WO2000018741A2 - Pyrazole compounds as cox-2 inhibitors - Google Patents

Pyrazole compounds as cox-2 inhibitors Download PDF

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Publication number
WO2000018741A2
WO2000018741A2 PCT/JP1999/005289 JP9905289W WO0018741A2 WO 2000018741 A2 WO2000018741 A2 WO 2000018741A2 JP 9905289 W JP9905289 W JP 9905289W WO 0018741 A2 WO0018741 A2 WO 0018741A2
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WIPO (PCT)
Prior art keywords
phenyl
chloro
pyrazole
sulfonyl
trifluoromethyl
Prior art date
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PCT/JP1999/005289
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French (fr)
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WO2000018741A3 (en
Inventor
Nobukiyo Konishi
Katsuya Nakamura
Hirofumi Yamamoto
Takashi Manabe
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Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from AUPP6231A external-priority patent/AUPP623198A0/en
Priority claimed from AUPQ2243A external-priority patent/AUPQ224399A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO2000018741A2 publication Critical patent/WO2000018741A2/en
Publication of WO2000018741A3 publication Critical patent/WO2000018741A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals

Definitions

  • This invention relates to novel pyrazole compounds and pharmaceutically acceptable salts thereof which have pharmacological activity, to a process for their production; and to a pharmaceutical composition containing the same.
  • One object of this invention is to provide novel pyrazole compounds and pharmaceutically acceptable salts thereof which have an inhibiting activity of COX-II.
  • Another object of this invention is to provide a process for production of the novel pyrazole compounds.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the pyrazole compound or a pharmaceutically acceptable salt thereof.
  • a still further object of this invention is to provide a use of the novel pyrazole compounds and pharmaceutically acceptable salts thereof for manufacturing a medicament for treating or preventing various diseases.
  • the present invention relates to novel pyrazole compounds and pharmaceutically acceptable 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.
  • the object pyrazole derivatives of this invention are new and can be represented by the following general formula (I) .
  • R 1 is halo (lower) alkyl, halogen or cyano
  • R 2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
  • R 3 is hydrogen, hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
  • R 4 is hydrogen or halogen
  • A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R 3 is hydrogen, R 2 is aryl substituted with lower alkenyl or A is lower alkyl substituted with oxo.
  • the object compound (I) can be prepared by one of the following processes 1 - 5.
  • R 1 , R 2 , R 3 , A, Q and n are each as defined above, R is lower alkyl, R 3 a is amino optionally substituted with hydroxy or lower alkyl, R 3 b is acyloxy,
  • R 3 c is lower alkylsulfonyl or lower alkyl sulfinyl, and R 3 d is hydroxy substituted with acyl.
  • “Pyrazolyl” includes 1 -pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5- pyrazolyl, in which preferable one is 5-pyrazolyl.
  • 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(halo) alkyl”, “lower alkylthio” and “lower alkylsulfonyl” may be a straight or branched one having 1 to 6 carbon atom(s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, in which preferable one is C. -C 4 alkyl.
  • Suitable “lower alkenyl” includes, for example, isopropenyl, vinyl, propenyl, betenyl, pentenyl, hexenyl, in which preferable one is isopropenyl.
  • Suitable "lower alkoxy” includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert- pentyloxy and hexyloxy, in which preferable one is C x - C 4 alkoxy.
  • Suitable “lower(halo)alkyl” includes, for example, trifluoromethyl, difluoromethyl, trichloromethyl. and the like.
  • Suitable "halogen” includes, for example, fluorine, chlorine, bromide and iodide.
  • Suitable "alkylene” includes, for example, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, ethylidene, and the like.
  • acyl and acyl moeity in the term “acyloxy” include acyl such as aliphatic acyl, aromatic acyl and heterocyclic acyl.
  • the aliphatic acyl includes saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g., formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hxanoyl, etc.) , alkylsulfonyl, such as lower alkylsufonyl (e.g.
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. , vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. , acryloyl, methacryloyl, crotonoyl, etc.) , cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. , cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.) , and the like.
  • the aromatic acyl may include C 6 - C 10 aroyl (e.g. , benzoyl, toluoyl, xyloyl, etc.), N-(C 6 - C 10 )arylcarbamoyl (e.g. , N-phenylcarbamoyl, N- tolylcarbamoyl, N-naphthylcarbamoyl, etc.) , C 6 - C 10 arenesulfonyl (e.g. , benzenesulfonyl, tosyl, etc.) , and the like.
  • C 6 - C 10 aroyl e.g. , benzoyl, toluoyl, xyloyl, etc.
  • N-(C 6 - C 10 )arylcarbamoyl e.g. , N-phenylcarbamoyl, N- tolylcarbamoy
  • the heterocyclic acyl may include heterocyclic carbonyl (e.g. , furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadeazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
  • heterocyclic carbonyl e.g. , furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadeazolylcarbonyl, tetrazolylcarbonyl, etc.
  • Suitable "aryl” includes, for examle, an aryl having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphtyl, in which preferable one is phenyl and tolyl.
  • Each of R 1 and R 2 may attached to any position of the pyrazole ring.
  • the preferred ones of the compound (I) are compounds having the formula (!')
  • R 1 is halo (lower) alkyl, halogen or cyano
  • R 2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
  • R 3 is hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
  • R 4 is hydrogen or halogen
  • A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R 3 is hydrogen, R 2 is aryl substituted with lower alkenyl or A is lower alkylene substituted with oxo, or its salt.
  • R 1 is trifluoromethyl, difluoromethyl, chlorine or cyano
  • R 2 is phenyl, tolyl, or phenyl or tolyl substituted with substituent(s) selected from the group consisting of chlorine, fluorine, bromine and methoxy,
  • R 3 is hydroxy, acetoxy, ethoxy, amino, methylamino, methylthio or methylsulfonyl
  • R 4 is hydrogen
  • A is dimethylene, trimethylene, methylene or pentamethylene, and n is 2.
  • the preferred one is the compound selected from the group consisting of (1) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-chloro-4- methoxyphenyl)pyrazole,
  • the more preferred one is the compound selected from the group consisting of
  • the compounds (I) 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 (I) 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 (e.g. sodium salt, potassium salt, cesium salt, etc.) , an alkaline earth metal salt (e.g. calcium salt, magnesium salt etc.) , an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g.
  • triethylamine salt pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc.) , etc.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methane sulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • the preferable example thereof is an acid addition salt.
  • the compound (I) 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.
  • the compound (1- 1 ) can be prepared by reacting the compound (II) or its salt with CH 3 COONa (sodium acetate) or (CH 3 CO) 2 0 (acetic anhydride), and then the oxydation. (First step)
  • the reaction is usually carried out at reflux temperature.
  • the solvents to be used are conventional solvents such as water, alcohol [e.g. , methanol, ethanol, isopropanol, 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 (e.g. , acetic acid) . (Oxydation)
  • the oxidizing agent to be used is MMPAC (magnesium monoperoxyphthalate) .
  • 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 [e.g. methanol, ethanol, etc.], a mixture thereof or the like.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (1-2) can be prepared by reacting a compound (IV) or its salt with a compound (V) or its salt.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. , methanol, ethanol, isopropanol, 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 (e.g. , acetic acid).
  • a conventional solvent such as water, alcohol [e.g. , methanol, ethanol, isopropanol, 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 (e.g. ,
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compound (1-4) or its salt can be prepared from the compound (1-3) or its salt.
  • Amination can preferably carried out by, for example, reacting the compound (1-4) with a mesylating reagent such as methanesulfonyl chloride and methane sulfonic anhydride to give a mesylate.
  • a mesylating reagent such as methanesulfonyl chloride and methane sulfonic anhydride.
  • the solvents to be used are, for example, dichloromethane, chloroform, tetrahydrofuran, or any other organic solvents which do not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the mesylate is reacted with an alkylamine (e.g. , methyl- amine, dimethylamine, ethylamine, etc.) or hydroxyamine.
  • alkylamine e.g. , methyl- amine, dimethylamine, ethylamine, etc.
  • the solvents to be used are, for example, acetonitrile, tetrahydrofuran, toluene, 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.
  • the compound (1-5) can be prepared from the compound (1-3).
  • the acylating agent to be used are, for example, a lower alkanoic anhydride (e.g. , acetic anhydride, etc.) , lower alkanoyl halide (e.g. , acetyl chloride, etc.) , and the like.
  • the reaction is usually carried out in a solvent such as dichloromethane, tetrahydrofuran, toluene, a solvent which does not adversely influence the reaction, or a mixture thereof.
  • a solvent such as dichloromethane, tetrahydrofuran, toluene, a 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.
  • the compound (1-7) can be prepared by reacting the compound (I- 6) with an oxidizing agent.
  • 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 [e.g. sodium periodate, etc.] , and the like.
  • peracid e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, monopersulfate compound (Oxone®), etc.
  • chromic acid e.g. permanganate
  • alkali metal periodate e.g. sodium periodate, etc.
  • 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 [e.g. 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.
  • the compound (II') can be prepared by reacting the compound (V) or its salt with a hydrazine derivative (VI) or its salt.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. , methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroforim, 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 (e.g. , acetic acid.)
  • a conventional solvent such as water, alcohol [e.g. , methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroforim, 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 (e.g
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (IV) can be prepared from the compound (1-5) or its salt in a similar manner to that of Process 2 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 (II) and (V) are, for example, an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) , an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.) , and the like.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • the object compound (I) possesses inhibiting activity of COX-II and possesses strong antiinflammatory, analgesic, antithrombotic, anti- cancer activities and so on.
  • the object compound (I) 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, osteo arthritis, gouty arthritis, juvenile arthritis, etc.], inflammatory skin condition [e.g.
  • inflammatory eye condition e.g. conjunctivitis, etc.
  • lung disorder in which inflammation is involved e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.
  • condition of the gastrointestinal tract associated with inflammation e.g.
  • 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 cyclo oxygenase 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,
  • the compound (I) of the present invention has much advantage, 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 arts.
  • COX-I and COX-II activity in vitro (i) 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 ⁇ M hematin and 5 mM tryptophan. Broken cells were centrifuged for 5 minutes at 1700 x g at 4°C and the supernatants were used as crude enzymes.
  • PBS phosphate buffered saline
  • Cyclooxygenase activities in the absence or presence of inhibitors were measured by determining the level of prostaglandin E 2 (PGE 2 ) synthesis from arachidonic acid.
  • Enzymes (1 ⁇ g for COX-I and/ or 3 ⁇ g 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°C .
  • the reaction was then started by the addition of arachidonic acid to the final concentration of 10 ⁇ M.
  • the reaction was terminated by 50 ⁇ l of HC1 (IN) after incubation at 30°C for 5 minutes.
  • PGE 2 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 PGE 2 formation using radioimmunoassay to detect the prostaglandin release.
  • the appropriate COX enzyme was incubated in 0.1 M Tris-HCl buffer (pH 7.3) containing hematin and tryptophan with the addition of arachidonic acid (10 ⁇ M) for 5 minutes at 37°C . Compounds were pre-incubated with the enzyme for 5 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after 5 minutes at 37°C by addition of 20 ⁇ l of IN HC1. PGE 2 formation was measured by radioimmunoassay (Amersham). (ii) Test Results : COX-I and COX-II activity in vitro :
  • the compound (I) 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 (I) 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 (I) 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 for oral, parenteral or external (topical) administration.
  • 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, 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.
  • the compound (I) 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 (I) 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 (I) 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 amide was added to Vilsmeier reagent, prepared from N,N-dimethylformamide ( 15 ml) and phosphorus oxychloride ( 1.8 ml), at 5°C and then the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the resulting precipitates were collected by filtration and dried at 50°C for 4 hours to afford the desired pyrazole nitrile (4. 1 g) . To this nitrile in dichloromethane (40 ml) was added by portions 3- chloroperbenzoic acid (2.84 g) at an ice-bath temperature.
  • the reaction mixture was diluted with dichloromethane ( 100 ml) and then washed successively with water, aqueous sodium carbonate solution and brine, and dried over MgS0 4 .
  • the evaporation of the solvent gave a gummy oil, which was crystallized in ethanol and collected by filtration to give 5-[4-(acetoxymethyl- sulfonyl)phenyl]-3-chloro- l-(3-chloro-4-methoxyphenyl)pyrazole (2.4 g) in 80.3% yield.
  • the analytical sample was obtained by re crystallization from ethanol.
  • Example 18 l-(4-Chloro-3-methoxyphenyl)-5- ⁇ 4-[(2-hydroxyethyl)sulfonyl]- phenyl ⁇ -3 -cyanopyrazole was prepared by a similar procedure to that of Example 3.
  • Example 46 l-(4-Isopropylphenyl)-5-[4-(acetoxymethylthio)phenyl]-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 10 and Example 19.
  • N- dimethylformamide 0.3 ml
  • a solution of the l-(3-chloro-4- methoxyphenyl) -5- ⁇ 4- [(3 -hydroxypropyl)sulfonyl] -phenyl ⁇ -3- (tr ⁇ luoromethyl)pyra--ole 147 mg
  • N, N-dimethylformamide 0.4 ml
  • methyl iodide 49mg
  • N- dimethylformamide 0.3 ml
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20 : 1) as an eluant, giving l-(3-chloro-4-methoxyphenyl)-5- ⁇ 4- [(methylcarbamoyl)methylsulfonyl]phenyl ⁇ -3-(trifluoromethyl)pyrazole (123 mg).
  • Example 63 The key intermediate, l-(4-methoxyphenyl)-5-(4-methylthiophenyl)- 3-difluoromethylpyrazole, was prepared by refluxing a mixture of 1 , 1- d ⁇ luoro-4-(4-methylthiophenyl)-2, 4-dioxobutane and 4-methoxyphenyl- hydrazine hydrochloride in acetic acid, which was converted to the desired product, 5-[4-(acetoxymet-hylsulfonyl)phenyl]-3-difluoromethyl- 1-[4- (methoxyphenyl)pyrazole, according to a similar manner to that of Preparation 11 , Example 19 and Example 20.
  • Example 73 l-(3-Chloro ⁇ henyl)-5- ⁇ 4-[(2-hydroxyethyl)sulfonyl]phenyl ⁇ -3- (triflu oromethyl) pyrazole was prepared by a similar procedure to that of Example 3.
  • step one the starting material was hydrolized by a similar method to that of Preparation 14, and followed by alkylation by a similar method to that of Example 3.
  • step one the starting material was hydrolized by similar method as that described for Preparation 14, and followed by alkylation by similar method to that described for Example 3. white crystals. mp ; 1 13-1 14°C

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Abstract

A compound of formula (I), wherein R1 is halo(lower)alkyl, halogen or cyano, R2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino, R3 is hydrogen, hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl, R4 is hydrogen or halogen, Q is pyrazolyl, A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R3 is hydrogen, R2 is aryl substituted with lower alkenyl or A is lower alkylene substituted with oxo, or its salt, processes for their preparation and pharmaceutical compositions.

Description

DESCRIPTION NOVEL COMPOUNDS Technical Field
This invention relates to novel pyrazole compounds and pharmaceutically acceptable salts thereof which have 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 Invention
One object of this invention is to provide novel pyrazole compounds and pharmaceutically acceptable salts thereof which have an inhibiting activity of COX-II.
Another object of this invention is to provide a process for production of the novel pyrazole compounds.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the pyrazole compound or a pharmaceutically acceptable salt thereof.
A still further object of this invention is to provide a use of the novel pyrazole compounds and pharmaceutically acceptable salts thereof for manufacturing a medicament for treating or preventing various diseases.
The present invention relates to novel pyrazole compounds and pharmaceutically acceptable 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. The object pyrazole derivatives of this invention are new and can be represented by the following general formula (I) .
Figure imgf000004_0001
wherein
R1 is halo (lower) alkyl, halogen or cyano,
R2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
R3 is hydrogen, hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
R4 is hydrogen or halogen,
Q is pyrazolyl,
A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R3 is hydrogen, R2 is aryl substituted with lower alkenyl or A is lower alkyl substituted with oxo.
The object compound (I) can be prepared by one of the following processes 1 - 5.
Process l
Figure imgf000005_0001
(II) or its salt
Figure imgf000005_0002
(1-1) or its salt
Process 2
Figure imgf000006_0001
or its salt
(IV)
Figure imgf000006_0002
or its salt
Process 3
Figure imgf000006_0003
Figure imgf000006_0004
or its salt
Process 4
Figure imgf000007_0001
(1-3)
Figure imgf000007_0002
or its salt
Process 5
oxydation
Figure imgf000007_0003
or its salt
Figure imgf000008_0001
or its salt
Reference Processes (1)
Figure imgf000008_0002
or its salt
(2)
Figure imgf000008_0003
or its salt (IV)
wherein R1, R2, R3, A, Q and n are each as defined above, R is lower alkyl, R3a is amino optionally substituted with hydroxy or lower alkyl, R3b is acyloxy,
R3c is lower alkylsulfonyl or lower alkyl sulfinyl, and R3d is hydroxy substituted with acyl.
"Pyrazolyl" includes 1 -pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5- pyrazolyl, in which preferable one is 5-pyrazolyl.
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(halo) alkyl", "lower alkylthio" and "lower alkylsulfonyl" may be a straight or branched one having 1 to 6 carbon atom(s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, in which preferable one is C. -C4 alkyl.
Suitable "lower alkenyl" includes, for example, isopropenyl, vinyl, propenyl, betenyl, pentenyl, hexenyl, in which preferable one is isopropenyl.
Suitable "lower alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert- pentyloxy and hexyloxy, in which preferable one is Cx - C4 alkoxy.
Suitable "lower(halo)alkyl" includes, for example, trifluoromethyl, difluoromethyl, trichloromethyl. and the like.
Suitable "halogen" includes, for example, fluorine, chlorine, bromide and iodide.
Suitable "alkylene" includes, for example, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, ethylidene, and the like.
Suitable "acyl" and acyl moeity in the term "acyloxy" include acyl such as aliphatic acyl, aromatic acyl and heterocyclic acyl.
The aliphatic acyl includes saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g., formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hxanoyl, etc.) , alkylsulfonyl, such as lower alkylsufonyl (e.g. , mesyl, ethyl sulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.) , carbamoyl, N- alkylcarbamoyl (e.g. , methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g. , methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. , vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. , acryloyl, methacryloyl, crotonoyl, etc.) , cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. , cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.) , and the like.
The aromatic acyl may include C6 - C10 aroyl (e.g. , benzoyl, toluoyl, xyloyl, etc.), N-(C6 - C10)arylcarbamoyl (e.g. , N-phenylcarbamoyl, N- tolylcarbamoyl, N-naphthylcarbamoyl, etc.) , C6 - C10 arenesulfonyl (e.g. , benzenesulfonyl, tosyl, etc.) , and the like.
The heterocyclic acyl may include heterocyclic carbonyl (e.g. , furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadeazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
Suitable "aryl" includes, for examle, an aryl having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphtyl, in which preferable one is phenyl and tolyl.
Each of R1 and R2 may attached to any position of the pyrazole ring.
The preferred ones of the compound (I) are compounds having the formula (!')
Figure imgf000011_0001
wherein
R1 is halo (lower) alkyl, halogen or cyano,
R2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
R3 is hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
R4 is hydrogen or halogen,
A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R3 is hydrogen, R2 is aryl substituted with lower alkenyl or A is lower alkylene substituted with oxo, or its salt.
The most preferred ones of the compound (I) are compounds having the formula (F) wherein
R1 is trifluoromethyl, difluoromethyl, chlorine or cyano, R2 is phenyl, tolyl, or phenyl or tolyl substituted with substituent(s) selected from the group consisting of chlorine, fluorine, bromine and methoxy,
R3 is hydroxy, acetoxy, ethoxy, amino, methylamino, methylthio or methylsulfonyl, R4 is hydrogen,
A is dimethylene, trimethylene, methylene or pentamethylene, and n is 2.
The preferred one is the compound selected from the group consisting of (1) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-chloro-4- methoxyphenyl)pyrazole,
(2) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-chloro-4-methoxy-phenyl)- 3-(trifluoromethyl)pyrazole,
(3) l -(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}-3-(triπuoromethyl)pyrazole,
(4) 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole ,
(5) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(6) l -(3-chloro-4-methoxyphenyl)-5-{4-{[2-(methylthio)ethyl]sulfonyl}- phenyl}-3-(trifluoromethyl)pyrazole,
(7) l -(3-chloro-4-methoxyphenyl)-5-{4-[(5-hydroxypentyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(8) l-(3-chloro-4-methoxyphenyl)-5-{4-[(4-hydroxybutyl)sulfonyl]- phenyl}- 3 - (triflu or omethyl) pyrazole ,
(9) l-(3-chloro-4-methoxyphenyl)-5-[4-(ethoxycarbonylmethylsulfonyl)- phenyl] -3 - (triflu oromethyl) pyrazole ,
(10) l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-methylaminoethyl)sulfonyl]- phenyl}-3- (trifluoromethyl)pyrazole,
(1 1) l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-aminoethyl)sulfonyl]phenyl}- 3 - (triflu or omethyl) pyr zole ,
(12) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-acetoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(13) 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-acetoxyethyl)- sulfonyl]phenyl}pyrazole ,
(14) l-(3-chloro-4-methoxyphenyl)-5-{4-{[2-(methylsulfonyl)ethyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole,
(15) 5-{4-[(acetoxymethyl)sulfonyl]phenyl}- l-(4-fluorophenyl)-3- (trifluoromethyl)pyrazole,
(16) l-(4-fluorophenyl-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole ,
(17) 5-{4-[(acetoxymethyl)sulfonyl]phenyl}- l -(4-chloro-3-methoxy- phenyl) -3 - cyanopyrazole ,
(18) l -(4-chloro-3-methoxyphenyl)-5-{4-[2-hydroxyethyl)sulfonyl]- phenyl}-3 -cyanopyrazole,
(19) 5-[4-(acetoxymethylthio)phenyl]- l -(3-chlorophenyl)-3- (trifluoromethyl)pyrazole,
(20) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-chlorophenyl)-3- (trifluoromethyl)pyrazole,
(21) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l -(4-methylphenyl)- pyrazole,
(22) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-methylphenyl)- pyrazole,
(23) 3-chloro- l-(4-isopropenyl-phenyl)-5-[4-(methylsulfinyl)- phenyljpyrazole,
(24) 5-[(4-acetoxymethylthio)phenyl]-3-chloro- l -(isopropenylphenyl)- pyrazole,
(25) 3-chloro- l-(4-isopropenylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}pyrazole ,
(26) 3-chloro- l -(4-isopropenylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyljpyrazole ,
(27) l-(4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(28) l-(4-methylphenyl)-5-{4-[(3-acetoxypropyl)sulfonyl] phenyl}-3- (trifluoromethyl)pyrazole,
(29) l-(4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole ,
(30) 5-[4-(acetoxymethylthio)phenyl]-3-trifluoromethyl- l-[(3-choloro-4- methyl)phenyl]pyrazole ,
(31) l-(3-chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole, (32) l-(3-chloro-4-methylphenyl)-5-{4-[(2-acetoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(33) l-(4-fluoro-3-methylρhenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(34) l-(4-fluoro-3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(35) l-(3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]ρhenyl}-3- (trifluoromethyl)pyrazole,
(36) l-(3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(37) l-(3-fluoro-4-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(38) l-(3-fluoro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole,
(39) 5-{4-[(acetoxymethyl)sulfinyl]-3-fluorophenyl}- l -(3-chloro-4- methoxy-phenyl)-3-(trifluoromethyl)pyrazole,
(40) l -(3-chloro-4-methoxyρhenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]-3- fluorophenyl}-3-(trifluoromethyl)pyrazole,
(41) l-(4-chloro-3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(42) l-( l-hydroxy- l-methylethyl)-5-[4-(methylthio)phenyl]-3-(trifluoro- methyl)pyrazole,
(43) l-(4-isopropenylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (triflu or omethyl) pyrazole,
(44) l-(3-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (triflu or omethyl) pyrazole,
(45) l-(3-chlorophenyl)-5-{4-[(2-methoxyethyl)sulfonyl]ρhenyl}-3- (triflu or omethyl) pyrazole,
(46) l -(4-isopropylphenyl)-5-[4-(acetoxymethylthio)phenyl]-3-(trifluoro- methyl) pyrazole,
(47) l-(4-isopropylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole ,
(48) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-cyano-4-methoxyphenyl)- 3-(trifluoromethyl)pyrazole,
(49) l -(3-cyano-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(50) l -(3-chloro-4-methoxyphenyl)-5-{4-[(3-methoxypropyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(51) l-(3-chloro-4-methoxyphenyl)-5-{4-[(N-hydroxycarbamoyl)- methylsulfonyl]phenyl}-3-(trifluoromethyl)pyrazole,
(52) l -(3-chloro-4-methoxyphenyl)-5-{4-[(methylcarbamoyl)methyl- sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole,
(53) l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-oxopropyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole,
(54) 5-{4-[(3-acetoxypropyl)sulfonyl]phenyl}- l-(3-chloro-4-methoxy- phenyl)-3-(trifluoromethyl)pyrazole,
(55) l -(3-chloro-4-methoxyphenyl)-5-{4-{[3-(dimethylamino)propyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole hydrochloride,
(56) l -(3-chloro-4-methoxyphenyl)-5-{4-{[2-(dimethylamino)ethyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole hydrochloride,
(57) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-chloro-4-methoxyphenyl)- 3-(difluoromethyl)pyrazole,
(58) l -(3-chloro-4-methoxyphenyl)-3-difluoromethyl-5-{4-[(3-hydroxy- propyl) sulfonyl]phenyl}pyrazole ,
(59) l-(3-chloro-4-methoxyρhenyl)-5-{4-{[2-(2-hydroxyethoxy)ethyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole,
(60) 5-[4-(acetoxymethylthio)phenyl]- l-(4-bromo-3-methoxyphenyl)-3- (trifluoromethyl)pyrazole,
(61) l -(4-bromo-3-methoxyρhenyl)-3-trifluoromethyl-5-{4-[(2- hydroxyethyl)sulfonyl]phenyl}pyrazole,
(62) l -(4-bromo-3-methoxyphenyl)-3-trifluoromethyl-5-{4-[(3-hydroxy- propyl) sulfonyl]phenyl}pyrazole , (63) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-difluoromethyl- l-[4- (methoxyphenyl)pyrazole,
(64) l-(4-methoxyphenyl)-3-difluoromethyl-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole ,
(65) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-bromophenyl)- pyrazole,
(66) l-(3-bromophenyl)-3-chloro-5-{4-(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(67) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -(3-fluoro-4-methyl- phenyl)pyrazole,
(68) 3-chloro- l -(3-fluoro-4-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulf onyl]phenyl}pyrazole ,
(69) 5-[(4-acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -(4-fluoro-3-methyl- phenyl)pyrazole ,
(70) 3-chloro- l-(4-fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole ,
(71) 3-chloro- l -(4-fluoro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole,
(72) 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole,
(73) l -(3-chlorophenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole ,
(74) 3-chloro- l -(4-isopropenylphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(75) 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-methoxyethyl)- sulfonyl]phenyl}pyrazole hydrochloride,
(76) 5-[4-(4-acetoxymethylthio)phenyl]-3-chloro- 1 -(4-chloro-3-methyl- phenyl) pyrazole,
(77) 3-chloro- l-(4-chloro-3-methylρhenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole,
(78) 3-chloro- l -(4-chloro-3-methylρhenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole ,
(79) 3-chloro- l -(3-chloro-4-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole ,
(80) 3-chloro- l-(3-chloro-4-methylρhenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole ,
(81) 3-chloro-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- l -(4-methyl- phenyl)pyrazole,
(82) 5-[4-(acetoxymethylthio)ρhenyl]-3-chloro- l -(3-methyl- phenyl) pyrazole,
(83) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-methylphenyl)- pyrazole,
(84) 3-chloro-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- l -(3-methyl- phenyl)pyrazole ,
(85) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-phenylpyrazole,
(86) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -phenylpyrazole,
(87) 3-chloro-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- l-phenyl- pyrazole,
(88) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(4-chloro-3-methoxy- phenyl) pyrazole,
(89) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -(4-chloro-3- methoxyphenyl)pyrazole,
(90) 3-chloro- l -(4-chloro-3-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole ,
(91) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(3-chlorophenyl)- pyrazole,
(92) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-chlorophenyl)- pyrazole,
(93) 3-chloro- l -(3-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole,
(94) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l -(4-chlorophenyl)- pyrazole, (95) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-chlorophenyl)- pyrazole,
(96) 3-chloro- l -(4-chlorophenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- pyrazole,
(97) 3-chloro- l-(4-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(98) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l -(4-fluorophenyl)- pyrazole,
(99) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-fluorophenyl)- pyrazole,
( 100) 3-chloro- l -(4-fluorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
( 101) 5-(4-methylphenyl)- l -{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(102) 5-(4-methylphenyl)- l -{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole, and
(103) 5-(4-chloro-3-methoxyphenyl)- l -{4-[(2-hydroxyethyl)- sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole.
The more preferred one is the compound selected from the group consisting of
( 1) l -(3-chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3 - (trifluor omethyl)pyrazole ,
(2) l -(3-fluoro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3 - (triflu oromethyl)pyrazole ,
(3) l-(4-fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3 - (triflu or omethyl) pyrazole ,
(4) l -(4-bromo-3-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(5) l -(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(6) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(7) 3-chloro- l -(4-isopropenylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}pyrazole ,
(8) 3-chloro- l -(4-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(9) 3-chloro- l -(4-chloro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole,
(10) 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole ,
( 1 1) 3-chloro- l -(4-chloro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole, and
(12) 5-(4-chloro-3-methoxyphenyl)- l -{4-[(2-hydoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole.
The compounds (I) 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 (I) 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 (e.g. sodium salt, potassium salt, cesium salt, etc.) , an alkaline earth metal salt (e.g. calcium salt, magnesium salt etc.) , an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc.) , etc. ; an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methane sulfonate, benzenesulfonate, p-toluenesulfonate, etc.) ; a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.) ; and the like, and the preferable example thereof is an acid addition salt.
The compound (I) 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 (I) which are suitable for biological studies. Process 1
The compound (1- 1 ) can be prepared by reacting the compound (II) or its salt with CH3COONa (sodium acetate) or (CH3CO)20 (acetic anhydride), and then the oxydation. (First step)
The reaction is usually carried out at reflux temperature. The solvents to be used are conventional solvents such as water, alcohol [e.g. , methanol, ethanol, isopropanol, 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 (e.g. , acetic acid) . (Oxydation)
The oxidizing agent to be used is MMPAC (magnesium monoperoxyphthalate) .
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 [e.g. 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 2
The compound (1-2) can be prepared by reacting a compound (IV) or its salt with a compound (V) or its salt.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. , methanol, ethanol, isopropanol, 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 (e.g. , acetic acid).
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming. Process 3
The compound (1-4) or its salt can be prepared from the compound (1-3) or its salt.
Amination can preferably carried out by, for example, reacting the compound (1-4) with a mesylating reagent such as methanesulfonyl chloride and methane sulfonic anhydride to give a mesylate. The solvents to be used are, for example, dichloromethane, chloroform, tetrahydrofuran, or any other organic solvents which do not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Then, the mesylate is reacted with an alkylamine (e.g. , methyl- amine, dimethylamine, ethylamine, etc.) or hydroxyamine. The solvents to be used are, for example, acetonitrile, tetrahydrofuran, toluene, 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 (1-5) can be prepared from the compound (1-3). The acylating agent to be used are, for example, a lower alkanoic anhydride (e.g. , acetic anhydride, etc.) , lower alkanoyl halide (e.g. , acetyl chloride, etc.) , and the like.
The reaction is usually carried out in a solvent such as dichloromethane, tetrahydrofuran, toluene, a 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. Process 5
The compound (1-7) can be prepared by reacting the compound (I- 6) with an oxidizing agent.
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 [e.g. 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 [e.g. 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. Reference Processes
( 1) The compound (II') can be prepared by reacting the compound (V) or its salt with a hydrazine derivative (VI) or its salt.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. , methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroforim, 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 (e.g. , acetic acid.)
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
(2) The compound (IV) can be prepared from the compound (1-5) or its salt in a similar manner to that of Process 2 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 (II) and (V) are, for example, an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) , an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.) , and the like.
The object compound (I) possesses inhibiting activity of COX-II and possesses strong antiinflammatory, analgesic, antithrombotic, anti- cancer activities and so on. The object compound (I) 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, osteo arthritis, gouty arthritis, juvenile arthritis, etc.], inflammatory skin condition [e.g. sunburn, burns, eczema, dermatitis, etc.], inflammatory eye condition [e.g. conjunctivitis, etc.] , lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], condition of the gastrointestinal tract associated with inflammation [e.g. 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 cyclo oxygenase 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 object compound (I) or a salt thereof is expected to be useful as therapeutical and /or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia.
The compound (I) of the present invention has much advantage, 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 arts.
In order to illustrate the usefulness of the object compound (I), the pharmacological test data of the compound (I) are shown in the following.
COX-I and COX-II activity in vitro: (i) 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 μM hematin and 5 mM tryptophan. Broken cells were centrifuged for 5 minutes at 1700 x g at 4°C 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 μg for COX-I and/ or 3 μg for COX-II) in a total volume of 200 μl of reaction buffer were incubated in the absence and presence of various concentrations of inhibitors for 5 minutes at 30°C . The reaction was then started by the addition of arachidonic acid to the final concentration of 10 μM. The reaction was terminated by 50 μl 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 incubated in 0.1 M Tris-HCl buffer (pH 7.3) containing hematin and tryptophan with the addition of arachidonic acid (10 μM) for 5 minutes at 37°C . Compounds were pre-incubated with the enzyme for 5 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after 5 minutes at 37°C by addition of 20 μl of IN HC1. PGE2 formation was measured by radioimmunoassay (Amersham). (ii) Test Results : COX-I and COX-II activity in vitro :
Figure imgf000025_0001
The compound (I) 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 (I) 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 (I) 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 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, 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 (I) 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 (I) 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 (I) 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 following Preparations and Examples are given for the purpose of illustrating this invention. Preparation 1
A mixture containing l -[4-(methylthio)phenyl]-4,4,4-trifluoro- butane- 1 , 3-dione (8.0 g) , (3-chloro-4-methoxy)phenylhydrazine hydrochloride (6.4 g) and acetic acid (45 ml) was stirred at 100- 1 lO'C. After 3 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 an oil (1 1.5 g) . The obtained product was used for next reaction without purification.
This oil was dissolved in dichloromethane ( 100 ml), and 3- chlorobenzoic acid (80%, 5.92 g) was added to this solution over a period of 15 minutes at an ice-bath temperature. After being stirred for 1 hour, the reaction mixture was diluted with dichloromethane (50 ml) and then washed with aqueous sodium carbonate solution (40 ml x 2) and brine. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate to give l -(3- chloro-4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]-3-(trifluoro- methyl) pyrazole (8.95 g) in 71% yield. IR (KBr) : 1505, 1270, 1235, 1 160, 1 135, 1050 cm 1 NMR (CDC13 , δ ) : 2.76(3H,s), 3.93(3H,s) , 6.80-7.67(8H,m) MASS : 415(M+ 1) Preparation 2
A mixture of tert-butyl nitrite (2.6 ml) and copper (II) chloride(2.3 g) in acetonitrile (25 ml) was heated at 60-65°C for 30 minutes. After the reaction mixture was cooled to room temperature, 3-amino- l-(3- chloro-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (5.0 g) was added to the mixture, and then the resulting mixture was stirred for 1.5 hours and concentrated in vacuo. The residue was partitioned between aqueous 10% hydrochloric acid solution and ethyl acetate. The organic layer was separated and washed with brine. The evaporation of the solvent followed by column chromatography on silica gel eluting with dichloromethane gave 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-[4- (methylthio)phenyl]pyrazole (3.1 g) in 58% yield. This product was oxydized by using 3-chloroperbenzoic acid, followed by an usual work- up, to give 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-[4-(methyl- sulfinyl)phenyl]pyrazole (2.6 g) in 80% yield. IR (KBr) : 1505, 1375, 1270, 1055 cm/1
NMR (CDC13 , δ ) : 2.75(3H,s), 3.92(3H,s) , 6.49( lH,s) , 6.82- 7.65(7H,m) MASS : 381 (M+ 1) Preparation 3
A mixture of methyl 4-(4-methylthiophenyl)-2,4-dioxobutanoate (5.0 g) and (4-chloro-3-methoxy)phenylhydrazine hydrochloride (5.2 g) in dioxane (30 ml) and ethanol (30 ml) was stirred at reflux temperature for 3 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate to give methyl (l -(4-chloro-3-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazol- 3-yl}carboxylate (6.4 g) in 83.0% yield.
NMR (CDCI3 , δ ) : 2.49(3H,s), 3.75(3H,s), 3.98(3H,s) , 6.75-7.33(8H,m) MASS : 389(M+ 1) Preparation 4
To methyl (l-(4-chloro-3-methoxyphenyl)-5-[4-(methylthio)- phenyl]pyrazol-3-yl}carboxylate (6.3 g) in formamide (35 ml) was added sodium methoxide (920 mg), and the resulting mixture was heated at 100°C under a nitrogen atmosphere. After 40 minutes the reaction mixture was cooled in an ice bath, and the resulting precipitates were collected by filtration and washed with ethyl acetate to give the desired pyrazole amide (4. 18 g). The amide was added to Vilsmeier reagent, prepared from N,N-dimethylformamide ( 15 ml) and phosphorus oxychloride ( 1.8 ml), at 5°C and then the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the resulting precipitates were collected by filtration and dried at 50°C for 4 hours to afford the desired pyrazole nitrile (4. 1 g) . To this nitrile in dichloromethane (40 ml) was added by portions 3- chloroperbenzoic acid (2.84 g) at an ice-bath temperature. After being stirred at the same temperature for 2 hours, the reaction mixture was diluted with dichloromethane (50ml) and washed successively with aqueous sodium carbonate solution and brine, and dried over magnesium sulfate. The evaporation of the solvent gave l -(4-chloro-3- methoxyphenyl)-3-cyano-5-[4-(methylsulfinyl)phenyl]pyrazole (4. 16 g) in 69.1% yield.
IR (KBr) : 2235, 1590, 1285, 1075 cm 1
NMR (CDC13 , δ ) : 2.76(3H,s) , 3.82(3H,s), 6.66-7.68(8H,m) MASS : 372(M+ 1) Preparation 5 l-(4-Fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3-(trifluoro- methyl)pyrazole was prepared by a similar procedure to that of Preparation 1.
IR (Neat) : 1605, 1245, 1 160, 1 135 cm' 1 NMR (CDCI3 , δ ) : 2.76(3H), 6.82( lH,s) , 7.03-7.67(7H,m) MASS: 369(M+ 1) Preparation 6
To a solution of 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-[4- (acetoxymethylsulfonyl)phenyl]pyrazole (2.0 g) in tetrahydrofuran(12 ml) and methanol (6 ml) was added aqueous IN NaOH solution (4.8 ml) at an ice-bath temperature. After 15 minutes, the reaction mixture was allowed to warm to room temperature. After 30 minutes the reaction mixture was concentrated under reduced pressure to give sodium 4-[3- chloro- 1 -(3-chloro-4-methoxyphenyl)pyrazol-5-yl]benzenesulfinate ( 1.8 g) as a powder.
IR (KBr) : 3400, 1505, 1370, 1265 cm'1
NMR (DMSO-d6, δ ) : 3.87(3H,s), 6.76(lH,s), 7.08-7.51(7H,m)
Preparation 7
Sodium 4-[ l-(3-chloro-4-methoxyphenyl)-3-(trifluoromethyl)- pyrazol-5-yl]benzenesulfinate was prepared by a similar procedure to that of Preparation 6. IR (KBr) : 1645, 1510, 1235, 1 135 cm 1 NMR (DMSO-d6) δ ) : 3.89(3H,s) , 7.15-7.58(8H,m) Preparation 8
Sodium 4-[l -(4-fluorophenyl)-3-(trifluoromethyl)pyrazol-5-yl]- benzenesulfinate was prepared by a similar procedure to that of Preparation 6. Preparation 9
Sodium 4-[ l-(4-chloro-3-methoxyphenyl)-3-cyanopyrazol-5-yl]- benzenesulfinate was prepared by a similar procedure to that of Preparation 6.
IR (KBr) : 2240, 1595, 1490, 1235 cm'1 NMR (DMSO-d6 , δ ) : 3.77(3H,s), 6.79-7.51 (8H,m) Preparation 10
A mixture of l-[4-(methylthio)ρhenyl]-4,4 ,4-trifuluoro-butane- 1 ,3-dione (2.5 g) and 3-chlorophenylhydrazine hydrochloride (2.1 g) in acetic acid (20 ml) was stirred at 120°C for 1.5hr. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and washed successively with saturated sodium carbonate solution and brine, dried over magnesium sulfate. The evaporation of the solvent gave l -(3-chlorophenyl)-5-[4- (methylthio)phenyl]-3-(trifluoromethyl)pyrazole (3.8 g). Preparation 1 1. To a solution of l-(3-chlorophenyl)-5-[4-(methylthio)phenyl]-3- (trifluoromethyl)pyrazole(3.8 g) in methylene chloride (40 ml) was added m-chloroperbenzoic acid (2.34 g: 70% purity) at 0-5°C with ice-water bath. After being stirred for 1 hour, the reaction mixture was washed with saturated sodium carbonate solution and brine, and dried over magnesium sulfate. The evaporation of the solvent gave l-(3- chlorophenyl)-5-[4-(methylsulfinyl)phenyl]-3-(trifluoromethyl)pyrazole (3.76 g) Preparation 12
To a solution of 5-[4-(acetoxymethylsulfonyl)phenyl]- l -(3-chloro- phenyl)-3-(trifluoromethyl)pyrazole (3.05 g) in methanol (75 ml) and tetrahydrofuran ( 15 ml) was added lN-NaOH solution (3.9 ml) at room temperature. After being stirred for 30 minutes, the reaction mixture was evaporated under reduced pressure. The residue was triturated with ethanol to give sodium 4-[l-(3-chlorophenyl)-3-(trifluoro- methyl)pyrazol-5-yl]benzenesulfinate (1.44 g). Preparation 13
3-Chloro- 1 -(4-methylphenyl)-5-[4-(methylthio)phenyl]pyrazole (2.8 g) was dissolved in dichloromethane (30 ml) and cooled with an ice. Meta-chloroperbenzoic acid (1.69 g) was added portionwise to this solution. After stirred for 1 hour, the reaction mixture was quenched with aqueous sodium thiosulfate solution. The aqueous layer was separated, and the organic layer was washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was triturated with isopropyl ether to give a powder, 3-chloro- l -(4-methylphenyl)-5-[4- (methylsulfinyl)phenyl]pyrazole (2.69 g).
NMR (DMSO-d6, δ ) ; 2.33 (3H, s), 2.75 (3H, s), 6.89 ( IH, s) , 7. 18 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz) , 7.67 (2H, d, J=8.4 Hz). IR (KBr): 3464, 3429, 31 16, 1041 , 2993, 2912 cm- 1. Mass m/e : 331 (M++ 1). Preparation 14
To a solution of 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l- (4-methylphenyl) pyrazole (2.65 g) in tetrahydrofuran (20 ml) was added IN NaOH (6.54 ml) at room temperature. After stirred for 1 hour, the reaction mixture was concentrated under reduced pressure. The obtained residue was partitioned between ethyl ether (20ml) and water (20ml). The aqueous phase was separated and concentrated under reduced pressure to give a powder, which was washed with isopropyl ether (20 ml) and collected by filtration, giving 4-[3-chloro- l-(4- methylphenyl)pyrazol-5-yl]benzenesulfinate (2.34 g). NMR (DMSO- d6, δ ) ; 2.32 (3H, s) , 6.75 ( IH, s) , 7. 13-7.25 (6H, m), 7.48 (2H, d, J=8.1 Hz) .
IR (KBr) : 3639, 3535, 3396, 3128, 1664, 1604 cm+ 1. Mass m/e : 333 (M+). Preparation 15
Sodium 4-[3-chloro- 1 -(4-isopropenylphenyl)pyra-zol-5- yl]benzenesulfinate was prepared according to a similar manner to that of Preparation 14.
IR (KBr) : 1645, 1565, 1550, 1515, 1375 cm'1 NMR (DMSO-d6) δ ) : 2.10(3H, s), 5.15(1H, m), 5.50(1H, m), 6.76(1H, s), 7.16-7.58(8H, m) Preparation 16 l-(4-Methylphenyl)-5-[4-(methylsulfinyl)phenyl]-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 1 1. IR (KBr) : 1510, 1465, 1275, 1235, 1 160, 1 125 cm 1 Preparation 17
Sodium 4-[ 1 -(4-methylphenyl)-3-(trifluoromethyl)pyrazol-5-yl]- benzenesulfϊnate was prepared by a similar procedure to that of Example 21 , Example 22 and Preparation 14. IR (KBr) : 1645, 1510, 1280, 1235, 1 160, 1 130 cm- 1
NMR (DMSO-d6, δ ) : 2.34(3H, s) , 7.14-7.44(9H, m) Preparation 18
1 - (4-Methoxyphenyl) -5- [4- (methylsulfinyl)phenyl] -3 - (triflu oromethyl) - pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 11.
IR (Neat) : 1510, 1465, 1240, 1160, 1130, 1100 cm 1 NMR (CDC13, δ ) : 2.75(3H, s), 3.86(3H, s), 6.80-7.63(9H, m). MASS : 381 (M++ 1) Preparation 19
Sodium 4-[l-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazol-5- yl]benzenesulfinate was prepared by a similar procedure to that of Example 19, Example 20 and Preparation 12. IR (KBr) : 1615, 1510, 1465, 1240, 1165, 1 130 cm 1 NMR (DMSO-d6) δ ) : 3.79(3H, s), 6.98-7.44(9H, m) Preparation 20
Sodium 4-[l-( 3 -chloro-4-methylphenyl)-3-(trifluoromethyl)pyrazol-5- yl]benzenesulfinate was prepared by a similar procedure to that of Example 20 and Preparation 12.
IR (KBr) : 3365, 1500, 1270, 1235, 1 160, 1 130 cm 1 NMR (DMSO-d6, S ) : 2.36(3H, s), 7.1 1 -7.53(8H, m) Preparation 21
1 -(4-Fluoro-3-methylphenyl)-5- [4-(methylsulfinyl)phenyl]-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 1 1. IR (Neat) : 1500, 1230, 1160, 1130 cm'1
NMR (CDCI3, δ ) 2.28(3H, s), 2.75(3H, s), 6.81(1H, s), 6.96-7.77(7H, m). MASS : 383(M++1) Preparation 22
Sodium 4-[l-(4-fluoro-3-met-hylphenyl)-3-(tr-iluoromethyl)pyrazol-5- yl]benzenesulfinate was prepared by a similar procedure to that of Example 19, Example 20 and Preparation 12.
IR (KBr) : 1590, 1575, 1502, 1460, 1415, 1250, 1165 cm'1
NMR (DMSO-d6, δ ) : 2.25(3H, s), 7.06-7.59(8H, m)
Preparation 23
1 - (3 -Methylphenyl) -5 - [4- (methylsulfinyl)phenyl] -3 - (triflu oromethyl) - pyrazole was prepared by a similar procedure to that of Preparation 10 and
Preparation 11.
IR (Neat) : 1240, 1 160, 1 130, 1090 cm'1
NMR (CDC13, δ ) : 2.35(3H, s), 2.78(3H, s), 6.81 (1H, s), 6.81-7.63(8H, m). MASS : 365(M++ 1) Preparation 24
Sodium 4-[l-(3-methylphenyl)-3-(trifluoromethyl)pyrazol-5- yl]benzenesulfinate was prepared by a similar procedure to that of Example 19, Example 20 and Preparation 12. IR (KBr) : 1615, 1465, 1275, 1240, 1160, 1130 cm'1 NMR (DMSO-d6, c5 ) : 2.33(3H, s), 6.99-7.44(9H, m) Preparation 25 l-(3-Fluoro-4-methylphenyl)-5-[4-(methylsulfϊnyl)phenyl]-3- (triflu oromethyl) pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 1 1.
IR (KBr) : 1685, 1505, 1460, 1270, 1245, 1160, 1130 cm 1 NMR (CDCI3, δ ) : 2.30(3H, s), 2.76(3H, s), 6.80(1H, s), 6.92-7.66(7H, m). MASS : 383(M+1) Preparation 26
Sodium 4-[l-(3-fluoro-4-methylphenyl)-3-(trifluoromethyl)pyrazol-5- yljbenzenesulfinate was prepared by a similar procedure to that of Example 19, Example 20 and Preparation 12. IR (KBr) : 1590, 1240, 1 165, 1 125 cm'1 NMR (DMSO-d6) δ ) : 2.26(3H, s), 7.02-7.47(8H, m) Preparation 27 l-(3-Chloro-4-methoxyphenyl)-5-(4-methylsulfinyl-3-fluorophenyl)-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of
Preparation 10. mp : 117-119°C
IR (KBr) : 1500, 1270, 1225, 1 155, 1130 cm 1
NMR (CDC13, δ ) : 2.52(3H, s), 3.93(3H, s), 6.73-7.47(7H, m).
MASS : 417(M++1)
Preparation 28
Sodium 2-fluoro-4-[l-(4-methoxy-3-chlorophenyl)-3-(trifluoromethyl)- pyrazol-5-ylJbenzenesulfmate was prepared by a similar procedure to that of Example 20 and Preparation 12. NMR (DMSO-d6) δ ) : 3.90(3H, s), 6.97-7.62(7H, m) Preparation 29 l-(4-Chloro-3-methylphenyl)-5-[4-(methylsulfmyl)phenyl]-3- (trϋluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 11. IR (Neat) : 1475, 1405, 1265, 1235, 1160, 1135 cm'1
NMR (CDCI3, δ ) : 2.37(3H, s), 2.75(3H, s), 6.81(1H, s), 6.91-7.77(7H, m). MASS : 399(M+1) Preparation 30
Sodium 4-[l-(4-chloro-3-met-hylphenyl)-3-(lτ-iluoromethyl)pyrazol-5- yl]benzenesuliinate was prepared by a similar procedure to that of Example 19, Example 20 and Preparation 12. IR (KBr) : 1610, 1475, 1270, 1240, 1160, 1135 cm 1 NMR (DMSO-d6, δ ) : 2.34(3H, s), 7.04-7.52(8H, m) Preparation 31
Sodium 4-[l-(4-isopropenylphenyl)-3-(trifluoromethyl)pyrazol-5- yl]benzenesulfinate was prepared by a similar procedure to that of Example 20 and Preparation 12. The obtained compound could not be chracterized by it spectroscopic data because of containing some by-products and the crude was used for the next reaction without purification. Preparation 32 1 - (3 -Methoxyphenyl) - 5- [4 - (methylsulfinyl)phenyl] -3 - (triflu oromethyl) - pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 11.
IR (Neat) : 1600, 1490, 1465, 1280, 1250, 1215, 1 160 cm'1 NMR (CDC13, δ ) : 2.75(3H, s), 3.76(3H, s), 6.78-8.13(9H, m). MASS : 381(M++1) Preparation 33
Sodium 4-[l-(3-methoxyphenyl)-3-(trifluoromethyl)pyrazol-5-yl]- benzenesulfinate was prepared by a similar procedure to that of Example 19, Example 20 and Pre artion 12.
IR (KBr) : 1605, 1490, 1465, 1435, 1280, 1250, 1220, 1 165, 1130 cm'1 NMR (DMSO-d6 δ ) : 3.72(3H, s), 6.82-7.62(9H, m) Preparation 34
Sodium 4-[l-(4-isopropylphenyl)-3-(trifluorometxιyl)pyrazol-5- yljbenzenesulfinate was prepared by a similar procedure to that of Example 20 and Preparation 12.
NMR (DMSO-d6, δ ) : 1.21 (6H, d, J=7.0Hz), 2.87-3.01(lH, m), 7.14-7.44(9H, m) Preparation 35 l-(3-Cyano-4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]-3- (trϋluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 10 and Preparation 11. mp : 148- 150°C
IR (KBr) : 2235, 1505, 1285, 1235, 1130 cm 1
NMR (CDCI3, δ ) : 2.77(3H, s), 3.98(3H, s), 6.82(1H, s), 6.95-7.69(7H, m). MASS : 406(M++ 1) Preparation 36
Sodium 4-[l-(3-cyano-4-methoxyphenyl)-3-(trifluoromethyl)pyrazol- 5-yl]benzenesu-iϊnate was prepared by a similar procedure to that of Preparation 12. IR (KBr) : 2230, 1645, 1505, 1280 cm'1 NMR (DMSO-d6, δ ) : 3.95(3H, s), 7.17-7.93(8H, m). Preparation 37
Sodium 4-[l-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)pyrazol- 5-yl]benzenesulfinate was prepared by a similar procedure to that of Preparation 6.
IR (KBr) : 1500, 1450, 1270, 1 170 cm 1 NMR (DMSO-d6, £ ) : 3.88(3H, s), 6.82-7.33(9H, m). Preparation 38
Sodium 4-[l-(4-bromo-3-methoxyphenyl)-3-(trifluoromethyl)pyrazol- 5-yl]benzenesulfinate was prepared by a similar manner to that of Example 20 and preparation 12.
IR (KBr) : 1590, 1475, 1405, 1255, 1225, 1 160 cm 1 NMR (DMSO-d6, c5 ) : 3.75(3H, s), 6.73-7.64(8H, m). Preparation 39
Sodium 4-[l-(4-methoxyphenyl)-3-(difluoromethyl)pyrazol-5- yljbenzenesulfϊnate was prepared by a similar procedure to that of Preparation 6.
IR (KBr) : 3401 , 3268, 1616, 1512, 1247, 1033 cm"1 NMR (DMSO-d6, δ ) : 3.78(3H, s), 6.82-7.44(9H, m). Preparation 40 l-(3-Bromophenyl)-3-chloro-5-[4-(methylthio)-phenyl]pyrazole was prepared by the treatment of 4-methylthiocinnamonitrile with 3- bromophenylhydrazine hydrochloride followed by dehydrogenation with MnO2, and chlorination via the corresponding diazonium salt as described in Preparation 2.
IR (Neat) : 1590, 1480, 1370, 1235, 1095 cm'1 NMR (CDC13, <5 ) : 2.49(3H, s), 5.77(1H, s), 7.09-7.59(8H, m). MASS : 379(M+) Preparation 41
Sodium 4-[l-(3-bromophenyl)-3-chloropyrazol-5-yl]benzenesu-iinate was prepared by a similar manner to that of Preparation 14. IR (KBr) : 3375, 3140, 1585, 1475, 1370, 1240 cm'1 Preparation 42
Sodium 4-[l-(3-fluoro-4-methylphenyl)-3-chloropyrazol-5-yl]- benzenesulfinate was prepared by a similar procedure to that of Preparation 6.
IR (KBr) : 1590, 1505, 1370 cm'1
NMR (DMSO-d6, δ ) : 2.24(3H, s), 6.77(1H, s), 6.92-7.68(7H, m). Preparation 43
Sodium 4-[l -(4-fluoro-3-methylphenyl)-3-chloropyrazol-5-yl]- benzenesulfinate was prepared by a similar procedure to that of Preparation 6.
IR (KBr) : 3375, 1500, 1375, 1230 cm 1
NMR (DMSO-d6, δ ) : 2.23(3H, s), 6.77(1H, s), 7.03-7.44(7H, m). Preparation 44
This starting material was prepared by the treatment of 4- methylthiocinnamonitrile and 4-chloro-3-methylphenylhydrazine hydrochloride followed by dehydrogenation with MnO2, which was converted to 3-chloro- l-(4-chloro-3-methylphenyl)-5-[4-(methylthio)phenyl]pyrazole by using a similar manner described in Preparation 2. NMR (CDC13, δ ) : 2.38(3H, s), 2.48(3H, s), 6.40(1H, s), 6.90(1H, dd, J=8.5 and 2.6Hz), 7.10-7.31 (6H, m). MASS : 349 (M+) Preparation 45
Sodium 4-[3-chloro- l-(4-chloro-3-methylphenyl)pyrazol-5- yl]benzenesulfmate was prepared by a similar procedure to that of Example 22 and Preparation 14. Preparation 46
Sodium 4-[3-chloro- l-(3-chloro-4-methylphenyl)pyrazol-5- yl]benzenesulfmate was prepared by a similar procedure to that of Preparation 13, Example 21 , Example 22 and Preparation 14. Preparation 47 3-Chloro- 1 -(3-methylphenyl)-5-[4-(met±ιylsulήιιyl)phenyl]pyrazole was obtained from 3-chloro- l-(3-methylphenyl)-5-[4-(methylthio)- phenyl]pyrazole in the similar manner that of Preparation 13. NMR (DMSO-d6, δ ) : 2.30(3H, s), 2.75(3H, s), 6.90(1H, s), 6.98-7.02(lH, m), 7.22-7.34(3H, m), 7.44(2H, d, J=8.3Hz), 7.67(2H, d, J=8.3Hz). IR (KBr) : 3120, 3049, 2989, 2910 cm 1. Mass m/e : 331 (M++l). Preparation 48
Sodium 4-[3-chloro- 1 -(3-methylphenyl)pyrazol-5-yl]benzenesulfinate was obtained from 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l-(3- methylphenyl)pyrazole in the similar manner that of Preparation 14. NMR (DMSO-d6, δ ) ; 2.31 (3H, s), 6.77(1H, s), 6.93-6.96(lH, m), 7.17-7.32(5H, m), 7.43(2H, d, J=8.1Hz).
IR (KBr) : 3623, 3396, 3363, 3059, 1668, 1616 cm'1' Mass m/e : 333 (M++ l). Preparation 49
3-Chloro- 1 -(3-chlorophenyl)-5-[4-(met-hylsulfinyl)phenyl]pyrazole was prepared by a similar procedure to that of Preparation 13. NMR (CDC13 δ ) : 2.75(3H,s), 6.51(1H, s), 7.05(1H, dt, J=8.2Hz), 7.28- 7.41(3H, m), 7.39(2H, d, J=8Hz), 7.64(2H, d, J=8Hz). IR (KBr) : 1047 cm'1 Mass(m/z) : 351 (M+ 1) Preparation 50
Sodium 4-[3-chloro- 1 -(3-chlorophenyl)pyrazol-5-yl]benzenesulfinate was prepared by a similar procedure to that of Preparation 14. NMR (DMSO-d6, δ ) : 6.80(1H, s), 7.13-7.25(4H, m), 7.24-7.47(4H, m), IR (KBr) : 1621 cm 1 mass (m/z) : 351(M) Preparation 51
3-Chloro- 1 -(4-chlorophenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole was prepared by a similar procedure to that of Preparation 13. NMR (CDCI3, δ ) : 2.76(3H, s), 6.50(1H, s), 7.20(2H, d, J=8.8Hz), 7.33(2H, d, J=9Hz), 7.37(2H, d, J=8Hz), 7.63(2H, d, J=8Hz). IR (KBr) : 1049 cm 1 mass (m/z) : 351(M+1) Preparation 52
Sodium 4-[3-chloro- 1 -(4-chlorophenyl)pyrazole-5-yl]benzenesulfinate was prepared by a similar procedure to that of Preparation 14. NMR (DMSO-d6, δ ) : 6.79(1H, s), 7.20(2H, d, J=8Hz), 7.29(2H, d, J=9Hz), 7.44(2H, d, J=8Hz), 7.50(2H, d, J=9Hz). IR (KBr) : 1617 cm 1 mass (m/z) : 351(M) Preparation 53
Sodium 4-[3-chloro- l-(4-fluorophenyl)pyrazole-5-yl]benzenesulfinate was prepared by a similar procedure to that of Preparation 14. NMR (DMSO-d6, δ ) : 6.79(1H, s), 7.20(2H, d, J=8Hz), 7.24-7.39(4H, m), 7.45(2H, d, J=8Hz). IR (KBr) : 1654 cm'1 mass (m/z) : 335(M) Preparation 54
5-(4-Met±ιylphenyl)-l-[4-(methylsulflnyl)phenyl]-3-(trifluoromethyl)- pyrazol was prepared by a similar procedure to that of Preparation 10 and Preparation 11. Preparation 55
Sodium 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol- 1- yljbenzenesuhinate was prepared by a similar procedure to that of Example 19, Example 20 and Preparation 12. IR (Neat) : 1645, 1565, 1465, 1235, 1135 cm'1 NMR (DMSO-d6, d) : 2.29(3H, s), 7.12-7.64(9H, m). Example 1
A mixture containing 3-chloro- l -(3-chloro-4-methoxyphenyl)-5- [(methylsulfinyl)phenyl]pyrazole (2.5 g), sodium acetate (2.0 g) and acetic anhydride (30 ml) was stirred at reflux temperature for 4 hours. The reaction mixture was cooled and the insoluble materials were removed by filtration. Toluene (50 ml) was added to the filtrate and then the mixture was concentrated under reduced pressure. To the residue was added toluene (50 ml) , and again the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with dichloromethane to give 5-[(acetoxymethylsulfinyl)phenyl]-3-chloro- l -(3-chloro-4- methoxyphenyl) -pyrazole as a synthetic intermediate. To the intermediate in a mixed solvent of dichloromethane (20 ml) and methanol (10 ml) was added magnesium monoperoxyphthlate (6.8 g) with stirring at an ice-bath temperature. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane ( 100 ml) and then washed successively with water, aqueous sodium carbonate solution and brine, and dried over MgS04. The evaporation of the solvent gave a gummy oil, which was crystallized in ethanol and collected by filtration to give 5-[4-(acetoxymethyl- sulfonyl)phenyl]-3-chloro- l-(3-chloro-4-methoxyphenyl)pyrazole (2.4 g) in 80.3% yield. The analytical sample was obtained by re crystallization from ethanol.
IR (KBr) : 1760, 1505, 1320, 1 150, 1060 cm'1
NMR (CDC13 , δ ) : 2.08(3H,s), 3.92(3H,s), 5.16(2H,s) , 6.55(lH,s), 6.84- 7.92(7H,m) MASS : 455(M)
Anal. Calcd for C 1 9 H 1 6 C 1 2 N2 O 5 S : C, 50.12 ; H, 3.54 ; N, 6.15 Found : C, 49.51 ; H, 3.41 ; N, 6.08 mp : 139- 140°C Example 2
5-[4-(Acetoxymethylsulfonyl)phenyl]- l-(3-chloro-4-methoxy- phenyl)-3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 1.
IR (KBr) : 1745, 1505, 1270, 1205, 1 155, 1 125 cm 1
NMR (CDC13 , δ ) : 2.09(3H), 3.94(3H,s) , 5. 16(2H,s), 6.87-7.94(8H,m)
MASS : 489(M+ 1) mp : 86 - 88°C
Example 3
A mixture of sodium 4-[ l -(3-chloro-4-methoxyphenyl)-3- (trifluoromethyl)pyrazol-5-yl]benzenesulfinate (200 mg) and 3- bromopropanol (82 mg) in N,N-dimethylformamide (0.5 ml) was heated at 100°C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4. The evaporation of the solvent gave a gummy oil, which was purified by column chromatography on silica gel with eluting a mixed solvent of ethyl acetate and n-hexane (2 : 1) to give l -(3- chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole (65 mg) as a powder. IR (Neat) : 3480, 1500, 1275, 1230, 1 140 cm'1
NMR (CDCI3 , δ ) : 1.88-2.05(3H,m) , 3.23-3.79(4H,m) , 3.94(3H,s) , 6.84- 7.93(8H,m) MASS : 475(M+ 1) Example 4
3-Chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 3. Purification by column chromatography on silica gel eluting with ethyl acetate followed by trituration in ethanol gave the desired product as a powder. IR (KBr) : 3505, 1505, 1310, 1270, 1 135 cm'1
NMR (CDCI 3 , δ ) : 2.62( lH,t,J=6.0Hz) , 3.35-4.07(4H,m) , 3.93(3H,s), 6.53(lH,s) , 6.84-7.93(7H,m) MASS : 427(M+ 1) Example 5 l-(3-Chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole was prepared by a similar manner to that of Example 3. After purification by column chromatography eluting with ethyl acetate, the desired product was obtained as a powder. IR (KBr) : 3440, 1665, 1500, 1275, 1230, 1 140 cm" 1
NMR (CDC13 , δ ) : 2.61 ( lH,t,J=6.2Hz) , 3.36-4.67(4H.m), 3.93(3H,s), 6.74-8.02(8H,m) MASS : 461(M+ 1) Example 6
A mixture of sodium 4-[l-(3-chloro-4-methoxyphenyl)-3- (trifluoro-methyl)pyrazol-5-yl]benzenesulfinate (300 mg) and 2- chloroethyl methylsulfide ( 101 mg) in N,N-dimethylformamide (0.75 ml) was heated at 100°C in the presence of catalytic amount of potassium iodide. After 1.5 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4 . The evaporation of the solvent gave a gummy oil, which was triturated with n-hexane to give l-(3-chloro-4- methoxyphenyl)-5-{4-{[2-(methylthio)ethyl]sulfonyl}phenyl}-3- (trifluoromethyl)pyrazole (274 mg) as a powder. IR (KBr): 1600, 1500, 1270, 1230, 1 135 cm'1
NMR (CDCl g , δ ) : 2. 10(3H,s), 2.70-4.27(4H,m) , 3.94(3H,s), 6.82- 7.92(8H, m) MASS : 491 (M+ 1)
Anal. Calcd for C2 0 H . 8 ClF3 N2 O3 S2 : C, 48.93 ; H, 3.69 ; N, 5.71 Found : C, 49.18 ; H, 3.68 ; N, 5.60 Example 7
A mixture of sodium 4-[l-(3-chloro-4-methoxyphenyl)-3- (trifluoromethyl)pyrazol-5-yl]benzenesulfinate (200 mg) and 5- chloropentanol (73 mg) in N,N-dimethylformamide (0.5 ml) was heated at 100°C in the presence of potassium iodide as a catalyst. After 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4 .
The evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with ethyl acetate to afford l-(3-chloro-4-methoxyphenyl)-5-{4-[(5-hydroxypentyl)sulfonyl]phenyl}-
3-(trifluoromethyl)pyrazole ( 186 mg) in 81.2% yield.
IR (Neat) : 3405, 1500, 1270, 1235, 1 140 cm 1
NMR (CDC13 , δ ) : 1.31- 1.85(5H,m), 3.08-3.70(6H,m) , 3.94(3H,s) , 6.82-
7.91 (8H,m)
MASS : 503(M+ 1)
Example 8
A mixture of sodium 4-[l-(3-chloro-4-methoxyphenyl)-3- (trifluoromethyl)pyrazol-5-yl]benzenesulfinate (200 mg) and 4- chlorobutanol (64 mg) in N,N-dimethylformamide (0.5 ml) was heated at 100°C in the presence of potassium iodide as a catalyst. Additional 4- chlorobutanol and potassium carbonate were added to the reaction mixture. After 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4 . The evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with ethyl acetate to afford l -(3-chloro-4-methoxyphenyl)-5-{4-[(4- hydroxybutyl)sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (42 mg) in 18.8% yield.
IR (Neat) : 3430, 1505, 1275, 1235, 1 140 cm'1 MASS : 489(M+ 1) Example 9
A mixture of sodium 4-[ l-(3-chloro-4-methoxyphenyl)-3- (trifluoromethyl)pyrazol-5-yl]benzenesulfinate (300 mg) and ethyl bromoacetate ( 126 mg) in N,N-dimethylformamide (0.8 ml) was heated at 100°C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4 . The evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with a mixed solvent of ethyl acetate and n-hexane ( 1 :2) to afford l -(3- chloro-4-methoxyphenyl)-5-[4-(ethoxycarbonylmethylsulfonyl)phenyl]-
3-(trifluoromethyl)pyrazole (200 mg) in 58.1% yield.
IR (KBr) : 1740, 1505, 1330, 1275, 1230, 1 160 cm'1
NMR (CDC13, δ ) : 1.22(3H,t,J=7.0Hz) , 3.92(3H,s) , 4.1 1 (2H,s) ,
4.16(2H,q,J=7.0Hz) , 6.85-7.96(8H,m)
MASS : 503(M+ 1)
Example 10
To a stirred solution of l -(3-chloro-4-methoxyphenyl)-5-{4-[(2- hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (100 mg) and triethylamine (26 mg) in dichloromethane (5 ml) was added dropwise a solution of methane sulfonyl chloride (25 mg) in dichloromethane (0.5 ml) at an ice-bath temperature. After 40 minutes the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate and then filtered. The filtrate was evaporated under reduced pressure to afford the desired mesylate. To the mesylate in acetonitrile (5 ml) was added 40% aqueous methylamine solution (42 mg) at room temperature and the resulting mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, and dried over MgSO4 . The obtained residue was purified by column chromatography on silica gel eluting with a mixed solvent of ethyl acetate and methanol (10 : 1) to give l-(3- chloro-4-methoxyphenyl)-5-{4-[(2-methylaminoethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole (72 mg) as a powder. IR (KBr) : 3405, 1605, 1505, 1315, 1275, 1230, 1 140 cm'1 NMR (CDCI 3 , δ ) : 2.05( lH,broad s) , 2,46(3H,s) , 3.07(2H,t,J=6.0Hz) , 3.38(2H,t,J=6.0Hz) , 3.94(3H,s) , 6.85-7.93(8H,m) MASS : 474(M+ 1) Example 1 1 l-(3-Chloro-4-methoxyphenyl)-5-{4-[(2-aminoethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole was prepared by a similar manner to that of Example 10.
IR (KBr) : 3465, 1500, 1275, 1230, 1 140 cm"1
NMR (CDC13 , δ ) : 3.03(2H,t,J=6.0Hz) , 3.25(2H,t,J=6.0Hz), 3.93(3H,s) , 6.85-7.91(8H,m) Example 12
A mixture of l -(3-chloro-4-methoxyphenyl)-5-{4-[(2- hydroxyethyl)-sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (70 mg) and acetic anhydride (0.5 ml) was heated at 150°C with stirring. After 2 hours, the reaction mixture was diluted with toluene (20 ml) and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with a mixed solvent of ethyl acetate and n-hexane ( 1 : 1) to give l -(3-chloro-4- methoxyphenyl)-5-{4-[(2-acetoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole (51 mg) as a powder. NMR (CDCI3, δ ) : 1.87(3H,s), 3.48(2H,t,J=6.0Hz) , 3.94(3H,s), 4.41 (2H,t,J=6.OHz) MASS : 503(M+ 1) Example 13
3-Chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-acetoxyethyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 12.
IR (KBr) : 1745, 1505, 1380, 1310, 1245, 1 135 cm"1 NMR (CDC13 , δ ) : 1.87(3H,s) , 3.47(2H,t,J=6.0Hz) , 3.93(3H,s) , 4.41 (2H,t,J=6.0Hz) , 6.52(lH,s), 6.84-7.91 (7H,m) MASS : 469(M-) mp : 1 13 - 1 14°C Example 14
To a solution of l -(3-chloro-4-methoxyρhenyl)-5-{4-{[2-(methyl- thio)ethyl]sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole ( 150 mg) in dichloromethane (5 ml) was added 3-chloroperoxybenzoic acid (70%, 201 mg) at room temperature for 2 days. The reaction mixture was partitioned between dichloromethane and water. The organic layer was separated and washed successively with aqueous sodium carbonate solution and brine, dried over MgSO4 . The evaporation of the solvent gave a gummy oil, which was purified by column chromatography on silica gel eluting a mixed solvent of dichloromethane and methanol (50 :
1), and then crystallized from ethanol to give l -(3-chloro-4- methoxyphenyl)-5-{4-{[2-(methylsulfonyl)ethyl]sulfonyl}phenyl}-3-
(trifluoromethyl)pyrazole (100 mg) in 59% yield.
IR (KBr) : 3430, 1560, 1500, 1375, 1315, 1230, 1140 cm"1
NMR (CDC13, δ) : 3.03(3H,d,10.0Hz), 3.36-4.52(4H,m), 3.94(3H,s),
6.87-7.94(8H,m)
MASS : 523(M+1)
Example 15
5-{4-[(Acetoxymethyl)sulfonyl]phenyl}- l-(4-fluorophenyl)-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 1.
IR (Neat) : 1770, 1605, 1335, 1240, 1200, 1 155 cm'1 NMR (CDCI3 , δ ) : 2.08(3H,s) , 5.17(2H,s), 6.88(lH,s), 7.00-7.95(7H,m) MASS : 443(M+ 1) Example 16 l-(4-Fluorophenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3.
IR (Neat) : 3502, 1605, 1315, 1280, 1245, 1 140 cm'1 NMR (CDCI3 , δ ) : 2.56( lH,t,J=6.0Hz) , 3.36-4.1 l (4H,m), 6.87( lH,s), 7.03-7.96(7H,m) MASS : 415(M+ 1) Example 17
5-{4-[(Acetoxymethyl)sulfonyl]phenyl}- l-(4-chloro-3-methoxy- phenyl) -3 -cyanopyrazole was prepared by a similar procedure to that of
Example 1.
IR (KBr) : 2240, 1765, 1595, 1490, 1330, 1240, 1195, 1145 cm'1
NMR (CDC13 , δ ) : 2.08(3H,s), 3.86(3H,s), 5.16(2H,s), 6.60-7.95(8H,m)
MASS : 446(M+1)
Example 18 l-(4-Chloro-3-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3 -cyanopyrazole was prepared by a similar procedure to that of Example 3.
IR (KBr) : 3500, 2240, 1590, 1485, 1305, 1235, 1 135 cm'1 NMR (CDC13 , δ ) : 2.52( lH,t,J=6.0Hz) , 3.36-4.10(4H,m) , 3.85(lH,s), 6.61-7.97(8H,m) MASS : 418(M+ 1)
Anal. Calcd for C . 9 H . 6 ClN3 O4 S : C, 54.61 ; H, 3.86 ; N, 10.06 Found : C, 54.36 ; H, 3.80 ; N, 9.98 Example 19
A mixture of l-(3-chlorophenyl)-5-[4-(methylsulfinyl)phenyl]-3- (triflu oromethyl) pyrazole (3.7 g) and sodium acetate (2.9 g) in acetic anhydride (20 ml) was refluxed for 4 hours. The reaction mixture was cooled to room temperature, and insoluble were removed by filtration and washed with toluene. The filtrates were evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and washed with saturated sodium carbonate solution and brine, and dried over magnesium sulfate. The evaporation of the solvent gave 5-[4-(acetoxymethylthio)phenyl]- l -(3- chlorophenyl)-3-(trifluoromethyl)pyrazole (3.6 g). Example 20
To a solution of 5-[4-(acetoxymethylthio)phenyl]- l -(3- chlorophenyl)-3-(trifluoromethyl)pyrazole (3.6 g) in methylene chloride (20 ml) and methanol ( 13 ml) was added magnesium monoperoxy- phthalate (7.3 g) at 0-5°C with ice-water bath. After being stirred at room temperature for 1 hour, the reaction mixture washed successively with saturated sodium carbonate solution and brine dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with isopropyl alcohol to give 5-[4-(acetoxymethylsulfonyl)- phenyl]- l-(3-chlorophenyl)-3-(trifluoromethyl)pyrazole (3.05 g). Example 21
To a stirred solution of 3-chloro- l -(4-methylphenyl)-5-[4-(methyl- sulfinyl)phenyl]pyrazole (2.65 g) in acetic anhydride (19 ml) was added sodium acetate (2.43 g) portionwise. After stirred for 3 hour at 180°C, the reaction mixture was cooled to room temperature and then filtered. The filter cake was washed with toluene (20 ml). The filtrate and the washing were combined and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (30 ml) and water (30 ml) . The organic layer was washed successively with aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silicagel eluting with a mixed solvent of ethyl acetate and n-hexane. The fractions containing a desired product were collected and then concentrated under reduced pressure to give 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(4- methylphenyl) pyrazole (2.89 g).
NMR (DMSO-d6, δ ) ; 2.05 (3H, s) , 2.33 (3H, s), 5.53 (2H, s) , 6.80 ( I H, s), 7.15-7.26 (6H, m) , 7.42 (2H, d, J=8.5 HZ).
IR (Neat): 3473, 3134, 3035, 2964, 2927, 2873, 1747, 1601 cm+ 1. Mass m/e : 373 (M++ 1). Example 22
A stirred solution of 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l - (4-methylphenyl)pyrazole (2.81 g) in methanol ( 10 ml) and dichloromethane ( 10 ml) was cooled with an ice. Monoperoxyphthalic acid magnesium salt (5.95 g) was added portionwise to this solution. After 1 hour the reaction mixture was poured into a mixture of water (20 ml) and dichloromethane (20 ml) . The organic layer was separated and washed successively with aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. Evaporation of the solvent followed by triturating the resulting residue with isopropyl ether gave
5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-methylphenyl)- pyrazole (2.71 g).
NMR (DMSO-d6) δ ) ; 2.04 (3H, s) , 2.34 (3H, s) , 5.44 (2H, s), 6.98 (IH, s),
7.17 (2H, d, J=8.5 Hz), 7.25 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5Hz, 1.8 hz) 7.89 (2H, dt, J=8.5Hz, 1.8 Hz)
IR (KBr): 3126, 3072, 3041 , 2993, 2929, 1768 cm+ 1.
Mass m/e : 405 (M++ 1).
Example 23
To a stirred solution of 3-chloro- l-(4-acetylphenyl)-5-[4-(methyl- sulfinyl)phenyl]pyrazole (1.0 g) in tetrahydrofuran (50 ml) was dropwise 1.14 N methyllithium diethyl ether solution (5 ml) at an ice-bath temperature under a nitrogen atomosphere. After the addition was completed, the reaction mixture was allowed to react at room temperature overnight. Aqueous ammonium chloride solution was added to the mixture at an ice-bath temperature. Extraction with ethyl acetate followed by washing with brine and evaporation under reduced pressure gave an oil, which was purified by a column chromatography on silica gel eluting with dichloromethane-methanol (50 : 1) to afford the desired alcohol. This alcohol was dissolved in benzene (10ml), and thionyl chloride (0.3 ml) and pyridine (2 ml) were added. The resulting mixture was heated at 150°C with stirring for 1 hour, and then poured into water. Extraction with ethyl acetate followed by washing with aqueous dilute hydrochloric acid solution and brine, and evaporation under reduced pressure gave a crude product, which was subjected to a column chromatography on silica gel eluting with dichloromethane-n-hexane (3 : 1) to give 3-chloro- l-(4-isopropenyl- phenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole (346 mg) in 50% yield. IR (KBr) : 1600, 1510, 1470, 1430, 1365, 1090 cm 1 NMR (CDClg, δ ) : 2.14(3H, s), 2.48(3H, s), 5.13(1H, m), 5.40(1H, m), 6.40(1H, s), 7.10-7.45(8H, m). MASS : 341(M++1) Example 24
5-[(4-(Acetoxymethylthio)phenyl]-3-chloro- l-(isopropenylphenyl)- pyrazole was prepared according to a similar manner to that of Preparation 13 and Example 21. IR (Neat) : 1745, 1515, 1375, 1210 cm"1
NMR (CDCI3, c5 ) : 2.1 1 (3H, s), 2.14(3H, s), 5.13(1H, m), 5.40(1H, m), 5.44(2H, s), 6.43(1H, s), 7.16-7.46(8H, m). MASS : 399(M++ 1) Example 25
3-Chloro- l-(4-isopropenylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}pyrazole was prepared by a similar procedure to that of Example 3. mp : 158-161°C
IR (KBr) : 1510, 1375, 1305, 1150, 1 1 10 cm"1
NMR (CDCI3, δ ) : 2.15(3H, s), 3.21(3H, s), 3.39(1H, t, J=6.0Hz), 3.76(2H, t, J=6.0Hz), 5.15(1H, m), , 5.40(1H, m), 6.53(1H, s), 7.17-7.89(8H, m). MASS : 417(M++1)
Anal. Calcd for C21H21C1N203S 1 /3H20 : C, 59.64; H, 5.16; N, 6.62. Found : C, 59.72; H, 4.98; N, 6.60. Example 26
3-Chloro- l-(4-isopropenylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyljpyrazole was prepared by a similar procedure to that of Example 3. mp : 122- 125°C
IR (KBr) : 3465, 3435, 1510, 1370, 1305, 1275, 1235, 1 130 cm- 1 NMR (CDC13, δ ) : 2. 15(3H, s) , 3.35-4.19(4H, m) , 5. 16(1H, m) , 5.41 (1H, m), 6.51 -7.91 (9H, m) . MASS : 403(M++ 1) Anal Calcd for C20H21C1N2O3S : C, 58.74; H, 4.85; N, 6.85. Found : C, 58.87; H, 4.69; N, 6.80. Example 27 l-(4-Methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3-
(trifluoromethyl)pyrazole was prepared by a similar procedure to that of
Example 3. mp : 102-104°C
IR (KBr) : 3480, 1510, 1465, 1280, 1235, 1 155, 1120 cm 1 NMR (CDC13, δ ) : 2.40(3H, s), 2.63(1H, t, J=6.0Hz), 3.34-4.19(4H, m), 6.82-7.91(9H, m). MASS : 411(M++1)
Anal. Calcd for C19H17F3N2O3S : C, 55.61 ; H, 4.17; N, 6.82. Found : C, 55.06 ; H, 4.09 ; N, 6.71. Example 28
1 -(4-Methylphenyl)-5-{4-[(3-acetoxypropyl)sulfonyl] phenyl}-3- (triiluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 95-96°C
IR (KBr) : 1735, 1285, 1235, 1 140 cm'1
NMR (CDCI3, δ ) : 2.03-2.16(2H, m), 2.08(3H, s), 2.40(3H, s), 3.14-3.22(2H, m), 4.13(2H, t, J=6.0Hz), 6.85(1H, s), 7.13-7.89(8H, m). MASS : 467(M++ 1)
Anal. Calcd for C22H21F3N2O4S : C, 56.56; H, 4.54; N, 6.00 Found :C, 56.73; H, 4.56; N, 5.94. Example 29 l-(4-Methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (t-rifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 96-98°C
IR (KBr) : 3545, 3480, 1605, 1525, 1315, 1270, 1235, 1165, 1130 cm 1 NMR (CDCI3, δ ) : 2.61 (1H, t, J=6.0Hz), 3.37(2H, t, J=6.0Hz), 3.84(3H, s), 4.03(2H, q, J=6.0Hz), 6.85-7.91(9H, m). MASS : 427(M++1)
Anal. Calcd for C19H17F3N2O4S : C, 53.52; H, 4.02; N, 6.57.
Found : C, 53.28 ; H, 3.99 ; N, 6.47.
Example 30
5- [4-(Acetoxymethylthio)phenyl]-3-triflu oromethyl- l-(3-choloro-4- _ methylphenyl)pyrazole was prepared by a similar method to that of Preparation 10, Preparation 1 1 and Example l9. IR (KBr) : 1745, 1500, 1465, 1230, 1210, 1 160, 1135 cm 1 NMR (CDClg, δ ) : 2.11(3H, s), 2.40(3H, s), 5.45(2H, s), 6.74(1H, s), 6.99- 7.44(7H, m). MASS : 441(M++1) Example 31 l-(3-Chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3.
IR (KBr) : 3495, 1500, 1315, 1275, 1235, 1 135 cm 1
NMR (CDCI3, δ ) : 2.41 (3H, s), 2.59(1H, t, J=6.0Hz), 3.38(2H, t, J=6.0Hz), 4.04(2H, q, J=6.0Hz), 6.85(1H, s), 6.97-7.95(7H, m). MASS : 445(M++ 1) Example 32 l-(3-Chloro-4-methylphenyl)-5-{4-[(2-acetoxyethyl)sulfonyl]phenyl}- 3- (triflu oromethyl)pyrazole was prepared by a similar procedure to that of Example 12 (S9803378). mp : 105-108°C
IR (KBr) : 1740, 1500, 1465, 1395, 1325, 1235, 1150 cm'1 NMR (CDClg, δ ) : 1.87(3H, s), 2.41(3H, s), 3.48(2H, t, J=6.0Hz), 4.18(2H, t, J=6.0Hz), 6.82-7.93(8H, m). MASS : 487(M++1)
Anal. Calcd for C21H18ClF3N2O4S : C, 51.80 ; H, 3.73 ; N, 5.75. Found : C, 51.94 ; H, 3.70 ; N, 5.67. Example 33 l-(4-Fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 80-83°C
IR (KBr) : 3480, 1500, 1310, 1280, 1230, 1 115 cm'1
NMR (CDC13, δ ) : 2.28(3H, s), 2.58(1H, t, J=6.0Hz), 3.37(2H, t, J=6.0Hz), 4.03(2H, q, J=6.0Hz), 6.85(1H, s), 6.97-7.94(7H, m). MASS : 429(M++1)
Anal. Calcd for C19H16F4N2O3S : C, 53. 27 ; H, 3.77 ; N, 6.54. Found : C, 53.03 ; H, 3.70 ; N, 6.53. Example 34 l-(4-Fluoro-3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 93-94°C
IR (KBr) : 1500, 1400, 1310, 1275, 1225, 1 160 cm 1
NMR (CDCI3, δ ) : 2.28(3H, s), 3.21(3H, s), 3.39(2H, t, J=6.0Hz), 3.76(2H, t, J=6.0Hz), 6.85(1H, s), 6.96-7.91 (7H, m).
MASS : 443(M++ 1) Anal. Calcd for C20H18F4N2O3S : C, 54.30; H, 4.10; N, 6.33. Found : C, 53.62 ; H, 3.93 ; N, 6.28. Example 35 l-(3-Methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (t-rifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 89-90°C
IR (KBr) : 1605, 1465, 1310, 1280, 1160, 1135 cm'1
NMR (CDCI3, δ ) : 2.36(3H, s), 3.20(3H, s), 3.39 (2H, t, J=6.0Hz), 3.75(2H, t, J=6.0Hz), 6.85(1H, s), 6.95-7.90(8H, m). MASS : 425(M++1)
Anal. Calcd for C20H19F3N2O3S l /3H2O : C, 55.81 ; H, 4.61 ; N, 6.51. Found : C, 55.89 ; H, 4.46 ; N, 6.63. Example 36
1 - (3-Methylphenyl) -5-{4- [(2 -hydroxyethyl) sulfonyl]phenyl}-3 - (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 92-93°C
IR (KBr) : 3475, 1510, 1465, 1310, 1280, 1240, 1160, 1115 cm'1 NMR (CDC13, δ ) : 2.37(3H, s), 2.60(1H, t, J=6.0Hz), 3.34-3.39(2H, m), 3.99-4.07(2H, m), 6.86(1H, s), 6.93-7.92(8H, m). MASS : 411 (M++1)
Anal. Calcd for C19H17F3N2O3S : C, 55.61 ; H, 4.17; N, 6.82. Found : C, 55.32 ; H, 4.16 ; N, 6.69. Example 37 l-(3-Fluoro-4-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 136-137°C
IR (KBr) : 1595, 1505, 1460, 1400, 1310, 1280, 1245, 1135 cm 1 NMR (CDC13, δ ) : 2.30(3H, s), 3.21(3H, s), 3.40(2H, t, J=6.0Hz), 3.77(2H, t, J=6.0Hz), 6.84(1H, s), 6.90-7.92(7H, m). MASS : 443(M++1)
Anal. Calcd for C20H18F4N2O3S : C, 54.30 ; H, 4.10 ; N, 6.33. Found : C, 54.38 ; H, 4.03 ; N, 6.31. Example 38 l-(3-Fluoro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 100-101°C
IR (KBr) : 3480, 1595, 1470, 1415, 1310, 1280, 1245, 1160, 1120 cm 1 NMR (CDC13, δ ) : 2.31 (3H, s), 2.60(2H, t, J=6.0Hz), 3.38(2H, t, J=6.0Hz), 4.04(2H, q, J=6.0Hz), 6.85(1H, s), , 6.91-7.95(7H, m). MASS : 429(M++ 1) Anal. Calcd for C19H16F4N2O3S : C, 3.27 ; H, 3.77 ; N, 6.54. Found : C, 53.32 ; H, 3.80 ; N, 6.44. Example 39
5-{ 4-[(Acetoxymethyl)sulfinyl]-3-fluorophenyl}- l-(3-chloro-4- methoxyphenyl)-3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of preparation 1 1 and Example 19. IR (Neat) : 1750, 1500, 1270, 1220, 1 150, 1135 cm'1
NMR (CDC13, δ ) : 2.10(3H, s), 3.94(3H, s), 5.41 (2H, s), 6.76-7.51(7H, m). MASS : 475(M+) Example 40 l-(3-Chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]-3- fluorophenyl}-3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. IR (KBr) : 3435, 1615, 1505, 1270, 1130 cm 1
NMR (CDC13, c5 ) : 2.43(1H, t, J=6.0Hz), 3.52-4.25(4H, m), 3.95(3H, s), 6.83-7.937(7H, m). MASS : 479(M++1) Example 41 l-(4-Chloro-3-meth.ylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 132- 133°C
IR (KBr) : 1475, 1405, 1305, 1275, 1240, 1 160, 1140 cm 1 NMR (CDCI3, δ ) : 2.38(3H, s), 3.21(3H, s), 3.40(2H, t, J=6.0Hz), 3.77(2H, t, J=6.0Hz), 6.85(1H, s), 6.90-7.92(7H, m). MASS : 459(M++ 1)
Anal. Calcd for C20H18C1F3N2O3S : C, 52.35; H, 3.95; N, 6.10. Found : C, 51.62 ; H, 3.84 ; N, 6.04. Example 42 l-(4-Isopropenylphenyl)-5-[4-(acetoxymethylthio)phenyl]-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 11 and Example 19. IR (Neat) : 1750, 1460, 1375, 1230, 1130 cm'1
NMR (CDC13, δ ) : 2.12(3H, s), 2.15(3H, s), 5.15(1H, m), 5.40(1H, m), 5.44(2H, s), 6.75(1H, s), 7.17-7.49(8H, m). MASS : 455(M++23) Example 43 l-(4-Isopropenylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 141-143°C
IR (KBr) : 1510, 1305, 1280, 1240, 1140 cm'1
NMR (CDC13, δ ) : 2.15(3H, s), 3.21 (3H, s), 3. 40(2H, t, J=6.0Hz), 3.76(2H, t, J=6.0Hz), 5.17(1H, m), 5.41(1H, m), 6.85(1H, s), 7.22-7.91 (8H, m). MASS : 451(M++1) Example 44
1 - (3 -Methoxyphenyl) -5-{4- [(2 -hydroxyethyl) sulfonyl]phenyl}-3 - (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 115-116°C
IR (KBr) : 3415, 1600, 1315, 1250, 1220, 1 170, 1 135 cm"1 NMR (CDCI3, c5 ) : 2.60(2H, t, J=6.0Hz), 3.37(2H, t, J=6.0Hz), 3.78(3H, s), 4.03(2H, q, J=6.0Hz), 6.76-7.93(9H, m). MASS : 427(M++1)
Anal. Calcd for C19H17F3N2O4S : C, 53.52 ; H, 4.02 ; N, 6.57. Found : C, 53.32 ; H, 4.08 ; N, 6.54. Example 45 l-(3-Chlorophenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (tr-iluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 59-61°C IR (KBr) : 1590, 1475, 1440, 1400, 1370, 1280, 1240, 1145 cm"1 NMR (CDCI3, δ ) : 3.21 (3H, s), 3.40(2H, t, J=6.0Hz); 3.76(2H, t, J=6.0Hz),
6.86(1H, s), 7.06-7.94(8H, m).
MASS : 445(M++1)
Anal. Calcd for C19H16ClF3N2O3S : C, 51.30 ; H, 3.63 ; N, 6.30.
Found : C, 51.14 ; H, 3.49 ; N, 6.26.
Example 46 l-(4-Isopropylphenyl)-5-[4-(acetoxymethylthio)phenyl]-3- (trifluoromethyl)pyrazole was prepared by a similar procedure to that of Preparation 10 and Example 19. IR (Neat) : 1750, 1510, 1465, 1375, 1230, 1 135 cm 1 NMR (CDCI3, δ ) : 1.25(6H, d, J=7.0Hz), 2.87-3.00(lH, m), 5.44(2H, s), 6.74(1H, s), 7.16-7.40(8H, m). MASS : 457(M++23) Example 47 l-(4-Isopropylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (triiluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 147- 150°C
IR (KBr) : 1510, 1465, 1305, 1280, 1240, 1 140 cm'1 NMR (CDC13, δ ) : 1.25(6H, d, J=7.0Hz), 2.84-2.98(lH, m), 3.20(3H, s), 3.39(2H, t, J=6.0Hz), 3.76(2H, t, J=6.0Hz), 6.84-7.90(9H, m). MASS : 453(M++ 1) Example 48
5-[4-(Acetoxymethylsulfonyl)phenyl]- l-(3-cyano-4-methoxyphenyl)-3- (triiluoromethyl)pyrazole was prepared by a similar procedure to that of Example 19 and Example 20.
IR (KBr) : 2230, 1750, 1505, 1290, 1225, 1155, 1 140 cm"1 NMR (CDCI3, δ ) : 2.17(3H, s), 3.98(3H, s), 5.00(2H, ABq, J= 10.0Hz), 6.84(1H, s), 6.96-7.73(7H, m). Example 49 l-(3-Cyano-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(tr-iluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3. mp : 142-143°C
IR (KBr) : 3510, 2230, 1505, 1285, 1235, 1135 cm'1
NMR (CDC13, δ ) : 2.57(1H, t, J=6.0Hz), 3.99(3H, s), 4.03(2H, t, J=6.0Hz
6.87(1H, s), 6.98-7.98(7H, m).
MASS : 474(M++23)
Anal. Calcd for C20H16F3N3O4S : C, 53.21 ; H, 3.57; N, 9.31.
Found : C, 52.68 ; H, 3.56 ; N, 9.14.
Example 50
To a stirred suspension of NaH (about 60%, 12 mg) in N, N- dimethylformamide (0.3 ml) was added a solution of the l-(3-chloro-4- methoxyphenyl) -5-{4- [(3 -hydroxypropyl)sulfonyl] -phenyl}-3- (trϋluoromethyl)pyra--ole (147 mg) in N, N-dimethylformamide (0.4 ml) at an ice bath temperature. After 15 minutes methyl iodide (49mg) in N, N- dimethylformamide (0.3 ml) was added to this mixture at the same temperature. After 15 minutes, the reaction mixture was allowed to react at room temperature for 30 minutes. The mixture was diluted with water and then neutralized by addition of aqueous HC1 dilute solution, and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4. The evaporation of solvent under reduced pressure gave a gummy oil, which was subjected to a column chromatography on silica gel eluting with a mixed solvent of ethyl acetate and n-hexane (2 : 1). Fractions containing the desired product were collected and concentrated under reduced pressure to give l-(3-chloro-4-methoxyphenyl)-5-{4-[(3- methoxypropyl)sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (73 mg). IR (Neat) : 1505, 1270, 1235, 1 145 cm'1
NMR (CDC13) δ ) : 1.95-2.04(2H, m), 3.18-3.47(4H, m) , 3.28(3H, s), 3.94(3H, s), 6.84-7.96(8H, m). Example 51
A mixture of l-(3-chloro-4-methoxyphenyl)-5-{4-[(ethoxycarbonyl)- methylsulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (200 mg), hydroxyamine hydrochloric acid (30 mg) and sodium bicarbonate (55 mg) in ethanol (5 ml) was refluxed with stirring for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4. The evaporation of the solvent followed by column chromatography on silica gel eluting with ethyl acetate gave l-(3- chloro-4-methoxyphenyl)-5-{4-[(N-hydroxycarbamoyl)methylsulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole (48 mg). IR (KBr) : 1740, 1505, 131 (5 5, 1275, 1230, 1160 cm"1 NMR (CDClg, δ ) : 3.91 (3H, s), 4.07(2H, s), 6.86-8.21 (8H, m). MASS : 490(M+1) Example 52
A mixture of l-(3-chloro-4-methoxyphenyl)-5-{4-[(ethoxycarbonyl)- methylsulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (250 mg) and 40% aqueous methylamine solution (0.5 ml) in ethanol (5 ml) was heated at reflux temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20 : 1) as an eluant, giving l-(3-chloro-4-methoxyphenyl)-5-{4- [(methylcarbamoyl)methylsulfonyl]phenyl}-3-(trifluoromethyl)pyrazole (123 mg).
IR (KBr) : 3380, 1670, 1505, 1270, 1230, 1 135 cm"1
NMR (CDC13, δ ) : 2.86(3H, d, J=5.0Hz), 3.93(3H, s), 4.01(2H, s), 6.58(1H, br s), 6.85-7.90(8H, m). MASS : 488(M+1) Example 53 l-(3-Chloro-4-methoxyphenyl)-5-{4-[(2-oxopropyl)sulfonyl]phenyl}-3- (trϋluoromethyl)pyrazole was prepared by a similar procedure to that of Example 7. IR (KBr) : 1725, 1505, 1325, 1270, 1235, 1 160 cm 1 NMR (CDC13, S ) : 2.42(3H, s), 3.94(3H, s), 4.17(2H, s), 6.86-7.89(8H, m). MASS : 473(M+1) Example 54
5-{4-[(3-Acetoxypropyl)sulfonyl]phenyl}- l-(3-chloro-4- methoxyphenyl)-3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 3 and Example 12. IR (KBr) : 1740, 1505, 1260, 1235, 1135 cm'1
NMR (CDC13, S ) : 2.05-2.15(2H, m), 2.09(3H, s), 3.15-3.23(2H, m), 3.94(3H, s), 4.13(2H, t, J=6.0Hz), 6.85-7.94(8H, m). MASS : 539(M+23) API-ES
Anal. Calcd for C22H20C1F3N205S : C, 51.12 ; H, 3.90 ; N, 5.42. Found : C, 50.78 ; H, 3.87 ; N, 5.42. Example 55 l-(3-Chloro-4-methoxyphenyl)-5-{4-{[3-(dimethylamino)propyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole hydrochloride was prepared by a similar procedure to that of Example 10. mp : 213-215°C
IR (KBr) : 2615, 1505, 1280, 1240, 1160 cm 1
NMR (DMSO-dg. S ) : 1.95-2.06(2H, m), 2.70(6H, s), 3.07-3.18(2H, m), 3.46- 3.54(2H, m), 4.01(3H, s), 7.20-7.97(8H, m) MASS : 502(M++l , free)
Anal. Calcd for C22H23C1F3N303S ■ HC1 : C, 49.08; H, 4.49 ; N, 7.80. Found : C, 48.83 ; H, 4.46 ; N, 7.69. Example 56 l-(3-Chloro-4-methoxyρhenyl)-5-{4-{[2- (d--met-hylammo)et-hyl]sulfonyl}-phenyl}-3-(trifluoromethyl)pyrazole hydrochloride was prepared by a similar procedure to that of Example 10. mp : 211-212°C
IR (KBr) : 2560, 2505, 2420, 1505, 1265, 1230, 1155 cm'1 NMR (DMSO-d6, δ ) 2.74(6H, s), 3.34-3.40(2H, m), 3.91 (3H, s), 3.91- 4.00(2H, m), 7.20-7.99(8H, m) MASS : 488(M++ l , free)
Anal. Calcd for C21H21ClF3N3O3S ■ HC1 : C, 48.10 ; H, 4.23 ; N, 8.01.
Found : C, 47.50 ; H, 4.20 ; N, 7.84.
Example 57
5-[4-(Acetoxymethylsulfonyl)phenyl]-l-(3-chloro-4-methoxyphenyl)-_3- (difluoromethyl)pyrazole was prepared according to a similar manner to that of Preparation 10, Preparation 11 , Example 19 and Example 20. IR (KBr) : 1765, 1500, 1330, 1265, 1230, 1150 cm'1
NMR (CDCI3, δ ) : 2.09(3H, s), 3.94(3H, s), 5.16(2H, s), 6.50-7.93(9H, m). MASS : 471(M++1) Example 58 l-(3-Chloro-4-methoxyphenyl)-3-difluoromethyl-5-{4-[(3-hydroxy- propyl)sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 120-122°C
IR (KBr) : 3465, 3440, 1505, 1455, 1410, 1300, 1290, 1265, 1145 cm 1 NMR (CDC13, δ ) : 1.63(1H, t, J=6.0Hz), 1.93-2.07(2H, m), 3.23-3.31(2H, m), 3.76(2H, q, J=6.0Hz), 3.94(3H, s), 6.52-7.92(9H, m). MASS : 457(M+)
Anal. Calcd for C20H19C1F2N2O4S : C, 52.58 ; H, 4.19 ; N, 6.13. Found : C, 52.66 ; H, 4.26 ; N, 5.99. Example 59 l-(3-Chloro-4-methoxyphenyl)-5-{4-{[2-(2-hydroxyethoxy)ethyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole was prepared by a similar procedure to that of Example 7. IR (Neat) : 3495, 1505, 1315, 1270, 1235, 1 140 cm 1 NMR (CDCI3, δ ) : 2.89-4.30(9H, m), 3.94(3H, s), 6.81-7.94(8H, m). MASS : 505(M++1) Example 60
The key intermediate, l-(4-bromo-3-methoxyphenyl)-5-(4- methylthiophenyl)-3-(trifluoromethyl)pyrazole, was prepared by refluxing a mixture of 1 , 1 , l-trifluoro-4-[4-(methylthio)phenyl]-2, 4-dioxobutane and 4-bromo-3-methoxyphenylhydrazine hydrochloride in acetic acid, which was converted to the desired product, 5-[4-(acetoxymethylthio)phenyl]- l- (4-bromo-3-met-hoxyphenyl)-3-(trifluoromet±-yl)pyrazole, according to a similar manner to that of Preparation 1 1 and Example 19. IR (Neat) : 1750, 1595, 1475, 1410, 1255, 1220 cm'1 NMR (CDC13, 5 ): 2.12(3H, s), 3.81(3H, s), 5.45(2H, s), 6.67-7.52(8H, m). MASS : 501(M+) Example 61 l-(4-Bromo-3-methoxyphenyl)-3-trifluoromethyl-5-{4-[(2-hydroxy- ethyl)sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 123-124°C
IR (KBr) : 3505, 1595, 1405, 1280, 1225, 1 135 cm 1
NMR (CDC13, S ) : 2.55(1H, t, J=6.0Hz), 3.39(2H, t, J=6.0Hz), 3.84(3H, s), 4.07(2H, q, J=6.0Hz), 6.59-7.97(8H, m). MASS : 505(M++2 )
Anal. Calcd for C19H16BrF3N2O4S : C, 45.16 ; H, 3.19 ; N, 5.54. Found : C, 45.15 ; H, 3.18 ; N, 5.43. Example 62 l-(4-Bromo-3-methoxyphenyl)-3-trifluoromethyl-5-{4-[(3-hydroxy- propyl)sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 61-65°C
IR (KBr) : 3430, 1595, 1475, 1405, 1310, 1255, 1225, 1 135 cm 1 NMR (CDCl3, d ) : 1.62(1H, t, J=6.0Hz), 1.95-2.08(2H, s), 3.23-3.31(2H, m), 3.77(2H, q, J=6.0Hz), 3.91(3H, s), 6.59-7.94(8H, m). MASS : 519(M+)
Anal. Calcd for C20H18BrF3N2O4S : C, 46.25 ; H, 3.49 ; N, 5.39. Found : C, 46.85 ; H, 3.89 ; N, 5.05. Example 63 The key intermediate, l-(4-methoxyphenyl)-5-(4-methylthiophenyl)- 3-difluoromethylpyrazole, was prepared by refluxing a mixture of 1 , 1- dϋluoro-4-(4-methylthiophenyl)-2, 4-dioxobutane and 4-methoxyphenyl- hydrazine hydrochloride in acetic acid, which was converted to the desired product, 5-[4-(acetoxymet-hylsulfonyl)phenyl]-3-difluoromethyl- 1-[4- (methoxyphenyl)pyrazole, according to a similar manner to that of Preparation 11 , Example 19 and Example 20. IR (KBr) : 1755, 1605, 1515, 1325, 1245, 1160 cm 1 NMR (CDC13, <5 ) : 3.84(3H, s), 5.15(2H, s), 6.51-7.89(9H, m). MASS : 437(M++1) Example 64 l-(4-Methoxyphenyl)-3-difluoromethyl-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 80-81°C
IR (KBr) : 3470, 1515, 1305, 1240, 1135 cm 1
NMR (CDC13, S ) :, 2.64(1H, t, J=6.0Hz), 3.37(2H, t, J=6.0Hz), 3.84(3H, s), 4.03(2H, q, J=6.0Hz), 6.51-7.90(9H, m). MASS : 409(M++1)
Anal. Calcd for C19H18F2N2O4S : C, 55.88 ; H, 4.44 ; N, 6.86. Found : C, 55.28; H, 4.37; N, 6.72. Example 65
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- l-(3-bromophenyl)- pyrazole was prepared by a similar manner to that of Preparation 13, Example 19 and Example 20.
IR (KBr) : 1760, 1585, 1480, 1370, 1330, 1205 cm'1 NMR (CDCl3, 5 ) : 2.09(3H, s), 5.16(2H, s), 6.56(1H, s), 7.01-7.93(8H, m). MASS : 469(M+) Example 66 l-(3-Bromophenyl)-3-chloro-5-{4-(3-hydrox\ ropyl)sulfonyl]phenyl}- pyrazole was prepared by a similar manner to that of Example 3. IR(Neat) : 3435, 1585, 1480, 1370, 1310, 1145 cm
NMR (CDCl3,d) ) : 1.63(1H, br s), 1.93-2.07(2H, m), 3.23-3.31(2H, m), 3.50-
3.76(2H, m), 6.54(1H, s), 7.05-7.92(8H, m).
MASS : 519(M++2)
Example 67
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- l-(3-fluoro-4-methyl- phenyl)pyrazole was prepared by a similar procedure to that of Preparation 13, Example 21 and Example 22.
IR (KBr) : 1770, 1595, 1505, 1435, 1370, 1320, 1195 cm"1 NMR (CDCl3, c5 ) : 2.09(3H, s), 2.29(3H, s), 5.30(2H, s), 6.54(1H, s), 6.83- 7.92(7H, m). MASS : 423(M++ 1) Example 68
3-Chloro- l-(3-fluoro-4-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 126-128°C
IR (KBr) : 1590, 1510, 1370, 1300, 1270, 1240, 1130 cm'1 NMR (CDC13, δ ) : 1.64(1H, t, J=6.0Hz), 1.94-2.08(2H, m), 3.23-3.31(2H, m), 3.75(2H, q, J=6.0Hz), 6.52(1H, s), 6.84-7.91 (7H, m). MASS : 409(M++1)
Anal. Calcd for C19H18ClFN2O3S : C, 5 5.81 ; H, 4.44 ; N, 6.85. Found : C, 56.00 ; H, 4.48 ; N, 6.55. Example 69
5-[(4-Acetoxymethylsulfonyl)phenyl]-3-chloro- l-(4-fluoro-3-methyl- phenyl)pyrazole was prepared by a similar manner to that of Preparation 13, Example 21 and Example 22.
IR (KBr) : 3135, 1765, 1595, 1500, 1375, 1335, 1240, 1200 cm 1 NMR (CDC13, 5 ) : 2.07(3H, s), 2.26(3H, s), 5.15(2H, s), 6.55(1H, s), 6.90- 7.90(7H, m). MASS : 423(M++1) Example 70
3-Chloro-l-(4-fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 115-1 17*0
IR (KBr) : 3465, 1500, 1370, 1310, 1280, 1230, 1 135 cm"1 NMR (CDC13> δ ) : 2.26(3H, s), 2.60(1H, t, J=6.0Hz), 3.37(2H, t, J=6.0Hz), 4.03(2H, t, J=6.0Hz), 6.54(1H, s), 6.91-7.91(7H, m). MASS : 395(M++1)
Anal. Calcd for C18H16ClFN2O3S : C, 54.75 ; H, 4.09 ; N, 7.09. Found : C, 54.51 ; H, 4.01 ; N, 6.98. Example 71
3-Chloro- l-(4-fluoro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 130-132°C
IR (KBr) : 3505, 3405, 1500, 1375, 1305, 1270, 1230, 1130 cm 1 NMR (CDC13, δ ) : 1.63(1H, t, J=6.0Hz), 1.93-2.07(2H, m), 2.26(3H, s), 3.22-3.29(2H, m), 3.76(2H, q, J=6.0Hz), 6.53(1H, s), 6.91-7.89(7H, m). MASS : 409(M++1)
Anal. Calcd for C19H18ClFN2O3S : C, 55.81 ; H, 4.44 ; N, 6.85. Found : C, 55.49 ; H, 4.39 ; N, 6.69. Example 72
3-Chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole was prepared by a similar manner to that of Example 3. mp : 132- 134°C
IR (KBr) : 3405, 1505, 1370, 1300, 1270, 1 135 cm"1
NMR (CDC13, δ ) : 1.64(1H, t, J=5.0Hz), 1.93-2.06(2H, m), 3.22-3.30(2H, m), 3.75(2H, q, J=6.0Hz), 3.93(3H, s), 6.52(1H, s), 6.84-7.92(7H, m). MASS : 441(M+) Anal. Calcd for C19H18Cl2N2O4S : C, 51.71 ; H, 4.1 1 ; N, 6.35. Found : C, 51.68 ; H, 4.17 ; N, 6.11. Example 73 l-(3-Chloroρhenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (triflu oromethyl) pyrazole was prepared by a similar procedure to that of Example 3.
IR (Neat) : 3460, 1590, 1475, 1280, 1235, 1135 cm"1
NMR (CDClg, δ ) : 3.38(2H, t, J=6.0Hz), 3.78(1H, t, J=6.0Hz), 4.01-4.19(2H, m), 6.84-7.96(9H, m). MASS : 431(M++ 1) Example 74
3-Chloro- l-(4-isopropenylphenyl)-5-(4-[(3-hydroxypropyl)sulfonyl]- phenyljpyrazole was prepared by a similar manner to that of Example 3. mp : 143-145°C
IR (KBr) : 3405, 1595, 1375, 1235, 1135 cm 1
NMR (CDClg, δ ) : 0.79-2.05(6H, m), 3.22-3.78(6H, m), 6.54(1H, s), 7.18- 7.90(8H, m). MASS : 417(M++1) Example 75
3-Chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-methoxyethyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 3. mp : 153-154°C
IR (KBr) : 1600, 1505, 1300, 1270, 1150 cm"1
NMR (CDC13> δ ) : 3.21(3H, s), 3.39(2H, t, J=6.0Hz), 3.75(2H, t, J=6.0Hz), 3.92(3H, s), 6.49(1H, s), 6.83-7.90(7H, m) MASS : 441(M+)
Anal. Calcd for C19H18Cl2N2O4S : C, 51.71 ; H, 4.1 1 ; N, 6.35. Found : C, 51.14 ; H, 3.95 ; N, 6.22. Example 76
5-[4-(4-Acetoxymethylthio)phenyl]-3-chloro- l-(4-chloro-3-methyl- phenyl)pyrazole was prepared was prepared by a similar procedure to that of Preparation 13 and Example 21.
NMR (CDC13, δ ) : 2.1 1 (3H, s), 2.35(3H, s), 5.44(2H, s), 6.42(1H, s), 6.89(1H, dd, J=8.3 and 2.4Hz), 7.13-7.41(6H, m).
Example 77
3-Chloro-l-(4-chloro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 3. mp : 101-103°C
NMR (CDCI3, δ ) : 2.36(3H, s), 2.60(1H, t, J=6.4Hz), 3.37(2H, m), 4.02(2H, m), 6.54(1H, s), 6.87(1H, dd, J=8.6 and 2.4Hz), 7.27(2H, m), 7.43(2H, d, J=8.6Hz), 7.90(2H, d, J=8.6Hz). MASS : 411(M+ )
Anal. Calcd for C18H16Cl2N2O3S : C, 52.56 ; H, 3.92 ; N, 6.81. Found : C, 52.52 ; H, 3.85 ; N, 6.75. Example 78
3-Chloro- 1 -(4-chloro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 3. mp : 113-115°C
NMR (CDClg, δ ) : 1.62(1H, t, J=5.2Hz), 1.97(2H, m), 2.35(3H, s), 3.25(2H, m), 3.75(2H, m), 6.53(1H, s), 6.87(1H, dd, J=8.6 and 2.4Hz), 7.28(2H, m), 7.41(2H, d, J=8.4Hz), 7.89(2H, d, J=8.4Hz). MASS : 425(M+) Example 79
3-Chloro- l-(3-chloro-4-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 3. mp : 105-106°C
NMR (CDCI3, δ ) : 1.67(1H, t, J=5.2Hz), 1.99(2H, m), 2.39(3H, s), 3.27(2H, m), 3.75(2H, q, J=5.7Hz), 6.53(1H, s), 6.94(1H, dd, J=8.0 and 2.2Hz), 7.18(1H, d, J=8.0Hz), 7.35(1H, d, J=2.2Hz), 7.41(2H, d, J=8.6Hz), 7.89(2H, d, J=8.6Hz).
MASS : 425(M+)
Anal. Calcd for C19H18Cl2N2O3S : C, 53.65 ; H, 4.27 ; N, 6.59.
Found : C, 53.60 ; H, 4.21 ; N, 6.51.
Example 80
3-Chloro- l-(3-chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole was prepared by a similar procedure to that of Example 3. mp : 108-110°C
NMR (CDClg, δ ) : 2.39(3H, s), 2.62(1H, t, J=6.4Hz), 3.37(2H, m), 4.04(2H, m), 6.53(1H, s), 6.94(1H, dd, J=8.0 and 2.2Hz), 7.23(1H, d, J=8.0Hz), 7.34(1H, d, J=2.2Hz), 7.42(2H, d, J=8.6Hz), 7.90(2H, d, J=8.6Hz). MASS : 413(M++2)
Anal. Calcd for C18H16Cl2N2O3S : C, 52.56; H, 3.92; N, 6.81. Found : C, 51.92 ; H, 3.85 ; N, 6.62. Example 81
3-Chloro-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- l-(4- methylphenyl)pyrazole was obtained from 4-[3-chloro- l-(4- methylphenyl)pyrazol-5-yl]benzenesulfinate in the similar manner that of Example 3.
NMR (DMSO-d6, δ ) : 1.60- 1.75(2H, m), 2.34(3H, s), 3.28-3.45(4H, m), 4.64(1H, t, J=5.3Hz), 6.96(1H, s), 7.18(2H, d, J=8.5Hz), 7.25(2H, d, J=8.5Hz), 7.51(2H, d, J=8.5Hz), 7.87(2H, d, J=8.5Hz). IR (KBr) : 3512, 3400, 3128, 2964, 2924, 2881 , 1601 cm'1. Mass m/e : 391 (M++l). Example 82
5-[4-(Acetoxymethylthio)phenyl]-3-chloro- 1 -(3-methylphenyl)pyrazole was obtained from 3-chloro-l -(3-methylphenyl)-5-[4-(methyl- sulfinyl)phenyl]pyrazole in a similar manner that of Example 21. NMR (DMSO-d6, δ ) : 2.04(3H, s), 2.31 (3H, s), 5.53(2H, s), 6.82(1H, s), 6.97- 7.01(1H, m), 7.20-7.34(5H, m), 7.42(2H, d, J=8.4Hz). IR (KBr) : 3654, 3118, 3047, 2958, 2924, 2868, 1738, 1603 cm 1. Mass m/e : 373 (M++l). Example 83
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -(3-methylphenyl)- pyrazole was obtained from 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(3- methylphenyl)pyrazole in the similar manner that of Example 22. NMR (DMSO-d6, δ ) : 2.03(3H, s), 2.31(3H, s), 5.44(2H, s), 6.98-7.02(lH, m), 7.00(1H, s), 7.21-7.34(3H, m), 7.54(2H, d, J=8.4Hz), 7.90(2H, d, J=8.4Hz). IR (KBr) : 3516, 3134, 3082, 3008, 2945, 1765 cm 1. Mass m/e : 405 (M++ l). Example 84
3-Chloro-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- l-(3-methylphenyl)- pyrazole was obtained from sodium 4-[3-chloro- l-(3-methylphenyl)- pyrazol-5-yl]benzenesulfinate in the similar manner that of Example 3. NMR (D SO-d6, δ ) : 2.30(3H, s), 3.48(2H, t, J=6.1Hz), 3.62-3.71(2H, m), 4.88(1H, t, J=5.3Hz), 6.97(1H, s), 6.95-7.03(lH, m), 7.20-7.34(3H, m), 7.49(2H, d, J=8.4Hz), 7.88(2H, d, J=8.4Hz). IR (KBr) :3464, 3406, 3132, 3055, 3960, 2916, 1601 cm 1. Mass m/e : 377 (M++ l). Example 85
5-[4-(Acetoxymethylthio)phenyl]-3-chloro- 1 -phenylpyrazole was prepared by a similar method to that of Example 21. yellow oil.
IR (Neat) : 1751 , 1738, 1598, 1490 cm 1.
NMR (DMSO-d6„ δ ) : 2.06(3H, s), 5.53(2H, s), 6.83(1H, s), 7.20-7.50(9H, m). MS (m/z) : 359(M+1). Example 86
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -phenylpyrazole was prepared by a similar method to that of Example 22. white crystals, mp : 139-142°C. IR (KBr) : 1758, 1594, 1492, 1434 cm 1.
NMR (DMSO-d6, δ ) : 2.03(3H, s), 5.43 (2H, s), 7.01(1H, s), 7.20-7.50(5H, m)
7.53(2H, dd, J=7, 2Hz), 7.89(2H, dd, J=7, 2Hz) ,
MS(m/z) : 391 (M+1).
Example 87
3-Chloro-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- l-phenylpyrazole was prepared by the two step procedure. In step one, the starting material was hydrolized by a similar method to that of Preparation 14, and followed by alkylation by a similar method to that of Example 3. white crystals, mp : 1 10-112°C
IR (KBr) : 3500, 3490, 3400, 1596, 1492 cm 1.
NMR (DMSO-d6, δ ) : 1.50- 1.80(2H, m), 3.30-3.50(4H, m), 4.65(1H, t, J=5Hz), 6.99(1H, s), 7.25-7.60(7H, m), 7.87(2H, d, J=8Hz) MS(m/z) : 377(M+1).
Anal. Calcd. for C18H17ClN2O3S : C, 57.37 ; H, 4.55 ; N, 7.43. Found (l /6H2O) : C, 56.92 ; H, 4.60 ; N, 7.37. Example 88
5-[4-(Acetoxymethylthio)phenyl]-3-chloro- l-(4-chloro-3-methoxy- phenyl)pyrazole was prepared by a similar method to that of Example 21. white crystals, mp : 120-124°C
IR (KBr) : 1737, 1594, 1488 cm 1.
NMR (DMSO-d6, δ ) : 2.04(3H, s), 3.75(3H, s), 5.53(2H, s), 6.79(1H, dd, J=8, 2Hz), 6.85(1H, s), 7.15(1H, s), 7.10-7.50(5H, m). MS(m/z) : 423(M+1), 425(M+3). Example 89
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- l-(4-chloro-3-methoxy- phenyl)pyrazole was prepared by a similar method to that of Example 22. white crystals, mp : 124-125°C IR (KBr) : 1766, 1594, 1490, 1459 cm 1.
NMR (DMSO-d6, δ ) : 2.04(3H, s), 3.75(3H, s), 5.44(2H, s), 6.79(1H, dd, J=8,
2Hz), 7.03(1H, s), 7.15(1H, d, J=2Hz), 7.46(1H, d, J=8Hz), 7.57(2H, d,
J=8Hz), 7.92(2H, d, J=8Hz).
MS(m/z) : 455(M+1), 457(M~3)
Example 90
3-Chloro- l-(4-chloro-3-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole was prepared by the two step procedure. In step one, the starting material was hydrolized by similar method as that described for Preparation 14, and followed by alkylation by similar method to that described for Example 3. white crystals. mp ; 1 13-1 14°C
IR (KBr) : 3519, 3465, 3403, 1594, 1488 cm1.
NMR (DMSO-d6, δ ) : 1.50-1.80(2H, m), 3.30-3.50(4H, m), 3.73(3H, s),
4.65(1H, t, J=5Hz), 6.79(1H, dd, J=8, 2Hz), 7.01(1H, s), 7.15(1H, d, J=2Hz),
7.47(1H, d, J=8Hz), 7.56(2H, d, J=8Hz), 7.91(2H, d, J=8Hz).
MS(m/z) : 441(M+1), 443(M+3).
Anal. Calcd for C18H17ClN2O3S : C, 51.71 ; H, 4.1 1 ; N, 6.35.
Found : C, 51.57 ; H, 4.06 ; N, 6.26.
Example 91
5-[4-(Acetoxymethylthio)phenyl]-3-chloro- l-(3-chlorophenyl)-pyrazole was prepared by a similar procedure to that of Example 21.
NMR (CDC13, c5 ) : 2.11 (3H, s), 5.44(2H, s), 6.44(lH,s), 7.06 ( IH ,pd, t, J=8Hz),
7.17(2H ,d, J=8Hz,), 7.19-7.43(3H, m), 7.40(2H, d, J=8Hz).
IR (Neat) : 1747 cm'1 mass (m/z) : 393(M+ 1)
Example 92
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -(3-chlorophenyl)- pyrazole was prepared by a similar procedure to that of Example 22.
NMR (CDC13, δ ) : 2.10(3H, s), 5.16(2H, s), 6.56(1H, s), 7.01 (1H, dt, J=8.1Hz), 7.26-7.47(3H, m), 7.44(2H, d, J=8Hz), 7.91 (2H, d, J=8Hz). IR (KBr) : 1766, 1328, 1151 cm'1 mass (m/z) : 425(M+1) Example 93
3-Chloro- l-(3-chlorophenyl)-5-{ 4-[(3-hydroxypropyl)sulfonyl]phenyl}- pyrazole was prepared a similar procedure to that of Example 3. NMR (CDC13, δ ) : 1.72(1H, t, J=5Hz,), 1.92-2.07(2H, m), 3.22-3.31(2H, m), 3.75(2H, q, J=6Hz), 6.55(1H, s), 7.04(1H, dt, J=8.2Hz), 7.23-7.45(lH, m), 7.42(2H, d, J=9Hz), 7.90(2H, d, J=9Hz). IR (KBr) : 3405, 1305 cm'1 mass (m/z) : 41 1(M+ 1) mp : 108- 1 10°C Example 94
5-[4-(Acetoxymethylthio)phenyl]-3-chloro- l-(4-chlorophenyl)pyrazole was prepared by a similar procedure to that of Example 21. NMR (CDC13, δ ) : 2.11(3H, s), 5.44(2H, s), 6.43(1H, s), 7.15(2H, d, J=9Hz), 7.21(2H, d, J=9Hz), 7.32(1H, d, J=9Hz), 7.39(2H, d, J=9Hz). IR (Neat) : 1745 cm 1 mass (m/z) : 393(M+l) Example 95
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- l-(4-chlorophenyl)- pyrazole was prepared by a similar procedure to that of Example 22. NMR (CDCI3, δ ) : 2.08(3H, s), 5.16(2H, s), 6.56(1H, s), 7.18(2H, d, J=9Hz), 7.35(2H, d, J=9Hz), 7.42(2H, d, J=9Hz), 7.90(2H, d, J=9Hz). IR (KBr) : 1758, 1330, 1149 cm'1 mass (m/z) : 425(M+ 1) Example 96
3-Chloro- l-(4-chlorophenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- pyrazole was prepared by a similar procedure to that of Example 3. NMR (CDCI3, δ ) : 2.61 (1H, t, J=6Hz), 3.35-3.40(2H, m), 4.00-4.09(2H, m), 6.54(1H, s), 7.19(2H, d, J=9Hz), 7.35(2H, d, J=9Hz), 7.42(2H, d, J=9Hz), 7.91 (2H, d, J=9Hz), 7.35(2H, d, J=8.9Hz), 7.42(2H, d, J=8.6Hz), 7.91(2H, d,
J=8.6Hz).
IR (KBr) : 3469, 1309 cm ! mass (m/z) : 397(M+1) mp : 150-151°C
Example 97
3-Chloro- l-(4-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- pyrazole was prepared by a similar procedure to that of Example 3 NMR (CDC13, δ ) : 1.67(1H, t, J=5Hz), 1.94-2.08(2H, m), 3.22-3.31 (2H, m), 3.77(2H, q, J=6Hz), 6.54(1H, s), 7.19(2H, d, J=9Hz), 7.35(2H, d, J=9Hz), 7.41(2H, d, J=9Hz), 7.89(2H, d, J=9Hz). IR (KBr) : 3403, 1305 cm ' mass (m/z) : 41 1(M+1) mp : 156-158°C Example 98
5-[4-(Acetoxymethylthio)phenyl]-3-chloro- l-(4-fluorophenyl)pyrazole was prepared by a similar procedure to that of Example 21. NMR (CDCI3, δ ) : 2.1 1(3H, s), 5.43(2H, s), 6.43(1H, s), 7.04(2H, t, J=9Hz), 7.14(2H, d, J=9Hz), 7.22-7.29(2H, m), 7.38(2H, d, J=9Hz). IR (Neat) : 1747 cm ' mass (m/z) : 377(M+ 1) Example 99
5-[4-(Acetoxymethylsulfonyl)phenyl]-3-chloro- 1 -(4-fluorophenyl)- pyrazole was prepared by a similar procedure to that of Example 22. NMR (CDCI3, δ ) : 2.08(3H, s), 5.15(2H, s), 6.56(1H, s), 7.08(2H, t, J=9Hz), 7.19-7.27(2H, m), 7.41 (2H, d, J=9Hz), 7.89(2H, d, J=9Hz). IR (KBr) : 1770, 1317, 1 157 cm * mass (m/z) : 409(M+ 1) Example 100
3-Chloro- l-(4-fluorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- pyrazole was prepared by a similar procedure to that of Example 3. NMR (CDCI3, δ ) : 1.63(1H, t, J=5Hz), 1.94-2.08(2H, m), 3.26(2H, t, J=8Hz),
2.77(q, J=5Hz), 6.54(1H, s), 7.07(2H, t, J=9Hz), 7.20-7.28(2H, m), 7.40(2H, d, J=8Hz), 7.88(2H, d, J=8Hz).
IR (KBr) : 3403, 1305 cm'1 mass (m/z) : 395(M+1) mp : 125-126°C
Example 101
5-(4-Methylphenyl)- 1 -{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole was prepared by a similar manner to that of Example 3.
IR (Neat) : 1595, 1465, 1320, 1270, 1240, 1 140 cm 1
NMR (CDCI3, δ ) : 2.38(3H, s), 3.22(3H, s), 3.39(2H, t, J=6.0Hz), 3.77(2H, t, J=6.0Hz), 6.75(1H, s), 7.08-7.92(9H, m). MASS : 425(M++ 1) Example 102
5 - (4-Methylphenyl) - 1 -{4- [(2 -hydroxyethyl) sulfonyl]phenyl}-3 - (trifluoromethyl)pyrazole was prepared by a similar manner to that of Example 3.
IR (Neat) : 3475, 1465, 1275, 1235, 1135 cm 1 Example 103
5-(4-Chloro-3-methoxyphenyl)- l-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(t-rifluoromethyl)pyrazole was prepared by a similar manner to that of Example 3.
IR (Neat) : 3480, 1665, 1475, 1315, 1280, 1240, 1140 cm 1 NMR (CDCI3, δ ) : 2.38(3H, s), 2.59 (IH, t, J=6.0Hz), 3.38(2H, t, J=6.0Hz), 4.04(2H, q, J=6.0Hz), 6.86(1H, s), 6.90-8.02(7H, m). MASS : 445(M++ 1)

Claims

CLAIMS 1. A compound of the formula (I):
Figure imgf000076_0001
wherein
R1 is halo (lower) alkyl, halogen or cyano,
R2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
R3 is hydrogen, hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
R4 is hydrogen or halogen,
Q is pyrazolyl,
A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R3 is hydrogen, R2 is aryl substituted with lower alkenyl or A is lower alkylene substituted with oxo, or its salt.
2. A compound of the formula (I')
Figure imgf000076_0002
wherein R1 is halo (lower) alkyl, halogen or cyano,
R2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
R3 is hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
R4 is hydrogen or halogen,
A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R3 is hydrogen, R2 is aryl substituted with lower alkenyl or A is lower alkylene substituted with oxo, or its salt.
3. The compound according to claim 2, wherein
R1 is trifluoromethyl, difluoromethyl, chlorine or cyano,
R2 is phenyl, tolyl, or phenyl or tolyl substituted with substituent(s) selected from the group consisting of chlorine, fluorine, bromine and methoxy,
R3 is hydroxy, acetoxy, ethoxy, amino, methylamino, methylthio or methylsulfonyl,
R4 is hydrogen,
A is dimethylene, trimethylene, methylene or pentamethylene, and n is 2.
4. The compound according to claim 3, which is a compound selected from the group consisting of
(1) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l-(3-chloro-4- methoxyphenyl) pyrazole ,
(2) 5-[4-(acetoxymethylsulfonyl)phenyl]- l -(3-chloro-4-methoxy-phenyl)- 3 - (triflu oromethyl) pyrazole ,
(3) l-(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(4) 3-chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole ,
(5) l -(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3 - (triflu oromethyl)pyrazole ,
(6) l-(3-chloro-4-methoxyphenyl)-5-{4-{[2-(methylthio)ethyl]sulfonyl}- phenyl}-3-(trifluoromethyl)pyrazole,
(7) l-(3-chloro-4-methoxyphenyl)-5-{4-[(5-hydroxypentyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(8) l-(3-chloro-4-methoxyphenyl)-5-{4-[(4-hydroxybutyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(9) l -(3-chloro-4-methoxyphenyl)-5-[4-(ethoxycarbonylmethylsulfonyl)- phenyl]-3-(trifluoromethyl)pyrazole,
( 10) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-methylaminoethyl)sulfonyl]- phenyl}-3- (trifluoromethyl)pyrazole,
(11) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-aminoethyl)sulfonyl]phenyl}- 3 - (triflu oromethyl) pyrazole ,
(12) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-acetoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(13) 3-chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-acetoxyethyl)- sulfonyl]phenyl}pyrazole ,
(14) l-(3-chloro-4-methoxyphenyl)-5-{4-{[2-(methylsulfonyl)ethyl]- sulfonyl}phenyl}- 3- (triflu oromethyl)pyrazole,
(15) 5-{4-[(acetoxymethyl)sulfonyl]phenyl}- l-(4-fluorophenyl)-3- (trifluoromethyl)pyrazole ,
( 16) l-(4-fluorophenyl-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(17) 5-{4-[(acetoxymethyl)sulfonyl]phenyl}- l-(4-chloro-3-methoxy- phenyl) -3 -cyanopyrazole,
( 18) l-(4-chloro-3-methoxyphenyl)-5-{4-[2-hydroxyethyl)sulfonyl]- phenyl}-3 -cyanopyrazole, (19) 5-[4-(acetoxymethylthio)phenyl]- l -(3-chlorophenyl)-3- (trifluoromethyl)pyrazole,
(20) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-chlorophenyl)-3- (trifluoromethyl)pyrazole,
(21) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(4-methylphenyl)- pyrazole,
(22) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-methylphenyl)- pyrazole,
(23) 3-chloro- 1 -(4-isopropenyl-phenyl)-5-[4-(methylsulfinyl)- phenyl]pyrazole ,
(24) 5-[(4-acetoxymethylthio)phenyl]-3-chloro- l -(isopropenylphenyl)- pyrazole,
(25) 3-chloro- l -(4-isopropenylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}pyrazole ,
(26) 3-chloro- l-(4-isopropenylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}pyrazole ,
(27) l-(4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(28) l-(4-methylphenyl)-5-{4-[(3-acetoxypropyl)sulfonyl] phenyl}-3- (trifluoromethyl)pyrazole,
(29) l-(4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(30) 5-[4-(acetoxymethylthio)phenyl]-3-trifluoromethyl- l-[(3-choloro-4- methyl)phenyl]pyrazole,
(31) l-(3-chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(32) l -(3-chloro-4-methylphenyl)-5-{4-[(2-acetoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(33) l-(4-fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(34) l -(4-fluoro-3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(35) l -(3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]ρhenyl}-3- (trifluoromethyl)pyrazole,
(36) l-(3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(37) l -(3-fluoro-4-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(38) l-(3-fluoro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyrazole,
(39) 5-{4-[(acetoxymethyl)sulfinyl]-3-fluorophenyl}- l-(3-chloro-4- methoxy-phenyl)-3-(trifluoromethyl)pyrazole,
(40) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]-3- fluorophenyl}-3-(trifluoromethyl)pyrazole,
(41) l -(4-chloro-3-methylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(42) l-(l-hydroxy- l-methylethyl)-5-[4-(methylthio)phenyl]-3-(trifluoro- methyl) pyrazole ,
(43) l-(4-isopropenylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(44) l-(3-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(45) l -(3-chlorophenyl)-5-{4-[(2-methoxyethyl)sulfonyl]ρhenyl}-3- (trifluoromethyl)pyrazole ,
(46) l -(4-isopropylphenyl)-5-[4-(acetoxymethylthio)phenyl]-3-(trifluoro- methyl)pyrazole ,
(47) l-(4-isopropylphenyl)-5-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole ,
(48) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-cyano-4-methoxyphenyl)- 3 - (triflu or omethyl) pyrazole ,
(49) l -(3-cyano-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole, (50) l-(3-chloro-4-methoxyphenyl)-5-{4-[(3-methoxypropyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyrazole,
(51) l-(3-chloro-4-methoxyphenyl)-5-{4-[(N-hydroxycarbamoyl)- methylsulfonyl]phenyl}-3-(trifluoromethyl)pyrazole,
(52) l-(3-chloro-4-methoxyphenyl)-5-{4-[(methylcarbamoyl)methyl- sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole,
(53) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-oxopropyl)sulfonyl]phenyl}- 3 - (triflu oromethyl)pyrazole ,
(54) 5-{4-[(3-acetoxypropyl)sulfonyl]phenyl}- l-(3-chloro-4-methoxy- phenyl)-3-(trifluoromethyl)pyrazole,
(55) l-(3-chloro-4-methoxyphenyl)-5-{4-{[3-(dimethylamino)propyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole hydrochloride,
(56) l-(3-chloro-4-methoxyphenyl)-5-{4-{[2-(dimethylamino)ethyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole hydrochloride,
(57) 5-[4-(acetoxymethylsulfonyl)phenyl]- l-(3-chloro-4-methoxyphenyl)- 3-(difluoromethyl)pyrazole,
(58) l-(3-chloro-4-methoxyphenyl)-3-difluoromethyl-5-{4-[(3-hydroxy- propyl) sulfonyl]phenyl}pyrazole ,
(59) l-(3-chloro-4-methoxyphenyl)-5-{4-{[2-(2-hydroxyethoxy)ethyl]- sulfonyl}phenyl}-3-(trifluoromethyl)pyrazole,
(60) 5-[4-(acetoxymethylthio)phenyl]- l -(4-bromo-3-methoxyphenyl)-3- (triflu oromethyl) pyrazole ,
(61) l-(4-bromo-3-methoxyphenyl)-3-trifluoromethyl-5-{4-[(2- hydroxyethyl)sulfonyl]phenyl}pyrazole,
(62) l -(4-bromo-3-methoxyphenyl)-3-trifluoromethyl-5-{4-[(3-hydroxy- propyl) sulfonyl]phenyl}pyrazole ,
(63) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-difluoromethyl- l-[4- (methoxyphenyl) pyrazole,
(64) l-(4-methoxyphenyl)-3-difluoromethyl-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole,
(65) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-bromophenyl)- pyrazole,
(66) l-(3-bromophenyl)-3-chloro-5-{4-(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(67) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-fluoro-4-methyl- phenyl)pyr azole ,
(68) 3-chloro- l-(3-fluoro-4-methylρhenyl)-5-{4-[(3-hydroxyρropyl)- sulfonyl]phenyl}pyrazole ,
(69) 5-[(4-acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-fluoro-3-methyl- phenyl)pyrazole ,
(70) 3-chloro- l -(4-fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyrazole ,
(71) 3-chloro- l -(4-fluoro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole,
(72) 3-chloro- l -(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulf onyl ] p h enyl}pyr azole ,
(73) l-(3-chloroρhenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole ,
(74) 3-chloro- l -(4-isopropenylphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyr azole ,
(75) 3-chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(2 -methoxyethyl)- sulfonyl]phenyl}pyr azole hydrochloride ,
(76) 5-[4-(4-acetoxymethylthio)ρhenyl]-3-chloro- l-(4-chloro-3-methyl- phenyl) pyrazole ,
(77) 3-chloro- l-(4-chloro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyr azole ,
(78) 3-chloro- 1 -(4-chloro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyr azole,
(79) 3-chloro- 1 -(3-chloro-4-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyr azole ,
(80) 3-chloro- 1 -(3-chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyr azole , (81) 3-chloro-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- l-(4-methyl- phenyl)pyr azole,
(82) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(3-methyl- phenyl)pyr azole,
(83) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-methylphenyl)- pyrazole,
(84) 3-chloro-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- l-(3-methyl- phenyl) pyrazole,
(85) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l -phenylpyrazole,
(86) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -phenylpyrazole,
(87) 3-chloro-5-{4-[(3-hydroxypropyl)sulfonyl]phenyl}- l -phenylpyrazole,
(88) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(4-chloro-3-methoxy- phenyl) pyrazole ,
(89) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(4-chloro-3- methoxyphenyl)pyr azole,
(90) 3-chloro- l-(4-chloro-3-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole ,
(91) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(3-chlorophenyl)- pyr azole,
(92) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l -(3-chlorophenyl)- pyr azole,
(93) 3-chloro- 1 -(3-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyr azole ,
(94) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(4-chlorophenyl)- pyr azole,
(95) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l-(4-chlorophenyl)- pyr azole,
(96) 3-chloro- 1 -(4-chlorophenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- pyr azole,
(97) 3-chloro- l -(4-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(98) 5-[4-(acetoxymethylthio)phenyl]-3-chloro- l-(4-fluorophenyl)- pyr azole,
(99) 5-[4-(acetoxymethylsulfonyl)phenyl]-3-chloro- l-(4-fluorophenyl)- pyr azole,
(100) 3-chloro- l-(4-fluorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyr azole,
(101) 5-(4-methylphenyl)-l-{4-[(2-methoxyethyl)sulfonyl]phenyl}-3- (trifluoromethyl)pyrazole,
(102) 5-(4-methylphenyl)- l-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-3- (triflu oromethyl) pyrazole, and
(103) 5-(4-chloro-3-methoxyphenyl)- l-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}-3-(trifluoromethyl)pyrazole.
5. The compound according to claim 4, which is a compound selected from the group consisting of
(1) l-(3-chloro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3 - (triflu or omethyl)pyr azole ,
(2) l-(3-fluoro-4-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3-(trifluoromethyl)pyr azole,
(3) l-(4-fluoro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]phenyl}- 3 -(triflu oromethyl) pyrazole,
(4) l-(4-bromo-3-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyr azole,
(5) l-(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyr azole,
(6) l-(3-chloro-4-methoxyphenyl)-5-{4-[(2-hydroxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyr azole,
(7) 3-chloro- 1 -(4-isopropenylphenyl)-5-{4-[(2 -hydroxyethyl)sulfonyl]- phenyl}pyr azole ,
(8) 3-chloro- l -(4-chlorophenyl)-5-{4-[(3-hydroxypropyl)sulfonyl]- phenyl}pyrazole ,
(9) 3-chloro- 1 -(4-chloro-3-methylphenyl)-5-{4-[(2-hydroxyethyl)- sulfonyl]phenyl}pyr azole ,
(10) 3-chloro- l-(3-chloro-4-methoxyphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyr azole ,
(1 1) 3-chloro- l-(4-chloro-3-methylphenyl)-5-{4-[(3-hydroxypropyl)- sulfonyl]phenyl}pyrazole, and
(12) 5-(4-chloro-3-methoxyphenyl)- l-{4-[(2-hydoxyethyl)sulfonyl]- phenyl}-3-(trifluoromethyl)pyr azole.
6. A process for preparing a compound of the formula (I):
Figure imgf000085_0001
wherein
R1 is halo (lower) alkyl, halogen or cyano,
R2 is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, cyano, nitro, lower alkenyl, amino, acyl and hydroxyimino,
R3 is hydrogen, hydroxy, acyloxy, lower alkoxy optionally substituted with lower alkoxy, amino optionally substituted with hydroxy or lower alkyl, lower alkylthio, or lower alkylsulfonyl,
R4 is hydrogen or halogen,
Q is pyrazolyl,
A is lower alkylene optionally substituted with oxo or hydroxy, and n is 0, 1 or 2, provided that when R3 is hydrogen, R2 is aryl substituted with lower alkenyl or A is lower alkylene substituted with oxo, or its salt, which comprises,
(1) reacting a compound of the formula (II)
Figure imgf000086_0001
(II) or its salt
wherein R1, R2, R4, Q and n are as defined above, with CH3COONa or (CH3CO)2O to give a compound of the formula (1- 1)
Figure imgf000086_0002
(1-1) or its salt
wherein R1, R2, R4, Q and n are as defined above, (2) reacting a compound of the formula (IV):
Figure imgf000086_0003
(IV) wherein R1, R2, R4 and Q are as defined above, with a compound (V): R3-A-Hal wherein A and R3 are as defined above, or its salt, to give a compound (1-2):
Figure imgf000087_0001
or its salt
wherein R1, R2, R3, R4, A and Q are as defined above, (3) subjecting a compound of the formula (1-3):
Figure imgf000087_0002
wherein R1, R2, R4, A, Q and n are as defined above, to animation to give a compound of the formula (1-4)
Figure imgf000087_0003
or its salt wherein R3a is amino optionally substituted with hydoxy or lower alkyl, and R1, R2, R4, A, Q and n are as defined above, (4) subjecting a compound of the formula (1-3)
Figure imgf000088_0001
(1-3)
wherein R1, R2, R4, A, Q and n are as defined above, to acylation to give a compound of the formula (1-5)
Figure imgf000088_0002
or its salt
wherein R3b is acyl, and R1, R2, R4, A, Q and n are as defined above, or (5) subjecting a compound of the formula (1-6)
Figure imgf000088_0003
or its salt wherein R is lower alkyl, and R1, R2, R4, A, Q and n are as defined above, to oxydation to give a compound of the formula (1-7)
Figure imgf000089_0001
or its salt
wherein R3c is lower alkylsulfonyl, and R1, R2, R4, A, Q and n are 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.
10. 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 neurodegenerative diseases in human beings or animals.
12. 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 neurodegenerative diseases in human beings or animals.
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WO2004000811A1 (en) * 2002-06-25 2003-12-31 Pharmacia Corporation Arylsulfonylhydroxamic acid and amide derivatives and their use as protease inhibitors
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CN107827820A (en) * 2017-11-10 2018-03-23 山东大学 Pyrazolines aminopeptidase N inhibitor and its preparation method and application
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Cited By (10)

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Publication number Priority date Publication date Assignee Title
WO2004000811A1 (en) * 2002-06-25 2003-12-31 Pharmacia Corporation Arylsulfonylhydroxamic acid and amide derivatives and their use as protease inhibitors
JP2006502980A (en) * 2002-06-25 2006-01-26 ファルマシア・コーポレーション Arylsulfonylhydroxamic acid and amide derivatives and their use as protease inhibitors
EP1539679A2 (en) * 2002-06-28 2005-06-15 Nitromed, Inc. Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxigenase-2 selective inhibitors, compositions and methods of use
EP1539679A4 (en) * 2002-06-28 2007-07-04 Nitromed Inc Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxigenase-2 selective inhibitors, compositions and methods of use
WO2004014430A1 (en) * 2002-08-07 2004-02-19 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a carbonic anhydrase inhibitor for the treatment of neoplasia
WO2004050632A1 (en) * 2002-12-02 2004-06-17 Fujisawa Pharmaceutical Co., Ltd. Pyrazole derivatives useful as cox-i inhibitors
US7183306B2 (en) 2002-12-02 2007-02-27 Astellas Pharma Inc. Pyrazole derivatives
JP2019504879A (en) * 2016-01-05 2019-02-21 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Benzothiazole amphiphile
CN107827820A (en) * 2017-11-10 2018-03-23 山东大学 Pyrazolines aminopeptidase N inhibitor and its preparation method and application
CN107827820B (en) * 2017-11-10 2020-01-07 山东大学 Pyrazoline aminopeptidase N inhibitor and preparation method and application thereof

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