WO1996038412A1 - Nouveaux composes et medicament anti-dermatite - Google Patents

Nouveaux composes et medicament anti-dermatite Download PDF

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Publication number
WO1996038412A1
WO1996038412A1 PCT/JP1996/001458 JP9601458W WO9638412A1 WO 1996038412 A1 WO1996038412 A1 WO 1996038412A1 JP 9601458 W JP9601458 W JP 9601458W WO 9638412 A1 WO9638412 A1 WO 9638412A1
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group
compound
benzyloxy
carbon atoms
hydrogen atom
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PCT/JP1996/001458
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English (en)
Japanese (ja)
Inventor
Masakazu Takeda
Yuko Yamazaki
Masaharu Kigawa
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Tsumura & Co.
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Publication of WO1996038412A1 publication Critical patent/WO1996038412A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the present invention relates to novel compounds and anti-dermatitis agents.
  • steroid compounds such as dexamethasone and prednisolone have been conventionally used.
  • steroid anti-dermatitis agents have serious side effects and are not suitable for long-term administration.
  • non-steroid anti-dermatitis agents such as indomethacin, which have relatively few side effects, have become mainstream.
  • the present inventors conducted research on various compounds with the aim of developing a new non-steroid anti-dermatitis agent effective for treating dermatitis. As a result, a new compound having an antidermatitis effect was found, and an invention of an antidermatitis agent containing the compound was completed.
  • the present invention provides a compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof.
  • [In the formula, represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 or 2 carbon atoms, an acetyloxy group or a benzyloxy group,
  • R 12 represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 or 2 carbon atoms or a benzyloxy group,
  • R 13 represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 or 2 carbon atoms, an acetooxy group or a benzyloxy group
  • R 4 represents a hydrogen atom, a hydroxyl group or a benzyloxy group.
  • R 2 to R i 4 are combinations shown in Table 1.
  • the present invention also provides a compound represented by the following formula (2) and a pharmaceutically acceptable salt thereof.
  • R 2 1 and R 2 2 are the same also is properly different, hydroxyl group, Benjiruokishi group, an alkoxy group having 1 to 6 carbon atoms, alkylamino amino group having 1 to 6 carbon atoms, Acquisition of full Riruokishi group, Represents a hydroxylamino group,
  • R 2 3 represents an alkoxy group of 1 to 2. carbon atoms
  • R 2 4 represents an alkoxy group of 1 to 2. carbon atoms, a hydroxyl group, Ben Jiruokishi group, 2-Chio Fen carbonyl O alkoxy group, a 2-Ji Ofe down methylcarbonyl O alkoxy group or a 2-inch offense Ruhoniruokishi group. However, to R 2 1 no R 2 4 is unless be a combination shown in Table 2. ]
  • the present invention also provides a compound represented by the following formula (3) and a pharmaceutically acceptable salt thereof.
  • R 3 1 is (are R 3 5, hydrogen atom or C 1 -C shows a 6 alkyl group) a hydrogen atom or a COOR 3 5 indicates,
  • R 32 represents an alkoxy group having 1 or 2 carbon atoms
  • R represents a benzyloxy group or a hydroxyl group
  • R 3 4 is a hydrogen atom, a hydroxyl group, a benzyl group, 4 - click throat benzyl group, 4 - C i one C 3 alkyl downy Njiru group, 3 - pyridyl one C i-C 3 alkyl group, Lee Midazoiru one C i one C 3 were alkyl group or represents a cinnamic acid C E one C 3 alkyl group.
  • the present invention also provides a compound represented by the following formula (4) and a pharmaceutically acceptable salt thereof.
  • R 4 1 and R 4 2 are the same also is properly different, represents an alkyl group of 1 hydrogen atom or a carbon atoms 6, R 4 3 and R 4 4 is the same also is properly different Represents a hydroxyl group, an alkoxy group having 1 or 2 carbon atoms or a benzyloxy group.
  • the present invention also provides a compound (5) represented by the following formula (5).
  • the present invention also provides an anti-dermatitis agent comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides an anti-dermatitis agent comprising a compound represented by the formula (2) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides an anti-dermatitis agent comprising the compound represented by the formula (3) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • an anti-dermatitis agent comprising a compound represented by the formula (4) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides an anti-dermatitis agent comprising the compound represented by the formula (5) and a pharmaceutically acceptable carrier.
  • the anti-dermatitis agent of the present invention includes an anti-contact dermatitis agent and an anti-edema agent.
  • the first and second compounds (1) and (2) of the present invention represented by the above formulas (1) and (2) are obtained by combining known reactions and operations to obtain the known diketone derivative (A).
  • the diketone derivative ( ⁇ ) may be obtained by any known production method.
  • ⁇ -silyloxystyrene derivatives can be converted to copper chloride (11), lead tetraacetate, silver oxide (1), copper trifluormethanesulfonate (1), manganese acetate ( ⁇ ), or sodium benzene.
  • the reaction is carried out in the presence of an oxidizing agent such as this.
  • the ⁇ -haloacetofphenone derivative is converted to bis (triphenylphosphine bromide).
  • ⁇ -Silyloxystyrene is prepared by using a corresponding acetophenone derivative in the presence of a salt such as lithium dialkyl amide or triethylamine, using silyl halide, silyl sulfonate or the like as a silylating agent. It can be obtained by reacting at room temperature to 180 ° C (preferably 0 to 180 ° C) in a nonprotonic organic solvent such as drofuran or dichloromethane.
  • a salt such as lithium dialkyl amide or triethylamine
  • Compounds (1) and (2) can be obtained directly or indirectly by condensing the butane 1,4-dione moiety of the diketone derivative (A).
  • the compound (B) means a diphenylfuran derivative in a broad sense including the compounds (1) and (2).
  • the condensation reaction of the diketone derivative (A) is desirably performed under acidic conditions, and the diketone derivative (A) is converted to a mineral acid such as hydrochloric acid or sulfuric acid, p-toluenesulfonic acid, Using organic acids such as trifluoroacetic acid and Louis acids such as aluminum chloride, and using dichloromethane, chlorofosolem, toluene, benzene, methanol, etc. alone or in a mixed organic solvent as the reaction solvent It is preferably achieved by reacting under heating conditions.
  • a mineral acid such as hydrochloric acid or sulfuric acid, p-toluenesulfonic acid
  • organic acids such as trifluoroacetic acid and Louis acids such as aluminum chloride
  • dichloromethane, chlorofosolem, toluene, benzene, methanol, etc. alone or in a mixed organic solvent as the reaction solvent It is preferably achieved by reacting under heating conditions.
  • the diketone derivative (A) is converted to phosphorus pentoxide, acetic anhydride
  • the furan derivative (B) can also be obtained by heating in a suitable organic solvent together with a dehydrating agent such as acetyl chloride.
  • (B) is obtained by subjecting the substituents such as debenzylation and acetylation of the substituents R 3 to R 6 at the 2- to 5-positions of the benzene ring as necessary. It can be converted to other diphenylfuran derivatives (B).
  • the debenzylation is carried out using a catalyst such as palladium-carbon catalyst, palladium hydroxide carbon catalyst, palladium chloride, palladium black, Raney nickel, nickel boride, etc., in a suitable organic solvent, hydrogen gas as a hydrogen source, Reducing conditions using an appropriate formate such as formic acid or ammonium formate, hexahexadiene or the like, or a method by using boron chloride in an organic solvent such as dichloromethane or the like. It is possible to achieve.
  • a catalyst such as palladium-carbon catalyst, palladium hydroxide carbon catalyst, palladium chloride, palladium black, Raney nickel, nickel boride, etc.
  • acetylation is carried out by using an acetylating agent such as acetic anhydride or acetyl chloride, and in the presence of a tertiary amine such as pyridine, triethylamine, 4,4-dimethylaminoviridine, etc., the acetylation itself is performed. This is achieved by reacting at 0 ° C to around room temperature in an organic solvent that is not converted into an organic solvent.
  • an acetylating agent such as acetic anhydride or acetyl chloride
  • a tertiary amine such as pyridine, triethylamine, 4,4-dimethylaminoviridine, etc.
  • the substituent R 2 at the 3- and 4-positions of the furan ring may be hydrolyzed, esterified, amidated, converted to a hydroxamic acid structure or converted to a sodium salt, as necessary.
  • the hydrolysis reaction is carried out under basic conditions
  • an alkaline hydroxide such as sodium hydroxide is reacted in water or a mixed solvent of an organic solvent such as alcohol and water at room temperature to 10 ° C. This can be achieved.
  • reaction When the reaction is performed under acidic conditions, use a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid in water or a water-containing organic solvent.
  • a mineral acid such as hydrochloric acid or sulfuric acid
  • an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid in water or a water-containing organic solvent.
  • Suitable salts include, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and organic amine salts that are pharmaceutically acceptable.
  • Can be Esterification of a carboxylic acid derivative is carried out by converting the carboxylic acid derivative into a corresponding acid chloride derivative with thionyl chloride or oxalyl chloride or the like, followed by an appropriate alcohol or amine.
  • amide or hydroxamic acid derivative with hydroxylamin, tertiary amines such as pyramide, triethylamine, and 4,4-dimethylaminopyridin are available.
  • a condensing agent such as dicyclohexylcarposimid, methylcyclophosphoric acid, or diphenylphosphoric acid azide is appropriately selected and used, and then reacted with alcoholamine.
  • a condensing agent such as dicyclohexylcarposimid, methylcyclophosphoric acid, or diphenylphosphoric acid azide
  • the compound containing a hydroxyl group is reacted with a corresponding benzylating agent such as benzyl halide.
  • a corresponding benzylating agent such as benzyl halide.
  • Both can be carried out by reacting in a suitable solvent in the presence of a base such as alkali carbonate or the like under cooling or heating.
  • the introduction of a silyl group can be achieved by cooling or heating a compound containing a hydroxyl group together with a silylating agent such as silyl halide in a suitable solvent in the presence of a base such as amine or alkali carbonate.
  • the removal of a certain benzyl group in the protecting group is as described above.
  • the silyl group can be removed by reacting with an acid such as hydrochloric acid or a fluorine compound such as potassium fluoride, ammonium fluoride or hydrofluoric acid in a suitable solvent. It is.
  • the first and second compounds (1). And (2) of the present invention can be obtained by condensing the diketone derivative (A) and further converting the substituents as necessary. Can be obtained directly or indirectly. Specific combinations of reactions and operations for obtaining the first and second compounds (1) and (2) will be described in Examples below.
  • the third compound (3) of the present invention represented by the above formula (3) can be prepared, for example, by converting a diketone derivative (A) and a primary amine into a common acid (eg, hydrochloric acid, acetic acid, p-para Reaction in the presence of toluenesulfonic acid) in an organic solvent such as tonolene, benzene, dichloromethane, culoformform, tetrahydrofuran, at room temperature to 100 ° C, preferably with heating. Further, if necessary, the above-mentioned substitution can be carried out to obtain directly or indirectly.
  • the compound (C) indicates a broadly defined diphenylpyrrolyl derivative containing the compound (3).
  • the fourth compound (4) of the present invention represented by the above formula (4) is an organometallic compound such as phenylmagnesium halide, phenylzincno, ride, phenylene tributyrinolezu, phenylinoleshydroxyborane or phenyldialkoxyborane.
  • the compound (F) represents a diphenylthiophene derivative in a broad sense including the compound (4).
  • the present invention provides a novel compound (5) represented by the following formula (5) as a non-steroid anti-dermatitis agent effective for treating dermatitis.
  • MeO 'OMe This compound (5) can be synthesized as follows. First, Compound I is, for example, Organic Preparations Produced International [ORGANIC
  • the compound (A) is condensed between carbon atoms at positions 1 and 4 of the butane moiety to obtain a compound (B) represented by the following formula (B).
  • the condensation reaction is carried out by reacting compound (A) with an inorganic acid such as hydrochloric acid or sulfuric acid, an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid, or aluminum chloride, boron trifluoride. It can be carried out by heating in a Lewis acid such as an ether complex.
  • the compound (A) can also be heated by heating the compound (A) in a suitable solvent together with a dehydrating agent such as phosphorus pentoxide, acetic anhydride, and acetyl chloride.
  • the compound (5) is obtained by converting the phenolic hydroxyl group of the compound (B) to an amino acid ester. That is, glycine is condensed with the compound (B) as an amino acid. Thereafter, compound (5) can be obtained by converting the introduced amino group into a hydrochloride.
  • the compound it is also possible to synthesize another amino acid ester derivative of (B) and convert the amino group to a hydrochloride.
  • the compounds (1) to (5) of the present invention described above have an anti-inflammatory effect and an anti-edema effect, and have an effect of reducing or curing dermatitis.
  • the present invention provides an anti-dermatitis agent comprising the compound (1) to (5) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the administration form of the anti-dermatitis agent of the present invention is not particularly limited, and can be appropriately selected as needed.
  • oral preparations such as tablets, capsules, granules, fine granules, powders or solutions, and parenteral preparations such as injections, external preparations or suppositories.
  • the anti-dermatitis agent of the present invention can be administered orally.
  • the weight of the active ingredient in the anti-dermatitis agent of the present invention varies depending on the age, sex, weight, or degree of disease of the patient. In the range of 1000 mg and it is preferable to administer this dose in several divided doses per day.
  • this compound For oral preparations, use this compound alone or, for example, It can be produced according to a conventional method using excipients such as carbohydrate, lactose, sucrose, mannite, carboxylmethylcellulose, corn starch or inorganic salts.
  • excipients such as carbohydrate, lactose, sucrose, mannite, carboxylmethylcellulose, corn starch or inorganic salts.
  • binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, flavors, and the like can be appropriately selected and used.
  • binders include starch, dextrin, arabia gum powder, gelatin, hydroxypropyl pilstarch, methinoresenololose, canoleboxime thizorese / rerose sodium sodium, hydroxypropinolate cellulose, crystalline cellulose, and ethyl cellulose.
  • examples include polyvinylpyrrolidone or macrogol.
  • disintegrants examples include starch, hydroxypropyl pils-starch, canolepoxymethinoresenorelose sodium, canoleboki shimetinorese / relosukanoresime, canolepoximetinolese / relose or low-substituted hyaluronan.
  • Droxypropylcellulose can be used.
  • the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, and polysorbate 80.
  • lubricant examples include talc, roux, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.
  • the fluidity promoter examples include light caustic anhydride, dry aluminum hydroxide gel, synthetic aluminum silicate and magnesium silicate.
  • the angiogenesis inhibitor of the present invention can also be administered as a suspension, emulsion, syrup or elixir. Such dosage forms may also contain flavoring or coloring agents.
  • the anti-dermatitis agent of the present invention can be administered as a parenteral agent.
  • the weight of the active ingredient in the anti-dermatitis agent of the present invention varies depending on the age, weight, and degree of disease of the patient, but is usually 1 to 30 per day for an adult. It is preferably within the range of O mg, and this dose is preferably administered by intravenous, intravenous, subcutaneous or intramuscular injection.
  • the present compound can be diluted with an appropriate diluent.
  • an appropriate diluent generally, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, sea buckwheat oil, soybean oil, corn oil, propylene glycol or polyethylene d'alicol can be used.
  • Parenteral preparations may further contain a bactericide, preservative or stabilizing agent as necessary.
  • injectables are filled and frozen in vials, etc., water is removed by a conventional freeze-drying technique, stored as a lyophilized product, and frozen immediately before use.
  • the liquid preparation can be reconstituted from the dried product and used.
  • the injection may further contain a tonicity agent, a stabilizer, a preservative, a soothing agent and the like, if necessary.
  • Other parenteral preparations include, for example, topical solutions, ointments and other suppositories, or suppositories for rectal administration. These preparations can be manufactured according to conventional methods.
  • the anti-dermatitis agent of the present invention can be, for example, a dosage form that is usually used as a dosage form of an external preparation.
  • the dosage form of this external preparation is, for example, various liquids, ointments, creams, cataplasms and the like, but is not particularly limited.
  • additives can be used according to the dosage form.
  • examples of these additives include the following.
  • hydrophilic polymer examples include carboxymethylcellulose or a salt thereof, polyacrylic acid or a salt thereof, carboxyvinyl polymer or a salt thereof, alginic acid or a salt thereof, and alginic acid.
  • Propyleneglycol monoester chitosan, hydroxypro pizorese 7 rerose, hydroxypropinole methylcellulose, hydroxyxeti / resenonorellose, etinoresenorelose, methinoresenolle mouth, polyvinylolinore porinore porinore porinore pionere Tomopolymers, polyvinyl metalates, polyethylene glycols, punorelonics, gelatins, methionolebininoleatenoles Maleic anhydride copolymers, soluble starch, pullulan, acrylics Examples include a methyl acrylate or a monoethyl hexyl acrylate copolymer.
  • this polyhydric alcohol examples include propylene glycol, 1,3-butyl Tylene glycol, glycerin, sorbitol, mannitol and the like.
  • hydrophilic polymers In addition to hydrophilic polymers, it is a substance added to the base material for external preparations.
  • cataplasms include kaolin, light silicic anhydride, hydrous silicon dioxide, silicic anhydride, magnesium metasilicate aluminate, aluminum hydroxide, magnesium hydroxide, synthetic aluminum silicate, talc, bentonite , Calcium carbonate, titanium oxide, aluminum glycinate, zinc oxide, etc. are added.
  • Ointments include cetanol, stearyl alcohol, cetostearlinoleic acid, stearic acid, white cellulose, hydrophilic ointment, water-absorbing ointment, plastibase, hydrophilic plastibase, macrogol, light anhydrous.
  • Caic acid, hydrated silicon dioxide, silicic anhydride, titanium oxide or zinc oxide are added.
  • liquid preparations there are added, for example, ethanol, stearyl alcohol, cetostearyl alcohol, stearic acid, light anhydrous silicic acid, hydrous silicon dioxide, anhydrous silicic acid and titanium oxide.
  • sodium edetate, citrate, sodium citrate, oxybenzone, asconolevic acid, tocopherone, jib'tinole hydroxytonolene, butinole hydroxyanisole examples include propyl gallate or sodium bisulfite.
  • PH regulator examples include tartaric acid, citric acid, lingic acid, lactic acid, hydrochloric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, sodium hydroxide, ammonia, urea, and ethylenediamine. And isopropanolamine, diethanolamine, triisopanolamine or triethanolamine.
  • absorption enhancers include ethanol, isopropyl alcohol, laurino real alcohol, oleyl alcohol, octyldodecanol, isopropyl myristate, isopropinolate adipate, gethysle sebacate, and diisenosuccinate.
  • absorption enhancers include ethanol, isopropyl alcohol, laurino real alcohol, oleyl alcohol, octyldodecanol, isopropyl myristate, isopropinolate adipate, gethysle sebacate, and diisenosuccinate.
  • examples include isopropyl, propylene glycol caprylate, medium-chain fatty acid triglyceride or squalane.
  • Emulsifier is a liquid crystal Emulsifier
  • emulsifiers include lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and polyoxyethylene cured casters.
  • examples include oil, polyoxyethylene alkyl ether or pull nick.
  • preservative examples include parabens such as methylparaben, ethylparaben or propylparaben, benzyl alcohol, benzalkonium chloride, benzenetonium chloride and chlorobutanol.
  • the anti-dermatitis agent of the present invention described above comprises the compound (1) Contains (4) as an active ingredient, has anti-inflammatory and anti-edema effects, and has the effect of reducing and curing dermatitis.
  • Dermatitis to which the anti-dermatitis agent of the present invention is applied includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, monetary eczema, Vida 1 lichen, and autosensitizing skin There are inflammation, depressive dermatitis and sebum deficiency dermatitis.
  • Contact dermatitis includes allergic dermatitis, non-allergic dermatitis, housewife eczema, progressive palmar keratoderma, mouth eczema, and diaper dermatitis.
  • the novel compound of the present invention has an anti-inflammatory effect and is useful for treating dermatitis.
  • the anti-dermatitis agent of the present invention includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, monetary eczema, Vida 1 lichen, self-sensitizing dermatitis, and stasis dermatitis It is also useful for treating dermatitis such as sebum deficiency dermatitis.
  • the reaction solution was concentrated under reduced pressure, 10% aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow oil, 4, -benzyloxy-3'-methoxy- ⁇ -trimethylsilyloxystyrene (3.27 g, yield 99.6%) Was obtained.
  • the physicochemical properties of the obtained compound are as follows.
  • the reaction solution was concentrated under reduced pressure, 10% aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 8.08 g of 3 ', 5, -dibenzyloxy- ⁇ -trimethylsilyloxystyrene as a brown oil in a quantitative yield.
  • the physicochemical properties of the obtained compound are as follows.
  • Getyl-2,5-bis (4-benzyloxy-3-methoxyphenyl) furan-3,4-dicarboxamide and dihexyl-2,5-bis (4-benzyloxy-3-methoxyphenyl) blane described above- 3,4-Dicarboxamide was debenzylated in the same manner as in Synthesis Example 12 to give colorless powders of getyl-2,5-bis (4-hydroxy-3-methoxyphenyl) furan-.
  • 2,5-bis (4-benzyloxy-3-methoxyphenyl) pyrroyl is prepared from 2,5-bis (4-benzyloxy-3-methoxybenzoyl) butane-1,4-dicarboxylate getyl.
  • M e methinole group
  • B n benzyl group
  • E t Echinole group
  • B n Benzinole group
  • B n 4 —Chlorobenzinole group
  • B n 4 —Methinolebenzyl group
  • 3 — P y M e 3 —Pyridylmethyl group
  • 1 — ImPr 3 (1—imidazolyl) propyl group
  • 4 MeCi 4 —methyl cinnamate Two
  • the reaction solution was extracted with 1 liter of ethyl acetate, and the obtained ethyl acetate layer was washed with a saturated aqueous solution of sodium thiosulfate, water, 2N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride. Washed with. Next, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to dryness.
  • the physicochemical properties of the product are as follows.
  • the physicochemical properties of the obtained compound (B) are as follows. Properties: colorless needles
  • ICR female mice (8 to 10 weeks old) were divided into 7 to 8 mice per group. Samples were dissolved in acetone at a concentration of lmgZ201. Inflammatory agent 1 2— O—Tetradecanol phorbol 1 13— Acetate (hereinafter referred to as TPA) (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in acetate at a concentration of 1 ⁇ g / 20 ⁇ l. The samples were applied to the right ear of a group of mice per sample at a rate of 1 ⁇ g / 20 ⁇ 1 / ear with a micro-mouth pipe. On the other hand, the same amount of acetone was applied to the left ear of the same mouse. After the application, cool air was blown on the ears to dry.
  • TPA Tetradecanol phorbol 1 13
  • TPA was applied to the right ear
  • lAg / 20 julZear was applied to the right ear.
  • the same amount of acetone was applied to the left ear of the same mouse. After application, the ears were blown with cold air to dry.
  • the swelling of the right ear was measured using a dual thickness gauge. The difference between the thickness of the right ear and the thickness of the left ear was determined as the amount of edema.
  • One group of mice to which the same amount of acetone was applied instead of the above sample was used as a control group. The edema amount of this control group was determined.
  • the edema inhibition rate was determined according to the following formula (I). The results are shown in Table 13. In addition, the statistical processing used the Dnnettt multiple comparison test.
  • Edema in control group Edema volume in sample group
  • the auricular edema suppression experiment is said to be suitable for the initial evaluation of the anti-inflammatory effect of drugs due to its simple operation and excellent quantitativeness and reproducibility. It is said that compounds having the following are useful as anti-dermatitis agents such as contact dermatitis and atopic dermatitis.
  • the first to fifth compounds (1) to (5) of the present invention have an anti-inflammatory (anti-inflammatory) action, an anti-edema action and an anti-edema action. Therefore, it was confirmed to be useful for the treatment of dermatitis.
  • the acute toxicity of the first to fifth compounds (1) to (5) of the present invention was examined by oral administration using ICR mice. No fatalities were observed when the drug was administered. From these results, it was confirmed that the compound of the present invention had low toxicity and high safety.
  • components (1), (4) and a part of component (2) were uniformly mixed, compression-molded with a conventional tableting machine, and then pulverized. Next, the remaining amounts of the components (3) and (2) were added and mixed, followed by compression molding using a conventional tableting machine to obtain tablets of 200 mg per tablet.
  • One tablet contains 20 mg of the compound (48), and an adult takes 3 to 10 tablets a day in several divided doses.
  • Ingredients (1) to (5) were uniformly mixed according to the above formula, compression-molded by a conventional compression molding machine, crushed by a crusher, and sieved to obtain granules. 1 g of this granule contains 100 mg of the compound (43) obtained in Example 9, and the adult takes 0.6 to 2 g per day in several doses.
  • the components (1) to (3) were uniformly mixed, and 200 mg of the mixture was filled into a No. 2 force capsule to obtain a capsule.
  • This force capsule contains 20 mg of the compound (42), and an adult takes 3 to 10 capsules a day several times.
  • Example 8 the component (5) was dissolved in the components (2) and (3), and the solution of the components (1) and (2) was added to this solution and emulsified to obtain an injection.
  • Example 8 the component (5) was dissolved in the components (2) and (3), and the solution of the components (1) and (2) was added to this solution and emulsified to obtain an injection.
  • Compound (56) is added to purified water to prepare a uniform solution. Other components are added to this solution and emulsified with a homomixer to obtain a primary emulsion. Further, the primary emulsion was treated five times with a Manton-Gaulin homogenizer at 300 kgcm 2 to obtain an emulsion lotion.
  • the above-mentioned water tank and oil phase were emulsified using a vacuum emulsifier, deaerated, and cooled to obtain a uniform emulsion ointment.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention porte sur des composés décrits dans la formule générale (1), des composés de 2,5-diphénylpyrrole et de 2,5-diphénylthiophène ainsi que sur leurs sels acceptables sur le plan pharmaceutique. Dans cette formule, R11 représente hydrogène, hydroxy, C1-2 alcoxy, acétoxy ou benzyloxy; R12 représente hydrogène, hydroxy, alcoxy C1-2 ou benzyloxy; R13 représente hydrogène, hydroxy, C1-2 alcoxy, acétoxy ou benzyloxy; et R14 représente hydrogène, hydroxy ou benzyloxy. Grâce à leurs effets anti-inflammatoires, les composés précités (1) et les composés de 2,5-diphénylpyrrole et de 2,5-diphénylthiophène s'avèrent utiles dans le traitement des dermatites.
PCT/JP1996/001458 1995-05-30 1996-05-30 Nouveaux composes et medicament anti-dermatite WO1996038412A1 (fr)

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JP7/132310 1995-05-30
JP7132310A JPH11228535A (ja) 1995-05-30 1995-05-30 新規化合物および抗皮膚炎剤

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Cited By (4)

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WO1999018095A1 (fr) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Derives d'arylfurane utilises comme inhibiteurs de phosphodiesterase iv (pde iv)
WO1999018099A1 (fr) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Derives d'arylthiophene utilises comme inhibiteurs de la phosphodiesterase iv
EP1013649A1 (fr) * 1998-12-22 2000-06-28 Chisso Corporation Composés liquides cristallins contenant un cycle furanique, compostion liquide cristalline et dispositif d'affichage à cristaux liquides
CN100371324C (zh) * 2004-09-07 2008-02-27 天津大学 二烷基、二芳基四取代杂环化合物、其制备方法及其应用

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JP5633067B2 (ja) * 2010-02-25 2014-12-03 独立行政法人産業技術総合研究所 フラン誘導体及びその製造方法

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US4595693A (en) * 1984-06-04 1986-06-17 Merck & Co., Inc. Method of use of 2,5-diaryl tetrahydrofurans and analogs thereof as PAF-antagonists
JPH01308227A (ja) * 1988-02-23 1989-12-12 Takeda Chem Ind Ltd プロテアーゼ阻害剤
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JPH0848681A (ja) * 1993-12-15 1996-02-20 Cird Galderma 新規な多環式芳香族化合物、これらを含む調剤用および化粧用組成物並びにこれらの用途

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JPH01308227A (ja) * 1988-02-23 1989-12-12 Takeda Chem Ind Ltd プロテアーゼ阻害剤
WO1994015594A1 (fr) * 1993-01-11 1994-07-21 Tsumura & Co. Inhibiteur de vascularisation et nouveau compose
JPH0848681A (ja) * 1993-12-15 1996-02-20 Cird Galderma 新規な多環式芳香族化合物、これらを含む調剤用および化粧用組成物並びにこれらの用途
JPH0827059A (ja) * 1994-07-04 1996-01-30 Bayer Ag ３，５−ジヒドロキシ−４−ブロモ安息香酸の製法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018095A1 (fr) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Derives d'arylfurane utilises comme inhibiteurs de phosphodiesterase iv (pde iv)
WO1999018099A1 (fr) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Derives d'arylthiophene utilises comme inhibiteurs de la phosphodiesterase iv
EP1013649A1 (fr) * 1998-12-22 2000-06-28 Chisso Corporation Composés liquides cristallins contenant un cycle furanique, compostion liquide cristalline et dispositif d'affichage à cristaux liquides
CN100371324C (zh) * 2004-09-07 2008-02-27 天津大学 二烷基、二芳基四取代杂环化合物、其制备方法及其应用

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