WO2006016399A1 - ヒドロキサム酸誘導体及びそれを有効成分とする医薬 - Google Patents
ヒドロキサム酸誘導体及びそれを有効成分とする医薬Info
- Publication number
- WO2006016399A1 WO2006016399A1 PCT/JP2004/011473 JP2004011473W WO2006016399A1 WO 2006016399 A1 WO2006016399 A1 WO 2006016399A1 JP 2004011473 W JP2004011473 W JP 2004011473W WO 2006016399 A1 WO2006016399 A1 WO 2006016399A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- phenyl
- group
- compound
- oxazolehexanamide
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to a hydroxamic acid derivative and a medicine containing the same as an active ingredient. More specifically, the present invention relates to a hydroxamic acid derivative having a basic chemical structure of N-hydroxy-2-thiazole or oxazole alkylamide, and interleukin-1 (IL-6) and It relates to a medicine that is effective as an inhibitor of TNF production.
- a hydroxamic acid derivative having a basic chemical structure of N-hydroxy-2-thiazole or oxazole alkylamide, and interleukin-1 (IL-6) and It relates to a medicine that is effective as an inhibitor of TNF production.
- Inflammatory reaction hematopoiesis, bone metabolism, allergic reaction, autoimmunity It plays an important role in ecological defense reactions such as diseases.
- Inflammatory site forces such as IL-6 and TNFa are produced from various cells such as immune system cells such as macrophages, fibroblasts, vascular endothelial cells, and osteoblasts. It exerts various physiological activities such as induction of differentiation, induction of acute phase protein production from hepatocytes, and induction of osteoclast differentiation by directly acting on bone marrow-derived macrophages, which are osteoclast precursor cells.
- Non-patent document 1 Non-patent document 2; Non-patent document 3
- Non-patent document 3 Non-patent document 3
- hydroxamic acid derivatives that have been disclosed as useful as inhibitors of cytoforce-in include the following.
- Patent Document 1 a hydroxamic acid derivative represented by the following general formula (a) is a TNF a release inhibitor from cells and inhibits a metalloproteinase involved in tissue disruption It is disclosed.
- Patent Document 2 discloses that an imidazole-substituted hydroxamic acid derivative represented by the following general formula (b) is useful as an inhibitor of matrix-degradable meta-oral proteinase.
- Patent Document 3 discloses that it has an action of suppressing the production of hydroxamic acid derivative TNF a represented by the following general formula (c).
- Patent Document 4 a hydroxamic acid derivative represented by the following general formula (d) inhibits human CD23 formation and is useful for the treatment of symptoms related to overproduction of soluble CD23 such as autoimmune diseases and allergies. Things are disclosed.
- Patent Document 5 discloses that a hydroxamic acid derivative having a hydroxyl group at the 6-position represented by the following general formula (e) suppresses IL-6 production. 6th place in this statement
- the hydroxyl group at the 6-position is a structural element necessary for expressing IL-6 production inhibitory activity.
- Patent Document 6 discloses that a hydroxamic acid derivative represented by the following general formula (f) suppresses the production of IL-6.
- the compounds specifically described in this publication are limited to compounds in which ring A and ring B in the following general formula (f) are phenyl groups.
- Patent Document 7 describes that an oxazole compound represented by the following general formula (g) is effective as an anti-inflammatory chiral IJ. However, IL-6 and / or TNF production is suppressed, and nothing is described.
- Patent Document 1 Japanese Patent Publication No. 9-503222
- Patent Document 2 Japanese Patent Publication No. 9-509940
- Patent Document 3 International Publication No.99 / 61412 Pamphlet
- Patent Document 4 Japanese Patent Publication No. 2000-503312
- Patent Document 5 JP 2002-80445 A
- Patent Document 6 International Publication No. 2002-074298 Pamphlet
- Patent Document 7 U.S. Pat.No. 3,578,671
- Non-Patent Document 1 Eur. J. Immunol, 18: 1797—1801 (1988)
- Non-Patent Document 2 Blood, 74 (4): 1360, (1989)
- Non-Patent Document 3 Allergies' immunity, Vol. 10, No. 9, 67-75 (2003)
- the present invention provides a compound that suppresses the production of IL-6 and / or TNFa and is useful for the prevention or treatment of various inflammatory diseases, autoimmune diseases and the like in which these site force-in factors are involved. There is a thing.
- a or B are the same or different and each represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent, Y represents an oxygen atom or a sulfur atom, and n represents 1 force 8 Represents an integer.
- a and B are phenyl groups, Y is an oxygen atom, and n is an integer of 2.
- a pharmaceutically acceptable salt or solvate thereof, or a prodrug form thereof [0012]
- the present invention relates to a pharmaceutical comprising the compound of the above formula (1), or a pharmaceutically acceptable salt or solvate thereof, or a prodrug form thereof as an active ingredient.
- the present invention is a compound of the above formula (1) (provided that A and B are phenyl groups, Y is an oxygen atom, and n is an integer of 2), or pharmaceutically acceptable.
- the present invention relates to a production inhibitor of interleukin-1 6 and / or TNFa comprising, as an active ingredient, a salt or a solvate thereof, or a prodrug form thereof.
- the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a prodrug form thereof, produces IL-6 and / or TNF ct of inflammatory site force in.
- these compounds of the present invention are useful as preventive or therapeutic agents for various inflammatory diseases, sepsis, multiple myeloma, osteoporosis, rheumatoid arthritis, Castleman's disease, inflammatory bowel disease, autoimmune diseases and the like. is there.
- a or B is the same or different and each represents a hydrogen atom, an alkyl group, or an aryl group optionally having a substituent, Represents an oxygen atom or a sulfur atom, and n represents an integer of 1 to 8.
- examples of the alkyl group include, for example, a methylol group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, Examples thereof include straight-chain or branched alkyl groups having 1 to 8 carbon atoms such as octyl group.
- aryl group examples include aryl groups having 6 to 10 carbon atoms such as a phenyl group and a naphthyl group.
- a phenyl group is preferable.
- These aryl groups may have a substituent, for example, a halogen atom such as a chlorine atom, a bromine atom or a fluorine atom; a methyl group, an ethyl group, a propyl group, or an isopropyl group.
- a linear or branched lower alkyl group having 1 to 6 carbon atoms such as a group, butyl group, isobutyl group, sec-butyl group, tert-butyl group; trifluoromethyl group, trichloromethyl group, 2 , 2,2_trifluoroethyl groups, etc., straight or branched halogen atoms having 1 to 6 carbon atoms
- Straight chain or branched lower alkenyl having 2 to 6 carbon atoms such as butyl group, aryl group, propene-1-yl group, butene-1-yl group, pentene-1-yl group, etc.
- a straight chain or branched lower alkynyl group having 2 to 6 carbon atoms such as an ethynyl group, a propyne-1-yl group, a butyne-1-yl group, a 1-methylbutyne-1-yl group; a methoxy group, Linear or branched lower alkoxy group having 1 to 6 carbon atoms such as toxyl group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group; formyl group, acetyl group An acyl group having 1 to 6 carbon atoms such as a propanoyl group; an acyl group having 2 to 6 carbon atoms such as an acetyloxy group and a propanoyloxy group; a methylamino group, a dimethylamino group, and an ethylamine group 1 to 6 lower alkyl-substituted amino groups such as
- a or B are the same or different and are each a hydrogen atom, an alkyl group, a phenyl group, a halogen atom, a lower alkyl group, a lower alkoxy group, or a halogenated lower alkyl group.
- a phenyl group substituted with is preferred.
- n represents an integer of 1 to 8
- n is preferably an integer of 5 or 6
- n is preferably an integer of 5.
- the compound represented by the above formula (1) of the present invention can be converted into a pharmaceutically acceptable salt or a solvate thereof, or a prodrug form thereof, if necessary.
- the pharmaceutically acceptable salt include metal salts, organic amine salts, acid addition salts and the like.
- the metal salt include alkali metals such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt.
- the acid addition salt include inorganic acid salts such as hydrochloride, phosphate and sulfate, and organic acid salts such as methanesulfonate.
- solvates include hydrates with water, solvates with organic solvents such as methanol and ethanol.
- Examples of the prodrug form of the compound of the above formula (1) include compounds that can be converted into the compound of the above formula (1) by gastric acid or enzyme in vivo. I can get lost.
- a compound alkylated with an alkyl group having 1 to 6 carbon atoms such as ethyl and propyl.
- a hydroxyl group and an amide of hydroxamic acid may be involved to form a ring.
- a compound selected from the following compound group is a preferred specific example; 5- [4- (1,1-dimethylethyl) phenyl] -N-hydroxy-4-phenyl-2-oxazoylhexanamide;
- Any of the compounds represented by the above formula (1) of the present invention can be produced by a known method. Below, the typical manufacturing method of these compounds is shown.
- the compound represented by the above formula (1) of the present invention synthesizes a 1,3-azole derivative in which an alkylcarboxylic acid is substituted at the 2-position of the basic skeleton of 1,3-oxazole or thiazole,
- This 1,3-azole derivative can be synthesized by converting the carboxyl group to a hydroxy group.
- a and B mean A and B in the above formula (1), and Y means an oxygen atom or a sulfur atom.
- n is an integer from 1 to 8
- R is an alkyl group
- X is a halogen atom.
- the carboxylic acid represented by the formula (A1) is reacted with the bis-haloketone represented by the formula (A2) in the presence of a base such as potassium carbonate, and the resulting ester represented by the formula (A3) is dissolved in acetic acid.
- An oxazole derivative in which Y in formula (A4) is an oxygen atom can be obtained by heating with an element source such as urea or ammonium acetate (reference: Heterocyclic Compounds, Wiley & Sonsjnc., 5, 302-323).
- the ester compound represented by the formula (A3) is obtained by mixing the acid halide represented by the formula (A5) with the ⁇ -hydroxyketone compound represented by the formula (A6) in the presence of pyridine trialkylamine or the like at room temperature. It can also be obtained by reacting at 100 ° C.
- an oxazole derivative in which Y in formula (A4) is an oxygen atom is obtained by converting an acid halide represented by formula (A5) into an ⁇ -a formula represented by formula (A7) in the presence of pyridine or trialkylamine. It can also be obtained by reacting a mino ketone body with a room temperature of 100 ° C and heating the resulting amide body represented by the formula ( ⁇ 8) in the presence of a dehydrating agent such as phosphorus pentachloride.
- an acid amide compound in which Y in the formula (A9) is an oxygen atom and an ⁇ represented by the formula (A10) -Oxazole derivatives can also be obtained by heating haloketones (Reference: Large Organic Chemistry, 15,6-45).
- the thiazole derivative in which Y in the formula (A4) is a sulfur atom can be obtained by heating the amide compound represented by the formula (A8) together with diphosphorus pentasulfide.
- a thiazole derivative can also be obtained by reacting a thiamide compound in which Y in formula (A9) is a sulfur atom with a halo-ketone body represented by formula (A10) at room temperature of 1-50 ° C.
- the carboxylic acid esters in the formulas (A3) and (A8) form a 1,3_azole ring and then, for example, at room temperature with an aqueous sodium hydroxide solution or the like according to a conventional method.
- carboxylic acid can be derived by acid precipitation.
- a and B represent A and B in the above formula (1), and Y represents an oxygen atom or a sulfur atom.
- X represents a halogen atom, and n represents an integer of 1 to 8.
- Conversion of the carboxylic acid derivative obtained according to Scheme A to a hydroxamic acid derivative is carried out by converting a carboxylic acid derivative represented by the formula (A4) into a halogenated thionyl compound or the like according to a conventional method (Al l). After making the acid halide, it can be reacted with hydroxyreamine in the presence of a base such as trialkylamine to obtain a hydroxamic acid derivative represented by the formula (A12).
- a base such as trialkylamine
- hydroxamic acid derivative represented by the above formula (1), a pharmaceutically acceptable salt or a solvate thereof, or a prodrug form thereof thus produced is used as an active ingredient.
- Drugs can usually be administered to mammals (including human patients) as tablets, capsules, powders, fine granules, solutions, syrups and other oral preparations, rectal preparations or injections.
- the compound of the present invention can also be administered as a single therapeutic agent or as a mixture with other therapeutic agents.
- compositions are generally administered in the form of a pharmaceutical composition.
- These preparations can be manufactured by conventional methods with the addition of pharmacologically and pharmaceutically acceptable additives.
- conventional excipients, lubricants, binders, disintegrants, wetting agents, coating agents, and other additives are used for oral administration such as tablets, capsules, powders, fine granules, and syrups. be able to.
- Liquids for oral administration may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or provided as dry syrups prepared in water or other suitable solvent before use. Also good.
- the above solutions can contain conventional additives such as suspending agents, perfumes, diluents or emulsifiers.
- Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, darissello gelatin, witetbuzole, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, preservatives as necessary. Etc. can be added.
- Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used. Specific examples of excipients used in the above composition are listed below.
- excipients include magnesium aluminate metasilicate, magnesium silicate, magnesium carbonate, calcium hydrogen phosphate, Avicel, various starches, dextrin, carboxymethyl starch (CMS), and lactose.
- binder examples include ethyl cellulose (EC), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium alginate, gelatin, polybulurpyrrolidone (PVP), and the like.
- Disintegrating agents include synthetic aluminum silicate, magnesium aluminate metasilicate, Cell, hydroxypropyl starch (CPS) and the like.
- anti-caking agent include light anhydrous key acid and synthetic aluminum key.
- the lubricant examples include synthetic cation anolyminum, anhydrous carboxylic acid, talc, and Avicel.
- corrigent examples include mannitol, citrate, sodium citrate, and sugar.
- Examples of the emulsifier include gelatin, macrogol (PEG), propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, and phospholipid.
- examples of the stabilizer include propylene glycol fatty acid ester, polyoxyethylenepolyoxypropylene glycol, and various natural and synthetic cyclodextrins.
- Absorption promoters include propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural synthetic cyclodextrins, and the like.
- solubilizers include ethanol, polyethylene glycol, propylene glycol fatty acid ester, propylene glycol, and various natural synthetic cyclodextrins.
- suspending agent include sodium alginate, gelatin, polypropylene alcohol, and sodium lauryl sulfate.
- the coating agent include magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethylethyl cellulose (CMEC), and the like.
- the colorant include tar pigments and caramel.
- the dosage when the compound of the present invention is administered to humans varies depending on the age, symptoms, etc. of the patient. In the case of normal adults, lmg—lOOOOmg / person / day, injection for oral or rectal administration It is about 500mg / person / day. However, these numerical values are merely examples, and the dosage may be appropriately increased or decreased depending on various conditions such as patient symptoms.
- the obtained acid chloride was dropped into a solution consisting of hydroxylamine hydrochloride (1.35 g), triethylamine (3.90 g) and 1,3-dimethyl-2-imidazolidinone (50 mL) and reacted overnight at room temperature. .
- the reaction mixture was poured into water (500 mL), diluted hydrochloric acid was added to adjust the pH to 3, and the target product was extracted with ethyl acetate (200 mL).
- the organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude product.
- the target title compound was produced in the same manner as in Example 1, (3).
- the target title compound was produced in the same manner as in Example 1, (3).
- the target title compound was produced in the same manner as in Example 11, (3).
- the target title compound was produced in the same manner as in Example 11, (3).
- aminoethylphenone hydrochloride 2.5 g was added with triethylamine (3.5 g) and 6- (formylformyl) hexaethyl ethylate at room temperature. Reacted for 3 hours.
- Phosphorus pentachloride (7.9 g) was added to amide compound (3.037 g) in toluene (lOOmL) and refluxed for 1.5 hours.
- Table 1 shows the compounds obtained in the above Examples.
- the compound number corresponds to the number assigned to the compound in each example.
- the test was conducted with reference to the method of G. Lozanski et al. (J. Rheumatol., Vol. 19, 921-926, 1992). Prepare 10 6 cells / mL THP-1 cells (Dainippon Pharmaceutical Co., Ltd.) using PRMI-1640 medium supplemented with 10% urinary fetal serum (FCS), 48-well mic mouthplate for 500 / i Lwell each. Seeded. To this, phorbol 12-myristate 13-acetate (PMA) 10 " 8 M was added and cultured for 24 hours to induce differentiation into macrophages.
- PMA phorbol 12-myristate 13-acetate
- test substance dilution or DMSO dilution 50 / i L to the well, 30 minutes at 37 ° C, C
- the compounds of the present invention showed strong activity against IL-6 and / or TNF a and production inhibitory activity.
- Example 25 the IL-6 and TNFa production inhibitory activity of the compound (4,5-diphenyl-2-oxazolehexanoic acid) obtained in Example 25 (2), which is the carboxylic acid derivative of Example 25, was measured. evaluated. Concentration ranges the test was carried out - in (1 X 10- 5 9 M) , it did not show any effectiveness.
- Test Example 1 the cells from which the culture supernatant was removed in Test Example 1 were prepared in a calo PRMI-1640 medium supplemented with 10% ushi fetal serum (FCS).
- FCS ushi fetal serum
- a 0.5 mg / mL solution of 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (MTT, Sigma) was added to each well and cultured for 3 hours. Centrifuge and cultivate The nutrient solution was removed, 100 ⁇ L of methanol was added to each well, and after cell lysis, the absorbance at a wavelength of 570 nm was measured.
- the compound of the present invention suppresses the production of IL-6 and / or TNF protein of inflammatory site force-in, while having low toxicity to cells. Therefore, the compound of the present invention is useful as a preventive or therapeutic agent for various inflammatory diseases, sepsis, multiple myeloma, osteoporosis, rheumatoid arthritis, Castleman's disease, inflammatory bowel disease, autoimmune diseases and the like.
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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PCT/JP2004/011473 WO2006016399A1 (ja) | 2004-08-10 | 2004-08-10 | ヒドロキサム酸誘導体及びそれを有効成分とする医薬 |
US11/659,810 US7521563B2 (en) | 2004-08-10 | 2004-08-10 | Hydroxamic acid derivative and medicine containing the same as active ingredient |
EP04771460A EP1787986A4 (en) | 2004-08-10 | 2004-08-10 | HYDROXAMINE ACID DERIVATIVE AND MEDICAMENT THEREFORE AS AN ACTIVE COMPONENT |
JP2006531076A JPWO2006016399A1 (ja) | 2004-08-10 | 2004-08-10 | ヒドロキサム酸誘導体及びそれを有効成分とする医薬 |
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PCT/JP2004/011473 WO2006016399A1 (ja) | 2004-08-10 | 2004-08-10 | ヒドロキサム酸誘導体及びそれを有効成分とする医薬 |
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WO2006016399A1 true WO2006016399A1 (ja) | 2006-02-16 |
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US (1) | US7521563B2 (ja) |
EP (1) | EP1787986A4 (ja) |
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WO (1) | WO2006016399A1 (ja) |
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KR101327323B1 (ko) | 2005-01-14 | 2013-11-11 | 에스케이바이오팜 주식회사 | 옥사졸 하이드록삼산 유도체 및 이들의 용도 |
WO2006075888A1 (en) * | 2005-01-14 | 2006-07-20 | Sk Corporation | Oxazole hydroxamic acid derivatives and use thereof |
WO2017151409A1 (en) | 2016-02-29 | 2017-09-08 | University Of Florida Research Foundation, Incorporated | Chemotherapeutic methods |
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JPH09209940A (ja) | 1996-01-30 | 1997-08-12 | Tokico Ltd | ポンプユニット |
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- 2004-08-10 WO PCT/JP2004/011473 patent/WO2006016399A1/ja active Application Filing
- 2004-08-10 JP JP2006531076A patent/JPWO2006016399A1/ja active Pending
- 2004-08-10 EP EP04771460A patent/EP1787986A4/en not_active Withdrawn
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Also Published As
Publication number | Publication date |
---|---|
JPWO2006016399A1 (ja) | 2008-05-01 |
US20070208065A1 (en) | 2007-09-06 |
EP1787986A4 (en) | 2007-08-22 |
US7521563B2 (en) | 2009-04-21 |
EP1787986A1 (en) | 2007-05-23 |
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