JPH11124331A - Antiinflammatory agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antiinflammatory agent containing a specific compound, effective for lowering the formation and activity of a specific factor in tissue, useful as an agent for the prevention and treatment of diseases relating to the specific factor e.g. diabetic complications such as retinopathy or inflammatory diseases such as rheumatoid arthritis and having low side effect. SOLUTION: This agent contains a compound of the formula [R is a (substituted)hydrocarbon group, etc.; Y is CO, etc.; (m) is 0 or 1; (n) is 0-2; X is CH or N; A is a bond, etc.; Q is oxygen atom, etc.; R<1> is H, etc.; L and M are each H, etc.] or its salt and exerts its action through a TNF(tumor necrosis factor)-α suppressing effect. A preferable example of the compound of the formula is 5-[4-[2-(5-ethyl-2-pyridyl) ethoxylbenzyl]-2,4-thiazolidinedione and its salt is preferably hydrochloride, etc. It is preferably administered at about 2-20 mg/kg per dose and 1-3 doses per day in the case of oral administration to adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an anti-inflammatory agent useful as an agent for preventing and treating inflammatory diseases involving TNF (tumor necrosis factor) -α.

[0002]

2. Description of the Related Art For example, the following documents 1) to 4) are known regarding the relationship between TNF-α and thiazolidine derivatives. 1) JP-A-7-285864 describes that a thiazolidine derivative suppresses the production and response of TNF. 2) The latest medicine, Vol. 52, No. 6, pp. 95-102 states that thiazolidine derivatives reduce the expression of TNFα,
Improving insulin resistance by α has been described. 3) Endocrinology, 134
Vol. 1, pp. 264-270, 1994, that the overexpression of TNFα and its receptor mRNA was at least partially normalized by treating diabetic animals with the insulin sensitizer pioglitazone. Are listed. 4) Endocrinology, 136
Vol. 4, No. 1, pp. 1474-1481, 1995, describe that insulin sensitizers provide anti-diabetic activity by antagonizing the inhibitory effect of TNFα.

On the other hand, regarding the relationship between inflammatory diseases and thiazolidine derivatives, for example, the following documents 5) to 6) are known. 5) WO 96/34943 describes a method for treating autoimmune, inflammatory or atherosclerotic diseases mediated by cytokines with a human 12-lipoxygenase inhibitor, wherein pioglitazone is used as the human 12-lipoxygenase inhibitor. That is, there is an example of 5- [4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione. 6) The Journal of Biological Chemistry, 271
Vol. 23, No. 13515-13522, 1996, 1- (3-allyl-4-oxothiazolidine-2-
Thiazolidinedione-related compounds such as (ylidene) -4-methylthiosemicarbazone have been described to have anti-arthritic activity. However, none of the above documents describe that the thiazolidine derivative is useful as an agent for preventing and treating inflammatory diseases involving TNF-α.

[0004]

The inflammatory response includes various acute and chronic reactions that occur when a stimulus is applied to a living body. Some of these reactions are advantageous to the living body for the purpose of eliminating foreign substances, while others are disadvantageous reactions that cause destruction of living tissues. Conventionally, treatment of inflammation has been performed with steroids, non-steroidal anti-inflammatory drugs, immunosuppressants, etc. These drugs suppress not only adverse reactions but also favorable reactions during inflammation. There is a problem. Therefore, there is a need for a drug that suppresses only a reaction that is adverse to the living body. In addition, various cytokines are thought to be produced in inflammation and regulate the inflammatory response. One of them, TNF-α, plays an important role in the expansion and prolongation of inflammation. Is believed to be For example, in rheumatoid arthritis, which is an inflammatory disease, it is thought that the production of TNF-α is enhanced, which results in destruction of joint tissues. In view of the above, a drug that specifically suppresses an inflammatory reaction involving TNF-α is expected as an anti-inflammatory drug with few side effects, and development of such a drug is required.

[0005]

Means for Solving the Problems The present invention provides: (1) a general formula

Embedded image [Wherein, R is an optionally substituted hydrocarbon or heterocyclic group; Y is -CO-, -CH (OH)-or -NR ^3- (where R ³ is an optionally substituted alkyl group; M is 0 or 1; n is 0,
X is CH or N; A is a bond or a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q is an oxygen atom or a sulfur atom; R ¹ is a hydrogen atom or an alkyl group, respectively. Ring E may further have 1 to 4 substituents, and the substituents may combine with R ¹ to form a ring. L and M each represent a hydrogen atom or may be bonded to each other to form a bond. An anti-inflammatory agent comprising a compound represented by the formula (I) or a salt thereof and acting through a TNF-α inhibitory effect; (2) the heterocyclic group represented by R is an oxygen atom other than a carbon atom as a ring-constituting atom; An anti-inflammatory agent according to the above (1), which is a 5- to 7-membered monocyclic heterocyclic group or a condensed heterocyclic group containing 1 to 4 heteroatoms selected from atoms, sulfur atoms and nitrogen atoms; (3) (4) the anti-inflammatory agent according to the above (3), wherein R is a heterocyclic group which may be substituted; (4) the anti-inflammatory agent according to the above (3), wherein the heterocyclic group is a pyridyl, oxazolyl or thiazolyl group; 5) Partial structural formula

Embedded image (6) the anti-inflammatory agent according to (1), wherein X is CH; (7) the anti-inflammatory agent according to (1), wherein R ¹ is a hydrogen atom; (8) the anti-inflammatory agent according to the above (1), wherein L and M are hydrogen atoms; (9) the compound is 5- [4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -2, The anti-inflammatory agent according to the above (1), which is 4-thiazolidinedione; and (10) the compound is (R)-(+)-5- [3- [4-
[2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl] propyl] -2,
The anti-inflammatory agent according to the above (1), which is 4-oxazolidinedione.

The hydrocarbon group in the optionally substituted hydrocarbon group represented by R includes an aliphatic hydrocarbon group,
Examples include an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, an araliphatic hydrocarbon group, and an aromatic hydrocarbon group. The number of carbon atoms in these hydrocarbon groups is preferably 1 to 14
It is. As the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable. Examples of the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, heptyl, octyl and the like, and a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, an alkyl group) etc);
For example, ethenyl, 1-propenyl, 2-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-
Octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-
Pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-
Hexadiynyl, 5-hexynyl, 1-heptynyl, 1
And -unsaturated aliphatic hydrocarbon groups having 2 to 8 carbon atoms such as octynyl (eg, alkenyl group, alkadienyl group, alkynyl group, alkadiynyl group and the like). As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable. Examples of the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl (eg, cycloalkyl group and the like) and 1-cyclopentenyl; 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3
An unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms such as -cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl (eg, cycloalkenyl group, cycloalkadienyl And the like).

The alicyclic-aliphatic hydrocarbon group includes those in which the alicyclic hydrocarbon group and the aliphatic hydrocarbon group are bonded (eg, cycloalkyl-alkyl group, cycloalkenyl-alkyl group, etc.). And among them, 4 to 9 carbon atoms
The alicyclic-aliphatic hydrocarbon group of is preferred. Examples of the alicyclic-aliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl,
Cyclopentenylmethyl, cyclohexylmethyl, 2-
Cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl,
Cycloheptylmethyl, cycloheptylethyl and the like can be mentioned. As the araliphatic hydrocarbon group, a carbon number of 7 to
Thirteen araliphatic hydrocarbon groups (eg, aralkyl groups, aryl-alkenyl groups, etc.) are preferred. Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 1-phenylpropyl; α-naphthylmethyl, α -Naphthylalkyl having 11 to 13 carbon atoms such as -naphthylethyl, β-naphthylmethyl, β-naphthylethyl; phenylalkenyl having 8 to 10 carbon atoms such as styryl and 4-phenyl-1,3-butadienyl; 2- (2-naphthyl And naphthylalkenyl having 12 to 13 carbon atoms such as vinyl).
As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group, etc.) is preferable. Examples of the aromatic hydrocarbon group include phenyl and naphthyl (α-naphthyl, β-naphthyl).

In the general formula (I), the heterocyclic group in the optionally substituted heterocyclic group represented by R is a heterocyclic group selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. A 5- to 7-membered monocyclic heterocyclic group or fused heterocyclic group containing 1 to 4 atoms is exemplified. Examples of the fused heterocyclic ring include a 5- to 7-membered monocyclic heterocyclic ring and a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. And fused rings. Specific examples of the heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6
-Pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2
-Imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2 , 4-oxadiazol-5-yl, 1,2,4-triazol-3-yl, 1,
2,3-triazol-4-yl, tetrazol-5
Il, benzimidazole-2-yl, indole-3
-Yl, 1H-indazole-3-yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,
3-b] pyridin-6-yl, 1H-imidazo [4.5
-B] pyridin-2-yl, 1H-imidazo [4,5-
c] pyridin-2-yl, 1H-imidazo [4,5-
b] pyrazin-2-yl, benzopyranyl, 3,4-dihydro-benzopyran-2-yl and the like. The heterocyclic group is preferably a pyridyl, oxazolyl or thiazolyl group.

In the general formula (I), the hydrocarbon group represented by R and the heterocyclic group represent 1 to 5 at substitutable positions.
And preferably 1 to 3 substituents.
Examples of the substituent include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and an optionally substituted amino group. And an optionally substituted acyl group, an optionally substituted hydroxy group, an optionally substituted thiol group, and an optionally esterified carboxyl group. Examples of the aliphatic hydrocarbon group include C1 to C15.
A linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.
Preferable examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl,
Pentyl, isopentyl, neopentyl, t.-pentyl, 1-ethylpropyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,
3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like.
Preferred examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, for example, vinyl, allyl, isopropenyl,
1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1
-Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2
-Hexenyl, 3-hexenyl, 4-hexenyl, 5-
Hexenyl and the like. Preferred examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
Hexinyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like can be mentioned.

The alicyclic hydrocarbon group may have 3 to 1 carbon atoms.
And two saturated or unsaturated alicyclic hydrocarbon groups, for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like. Preferred examples of the cycloalkyl group include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2. 2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.
2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like. Preferable examples of the cycloalkenyl group include a cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-cycloalkenyl group.
Cyclopenten-1-yl, 3-cyclopenten-1-
Yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Preferred examples of the cycloalkadienyl group include cycloalkadienyl groups having 4 to 10 carbon atoms, for example, 2,4-cyclopentadiene-1.
-Yl, 2,4-cyclohexadien-1-yl, 2,5
-Cyclohexadien-1-yl and the like. The aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and preferable examples thereof include an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Preferred examples of the aromatic heterocyclic group include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen other than carbon as ring-constituting atoms, such as triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl 5 to 7-membered aromatic monocyclic heterocyclic group contained; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoyl Isoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl , Thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1, Oxygen atoms other than carbon atoms as ring-constituting atoms, such as 2,4-triazolo [4,3-b] pyridazinyl,
A bicyclic or tricyclic aromatic fused heterocyclic group containing 1 to 5 hetero atoms selected from a sulfur atom and a nitrogen atom is exemplified.

Preferred examples of the non-aromatic heterocyclic group include, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpholino, Thiomorpholino and the like. Examples of halogen atoms include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being especially preferred. Examples of the amino group which may be substituted include, for example, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, and 3 carbon atoms.
To 10 cycloalkenyl groups, C1 to C13 acyl groups (eg, C2 to C10 alkanoyl groups, C7 to C7
13 arylcarbonyl group) or 6 to 12 carbon atoms
And an amino group (-NH ₂ group) which may be mono- or di-substituted by an aryl group or the like. Examples of the substituted amino group include methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino and the like. Is mentioned.
Examples of the acyl group in the optionally substituted acyl group include an acyl group having 1 to 13 carbon atoms, specifically formyl, for example, an alkyl group having 1 to 10 carbon atoms, and 3 to 10 carbon atoms.
A cycloalkyl group, an alkenyl group having 2 to 10 carbon atoms,
A cycloalkenyl group having 3 to 10 carbon atoms, 6 to 12 carbon atoms
And a group in which an aryl group or an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, etc.) is bonded to a carbonyl group. Preferred examples of the acyl group include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl,
Examples include cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like. Examples of the substituent in the substituted acyl group include alkyl having 1 to 3 carbons, for example, 1 carbon
To 3 alkoxy groups, halogens (eg, chlorine, fluorine, bromine, etc.), nitro, hydroxy, amino and the like.

In the optionally substituted hydroxy group, examples of the substituted hydroxy group include an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group and an aryloxy group. Preferable examples of the alkoxy group include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy,
t.-butoxy, pentyloxy, isopentyloxy,
Neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy. And the like. Preferable examples of the aralkyloxy group include an aralkyloxy group having 7 to 10 carbon atoms, such as phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.).
Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, more preferably an alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.). . Preferred examples of the aryloxy group include aryloxy groups having 6 to 14 carbon atoms, such as phenoxy,
Naphthyloxy and the like. The aryloxy group may have one or two substituents, and examples of such a substituent include halogen (eg, chlorine, fluorine, bromine and the like). Examples of the substituted aryloxy group include 4-chlorophenoxy and the like.

In the optionally substituted thiol group, examples of the substituted thiol group include an alkylthio group, a cycloalkylthio group, an aralkylthio group and an acylthio group. Preferred examples of the alkylthio group include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio,
t-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like. Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Preferred examples of the aralkylthio group include aralkylthio groups having 7 to 10 carbon atoms, such as phenyl-C _1-4 alkylthio (eg, benzylthio,
Phenethylthio) and the like. Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, and more preferably an alkanoylthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).

Examples of the carboxyl group which may be esterified include, for example, an alkoxycarbonyl group, an aralkyloxycarbonyl group and an aryloxycarbonyl group. Preferable examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 2 to 5 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Preferable examples of the aralkyloxycarbonyl group include an aralkyloxycarbonyl group having 8 to 10 carbon atoms, such as benzyloxycarbonyl. Preferable examples of the aryloxycarbonyl group include an aryloxycarbonyl group having 7 to 15 carbon atoms, such as phenoxycarbonyl and p-tolyloxycarbonyl. The substituent in the hydrocarbon group and the heterocyclic group represented by R is
Preferred are an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group and an aryl group having 6 to 14 carbon atoms, and more preferred are _C1-3 alkyl, furyl, thienyl, phenyl and naphthyl.

In the general formula (I), the substituent on the hydrocarbon group and the heterocyclic group represented by R may be an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. When it is a group, it may further have one or more suitable substituents, preferably 1 to 3, and examples of such a substituent include an alkyl group having 1 to 6 carbon atoms and a carbon number of 2 Alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, 6 to 14 carbon atoms
Aryl groups (eg, phenyl, naphthyl, etc.), aromatic heterocyclic groups (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic groups (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino) , Pyrrolidino, piperazino, etc.), aralkyl group having 7 to 9 carbon atoms, amino group, N-mono (C _1-4 ) alkylamino group, N, N-di (C _1-4 ) alkylamino group, 2 carbon atoms To 8 acylamino groups (eg, acetylamino, propionylamino, benzoylamino, etc.), an amidino group, an acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group having 2 to 8 carbon atoms), a carbamoyl group, N-mono (C _1-4 ) alkylcarbamoyl group, N, N-di (C _1-4 ) alkylcarbamoyl group, sulfamoyl group, N-mono (C _1-4 ) alkylsulfur Amoyl group,
An N, N-di (C _1-4 ) alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms,
Hydroxy group, alkoxy group having 1 to 4 carbon atoms, 2 carbon atoms
Alkenyloxy group having 5 to 5 carbon atoms, cycloalkyloxy group having 3 to 7 carbon atoms, aralkyloxy group having 7 to 9 carbon atoms, aryloxy group having 6 to 14 carbon atoms (eg, phenyloxy, naphthyloxy, etc.), mercapto group , Having 1 to 1 carbon atoms
4, an alkylthio group having 4 to 7 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio, etc.), a sulfo group, a cyano group, an azido group, a nitro group, a nitroso group, a halogen atom ( For example, fluorine, chlorine, bromine and iodine). In the general formula (I), R is preferably an optionally substituted heterocyclic group. R is more preferably C _1-3 alkyl,
Pyridyl optionally having 1 to 3 substituents selected from furyl, thienyl, phenyl and naphthyl;
An oxazolyl or thiazolyl group.

In the general formula (I), Y is -CO-, -CH
(OH) - or -NR ³ - the shows, -CH (OH)
-Or -NR ³ -is preferred, and more preferably -C
H (OH)-. Here, as the alkyl group in the optionally substituted alkyl group represented by R ³ , an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, t-butyl and the like. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine) and an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec.-butoxy, t.-). Butoxy), a hydroxy group, a nitro group, an acyl group having 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, etc.).
R ³ is preferably an alkyl group having 1 to 4 carbon atoms, particularly preferably methyl. m represents 0 or 1, and is preferably 0. n represents 0, 1 or 2, and is preferably 0 or 1. X represents CH or N, preferably CH.

In the general formula (I), A represents a bond or a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms. The aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated. Specific examples thereof include _{-CH 2 -, - CH (CH} 3) -, - (CH 2) 2 -,
_{-CH (C 2 H 5) -} , - (CH 2) 3 -, - (CH 2)
₄ -,-(CH ₂ ) ₅ -,-(CH ₂ ) ₆ -,-(CH ₂ ) ₇
-, For example, -CH = CH-, -C (C
_{H 3) = CH -, -} CH = CH-CH 2 -, - C (C
_{2 H 5) = CH -,} - CH 2 -CH = CH-CH 2 -, - C
_{H 2 -CH 2 -CH = CH-} CH 2 -, - CH = CH-C
_{H = CH-CH 2 -,} - CH = CH-CH = CH-CH
And unsaturated compounds such as な ど CH—CH ₂ —. A
Is preferably a bond or a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and the aliphatic hydrocarbon group is preferably further saturated. A is more preferably a bond, -CH ₂ - is particularly preferably a bond or - - or _{- (CH 2) 2 (CH} 2) 2 - is. Examples of the alkyl group represented by R ¹ include an alkyl group having 1 to 4 carbon atoms,
Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl and the like. R ¹ is preferably a hydrogen atom.

In the general formula (I), a partial structural formula

Embedded image Wherein each symbol is as defined above. ]. Ring E may further have 1 to 4 substituents at any substitutable position. Examples of such a substituent include an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, a nitro group, and an optionally substituted amino group. These are the same as those described as the substituents of the hydrocarbon group and the heterocyclic group represented by R.

Ring E, ie a partial structural formula

Embedded image [In the formula, R ² represents a hydrogen atom, an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, a nitro group or an optionally substituted amino group. ]. Alkyl group represented by R ^2, an optionally substituted hydroxy group, a halogen atom, as the optionally substituted acyl group and optionally substituted amino group, a hydrocarbon group both represented by R And the same as those described as the substituent for the heterocyclic group. R ² is preferably a hydrogen atom,
It is a hydroxy group or a halogen atom which may be substituted. R ² is more preferably a hydrogen atom or an optionally substituted hydroxy group, particularly preferably a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms.

L and M are a hydrogen atom or a bond bonded to each other, and are preferably a hydrogen atom. In the general formula (I), a compound in which L and M are bonded to each other to form a bond:

Embedded image Wherein each symbol is as defined above. ] Has a (E) -form and a (Z) -form with respect to the double bond at the 5-position of the azolidinedione ring.

Compounds in which L and M each represent a hydrogen atom:

Embedded image Wherein each symbol is as defined above. ], There are (R) -form and (S) -form optical isomers due to the asymmetric carbon at the 5-position of the azolidinedione ring, and these compounds are (R) -form and (S) -form. Includes optically active and racemic forms.

Preferred examples of the compound represented by the general formula (I) include, for example, a compound in which R has 1 to 3 substituents selected from C _1-3 alkyl, furyl, thienyl, phenyl and naphthyl. A pyridyl, oxazolyl or thiazolyl group; Y is -CH (OH)-or-
NR ³ - (and R ³ is methyl); n is 0 or 1; is X C
H: A is a bond or-(CH ₂ ) _2- ; R ¹ is a hydrogen atom; Ring E, ie, a partial structural formula

Embedded image And R ² is a hydrogen atom or a C _1-4 alkoxy group; and compounds in which L and M are hydrogen atoms.

Preferred specific examples of the compound represented by the general formula (I) include: 1) 5- [4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidine Dione, 2) 5- [4- [2-hydroxy-2- (5-methyl-
2-phenyl-4-oxazolyl) ethoxy] benzyl] -2,4-thiazolidinedione, 3) (R)-(+)-5- [3- [4- [2- (2-furyl) -5-methyl -4-oxazolylmethoxy] -3
-Methoxyphenyl] propyl] -2,4-oxazolidinedione, 4) (S)-(-)-5- [3- [4- [2- (2-furyl) -5-methyl-4-oxazolyl Methoxy] -3
-Methoxyphenyl] propyl] -2,4-oxazolidinedione, 5) 5- [3- [3-fluoro-4- (5-methyl-2
-Phenyl-4-oxazolylmethoxy) phenyl] propyl] -2,4-oxazolidinedione, 6) 5- [5- [3-methoxy-4- (5-methyl-2)
-Phenyl-4-oxazolylmethoxy) phenyl] pentyl] -2,4-oxazolidinedione, 7) 5- [3- [3,5-dimethoxy-4- [2-
[(E) -styryl] -4-oxazolylmethoxy] phenyl] propyl] -2,4-oxazolidinedione, 8) 5-[[4-[(3,4-dihydro-6-hydroxy-2,5 , 7,8-Tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl]-
2,4-thiazolidinedione, 9) 5-[[4- [2- (methyl-2-pyridylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (these compounds are referred to as Simply referred to as Compound No. 1, Compound No. 2, etc.). Of these, compounds Nos. 1, 3, 8, and 9 are preferred, and compounds Nos. 1 and 3 are particularly preferred.

The salt of the compound (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid. And salts with basic or acidic amino acids. Preferred examples of the salt with an inorganic base include, for example, sodium salt,
Alkali metal salts such as potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts. Preferred examples of the salt with an organic base include, for example, trimethylamine,
Salts with triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like can be mentioned. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. It is. Among the above-mentioned salts, hydrochloride, sodium salt and potassium salt are most preferred.

Compound (I) of the present invention or a salt thereof is described in, for example, JP-A-55-22636 (EP-A-8203),
JP-A-60-208980 (EP-A-15584)
5), JP-A-61-286376 (EP-A-2084)
20), JP-A-61-085372 (EP-A-177)
353) and JP-A-61-267580 (EP-A-19).
3256), JP-A-5-86057 (WO-A-921)
8501), JP-A-7-82269 (EP-A-605)
228), JP-A-7-101945 (EP-A-612)
743), EP-A-643050 and EP-A-7
10659 (Japanese Patent Application Laid-Open No. 9-194467) or the like or a method analogous thereto.

The compound (I) of the present invention or a salt thereof (hereinafter, simply abbreviated as the compound of the present invention) is useful as an anti-inflammatory agent acting through a TNF-α inhibitory effect. Further, the toxicity of the compound of the present invention is low. Here, the TNF-α inhibitory effect is defined as the effect of lowering the amount of TNF-α production in living tissues (eg, skeletal muscle, monocytes, macrophages, neutrophils, fibroblasts, epithelial cells, astrocytes, etc.) or TNF-α.
-Α activity lowering effect. The anti-inflammatory agent of the present invention includes mammals (eg, humans, mice, rats, rabbits, dogs, cats,
Cattle, horses, pigs, monkeys, etc.) as prophylactic and therapeutic agents for inflammatory diseases involving TNF-α.
Here, the inflammatory disease involving TNF-α refers to TNF-α.
-Is an inflammatory disease that develops due to the presence of-[alpha] and can be treated through its TNF- [alpha] inhibitory effect. Such inflammatory diseases include, for example, diabetic complications (eg, retinopathy, nephropathy,
Neuropathy, macrovascular disorder, etc.), rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, inflammation after surgery / trauma, remission of swelling, neuralgia, laryngitis, cystitis, hepatitis, pneumonia, etc. Is mentioned.

As the anti-inflammatory agent of the present invention, the compound of the present invention may be used as it is, but it is usually used as a pharmaceutical composition obtained by mixing the compound of the present invention with a known pharmacologically acceptable carrier. Used. Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , A solubilizing agent, a suspending agent, an isotonic agent, a buffer, a soothing agent and the like. If necessary, preservatives,
Pharmaceutical additives such as antioxidants, colorants, sweeteners and the like can also be used. Suitable examples of excipients include, for example, lactose,
Sucrose, D-mannitol, starch, crystalline cellulose,
Light silicic anhydride and the like can be mentioned. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of disintegrants include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium,
And sodium carboxymethyl starch.

Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, tricaprylin and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like.
Preferred examples of the buffer include phosphate, acetate, and the like.
Buffers such as carbonates and citrates are included. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The above pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, the method described in the Japanese Pharmacopoeia. Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets, capsules (including soft capsules and microcapsules), powders, granules, and syrups; and injections, suppositories, pellets, and drops. Parenteral preparations can be mentioned, which can be safely administered orally or parenterally, respectively. The dose of the anti-inflammatory agent of the present invention varies depending on the administration subject, administration route, symptoms and the like. For example, when orally administered to an adult patient, the compound of the present invention as an active ingredient is usually administered in a single dose. 0.1mg /
kg to about 30 mg / kg, preferably about 2 mg / kg to about 20 mg / kg
It is preferable to administer this amount, and it is desirable to administer this amount 1 to 3 times a day.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in detail below with reference to examples and test examples, but the present invention is not limited to these examples. Example 1 2479.5 g of hydrochloride of compound No. 1 (2250 as compound No. 1)
g), 13930.5 g of lactose and 540 g of carboxymethylcellulose calcium (carmellose calcium) were placed in a fluidized granulation dryer (manufactured by Powrex), preheated and mixed, and sprayed with 7500 g of an aqueous solution in which 450 g of hydroxypropylcellulose was dissolved, and granulated. I got the end. 16820 g of the obtained granulated powder was passed through a cutter mill (manufactured by Showa Kagaku Kikai Kosakusho) to obtain a sized powder. The obtained sized powder 16530 g, carmellose calcium 513 g and magnesium stearate 57 g were mixed into a mixed powder using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho), and 16800 g of the mixed powder was pressed using a tableting machine (manufactured by Kikusui Seisakusho). Tablets were obtained to give 140,000 tablets having the following composition and containing 15 mg of Compound No. 1 per tablet.

Example 2 In the same manner as in Example 1, 30 mg of Compound No. 1 per tablet
140,000 tablets having the following composition were obtained.

Example 3 In the same manner as in Example 2, 45 mg of compound No. 1 per tablet
140,000 tablets having the following composition were obtained.

Test Example 1 (Mice Plasma TNF-α Level Decreasing Effect) Using KKA ^y mice, a hereditary obesity / diabetes model,
The amount of TNF-α in plasma was measured, and TNF of the compound of the present invention was measured.
The α-suppressing effect was evaluated. That is, 18 males (10 weeks old) of KKA ^y mice, a hereditary obesity / diabetes model, were divided into 2 groups (9 each), and one group (control group) was a commercially available powdered feed (CE-2, Japan). Clair) and other groups (drug administration groups)
Was fed freely with the powdered feed containing 0.001% (w / w) of the hydrochloride salt of Compound No. 1 and bred for 4 days. The average drug dose per mouse was 16 mg / kg body weight / day. On day 4, the mice were sacrificed and blood was collected in tubes containing heparin. The collected blood was centrifuged, and TNF-α in plasma was quantified by an enzyme immunoassay based on the biotin-streptavidin method. Specifically, anti-TNF-α diluted with 0.05 M Tris-HCl buffer (pH 8.0) was added to each well of a 96-well polystyrene microtiter plate (Falcon, USA).
Antibody IgG (Genzyme, USA) solution (1
(00 μg / ml) was added in 5 μl portions and left at room temperature for 2 hours.
Anti-TNF-α antibody IgG was adsorbed. After removing the excess antibody solution, each well was filled with 0.1 M Tris-HCl buffer (pH
7.6) [0.4 M sodium chloride, 0.1% (w / w) bovine serum albumin, 0.1% (w / w) bovine serum albumin, 0.1% (w
/ w) containing sodium azide and 1 mM magnesium chloride] (hereinafter abbreviated as washing buffer).

To each well, 10 μl of plasma or a standard solution of TNF-α (Serotec, UK) was added and left at room temperature for 2.5 hours. After washing each well with the washing buffer, the biotinylated anti-TNF-α diluted with the washing buffer was used.
20 μl of antibody IgG solution (35 ng / ml) was added at 4 ° C.
Left overnight. After washing each well with a washing buffer, β-D-galactosidase-labeled streptavidin [Boehringer Mannheim (Boehring
er Mannheim) GmbH, Germany] and add 1 μl at room temperature.
Left for hours. Next, after each well was washed with a washing buffer, the β-D-galactosidase activity of the immune complex immobilized on the solid phase was measured. That is, the substrate [60
mM 4-methylumbelliferyl-β-D-galactoside, Sigma, USA] was added in an amount of 30 μl to initiate the enzyme reaction. After reacting at room temperature for 4 hours, 0.13 ml of 0.1 M glycine-sodium hydroxide buffer (pH 10.3) was added to stop the enzyme reaction. The fluorescence intensity of the generated 4-methylumbelliferone was measured at an excitation wavelength of 350 nm and a measurement wavelength of 460 nm using a fluorometer (Cyto Fluor II, PerSeptive Biosystems, USA). It was measured. Next, the amount of TNF-α was calculated from the obtained fluorescence intensity using a separately prepared dose-effect curve of TNF-α. The results are shown in [Table 1].

[Table 1] TNF-α content in plasma (pg / ml) Mean ± standard deviation; significant difference from control group (**: p <0.01) As is clear from Table 1, the compound of the present invention significantly reduced the amount of TNF-α in mouse plasma.

Test Example 2 (Rotary plasma TNF-α lowering effect) TNF-α in plasma was measured using Wistar fatty rats, a hereditary obesity / diabetes model.
The amount was measured, and the TNF-α inhibitory effect of the compound of the present invention was evaluated. That is, the hydrochloride of Compound No. 1 was orally administered by gavage to a male (16 weeks old) of Wistar fatty (Wistar fatty) rat, a hereditary obesity / diabetes model, at a dose of 3 mg / kg body weight / day using a gastric tube. . Before the drug administration, 1, 2, 3, and 4 days after the drug administration, 10 rats were sacrificed and blood was collected. In addition, as a normal group, 10 male Wistar lean rats (16 weeks old) were sacrificed without drug administration, and blood was collected. The collected blood was centrifuged, and TNF-α in plasma was quantified in the same manner as in Test Example 1. The results are shown in [Table 2].

[Table 2] TNF-α content in plasma (pg / ml) Mean value ± standard deviation; significant difference from control group (*: p <0.05) As is clear from Table 2, the compound of the present invention reduced the amount of TNF-α in rat plasma over time.

Test Example 3 (TNF-α Level Decreasing Effect in Rat Skeletal Muscle) TNF-α levels in skeletal muscle were determined using Wistar fatty rats, a hereditary obesity / diabetes model.
The amount of α was measured, and the TNF-α inhibitory effect of the compound of the present invention was evaluated. That is, the hydrochloride salt of Compound No. 1 was administered to male (16 weeks old) Wistar fatty (Wistar fatty) rat, a hereditary obesity / diabetes model, in the same manner as in Test Example 2. Before the drug administration, 1, 2, 3, and 4 days after the drug administration, 10 rats were sacrificed and skeletal muscle was collected. In addition, as a normal group, Wistar lean
Ten male rats (16 weeks old) were sacrificed without drug administration,
Skeletal muscle was collected. Give the collected skeletal muscle 20% of its wet weight
0.1 M Tris-HCl buffer (pH 7.6) by weight [1 M sodium chloride, 2% (w / w) bovine serum albumin, 2 mM ethylenediaminetetraacetic acid disodium salt (EDT
A), containing aprotinin (80 trypsin inhibition units / liter) and 0.02% (w / w) sodium azide]
After sonication, the mixture was centrifuged at 15,000 rpm for 30 minutes to obtain a supernatant. TNF-α in the obtained supernatant was quantified in the same manner as in Test Example 1. The results are shown in [Table 3].

[Table 3] TNF-α content in skeletal muscle (pg / g wet weight) Mean value ± standard deviation; significant difference from control group (*: p <0.05, **: p <0.01) As is clear from Table 3, the compound of the present invention reduced the amount of TNF-α in rat skeletal muscle. It decreased significantly and almost over time.

Test Example 4 (Effect of reducing the production of neutrophil active oxygen) The effect of the compound of the present invention on the production of neutrophil active oxygen in vitro was evaluated by measuring the amount of intracellular peroxide. That is, Wister
r) Heparinized venous blood was collected from a male rat (6 weeks old), and the collected blood was mixed with an equal volume of a 3% (w / w) aqueous dextran solution for separating blood cells. After leaving the mixture for 30 minutes,
The precipitate obtained by centrifugation is suspended in physiological saline,
This suspension was used for Ficoll-Hypaq
ue) solution (Sigma, USA) and centrifuged. Erythrocytes were removed from the resulting sediment by a hemolysis operation, and neutrophils were separated. The hemolysis operation was performed as follows. That is, 0.2% (w /
w) 4 ml of an aqueous solution of sodium chloride was added, and the cells were immediately suspended and allowed to stand for 20 to 30 seconds to destroy red blood cells. Then, 4 ml of an ice-cooled 1.6% (w / w) aqueous sodium chloride solution was added to the obtained suspension and mixed to obtain a mixed solution isotonic with red blood cells before disruption. The mixture was centrifuged at 150 xg for 5 minutes at 4 ° C, the supernatant was discarded, and the precipitate was washed with PBS (phosphate buffer sal
ine). The neutrophils obtained in this way are washed with physiological saline, and then washed with a minimum essential medium (minimum essential medium).
medium) to prepare a neutrophil suspension. The obtained neutrophil suspension was fractionated into tubes such that the number of neutrophils per tube was 106. Then, the hydrochloride of Compound No. 1 or Compound No. 8 was added to the resulting tube at a concentration of 1 μM, and after culturing for 1 hour,
A fluorescent dye [DCFH-DA (2 ′, 7′-dichlorofluorescein diacetate)] was added, and FAC scan (FAC scan) was performed.
Scan) (Becton Dickington, USA) to measure the fluorescence intensity. As a control group, the fluorescence intensity when no drug was added was measured. The relative value of the fluorescence intensity of the drug-added group was calculated when the fluorescence intensity of the control group was set to 100, and this was defined as the amount of peroxide due to neutrophil-derived active oxygen. The results are shown in [Table 4].

[0039]

[Table 4] Fluorescence intensity and peroxide amount As is clear from Table 4, the compound of the present invention suppressed the production of active oxygen by neutrophils. TNF-α includes monocytes, macrophages, neutrophils, fibroblasts, epithelial cells,
Produced from various cells such as astrocytes. In neutrophils, TNF-α enhances the production of active oxygen,
It has been suggested that this is closely related to the development of rheumatoid arthritis [Clin. Exp. Rheumat
ol.), 15, 233-237, 1997; Inflammation, 20, 427-438, 1996)]. Therefore, from the results of Test Example 4, it is considered that the compound of the present invention exhibited an active oxygen production inhibitory effect by decreasing TNF-α production or TNF-α sensitivity of neutrophils.

[0040]

The anti-inflammatory agent of the present invention is useful for treating inflammatory diseases involving TNF-α (eg, diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorder, etc.), rheumatoid arthritis, etc. Osteoarthritis, osteoarthritis, low back pain, gout, inflammation after surgery and trauma, remission of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, etc.).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 413/12 307 C07D 413/12 307 413/14 307 413/14 307 417/06 213 417/06 213 417/12 213 417 / 12 213 263 263 311 311

Claims (10)

[Claims] 1. A compound of the general formula [Wherein, R is an optionally substituted hydrocarbon or heterocyclic group; Y is -CO-, -CH (OH)-or -NR ^3- (where R ³ is an optionally substituted alkyl group; M is 0 or 1; n is 0,
X is CH or N; A is a bond or a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q is an oxygen atom or a sulfur atom; R ¹ is a hydrogen atom or an alkyl group, respectively. Ring E may further have 1 to 4 substituents, and the substituents may combine with R ¹ to form a ring. L and M each represent a hydrogen atom or may be bonded to each other to form a bond. ] Or a salt thereof, and acts via a TNF- [alpha] inhibitory effect. 2. A 5- to 7-membered monocyclic group wherein the heterocyclic group represented by R contains 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms. The anti-inflammatory agent according to claim 1, which is a heterocyclic group or a fused heterocyclic group. 3. The anti-inflammatory agent according to claim 1, wherein R is an optionally substituted heterocyclic group. 4. The anti-inflammatory agent according to claim 3, wherein the heterocyclic group is a pyridyl, oxazolyl or thiazolyl group. 5. A partial structural formula: The anti-inflammatory agent according to claim 1, which is: 6. The anti-inflammatory agent according to claim 1, wherein X is CH. 7. The anti-inflammatory agent according to claim ¹ , wherein R ¹ is a hydrogen atom. 8. The anti-inflammatory agent according to claim 1, wherein L and M are hydrogen atoms. (9) the compound is 5- [4- [2- (5-ethyl-
The anti-inflammatory agent according to claim 1, which is 2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione. (10) the compound of (R)-(+)-5- [3-
[4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl] propyl]
The anti-inflammatory agent according to claim 1, which is -2,4-oxazolidinedione.