[go: up one dir, main page]

WO1999025695A1 - Composes 5-arylpyrazole - Google Patents

Composes 5-arylpyrazole Download PDF

Info

Publication number
WO1999025695A1
WO1999025695A1 PCT/JP1998/005041 JP9805041W WO9925695A1 WO 1999025695 A1 WO1999025695 A1 WO 1999025695A1 JP 9805041 W JP9805041 W JP 9805041W WO 9925695 A1 WO9925695 A1 WO 9925695A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
formula
halogen
carboxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1998/005041
Other languages
English (en)
Inventor
Katsuya Nakamura
Tadashi Terasaka
Takashi Ogino
Yuka Noda
Takashi Manabe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to JP52812799A priority Critical patent/JP2002509554A/ja
Publication of WO1999025695A1 publication Critical patent/WO1999025695A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms

Definitions

  • This invention relates to 5-arylpyrazole compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same .
  • one object of this invention is to provide the 5-arylpyrazole compounds, which have a COX-II inhibiting activity.
  • Another object of this invention is to provide a process for production of the 5-arylpyrazole compounds.
  • a further object of this invention is to provide a pharmaceutical composition containing, as active ingredients, the 5-arylpyrazole compounds.
  • Still further object of this invention is to provide a use of the 5-arylpyrazole compounds for manufacturing a medicament for treating or preventing various diseases.
  • the new 5-arylpyrazole compounds of this invention can be represented by the following general formula (I):
  • R 1 is aryl optionally substituted with substituent (s) selected from the group consisting of halogen, nitro, amino, esterified carboxy, carboxy, carbamoyl, cyano and lower alkoxy, R **** is hydrogen, amino, halogen, estrified carboxy, carboxy, carbamoyl, cyano, or lower alkyl substituted with halogen,
  • R ** ' is hydrogen, aryl optionally substituted with halogen, or lower alkyl optionally substituted with hydroxy, amino or carboxy
  • R is aryl substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl, and lower alkylsulfamoyl
  • A is lower alkylene, and its salt.
  • the compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers .
  • This invention includes both mixtures and separate individual isomers.
  • the compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tauto ers .
  • the compound of the formula (I) and its salt can be in a form of a solvate, which is included within the scope of the present invention.
  • the solvate preferably include a hydrate and an ethanolate.
  • radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
  • the object compound (I) or its salt can be prepared by the following process.
  • R , R , R and A are each as defined above, R is hydrogen, esterified carboxy, carbamoyl, cyano, or lower alkyl substituted with halogen, R ⁇ is esterified carboxy or carboxy, R ⁇ is aryl substituted with lower alkylthio, Rk is aryl substituted with lower alkylsulfinyl or lower alkylsulfonyl, and X 1 is a leaving group.
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable “lower alkyl” and lower alkyl moiety in the terms “lower alkylthio”, “lower alkylsulfinyl” , “lower alkylsulfonyl”, “lower alkylsulfamoyl” and “lower alkoxy” may be a straight or branched one, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like, in which preferable one is methyl.
  • Suitable "lower alkyl substituted with halogen” may be difluoromethyl, trifluoromethyl, or the like.
  • Suitable "lower alkylene” may be straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, hexamethylene, or the like, perferably one having 1 to 3 carbon atom(s), more preferably methylene.
  • Suitable "halogen” may be fluoro, chloro, bromo or iodo.
  • Suitable "aryl” may be phenyl, naphtyl, tolyl, xylyl, ethylphenyl, propylphenyl, or the like.
  • Suitable "esterified carboxy” may be substituted or unsubstituted lower alkoxycarbonyl [e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, 2 , 2 , 2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g., phenoxycarbonyl, 4-nitrophenoxycarbonyl, etc.], substituted or unsubstituted ar (lower) alkoxycarbonyl [e.g. benzyloxycarbonyl, 4- nitorobenzyloxycarbonyl, etc.], or the like.
  • lower alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, 2 , 2 , 2-trichloroethoxycarbonyl, etc.
  • Suitable “leaving group” may be halogen, acyloxy [e.g., acetyloxy, trifluoroacetyloxy, etc.], lower alkylsulfonyloxy [e.g., methanesulfonyloxy, etc.], triarylphosphinoxy [e.g., -0-P + (C ⁇ H 5 ) 3 , etc.], or the like.
  • Suitable salts of the compounds (I) and (1-1) to (I- 10), and the compounds (II) to (VI) are pharmaceutically acceptable conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g
  • the compound (1-1) or its salt can be prepared by reacting the compound (II) or its salt with a hydrazine derivative (III) or its salt.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N- dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof, preferably, acidic solvent such as alkanoic acid (e.g., acetic acid) .
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N- dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof, preferably, acidic solvent such as alkanoic acid (e.g., acetic acid
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (1-2) or its salt can be prepared by reacting the compound (IV) or its salt with the compound (III) or its salt.
  • the compound (I) or its salt can be prepared by reacting the compound (V) or its salt with the compound (VI) or its salt .
  • Suitable inorganic base may include an alkali metal
  • alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • alkali metal hydrogen carbonate e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkali metal carbonate e.g., sodium carbonate, etc.
  • alkali earth metal carbonate e.g., sodium carbonate, etc.
  • alkali earth metal carbonate calcium carbonate, etc.
  • Suitable organic base may include tri (lower) alkylamine [e.g. triethylamine, N, N-diisopropylethylamine, etc.], alkyl lithium [e.g. methyl lithium, butyl lithium, etc.], lithium diisopropylamide, lithium hexamethyldisirazido, alkali metal hydride [e.g., sodium hydride, potassium hydride, etc.] or the like.
  • tri (lower) alkylamine e.g. triethylamine, N, N-diisopropylethylamine, etc.
  • alkyl lithium e.g. methyl lithium, butyl lithium, etc.
  • lithium diisopropylamide e.g. methyl lithium, butyl lithium, etc.
  • lithium hexamethyldisirazido e.g., sodium hydride, potassium hydride, etc.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (1-4) or its salt can be prepared by reacting a compound (1-3) or its salt with an oxidizing agent.
  • the suitable oxidizing agent may be hydrogen peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, Jones reagent, peracid [e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, monopersulfate compound (oxone®) , etc.], chromic acid, potassium permanganate, alkali metal periodate [e.g. sodium periodate, etc.], and the like.
  • This reaction is usually carried out in a solvent which does not adversely influence the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, an alcohol [e.g. methanol, ethanol, etc.], a mixture thereof or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compound (1-6) or its salt can be prepared from the compound (1-5) or its salt by the following methods.
  • nitrite compound may be alkali metal nitrite [e.g. sodium nitrite, potassium nitrite, etc.], alkyl nitrite [e.g. isoamyl nitrate, tert-butyl nitrite, etc.], and the like.
  • the reaction is preferably carried out in the presence of an acid [e.g. hydrochloric acid sulfuric acid, etc.].
  • the reaction is usually carried out in a solvent such as water, tetrahydrofuran, dioxane, acetonitrile, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.
  • a solvent such as water, tetrahydrofuran, dioxane, acetonitrile, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.
  • the reaction temperature is not critical and the reaction can be carried out under cooling to warming.
  • the reaction is preferably carried out in the presence of alkali metal halide [e.g. sodium chloride, etc.] and an inorganic acid [e.g. hydrochloric acid, etc. ] .
  • alkali metal halide e.g. sodium chloride, etc.
  • an inorganic acid e.g. hydrochloric acid, etc.
  • the reaction is usually carried out in a solvent such as water, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof .
  • a solvent such as water, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof .
  • the reaction temperature is not critical and the reaction can be carried out warming to heating.
  • the compound (1-8) or its salt can be prepared by subjecting the compound (1-7) or its salt to amidation reaction.
  • Amidation reaction can be carried out in a conventional manner, which is capable of converting carboxy group or protected carboxy group to carbamoyl group.
  • Amidation can preferably carried out by, for example, (i) reacting the compound (1-7), wherein R is esterified carboxy, with alkanoylamine (e.g., aceamide, formamide, etc.) in the presence of organic base (e.g., sodium alkoxide, etc.) or (ii) reacting the compound (1-7), wherein R is carboxy, or its salt, with ammonia or its salt in the presence of condensing agent.
  • alkanoylamine e.g., aceamide, formamide, etc.
  • organic base e.g., sodium alkoxide, etc.
  • the reaction is usually carried out in a conventional solvent such as alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • alcohol e.g., methanol, ethanol, isopropyl alcohol, etc.
  • tetrahydrofuran e.g., dioxane, toluene
  • methylene chloride e.g., ethanol, isopropyl alcohol, etc.
  • the compound (1-10) or its salt can be prepared by subjecting the compound (1-9) or its salt to dehydration reaction.
  • Dehydration reaction can be carried out in the conventional manner, which is capable of dehydrating a carbamoyl group to cyano group, and suitable dehydrating agent may be phosphorus compound (e.g., phosphorus oxychloride, etc.) or the like.
  • suitable dehydrating agent may be phosphorus compound (e.g., phosphorus oxychloride, etc.) or the like.
  • the reaction is usually carried out in a conventional solvent such as alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • a conventional solvent such as alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • Suitable organic base may be tri (lower) alkylamine [e.g., triethylamine, N, -diisopropylethylamine, etc.], alkyl magnesium bromide [e.g., methyl magnesium bromide, ethyl magnesium bromide, etc.], alkyl lithium [e.g., methyl lithium, butyl lithium, etc.], lithium diisopropylamide, lithium hexamethyldisirazido, or the like.
  • alkylamine e.g., triethylamine, N, -diisopropylethylamine, etc.
  • alkyl magnesium bromide e.g., methyl magnesium bromide, ethyl magnesium bromide, etc.
  • alkyl lithium e.g., methyl lithium, butyl lithium, etc.
  • lithium diisopropylamide lithium hexamethyldisirazido, or the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform,
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the object compound (I) or pharmaceutically acceptable salts thereof of this invention possesses COX-II inhibiting activity and possesses strong antiinflammatory, antipyretic, analgesic, antithrombotic, anti-cancer activities, and so on.
  • the object compound (I) and pharmaceutically acceptable salt thereof therefore, are useful for treating and/or preventing COX-II mediated diseases, inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or animals by using administered systemically or topically. More particularly, the object compound (I) and pharmaceutically acceptable salts thereof are useful for treating and/or preventing inflammation and pain in joint and muscle [e.g.
  • rheumatoid arthritis rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.
  • inflammatory skin condition e.g. sunburn, burns, eczema, dermatitis, etc.
  • inflammatory eye condition e.g. conjunctivitis, etc.
  • lung disorder in which inflammation is involved e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.
  • condition of the gastrointestinal tract associated with inflammation e.g.
  • aphthous ulcer Chrohn ' s disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.
  • gingivitis inflammation, pain and tumescence after operation or injury, pyrexia, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sj ⁇ gren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimers disease,
  • Ten female Sprague-Dawley rats were used per group.
  • a dose of 0.5 mg of Mycobacterium tuberculosis (strain M37 BA) suspended in 0.05 ml of liquid paraffin was injected subcutaneously in the right hind paw.
  • the injection of mycobacterial adjuvant produced local inflammatory lesions (primary lesion) and then about 10 days later, secondary lesions in both the injected and uninjected paws.
  • the volumes of both paws before and on days 23 after the injection was measured as percent inhibition in comparison to vehicle-treated controls.
  • the drug was given orally once a day for 23 consecutive days from day 1 after the injection.
  • Cyclooxygenase activities in the absence or presence of inhibitors were measured by determining the level of prostaglandin ⁇ 2 (PGE 2 ) synthesis from arachidonic acid.
  • Enzymes (1 ⁇ g for COX-I and/or 3 ⁇ g for COX-II) in a total volume of 200 ⁇ l of reaction buffer were incubated in the absence or presence of various concentrations of inhibitors for 5 minutes at 30°C. The reaction was then started by the addition of arachidonic acid to the final concentration of 10 ⁇ M. The reaction was terminated by 50 ⁇ l of 1N-HC1 after incubation at 30°C for 5 minutes.
  • PGE 2 was extracted with ethyl acetate, concentrated under a stream of nitrogen and analyzed by a radio immunoassay kit (Amersham) according to the manufacture's instructions.
  • COX inhibiting activity of the test compound was assayed as PGE formation using radioimmunoassay to detect a prostaglandin release.
  • the appropriate COX enzyme was incubated in 0.1 M Tris-HCl buffer (pH 7.3) containing hematin and tryptophan with the addition of arachidonic acid (10 ⁇ M) for 5 minutes at 37°C. Compounds were pre-incubated with the enzyme for 5 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after 5 minutes at 37°C by addition of 20 ⁇ l of IN HC1. PGE 2 formation was measured by radioimmunoassay (Amersham) .
  • the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives .
  • therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
  • Example 9 A mixture of methanesulfonyl chloride (1.05 g) and
  • N-Chlorosuccinimide 25 mg
  • l-benzyl-4- ( 4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] pyrazole 50 mg
  • acetic acid 5 ml
  • the reaction mixture was stirred for additional 30 minutes at 75°C and poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, and brine successively, dried, and concentrated to dryness.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Transplantation (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I) et son sel, utiles en tant que médicament. Dans ladite formule (I) R1 représente aryle éventuellement substitué par un ou plusieurs substituant(s) choisis dans le groupe constitué d'halogène, nitro, amino, carboxy estérifié, carboxy, carbamoyle, cyano et alcoxy inférieur; R2 représente hydrogène, amino, halogène, carboxy estérifié, carboxy, carbamoyle, cyano ou alkyle inférieur substitué par halogène; R3 représente hydrogène, aryle éventuellement substitué par halogène, ou alkyle inférieur éventuellement substitué par hydroxy, amino ou carboxy; R4 représente aryle substitué par un ou plusieurs substituants choisis dans le groupe composés d'halogène, alcoxy inférieur, alkylthio inférieur, alkylsulfinyle inférieur, alkylsulfonyle inférieur, sulfamoyle et alkylsulfamoyle inférieur; et A représente alkylène inférieur.
PCT/JP1998/005041 1997-11-18 1998-11-10 Composes 5-arylpyrazole Ceased WO1999025695A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP52812799A JP2002509554A (ja) 1997-11-18 1998-11-10 ５−アリールピラゾール化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP0423A AUPP042397A0 (en) 1997-11-18 1997-11-18 5-arylpyrazole compounds
AUPP0423 1997-11-18

Publications (1)

Publication Number Publication Date
WO1999025695A1 true WO1999025695A1 (fr) 1999-05-27

Family

ID=3804703

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/005041 Ceased WO1999025695A1 (fr) 1997-11-18 1998-11-10 Composes 5-arylpyrazole

Country Status (3)

Country Link
JP (1) JP2002509554A (fr)
AU (1) AUPP042397A0 (fr)
WO (1) WO1999025695A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029029A1 (fr) * 2002-09-26 2004-04-08 Agro-Kanesho Co.,Ltd. Procede de production d'un derive de pyrazole
WO2004080999A1 (fr) * 2003-03-14 2004-09-23 Biolipox Ab Composes de pyrazole utilises dans le traitement de l'inflammation
WO2006032852A1 (fr) * 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2006114313A1 (fr) * 2005-04-26 2006-11-02 Glaxo Group Limited Composes de pyrazole utilises comme ligands des recepteurs de la prostaglandine
US7172769B2 (en) 1999-12-08 2007-02-06 Pharmacia Corporation Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect
WO2007042817A1 (fr) * 2005-10-13 2007-04-19 Biolipox Ab Naphthalene-disulfonamides convenant pour le traitement d'une inflammation
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
EP1542972A4 (fr) * 2002-07-29 2008-01-23 Nitromed Inc Inhibiteurs selectifs de la cyclo-oxygenase-2, compositions et procedes d'utilisation
WO2008129276A1 (fr) * 2007-04-19 2008-10-30 Boehringer Ingelheim International Gmbh Disulfonamides utiles dans le traitement de l'inflammation
WO2009127612A1 (fr) * 2008-04-14 2009-10-22 Syngenta Participations Ag Nouveaux dérivés de pyrazole
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090081020A (ko) * 2006-11-13 2009-07-27 노파르티스 아게 Ｋｓｐ 억제제로서의 치환된 피라졸 및 트리아졸 화합물

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418845A1 (fr) * 1989-09-22 1991-03-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés de pyrazole, leur procédé de préparation et composition pharmaceutique les contenant
DE4126543A1 (de) * 1991-08-10 1993-02-11 Chem & Pharm Patent Hold Ltd 3(5)-(hydroxyaryl)-pyrazole und ihre verwendung als wirkstoffe in arzneimittel
WO1995015318A1 (fr) * 1993-11-30 1995-06-08 G.D. Searle & Co. Pyrazoles trisubstitues en 1,3,5 pour le traitement de l'inflammation
WO1995015316A1 (fr) * 1993-11-30 1995-06-08 G. D. Searle & Co. Benzenesulfonamides de pyrazolyle substitues destines au traitement des inflammations
US5486534A (en) * 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
WO1997013755A1 (fr) * 1995-10-09 1997-04-17 Fujisawa Pharmaceutical Co., Ltd. Pyrazoles 1,3,5-trisubstitues pour le traitement des inflammations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418845A1 (fr) * 1989-09-22 1991-03-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés de pyrazole, leur procédé de préparation et composition pharmaceutique les contenant
DE4126543A1 (de) * 1991-08-10 1993-02-11 Chem & Pharm Patent Hold Ltd 3(5)-(hydroxyaryl)-pyrazole und ihre verwendung als wirkstoffe in arzneimittel
WO1995015318A1 (fr) * 1993-11-30 1995-06-08 G.D. Searle & Co. Pyrazoles trisubstitues en 1,3,5 pour le traitement de l'inflammation
WO1995015316A1 (fr) * 1993-11-30 1995-06-08 G. D. Searle & Co. Benzenesulfonamides de pyrazolyle substitues destines au traitement des inflammations
US5486534A (en) * 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
WO1997013755A1 (fr) * 1995-10-09 1997-04-17 Fujisawa Pharmaceutical Co., Ltd. Pyrazoles 1,3,5-trisubstitues pour le traitement des inflammations

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7172769B2 (en) 1999-12-08 2007-02-06 Pharmacia Corporation Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
EP1542972A4 (fr) * 2002-07-29 2008-01-23 Nitromed Inc Inhibiteurs selectifs de la cyclo-oxygenase-2, compositions et procedes d'utilisation
WO2004029029A1 (fr) * 2002-09-26 2004-04-08 Agro-Kanesho Co.,Ltd. Procede de production d'un derive de pyrazole
WO2004080999A1 (fr) * 2003-03-14 2004-09-23 Biolipox Ab Composes de pyrazole utilises dans le traitement de l'inflammation
WO2006032852A1 (fr) * 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2006114313A1 (fr) * 2005-04-26 2006-11-02 Glaxo Group Limited Composes de pyrazole utilises comme ligands des recepteurs de la prostaglandine
WO2007042817A1 (fr) * 2005-10-13 2007-04-19 Biolipox Ab Naphthalene-disulfonamides convenant pour le traitement d'une inflammation
WO2008129276A1 (fr) * 2007-04-19 2008-10-30 Boehringer Ingelheim International Gmbh Disulfonamides utiles dans le traitement de l'inflammation
WO2009127612A1 (fr) * 2008-04-14 2009-10-22 Syngenta Participations Ag Nouveaux dérivés de pyrazole
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Also Published As

Publication number Publication date
JP2002509554A (ja) 2002-03-26
AUPP042397A0 (en) 1997-12-11

Similar Documents

Publication Publication Date Title
FI102535B (fi) Menetelmä valmistaa farmaseuttisesti käyttökelpoisia 1,3,5-trisubstitu oituja pyratsolijohdannaisia
EP0178035B1 (fr) 1,N-Diarylpyrazol-3-amines anti-inflammatoires, compositions les contenant et leur préparation
CA2234511A1 (fr) Pyrazoles 1,3,5-trisubstitues pour le traitement des inflammations
JP4426660B2 (ja) ピラゾール誘導体、その製法および医薬としてのその使用
KR101302796B1 (ko) 시클로헥실 아미드 유도체 및 ｃｒｆ－１ 수용체 길항제로서의 그의 용도
Tsuji et al. Studies on anti-inflammatory agents. IV. Synthesis and pharmacological properties of 1, 5-diarylpyrazoles and related derivatives
WO1999032454A1 (fr) Heteroaromatiques contenant de l'azote, presentant des groupes p1 a substitution ortho, et utilises en tant qu'inhibiteurs du facteur xa
HRP970698A2 (en) NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
EP1874303A1 (fr) Composes de pyrazole utilises comme ligands des recepteurs de la prostaglandine
EP0554829A2 (fr) Dérivés du pyrazole à activité anti-inflammatoire, analgésique et antithrombotique
WO2000071120A1 (fr) Composes antibacteriens
JP2008525404A (ja) 治療剤
WO1999025695A1 (fr) Composes 5-arylpyrazole
EP1442026B1 (fr) Derives de triazole utiles comme inhibiteurs de la cyclooxygenase (cox)
US6548512B1 (en) Nitrogen containing heteroaromatics as factor Xa inhibitors
US6316485B1 (en) 1,5-diphenylpyrazole derivatives
JP2002527508A (ja) 抗炎症活性を有する新規なイミダゾール類
JP4177435B2 (ja) 治療薬
US5250700A (en) Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents
WO1996020177A1 (fr) Derives pyrimidiniques
EP0127371B1 (fr) 1,N-Diaryl-4,5-dihydro-1H-pyrazol-3-amines, compositions les contenant et leurs procédés de préparation
WO2000018741A2 (fr) Nouveaux composes
AU750356B2 (en) 1,5-diphenylpyrazole derivatives
JPH10291982A (ja) 新規複素環化合物
LT4673B (lt) Azoto heteroaromatiniai junginiai kaip faktoriaus xa inhibitoriai

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase