WO2003080592A1 - Composés 2-pyrone et utilisation de ceux-ci - Google Patents

Composés 2-pyrone et utilisation de ceux-ci Download PDF

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WO2003080592A1
WO2003080592A1 PCT/JP2003/003392 JP0303392W WO03080592A1 WO 2003080592 A1 WO2003080592 A1 WO 2003080592A1 JP 0303392 W JP0303392 W JP 0303392W WO 03080592 A1 WO03080592 A1 WO 03080592A1
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group
pyrone compound
compound according
compound
pyrone
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PCT/JP2003/003392
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English (en)
Japanese (ja)
Inventor
Junya Takahashi
Kiyoshi Higashi
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Sumitomo Chemical Company, Limited
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Priority to AU2003220931A priority Critical patent/AU2003220931A1/en
Publication of WO2003080592A1 publication Critical patent/WO2003080592A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones

Definitions

  • the present invention relates to 2-pyrone compounds and uses thereof.
  • TGF-0 one of the cytokines
  • TGF-0 has been shown to increase the expression level of type I collagen gene, enhance collagen production, and thus contribute to tissue fibrosis [Lab. Inves t., 63, 171, (1990), J. Invest. Derma tol., 94, 365, (1990)].
  • X is a hydrogen atom, a halogen atom, a halogen atom or a C1-C4 alkyl group, a nitro group, a CI-C4 alkoxy group which may be substituted by a C1-C4 alkoxy group, or WR represents one group (W represents an oxygen atom or a sulfur atom, R 1 represents a C 1 -C 4 alkyl group substituted with a halogen atom), and R represents a C 1 -C 4 alkyl group, C 3- Represents a C 4 alkenyl group or a C 3 -C 4 alkynyl group. ]
  • R a represents a Echiru group or Ariru group.
  • R 2 represents an ethoxy group, a methoxymethyl group, or a 1,2,2-tetraphenylolethoxy group.
  • a type I collagen gene transcription inhibitory composition comprising the 2-pyrone compound according to item 1 as an active ingredient and an inert carrier (hereinafter referred to as the transcription inhibitory composition of the present invention) is there. ) ;
  • a composition for improving tissue fibrosis characterized by containing the 2-pyrone compound described in 1 above as an active ingredient and an inert carrier (hereinafter referred to as the fibrosis improving composition of the present invention) There is.);
  • a method for improving tissue fibrosis which comprises administering to a mammal patient in need of such treatment an effective amount of the 2-pyrone compound described in 1 above. How to
  • composition for suppressing the action of TGF- according to the preceding item 31, for obtaining a hair-growing effect by inhibiting the promotion of the transition of the hair to the catagen phase by TGF- / 3 and leading to prolongation of the hair growth period.
  • a hair-growing composition characterized by containing the 2-pyrone compound described in 1 above as an active ingredient and an inert carrier (hereinafter sometimes referred to as the hair-growing composition of the present invention);
  • a hair-growing method comprising administering an effective amount of a 2-pyrone compound according to item 1 to a mammalian patient in need of hair-growing treatment;
  • halogen atom in X examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a halogen atom fluorine atom, chlorine atom, bromine atom, iodine atom
  • a CI—C4 alkyl group which may be substituted by a CI—C4 alkoxy group is, for example, a methyl group, a trifluoromethyl And a methoxymethyl group.
  • Examples of the C1-C4 ⁇ -oxy group in X include a methoxy group and an ethoxy group.
  • Halogen atom in R 1 (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom)
  • Examples of the C 1-C 4 alkyl group substituted by, for example, one or more C 1 one C 4 alkyl group substituted with a fluorine atom Difluoromethyl group, trifluoromethyl group, 1,1,2,2-tetrafluoroethyl group and the like.
  • W represents an oxygen atom or a sulfur atom
  • R 1 is representative of a C 1 one C 4 alkyl group substituted by a halogen atom), for example, substituted with one or more fluorine atoms C 1-C4 alkoxy groups such as difluoromethoxy, trifluoromethoxy, trifluoromethylthio, 1,1,2,2-tetrafluoroethoxy, etc.
  • Examples of the C 1 -C 4 alkyl group, C 3 -C 4 alkyl group or C 3 -C 4 alkyl group in R include a methyl group, an ethyl group, and an aryl group.
  • Embodiments of the compound (I) of the present invention include the following embodiments c
  • R 3 represents a chlorine atom, a trifluorenomethyl group, a difluoromethoxy group or a trifluoromethoxy group, and R represents a C 1 -C 4 alkyl group, a C 3 -C 4 alkenyl group or a C 3 _C 4 represents an alcohol group.
  • R represents a C1-C4 alkyl group, a C3-C4 alkenyl group or a C3-C4 alkenyl group.
  • R represents a C 1 -C 4 alkyl group, a C 3 -C 4 alkyl group or a C 3 -C 4 alkyl group.
  • R represents a C 1 -C 4 alkyl group, a C 3 -C 4 alkenyl group or a C 3 -C 4 alkenyl group.
  • R represents a C 1 -C 4 alkyl group, a C 3 -C 4 alkenyl group or a C 3 -C 4 alkyl group.
  • R 5 is a halogen atom, a C 1 -C 4 alkyl group optionally substituted with a halogen atom or a C 1 -C 4 alkoxy group, or a C 1 -C 4 alkoxy group substituted with a halogen atom.
  • R represents a C 1 -C 4 alkyl group, a C 3 -C 4 alkenyl group or a C 3-
  • R a represents a Echiru group or Ariru group.
  • examples of the C1-C4 alkyl group, C3-C4 alkenyl group or C3-C4 alkynyl group in R include, for example, a methyl group, an ethyl group, and an aryl group.
  • halogen atom examples include a chlorine atom and the like.
  • Examples of the C 1 -C 4 alkyl group which may be substituted with a halogen atom or a C 1 -C 4 alkoxy group include a methyl group, a trifluoromethyl group, and a methoxymethyl group.
  • Examples of the C 1 -C 4 alkoxy group substituted by a halogen atom include a difluoromethoxy group, a trifluoromethoxy group, and a 1,1,2,2-tetrafluoroethoxy group.
  • the compound (I) of the present invention is represented by the formula (XIII), wherein X represents the same meaning as described above. (Hereinafter, may be referred to as the present intermediate (II)) by alkylation, alkenylanilide or alkynylani.
  • Examples of the method of alkylation, alkenyliyi or alkyliyirou include a compound represented by the formula (XIII) and a compound represented by the formula (XIV)
  • R represents the same meaning as described above, and Y represents a leaving group.
  • an alkenylating agent or an alkynylating agent [hereinafter may be referred to as compound (XIV). ]
  • a base an alkenylating agent or an alkynylating agent
  • the reaction of the compound represented by the formula (XIII) with the compound (XIV) in the presence of a base is usually performed in a solvent.
  • the solvent used include acid amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide; and phosphoric amide compounds such as hexamethylphosphoramide.
  • ketones such as aceton and methyl ethyl ketone.
  • Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride, carbonates of alkali metal such as sodium carbonate and carbonated carbonate, and silver oxide. .
  • alkylating agent, alkenylating agent or alkynyl agent used in the reaction examples include alkyl sulfonic acid esters such as methyl methanesulfonate and aryl sulfonic acid esters such as ethyl p-toluenesulfonate. And sulphates such as dimethyl sulfate and halides such as butyl bromide, aryl bromide and propargyl bromide.
  • the amount of the reagent used in the reaction is usually 1 mole to 2 moles per 1 mole of the compound represented by the formula (XIII), and the compound (XIV) is usually 1 mole to 2 moles. Ratio.
  • the reaction temperature is usually in the range of 0 ° C to 100 ° C, and the reaction time is usually 1 hour to 200 ° C. Within the time range.
  • the compound (I) of the present invention can be isolated by performing post-treatment operations such as extraction of the reaction mixture with an organic solvent and drying and concentration of the organic layer.
  • the isolated compound (I) of the present invention can be further purified by chromatography, recrystallization and the like.
  • R 2 represents an ethoxy group, a methoxymethyl group, or a 1,2,2-tetraphenylolethoxy group.
  • Table 2 Compound No. (1) ⁇ : c illustrate the present invention compound (I) represented by (14) Table 2 Compound (I) of the present invention Table 2
  • Table 3 illustrates the compounds (I) of the present invention represented by the compound numbers (15) to (28). C Table 3 Compounds of the present invention (I)
  • the compound (I) of the present invention has an ability to suppress the transcription of a type I collagen gene. This ability is important for improving tissue fibrosis by reducing the expression of the type I collagen gene and leading to a decrease in collagen accumulation. Therefore, the compound (I) of the present invention is a composition (medicine, cosmetics, food additive, etc.) for improving tissue fibrosis by reducing the expression level of type I collagen gene and leading to a reduction in collagen accumulation. Etc.) can be used as active ingredients.
  • Diseases to which the transcription-suppressing composition of the present invention or the fibrosis-improving composition of the present invention can be applied include tissues that fibrillate and harden due to excessive accumulation of collagen, and as a result, the function of organs / tissues is reduced. Diseases that cause formation (ie, fibrosis) can be mentioned. For example, cirrhosis, interstitial lung disease, chronic renal failure (or a disease that leads to chronic renal failure), hyperplasia scars after inflammation, postoperative scars ⁇ burn scars, scleroderma, arteriosclerosis, hypertension, etc. Illnesses and abnormalities 3392
  • the transcription-suppressing composition of the present invention and the fibrosis-improving composition of the present invention contain the present compound (I) and an inert carrier.
  • the compound (I) of the present invention contained in these compositions is usually 0.01% to 99.99% by weight, and the inert carrier is usually 99.99% to 0.01% by weight. %.
  • the inert carrier is a pharmaceutically acceptable carrier or excipient, and the transcription-suppressing composition and the fibrosis-improving composition of the present invention further include a pharmaceutical additive, a cosmetic additive, a food additive, and the like. May contain.
  • the compound (I) of the present invention inhibits the ability of TGF- to promote the transcription of type I collagen gene, as shown in Example 54 described later.
  • the compound (I) of the present invention is a TGF- / S antagonist having the ability to suppress the action of T.GF-. Therefore, the compound (I) of the present invention can also be used as an active ingredient of a composition for inhibiting the action of TGF-3.
  • TGF- / 3 is known to have the ability to promote the transition from the anagen phase to the catagen phase in the hair growth cycle [J. Invest. De Rma tol., 111, 948-954 ( 1998), FASEB J., 16, 1967-1969 (2002)]. Furthermore, it has been reported that anti-TGF-5 antibody and TGF-0 inhibitor F etuin and the like act antagonistically to the hair growth inhibitory effect of TGF-, and exhibit a hair growth promoting effect.
  • it can be used as a composition (pharmaceuticals, cosmetics, food additives, etc.) for obtaining a hair-growth effect.
  • Such a TGF-suppressing composition of the present invention and a hair-growing composition of the present invention contain the present compound (I) and an inert carrier.
  • the present compound (I) contained in these compositions is usually 0.01% to 99.99% by weight, and the inert carrier is usually 99.99% to 0.01%. % By weight.
  • the inert carrier is a pharmaceutically acceptable carrier and an excipient, and the TGF- ⁇ inhibitory composition and the hair restoration composition of the present invention further include a pharmaceutical additive and cosmetics. It may contain additives, food additives, etc.
  • Pharmaceutically acceptable carriers, excipients, pharmaceutical additives, food additives, cosmetic additives, etc. used in the composition can be appropriately selected according to the specific use of the composition. .
  • the form of the composition may be, for example, various solids, liquids, and the like, depending on the specific application.
  • specific forms include, for example, powders, fine granules, granules, tablets, syrups, capsules, suspending agents, Examples include oral preparations such as emulsion preparations, extracts and pills, injection preparations, transdermal absorption preparations such as external preparations and ointments, and parenteral preparations such as suppositories and topical preparations.
  • Oral IJ includes, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polypyrrolepyrrolidone, crystalline cellulose, soy lecithin, sucrose, fatty acid esters, Carriers such as luk, magnesium stearate, polyethylene glycol, magnesium silicate, and caustic anhydride, excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, diluents, preservatives, coloring It can be manufactured according to a usual method using pharmaceutical additives such as agents, fragrances, stabilizers, humectants, preservatives, and antioxidants.
  • pharmaceutical additives such as agents, fragrances, stabilizers, humectants, preservatives, and antioxidants.
  • the dosage varies depending on the age, sex, body weight, degree of disease, type of the composition of the present invention, dosage form, etc. of the mammal to be administered.
  • About 1 mg to about 2 g of the ingredient, preferably about 5 mg to about 1 g of the active ingredient may be administered.
  • the above-mentioned daily dose can be administered once or in several divided doses.
  • injections include water-soluble solvents such as physiological saline and sterilized Ringer's solution, water-insoluble solvents such as vegetable oils and fatty acid esters, isotonic agents such as pudose and sodium chloride, and dissolution aids. It can be produced according to a usual method using pharmaceutical additives such as agents, stabilizers, preservatives, suspending agents and emulsifiers. Liquid preparations for external use, transdermal absorption agents such as gel ointments, suppositories for rectal administration, and the like can also be produced according to ordinary methods. In order to administer such a parenteral preparation, injection (subcutaneous, intravenous, etc.), transdermal administration, or rectal administration may be used.
  • water-soluble solvents such as physiological saline and sterilized Ringer's solution
  • water-insoluble solvents such as vegetable oils and fatty acid esters
  • isotonic agents such as pudose and sodium chloride
  • dissolution aids such as agents, stabilizers,
  • the agent can be produced, for example, by incorporating the compound (I) of the present invention into a pellet of a sustained-release polymer such as ethylene-butyl acetate polymer.
  • the pellet may be surgically implanted into the tissue to be treated.
  • the dosage varies depending on the age, sex, body weight, degree of disease, the type of the composition of the present invention, the dosage form, etc. of the mammal to be administered. You may administer from 0.1 mg to about 50 mg. In addition, the above-mentioned daily dose can be administered once or in several divided doses.
  • the compound (I) of the present invention When the compound (I) of the present invention is used by adding it to cosmetics, specific forms of the cosmetics to which the compound is added include, for example, liquid, milky, cream, lotion, ointment, gel, Aerosol, mousse, etc. can be mentioned. Lotions can be manufactured according to ordinary methods using, for example, cosmetic additives such as suspending agents, emulsifiers, and preservatives.
  • the dose varies depending on the age, sex, body weight, degree of disease, the type of the composition of the present invention, the dosage form, etc., of the mammal to be administered, but is usually about 0.01 mg as an active ingredient in a human adult. About 5 O mg may be administered.
  • the above-mentioned daily dose can be administered once or in several divided doses.
  • specific forms of the food to which the additive is added include, for example, powders, tablets, drinks, ingestible gels and syrups.
  • Mixed liquids for example, seasonings, Japanese sweets, western confectionery, ice confectionery, beverages, spreads, pastes, pickles, canned bottles, processed meat, fish and fishery products, processed milk and eggs, processed vegetables, and processed fruit products And general foods and drinks such as processed cereals, etc.
  • the dosage varies depending on the age, sex, weight, degree of disease, the type of the composition of the present invention, the dosage form, etc. of the mammal to be administered. About 500 mg may be administered.
  • the above-mentioned daily dose can be administered once or in several divided doses.
  • Hexamethylphosphoramide 32 74 g of sodium hydride (60% oil, 1 "raw) was suspended in 2 ml of 1-ml, and 4-hydroxy 3- [3-phen-nore 1- was suspended at about 0 ° C. Oxo-2-propioninole] —6-methyl-2H-pyran-2-one (4.77 g) was added, and the mixture was heated to room temperature and stirred for 37 minutes. After that, the mixture was stirred for 2 days at room temperature, and then the reaction mixture was poured into ice water and extracted with ethyl acetate.The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the obtained genomic DNA solution (equivalent to genomic DNA), an oligonucleotide having the nucleotide sequence of SEQ ID NO: 1 and an oligonucleotide having the nucleotide sequence of SEQ ID NO: 2 (10 pmo 1 / ⁇ 1) 1 ⁇ l each, distilled water 29 1, ⁇ a Ka Ra LA Taq (Takara Shuzo, catalog number RRO 02A) buffer 5 ⁇ 1, Mg 2+ solution 51, dNTP miture 5 u 1 and 0.51 was mixed with TaKaRaLATaq (Takara Shuzo, catalog number RR0O2A).
  • the obtained mixture was kept at 94 ° C for 5 minutes, and then 30 cycles of 94 ° C, 1 minute, then 60 ° C, 1 minute, and 72 ° C, 1 minute were taken as one cycle. .
  • the mixture was subjected to 2% agarose gel electrophoresis to recover about 0.5 kb of DNA.
  • the recovered DNA was treated with phenol / chloroform and then precipitated with ethanol to recover the DNA.
  • the recovered DNA was dissolved in ultrapure water, Nhel 2.51 and Hindill 2.51 were added to the solution, and the mixture was kept at 37 ° C for 3 hours.
  • the lysate was subjected to 2% agarose gel electrophoresis to recover about 0.5 kb of DNA.
  • the collected DNA was precipitated with ethanol to recover the DNA again (hereinafter, referred to as collagen mouth motor DNA).
  • Luc vector DNA DNA
  • Escherichia coli 5Hd ⁇ ⁇ , Cat. No. DNA-903
  • the seeds were seeded on an LB plate containing g / m 1 ampicillin sodium (Nacalai, Cat. No.
  • Plasmid DNA was prepared from the resulting culture using AUTOMAT IC DNA I SOLATION SYSTEM PI-50 (KURABO). The nucleotide sequence of the prepared plasmid DNA was analyzed using a DNA sequencer. As a result, the plasmid (hereinafter, referred to as COL-Luc) contains 342 to 1557 bases (the transcription start point is +1) of the transcription regulatory region of the human type I collagen ⁇ 2 chain gene.
  • the culture supernatant was removed from the dish, the cells were washed twice with PBS, and the cells were detached by adding PBS lm1 containing 0.25% trypsin. After adding D-MEM (+) to the cells and mixing well, the cell suspension was dispensed in 1 ml portions into a 12-well plate, and this was added at 37 ° C and 5% CO 2. The cells were cultured under an atmosphere for 1 hour.
  • the compound (I) of the present invention represented by the compound number (1) to (8) or (10) to (28) is added to the cells cultured in this manner so that the dimethyl sulfoxide is adjusted to 1 mM. (Hereinafter, referred to as DMSO) were added to each solution (final concentration: ⁇ ).
  • DMSO dimethyl sulfoxide
  • a solution prepared by dissolving the compound in DMS O to 10 mM was added (final concentration: 10 M ).
  • DMSO was added to the rice cake.
  • TGF-j3 the (P epro T ech) 5 xg / ml aqueous solution or distilled water was 1 1 added and further cultured for 24 hours under 3 7 ° C, 5% CO z atmosphere.
  • a cell lysing agent Toyo Ink, Cat. No. PD10
  • a cell scraper Na1gen, Cat. No. The cells were detached from the vessel wall using 1 79 6 9 3). After recovering the obtained cell suspension, the cell suspension was centrifuged (15,000 rpm, 4 ° C, 5 minutes) to recover the supernatant.
  • the recovered supernatant 5a1 or cell lysis reagent 51 is pre-dispensed into a 96-well plate and diluted 5-fold with a Protein Assay solution (Bio-Rad, Cat. No. 500-0006) 200 After shaking and mixing in addition to 1, the absorbance at 595 nm in each well was measured using a microplate reader (Bio-Rad, Benemark). Based on the obtained value, the transcription activity was calculated according to the following equation.
  • Transcription activity [Light emission (supernatant added) One light emitted (cell lysing agent added)] / [595 nm absorbance (supernatant added)-595 nm absorbance (cell lysate added)]
  • the inhibitory effect of the test compound on the transcription promoting ability of the type I collagen gene possessed by TGF- ⁇ S was calculated as the degree of inhibition according to the following formula.
  • the degree of inhibition of the compound (I) of the present invention represented by the compound numbers (1) to (28) was 70 or more. It was confirmed that these compounds have the ability of TGF- to inhibit the type I collagen gene transcription promoting ability and suppress the type I collagen gene transcription.
  • Example 55 Improvement of diabetic nephropathy by administration of compound (I) of the present invention
  • a feed containing the compound of the present invention was prepared.
  • the body weight and food intake per mouse were measured every two weeks of breeding, and the amount of the test substance mixed with the basal feed was determined based on the measured values.
  • the thus-prepared feed containing the compound of the present invention was fed freely to the above diabetic nephropathy model animal for 8 weeks (compound administration group).
  • compound administration group As a P-easy control administration group, the above diabetic nephropathy model animals were bred while freely feeding on a basal feed, and halofuginone, a TGF-iS inhibitor, was administered intraperitoneally every other day.
  • one group of the above-mentioned diabetic nephropathy model animals was bred with free access to a basal feed.
  • one group of the above-described control animals was bred with free access to a basal feed.
  • Non-administration group Nephropathy mote 0 60.91
  • Control group Control animal 0 37.21 p 0.05 Industrial applicability
  • a composition for improving tissue fibrosis by reducing the expression level of type I collagen gene in tissue and reducing the amount of collagen accumulated ie, a collagen accumulation inhibitor or a therapeutic agent for fibrosis
  • the development of 'offer is possible.

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Abstract

L'invention concerne des composés 2-pyrone représentés par la formule générale (I); dans cette formule, X représente halogène, alkyle C1-4 éventuellement substitué par alkoxy C1-4, etc. L'invention concerne également des compositions inhibant la transcription génique du collagène de type I, lesquelles compositions contiennent le composé 2-pyrone susmentionné en tant que principe actif, lequel est associé à un excipient inerte. Cette invention concerne également une méthode thérapeutique permettant d'améliorer la fibrose tissulaire, laquelle méthode se caractérise par l'administration d'une dose efficace du composé 2-pyrone susmentionné à un sujet mammifère nécessitant un tel traitement.
PCT/JP2003/003392 2002-03-27 2003-03-20 Composés 2-pyrone et utilisation de ceux-ci WO2003080592A1 (fr)

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AU2003220931A AU2003220931A1 (en) 2002-03-27 2003-03-20 2-pyrone compounds and use thereof

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JP2002-88575 2002-03-27
JP2002088574 2002-03-27
JP2002088575 2002-03-27
JP2002-88574 2002-03-27
JP2002290843 2002-10-03
JP2002-290843 2002-10-03

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WO2003080592A1 true WO2003080592A1 (fr) 2003-10-02

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PCT/JP2003/003392 WO2003080592A1 (fr) 2002-03-27 2003-03-20 Composés 2-pyrone et utilisation de ceux-ci

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
WO2005028441A1 (fr) * 2003-09-17 2005-03-31 Sumitomo Chemical Company, Limited Derives de cinnamoyle et utilisation de ceux-ci
WO2005028463A1 (fr) * 2003-09-17 2005-03-31 Sumitomo Chemical Company, Limited Compose cinnamoyle et utilisation associee
WO2005085241A1 (fr) * 2004-03-05 2005-09-15 Taisho Pharmaceutical Co., Ltd. Derive de thiazole
WO2006100922A1 (fr) * 2005-03-02 2006-09-28 Sumitomo Chemical Company, Limited Dérivé de cinnamoyle et ses applications
WO2007136125A1 (fr) * 2006-05-22 2007-11-29 Sumitomo Chemical Company, Limited Composé ayant un noyau hétérocyclique et son utilisation
US7989478B2 (en) * 2003-09-17 2011-08-02 Sumitomo Chemical Company, Limited Cinnamoyl compound and use of the same

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028441A1 (fr) * 2003-09-17 2005-03-31 Sumitomo Chemical Company, Limited Derives de cinnamoyle et utilisation de ceux-ci
WO2005028463A1 (fr) * 2003-09-17 2005-03-31 Sumitomo Chemical Company, Limited Compose cinnamoyle et utilisation associee
US7989478B2 (en) * 2003-09-17 2011-08-02 Sumitomo Chemical Company, Limited Cinnamoyl compound and use of the same
AU2004274328B2 (en) * 2003-09-17 2011-11-10 Sumitomo Chemical Company, Limited Cinnamoyl compound and use of the same
US8524729B2 (en) 2003-09-17 2013-09-03 Sumitomo Chemical Company, Limited Cinnamoyl derivatives and use thereof
WO2005085241A1 (fr) * 2004-03-05 2005-09-15 Taisho Pharmaceutical Co., Ltd. Derive de thiazole
US7678810B2 (en) 2004-03-05 2010-03-16 Taisho Pharmaceutical Co., Ltd Thiazole derivative
WO2006100922A1 (fr) * 2005-03-02 2006-09-28 Sumitomo Chemical Company, Limited Dérivé de cinnamoyle et ses applications
WO2007136125A1 (fr) * 2006-05-22 2007-11-29 Sumitomo Chemical Company, Limited Composé ayant un noyau hétérocyclique et son utilisation

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