1 of the present invention is unsubstituted or substituted Benzyl, or phenyl, a better glycoprotein proliferation inhibitory activity is exhibited (see Experimental Examples below).

Thus, the inventors of the present invention conducted further experiments for the same glioblastoma proliferation inhibition activity by synthesizing derivatives from the compound wherein R ^{1 in} the representative formula 1 of the present invention is unsubstituted or substituted benzyl or phenyl. As a result, R ¹ In the case of introducing a substituent at the 3 rd or 4 th position of the phenyl, the more excellent glioma cell proliferation inhibiting activity was confirmed than in the case of the phenyl (see Experimental Example below).

However, the above results are only illustrative and can be explained differently in terms of individual compounds, and the present invention includes them.

Meanwhile, the present inventors evaluated the inhibitory activity (IC50) of HDAC 1, 6, and 8 against 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 And it was found that the compound was effective as a pharmaceutical composition for the prevention or treatment of glioblastoma and an active ingredient of a health functional food composition (see Experimental Examples below).

Therefore, the active ingredient compound represented by formula (1) according to the present invention is an inhibitory compound having HDAC inhibitory activity, and thus it can be said that it is a candidate group that is excellent for the treatment of glioblastoma, and furthermore, From the proliferation inhibitory activity test, the active ingredient compound of the present invention can be provided as an active ingredient of a medicament for preventing or treating substantial glioblastoma, or a health functional food composition for preventing or improving.

Further, the present invention provides a method for treating a glioblastoma comprising administering to a subject a compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in a therapeutically effective amount .

Herein, the glioblastoma can be understood to mean a disease including all of a glioblastoma, a subspecies thereof, and mutants thereof, as described in the present specification.

The therapeutically effective amount refers to an amount sufficient to treat, prevent, or ameliorate the symptoms or conditions of the subject upon administration into the body, depending on the administration method. In addition, the amount may vary depending on the body weight, age, sex, condition, and family history of the subject to be administered. In the present invention, the treatment method can set different doses depending on different conditions.

The "effective amount" may be an amount effective to prevent, improve, or treat a glioblastoma. In other embodiments, an "effective amount" of a compound is an amount that is capable of inhibiting the proliferative activity of a glioblastoma or killing cells of a glioblastoma.

The compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective in treating the disease. The exact amount required will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" means a physically discrete unit of formulation suitable for the subject to be treated, as used herein. It will also be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors including: the severity of the disease and disorder to be treated; The activity of the specific compound employed; Specific composition; Age, weight, general health, gender and diet of the subject; The time of administration, the route of administration, and the rate of excretion of the particular compound employed; Duration of treatment; The particular compound used alone or coadministered, and other factors well known in the medical arts.

On the other hand, the term "subject" can be understood to mean an animal, such as a mammal, as used herein, such as a mouse or the like, preferably a human.

The present invention also provides the use of a compound represented by the above-mentioned formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis or treatment of a glioblastoma.

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 > Preparation of para-toluene thiosulfonyl-R2

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, and then the reaction was quenched 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 and allowed to stand at 0 ° C, stirred for 2 hours, and quenched 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.

Example 19 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 allowed to stand at 0 ° C, stirred for 2 hours, and the reaction quenched 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 20 Preparation of (Z) -1-allyl-2- (3- (phenylsulfinyl) prop-1-enyl)

Following the procedure of Example 19, 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 21 Preparation of (E) -1- (3- (phenylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 19 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 19 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 22 Preparation of (Z) -1- (3- (phenylsulfinyl) prop-1-enyl) -2-propyldisulfane

Following the procedure of Example 21, 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 23 Preparation of (E) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 19 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 19 to obtain 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), 6.09 (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 24 Preparation of (Z) -1-benzyl-2- (3- (phenylsulfinyl) prop-1-enyl)

Following the procedure of Example 23, 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 25 Preparation of (E) -1- (4-fluorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 19 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 19 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 26 Preparation of (Z) -1- (4-fluorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 25 was repeated except that the stereoisomer was obtained as 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), 6.23 (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 27 Preparation of (E) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 19 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 19 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 28 Preparation of (Z) -1- (4-methoxybenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

Following the procedure of Example 27, 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 29 Preparation of (E) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

Following the procedure of Example 28, the stereoisomer was obtained as 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 30 Preparation of (Z) -1- (4-chlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 19 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 19 to obtain 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 31 Preparation of (E) -1- (3,4-dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

The procedure of Example 19 was repeated, except that the compound of Preparation 7 was used instead of the compound of Preparation 1 used in Step 3 of Example 19 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 32 Preparation of (Z) -1- (3,4-dichlorobenzyl) -2- (3- (phenylsulfinyl) prop-1-enyl)

Following the procedure of Example 31, 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 33 Preparation of (E) -1-allyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Isobutyronitrile Im OY corresponding to the Example 19 using benzene thiol in step 1, the titanium or its salt _{(Ph-SC (¼NH 2)} NH 2 þ Br,) in place of 3-methoxy-benzene-thiol or equivalent The target compound was obtained in a similar manner to Example 19, except that the isothiourone salt (3-methoxyphenyl-SC (¼NH ₂ ) NH ₂ þ Br) was used.

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

The procedure of Example 33 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 35 Preparation of (E) -1- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 33 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 33 to obtain the desired 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 36 Preparation of (Z) -1- (3- (3-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

Following the procedure of Example 35, 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 37 Preparation of (E) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 33 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 33 to obtain the desired 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 38 Preparation of (Z) -1-benzyl-2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 37, 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 39 Preparation of (E) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 33 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 33 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 40 Preparation of (Z) -1- (4-fluorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 39, 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 41 Preparation of (E) -1- (4-chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 33 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 33 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 42 Preparation of (Z) -1- (4-chlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 41, 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 43 Preparation of (E) -1- (3,4-dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 33 was repeated, except that the compound of Preparation 7 was used instead of the compound of Preparation 1 used in Step 3 of Example 33 to obtain the desired 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 44 Preparation of (Z) -1- (3,4-dichlorobenzyl) -2- (3- (3-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 43, 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 45 Preparation of (E) -1-allyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Isobutyronitrile Im OY corresponding to the Example 19 using benzene thiol in step 1, the titanium or its salt _{(Ph-SC (¼NH 2)} NH 2 þ Br,) in place of 4-methoxybenzene thiol or equivalent The target compound was obtained in a similar manner to Example 19, except that the isothiourone salt (4-methoxyphenyl-SC (NNH ₂ ) NH ₂ Br 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 46 Preparation of (Z) -1-allyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 45, 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 47: Preparation of (E) -1- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

The procedure of Example 45 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 45 to obtain the target 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 48 Preparation of (Z) -1- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) -2-propyldisulfane

Following the procedure of Example 47, 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 49 Preparation of (Z) -1-benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 45 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 45 to obtain 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 50 Preparation of (Z) -1-benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 49, the stereoisomer was obtained as 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 51: Preparation of (E) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 45 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 45 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 52 Preparation of (Z) -1- (4-fluorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 51, 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 53 Preparation of (E) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 45 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 45 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 54 Preparation of (Z) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

Following the procedure of Example 53, 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 55: Preparation of (E) -1- (3,4-dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 45 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 45 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 56 Preparation of (Z) -1- (3,4-dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl)

The procedure of Example 55 was repeated except that 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-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. IR (NaCl) cm- ¹ ; HRMS-ESI

≪ Comparative Example 2 > Preparation of Z-azoene (Z-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.

The chemical structures of the compounds prepared in Examples 1 to 56 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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56

EXPERIMENTAL EXAMPLE 1 Evaluation of HDAC Inhibitory Activity In order to evaluate the inhibitory activity against the histone deacetylation (HDAC) enzyme of the present active compound, 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 recombinant HDAC enzyme was cultured by treating each of the diluted compound of the present invention, the SAHA or the comparative compound. 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. The reaction was then quenched with trypsin for 20 min at room temperature to allow the glare signal to 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 ratio 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 2.

In addition, SAHA (Vorinostat) was used as a reference compound to exhibit inhibitory activity against HDAC 8 in a percentage, and the results are shown in Table 2.

	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 19	E	Phenyl	Ally				32.1
Example 20	Z	Phenyl	Ally				37.5
Example 21	E	Phenyl	profile				43.8
Example 22	Z	Phenyl	profile				115.2
Example 23	E	Phenyl	benzyl				88.6
Example 24	Z	Phenyl	benzyl	3.89	49.15	0.043	129.1
Example 25	E	Phenyl	4-FB				37.1
Example 26	Z	Phenyl	4-FB				24.9
Example 27	E	Phenyl	4-MB				48.7
Example 28	Z	Phenyl	4-MB				73.8
Example 29	E	Phenyl	4-CB				74.4
Example 30	Z	Phenyl	4-CB				105.4
Example 31	E	Phenyl	3,4-DCB				76.6
Example 32	Z	Phenyl	3,4-DCB				146.4
Example 33	E	3-MP	Ally				84.6
Example 34	Z	3-MP	Ally				105.3
Example 35	E	3-MP	profile				78.4
Example 36	Z	3-MP	profile	3.52	1.10	0.035	147.2
Example 37	E	3-MP	benzyl				88.1
Example 38	Z	3-MP	benzyl				114.3
Example 39	E	3-MP	4-FB				109.2
Example 40	Z	3-MP	4-FB				122.9
Example 41	E	3-MP	4-CB				72.6
Example 42	Z	3-MP	4-CB	1.27			140.4
Example 43	E	3-MP	3,4-DCB				138.9
Example 44	Z	3-MP	3,4-DCB				161.9
Example 45	E	4-MP	Ally				39.8
Example 46	Z	4-MP	Ally				73.5
Example 47	E	4-MP	profile				69.9
Example 48	Z	4-MP	profile				52.9
Example 49	Z	4-MP	benzyl	4.55	0.55	0.037	150.4
Example 50	E	4-MP	benzyl				74.6
Example 51	E	4-MP	4-FB				111.7
Example 52	Z	4-MP	4-FB				68.1
Example 53	E	4-MP	4-CB				107.2
Example 54	Z	4-MP	4-CB				98.7
Example 55	E	4-MP	3,4-DCB				106.1
Example 56	Z	4-MP	3,4-DCB				55.5

(In Table 2, inhibitory activity (%): (HDAC inhibitory activity of the compound of Example / 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 2, the active ingredient compounds of the present invention were found to have inhibitory activity against HDAC 1, 6 and 8, and in particular, about 30 to 100-fold selective inhibitory activity against HDAC 8 and HDAC 8 . In particular, in Example 36, the IC ₅₀ value for HDAC8 was found to be 35 nM, indicating that the selective inhibitory activity was excellent.

<Experimental Example 2> Evaluation of proliferation inhibitory activity on glioblastoma

In order to evaluate the proliferation inhibitory activity of the active ingredient compound of the present invention on the glioblastoma cell line, the following experiment was conducted.

Specifically, TS cells derived from a glioblastoma patient (TS13-64) were inoculated in a 96-well plate and cultured at 37 ° C for 24 hours, and then cultured in the same manner as in Examples 22, 24, 12, 18, 32, 49, 51, 36, 40, and 42 compounds, and LS Cat.No.CCK-3000, a D-Plus CCK / cell viability assay kit, was used for cell survival analysis. WST was treated at a concentration of 10 μl / well Followed by incubation at 37 ° C for 2 hours. Thereafter, the absorbance at 450 nm was measured using a Versa MAX microplate reader, and the change in absorbance versus the untreated control (control) was calculated as the cell survival rate. The results are shown graphically in FIGS. 1 a and b.

1A and 1B, the proliferation inhibitory activity of the compound of Example of the present invention on the glioblastoma cell line can be confirmed. In particular, the compounds of Examples 49 and 51 have the best proliferation inhibitory activity.

Therefore, it can be seen that the active ingredient compound according to the present invention can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of glioblastoma.

Experimental Example 3 Evaluation of proliferation inhibitory activity on glioblastoma 2

In addition, TS cells (TS 13-64, TS 14-15, TS 15-88) derived from a glioblastoma patient were inoculated in a 96-well plate and cultured at 37 ° C for 24 hours, 51 and Pan-HDAC inhibitors SAHA and PCI34051 were used as a positive control for 72 hours at 5 uM to observe the proliferation inhibitory activity and ATP production of the glioblastoma.

For the analysis of cell viability, LS cat.no.CCK-3000, a D-Plus CCK / cell viability assay kit, was used. WST was treated at a concentration of 10 μl / well and cultured at 37 ° C for 2 hours Respectively. The absorbance was then measured at 450 nm using a Versa MAX microplate reader and the change in absorbance versus untreated control was calculated as the cell viability.

The results of this experiment are shown in Fig. 2 (graph of inhibition of proliferation of glioma) and Fig. 3 (graph of ATP production change).

2, excellent anticancerous cell proliferation inhibitory activity of the compound of Example of the present invention is confirmed compared to the positive control groups of SAHA and PCI34051.

3, when the compound of the present invention was treated, significant inhibition of ATP production was observed compared to PCI34051 and it was comparable to that of SAHA, or in the case of TS 15-88, Inhibitory activity.

&Lt; Experimental Example 4 > Evaluation of glioblastoma tumor morphogenesis inhibitory activity

In order to observe and evaluate the glioblastoma tumorigenesis inhibitory activity of the effective ingredient compounds of the present invention, the following experiment was conducted.

In the TS cells (TS 13-64, TS 14-15, TS 15-88) derived from glioblastoma patients as in Experimental Example 3, the compounds of Examples 49 and 51 and Pan-HDAC Inhibitors SAHA and PCI34051 As a positive control, the cells were treated with 5 uM for 72 hours, and single tumor cells were cultured for 3 weeks to observe tumor formation.

Fig. 4 shows photographs of tumor shedding according to each treatment compound, Fig. 5 shows the ratio of tumor radius and tumor sphere forming wells, and Fig. 6 shows the results of stem cell stemming Expression of the genes was confirmed.

4 and 5, it can be seen that the compound of the present invention of the present invention inhibits tumor formation more significantly compared with PCI34051, and that the compounds of the present invention were treated according to the treatment to decrease the tumor radius and the tumor- It is confirmed that the ratio is significantly reduced.

In addition, in the Western blot of FIG. 6, it is confirmed that the expression of stem cell-related genes is inhibited by the treatment of the compounds of the examples of the present invention.

&Lt; Experimental Example 5 > Evaluation of the inhibitory effect on the glioblastoma infiltration

In order to evaluate the inhibitory activity against the ability of the active ingredient compound of the present invention to infiltrate the glioblastoma, the following experiment was conducted.

In the TS cells (TS 13-64, TS 14-15, TS 15-88) derived from glioblastoma patients as in Experimental Example 3, the compounds of Examples 49 and 51 and Pan-HDAC Inhibitors SAHA and PCI34051 As a positive control, the cells were treated with 5 uM for 72 hours and invasion assay was performed using a 3D invasion assay platform.

FIG. 7 shows a photograph of the tumor according to iron of each compound (photograph of inset immediately after cell transplantation (treatment time 0 hours)), FIG. 8 shows the measurement of the infiltration range of the tumor, and FIG. 9 shows Western blot The expression of infiltration-related genes was confirmed and shown.

Referring to FIGS. 7 and 8, the compound of the present invention exhibits an infiltration inhibitory activity superior to that of PCI34051, confirming similar or superior infiltration inhibitory activity (that is, an effect of reducing tumor metastatic ability) in comparison with SAHA.

9 shows Western blotting, it is confirmed that the expression of the infiltration-related genetic genes is suppressed according to the treatment of the compound of the Example of the present invention.

Therefore, it can be seen that the active ingredient compound according to the present invention can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of glioblastoma.

The active ingredient compound according to the present invention was found to be able to inhibit histone deacetylated (HDAC) enzyme at a nanomolar or micromole unit concentration, and to inhibit proliferation and cell death of glioblastoma. There is a useful effect that can be provided by a pharmaceutical composition for the prevention or treatment of glioblastoma containing the active ingredient.

Claims (8)

1. A pharmaceutical composition for preventing or treating a glioblastoma comprising a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

   [Chemical Formula 1]

   

   (In the formula 1,

   R ¹ is allyl, unsubstituted or substituted benzyl, or unsubstituted or substituted phenyl,

   Wherein said substituted phenyl and substituted benzyl are independently 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 and the C is one or more substituents selected from the group consisting of a straight or branched chain alkoxy of _{1 to 5} may be substituted,

   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 an unsubstituted or substituted C &lt; _1-3 &gt; straight or branched alkoxy).
2. The method according to claim 1,

   R ¹ is allyl, unsubstituted or substituted benzyl, or unsubstituted or substituted phenyl,

   Wherein said substituted phenyl and substituted benzyl are independently 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 Lt; / RTI &gt; may be substituted with one or more substituents selected from the group consisting of &lt; RTI ID = 0.0 &gt;

   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, a stereoisomer thereof or a A pharmaceutical composition for preventing or treating a glioblastoma comprising a pharmaceutically acceptable salt as an active ingredient.
3. The method according to claim 1,

   R ² is 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- compound, characterized in that optionally substituted with one or more substituents selected from the group consisting of the ₃ straight or branched alkoxy, prevention of glioblastoma containing its stereoisomers or a pharmaceutically acceptable salt thereof as an active ingredient or A pharmaceutical composition for therapeutic use.
4. The method according to claim 1,

   R ² is

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   or

   

   Or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as an active ingredient. The present invention also provides a pharmaceutical composition for preventing or treating a glioblastoma comprising the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
5. The method according to claim 1,

   The pharmaceutical composition for preventing or treating a glioblastoma comprising the compound, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the compound represented by the formula (1) is any one selected from the following group :

   (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;

   (18) (Z) -1- (3- (Phenylsulfinyl) prop-1-enyl) -2- (4-methoxybenzyl) dicyclene;

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

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

   (21) (E) -1- (3- (phenylsulfinyl) prop-1-enyl) -2-propyldisulfane;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

   (50) (Z) -1-benzyl-2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

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

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

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

   (54) (Z) -1- (4-chlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) dicyclene;

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

   (56) (Z) -1- (3,4-Dichlorobenzyl) -2- (3- (4-methoxyphenylsulfinyl) prop-1-enyl) diesulfan.
6. The method according to claim 1,

   Wherein said compound inhibits HDAC (Histone deacetylase) to prevent or treat glioblastoma.
7. The method according to claim 6,

   Wherein the compound exhibits excellent inhibitory activity against HDAC8, and thus the pharmaceutical composition is characterized by preventing or treating a glioblastoma.
8. A health functional food composition for preventing or ameliorating a glioblastoma comprising a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

   [Chemical Formula 1]

   

   (In the formula 1,

   R ¹ is allyl, unsubstituted or substituted benzyl, or unsubstituted or substituted phenyl,

   Wherein said substituted phenyl and substituted benzyl are independently 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 and the C is one or more substituents selected from the group consisting of a straight or branched chain alkoxy of _{1 to 5} may be substituted,

   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 &lt; 1 &gt; ₃ straight or branched alkoxy).

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