KR100484526B1 - Thione derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention provides a thion derivative represented by the following formula (1) or a nontoxic salt thereof.

According to the present invention, it is possible to provide a thion derivative or its non-toxic salt having antipyretic, analgesic, anti-inflammatory effect and improved side effects, a preparation method thereof, and a pharmaceutical composition containing the same.

Description

Thione derivatives, processes for the preparation, and pharmaceutical compositions containing the same}

The present invention relates to a thion derivative or a non-toxic salt thereof having antipyretic, analgesic and anti-inflammatory effects, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.

Most nonsteroidal anti-inflammatory drugs show their anti-inflammatory, analgesic, and antipyretic effects through inhibition of an enzyme called cyclooxoygenase or prostaglandin G / H synthase, and also inhibits hormonal contractions caused by hormones and some Inhibits the growth of cancer. Initially, only the constitutive enzyme found in cattle, cyclooxygenase-1 (COX-1), was known. Recently, the causative form of cyclooxygenase-2 (COX-2) has been identified. Cyclooxygenase-2 is clearly different from cyclooxygenase-1 and is easily induced by mitogen, endotoxin, hormones, growth factors and cytokines and the like.

Prostaglandins play a pathological and physiological role. Cyclooxygenase-1, a constitutive enzyme, is involved in the secretion of basic endogenous prostaglandins and plays an important role in physiological aspects such as maintaining the state of the stomach and blood circulation of the kidneys. Cyclooxygenase-2, on the other hand, is caused by inflammatory factors, hormones, growth factors and cytokines and the like, and thus plays a major role in the pathological effects of prostaglandins. Therefore, inhibitors selective for cyclooxygenase-2 are expected to have no side effects due to mechanisms of action, and anti-inflammatory, analgesic and antipyretic effects, compared to conventional nonsteroidal anti-inflammatory drugs. It is expected to inhibit inhibition and some types of cancer growth. In particular, side effects such as gastrointestinal toxicity and kidney toxicity are expected to be low. It is also expected to prevent the synthesis of contractile prostanoids and thus inhibit the contraction of smooth muscles induced by prostanoids, and thus are expected to be useful for diseases related to premature birth, menstrual irregularities, asthma and eosinophils. In addition, it is expected to be useful in the treatment of osteoporosis, glaucoma, colorectal cancer, prostate cancer and dementia. For the usefulness of inhibitors selective to cyclooxygenase-2, see John Vane, Towards a better aspirin in Nature, 367, pp. 215-216, 1994; Bruno Battistini, Regina Botting and YS Bakhle, COX-1 and COX-2: Toward the Development of More Selective NSAIDs in Drug News and Perspectives, Vol. 7, 501-512, 1994; Urology, 58, 127, 2001; David B. Reitz and Karen Seibert, Selective Cyclooxygenase Inhibitors in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995). . Existing drugs known as inhibitors that selectively act on cyclooxygenase-2 take a wide variety of forms in their structure. The structure most commonly studied and thus designed with the most candidates is the structure of the diaryl heterocycle, i.e., a tricyclic system, which is essentially a sulfonamide or methylsulfone group in one phenyl.

 According to US Pat. No. 5,466,823, a compound of formula 88 (celecoxib) is disclosed. The following celecoxibs are substituted pyrazole benzene sulfonamide derivatives.

According to WO 95/00501 a compound (lofecoxib) having the general formula 89 is disclosed. Rofecoxib has a diaryl heterocycle structure like celecoxib but has a furanone structure as a heterocycle.

U.S. Patent No. 5,633,272 describes a compound (Valdecoxib), such as Formula 90 below. Valdecoxib has a phenyl sulfonamide structure like celecoxib but has an isoxazole structure as a heterocycle.

The compounds of Formulas 88-90 are all selective inhibitors of COX-2 and have anti-inflammatory analgesic effect without side effects compared to conventional nonsteroidal anti-inflammatory agents.

Accordingly, the present inventors have conducted continuous research to develop novel compounds having excellent selectivity as inhibitors of cyclooxygenase-2, and as a result, found that derivatives having a thion structure have excellent selective inhibitory effects on COX-2. The present invention has been completed.

Accordingly, an object of the present invention is to provide a thion derivative having excellent selectivity or a nontoxic salt thereof as a cyclooxygenase-2 inhibitor.

It is also an object of the present invention to provide a method for preparing the thion derivative or non-toxic salt thereof.

It is also an object of the present invention to provide a pharmaceutical composition having an antipyretic, analgesic, anti-inflammatory effect comprising the thion derivative or a non-toxic salt thereof as an active ingredient.

The present invention relates to a thion derivative represented by the following formula (1) or a non-toxic salt thereof.

[ Formula 1 ]

In Chemical Formula 1,

A and B are each independently O, S, NR ² , wherein R ² is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, or aryl;

Ar is aryl; Heteroaryl; C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, trifluoromethyl, nitro, acetoxy, amine, C ₁ -C ₃ alkyl amine, C ₁ -C ₃ dialkylamine, hydroxy, C ₁ -C ₃ hydroxy alkyl, and aryl or heteroaryl substituted with 1 to 5 selected groups from the group consisting of thioxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₄ alkylamino, or di-C ₁ -C ₄ alkylamino .

Among the above compounds,

A and B are each independently S or NH;

Ar is phenyl; Phenyl substituted with 1 to 5 selected groups from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, trifluoromethyl, acetoxy, and nitro; Pyridyl; Or naphthyl;

Preferred are thion derivatives or non-toxic salts thereof, wherein R ¹ is hydrogen or halogen.

The compound represented by Formula 1 may exist in the form of a non-toxic salt. Non-toxic salts herein means pharmaceutically acceptable non-toxic salts, including organic salts and inorganic salts.

The compound of Formula 1 may be present in the form of a salt with a pharmaceutically acceptable organic or inorganic acid.

Organic or inorganic acid salts of the compounds of Formula 1 include acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, Ethylenediaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, isetionic acid, lactic acid, maleic acid, malic acid, manderic acid, methanesulfonic acid, music acid, 2-naphthalenedisulfonic acid Salts with nitric acid, oxalic acid, parnoic acid, pentothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, or 10-undecenoic acid However, the present invention is not limited thereto, and salts with succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, or tartaric acid are preferable.

Thion derivatives or non-toxic salts thereof of the present invention

4- (4-ethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (4-bromophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-phenyl- [1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-methoxyphenyl- [1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4- (2-trifluoromethylphenyl)-[1,2] dithiol-3-thione;

4- (4-chlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-pyridin-4-yl- [1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-pyridin-3-yl- [1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-pyridin-2-yl- [1,2] dithiol-3-thione;

4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (2,5-dimethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (3,5-dimethylphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4- (3-methoxyphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4- (2-nitrophenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4- (3-trifluoromethylphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-o-tolyl- [1,2] dithiol-3-thione;

4- (2-chlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (2,4-dichlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (2-chloro-4-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (3,4-dimethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (2-bromophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (2-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (2,4-difluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

4- (3,4-difluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-naphthalen-2-yl- [1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4-pentafluorophenyl- [1,2] dithiol-3-thione;

4- (4-isopropylphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

5- (4-methanesulfonylphenyl) -4- (4-propoxyphenyl)-[1,2] dithiol-3-thione;

Acetic acid 4- [5- (4-methanesulfonylphenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] phenyl ester;

5- (2-chloro-4-methanesulfonylphenyl) -4- (4-ethoxyphenyl)-[1,2] dithiol-3-thione;

5- (2-chloro-4-methanesulfonylphenyl) -4- p -tolyl- [1,2] dithiol-3-thione;

4- (4-bromophenyl) -5- (2-chloro-4-methanesulfonylphenyl)-[1,2] dithiol-3-thione;

5- (2-chloro-4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione;

5- (3-fluoro-4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione;

5- (3-fluoro-4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione;

Acetic acid 4- [5- (3-fluoro-4-methanesulfonylphenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] -phenyl ester;

5- (4-methanesulfonylphenyl) -4- p -tolyl-1,2-dihydropyrazole-3-thione;

4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dihydropyrazole-3-thione and

More preferred are compounds selected from the group consisting of 4- (4-chlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dihydropyrazole-3-thione or nontoxic salts thereof.

The present invention includes a propionic acid derivative of the following formula (2) as a synthetic intermediate of the thione derivative of the formula (1).

In Formula 2, R ¹ and Ar are as defined in Formula 1, R ³ represents C ₁ -C ₄ alkyl.

In addition, the present invention provides a thion derivative of Formula 1a comprising reacting a propionic acid derivative of Formula 2 with a phosphorus penta sulfide, Lawensson's Reagent, beta-oxothioxane, or beta-oxothiooxane potassium salt. Methods for preparing non-toxic salts thereof include:

[Formula 2]

R ¹ and Ar are as defined in Chemical Formula 1, and R ³ represents C ₁ -C ₄ alkyl.

The phosphorus pentasulfide is most preferred among the phosphorus pentasulfide, Lawsonson's reagent, beta-oxothioxane and betaoxothiooxane potassium salt used for the introduction of the thion structure in the reaction.

As the solvent for the reaction, a non-reactive organic solvent usually used in organic synthesis may be used. Examples thereof include benzene, toluene, xylene, and the like. Most preferably, toluene is used.

The reaction can be completed by heating to the boiling point of the solvent to be used, for example, when toluene is used as the solvent, the reaction can be completed by heating and refluxing at the boiling point.

The propionic acid derivative of Formula 2 may be prepared by reacting a compound of Formula 3 with a compound of Formula 4 in the presence of a base:

R ¹ and Ar are as defined in Chemical Formula 1, and R ³ represents C ₁ -C ₄ alkyl.

Bases usable in the reaction include, but are not limited to, sodium hydride, potassium carbonate, potassium hydroxide, and the like. Sodium hydride in the base is preferred.

The present invention also encompasses a process for preparing a thione derivative of Formula 1b or a non-toxic salt thereof comprising reacting the compound of Formula 1a with NHR ² NHR ² or NHR ² OH in the presence of a base:

[ Formula 1a ]

A 'and B' are each independently S or NR ² , provided that A 'and B' cannot be S at the same time, wherein Ar and R ² are as defined in Formula 1.

Bases usable in the reaction include calcium carbonate, potassium hydroxide, or water

Sodium oxide, and the like, but is not limited thereto. Of the bases, potassium hydroxide is preferred.

Separation and purification of the reaction product may be carried out through a process such as concentration, extraction, and the like, which are commonly performed in organic synthesis, and may be preferably separated and purified through a separate purification operation by column chromatography on silica gel. .

Continuously expressing a preferred embodiment of the production method of the formula (1a) and (1b) described above are as follows.

In Scheme 1, A ', B', Ar, R ¹ , R ² and R ³ are as defined above.

When R ^{1 in the} compound of Formula 1a of the present invention is fluorine, it may also be prepared by a method such as

In Scheme 2, Ar and R ³ are as defined above.

The present invention provides a pharmaceutical composition having an antipyretic, analgesic and anti-inflammatory effect, which contains a therapeutically effective amount of a thion derivative or a non-toxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

Such pharmaceutical compositions include the compounds of Formula 1 or their pharmaceutically acceptable salts with selective inhibitory activity against cyclooxygenase-2, and thus can be used as antipyretic, analgesic, anti-inflammatory agents with minimal side effects. have.

Conventional nonsteroidal anti-inflammatory agents are not only cyclooxygenase-2 involved in the synthesis of pathological prostaglandins, but also cyclos, which are involved in the secretion of basic endogenous prostaglandins and play important roles in physiological aspects such as maintaining the state of the stomach and blood circulation of the kidneys. Oxygenase-1 was inhibited indiscriminately and had various side effects.

In contrast, the compounds of Formula 1 and their pharmaceutically acceptable salts have a selective inhibitory activity on cyclooxygenase-2, and thus, conventional nonsteroidal antipyretics that indiscriminately inhibit cyclooxygenase-1, It can minimize the side effects of analgesic and anti-inflammatory drugs.

Therefore, a pharmaceutical composition comprising a compound of formula (1) or a non-toxic salt thereof and a pharmaceutically acceptable carrier or excipient may be used as a substitute for a typical nonsteroidal anti-inflammatory agent, in particular of conventional nonsteroidal antipyretic, analgesic, anti-inflammatory agents. Alternative drugs with improved side effects are useful in patients with peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal bleeding, hypoprothrombinemia, and the like.

The pharmaceutical compositions of the present invention can be used for both pathological prostaglandin related inflammatory diseases, and are particularly useful for osteoarthritis and rheumatoid arthritis requiring high doses of administration.

The pharmaceutical composition may be administered to the adult 1mg / day to 1000mg / day based on the compound of Formula 1 or a non-toxic salt thereof as the active ingredient, it can be increased or decreased depending on the severity of the disease.

The pharmaceutical compositions may be in the form of tablets, effervescent tablets, capsules, granules, powders, sustained release tablets, sustained release capsules (alone and complex unit preparations), ampoules for intravenous and intramuscular injection and infusions, suspensions It may be administered in the form of suppositories or in other suitable pharmaceutical forms.

Sustained release pharmaceutical forms may contain the active compound in complete or partial sustained release form with or without the initial dosage content.

The active compounds may be present together or as partly or completely separate formulations, such that individual administration or staged administration may also be possible.

When these completely separate formulations are present, they cooperate with each other and contain each active compound in the dosage unit in the same amount and corresponding weight ratio that may be present in the mixture in which they are combined.

Preferred are orally administrable pharmaceutical compositions containing the indicated combinations.

To prepare pharmaceutical formulations containing such combinations, the active compounds are formulated in the indicated amounts in a preferred manner with physiologically resistant excipients and / or diluents and / or adjuvants.

Examples of excipients and auxiliaries include natural sugars such as gelatin, sucrose or lactose, lecithin, pectin, starch (eg corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate , Gum arabic, alginic acid, tylose, talc, lycopodium, silicic acid, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methoxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, 12 carbon atoms To 22 fatty acids, emulsifiers, oils and fats, in particular also vegetable glycerol esters and polyglycerol esters of saturated fatty acids, polyglycols such as mono or polyhydric alcohols and polyethylene glycols, monohydric aliphatic alcohols having 1 to 20 carbon atoms, or Glycol, glycerol, diethyl Glycol, the 1,2-propylene glycol, sorbitol, Nicole only carbon atoms such as a polyhydric alcohol having 2 to 22 aliphatic saturated or unsaturated fatty acid ester.

Further suitable auxiliaries are also substances which cause disintegration (so-called disintegrants), crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, microcrystalline cellulose. Known coating materials can also be used. Polymers and copolymers of acrylic acid and / or methacrylic acid and / or esters thereof, zein, ethylcellulose, ethylcellulose succinate, shellac and the like.

Plasticizers suitable as coating materials can be citric acid esters and tartaric acid esters, glycerol and glycerol esters, polyethylene glycols of various chain lengths. It is suitable for the preparation of water or physiologically acceptable organic solvents such as alcohol and fatty alcohol solutions or suspensions.

In liquid formulations, it may be necessary to use preservatives such as solvate potassium, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, antioxidants such as ascorbic acid and fragrance enhancers such as peppermint oil.

In the preparation of the formulations, known and conventional solubilizers, or emulsifiers, such as polyvinylpyrrolidone and polysorbate 80 can be used.

Additional examples of suitable excipients and auxiliaries can be found in the literature (Dr. H. P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" [Encyclopaedia of auxiliaries for pharmacy, cosmetics and related fields].

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. However, these Examples and Experimental Examples are only for better understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Example 1

2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

499 mg of (4-ethoxyphenyl) -acetic acid ethyl ester and 480 mg of carbonyldiimidazole were added to 0.5 g of 4-methanesulfonylbenzoic acid, dissolved in 10 ml of dimethylformamide, and slowly added dropwise 119 mg of sodium hydride for 12 hours at room temperature. I was. After diluting with water, the mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, and then 0.9 g (yield 92%) of a light yellow liquid title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.65 (d , 2H, J = 8.4 Hz), 5.56 (s, 1H), 4.12 (q, 2H, J = 6 Hz), 3.98 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33-1.31 ( m, 6H)

Example 2

2- (4-Bromophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

In Example 1, except that 700 mg of 4-bromophenyl) -acetic acid ethyl ester instead of (4-ethoxyphenyl) -acetic acid ethyl ester was reacted in the same manner as in Example 1 to give 1.2 g of the title compound as a liquid. Yield 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ8.15 (d, 2H, J = 8.4 Hz), 8.05 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.4 Hz), 6.94 ( d, 2H, J = 8.4 Hz), 5.55 (s, 1 H), 4.12 (q, 2H, J = 6 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 3

3- (4-Methanesulfonylphenyl) -3-oxo-2-p-tolyl-propionic acid ethyl ester

1.5 g (yield 83%) of the liquid title compound was reacted in the same manner as in Example 1, except that 890 mg of p-tolyl acetate ethyl acetate was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.03 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.93 (d , 2H, J = 8.4 Hz, 5.56 (s, 1 H), 4.12 (q, 2H, J = 6 Hz), 3.02 (s, 3H), 2.33 (s, 2H), 1.33 (t, 3H, J = 4.0 Hz)

Example 4

3- (4-Methanesulfonylphenyl) -3-oxo-2-phenyl-propionic acid methyl ester

In the same manner as in Example 1, except that 940 mg of phenyl acetic acid methyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1, 1.3 g (yield 80%) of the title compound was obtained. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, 2H, J = 8.4 Hz), 8.05 (d, 2H, J = 8.4 Hz), 6.97-6.94 (m, 5H), 5.56 (s, 1H) , 3.75 (s, 3H), 3.02 (s, 3H)

Example 5

3- (4-Methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester

1.5 g (yield 83%) of the liquid title compound was reacted in the same manner as in Example 1, except that 970 mg of 4-methoxyphenyl acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. ) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, 2H, J = 8.4 Hz), 8.05 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.93 (d , 2H, J = 8.4Hz), 5.56 (s, 1H), 4.12 (q, 2H, J = 6.0Hz), 3.79 (s, 3H), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 6

3- (4-Methanesulfonylphenyl) -3-oxo-2- (2-trifluoromethylphenyl) -propionic acid ethyl ester

In Example 1, except that 900 mg of 2- (trifluoromethyl-phenyl) acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester to react in the same manner as in Example 1 to give a liquid title compound 0.5. g (yield 65%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.33 (d, 1H, J = 6.8 Hz), 7.14 (t , 1H, J = 6.0 Hz), 7.00-7.68 (m, 2H), 5.53 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (S, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 7

2- (4-Chlorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

1.5 g (yield 78%) of the title compound was reacted in the same manner as in Example 1, except that 990 mg of 4-chlorophenyl-acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. ) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.92 (d , 2H, J = 8.4Hz), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0Hz)

Example 8

2- (3,4-Dichlorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

Reaction was carried out in the same manner as in Example 1, except that 990 mg of 3,4-dichlorophenyl-acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1, and 1.7 g (yield) of the liquid title compound. 85%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.09 (d, 1H, J = 6.8 Hz), 7.01 (s , 1H), 6.88 (d, 1H, J = 6.8 Hz), 5.53 (s, 1 H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 9

3- (4-Methanesulfonylphenyl) -3-oxo-2-pyridin-4-yl-propionic acid ethyl ester

1.5 g of liquid title compound (yield) in the same manner as in Example 1, except that 800 mg of pyridin-4-yl-acetic acid ethyl ester was used instead of (4-ethoxy-phenyl) -acetic acid ethyl ester in Example 1. 78%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.55 (d, 2H, J = 4.00 Hz), 7.85 (d, 2H, J = 9.2 Hz), 7.39 (d, 2H, J = 9.2 Hz), 6.99 (d , 2H, J = 4.0 Hz), 5.50 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 10

3- (4-Methanesulfonylphenyl) -3-oxo-2-pyridin-3-yl propionic acid ethyl ester

Except for using 1 g of pyridin-3-yl-acetic acid ethyl ester instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1, 1.35 g (yield 78) of the liquid title compound was obtained in the same manner as in Example 1. %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 8.24 (d, 1H, J = 4.0 Hz), 7.92 (d, 2H, J = 8.0 Hz), 7.54 (d, 1H, J = 4.0 Hz), 7.45 (d, 2H, J = 8.0 Hz), 7.32 (t, 1H, J = 6.0 Hz), 5.50 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.03 (s , 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 11

3- (4-Methanesulfonylphenyl) -3-oxo-2-pyridin-2-yl propionic acid ethyl ester

Except for using 1 g of pyridin-2-yl-acetic acid ethyl ester instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1, 1.35 g (yield 78) of the liquid title compound was obtained in the same manner as in Example 1. %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, 1H, J = 6.8 Hz), 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.27-7.22 (m, 3H), 5.56 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.14 (s, 3H), 1.37 (t, 3H, J = 4.0 Hz)

Example 12

2- (4-fluorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

In Example 1, except that 1 g of (4-fluorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester, the reaction was carried out in the same manner as in Example 1 to give 1.54 g of the liquid title compound ( Yield 85%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.09-7.04 (m, 4H), 5.55 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 13

2- (2,5-dimethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

The liquid title compound was reacted in the same manner as in Example 1, except that 560 mg of 2,5-dimethoxy-phenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 0.9 g (90% yield) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.92 (d , 2H, J = 8.4Hz), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0Hz)

Example 14

2- (3,5-dimethylphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

810 mg of the liquid title compound was reacted in the same manner as in Example 1, except that 460 mg of (3,5-dimethylphenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. Yield 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.92 (d , 2H, J = 8.4Hz), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0Hz), 3.02 (s, 3H), 2.32 (s, 6H), 1.33 (t, 3H, J = 4.0 Hz)

Example 15

3- (4-Methanesulfonylphenyl) -2- (3-methoxyphenyl) -3-oxo-propionic acid ethyl ester

860 mg (yield) of the liquid title compound was obtained in the same manner as in Example 1, except that 460 mg of (3-methoxyphenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 92%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.03 (t, 1H, J = 4.2 Hz), 6.57-6.58 (m, 3H), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.72 (s, 3H), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 16

3- (4-Methanesulfonylphenyl) -2- (2-nitrophenyl) -3-oxo-propionic acid ethyl ester

830 mg of the liquid title compound was obtained in the same manner as in Example 1, except that 500 mg of (2-nitrophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.07 (d, 1H, J = 6.4 Hz), 8.04 (t, 1H, J = 4.2 Hz), 7.53-7.52 (m, 1H), 7.33-7.32 (m, 2H), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 17

3- (4-Methanesulfonylphenyl) -3-oxo-2- (3-trifluoromethylphenyl) -propionic acid ethyl ester

830 mg of the liquid title compound was reacted in the same manner as in Example 1, except that 500 mg of (3-trifluoromethyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. Yield 85%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.26-25 (m, 2H), 7.07-7.06 (m, 2H), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.72 (s, 3H), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 18

3- (4-Methanesulfonylphenyl) -3-oxo-2-o-tolyl-propionic acid ethyl ester

820 mg (yield 91%) of the liquid title compound was reacted in the same manner as in Example 1, except that 420 mg of o-tolyl-acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.95-6.93 (m, 4H), 5.55 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 2.35 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 19

2- (2-Chlorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

880 mg of the liquid title compound was obtained in the same manner as in Example 1, except that 490 mg of (2-chlorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.97-6.98 (m, 4H), 5.55 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 20

2- (2,4-Dichlorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 1, except that 470 mg of (2,4-dichlorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1 to give 800 mg of a liquid title compound ( Yield 85%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.16 (s, 1H), 7.03-7.01 (m, 2H) , 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 21

2- (2-Chloro-4-fluorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 1, except that 520 mg of (2-chloro-4-fluorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1 to give a liquid title. 836 mg (88% yield) of compound were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.98 (t, 1H, J = 6.0 Hz), 6.86 (d , 1H, J = 5.6 Hz, 6.73 (d, 1H, J = 5.6 Hz), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t , 3H, J = 4.0 Hz)

Example 22

2- (3,4-dimethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

760 mg of the liquid title compound was reacted in the same manner as in Example 1, except that 560 mg of (3,4-dimethoxyphenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. (Yield 80%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.53-6.51 (m, 2H), 6.46 (s, 1H) , 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.73 (s, 6H), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 23

2- (2-Bromophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

900 mg (yield) of the liquid title compound was obtained in the same manner as in Example 1, except that 660 mg of (2-bromophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 85%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.99-6.97 (m, 4H), 5.55 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 24

2- (2-Fluorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 1, except that 440 mg of (2-fluorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1 to give 800 mg of a liquid title compound (yield). 88%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.03-7.01 (m, 4H), 5.55 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 25

2- (2,4-Difluorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

The title compound was reacted in the same manner as in Example 1, except that 480 mg of (2,4-difluorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 849 mg (89% yield) were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.02-7.01 (m, 2H), 6.56 (m, 1H) , 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 26

2- (3,4-Difluorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

The title compound was reacted in the same manner as in Example 1, except that 480 mg of (3,4-difluorophenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 874 mg (92% yield) were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.83-6.81 (m, 2H), 6.75 (m, 1H) , 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 27

3- (4-Methanesulfonylphenyl) -2-naphthalen-2-yl-3-oxo-propionic acid ethyl ester

In Example 1, except that 530 mg of naphthalen-2-yl-acetic acid ethyl ester instead of (4-ethoxyphenyl) -acetic acid ethyl ester was reacted in the same manner as in Example 1, to give 870 mg of a liquid title compound (yield 88%). ) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.68-7.64 (m, 3H), 7.46 (s, 1H) , 7.31-7.30 (m, 2H), 7.16-7.15 (m, 1H), 5.55 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33 (t, 3H , J = 4.0 Hz)

Example 28

3- (4-Methanesulfonylphenyl) -3-oxo-2-pentafluorophenyl-propionic acid ethyl ester

880 mg (yield 85%) of the liquid title compound was reacted in the same manner as in Example 1, except that 550 mg of pentafluorophenyl acetic acid methyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 5.53 (s, 1H), 4.12 (q, 2H, J = 6.0 Hz), 3.01 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 29

2- (4-isopropoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

860 mg of liquid title compound (yield) was reacted in the same manner as in Example 1, except that 500 mg of (4-isopropoxyphenyl) acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 88%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.65 (d , 2H, J = 8.4 Hz, 5.56 (s, 1 H), 4.12 (q, 2H, J = 6 Hz), 4.04-4.02 (m, 1 H), 3.02 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3 H), 1.31 (t, 3 H, J = 4.0 Hz)

Example 30

3- (4-Methanesulfonylphenyl) -3-oxo-2- (4-propoxyphenyl) -propionic acid ethyl ester

In the same manner as in Example 1, except that 500 mg of (4-propoxyphenyl) acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1 to give 890 mg of a liquid title compound (yield 92 %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.65 (d , 2H, J = 8.4Hz), 5.56 (s, 1H), 4.12 (q, 2H, J = 6Hz), 3.94-3.95 (m, 2H), 3.02 (s, 3H), 1.75-1.74 (m, 2H ), 1.30-1.28 (m, 6H)

Example 31

2- (4-acetoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

848 mg (yield) of the liquid title compound was obtained in the same manner as in Example 1, except that 500 mg of (4-acetoxyphenyl) -acetic acid ethyl ester was used instead of (4-ethoxyphenyl) -acetic acid ethyl ester in Example 1. 84%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.95 (d , 2H, J = 8.4Hz), 5.56 (s, 1h), 4.12 (q, 2H, J = 6.0Hz), 3.12 (s, 3H), 2.08 (s, 3H), 1.30 (t, 3H, J = 4.0 Hz)

Example 32

3- (2-Chloro-4-methanesulfonylphenyl) -2- (4-ethoxyphenyl) -3-oxo-propionic acid ethyl ester

Reaction was carried out in the same manner as in Example 1, except that 500 mg of 2-chloro-4-methanesulfonyl benzoic acid was used instead of 4-methanesulfonylbenzoic acid in Example 1 to obtain 670 mg (yield 75%) of the title compound. It was.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, 1H, J = 7.2 Hz), 8.05 (s, 1H), 7.92 (d, 1H, J = 7.2 Hz), 6.95-6.94 (m, 4H) , 5.56 (s, 1H), 4.12 (q, 2H, J = 6 Hz), 3.98 (q, 2H, J = 6.0 Hz), 3.02 (s, 3H), 1.33-1.31 (m, 6H)

Example 33

3- (2-Chloro-4-methanesulfonylphenyl) -3-oxo-2-p-tolyl-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 3, except that 500 mg of 2-chloro-4-methanesulfonyl benzoic acid was used instead of 4-methanesulfonylbenzoic acid in Example 3 to obtain 740 mg (yield 88%) of the title compound. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, 1H, J = 7.2 Hz), 8.05 (s, 1H), 7.92 (d, 1H, J = 7.2 Hz), 6.95-6.94 (m, 4H) , 5.56 (s, 1H), 4.12 (q, 2H, J = 6 Hz), 3.02 (s, 3H), 2.35 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 34

2- (4-Bromophenyl) -3- (2-chloro-4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

In the same manner as in Example 2, except for using 500 mg of 2-chloro-4-methanesulfonylbenzoic acid instead of 4-methanesulfonylbenzoic acid in Example 2, 764 mg (yield 84%) of the title compound was obtained. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, 1H, J = 7.2 Hz), 8.05 (s, 1H), 7.92 (d, 1H, J = 7.2 Hz), 6.98-6.97 (m, 4H) , 5.55 (s, 1H), 4.13 (q, 2H, J = 6 Hz), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 35

3- (2-Chloro-4-methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 5, except that 500 mg of 2-chloro-4-methanesulfonylbenzoic acid was used instead of 4-methanesulfonylbenzoic acid in Example 5 to obtain 791 mg (yield 87%) of the title compound. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, 1H, J = 7.2 Hz), 8.05 (s, 1H), 7.92 (d, 1H, J = 7.2 Hz), 6.95-6.94 (m, 4H) , 5.56 (s, 1H), 4.13 (q, 2H, J = 6 Hz), 3.75 (s, 3H), 3.02 (s, 3H), 1.33 (t, 3H, J = 4.0 Hz)

Example 36

3- (3,4-Difluorophenyl) -3-oxo-2-p-tolyl-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 3, except that 1 g of 3,4-difluoro benzoic acid was used instead of 4-methanesulfonylbenzoic acid in Example 3 to obtain 1.73 g (yield 82%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.17 (d, 2H, J = 7.6 Hz), 7.05-7.03 (m, 3H), 6.99 (d, 2H, J = 7.6 Hz), 5.52 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 2.35 (s, 3H), 1.30 (t, 3H, J = 4.0 Hz)

Example 37

3- (3,4-Difluorophenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester

The reaction was carried out in the same manner as in Example 5, except that 500 mg of 3,4-difluorobenzoic acid was used instead of 4-methanesulfonylbenzoic acid in Example 5 to obtain 850 mg (yield 85%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.16 (d, 2H, J = 7.6 Hz), 7.04-7.02 (m, 3H), 6.99 (d, 2H, J = 7.6 Hz), 5.52 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 3.82 (s, 3H), 1.30 (t, 3H, J = 4.0 Hz)

Example 38

2- (4-acetoxyphenyl) -3- (3,4-difluorophenyl) -3-oxo-propionic acid ethyl ester

In the same manner as in Example 31, except that 416 mg of 3,4-difluorobenzoic acid was used instead of 4-methanesulfonylbenzoic acid in Example 31, 830 mg (yield 87%) of the title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.17 (d, 2H, J = 7.6 Hz), 7.05-7.03 (m, 3H), 6.99 (d, 2H, J = 7.6 Hz), 5.52 (s, 1H) , 4.12 (q, 2H, J = 6.0 Hz), 2.32 (s, 3H), 1.30 (t, 3H, J = 4.0 Hz)

Example 39

4- (4-ethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

0.68 g of phosphorus penta sulfide was dissolved in 10 ml of toluene, and then 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was added for 4 hours at 110 ° C. It was refluxed to a degree. After cooling the reaction vessel, ammonia water was slowly added to adjust the pH to about 8-8.5, water was added thereto, diluted, and ethyl acetate was added for extraction. The obtained organic layer was dried over anhydrous magnesium sulfate to blow off a solvent, and then recrystallized with n-hexane to give 180 mg (yield 60%) of a red solid title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88 (d, 2H, J = 8.4 Hz), 7.45 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 6.8 Hz), 6.85 (d , 2H, J = 6.8 Hz), 4.02 (q, 2H, J = 6.8 Hz), 3.05 (s, 3H), 1.42 (t, 3H, J = 4.0 Hz)

EI Mass (M +): 408

Melting Point: 210-212 ℃

Example 40

4- (4-bromophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (4-bromophenyl) -3- (4 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 210 mg (68% yield) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.45 (d, 2H, J = 8.4 Hz), 7.19 (d , 2H, J = 8.4 Hz), 3.05 (s, 3H)

EI Mass (M +): 443

Melting Point: 238-240 ℃

Example 41

5- (4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-p-tolyl-propionic acid ethyl ester was used to obtain 200 mg of a liquid title compound (yield 65%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.89 (d, 2H, J = 9.0 Hz), 7.46 (d, 2H, J = 9.0 Hz), 7.16 (d, 2H, J = 9.0 Hz), 6.99 (d , 2H, J = 9.0 Hz), 3.05 (s, 3H), 2.34 (s, 3H)

EI Mass (M +): 378

Melting point: 240-242 ℃

Example 42

5- (4-methanesulfonylphenyl) -4-phenyl- [1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester Reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-phenyl-propionic acid ethyl ester was used to obtain 160 mg (50% yield) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, 2H, J = 6.0 Hz), 7.44 (d, 2H, J = 6.0 Hz), 7.35 (t, 3H, J = 4.0 Hz), 7.12-7.10 (m, 2 H), 3.04 (s, 3 H)

EI Mass (M +): 364

Melting point: 200-202 ℃

Example 43

5- (4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -2- (instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 4-methoxyphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 120 mg (40% yield) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 9.0 Hz), 7.46 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 6.0 Hz), 6.88 (d , 2H, J = 6.0 Hz), 3.81 (s, 3H), 3.05 (s, 3H)

EI Mass (M +): 394

Melting point: 220-222 ℃

Example 44

5- (4-methanesulfonylphenyl) -4- (2-trifluoromethylphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2- (2-trifluoromethylphenyl) -propionic acid ethyl ester was used to obtain 160 mg (51% yield) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.92 (d, 2H, J = 6.0 Hz), 7.63 (d, 2H, J = 6.0 Hz), 7.46 (d, 1H, J = 9.0 Hz), 7.35 (d , 1H, J = 9.0Hz), 7.24-7.21 (m, 2H), 3.05 (s, 3H)

FAB Mass (M + 1): 433

Melting point: 240-242 ℃

Example 45

4- (4-chlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (4-chlorophenyl) -3- (4- instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.4 g of methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 180 mg of a liquid title compound (yield 45%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.0 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.07 (d , 2H, J = 8.0 Hz), 2.98 (s, 3H)

EI Mass (M +): 399

Melting Point: 233-235 ℃

Example 46

4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (3,4-dichlorophenyl) -3- (instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.4 g of 4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 200 mg of a liquid title compound (yield 48%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 2H, J = 8.0 Hz), 7.49 (d, 2H, J = 8.0 Hz), 7.44 (d, 1H, J = 8.0 Hz), 7.35 (s , 1H), 7.07 (d, 1H, J = 8.0 Hz), 3.09 (s, 3H)

EI Mass (M +): 433

Example 47

5- (4-methanesulfonylphenyl) -4-pyridin-4-yl- [1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-pyridin-4-yl propionic acid ethyl ester was used to obtain 180 mg of a liquid title compound (yield 60%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.55 (d, 2H, J = 4.0 Hz), 7.85 (d, 2H, J = 9.2 Hz), 7.39 (d, 2H, J = 9.2 Hz), 6.99 (d , 2H, J = 4.0Hz), 2.98 (s, 3H) EI Mass (M +): 365

Melting point: 245-247 ℃

Example 48

5- (4-methanesulfonylphenyl) -4-pyridin-3-yl- [1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-pyridin-3-yl propionic acid ethyl ester was used to obtain 189 mg (yield 61%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 8.25 (d, 2H, J = 4.0 Hz), 7.92 (d, 2H, J = 8.0 Hz), 7.54 (d, 1H, J = 4.0 Hz), 7.45 (d, 2H, J = 8.0 Hz), 3.03 (s, 3H) EI Mass (M +): 365

Example 49

5- (4-methanesulfonylphenyl) -4-pyridin-2-yl- [1,2] dithiol-3-thione

(4-ethoxyphenyl) the embodiment 2 in Example 39 3- (4-methanesulfonyl-phenyl) -3-oxo-propionic acid ethyl ester 0.3g instead of 3 - (4-methanesulfonyl-phenyl) -3-oxo The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-pyridin-2-yl propionic acid ethyl ester was used to obtain 189 mg (yield 61%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.55 (m, 1H), 7.87 (dt, 2H, J = 8.6 Hz, J = 2.1 Hz), 7.75 (ddd, 1H. J = 9.5 Hz, J = 2.1 Hz , J = 1.8Hz), 7.50 ( dt, 2H, J = 8.6Hz, J = 2.1Hz), 7.40 (dt, 1H, J = 7.9Hz, J = 1.0Hz), 7.26 (ddd, 1H, J = 7.6 Hz, J = 5.1 Hz, J = 1.7 hZ), 3.04 (s, 3H)

EI Mass (M +): 365

Example 50

4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (4-fluorophenyl) -3- (4 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 195 mg (yield 63%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.0 Hz), 7.44 (d, 2H, J = 8.0 Hz), 7.09-7.04 (m, 4H), 3.05 (s, 3H)

EI Mass (M +): 382

Melting Point: 195-197 ℃

Example 51

4- (2,5-dimethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (2,5-dimethoxyphenyl) -3- instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 180 mg (60% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.87 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.4 Hz), 6.87 (dd, 1H, J = 12.0 Hz, J = 2.8 Hz ), 6.78 (d, 1H, J = 12 Hz), 6.62 (d, 1H, J = 2.8 Hz), 3.72 (s, 3H), 3.53 (s, 3H), 3.03 (s, 3H)

EI Mass (M +): 424

Melting Point: 176-177 ℃

Example 52

4- (3,5-dimethylphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (3-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester instead of 0.3 g of 2- (3,5-dimethylphenyl) -3- ( The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 210 mg (66% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 6.96 (s, 1H), 6.69 (s, 2H), 3.03 (s, 3H), 2.37 (s, 6H)

EI Mass (M +): 392

Melting Point: 164-165 ℃

Example 53

5- (4-methanesulfonylphenyl) -4- (3-methoxyphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -2- (instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 3-methoxyphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 210 mg (66% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.24 (t, 1H, J = 8.2 Hz), 6.88 (d , 1H, J = 7.2 Hz), 6.69 (s, 1H), 6.65 (d, 1H, J = 7.2 Hz), 3.71 (s, 3H), 3.04 (s, 3H)

EI Mass (M +): 394

Melting Point: 212-213 ℃

Example 54

5- (4-methanesulfonylphenyl) -4- (2-nitrophenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -2- (instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester Reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-nitrophenyl) -3-oxo-propionic acid ethyl ester was used to obtain 217 mg (yield 70%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, 1H, J = 6.8 Hz), 7.89 (d, 2H, J = 8.4 Hz), 7.56-7.54 (m, 4H), 7.01 (d, 1H, J = 6.8 Hz), 3.04 (s, 3H)

EI Mass (M +): 409

Melting Point: 170-171 ℃

Example 55

5- (4-methanesulfonylphenyl) -4- (3-trifluoromethylphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2- (3-trifluoromethylphenyl) -propionic acid ethyl ester was used to obtain 240 mg (yield 78%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.4 Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.49 (t, 1H, J = 8.0 Hz), 7.43 (d , 2H, J = 8.4 Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.29 (s, 1 H), 3.04 (s, 3 H)

EI Mass (M +): 432

Melting point: 188-189 ℃

Example 56

5- (4-methanesulfonylphenyl) -4-o-tolyl- [1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-o-tolyl-propionic acid ethyl ester was used to obtain 173 mg (56% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.87 (d, 2H, J = 8.4 Hz), 7.46 (d, 2H, J = 8.4 Hz), 7.30 (d, 1H, J = 7.6 Hz), 7.22-7.17 (m, 2H), 6.96 (d, 1H, J = 7.6 Hz), 3.04 (s, 3H), 2.10 (s, 3H)

EI Mass (M +): 378

Melting Point: 165-166 ℃

Example 57

4- (2-chlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (2-chlorophenyl) -3- (4- instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 210 mg of a liquid title compound (yield 68%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4 Hz), 7.43 (dd, 1H, J = 9.2 Hz, J = 1.6 Hz ), 7.32 (m, 2H), 7.12 (dd, 1H, J = 9.2 Hz, J = 1.6 Hz), 3.05 (s, 3H)

EI Mass (M +): 398

Melting Point: 161-162 ℃

Example 58

4- (2,4-dichlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (2,4-dichlorophenyl) -3- (instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 198 mg (64% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.43 (s, 1H), 7.30 (d, 1H, J = 8.4 Hz), 7.07 (d, 1 H, J = 8.4 Hz), 3.07 (s, 3 H)

EI Mass (M +): 433

Melting Point: 176-177 ℃

Example 59

4- (2-chloro-4-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39 2- (2-chloro-4-fluorophenyl)-instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 164 mg (yield 53%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4 Hz), 7.07 (dd, 1H, J = 5.6 Hz, J = 2.4 Hz ), 7.03 (dd, 1H, J = 8.4 Hz, J = 6.0 Hz), 6.93 (td, 1H, J = 6.0 Hz, J = 2.4 Hz), 2.97 (s, 3H)

EI Mass (M +): 416

Melting point: 184-185 ℃

Example 60

4- (3,4-dimethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester instead of 0.3 g of 2- (3,4-dimethoxyphenyl) -3- The reaction was carried out in the same manner as in Example 39, except that 0.3 g of (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 155 mg (50% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4 Hz), 6.73 (d, 1H, J = 8.4 Hz), 6.61 (d , 1H, J = 2.0Hz), 6.53 (dd, 1H, J = 7.2Hz, J = 2.0Hz), 3.78 (s, 3H), 3.66 (s, 3H), 2.96 (s, 3H)

EI Mass (M +): 424

Melting Point: 182-183 ℃

Example 61

4- (2-bromophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (2-bromophenyl) -3- (4 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester Reaction was carried out in the same manner as in Example 39, except that 0.3 g of methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 186 mg of a liquid title compound (yield 60%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, 2H, J = 8.4 Hz), 7.52-7.50 (m, 1H), 7.46 (d, 2H, J = 8.4 Hz), 7.25-7.23 (m, 1H), 7.16-7.14 (m, 1H), 7.01-7.00 (m, 1H), 3.05 (s, 3H)

EI Mass (M +): 443

Melting Point: 179-180 ℃

Example 62

4- (2-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (2-fluorophenyl) -3- (4 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 170 mg (yield 55%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.30-7.29 (m, 1H), 7.09-7.06 (m, 2H), 6.94 (t, 1H, J = 9.3 Hz), 3.05 (s, 3H)

EI Mass (M +): 382

Melting Point: 173-174 ℃

Example 63

4- (2,4-difluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (2,4-difluoro) -3- instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 179 mg (yield 58%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.12 (dd, 1H, J = 16.8 Hz, J = 8.6 Hz ), 6.87-6.84 (m, 1 H), 6.69-6.66 (m, 1 H), 3.0 (s, 3 H)

EI Mass (M +): 400

Melting Point: 148-149 ℃

Example 64

4- (3,4-difluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

2- (3,4-difluorophenyl) -3 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester in Example 39 Reaction was carried out in the same manner as in Example 39, except that 0.3 g of-(4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 182 mg (yield 59%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.4 Hz), 7.05-7.01 (m, 1H), 6.94-6.90 (m, 1H), 6.74-6.72 (m, 1H), 3.0 (s, 3H)

EI Mass (M +): 400

Melting Point: 193-194 ℃

Example 65

5- (4-methanesulfonylphenyl) -4-naphthalen-2-yl- [1,2] dithiol-3-thione

3- (4-methanesulfonylphenyl) -2-naphthalene instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester in Example 39 The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-yl-3-oxo-propionic acid ethyl ester was used to obtain 188 mg (60% yield) of the liquid title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, 2H, J = 8.4 Hz), 7.70-7.65 (m, 6H), 7.37-7.35 (m, 3H), 3.04 (s, 3H)

EI Mass (M +): 414

Example 66

5- (4-methanesulfonylphenyl) -4-pentafluorophenyl- [1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2-pentafluorophenyl-propionic acid ethyl ester was used to obtain 200 mg (65% yield) of the liquid title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4 Hz), 3H), 3.13 (s, 3H)

EI Mass (M +): 454

Melting Point: 181-182 ℃

Example 67

4- (4-isopropylphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39, 2- (4-isopropoxyphenyl) -3- (2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester instead of 0.3 g) The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 210 mg (68% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz),

7.06 (d, 2H, J = 8.8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 4.52-4.50 (m, 1H), 3.06 (s, 3H), 1.32 (s, 3H), 1.31 (s , 3H)

EI Mass (M +): 422

Melting Point: 179-180 ℃

Example 68

5- (4-methanesulfonylphenyl) -4- (4-propoxyphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (4-methanesulfonylphenyl) -3-oxo instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester Reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2- (4-propoxyphenyl) -propionic acid ethyl ester was used to obtain 207 mg (yield 67%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, J = 8.8 Hz), 6.84 (d , 2H, J = 8.8 Hz, 3.90 (s, 3H), 3.05 (s, 3H), 1.79-1.78 (m, 2H), 1.19 (t, 3H, J = 8.0 Hz),

EI Mass (M +): 422

Melting Point: 177-178 ℃

Example 69

Acetic acid 4- [5- (4-methanesulfonylphenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] phenyl ester

In Example 39, 2- (4-acetoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester instead of 0.3 g of 2- (4-acetoxyphenyl) -3- (4 The reaction was carried out in the same manner as in Example 39, except that 0.3 g of -methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 140 mg (yield 45%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, 2H, J = 9.4 Hz), 7.48 (d, 2H, J = 9.4 Hz), 7.19 (d, 2H, J = 7.6 Hz), 7.03 (d , 2H, J = 7.6 Hz), 3.08 (s, 3H), 2.49 (s, 3H)

EI Mass (M +): 422

Melting Point: 241-243 ℃

Example 70

5- (2-chloro-4-methanesulfonylphenyl) -4- (4-ethoxyphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (2-chloro-4-methanesulfonylphenyl) instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2- (4-ethoxyphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 170 mg (yield 55%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, 1H, J = 1.6 Hz), 7.69 (dd, 1H, J = 6.4 Hz, J = 2.0 Hz), 7.32 (d, 1H, J = 8.0 Hz ), 6.88 (d, 2H, J = 8.4 Hz), 6.62 (d, 2H, J = 8.4 Hz), 3.81 (q, 2H, J = 7.2 Hz), 2.98 (s, 2H), 1.23 (t, 3H) , J = 4.0 Hz)

EI Mass (M +): 443

Melting point: 190-191 ℃

Example 71

5- (2-chloro-4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione

In Example 39, 3- (2-chloro-4-methanesulfonylphenyl) instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 3-oxo-2-p-tolyl-propionic acid ethyl ester was used to obtain 173 mg (56% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 1H, J = 1.6 Hz), 7.83 (dd, 1H, J = 6.0 Hz, J = 2.0 Hz), 7.51 (d, 1H, J = 8.0 Hz ), 7.11 (d, 2H, J = 8.4 Hz), 7.02 (d, 2H, J = 8.4 Hz), 3.09 (s, 3H), 2.32 (s, 3H)

EI Mass (M +): 413

Melting point: 188-189 ℃

Example 72

4- (4-bromophenyl) -5- (2-chloro-4-methanesulfonylphenyl)-[1,2] dithiol-3-thione

In Example 39 2- (4-bromophenyl) -3- (2 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester Reaction was carried out in the same manner as in Example 39, except that 0.3 g of -chloro-4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 192 mg (yield 62%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, 1H, J = 1.6 Hz), 7.86 (dd, 1H, J = 8.0 Hz, J = 1.6 Hz), 7.51 (d, 1H, J = 8.0 Hz ), 7.11 (d, 2H, J = 8.4 Hz), 7.02 (d, 2H, J = 8.4 Hz), 3.09 (s, 3H)

EI Mass (M +): 477

Melting Point: 194-195 ℃

Example 73

5- (2-chloro-4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione

In Example 39, 3- (2-chloro-4-methanesulfonylphenyl) instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester The reaction was carried out in the same manner as in Example 39, except that 0.3 g of 2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester was used to obtain 195 mg (yield 63%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, 1H, J = 1.6 Hz), 7.87 (dd, 1H, J = 8.0 Hz, J = 1.6 Hz), 7.52 (d, 1H, J = 8.0 Hz ), 7.12 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 4.25 (s, 3H), 3.09 (s, 3H)

EI Mass (M +): 428

Melting Point: 192-193 ℃

Example 74

5- (3,4-difluorophenyl) -4-p-tolyl- [1,2] dithiol-3-thione

5- (3,4-difluorophenyl) -4 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester in Example 39 The reaction was carried out in the same manner as in Example 39, except that 0.5 g of -p-tolyl- [1,2] dithiol-3-thione was used to obtain 293 mg (52% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.15 (d, 2H, J = 7.6 Hz), 7.03-7.01 (m, 3H), 6.98 (d, 2H, J = 7.6 Hz), 2.33 (s, 3H)

EI Mass (M +): 336

Melting point: 140-142 ℃

Example 75

5- (3,4-difluorophenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione

3- (3,4-difluorophenyl) -3 instead of 0.3 g of 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester in Example 39 above Reaction was carried out in the same manner as in Example 39, except that 0.5 g of oxo-2-p-tolyl-propionic acid ethyl ester was used to obtain 274 mg (52% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.16 (d, 2H, J = 7.6 Hz), 7.04-7.02 (m, 3H), 6.99 (d, 2H, J = 7.6 Hz), 3.82 (s, 3H)

EI Mass (M +): 352

Melting Point: 143-145 ℃

Example 76

Acetic acid 4- [5- (3,4-difluorophenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] -phenyl ester

In Example 39, 2- (4-acetoxyphenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester instead of 0.3 g of 2- (4-acetoxyphenyl) -3- (3 The reaction was carried out in the same manner as in Example 39, except that 0.5 g of, 4-difluorophenyl) -3-oxo-propionic acid ethyl ester was used to obtain 267 mg (51% yield) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.17 (d, 2H, J = 7.6 Hz), 7.05-7.03 (m, 3H), 6.99 (d, 2H, J = 7.6 Hz), 2.32 (s, 3H)

EI Mass (M +): 380

Melting Point: 147-149 ℃

Example 77

5- (3-fluoro-4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione

5- (3,4-difluorophenyl) -4-p-tolyl- [1,2] dithiol-3-thione (0.1 g) prepared in Example 74 was dissolved in dimethyl sulfoxide, followed by sodium methane. Sulfate (33 mg) was added and the reaction was carried out at 80 ° C. for about 3 hours. After the reaction was completed, water was added, diluted, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then separated by flash chromatography (ethyl acetate: hexane = 1: 2) to obtain 66 mg of a red solid (56% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.90-7.89 (m, 1H), 7.15-7.12 (m, 4H), 7.00-6.98 (m, 2H), 3.21 (s, 3H), 2.34 (s, 3H )

EI Mass (M +): 396

Melting Point: 205-207 ℃

Example 78

5- (3-fluoro-4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione

5- (3,4- prepared in Example 75 instead of 5- (3,4-difluorophenyl) -4-p-tolyl- [1,2] dithiol-3-thione in Example 78 58 mg (yield 50) of the title compound as a solid was reacted in the same manner as in Example 78, except that difluorophenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione was used. %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.85 (t, 1H, J = 1.2 Hz), 7.17 (dd, 1H, J = 10.0 Hz, J = 2.0 Hz), 7.15 (dd, 1H, J = 10.0 Hz , J = 2.0 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 3.74 (s, 3H), 3.20 (s, 3H)

EI Mass (M +): 352

Melting Point: 150-152 ℃

Example 79

Acetic acid 4- [5-3-fluoro-4-methanesulfonylphenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] -phenyl ester

The acetic acid 4- [5- prepared in Example 76 instead of 5- (3,4-difluoro-phenyl) -4-p-tolyl- [1,2] dithiol-3-thione in Example 78 above. The reaction was carried out in the same manner as in Example 78, except that (3,4-difluoro-phenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] -phenyl ester was used. 60 mg (52% yield) of the title compound were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.85 (t, 1H, J = 1.2 Hz), 7.17-7.01 (m, 4H), 6.92 (d, 2H, J = 8.0 Hz), 3.14 (s, 3H) , 2.29 (s, 3H)

EI Mass (M +): 440

Melting Point: 200-201 ℃

Example 80

5- (4-methanesulfonylphenyl) -4-p-tolyl-1,2-dihydropyrazole-3-thione

30 mg of potassium hydroxide was added to 0.1 g of 5- (4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione, dissolved in 5 ml of ethanol, and then hydrazine (2eq) was added thereto. At reflux for 12 hours. A change of color from red to yellow was observed. After distilling ethanol under reduced pressure, water was added and ethyl acetate was added for extraction. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Recrystallization with n-hexane gave 56 mg (yield 62%) of the title compound as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, 2H, J = 7.6 Hz), 7.58 (d, 2H, J = 7.6 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.16 (s , 2H, J = 8.0 Hz), 3.04 (s, 3H), 2.38 (s, 3H)

EI Mass (M +): 344

Melting Point: 198-200 ℃

Example 81

4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dihydropyrazole-3-thione

In Example 81, 4- (3,4-dichlorophenyl) -5- instead of 0.1 g of 5- (4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione The reaction was carried out in the same manner as in Example 81, except that 0.1 g of (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione was used to obtain 58 mg (63% yield) of the liquid title compound.

¹ H-NMR (400 MHz, CDCl 3) δ 7.83 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J = 8.0 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.16 (s, 1H), 7.07 (d, 1H, J = 8.0 Hz), 3.20 (s, 3H)

FAB Mass (M + 1): 399

Melting Point: 192-193 ℃

Example 82

4- (4-chlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dihydropyrazole-3-thione

In Example 81, 4- (4-chlorophenyl) -5- (instead of 0.1 g of 5- (4-methanesulfonyl-phenyl) -4-p-tolyl- [1,2] dithiol-3-thione; The reaction was carried out in the same manner as in Example 81, except that 0.1 g of 4-methanesulfonylphenyl)-[1,2] dithiol-3-thione was used to obtain 62 mg of a liquid title compound (yield 68%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H, J = 8.0 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.28 (d , 2H, J = 8.4 Hz), 3.19 (s, 3H)

FAB Mass (M + 1): 365

Melting Point: 211-213 ° C

Pharmacological Experimental Example

Determination of Selective Inhibitory Activity on Cyclooxygenase-2

1. Experiment Method

In order to pharmacologically verify the selective inhibitory activity of the cyclooxygenase-2 enzyme of the compound according to the present invention, the enzyme inhibitory activity on cyclooxygenase-1 and cyclooxygenase-2 was respectively as follows. Measured by.

1) Screening of Inhibitory Effect of Cyclooxygenase-1 Using U-937

The cultured U-937 (Human lymphoma cell) (obtained from Korea Cell Line Bank, Accession No .: 21593) was collected by centrifugation and diluted to 1x10 ⁶ cells / ml using 1xHBSS (Hank's balanced salt solution). 1 ml was dispensed for each well of the well plate. 5 μl of DMSO and 5 μl each of the sample solution diluted in 1 μM and dissolved in DMSO were mixed and incubated at 37 ° C. for 15 minutes in a CO ₂ incubator. A stock solution prepared by dissolving arachidonic acid used as a substrate in ethanol at a concentration of 10 mM was diluted 10-fold with 1 × HBSS to prepare a 1 mM solution. 10 μl of 1 mM arachidonic acid solution was added to each well treated with the material, followed by incubation at 37 ° C. for 30 minutes in a CO ₂ incubator. The cell solution of each well was collected in a centrifuge test tube, and then centrifuged at 4 ° C. and 10,000 rpm for 5 minutes. The concentration of PGE2 in the supernatant separated from the cells collected by centrifugation was determined using a monoclonal kit (Cayman Chemicals), and the concentration of PGE2 of each substance was compared with that of the DMSO group. The inhibitory effect of the substance on the cyclooxygenase-1 enzyme was determined by determining the production inhibition rate.

2) Screening of Cyclooxygenase-2 Inhibitory Effect Using Raw 264.7 Cell Line

Raw 264.7 cells (obtained from Korea Cell Line Bank, Accession No .: 40071) were inoculated with 2 × 10 ⁶ cells per well of a 12 well plate, treated with 250 μM of aspirin, and incubated at 37 ° C. for 2 hours. After changing to fresh medium, each sample was treated (10 nM concentration) and incubated for 30 minutes. Each well was treated with interferon γ (100 units / ml) and lipopolysaccharide (LPS, 100ng / ml), followed by incubation for 18 hours. Then, the medium was transferred to another test tube, and PGE2 was quantified using an EIA kit (Cayman Chemicals).

2. Experimental Results

The experimental results are shown in Table 1 below.

% Inhibition = (corrected PGE2 concentration for interferonγ and LPS-corrected PGE2 concentration for search sample) / (corrected PGE2 concentration for interferonγ and LPS) X 100

Cyclooxygenase (COX) inhibitory effect (% inhibition)   compound COX-1 (1 uM) COX-2 (30nM)   Reference substance (Valdecoxib) 28.8 19 Example 39 15 36.6 Example 40 18.3 35.7 Example 41 20.1 24.5 Example 42 24.5 20.1 Example 43 19.3 38.4 Example 44 25.5 20.1 Example 45 19.6 22.1 Example 46 24.6 21.0 Example 47 22.5 21.4 Example 48 23.6 24.2 Example 49 28.0 19.5 Example 50 27.2 19.6 Example 51 27.6 19.8 Example 52 26.6 19.1 Example 53 26.7 21.6 Example 54 22.4 26.3 Example 55 27.6 20.2 Example 56 20.6 25.6 Example 57 20.7 21.1

Example 58 24.2 20.1 Example 59 23.2 19.7 Example 60 26.5 19.3 Example 61 23.3 20.1 Example 62 26.6 21.0 Example 63 20.3 21.3 Example 64 21.6 19.8 Example 65 22.6 20.1 Example 66 28.2 19.2 Example 67 27.5 23.3 Example 68 25.5 22.7 Example 69 24.8 21.3 Example 70 17.5 36.0 Example 71 20.3 21.0 Example 72 28.1 19.3 Example 73 25.6 20.1 Example 74 26.5 19.2 Example 75 26.6 19.6 Example 76 21.6 20.3 Example 77 15.2 31.5 Example 78 18.5 32.5 Example 79 19.5 30.2 Example 80 25.6 23.2 Example 81 24.9 24.6 Example 82 24.3 22.2

Looking at the results of in vitro experiments on the inhibition of the cyclooxygenase-1 and cyclooxygenase-2 are as follows.

According to the experimental results, in all the examples shown above, the ratio of% of cyclooxygenase-2 to% of cyclooxygenase was significantly superior to that of the reference material (vladecoxib). This indicates that the selective inhibitory effect of cyclooxygenase-2 on cyclooxygenase-1 is superior to the reference material.

The novel compound according to the present invention is an alternative drug with improved side effects of the existing nonsteroidal anti-inflammatory drugs, and is used in patients with peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal bleeding, hypoprothrombinemia, etc. It is useful and is expected to be useful as a therapeutic agent for inflammatory diseases such as osteoarthritis and rheumatoid arthritis.

Claims (8)

Thion derivative represented by the following formula (1) or a non-toxic salt thereof: [Formula 1] In Chemical Formula 1, A and B are each independently O, S, NR ² , wherein R ² is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, or aryl; Ar is phenyl; Phenyl substituted with 1 to 5 selected groups from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, trifluoromethyl, acetoxy, and nitro; Pyridyl; Or naphthyl; R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₄ alkylamino, or di-C ₁ -C ₄ alkylamino . The method of claim 1, A and B are each independently S or NH; Ar is phenyl; Phenyl substituted with 1 to 5 selected groups from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, trifluoromethyl, acetoxy, and nitro; Pyridyl; Or naphthyl; R ¹ is hydrogen or halogen, a thion derivative or a non-toxic salt thereof. The method according to claim 1 or 2, 4- (4-ethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (4-bromophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-tolyl- [1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-phenyl- [1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-methoxyphenyl- [1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4- (2-trifluoromethylphenyl)-[1,2] dithiol-3-thione; 4- (4-chlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-pyridin-4-yl- [1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-pyridin-3-yl- [1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-pyridin-2-yl- [1,2] dithiol-3-thione; 4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (2,5-dimethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (3,5-dimethylphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4- (3-methoxyphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4- (2-nitrophenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4- (3-trifluoromethylphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-o-tolyl- [1,2] dithiol-3-thione; 4- (2-chlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (2,4-dichlorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (2-chloro-4-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (3,4-dimethoxyphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (2-bromophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (2-fluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (2,4-difluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 4- (3,4-difluorophenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-naphthalen-2-yl- [1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4-pentafluorophenyl- [1,2] dithiol-3-thione; 4- (4-isopropylphenyl) -5- (4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 5- (4-methanesulfonylphenyl) -4- (4-propoxyphenyl)-[1,2] dithiol-3-thione; Acetic acid 4- [5- (4-methanesulfonylphenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] phenyl ester; 5- (2-chloro-4-methanesulfonylphenyl) -4- (4-ethoxyphenyl)-[1,2] dithiol-3-thione; 5- (2-chloro-4-methanesulfonylphenyl) -4- p -tolyl- [1,2] dithiol-3-thione; 4- (4-bromophenyl) -5- (2-chloro-4-methanesulfonylphenyl)-[1,2] dithiol-3-thione; 5- (2-Chloro-4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione: 5- (3-fluoro-4-methanesulfonylphenyl) -4-p-tolyl- [1,2] dithiol-3-thione; 5- (3-fluoro-4-methanesulfonylphenyl) -4- (4-methoxyphenyl)-[1,2] dithiol-3-thione; Acetic acid 4- [5- (3-fluoro-4-methanesulfonylphenyl) -3-thioxo-3H- [1,2] dithiol-4-yl] -phenyl ester; 5- (4-methanesulfonylphenyl) -4- p -tolyl-1,2-dihydropyrazole-3-thione; 4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dihydropyrazole-3-thione and A thion derivative or nontoxic salt thereof selected from the group consisting of 4- (4-chlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dihydropyrazole-3-thione. Propionic acid derivatives represented by Formula 2 below: [Formula 2] R ¹ and Ar are as defined in claim 1, R ³ represents C ₁ -C ₄ alkyl. A method for preparing a thione derivative of Formula 1a or a non-toxic salt thereof comprising reacting a propionic acid derivative of Formula 2 with a phosphorus pentasulfide, a Lawson reagent, a beta-oxothioxane, or a beta-oxothiooxane potassium salt. [Formula 1a] [Formula 2] R ₁ and Ar are as defined in claim 1, R ₃ represents C ₁ -C ₃ alkyl. The propionic acid derivative of Formula 2 is prepared by reacting a methanesulfonylbenzoic acid derivative of Formula 3 and derivatives of Formula 4 with an arylacetic acid ester derivative of Formula 5 in the presence of a base. Method for preparing thion derivative or nontoxic salt thereof. [Formula 3] [Formula 4] R ¹ and Ar are as defined in claim 1, R ³ represents C ₁ -C ₄ alkyl. A process for preparing a thion derivative of Formula 1b or a non-toxic salt thereof comprising reacting Formula 1a with NHR ² NHR ² or NHR ² OH in the presence of a base: [Formula 1a] [Formula 1b] A 'and B' are each independently S or NR ² , provided that A 'and B' cannot be S at the same time, wherein Ar and R ² are as defined in claim 1. A pharmaceutical agent having antipyretic, analgesic and anti-inflammatory effect, which contains a therapeutically effective amount of the thion derivative according to any one of claims 1 to 3 or a non-toxic salt thereof as an active ingredient and includes a pharmaceutically acceptable carrier. Composition.