WO2004037793A1

WO2004037793A1 - Pyrazole-4-alkanoate derivatives inhibiting cyclooxygenase and 5-lipoxygenase

Info

Publication number: WO2004037793A1
Application number: PCT/JP2003/013596
Authority: WO
Inventors: Katsuhiro Kawano; Makoto Taniguchi; Atsushi Igarashi; Mie Yamada; Kenji Naito; Yoshihiro Toyota
Original assignee: Wakamoto Pharmaceutical Co., Ltd.
Priority date: 2002-10-24
Filing date: 2003-10-24
Publication date: 2004-05-06
Also published as: AU2003275637A1

Abstract

A pyrazole-4-alkanoate derivative represented by the following general formula (I): wherein each substituent is as defined in claim 1; a pharmacologically acceptable salt thereof and a medicinal composition containing the derivative. Because of inhibiting the production of both of prostaglandin and leukotriene at the same time, the above derivative is useful as an antirheumatoid drug, an antiinflammtory drug or an analgesic drug.

Description

Specification

Pyrazole-4-alkanoic acid derivatives that inhibit cyclooxygenase and 5-lipoxygenase

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. In the cyclooxygenase pathway, arachidonic acid is metabolized to prostaglandins by the action of cyclooxygenase. In the lipoxygenase pathway, 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 (NSAID's) such as acetylsalicylic acid, indomethacin, ibuprofen, and diclofenac sodium are widely used as anti-inflammatory and analgesic 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.

Regarding the reduction of ulcers, which is a side effect of NSAIDS, compounds that selectively inhibit inducible cyclooxygenase (COX-2) are known. Specifically, celecoxib [J. Med. Chem., 40, 1347 (19997) by TD. Penning, etc.] is known.

Conventional NSAID's have inhibited prostaglandin production by inhibiting cyclooxygenase and exerted an anti-inflammatory effect, but at the same time, inhibited lipoxygenase and inhibited leukotriene production to provide powerful anti-inflammatory / An analgesic effect is expected. It is known that leukotrienes are involved in one of the causes of ulcers caused by NSAID's. In fact, ML-300, which exhibits anti-inflammatory activity without inhibiting ulcers by inhibiting cyclooxygenase and 5-lipoxygenase [J. Org. Chem by J. Cossy et al. , 62, 790 (19997)] have been reported.

It is described that pyrazole derivatives can be used for treating inflammation. U.S. Pat. Nos. 4,146,721 and 4,325,962 to G. Rainer et al. Disclose 1,5-diarylpyrazole-4 as having anti-inflammatory activity. It describes monoacetic acids, specifically, 3-methyl-1,5-diphenylvinylazole-4-acetic acid. However, there is no description about cyclooxygenase, 5-lipoxygenase and ulcer. Summary of the Invention

In view of the above situation, 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.

And Ar ² may have the same or different substituents

(In the formula, 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. CH ₃

X is the formula — CH ₂ —, — CH ₂ — CH ₂ —, one CH = CH—, — C≡C— — CH ₂ — NH-. -CH-NH-

CH ₃ CH ₃ One CH ₂ — S—

II

-CH ₂ — O— -CH-1 0-1 -CH-S-, On ο

(Where n represents an integer of 0, 1 or 2) or 1 c-1, Y is a formula

(In the 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.

Detailed Disclosure of the Invention

Hereinafter, the present invention will be described in detail.

Examples of the alkanoic acid 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. Examples of 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 trimethamine. When the compound represented by the general formula (I) or a pharmacologically acceptable salt is used 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 (Π) into a compound represented by the formula (ΙΠ) Can be prepared by reacting the compound with a hydrazine compound represented by the formula (1) in a reaction inert solvent, followed by a hydrolysis reaction. 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. Can be. 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. 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

Conduct for 20 hours.

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, 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. Thus, the desired compound (VI) is obtained.

Reaction step 2 illustrates a method for preparing the compounds represented by formulas ( _Ia ) and (Ib). Reaction step 2

Hydrolysis

(lb)

In the formula, 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 The reaction is carried out with 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. Thus, the target compound (lb) is obtained. 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. 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. Thus, 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. Thus, 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. Thus, 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. Thus, 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. It is carried out in the presence of a quaternary base such as ammonium fluoride. 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. Thus, 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. Examples of 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. Examples of 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.

The hydrolysis reaction of the pyrazole compound represented by the formulas (Ii), (Ij), (Im) and (Io) is carried out in the same manner as in the hydrolysis in the reaction step 2. Thus, the desired compounds (Ik), (I1), (In) and (Ip) are obtained. Reaction step 5 illustrates a method for preparing the compounds represented by formulas (Id) and (Is). Reaction step 5

Hydrolysis

(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. Examples of 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. Thus, 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. In addition, 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. to 100 ° C., for about 1 hour to 20 hours. carry out. Thus, 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. Thus, the target compound (Iu) is obtained.

Reaction step 7 illustrates a method for preparing the compounds represented by the formulas (IX) and (Iy).

In the formula, Z represents NH or O.

The compound represented by the formula (ΧΠ) 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. Thus, the target compound (ΧΠ) is obtained. The compound represented by the formula (IX) can be obtained by converting the alcohol represented by the formula (ΧΠ) with the Mitsunobu reagent and the formula ΧΠ! ~ 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, Ν, Ν, Ν', Ν, -tetramethylazodicarboxamide, cyanomethylene tree η-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_η-ptynolephosphine, The reaction is performed in the presence of tricyclohexynolephosphine, tri-η-hexynolephosphine, tri-η-octylphosphine, triphenylphosphine, or the like. This reaction is generally carried out at a temperature of about 180 ° C to about 140 ° C, preferably at a temperature of 110 ° C (100 ° C) for about 1 hour to 20 hours. Thus, the target compound (Ix) is obtained.

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).

(CH ₂ ) mCO T H

Hydrolysis

(Iaa) The compound represented by the formula (Iz) must be prepared by reacting the aldehyde derivative represented by the formula (IV) with an aniline derivative (XVI) using a reducing agent in a reaction inert solvent. Can be. Suitable solvents for this reaction include alcohols (eg, ethanol, trifluoroethanol, methanol, propanol, isopropanol, and butanol), DMSO, DMF, acetic acid, DMA, THF, and NMP. be able to. Examples of the reducing agent used in this reaction include sodium borohydride. The reaction is generally performed at a temperature of about -80 ° C to about 100 ° C, preferably at a temperature of about 40 ° C to 80 ° C for about 1 hour to 20 hours. Thus, the target compound (Iz) is obtained.

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. Thus, 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. 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. Thus, the target compound (I ab) is obtained.

The hydrolysis reaction of the pyrazole compound represented by the formula (Iab) is carried out in the same manner as the hydrolysis in the reaction step 2. Thus, the target compound (lac) is obtained. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to pharmacological experimental examples, examples, and reference examples, but the present invention is not limited thereto. Pharmacological experiment example

Inhibitory effect of prostaglandin E ₂ (PGE ₂ ) production from RAW264.7 cells Experimental method

Float RAW 264.7 cells (ATCC TIB 71) into Dulbeccos Modified Eagle's medium (DMEM; Nissui Pharmaceutical) containing 10% FBS (Cansera International) ( 3 × 10 ⁴ cells / m 1), and 150 μ 1 / wel 1 was dispensed into 96 we 11 plates. C_〇 ₂ incubator (37 ° C, 5% C0 2; SANYO Co.) at approximately 24 hours of culture, the test drug diluted to a predetermined concentration in the we 1 1 and 1 0 mu 1 Attachment IJtl. After incubation for about 24 hours in a CO ₂ incubator, add 20 / i 1 of a mixture of WST-1 and 1-methoxy PMS to _each we11, mix and incubate in a 更に₂ incubator for another 3 hours. . Immediately after the incubation was completed, the absorbance was measured using an ELIS II plate reader (Microplate Manager 4.0, manufactured by Bio-Rad Laboratories) at a measurement wavelength of 450 nm and a reference wavelength of 630 nm. The absorbance value of RAW 264.7 cells grown in culture medium alone after 24 hours was 100, and the absorbance value of culture medium alone was 100%. 2003/013596

18

The cell viability (%) was determined as 0. Inhibitory effect of leukotriene B ₄ (LTB ₄ ) production from mouse mast cells

The MC / 9. Self (mouse mast cell line) cultured in DMEM was washed twice with a Ty rode solution, adjusted to 1 or 3 x 10 ⁶ ce 11 s / m 1 and the sample tube was adjusted. Was dispensed in 1 ml portions for use in the experiment. After dispensing, the cells are cooled on ice, pre-incubated at 37 ° C for 10 minutes, treated with the test drug diluted to the specified concentration, and then 0.3 // g / ml of A23187 (manufactured by Sigma) is added. in addition to stimulation, ₄ production amount LTB in after 30 minutes the supernatant was measured by the C a ₇ 11111 companies made £ IA enzyme immunoassay using a kit. result

Production inhibitory effect of LTB ₄ and PGE ₂ for each compound (shown in Example No. in the embodiment) shown in Table 1. table

Example No. PGE ₂ 10- ⁷ M inhibition rate _{(%) LTB 4 1 (T} 6 M inhibition rate (%)

12 94 44.3

13 99 101.5

16 96 97.9

43 99 59.9

44 99 79.9

46 93 82.7

58 85 96.1

60 80 91.3

61 71 97.5

85 76 96

86 75 91.9

92 95 93.7

93 89 79.5 94 98 75

145 61 44.7

148 68 40.8 Oral toxicity test

Male Sprague-Dawley male rats aged 7 to 8 weeks (manufactured by Nippon Charles Riva Co., Ltd.) were orally administered 1 OmL / kg of a 0.5% sodium carboxymethylcellulose solution of the test drug, and The survival rate after hours was measured. , Mouth

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. Table 2

[Reference Example 1] Synthesis of ethyl [3-formyl-1,5-bis (4-methoxyphenyl) -11-pyrazole-4-yl] acetate

To a suspension of 4-methoxyphenylhydrazine hydrochloride (1.61 g, 9.20 mmol) in ethanol (40 ml) was added sodium hydrogencarbonate (0.84 g, 10.0 mmol) and the mixture was added at room temperature. Stir for 1 hour.

A solution of ethyl 5,5-diethoxy-3- (4-methoxybenzoyl) -4-oxopentanoate (2.5 g, 8.36 mmo 1) in ethanol (10 ml) was prepared. It was added dropwise at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. THF (30 ml) and 1 N hydrochloric acid (12 ml) were added to the residue, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the reaction solution was extracted with ether. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 9/1) to give the title compound (2.17 g, 6.0%).

One _{NMR (CDC 1 3) δ 1.} 26 (3 Η, t, J = 7. 3 H z), 3. 75 (2H, s), 3. 80 (3H, s), 3. 84 (3 H , s), 4.16 (2H, t, J = 7.3Hz), 6.82 (2H, d, J = 9.5Hz), 7.15-7.23 (3H, m) , 7.31-7.40 (3H, m), 10.2 (1H, s)

F ABMS 395 (M + 1) The compounds shown in Table 3 below were obtained in the same manner as in Reference Example 1.

Table 3 Reference FABMS

NMR data

Example number R ¹⁰ R ¹¹ R ¹² R ¹³ Data

CDC1 ₃ δ

No.m / e (m + l)

1.26 (3H, t _> J = 7.3Hz), 3.75 (2¾s), 4.16 (2H _> t _> J = 7.3Hz), 7.

2 H H H Et 335

15-7.40 (10H, m), 10.14 (lH, s)

_{1.27 (3H, t; J =} 7.3Hz), 3.74 (2H 5 s) 5 4.17 (2H, tJ = 7.3Hz), 7.

3 H CI H Et 369

14f2H, dJ = 8.8Hz), 7.24-7.39 (7H, m), 10.13 (lH, s) OV / sa sAsa £ 6: / 12 / 0S6S20 £ 9

/ v: / O 96S20S0ifcl £ ε6 /-/-εοsa sAV

[Reference Example 25] Synthesis of ethyl [3- (hydroxymethyl) -1,5-bis (4-methoxyphenyl) 1-1J-pyrazole-4-yl] acetate

Sodium borohydride (0.03 g, 0.76 mmo 1) was added to a ethanol solution (40 m 1) of the compound of Reference Example 1 (1, 0 g, 2.54 mmo 1), and the mixture was stirred at room temperature for 1 hour. . After completion of the reaction, the reaction solution was cooled with ice, acidified with ethanolic hydrochloric acid, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate = 3/1) to give the title compound (0.85 g, 85.0%).

^{_{X H-NMR (CDC 1 3}} ) δ 1. 27 (3 H, t, J = 7. 3 H z), 2. 8 2 (1 H, t, J = 5. 9Hz), 3. 52 (2 H, s), 3.77 (3 H, s), 3.80 (3 H, s), 4.17 (2 H, q, J = 7.3 Hz), 4.79 (2 H, s) d, J = 5.9Hz, 6.78 (2H, d, J = 8.8Hz), 7.13 (2H, d, J = 8.8Hz), 7.15 to 7.22 ( 2H, m), 7.30-7.38 (3H, m)

FABMS 397 (M + 1) The compounds shown in Table 4 below were obtained in the same manner as in Reference Example 25.

Table 4

96s2 / v: 0 £ 00ifcl> d / £ 6 OAV

O / sa sAV //: / οοί1 £ εϊοε

[Reference Example 49] Synthesis of ethyl [3- (bromomethyl) -1,5-bis (4-methoxyphenyl) _1 J-pyrazole-41-yl] acetate

To a solution of the compound of Reference Example 25 (1.0 g, 2.54 mmo 1) in acetonitrile (4 Om 1) was added motriphenolephosphorane (0.28 g, 1.02 mm 01) at the dibu mouth. The mixture was stirred on ice for 1 hour. After the completion of the reaction, the precipitated crystals were collected by filtration. Benzene was added to the crystals, the mixture was filtered while hot, and the collected crystals were dried under reduced pressure to give the title compound (1.00 g, 85.9%). One _{NMR (CDC 1 3) δ 1.} 28 (3 Η, t, J = 7. 3 H z), 3. 56 (2H, s), 3. 77 (3H, s), 3. 79 (3H, s), 4.18 (2H, q

g 挲

. Mine 丄 «ェ截 ^; 6 Μ ^ 0

(τ +) 0 9 s Ma (ra Ή ε) 8 ε · z-o ε-1

• Ζ-8 Τ 'L' (ζ Η 8 '8 = Γ' Ρ 'ΗΖ) 8 \' L '( ^ζ Ή Ζ) 8 Ζ' 9 '(s ΉΖ) 8 9''( ^ζ Η S' 1 = ί '

2Ζ

96SCT0 / C00Zdf / X3d t6LLZ0ltmi OJSX

[Reference Example 73] Synthesis of ethyl 4_ [3-formyl-11,5-bis (4-methoxyphenyl) -11-pyrazole-41-yl] ptanoate

In the same manner as in Reference Example 1, ethyl 7,7-diethoxy 5- (4-methoxybenzoyl) -1,4-oxohepta was used instead of ethyl 3- (4-methoxybenzoyl) -1,4-oxo-1,5-phenylpentanoate. The title compound was obtained in a yield of 50.4% using noate.

^{_{X H-NMR (CDC 1 3}} ) δ 1. 20 (3H, t, J = 7. 3Hz), 1. 8 1 - 1. 94 (2H, m), 2. 27 (2 H, t, J = 7.3 Hz, 2.72 (2 H, dd, J = 8.1, 7.3 Hz), 3.80 (3H, s), 3.82 (3H, s), 4.05 ( 2H, q, J = 7.3 Hz, 6.82 (2H, d, J = 9.5 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.08 (2H , d, J = 8.8 Hz), 7.17 (2H, d'J = 9.5 Hz), 10.2 (11-1, s) FABMS 4 2 3 (M + 1 )

[Reference Example 74] Synthesis of ethyl 4- [3- (hydroxymethyl) -11,5-bis (4-methoxyphenyl) -11H-pyrazole-4-yl] butanoate

In the same manner as in Reference Example 25, the title compound was obtained in a yield of 83.3% using the compound of Reference Example 73 instead of the compound of Reference Example 1.

^{_{: H-NMR (CDC 1 3}} ) δ 1. 22 (3H, t, J = 7. 3 H z), 1. 76 - 1. 88 (2H, m), 2. 25 (2H, t, J = 7.3Hz), 2.35-2.43 (1H, m), 2.49 -2.57 (2H, m), 3.77 (3H, s), 3.82 (3H, s) , 4.08 (2H, q, J = 7.3 Hz), 4.78 (2 H, d, J = 5.9 Hz), 6.78 (2 H, d, J = 8.8 Hz), 6.78 86 (2H, d, J = 8.8 Hz), 7.06-7.13 (4 H, m) F ABMS 4 2 5 (M + 1).

[Reference Example 75] Synthesis of ethyl 4- [3- (bromomethyl) _1,5-bis (4-methoxyphenyl) -11 ^ -pyrazole-4-yl] butanoate

In the same manner as in Reference Example 49, the title compound was obtained in a yield of 83.3% using the compound of Reference Example 74 instead of the compound of Reference Example 25.

'H-NMR (CD C 1 3) δ 1. 22 (3 H, t, J = 7. 3 H z), 1. 7 7 - 1. 89 (2 H, m), 2. 27 (2 H , t, J = 7.3 Hz), 2.52-2.61 (2H, m), 3.77 (3I-I, s), 3.82 (3H, s), 4. 08 (2H, q, J = 7.3I-Iz), 4.63 (2H, s), 6.77 (21-1, d, J = 8.8Hz), 6.86 (2 H, d, J = 8.8 Hz), 7.05—7.14 (4H, m)

F ABMS 48 8 (M + 1)

[Reference Example 76] Synthesis of benzyl [3-formyl-1-1- (4-methoxyphenyl) -15- (2-pyridyl) -1-1 JJ-pyrazole_4-yl] acetate

In the same manner as in Reference Example 1, ethyl 3- (4-methoxybenzoyl) _4-oxo-5-pheninolepentanoate was replaced by ethyl 2-benzyl-1,4,4-jetoxyl (2-pyridyl) Yield of the title compound using 1,3-butanedione 3 ^{X H-NMR (CD C 1} 3) S 3. 82 (3H, s), 4. 07 (2H, s), 5. 12 (2H, s), 6. 86 (2H, d, J = 8. 8 Hz), 7.05 (1 H, d, J = 8.1 Hz), 7.23 (4H, d, J = 8.8 Hz), 730-7.36 (5 H, m), 7 54- 7.61 (1 H, m), 8.58—86 1 (1 H, m), 10.14 (1 H, s)

F ABMS 4 28 (M + 1)

[Reference Example 77] Synthesis of ethyl [3- (1-hydroxyhexyl) -11,5-bisethoxyphenyl) 1-1 ^ -pyrazole-41-yl] acetate

A 3.0 M methylmagnesium bromide dimethyl ether solution (0.84 ml, 2.84 ml) was added to a dimethyl ether solution (20 ml) of the compound of Reference Example 1 (1.0 g, 2.54 mmo 1). 54 mmol) and stirred for 1 hour under ice cooling. After completion of the reaction, the reaction solution was extracted with getyl ether. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl ester = 3Z1) to give the title compound (0.84 g, 81.0%).

^{X H-NMR (CD C 1} 3) 6 1. 26 (3H, t, J = 5. 8Hz), 1. 6 5 (3H, d, J = 6. 8Hz), 3. 03 (1H, brs) , 3.51 (2H, dd, J = 16.6, 28.8 Hz), 3.77 (3H, s), 3.80 (3H, s), 4.17 (2H, q, J = 5.8 Hz), 5.06 (1 H, q, J = 6.8 H z), 6.76-6.88 (4 H, m), 7.01-7.13 (4H, m) F ABMS 4 1 1 (M + 1)

[Reference Example 78] Etyl [3- (1-promoethyl) 1,5-bis

Synthesis of [Ciphenyl) 1-1J / -pyrazole-4-yl] acetate

In the same manner as in Reference Example 49, the title compound was obtained in a yield of 85.6% using the compound of Reference Example 77 instead of the compound of Reference Example 25.

^{X H-NMR (CD C 1} 3) δ 1. 25 (3 H, t, J = 5. 8Hz), 1. 8 5 (3 H, d, J = 6. 8 H z), 3. 50 ( 2H, dd, J = 16.6, 28.8 Hz), 3.77 (3H, s), 3.81 (3H, s), 4.15 (2H, q, J = 5 .8Hz), 5.08 (1 H, q, J = 6.8 H z), 6.76-6, 88 (4 H, m), 7.0 1-7.1 3 (4 H, m )

F ABMS 4 74 (M + 1)

[Example 1] Synthesis of ethyl [3-benzyl-l, 5-bis (4-methoxyphenyl) -l-i-pyrazolone-l-ynole] acetate

A solution of 4-methoxyethoxy-hydrazine hydrochloride (10.84 g, 10.6 mmo 1) in ethanol (40 ml) was added to sodium bicarbonate (1.08 g, 12.2 g). 8 mmo 1) was added and the mixture was stirred at room temperature for 1 hour.

Ethynole 3- (4-methoxybenzoinole) -14-oxo-5-phenylpentanoate (2.8 g, 8.36 mmo 1) in ethanol solution (1 O m 1) at room temperature It was dropped. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel gel chromatography (eluent: hexane Z ethyl acetate = 9-1) to give the title compound (2.9 g, 60.2%). _{^ -NMR (CDC 1 3) δ} 1 · 2 4 (3 H, t, J = 7. 3 H z), 3. 2 5 (2 H, s), 3. 3 4 (2H, s), 3 . 7 8 (3H, s), 3.81 (3H, s), 4.15 (2H, t, J = 7.3Hz), 6.77-6.87 ( 4 H, m), 7.1 3-7.31 (9 H, m)

F ABMS 4 5 7 (M + 1)

Example 2 Synthesis of ethyl [1,5_bis (4-methoxyphenyl) -13- (2-phenethyl) -11-pyrazol-41-yl] acetate

In the same manner as in Example 1, ethyl 3- (4-methoxybenzoyl) -4-1-oxo-5-phenylpentanoate was replaced by ethyl 3- (4-methoxybenzoyl) -4-1-oxo-5-phenylhexanoate. To give the title compound in 62.0% yield.

'H-NMR (CD C 1 3) δ 1. 2 4 (3 H, t, J = 7. 3 H z), 2. 9 9 - 3. 0 3 (4H, m), 3. 3 4 ( 2 H, s), 3.78 (3 H, s), 3.81 (3H, s), 4.15 (2H, t, J = 7.3Hz), 6.77-6.87 (4H, m), 7.13-7.31 (9H, m )

F ABMS 4 7 1 (M + 1)

Example 3 Synthesis of [3-benzyl_1,5-bis (4-methoxyphenyl) -l-if-pyrazole-41-yl] acetic acid

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%). _{^ -NMR (CDC 1 3) δ} 3. 26 (2H, s), 3. 77 (3 H, s), 3. 79 (3 H, s), 6. 77-6. 98 (4H, m) , 7.10—7.18 (5 H, m), 7.27- 7.64 (4 H, m)

F ABMS 42 9 (M + 1) 596

37

Example 4 Synthesis of [1,5-bis (4-methoxyphenyl) -13- (2-phenyl) -1-pyrazole-4-yl] acetic acid

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 Η, s), 3. 76 (3Η, s), 3. 79 (3Η, s), 6 . 76— 6.85 (4 Η, m), 7.10-7.26 (9 Η, m)

F ABMS 443 (M + 1)

Example 5 Synthesis of ethyl [3- (anilinomethinole) -11,5-bis (4-methoxypheninole) -11J-pyrazole-41-isole] acetate

In a solution of the compound of Reference Example 49 (0.04 g, 0.519 mmo l) and anhydrous potassium carbonate (0.07 g, 0.415 mmo 1) in dimethyl / levonoremamide (3 ml), Aniline (0.15 g, 0.346 mmo 1) was added, and the mixture was stirred at 50 ° C for 17 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate = 7/1) to give the title compound (0.12 g, 76.6%). _{iH- NMR (CDC 1 3) 8} 1. 29 (6 H, t, J = 6. 8Hz), 3. 58 - 3. 8 1 (4H, m), 4. 9 1 (1H, s), 6 . 59 (1 H, s), 7.42 — 7.58 (3H, m), 7.89-7.98 (2 H, m)

FABMS 3 9 5 (M + 1)

Table 6

96SClO / COOZdf / X3d £ 6LL £ 0 / 00Z OAV OAV / sa s SUl¾H ^ ss

/ O ε6 /-/-εοsa AV / v: 6s £ sssfcl £ 9 ε Dimension

O / AV Say OZ £ 6 /: / 2SSS 9 £

The compounds shown in Table 7 below were obtained in the same manner as in Example 5.

Table 7

9

96SClO / £ OOZdf / X3d £ 6LL £ 0 / P00Z OAV

96SCT0 / C00Zdf / X3d £ 6LL £ 0 / 00Z OAV

Table 8

O / AV £ 6 V: / osfcl296s20 £ Dimensions

Table 9

[Example 8 1] Synthesis of ethyl [1,5-bis (4-methoxyphenyl) -13- (phenoxymethyl) -11-if-pyrazol-4-yl] acetate

To a solution of phenol (0.04 g, 0.415 mmo 1) and tetraethylammonium-fluoride (0.19 g, 1.04 mmo 1) in THF (5 ml) was added Reference Example 25. The compound (0.15 g, 0.346 mmol) was added, and the mixture was stirred at 50 ° C for 17 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate = 7-1) to give the title compound (0.10 g, 62.6%).

^{X H-NMR (CD C 1} 3) δ 1. 1 7 (3H, d, J = 7. 3 H z), 3. 5 5 (2 H, s), 3. 78 (3H, s), 3 .8 1 (3H, s), 4.08 (2H, q, J = 7.3 Hz), 5.22 (2 H, s), 6.80 (2H, d, J = 9.3 H z), 6.86 (2H, d, J = 8.8 Hz), 6.92-- 7.09 (3 H, m), 7.10-7.19 (4 H, m), 7.25-7.34 (2H, m)

F ABMS 47 3 (M + 1)

Table 10

Dimension ^

/ β length S £ 6v: / fcl2S20S0z 96

The compounds shown in Table 11 below were obtained in the same manner as in Example 81.

Table 11

[Example 1 1 1] Ethyl [3-[(2,5-dichlorophenoxy) methyl] -1-5 (4-funorelopheninole) 1-11 (4-methoxyphenenole) 1 l J-pyrazol 1 4 Synthesis of Acetate

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.

_{'H-NMR (CDC 1 3} ) δ 3. 01 -3. 04 (4Η, m), 3. 35 (2H, s), 3. 76 (3H, s), 3. 79 (3H, s), 6.76- 6.85 (4 H, m), 7.10-7.26 (9 H, m)

FABMS 443 (M + 1) [Example 1 1 2] Synthesis of ethyl [3-[(3-amino-arino) methyl] -11,5-bis (4-methoxyphenyl) -1-l ^ -pyrazol-4-yl] acetate

To a solution of the compound of Example 26 (0.04 g, 0.519 mmo 1) in ethanol (3 m 1) was added 10% palladium on carbon (0.15 g). Stirred for hours. After the completion of the reaction, 10% palladium carbon was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/1) to give the title compound (0.12 g, 76.6%). _{- NMR (CDC 1 3) δ} 1. 29 (6 Η, t, J = 6. 8 H z), 3. 5 8 one 3. 8 1 (4H, m) , 4. 9 1 (l H, s ), 6.59 (1H, s), 7.42

-7.58 (3 H, m), 7.89-7.98 (2 H, m)

F ABMS 3 9 5 (M + 1)

[Example 1 1 3] Synthesis of ethyl [3 [(2-aminophenoxy) methyl] — 1, 5-bis (4-methoxypheninole) 1 //-pyrazole-4-yl] acetate

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.

_{^ -NMR (CDC 1 3) δ} 1. 1 7 (3Η, t, J = 7. 3 H z), 3. 5 3 3013596

59

(2 H, s), 3.78 (3 H, s), 3.81 (3 H, s), 4.09 (2 H, q

,] = 7.3 Hz, 5.22 (2 H, s), 6.70—6.87 (7H, m), 7.01-7.17 (5H, m)

F ABMS 4 8 8 (M + 1)

[Example 1 1 4] Synthesis of ethyl [3-[(3-aminophenoxy) methyl] -1, 5-bis (4-methoxyphenyl) -11-pyrazole-4-inole] acetate

The title compound was obtained in a yield of 85.2% in the same manner as in Example 112, except that the compound of Example 95 was used instead of the compound of Example 26. _{XH-NMR (CDC 1 3)} δ 1. 2 9 (6 Η, t, J = 6. 8 H z), 3. 5 8 - 3. 8 1 (4H, m), 4. 9 1 (1 H , s), 6.59 (1H, s), 7.42-7.58 (3H, m), 7.89-7.98 (2H, m)

F ABMS 4 8 8 (M + 1)

[Example 1 15] Synthesis of [3- (3-anilinomethyl) _1,5-bis (4-methoxyphenol) 1: L-pyrazole-4-yl] acetic acid

In the same manner as in Example 3, the title compound was obtained in a yield of 86.5% using the compound of Example 5 instead of the compound of Example 1. ^{_{X H-NMR (CDC 1 3}} ) δ 1. 29 (6H, t, J = 6. 8 H z), 3. 58 - 3. 8 1 (4H, m), 4. 91 (1 H, s) , 6.59 (1H, s), 7.42-7.58 (3H, m), 7.89—7.98 (2H, m)

F ABMS 395 (M + 1) The compounds shown in Table 12 below were obtained in the same manner as in Example 115.

Table 1 2

6

62

9

96SClO / COOZdf / X3d ε6

Compounds shown in Table 13 below were obtained in the same manner as in Example 115.

Table 13

O / AV: vl £ / osfc6s20 £ 9

The compounds shown in the following Table 14 were obtained in the same manner as in Example 115.

Table 14

Compounds shown in the following Table 15 were obtained in the same manner as in Example 115.

Table 15

Example 201 Synthesis of [3- (3-fuunoxymethyl) -1,5-bis (4-methoxyphenyl) _1-pyrazole-4-yl] acetic acid

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.

^{J H-NMR (CD C 1} 3) δ 3. 60 (2Η, s), 3. 78 (3 H, s), 3. 81 (3 H, s), 5. 25 (2H, s), 6 80 (2H, d, J = 9.3 Hz), 6.87 (2H, d, J = 8.8 Hz), 6.93-7.18 (7 H, m), 7 . 25-7. 34 (2H, m) FABMS 445 (M + 1)

Table 16

/ Sasa 01 O / u £ 6AV 96Sf / drd losoz

The compounds shown in the following Table 17 were obtained in the same manner as in Example 201.

Table 17

Example 232 Synthesis of [3- (3-phenoxymethyl) -11,5-bis (4-methoxyphenyl) -11J-pyrazol-41-yl] diacid

In the same manner as in Example 5, using thiophenol instead of aniline, the title compound was obtained in a yield of 57.8. /. I got it.

^{X H-NMR (CD C 1} 3) δ 1. 25 (3H, d, J = 7. 3 H z), 3. 5 2 (2H, s), 3. 77 (3 H, s), 3. 8 1 (3 H, s), 4.15 (2H, q, J = 7.3 Hz), 4.31 (2H, s), 6.76 (2 H, d, J = 9.3 Hz ), 6.85 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 9.3 Hz), 7.12 (21-I, d, J = 8 8 Hz), 7. 16—7.33 (3 H, m), 7.42-7.48 (2 H, m)

F ABMS 48 9 (M + 1)

Example 233 Synthesis of ethyl [3- [1-1 [(4_fluorophenyl) sulfanyl] ethyl] —1,5-bis (4-methoxyphenyl) -11-pyrazole-14-yl] acetate

In the same manner as in Example 5, the title compound was obtained in a yield of 63.2 ° / using the compound of Reference Example 78 instead of the compound of Reference Example 49 and 4-fluorothiophenol instead of arin. Obtained with o. ^{_{X H-NMR (CDC 1 3}} ) δ 1. 25 (3H, d, J = 7. 3 H z), 1. 66 (3H, d, J = 6. 8Hz), 3. 59 (2 H, dd , J = 16.6, 28.8 Hz), 3.76 (3H, s), 3.80 (3H, s), 4.44 (1 H, q, J fi. 8Hz), 6.73- 6.81 (4H, m), 6.90-6. 96 (2H, m), 7.00-7.09 (4H, m), 7.3 3—7.37 (2H, m) F ABMS 5 2 1 (M + 1)

[Example 234] Synthesis of [3- (3-fuunoxymethyl) -11,5-bis (4-methoxyphenol) -11J-pyrazol-4-yl] acetic acid

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.

'H-NMR (CD C 1 3) S 3. 58 (2 H, s), 3. 77 (3H, s), 3. 80 (3H, s), 4. 32 (2H, s), 6. 76 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8Hz), 7.14-7.32 (3H, m), 7.41-7.48 (2H, m)

F ABMS 4 6 1 (M + 1) [Example 23] Synthesis of ethyl [1,5-bis (4-methoxypropyl) -13-[(phenylsulfiel) methyl] -11-pyrazole-41-yl] acetate

Example 2 To a solution of the compound of 32 (300 mg, 0.615 mmol) in 5 ml of THF was added 14 Omg of metaperbenzoic acid (0.5 mmol), and the mixture was stirred under ice cooling for 1 hour. . After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 13) to give the title compound in a yield of 42.5%.

^{X H-NMR (CD C 1} 3) δ 1. 25 (3 H, t, J = 7. 3 H z), 3. 3 2 - 3. 5 7 (2H, m), 3. 7 7 (3 H, s), 3.81 (3H, s), 4.14 (3H, q, J = 7.3Hz), 4.18-4.38 (2H, m), 6.74- 7.1 1 1 (8H, m), 7.49-7.64 (5H, m)

F ABMS 505 (M + 1) [Example 2 36] Ethyl [1,5-bis (4-methoxyphenyl) -13 _ [(phenylsulfoyl) methyl] -11-pyrazole-14-yl] acete One-piece synthesis

In the same manner as in Example 23, the title compound was obtained in a yield of 37.8%. _{H-NMR (CDC 1 3)} δ 1. 28 (3 Η, t, J = 7. 3 Hz), (2H, s), 3.75 (3H, s), 3.81 (3H, s), 4.15 (3H, q, J = 7.3 Hz), 4.66 (2H, s), 6 . 7 1 (2H, d, J = 8.8Hz), 6.73-6.88 (4H, m), 7.08 (2H, d, J = 8.8Hz), 7.50 -7.83 (5 H, m)

F ABMS 5 2 1 (M + 1)

Example 237 Synthesis of [1,5-bis (4-methoxyphenyl) -13-[(phenylsulfinyl) methinole] -1 17 / -pyrazole-41-yl] acetic acid

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.

^{_{X H-NMR (CDC 1 3}} ) δ 3 - 53 (2 Η, s), 3. 77 (3 H

8 1 (3H, s), 4.83 (2H, s), 6.77-6.88 (4H

00-7.14 (4H, m), 726-7.56 (5H, m)

F ABMS 47 7 (M + 1)

Example 238 Synthesis of [1,5-bis (4-methoxyphenyl) -13-[(phenylsulfonyl) methyl] -11Jf-pyrazol-4-yl] acetic acid

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

_{^ -NMR (CDC 1 3) S} 3. 7 2 (2 H, s), 3. 75 (3 H, s), 3. 8 1 (3H, s), 4. 66 (2H, s), 6 .72 (2H, d, J = 8.8 Hz), 6.86 (4H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 7 . 5 1 -7. 67 (3H, m), 7.83 (2H, d, J = 8.8Hz) F ABMS 49 3 (M + 1)

[Example 239] Synthesis of ethyl [3- [hydroxy (fuyl) methyl] -1, 5-bis (4-methoxyphenyl) -11-if-pyrazol-4-yl] acetate

In a nitrogen atmosphere, metal magnesium (0.02 g, 1.06 mmo 1) in ethanol (5 m 1), and at night, bromobenzene (0.16 g, 1.0 mmo) and iodine (small amount) ) Was added and the mixture was refluxed for 30 minutes. A solution of the compound of Reference Example 1 (0.2 g, 0.558 mmol) in ether (2 ml) was added dropwise (dropping time: 15 minutes), and the mixture was heated under reflux for 2.5 hours. A saturated ammonium chloride solution was added to the reaction solution, and extracted with ether. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: benzene / ethyl acetate = 9/1) to give the title compound (0.17 g, 62.5%).

'H-NMR (CD C 1 3) δ 1. 2 1 (3 H, t, J = 7. 3Hz), 3. 0 2 - 3. 1 9 (2H, m), 3. 78 (3H, s ), 3.80 (3H, s), 3.93-3.97 (1H, m), 4.05 (2H, q, 1 = 7.3Hz), 6.04 (1H, d, J = 5.9Hz), 6.77- 6.86 (4H, m), 7.03-7. 1 9 (4H, m), 7.22-7.38 (3H, m), 7.44—7.54 (2H, m)

F ABMS 4 73 (M + 1) [Example 240] Synthesis of [3- [hydroxy (phenyl) methyl]-1,5-bis (4-methoxyphenyl)-1 f-pyrazole_4_yl] acetic acid

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. One _{NMR (CD C 1 3) δ} 3. 2 1 (2Η, s), 3. 78 (3H, s), 3. 79 (3 H, s), 6. 1 1 (1 H, s), 6 .80 (2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 7 . 16 (2H, d, J = 8.8Hz), 7.22-7.38 (3H, m), 7.47-7.52 (2H, m)

F ABMS 44 5 (M + 1)

[Example 241] Synthesis of ethyl [1,5-bis (4-methoxyphenyl) -13- [methoxy (phenyl) methyl] -11-pyrazole-41-yl] acetate

Example 23 Compound of 9 (0.lg, 0.22 2mmo1), silver oxide (I) (0. Methyl iodide (0.04 g, 0.254 mmol) was added to a solution of acetonitrile (2 ml) in 0.05 g, 0.22 mmol 2) and stirred at room temperature for 2 days. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 9/1) to give the title compound (0.09 g, 91.3%).

^{_{X H-NMR (CDC 1 3}} ) δ 1. 20 (3 Η, d, J = 7. 3 H z), 3. 30

(2 H, s), 3.44 (3Η, s), 3.78 (3 H, s), 3.79 (3 H, s)

), 3.89-4.08 (2Η, m), 5.55 (1 H, s), 6.75-6.87

(4 Η, m), 7.13 (2 Η, d, J = 8.8 Hz),, 7.16 (2 H, d, J

= 8. 8Η ζ), 7.20-7.39 (3H, m), 7., 46-7.54 (2H, m)

F ABMS 48 7 (Μ + 1)

[Example 242] Synthesis of [1,5-bis (4-methoxyfif :: nil) -13- [methoxy (phenyl) methynole 1-1-pyrazole-14-yl] acetic acid

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.

^{_{X H-NMR (CDC 1 3}} ) S 3. 21- 3. 3 9 (2H, m), 3. 57 (3 H, s), 3. 78 (3H, s), 3. 79 (3H, s ), 5.66 (1H, s), 6.80 (2H, d, J = 9.3Hz), 6.84 (2H, d, J = 8.8Hz), 7.11 (-2 H, d, J = 8.8 Hz), 7.15 (2H, d, J = 9.3 Hz), 7.24 to 7.33 (1 H, m), 7.34 to 7.42 ( 2 H, m), 7.47-- 7. 54 (2H, m)

F ABMS 4 5 9 (M + 1)

[Example 243] Synthesis of ethyl [3-benzoyl-1,5-bis (4-methoxyphenyl) 1-1 / J-pyrazole-4-yl] acetate

Manganese dioxide (lg) was added to a solution of the compound of Example 239 (0.2 g, 0.423 mmo 1) in 1,2-dichloromethane (5 ml), and the mixture was heated under reflux for 1.5 hours. did. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 3: 1) to give the title compound (0.13 g, 64.3%). _{aH-NMR (CDC 1 3)} δ ΐ. 25 (3 H, d, J = 7. 3Hz), 3. 7 8 (2 H, s), 3. 79 (3 H, s), 3. 83 ( 3 H, s), 4.17 (2H, q, J = 7.3 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8 .8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.42-7.60 (3H, m), 8 . 29-8. 37 (2H, m)

F ABMS 4 7 1 (M + 1) [Example 2 44] Synthesis of [3-benzoyl-1,5-bis (4-methoxyphenyl) -11f-pyrazole-4-yl] acetic acid

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.

^{X H-NMR (CD C 1} 3) S 3. 6 8 (2 H, s), 3. 8 0 (3 H, s), 3. 8 4 (3 H, s), 6. 8 5 (2 H, d, J = 8.8 Hz), 6.93 (2 H, d, J = 8.8 Hz), 7.18-7.29 (4H, m), 7.5 0-7.70 (3H, m), 8.34 -8.41 (2H, m)

F ABMS 4 4 3 (M + 1)

[Example 24 5] Synthesis of ethyl [3- [dimethoxy (phenyl) methyl] -11,5-bis (4-methoxyphenyl) -11f-pyrazole-4-yl] acetate

Example 24 To a solution of the compound of 0.3 (0.3 g, 0.638 mmol) and trimethyl orthoformate (0.68 g, 638 mmol) in methanol (7 ml) was added p. —Tonoene sulfonic acid monohydrate (0.12 g, 0.638 mmo 1) was added, and the mixture was heated under reflux for 2 days. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue (eluent: hexane / Ethyl acetate = 2/1) to give the title compound (0.09 g, 27.1%).

_{^ -NMR (CDC 1 3) δ} 1. 1 4- 1. 2 7 (3 Η, m), 3. 1 8 (6 H, s), 3. 2 6 (2 H, s), 3. 7 6 (3H, s), 3.78 (3H, s), 4.02 (2H, q, J = 7.3Hz), 6.75 (2H, d, J = 9 .3 Hz), 6.80 (2 H, d, J = 8.8 Hz), 7.06-7.19 (4H, m), 7.22-7.38 ( 3 H, m), 7.60-7.67 (2 H, m)

F ABMS 5 1 7 (M + 1)

[Example 2 46] [3- [Dimethoxy (phenyl) methyl] 1-1,5

Synthesis of 1-pyrazole-4yl] acetic acid

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.

^{J H-NMR (CD C 1} 3) S 3. 2 5 (6 H, s), 3. 3 9 (2 H, s), 3. 7 6 (3 H, s), 3. 7 9 (3 H, s), 6.75 (2H, q, J = 8.8Hz), 6.83 (2H, q, J = 8.8Hz), 7.11 (2H , d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.24—7.39 (3H, m), 7.60 -7.68 (2 H, m)

F ABMS 4 8 9 (M + 1) TJP2003 / 013596

[Example 247] Ethyl [3-[((E) -12- (4-chlorophenyl) ethenyl]]-1,5-bis (4-methoxyphenyl) 1-1-pyrazole-4-yl] acetate and ethyl Synthesis of [3 -— ((Z) -2- (4-chlorophenyl) ethenyl) -1-1,5-bis (4-methoxyphenyl) -1-Jf-pyrazonole-1-yl] acetate

E body Z body

0.57 g (5.08 mmo 1) of potassium t-butoxide was added to a solution of 2.32 g (5.3 2 mmo 1) of 4-phenylphenol benzizretrifinolephosphonium bromide in 25 ml of THF at room temperature. The mixture was stirred for 30 minutes. Next, a solution of 1 g (2.54 mmo 1) of the compound of Reference Example 1 in THF and Oml was added, and the mixture was stirred for 18 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate Z hexane = 1/5). Title compound E form 80 mg (35.0% yield), Z form 60 mg (25.9% yield) Got

E body

_{^ -NMR (CDC 1 3) δ} 1. 26 (3 H, t, J = 7. 3 Hz), 3. 54 (2H, s), 3. 79 (3H, s), 3. 82 (3H, s), 4.18 (2H, q, J = 7.3Hz), 6.8 1 (2H, d, J = 8.8Hz), 6.88 (2H, d, J = 8.8Hz) ), 7.16-7.21 (4H, m), 7.30-7.34 (4H, m), 7.45 (2H, d, J = 8.8 Hz)

FABMS 50 3 (M + 1) z body

^{_{X H-NMR (CDC 1 3}} ) 6 1. 1 9 (3 H, t, J = 7. 3 H z), 3. 26 (2H, s), 3. 78 (3H, s), 3. 81 (3H, s), 4.05 (2H, q, J = 7.3Hz), 6.56 (2H, d, J = 12.2Hz), 6.67 (1H, d, J = 1 2.2 Hz), 6.75 (1 H, d, J = 8.8 Hz), 6.86 (2 H, d, J = 8.8 Hz), 7.10-7.15 (4H , M), 7.24 (1H, d, J = 8.8 Hz), 7.36-7.38 (1H, m), 7.56 (2H, d, J = 8.3 Hz)

FABMS 50 3 (M + 1) In the same manner as in Example 247, the following compounds shown in Table 18 were obtained.

Table 18

O / sAV £ 6sa v: / osfcl296s20 £

88

96S £ l0 / £ 00idf / X3d C6 .. £ 0 / 00i OAV / v: / O 96S20S0ifcl £ ε6 /-/-εοsa sAV

[Example 2 69] ethyl [3-[(E) -2- (4-chlorophenyl) ethyl] 1-1- (4-methoxyphenyl) 1 5- [4- Ninole) phenyl] 1-1-pyrazole-41-yl] acetate and ethyl [4— (Metinolesul Honore) Feninole] 1 1 Jf-Pyrazonore 1 4-Innole] Synthesis of acetate

E-form Z-form The title compound E-form yield 32.5%, Z-form yield 10.10 in the same manner as in Example 24.7, using the compound of Example 15 in place of the compound of Example 1. Obtained at 3%.

E body

^{X H-NMR (CD C 1} 3) δ 1. 2 8 (3 H, t, J = 7. 3 H z), 3. 0 9 (3 H, s), 3. 5 5 (2 H, s ), 3.81 (3H, s), 4.21 (2H, q, J = 7.3Hz), 6.83 (2H, d, J = 9.3Hz), 7.10-7.18 (3H, m), 7.31-7.52 (7H, m), 7.93 (2H, d, J = 8.3Hz)

F ABMS 5 5 2 (M + 1) z body

_{iH- NMR (CDC 1 3) 5} 1. 2 0 (3 H, t, J = 7. 3 H z), 3. 0 8 (3 H, s), 3. 2 7 (2H, s), 3 .80 (3H, s), 4.06 (2H, q, J = 7.3Hz), 6.56 (1H, d, J = 12.2Hz), 6.73 (1H, d, J = 12.2Hz), 6.8 1 (2H, d, J = 8.8Hz), 7.08 (2H, d, J = 9.3Hz) ), 7.25 (2H, d, J = 7.3 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8. 3Hz), 7.9 1 (2H, d, J = 8.8Hz)

F ABMS 5 5 2 (M + 1)

[Example 27 00] ethyl [3-[(E) -2- (2,5-dichlorophenyl) phenyl]]-1,5-bis (4-methoxyphenyl) 1-1-pyrazonolle-4-yl ] Synthesis of acetate

0.57 g (5.08 mm) of benzinoletriphenolephosphonium bromide in a solution of 2.31 g (5.32 mmo 1) in 5 ml of THF at room temperature was added. o 1) was added and the mixture was stirred for 30 minutes. Next, a solution of 1 g (2.54 mmol) of the compound of Reference Example 1 in THF 1 Om1 was added, and the mixture was stirred for 18 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/5) to obtain 42 Omg (yield 39.5%) of the title compound. _{'H-NMR (CDC 1 3} ) δ 1. 2 7 (3 H, t, J = 7. 3 H z), 3. 5 7 (2H, s), 3. 7 9 (3H, s), 3 . 8 2 (3 H, s), 4.19 (2H, q ,] = 7.3 Hz), 6.8 1 (2 H, d, J = 9.3 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.1 4-7.22 (6 H, m), 7.3 1 (1 H, d,

J = 8.3 Hz), 7.60 (1H, d, J = 16.6Hz), 7.67—7.68 (1H, m)

FABMS 538 (M + 1) In the same manner as in Example 27, the following compounds shown in Table 20 were obtained.

Table 20

TJP2003 / 013596

93

[Example 2 7 3] [3 -— ((E) -1-2- (4-chlorophenol) ethenyl) 1-1-1 (4-methoxyphenol)-5-[4-1 (methyles / rehoni / re ) Synthesis of phenyl] 1 H-pyrazole-4-yl] acetic acid

E-form In the same manner as in Example 3, the title compound was obtained in a yield of 86.0% by using the E-form compound of Example 269 instead of the compound of Example 1. E body

^{X H-NMR (CD C 1} 3) δ 3. 0 8 (3 H, s), 3. 5 9 (2 H, s), 3. 8 0 (3 H, s), 6. 8 3 (2H , D, J = 8.8 Hz), 7.07-7.17 (3 H, m), 7.29-7.38 (3 H, m), 7.44-7 . 48 (4 H, m), 7.92 (2 H, d, J = 8.8 Hz)

F ABMS 524 (M + 1) In the same manner as in Example 27, the following compounds shown in Table 21 were obtained.

Table 2 1

[Example 292] [3-[(Z) -2- (4-chlorophenyl! Enyl) ether] — 1- (4-methoxyphenyl) -1-5- [4- (methylsulfonyl) phenyl] — 1 H-pyrazole 4-yl] Synthesis of acetic acid

Z-isomer In the same manner as in Example 3, the title compound was obtained in a yield of 87.0% using the Z-isomer of Example 269 instead of the compound of Example 1.

_{^ -NMR (CD C 1 3)} S 3. 08 (3 H, s), 3. 27 (2 H, s), 3. 80 (3 H, s), 6. 5 5 (1 H, d, J = 12.2 Hz), 6.74 (1H, d, J = 12.2Hz), 6.81 (2H, d, J = 9.3Hz), 7.08 ( 2H, d, J = 8.8Hz), 7.23 (2H, d, J = 8.8Hz), 7.43 (2H, d, J = 8.3Hz), 7.50 (2H, d, J = 8.8Hz), 7.91 (2H, d, J = 8.3Hz)

F ABMS 5 24 (M + 1) The compounds shown in Table 22 below were obtained in the same manner as in Example 29-2.

Table 2 2

Table 23

[Example 303] Synthesis of ethyl 4- [3- (anilinomethyl) -11,5-bis (4-methoxyphenyl) -11 1 JJ-pyrazole_4-yl] ptanoate

In the same manner as in Example 5, the title compound was obtained in a yield of 72.0% using the compound of Reference Example 75 instead of the compound of Reference Example 49.

^{X H-NMR (CD C 1} 3) δ 1. 2 1 (3 H, t, J = 7. 3 H z), 1. 6 9 - 1. 8 4 (2 H, m), 2. 2 3 (2 H, t, J = 7.3 Hz), 2.46-2.56 (2 H, m), 3.78 (3 H, s), 3.8 1 (3 H, s), 4.07 (2H, q, J = 7.3Hz), 4.39 (2H, s), 4.42 (1H, br), 6.68—6 . 8 9 (7 H, m), 7.05—7.25 (6 H, m)

F ABMS 500 (M + 1)

Example 304 Synthesis of ethyl 4- [1,5-bis (4-methoxyphenyl) -13- (phenoxymethyl) -1H-pyrazole-4-yl] butanoate

In the same manner as in Example 81, the title compound was obtained in a yield of 87.2% using the compound of Reference Example 75 instead of the compound of Reference Example 25. One _{NMR (CD C 1 3) δ} 1. 1 7 (3 Η, t, J = 7. 3 H z), 1. 7 5 - 1. 9 0 (2 H, m), 2. 2 2 (2 H, t, J = 7.3 Hz), 2.5 1—2.63 (2H, m), 3.77 (3H, s), 3.82 (3H, s) , 4.00 (2 H,, J = 7.3 Hz), 5.16 (2 H, s), 6.78 (2 H, d, J = 8. 8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.93—7.01 (1H, m), 7.05-7.16 (6 H, m), 7.27-7.34 (2H, m) F ABMS 5 0 1 (M + 1)

[Example 3 05] Synthesis of 4- [3- (anilinomethyl) -11,5-bis (4-methoxyphenyl) -11if-pyrazol-41-yl] butanoic acid

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. _{- NMR (CDC 1 3) δ} 1. 7 2 8 5 (2 Η, m), 2. 28 (2 t, J = 6. 8 Η ζ), 2. 4 9 - 2. (2 Η, m) , 3.77 (3Η, 3.80 (3Η, s), 6.68-6. (7Η, m), 7.04-7.26-, m)

F ABMS 4 7 3 (Μ + 1)

[Example 30] 41- [1,5-bis (4-methoxyphenyl) -13- (pheno

-1 H—Pyrazol-41-yl] ptanoic acid

In the same manner as in Example 207, the title compound was obtained in 92.6% yield using the compound of Example 304 instead of the compound of Example 81. _{^ -NMR (CDC 1 3) 6} 1. 76 - 1. 90 (2 H, m), 2. 27 (2H, t, J = 7. 3 H z), 2. 55 - 2. 63 (2H, m), 3.77 (3H, s), 3.80 (3H, s), 5.16 (2H, s), 6.78 (2H, d, J = 8.8 Hz), 6.85 ( 2H, d, J = 8.8 Hz), 6.93—7.01 (1H, m), 7.04—7.17 (6H, m), 7.26—7.34 (2 H, m) F ABMS 4 7 3 (M + 1)

[Example 307] Synthesis of ethyl [1,5-bis (4-methoxyphenyl) _3_neretynyl) -11 / J-pyrazol-4-yl] acetate

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. 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 residue was purified by silica gel column chromatography (eluent: ethyl acetate Z hexane = 15) to obtain 45 mg (yield 14.1%) of the title compound.

^{X H-NMR (CD C 1} 3) δ 1. 22 (3H, t, J = 7. 3Hz), 3. 5 8 (2 H, s), 3. 78 (3H, s), 3. 81 ( 3H, s), 4.14 (2H, q, J = 7.3Hz), 6.78-6.88 (4H, m), 7.14-7.20 (5 H, m), 7.33-7.35 (2H, m), 7.54-7.57 (2H, m) F ABMS 467 (M + 1)

[Example 308] Synthesis of [1,5-bis (4-methoxyphenyl) -3- (phenelethynyl) -1-pyrazole-4-yl] acetic acid

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.

_{^ -NMR (CD C 1 3)} δ 3. 6 3 (2 H, d, J = 7. 3 H z), 3. 79 (3 H, s), 3. 8 1 (3 H, s), 6.78-- 6.89 (4 H, m), 7.13-7.20 (5H, m), 7.33-7.35 (2H, m), 7.54-- 7.57 (2 H, m)

F ABMS 43 9 (M + 1) [Example 309] ethyl [3- [1- (4-chloroph; n-oxy) ethyl] -11,5-bis (4-methoxyphenyl) -11 J-pyrazole-4— Synthesis of Acetate

333 mg (0.81 mmol) of the compound of Reference Example 77, 319 mg (1.22 mmol) of tri-n-butylphosphine, 104 mg (0.81 mm) Add 1,1,1-asobis (N, N-dimethylformamide) 210 mg (1.22 mmo 1) to a 5 ml solution of benzene 5 mm 1 at 0 ° C and stir at the same temperature for 10 minutes. did. Then, the mixture was brought to room temperature and stirred for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = lZl 0) to give 345 mg (yield 82.3%) of the title compound.

ifi one _{NMR (CDC 1 3) 8 1.} 1 6 (3H, t, J = 6. 8 H z), 1. 74 (3H, d, J = 6. 3 H z), 3. 48 (2 H , dd, J = 16.6, 28.8 Hz), 3.78 (3H, s), 3.79 (3H, s), 4.00 (2H, q, J = 6 .8H z), 5.58 (1H, q, J = 6.3 Hz), 6.77—6.96 (4H, m), 7.09-7.10 (2 H, m), 7.12-7.2 1 (6 H, m) F ABMS 5 2 2 (M + 1)

Table 2 4

/ β s s £ 6 /: / 1220SS 96S Dimension CH

[Example 3 16] Synthesis of [3- [1-1-[(4-fluorophenyl) sulfanyl] ethyl] —1,5-bis (4-methoxyphenyl) -11-if-pyrazole-14-yl] acetic acid

In the same manner as in Example 3, the title compound was obtained in a yield of 87.8% using the compound of Example 233 instead of the compound of Example 1. ^{_{a H-NMR (CDC 1 3}} ) δ 1. 66 (3 H, d, J = 6. 8 H z), 3. 5 9 (2H, dd, J = 1 6. 6, 28. 8Hz), 3 76 (3H, s), 3.80 (3H, s), 4.44 (1 H, q, J = 6.8 Hz), 6.73-6.8 1 (4

H, m), 6.90-6. 96 (2 H, m), 7.00—7.09 (4H, m), 7

. 3 3-7. 3 7 (2 H, m)

F ABMS 49 3 (M + 1) The compounds shown in Table 25 below were obtained in the same manner as in Example 3 16

g s ¾

901

96SCT0 / C00Zdf / X3d £ 6LL £ 0 / 00Z OAV [Example 3 2 4] Synthesis of sodium salt of (1,5-bis (4-methoxyphenyl) -13-{[2- (trifluoromethyl) phenoxy] methyl} -11H-pyrazole-4-yl) acetic acid

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.

'H-NMR (CD C 1 3) δ 3. 1 9 (2 H, s), 3. 4 2 (3 H, s), 3. 6 9 (3 H, s), 5. 1 8 (2 H, s), 6.55-6.63 (4 H, m), 6.8 1—6.93 (5H, m), .7.36 (1H, d, J = 7.8 Hz)

F ABMS 354 (M + Na) In the same manner as in Example 32, the following compounds shown in Table 26 were obtained. Table 26

Industrial potential

Since 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.

Claims

Claims General formula (

H H

Three

o

[Wherein, Ar ¹ and Ar ² may have the same or different substituents

R ¹ represents a hydrogen atom, a lower alkyl group or a benzyl group.

m represents an integer of 1 to 3. _CH X has the formula — CH ₂ —, — CH ₂ — CH ₂ — one CH = CH—, one C≡C one — CH ₂ — NH—, one CH—NH

CH ₂ — S—

II

-CH ₂ — 0— CH-S—

(Wherein, n represents an integer of 0, 1 or 2) or 1 C-1.

(Wherein 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 nitro group, an amino group group, Shiano group, or a group represented by the formula one C0 ₂ R ⁶ (R ^s is a hydrogen atom or a lower alkyl group), or, means pyridyl group optionally have a same or different substituents )). ] Or a pharmacologically acceptable salt thereof.

2. A pharmaceutical composition comprising the pyrazole-4-monoarnic acid derivative according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, wherein the production of both prostaglandin and leukotriene is simultaneously suppressed.

4. The pharmaceutical composition according to claim 2, which is an antirheumatic drug, an anti-inflammatory drug or an analgesic.