WO2004037793A1 - Derives pyrazole-4-alcanoate inhibant la cyclo-oxygenase et la 5-lipoxygenase - Google Patents

Derives pyrazole-4-alcanoate inhibant la cyclo-oxygenase et la 5-lipoxygenase Download PDF

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Publication number
WO2004037793A1
WO2004037793A1 PCT/JP2003/013596 JP0313596W WO2004037793A1 WO 2004037793 A1 WO2004037793 A1 WO 2004037793A1 JP 0313596 W JP0313596 W JP 0313596W WO 2004037793 A1 WO2004037793 A1 WO 2004037793A1
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compound
reaction
group
pyrazole
formula
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PCT/JP2003/013596
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English (en)
Japanese (ja)
Inventor
Katsuhiro Kawano
Makoto Taniguchi
Atsushi Igarashi
Mie Yamada
Kenji Naito
Yoshihiro Toyota
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Wakamoto Pharmaceutical Co., Ltd.
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Priority to AU2003275637A priority Critical patent/AU2003275637A1/en
Publication of WO2004037793A1 publication Critical patent/WO2004037793A1/fr

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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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel pyrazole-4-alnic acid derivative, a pharmacologically acceptable salt thereof, and a pharmaceutical composition using the same. More specifically, the present invention provides a pyrazole-containing compound having a substituent at the 3-position and 4-position of the 1,5-diarylpyrazole ring, and in particular, the 4-position substituent is arnic acid. (4) The present invention relates to a monoarnic acid derivative, a pharmacologically acceptable salt thereof, and a pharmaceutical composition using the same. Background art
  • Arachidonic acid cascades are known to occur by two different pathways.
  • arachidonic acid is metabolized to prostaglandins by the action of cyclooxygenase.
  • arachidonic acid is metabolized to leukotrienes by the action of lipoxygenase.
  • Ikotorien is is clear that there is a physiological effect that is different from the prostaglandin. especially since LTB 4 is to have a strong leukocyte migratory activity, inflammation via the leukocyte accumulation in inflamed station plant It is thought to be involved in progression and provide an important step against subsequent tissue damage caused by cytokines etc. Synovial fluid from patients with chronic articular rheumatism has been reported to have high LTB4 levels. This suggests involvement in the disease state.
  • Non-steroidal anti-inflammatory drugs such as acetylsalicylic acid, indomethacin, ibuprofen, and diclofenac sodium are widely used as anti-inflammatory and analgesic drugs.
  • NSAID's Non-steroidal anti-inflammatory drugs
  • These existing anti-inflammatory drugs work by inhibiting the cyclooxygenase of the arachidonic acid cascade, but also affect other prostaglandin-regulating processes that are not involved in the inflammatory process. That is, many NSAID's can cause serious side effects, including life-threatening ulcers, when used at high doses.
  • An alternative to NSAID's is the use of steroids, This has even more serious side effects, especially when long-term treatment is performed.
  • the present invention provides a pharmaceutical composition having extremely high safety and utility, which is completely different in structure and action from currently used anti-inflammatory drugs, especially for anti-inflammatory and analgesic drugs.
  • the purpose is to create useful compounds.
  • the present inventors have made intensive studies and have found that a compound represented by the following general formula (I) satisfactorily solves the above object, and thus completed the present invention. That is, the compound of the present invention is a pyrazole-41-alkanoic acid derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.
  • Ar 2 may have the same or different substituents
  • R 2 and R 3 represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a methanesulfonyl group, or a sulfonamide group which may have the same or different substituents. Or a pyridyl group which may have the same or different substituents.
  • R 1 represents a hydrogen atom, a lower alkyl group or a benzyl group (B n).
  • m represents an integer of 1 to 3.
  • Y is a formula
  • R 4 and R 5 may be the same or different and may have a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkyl group substituted with a halogen atom, a -toro group, amino group, Shiano group, or a group represented by the formula one C0 2 R 6 (R 6 is a hydrogen atom or a lower alkyl group), or a pyridyl group which may have a same or different substituents Means a group represented by
  • a pharmaceutical composition containing the pyrazole-4-alkanoic acid derivative of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is also one of the present invention.
  • the pharmaceutical composition of the present invention is capable of producing both prostaglandin and leukotriene. At the same time.
  • Such a pharmaceutical composition of the present invention can be used as an antirheumatic drug, an anti-inflammatory drug or an analgesic.
  • alkanoic acid examples include acetic acid, propionic acid, and butyric acid, and acetic acid is preferred.
  • Examples of the lower alkyl group represented by 1 to! ⁇ 6 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and secondary butyl, and preferably methyl.
  • Examples of the halogen atom include fluorine, chlorine, bromine and iodine, and chlorine is preferable.
  • Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, and an isobutoxy group.
  • Examples of the lower alkyl group which may be substituted with a halogen atom include, for example, a trifluoromethyl group.
  • the physiologically acceptable salt means a salt prepared from a physiologically acceptable non-toxic base including an inorganic base and an organic base.
  • salts derived from an indefinite base include salts of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. And preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from organic bases include, for example, primary, secondary and tertiary amines, substituted amines, including naturally-substituted amines, cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, cafe N, N'-dibenzinoleethylene diamine, getinoleamine, 2 _ dimethylaminoethanol, 2-dimethylaminoethananol, ethanolamine, ethylenediamine, N-ethynolemo / leforin, N-ethinolepiperidine, glucamine, gu ⁇ / cosamine, histidine, hydravamine, isopropinoleamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, proforce, purine, theopromine, Triethylamine, tripropylamine, trimethylamine Tripropyl ⁇ Min, a salt such as
  • a pharmaceutical preparation containing as an active ingredient usually, a pharmacologically acceptable carrier, excipient, diluent, Mix as pharmaceutically acceptable excipients such as solubilizers, tablets (including sugar-coated tablets, film-coated tablets), capsules, powders, granules, injections, drops, suppositories, cataplasms, eye drops Etc. can be administered orally or parenterally.
  • the dose may vary depending on the sex, age, weight or condition of the patient, but it is usually administered in the range of 1 to 200 mg orally per adult.
  • a pharmaceutical composition containing the present compound represented by the general formula (I) or a pharmacologically acceptable salt as an active ingredient has potent anti-inflammatory properties by simultaneously inhibiting the production of both prostaglandin and leukotriene. / Since it can exert an analgesic effect, it can be used as an antirheumatic drug, an anti-inflammatory drug, an analgesic, etc.
  • the compound represented by the general formula (I) can be prepared by various synthetic routes. Representative preparation methods are outlined below. Unless otherwise indicated, A r A r 2, R ⁇ R 2, R 3, R 4, R 5, R 6, m, n, X and Y is a meaning as defined above herein .
  • Reaction step 1 illustrates a method for preparing a compound of formula (VI) via pyrazole ring formation. Reaction process
  • the compound represented by the formula (IV) is obtained by converting a diketone compound represented by the formula ( ⁇ ) into a compound represented by the formula ( ⁇ )
  • Suitable solvents for use in the reaction with hydrazine compounds include alcohols (eg, ethanol, trifluoroethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, and NMP.
  • Preferred solvents for use in this reaction are methanol, ethanol, and acetic acid.
  • the reaction is carried out using a suitable base such as n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine, etc. Perform in the presence.
  • a suitable base such as n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine, etc. Perform in the presence.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C, for about 1 hour to
  • the subsequent hydrolysis reaction is carried out in an inert solvent such as methanol, ethanol, THF or dioxane, using an acidic aqueous solution such as hydrochloric acid or sulfuric acid.
  • This reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 hour to 20 hours.
  • the reduction reaction of the pyrazole compound represented by the formula (IV) is carried out using sodium borohydride, lithium aluminum hydride, sodium borohydride cyanide, or the like in an inert solvent such as methanol, ethanol, THF, or dioxane. .
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 to 20 hours.
  • the halogenation reaction of the pyrazole compound represented by the formula (V) is carried out in a solvent such as water, THF, dioxane, benzene, toluene, acetone, and acetonitrile in a solvent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride,
  • a solvent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride
  • the reaction is performed using phosphorus pentabromide, triphenylphosphite methyl chloride, triphenylenophosphite dibromide, triphenylenophosphine dibromide, thionyl chloride and the like.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 hour to 20 hours.
  • Reaction step 2 illustrates a method for preparing the compounds represented by formulas ( Ia ) and (Ib). Reaction step 2
  • Z represents NH, 0, S.
  • the compound represented by the formula (Ia) can be prepared by reacting a bromo compound represented by the formula () with a compound represented by the formula (V) in a reaction inert solvent.
  • Suitable solvents to use include alcohols (eg, ethanol, trifluoroethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, and NMP.
  • Preferred solvents for use in the reaction are DMF and THF
  • a suitable base such as n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, sodium carbonate, In the presence of quaternary bases such as cesium carbonate, potassium tert-butoxide, triethylamine, pyridine-tetrabutylammonium fluoride, etc.
  • the reaction is generally carried out at a temperature of about 0 ° C. to about 140 ° C., preferably at a temperature of 0 ° C. to 60 ° C. for about 1 hour to 20 hours.
  • the desired compound (la) is obtained.
  • the hydrolysis reaction of the pyrazole compound represented by the formula (lb) is carried out in an inert solvent such as methanol, ethanol, THF, or dioxane, using an aqueous alkali solution such as an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution. You.
  • the reaction is generally performed at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 hour to 20 hours.
  • Reaction step 3 illustrates a method for preparing the compounds represented by formulas (Ic) to (Ih).
  • the compound represented by the formula (Ic) can be prepared by reacting the aldehyde compound represented by the formula (IV) with a phosphonium salt in a reaction inert solvent.
  • Suitable solvents for use in this reaction include alcohols (e.g., ethanol, ethanol, trifluorophenol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, and NMP. it can.
  • Preferred solvents for use in this reaction are DMF and THF.
  • Examples of the phosphonium salt (X) used for this reaction include benzyl triphenyl phospho-bromo bromide.
  • This reaction is carried out using a suitable base, for example, n-butyl lithium (n-BuLi), sodium bicarbonate, sodium hydride, carbon dioxide, It is carried out in the presence of quaternary bases such as cesium carbonate, potassium tert-butoxide, triethylamine, pyridine and tetrabutylammonium fluoride.
  • a suitable base for example, n-butyl lithium (n-BuLi), sodium bicarbonate, sodium hydride, carbon dioxide
  • quaternary bases such as cesium carbonate, potassium tert-butoxide, triethylamine, pyridine and tetrabutylammonium fluoride.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 60 ° C for about 1 hour to 20 hours.
  • the desired compounds (Ic and Id) are obtained.
  • the bromoaddition reaction of the pyrazole compound represented by the formula (Ic) is carried out in a solvent such as water, THF, dioxane, benzene, toluene, acetone, acetonitrile, acetic acid or the like in a solvent such as phosphorus tribromide, phosphorus pentabromide, This is carried out using luphosphite dibromide, triphenyl phosphine dibromide or the like.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 hour to 20 hours.
  • the alkyne reaction of the pyrazole compound represented by the formula (IX) is carried out by using alcohol (for example, ethanol, trifluoroethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, In a solvent such as acetonitrile and NMP, a suitable base such as n-butyllithium (n-BuLi), sodium hydrogencarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, It is carried out in the presence of a quaternary base such as triethylamine, pyridine, sodium amide or tetrabutylammonium fluoride.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 hour to 20 hours.
  • the target compound (Ig) is obtained.
  • the hydrolysis reaction of the pyrazole compounds represented by the formulas (Ic), (Id) and (Ig) is carried out in the same manner as the hydrolysis in the reaction step 2.
  • the target compounds (Ie), (If) and (Ih) are obtained.
  • Reaction step 4 illustrates a method for preparing the compounds represented by formulas (Ii) to (Ip). Reaction step 4
  • the compound represented by the formula (Ii) can be prepared by reacting the aldehyde represented by the formula (IV) with a Grignard reagent in a reaction inert solvent.
  • Suitable solvents for use in this reaction include alcohols (eg, ethanol, trifluoroethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, and NMP. be able to.
  • Grignard reagents used in this reaction include phenylmagnesium bromide, phenylmagnesium chloride, phenolmagnesium chloride and the like.
  • the reaction is generally performed at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 100 ° C for about 1 hour to 20 hours.
  • the target compound (I i) is obtained.
  • the compound represented by the formula (I j) can be prepared by alkylating an alcohol compound represented by the formula (I i).
  • suitable solvents for use in this reaction include alcohols (eg, ethanol, trifluoroethanol, methanol). , Propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, and NMP.
  • the reaction is carried out using a suitable base, for example, n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine-tetrabutyl.
  • Alkylating agents include methyl iodide, methyl bromide and methyl chloride.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 60 ° C for about 1 hour to 20 hours.
  • the target compound (I j) is obtained.
  • the compound represented by the formula (Im) can be prepared by oxidizing an alcohol compound represented by the formula (Ii).
  • suitable solvents for this reaction include alcohols (eg, ethanol, trifluoroethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF S 1,2-dichloroethane. , Dichloromethane and NMP.
  • the oxidizing agent include manganese dioxide and potassium permanganate. This reaction is generally performed at a temperature of about 0 ° C to about 140 ° C for about 1 hour to 20 hours. Thus, the target compound (Im) is obtained.
  • the compound represented by the formula (Io) can be prepared by alkylating a ketone represented by the formula (Im).
  • suitable solvents for use in this reaction include alcohols (eg, ethanol, ethanol, trif-olenor, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA THF, 1,2-dichloroethane, dichloromethane. And NMP.
  • This reaction is carried out in the presence of a suitable acid, for example, tosylic acid, hydrochloric acid, acetic acid and the like.
  • the alkylating agent include trimethyl orthoformate.
  • the reaction is generally performed at a temperature of about 0 ° C to about 140 ° C for about 1 hour to 20 hours. Thus, the target compound (Io) is obtained.
  • reaction step 5 illustrates a method for preparing the compounds represented by formulas (Id) and (Is).
  • the compound represented by the formula (Ir) can be prepared by oxidizing the compound represented by the formula (Iq).
  • suitable solvents for this reaction include alcohols (e.g., ethanol, trifnoreo ethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, dichloromethane, 1 , 2-dichloroethane, chloropho / rem and NMP.
  • the oxidizing agent include perbenzoic acid, metabenzo-perbenzoic acid, and hydrogen peroxide.
  • the reaction is generally performed at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 50 ° C for about 1 hour to 20 hours.
  • the target compound (I r) is obtained.
  • the hydrolysis reaction of the pyrazole aldehyde compound represented by the formula (Ir) is performed in the same manner as in the hydrolysis in the reaction step 2. Thus, the target compound (Is) is obtained.
  • Reaction step 6 illustrates a method for preparing the compounds represented by formulas (It) and (Iu). Reaction step 6
  • the compound represented by the formula (I t) can be prepared by reacting the aldehyde compound represented by the formula (IV) with carporeanone derived from an alkyl phosphonate in a reaction inert solvent. It can.
  • Suitable solvents for use in this reaction include alcohols (e.g., ethanol, trifolenoole ethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, and NMP. it can.
  • the reaction is carried out using a suitable base, for example, n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine. It is carried out in the presence of a quaternary base such as tetrabutylammonium-dimethyl fluoride.
  • a suitable base for example, n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine.
  • a quaternary base such as tetrabutylammonium-dimethyl fluoride.
  • a suitable phase transfer catalyst such as a quaternary ammonium ion such as tri-ammonium chloride, 1-aza-15-crown-15, 15-crown-5 It is carried out in the presence of a crown ether such as Examples of the alkyl phosphonic acid ester used in this reaction include ethyl 3-chlorobenzene phosphine, ethyl 2,5-dichlorobenzene benzolephosphonate, and 2-chloro-141-fluorene. And benzylphosphonate.
  • the reaction is generally carried out at a temperature of about 110 ° C. to about 140 ° C., preferably at a temperature of 110 ° C.
  • the target compound (It) is obtained.
  • the hydrolysis reaction of the pyrazole compound represented by the formula (Ir) is performed in the same manner as in the hydrolysis in the reaction step 2.
  • the target compound (Iu) is obtained.
  • Reaction step 7 illustrates a method for preparing the compounds represented by the formulas (IX) and (Iy).
  • Z represents NH or O.
  • the compound represented by the formula ( ⁇ ) can be prepared by reacting the aldehyde form represented by the formula (IV) with an alkylating agent in a reaction inert solvent.
  • suitable solvents for use in this reaction include alcohols (eg, ethanol, trifanolanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, sulfuric acid, DMA , THF and NMP.
  • Examples of the alkylating agent used in this reaction include methylmagnesium bromide, methylmagnesium chloride, methyllithium and the like.
  • the reaction is generally carried out at a temperature of about 80 ° C to about 140 ° C, preferably at a temperature of about 40 ° C to 100 ° C for about 1 hour to 20 hours.
  • the target compound ( ⁇ ) is obtained.
  • the compound represented by the formula (IX) can be obtained by converting the alcohol represented by the formula ( ⁇ ) with the Mitsunobu reagent and the formula ⁇ ! ⁇ XV by reacting in a reaction inert solvent Can be prepared.
  • Suitable solvents for use in this reaction include benzene, Tonoreen, DMSO, DMF, and DMA S THF and NMP.
  • the Mitsunobu reagent used for this reaction is dibenzylazodiformate, getylazodiformate, diisopropylazodiformate, dimethylazodiformate, 1,1 '-(azodicarbonyl) dipiperidine, ⁇ , ⁇ , ⁇ ', ⁇ , -tetramethylazodicarboxamide, cyanomethylene tree ⁇ -butylphosphorane, and the like.
  • the reaction is carried out with a suitable phosphine, for example, dicyclohexylphenylphosphine, getinolepheninolephosphine, (4-dimethyl / leaminopheninole) dipheninole phosphine, dipheninolein 2-pyridinolephosphine, tri_ ⁇ -ptynolephosphine,
  • a suitable phosphine for example, dicyclohexylphenylphosphine, getinolepheninolephosphine, (4-dimethyl / leaminopheninole) dipheninole phosphine, dipheninolein 2-pyridinolephosphine, tri_ ⁇ -ptynolephosphine
  • the reaction is performed in the presence of tricyclohexynolephosphine, tri- ⁇ -hexynolephosphine, tri- ⁇ -octylphos
  • the hydrolysis reaction of the pyrazole compound represented by the formula (Ix) is performed in the same manner as in the hydrolysis in the reaction step 2. Thus, the target compound (Iy) is obtained.
  • Reaction step 8 illustrates a method for preparing the compounds represented by formulas (I Z ) and (I aa).
  • the hydrolysis reaction of the pyrazole compound represented by the formula (I z) is performed in the same manner as in the hydrolysis in the reaction step 2.
  • the target compound (Iaa) is obtained.
  • Reaction step 9 illustrates a method for preparing the compounds represented by the formulas (I Z ) and (I aa). Reaction step 9
  • the compound represented by the formula (I ab) can be prepared by reacting the promo-form represented by the formula (W) with an arin derivative (XW) in a reaction inert solvent.
  • Suitable solvents for use in this reaction include anocol (eg, ethanol, trifnoreoethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetate-DMA, THF- and NMP. thing JP2003 / 013596 is made.
  • the reaction is carried out using a suitable base, for example, n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine-tetrabutylpyran. It is carried out in the presence of a quaternary base such as sodium fluoride.
  • a suitable base for example, n-butyllithium (n-BuLi), sodium bicarbonate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine-tetrabutylpyran. It is carried out in the presence of a quaternary base such as sodium fluoride.
  • the reaction is generally carried out at a temperature of about 0 ° C to about 140 ° C, preferably at a temperature of 0 ° C to 60 ° C for about 1 hour to 20 hours.
  • the target compound (I ab) is
  • Float RAW 264.7 cells ATCC TIB 71
  • Dulbeccos Modified Eagle's medium DMEM; Nissui Pharmaceutical
  • FBS Cansera International
  • C_ ⁇ 2 incubator 37 ° C, 5% C0 2; SANYO Co.
  • the test drug diluted to a predetermined concentration in the we 1 1 and 1 0 mu 1 Attachment IJtl.
  • Table 2 shows the administration of the compound (indicated by the example number in Examples) per 1 kg of body weight and the survival rate.
  • Example 2 To a solution of the compound of Example 1 (0.1 g, 0.219 mmo 1) in ethanol (3 ml) was added a 4 N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was washed with ether. The aqueous layer was acidified with hydrochloric acid by adding a 4 N aqueous solution of hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.08 g, 85.0%).
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 87.2% using the compound of Example 2 instead of the compound of Example 1.
  • One NMR (CDC 1 3) 6 3. 01 - 3. 04 (4H, m), 3. 35 (2 ⁇ , s), 3. 76 (3 ⁇ , s), 3. 79 (3 ⁇ , s), 6 . 76— 6.85 (4 ⁇ , m), 7.10-7.26 (9 ⁇ , m)
  • Example 81 The title compound was obtained in a yield of 87.2% in the same manner as in Example 1, except that 2,5-dichlorophenol was used instead of phenol.
  • Example 112 In the same manner as in Example 112, the title compound was obtained in a yield of 87.2% by using the compound of Example 94 instead of the compound of Example 26.
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 87.2% by using the compound of Example 81 instead of the compound of Example 1.
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 57.8 ° / using the compound of Example 188 instead of the compound of Example 1. I got it.
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 82.5 ° / using the compound of Example 235 instead of the compound of Example 1. I got it.
  • Example 236 In the same manner as in Example 3, the compound of Example 236 was used instead of the compound of Example 1. To give the title compound in 73.5% yield
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 80.0% using the compound of Example 239 instead of the compound of Example 1.
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 80.0% using the compound of Example 241 instead of the compound of Example 1.
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 64.3% using the compound of Example 24 in place of the compound of Example 1.
  • Example 3 In the same manner as in Example 3, the title compound was obtained in a yield of 94.7 using the compound of Example 245 instead of the compound of Example 1. /. I got it.
  • Example 115 In the same manner as in Example 115, the title compound was obtained in a yield of 96.8% using the compound of Example 303 instead of the compound of Example 5.
  • Example 25 To a solution of 0.4 g (0.85 mmol) of the compound of 1 in 5 ml of acetic acid was added 0.41 g (1.28 mmol) of pyridinium tribromide at room temperature, and the mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained jib mouth was dissolved in 5 ml of dimethyl sulfoxide, 0.13 g (3.4 lmmo 1) of sodium amide was added, and the mixture was stirred at 70 ° C. for 2 hours.
  • Example 207 In the same manner as in Example 207, the title compound was obtained in a yield of 72.6% using the compound of Example 307 instead of the compound of Example 81.
  • Example 1 19.8 ml (19.8 mmo 1) of sodium hydroxide was added to 7 g (19.8 mmo 1) of the compound of 66, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 7.2 g of the title compound.
  • the present invention has the above-mentioned constitution, it is possible to provide a compound which is particularly useful for anti-inflammatory and analgesic, has extremely high safety and usefulness, and a pharmaceutical composition containing the compound as an active ingredient.

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Abstract

La présente invention concerne un dérivé pyrazole-4-alcanoate représenté par la formule (I) dans laquelle chaque substituant est tel que défini dans la revendication n°1; un sel pharmacologiquement acceptable de ce dérivé et une composition médicinale contenant ledit dérivé. Etant donné que ce dérivé inhibe la production de prostaglandine et de leucotriène en même temps, on l'utilise en tant que médicament anti-rhumatoïde, en tant que médicament anti-inflammatoire ou en tant que médicament analgésique. Formule (I)
PCT/JP2003/013596 2002-10-24 2003-10-24 Derives pyrazole-4-alcanoate inhibant la cyclo-oxygenase et la 5-lipoxygenase WO2004037793A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2008003978A3 (fr) * 2006-07-06 2008-12-31 Phytopharm Plc Composés chimiques
EP2135865A1 (fr) 2008-06-17 2009-12-23 Bayer CropScience AG Acides de vinaigre substitués 1-(diazinyle)pyrazole-4-yl, leur procédé de fabrication et d'utilisation en tant qu'herbicides et régulateurs de croissance de plantes
EP2194052A1 (fr) 2008-12-06 2010-06-09 Bayer CropScience AG Acides de vinaigre 1-(thiazolyl) et 1-(Isothiazolyl)pyrazole-4-yl substitués, leur procédé de fabrication et d'utilisation en tant qu'herbicides et régulateurs de croissance des plantes
WO2011073098A1 (fr) 2009-12-15 2011-06-23 Bayer Cropscience Ag Acides 1-(hétéroaryl)-pyrazol-4-yl-acétiques, procédés de production et utilisation desdits acides comme herbicides et régulateurs de la croissance des plantes

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008003978A3 (fr) * 2006-07-06 2008-12-31 Phytopharm Plc Composés chimiques
US7589123B2 (en) 2006-07-06 2009-09-15 Phytopharm Plc Chemical compounds
EP2135865A1 (fr) 2008-06-17 2009-12-23 Bayer CropScience AG Acides de vinaigre substitués 1-(diazinyle)pyrazole-4-yl, leur procédé de fabrication et d'utilisation en tant qu'herbicides et régulateurs de croissance de plantes
EP2194052A1 (fr) 2008-12-06 2010-06-09 Bayer CropScience AG Acides de vinaigre 1-(thiazolyl) et 1-(Isothiazolyl)pyrazole-4-yl substitués, leur procédé de fabrication et d'utilisation en tant qu'herbicides et régulateurs de croissance des plantes
WO2011073098A1 (fr) 2009-12-15 2011-06-23 Bayer Cropscience Ag Acides 1-(hétéroaryl)-pyrazol-4-yl-acétiques, procédés de production et utilisation desdits acides comme herbicides et régulateurs de la croissance des plantes

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