WO2007008037A1 - Nouveaux derives d'acide hydroxamique a base de chromene-2-one qui presentent une activite anti-inflammatoire, preparation de ceux-ci et composition contenant ceux-ci, utilisee pour traiter des maladies inflammatoires - Google Patents

Nouveaux derives d'acide hydroxamique a base de chromene-2-one qui presentent une activite anti-inflammatoire, preparation de ceux-ci et composition contenant ceux-ci, utilisee pour traiter des maladies inflammatoires Download PDF

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WO2007008037A1
WO2007008037A1 PCT/KR2006/002743 KR2006002743W WO2007008037A1 WO 2007008037 A1 WO2007008037 A1 WO 2007008037A1 KR 2006002743 W KR2006002743 W KR 2006002743W WO 2007008037 A1 WO2007008037 A1 WO 2007008037A1
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oxo
methyl
chromen
group
hydroxy
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Myung Hwa Kim
Bo Young Joe
Jong Hee Choi
Kwang Hee Kim
Byung Kyu Oh
Kwang Woo Chun
Chun Ho Park
Gyoon Hee Han
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Jeil Pharmaceutical Co Ltd
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Jeil Pharmaceutical Co Ltd
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Priority claimed from KR1020060065157A external-priority patent/KR100794515B1/ko
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation thereof and a composition containing the same for treating inflammatory disease.
  • the inflammation caused by mechanical scars or various infection of bacteria et al is a normal response of human body associated with an edema, a pain etc.
  • the syndrome of arthritic inflammation occurs temporally, however, it causes to long- term and eventual deformity if it is progressed to be severe.
  • the arthritic disease can be classified into several diseases according to the respective disease such as rheumatoid arthritis (RA), rheumatic inflammation related disease etc.
  • RA rheumatoid arthritis
  • rheumatic inflammation related disease etc Among them, in particular, arthritic inflammation is the most frequently occurred and chronic disease characterized in the inflammatory change at the synovial membrane of the inner layer of articular capsule, which may progress to effect on all the joints of human body and become worse to be a disabled person.
  • a progressive arthritic disease such as rheumatic arthritis gives rise to joint obstacle such as a joint aberrance and acampsia, which often results in severe physical disorder caused by
  • OA osteoarthritis
  • the injury of synovial fluid may promotes the dissociation of proteoglycan (PG) as a result of the interaction between synovial cells and cartilage cells.
  • PG proteoglycan
  • the activated synovial cells reproduce numerous factors which may induce the loss of articular cartilage, for example, interleukin-1, tumor necrosis factor (TNF- ⁇ ) and prostaglandins.
  • the direct injury of cartilage cells further accelerates the reproduction of matrix metalloprotease (MMP) activating enzymes such as collagenase, stromelycin and gelatinase and various inflammatory mediators.
  • MMP matrix metalloprotease
  • joint cartilage Wherever the function of joint cartilage reduces, it gives rise to occurring OA diseases.
  • the decrease of PGs at OA joint tissue reduces the resilence of cartilage, which endows cartilage cell, subcar- tilaginous osteocyte and synovial cell with a mechanical stress.
  • Both of OA and rheumatic arthritis (RA) are representative diseases destructing joint cartilage and being characterized in topical erosion of cartilage surface.
  • RA rheumatic arthritis
  • proteinase i.e., serine, cystein, aspartic acid and metalloprotease
  • the metalloprotease one of the proteinase, has been reported to be an important factor for the extra-cellular substrate hydrolyzing action of joint cartilage in OA and PA patients and further the increased activity of colagenase and stromelysin has been found in the cartilage of OA patient, of which activity is closely interrelated with the severity of OA or PA disease (Mankin et al., Arthritis Rheum., 21, pp761-766, (1978); Woessner et al., Arthritis Rheum., 26, pp63-68, (1983) and Ibid., 27, pp305-312, (1984)).
  • Aggrecanase has been also found in OA and PA patient recently and it shows metalloprotease enzyme similar activity and provides with the specific fragmented product of proteoglycans (Lohmander L. S. et al., Arthrits Rheum., 36, ppl214-1222, 1993),
  • TNF Tumor Necrosis Factor
  • TNF-C Tumor Necrosis Factor-Convertase
  • PCT WO 92/213260 Al discloses N-carboxyalkylpeptidyl compounds useful as an enzyme inhibitor of hydroxamates and carboxylates matrix MMP;
  • PCT WO 90/05716 Al and PCT WO 92/13831 Al disclose an hydroxamate matrix colagenase inhibitor;
  • PCT WO 94/2446 Al discloses natural amino acid derivatives useful as an MMP inhibitor;
  • PCT WO 95/9841 Al discloses hydroxamate derivatives useful as a cytokine inhibitor;
  • GB A 2,268, 934 and PCT WO 94/24140 Al disclose a hydroxamate inhibitor of MMP inhibiting TNF reproduction, the disclosure of which cited documents are incorporated herein by reference.
  • NSAID Non-steroidal anti-inflammatory drug
  • aspirin piroxicam
  • indomethacin gold agents
  • aurothioglucose gold sodium thiomalate an auranofin etc
  • anti-rheumatic drug such as chloroquinone, D-penicillamine etc
  • gout inhibitors such as colchicines
  • immuno-suppressing agents such as cyclophosphamide, azathioprine, methotrexate, levamisole etc have been prescribed till now.
  • the treatment with conventional drugs has not provided with satisfactory efficacy and has various adverse effects, which limits the usage of conventional drugs
  • anti-inflammatory drugs such as asprin or butazolin have been used to alleviate the syndrome of OA and PAs, however, the consistent administration of the drugs is difficult because of their adverse effects, for example, i.e., severe stomach irritation resulting in gastritis, stomach ulcer etc.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a novel chromen-2-one based hydroxamic acid derivatives and the pharmacologically acceptable salt thereof as an active ingredient in an effective amount to treat and prevent inflammation diseases.
  • the present invention also provides a use of novel chromen-2-one based hydroxamic acid derivatives and the pharmacologically acceptable salt thereof for the preparation of pharmaceutical composition to treat and prevent inflammatory diseases.
  • the present invention also provides a method of treating or preventing inflammatory disease in a mammal comprising administering to said mammal an effective amount of novel chromen-2-one based hydroxamic acid derivatives and the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof.
  • the present invention provides a novel compound represented by the following general formula (I), the pharmaceutically acceptable salt and the isomer thereof:
  • R is C 1 -C 3 lower alkyl or benzyl group; [22] n is an integer of 0 to 3;
  • X is a nitrogen or carbon atom
  • R , R , R , and R is independently at least one group selected from hydrogen atom, hydroxyl group, nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkenyl or C 1 -C 4 lower alkoxy group;
  • R and R is independently at least one group selected from hydrogen atom, or C 1 -C straight or branched alkyl, alkenyl or alkynyl group substituted with hydrogen atom, nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group, or C -C straight or branched alkyl, alkenyl, alkynyl, or alkoxy group linked with un-substituted phenyl group or substituted phenyl group with A or A 2 group;
  • A is independently at least one group selected from nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group, hydroxyl group, acetyl group, acetoxy group, alkyl carbonyl group, alkyl ester group, or C -C straight or branched alkyl, alkenyl, alkynyl, or alkoxy group substituted with at least one group selected with C -C alkoxy group, C -C dialkylamine, C -C monoalkyl amine or amine group:
  • A is Y-(CH )o-P of which P is at least one group selected from 5 to 7-membered cyclic ring, aryl aromatic ring, heterocyclic ring or fused ring or directly-linked ring with the combination thereof which may be optionally substituted with at least one R' group, of which R 1 is selected from hydrogen atom, nitro group, halogen atom group, amine group, acetamide group, hydroxyl group, carbonamide group, sulfonamide group, carbonyl group, or C -C lower alkyl, alkenyl, or alkoxy group, Y is carbon atom or hetero atom selected from O, N or S, and o is an integer of 1 to 20, provided that both of R and R are not hydrogen atoms simultaneously;
  • X is a nitrogen or carbon atom; R , R , R , R , and R is independently at least one
  • R and R is hydrogen atom and another is independently at least one group selected from C -C straight or branched alkyl, alkenyl or alkynyl, or C -C straight or branched alkyl, alkenyl, alkynyl, or alkoxy group linked with un-substituted phenyl group or substituted phenyl group with A or A group;
  • A is independently at least one group selected from nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group, hydroxyl group, acetyl group, acetoxy group, alkyl carbonyl group, alkyl ester group, or C -C straight or branched alkyl, alkenyl, alkyn
  • the present invention also provides the compounds represented by following general formula (II), the pharmaceutically acceptable salt or the isomer thereof:
  • R is a hydroxyl group, -NHOH; [37] n is an integer of 0 to 3 ; [38] X is a nitrogen or carbon atom; [39] R , R , R , R , and R is independently at least one group selected from hydrogen atom, hydroxyl group, halogen atom group, amine group, C -C lower alkyl, C -C lower alkenyl or C 1 -C 4 lower alkoxy group;
  • R 8 and A 3 is hydrogen atom, or an un-substituted or substituted C 1 -C 20 straig °ht or branched alkyl alkenyl or alkynyl group with independently at least one group selected from hydrogen atom, nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group or phenyl group, provided that both of R 8 and
  • A are not hydrogen atoms simultaneously
  • n is an integer of 0 to 2; R , R , R , R , and R is independently at least one group selected from hydrogen atom, hydroxyl group, halogen atom group, amine group, C 1 -C 4 lower alkyl, C -C lower alkenyl or, C -C lower alkoxy group; one of R 8 and A 3 is hydrogen atom and another is independently at least one group selected from hydrogen atom, or an , un-substituted or substituted C -C straight or branched alkyl alkenyl group with independently at least one group selected from hydrogen atom, nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group or phenyl group, are more desirable.
  • the most preferred compound of general formula (II) is one selected from the group consisting of;
  • the present invention also provides the compounds represented by following general formula (III), the pharmaceutically acceptable salt or the isomer thereof:
  • R is a hydroxyl group, -NHOH
  • n is an integer of 0 to 3 ;
  • m is an integer of 1 to 10;
  • X is a nitrogen or carbon atom
  • R , R , R , and R is independently at least one group selected from hydrogen atom, hydroxyl group, halogen atom group, amine group, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkenyl or C 1 -C 4 lower alkoxy group;
  • A is independently at least one group selected from nitro group, halogen atom group, amine group, acetamide group, carbonainide group, sulfonamide group, hydroxyl group, acetyl group, acetoxy group, alkyl carbonyl group, alkyl ester group, or C 1 -C 20 straight or branched alkyl, alkenyl, alkynyl, or alkoxy group substituted with at least one group selected with C 1 -C 5 alkoxy group, C 1 -C 5 dialkylamine, C 1 -C 5 monoalkyl amine or amine group.
  • R is -NHOH; n is an integer of 0 to 2; m is an integer of 1 to 5; R , R , R , and R is independently at least one group selected from hydrogen atom, halogen atom group, amine group, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkenyl or C 1 -C 4 lower alkoxy group; A is independently at least one group selected from nitro group, halogen atom group, amine group, acetamide group, carbonamide group, sulfonamide group, hydroxyl group, acetyl group, acetoxy group, alkyl carbonyl group, alkyl ester group, or C 1 -C 10 straight or branched alkyl, alkenyl, alkynyl, or alkoxy group substituted with at least one group selected with C 1 -C 5 alkoxy group, C 1 -
  • the most preferred compound of general formula (III) is one selected from the group consisting of; [82] N- hydroxy-4-(4-hydroxy-phenyl)-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-butylaniid e, [83] 6-[4-(3-hydroxy-propoxy)-phenyl]-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-he xanoic acid hydroxyamide, [84] 6-[4-(3-methoxy-propoxy)-phenyl]-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-he xanoic acid hydroxyamide, [85] Acetic acid 4-[3-hydroxycarbainoyl-4-(6-methyl-2-oxo-2H-chromen-3-yl)-butyl] - phenyl ester, [86] 2-[3-(2-dimethylamino-ethoxy)-
  • R is a hydroxyl group, -NHOH
  • n is an integer of 0 to 3;
  • m is an integer of 1 to 10;
  • X is independently selected from a nitrogen or carbon atom
  • R , R , R , and R is independently at least one group selected from hydrogen atom, hydroxyl group, halogen atom group, amine group, C -C lower alkyl, C -C lower alkenyl or C -C lower alkoxy group;
  • P is 5 to 7-membered cyclic ring, aryl ring, heterocyclic ring or the fused ring or directly-linked ring with the combination thereof, which may be optionally substituted with at least one R' group, of which R' is selected from hydrogen atom, nitro group, halogen atom group, C -C dialkylamine, C -C monoalkylamine, amine group, acetamide group, acetoxy group, hydroxyl group, carbonamide group, sulfonamide group, carbonyl group, or C -C alkyl, alkenyl, or alkoxy group,
  • Y is O, N or C atom
  • [116] o is an integer of 1 to 6.
  • R is hydroxyl group, -NHOH; n is an integer of 0 to 2; m is an integer of 1 to 5; X is carbon atom; R , R , R , R , and R is independently at least one group selected from hydrogen atom, hydroxyl group, halogen atom group, amine group, C -C lower alkyl, C -C lower alkenyl or C -C lower alkoxy group; P is 5 to 7-membered aromatic ring such as phenyl ring, cyclic ring such as cyclopentane, cy- clohexane, heterocyclic ring such as pyrrole, piperidine, piperazine, pyrimidine, pyridazine, pyrrolidine, morpholine, thiazole an the like or the fused ring such as 10 to
  • quinoline 20-membered quinoline, quinazoline, indole and the like, which may be optionally substituted with at least one group selected from hydrogen atom, halogen atom group, amine group, hydroxyl group, carbonyl group, or C -C alkyl, alkenyl, or alkoxy group;
  • Y is O, N or C atom, and o is an integer of 1 to 5, are more desirable.
  • the most preferred compound of general formula (IV) is one selected from the group consisting of; [119] 2-(4-benzyloxy-benzyl)-N-hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-pro ⁇ iona mide, [ 120] 4-(4-benzyloxy-phenyl)-N-hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-b utyr amide, [121] 2-(3-benzyloxy-benzyl)-N-hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-propiona mide [122] 4-(3-benzyloxy-phenyl)- ⁇ /-hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-b utyr amide, [123] N- hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2--pro
  • inventive compounds represented by general formula (I) to (IV) can be transformed into their pharmaceutically acceptable salt and solvates by the conventional method well known in the art.
  • acid-addition salt thereof formed by a pharmaceutically acceptable free acid thereof is useful and can be prepared by the conventional method.
  • the salts are precipitated by the water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile to prepare acid addition salt thereof and further the mixture of equivalent amount of compound and diluted acid with water or alcohol such as glycol monomethylether, can be heated and subsequently dried by evaporation or filtrated under reduced pressure to obtain dried salt form thereof.
  • organic acid or inorganic acid can be used as a free acid of above-described method.
  • organic acid such as methansulfonic acid, p-toluensulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonylic acid, vanillic acid, hydroiodic acid and the like, and inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used herein.
  • the pharmaceutically acceptable metal salt form of inventive compounds may be prepared by using base.
  • the alkali metal or alkali-earth metal salt thereof can be prepared by the conventional method, for example, after dissolving the compound in the excess amount of alkali metal hydroxide or alkali-earth metal hydroxide solution, the insoluble salts are filtered and remaining filtrate is subjected to evaporation and drying to obtain the metal salt thereof.
  • sodium, potassium or calcium salt are pharmaceutically suitable and the corresponding silver salt can be prepared by reacting alkali metal salt or alkali-earth metal salt with suitable silver salt such as silver nitrate.
  • the pharmaceutically acceptable salt of the compound represented by general formula (I) to (IV) comprise all the acidic or basic salt which may be present at the compounds, if it does not indicated specifically herein.
  • the pharmaceutically acceptable salt of the present invention comprise the salt of hydroxyl group such as the sodium, calcium and potassium salt thereof; the salt of amino group such as the hydrogen bromide salt, sulfuric acid salt, hydrogen sulfuric acid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetate salt, succinate salt, citrate salt, tartarate salt, lactate salt, mandelate salt, methanesulfonate(mesylate) salt and p - toluenesulfonate (tosylate) salt etc, which can be prepared by the conventional method well known in the art.
  • the compounds of the present invention comprise all the optically active isomers, R or S stereoisomers and the mixtures thereof.
  • Present invention also comprises all the uses of racemic mixture, more than one optically active isomer or the mixtures thereof as well as all the preparation or isolation method of the diastereomer well known in the art.
  • the compounds of the invention of formula (I) to (IV) may be chemically synthesized by the methods which will be explained by following reaction schemes hereinafter, which are merely exemplary and in no way limit the invention.
  • the reaction schemes show the steps for preparing the representative compounds of the present invention, and the other compounds also may be produced by following the steps with appropriate modifications of reagents and starting materials, which are envisaged by those skilled in the art.
  • 1-chlorocarbonyl butyric acid methyl- 1 -ester under an organic solvent in the presence of base such as triethylamine, diethylisopropylamine etc to synthesize compound (II).
  • base such as triethylamine, diethylisopropylamine etc
  • an organic solvent such as dichloromethane, chloroform etc is preferable and the base in the amount of 2 to 3 equivalents to the compound (I) can be used. It is preferable the reaction is performed at the temperature ranging from 0 0 C to R. T.
  • step 1 the compound (II) obtained in step 1 is reacted with DBU
  • step 2 the compound (III) obtained in step 2 is reacted with LIHMDS (Lithium hexamethyldisilazane) and alkylating agent such as methyl iodide, aryl bromide, benzyl bromide etc under organic solvent such as THF, diethyl ether etc to afford the compound (IV).
  • LIHMDS Lithium hexamethyldisilazane
  • alkylating agent such as methyl iodide, aryl bromide, benzyl bromide etc under organic solvent such as THF, diethyl ether etc.
  • organic solvent such as THF, diethyl ether etc
  • step 3 the compound (IV) obtained in step 3 is reacted with hydroxyl amine or amine salt to synthesize purposed compound (V) in case that X is NHOH in general formula I compounds.
  • step 3 it is preferable to use potassium hydroxamide (KONH ) in the amount of 2 to 3 equivalents to the compound (IV) at the temperature ranging from 0 0 C to R. T.
  • R1 H, Cl 1 F. Me, OMe
  • 2,2-dimethyl-l,3-dioxane-4,6 ⁇ dione is reacted with borane dimethylamine chelating agent under an dried alcohol solution to synthesize compound (VII).
  • an alcohol solution such as methanol, ethanol etc is preferable and it is preferable the reaction is generally performed at R. T.
  • step 2 the compound (VII) obtained in step 1 is reacted with N,N-dimethyl methylene ammonium iodide salt under an organic solvent to synthesize the compound (VIII) through Mannich reaction.
  • an organic solvent such as methanol, ethanol, benzyl alcohol etc are preferable and it is preferable the reaction is performed at about 65 0 C regardless of using solvent.
  • step 2 the compound (VIII) obtained in step 2 is reacted with triethylphospho- noacetate (TEPA) under an organic acid such as THF in the presence of base such as sodium hydride etc to afford the compound (IX).
  • TEPA triethylphospho- noacetate
  • the base in the amount of 1.2 to 1.5 equivalents to TEPA is preferable and it is s preferable the temperature of the reaction starts from 0 0 C to form TEPA anion and increases to R. T. to react with acrylate.
  • step 3 the compound (IX) obtained in step 3 is dissolved in organic solvent, preferably, THF, reacted with t-lithium butoxide for about 30 mins and the reaction mixture is reacted with aldehyde compound to synthesize compound (X). It is preferable that the reaction is performed at R. T. and the salt in the amount of 1 to 2 equivalents to the compound (IX) is preferably used.
  • organic solvent preferably, THF
  • step 4 the compound (X) obtained in step 4 is subjected to de-protection step under acid solution such as hydrochloric acid and then to cyclization step under appropriate organic solvent such as xylene etc at high temperature such as at about 16O 0 C to synthesize compound (XI).
  • acid solution such as hydrochloric acid
  • cyclization step under appropriate organic solvent such as xylene etc at high temperature such as at about 16O 0 C to synthesize compound (XI).
  • step 5 the compound (XI) obtained in step 5 is subjected to similar procedure to the 4 l step preparing compound (V) in above Scheme 1 to synthesize compound ( XII).
  • 2-dimethyl-l,3-dioxane-4,6-dione is dissolved in appropriate solvent such as dried dichloromethane and DCC dissolved in dried dichloromethane is dropwisely added thereto under an inert solvent to synthesize compound (XIV).
  • an inert solvent such as dichlromethane, chloroform etc is preferable and it is preferable the reaction is generally performed in the temperature ranging from cold temperature to R. T.
  • step 2 the compound (XIV) obtained in step 1 is dissolved in appropriate solvent such as dichloromethane with cooling and mixture of acetic acid and sodium borohydride are dropwisely added thereto under an organic solvent to synthesize the compound (XV).
  • appropriate solvent such as dichloromethane
  • an organic solvent which do not harmful affect on the reaction such as dichloromethane, chloroform, tetrahydrofuran, diethylether etc are preferable and it is preferable the reaction is performed performed in the temperature ranging from cold temperature to R. T.
  • the compound (XIX) can be synthesized from the compound (XV) obtained in step 2 with similar method to the condition consisting of four steps to prepare compound (XI) disclosed in Scheme 2.
  • step 6 the compound (XIX) obtained in step 6 is dissolved in an organic solvent, preferably, ethylacetate, and reacted with reducing agent such as 10% Pd/C under H gas at R. T. to synthesize compound (XX) under an organic solvent such as methanol, ethanol, THF etc.
  • an organic solvent such as methanol, ethanol, THF etc.
  • the compound (XX) obtained in step 7 is reacted with piperidine alkyl chloride HCl salt in the presence of base to synthesize compound (XXI).
  • catalytic amount of sodium iodide or potassium iodide can be used in the reaction.
  • the reaction is preferably performed under the organic solvent which does not harmful affect on the reaction, for example, DMF, alcohol such as methanol, ethanol etc or water in the temperature ranging from R.T. to warm temperature, preferably, warm temperature.
  • step 8 the compound (XXI) obtained in step 8 is subjected to similar procedure to the 4 th step preparing compound (V) in above Scheme 1 to synthesize compound ( XXII).
  • the compound (XXa) which can be obtained by the procedure disclosed in Scheme 3 is reacted with tosyl alkyl chloride in the presence of base such as potassium carbonate etc to synthesize compound (XXI).
  • base such as potassium carbonate etc
  • the base in the reaction such as sodium carbonate, potassium carbonate, cesium carbonate, etc with the catalytic amount can be preferably used under an organic solvent which do not harmful affect on the reaction, for example DMF, alcohol such as methanol, ethanol etc or acetone in the temperature ranging from R.T. to warm temperature, preferably, warm temperature.
  • step 2 the compound (XXI) obtained in step 1 is reacted with pyrrolidine under identical solvent and base with those used in step 1, to synthesize the compound (XXII).
  • the reaction is performed in the temperature ranging from R.T. to warm temperature, preferably, warm temperature.
  • step 2 the compound (XXII) obtained in step 2 is subjected to similar procedure to the 4 th step preparing compound (V) in above Scheme 1 to synthesize compound (XXIII).
  • aldehyde compound (XXV) is synthesized from compound (
  • 2-(4-benzyloxy-phenyl)-ethylamine hydrochloride is dissolved in organic solvent such as THF.
  • organic solvent such as THF.
  • Triethylamine is added thereto prepared by the procedure well-known in the art and reacted with condensation to synthesize imine compound.
  • an organic solvent which does not harmful effect on the condensation reaction such as toluene, benzene, alcohol, water etc together with generally used base in condensation of amine and aldehyde such as diisopropylamine, pyridine, piperidine etc are preferable and it is preferable the reaction is performed in the temperature ranging from R.T. to warm temperature, preferably, warm temperature.
  • the imine compound is dissolved in organic solvent such as mixture of methanol and THF and reducing agent such as acetic acid and sodium cyanoborohydride are added thereto to synthesize secondary amine compound (XXVI).
  • organic solvent such as mixture of methanol and THF
  • reducing agent such as acetic acid and sodium cyanoborohydride
  • a reducing agent such as potassium borohydride, sodium hydride etc can be used and an organic solvent which does not harmful effect on the reaction such as alcohol, toluene, benzene, THF, alcohol etc are preferable and it is preferable the reaction is performed in the temperature ranging from cooled temperature to R.T.
  • step 3 the compound (XXVI) obtained in step 3 and di-tert-butyl dicarbonate dissolved in an organic solvent, preferably, dichloromethane, are reacted with aminopyridine to synthesize compound (XXVII).
  • organic solvent preferably, dichloromethane
  • step 4 the compound (XXVII) obtained in step 4 is dissolved in ethylacetate and subjected to reduction in the presence of Pd/C under H2 gas to synthesize compound (XXVIII). Both of steps 4 and 5 may be subjected to reaction under the condition of de-benzylation reaction of alcohol and introduction condition of amine protecting group.
  • step 5 the compound (XXVIII) obtained in step 5 is reacted with
  • the base which may be used in ether formation reaction, i.e., etherification reaction between alcohol and alkyl halide is preferably used and the reaction is preferably performed under the organic solvent which does not harmful affect on the reaction, for example, dichloromrthane, chloroform, THF, diethylether, toluene, DMF, benzene etc in the temperature ranging from cooled temperature to R.T.
  • step 6 the compound (XXIX) obtained in step 6 is subjected to deprotection reaction of amine using acid preferably, 4N-HC1 solution to afford compound (XXX).
  • step 7 the compound (XXX) obtained in step 7 is dissolved in pyridine and reacted with hydroxycarbamic acid phenyl ester in the temperature ranging from R.T. to warm temperature to synthesize compound (XXXI).
  • the compound (XXXIII) obtained in step 1 is reacted with me- sylchloride under an organic solvent in the presence of base to synthesize the compound (XXXIV).
  • the base in the reaction such as diisopropylamine, pyridine, piperidine etc can be preferably used under an organic solvent which does not harmful effect on the reaction, for example toluene, THF, ether, chloroform, etc in the temperature ranging from cooled temperature to R.T. to warm temperature.
  • the compound (XXXIV) obtained in step 2 dissolved in DMF is subjected to condensation with diethyl nialonate in the presence of base to synthesize the compound (XXXV).
  • the base such as calcium carbonate, sodium hydride, cesium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide etc is used under an organic solvent which does not harmful effect on the reaction, for example toluene, alcohol, dichloromethane, etc in the temperature ranging from R.T. to warm temperature, preferably, warm temperature.
  • step 3 the compound (XXXV) obtained in step 3 is hydrolyzed to produce the compound (XXXVI).
  • equivalent amount of potassium hydroxide to the compound (XXXV) dissolved in ethanol under cooled temperature is dropwisely added thereto at R. T. to synthesize the compound (XXXVI).
  • the compound (XXXVI) obtained in step 4 is reacted under base in formaldehyde solution to produce the compound (XXXVII).
  • the base such as diethyl amine, ethyl amine HCl, piperidine, diethyl amine, pyridine etc is used under an organic solvent which does not harmful effect on the reaction, for example water, DMSO, ethanol, DMF, etc in the temperature ranging from R.T. to warm temperature, preferably, warm temperature.
  • step 5 the compound (XXXVII) obtained in step 5 is subjected to similar procedure to the steps preparing compound (XIX) from the compound (XVI) disclosed in above Scheme 3 to synthesize compound (XXXVIII).
  • step 6 the compound (XXXVIII) obtained in step 6 is oxidized using PDC to compound (XXXIX), which is subjected to similar procedure to the steps preparing compound (XXVI) from the compound (XXV) disclosed in above Scheme 5 to synthesize compound (XXXX).
  • step 7 the compound (XXXX) obtained in step 7 is subjected to similar procedure to the 4 ! step preparing compound (V) from the compound (IV) disclosed in above Scheme 1 to synthesize compound (XXXXI).
  • novel chromen-2-one based hydroxamic acid prepared by the above-described method represented by general formulae (I) to (IV) shows strong inhibiting activity for the reproduction of TNF- ⁇ , therefore the compounds can be useful in treating or alleviating pain diseases or inflammatory diseases, specifically, the disease caused by over-production of TNF- ⁇ .
  • composition comprising an efficient amount of the compound represented by general formula (I) to (TV) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to inhibit the over-production of TNF- ⁇ together with pharmaceutically acceptable carriers or diluents.
  • It is another object of the present invention to provide the pharmaceutical composition comprising an efficient amount of the compound represented by general formula (I) to (IV) or the pharmaceutically acceptable salt thereof as an active ingredient in amount effective to alleviate or treat pain diseases or inflammatory diseases, specifically, the disease caused by over-production of TNF- ⁇ together with pharmaceutically acceptable carriers or diluents.
  • a method of inhibiting over-production of TNF- ⁇ comprising administering a therapeutically effective amount of the compound represented by general formula (I) to (IV) or the pharmaceutically acceptable salt thereof into the mammals including human suffering from said the disease caused by over-production of TNF- ⁇ .
  • a method of treating or alleviating pain diseases or inflammatory diseases comprising administering a therapeutically effective amount of the compound represented by general formula (I) to (IV) or the pharmaceutically acceptable salt thereof into the mammals including human suffering from said diseases, specifically, the disease caused by over-production of TNF- ⁇ .
  • TNF- ⁇ disclosed herein comprises arthritis, for example, rheumatic arthritis, spondy- loathopathies, gout, osteoarthritis, SLS (systemic lupus erythematosus) and juvenile arthritis, preferably, rheumatic arthritis, gout etc.
  • inflammatory disease especially "inflammatory disease caused by overproduction of TNF- ⁇ ” disclosed herein comprises myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, burns, inflammatory bowel disease, Crohn's disease, type I diabetes, psoriasis, preferably, gingivitis, synovitis etc.
  • the compound according to the present invention can be provided as a phar- maceutical composition containing pharmaceutically acceptable carriers, adjuvants or diluents.
  • the compound of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection.
  • suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them.
  • the compound of the present invention can be formulated in the form of ointments and creams.
  • the compound of the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the compound of the present invention may be formulated into preparations for injections by dissolving, suspending, or emulsifying them in aqueous solvents such as normal saline, 5% Dextrose, or non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • aqueous solvents such as normal saline, 5% Dextrose, or non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • the formulation may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the desirable dose of the inventive compound varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount ranging 0.0001 - 100 mg/kg, preferably 0.001 100 mg/kg by weight/day of the inventive compound of the present invention.
  • the dose may be administered in single or divided into several times per day.
  • the compound should be present between 0.0001 to 50% by weight, preferably 0.0001 to 10% by weight based on the total weight of the composition.
  • composition of present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) via various routes.
  • a subject animal such as mammals (rat, mouse, domestic animals or human)
  • AU modes of administration are contemplated, for example, administration can be made by inhaled, orally, rectally or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection.
  • the present invention provides a novel chromen-2-one based hydroxamic acid derivatives and the pharmacologically acceptable salt thereof showing strong inhibiting activity for the reproduction of TNF- ⁇ .
  • the present invention also provides a pharmaceutical composition comprising a novel chromen-2-one based hydroxamic acid derivatives and the pharmacologically acceptable salt thereof as an active ingredient in an effective amount to treat and prevent inflammation diseases.
  • Fig. 1 shows the effects of the compound in example 113 (10, 30 and lOOmg/kg) on TNF- ⁇ reproduction
  • Fig. 2 shows the effects of the compound in example 113(30mg/kg) on TNF- ⁇ reproduction
  • Fig. 3 presents the toxicity tests of the compound in example 113 on female mice
  • Fig. 4 presents the toxicity tests of the compound in example 113 on male mice
  • Example 23 2-(6-methyI-2-oxo-2H-chromen-3-yImethyl)-dodecanoic acid hydroxyamide [373]
  • Example 24 3-
  • Example 28 N - hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2-[4-(2-morpholin-4-yl-etoxy)-benz yl]-propionamide [391]
  • Example 29 N - hydroxy-3-(6-methy-2-oxo-2H-chromen-3-yl)-2-[4-(3-morpholin-4-yl-propoxy)-be nzyl]-propionamide
  • Example 30 V -hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2-[4-(
  • Example 31 N - hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2-[3-(3-pyridin-4-yl-propoxy)-benz yl]-propionamide [394]
  • Example 32 N - hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2-[3-(3-morpholin-4-yl-propoxy)-be nzyl] -propionamide [395]
  • Example 33 N - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(2-piperidin-l-yl-ethoxy
  • Example 35 N - hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2-[3-(3-piperidin-l-yl-propoxy)-ben zyl]-propionamide [398]
  • Example 36 N - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(3-morpholin-4-yl-prop oxy)-phenyl] -butyramide [399]
  • Example 37 N hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(3-morpholin-4-yl-prop oxy)-phenyl] -butyramide
  • Example 46 JV - hydroxy-3-(6-methyl-2-oxo-2H-chromen-3-yl)-2-[3-(2-methyl-quinolin-4-yl-metho xy)-benzyl]-propionamide [409]
  • Example 47 JV - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[3-(4-pyridin-4-yl-butoxy)- phenyl]-butyramide [410]
  • Example 48 Example 48.
  • Example 51 JV - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(3-piperidin-l-yl-propo xy)-phenyl]-butyramide [414]
  • Example 53 Example 53.
  • Example 72 4-[4-(2-diethylamino-ethoxy)-phenyl]- N - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-butyramide [434]
  • Example 72 4-[4-(2-diisopropylamino-ethoxy)-phenyl]- N - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-butyramide [435]
  • Example 73 N -hydroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[3-(2- piperidin-l-yl-ethoxy)-phenyl]-butyramide [436]
  • Example 74 4-[4-(2-diethylamino-ethoxy)-phenyl]- N - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-butyramide [4
  • Example 90 4-[3-hydroxycarbamoyl-4-(6-methyl-2-oxo-2H-chromen-3-yl)-butyl]-phenyl ester [452]
  • Example 90 iV - hydroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-4- ⁇ 4-[3-(4-methyl-piperazin- l-yl)-propoxy]-phenyl ⁇ -butyramide [453]
  • Example 91 4-[4-(2-diethylamino-ethoxy)-phenyl]- N - hydroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-butyramide [454]
  • Example 92 4-[3-hydroxycarbamoyl-4-(6-methyl-2-oxo-2H-chromen-3-yl)-butyl]-phenyl ester [452]
  • Example 90 iV - hydroxy-2-(7
  • Example 94 2-(7-fluoro-2-oxo-2H-chromen-3-ylmethyl)- N -hydroxy-4-[4-(2- morpholin-4-yl-ethoxy)-phenyl]-butyramide [457]
  • Example 95 2-(7-chloro-2-oxo-2H-chromen-3-ylmethyl)- JV -hydroxy-4-[4-(3- piperidin-l-yl-propoxy)-phenyl]-butyramide [458]
  • Example 96 2-(7-fluoro-2-oxo-2H-chromen-3-ylmethyl)- N -hydroxy-4-[4-(2- morpholin-4-yl-ethoxy)-phenyl]-butyramide [457]
  • Example 95 2-(7-chloro-2-oxo-2H-chromen-3-ylmethyl)- JV -hydroxy-4-[4-(3- piperidin-l-yl-propoxy)-phenyl
  • Example 102 N - hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4- ⁇ 4-[3-(4-oxo-piperidin-l-yl )-propoxy]-phenyl ⁇ -butyramide [476]
  • Example 103 N -hydroxy-2-(6-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(3- pyrrolidin-l-yl-propoxy)-phenyl]-butyramide [477]
  • Example 104 Example 104 .
  • Triethylphosphonoacetate (21ml, 104.71mmol) was dissolved in dried THF (300ml. Thereafter, the temperature was lowered to 0°C. thereto sodium hydride (4.2g, 104.71mmol) was added, and the reaction mixture was stirred for 1 hour.
  • Step 10 Preparation of N- hydroxy-2-(6-methyl-2-oxo-2H-cromen-3-ylmethylV4-r4-(3-morpholin-4-yl-propylam ino)-phenyl1-butyramide
  • Example 110 JV -hydroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(2- morpholin-4-yl-ethoxy)-phenyl]-butyramide hydrochloride [532]
  • Example 111 JV -hydroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(3- morpholin-4-yl-propoxy)-phenyl]-butyramide hydrochloride [533]
  • Step 7 Preparation of (2-r4-(2-diethylamino-ethoxyVphenyl1 - ethyll-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-carbamic acid tert-butyl ester
  • Step 8 Preparation of 3-( ⁇ 2-r4-(2-diethylamino-ethoxy)-phenyn - ethylamino ⁇ -methyl)-7-methyl-chromen-2-one [565]
  • Step 9 Preparation of (2-r4-(2-diethylamino-ethoxy)-phenyl1 - ethyl ⁇ -(7-methyl-2-oxo-2H-chromen-3-vlmethyl)-amine- N -carbohvdroxamic acid
  • Step 1 Preparation of methyl 2-(4-[4-(tert-butyldimethylsilanyloxyV butyl] phenyl) acetate
  • Step 7 Preparation of ethyl 4- ⁇ 4-r3-(tert-butyl-dimethyl-silanyloxy)-propyl1 - phenyl ⁇ -2-methylene-butyric acid ethyl ester
  • Step 8 Preparation of 2-(2- ⁇ 4-[4-( tert -butyl-dimethvi-silanyloxy)- butyl] - phenyl ⁇ -ethyl) -4-(dimethoxy-phosphonyl)-pentanedioic acid diethyl ester [619]
  • Step 11 Preparation of 4-r4-f4-tert-butvldimethvlsirvlbutyl)phenyl] - 2-r(7-methyl-2-oxo-2H-chromen-3-yl)methyllbutyric acid ethyl ester and 4-[4-(4-hydroxybutyl)phenethyl1-2-[(7-methyl-2-oxo-2H-chromen-3-yl)methyllbutyric acid ethyl ester
  • Step 14 Preparation of 2-(7-methyl-2-oxo-2H-chromen-3-ylmethyl)-4-[4-(4- piperidin-1-yl-butylVphenyli- butyric acid ethyl ester
  • Step 15 Preparation of iV-hvdroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethylV4- r4-(4-piperidin- 1 -yl-butyl)- phenyl] -butyramide
  • Step 16 Preparation of N - hydroxy-2-(7-methyl-2-oxo-2H-chromen-3-ylmethylV4-[4-(4-piperidin-l-yl-butyl)-ph eny 11 -butyramide hydrochloride
  • Step 1 Preparation of glucotaconic acid diethyl ester
  • Glutaconic acid (Ig, 9.7mmol) was dissolved in ethanol (20ml). Catalytic amount of sulfuric acid was added thereto. The reaction mixture was refluxed for 12 hour. The resultant was concentrated under reduced pressure to remove solvent, and dissolved in ethyl acetate. Combined organic layer was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.3g (yield: 90.0%, white solid) of the target compound.
  • the amount of formed fluorescent material was determined by two spectroscopic method, i.e., Perkin-Elmer LS50B (method 1) and Perkin-Elmer Wallac 2100 En VisionTM Microplate Reader (method 2) to compare with negative control group.
  • Mca product, a photoreactor showed fluorescence and it was absorbed at two excitation wavelengths, i.e., 324 nm (method 1) or 340 nm (Method 2) to determine at two fluorescence regions, i.e., 420nm (method 1) or 400 nm (Method 2) which are closely correlated with enzyme activity.
  • Table 8 (Method 1) and Table 9 (Method 2) it has been confirmed that compounds of the present invention showed potent TACE inhibition activity.
  • RAW 264.7 cells ATCC, USA
  • a mouse macrophage cell line was seeded onto each well of 96-well microtiter plate (Nunc, Sweden) to the concentration ranging 5x10 cells/ml, and incubated in DMEM/HG (Dulbeco's modified eagles medium) media containing 10% FBS (fetal bovine serum) at 37°C in 5% CO incubator and cultured at 37°C for 24 hours.
  • DMEM/HG Dulbeco's modified eagles medium
  • FBS fetal bovine serum
  • the cell was treated with various concentrations of the compounds of the present invention ranging from 0.1 to 10 mM and LPS (Sigma, USA) in the final concentration of 1 mg/ml to activate the cell simultaneously.
  • the treated cells were cultured at 37 0 C for 24 hours in 5% CO incubator and the cultured cells were collected at 24 hours
  • mice (mean body weight 25 ⁇ 5g, CORE TECH Inc.) was performed using by the compounds in Example 113.
  • Various dose of test samples (50mg/kg, 100mg/kg, 150mg/kg and 200mg/kg) dissolved in distilled water as shown in Table 13 and water were intravenously administrated into five groups consisting of 10 mice (five male and 5 female), i.e., T2, R3, T4 and T5 (test groups) and Tl (negative control group) and the mortality, clinical signs, body weight changes and gross findings in mice were observed for 1 week.
  • mice were divided into four groups consisting of 5 rats for each group, i.e., Tl treated with only solvent as a negative control group, T2 treated with 10mg/kg of in- domethacin, T3 treated with 30mg/kg of the compound in Example 113 and T4 treated with 100mg/kg of the compound in Example 113 respectively.
  • Indomethacin was diluted with mixture solution of DMSO, Tween 80 and H O (1:4:95) to use as a positive control group and the compound prepared in Example 113 was diluted with mixture solution of ethanol, PEG(polyethylene glycol) 400 and H 0(5:20:75) to use as a test group.
  • the thickness ratio of ankle ⁇ %) [(maximum thickness of rat paw edema) -(the thickness of pre-treated rat paw edema) /(the thickness of pre- treated rat paw edema) ] x 100
  • a novel chromen-2-one based hydroxamic acid derivatives have strong inhibiting activity for the reproduction of TNF- ⁇ therefore, it can be used as the therapeutics for treating and preventing inflammatory diseases.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés d'acide hydroxamique à base de chromène-2-one qui présentent une activité anti-inflammatoire, ainsi que la préparation de ceux-ci et une composition contenant ceux-ci, utilisée pour traiter des maladies inflammatoires.
PCT/KR2006/002743 2005-07-12 2006-07-12 Nouveaux derives d'acide hydroxamique a base de chromene-2-one qui presentent une activite anti-inflammatoire, preparation de ceux-ci et composition contenant ceux-ci, utilisee pour traiter des maladies inflammatoires Ceased WO2007008037A1 (fr)

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KR10-2005-0062827 2005-07-12
KR20050062827 2005-07-12
KR10-2006-0065157 2006-07-12
KR1020060065157A KR100794515B1 (ko) 2005-07-12 2006-07-12 항염증 활성을 갖는 크로멘-2-온 모핵 히드록사민 산유도체, 이의 제조방법 및 이를 포함하는 염증 질환의치료를 위한 조성물

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012005229A1 (fr) 2010-07-08 2012-01-12 科研製薬株式会社 Dérivé de n-hydroxyformamide et produit pharmaceutique le contenant
CN106946897A (zh) * 2017-02-28 2017-07-14 牡丹江医学院 一种治疗胆囊炎的药物及其应用
CN114349633A (zh) * 2018-04-13 2022-04-15 华烁科技股份有限公司 戊烯二酸二酯的制备方法

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EP0736529A1 (fr) * 1995-04-05 1996-10-09 F. Hoffmann-La Roche Ag Réactifs améliorés pour essais immunologiques pour la détection de cannabinoides
WO2002085882A1 (fr) * 2001-04-24 2002-10-31 Arxy Therapeutics Derives de coumarine pouvant etre utilises comme anticoagulants

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EP0736529A1 (fr) * 1995-04-05 1996-10-09 F. Hoffmann-La Roche Ag Réactifs améliorés pour essais immunologiques pour la détection de cannabinoides
WO2002085882A1 (fr) * 2001-04-24 2002-10-31 Arxy Therapeutics Derives de coumarine pouvant etre utilises comme anticoagulants

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012005229A1 (fr) 2010-07-08 2012-01-12 科研製薬株式会社 Dérivé de n-hydroxyformamide et produit pharmaceutique le contenant
CN106946897A (zh) * 2017-02-28 2017-07-14 牡丹江医学院 一种治疗胆囊炎的药物及其应用
CN114349633A (zh) * 2018-04-13 2022-04-15 华烁科技股份有限公司 戊烯二酸二酯的制备方法

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