AU750356B2 - 1,5-diphenylpyrazole derivatives - Google Patents

Description

P:\OPER\Kblm\9(I138-98 spc.dc-09/M)5)2 -1-

DESCRIPTION

DERIVATIVES

Technical Field This invention relates to novel pyrazole compounds and the salts thereof having pharmacological activity; to a process for their production; and to a pharmaceutical composition containing the same.

Background of Art Some pyrazole derivatives having antiinflammatory and analgesic activities have been known as described, for example, in Canadian Patent 1 130 808, and EP Patent Publication Nos. 248 594, 272 704, 293 220, 418 845 and 554 829, and WO Patent Publication Nos. 95/15315, 95/15316, 95/15317, 95/15318, 96/14302 and 97/15271.

Disclosure of the Invention One advantage of at least one embodiment of this invention is that novel pyrazole compounds and salts thereof which have an inhibiting activity of cyclooxygenase-2 may be provided.

Another advantage of at least one embodiment of this invention is that a process for production of the novel pyrazole compounds may be provided.

A further advantage of at least one embodiment of this invention is that a pharmaceutical composition containing, as an active ingredient, the pyrazole compound or a salt thereof may be provided.

Advantageously at least one embodiment of this invention also may provide a use of the novel pyrazole compounds and salts thereof for manufacturing a medicament for treating or preventing various diseases.

The present invention relates to the novel pyrazole compounds and the salts thereof, which have pharmaceutical activity such as inhibiting activity of cyclooxygenase- 2 (hereinafter described as COX-II), to a process for their production, to a pharmaceutical composition containing the same, and to a use thereof.

According to a first aspect of the present invention, there is provided a compound of the formula C R2 CHaSO2 wherein R' is chlorine, difluoromethyl, trifluoromethyl or cyano, and R2 is a group having the following formula

X

x

Y

2 Y2 wherein X is halogen, cyano, nitro or amino, Y' is lower alkyl or lower alkoxy, Y2 is lower alkyl or lower alkoxy, and Z is halogen, and a pharmaceutically acceptable salt thereof.

The compound of formula can be prepared by one of the following processes 1 4.

Process 1 0 0 R' a CH3S02 (or -1) or its salt

R

2

-NH-

N H2 (III) I or its salt

RN

ZJ R' CH3SO2 (I-1) WO 99/15505 Process 2 PCT/JP98/04 150 Oxidation CH3 SO.

CH 3S

(IV)

Process 3

N

R 2 CH3 SO2

MV

or its salt 1) amidation 2) dehydration CH1 (1-2) Process 4 .2 Cl Chlorination

N

R 2 CH3 SO2 (1-3) CH3 SO;

(VI)

or its salt Reference Processes R 2 -NHi-NH2 a (III) or its salt CH3S (11-2) or its salt CH3 S

(IV-I)

P.%PER1Kb,A9X13-99 ,p.d-O1JA15IO 2

(III)NH

or its salt CH3SO2' or its salt MV or its salt CH3SO2 /\CH=CH-CN R2 -NH-NH2

(I'T)

or its salt

(VII)

CH3 SO:

(VI)

or its salt wherein R' and R 2 are each as defined above, R'a is difluoromethyl or trifluoromethyl, and

R

3 is carboxy or esterified carboxy.

According to a second aspect of the invention, there is provided a process for preparing a compound of the formula

-N~

'2

R

CH

3

SO

2 wherein R1 is chlorine, difluoromethyl, trifluoromethyl or cyano, R 2 is a group having the following formula P:\OPER\Kbl9W13X-98 sp.doc-O9.A 5A12 4Awherein X is halogen, cyano, nitro or amino, Y' is lower alkyl or lower alkoxy,

Y

2 is lower alkyl or lower alkoxy, Z is halogen, or or a pharmaceutically acceptable salt, which comprises, reacting a compound of the formula (II-1):

O

(II-1) wherein R'a is difluoromethyl or trifluoromethyl, or its salt, with a compound of the formula (III): R2-NH-NH 2

(III)

wherein R 2 is as defined above or its salt, to give a compound of the formula (I-1) wherein R'a and R 2 are as defined above, oxidizing a compound of the formula (IV): 4B N (IV) 2

R

CH3S wherein R' and R 2 are as defined above to give a compound of the formula

R'

N' (I) 1 2 CH3SO2 wherein R' and R 2 are as defined above subjecting a compound of the formula

R

3

I(V)

CH3S02 wherein

R

3 is carboxy or esterified carboxy and R 2 is as defined above, or its salt, to amidation and then dehydration, to give a compound of the formula

CN

N (I-2) A R CH3SO2 wherein R 2 is as defined above, or subjecting a compound of the formula (VI) P:10PER\Kb\9WX)38-L9 spc.do-)'9A)5102 4C NH2

N

N(VI)

R2 CH3S02 wherein R 2 is as defined above, or its salt, to chlorination to give a compound of the formula

CI

N

N (1-3) R2 CH3S02 wherein R 2 is as defined above.

According to a third aspect of the invention, there is provided a method for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases which comprises administering an effective amount of the compound of the invention to human beings or animals.

In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

Suitable "lower alkyl" and lower alkyl moiety in the terms "lower alkoxy" may be a straight or branched one such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert- 0 butyl, pentyl, hexyl, and the like, in which preferable one is methyl.

P.OPER\Kbm\9(X)3R-98 spc.doc- A15)2 -4D Suitable "lower alkoxy" may be methoxy, ethoxy, and the like, in which preferable one is methoxy.

Suitable "halogen" may be fluorine, chlorine, bromine and iodine.

Suitable "esterified carboxy" may be lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like, in which preferable one is ethoxycarbonyl.

In the compounds the preferred ones are recited.

Compounds having the formula (I) wherein R' is chlorine, difluoromethyl, trifluoromethyl or cyano, and

R

2 is a group having the formula Y' or Z X Y2 wherein X is halogen, cyano or nitro, Y' is lower alkyl or lower alkoxy,

Y

2 is lower alkyl or lower alkoxy, and Z is halogen.

Compounds having the formula (I) wherein R' is chlorine, and

R

2 is a group having the formula

Y'

X

wherein X is halogen or cyano, and is lower alkoxy.

Compounds having the formula (I) wherein R' is trifluoromethyl, and

R

2 is a group having the formula -%z y 2 wherein Y 2 is lower alkyl, and Z is hydrogen.

Compounds having the formula (I) wherein R' is chlorine or trifluoromethyl, and

R

2 is a group having the formula wherein Y' is ethyl, n-propyl or isopropyl.

The more preferred one is the compound selected from the group consisting of 3-chioro-1- (3-cyano-l4-methoxyphenyl [4-(methylsulfonyl) phenyl ]pyrazole, 3-chioro-1- (3-chloro-U-methoxyphenyl) (methylsulfonyl) phenyl ]pyrazole, 3-chloro- (3-chloro--4-methylPhenYl [4-(methylsulfonyl) phenyl] pyrrazole, 3-chloro- (3-fluoro U-methylphenyl (methylsulfonyl) phenyl Jpyrazole, 1- (3-fluoro-4-methoxyphenyl) 5- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole, 3- (difluoromethyl) -1 -(3-fluoro-4-methoxyphenyl.) (methylsulfonyl)phenyllpyrazole, 3-chloro- (4-chloro-3-methylphenyl) [U-(methylsulfonyl)phenyaj pyrazole, i-C 4-chloro-3-methoxyphenyl) (Methylsulfonyl) phenyllpyrazole- 3-carbonitrile, and (11) 3-chioro-1- (3-chloro-U--ethylphenyl) [U-(methylsult'onyl)pheny] pyrazole.

The compounds MI according to the present invention may contain one or more asymmetric centers, and thus they can exist as enantiomers or diastereoisomers, and the invention includes both mixtures and separate individual isomers.

Suitable salts of the compounds MI are conventional pharmaceutically acceptable salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt calcium salt, WO 99/15505 PCT/JP98/04150 magnesium salt etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.; an inorganic acid addition salt hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, ptoluenesulfonate, etc.); a salt with a basic or acidic amino acid arginine, aspartic acid, glutamic acid, etc.); and the like, and the preferable example thereof is an acid addition salt.

The compound according to the present invention can be in the form of a solvate, which was included within the scope of the present invention. The solvate preferably includes a hydrate, an ethanolate, and so on.

Also included in the scope of invention are radiolabelled derivatives of compounds which are suitable for biological studies.

Process 1 The compound can be prepared by reacting the compound (II-1) or its salt with a hydrazine derivative (III) or its salt.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof, preferably, acidic solvent such as alkanoic acid acetic acid).

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

Process 2 The compound can be prepared by reacting a compound (IV) with an oxidizing agent.

WO 99/15505 PCT/JP98/04150 The suitable oxidizing agent may be hydrogen peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, Jones reagent, peracid [e.g.

peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, monopersulfate compound (Oxone®), etc.], chromic acid, potassium permanganate, alkali metal periodate sodium periodate, etc.], and the like.

This reaction is usually carried out in a solvent which does not adversely influence the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, an alcohol methanol, ethanol, etc.], a mixture thereof or the like.

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

Process 3 The compound can be prepared from the compound or its salt by the following methods. Namely, the compound or its salt can be subjected to an amidation to give a corresponding carbamoyl derivatives, and then (ii) the corresponding carbamoyl derivatives can be subjected to a dehydration to give the compound (I- 2).

Amidation is carried out in a conventional manner, which is capable of converting carboxy group or protected carboxy group to carbamoyl group. Amidation can preferably carried out by, for example, reacting the compound wherein R 2 is esterified carboxy, with alkanoylamine acetamide, formamide, etc.) in the presence of organic base sodium alkoxide, etc.) or (ii) reacting the compound wherein R 2 is carboxy, or its salt, with ammonia or its salt in the presence of condensing agent.

Dehydration is carried out in the conventional manner, which is capable of dehydrating a carbamoyl group to cyano group, and suitable dehydrating agent may be phosphorus compound phosphorus oxychloride, etc.) or the like.

The reaction is usually carried out in a conventional solvent such as alcohol methanol, ethanol, isopropyl alcohol, etc.], WO 99/15505 PCT/JP98/04150 tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

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

Process 4 The compound can be prepared by the following methods.

Namely, 1) the compound (VI) or its salt is firstly reacted with a nitrite compound, and then 2) the resulting product is reacted with cuprous chloride.

Suitable nitrite compound may be alkali metal nitrite [e.g.

sodium nitrite, potassium nitrite, etc.], alkyl nitrite isoamyl nitrate, tert-butyl nitrite, etc.], and the like.

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

The reaction is usually carried out in a solvent such as water, tetrahydrofuran, dioxane, acetonitrile, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.

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

In the second step, the reaction is preferably carried out in the presence of alkali metal halide sodium chloride, etc.] and an inorganic acid hydrochloric acid, etc.].

The reaction is usually carried out in a solvent such as water, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.

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

Reference Processes The compound and (VI) are prepared by reacting the compound (III) with the compounds (11-3) and (VII) respectively in a similar manner to those of Process 1 and below mentioned Preparations.

The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.

Suitable salts of the compounds (III) and (VI) include an organic acid addition salt formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt hydrochloride, hydrobromide, sulfate, phosphate, etc.], and the like.

Suitable salts of the compound (11-3) and are an alkali metal salt sodium salt, potassium salt, etc.], an alkaline earth metal salt calcium salt, magnesium salt, etc.], and the like.

The compounds of formula possess inhibiting activity of COX-II and possess strong antiinflammatory, analgesic, antithrombotic, anti-cancer activities and so on. The object compound and pharmaceutically acceptable salts thereof, therefore, are useful for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or animals, and more particularly for the treatment and/or prevention of inflammation and pain in joint and muscle [e.g.

rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.], inflammatory skin condition sunburn, burns, eczema, dermatitis, etc.], inflammatory eye condition conjunctivitis, etc.], lung disorder in which inflammation is involved asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], condition of the gastrointestinal tract associated with inflammation aphthous ulcer, Chrohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.], gingivitis, inflammation, pain and tumescence after operation or injury, pyrexia, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodosa, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease, and the like.

Additionally, the compounds of formula or a salt thereof are expected to be useful as therapeutical and/or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia.

The compounds of formula of the present invention have advantages, such as more selective inhibitory activity of COX-II, stronger activity, more suitable half-life, decreased adverse effect, or the like, compared to the known pyrazole compounds shown in the prior art.

In order to illustrate the usefulness of the compounds of formula the pharmacological test data of the compound are shown in the following.

ANTIINFLAMMATORY ACTIVITY Effect on adjuvant arthritis in rats Test Method Ten female Sprague-Dawley rats were used per group. A dose of mg of Mycobacterium tuberculosis (strain M37 BA) suspended in 0.05 ml of liquid paraffin was injected subcutaneously in the right hind paw. The injection of mycobacterial adjuvant produced local inflammatory lesions (primary lesion) and then about 10 days later, secondary lesions in both the injected and uninjected paws. The volumes of both paws before and on days 23 after the injection was measured as percent inhibition in comparison to vehicle-treated controls. The drug was given orally once a day for 23 consecutive days from day 1 after the injection.

(ii) Test Results WO 99/15505 PCT/JP98/04150 ANTIINFLAMMATORY ACTIVITY Test compound Dose Inhibition of secondary (Example No.) (mg/kg) lesion (uninjected paw) 1 1.0 10-(8) 1.0 COX-I and COX-II activity in vitro Test Method a. Preparation of the recombinant cyclooxygenase (COX) The human cyclooxygenase COX-I and COX-II were expressed in transfected Chinese hamster ovary (CHO) cells. Monolayer cultures of semi-confluent CHO cells stably expressing COX-I and COX-II were washed twice and scraped into phosphate buffered saline (PBS). The cells were centrifuged at 200 x g for 5 minutes and the cell pellet was sonicated in reaction buffer containing 100 mM Tris-HCl (pH 7.4), 2 gM hematin and 5 mM tryptophan. Broken cells were centrifuged for minutes at 1700 x g at 41C and the supernatants were used as crude enzymes.

Cyclooxygenase activities in the absence or presence of inhibitors were measured by determining the level of prostaglandin E2 (PGE2) synthesis from arachidonic acid. Enzymes (1 g for COX-I and/or 3 gg for COX-II) in a total volume of 200 l of reaction buffer were incubated in the absence and presence of various concentrations of inhibitors for 5 minutes at 30 TC. The reaction was then started by the addition of arachidonic acid to the final concentration of uM. The reaction was terminated by 50 pg1 of HC1 (IN) after incubation at 30'C for 5 minutes. PGE2 was extracted with ethyl acetate, concentrated under a stream of nitrogen and analyzed by a radio immunoassay kit (Amersham) according to the manufacture's instructions.

b. Assay for human recombinant COX-I and COX-II activity COX activity was assayed as PGE2 formation using radioimmunoassay to detect the prostaglandin release. The appropriate COX enzyme was 1 2 WO 99/15505 PCT/JP98/04150 incubated in 0.1 M Tris-HCl buffer (pH 7.3) containing hematin and tryptophan with the addition of arachidonic acid (10 M) for minutes at 37 0 C. Compounds were pre-incubated with the enzyme for minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after minutes at 37 0 C by addition of 20 1l of IN HC1. PGE2 formation was measured by radioimmunoassay (Amersham).

(ii) Test Results COX-I and COX-II activity in vitro Test compound Human COX-II Human COX-I (Example No.) ICso(g M) ICso( p M) 3-(16) <1 >100 6 <1 >100 10-(8) <1 >100 The compound and a pharmaceutically acceptable salt thereof, are used as a medicament by intravenous, intracutaneous, intramuscular, pulmonary, or oral administration, or insufflation to human beings or animals.

A pharmaceutical composition of the present invention is a homogeneous mixture which comprises one of the compounds or pharmaceutically acceptable salts thereof, as an active ingredient, in association with a pharmaceutically acceptable carrier or excipient.

The pharmaceutical composition is manufactured by mixing the sufficient amount of the compound or a salt thereof as an active ingredient with a pharmaceutically non-toxic carrier or excipient to give homogeneous mixture. The pharmaceutically non-toxic carriers and excipients may be organic or inorganic and solid or liquid, and can be any of the conventional ones suitable for oral, parenteral or external (topical) administration.

For therapeutic purpose, the pharmaceutical composition of the present invention can be used in a form of a pharmaceutical preparation, for example, in a solid, semisolid, or liquid form. The pharmaceutical preparations may be capsules, tablets, dragees, WO 99/15505 PCT/JP98/04150 granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

In the pharmaceutical composition the compound or a pharmaceutically acceptable salt thereof is included in an sufficient amount to have the desired effects of aforementioned pharmaceutical activities on the aforesaid diseases in human beings or animals.

While the dosage of therapeutically effective amount of the compound will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

The patents, patent applications and publications cited herein are incorporated by reference.

The following Preparations and Examples are given for the purpose of illustrating this invention.

Preparation 1 To acetic anhydride (20 ml) was added 70% nitric acid (2 ml) dropwise in an ice-bath. During the addition, the internal temperature of the mixture temporarily rose to 25 'C and dropped to 0OC. To the mixture was added 1-(4-methoxyphenyl)-5-[4- (methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.0 g) portionwise. The reaction mixture was allowed to stir for 5 hours and poured into ice-water. The precipitate formed was collected by filtration and dried to give 1-(4-methoxy-3-nitrophenyl)-5-[4- (methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.15 g).

An analytical sample was prepared by recrystallization from ethanol.

mp 175-1770C (ethanol) WO 99/15505 PCT/JP98/04150 IR (KBr) 1540, 1361, 1313, 1160, 1141 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.96 (3H, 7.39 (1H, 7.44 (1H, d, J=8Hz), 7.5-7.7 (2H, 7.65 (1H, dd, J=2, 8Hz), 7.9-8.0 (2H, 8.09 (1H, d, J=2Hz) MASS 442 (M+H) Preparation 2 A mixture of 1-(4-methoxy-3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.15 activated carbon (2.15 g), anhydrous iron(III) chloride (100 mg), hydrazine monohydrate (2.2 ml), ethanol (75 ml), and tetrahydrofuran (75 ml) was refluxed for hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; 10:1 chloroform-ethyl acetate to 100:10:1 chloroform-ethyl acetate-methanol) to give the product, which was dissolved in ethyl acetate (10 ml) and treated with a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The resultant solid was collected by filtration to give 1-(3-amino-4methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole hydrochloride (1.92 g).

mp 214-220°C (ethanol) IR (KBr) 3424, 2003, 1631, 1313, 1160, 1157, 1132 cm-' NMR (DMSO-d6, 6) 3.26 (3H, 3.87 (3H, 5.0-7.0 (3H, br 6.98 (1H, dd, J=2, 8Hz), 7.09 (1H, d, J=8Hz), 7.23 (1H, d, J=2Hz), 7.34 (1H, 7.5-7.6 (2H, m), 7.9-8.0 (2H, m) MASS 412 (M+H) Preparation 3 A solution of sodium nitrite (6 g) in water (50 ml) was added dropwise to a solution of 3-chloro-4-methoxyaniline (10 g) in concentrated hydrochloric acid (30 ml) at 0OC with stirring. After the addition was completed, the reaction mixture was stirred at the WO 99/15505 PCT/JP98/04150 same temperature for 1 hour. A solution of stannous chloride dihydrate (50 g) in concentrated hydrochloric acid (30 ml) was added dropwise at OC. The resulting mixture was stirred for 2 hours at the same temperature. The resulting precipitate was collected by filtration, washed with ice water and dried in vacuo at 50 0 C to afford (3-chloro-4-methoxyphenyl)hydrazine hydrochloride (11.5 g) as a yellow brown solid.

mp 240-250 0 C (decomp.) IR (Nujol) 3200, 2700, 1600, 1570, 1505, 1290 cm-' NMR (DMSO-d6, 6) 3.80 (3H, 6.98 (1H, dd, J=2.7, 8.9Hz), 7.09-7.17 (2H, m) 8.12 (1H, br 10.14 (3H, br s) MASS 173 Preparation 4 The mixture containing 4,4-difluoro- [(4-methylthio)phenyl]butane-1,3-dione (1.0 (3-chloro-4-methoxyphenyl)hydrazine hydrochloride (0.94 g) and acetic acid (20 ml) was stirred at 100- 110 C. After 2 hours, the reaction mixture was concentrated in vacuo. The resultant residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 1-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)- 5-[4-(methylthio)phenyl]pyrazole (2.10 g) as an oil.

NMR (CDC13, 6) 2.48 (3H, 3.91 (3H, 6.75-7.26 (2H, 6.69 (1H, 7.13 (2H, d, J=8.0Hz), 7.18 (2H, d, J=8.0Hz), 7.45 (1H, d, MASS 381 (M+H) Preparation The following compounds described in to (11) were obtained according to a similar manner to that of Example 2.

Ethyl 1-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate IR (KBr) 3008, 1712, 1309, 1224, 1153 cm-' NMR (CDC13, 6) 1.43 (3H, t, J=7.1Hz), 2.28 (3H, d, J=1.6Hz), WO 99/15505 PCT/JP98/04150 3.07 (3H, 4.47 (2H, q, J=7.lHz), 6.95-7.00 (2H, i), 7.13 (1H, 7.31 (1H, d, J=7.OHz), 7.42 (2H, d, J=8.6Hz), 7.90 (2H, d, J=8.6Hz) MASS 403 Ethyl 1- (4-chloro-3-methylphenyl) (methylsulfonyl)phenyl]pyrazole-3-carboxylate IR (KBr) 3127, 3000, 1710, 1313, 1234, 1151 cm-' NMR (CDC13, 6) 1.43 t, J=7.Hz), 2.38 (3H, s), 3.08 (3H, 4.47 (2H, q, J=7.lHz), 6.93 (1H, dd, J=8.4, 2.3Hz), 7.30 d, J=8.41z), 7.37 (1H, d, J=2.3Hz), 7.43 (2H, d, J=8.6Hz), 7.92 d, J=8.6Hz) MASS 419*(M+H)+ 1121 (37Ci) Ethyl 1-(4-bromo-3-methylphenyl) [4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate IR (KBr) 3126, 3004, 1710, 1315, 1234, 1153 cm' NMR (CDC3, 6) 1.43 (31, t, J=7.lHz), 2.40 (31, s), 3.08 (3H, 4.47 (2H, q, J=7.lHz), 6.84 (1H, dd, J=8.4, 2.6Hz), 7.13 7.37-7.47 m), 7.49 d, J=8.4Hz), 7.92 (2H, d, MASS 463 79 Br), 1165 8 Br) Ethyl 1- (4-f luoro-3-methoxypheryl) [4-(inethylsulfonyl)phenyl]pyrazole-3-carboxylate IR (KBr) 3004, 2923, 1714, 1313, 1263, 1224, 1155 cm-' NMR (CDCl3, 6) 1.44 t, J=7.1Hz), 3.08 (31, s), 3.85 4.47 (21, q, J=7.lHz), 6.71 m), 6.98-7.14 7.43 d, J=8.5Hz), 7.92 (2H, d, MASS 419 Ethyl 1-(4-chloro-3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate IR (KBr) 2981, 1722, 1311, 1251, 1220, 1153 cm-' NMR (CDCl3, 6) 1.44 t, J=7.lHz), 3.08 (31, s), 3.85 (31, 4.47 (2H, q, J=7.lHz), 6.68 (11, dd, WO 99/15505 PCT/JP98/04150 J=8.4, 2.3Hz), 7.05 (1H, d, J2.3Hz), 7.14 (1H, s), 7.31 (1H, d, J=8.4Hz), 7.44 (2H, d, J=8.6Hz), 7.92 (2H, d, J=8.6Hz) Ethyl 1-(4-bromo-3-methoxyphenyl) -5-[4-(methylsulfonyl phenyl] pyrazole-3-carboxylate IR (KBr) 2979, 1724, 1311, 1251, 1220, 1151 cm-' NMR (CDCi 3 6) 1.44 (3H, t, J=7.lHz), 3.08 (3H, s), 3.84 (3H, 4.47 (2H, q, J=7.lHz), 6.62 (1H, dd, J=8.4, 2.2Hz), 7.01 (1H, 7.08-7.51 (4H, i), 7.92 (2H, d, J=8.2Hz) MASS 479 (79Br), 481 (M+H) 4 81 Br) Ethyl 1-(3-fluoro-4-methylphenyl) -5-14-(methylsulfonyl)phenyl3pyrazole-3-carboxylate IR (KBr) 3002, 1714, 1313, 1276, 1241, 1189, 1151 NMR (CDCl 3 6) 1.43 (3H, t, J=7.lHz), 2.31 (3H, d, J=1.8Hz), 3.08 (3H, 4.46 (2H, q, J=7.lHz), 6.93 dd, J=8.3, 2.0Hz), 7.08 dd, 7.13 (1H, 7.20 (1H, d, J=8.3Hz), 7.42 (2H, d, J=8.5Hz), 7.91 (2H, d, MASS 403 Ethyl 1-(3-chloro-4-methylphenyl) -5-14- (methylsulfonyl phenyl]pyrazole-3-carboxylate IR (KBr) 3000, 1712, 1313, 1232, 1151 cm-' NMR (CDCl3, 6) 1.43 (3H, t, J=7.lHz), 2.41 (3H, s), 3.08 (3H, 4.47 (2H, q, J=7.lHz), 6.98 (1H, dd, J=8.1, 2.2Hz), 7.13 (1H, 7.20 d, J=8.1Hz), 7.43 (2H, d, J=8.6Hz), 7.47 (1H, d, J=2.2Hz), 7.92 (21, d, J=8.6Hz) MASS 419 (3C1), 421 (31C1) Ethyl 1-(3-bromo-4-methyiphenyl) (methylsulfonyl)phenyl]pyrazoie-3-carboxylate IR (KBr) 2983, 1718, 1311, 1232, 1153 cm-1 NMR (CDCl 3 6) 1.43 t, J=7.lHz), 2.43 (3H, s), WO 99/15505 PCT/JP98/04150 3.08 (3H, 4.117 (21, q, J=7.lHz), 7.01 (1H, dd, J=8.1, 2.2Hz), 7.12 (1H, 7.20 d, J=8.lHz) 7.43 (2H, d, J=8.6Hz), 7.66 (1H, d, J=2.2Hz), 7.92 (2H, d, J=8.6Hz) ASS 463 79 Br), 465 8 'Br) Ethyl 1- (3-fluoro-4-methoxyphenyl) -5-[4-(methylsulfonyl) phenyl] pyrazole-3-carboxylate IR (KBr) 3012, 2987, 1700, 1311, 1278, 1230, 1147 cm- 1 NMR (CDCl3, 6) 1.43 (31, t, J=7.lHz), 3.08 s), 3.92 4.47 (2H, q, J=7.lHz) 6.89 d, J=8.9Hz), 6.99 dc, J=8.9, 2.3Hz), 7.11-7.26 (2H, 7.43 (2H, d, J=8.5Hz), 7.91 (2H, d, MASS 419 (11) Ethyl 1-(3-chloro-4-methoxyphenyl) (methylsulfonyl) phenyll pyrazole-3-carboxylate IR (KBr) 2979, 1718, 1313, 1272, 1226, 1151 cm-' NMR (CDCl 3 6) 1.43 t, J=7.1Hz), 3.08 s), 3.93 (31, 4.47 (2H, q, J=7.lHz), 6.87 d, J=8.8Hz), 7.06 (11, dd, J=8.8, 2.6Hz), 7.12 (1H, 7.43 (2H, c, J=8.5Hz), 7.50 (1H, d, J=2.6Hz), 7.91 (2H, d, MASS 435 437 ("Ci) Preparation 6 The following compound was obtained according to a similar manner to that of Preparation 1.

1- (4-Methoxy-3-nitrophenyl) (inethylsulfonyl) phenyl pyrazole-3-carbonitrile IR (KBr) 3072, 3021, 2242, 1535, 1363, 1311, 1282, 1151 cm' NMR (CDCl3, 6) 3.10 (311, 4.02 (31, 6.98 (1H, 7.12 (11, c, J=9.11z), 7.41-7.48 (31, 7.81 d, J=2.7Hz), 7.99 c, MASS 399 (M+HV WO 99/15505 PCT/JP98/04150 Preparation 7 A mixture of 1-(4-methoxy-3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (1.8 g) and ammonium chloride(0.18 g) in ethanol-water (50 ml) was stirred under 90'C. After several minutes, iron (powder) (1.8 g) was added and the resulting mixture was stirred for 1.5 hours at same temperature. After cooling, the insoluble material was filtrated off and washed with tetrahydrofuran.

The filtrate was concentrated under reduced pressure to give a material which on treatment with 4N hydrogen chloride in ethyl acetate afforded 1- (3-amino-4-methoxyphenyl) (methylsulfonyl)phenyl]pyrazole-3-carbonitrile hydrochloride (1.8 g).

IR (KBr) 3400, 2842, 2244, 1303, 1282, 1147 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.86 (3H, 6.86 (1H, dd, J=8.6, 2.0Hz), 7.03 (1H, d, J=8.6Hz), 7.05 (1H, d, J=2.0Hz), 7.55 (2H, d, J=8.4Hz), 7.94 (2H, d, J=8.4Hz) MASS 369 (M+H) Preparation 8 To a mixture of (3-methoxyphenyl)hydrazine (6 g) and 3-[4- (methylthio)phenyl]acrylonitrile (5.7 g) in methanol (100 ml) was added sodium methoxide (28 wt. solution in methanol) (18 ml) at ambient temperature. The mixture was heated to dryness under nitrogen at 140CC for 30 minutes. The resultant orange mass was partitioned between dichloromethane and ice water. The organic layer was dried over magnesium sulfate, and then filtered. This filtrate was evaporated in vacuo. The resultant mass was dissolved in ethyl acetate (150 ml) and refluxed for 1 hour in the presence of magnesium(IV) oxide (20 This mixture was cooled, and filtered.

The filtrate was evaporated in vacuo. The resultant mass was purified by column chromatography on silica gel using dichloromethane as eluent to give 1-(3-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-yl}amine (5.2 g).

IR (Nujol) 3450, 3320, 3220, 1630, 1600 cm-' 2 0 WO 99/15505 PCT/JP98/04150 NMR (DMSO-d6, 6) 2.47 (3H, 3.66 (3H, 4.98 (2H, 5.81 (1H, 6.61-6.79 (3H, 7.12-7.25 (41, m) MASS 312 Preparation 9 The following compounds described in to (11) were obtained according to a similar manner to that of Preparation 8.

-(4-Fluoro-3-methylphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-yl amine NMR (DMSO-d6, 6) 2.18 and 2.19 (total 3H, 2.45 (3H, 4.92 (2H, 5.81 (1H, 6.80-6.88 (1H, 7.02-7.23 (6H, m) IR (KBr) 3303, 3205, 1625, 1563, 1508 cm-' MASS 300 (4-Chloro-3-methylphenyl) (methylthio)phenyl] pyrazol-3-yllamine IR (Nujol) 1630, 1600 cm 1 NMR (DMSO-d6, 6) 2.27 (3H, 2.47 (3H, 5.00 (2H, 5.83 (1H, 6.70-6.85 i) 7.11-7.39 (6H, m) MASS 330 (4-Broio-3-iethylphenyl) -5-[4-(methylthio)phenyl]pyrazol-3-yllamine IR (Nujol) 3450, 1630 cm-' NMR (DMS0-d6, 6) 2.29 (3H, 2.47 (3H, 5.00 (2H, 5.83 (1H, 6.71-6.77 (1H, 7.14 (211, d, J=8.5Hz), 7.23 (2H, d, J=8.5Hz), 7.29 (1H, d, J=1.6Hz) 7.46 (1H, d, J8.6Hz) MASS 375 1- (4-Chloro-3-methoxyphenyl) -5-[4-(methylthio)phenyl]pyrazol-3-yllamine IR (Nujol) 3450, 3300, 3200, 1630, 1600 cm NMR (DMSO-d6, 6) 2.47 (3H, 3.70 (3H, 5.06 WO 99/15505 PCT/JP98/04150 (2H, 5.83 (1H, 6.59 (1H, dd, J=8.5, 2.3H), 6.98 d, J=2.3Hz), 7.16 (2H, d, J=8.6Hz), 7.26 (2H, d, J=8.6Hz), 7.31 (2H, d, J=8.51z) MASS 346 l-(3-Fluoro-4-methylphenyl)-5-L-(methylthio)phenyllpyrazol-3-yllamine IR (KBr) 3295, 3195, 1625, 1513 cm-' NMR (DMSO-d6, 6) 2.19 (31, 2.47 (3H, 5.02 5.82 6.80 (1H, dd, J=8.1, 1.9Hz), 6.96 (1H, dd, J=11.1, 1.9Hz), 7.12-7.25 (5H, m) MASS 314 1-(3-Chioro-L-methyiphenyl) (methylthio)phenyl pyrazol-3-yllamine IR (Nujol) 3450, 3400, 3200, 1630, 1610 cm-1 NMR (DMSQ-d6, 6) 2.29 (31, 2.47 (3H, 5.03 (211, 5.82 6.89 (1H, dd, J=8.2, 2.1Hz), 7.13-7.27 (6H, m) MASS 330 (3-Bromo-LI-methylphenyl) (methylthio)phenyllpyrazol-3-yllamine This compound was used in the next reaction without purification.

1 -(3-Chioro-L-methoxyphenyl) E4-(methylthio)phenyl] pyrazol-3-yl)amine IR (Nujol) 3450, 3300, 3200, 1645 cm-' NMR (DMS0-d6, 6) 2.47 (31, 2.50 4.95 (2H, 5.80 6.96-7.28 (7H, m) MASS 346 l-(4-Ethylphenyl) -5-E4-(methyithic) phenyl]pyrazol-3-yl }amine crystals mp 128-132 0

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IR (Nujol) 3490, 3460, 1620, 1600 cm- 1 NMR (DMSO-d6, 6) 1.13-1.23 2.54 s), 22 WO 99/15505 PCT/JP98/04150 2.52-2.64 (2H, 4.91 (2H, br 5.79 (1H, s), 7.03-7.56 (8H, m) MASS 309 (M+H) (Methylthio)phenyl] -1-(4-n-propylphenyl)pyrazol-3-yl}amine crystals mp 140-1420C IR (KBr) 3450, 3303, 3193, 1630, 1515 cm-' NMR (DMSO-d6, 6) 0.88 (3H, t, J=7Hz), 1.51-1.63 (2H, m), 2.46 (3H, 2.49-2.52 (2H, 4.92 (2H, br s), 5.79 (1H, 7.01-7.22 (8H, m) MASS 324 (M+H) (11) 4 -Isopropylphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-yl}amine crystals mp 148-1500C IR (KBr) 3450, 3305, 3197, 1631, 1513 cn-' NMR (DMSO-d6, 6) 1.18 (6H, d, J=7Hz), 2.46 (3H, s), 2.83-2.91 (1H, 4.92 (2H, br 5.79 (1H, s), 7.01-7.22 (8H, m) MASS 324 (M+H) Preparation The following compounds described in to were obtained according to a similar manner to that of Preparation 3.

4 -Fluoro-3-methylphenyl)hydrazine hydrochloride IR (KBr) 3002, 1585, 1550 cm NMR (DMSO-d6, 6) 2.18 (3H, 6.8-7.15 (3H, m) (3-Fluoro-4-methylphenyl)hydrazine hydrochloride IR (KBr) 2994, 1631, 1585, 1515 cm-' NMR (DMSO-d6, 6) 2.13 (3H, 6.70-6.86 (2H, m), 7.16 (1H, t, Preparation 11 To a solution of 3-chloro-1-(3-methoxyphenyl)-5-[4- 2 3 WO 99/15505 PCT/JP98/04150 (methylsulfonyl)phenyl]pyrazole (575 mg) in acetic anhydride (10 ml) and acetic acid (1 ml) was added nitric acid (fuming) (500 ml) at 0 OC. After being stirred at 0OC for 2 hours, the reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was evaporated in vacuo, and purified by column chromatography using dichloromethane as eluent to give 3-chloro-1-(3-methoxy-4-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (590 mg).

mp 170-1751C IR (Nujol) 1615, 1590 cm-' NMR (DMSO-d6, 6) 3.26 (3H, 3.80 (3H, 6.95 (1H, dd, J=8.7, 2.1Hz), 7.34 (1H, d, J=2.0Hz), 7.60 (2H, d, J=8.4Hz), 7.95 (2H, d, J=8.6Hz), 7.97 (2H, d, J=8.4Hz) MASS 408 (M+H) 4 Preparation 12 To a solution of 3-chloro-1-(3-methoxy-4-nitrophenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole (900 mg) in ethanol (30 ml) and tetrahydrofuran (30 ml) were added active carbon (3 hydrazine monohydrate (2 ml) and ferric chloride (50 mg). The mixture was refluxed for 2 hours, and filtered. The filtrate was evaporated in vacuo and partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give 1-(4-amino-3-methoxyphenyl)-3-chloro- (methylsulfonyl) phenyl]pyrazole (820 mg).

IR (Nujol) 3350, 1630, 1600 cu-' NMR (DMSO-d6, 6) 3.23 (3H, 3.83 (3H, 5.08 (2H, 6.56 (2H, 6.81 (1H, 6.90 (1H, s), 7.51 (2H, d, J=8.3Hz), 7.90 (2H, d, J=8.3Hz) MASS 378 (M+H) Preparation 13 A mixture of 2-methoxy-5-nitrobenzonitrile (14 ammonium chloride (5 the powder of reduced iron (9 g) in methanol was 2 4 WO 99/15505 PCT/JP98/04150 refluxed for 4 hours and cooled. The reaction mixture was filtered and the filtrate was poured into water. The resultant precipitates were filtered and washed with water to give 3-cyano-4-methoxyaniline (7.7 g).

IR (KBr) 3420, 3320, 2220 cm-' NMR (DMSO-d6, 6) 3.76 (3H, 5.05 (2H, br 6.79 (1H, d, J=2.7Hz), 6.86 (1H, dd, J=8.9, 2.7Hz), 6.96 (1H, d, J=8.9Hz) MASS 149 (M+H) Preparation 14 A solution of sodium nitrite (4.0 g) in water (7 ml) was added to an ice cooled mixture of 3-cyano-4-methoxyaniline (7.7 g) and concentrated hydrochloric acid (21 ml). The mixture was stirred at 0 0C for 30 minutes. To the resultant mixture a solution of tin(II) chloride dihydrate (49 g) and concentrated hydrochloric acid (5 ml) was added at 0OC and stirred for 1 hour. The precipitates were filtered and washed with ice cooled concentrated hydrochloric acid (10 ml) to give crude (3-cyano-4-methoxyphenyl)hydrazine hydrochloride (14.8 g).

NMR (DMSO-d6, 6) 3.87 (3H, 7.24 (1H, d, 7.30-7.37 (2H, comp. 8.27 (1H, br 10.15 (3H, br s) Preparation A stirred mixture of (3-cyano-4-methoxyphenyl)hydrazine hydrochloride (3.7 3-[4-(methylthio)phenyl]acrylonitrile (2.3 g) and sodium methoxide (0.9 g) in methanol 13 ml was gradually heated to 1401C under atmospheric pressure and N2 atmosphere, and continued to heat for 8 hours at 1400. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]-2-pyrazoline-3-amine (4.0 g).

Preparation 16 A mixture of 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl] -2-pyrazoline-3-amine (4.0 g) and manganese(IV) oxide (6.0 g) in 2 WO 99/15505 PCT/JP98/04150 toluene (100 ml) was stirred at ambient temperature for 8 hours. The insoluble material was filtered and washed with ethyl acetate. The resulting solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel eluting with a mixture of acetone and dichloromethane to give partially purified 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-amine (1.1 g).

IR (KBr) 2225 cm-' Preparation 17 A solution of sodium nitrite (0.36 g) in water (0.5 ml) was added to an ice cooled mixture of 1-(3-cyano-4-methoxyphenyl)-5-[4- (methylthio)phenyl]pyrazol-3-amine (1.08 concentrated hydrochloric acid (15 ml) and acetic acid (35 ml). The mixture was stirred at OC for 30 minutes and added portionwise to a mixture of cuprous chloride (1.37 g) and concentrated hydrochloric acid (10 ml) at ambient temperature. The mixture was refluxed for 1 hour, poured into water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with toluene to give 3-chloro-1-(3-cyano-4-methoxyphenyl)-5- [4-(methylthio)phenyl]pyrazole (0.29 g).

IR (Film) 2230, 1600, 1500 cm-' NMR (CDC13, 5) 2.49 (3H, 3.95 (3H, 6.41 (1H, 6.92 (1H, d, J=9.0Hz), 7.09 (2H, d, J=8.6Hz), 7.19 (2H, d, J=8.6Hz), 7.42 (1H, dd, J=9.0, 2.7Hz), 7.54 (1H, d, J=2.7Hz) MASS 356 (M+H) 4 Preparation 18 The following compounds described in to were obtained according to a similar manner to that of Preparation 11.

3-Chloro- -(4-ethyl-3-nitrophenyl)-5-[ 4-(methylsulfonyl)phenyl]pyrazole crystals WO 99/15505 PCT/JP98/04150 mp 134-135 0

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IR (KBr) 1577 cm-' NMR (DMSO-d6, 6) 1.21 (3H, t, J=7Hz), 2.84 (2H, q, J=7Hz), 3.25 (3H, 7.02 (1H, 7.48-7.61 (4H, i), 7.89-7.94 (3H, m) MASS 406 408 3-Chloro-5-[4-(methylsulfonyl)phenyll-l-( 3-nitro-4-n-propylphenyl)pyrazole crystals mp 42-46 0

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IR (KBr) 1535 cm-' NMR (DMSO-d6, 6) 0.91 (3H, t, J=7Hz), 1.54-1.65 (2H, m), 2.79 (2H, t, J=7Hz), 3.25 (3H, 7.07 (1H, s), 7.46-7.61 (4H, 8.27-8.32 (3H, m) MASS 420 1-( 1 -Isopropyl-3-nitrophenyl) -5-[4-(methylsulfonyl)phenyl- 3-(trifluoromethyl)pyrazole crystals mp 64-69 0

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IR (KBr) 1536 cm-' NMR (DMSO-d 6 6) 1.25 (6H, d, J=7Hz), 3.20 (1H, m), 3.27 (3H, 7.42 (1H, 7.76-7.59 (4H, i), 7.89 (2H, d, J=9Hz), 7.97 s) MASS 454 (M+H) 4 Preparation 19 The following compounds described in to were obtained according to a similar manner to that of Preparation 12.

1- (3-Amino-4-ethylphenyl) -3-chloro-5-[4- (methylsulfonyl)phenyl]pyrazole crystals mp 158-160'C IR (KBr) 3462, 3442, 3351 cm-' NMB (DMSO-d6, 6) 1.30 (3H, t, J=7Hz), 2.43 (2H, q, J=7Hz), WO 99/15505 PCT/JP98/04150 3.24 (3H, 5.19 (2H, br 6.30 (1H, dd, J=8, 2Hz), 6.62 (1H, d, J=2Hz), 6.8-6.9 (2H, m), 7.52 (2H, d, J=8Hz), 7.91 (2H, d, J=8Hz) MASS 376 (M+H) 1- (3-Amino-4-n-propylphenyl) -3-chloro-5- 4- (methylsulfonyl) phenyl]pyrazole crystals mp 152-154 0

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IR (KBr) 3461, 3350, 1628, 1595 cm-' NMR (DMSO-d6, 6) 0.92 (3H, t, J=7Hz), 1.48-1.59 (2H, m), 2.41 (2H, t, J=7Hz), 3.60 (3H, 5.19 (2H, br s), 6.27 (1H, dd, J=8, 2Hz), 6.61 (1H, d, J=2Hz), 6.12-6.57 (2H, 7.51 (2H, d, J=8Hz), 7.90 (2H, d, J=8Hz) MASS 390 (M+H) 1 -(3-Amino-4-isopropylphenyl)-5-[4-(methylsulfonyl)phenyl 3-(trifluoromethyl)pyrazole crystals mp 134-135 0

C

IR (KBr) 3430, 3359, 1635, 1506 cm-' NMR (DMSO-d6, 6) 1.14 (6H, d, J=7Hz), 2.97 (1H, m), 3.26 (3H, 5.29 (1H, br 6.37 (1H, dd, J=8, 2Hz), 6.69 (1H, d, J=2Hz), 7.03 (1H, d, J=8Hz), 7.31 (1H, s), 7.58 (2H, d, J=9Hz), 7.93 (2H, d, J=9Hz) MASS 424 (M+H) Preparation Into a 1 1 round bottom flask were added cupric chloride (anhydrous) (7.77 acetonitrile (150 ml), lithium chloride (anhydrous) (6.13 g) and n-butyl nitrate (4.47 g) at 20 to 25 0 C under nitrogen gas. While stirring, {1-(3-chloro-4-methoxyphenyl)-5-[4- (methylthio)phenyl]pyrazol-3-yl}amine (10.0 g) was added for minutes at the same temperature. The reaction mixture was stirred for 2 hours and then refluxed for additional 2 hours. After the reaction 2 8 WO 99/15505 PCT/JP98/04150 was completed, IN hydrochloric acid (325 ml) and ethyl acetate (150 ml) were added for quenching. The organic layer was separated and washed with brine (180 ml) and then evaporated to give a crude object compound as an oil, which was purified by silica gel column chromatography (Si02 50 g, toluene n-heptane 3 and evaporated to give a pure 3-chloro-1-(3-chloro-4-methoxyphenyl)-5- 4- (methylthio)phenyl]pyrazole (7.77 g).

NMR (CDC13, 6) 2.48 (3H, 3.91 (3H, 6.39 (1H, s), 6.80-7.44 (7H, m) MASS 365 (M+H) Example 1 To a solution of 1-[4-(methylthio)phenyl]-4,4,4-trifluorobutane- 1,3-dione (2 g) in acetic acid (30 ml) was added 3-tolylhydrazine hydrochloride (1.27 The mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the resultant oil was dissolved in methanol (100 ml). To this solution was added a solution of Oxone® (potassium peroxy monosulfate) (9.8 g) in water (20 ml) at room temperature. The mixture was stirred for 1 hour and then filtered. The filtrate was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and purified by column chromatography on silica gel using dichloromethane as eluent to give 1-(3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3- (trifluoromethyl)pyrazole (1.98 g).

IR (Nujol) 1600 cm-' NMR (DMSO-d 6 6) 2.33 (3H, 3.25 (3H, 7.06- 7.13 (1H, 7.32-7.39 (4H, 7.56 (2H, d, J=6.7Hz), 7.93 (2H, d, J=6.7Hz) MASS 381 (M+H) Example 2 A mixture of 1-[4-(methylsulfonyl)phenyl]-4,4,4-trifluorobutane- 29 WO 99/15505 PCT/JP98/04150 1,3-dione (620 mg) and (3-methyl-4-chlorophenyl)hydrazine hydrochloride (425 mg) in acetic acid (2 ml) was refluxed for 1 hour.

After cooling, the solvent was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo. The residue was recrystallized from ethanol to afford 1-(4-chloro-3-methylphenyl)-5- [4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (569 mg).

mp 152.0-154.

0 c IR (KBr) 3128, 3070, 1317, 1286, 1238, 1161, 1128 cm- 1 NMR (CDC13, 6) 2.39 (3H, 3.08 (3H, 6.85 (1H, 6.92 (1H, dd, J=8.4, 2.7Hz), 7.32 (1H, d, J=8.4Hz), 7.33 (1H, d, J=2.7Hz), 7.43 (2H, d, J=8.6Hz), 7.93 (2H, d, J=8.6Hz) MASS 415 (M+H) 4 Elemental Analysis for CiaHiC1F3N202S Calcd. C: 52.12, H: 3.40, N: 6.75 Found C: 51.82, H: 3.30, N: 6.68 Example 3 The following compounds described in to (18) were obtained in a similar manner to that of Example 2.

1-(4-Fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole mp 134-136c3 (ethanol) IR (KBr) 1602, 1315, 1222, 1160, 1157, 1130, 1101 cm-' NMR (DMSO-d6, 6) 2.25 (3H, d, J=1Hz), 3.25 (3H, s), 7.1-7.6 (2H, 7.37 (1H, 7.4-7.6 (3H, m), 7.9-8.0 (2H, m) MASS 399 1-(4-Bromo-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]- 3-(trifluoromethyl)pyrazole 3 0 WO 99/15505 PCT/JP98/04150 mp 127.0-129.0 0

C

IR (KBr) 3134, 3093, 1315, 1238, 1165, 1128 cm-' NMR (CDC13, 6) 2.41 (3H, 3.09 (3H, 6.84 (1H, dd, J=8.4, 2.6Hz), 6.85 (1H, 7.34 (1H, d, J=2.6Hz), 7.44 (2H, d, J=8.6Hz), 7.51 (1H, d, J=8.4Hz), 7.94 (2H, d, J=8.6Hz) MASS 459 (M+H) 4 461 8 Br) Elemental Analysis for CiaHilBrF3N202S Calcd. C: 47.07, H: 3.07, N: 6.10 Found C: 47.19, H: 3.05, N: 6.04 1-(4-Fluoro-3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole mp 159-160'C (ethanol) IR (KBr) 1612, 1317, 1222, 1162, 1155, 1114 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.76 6.8-7.0 (1H, 7.2-7.4 (2H, 7.38 (1H, 7.5-7.6 (2H, 7.9-8.0 (2H, m) MASS 415 1-(-Chloro-3-iethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoroiethyl)pyrazole mp 157-158C (ethanol) IR (Br) 1596, 1592, 1315, 1307, 1114, 1106, 1101 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.74 (3H, 6.8-7.0 (1H, 7.2-7.3 (1H, 7.39 (1H, 7.4-7.7 (3H, 7.9-8.0 (2H, m) MASS 431 1-(4-Bromo-3-iethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trlfluoroiethyl)pyrazole mp 156-157 0 C (3:1 n-hexane-ethyl acetate) IR (KBr) 1592, 1313, 1162, 1157, 1133 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.75 (3H, 6.85 (1H, dd, J=2, 8Hz), 7.20 (1H, d, J=2Hz), 7.39 (1H, 7.5-7.7(3H, 7.9-8.0 (2H, m) WO 99/15.505 PCT/JP98/04150 MASS 475 1-(3-Fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole mp 158.0-160.0 0

C

IR (KBr) 3132, 3078, 1315, 1161, 1128 cm- 1 NMR (CDC13, 6) 2.31 (3H, d, J=1.9Hz), 3.09 (3H, s), 6.84 (1H, 6.92 (1H, dd, J=8.1, 2.1Hz), 7.05 d, J=9.7Hz), 7.19 (1H, t, J=7.7Hz), 7.44 (2H, d, J=8.5Hz), 7.93 (2H, d, MASS 399 Elemental Analysis for CiaHi'FlN2OS Calcd. C: 54.27, H: 3.54, N: 7.03 Found C: 54.39, H: 3.48, N: 7.01 1-(3-Chloro-4-methylphenyl)-5-Cu-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole mp 136.5-138.5cC IR (KBr) 1315, 1236, 1163 cm- 1 NMR (CDCl3, 6) 2.41 (3H, 3.08 (3H, 6.84 (1H, 6.98 (1H, dd, J=8.3, 2.2Hz), 7.22 (1H, d, J=8.3Hz), 7.42 (1H, 7.44 (2H, d, J=8.6Hz), 7.94 (2H, d, J=8.6Hz) MASS 1415 1417 Elemental Analysis for Ci aHi 4ClF3N202S -1/2H20 Calcd. C: 51.01, H: 3.57, N: 6.61 Found C: 51.15, H: 3.26, N: 6.60 1-(3-Bromo-4-methyiphenyl)-5-[4-(methylsulfonyl)phenyl]- 3-(trifluoromethyl)pyrazole mp 159.0-161.0 0

C

IR (KBr) 1313, 1234, 1162, 1147 cm-' NMR (CDCl3, 6) 2.43 (3H, 3.08 (3H, 6.84 (1H, 7.02 (1H, dd, J=8.2, 2.2Hz), 7.22 (1H, d, J=8.2Hz), 7.44 (2H, d, J=8.6Hz), 7.61 (1H, d, J=2.2Hz), 7.94 (2H, d, J8.6Hz) 3 2 WO 99/15505 PCT/JP98/04150 MASS 459 461 81 Br) Elemental Analysis for C18Hi'BrF3N202S -0.3H20 Calcd. C: 146.53, H: 3.17, N: 6.03 Found C: 46.58, H: 2.95, N: 6.01 1 (3-Fluoro-14-methoxyphenyl) [14- (methylsulfonyl) phenyl]-3-(trifluoromethyl)pyrazole mp 178.5-180.50C IR (KBr) 3070, 3016, 1317, 1282, 1238, 1160, 1139, 1097 cm-' NMR (CDCl3, 5) 3.09 (3H, 3.93 (3H, 6.84 (1H, 6.88-7.15 (3H, 7.43 (2H, d, J=8.6Hz), 7.93 (2H, d, J8.6Hz) MASS 4115 Elemental Analysis for C1aH1FN203S Calcd. C: 52.17, H: 3.141, N: 6.76 Found C: 52.23, H: 3.142, N: 6.70 1- (3-Chloro-4-methoxyphenyl) (methylsulfonyl) phenyl]-3-(trifluoromethyl)pyrazole mp 184.0-186.

0

C

IR (KBr) 3016, 1315, 1280, 1228, 1159, 1137 cm-' NMR (CDCl3, 5) 3.08 (3H, 3.94 (3H, 6. 84 (1H, 6.88 (1H, d, J=8.6Hz), 7.06 (1H, dd, J=8.6, 2.6Hz), 7.44 (2H, d, J8.6Hz), 7.145 (1H, 7.93 (2H1, d, J=8.6Hz) MASS 431 (35C1), 433 (M+H) 4 (31Cl) Elemental Analysis for CiaHikClF3N203S- 1/2H2O Calcd. C: 49.15, H: 3.414, N: 6.37 Found C: 49.03, H: 3.18, N: 6.27 (11) 3-(Difluoromethyl)-l-(4-fluoro-3-methylphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 1514-155 0 C (ethanol) IR (KBr) 1504, 1315, 1155 cm- 1 NMR (DMSO-d 6 6) 2.24 (3H, d, J=1Hz), 3.214 (3H, s), 7.12 (1H, 7.14 (1H, t, J=54Hz), 7.0-7.3 (2H, m), 3 3 WO 99/15505 PCT/JP98/04150 7.4-7.5 7.5-7.6 (2H, 7.9-8.0 (2H, m) MASS 381 (12) 4-Chloro-3-methylphenyl) -3-(difluoromethyl) (methylsufonyl)phenyl]pyrazole mp 1115-146 0 C (ethanol) IR (KBr) 1600, 1315, 1153 cm- 1 NMR (DMSO-d6, 6) 2.3 (3H, 3.25 (3H, 7.08 (1H, dd, J=2, 8Hz), 7.11 (1H, 7.13 t, J=54Hz), 7.44 (1H, d, J=8Hz), 7.50 d, J=2Hz), 7.5-7.6 (2H, 7.9-8.0 (2H, M) MASS 397 (13) 1-(4-Bromo-3-methylphenyl)-3-(difluoromethyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 141-142C (ethanol) IR (KBr) 1598, 1307, 1147 cm-' NMR (DMS0-d6, 6) 2.35 (3H, 3.25 (3H, 6.99 dd, J=2, 8Hz), 7.13 7.15 t, J=54Hz), 7.50 (1H, d, J=8Hz), 7.5-7.6 (2H, 7.64 (1H, d, J=2Hz), 7.9-8.0 (2H, m) MASS 441 (14) 3-(Difluoroethyl)-l-(3-fluoro-4-methylphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 161-162 0 C (ethanol) IR (KBr) 1625, 1594, 1313, 1157 cm- 1 NMR (DMS0-d6, 6) 2.26 (3H, d, J=lHz), 3.25 s), 7.03 dd, J=2, 8Hz), 7.12 7.15 t, J=54Hz), 7.2-7.5 (2H, 7.5-7.6 (2H, 7.9-8.0 (2H, m) MASS 381 1- (3-Chloro-4-iethylphenyl) (difluoromethyl) (methylsulfonyl)phenyl]pyrazole mp 137-1390C (ethanol) IR (KBr) 1602, 1313, 1151 cm-' 3 4 WO 99/15505 PCT/JP98/04150 NMR (DMS0-d6, 6) 2.36 (3H, 3.25 (3H, 7.1-7.2 (1H, 7.12 (1H, 7.15 (1H, t, J=54Hz), 7.42 (1H, d, J=8Hz), 7.53 (1H, d, J=2Hz), 7.5-7.6 (2H, i), 7.9-8.0 (2H, m) MASS 397 (16) 1-(3-Bromo-4-methylphenyl)-3-(difluoroethyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 136-138 0 C (ethanol) IR (KBr) 1602, 1309, 1147 cmE' NMR (DMSO-d6, 6) 2.37 (3H, 3.25 (3H, 7.12 7.15 t, J=54Hz), 7.18 dd, J=2, 8Hz), 7.41 (1H, d, J=8Hz), 7.5-7.6 (2H, 7.68 (1H, d, J=2Hz), 7.9-8.0 (2H, m) MASS 441 (17) 3-(Difluoromethyl)-1-(3-fluoro-4-methoxyphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 185-186 0 C (ethanol) IR (KBr) 1596, 1313, 1153 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.87 (3H, 7.11 (1H, 7.13 (1H, t, J=54Hz), 7.1-7.3 (2H, m), 7.3-7.5 7.5-7.6 (2H, 7.9-8.0 (2H, m) MASS 397 (18) 1-(4-Isopropyiphenyl)-5-[4-(methylsulfonyl)phenyl]-3- (trifluoroiethyl)pyrazole crystals mp 144-146 0

C

IR (KBr) 1602, 1506, 1469 cm-' NMR (DMSO-d6, 6) 1.21 (6H, d, J=7Hz), 2.96 (1H, in), 3.26 (3H, 7.35 7.30-7.38 (OH, i), 7.56 (21, d, J=9Hz), 7.93 (2H, d, J=9Hz) MASS 409 (MH)+ Example 4 3 WO 99/15505 PCT/JP98/04150 To a solution of 1-(3-amino-4-methoxyphenyl)-5-[4- (methylsulfonyl) phenyl] -3-(trifluoromethyl) pyrazole hydrochloride (0.80 g) in ca. 24% hydrobromic acid (16 ml) was added a solution of sodium nitrite (0.14 g) in water (1 ml) while the internal temperature of the reaction mixture was maintained below 0C. The above mixture was added to an ice-cooled solution of copper(I) bromide (0.30 g) in ca. 24% hydrobromic acid (8 ml) and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with chloroform) to give the product, which was recrystallized from diisopropyl ether (3 ml)-ethyl acetate (3 ml) to give 1-(3-bromo-4methoxyphenyl) (methylsulfonyl) phenyl] (trifluoromethyl)pyrazole (0.39 g).

mp 164-166C (1:1 diisopropyl ether-ethyl acetate) IR (KBr) 1600, 1315, 1164, 1157, 1137 cm-' NMR (DMSO-ds, 6) 3.25 (3H, 3.89 (3H, 7.17 (1H, d, J=8Hz), 7.3-7.4 (1H, 7.35 (1H, s), 7.5-7.7 (2H, 7.75 (1H, d, J=2Hz), 7.9-8.0 (2H, m) MASS 475 (M+H) Example To a solution of 1-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)- 5-[4-(methylthio)phenyl]pyrazole (2.0 g) in dichloromethane (50 ml) was added portionwise m-chloroperbenzoic acid (2.3 g, 80% purity) at 0 C with stirring. After being stirred at room temperature for 2 hours, the reaction mixture was treated with aqueous solution of sodium thiosulfate and then partitioned between dichloromethane and water. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After evaporation of the solvent, the crude solid was recrystallized from ethanol to give l-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-5-[4- (methylsulfonyl)phenyl]pyrazole (1.8 g).

3 6 WO 99/15505 PCT/JP98/04150 mp 169-171 C IR (Nujol) 1600, 1510, 1440, 1410, 1350, 1310, 1275, 1150 cm-' NMR (DMSO-d6, 6) 3.25 (3H, 3.89 (3H, 6.87- 7.41 (4H, 7.56 (1H, 7.57 (1H, d, J=8.2Hz), 7.94 (2H, d, MASS 413 (M+H) Example 6 A mixture of sodium methoxide (169 mg) and ethyl 1-(4-fluoro-3methylphenyl)-5-[4- (methylsulfonyl)phenyl] pyrazole-3-carboxylate (420 mg) in formamide (5 ml) was warmed at 11000 for 30 minutes. The reaction mixture was poured into ice-water (50 ml) and the precipitate was collected by filtration, and washed with water and dried in vacuo. To an ice-cooled solution of POC13 (0.23 ml) in dimethylformamide (3 ml) was added the residue by small portions under nitrogen atmosphere. After 2 hours, the mixture was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo.

The resulting residue was purified by column chromatography on silica gel using chloroform and was recrystallized from ethanol to afford 1- (4-fluoro-3-methylphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole-3carbonitrile (297 mg).

mp 143.5-144.50C IR (KBr) 3118, 2242, 1311, 1232, 1189, 1155 cm-' NMR (CDC13, 6) 2.29 (3H, d, J=2.0Hz), 3.08 (3H, s) 6.91-7.26 (4H, 7.13 (1H, 7.39 (2H, d, 7.93 (2H, d, MASS 356 (M+H) Elemental Analysis for Ci 8Hi 4FN302S Calcd. C: 60.83, H: 3.97, N: 11.82 Found C: 60.57, H: 3.96, N: 11.73 Example 7 The following compounds described in to (10) were obtained according to a similar manner to that of Example 6.

3 7 WO 99/15505 PCT/JP98/04150 1-(4-Chloro-3-methylphenyl) (methylsulfonyl)phenyl]pyrazole-3-carbonitrile mp 163.0-164.0'C IR (KBr) 3118, 3010, 1710, 2240, 1313, 1155 cm-' NMR (CDC13, d) 2.39 (31, 3.09 (31, 6.92 (1H, dd, J=8.4, 2.5Hz), 6.96 7.30 d, 7.34 d, J=8.4z), 7.42 (2H, d, 7.95 (2H, d, MASS 372 (35C1), 374 (37C) 1- (4-Bromo-3-methylphenyi) (methylsulfonyi)pheny]pyrazole-3-oarbonitrile mp 151.5-152.50C IR (KBr) 3120, 3010, 2242, 1313, 1153 cm-' NMR (CDC13, 5) 2.41 (31, 3.09 (31, 6.83 (1H, dd, J=8.4, 2.3 Hz), 6.96 (1H, 7.30 (1H, d, J=2.3Hz), 7.42 d, J=8.6Hz), 7.53 d, J=8.4Hz), 7.95 (21, d, J=8.6Hz) MASS 416 418 8 Br) 1 -(4-Fiuoro-3-methoxyphenyi) [4-(methylsuifonyl) phenyl)pyrazoie-3-carbonitrile mp 169.0-171.0 0

C

IR (KBr) 3126, 3085, 2242, 1309, 1268, 1249, 1149 cm-' NMR (CDC1 3 8) 3.08 d, J=1.9z), 3.85 (3H, s), 6.65 6.97-7.06 (3H, 7.43 (2H, d, 7.92 (2H, d, MASS 372 1- (4-Chioro-3-iethoxyphenyl) -5-14-(inethyisuifonyl)phenyl]pyrazoie-3-carbonitrile mp 203.0-205.0 0

C

IR (KBr) 3120, 2252, 1309, 1238, 1147 cm-' NMR (CDC1 3 3) 3.09 3.85 6.64 (1H, dd, J=8.4, 2.4Hz), 6.97 7.00 (1H, d, J=2.4Hz), 7.33 d, J=8.4z), 7.44 d, 3 8 WO 99/15505 PCT/JP98/04150 7.96 (2H, d, MASS 388 390 37 C1) 1-(4-Bromo-3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile mp 212.5-214.5 0

C

IR (KBr) 3118, 2252, 1307, 1236, 1149 cm- NMR (CDC13, 5) 3.09 (3H, 3.85 (3H, 6.56 (1H, dd, J=8.4, 2.3Hz), 6.96 (1H, d, J=2.3Hz), 7.44 (2H, d, J=8.3Hz), 7.51 (1H, d, J=8.4Hz), 7.96 (2H, d, J=8.3Hz) MASS 432 434 8 'Br) 1-(3-Fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile mp 167.0-168.0 0

C

IR (KBr) 3129, 3072, 2250, 1363, 1149 cm-' NMR (CDCl3, 5) 2.32 (3H, d, J=1.9Hz), 3.09 (3H, s), 6.90 (11, dd, J=8.1, 2.1Hz), 6.95 (1H, 7.03 (1H, dd, J=9.5, 2.1Hz), 7.19 (1H, t, J=8.lHz), 7.42 (2H, d, J8.6Hz), 7.95 (2H, d, J=8.6Hz) MASS 356 Elemental Analysis for CisH14FN3O2S 1/2H 2 0 Calcd. C: 59.33, H: 4.15, N: 11.53 Found C: 59.53, H: 3.88, N: 11.50 1-(3-Chloro-4-methylphenyl) -5-14-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile mp 174-.5175.50C IR (KBr) 3120, 3012, 2244, 1317, 1151 cm-' NMR (CDCl3, 2.42 (3H, 3.08 (3H, 6.95-7.00 (2H, 7.24 (1H, d, J=8.4Hz), 7.40 (1H, 7.42 (2H, d, J=8.3Hz), 7.95 (2H, d, J=8.3Hz) MASS 372 374 (37Cl) Elemental Analysis for C18HiuClN 3

O

2

S

Calcd. C: 58.14, H: 3.79, N: 11.30 Found C: 57.88, H: 3.74, N: 11.14 3 9 WO 99/15505 PCT/JP98/04150 1- (3-Bromo-4-methylphenyl) (methylsulfonyl) phenylI pyrazole-3-carbonitrile mp 179.0-180.0 0

C

IR (KBr) 3120, 3010, 2246, 1317, 1151 cm-' NMR (CDC13, 6) 2. 44 3.08 (3H, 6.96 (1H, 7.01 dd, J=8.1, 2.1Hz), 7.24 d, J=8.lHz), 7.42 (2H, d, J=8.6Hz), 7.58 (11, d, J=2.lHz), 7.95 (21, d, J=8.6Hz) MASS 416 1418 81 Br) 1-(3-Fluoro-4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile mp 192.0-193.0 0

C

IR (KBr) 3068, 3016, 2252, 1315, 1278, 1151 cm-' NMR (CDC13, 5) 3.09 (3H, 3.94 (31, 6.94-6.96 7.12 (1H, dd, J=10.1, 2.1Hz), 7.42 (2H, d, 7.94 (2H, d, MASS 372 1 -(3-Chloro-4-methoxyphenyl) (methylsulfonyl) phenyl]pyrazole-3-carbonitrile mp 201.0-203 0

C

IR (KBr) 3016, 2250, 1311, 1274, 1151 cm-' NMR (CDCl3, 6) 3.08 (31, 3.95 (31, 6.89 (1H, d, J8.8Hz), 6.95 7.05 dd, J=8.8, 2.6Hz), 7.42 (2H, d, J=8.6Hz), 7.43 d, J=2.6Hz), 7.95 (2H, d, J=8.6Hz) MASS 388 390 (3"C) Example 8 The following compound was obtained according to a similar manner to that of Example 4.

1- (3-Bromo--methoxyphenyl) [14- (methylsulfonyl) phenyl)pyrazole-3-carbonitrile mp 184.0-186.0'C IR (KBr) 3064, 3016, 2240, 1309, 1274, 1151 cm-' WO 99/15505 PCT/JP98/04150 NMR (CDC13, 5) 3.08 (3H, 3.94 (3H, 6.86 (1H, d, J=8.8Hz), 6.95 (1H, 7.09 (1H, dd, J=8.8, 2.6Hz), 7.42 (2H, d, J=8.4Hz), 7.60 (1H, d, J=2.6Hz), 7.95 (2H, d, J=8.4Hz) MASS 432 434 (M+H) 8 'Br) Elemental Analysis for CisHi BrN303S Calcd. C: 50.01, H: 3.26, N: 9.72 Found C: 49.75, H: 3.15, N: 9.59 Example 9 To a solution of {1-(3-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-yl}amine (5 g) in acetic acid (40 ml) and hydrochloric acid (10 ml) was added sodium nitrite (1.7 g) in water (3 ml) at 0°C.

This mixture was stirred at 0 'C for 1 hour. The diazonium salt prepared above was added to a solution of copper(I) chloride (7 g) in hydrochloric acid (10 ml) at 0 0 C, and then allowed to warm to ambient temperature. After 1 hour, the reaction mixture was poured into ice water, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was evaporated in vacuo and purified by column chromatography on silica gel eluting with a mixed solution of dichloromethane and n-hexane (1: The desired product was dissolved in methanol (100 ml). A solution of Oxone® (potassium peroxy monosulfate) (20 g) in water was added at room temperature and the resultant mixture was stirred for 1 hour and then filtered. The filtrate was extracted with dichloromethane, and washed with water twice. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was evaporated in vacuo to give 3-chloro-1-(3-methoxyphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole (1.32 g).

mp 103-104C IR (Nujol) 1600 cm-' NMR (DMSO-d6, 6) 3.24 (3H, 3.71 (3H, 6.71- 6.82 (1H, 6.93-7.03 (3H, 7.29-7.37 (1H, m), 7.53 (2H, d, J=8.5Hz), 7.92 (2H, d, WO 99/15505 PCT/JP98/04150 MASS 363 Example The following compounds described in to (114) were obtained according to a similar manner to that of Example 9.

3-Chloro-l-(4-fluoro-3-methylphenyl)-5-[L- (methylsulfonyl)phenyl]pyrazole IR (KBr) 1598, 1502 cm-' NMR (CDCl3, 6) 2.26 and 2.27 (total 3H, each 3.07 (3H, 6.52 (1H, 6.92 (1H, t, J=3.3Hz), 6.96 (1H, t, J=8.6Hz), 7.21-7.26 (1H, 7.40 (2H, dt, 1.9Hz), 7.90 (2H, dt, J=8.5, 1.8Hz).

MASS 365 3-Chioro-l-(4-chloro-3-methylphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 180-181 C IR (Nujol) 1625, 1590 cm-' NMR (DMSO-d6, 6) 2.33 (3H, 3.25 6.98 (1H, 7.05 (1H, dd, J=8.4, 2.5Hz), 7.44-7.49 (2H, 7.53 (2H, d, J=8.5Hz), 7.93 (2H, d, MASS 382 1-(4-Bromo-3-methylphenyl)-3-chloro-5-14- (methylsulfonyl)phenyl]pyrazole mp 146-148 0

C

IR (Nujol) 1600 cm- 1 NMR (DMSO-d6, 6) 2.35 (3H, 3.25 6.93- 6.99 (1H, 6.99 (1H, 7.48 (1H, d, J=2.4Hz), 7.54 (2H, d, J=8.4Hz), 7.61 (1H, d, J8.5Hz), 7.94 (1H, d, J=8.4Hz) MASS 426 (M+H) 3-Chloro--(4-chloro-3-methoxyphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 165-1660C IR (Nujol) 1590 cm-' WO 99/15505 PCT/JP98/04150 NMR (DMSO-d6, 6) 3.25 (3H, 3.76 (3H, 6.81 dd, J=8.4, 2.3Hz), 7.00 (1H, 7.18 (1H, d, J=2.3H), 7.47 (1H, d, J=8.4Hz), 7.56 (2H, d, J=8.51), 7.95 (1H, d, MASS 398 (M+H)4 3-Chloro-l-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole mp 160-162 0

C

IR (KBr) 1614, 1590, 1509 cm- 1 NMR. (DMSO-d6, 8) 2.25 and 2.26 (total 3H, each s), 3.25 6.97 7.00 dd, J=8.8, 1.9Hz), 7.25 dd, J=10.3, 2.0Hz), 7.34 (1H, t, J=8.3Hz), 7.53 (2H, d, J=8.4Hz), 7.93 (2H, d, J=8.41z) MASS 365 3-Chloro--(3-chloro-4-methylphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole mp 159-161 0 IR (Nujol) 1610 cm- NMR (DMSO-d6, 8) 2.35 (3H, 3.25 (31, 6.98 (1H, 7.11 dd, J=8.2, 2.Hz), 7.39 d, J=8.3Hz), 7.51 d, J=2.2Hz), 7.54 (2H, d, J=8.4Hz), 7.94 (2H, d, J=8.4Hz) MASS 382 1-(3-Bromo-4-methylphenyl)-3-chloro-5-[4- (methylsulfonyl)phenyl]pyrazole IR (Nujol) 1600 cm- 1 NMR (DMSO-dB, 8) 2.37 3.25 7.14 dd, J=8.1, 2.2Hz), 6.69 (1H, 7.39 (1H, d, J=8.3Hz), 7.54 (2H, d, J=8.5Hz), 7.65 d, J=2.2Hz), 7.94 (2H, d, MASS 426 3-Chloro-1-(3-chloro-4-methoxyphenyl)-5-[L- (methylsulfonyl)phenyl]pyrazole 4 3 WO 99/15505 PCT/JP98/04150 mp 179-180 0

C

IR (Nujol) 1600 cm- NMR (DMSO-d6, 6) 3.25 (31, 3.89 (31, 6.97 7.17 d, J8.8Hz), 7.23 d, J=8.8Hz), 7.53 d J8.6Hz), 7.55 7.93 (2H, d, MASS 398 3-Chloro-1 -(4-ethylpheny1) -5-14- (methylsulfonyl)phenyl] pyrazole crystals mp 167-169 0

C

IR (Nujol) 1510 cm-' NMR (DMSO-ds, 6) 1.19 (3H, t, J=8Hz), 2.65 (2H, q, J=8Hz), 3.25 (31, 6.95 7.22 d, J=9Hz), 7.29 (2H, d, J=9Hz), 7.50 (2H, d, J=9Hz), 7.92 (2H, d, J=9Hz) MASS 361 3-Chloro-l-(3-chloro--ethylphenyl)-5-4-(methylsulfonyl)pheny]pyrazole crystals np 125-127-C IR (KBr) 1598, 1490 cm-' NMR (DMSO-d 6 6) 1.18 t, J=7Hz), 2.72 (21, q, J=7Hz), 3.25 6.98 d, J=2Hz), 7.13 dd, J=8, 2Hz), 7.39 dd, J=8, 2Hz), 7.50 d, J2Hz), 7.55 (2H, d, J=8Hz), 7.91 d, J=8Hz) MASS 395 397 (M+H) 4 37 C1) (11) 3-Chloro-5-[4-(methylsulfonyl)phenyl]-1-(4-n-propylphenyl)pyrazole crystals np 143-1440C IR (KBr) 1513 cm-' NMB (DMSQ-d6, 6) 0.89 t, J=7Hz), 1.54-1.65 (2H, m), 4 4 WO 99/15505 PCT/JP98/04150 2.59 (2H, t, J=7Hz), 3.25 (3H, 6.96 (1H, s), 7.19-7.30 (4H, 7.50 (2H, d, J=9Hz), 7.90 (2H, d, J=9Hz) MASS 375 (12) 3-Chloro-l-(3-chloro-4-n-propylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole crystals up 119-122oC IR (KBr) 1602, 1490 cm-' NMR (DMS0-d6, 6) 0.92 (3H, t, J=7Hz), 1.57 (2H, dt, J=7Hz), 2.69 (2H, t, J=7Hz), 3.25 (3H, 6.99 (1H, s), 7.13 (1H, dd, J=8, 2Hz), 7.38 (1H, d, J=8Hz), 7.51 (1H, d, J=2Hz), 7.54 (2H, d, J=8Hz), 7.94 (2H, d, J=8Hz) MASS 409 (13) 1-(3-Chloro-4-isopropylphenyl)-5-[4- (iethylsulfonyl)phenyl- 3-(trifloromethyl)pyrazole crystals mp 84-86 0

C

IR (KBr) 1602, 1490, 1469 cm- 1 NMR (DMSO-d6, 6) 1.21 (6H, d, J=7Hz), 3.30 (1H, m), 3.27 (3H, 7.27-7.63 (6H, 7.69 (2H, d, J=9Hz) MASS 443 (14) 3-Chloro-l-(-isopropyiphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole crystals mp 146-148 0

C

IR (KBr) 1513 cm-' NMR (DMSO-d6, 8) 1.21 (6H, d, J=7Hz), 2.90-2.97 (1H, i), 3.25 (31, 6.96 7.10-7.40 (4H, i), 7.51 (2H, d, J=9Hz), 7.9 (2H, d, J=9Hz) MASS 375 Example 11 A solution of sodium nitrite (0.1 g) in water (0.2 ml) was added 4 WO 99/15505 PCT/JP98/04150 a solution of 1-(4-amino-3-methoxyphenyl)-3-chloro-5-[4- (methylsulfonyl)phenyl]pyrazle (0.38 g) in concentrated hydrochloric acid (2 ml) at 0C with stirring. The reaction mixture was stirred at 0'C for 1 hour. 42% Tetrafluoroboric acid (0.5 ml) was added to the solution containing the diazonium salt at 0C. The resulting mixture was stirred at 0C for 2 hours and then left in a refrigerator overnight. The resulting precipitate was collected by filtration, washed with ice water and dried in vacuo, which was heated at 180-200'C for 10 minutes. Ice water was added and the resulting mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel using a mixture of isopropyl ether and tetrahydrofuran as eluent to give 3chloro-- (4-fluoro-3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole mp 140-145iC (decomp.) IR (Nujol) 1600, 1510, 1310, 1250, 1150 cm-' NMR (DMSO-d6, 6) 3.89 (3H, 4.01 (3H, 6.56 (1H, 6.95 (1H, d, J=6.0Hz), 7.21-7.32 (2H, m), 7.53 (2H, d, J=8.0Hz), 7.92 (2H, d, MASS 365 (M+H) Example 12 A solution of m-chloroperbenzoic acid (0.40 g) in dichloromethane (4 ml) was added dropwise to a solution of 3-chloro-1-(3-cyano-4methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (0.23 g) in dichloromethane (5 ml) and stirred at OC for 1 hour. The mixture was washed with an aqueous solution of sodium bicarbonate, 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 to give crystals of 3-chloro-1-(3-cyano-4-methoxyphenyl)-5- [4-(methylsulfonyl)phenyl]pyrazole (197 mg).

4 6 WO 99/15505 PCT/JP98/04150 mp 191-194C IR (Nujol) 2235, 1604, 1310, 1150 cm-' NMR (CDC13, 6) 3.10 (3H, 3.98 (3H, 6.54 (1H, 6.95 (1H, d, J=9.0Hz), 7.38 (1H, dd, 2.6Hz), 7.40 (2H, d, J=8.6Hz), 7.54 (1H, d, J=2.6Hz), 7.94 (2H, d, J=8.6Hz) MASS 388 (M+H) Example 13 To a stirred solution of 3-chloro-1-(4-methoxyphenyl)-5-[4- (methylsulfonyl)phenyl]pyrazole (278 mg) in a mixture of acetic anhydride (5 ml) and acetic acid (5 ml), nitric acid (sp. gr. 1.42) ml) was added at After 30 minutes, the resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crystals. The resulting crystals were washed with ethyl acetate to give 3-chloro-1-(4-methoxy-3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (297 mg).

mp 178-180 0 C (decomp.) IR (Nujol) 1620, 1600, 1535 cm-' NMR (CDCl3, 6) 3.09 (3H, 4.00 (3H, 6.55 (1H, 7.07 (1H, d, J=9.0Hz), 7.40 (1H, dd, 2.7Hz), 7.44 (2H, d, J=8.5Hz), 7.75 (1H, d, J=2.7Hz), 7.95 (2H, d, MASS 408 (M+H) Industrial Applicability The compound and a salt thereof of the present invention have selective inhibitory activity of COX-II and are useful for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, thrombosis, cancer or neurodegenerative diseases and the like.

This application is based on application No. P09414 filed in Australia, the content of which is incorporated hereinto by reference.

P:kOPER\KblslI)138-98 spe.doc. 0949) 2 47A The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (11)

1. A compound of the formula N N(I) R 1 CH3S02 wherein R' is chlorine, difluoromethyl, trifluoromethyl or cyano, and R 2 is a group having the following formula Y' or Z X Y2 wherein X is halogen, cyano, nitro or amino, Y' is lower alkyl or lower alkoxy, Y 2 is lower alkyl or lower alkoxy, and Z is halogen, or a pharmaceutically acceptable salt thereof.

2. A compound of the formula CH 3 SO 2 P.AOPERXKbnuWOO38-9X spc.dwc4i9JO5A)2 49 wherein R' is chlorine, difluoromethyl, trifluoromethyl or cyano, and R 2 is a group having the formula wherein X is halogen, cyano or nitro, Y' is lower alkyl or lower alkoxy, Y2 is lower alkyl or lower alkoxy, and Z is halogen.

3. The compound according to claim 1, wherein R' is chlorine and R 2 is a group having the formula wherein X is halogen or cyano, and Y' is lower alkoxy.

4. The compound according to claim 1, which is a compound selected from the group consisting of 3 -chloro-l1-(3 -cyano-4-methoxyphenyl)-5- [4-(methylsulfonyl)phenyl]pyrazole, 3 -chloro-l1-(3 -chloro-4-methoxyphenyl)-5 -[4-(methylsulfonyl)phenyl]pyrazole, 3 -chioro-l1-(3 -chloro-4-methylphenyl)-5 -[4-(methylsulfonyl)phenyl]pyrazole, 3 -chloro- 1-(3 -fluoro-4-methylphenyl)-5- [4-(methylsulfonyl)phenyl]pyrazole, 1 -fluoro-4-methoxyphenyl)-5- [4-(methylsulfonyl)phenyl] -3- (trifluoromethyl)pyrazole, 3 -(difluoromethyl)- 1-(3 -fluoro-4-methoxyphenyl)-5- [4- 'ZO ethylsulfonyl)phenyl]pyrazole, P:XOPER\Kb.W(I3l-98 p 49JA)2 50 3 -chioro-l1-(4-chloro-3 -methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole, and 1 -(4-chloro-3 -methoxyphenyl)-5 -[4-(methylsulfonyl)-phenyl jpyrazole-3 -carbonitrile The compound according to claim 1, which is (11) 3 -chioro-l1-(3 -chloro-4-ethylphenyl)-5 -[4-(methylsulfonyl)phenyl]pyrazole

6. A process for preparing a compound of the formula CH 3 SO 2 wherein R' is chlorine, difluoromethyl, trifluoromethyl or cyano, R 2is a group having the following formnula wherein X is halogen, cyano, nitro or amino, Y' is lower alkyl or lower alkoxy, y2 is lower alkyl or lower alkoxy, Z is halogen, or or a pharmaceutically acceptable salt, which comprises, reacting a compound of the formula (11-1): P \OPER\Kb W\II(I38-98 sp .doc)~AM2 -51 (11-1) wherein R' a is difluoromethyl or trifluoromethyl, or its salt, with a compound of the formula (111): R 2-NH-NH 2 (III) wherein R 2 is as defined above or its salt, to give a compound of the formula 1) wherein R'Ia and R 2 are as defined above, oxidizing a compound of the formula (IV): R1 S(IV) Z'r R 2 CH3S wherein R' and R 2 are as defined above to give a compound of the formula rN' (I) I HR 2 CH3SO2 wherein R' and R 2 are as defined above subjecting a compound of the formula SR 3 N(V) K 2 CH3SO wherein R 3 is carboxy or esterified carboxy and R 2 is as defined above, or its salt, to amidation and then dehydration, to give a compound of the formula (1-2) CN N (1-2) R 2 CHaSO2 wherein R 2 is as defined above, or subjecting a compound of the formula (VI) 2 P:\OPER\Kbm\I9X)3-9iX spc.doc-09i)S/O2 -53 NH 2 N N (VI) R 2 CH3SO2 wherein R 2 is as defined above, or its salt, to chlorination to give a compound of the formula CI N N (1-3) R2 CH3SO2 wherein R 2 is as defined above.

7. A pharmaceutical composition comprising the compound of claim 1, as an active ingredient, in association with a pharmaceutically non-toxic carrier or excipient.

8. A compound of claim 1 for use as a medicament.

9. A COX-II inhibiting agent comprising the compound of claim 1. A method for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases which comprises administering an effective amount of the compound of claim 1 to human beings or animals.

11. Use of the compound of claim 1 for the manufacture of a medicament for treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or R eurodegenerative diseases in human beings or animals. 7 A compound of claim 1, substantially as hereinbefore described with reference to P:\OPERKbm\90038-98 spe.doc-21/05/02 -54- the Examples.

13. A process of claim 6, substantially as hereinbefore described with reference to the Examples.

14. A compound of formula prepared by a process of claim 6 or claim 13. DATED this 13th day of May, 2002 Fujisawa Pharmaceutical Co., Ltd. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants