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WO1996026921A1 - Nouveaux derives de biphenyle ou leurs sels, et agents anti-inflammatoires contenant lesdits derives ou leurs sels - Google Patents

Nouveaux derives de biphenyle ou leurs sels, et agents anti-inflammatoires contenant lesdits derives ou leurs sels Download PDF

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Publication number
WO1996026921A1
WO1996026921A1 PCT/JP1996/000499 JP9600499W WO9626921A1 WO 1996026921 A1 WO1996026921 A1 WO 1996026921A1 JP 9600499 W JP9600499 W JP 9600499W WO 9626921 A1 WO9626921 A1 WO 9626921A1
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group
biphenyl
nmr
difluorophenoxy
solvent
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PCT/JP1996/000499
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English (en)
Japanese (ja)
Inventor
Hisaaki Chaki
Hiroshi Kuroda
Shinji Makino
Jun Nitta
Keiichi Tanaka
Takihiro Inaba
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Toyama Chemical Co., Ltd.
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Priority to AU48444/96A priority Critical patent/AU4844496A/en
Publication of WO1996026921A1 publication Critical patent/WO1996026921A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
    • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton

Definitions

  • Novel biphenyl derivative or salt thereof and anti-inflammatory agent containing them Novel biphenyl derivative or salt thereof and anti-inflammatory agent containing them
  • the present invention relates to the general formula [1]
  • R 1 is a lower alkyl or aryl group which may be substituted with a halogen atom or an amino group which may be protected;
  • R 2 is an aryl group which may be substituted or General formula
  • R is an optionally substituted alkyl, alkenyl, alkylsulfonyl, cycloalkyl, aryl, aralkyl or heterocyclic group
  • Z is an oxygen atom, a sulfur atom
  • R 3 and R 4 may be the same or different and are a hydrogen atom, a halogen atom, a methylene group, a carbonyl group or a vinylene group which may be substituted with a hydroxyl group
  • the present invention relates to a biphenyl derivative represented by or a salt thereof, and a COX-2 selective inhibitor containing them and ⁇ : an inflammatory agent.
  • non-steroidal anti-inflammatory drugs such as aspirin and indomethacin have been provided for the treatment of inflammatory diseases including rheumatoid arthritis.
  • the main mechanism of action of these non-steroid acidic anti-inflammatory drugs is the inhibition of the biosynthesis of brostaglandin (PG) based on the inhibitory action of cyclooxygenase (c OX).
  • PG brostaglandin
  • c OX cyclooxygenase
  • clinical side effects such as gastrointestinal tract disorders and renal disorders are also due to COX inhibitory effects, and the onset of anti-inflammatory effects and the occurrence of side effects can be said to be two sides of the same coin.
  • COX-2 the conventional type was named COX-11 was found as an isozyme for this COX.
  • COX-1 is a constitutive enzyme
  • COX-2 is an inducible enzyme, which is an enzyme that is specifically induced at the site of inflammation by inflammation.
  • drugs that selectively inhibit COX-2 may be anti-inflammatory agents with few side effects [Inflammation and Immunity, Vol. 3, No. 1, pp. 14-36 (1995) [Nature, Vol. 367, pp. 215-216 (1994)].
  • the present inventors have conducted intensive studies and as a result, have found that the compound of the general formula [1] or a salt thereof has a COX-2 selective inhibitory activity, and has extremely excellent anti-inflammatory and antipyretic properties. It has analgesic and anti-arthritic effects, and further has found that side effects such as gastrointestinal tract disorders are extremely small, thereby completing the present invention.
  • each term is, unless otherwise specified, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an acyl group is, for example, a formyl group, an acetyl or propionyl group.
  • Ari Alkyl groups include, for example, phenyl and naphthyl; alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, Linear or branched C M, such as hexyl, heptyl and octyl.
  • alkyl group refers to, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio and octylthio; Linear or branched C.
  • alkylthio group means, for example, methylsulfinyl, ethylsulfinyl, n -propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, ten-butylsulfinyl, pentyl Linear or branched C M, such as sulfinyl, hexylsulfinyl, heptylsulfinyl and octylsulfinyl.
  • Alkylsulfinyl group; alkylsulfonyl group means, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, ⁇ -butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl Linear or branched C,.
  • alkylsulfonyl groups such as, hexylsulfonyl, heptylsulfonyl and octylsulfonyl; alkylsulfonyloxy groups; for example, methylsulfonyloxy, ethyl Sulfonyloxy, ⁇ -propylsulfonyloxy, isopropylsulfonyloxy, ⁇ -butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, ten-butylsulfonyloxy, pentylsulfonoxy Linear or branched C M, such as niloxy, hexylsulfonyloxy, heptylsulfonyloxy and octylsulfonyloxy.
  • alkylsulfonylamino group means, for example, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, Linear or branched such as isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, heptylsulfonylamino and octylsulfonylamino Branched C M.
  • Alkylsulfonylamino group lower alkenyl
  • the group for example, vinyl, Ariru, Burope alkenyl, isopropenyl base alkenyl, butenyl, c 2 straight chain and branched, such Isobuassociatedu and pentenyl, alkenyl group;.
  • An alkenyl group for example, Biel, Ariru, Burope alkenyl, isopropenyl two Le, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl and O click thenyl C 2 straight chain or branched, such as, 0 alkenyl group;.
  • alkoxy groups Is a linear or branched C M such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy.
  • An alkoxycarbonyl group; an alkoxycarbonyl group is, for example, a linear or branched group such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
  • the aralkyl groups such as benzyl, Jifue two Rumechiru, ar-C such as trityl and phenethyl, 5 alkyl groups;; C alkyl O propoxycarbonyl two Le group.
  • the cycloalkyl group in even ', Shikurobu A C w cycloalkyl group such as mouth pill, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a lower alkyl group is, for example, methyl, ethyl, ⁇ -propyl, isopropyl, n -butyl, sec-butyl, isobutyl, text- butyl and linear pentyl also properly is branched C, 5 alkyl groups;.
  • a lower alkoxy group for example, main butoxy, ethoxy, .eta.
  • Purobokishi isopropoxy, [pi —A straight chain such as butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentyloxy
  • the heterocyclic group for example, Azechijiniru, thienyl, furyl, pyrrolyl, Lee Mi Dazoriru, pyrazolyl, thiazolyl, isothiazolyl, Okisazoriru, Isookisazoriru, furazanyl, pyrrolidinyl, pyrrolinyl , Imidazolidinyl, imidazolinyl, virazolidinyl, vilazolinyl, 1,3,4-year-old oxaziazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 — Triazolyl, 1,2,4—triazolyl, tetrazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl,
  • a lower alkoxycarbonyl group is, for example, methoxycarbonyl, ethoxycarbonyl, ⁇ -propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy force
  • C alkoxycarbonyl groups such as rubonyl, ten-butoxycarbonyl and pentoxycarbonyl
  • lower alkylidene groups include, for example, C alkylidene such as methylene, ethylidene, propylidene and isopropylidene
  • a lower alkyl group for example, Lay methylthio, Echiruchio, n- propylthio, isopropylthio, n- butylthio, iso Chio, sec- Puchiruchio, also linear, such as ten- Puchiruchio and pentylthio
  • the branched c, 5 a Arukiruchio group;.
  • the lower alkylsulfonyl group for example, methylsulfonyl, Echirusuruhoniru, n- Bro pills sulfonyl, isopropyl sulfonyl, .pi. butylsulfonyl, iso-butylsulfonyl, sec- Buchirusuruho .
  • sulfonyl tert- butylsulfonyl and pentylsulfonyl straight-chain or branched C, such as, 5 alkylsulfonyl two Le group; and halogeno-lower alkyl group, for example, Furuoromechiru, chloromethyl, bromomethyl, dichloromethyl, .
  • the Dorokishi lower alkyl group for example, human Dorokishimechiru arsenide de ⁇ Kishi C such as human Dorokishechiru and hydroxycarboxylic propyl, 5 alkyl group;
  • the ⁇ Mi-lower- ⁇ alkyl group e.g., aminomethyl, amino aminoethyl and Ami knob opening pill of any ami no C, 5 alkyl groups;
  • a lower alkoxy force carbonyl-lower alkyl group for example, main butoxycarbonyl methyl, ethoxycarbonylmethyl, .pi. propoxy carbonyl methyl, main butoxycarbonyl E chill And d Kishikarubo the C alkoxycarbonyl over C alkyl group such as a secondary Ruechi le;
  • the cyclic amino group may be, for example, either a saturated cyclic amino group or an unsaturated cyclic amino group, and may further contain one or more nitrogen atoms, oxygen atoms, sulfur atoms, etc. in the ring. It may contain atoms and a carbonyl carbon, and may be monocyclic or bicyclic, and more specifically, aziridine-11-yl, azetidine-11-yl , Pyrrolidine- 1 -yl, pyrroline-1 -yl, pyrrole-1-1 -yl, dihydropyridine-1-1 -yl, pyridino, dihydrodolazepine-1-1, and perhydroroazepine-1- A saturated or unsaturated monocyclic 3- to 7-membered cyclic amino group having one nitrogen atom such as diyl; imidazole-11-yl, imidazolidin-11-yl, imidazoline-11- Yl, villazolidine 1-yl, .
  • Perazine 1-yl 1, 4-dihydropyrazine 1-yl, 1,2-dihydropyrazine Saturated or unsaturated monocyclic 3- to 7-membered cyclic amino groups having 2 nitrogen atoms, such as limidine-11-yl, perhydropyrazine-11-yl and homopiperazine-11-yl; 1,, 1,4-triazole-l, 1,2,3-triazo-l-yl.
  • 1,2-dihydro-l, 2,4-triazine-l-yl and Perhydrol-S-tril Saturated or unsaturated monocyclic 317-membered cyclic amino groups having 3 or more nitrogen atoms such as azine-11-yl; oxazolidin-13-yl, isoxoxazolidine-12-yl, morpholino 1,3-oxazolidin-1-yl, thiazolidine-111-yl, isothiazolidine-111-yl, thiomorpholino, homothiomorpholine-1-1-yl and 1,2,4-thiadiazolin-2-yl Selected from oxygen and sulfur atoms in addition to nitrogen atom Saturated or unsaturated monocyclic having 1 to 4 heteroatoms
  • spiro- or cross-linked saturated or unsaturated 5-membered cyclic amino groups such as nonane-2-yl and 7-azabicyclo [2.2.1] heptane-7-yl; alkylamino groups; is, for example, Mechiruami Roh, Echirua Mi Roh, Puropirua Mi Roh, to Kishiruami Bruno, Hepuchiruami Bruno, Jimechiruami Bruno, Jechiruami Bruno, mono- or di-C M such Kishiruami Bruno and Mechiruechiruami Bruno to di.
  • the lower Arukiruami amino group for example, Mechiruami Bruno, Echiruami Bruno, Puropiruami Bruno, Jimechiruamino, the Jechiruami Roh and methyl E chill ⁇ Mino of any mono- or di-C M alkyl amino group;
  • Arukiruami amino group and a lower Arukokishii amino group Is, for example, a C alkoxyamino group such as methoxyimino and ethoxyimino;
  • a lower alkylamino lower alkyl group is, for example, methylaminomethyl, methylaminoethyl, ethylaminomethyl, methylaminobutamin.
  • Mono or di-C alkylamino such as pill, propylaminoethyl, dimethylaminomethyl, dimethylaminomethyl, dimethylaminoethyl and dimethylaminopropyl .
  • the Ariruokishi group e.g., phenoxy and the groups represented by like naphthoquinone preparative alkoxy;; c, 5 alkyl groups and the alkoxy O hexa Lil group, for example, c M0 such main Tokisa Lil and ethoxalyl Arukiruokishio the Kisariru group; alkoxy Okisariruamino groups, e.g., C M such main Tokisariruamino and Etokisarirua amino. Each represents an alkyloxyoxalylamino group.
  • each group in R 2 , R ⁇ R 4 and R ′ is, for example, a halogen atom, a cyano group, a nitro group, an azide group, an optionally protected carboxyl group, an optionally protected hydroxyl
  • Examples of the substituent of the imino group in Z include groups such as a lower alkyl group and an aryl group.
  • the protecting group for the hydroxyl group and the hydroxy lower alkyl group includes all groups which can be usually used as a protecting group for the hydroxyl group, for example, ', benzyloxycarbonyl, 4-nitro Benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ten-butoxycarbonyl, 1.1 —Dimethylpropoxycarbonyl, isop or rh.
  • Xyloxycarbonyl isobutyloxycarbonyl, diphenylmethoxycarbo Nyl, 2,2,2-trichloromouth ethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycal Bonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, aryloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-11-naphthyloxycarbonyl, 8-quino Acetyl groups such as riloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxy
  • amino-protecting groups include all groups that can normally be used as amino-protecting groups, for example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, ⁇ -nitrobenzyloxycarbonyl, 0—Bromobenzyloxycarbonyl, (Mono, G, Tri) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, Cyclopentanecarbonyl, benzoyl, tert-amyloxycarbonyl, ten-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl , 2 monofurfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succ
  • one Grade alkyl one phosphoryl group 5- methyl-2 Okiso 2 Eta - 1, such as a lower alkyl-substituted silyl group such as 3-Jiokisoru one 4- Irumechiru oxygen-containing heterocyclic alkyl groups and trimethylsilyl like can be mentioned.
  • the protecting groups for the carboxyl group and the carboxy lower alkyl group include all groups that can be used as a protecting group for a normal carboxyl group, for example, methyl, ethyl, ⁇ -propyl, lower alkyl groups such as iso-propyl, 1,1-dimethylpropyl, n-butyl and ten-butyl; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and Al-lower alkyl groups such as bis (p-methoxyphenyl) methyl; lower-alkyl groups such as acetylmethyl, benzoylmethyl, p-2-trobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl Oxygen-containing heterocyclic groups such as 2-tetrahydrobilanyl
  • Examples of the salt of the compound of the general formula [1] include a commonly known salt in a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.
  • Examples of the salt in the basic group include: salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; Salt strength with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid. ⁇
  • Examples of salts in acidic groups include sodium and potassium.
  • Salts with alkaline metals such as lime; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, ⁇ , dimethylaniline, dimethyl To biperidine, ⁇ -methylmorpholine, getylamine, dicyclo Shi Ruami down, pro force Lee down, Jibenjiruami down, Nyu- benzyl-Fuenechirua Mi emissions, 1 Efuenami emissions and New, New '- nitrogen such dibenzylethylenediammonium ⁇ Min Motoyu And the like, and preferably, a physiologically acceptable salt.
  • the present invention includes those isomers, It also includes solvates, hydrates and crystals of various shapes.
  • R ′ is a lower alkyl or amino group
  • R: is a general formula—Z—R 5 (R 5 is a lower alkyl group or a substituent which may be substituted with a halogen atom, hydroxyl or oxo group.
  • Z represents an oxygen atom, a sulfur atom, a methylene group, a carbonyl group or a vinylene group.
  • R ′ is a group represented by R ′ and Are the same or different, and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally protected amino group, an optionally protected carboxyl group, an acyl group, an alkoxycarbonyl group or a substituted may be alkyl, alkoxy, Cal Bamoiru is preferably a compound alkylamino or Ashiruamino group, R: is the formula Z- R 5 (R is optionally substituted with a halogen atom cycloalkyl Le, pyridyl or phenyl group the; Z is an oxygen atom, a methylene group, c indicating a carbonyl group or a vinylene group) is a group represented by , R and R 4 are one or more and are more preferably
  • R 1 is a methyl or amino group
  • R 2 is a group of the general formula Z—R 5 (R 5 is a pyridyl or phenyl group optionally substituted by a halogen atom; Z is an oxygen atom .)
  • R and K 4 are the same or different dates, hydrogen atom, Shiano group, also is properly nitro group or a carboxyl group substituted with a halogen atom
  • Compound is a alkyl group is even more preferred.
  • Representative compounds of the compound of the present invention include, for example, the following compounds. . 2— (24-Difluorophenoxy) 1-4-methylthio 14-1-2tro 1,1,1-biphenyl
  • the biphenyl derivative of the general formula [1] or a salt thereof can be produced, for example, according to the following production method. Manufacturing method ⁇
  • R ', R - ⁇ R and R have the same meaning as described above, B U means a blanking ethyl group.”
  • Examples of the salts of the compounds represented by the general formulas [la], [lb], [lc] and [2] include the same salts as described for the compounds represented by the general formula [ ⁇ ].
  • the compound of the general formula [la] can be obtained, for example, by the method described in The Chemical Society of Japan, No. 3, pp. 520-526 (1985). Specifically, for example, it can be obtained by reacting a compound of the formula [2] with a compound of the formula [3] in the presence or absence of a palladium coordination compound as a catalyst.
  • Examples of the palladium coordination compound used in this reaction include tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) norazidium ( ⁇ ), lid and benzyl (chloro) bis ( Triphenylphosphine) palladium ( ⁇ ) and palladium acetate ( ⁇ ).
  • the amount of the catalyst to be used may be 0.001-1 times the molar amount of the compound of the general formula [2], preferably 0.01 to 0.05 times the molar amount.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran.
  • Halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as ⁇ , ⁇ -dimethylformamide; and sulfoxides such as dimethyl sulfoxide.
  • These solvents may be used alone or in combination of two or more. This reaction is carried out usually at 40 to reflux, preferably at 70-0, for 30 minutes to 72 hours, preferably for 1 to 5 hours.
  • the compound of the general formula [la] can also be obtained, for example, by the method described in Tetrahedron Letters, Vol. 28, pp. 5093-5096 (1987). Specifically, for example, it can be obtained by reacting a compound of the general formula [2] with a compound of the general formula [4]. This reaction may be usually performed using a palladium coordination compound as a catalyst in the presence of a base.
  • the compound of the general formula [la] in which R : is a styryl group is a compound of the general formula [2] in which the group corresponding to R 2 is a formyl group in the same manner as the compound of the general formula [4]. Then, the formyl group corresponding to R : in the compound of the general formula [la] can be converted into a styryl group by a conventional method.
  • Palladium coordination compounds used in this reaction include, for example, tetrakis (triphenylphosphine) palladium (0), bis (trifininylphosphine) palladium (II) chloride, Benji Bis (triphenylphosphine) palladium (II) and palladium sulfate ( ⁇ ).
  • the amount of the catalyst to be used may be 0.0011 to 11 times mol, preferably 0.01 to 0.05 times mol, based on the compound of the general formula [2 ⁇ ] c.
  • Alkali carbonates such as sodium hydrogencarbonate and sodium carbonate
  • alkali hydroxides such as sodium hydroxide and potassium hydroxide
  • alkali metal alcoholates such as sodium methoxide and sodium ethoxide
  • organic bases such as triethylamine and pyridine.
  • the amount of the base to be used may be 1 to 10 times mol, preferably 2 to 4 times mol for the compound of the general formula [2].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dioxane and tetrahydrofuran
  • Halogenated hydrocarbons such as oral form and methylene chloride
  • alcohols such as methanol and ethanol
  • amides such as N, N-dimethylformamide
  • sulfoxides such as dimethyl sulfoxide, and water.
  • solvents may be used alone or in combination of two or more. This reaction is carried out usually at 40 to under reflux, preferably at 70-0 for 30 minutes to 72 hours, preferably for 1 to 5 hours.
  • the compound of the formula [lc] can be obtained, for example, by the method described in The Chemical Society of Japan, No. 3, 520-526— (1985). Specifically, it can be obtained, for example, by reacting a compound of the general formula [2] with a compound of the single-arm type [5]. This reaction is usually performed using a palladium coordination compound as a catalyst.
  • Palladium coordination compounds used in this reaction include, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) no, radium () chloride, benzyl Bis (triphenylphosphine) palladium (II) and palladium (II) acetate;
  • the amount of the catalyst used may be 0.001 to 1 times, preferably 0.01 to 0.05 times the mol of the compound of the general formula [2].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane and tetrahydrofuran.
  • Ethers Halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as ⁇ , ⁇ -dimethylformamide; and dimethyl sulfoxide
  • This reaction may be carried out usually at 40 * C under reflux, preferably at 70-120, for 30 minutes-72 hours, preferably for 1-5 hours.
  • the compound of the general formula [lc] can also be obtained, for example, by the method described in Tetrahedron Letters, Vol. 28, pp. 5093-5096 (1987). Specifically, for example, it can be obtained by reacting a compound of the general formula [2] with a compound of the general formula [6]. This reaction may be usually carried out using a palladium coordination compound as a catalyst in the presence of a base.
  • Palladium coordination compounds used in this reaction include, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, benzyl ) Bis (triphenylphosphine) nordum (II) and palladium (II) acetate.
  • the amount of the catalyst used may be 0.001-1 times mole, and preferably 0.01-0.05 times mole, of the compound of the single-arm type [2].
  • Bases used in this reaction include alkali carbonates such as sodium hydrogencarbonate and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alcoholates such as sodium methoxide and sodium ethoxide. And organic bases such as triethylamine and pyridine.
  • the base may be used in an amount of 1 to 10 moles, preferably 2 to 4 moles, per mole of the compound of the general formula [2].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran Halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; amides such as ⁇ , ⁇ -dimethylformamide; sulfoxides such as dimethyl sulfoxide and water. These solvents may be used alone or in combination of two or more.
  • the reaction is usually carried out at 40 to reflux, preferably 70-120, for 30 minutes-72 hours, preferably It should be carried out for one to five hours.
  • the compound of the general formula [lb] can be obtained, for example, by oxidizing the compound of the general formula [la].
  • the oxidizing agent to be used in this reaction is not particularly limited as long as it is a commonly used oxidizing agent.
  • oxidizing agents such as trifluoroperacetic acid, peracetic acid, perbenzoic acid and m-chloroperbenzoic acid. Acid; hydrogen peroxide; chromic acid and potassium permanganate.
  • the amount of the oxidizing agent to be used may be 0.5 to 1.5 times mol, preferably 0.8 to 1.2 times mol, of the compound of the general formula [la].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; and halogens such as methylene chloride and chloroform. Hydrocarbons; alcohols such as methanol and ethanol; esters such as ethyl acetate; organic acids such as formic acid and drunk acid; and water. These solvents may be used alone or in combination of two or more. May be. This reaction is usually carried out under reflux from o t :, preferably at 0 to 30 for 30 minutes to 24 hours, preferably for 30 minutes to 12 hours.
  • the compound of the general formula [k] can be obtained, for example, by oxidizing a compound of the general formula [la] or [lb].
  • the oxidizing agent used in this reaction is not particularly limited as long as it is a commonly used oxidizing agent.
  • the amount of the oxidizing agent to be used may be 1.5 to 5 times the molar amount of the compound of the general formula [la], and is preferably .5 to 2.5 times the molar amount.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride and chloroform.
  • Halogenated hydrocarbons alcohols such as methanol and ethanol; esters such as ethyl acetate; organic acids such as formic acid and acetic acid; water; and the like. These solvents may be used alone or in combination. Is also good.
  • This reaction is carried out usually from 0 to under reflux, preferably from 0 to 30, for 30 minutes to 24 hours, preferably for 30 minutes to 2 hours.
  • the compound of the general formula [1] or a salt thereof obtained in this manner is subjected to, for example, an oxidation reaction using perbenzoic acid, manganese dioxide or dichromic acid, catalytic reduction, or a hydride such as lithium aluminum hydride.
  • Reduction and reduction reactions using metals such as iron transfer reactions such as Wolff rearrangement, alkylation, acylation, amidation, sulfonylation, cyclization, substitution such as conversion of nitrile to amidine Reaction, a halogenation reaction using carbon tetrabromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, or the like, a dehydration reaction or a hydrolysis reaction such as acid hydrolysis or alkali hydrolysis. Derivation to another compound of general formula [1] or a salt thereof by subjecting to a reaction or combining them as appropriate be able to. Further, it can be isolated and purified according to a conventional method such as extraction, crystallization and column chromatography.
  • the one-branched [2] bromophenyl derivative or a salt thereof can be produced, for example, according to the following production method.
  • R : , R 1 and R 4 have the same meanings as described above, and R is an optionally substituted lower alkyl, lower alkenyl, lower alkylsulfonyl, cycloalkyl, aryl.
  • R 2C is a substituted or unsubstituted aryl group or a group represented by the general formula: Z′—R, wherein R 5 has the same meaning as described above; Z 1 represents an oxygen atom, a sulfur atom, or an optionally substituted imino group.
  • R and R are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, an azide group, a nitro group, a carboxyl group, a hydroxyl group, an
  • Oyobi 1 "are the same or different, a hydrogen atom, a halogen atom, Shiano group, a force Ruboxyl group, hydroxy group, acyl group, alkoxycarbonyl group or optionally substituted alkyl, alkenyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, alkylsulfonylamino, aryloxy, cycloalkyl, cylvamoyl RR “, RR", RR, sulphamoyl, acylamino, oxa mouth, alkoxyoxalyl, alkoxyoxalylamino, a nitrogen-containing heterocyclic carbonyl, aryl or heterocyclic group bonded via a nitrogen atom; 4f , R 4f and R are the same or different, Hydrogen atom, halogen atom, cyan
  • the compound of the general formula [2] can be obtained, for example, by reacting the compound of the general formula [16] with a halide such as an alkyl halide or aryl halide in the presence or absence of a base.
  • a halide such as an alkyl halide or aryl halide
  • the halide used in this reaction includes, for example, methyl iodide, cyclohexyl bromide and bromobenzene, and the amount of the halide is 115 times the molar amount of the compound of the general formula [16]. Should be fine.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction; ', for example, amides such as ⁇ , ⁇ -dimethylformamide; sulfoxides such as dimethyl sulfoxide Ketones such as acetone; alcohols such as methanol and ethanol; water; and collidine and the like. These solvents may be used alone or in combination of two or more.
  • Bases used in this reaction include, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tetrabutoxide; alkali metal alkoxides such as sodium hydride and lithium hydride. Hydrides; alkaline metal carbonates such as carbonated carbonate and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide. The amount of the base used is the general formula
  • the catalyst used in this reaction include copper powder, cuprous oxide, cuprous chloride, and 8-hydroxyquinoline-cuprous chloride. It may be 0.01 to 2 times the mole of the compound of [16].
  • This reaction is usually carried out at -20 to 160 for 30 minutes to 24 hours.
  • diphenyliodium bromide and diphenyl chloride are used in place of the halide, the compound of the general formula [2] in which R 2 is phenoxy can be obtained.
  • the compound of the general formula [2] can be obtained by subjecting the compound of the general formula 6 ] to a Mitsunobu reaction in the presence of alcohol, triphenylphosphine, getyl azodicarboxylate and the like.
  • the alcohol used in this reaction includes Preferably, isopropyl alcohol and cyclohexanol are exemplified.
  • the amount of the alcohol, triphenylphosphine and getyl azodicarboxylate used in this reaction may be 1-3 times the mole of the compound of the general formula [16].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane and tetrahydrofuran. Ethers such as; halogenated hydrocarbons such as chloroform and methylene chloride;
  • Amides such as ⁇ , ⁇ -dimethylformamide; sulfoxides such as dimethyl sulfoxide; and the like. These solvents may be used alone or in combination of two or more.
  • the reaction is usually carried out at -20 to reflux, preferably at -20 to 50, for 30 minutes to 24 hours, preferably for 30 minutes to 4 hours.
  • the compound of the general formula [16] can be prepared, for example, by the method described in Journal of Chemical. Perkin 1 (J. Chem. So Perkin I), 802-804 (1977). Can be manufactured.
  • the compound of the general formula [2] can be obtained, for example, by reacting the compound of the general formula [17] with a nitrite in the presence or absence of an acid, and then converting the obtained compound to a bromide. It can be obtained by reacting with cuprous copper.
  • a nitrite compound used in this reaction include aluminum nitrite such as sodium nitrite and potassium nitrite; and alkyl nitrite such as tertiary butyl nitrite.
  • the amount of the nitrite compound used may be 0.5 to 5 times the mol of the compound of the general formula [].
  • Examples of the acid used in this reaction include hydrochloric acid and sulfuric acid, and the amount of the acid used may be 150-fold molar amount to the compound of the general formula [III].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include water, acetic acid, tetrahydrofuran, dioxane, and acetate nitrile.
  • the solvents may be used alone or in combination of two or more. This reaction may be carried out at -20 to 50 for 30 minutes to 24 hours.
  • the obtained compound can be reacted in the presence of an alkali metal halide such as sodium bromide and an inorganic acid with hydrobromic acid or the like.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. However, examples thereof include water, acetic acid, tetrahydrofuran, and dioxane, and these solvents may be used alone or as a mixture of two or more.
  • the reaction, the reaction temperature in particular not limited force?, For example, under cooling or warming,
  • the compound of the general formula [2] can be obtained by reacting the compound of the general formula [18] with an alcohol, phenol or thiophenol in the presence or absence of a base or in the presence or absence of a catalyst. Can be obtained.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. Ketones such as acetone; alcohols such as methanol and ethanol; collidine; and the like. These solvents may be used alone or in combination of two or more.
  • Bases used in this reaction include, for example, alkali metal alkoxides such as sodium methoxide, sodium methoxide and potassium ten-butoxide; alkalis such as sodium hydride and hydrogenation hydride.
  • Examples of the alcohols, phenols and thiocyanols used in this reaction include 2,4-difluorophenol, 2,4-difluorothiophenol and ethanol. 18] with respect to the molar amount of 1 to 5 times.
  • Examples of the catalyst used in this reaction include copper powder, cuprous oxide, cuprous chloride, and 8-hydroxyquinoline cuprous chloride.
  • the amount of the catalyst used is expressed by the general formula [18J It may be 0.01 to 2 moles per mole of the compound. This reaction is usually carried out at -20 to 160 for 30 minutes to 24 hours.
  • the compound of the general formula [18] can be found, for example, in The 'Journal' of 'Organic-Chemistry, Vol. 44, No. 11, pp. 1784-1787 (1979). It can be manufactured by the method described above.
  • the compound of the general formula [17] can be obtained by reducing the compound of the single-arm type [8].
  • This reaction can be performed using the usual method for reducing nitro groups to amino groups.
  • a method using catalytic reduction using palladium monocarbon, Raney nickel or platinum, a method using iron or tin, a method using sodium sulfide ammonium monochloride, and the like can be mentioned.
  • iron when used, it may be used in an amount of 0.1 to 20 times the molar amount of the compound of the general formula [8], and ammonium chloride or the like is used as a reaction accelerator. Is 0.1 to 3 times the molar amount of the compound of the general formula [8].
  • the solvent used in this reaction is a solvent which does not adversely adverse influence on the reaction, especially limiting force f, for example, alcohols such as methanol Contact and ethanol; ethers such as Jiokisan and as tetrahydrofuran; water; acetic acid And these solvents may be used alone or in combination of two or more.
  • This reaction is usually carried out at -20 to 160t: for 30 minutes to 24 hours.
  • the compound of the general formula [8] can be produced, for example, by reacting a compound of the general formula [7] with an alcohol, phenol or thiophenol in the presence or absence of a base, in the presence or absence of a catalyst.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • amides such as ⁇ , ⁇ -dimethylformamide
  • sulfoxides such as dimethyl sulfoxide Ketones such as acetone
  • alcohols such as methanol and ethanol
  • collidine and these solvents may be used alone or in combination of two or more.
  • Bases used in this reaction include, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydrides such as sodium hydride and hydrogen hydride. Alkali metal carbonates such as carbonated sodium and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide; and the like.
  • the base may be used in an amount of about 13-fold the amount of the compound of the general formula [7].
  • the alcohols, phenols and thiophenols used in this reaction include, for example, 2,4-difluorophenol, 2,4-difluorothiophenol and ethanol. Expression
  • Catalysts used in this reaction include copper powder, cuprous oxide, cuprous chloride, and 8-hydroxyquinoline monochloride. Copper may be used, and the amount of the catalyst used may be 0.01 to 2 times the molar amount of the compound of the general formula [7]. This reaction is usually carried out at -20 to 160 for 30 minutes to 24 hours.
  • the compound of the general formula [7] can be prepared, for example, by the method described in Chemical 'Pharmaceutical Bultin (Chem. Pharm. Bull), Vol. 40, No. 9, pp. 2399-2409 (1992). It can be manufactured by such as.
  • the compound of the general formula [17] can be obtained by subjecting the compound of the general formula [11] to a deacetylation reaction in the presence of an acid.
  • the solvent used in this reaction include a mixed solvent of water and a water-organic solvent (for example, methanol, ethanol, dioxane, tetrahydrofuran and the like).
  • Acids used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as p-toluenesulfonic acid.
  • the acid may be used in an amount of 0.1 to 50 moles per mol of the compound of the general formula [11]. This reaction is usually carried out at 0 to 150 for 30 minutes to 24 hours.
  • the compound of the general formula [10] can be obtained by subjecting the compound of the general formula [9] to an acetylation reaction in the presence or absence of a base, in the presence or absence of a solvent.
  • the Asechiru agent used in this reaction include forces such as acetic anhydride and ⁇ seven Chi Rukurori de sigma.
  • the acetylating agent may be used in an amount of 1 to 5 times the molar amount of the compound of the general formula [9].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • the solvent examples include halogenated hydrocarbons such as methylene chloride and chloroform-form; ,, ⁇ -dimethylforme Amides such as amides and ,, ⁇ -dimethylacetamide; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate; and amides such as acetonitrile These solvents may be used alone or in combination of two or more.
  • the base used in this reaction include organic amines such as dimethylaminopyridine, triethylamine and pyridine; and alkali metal carbonates such as potassium carbonate and sodium carbonate.
  • the amount of the base used may be 11 to 13 times the molar amount of the compound of the general formula [9].
  • the compound of the general formula [11] can be obtained by subjecting the compound of the single-armed type [10] to coupling with aryltributyltin or arylboric acid. This reaction is carried out under the same conditions as for the production of the compound of the single-arm type [la], and is usually carried out at 40 to 160 for 30 minutes to 24 hours.
  • the compound of the general formula [17] can be obtained by subjecting the compound of the general formula [12] to a demesification reaction in the presence or absence of a solvent in the presence of an acid.
  • Acids used in this reaction include methanesulfonic acid and polyphosphoric acid. The acid may be used in an amount of 1 to 100 times the molar amount of the compound of the general formula [].
  • the solvent used in this reaction include aromatic hydrocarbons such as benzene and toluene; and halogenated hydrocarbons such as methylene chloride and dichloroethane. This reaction is usually carried out at 0 to 150 for 30 minutes to 24 hours.
  • the compound of the general formula [12] can be prepared, for example, by the method described in Chemical 'Pharmaceutical-Bultin, Vol. 40, No. 9, pp. 2399-2409 (1992), etc. Can be manufactured.
  • the compound of the general formula [17] can be obtained by subjecting the compound of the general formula [15] to a deacetylation reaction in the presence of an acid.
  • the solvent used in this reaction include a mixed solvent of water and a water-organic solvent (for example, methanol, ethanol, dioxane, tetrahydrofuran and the like).
  • Acid catalysts used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as p-toluenesulfonic acid.
  • the amount of the acid catalyst used may be 0.1 to 50 times mol of the compound of the general formula [15]. This reaction is usually performed at 0-150 for 30 minutes and 24 hours.
  • the compound of the general formula [15] can be obtained by subjecting the compound of the general formula [14] to ordinary ditrophy in the presence or absence of a solvent.
  • the nitrifying agent used in this reaction include concentrated nitric acid, a mixed acid of nitric acid and acetic anhydride, and a mixed acid of nitric acid and sulfuric acid.
  • the amount of the nitrating agent to be used may be 115-fold molar amount to the compound of the general formula [14].
  • the solvent used in this reaction for example, be used, such as acetic force f, typically at 0 150, may be carried out 10 minutes a 24 hours.
  • the compound of the general formula [14] is obtained by converting the compound of the general formula [13] in the presence or absence of a base. It can be obtained by subjecting it to acetylation below.
  • the acetylating agent used in this reaction include acetic anhydride and acetyl chloride.
  • the amount of the acetylating agent to be used may be 115-fold molar amount to the compound of the general formula [13].
  • Examples of the base used in this reaction include organic amines such as triethylamine and pyridin; and alkali metal carbonates such as potassium carbonate and sodium carbonate.
  • the base may be used in an amount of 11 to 13 moles based on the compound of the general formula [13].
  • the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
  • halogenated hydrocarbons such as methylene chloride and chloroform; N, N-dimethylformamide And amides such as N, N-dimethylacetamide; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate; nitriles such as acetonitrile.
  • These solvents may be used alone or as a mixture of two or more. This reaction is usually carried out at -20 to 160 for 10 minutes to 24 hours.
  • the compound of the general formula [13] can be produced, for example, by the method described in JP-A-2-268.
  • Examples of the salts of the compounds represented by the general formulas [2] and [7] to [18] include the same salts as described for the compound represented by the general formula [1].
  • isomers for example, optical isomers, geometric isomers and tautomers
  • the present invention It encompasses all isomers and extends to all crystal forms and hydrates.
  • compounds having an amino group, a hydroxyl group or a carboxyl group may be protected by a conventional protecting group. After the reaction, these protecting groups can be removed as necessary by a method known per se.
  • the compounds of general formulas [2] and [7]-[18] or salts thereof obtained in this way can be used, for example, in an oxidation reaction using perbenzoic acid, manganese dioxide or dichromic acid, etc.
  • WoHT Wolf
  • reactions known per se such as halogenation reactions using carbon tetrabromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or thionyl chloride, dehydration reactions or hydrolysis reactions such as acid hydrolysis and alkali hydrolysis
  • the compound of the general formula [2] and the compound of the formula [7]-[18] or a salt thereof can be derived by subjecting the compound to or by combining them as appropriate. Further, it can be isolated and purified according to a conventional method such as extraction, crystallization, and column chromatography.
  • the compound of the present invention when used as a medicament, it may be formulated by a generally known method, and may optionally be mixed with excipients, carriers and diluents which are usually used for the formulation. These may be administered in the form of tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powders, suppositories, ointments or injections according to the usual methods. It can be administered parenterally. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, weight, and condition of the patient. Usually, for adults, about 0.05 to 100 mg / kg orally or non-orally It may be administered orally (eg, by injection, infusion or administration to the rectal site) and may be given in one or several divided doses.
  • COX-1 the microbes of the hedging gland gland microsome (manufactured by Edman Technology Co., Ltd.) are used, and as the COX-2, the purified product of the hitx placenta-derived COX-2 (manufactured by Caiman Chemical) is used.
  • the conditions for measuring the COX-1 activity are determined according to the method of Procaccini et al. [Biochem. Pharmacol., Vol. 26, No. 105, pp. 1057 (1977)]. . That is, a test compound (final concentration 1) dissolved in 0.5 ml of 50 mM Tris buffer (pH 8.0) containing 100 ⁇ g / ml final concentration of microbeads of hedging seminal gland, 5 mM epinephrine and 5 mM glutathione was used. Or 100 ⁇ g ml), pretreat at 37 for 2 minutes. 0.04 Ci [l - '4 C ] Arakido LOnmol arachidonic acid containing acid (manufactured by Amersham) is added (final concentration: 20 M).
  • the measurement of the COX activity is carried out according to the method of Yanagi and Komatsu [Biochemical Pharmacol., Vol. 25, pp. 937-941 (1976)]. That is, 2 ml of a mixture of n-hexane ethyl acetate (2: 1) is added to the reaction solution to stop the reaction, and arachidonic acid is extracted into the organic layer by centrifugation. After repeating the same extraction procedure twice, add 1 ml of ethanol to the aqueous layer, stir, and transfer the entire amount of the supernatant obtained by centrifugation to a vial for liquid scintillation counter to fractionate. .
  • the collected organic layer is used as the arachidonic acid fraction, and 1 ml of the fraction is collected into a vial for liquid scintillation counter.
  • Each fraction of radioactivity was measured by a liquid core guides laser Chillon counter to calculate the ratio of the radioactivity of PGE 2 fraction of the total radioactivity. This was a PG conversion, a decrease in the conversion rate due to the test compound for controls containing only 1% final concentration of dimethyl sulfoxide, and c the results expressed by COX activity inhibition rate shown in Table 1.
  • Test example 2 Adjuvant arthritis inhibitory effect
  • the adjuvant arthritis inhibitory effect was determined according to the method described in Araieistoff-Forschung, Vol. 42 (11), Vol. 7, No. 7, pp. 935-944.
  • a group of five male rats of the Lewis-Lewis strain (weight: 190-230 g) was used.
  • a group of 5 rats was used to suspend and dry mycobacterium tuberculosis at a rate of 6 mg / ml in liquid paraffin as an adjuvant and a biopsy.
  • 0.1 ml was injected intradermally into the ridge.
  • On the 14th day after adjuvant treatment they were divided into groups according to the swelling volume of both hind limbs (Dayl4).
  • Oral administration at a rate of / 100g body weight.
  • the swelling volume of both hind limbs was measured, and the inhibition rate was determined by the following formula. ⁇
  • Inhibition rate (1 - (Day ] 4 edema rate of edema rate dose groups Dayl 8 of dose group) Bruno (edema rate Dayl4 edema rate / ⁇ group Dayl8 of ⁇ group) ) X 100
  • a hard gelatin capsule is prepared using the following ingredients.
  • the above is filled into hard capsules by a conventional method as a material for one capsule.
  • a tablet is prepared using the following ingredients.
  • a tablet is prepared using the following ingredients.
  • a tablet is prepared using the following ingredients.
  • Talc 2mg A total of 225mg or more shall be converted into tablets by the usual method using 1 tablet as an ingredient.
  • a tablet is prepared using the following ingredients.
  • Magnesium stearate 3 mg Total 333 mg or more is converted into tablets by the usual method using 1 tablet as the ingredient.
  • the present invention is not limited to these.
  • the mixing ratios in the eluents were all dose ratios, and silica gel column chromatography was performed using silica gel 60, 70-230 mesh [silica gel 60, 70-230 mesh (Merck)].
  • the solvent described in parentheses after the melting point indicates a solvent for recrystallization of the crystal whose melting point was measured.
  • the abbreviations used below have the following meanings.
  • IRineaDcm 1 1520, 1505,1345
  • the obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. To the obtained residue is added isopropyl ether, and the mixture is filtered to obtain 2.20 g of a pale yellow solid. The obtained solid is recrystallized from acetonitrile to obtain 2.00 g of pale yellow crystals of 2-hydroxy-14'-methylsulfonyl-14-212tro 1,1,1'-biphenyl.
  • 2-Benzoyl 4'-Methylsulfonyl 4-1-nitro-1,1'-biphenyl 1.00 g is dissolved in a mixed solvent of ethanol 5 ml, water 5 ml and tetrahydrofuran 10 ml, and ice-cooled Below, 0.10 g of sodium borohydride is added over 10 minutes, and the mixture is stirred at the same temperature for 1 hour.
  • the reaction mixture is added to a mixed solvent of water and ethyl acetate, adjusted to pH 2.0 with 1 N hydrochloric acid, and the organic layer is separated.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained solid is recrystallized from acetonitrile to give 0.65 g of colorless crystals of 2- (c-hydroxybenzyl) 14,1-methylsulfonyl-412-trow. 1.)-Biphenyl.
  • the reaction mixture was introduced into a mixture of ice water and ethyl acetate.
  • the obtained organic layer was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was recrystallized from acetonitrile Colorless ⁇ B
  • the reaction mixture is added to ice water, adjusted to pH 2.0 with 1 N hydrochloric acid, and extracted with ethyl acetate.
  • the obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 0.44 g of a colorless solid.
  • the obtained solid was recrystallized from isopropyl alcohol to give colorless crystals of 3- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) acrylic acid 0.30 get g.
  • Example 37 The compounds in Table 10 are obtained in the same manner as in Example 9.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • 10 ml of 6 N hydrochloric acid and 10 ml of 1,4-dioxane are added to the obtained residue, and the mixture is stirred at room temperature for 24 hours.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • 0.10 g of 60% sodium hydride is added to 5 ml of tetrahydrofuran solution containing 0.51 ml of ethyl phosphonoacetate under ice-cooling. Subsequently, 5 ml of a tetrahydrofuran solution of 0.90 g of 2- (2,4-difluorophenoxy) -15- (2-formylethenyl) -14'-methylthio-11,1-biphenyl is added dropwise, and the mixture is stirred at room temperature for 1 hour. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer.
  • the reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pHl.O with 2N hydrochloric acid, and the organic layer is separated.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. After dissolving the obtained residue in 10 ml of toluene, 0.50 g of aluminum silicate is added and heated under reflux for 1 hour. After filtering off the insoluble matter and distilling off the solvent under reduced pressure, a colorless oily substance, 2- (2,4-difluorophenoxy) -15- (1-formylethyl) -14'-methylsulfonyl-1,1,1 0.80 g of -biphenyl is obtained.
  • the obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained residue is purified by column chromatography [eluent: ethyl acetate] to give colorless crystals 2- (4- (2,4-difluorophenoxy) -3- (4-methylsulfonylphenyl) phenyl ) 0.02 g of propionic acid is obtained.
  • the obtained oil is added to 20 ml of 50% acetone water, 0.42 g of silver nitrate is added at room temperature, and the mixture is stirred for 4 hours.
  • the filtrate is added to a mixture of water and ethyl acetate, and the organic layer is separated.
  • the obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained oil is added to 20 ml of 50% acetone water, 0.42 g of silver nitrate is added at room temperature, and the mixture is stirred for 4 hours.
  • Example 64 6-cyano 6-methylheptyloxy) 1-2- (2,4-difluorophenoxy) -14-methylsulfonyl-1,1,1-biphenyl 0.40 g of concentrated sulfuric acid 2 ml, acetic acid Dissolve in a mixture of 4 mJ and 4 ml of water and ripen at reflux for 3 days. The reaction mixture is added to a mixture of ice water and * ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the obtained oil is dissolved in 0.66 ml of 1 N aqueous sodium hydroxide solution, washed with ethyl ether, and the solvent is distilled off under reduced pressure.
  • Ethyl ether was added to the obtained residue, and the residue was collected by filtration to give colorless crystals of 7- (3- (2,4-difluorophenoxy) -14- (4-methylsulfonylphenyl) phenoxy) -1,2,2-dimethylheptane 0.30 g of the acid is obtained as the sodium salt.
  • 2-Hydroxy-4 Methoxy-4-methylsulfonyl-1,1'-biphenyl 1.50 g, 1N aqueous sodium hydroxide solution 6.5 ml, water 8.5 ml and diphenylethanol chloride 1.71 g are heated and refluxed for 2 hours. Let it. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

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Abstract

L'invention concerne des dérivés de biphényle représentés par la formule générale (1), ou leurs sels, présentant d'excellents effets anti-inflammatoire, antipyrétique/analgésique et antiarthritique, et pouvant être utilisés sous forme de médicaments. Dans la formule (1), R1 représente alkyle inférieur, aryle ou amino; R2 représente aryle ou -Z-R5 (R5 représentant alkyle, alcényle, alkylsulfonyle, aryle, etc., et Z représentant oxygène, soufre, imino, etc.); R3 et R4 représentent chacun hydrogène, halogéno, cyano, azido, nitro, amino, carboxy, hydroxy, acyle, alcoxycarbonyle, alkyle, alcényle, alcoxy, alkylthio, etc.; et n est égal à 0, 1 ou 2.
PCT/JP1996/000499 1995-03-01 1996-03-01 Nouveaux derives de biphenyle ou leurs sels, et agents anti-inflammatoires contenant lesdits derives ou leurs sels WO1996026921A1 (fr)

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AU48444/96A AU4844496A (en) 1995-03-01 1996-03-01 Novel biphenyl derivatives or salts thereof, and anti-inflammatory agents containing the same

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JP7/66903 1995-03-01
JP06690395A JP3802581B2 (ja) 1995-03-01 1995-03-01 新規なビフェニル誘導体またはその塩およびそれらを含有する抗炎症剤

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Cited By (15)

* Cited by examiner, † Cited by third party
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WO1997032853A1 (fr) * 1996-03-08 1997-09-12 Novartis Ag Composes triaryles
ES2158809A1 (es) * 1999-10-18 2001-09-01 Menarini Lab Nuevos derivados sulfonados como inhibidores de la ciclooxigenasa ii.
WO2002002539A1 (fr) * 2000-06-29 2002-01-10 Abbott Laboratories Derives d'aryle phenylheterocyclyle sulfures et leur utilisation en tant qu'agents immunosuppresseurs anti-inflammatoires inhibant l'adherence cellulaire
WO2003070686A1 (fr) * 2002-02-21 2003-08-28 Asahi Kasei Pharma Corporation Derive de l'acide phenylalcanoyle substitue et son utilisation
US6706724B2 (en) * 2000-12-21 2004-03-16 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2006006065A1 (fr) * 2004-07-08 2006-01-19 Warner-Lambert Company Llc Modulateurs d'androgenes
US7172769B2 (en) 1999-12-08 2007-02-06 Pharmacia Corporation Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect
US7473711B2 (en) 2004-04-22 2009-01-06 Pfizer Inc. Androgen modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
US7695736B2 (en) 2001-04-03 2010-04-13 Pfizer Inc. Reconstitutable parenteral composition
WO2010112211A1 (fr) 2009-03-31 2010-10-07 Technische Universität München Procédé d'arylation de phénols et d'éthers phényliques à noyau substitué
US8334314B2 (en) 2008-04-28 2012-12-18 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
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

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1849762B1 (fr) * 2006-04-21 2009-07-15 Cellzome Limited Acides biphényl carboxyliques substitués et leurs dérivés

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JPH03503771A (ja) * 1989-01-27 1991-08-22 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング ビフェニリルエタン類および液晶相
JPH04154737A (ja) * 1989-02-08 1992-05-27 Otsuka Pharmaceut Co Ltd 神経細胞変性修復又は保護剤
JPH05501266A (ja) * 1990-06-11 1993-03-11 イギリス国 液晶チオール化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03503771A (ja) * 1989-01-27 1991-08-22 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング ビフェニリルエタン類および液晶相
JPH04154737A (ja) * 1989-02-08 1992-05-27 Otsuka Pharmaceut Co Ltd 神経細胞変性修復又は保護剤
JPH05501266A (ja) * 1990-06-11 1993-03-11 イギリス国 液晶チオール化合物

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US6410547B1 (en) 1996-03-08 2002-06-25 Novartis Ag Phenylpyridine derivatives useful as phosphodiesterase inhibitors
US6090817A (en) * 1996-03-08 2000-07-18 Novartis Ag Phenylpyridine derivatives useful as phosphodiesterase inhibitors
US6258843B1 (en) 1996-03-08 2001-07-10 Novartis Ag 4-oxy-3-(aryl)phenyl-arylcarbonyloxy compounds useful as phosphodiesterase inhibitors
WO1997032853A1 (fr) * 1996-03-08 1997-09-12 Novartis Ag Composes triaryles
US6288092B1 (en) 1996-03-08 2001-09-11 Novartis Ag Triaryl compounds
ES2158809A1 (es) * 1999-10-18 2001-09-01 Menarini Lab Nuevos derivados sulfonados como inhibidores de la ciclooxigenasa ii.
US7172769B2 (en) 1999-12-08 2007-02-06 Pharmacia Corporation Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect
WO2002002539A1 (fr) * 2000-06-29 2002-01-10 Abbott Laboratories Derives d'aryle phenylheterocyclyle sulfures et leur utilisation en tant qu'agents immunosuppresseurs anti-inflammatoires inhibant l'adherence cellulaire
US6787542B2 (en) 2000-06-29 2004-09-07 Icos Corporation Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
AU2001268718B2 (en) * 2000-06-29 2006-01-05 Abbott Laboratories Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US7129247B2 (en) 2000-06-29 2006-10-31 Abbott Laboratories Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6706724B2 (en) * 2000-12-21 2004-03-16 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7695736B2 (en) 2001-04-03 2010-04-13 Pfizer Inc. Reconstitutable parenteral composition
AU2003211384B2 (en) * 2002-02-21 2008-12-11 Asahi Kasei Pharma Corporation Substituted phenylalkanoic acid derivative and use thereof
CN100387576C (zh) * 2002-02-21 2008-05-14 旭化成制药株式会社 取代苯基链烷酸衍生物及其用途
WO2003070686A1 (fr) * 2002-02-21 2003-08-28 Asahi Kasei Pharma Corporation Derive de l'acide phenylalcanoyle substitue et son utilisation
JP2009167217A (ja) * 2002-02-21 2009-07-30 Asahi Kasei Pharma Kk 置換フェニルアルカン酸誘導体及びその用途
JP2009167216A (ja) * 2002-02-21 2009-07-30 Asahi Kasei Pharma Kk 置換フェニルアルカン酸誘導体及びその用途
KR100938950B1 (ko) * 2002-02-21 2010-01-26 아사히 가세이 파마 가부시키가이샤 치환 페닐 알칸산 유도체 및 그 용도
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7473711B2 (en) 2004-04-22 2009-01-06 Pfizer Inc. Androgen modulators
US7670613B2 (en) 2004-07-08 2010-03-02 Pfizer Inc. Androgen modulators
WO2006006065A1 (fr) * 2004-07-08 2006-01-19 Warner-Lambert Company Llc Modulateurs d'androgenes
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
US7799823B2 (en) 2005-05-05 2010-09-21 Warner-Lambert Company Llc Androgen modulators
US8334314B2 (en) 2008-04-28 2012-12-18 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
US8772327B2 (en) 2008-04-28 2014-07-08 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
WO2010112211A1 (fr) 2009-03-31 2010-10-07 Technische Universität München Procédé d'arylation de phénols et d'éthers phényliques à noyau substitué
DE102009015697A1 (de) 2009-03-31 2010-10-07 Markus Dr. Heinrich Verfahren zur Arylierung von ringsubstituierten Phenolen und Phenylethern
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

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AU4844496A (en) 1996-09-18
JP3802581B2 (ja) 2006-07-26

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