KR20160147420A - Composition for preventing or treating neuromyelitis optica, comprising tryptophan derivatives or pharmaceutical acceptable salts thereof - Google Patents

Abstract

The present invention relates to a vinylsulfone derivative compound which acts to prevent binding of NMO-IgG and aquaporin 4, pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating neuromyelitis optica comprising the same, as an active ingredient.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for preventing or treating optic nerve spondylitis comprising a vinylsulfone derivative, a pharmaceutically acceptable salt thereof and an active ingredient thereof,

The present invention relates to a vinylsulfone derivative compound, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating optic nerve spondylitis containing the same as an active ingredient.

Neuromyelits optica (NMO) is one of the most common invasive brain diseases. It is an inflammatory dehydrative autoimmune disease affecting the central nervous system and optic nerve. Optic neuritis is distinguished from other diseases by the presence of NMO-IgG, a optic neuritis specific antibody to the water transport pathway protein, aquaporin 4, which is mainly expressed in astrocytes. The optic neuropathy myelitis specific antibody is found in about 75% of patients. The aquaporin 4 protein is a major antigen of NMO-IgG and is mainly distributed in astrocytes that constitute a blood-brain barrier that protects the brain and central nervous system from inflammatory cells. Binding of NMO-IgG to aquaporin 4 is a key mechanism in the pathogenesis of optic neuritis. NMO-IgG, an optic nerve spindle-specific antibody, binds to an antigen, aquaporin 4, to induce cognitive cytotoxicity or antibody-dependent cell-mediated cytotoxicity, damaging astrocytes and causing optic neuritis.

Currently, anticancer drugs, immunosuppressants, immunomodulators, and blood purification therapies are mostly used as therapeutic agents for optic neuritis, and clinical trials for the safety of this antibody are in progress. However, it is very urgent and important to develop therapeutic agents that minimize these side effects and maximize efficacy, as immunosuppressants are highly toxic and have severe side effects such as central nervous system infection, leukemia, cardiac toxicity, or death. Nevertheless, the pathology of severe brain diseases has not yet been well known, so there is no basic treatment, and rare diseases such as optic neuropathy are under development.

U.S. Patent Publication No. 2014-0170140 discloses a method for treating optic neuropathy with basic NMO therapy such as monotherapy or immunosuppressant or plasma separation using an antibody binding to aquaporin 4, In patent No. 7872032, a 1,3,4-oxadiazol-2-one derivative or a stereoisomer isomer thereof or a solvate thereof or a pharmaceutically acceptable salt thereof as a peroxide activator receptor agonist delta modulating substance is used to treat multiple Inflammatory bowel disease, inflammatory bowel disease, scleroderma, optic neuritis, and the like.

Compared with multiple sclerosis with symptoms similar to those with optic neuritis, multiple sclerosis was reported to be relatively high in the West, while optic nerve sheath inflammation was reported to be high in Asia, including Korea and China. As multiple sclerosis has already been developed in a large market in Western countries, optic nerve spondylitis is expected to form a big market in Asia, including Korea and China, soon after the development of therapeutic drugs.

The first problem to be solved by the present invention is to provide a vinylsulfon derivative and its pharmaceutically acceptable salt which serve to prevent the binding of NMO-IgG and aquaporin 4 protein.

A second object of the present invention is to provide a process for preparing the vinyl sulfone derivative.

A third object of the present invention is to provide a pharmaceutical composition containing the carbazole derivative and a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient to treat or prevent optic neuritis or degenerative nervous system diseases.

In order to achieve the above-mentioned object, an aspect of the present invention is to provide a vinylsulfone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

[Formula 1]

_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in.

Another aspect of the present invention is to provide a process for preparing a vinylsulfon derivative represented by the above formula (1) by reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) in an organic solvent .

(2)

(3)

Another aspect of the present invention is to provide a pharmaceutical composition for preventing or treating optic neuritis, which comprises as an active ingredient, a vinylsulfon derivative represented by the above formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof.

Another aspect of the present invention is to provide a pharmaceutical composition for preventing or treating a degenerative neurological disease comprising the vinylsulfone derivative represented by the formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

Another aspect of the present invention relates to a pharmaceutical composition comprising a combination of a compound inhibiting the binding of NMO-IgG and aquaporin 4 protein comprising a vinylsulfone derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient Inhibitor < / RTI >

The vinylsulfone derivative or its pharmaceutically acceptable salt or solvate thereof according to the present invention can prevent the cell death caused by the binding of NMO-IgG and the aquaporin 4 protein, so that the NMO-IgG and the aquaporin 4 protein In particular, optic neuritis, degenerative nervous system diseases, and the like.

1 is a diagram illustrating a lactate dehydratase secretion test according to an embodiment of the present invention.
FIG. 2 is a graph of LDH-releasing results obtained by treating IgG of patients with generalized IgG and optic neuropathy (NMO) with U87MG and U87MG-AQP4, respectively, according to an embodiment of the present invention.
FIG. 3 is a diagram illustrating an indirect immunofluorescent antibody assay method for confirming whether a compound produced according to an embodiment of the present invention inhibits AQP4 and NMO-IgG binding.
FIG. 4 is a result of indirect immunofluorescent antibody test showing the inhibition of AQP4 and NMO-IgG binding of the compound prepared according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail.

According to one aspect of the present invention, there is provided a vinylsulfone derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

[Formula 1]

_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in.

In the present invention, the halogen group may be selected from among fluoro, chloro, bromo and iodo,

Alkyl groups of the C _{1 -7} can be a straight-chain or branched alkyl, a, can be specifically selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, hexyl and heptyl, the

Alkyl group of the halogenated C _{1 -7} can be selected from methyl, trifluoromethyl and ethyl trifluoroacetate in trifluoroacetic acid,

Alkyloxy of C _{1 -7} wherein the group may be selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy and heptyloxy,

Alkoxy of the halogenated C _{1 -7} group may be selected from propoxy as trifluoromethoxy, trifluoroethoxy ethoxy and trifluoromethyl,

The alkylcarbonyl group is a C _{1 -7} can be chosen from acetyl, propionyl, 1-butane is on.

The vinylsulfone derivative represented by the above formula (1) according to the present invention is characterized in that a phenyl group containing a methoxy group is bonded to a sulfone group and a phenyl-O-CH ₂ -aryl group is bonded to a vinyl group. The aryl of the phenyl-O-CH ₂ -aryl group may be phenyl in which 1 to 5 carbon atoms are optionally substituted with R ₁ to R ₅ .

In particular, the structural features of the phenyl-O-CH ₂ -aryl group bonded to the vinyl group of the vinyl sulfone derivative represented by the above formula (1) of the present invention are that the compound represented by the above formula (1) is a mixture of NMO IgG and aquaporin 4 protein binding.

Specifically, when an alkyl group, an alkoxy group, an alkylamine group, an amide group or the like is bonded instead of the phenyl-O-CH ₂ -aryl group bonded to the vinyl group, the ability to inhibit binding of the protein of the NMO IgG and aquaporin 4 Even when the phenyl group is bonded, when the substituent substituted on the phenyl is other than the -O-CH ₂ -aryl group, for example, a halogen, a halogenated alkyl, a nitro, an alkoxy, etc., the NMO IgG and the aquaporin 4 But does not show the ability to inhibit protein binding.

In the present invention, the pharmaceutically acceptable salt is not particularly limited as long as it is commonly used in the art. Specific examples thereof include inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid or nitric acid, The salt may be formed using an organic acid such as sulfonic acid, but is not limited thereto.

Examples of the carboxylic acid include acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, succinic acid, propionic acid, glycolic acid, stearic acid and lactic acid, Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and naphthalenedisulfonic acid, but the types of the carboxylic acid and sulfonic acid are not limited to the above-mentioned compounds.

In the present invention, the vinylsulfone derivative represented by the formula (1) may be any one selected from compounds represented by the following compounds 1 to 13.

Compound 1: (E) -1- (benzyloxy) -4- (2 - ((4-methoxyphenyl) sulfonyl) vinyl) benzene;

Compound 2: (E) -1-Trifluoromethyl-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 3: (E) -1-fluoro-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 4: (E) -1-chloro-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 5: (E) -1-Trifluoromethyl-3 - ((4-2 - ((2-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 6: (E) -1-fluoro-3 - ((4-2 - ((2-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 7: (E) -1-methoxy-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 8: (E) -1-Trifluoromethyl-4 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl) benzene;

Compound 9: (E) -1 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) -3-nitrobenzene;

Compound 10: (E) -3 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) benzoic acid;

Compound 11: (E) -3 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) phenol;

Compound 12: (E) -1 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) -3- (trifluoromethoxy) benzene;

Compound 13: (E) -1- (3 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) phenyl) ethanone;

Meanwhile, the present invention provides a process for producing a vinylsulfone derivative represented by the following formula (1) by reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) in an organic solvent.

[Chemical Formula 1]

(2)

(3)

In the above Chemical Formula 1 or Chemical Formula 2,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above.

The organic solvent may be selected from the group consisting of acetonitrile, methylene chloride, dichloroethane, tetrahydrofuran, lower alcohol, N, N-dimethylformamide, dimethylsulfoxide, ethyl acetate, dioxane, chloroform, benzene and toluene have.

The reaction can be carried out by stirring at a temperature in the range of -80 to 0 캜 for 0.5 to 5 hours, and a base can be added for the purpose of improving the reactivity. The base may preferably be N-butyllithium, but is not limited thereto.

In the present invention, the low-priced alcohol means methanol, ethanol, propanol or butanol.

According to an embodiment of the present invention, the reaction mixture may be purified using a conventional purification method, and preferably purified by column chromatography using silica gel to obtain the target compound represented by the formula 1 A vinylsulfonic acid derivative can be obtained.

The vinylsulfonic acid derivative represented by the above formula (1) can be produced in the form of a pharmaceutically acceptable salt by using an inorganic acid such as hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid or nitric acid or an organic acid such as carboxylic acid or sulfonic acid And examples of the carboxylic acid and sulfonic acid are as defined above.

According to one embodiment of the present invention, the compound represented by the formula (3) can be produced by oxidizing a compound represented by the following formula (4).

[Chemical Formula 4]

According to the present invention, the oxidation is carried out using an oxidizing agent selected from hydrogen peroxide, m-chloroperoxibenzoic acid (mCPBA), magnesium monoperoxyphthalate (MMPP) and sodium hypochlorite (NaOCl) , Preferably m-chloro peroxide benzoic acid.

According to the present invention, the reaction can be carried out by stirring in an organic solvent at -40 to 25 ° C, and the organic solvent is selected from the group consisting of acetonitrile, methylene chloride, dichloroethane, tetrahydrofuran, lower alcohol, N, Amide, dimethylsulfoxide, ethyl acetate, dioxane, chloroform, benzene and toluene.

On the other hand, the compound represented by the formula (4) can be produced by reacting a compound represented by the following formula (5) with a benzenethiol derivative represented by the following formula (6) in the presence of cesium carbonate (Cs ₂ CO ₃ ) .

[Chemical Formula 5]

[Chemical Formula 6]

According to the present invention, the compound of formula (5) can be prepared by reacting diethyl hydroxymethyl phosphate with 4-toluenesulfonyl chloride in a base and an organic solvent. The organic solvent is as defined above, and the base is not particularly limited as long as it is used for adding a tosyl group to the diethyl hydroxymethyl phosphate, and may be, for example, triethylamine.

On the other hand, the above-mentioned production method is represented by the following Reaction Scheme 1.

[Reaction Scheme 1]

In the meantime, the present invention relates to a pharmaceutical composition comprising NMO-IgG (Neuro myelitis Optica-IgG) and aquaporin 4 (hereinafter, referred to as " aquaporin "), which contains, as an active ingredient, a vinylsulfone derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof. 4, AQAP4) protein.

Aquaporin 4 is located at the end of the astrocyte surrounding the blood-brain barrier, and serves as a pathway for transporting moisture through the cell membrane. NMO-IgG, a specific antibody to optic neuritis, binds to the aquaporin 4, a water channel protein, to trigger an immune response.

The vinylsulfone derivative represented by the above formula (1), or a pharmaceutically acceptable salt or solvate thereof, plays a role in inhibiting complement-dependent cytotoxicity (CDC) by an aquaporin 4 autoantibody. Therefore, the vinylsulfone derivative represented by the above formula (1) or its pharmaceutically acceptable salt or solvate thereof may act as a binding inhibitor for inhibiting the binding of the NMO-IgG and the aquaporin 4 protein.

The present invention provides a pharmaceutical composition for preventing or treating optic neuritis, which comprises as an active ingredient, a vinylsulfon derivative represented by the above formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof.

According to the present invention, the term "optic nerve spondylitis" means a disease characterized by optic neuritis of the monocular or bilateral and longitudinally extensive myelitis involving more than three segments of the vertebra.

The optic neuropathy is a major pathogenesis and progression mechanism in which the anti-aqua autoantibody binds to aquaporin 4 present in astrocytes and induces complement-dependent cytotoxicity, thereby causing destruction of the blood brain barrier (BBB) .

According to the present invention, the above-mentioned vinylsulfone derivative or its pharmaceutically acceptable salt or solvate thereof may be formulated by a conventional formulation method by mixing with a conventional carrier, adjuvant or diluent, and formulated into a form suitable for oral administration or parenteral administration .

Examples of the carrier, adjuvant or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, poly Vinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When formulating the composition, the composition may further contain conventional fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like, and lubricants such as magnesium stearate and talc may be further added.

The oral administration may be in the form of tablets, capsules, solutions, syrups, suspensions, etc. In the case of parenteral administration, it may be prepared in the form of injections for peritoneal, subcutaneous, muscular and transdermal administration.

According to one embodiment of the present invention, the pharmaceutical composition is one which prevents the binding of NMO-IgG and aquaporin 4 protein, and is characterized in that 1 day of the vinylsulfone derivative of the formula 1 or a pharmaceutically acceptable salt thereof of the formula The effective dose may be 0.01 to 1000 mg / day on an adult basis. The dose may vary depending on the patient's age, body weight, sex, dosage form, health condition and disease severity. And may be administered once to several times a day at intervals.

Therefore, the vinylsulfone derivative represented by the above formula (1) or a pharmaceutically acceptable salt or solvate thereof according to the present invention can prevent or suppress complement-dependent cytotoxicity by the anti-aquaporin 4 autoantibody It can be used as a remedy for optic neuritis.

The present invention also provides a pharmaceutical composition for the treatment or prevention of degenerative neurological diseases comprising, as an active ingredient, a vinylsulfone derivative represented by the above formula (1) or a pharmaceutically acceptable salt or solvate thereof according to the present invention.

According to the present invention, the degenerative neurological disease may be any one selected from DeVic disease, multiple sclerosis and Lou Gehrig's disease.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. It will be apparent to those skilled in the art, however, that these examples are for the purpose of describing the present invention more specifically and that the scope of the present invention is not limited thereby.

Example

Production Example 1. Synthesis of (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate

Diethylhydroxymethylphosphonate (10 g, 0.06 mol) was dissolved in methylene chloride (MC) and triethylamine (9.80 mL, 0.07 mmol) and 4-toluenesulfonyl chloride (13.3 g, 0.07 mol) And the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (ethyl acetate / n-hexane 1: 3) to obtain (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (10 g) in a yield of 52% .

Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H ), 1.31 (t, J = 7.4 Hz, 6 H)

Production Example 2. Synthesis of diethyl (4-methoxyphenylthio) methylphosphonate or diethyl (2-methoxyphenylthio) methylphosphonate

Methoxy-substituted benzenethiol (1.0 eq) was dissolved in DMF, cesium carbonate (Cs ₂ CO ₃ ; 1.2 eq) and the compound synthesized in Preparation Example 1 (1.2 eq) were added in turn, Lt; / RTI > When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography (ethyl acetate / n-hexane 3: 1) to obtain the desired compound.

Production Example 2.1. Diethyl (4-methoxyphenylthio) methylphosphonate

Colorless oil; Yield: 84%; Rf = 0.3 (hexane / EtOAc 1/2); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.46 (d, J = 6.8 Hz, 2H), 6.84 (d, J = 6.4 Hz, 2H), 4.14-4.08 (m, 4H), 3.79 (s, 3H ), 3.09 (d, J = 12.8 Hz, 2H), 1.30 (t, J = 7.0 Hz,

Preparation 2.2 Diethyl (2-methoxyphenylthio) methylphosphonate

Colorless oil; Yield: 87%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.42 (dd, J = 1.6, 7.7 Hz, 1H), 7.24 (m, 1H), 6.91 (td, J = 1.1, 7.6 Hz, 1H), 6.85 (d J = 8.2 Hz, 1H), 4.07-4.13 (m, 4H), 3.88 (s, 3H), 3.20 (s,

Production Example 3. Synthesis of diethyl (4-methoxyphenylsulfonyl) methylphosphonate or diethyl (2-methoxyphenylsulfonyl) methylphosphonate

The compound (1.0 eq) synthesized in Preparation Example 2 was dissolved in methylene chloride, mCPBA (2.2 eq) was added at 0 占 폚, and the mixture was stirred at room temperature for 2 hours. After the reaction was terminated with sodium sulfite, the reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / n-hexane 1: 1 to 1: 3) to obtain the desired compound.

Production Example 3.1. Diethyl (4-methoxyphenylsulfonyl) methylphosphonate

Yield: 96%; _{1 H NMR (400MHz, CDCl 3} ) δ 7.92 (d, J = 8.9 Hz, dH), 7.02 (d, J = 8.9 Hz, 2H), 4.13-4.21 (m, 4H), 3.88 (s, 3H), 1H), 3.74 (s, 1H), 1.31 (t, J = 7.0 Hz, 6H)

Production Example 3.2. Diethyl (2-methoxyphenylsulfonyl) methylphosphonate

Yield: 95%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.96 (dd, J = 1.7, 7.8 Hz, 1H), 7.60 (ddd, J = 1.72, Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.07-4.15 (m, 4H), 4.06 (s, 1H), 4.02 (s, )

Production Example 4. Synthesis of 4- (substituted benzyloxy) benzaldehyde

After dissolving 4-hydroxybenzaldehyde (1.0 eq) and substituted benzyl bromide (1.05 eq) in acetone (0.1 M), K ₂ CO ₃ (4.00 eq) And heated to reflux. After completion of the reaction, it was filtered off and the reaction mixture was extracted between EtOAc and water and the organic layer was removed with a small amount of water using a Na ₂ SO _4, was distilled under reduced pressure to remove the solvent, and then dried under vacuum. Then, it was separated and purified by column chromatography using EtOAc: Hex to obtain the following three compounds.

Production Example 4.1. 4- (Benzyloxy) benzaldehyde

Yield: 90%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.89 (s, 1H), 7.84 (dd, J = 2.0, 6.8 Hz, 2H), 7.31-7.46 (m, 5H), 7.04-7.11 (m, 2H), 5.16 (s, 2 H)

Production Example 4.2. 4 - ((4-Trifluoromethylbenzyl) oxy) benzaldehyde

Yield: 42%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.91 (s, 1H), 7.87 (dt, J = 2.3, 8.8 Hz, 2H), 7.72 (s, 1H), 7.58-7.66 (m, 2H), 7.51-7.57 (m, IH), 7.09 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H)

Production Example 4.3. 4 - ((4-fluorobenzyl) oxy) benzaldehyde

Yield: 55%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.90 (s, 1H), 7.85 (dd, J = 1.8, 6.9 Hz, 2H), 7.34-7.39 (m, 1H), 7.00-7.26 (m, 5H), 5.15 (s, 2 H)

Example

The compound (1 eq) synthesized in Preparation Example 3.1 or 3.2 was dissolved in anhydrous THF (0.1 M) and then cooled to -78 ° C using dry ice and acetone. n-BuLi (1.05 eq, 2.0 M in cyclohexane) was slowly added dropwise to the solution, stirred for 1 hour, and benzaldehyde (1.1 eq) synthesized in Preparations 4.1 to 4.3 was added thereto and reacted again for 1 hour. After the reaction was completed with a small amount of water, the reaction mixture was extracted with water and EtOAc. The organic layer was washed with anhydrous Na ₂ SO ₄ to remove a small amount of water, distilled under reduced pressure, and the solvent was removed. Then, it was separated and purified by column chromatography using EtOAc: Hex to obtain the desired compounds of Examples 1 to 8 below.

Example  1. (E) -1- ( Benzyloxy ) -4- (2 - ((4- Methoxyphenyl ) Sulfonyl ) Vinyl) benzene; Compound 1

Yield: 73%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.86 (dd, J = 2.0, 6.9 Hz, 2H), 7.57 (d, J = 15.4 Hz, 1H), 7.30-7.47 (m, 5H), 6.93-7.03 (m 2H), 3.87 (s, 3H), 4.69 (d, J =

Example  2. (E) -1- Trifluoromethyl -3 - ((4-2 - ((4- Methoxyphenyl ) Sulfonyl )vinyl) Pe Melted) methyl )benzene; Compound 2

Yield: 85%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.86 (dt, J = 2.4, 8.9 Hz, 2H), 7.69 (s, 1H), 7.57-7.63 (m, 2H), 7.48-7.57 (m, 2H), 2H), 6.95-7.03 (m, 4H), 6.71 (d, J = 15.4 Hz, 1H), 5.13 (s, 2H), 3.86

Example  3. (E) -1- Fluoro -3 - ((4-2 - ((4- Methoxyphenyl ) Sulfonyl )vinyl) Phenoxy ) methyl )benzene; Compound 3

Yield: 89%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.86 (dt, J = 2.4, 8.9 Hz, 2H), 7.57 (d, J = 15.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.31- 2H), 3.87 (s, 3H), 3.70 (d, J =

Example  4. (E) -1- Chloro -3 - ((4-2 - ((4- Methoxyphenyl ) Sulfonyl )vinyl) Phenoxy ) methyl )benzene; Compound 4

Yield: 83%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.83 (dt, J = 2.2, 8.8 Hz, 2H), 7.56 (d, J = 15.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.33- 2H), 3.85 (s, 3H), 7.38 (m, 1H), 7.11-7.20 (m, 2H), 6.93-7.05

Example  5. (E) -1- Trifluoromethyl -3 - ((4-2 - ((2- Methoxyphenyl ) Sulfonyl )vinyl) Phenoxy ) methyl )benzene; Compound 5

Yield: 90%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (dd, J = 1.6, 7.8 Hz, 1H), 7.64 (d, J = 15.4 Hz, 1H), 7.50-7.58 (m, 1H), 7.44 (d, 2H, J = 8.8 Hz, 2H), 7.30-7.38 (m, 1H), 6.90-7.22 (m, 8H)

Example  6. (E) -1- Fluoro -3 - ((4-2 - ((2- Methoxyphenyl ) Sulfonyl )vinyl) Phenoxy ) methyl )benzene; Compound 4

Yield: 90%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.01 (dd, J = 1.6, 7.8 Hz, 1H), 7.62 (d, J = 15.4 Hz, 1H), 7.50-7.58 (m, 1H), 7.45 (d, 2H), 3.96 (s, 3H), 3.40 (s, 3H)

Example  7. (E) -1- Methoxy -3 - ((4-2 - ((4- Methoxyphenyl ) Sulfonyl )vinyl) Phenoxy ) methyl )benzene; Compound 7

Yield: 82%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.81 (dt, J = 2.4, 8.9 Hz, 2H), 7.52 (d, J = 15.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.30- 2H), 5.06 (s, 2H), 3.86 (s, 3H), 7.71 (d, J = , 3.64 (s, 3 H)

Example  8. (E) -1- Trifluoromethyl -4 - ((4-2 - ((4- Methoxyphenyl ) Sulfonyl )vinyl) Phenoxy ) methyl )benzene; Compound 8

Yield: 81%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.80 (dt, J = 2.2, 8.8 Hz, 2H), 7.56 (d, J = 15.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.30- 2H), 7.38 (m, 2H), 7.11-7.21 (m, 2H), 6.90-7.04 (m, 4H), 6.71 (d, J =

Example  9. (E) -1 - ((4- (2- (4- Methoxyphenylsulfonyl )vinyl) Phenoxy ) methyl ) -3-nitrobenzene; Compound 9

Yield: 80%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.10-8.24 (m, 2H), 7.50-7.63 (m, 2H), 7.30-7.42 (m, 2H), 6.91-7.22 (m, 8H), 5.08 (s, 2H), 3.94 (s, 3H)

Example  10. (E) -3 - ((4- (2- (4- Methoxyphenylsulfonyl )vinyl) Phenoxy ) methyl ) Benzoic acid Child Seed; Compound 10

Yield: 78%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.12-8.23 (m, 2H), 7.50-7.64 (m, 2H), 7.32-7.42 (m, 2H), 6.91-7.26 (m, 8H), 5.09 (s, 2H), 3.95 (s, 3H)

Example  11. (E) -3 - ((4- (2- (4- Methoxyphenylsulfonyl )vinyl) Phenoxy ) methyl )phenol; Compound 11

Yield: 78%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.60-7.89 (m, 4H), 7.30-7.42 (m, 2H), 6.89-7.24 (m, 8H), 5.08 (s, 2H), 3.96 (s, 3H)

Example  12. (E) -1 - ((4- (2- (4- Methoxyphenylsulfonyl )vinyl) Phenoxy ) methyl ) -3- ( Trifluoromethoxy )benzene;

Yield: 85%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.68-7.84 (m, 2H), 7.54 (d, J = 15.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.30-7.39 (m, 1H 2H), 5.08 (s, 2H), 3.90 (s, 3H), 6.90 (d, J =

Example  13. (E) -1- (3 - ((4- (2- (4- Methoxyphenylsulfonyl )vinyl) Phenoxy ) methyl ) Phenyl ) Ethanone;

Yield: 83%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.54-7.84 (m, 3H), 7.42 (d, J = 8.8 Hz, 2H), 7.30-7.39 (m, 1H), 7.09-7.23 (m, 2H), 6.93 3H), 2.54 (s, 3H), 3.85 (s, 3H)

Test Example  One. Lactate dehydrogenase  secretion( actate dehydrogenase release assay ; LDH  assay

Complement dependent cytotoxicity (CDC) was performed by the LDH assay as shown in FIG.

The complement dependent cytotoxicity inhibition was assessed by LDH-releasing (compelent dependent cytotoxicity) of complement-dependent cytotoxicity by treating IgG and human complement of NMO patients using the CytoTox-ONE Homogeneous Membrane Integrity Assay Kit (Promega, Madison, Were measured by the degree of decrease. U87MG-AQP4 over-expressed stable cells were stained with complete medium [10% fetal bovine serum (FBS, Thermo Scientific), 1% penicillin / streptomycin (Penstripe, Gibco), 400 ng / mL G418-disulfate (Duchefa Biochemie) DMEM medium, and the cells were seeded at 2.5 × 10 ⁴ cells / well in a 96-well plate and incubated at 37 ° C. for 2 days. Thereafter, the medium was removed, washed once with HBSS (Sigma), and then treated with 50 μL of 0.2% DMSO-containing candidate substances at a concentration of 50 μL of NMO-IgG 100 μg / mL and 5% human complement Mixed and reacted in 96 wells.

After 1 hour, 100 μL of LDH-detecting reagent was added. After 10 minutes, fluorescence was measured in a microplate reader at excitation 560 nm and emission 590 nm, which is shown in FIG.

Test Example  2. Complement dependent cytotoxicity ( CDC ) assay  Legal verification

The CDC assay is a method for measuring the cytotoxicity due to the damage of the cell membrane due to IgG binding of complement with the AQP-4 binding of NMO-IgG. Using the lactate dehydrogenase (LDH) exiting the damaged cell according to the method of Test Example 1, cytotoxicity LDH assay was performed. To validate this method, CDC assays were performed in both U87-MG cell lines and control cell lines transfected with AQP-4. In addition, the efficacy evaluation system was verified by comparing the IgG of NMO patients with the IgG of healthy persons.

As shown in FIG. 2, CDQ was found to be dependent on the concentration of AQP-4 when treated with IgG from NMO patients. Thus, the CDC assay method used in the present invention proved that NMO-IgG is caused by binding with AQP-4.

Test Example  3. Complement dependent cytotoxicity ( CDC ) assay

In order to confirm whether the compounds according to the present invention inhibited the cell death caused by NMO-IgG, the compounds according to the present invention and the LDH assay (CDC assay) were used to compare LDH release Compounds with low numbers were derived.

The LDH release values for the CDC assay of the compounds prepared in Examples 1 to 8 were calculated at the percent exchange rate relative to the control (100%), and are shown in Table 1 below. As shown in Table 1, the compounds of the examples according to the present invention showed lower or similar LDH release values than the previously reported active compound arbidol. Thus, it was confirmed that the compounds according to the present invention have an effect of inhibiting the cell death caused by NMO-IgG.

division CDC assay (LDH relese% compared to the control) Example 1 70.2 Example 2 56.6 Example 3 65.8 Example 4 71.6 Example 5 64.1 Example 6 63.6 Example 7 98.2 Example 8 88.2 arbidol 78.5

Test Example  4. AQP4 Wow NMO - IgG  Inhibition of binding Indirect immunofluorescent antibody  Test method Indirect  Immunofluorescence antibody assay )

Indirect immunofluorescent antibody test was performed to confirm whether the compound according to the present invention inhibits the binding of AQP4 and NMO-IgG. A stable cell line in which AQP4 is overexpressed was treated with NMO-IgG and secondary antibody with FITC fluorescent material was reacted to measure the degree of binding, thereby confirming whether the compound according to the present invention decreases the binding level.

U87MG-AQP4 over-expressed stable cells were stained with complete medium [10% fetal bovine serum (FBS, Thermo Scientific), 1% Penicillin / Streptomycin (Gibco), 400 ng / mL G418-disulfate (Duchefa Biochemie) The cells were mixed with DMEM medium at a density of 2.5 × 10 ⁴ cells / well in a 96-well plate, and cultured in a 37 ° C. incubator for 2 days. After washing, 4% paraformaldehyde solution was applied and fixed for 15 minutes. After 4% PFA was aspirated, it was incubated in blocking buffer [1% Bovine Serum Albumin, 6 mM Glucose in PBS] for 20 min. Blocking buffer was aspirated, and 50 μL of 0.2% DMSO-containing candidate substances were treated at different concentrations. Then, 50 μL of NMO-IgG 100 μg / μL was mixed and reacted in 96 wells. After 1 hour of reaction, the cells were washed with blocking buffer and then FITC-conjugated goat anti-human IgG antibodies (Sigma) diluted 500-fold were added to each well. After incubating for 30 minutes in a 37 ° C incubator, the cells were washed and observed under a fluorescence microscope. Fluorescence of the secondary antibody was measured in a multiplate reader (Operetta, Perkin Elmer) equipped with an automated system, and a compound with lower numerical value than NMO-IgG bound wells was derived.

Compounds according to the present invention inhibited the binding of AQP4 and NMO-IgG by indirect immunofluorescent antibody assay as in the CDC assay. In particular, as shown in Fig. 4 below, the compound of Example 2 showed the binding inhibition effect of AQP4 and NMO-IgG, which is superior to the known compound arbidol.

Based on the above results, the compounds according to the present invention inhibit the binding of AQP4 and NMO-IgG, thereby significantly reducing the cytotoxicity caused thereby. Therefore, AQA4 binds to anti-aquaporin 4 autoantibodies, And can be usefully used as a therapeutic agent for a disease caused by inducing cytotoxicity, specifically, optic neuritis.

Claims (12)

A vinylsulfon derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

[Formula 1]
_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in. The method according to claim 1,
Alkyl group of the halogenated C _{1 -7} is selected from halogenated methyl, halogenated ethyl, propyl halide, butyl halide, pentyl halide, hexyl halide, and halogenated heptyl,
Wherein the halogen is selected from the group consisting of a fluoro group, a chloro group and a bromo group, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Vinyl sulfone derivative or acceptable salt thereof, chemical agent, characterized in that the alkyl group of the halogenated C _{1 -7} is selected from methyl, trifluoromethyl and ethyl trifluoroacetate as trifluoropropyl. The method according to claim 1,
Alkoxy groups are trifluoromethoxy, trifluoroethoxy and in the in-trifluoro-propoxy vinyl sulfone derivative or a pharmaceutically acceptable salt thereof, wherein the chemical is selected from the halogenated C _{1 -7.} The method according to claim 1,
The vinylsulfone derivative represented by the above formula (1)
(E) -1- (benzyloxy) -4- (2 - ((4-methoxyphenyl) sulfonyl) vinyl)
(E) -1-trifluoromethyl-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl)
(E) -1-fluoro-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl)
(E) -1-chloro-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl)
(E) -1-trifluoromethyl-3 - ((4-2 - ((2-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl)
(E) -1-fluoro-3 - ((4-2 - ((2-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl)
(E) -1-methoxy-3 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy)
(E) -1-trifluoromethyl-4 - ((4-2 - ((4-methoxyphenyl) sulfonyl) vinyl) phenoxy) methyl)
(E) -1 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl)
(E) -3- ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) benzoic acid,
(E) -3- ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) phenol,
(E) -1 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) -3- (trifluoromethoxy) benzene and
(E) -1- (3 - ((4- (2- (4-methoxyphenylsulfonyl) vinyl) phenoxy) methyl) phenyl) ethanone. Acceptable salts. A process for producing a vinyl sulfone derivative represented by the following formula (1) by reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) in an organic solvent:
[Chemical Formula 1]

(2)

(3)

In the above Chemical Formula 1 or Chemical Formula 2,
_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in. The method according to claim 6,
Wherein the compound represented by the formula 3 is prepared by oxidizing a compound represented by the following formula 4:
[Chemical Formula 4]

8. The method of claim 7,
Wherein the compound represented by Formula 4 is prepared by reacting a compound represented by Formula 5 with a benzenethiol derivative represented by Formula 6 below:
[Chemical Formula 5]

[Chemical Formula 6]

A pharmaceutical composition for preventing or treating optic neuritis, comprising a vinylsulfon derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient:
[Chemical Formula 1]

[Formula 1]
_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in. A pharmaceutical composition for treating or preventing a degenerative neurological disease comprising, as an active ingredient, a vinylsulfone derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof:
[Chemical Formula 1]

[Formula 1]
_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in. 11. The pharmaceutical composition according to claim 10, wherein the degenerative neurological disease is selected from degenerative diseases, multiple sclerosis and Lou Gehrig's disease. A binding inhibitor that inhibits the binding of an NMO-IgG (Neuro myelitis Optica-IgG) containing a vinylsulfon derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient to an aquaporin 4 protein :
[Chemical Formula 1]

[Formula 1]
_{R 1, R 2, R 3} , R 4 and R ₅ are the same or different and each is independently hydrogen, nitro, COOH, hydroxy, halogen group, an alkyl group of the alkyl group of C _{1 -7,} halogenated C _{1 -7} together , is selected from an alkyl carbonyl group in the alkyloxy group of C _{1 -7,} halogenated C _{1 -7} alkyloxy and C _{1 -7} in.

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