KR19990063989A - 1,3,5-trisubstituted pyrazole compounds for the treatment of inflammation - Google Patents

Abstract

The present invention relates to the following compounds (I) and pharmaceutically acceptable salts thereof, to methods of preparing them and to pharmaceutical compositions.

Formula I

Wherein R ¹ is hydroxyethyl, 1-hydroxy-1-methylethyl, hydrogen, halogen, nitro or sinano,

R ² is lower alkyl optionally substituted with chloro, cyano or halogen,

R ³ is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl,

Provided that when R ¹ is hydrogen, halogen, nitro or cyano, R ² is chloro.

Description

1,3,5-trisubstituted pyrazole compounds for the treatment of inflammation

The present invention relates to novel pyrazole compounds having pharmaceutical activity, methods for their preparation and pharmaceutical compositions containing them.

More specifically, the present invention relates to novel pyrazole compounds having a pharmaceutical activity such as inhibiting the activity of cyclooxygenase-2 (hereinafter abbreviated as COX-II), a preparation method thereof, and a pharmaceutical composition containing the same. .

It is a first object of the present invention to provide a novel pyrazole compound that inhibits the activity of COX-II.

It is a second object of the present invention to provide a method for preparing the pyrazole compound.

It is a third object of the present invention to provide a pharmaceutical composition containing the pyrazole compound as an active ingredient.

A fourth object of the present invention is to provide a method for preparing a drug for preventing or treating various diseases using the pyrazole compound.

Some pyrazole derivatives having anti-inflammatory and analgesic activity are already known, for example Canadian Patent No. 1 130 808, European Patent Publication Nos. 248 549, 272 704, 293 220, 418 846 And 554 829, International Patent Application Nos. 95/15315, 95/15316, 95/15317, and 95/15318.

The pyrazole derivatives of the present invention and their pharmaceutically acceptable salts are novel and can be represented by the following formula (I).

Wherein R ¹ is hydroxyethyl, 1-hydroxy-1-methylethyl, hydrogen, halogen, nitro or sinano,

R ² is lower alkyl optionally substituted with chloro, cyano or halogen,

R ³ is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl,

Provided that when R ¹ is hydrogen, halogen, nitro or cyano, R ² is chloro.

The compound of formula (I) or a salt thereof may be prepared by the following scheme.

Reference Scheme

In the above schemes, R ¹ , R ² and R ³ are each as defined above,

R ¹ _a is acetyl,

R ¹ _b is 1-hydroxyethyl,

R ¹ _c is carboxy,

R ¹ _d is 1-hydroxy-1-methylethyl,

R ¹ _e is carboxymethyl,

R ¹ _f is 2-hydroxyethyl,

R ¹ _g is hydrogen, halogen, nitro or cyano,

R ¹ _h is lower alkanoyl, hydroxyethyl, 1-hydroxy-1-methylethyl, hydrogen, halogen, nitro or cyano,

R ² _a is lower alkyl optionally substituted with cyano or halogen,

R ² _b is lower alkyl optionally substituted with hydrogen, cyano or halogen,

R ³ _a is lower alkylthio,

R ³ _b is lower alkylsulfinyl or lower alkylsulfonyl.

In the foregoing description of the present invention and the following detailed description, suitable examples of various definitions falling within the scope of the present invention will be described below.

"Lower" means a group having from 1 to 6 carbon atoms, unless otherwise specified.

"Hydroxyethyl" means 1-hydroxyethyl or 2-hydroxyethyl.

Suitable "lower alkyl" and lower alkyl moieties in "lower alkylthio", "lower alkylsulfinyl" and "lower alkylsulfonyl" are straight chains such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. Or branched, of which methyl is preferred.

Suitable "lower alkylthios" are methylthio, ethylthio, propylthio and the like, of which methylthio is preferred.

Suitable "lower alkylsulfinyl" are methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like, of which methylsulfinyl is preferred.

Suitable "lower alkylsulfonyls" are methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, of which methylsulfonyl is preferred.

Suitable "halogens" are fluoro, chloro, bromo and iodo.

Suitable "lower alkyl substituted with halogen" are difluoromethyl, trifluoromethyl and the like.

Suitable “lower alkanoyls” are formyl, acetyl, propionyl, butyryl, isobutyryl and the like.

Suitable pharmaceutically acceptable salts of compound I can be converted to non-toxic salts, for example organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, Toluenesulfonate, etc.], inorganic acid addition salts (for example, hydrochloride, hydrobromide, sulfate, phosphate, etc.), and salts of amino acids (for example, aspartic acid salt, glutamic acid salt, etc.).

Since Compound I and pharmaceutically acceptable salts of the present invention have one or more asymmetric centers, they may exist as enantiomers or diastereomers, and the present invention also includes mixtures and individual isomers thereof.

Compounds I and pharmaceutically acceptable salts of the present invention may be in sorbate form, which is also within the scope of the present invention. Examples of preferred solvates include hydrates, ethanolates and the like.

Radiolabeled derivatives of Compound I also fall within the scope of the present invention, which derivatives are useful for physiological studies.

Scheme 1

Compound Ia or a salt thereof can be prepared by reacting compound II or a salt thereof with a reducing agent.

Examples of suitable reducing agents include diborane, sodium borohydride, lithium aluminum hydride and the like.

This reaction can be carried out in conventional solvents such as diethyl ether, tetrahydrofuran or in the presence of other organic solvents that do not adversely affect the reaction.

The reaction temperature is not critical and the reaction can be carried out under cooling or heating.

Scheme 2

Compound Ib or a salt thereof can be prepared by reacting a reactive derivative or salt thereof in compound III or a carboxyl group thereof with an alkylating agent.

Examples of suitable reactive derivatives for the carboxy group of compound III include esters, acid anhydrides and the like. Suitable examples of reactive derivatives include symmetric acid anhydrides; Acid anhydrides mixed with acids such as 1,1'-carbonyl diimidazole or aliphatic acid (eg, acetic acid, pivalic acid, etc.), substituted phosphoric acid (eg, dialkylphosphoric acid, diphenylphosphoric acid, etc.) ; Lower alkyl esters [eg, methyl esters, ethyl esters, propyl esters, hexyl esters, etc.], substituted or unsubstituted ar (lower) alkyl esters [eg, benzyl esters, p-chlorobenzyl esters, etc.], substituted or substituted Esters such as aryl esters (eg, phenyl esters, tolyl esters, 4-nitrophenyl esters, 2,4-dinitrophenyl esters, pentachlorophenyl esters, naphthyl esters, etc.) or N, N-dimethylhydroxy Esters with amines, N-hydroxysuccinimides, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole.

Suitable alkylating agents are organometallic compounds such as alkyl lithium (eg methyl lithium, ethyl lithium, etc.), alkyl magnesium halides (eg methyl magnesium bromide, ethyl magnesium bromide, etc.).

This reaction can be carried out in a conventional solvent such as diethyl ether, terahydrofuran, or in any other solvent that does not adversely affect the reaction.

The reaction temperature is not critical and the reaction can be carried out under cooling or heating.

Scheme 3

Compound Ic or a salt thereof can be prepared by reacting compound II or a salt thereof with an alkylating agent.

Since this reaction can be carried out in a manner substantially similar to that of Scheme 2, the reaction mode and reaction conditions (eg, reaction solvent, reaction temperature, etc.) of this reaction are as described in Scheme 2.

Scheme 4

Compound Ie or a salt thereof may be prepared by reacting compound Id or a salt thereof with an oxidizing agent.

Suitable oxidizing agents include hydrogen peroxide, cumene hydroperoxide, t-butyl hydroperoxide, Jones reagent, peracids (e.g., peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, monopersulfate compounds (oxone®), etc.), chromic acid , Potassium permanganate and alkali metal periodate (eg, sodium periodate).

This reaction is usually carried out in a solvent which does not adversely affect the reaction, such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, alcohols (eg, methanol, ethanol, etc.), mixtures thereof, and the like.

The reaction temperature is not critical and the reaction can usually be carried out under cooling to warming.

Scheme 5

Compound If or a salt thereof can be prepared by reacting a reactive derivative or salt thereof at compound IV or a carboxyl group thereof with a reducing agent.

Suitable reducing agents include diborane, sodium borohydride, lithium aluminum hydride and the like. When using a chiral reducing agent such as a combination of borane and (R) or (S) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine, The chiral compound If can be obtained.

This reaction is carried out in conventional solvents such as ethyl ether, tetrahydrofuran or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction can usually be carried out under cooling or heating.

Scheme 6

Compound Ig or a salt thereof can be prepared by the following method.

That is, 1) Compound V or a salt thereof was first reacted with a nitrite compound, and 2) the resulting product was reacted with cuprous chloride.

Suitable nitrite compounds include alkali metal nitrites (eg, sodium nitrite, potassium nitrite and the like), alkyl nitrites (eg isoamyl nitrite, t-butyl nitrite and the like).

In the first step, the reaction is preferably carried out in the presence of an acid (eg hydrochloric acid, sulfuric acid, etc.).

The reaction can be carried out in water, solvents such as tetrahydrofuran, dioxane, acetonitrile, any other organic solvent which does not adversely affect the reaction or mixtures thereof.

The reaction temperature is not critical and the reaction can usually be carried out under cooling to warming.

In the second step, the reaction is preferably carried out in the presence of alkali metal halides (eg sodium chloride, etc.) and inorganic acids (eg hydrochloric acid, etc.).

The reaction can be carried out in water, a solvent such as tetrahydrofuran, dioxane, any other organic solvent which does not adversely affect the reaction or mixtures thereof.

The reaction temperature is not critical and the reaction can usually be carried out under warming to heating.

Reference Scheme

Compounds VIII or salts thereof, which are included in Compound I and are useful as starting compounds in the process for the preparation of these compounds, can be prepared from compounds VI or salts thereof and compound VII or salts thereof by the following methods.

First, compound VII was converted to the corresponding hydrazine derivative by reaction with metal nitrite (eg, sodium nitrite, etc.) and reducing agent (eg, tin chloride, etc.) under acidic conditions. The hydrazine derivative was then reacted with compound VI to produce compound VIII.

The reaction adversely affects water, alcohols such as methanol, ethanol, isopropyl alcohol, etc., conventional solvents such as tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide, or the reaction. It may be carried out in any other organic solvent or mixture thereof which does not affect.

The reaction temperature is not critical and the reaction can be carried out under cooling to warming.

The compound produced by the above method can be separated and purified by conventional methods such as milling, recrystallization, column chromatography, reprecipitation, and the like.

Suitable salts of compounds Ia to Ig, II, V, VI, VII and VIII may be the same as those exemplified for compound I.

Suitable salts of compounds III and IV are alkali metal salts (eg sodium salts, potassium salts and the like), alkaline earth metal salts (eg calcium salts, magnesium salts and the like) and the like.

The target compound I or a pharmaceutically acceptable salt thereof has an inhibitory activity of COX-II and has a strong anti-inflammatory activity, analgesic activity, antithrombogenicity, anticancer activity and the like. Compound of interest I and its pharmaceutically acceptable salts are useful for treating and / or preventing inflammatory diseases, various pains, collagen diseases, autoimmune diseases, various immune diseases, thrombosis, cancer and neurodegenerative diseases of humans or animals, specifically Inflammation and pain in joints and muscles [eg, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, combustible arthritis, etc.], inflammatory skin diseases [eg, sunburn, burns, eczema, dermatitis, etc.], inflammatory eye diseases [eg, Conjunctivitis, etc.], pulmonary diseases associated with inflammation [eg, asthma, bronchitis, pigeon breeder disease, farmer's lung disease, etc.], gastrointestinal disorders associated with inflammation [eg, aphthous ulcers, Crohn's disease, atopic gastritis, gastritis variolofoam, Ulcerative colitis, celiac disease, local ileitis, irritable bowel syndrome, etc.], gingivitis, inflammation, pain and hypertrophy after surgery or injury, other symptoms related to fever, pain and inflammation, Particularly diseases of which lipooxygenase and cyclooxygenase products are factors, systemic lupus erythematosus, scleroderma, polymyositis, tendonitis, bursitis, nodular periarteritis, rheumatoid fever, Sjogren's syndrome, Besett's disease, thyroiditis, types I Useful to treat and / or prevent diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease and the like. Alternatively, the desired compound I or a salt thereof is expected to be useful as a therapeutic and / or prophylactic agent for diseases caused by cardiovascular or cerebral vascular disease, hyperglycemia and hyperlipidemia.

To illustrate the use of the desired compound I, the pharmacological data of compound I is shown below.

[A] anti-inflammatory activity:

Effect on Adjuvant Arthritis in Rats

(i) test method

Ten Sprague Dawley rats were used for each group. 0.5 mg of Mycobacterium tuberculosis (strain M37BA) suspended in 0.05 ml of liquid paraffin was injected subcutaneously in the right hind paw. Mycobacterium tuberculosis adjuvant produced local inflammatory lesions (primary lesions), and secondary lesions developed in both injected and non-injected paws after about 10 days. The volume of both feet after and 23 days after injection was measured as% inhibition compared to the control treated with excipients. One day after the injection, the drug was administered orally once a day for 23 consecutive days.

(ii) test results

Test Compound (Example Number) Dose (mg / kg) Inhibition rate of secondary lesions (uninjected feet) (%) 12 3.2 ≥95 13-2) 3.2 ≥95 Ibuprofen 100 79.6

[B] analgesic activity:

Inflammatory hyperalgesia induced by brewer's yeast in rats:

(i) Test method:

Ten Sprague Dawley male mice were used for each group. 0.1 ml of 5% brewer's yeast suspended in 0.5% methylcellulose was injected into the right hind paw. The pain threshold was measured by applying pressure to the feet 3 hours after the yeast injection and recording the pressure when the rat crouched.

The drug was administered orally 2 hours after the yeast injection. Pain thresholds in treated animals were compared to control animals.

(ii) test results

Test Compound (Example Number) Dose (mg / kg) Relative Efficacy (Control = 1.0) One 10 ≥1.4

[C] ex vivo COX-I and COXX-II activity:

(i) Test method:

a. Preparation of Recombinant Cyclooxygenase (COX)

Human cyclooxygenases COX-I and COX-II were transfected into infected Chinese hamster ovary (CHO) cells. Monolayer cultures of semi-confluent CHO cells stably expressing COX-I and COX-II were washed twice with phosphate buffered saline (PBS) and discarded. Cells were centrifuged at 200 × g for 5 minutes and cell pellets were sonicated in reaction buffer containing 100 mM Tris-HCl (pH 7.4), 2 μM hematin and 5 mM tryptophan. The segmented cells were centrifuged at 1700 × g for 5 minutes and the supernatant was used as crude enzyme.

Cyclooxygenase activity in the presence or absence of the inhibitor was measured by measuring the concentration of prostaglandin E ₂ (PGE ₂ ) in arachidonic acid. Enzymes (1 μg of COX-I and / or 3 μg of COX-II) dissolved in 200 μl of the total amount of reaction buffer were incubated at 30 ° C. for 5 minutes in the presence or absence of inhibitors of various concentrations. The reaction was then initiated by adding arachidonic acid to a final concentration of 10 μΜ. The reaction was completed by adding 50 μl of HCl (1N), and then incubated at 30 ° C. for 5 minutes. PGE ₂ was extracted with ethyl acetate, concentrated under nitrogen stream and analyzed according to the procedure of radioimmunoassay kit (Amersham).

b. Evaluation of Human Recombinant COX-I and COX-II Activity

COX activity was assessed by PGE ₂ formation using radioimmunoassay to detect prostaglandin release. Appropriate COX enzymes were incubated in 0.1M Tris-HCl buffer (pH 7.3) containing hematin and tryptophan with addition of arachidonic acid (10 μM) at 37 ° C. for 5 minutes. The compound was preincubated with the enzyme for 5 minutes before the addition of arachidonic acid. Any reaction between arachidonic acid and enzyme was stopped after 5 minutes by adding 20 μl of 1N HCl at 37 ° C. PGE ₂ formation was measured by radioimmunoassay (Amersham).

(ii) test results:

Test Compound (Example Number) Human body COX-IIIC ₅₀ (μM) Human body COX-IIC ₅₀ (μM) 13-2) <0.1 ≥60

[D] Toxicity of Compound I:

Toxicity tests were performed by repeated oral administration of the compound described in Example 13-2) to SD rats and 32 mg / kg once daily for 14 consecutive days, but no dead rats were found.

For therapeutic purposes, compounds I and pharmaceutically acceptable salts thereof of the present invention may be used as active ingredients to form at least one of the above compounds and a pharmaceutically acceptable carrier or oral, parenteral or external (topical) such as organic solids or inorganic solids. Pharmaceutical formulations comprising mixtures with liquid excipients suitable for administration. The pharmaceutical preparations may be capsules, tablets, sugars, granules, inhalants, suppositories, solvents, lotions, suspensions, emulsions, ointments, gels and the like. If desired, these formulations may include adjuvants, stabilizers, hydrating or emulsifying agents, buffers and other widely used additives.

The therapeutically effective dose of Compound I will vary depending on the age and symptoms of the patient, but the average single dose of Compound I effective for treating the aforementioned diseases is 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg. Typically, the daily dose is 0.1 mg / body to 1,000 mg / body.

The present invention will be described according to the production methods and examples which are only examples.

Preparation method 1

(1) Sodium methoxide (2.6 g) and ethyl 1- (4-acetylphenyl) -5- [4- (methylthio) phenyl] pyrazole-3 dissolved in N, N-dimethylformamide (60 ml) A mixture of carboxylate (6.4 g) was stirred at 100 ° C. for 1.5 h. The resulting mixture was poured into water (200 ml). The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 1- (4-acetylphenyl) -5- [4- (methylthio) phenyl] pyrazole-3-carboxamide (5.0 g) Obtained.

Melting Point: 112 ~ 115 ℃

IR (new sol): 3400, 1680, 1600, 1200 cm ^-1

(2) A phosphorous acid oxychloride solution (2.78 ml) dissolved in N, N-dimethylformamide (60 ml) was stirred at 0 ° C for 30 minutes. To this solution was added 1- (4-acetylphenyl) -5- [4- (methylthio) phenyl] pyrazole-3-carboxamide (5.0 g) in one portion. After 30 minutes more stirring, the resulting mixture was poured into ice water (100 ml). The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 1- (4-acetylphenyl) -5- [4- (methylthio) phenyl] pyrazole-3-carbonitrile (3.76 g). Obtained.

Melting Point: 124 ~ 125 ℃

IR (new sol): 2250, 1690, 1680, 1510 cm ^-1

Preparation method 2

A mixture of 4-aminoacetophenone (10 g) and sodium nitrite (5.1 g) dissolved in acetic acid (55 ml) was stirred at 10 ° C. for 1 hour. Concentrated hydrochloric acid (25 ml) and tin chloride dihydrate (41 g) were added to the resulting mixture, which was stirred for 30 minutes at 0 ° C. 1- [4- (methylthio) phenyl] butane-1,3-dione (15.4 g) was added to the reaction mixture and stirred at ambient temperature for 1 hour. The mixture was stirred at 100 ° C. for 3 hours and poured into ice water. The obtained precipitate was filtered, washed with water and dried under reduced pressure to give 1- (4-acetylphenyl) -3-methyl-5- [4- (methylthio) phenyl] pyrazole (24.6 g).

IR (new sol): 1680, 1600 cm ^-1

NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 2.47 (3H, s), 2.57 (3H, s), 6.48 (1H, s), 7.16 (2H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.6 Hz), 7.96 (2H, d, J = 8.6 Hz)

MASS (m / z): 323 (M + 1)

Preparation method 3

(1) 1- (4-acetylphenyl) -5- [4- (methylsulfonyl) phenyl] -3- (tri dissolved in a mixture of 1,4-dioxane (40 ml) and methanol (120 ml) To a mixture of fluoromethyl) pyrazole (7.85 g) and perchloric acid (70%, 23.6 ml) was added thallium (III) nitrate trihydrate (14.32 g) and stirred overnight at ambient temperature. The resulting mixture was added to water (140 ml), extracted with toluene, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and toluene (1: 5) to give the crystal of methyl 4- [5- [4- (methylsulfonyl) phenyl] -3- (trifluoro). Methyl) pyrazol-1-yl] phenyl acetate (4.66 g) was obtained.

mp: 136-138 ℃

IR (new sol): 1735, 1605, 1310, 1230 cm ^-1

NMR (CDCl ₃ , δ): 3.08 (1H, s), 3.67 (2H, s), 3.71 (3H, s), 6.84 (1H, s), 7.10-8.00 (8H, m)

MASS (m / z): 439 (M + 1)

(2) Methyl 4- [5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole-1 dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (10 ml) -Yl] phenylacetate (1.00 g) and 1N sodium hydroxide (5 ml) were stirred at ambient temperature for 1 hour. The resulting mixture was acidified with hydrochloric acid. The precipitate was filtered off and washed with water. The filtrate was recrystallized with ethanol to give crystalline 4- [5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazol-1-yl] phenylacetic acid (0.75 g). .

mp: 184-186 ° C

IR (new sol): 1710, 1605, 1305, 1235 cm ^-1

NMR (CDCl ₃ , δ): 3.09 (1H, s), 3.71 (3H, s), 6.85 (1H, s), 7.27 (2H, d, J = 8.7 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5 Hz)

MASS (m / z): 425 (M + 1)

Elemental Analysis of C ₁₉ H ₁₅ F ₃ N ₂ O ₄ S

Theoretic: C 53.77, H 3.56, N 6.60

Found: C 53.44, H 3.38, N 6.36

Recipe 4

(1) 4-chlorophenylhydrazine hydrochloride (4.0 g) was added to a solution of sodium (0.5 g) in ethanol (50 ml) and the mixture was refluxed for 1 hour. 3- [4- (methylthio) phenyl] acrylonitrile (3.0 g) was added to the cooled mixture and the resulting mixture was refluxed overnight. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and toluene (1: 9) to give 1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] -2-pyrazoline 3-amine (3.4 g) was obtained.

NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 2.50 (1H, dd, J = 16.4, 5.7 Hz), 3.44 (1H, dd, J = 16.4, 10.8 Hz), 4.98 (1H, dd , J = 10.8, 5.7 Hz), 5.84 (2H, br s), 6.62 (2H, d, J = 9.0 Hz), 7.02 (2H, d, J = 9.0 Hz), 7.02 (4H, s)

MASS (m / z): 318 (M + 1)

(2) 1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] -2-pyrazolin-3-amine (3.4 g) dissolved in dichloromethane (500 ml) and manganese oxide (2.7) The mixture of g) was stirred at ambient temperature for 2 hours. Insoluble matter was filtered off and the filtrate was dried to concentrate. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4: 1) to give 1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] -2-pyrazole 3-amine (0.82 g) was obtained.

NMR (DMSO-d ₆ , δ): 2.47 (3H, s), 5.02 (2H, br s), 5.83 (1H, s), 7.14 (4H, d, J = 9 Hz), 7.24 (2H, d, J = 9 Hz), 7.38 (2H, d, J = 9 Hz)

MASS (m / z): 316 (M + 1)

Recipe 5

(1) 5- [4- (methylthio) phenyl] -1-phenyl-2-pyra from 3- [4- (methylthio) phenyl] -acrylonitrile using a method similar to the preparation 4- (1) Sleepin-3-amine was prepared.

NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 2.48 (1H, dd, J = 16, 6 Hz), 3.41 (1H, dd, J = 16, 10 Hz), 4.93 (1H, dd, J = 10, 6 Hz), 5.73 (2H, br s), 6.49 (1H, t, J = 7 Hz), 6.65 (2H, d, J = 8 Hz), 7.00 (2H, dd, J = 7, 8 Hz), 7.22 (4H, s)

MASS (m / z): 284 (M + 1)

(2) 5- [4- (methylthio) phenyl from 5- [4- (methylthio) phenyl] -1-phenyl-2-pyrazolin-3-amine using a method similar to the preparation 4- (2) ] -1-phenylpyrazol-3-amine was prepared.

NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 4.95 (2H, br s), 5.82 (1H, s), 7.09-7.36 (9H, complex m)

MASS (m / z): 282 (M + 1)

Preparation method 6

A solution of 5- [4- (methylthio) phenyl] -1- (4-nitrophenyl) pyrazole-3-carboxylic acid (4.8 g) dissolved in thionyl chloride (50 ml) was refluxed for 3 hours and Concentrated under reduced pressure. The residue solution in tetrahydrofuran (50 ml) was added dropwise to a solution of sodium azide (1.1 g) dissolved in a mixture of acetone (40 ml) and water (20 ml) at 0 ° C. The mixture was stirred for 1 hour and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give an oil (5.1 g). A solution of oil (5.1 g) dissolved in N, N-dimethylformamide (50 ml) was stirred at 100 ° C. to 110 ° C. for 2 hours and concentrated under reduced pressure. The residue was triturated in a mixture of diisopropyl ether and ethyl ether to give a powder (4.2 g). The mixture of powder (4.2 g) and concentrated hydrochloric acid (70 ml) was refluxed for 3 hours and cooled to 0 ° C. The reaction mixture was adjusted to pH = 10 with aqueous sodium hydroxide solution and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate and dried under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of acetone and dichloromethane (1:10) to give a yellow powder of 5- [4- (methylthio) phenyl] -1- (4-nitrophenyl) pyrazole. 3-amine (2.1 g) was obtained.

mp: 195-196 ℃

IR (new sol): 3400, 3320, 1515, 1330 cm ^-1

NMR (CDCl ₃ , δ): 2.51 (3H, s), 5.94 (1H, s), 7.15 (2H, d, J = 8.7 Hz), 7.23 (2H, d, J = 8.7 Hz), 7.38 (2H, d, J = 9.2 Hz), 8.13 (2H, d, J = 9.2 Hz)

MASS (m / z): 327 (M + 1)

Preparation method 7

A solution of 1- (4-cyanophenyl) -5- [4- (methylthio) phenyl] pyrazole-3-carboxylic acid (2 g) dissolved in thionyl chloride (20 ml) was refluxed for 3 hours and Concentrated under reduced pressure. The residue solution in tetrahydrofuran (20 ml) was added dropwise to a mixture of sodium azide (0.7 g) and sodium bicarbonate (0.5 g) dissolved in a mixture of acetone (20 ml) and water (10 ml) at 0 ° C. . The mixture was stirred for 1 hour and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. A solution of the residue dissolved in N, N-dimethylformamide (20 ml) was stirred at 100 ° C. to 110 ° C. for 1 hour and poured into ice water. The resulting residue was collected, washed with water and dried under reduced pressure. The mixture of product and concentrated hydrochloric acid (40 ml) was refluxed for 4 hours and adjusted to pH = 10 with aqueous sodium hydroxide solution. The reaction mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of methanol and chloroform (1:10) to afford 4- [5- [4- (methylthio) phenyl] -3-aminopyrazol-1-yl] benzoic acid. (0.75 g) was obtained.

IR (new sol): 1605, 1510 cm ^-1

NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 4.95 (2H, br s), 5.83 (1H, s), 7.04 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.78 (2H, d, J = 8.3 Hz)

MASS (m / z): 326 (M + 1)

Preparation Method 8

(1) Sodium nitrite (2.95 g) was added to a solution of 4-aminoacetophenone (5.42 g) dissolved in acetic acid (42 ml) at room temperature. After stirring for 30 minutes, hydrochloric acid (16.8 ml) was added to the mixture at 5 ° C, and the resulting mixture was stirred for 20 minutes. Tin chloride dihydrate (23.28 g) was added in portions over 5 minutes at 5 ° C. and the resulting mixture was stirred at the same temperature for 20 minutes. 1- [4- (methylthio) phenyl] -4,4-difluoro-1,3-dioxobutane (7.0 g) was added at 25 ° C. and the mixture was stirred at 45 ° C. for 1 hour. Water (182 ml) was added to the mixture at 20 ° C. After stirring for 1 hour, the resulting precipitate was collected by filtration and washed with water. After drying at 40 ° C. under vacuum overnight, water (67 ml) was added dropwise to the crude product solution in acetone. After stirring for 1 h at 20 ° C., the resulting precipitate was collected by filtration, washed with a mixture of acetone and water (3: 2, 31 ml) and dried overnight at 40 ° C. under vacuum to give 1- (4-acetylphenyl ) -3-difluoromethyl-5- [4- (methylthio) phenyl] pyrazole (8.63 g) was obtained.

(2) 1- (4-acetylphenyl) -3-difluoromethyl-5- (4-methylthiophenyl) pyrazole (8.5 g), tetrabutylammonium hydrogen sulfate (1.61 g), oxone (registered trademark) (30.58 g; 2KHSO ₅ KHSO ₄ K ₂ SO ₄ ), a mixture of ethyl acetate (128 ml) and water (85 ml) was heated under reflux for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with brine and dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate at 40 ° C. and then the resulting solution was cooled to room temperature. The solution was stirred for 1 hour while cooling with an ice bath. The obtained precipitate was collected by filtration, washed with cold ethyl acetate (13 ml) and stirred overnight at 40 ° C. under vacuum to give crude crystals (6.67 g).

The resulting crude crystals (6.50 g) were dissolved in 90% aqueous ethanol solution (91 ml; 82 ml ethanol and 9 ml water) at 75 ° C. After stirring for 30 minutes, the filtrate was slowly cooled to 65 ° C. and seed crystals were added. The temperature of the mixture was cooled to 60 ° C. and maintained for 30 minutes in the temperature range of 55-60 ° C. After cooling to 25 ° C. over 1 hour, the temperature range was maintained at 25 to 30 ° C. for at least 1 hour. The obtained precipitate was collected by filtration, washed with ethanol and dried under vacuum at 40 ° C. for at least 1 hour to obtain 1- (4-acetylphenyl) -3-difluoromethyl-5- [4- (methylsulfonyl) Phenyl] pyrazole (5.85 g) was obtained.

mp: 145-152 ℃

IR (new sol): 1682, 1602, 1314, 1154 cm ^-1

NMR (CDCl ₃ , δ): 2.63 (3H, s), 3.09 (3H, s), 6.80 (1H, t, J = 54.7 Hz), 6.85 (1H, s), 7.38 (2H, d, J = 8.7 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.94 (2H, d, J = 8.5 Hz), 7.99 (2H, d, J = 8.7 Hz)

MASS (m / z): 391 (M + 1)

Example 1

To a stirred solution of 1- (4-acetylphenyl) -5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole (0.72 g) in methanol (7 ml) sodium borohydride ( 80 mg) was added in portions at 15 ° C. The resulting mixture was stirred at ambient temperature for 1 hour, treated with acetic acid (1 ml) and then concentrated under reduced pressure. To the residue was added a mixture of ethyl acetate and water and stirred. The organic layer was separated and washed with aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is crystallized with toluene and filtered to crystallize 1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole (0.54 g) was obtained.

mp: 138-140 ℃

IR (new sol): 3500, 1605, 1500, 1300 cm ^-1

NMR (DMSO-d ₆ , δ): 1.33 (3H, d, J = 6 Hz), 3.26 (3H, s), 4.77 (1H, m), 5.32 (1H, br d, J = 4 Hz), 7.33 (2H , d, J = 8Hz), 7.35 (1H, s), 7.45 (2H, d, J = 8Hz), 7.57 (2H, d, J = 8Hz), 7.93 (2H, d, J = 8Hz)

MASS (m / z): 411 (M ⁺¹ ), 393 (M ⁺¹ -18)

Example 2

The following compounds (1) to (4) were prepared according to the method similar to Example 1.

(1) 1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole

mp: 98-99 ℃

IR (new sol): 3450, 1605, 1500, 1270, 1230 cm ^-1

NMR (CDCl ₃ , δ): 1.49 (3H, d, J = 6 Hz), 1.72 (1H, br s), 2.48 (3H, s), 4.93 (1H, q, J = 6 Hz), 6.72 (1H, s ), 7.12 (2H, d, J = 9 Hz), 7.18 (2H, d, J = 9 Hz), 7.29 (2H, d, J = 9 Hz), 7.38 (2H, d, J = 9 Hz)

MASS (m / z): 379 (M ⁺¹ )

(2) 3-difluoromethyl-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] pyrazole

mp: 144-146 ° C

IR (new sol): 3400, 1600, 1310, 1150 cm ^-1

NMR (CDCl ₃ , δ): 1.50 (3H, d, J = 6 Hz), 2.05 (1H, br s), 3.08 (3H, s), 4.95 (1H, q, J = 6 Hz), 6.78 (1H, t , J = 5.5Hz), 6.83 (1H, s), 7.25 (2H, d, J = 8Hz), 7.41 (2H, d, J = 8Hz), 7.44 (2H, d, J = 9Hz), 7.89 (2H , d, J = 9 Hz)

MASS (m / z): 393 (M ⁺¹ ), 375 (M ⁺¹ -18)

(3) 1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] -pyrazole-3-carbonitrile

Pale yellow oil

IR (Film): 3450, 2250, 1605, 1510, 1480 cm ^-1

(4) 1- [4- (1-hydroxyethyl) phenyl] -3-methyl-5- [4- (methylthio) phenyl] pyrazole

IR (new sol): 3250, 1600 cm ^-1

NMR (DMSO-d ₆ , δ): 1.32 (3H, d, J = 6 Hz), 2.25 (3H, s), 2.46 (3H, s), 4.73 (1H, m), 5.24 (1H, d, J = 4 Hz), 6.40 (1H, s), 7.12 (2H, d, J = 8 Hz), 7.17 (2H, d, J = 8 Hz), 7.21 (2H, d, J = 8 Hz), 7.35 (2H, d, J = 8 Hz).

MASS (m / z): 325 (M + 1)

Example 3

Methyl lithium solution in ether to a stirred solution of 4- [5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazol-1-yl] benzoic acid (18 g) in ether (100 ml) (1.2N solution; 130 ml) was added slowly at ambient temperature. The resulting mixture was refluxed for 1.5 hours and then cooled. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted several times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. This oil was crystallized with isopropyl ether to give 1- (4-acetylphenyl) -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole (8.5 g).

mp: 138-140 ℃

IR (new sol): 1690, 1600, 1270, 1240 cm ^-1

NMR (CDCl ₃ , δ): 2.49 (3H, s), 2.62 (3H, s), 6.75 (1H, s), 7.12 (2H, d, J = 9 Hz), 7.20 (2H, d, J = 9 Hz) , 7.43 (2H, d, J = 9 Hz), 7.96 (2H, d, J = 9 Hz)

The following compounds were obtained as by-products.

1- [4- (1-hydroxy-1-methylethyl) phenyl] -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole

Yellow oil

IR (new sol): 3400, 1600, 1500, 1470, 1440, 1230 cm ^-1

NMR (CDCl ₃ , δ): 1.57 (3H, s), 1.58 (3H, s), 2.48 (3H, s), 6.72 (1H, s), 7.13 (2H, d, J = 9 Hz), 7.18 (2H , d, J = 9 Hz), 7.24 (2H, d, J = 9 Hz), 7.49 (2H, d, J = 9 Hz)

MASS (m / z): 393 (M ⁺¹ )

Example 4

1- [4- (1-hydroxy-1-methylethyl) phenyl] -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole (1.1 in dichloromethane (30 ml) A mixture of g) and m-chloroperbenzoic acid (0.55 g) was stirred at 5 ° C for 30 minutes. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was treated by column chromatography on silica gel and eluted with dichloromethane. Fractions with the desired compound were combined and concentrated under reduced pressure to give an amorphous powder. The powder was washed with n-hexane to give 1- [4- (1-hydroxy-1-methylethyl) phenyl] -5- [4- (methylsulfinyl) phenyl] -3- (trifluoromethyl) pyra Obtained sol (0.54 g).

IR (knit): 3400, 1600, 1500, 1470, 1440 cm ^-1

NMR (CDCl ₃ , δ): 1.59 (6H, s), 2.76 (3H, s), 6.81 (1H, s), 7.26 (2H, d, J = 9 Hz), 7.40 (2H, d, J = 8 Hz) , 7.51 (2H, d, J = 9 Hz), 7.62 (2H, d, J = 8 Hz)

MASS (m / z): 409 (M ⁺¹ ), 391 (M ⁺¹ -18)

Example 5

1- [4- (1-hydroxy-1-methylethyl) phenyl] -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole (1.5 in dichloromethane (35 ml) A mixture of g) and m-chloroperbenzoic acid (1.45 g) was stirred at ambient temperature for 1 hour. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was treated by column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. Fractions with the desired compound were combined and concentrated under reduced pressure to give a white powder. The powder was crystallized from a mixture of ethanol and water to give 1- [4- (1-hydroxy-1-methylethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) Pyrazole (0.52 g) was obtained.

mp: 147-148 ℃

IR (new sol): 3550, 1610, 1500, 1410 cm ^-1

NMR (CDCl ₃ , δ): 1.60 (6H, s), 3.09 (3H, s), 6.85 (1H, s), 7.26 (2H, d, J = 9 Hz), 7.45 (2H, d, J = 8 Hz) , 7.53 (2H, d, J = 9 Hz), 7.91 (2H, d, J = 8 Hz)

MASS (m / z): 425 (M + 1)

Example 6

1N methylmagnesium bromide in tetrahydrofuran to a solution of 1- (4-acetylphenyl) -3-methyl-5- [4- (methylthio) phenyl] pyrazole (2.0 g) in tetrahydrofuran (50 ml) A solution (31 ml) was added and stirred at 0 ° C for 5 hours. To the mixture obtained water was added, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (5: 1) to give 1- [4- (1-hydroxy-1-methylethyl) phenyl] -3-methyl-5- [4- (methylthio) phenyl] pyrazole (0.64 g) was obtained.

NMR (DMSO-d ₆ , δ): 1.42 (6H, s), 2.25 (3H, s), 2.46 (3H, s), 5.09 (1H, s), 6.40 (1H, s), 7.13 (2H, d , J = 8.7Hz), 7.15 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.7Hz), 7.46 (2H, d, J = 8.6Hz)

MASS (m / z): 339 (M + 1)

Example 7

The following compounds (1) to (4) were prepared according to the method similar to Example 4.

(1) 1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfinyl) phenyl] -3- (trifluoromethyl) pyrazole

Amorphous powder

IR (knit): 1610, 1500, 1470, 1400 cm ^-1

NMR (CDCl ₃ , δ): 1.50 (3H, d, J = 6 Hz), 2.75 (3H, s), 4.95 (1H, q, J = 6 Hz), 6.82 (1H, s), 7.28 (2H, d, J = 8Hz), 7.40 (2H, d, J = 9Hz), 7.40 (2H, d, J = 8Hz), 7.62 (2H, d, J = 9Hz)

MASS (m / z): 377 (M ⁺¹ -18)

(2) 1- [4- (1-hydroxyethyl) phenyl] -3-methyl-5- [4- (methylsulfinyl) phenyl] pyrazole

IR (CHCl ₃ ): 3350, 1610 cm ^-1

NMR (DMSO-d ₆ , δ): 1.32 (3H, d, J = 6.4 Hz), 2.28 (3H, s), 2.76 (3H, s), 4.74 (1H, qd, J = 6.4, 4.4 Hz), 5.24 (1H, d, J = 4.4 Hz), 6.53 (1H, s), 7.18 (2H, d, J = 8.4 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4 Hz)

MASS (m / z): 341 (M + 1)

(3) 1- [4- (1-hydroxy-1-methylethyl) phenyl] -3-methyl-5- [4- (methylsulfinyl) phenyl] pyrazole

mp: 121-122 ℃

NMR (DMSO-d ₆ , δ): 1.42 (6H, s), 2.28 (3H, s), 2.76 (3H, s), 5.10 (1H, s), 6.53 (1H, s), 7.16 (2H, d , J = 8.5 Hz), 7.40 (2H, d, J = 8.3 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.3 Hz)

MASS (m / z): 355 (M + 1)

(4) 1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfinyl) phenyl] pyrazole-3-carbonitrile

Amorphous powder

IR (knit): 3400, 2280, 1600, 1510 cm ^-1

NMR (CDCl ₃ , δ): 1.51 (3H, d, J = 7 Hz), 2.15 (1H, d, J = 4 Hz), 2.75 (3H, s), 4.95 (1H, dd, J = 7, 4 Hz), 6.93 (1H, s), 7.25 (2H, d, J = 4 Hz), 7.37 (2H, d, J = 9 Hz), 7.42 (2H, d, J = 9 Hz), 7.63 (2H, d, J = 9 Hz)

MASS (m / z): 352 (M ⁺¹ ), 334 (M ⁺¹ -18)

Example 8

1- [4- (1-hydride) from 1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] pyrazole-3-carbonitrile in a similar manner to Example 5 Oxyethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] pyrazole-3-carbonitrile was prepared.

mp: 112-113 ℃

IR (new sol): 3350, 2250, 1510, 1310 cm ^-1

NMR (CDCl ₃ , δ): 1.52 (3H, d, J = 6 Hz), 1.97 (1H, br s), 3.08 (3H, s), 4.97 (1H, q, J = 6 Hz), 6.97 (1H, s ), 7.25 (2H, d, J = 9 Hz), 7.42 (2H, d, J = 8 Hz), 7.44 (2H, d, J = 9 Hz), 7.92 (2H, d, J = 8 Hz)

MASS (m / z): 368 (M ⁺¹ ), 350 (M ⁺¹ -18)

Example 9

Tetrahydrofuran to a mixture of 4- [5- (4-methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazol-1-yl] phenylacetic acid (1.00 g) in tetrahydrofuran (10 ml). 1M borane solution in (5 ml) was added and stirred at ambient temperature overnight. Several drops of acetic acid were added to the resulting mixture. The mixture was concentrated under reduced pressure and water was added to the output. The mixture was extracted with ethyl acetate, washed with brine, dried, concentrated under reduced pressure and recrystallized from a mixture of ethanol and water to give white crystals of 1- [4- (2-hydroxyethyl) phenyl] -5- [ 4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole (0.70 g) was obtained.

mp: 132-134 ℃

IR (new sol): 3505, 1605, 1300, 1280, 1235 cm ^-1

NMR (CDCl ₃ , δ): 1.46 (1H, br s), 2.92 (2H, t, J = 6.5 Hz), 3.89 (2H, br t, J = 6.5 Hz), 6.85 (1H, s), 7.23 ( 2H, d, J = 8.7 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz)

MASS (m / z): 411 (M + 1)

Example 10

A solution of sodium nitrite (0.22 g) in water (5 ml) was ice-cold 1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] pyrazol-3-amine (0.82 g) and concentrated hydrochloric acid. (3 ml) was added to the mixture. The mixture was stirred at 0 ° C. for 30 minutes and added to the mixture of cuprous chloride (0.51 g) and concentrated hydrochloric acid (5 ml) at ambient temperature. The mixture was refluxed for 1 hour and extracted with dichloromethane. The extract was washed with water, dried and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel eluting with toluene to give 3-chloro-1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] pyrazole (0.38 g) as crystals. It was.

NMR (DMSO-d ₆ , δ): 2.47 (3H, s), 6.80 (1H, s), 7.17 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.7 Hz), 7.32 ( 2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz)

MASS (m / z): 335 (M + 1)

Example 11

The following compounds (1) to (3) were prepared according to the method similar to Example 10.

(1) 3-chloro-5- [4- (methylthio) phenyl] -1-phenylpyrazole

NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 6.78 (1H, s), 7.15 (2H, d, J = 8.7 Hz), 7.23 (2H, d, J = 8.7 Hz), 7.24- 7.31 (2H, m), 7.41-7.46 (3H, m)

MASS (m / z): 301 (M + 1)

(2) 3-chloro-1- (4-fluorophenyl) -3- [4- (methylthio) phenyl] -pyrazole

NMR (CDCl ₃ , δ): 2.48 (3H, s), 6.40 (1H, s), 7.03 (2H, t, J = 9.1 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.7 Hz), 7.26 (2H, dd, J = 9.1, 4.8 Hz)

MASS (m / z): 319 (M + 1)

(3) 3-chloro-5- [4- (methylthio) phenyl] -1- (4-nitrophenyl) -pyrazole

mp: 195-197 ℃

IR (new sol): 1525, 1375, 1345 cm ^-1

NMR (CDCl ₃ , δ): 2.50 (3H, s), 6.46 (1H, s), 7.13 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 9.0 Hz), 8.20 (2H, d, J = 9.0 Hz)

MASS (m / z): 346 (M + 1) ⁺

Example 12

A solution of m-chloroperbenzoic acid (0.49 g) in dichloromethane (10 ml) was added to a solution of 3-chloro-1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] pyrazole (0.38 g). It was added dropwise and stirred at ambient temperature for 1 hour. The mixture was washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (50: 1) to give 3-chloro-1- (4-chlorophenyl) -5- [4- (methylsulfonyl) as crystals. Phenyl] pyrazole was obtained.

mp: 177-178 ℃

IR (New sol): 1310, 1140 cm ^-1

NMR (DMSO-d ₆ , δ): 3.25 (3H, s), 6.99 (1H, s), 7.35 (2H, d, J = 8.8 Hz), 7.53 (4H, d, J = 8.7 Hz), 7.94 ( 2H, d, J = 8.5 Hz)

MASS (m / z): 367 (M + 1)

Elemental Analysis of C ₁₆ H ₁₂ Cl ₂ N ₂ O ₂ S

Theoretic: C 52.33, H 3.29, N 7.63

Found: C 52.73, H 3.44, N 7.70

Example 13

The following compounds (1) to (3) were prepared according to the method similar to Example 12.

(1) 3-chloro-5- [4- (methylsulfonyl) phenyl] -1-phenylpyrazole

mp: 187-188 ℃

IR (new sol): 1600, 1310, 1150 cm ^-1

NMR (DMSO-d ₆ , δ): 3.23 (3H, s), 6.97 (1H, s), 7.29-7.35 (2H, m), 7.40-7.47 (3H, m), 7.50 (2H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.5 Hz)

MASS (m / z): 333 (M + 1)

Elemental Analysis of C ₁₆ H ₁₃ ClN ₂ O ₂ S

Theoretic: C 57.74, H 3.94, N 8.42

Found: C 57.81, H 3.90, N 8.05

(2) 3-chloro-1- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] pyrazole

mp: 173 ℃

IR (new sol): 1600, 1310, 1150 cm ^-1

NMR (DMSO-d ₆ , δ): 3.24 (3H, s), 6.97 (1H, s), 7.30 (2H, t, J = 9.2 Hz), 7.40 (2H, dd, J = 9.2, 5.1 Hz), 7.51 (2H, d, J = 8.6H), 7.92 (2H, d, J = 8.6 Hz)

MASS (m / z): 351 (M + 1)

Elemental Analysis of C ₁₆ H ₁₂ ClFN ₂ O ₂ S

Theoretic: C 54.78, H 3.45, N 7.99

Found: C 54.63, H 3.35, N 7.88

(3) 3-chloro-5- [4- (methylsulfonyl) phenyl] -1- (4-nitrophenyl) pyrazole

mp: 189-191 ℃

IR (new sol): 1525, 1345, 1315, 1155 cm ^-1

NMR (CDCl ₃ , δ): 3.11 (3H, s), 6.59 (1H, s), 7.45 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8.4 Hz), 8.24 (2H, d, J = 9.0 Hz)

MASS (m / z): 378 (M + 1)

Elemental Analysis of C ₁₆ H ₁₂ ClN ₃ O ₄ S

Theoretic: C 50.93, H 3.18, N 11.14

Found: C 50.63, H 3.30, N 11.18

Example 14

A solution of m-chloroperbenzoic acid (0.68 g) in dichloromethane (5 ml) was diluted with ice of 3-chloro-1- (4-chlorophenyl) -5- [4- (methylthio) phenyl] pyrazole (1.0 g). It was added dropwise to the salt cooling solution and stirred for 40 minutes at 0 ° C. The mixture was washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of acetone and dichloromethane (1:10) to give 3-chloro-1- (4-fluorophenyl) -5- [4- (methylsulphi) as an amorphous powder. Nil) phenyl] pyrazole (0.25 g) was obtained.

IR (New sol): 1510, 1050 cm ^-1

NMR (CDCl ₃ , δ): 2.75 (3H, s), 6.50 (1H, s), 7.05 (2H, t, J = 9.0 Hz), 7.25 (2H, dd, J = 9.0, 4.8 Hz), 7.36 ( 2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.6 Hz)

MASS (m / z): 335 (M + 1)

Example 15

A solution of sodium nitrite (0.5 g) in water (5 ml) was 4- [3-amino-5- [4- (methylthio) phenyl] pyrazol-1-yl in 20% hydrochloric acid solution (30 ml) at 0 ° C. ] Added dropwise to the mixture of benzoic acid (1.5 g). The reaction mixture was stirred for 30 min at 0 ° C. and added in portions to a mixture of cuprous chloride (1.0 g) and concentrated sulfuric acid (10 ml). The mixture was refluxed for 2 hours and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The mixture of the residue in thionyl chloride (15 ml) was refluxed for 2 hours and then concentrated under reduced pressure. The residue solution in tetrahydrofuran was added dropwise to a stirred mixture of ammonium hydroxide (28%, 5 ml) and tetrahydrofuran (20 ml) at 0 ° C. and stirred at the same temperature for 1 hour. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. A phosphorous acid oxychloride (2.0 g) solution in N, N-dimethylformamide (10 ml) was stirred at 5 ° C. for 30 minutes. To this solution was added the residue solution in N, N-dimethylformamide and stirred at 5 ° C. for 2 hours. The reaction mixture was poured into ice water and the resulting precipitate was collected. The precipitate was washed with water and dried. To a precipitate solution in dichloromethane (50 ml) was added dropwise a solution of m-chloroperbenzoic acid (1.7 g) in dichloromethane (40 ml) at 5 ° C. and stirred at ambient temperature for 1 hour. The resulting mixture was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and n-hexane (1: 3) to give 3-chloro-1- (4-chlorophenyl) -5- [4- (methylsulfonyl) Phenyl] pyrazole (155 mg) was obtained.

mp: 160-165 ° C (decomposition)

IR (new sol): 2240, 1605, 1510, 1310, 1150 cm ^-1

NMR (CDCl ₃ , δ): 3.09 (3H, s), 6.56 (1H, s), 7.39 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz)

MASS (m / z): 358 (M + 1)

Example 16

Borane-dimethyl sulfide in a mixture of (S) -5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidin (1.99 g) in dichloromethane (30 ml) The complex (14.0 ml) was added under a nitrogen atmosphere at room temperature and the resulting mixture was stirred for 1 hour. A solution of 1- (4-acetylphenyl) -3-difluoromethyl-5- [4- (methylthio) phenyl] -pyrazole (20.69 g) in dichloromethane (120 ml) was added dropwise to the mixture at -20 ° C. It was. After standing at 5 ° C. overnight, methanol (38.5 ml) was added to the reaction mixture and the resulting solution was concentrated under reduced pressure. After evaporation, additional methanol (38.5 ml) was added three times. After evaporation, additional toluene (38.5 ml) was added three times. The resulting product was purified by column chromatography on silica gel eluting with 10% ethyl acetate in dichloromethane → dichloromethane and recrystallized from a mixture of ethanol and water (2: 1) to give (+)-3-difluoromethyl-1 -[4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] pyrazole (16.4 g) was obtained.

mp: 59.67 ℃

IR (New sol): 3700-3100, 1600, 1342, 1162 cm ^-1

NMR (CDCl ₃ , δ): 1.50 (3H, d, J = 6.5 Hz), 1.91 (1H, d, J = 3.7 Hz), 2.48 (3H, s), 4.93 (1H, dq, J = 6.5, 3.7 Hz), 6.70 (1H, s), 6.76 (1H, dd, J = 55.0 Hz), 7.15 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.5 Hz)

MASS (m / z): 361 (M + H) ⁺

[α] _D ^27.9 = 13.38 (c = 1.050, CH ₃ OH)

Example 17

(+)-3-difluoromethyl-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] pyrazole (14.4 g), sodium bicarbonate (14.4 g) To a mixture of, dichloromethane (100 ml) and water (160 ml) m-chloroperbenzoic acid (80%, 15.18 g) was added over 15 minutes with vigorous stirring at 0 ° C. The resulting mixture was stirred at the same temperature for 1.5 hours. After adding water, the organic layer was separated, washed with an aqueous solution of sodium bisulfite and sodium bicarbonate and brine, and dried over magnesium sulfate. The resulting solution was concentrated under reduced pressure and recrystallized from ethanol (100 ml) to give (+)-3-difluoromethyl-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methyl Sulfonyl) phenyl] pyrazole (13.43 g) was obtained.

mp: 149-150 ℃

IR (New sol): 3503, 1610, 1323, 1143 cm ^-1

NMR (DMSO-d ₆ , δ): 1.34 (3H, d, J = 6.4 Hz), 3.26 (3H, s), 4.77 (1H, qd, J = 6.4, 4.4 Hz), 5.30 (1H, d, J = 4.4 Hz), 7.11 (1H, s), 7.15 (1H, d, J = 54.3 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.54 ( 2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5 Hz)

MASS (m / z): 393 (M + H) ⁺

[α] _D ^28.7 = 11.78 (c = 1.570, CH ₃ OH)

Example 18

The following compounds (1) to (3) were prepared according to the method similar to Example 16.

(1) (-)-3-difluoromethyl-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] pyrazole

mp: 60-68 ℃

[a] _D ^27.6 = -12.95 (c = 1.004, CH ₃ OH)

(2) (+)-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole

NMR (CDCl ₃ , δ): 1.49 (3H, d, J = 6.5 Hz), 2.48 (3H, s), 4.93 (1H, q, J = 6.5 Hz), 6.72 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz)

[α] _D ²⁵ = 11.74 (c = 2.535, CH ₃ OH)

(3) (-)-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylthio) phenyl] -3- (trifluoromethyl) pyrazole

NMR (CDCl ₃ , δ): 1.49 (3H, d, J = 6.4 Hz), 2.48 (3H, s), 4.93 (1H, q, J = 6.4 Hz), 6.72 (2H, s), 7.12 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz)

[a] _D ²⁶ = -7.22 (c = 1.89, CH ₃ OH)

Example 19

The following compounds (1) to (3) were prepared according to the method similar to Example 17.

(1) (-)-3-difluoromethyl-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] pyrazole

mp: 150-151 ℃

IR (new sol): 3510, 1610, 1325, 1148 cm ^-1

NMR (CDCl ₃ , δ): 1.51 (1H, d, J = 6.5 Hz), 1.97 (1H, d, J = 3.6 Hz), 3.08 (3H, s), 4.96 (1H, qd, J = 6.4, 3.6 Hz), 6.78 (1H, dd, J = 54.8 Hz), 6.83 (1H, s), 7.25 (1H, d, J = 7.4 Hz), 7.41 (1H, d, J = 7.4 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.5 Hz)

MASS (m / z): 393 (M + H) ⁺

[α] _D ^28.7 = -12.94 (c = 1.103, CH ₃ OH)

(2) (+)-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole

mp: 120-121 ℃

NMR (CDCl ₃ , δ): 1.50 (3H, d, J = 6.5 Hz), 1.95 (1H, d, J = 3.7 Hz), 3.08 (3H, s), 4.96 (1H, qd, J = 6.5, 3.7 Hz), 6.85 (1H, s), 7.27 (2H, d, J = 8.45 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz)

MASS (m / z): 411 (M + H) ⁺

[α] _D ²⁸ = 8.5 (c = 1.000, EtOH)

(3) (-)-1- [4- (1-hydroxyethyl) phenyl] -5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole

mp: 124-129 ℃

Claims (10)

A compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Formula I Wherein R ¹ is hydroxyethyl, 1-hydroxy-1-methylethyl, hydrogen, halogen, nitro or sinano, R ² is lower alkyl optionally substituted with chloro, cyano or halogen, R ³ is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, Provided that when R ¹ is hydrogen, halogen, nitro or cyano, R ² is chloro. The compound of claim 1, wherein R ¹ is hydroxyethyl or 1-hydroxy-1-methylethyl, R ² is lower alkyl optionally substituted with cyano or halogen, R ³ is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl. The compound of claim 1, wherein R ¹ is hydrogen, halogen, nitro or cyano, R ² is chloro, R ³ is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl. The compound of claim 3, wherein R ¹ is hydrogen or halogen. a) reducing the following compound II or a salt thereof to prepare the following compound Ia or a salt thereof; b) alkylating a reactive derivative or salt thereof at the following compound III or a carboxyl group thereof to produce the following compound Ib or a salt thereof, or c) the following compound II or a salt thereof is alkylated in an acetyl group to prepare the following compound Ic or a salt thereof, d) oxidizing the following compound Id or a salt thereof to prepare the following compound Ie or a salt thereof, or e) reducing the reactive derivative or salt thereof at the following compound IV or a carboxyl group thereof to produce the following compound If or a salt thereof, or f) chlorinating the following compound V or a salt thereof to produce the following compound Ig or a salt thereof, A process for preparing a compound represented by formula (I) or a salt thereof. Formula I Formula II Formula Ia Formula III Formula Ib Formula Ic Chemical Formula Id Formula Ie Formula IV Formula If Formula V Formula Ig In each formula, R ¹ is hydroxyethyl, 1-hydroxy-1-methylethyl, hydrogen, halogen, nitro or sinano, R ² is lower alkyl optionally substituted with chloro, cyano or halogen, R ³ is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, (Wherein R ² is chloro when R ¹ is hydrogen, halogen, nitro or cyano), R ¹ _a is acetyl, R ² _a is lower alkyl optionally substituted with cyano or halogen, R ¹ _b is 1-hydroxyethyl, R ¹ _c is carboxy, R ¹ _d is 1-hydroxy-1-methylethyl, R ³ _a is lower alkylthio, R ³ _b is lower alkylsulfinyl or lower alkylsulfonyl, R ¹ _e is carboxymethyl, R ¹ _f is 2-hydroxyethyl, R ¹ _g is hydrogen, halogen, nitro or cyano. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient with a pharmaceutical nontoxic carrier or excipient. A compound according to claim 1, useful as a medicament. COX-II inhibitor comprising the compound of claim 1. Treating and / or preventing the disease by administering an effective amount of a compound of claim 1 to a human or animal suffering from an inflammatory disease, various pains, collagen diseases, autoimmune diseases, various immune diseases, analgesics, thrombosis, cancer or neurodegenerative diseases How to. A compound for treating and / or preventing inflammatory diseases, various pains, collagen diseases, autoimmune diseases, various immune diseases, analgesics, thrombosis, cancer or neurodegenerative diseases of humans or animals using the compounds of claim 1 How to.