JPH11180952A - 2-oxindole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having inhibitory actions on the production of cytokinine as a etiologic agent for an inflammatory disease such as chronic rheumatoid arthritis, etc. SOLUTION: This compound is shown by formula I R1 is H, a halogen, a lower alkyl or the like; X is a group of the formula CO-CH=CH-Z [Z is a group of formula II or formula III (R2 and R3 are each H, an acyl or a lower alkyl) or the like] or an aryl of the formula IV (R4 is H, a halogen, a lower alkyl or the like); Y1 and Y2 are each H, a group of the formula C(R5 R6 )-[C(R7 R8 )]n -COR9 (R5 to R8 are each H or a lower alkyl; R9 is OH, a lower alkoxy, amino or the like; (n) is 0 or 1) or the like; A, B, D and E are each N or C} such as ethyl 1-(3,4-dimethoxycinnamoyl)-2-oxindole-3-acetate. The compound of formula I is obtained by introducing an unsaturated acetic ester residue by a Witting reaction or the like to give an intermediate and acylating the amide group of the intermediate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel 2-oxindole derivative or a salt thereof, and a pharmaceutical use thereof. Since the 2-oxindole derivative or a salt thereof provided by the present invention has an action of suppressing the production of cytokines such as interleukin and tumor necrosis factor (TNF), for example, allergic diseases, systemic lupus erythematosus, chronic joint Useful for the treatment or prevention of diseases involving cytokines such as rheumatism, scleroderma, hepatitis, pancreatitis, inflammatory bowel disease, glomerulonephritis, toxin shock syndrome, sepsis or osteoporosis, preferably for the treatment or prevention of autoimmune diseases is there.

[0002]

2. Description of the Related Art Cytokines are humoral factors that are produced by various cells and exert their effects in small amounts locally. Cytokines play a central role in normal immune response and host defense, while increased or decreased cytokine production and abnormal responsiveness to cytokines are involved in the formation of various disease states. In rheumatoid arthritis, which is a systemic autoimmune disease in which the joint is the main site of the lesion, inflammatory cytokines such as IL-1, IL-6, and TNF-α are particularly involved.
It forms pathological conditions such as T cell infiltration into synovial tissue and activation of T cells, angiogenesis, activation of synovial cells, and joint destruction associated with cartilage and bone resorption. In addition, cytokines such as IL-1, IL-6, and TNF-α are excessively present in synovial fluid of rheumatoid arthritis patients, and these cytokines are correlated with disease activity of rheumatoid arthritis. It has been recognized that.

Heretofore, non-steroidal anti-inflammatory drugs (NSAIDs) have been used as first-line drugs for rheumatoid arthritis. However, treatment with NSAIDs
Although analgesic action can be expected, the progress of bone destruction cannot be prevented, and it is only a so-called symptomatic treatment. Thus, IL-1, IL-6 and T involved in the pathogenesis of rheumatoid arthritis
Attempts have been made to control excessive production of cytokines such as NF-α, and such compounds include 3,4-
Dihydro-2 (1H) -quinolinone derivatives
320133) and 2,3-diarylquinoline derivatives (JP-A-7-53546).

[0004]

An object of the present invention is to produce cytokines, such as IL-1, IL-6 and TNF-α, which are considered to be major causative agents of inflammatory diseases such as rheumatoid arthritis. It is an object of the present invention to provide a novel compound which has an effect of suppressing odor and is highly safe. Also,
An object of the present invention is to provide a cytokine production inhibitor comprising the compound or a pharmacologically acceptable salt thereof as an active ingredient, and an agent for preventing or treating an autoimmune disease.

[0005]

Means for Solving the Problems The present inventors have made intensive studies in order to achieve the above object, and found that a novel 2-oxindole derivative represented by the following general formula (I) or a salt thereof is obtained. It has been found that it has excellent characteristics meeting the above-mentioned object. The present invention is based on such findings.

That is, the present invention provides a compound represented by the general formula (I):

[0007]

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[Wherein R ₁ is a hydrogen atom, a halogen atom,
A lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group which may be branched, a lower alkylthio group which may be branched, an amino group, A lower alkylamino group, a lower dialkylamino group or a nitro group which may be branched. X is -CO-CH = CH-Z wherein Z is a formula:

[0009]

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(R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.) ], Or the formula:

[0011]

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(Wherein R ₄ represents a hydrogen atom, a halogen atom,
A lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group which may be branched, a lower alkylthio group which may be branched, an amino group, A lower alkylamino group, a lower dialkylamino group or a nitro group which may be branched. ) Represents an aryl group. Y ₁ and Y ₂ are the same or different and are each a hydrogen atom or —C (R ₅ R
₆ )-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group, and R ₉ is A hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or a lower dialkylamino group which may be branched; n is 0 or 1), or Y ₁ and Y ₂
In both, ＝ CR _10- [C (R ₁₁ R ₁₂ )] n-COR ₁₃ (wherein R ₁₀ , R ₁₁ and R ₁₂ are the same or different and are a hydrogen atom or a lower alkyl group which may be branched) And R ₁₃
Represents a hydroxyl group, an optionally branched lower alkoxy group, an amino group, an optionally branched lower alkylamino group or an optionally branched lower dialkylamino group. n is 0 or 1. ). A, B, D and E
Represents the same or different and represents a nitrogen atom or a carbon atom. However, when Y ₁ is a hydrogen atom, Y ₂ is not a hydrogen atom. A 2-oxindole derivative or a salt thereof.

Further, in general formula (I), X is
-CO-CH = CH-Z wherein Z is the following formula:

[0014]

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(R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.) And Y
₁ is —C (R ₅ R ₆ ) —COR ₉ (wherein R ₅ and R ₆ are the same or different and each represent a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group or a lower branched group; Alkoxy group,
Represents an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. ) And Y ₂ is hydrogen, wherein the 2-oxindole derivative or a pharmaceutically acceptable salt thereof; X is -CO-C
H = CH-Z wherein Z is the following formula:

[0016]

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(R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.) And Y
₁ is —C (R ₅ R ₆ ) —COR ₉ (wherein R ₅ and R ₆ are the same or different and each represent a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group or a lower branched group; Alkoxy group,
Represents an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. Wherein Y ₂ is —C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R ₈ are the same or different , A hydrogen atom or a lower alkyl group, and R ₉ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. Is 1.), or a pharmacologically acceptable salt thereof, wherein X is -CO-CH = CH-Z, wherein Z is the following formula:

[0018]

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(R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.) And Y
₁ and Y ₂ are both ＝ C (R ₁₀ ) -COR ₁₃ (wherein R ₁₀
Represents a hydrogen atom or a lower alkyl group which may be branched, R ₁₃ represents a hydroxyl group, a lower alkoxy group which may be branched,
Represents an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. )), Or a pharmacologically acceptable salt thereof, wherein X is -CO-C
H = CH-Z wherein Z is the following formula:

[0020]

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(R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.) And Y
₁ and Y ₂ are the same —C (R ₅ R ₆ ) — [C (R ₇ R ₈ )] n-CO
R ₉ (wherein, R ₅ , R ₆ , R ₇ and R ₈ are the same or different and each represent a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, X represents a lower alkylamino group which may be branched or a lower dialkylamino group which may be branched, wherein n is 1.), or a pharmaceutically acceptable salt thereof; But the formula:

[0022]

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(Wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group which may be branched. A lower alkylthio group which may be branched, an amino group, a lower alkylamino group which may be branched, a lower dialkylamino group which may be branched or a nitro group), wherein Y ₁ and Y ₂ are Same or different, a hydrogen atom or -C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n
—COR ₉ (wherein, R ₅ , R ₆ , R ₇ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group;
₉ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. n is 0 or 1. (Wherein Y ₁ and Y ₂ are not hydrogen atoms at the same time), or Y ₁ and Y ₂ are both ＝ CR ₁₀ —CO
R ₁₃ (wherein, R ₁₀ represents a hydrogen atom or a lower alkyl group which may be branched; R ₁₃ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or The 2-oxindole derivative or a pharmacologically acceptable salt thereof, which forms a lower dialkylamino group which may be branched;
Or, X is a formula:

[0024]

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(Wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group which may be branched. A lower alkylthio group which may be branched, an amino group, a lower alkylamino group which may be branched, a lower dialkylamino group which may be branched or a nitro group), wherein Y ₁ and Y ₂ are Same -C
_{(R 5 R 6) - [} C (R 7 R 8)] n-COR 9 ( wherein, R _5, R _6,
R ₇ and R ₈ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ₉ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or Represents a lower dialkylamino group which may be substituted. n is 1. )) Or a salt thereof.

The present invention also relates to a pharmaceutical composition containing the above-mentioned 2-oxindole derivative or a pharmacologically acceptable salt thereof as an active ingredient, in particular, an inhibitor of cytokine production and an agent for preventing / treating an autoimmune disease. .

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION In the 2-oxindole derivative (I) of the present invention, the halogen represented by R ₁ and R ₄ means chlorine, bromine, iodine and fluorine. Preferred are chlorine, bromine and fluorine.

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
A lower alkyl or an optionally branched lower alkyl group represented by R ₈ , R ₁₀ , R ₁₁ and R ₁₂ has 1 carbon atom.
To 6 linear or branched alkyl groups, for example,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, te
Examples thereof include an rt-pentyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, and an isohexyl group. Preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. The acyl group represented by R ₂ and R ₃ is a group having 1 carbon atom composed of the lower alkyl group.
And 6 lower alkanoyl groups, preferably formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, methylethylacetyl group, and trimethylacetyl group.

Examples of the cycloalkyl group having 3 to 7 carbon atoms represented by R ₁ and R ₄ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

The optionally branched lower alkoxy group represented by R ₁ , R ₄ , R ₉ and R ₁₃ means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, preferably Represents a methoxy group, an ethoxy group, a propoxy group, or a tert-butoxy group.

The lower branched alkylthio group represented by R ₁ and R ₄ means a linear or branched alkylthio group having 1 to 6 carbon atoms, preferably a methylthio group or an ethylthio group. It is.

R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₀ , R
₁₁ and A branched may be a lower alkyl amino group represented by R _12, means a straight or branched alkylamino group having 1 to 6 carbon atoms, preferably a methyl group, an ethylamino group , Propylamino and butylamino groups. The lower dialkylamino group which may be branched refers to a linear or branched dialkylamino group having 1 to 6 carbon atoms, and is preferably a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group. Group.

The 2-oxindole derivative (I) of the present invention may exist in the form of a salt or hydrate as having excellent properties. Examples of such salts include, but are not limited to, inorganic salts such as hydrochloride, hydrobromide, sulfate, and phosphate, maleate, tartrate, citrate, succinate, and methane. Organic salts such as sulfonic acid salts, metal salts such as Na, Ca, K, Mg or Al, and ammonium salts can be exemplified. When the salt is used in a pharmaceutical composition, it is preferably a pharmacologically acceptable salt. The hydrate is not particularly limited, but may be 0.1 to 1 with respect to one molecule of the 2-oxindole derivative of the present invention or a salt thereof.
A hydrated molecule of water can be exemplified.

The compound (I) of the present invention has various stereoisomers and tautomers, and all of these isomers are included in the present invention. When the molecule contains an asymmetric center, the configuration of the asymmetric center may be either R or S, or a mixture thereof. Then, they can be obtained by using an optically active compound as a starting material, or by purifying the obtained isomer mixture by column chromatography or recrystallization.

Representative examples of the compound (I) of the present invention are shown below. (A) Ethyl 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3-acetate (Compound 1) (b) Ethyl 5-chloro-1- (3,4-dimethoxycinnamoyl) -2- Oxindole-3-acetate (Compound 2) (c) 1- (3,4-Dimethoxycinnamoyl) -2-oxindole-3-acetic acid (Compound 3) (d) Ethyl 5-chloro-1- (3, 4-Dihydroxycinnamoyl) -2-oxindole-3-acetate (Compound 4) (e) N-ethyl-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3-acetamide (Compound 5) (F) Diethyl 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-diacetate (Compound 6) (g) Diethyl 1- (3,4-dihydroxycinnamoyl) -2-
Oxindole-3,3-diacetate (Compound 7) (h) Ethyl [(E) -1- (3,4-dimethoxycinnamoyl) -2
-Oxindole-3-ylidene] acetate (compound 8) (i) [(E) -5-chloro-1- (3,4-dimethoxycinnamoyl)
(2-oxindole-3-ylidene] acetic acid (compound 9) (j) diethyl 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 10) (k) diethyl 5 -Chloro-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 11) (l) Diethyl 5-amino-1- (3,4-dimethoxycinnamoyl) -2 -Oxindole-3,3-dipropionate (compound 12) (m) Diethyl 5-amino-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate hydrochloride (compound 13) (N) diethyl 1- (3,4-dihydroxycinnamoyl) -2-
Oxindole-3,3-dipropionate (Compound 1
4) (o) 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionic acid (compound 15) (p) N, N'-diethyl-1- (3,4- (Dimethoxycinnamoyl)
2-q-oxindole-3,3-dipropionamide (compound 16) (q) 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionamide (compound 17) (r ) Diethyl 4-aza-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 18) (s) Diethyl 4-aza-1- (3,4-dihydroxycinnamoyl) ) -2-oxindole-3,3-dipropionate (Compound 19) (t) diethyl 4-aza-1- (3,4-dihydroxycinnamoyl) -2-oxindole-3,3-dipropionate hydrochloride ( Compound 20) (u) Diethyl 6-aza-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (Compound 21) (v) Diethyl 6-aza-1- (3, 4-dihydroxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 22) (w) die 1- [3- (2-pyridyl) acryloyl] -2-oxindole-3,3-dipropionate hydrochloride (compound 23) (x) ethyl [(E) -1-phenyl-2-oxindole-3 -
[Ylidene] acetate (compound 24) (y) ethyl [(E) -5-chloro-1- (4-chlorophenyl) -2-
Oxindole-3-ylidene] acetate (Compound 2
5) (z) Ethyl [(E) -5-methyl-1- (4-methylphenyl) -2-
Oxindole-3-ylidene] acetate (Compound 2
6) (aa) Ethyl [(E) -5-methoxy-1- (4-methoxyphenyl) -2-oxindole-3-ylidene] acetate (compound 27) (bb) [(E) -1-phenyl- 2-oxindole-3-ylidene] acetic acid (compound 28) (cc) ethyl 1-phenyl-2-oxindole-3-acetate (compound 29) (dd) 1-phenyl-2-oxindole-3,3- Diacetic acid (Compound 30) (ee) 1-Phenyl-2-oxindole-3,3-dipropionic acid (Compound 31) (ff) Diethyl 6-aza-1- [3- (2-pyridyl) acryloyl]- 2-oxindole-3,3-dipropionate (compound 32) (gg) diethyl 6-aza-1- [3- (2-pyridyl) acryloyl] -2-oxindole-3,3-dipropionate hydrochloride (compound 33) The compound (I) of the present invention can be produced according to a conventional method. More specifically, for example, A, B,
It can be manufactured according to the manufacturing method of C, D, E and F.

(1) Manufacturing method A:

[0037]

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Wherein R ₁ , A, B, D and E are as defined above. Y ₁ is —C (R ₅ R ₆ ) —COR ₉ (where R _{5 is}
And R ₆ are the same or different and represent a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or branched. Represents a good lower dialkylamino group. ) And Z is the formula:

[0039]

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[R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched. ]. (I) Compound (II) as a starting material can be obtained, for example, from Journal of Organic Chemistry (Journal of Organic Chemistry).
anic Chemistry), vol. 44, p. 628 (1979).

(Ii) First, starting material (II) is prepared, for example, from US Pat. No. 3,428,649 (1969) or Annalen der Hemy, Justus Liebigs (Annalen der)
According to the method described in Chemie, Justus Liebigs, p. 717 (1978), a Wittig reaction using triphenylphosphorane or triphenylphosphonium salt or a Horner reaction using a phosphonate ester gives a 3-position at the heterocyclic ring. = CR ₁₀ -COR ₁₃ (wherein R ₁₀ and R ₁₃ are as defined above), and an unsaturated acetic acid residue, unsaturated acetic ester residue or unsaturated acetic amide residue is introduced. Then, the unsaturated bond, for example by reduction with a suitable reducing agent such as zinc, -C in the position (R ₅ R ₆₎
An intermediate (VI) into which Y ₁ and a hydrogen atom represented by —COR ₉ (R ₅ , R ₆ and R ₉ are as described above) and a hydrogen atom are introduced is obtained.

In general, according to the Wittig reaction or the Horner reaction, an unsaturated acetate residue is introduced. For this reason, when introducing an unsaturated acetic acid residue, the carboxylic acid moiety of triphenylphosphorane, triphenylphosphonium salt and phosphonate ester is protected with an appropriate protecting group.
A Wittig reaction or a Horner reaction is performed, and after the reaction, a method of removing a protecting group to obtain an unsaturated acetic acid residue can be employed. Alternatively, it may be introduced once as an unsaturated acetic acid ester residue, and after the introduction, the unsaturated acetic acid ester residue may be converted into an unsaturated acetic acid residue. The conversion of the unsaturated acetic acid ester residue to the unsaturated acetic acid residue can be carried out by reducing the unsaturated acetic acid ester residue to a saturated acetic acid ester residue and then converting the same to a saturated acetic acid residue. The conversion of the saturated acetic acid ester residue to the saturated acetic acid residue is carried out by the following reaction (iii) by substituting the substituent -CO-CH = CH-
It may be performed after introducing Z (Z is the same as described above).

The introduction of the acetic acid amide residue is performed by a Wittig reaction using a triphenylphosphane or triphenylphosphonium salt having an acid amide as a partial structure, or a Horner reaction using a phosphonic acid ester. In this case, the reaction can be carried out by reducing the residue with an appropriate reducing agent such as zinc after converting the residue into an unsaturated acetic acid amide residue. Furthermore, after once introducing an unsaturated acetic acid ester residue, a saturated acetic acid ester residue, an unsaturated acetic acid residue or a saturated acetic acid residue, it can be converted to an acid amide residue by a known method. Furthermore, after introducing a substituent at the 1-position of the heterocycle in the following reaction (iii), the 3-position saturated acetic acid ester or saturated acetic acid may be converted to acetic acid amide.

(Iii) Next, the intermediate (VI) produced by the above-described method is subjected to a known acylation reaction of an amide group to give a substituent -CO-CH = CH-Z (Z
Is the same as above. ). Thereby, the compound (I-1) of the present invention is obtained.

The method for introducing the substituent is not particularly limited. For example, an inert solvent such as tetrahydrofuran, benzene, N, N-dimethylformamide or dimethylsulfoxide is added to the intermediate (VI), and the temperature is lowered from -80 ° C to 20 ° C. After cooling to an appropriate temperature of up to ° C., a base such as sodium hydride, potassium tert-butoxide, n-butyllithium, preferably sodium hydride is reacted, and an acid halide or an acid anhydride corresponding to the substituent is further reacted. The reaction may be carried out at an appropriate temperature from -80 ° C to the reflux temperature of the solvent.

As the corresponding acid halide, an acid chloride is preferable, and more specifically, 3,4-dihydroxy which may be protected with 3,4-dimethoxycinnamoyl chloride, tert-butyldimethylsilyl group or the like. Cinnamoyl chloride can be exemplified. At this time, when an acid chloride in which a hydroxyl group is protected is used as an acid chloride, it is needless to say that the protecting group needs to be removed by a known method at any appropriate stage of the reaction step. For example, when the protecting group is a tert-butyldimethylsilyl group, it can be removed with tetrabutylammonium fluoride, hydrochloric acid or the like.

(2) Manufacturing method B

[0048]

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Wherein R ₁ , A, B, D and E are as defined above. Z is the formula:

[0050]

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[R ₂ and R ₃ are the same or different and each represent a hydrogen atom, an acyl group, or a lower alkyl group which may be branched. ]. Y ₁ is -C (R ₅ R ₆ ) -C
OR ₉ (wherein, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower group which may be branched. An alkylamino group or a lower dialkylamino group which may be branched), and Y ₂ is —C (R ₅ R ₆ )
-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₉ is a hydroxyl group, Represents a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched; n is 0 or 1.). W is a protecting group. (I) First, the intermediate (VI) prepared as described above
The intermediate (VII) is prepared by introducing a protecting group (W) on the nitrogen of the amide group at position 1. The protecting group is not particularly limited as long as it becomes a protecting group on the nitrogen of the amide group, and may be any protecting group. For example, lower acyl groups such as formyl group, acetyl group and propionyl group, tert-butyloxycarbonyl group (Boc group), benzyloxycarbonyl group (Z group) and the like can be mentioned. The introduction of the protecting group is the same as the usual introduction reaction of an amino group, imino group or amide group, and is not particularly limited. Usually, for example, the intermediate (V
The reaction can be carried out by adding an inert solvent such as xylene to I) and the protecting group, further adding an acid anhydride such as acetic anhydride and heating to reflux.

(Ii) Next, a substituent -C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n-COR ₉ represented by Y ₂ at the 3-position of the heterocycle (wherein R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and n are as described above.)
To obtain an intermediate (VIII). The introduction method is, for example, that tetrahydrofuran, benzene,
An inert solvent such as N, N-dimethylformamide or dimethylsulfoxide is added, and the mixture is cooled to a suitable temperature between -80 ° C and 20 ° C, and sodium and potassium tert.
A base such as -butoxide and n-butyllithium, preferably sodium hydride is reacted, and a halide corresponding to the above substituent is reacted at a suitable temperature from -80 ° C to the reflux temperature of the solvent. Examples of the halide include chloride, bromide, iodide, and the like, with bromide being preferred.

(Iii) Next, the protecting group (W) in the intermediate (VIII) is removed to obtain an intermediate (IX). The removal method is not particularly limited as long as it removes a protecting group on the nitrogen of the usual amide group. For example, the intermediate (VIII) has water, ethanol,
A solvent such as methanol is added, and the mixture is reacted with an alkali such as sodium hydroxide or potassium hydroxide at an appropriate temperature from -20 ° C to room temperature.

(Iv) Substituent —CO—CH ＝ CH—Z (Z) at the 1-position of the obtained intermediate (IX) according to the method described above.
Is the same as above. ) To obtain the compound (I-2) of the present invention.

(3) Manufacturing method C

[0056]

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Wherein R ₁ , A, B, D and E are the same as above. Z is the formula:

[0058]

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[R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched. ]. Y ₁ and Y ₂ are both ＝ CR ₁₀ —COR ₁₃ (wherein R ₁₀ represents a hydrogen atom or a lower alkyl group which may be branched, R ₁₃ is a hydroxyl group, a lower alkoxy group which may be branched, An amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched). First, a substituent —CO—CH ＝ CH—Z is added to the amide group at the 1-position of the heterocycle of the starting material (II) according to the method described above.
(Z is the same as described above) to give an intermediate (X).
Then, according to the method described in (1) (ii) for the production method A, ３CR ₁₀ -CO
By introducing an unsaturated acetic acid residue, an unsaturated acetic acid ester residue or an unsaturated acetic acid amide residue represented by R ₁₃ (wherein R ₁₀ and R ₁₃ are as defined above), the compound of the present invention is obtained. (I-3) can be obtained.

(4) Manufacturing method D

[0061]

Embedded image

Wherein R ₁ , A, B, D and E are the same as above. Z is the formula:

[0063]

Embedded image

[R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched. ]. Y ₁ and Y ₂ are the same-
_{C (R 5 R 6) -C} (R 7 R 8) n-COR 9 ( wherein, R _5, R _6,
R ₇ and R ₈ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ₉ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or Represents a lower dialkylamino group which may be substituted. n is 1. (I) The starting material (III) can be obtained, for example, from Chemistry an Industry (London).
d Industry (London), p. 1652 (1965), Journal of the Chemical Society Parkin Transaction 1 (Journal of the Chemical Society, P.
erkin Transactions 1), p. 1531 (1974), or Chemical Heterocyclic Compounds (English Tran)
slation)), vol. 13, p. 1224 (1977) and the like.

(Ii) First, in the presence of sodium ethoxide, potassium tert-butoxide, sodium, sodium hydride, preferably sodium ethoxide, potassium tert-butoxide, an excess, preferably twice, By reacting the above acrylate, the same substituent -C (R ₅ R ₆ ) -C (R ₇ R ₈ ) n-COR represented by Y _{1 and} Y ₂ at the 3-position of the hetero ring is obtained. ₉ (where
R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as described above. ) Is introduced to give an intermediate (XI).

(Iii) Next, at the 1-position of the intermediate (XI), the substituent -CO-CH = CH-Z
(Z is the same as described above), whereby the compound (I-4) of the present invention can be obtained.

(Iv) Compound (I-4) wherein R ₉ in Y ₁ and Y ₂ is a hydroxyl group, an amino group, a lower alkylamino group which may be branched or a lower dialkylamino group which may be branched. ) Can be produced by a known method using the compound (I-4) in which R ₉ is a lower alkoxy group which may be branched. Compounds (I-) wherein R ₉ is an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched.
In the case of producing 4), the compound can be produced by a known method using compound (I-4) in which R ₉ is a hydroxyl group as a raw material.

(V) Further, R ₉ in the Y ₁ and Y ₂ groups is a hydroxyl group, an amino group, a lower alkylamino group which may be branched or a lower dialkylamino group which may be branched (分岐 -4). when producing the by known methods from intermediate R ₉ is branched may be a lower alkoxy group (XI), R ₉ is a hydroxyl group, an amino group, which may lower alkylamino group or branched branches Intermediate (XI), which is a lower dialkylamino group, may be produced, and the substituent -CO-CH = CH-Z (Z
Is the same as above. ) Can give the corresponding compound (I-4) of the present invention. Moreover, the intermediate having Y ₁ and Y ₂ R ₉ is an amino group in the group, branched may be a lower alkyl amino group or a branched optionally lower dialkylamino group of (XI), R ₉ has the hydroxyl group Intermediate (X
The compound of the present invention (I-4) corresponding thereto can be produced by a known method from I).

(Vi) The method for introducing the substituent —CO—CH ＝ CH—Z (Z is the same as described above) at the 1-position of the intermediate (XI) is not limited to the above-mentioned method, and the following method can be used. It can also be implemented by a method. For example, an inert solvent such as tetrahydrofuran, benzene, N, N-dimethylformamide or dimethylsulfoxide is added to the intermediate (XI), and the mixture is added at -80 ° C.
To a suitable temperature of from 20 ° C. to 20 ° C. to react with a base such as sodium hydride, potassium tert-butoxide, n-butyllithium or the like, preferably sodium hydride, and further, bromoacetyl bromide, bromoacetyl chloride or chloroacetyl. Intermediate (XII) is obtained by reacting chloride, preferably bromoacetyl bromide or bromoacetyl chloride, at a suitable temperature from -80 ° C to the reflux temperature of the solvent. Next, an inert solvent such as tetrahydrofuran, benzene or toluene is added to the intermediate (XII) and reacted with triphenylphosphine or triethylphosphite at an appropriate temperature from room temperature to the reflux temperature of the solvent. Intermediate (XIII). Then, in the presence of a base such as triethylamine, sodium ethoxide, potassium tert-butoxide or sodium hydride, preferably triethylamine or sodium ethoxide, the reaction with an aldehyde represented by Z-CHO (Z is the same as described above). The compound of the present invention (I
-4) can be obtained.

The intermediate (XII) and the intermediate (X
The conversion of the amide group at the 1-position on the nitrogen in the step of converting to the compound of the present invention (III) via III) is carried out by converting the intermediate (VI) to the compound of the present invention (I-1), or It can be applied to the conversion of the intermediate (IX) to the compound (I-2) of the present invention.

(5) Manufacturing method E

[0072]

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[Wherein R ₁ , A, B, D and E are as defined above. R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms,
Trifluoromethyl group, hydroxyl group, optionally branched lower alkoxy group, optionally branched lower alkylthio group, amino group, optionally branched lower alkylamino group, optionally branched lower dialkylamino group or nitro group It is.
Y ₁ and Y ₂ are the same or different and are each a hydrogen atom or-
C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ ,
R ₆ , R ₇ and R ₈ are the same or different and each represents a hydrogen atom or a lower alkyl group; R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched; Or a lower dialkylamino group which may be branched. n is 0 or 1. ) Or
Y ₁ and Y ₂ are both = CR ₁₀ -COR ₁₃ (wherein R ₁₀
Represents a hydrogen atom or a lower alkyl group which may be branched, R ₁₃ represents a hydroxyl group, a lower alkoxy group which may be branched,
Represents an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. ) Is formed. However, when Y ₁ is a hydrogen atom, Y ₂ is not a hydrogen atom. (I) The starting material (IV) is, for example,
Chimica (Rome), 57, 492 (1967).

(Ii) In the 3-position of the heterocycle of the starting material (IV),
According to the method described in (1) (ii) regarding the production method A,
= CR ₁₀ -COR ₁₃ (wherein R ₁₀ and R ₁₃ are as described above), by introducing an unsaturated acetic acid residue, an unsaturated acetic acid ester residue or an unsaturated acetic acid amide residue, It can be converted to the corresponding compound (I-5) of the present invention.

(Iii) The compound (I-5) having a substituent = CR ₁₀ -COR _{13 at the} 3-position obtained above (wherein R ₁₀ and R ₁₃ are as defined above) was prepared by a method of producing the compound (I-5). By reduction with the reducing agent described for A, -C
The compound (I-5) of the present invention into which Y ₁ and a hydrogen atom (Y ₂ ) represented by (R ₅ R ₆ ) —COR ₉ (R ₅ , R ₆ and R ₉ are the same as described above) has been introduced. Obtainable. further,
By the methods described in connection with the production method B, the Y ₂ is -
_{C (R 5 R 6) -} [C (R 7 R 8)] n-COR 9 (R 5, R 6, R
₇ , R ₈ , R ₉ and n are the same as described above. ) Can be obtained.

(6) Manufacturing method F

[0077]

Embedded image

Wherein R ₁ , A, B, D and E are as defined above. R ₄ is a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group which may be branched, a lower alkylthio group which may be branched. , An amino group, a lower alkylamino group which may be branched, a lower dialkylamino group or a nitro group which may be branched. Y ₁ and Y ₂ are the same —C (R ₅ R ₆ ) — [C (R ₇ R ₈ )] n-COR
₉ (wherein, R ₅ , R ₆ , R ₇ and R ₈ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a branched Represents an optionally substituted lower alkylamino group or an optionally branched lower dialkylamino group, wherein n is 1.) (I) The starting material (V) is, for example, Journal of Medicinal Chemistry (Journal of Medicinal Chemistry)
al Chemistry), vol. 8, p. 626 (1965).

(Ii) In the third position of the starting material (V), the production method D
And the same represented by Y ₁ and Y ₂
-C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R
₆ , R ₇ , R ₈ , R ₉ and n are as described above. ) To obtain the compound of the present invention (I-6).

The compound (I) of the present invention thus obtained may be further purified, if necessary, by a conventional method such as a liquid separation method and a silica gel column chromatography.

The salts and hydrates of the compound (I) of the present invention can be produced by usual salt-forming reactions and hydrate-forming reactions.
It can be purified.

The compound (I) of the present invention and a pharmacologically acceptable salt thereof have an effect of significantly suppressing cytokine production, as shown in the test examples.

The cytokine is a general term for a group of humoral factors responsible for the main intercellular communication in the immune system and the hematopoietic system, for example, lymphokine,
Monokine, interferon, interleukin (I
L), colony stimulating factor (CSF), tumor necrosis factor (T
NF), TGF-β, PDGF and the like. Preferably, they are interleukin and tumor necrosis factor, more specifically, IL-1, IL-6 or TNF-α.

The compound (I) of the present invention has low toxicity and is therefore useful as a cytokine production inhibitor for humans and mammals (eg, mice, rats, rabbits, dogs, cats, etc.).

That is, the compound (I) of the present invention is useful as an agent for preventing or treating various diseases caused by cytokine production, particularly production of IL-1, IL-6, TNF-α and the like. For example, rheumatoid arthritis, sepsis, asthma, inflammatory bowel disease, systemic lupus erythematosus, systemic scleroderma, Behcet's disease, periarteritis nodosa, ulcerative colitis, active chronic hepatitis, glomerulonephritis, deformity Examples include arthritis, gout, atherosclerosis, psoriasis, osteoporosis and the like.

As the pharmaceutical administration form when the compound (I) of the present invention or a pharmacologically acceptable salt thereof is used as a pharmaceutical composition, various pharmaceutical administration forms are widely adopted depending on the purpose. Examples of the form include tablets, pills, powders, granules, fine granules, capsules, liquids,
Examples include oral preparations such as suspensions and emulsions, and parenteral preparations such as injections, drops, suppositories, ointments, plasters, patches and aerosols. These administration agents are formulated by conventional formulation methods generally known in the art.

In the form of tablets, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, simple syrup, glucose solution, Starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters Disintegrators such as glycerol, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, etc .; Agents, glycerin, humectants, such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used.

When the pill is formed into a pill, the carrier may be, for example, an excipient such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, a binder such as gum arabic, tragacanth, gelatin or the like. Laminaran,
Disintegrators such as agar can be used.

The tablets, pills, granules and the like may be in the form of a usual coating as required, such as sugar coating, gelatin encapsulating agent, enteric encapsulating agent, film coating agent and the like. The tablet may be a multilayer tablet such as a double tablet.

Capsules are prepared by mixing a compound of the present invention or a salt thereof with the above-mentioned various carriers and filling the resulting mixture in a hardened gelatin capsule, soft capsule or the like, according to a conventional method.

When preparing an oral liquid preparation, a carrier such as a flavoring agent, a buffering agent, a stabilizer and the like are added to the active ingredient of the present invention, if necessary, and then, a liquid solution for internal use, a syrup,
An elixir or the like can be produced. In this case, sucrose, orange peel, citric acid, tartaric acid and the like can be used as a flavoring agent, sodium citrate and the like can be used as a buffer, and tragacanth, gum arabic, gelatin and the like can be used as a stabilizer.

When preparing an injection or infusion, the compound of the present invention or a salt thereof may be added, if necessary, to a carrier such as a pH adjuster, a buffer, a stabilizer, a local anesthetic, an isotonic agent or the like. By adding a diluent, an injection or drip for intravenous, intramuscular, subcutaneous, intradermal or intraperitoneal use can be produced by a conventional method. Sodium citrate, sodium acetate, sodium phosphate and the like as pH adjusters and buffers, sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like as stabilizers, and hydrochloric acid as a local anesthetic Procaine, lidocaine hydrochloride and the like can be used, and as the tonicity agent, salt, glucose or glycerin can be used. Examples of the diluent include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.

It is preferable that the injection or infusion is sterilized and isotonic with blood.

A suppository can be prepared according to a conventional method after adding a base and, if necessary, a surfactant to the compound of the present invention or a salt thereof. As the base, for example, oily bases such as macrogol, lanolin, cocoa oil, fatty acid triglyceride, and Witepsol (manufactured by Dynamite Novels) can be used.

When preparing ointments, bases, stabilizers, wetting agents, and the like usually used for the compound of the present invention or a salt thereof are used.
A carrier such as a preservative is blended if necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.

The patch can be prepared by applying the above-mentioned ointment, paste, cream, gel or the like to a usual support in a conventional manner. Examples of the support include a woven or non-woven fabric made of cotton, cloth, and synthetic fiber, a film or foam sheet of soft vinyl chloride, polyethylene, polyurethane, or the like.

The pharmaceutical composition of the present invention may further contain a coloring agent, a preservative, and / or a preservative, as long as the effects of the present invention are not impaired.
Conventional additives such as flavors, flavors, sweeteners, and the like, and other pharmaceuticals can also be incorporated.

The method of administering the pharmaceutical composition of the present invention is not particularly limited, and is appropriately selected and determined according to various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. Specific examples include parenteral administration such as oral administration, intravenous administration, subcutaneous / intradermal administration, intramuscular administration, intraarticular administration, rectal administration, transmucosal administration, etc., and preferably oral administration, intravenous administration, and the like. Administration and intra-articular administration.

The amount of the compound of the present invention or a salt thereof to be incorporated in each unit dosage form can be variously selected depending on the patient's condition and dosage form, and cannot be uniformly defined. It is preferably 10 to 1000 mg, about 10 to 100 mg for injection, and 1000 mg for suppositories.

The daily dose of the drug having the above-mentioned dosage form depends on the type of the disease, the symptom / severity of the patient, weight, age, sex, tolerance of the drug, and other conditions. Although it is appropriately selected, it is usually about 0.1 to 500 mg / kg, preferably 0.2 to 300 mg / day for an adult.
mg / kg, which can be administered once or several times a day.

[0101]

EXAMPLES The present invention will be further described below with reference to Reference Examples and Examples. However, the present invention is not limited to these examples. In addition, the physical property values of the compounds prepared in each Example are shown in Tables 1 to 7 (in some NMR spectrum data, no hydroxyl group peak was detected).

REFERENCE EXAMPLE 1 Ethyl 2-oxindole-3-acetate This compound is disclosed in US Pat. No. 3,428,649 by J. Plostnieks.
Can be synthesized according to the method described in the above item.

Specifically, isatin (2.90 g, 19.
7 mmol) and dichloromethane (50 ml),
(Carboethoxymethylene) triphenylphosphorane (6.90 g, 19.8 mmol) was added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was concentrated under reduced pressure. Methanol was added to the residue, the precipitated crystals were collected by filtration, and ethyl [(E) -2-
Oxindole-3-ylidene] acetate (3.0
0 g, 70%). Acetic acid (30 ml) and water (5 ml) were added to this, zinc dust (1.50 g) was added little by little, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was filtered. The filtrate was washed with 1N sodium hydroxide and water, and the organic layer was separated and dried over anhydrous sodium sulfate.
Then, concentrate under reduced pressure to give the title compound (2.90 g, 96%)
I got The compound was used without purification.

Reference Example 2 Ethyl 1-acetyl-2-oxindole-3-acetate Ethyl 2-oxindole-3-acetate (4.0
Xylene (50 ml) and acetic anhydride (5 ml, 53.0 mmol) were added to 0 g, 18.2 mmol), and the mixture was heated under reflux overnight. Ethyl acetate was added to the reaction solution, washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give 4.51 g (95%) of the title compound.
%).

Reference Example 3 1- (3,4-Dimethoxycinnamoyl) isatin Tetrahydrofuran (100 ml) was added to isatin (13.0 g, 88.4 mmol), and sodium hydride (3.80 g, 95.95 g) was added under ice-cooling. 0 mmol) was added in small portions. After stirring for 5 minutes, 3,4-dimethoxycinnamoyl chloride (20.7 g, 91.3 mmol) was added and 1
Stirred for 0 minutes. The reaction solution was poured into water, and the precipitated title compound (22.3 g, 75%) was collected by filtration. The compound was used without purification.

REFERENCE EXAMPLE 4 Diethyl 2-oxindole-3,3-dipropionate This compound was prepared according to the method of Annale by L. Horner.
n), vol. 548, p. 117 (1941).

Specifically, sodium (1.83 g, 7
9.6 mmol) was dissolved in ethanol (50 ml), and 2-oxindole (9.05 g, 68 mmol) was added. After stirring at 60 to 70 ° C. for 10 minutes, ethyl acrylate (24 ml, 0.221 mol) was added. The mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid (100 ml) was added to the residue, and the mixture was extracted with chloroform. The extract was washed with 1N hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1).
0: 1) and 13.56 g (60%) of the title compound
I got

Reference Example 5 Diethyl 1-bromoacetyl-2-oxindole-3,3-dipropionate Diethyl 2-oxindole-3,3-dipropionate (7.05 g, 21.1 mmol) was added to benzene (30%).
0 ml) and sodium hydride (1.27 g, 3
2.0 mmol) and stirred at room temperature for 15 minutes.
Bromoacetyl bromide (6.40 g, 32.0 mmol
l) was added and the mixture was stirred at room temperature for 90 minutes. The reaction solution was poured into a saturated sodium carbonate solution (200 ml), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane: acetonitrile = 10
0: 1) to give 5.91 g (62%) of the title compound. Example 1 Ethyl 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3-acetate (Compound 1) Ethyl 2-oxindole-3-acetate (2.5
Benzene (50 ml) was added to sodium hydride (0.47 g, 11.8 m) under ice cooling.
mol) was added. After the bubbling stopped, 3,4-dimethoxycinnamoyl chloride was added, and the mixture was stirred at 60 to 70 ° C. for 4 hours, and further heated under reflux for 2 hours. The reaction was cooled on ice,
Sodium hydride (0.50 g, 12.5 mmol) was added, stirred for 30 minutes, and further heated to reflux for 1 hour. The reaction solution was washed with 1N hydrochloric acid and water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 7:
Purification in 3) and recrystallization from 2-butanone gave 1.00 g (21%) of the title compound.

Example 2 Ethyl 5-chloro-1- (3,
4-dimethoxycinnamoyl) -2-oxindole-3-acetate (compound 2) In Example 1, ethyl 2-oxindole-3
The same reaction and purification were carried out using ethyl 5-chloro-2-oxindole-3-acetate instead of -acetate to obtain the title compound in a yield of 55%.

Example 3 1- (3,4-Dimethoxycinnamoyl) -2-oxindole-3-acetic acid (Compound 3) In Example 1, ethyl 2-oxindole-3
Tert-butyl 1 prepared using tert-butyl 2-oxindole-3-acetate instead of acetate
-(3,4-dimethoxycinnamoyl) -2-oxindole-3-acetate (0.95 g, 2.17 mmol)
l) was dissolved in anisole (5 ml), trifluoroacetic acid (0.4 ml) was added, and the mixture was stirred at room temperature. 30 minutes and 2
After hours, trifluoroacetic acid (0.6 ml and 0.5 ml)
After stirring at room temperature for a total of 3 hours, hexane was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 0.59 g (71%) of the title compound.

Example 4 Ethyl 5-chloro-1- (3,
4-Dihydroxycinnamoyl) -2-oxindole-3-acetate (Compound 4) In Example 2, ethyl 5-chloro-2-oxindole-3-acetate was replaced with 3,4-dimethoxycinnamoyl chloride instead of 3,4-dimethoxycinnamoyl chloride. , 4-Di-tert-butyldimethylsilyloxycinnamoyl chloride, reacting with ethyl 5-chloro-1- (3,4-di-tert-butyldimethylsilyloxycinnamoyl) -2-oxindole-3-acetate Was obtained in a yield of 19%. Ethyl 5-chloro-1- (3,4-di-tert-butyldimethylsilyloxycinnamoyl) -2-oxindole-3-acetate (3.10 g, 4.80 mmol) was dissolved in tetrahydrofuran (30 ml) and iced. Under cooling, a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (15 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After adding a saturated ammonium chloride solution, the mixture was extracted with ethyl acetate.
The extract was washed with 1N hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from chloroform-hexane and recrystallized from 2-propanol to obtain 0.62 g (31%) of the title compound.

Example 5 N-ethyl-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3-
Acetamide (Compound 5) 1- (3,4-Dimethoxycinnamoyl) -2-oxindole-3-acetic acid (Compound 3) (0.95 g, 2.4
9 mmol), dichloromethane (20 ml) was added, and oxalyl chloride (0.40 g, 3.15 mmol) and N,
N-dimethylformamide (1 drop) was added, stirred for 15 minutes and concentrated under reduced pressure. The residue was treated with dichloromethane (20 m
l), ethylamine (0.5 ml) was added under ice-cooling, and the mixture was stirred for 10 minutes. After water was added to the reaction solution and the mixture was acidified with hydrochloric acid, the organic layer was separated and washed sequentially with saturated saline, saturated sodium bicarbonate solution and saturated saline. After dehydration with anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from chloroform-hexane to give the title compound (0.60).
g (59%).

[0113]

[Table 1]

Example 6 Diethyl 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-
Diacetate (compound 6) Ethyl 1-acetyl-2-oxindole-3-acetate (2.51 g, 9.61 mmol) was dissolved in tetrahydrofuran (30 ml), and cooled with ice under a stream of nitrogen.
After adding sodium hydride (0.50 g, 12.5 mmol) and stirring for 20 minutes, ethyl bromoacetate (1.83) was added.
g, 11.0 mmol) and stirred at room temperature for 1 hour. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (20 ml) and 1N sodium hydroxide solution (5 ml) were added to the residue.
, And the mixture was stirred at room temperature for 2 hours.
Extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain diethyl 2-oxindole-3,3-diacetate in a yield of 67%. This intermediate was reacted with 3,4-dimethoxycinnamoyl chloride in the same manner as in Example 1 to obtain the title compound in a yield of 84%.

Example 7 Diethyl 1- (3,4-dihydroxycinnamoyl) -2-oxindole-3,3
-Diacetate (compound 7) In Example 6, diethyl 2-oxindole-
3,3-Diacetate is reacted with 3,4-di-tert-butyldimethylsilyloxycinnamoyl chloride instead of 3,4-dimethoxycinnamoyl chloride, and diethyl 1- (3,4-di-tert-butyl) is reacted. After obtaining dimethylsilyloxycinnamoyl) -2-oxindole-3,3-diacetate, the tert-butyldimethylsilyl group was removed with tetrabutylammonium fluoride in the same manner as in Example 4 to yield the title compound. Obtained at 41%.

Example 8 Ethyl [(E) -1- (3,4
-Dimethoxycinnamoyl) -2-oxindole-
3-Ylidene] acetate (compound 8) 1- (3,4-dimethoxycinnamoyl) isatin (2.
00g, 5.90mmol) in dichloromethane (50m
l), and (Carboethoxymethylene) triphenylphosphorane (2.10 g, 6.0 mmol) was further added. The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The crystals of the residue were washed with methanol to give the title compound (1.80 g, 7
5%).

Example 9 [(E) -5-chloro-1-
(3,4-Dimethoxycinnamoyl) -2-oxindole-3-ylidene] acetic acid (compound 9) In Example 8, 1- (3,4-dimethoxycinnamoyl) isatin and (carbethoxymethylene) triphenylphospho Instead of orchids, each 5-chloro-1
-(3,4-dimethoxycinnamoyl) isatin and (t
ert-butoxycarbonylmethylene) triphenylphosphorane to give tert-butyl [(E) -1- (3,4-
Dimethoxycinnamoyl) -2-oxindole-3
[Ylidene] acetate was obtained in a yield of 89%, the tert-butyl group was removed by the method of Example 3, and recrystallized from N, N-dimethylformamide-methanol to obtain the title compound in a yield of 67%. Was.

Example 10 Diethyl 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3
-Dipropionate (Compound 10) Diethyl 2-oxindole-3,3-dipropionate (4.06 g, 12.2 mmol) was added to benzene (50%).
of sodium hydride (0.58 ml) under ice-cooling.
g, 14.5 mmol) was added little by little, and after stirring for 15 minutes, 3,4-dimethoxycinnamoyl chloride (3.
41 g, 15.0 mmol) and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) and recrystallized from chloroform-hexane to give the title compound (3.
37g, 54%).

[0119]

[Table 2]

Example 11 Diethyl 5-chloro-1-
(3,4-Dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (Compound 11) In Example 10, diethyl 5-chloro-2- instead of diethyl 2-oxindole-3,3-dipropionate The same reaction and purification were carried out using oxindole-3,3-dipropionate to obtain the title compound in a yield of 7%.
Obtained at 4%.

Example 12 Diethyl 5-amino-1-
(3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (Compound 12) In Example 10, diethyl 5-oxindole-3,3-dipropionate was replaced with diethyl 5-
(N-benzylideneamino) -2-oxindole-
The same reaction was carried out using 3,3-dipropionate and recrystallized from ethanol to give diethyl 5- (benzylideneamino) -1- (3,4-dimethoxycinnamoyl)-
2-Oxindole-3,3-dipropionate was obtained with a yield of 84%. Next, the compound was treated with 1N hydrochloric acid to remove the benzylidene group, and recrystallized from methanol to obtain the title compound in a yield of 78%.

Example 13 Diethyl 5-amino-1-
(3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate hydrochloride (compound 1
3) Diethyl 5-amino-1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 12) was suspended in ethanol, reacted with hydrochloric acid, and re-dissolved in ethyl acetate-hexane. Crystallization afforded the title compound in 87% yield.

Example 14 Diethyl 1- (3,4-dihydroxycinnamoyl) -2-oxindole-3,
3-Dipropionate (Compound 14) In Example 10, 3,4-dimethoxycinnamoyl chloride was replaced with 3,4-di-tert-butyldimethylsilyloxycinnamoyl chloride to give diethyl 2
-Oxyindole-3,3-dipropionate, reacting with diethyl 1- (3,4-di-tert-butyldimethylsilyloxycinnamoyl) -2-oxindole-
After converting into 3,3-dipropionate, the tert-butyldimethylsilyl group was removed in the same manner as in Example 4,
Recrystallization from chloroform-hexane gave the title compound in 46% yield.

Example 15 1- (3,4-Dimethoxycinnamoyl) -2-oxindole-3,3-dipropionic acid (Compound 15) In Example 10, diethyl 2-oxindole-3,3-dipropionate Di-tert-butyl instead of
The same reaction and purification were carried out using 2-oxindole-3,3-dipropionate to obtain di-tert-butyl 1-.
(3,4-Dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate was obtained in a yield of 40%. Next, the tert-butyl group was removed and recrystallized from 2-propanol in the same manner as in Example 2 to obtain the title compound in a yield of 40%.

[0125]

[Table 3]

Example 16 N, N'-diethyl-1-
(3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionamide (compound 16) 1- (3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionic acid (Compound 13) was converted into an acid chloride in the same manner as in Example 5, further reacted with ethylamine, and recrystallized from chloroform-hexane to give the title compound in a yield of 31%.

Example 17 1- (3,4-Dimethoxycinnamoyl) -2-oxindole-3,3-dipropionamide (compound 17) 1- (3,4-Dimethoxycinnamoyl) -2-oxindole -3,3-Dipropionic acid (compound 13) was converted into an acid chloride in the same manner as in Example 5, further reacted with aqueous ammonia, and washed by heating with ethanol to obtain the title compound in a yield of 80%. .

Example 18 Diethyl 4-aza-1-
(3,4-dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 18) In Example 10, diethyl 4-aza-2-yl was used instead of diethyl 2-oxindole-3,3-dipropionate. The same reaction and purification were carried out using oxindole-3,3-dipropionate to give the title compound in a yield of 23.
%.

Example 19 Diethyl 4-aza-1-
(3,4-dihydroxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 19) In the same manner as in Example 12, diethyl 4-aza-2-
Oxindole-3,3-dipropionate and 3,4-
Di-tert-butyldimethylsilyloxycinnamoyl chloride is reacted and purified, and diethyl 4-aza-1-
(3,4-di-tert-butyldimethylsilyloxycinnamoyl) -2-oxindole-3,3-dipropionate. Then, in the same manner as in Example 4,
The tert-butyldimethylsilyl group was removed and crystallized from cyclohexane to give the title compound in 40% yield.

Example 20 Diethyl 4-aza-1-
(3,4-dihydroxycinnamoyl) -2-oxindole-3,3-dipropionate hydrochloride (compound 20) diethyl 4-aza-1- (3,4-dihydroxycinnamoyl) -2-oxindole-3 , 3-Dipropionate was dissolved in dichloromethane, converted into a hydrochloride with hydrogen chloride gas, and crystallized from ether-cyclohexane to give the title compound in 69% yield.

[0131]

[Table 4]

Example 21 Diethyl 6-aza-1-
(3,4-Dimethoxycinnamoyl) -2-oxindole-3,3-dipropionate (Compound 21) In Example 10, diethyl 6-aza-2-yl was used instead of diethyl 2-oxindole-3,3-dipropionate. The same reaction and purification were carried out using oxindole-3,3-dipropionate to give the title compound in a yield of 45.
%.

Example 22 Diethyl 6-aza-1-
(3,4-dihydroxycinnamoyl) -2-oxindole-3,3-dipropionate (compound 22) In Example 21, instead of 3,4-dimethoxycinnamoyl chloride, 3,4-di-tert-butyldimethyl Using silyloxycinnamoyl chloride, diethyl
Reaction with 6-aza-2-oxindole-3,3-dipropionate gives diethyl 6-aza-1- (3,4-
Di-tert-butyldimethylsilyloxycinnamoyl)-
After converting into 2-oxindole-3,3-dipropionate, the tert-butyldimethylsilyl group was removed in the same manner as in Example 4, and recrystallized from ethanol to obtain the title compound. Example 23 Diethyl 1- [3- (2-pyridyl) acryloyl] -2-oxindole-3,3-dipropionate hydrochloride (Compound 23) Diethyl 1-bromoacetyl-2-oxindole-3,3-dipronate (5.91 g, 13.0 mmo
l) and triphenylphosphine (3.41 g, 13.0).
mmol) was dissolved in benzene (150 ml) and stirred at room temperature overnight and at 70 ° C. for 2 hours. Triethylamine was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes.
-Aldehyde (2.09 g, 19.5 mmol) was added in small portions and stirred at room temperature for 50 minutes. The reaction solution was washed with saturated saline and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: acetonitrile), and diethyl 1- [3- (2-pyridyl) acryloyl] -2 was purified.
-Oxindole-3,3-dipropionate was obtained in a yield of 38%. This was dissolved in ether, reacted with hydrogen chloride gas, and recrystallized from acetone-ether to give the title compound in a yield of 74%.

Example 24 Ethyl [(E) -1-phenyl-2-oxindole-3-ylidene] acetate (Compound 24) In Example 8, 1- (3,4-dimethoxycinnamoyl) isatin was used in place of 1- (3,4-dimethoxycinnamoyl) isatin. (Carboethoxymethylene) triphenylphosphorane was reacted with 1-phenylisatin, and the obtained crystals were recrystallized from 2-propanol to give the title compound in 59% yield.

Example 25 Ethyl [(E) -5-chloro-1- (4-chlorophenyl) -2-oxindole-3-ylidene] acetate (Compound 25) In Example 8, 1- (3,4- (Carboethoxymethylene) triphenylphosphorane was reacted with 5-chloro-1- (4-chlorophenyl) isatin in place of dimethoxycinnamoyl) isatin, and the obtained crystals were recrystallized from ethyl acetate. 59% yield of title compound
I got it.

[0136]

[Table 5]

Example 26 Ethyl [(E) -5-methyl-1- (4-methylphenyl) -2-oxindole-3-ylidene] acetate (Compound 26) In Example 8, 1- (3,4 -Carboxethoxymethylene) triphenylphosphorane was reacted using 5-methyl-1- (4-methylphenyl) isatin instead of -dimethoxycinnamoyl) isatin, and the resulting crystals were treated with ethyl acetate-hexane. Recrystallization afforded the title compound in 53% yield.

Example 27 Ethyl [(E) -5-methoxy-1- (4-methoxyphenyl) -2-oxindole-3-ylidene] acetate (Compound 27) In Example 8, 1- (3,4 (Carboxyethoxymethylene) triphenylphosphorane using 5-methoxy-1- (4-methoxyphenyl) isatin in place of -dimethoxycinnamoyl) isatin, and recrystallizing the resulting crystals with 2-propanol. Crystallization gave the title compound in 29% yield.

Example 28 [(E) -1-phenyl-2]
-Oxindole-3-ylidene] acetic acid (compound 2
8) In Example 9, (tert-butoxycarbonylmethylene) triphenylphosphorane was reacted by using 1-phenylisatin instead of 5-chloro-1- (3,4-dimethoxycinnamoyl) isatin. Tert-butyl [(E) -1-phenyl-2-oxindole-
[3-ylidene] acetate was obtained with a yield of 69%. Then, the tert-butyl group was removed in the same manner as in Example 3,
The crystals were recrystallized from 2-propanol-methanol to give the title compound in a yield of 76%.

Example 29 Ethyl 1-phenyl-2-
Oxindole-3-acetate (Compound 29) Ethyl [(E) -1-phenyl-2-oxindole-3-ylidene] acetate (Compound 24) was reduced in the same manner as in Reference Example 1 and recrystallized from cyclohexane. The title compound was obtained in a yield of 78%.

Example 30 1-phenyl-2-oxindole-3,3-diacetate (Compound 30) 1-phenyl-2-oxindole (1.50 g, 7.
Tetrahydrofuran (30 ml) was added to 17 mmol), and then sodium hydride (0.70 g, 1
After stirring for 10 minutes, ethyl bromoacetate (2.40 g, 14.3 mmol) was added to add 1
Stir for 5 minutes. Water was added to the reaction solution, the mixture was acidified with 1N hydrochloric acid, extracted with chloroform, and the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethanol (20 ml) and 1N sodium hydroxide solution (20 ml) were added to the residue (3.44 g), and the mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. Water was added to the residue, the mixture was acidified with hydrochloric acid, extracted with chloroform, and the obtained extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-cyclohexane to give the title compound (0.82 g, yield 36%).

Example 31 1-Phenyl-2-oxindole-3,3-dipropionic acid (Compound 31) Sodium (0.16 g, 6.96 mmol) was dissolved in ethanol (50 ml), and 1-phenyl-2- Add oxindole (1.50 g, 7.17 mmol) and add 20
After stirring for minutes, ethyl acrylate (1.45 g, 14.
4 mmol) and heated under reflux for 20 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, acidified with hydrochloric acid, and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain diethyl 1-phenyl-2-oxindole-3,3-dipropionate, and hydrolyzed in the same manner as in Example 25. Decompose,
Recrystallization from ethanol gave the title compound (1.22 g, yield 48%).

[0143]

[Table 6]

Example 32 Diethyl 6-aza-1-
[3- (2-Pyridyl) acryloyl] -2-oxindole-3,3-dipropionate (Compound 32) Diethyl 6-aza-2-oxindole-3,3-dipropionate (2.50 g, 7.7 mmol) Dissolve in benzene (200 ml), add sodium hydride (0.30 g, 7.5 mmol) under ice cooling, stir for 10 minutes, and then add bromoacetyl bromide (1.51 g, 7.5 mmol).
l) was added. After stirring at room temperature for 10 minutes, a saturated sodium hydrogen carbonate solution (100 ml) was added to the reaction solution, and the mixture was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then triphenylphosphine (1.97 g, 7.7)
mmol) and stirred at 50 ° C. for 2 hours. Triethylamine (1.0 ml, 7.2 mmol) and pyridine-2-aldehyde (0.80 g, 7.5 mmol) were added to the reaction solution.
Was added and stirred at 50 ° C. for 2 hours. The reaction solution was washed with saturated saline, and the organic layer was extracted with 1N hydrochloric acid. The obtained extract was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The obtained extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3) and recrystallized from 2-propanol to give the title compound (0.59 g, yield 17%).

Example 33 Diethyl 6-aza-1-
[3- (2-pyridyl) acryloyl] -2-oxindole-3,3-dipropionate hydrochloride (compound 33) diethyl 6-aza-1- [3- (2-pyridyl) acryloyl] -2-oxindole -3,3-Dipropionate (Compound 32) was dissolved in ethanol, reacted with hydrochloric acid, and recrystallized from 2-propanol to obtain the title compound (31% yield).

[0146]

[Table 7]

[0147]

Test Examples In order to confirm that the compounds of the present invention suppress the production of various cytokines, the following tests were performed. (1) Measurement of inhibitory action on IL-1 production [Method] Human venous blood was collected and Ficoll-Paque PLUS (Phar
macia) and mononuclear cells were obtained by double layer specific gravity centrifugation. R containing 10% of fetal calf serum (FCS)
It was dispersed in a PMI1640 culture solution. This was seeded at 2 × 10 ⁶ / ml / well in a culture 24-well plate (CORNING).
Thereafter, a DMSO solution containing the compound of the present invention (final concentration of DMSO: 0.1%) and lipopolysaccharide (LPS: DIFCO) (final concentration: 50 ng / ml) were added, and the mixture was added under an atmosphere of 5% CO _2.
C. for 24 hours. Thereafter, the culture supernatant was added to IL-1.
Stored at -80 ° C until production was measured. For the measurement of the amount of IL-1, the diluted mononuclear cell supernatant was used for titerZyme human
The amount of IL-1 was measured using an IL-1 EIA kit (PerseptiveBiosystem), and the amount of IL-1 was calculated from the obtained human IL-1 standard curve to determine the production inhibition rate at a compound concentration of 5 μM and 10 μM of the present invention.

[Results] Table 8 shows that the compounds in the examples were 5 μM.
Shows the suppression rate in FIG.

As can be seen from the above, the compound of the present invention enhanced the inhibitory action of control compound (1) tenidap sodium and control compound (2) tenidap sodium on IL-1 production by 6-chloro-1- (3, 4-Dihydroxycinnamoyl) -3,4-dihydro-2 (1H) -quinolinone (JP-A-5-320133) showed superior activity.

(2) Measurement of IL-6 production inhibitory action [Method] A part of the mononuclear cell supernatant obtained in (1) was collected and subjected to IL-6 measurement. This supernatant was stored at -80 ° C until measurement of IL-6. The measurement of IL-6 activity was performed by measuring MH60 · B in which proliferation was observed in the presence of IL-6.
The determination was performed based on the cell growth inducing factor activity using SF2 cells (mouse hybridoma). That is, MH60
The BSF2 cells 1 × 10 ⁴ / 100μl / well were seeded in addition mononuclear cell supernatant 100 [mu] l / well diluted to 44
Cultured for hours. Cell proliferation was measured by measuring 100% of the culture supernatant.
After removing μl / well, 5 mg / ml MTT reagent (CHEMICON
INTERNATIONAL) (10 μl / well), and cultured at 37 ° C. for 4 hours in a 5% CO ₂ atmosphere. The resulting formazan was solubilized with a 0.04 N hydrochloric acid / 2-propanol mixed solution (100 μl / well), and the absorption wavelength was 570 nm. By measuring the absorbance at. The reference wavelength used was 650 nm. Further, the amount of IL-6 was calculated from a standard curve obtained by adding a standard human IL-6 to the same cultured cells, and the production inhibitory rate under the compound of the present invention at 5 μM and 10 μM was determined.

[Results] Table 8 shows compounds (5 μm) in Examples.
M) shows the suppression rate. As can be seen from the above, the compound of the present invention was obtained by enhancing the inhibitory effect of control compound (1) tenidap sodium and control compound (2) tenidap sodium on IL-1 production by 6-chloro-1- (3,4-dihydroxy). Cinnamoyl) -3,4-dihydro-2 (1
Excellent activity was exhibited as compared to H) -quinolinone.

(3) Measurement of TNF-α production inhibitory action [Method] A part of the mononuclear cell supernatant obtained in (1) was collected and subjected to TNF-α measurement. The supernatant was stored at -80 ° C until TNF-α was measured. The measurement of TNF-α activity is based on WE in which growth is inhibited in the presence of TNF-α.
The determination was performed based on the cell growth inhibitory activity using HI-164 cells (mouse fibroblast cell line). That is, WEH
I-164 cells were seeded ^{4 × 10 4 / 100μl / well} , mononuclear cell supernatant 100 [mu] l / well and AMD diluted to
-Mannitol (SIGMA) (AMD-mannitol final concentration; 1 µg / ml) was added and cultured for 20 hours. Cell proliferation was measured after removing 100 μl / well of culture supernatant.
mg / ml MTT reagent (CHEMICONINTERNATIONAL) 10μ
l / well, and cultured at 37 ° C. for 4 hours in a 5% CO ₂ atmosphere. The resulting formazan was solubilized with a 0.04 N hydrochloric acid / 2-propanol mixture 100 μl / well, and the absorbance at an absorption wavelength of 570 nm was measured. It was performed by measuring. The control wavelength used was 650 nm. Also, standard human TN
From the standard curve obtained by adding F-α to the same cultured cells, TN
The amount of F-α was calculated, and 5 μM and 10 μM of the compound of the present invention were obtained.
The production inhibition rate below was determined.

[Results] Table 8 shows 5 μm of the compounds in the examples.
M, the compound of the present invention enhanced the inhibitory effect of control compound (1) tenidap sodium and control compound (2) tenidap sodium on IL-1 production by 6-chloro-1- (3 , 4-dihydroxycinnamoyl) -3,4-dihydro-2 (1H) -quinolinone.

[0154]

[Table 8]

(4) IC _{50 of} cytokine production inhibitory action
Value [Method] According to the methods of (1), (2) and (3), the compounds (0.8 μM, 1.6 μM, 3.1 μM, 6.3 μM,
IL-1, TNF by 12.5 μM, 25 μM and 50 μM)
-Α and IL-6 production inhibition rates were calculated, and the values were determined according to Yukms Statistical Library II Bioassay Ver. 5 by the Probit method using the (Yukkumusu Co., Ltd.), IC ₅₀
Values were calculated. Among the compounds in the examples, those for which a good linear relationship was not obtained in the inhibition rate of each concentration were determined by IC
_The concentration range including ₅₀ values is shown.

[Results] Table 9 shows the IC ₅₀ values of the compounds in the examples.
Indicates a value. As can be seen, the compounds of the present invention are:
6-chloro-1- (3,4-dihydroxycinnamoyl) -3,4-dihydro-2 which enhanced the inhibitory effect of control compound (1) tenidap sodium and control compound (2) tenidap sodium on IL-1 production. Excellent activity was shown as compared to (1H) -quinolinone.

[0157]

[Table 9]

(5) Cytotoxicity [Method] A part of the mononuclear cell supernatant obtained in (1) was collected and subjected to cytotoxicity measurement. The supernatant was stored at 4 ° C. until cytotoxicity was determined. Cytoto
Using the xicity Detecti-on Kit (BOEHRINGER MANNHEIM), the LDH activity in the mononuclear cell supernatant was measured, and the dead cell ratio (%) in all cells was calculated.

[Results] Table 8 shows 5 μM of the compounds in the examples.
However, no toxicity to cells was observed at the concentration at which cytokine production was suppressed.

[0160]

According to the above test, the compound of the present invention has low toxicity and remarkably suppresses the production of cytokines such as IL-1, IL-6 and TNF-α. Therefore, the compound of the present invention is useful for the treatment of autoimmune diseases such as rheumatoid arthritis. Or it is expected to be used as a prophylactic agent.

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[Procedure amendment]

[Submission date] April 7, 1998

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0032

[Correction method] Change

[Correction contents]

In the present specification, the lower alkylamino group which may be branched means a linear or branched alkylamino group having 1 to 6 carbon atoms, preferably a methylamino group, an ethylamino group, A propylamino group and a butylamino group. The lower dialkylamino group which may be branched refers to a linear or branched dialkylamino group having 1 to 6 carbon atoms, and is preferably a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group. Group.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0036

[Correction method] Change

[Correction contents]

(1) Manufacturing method A

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0042

[Correction method] Change

[Correction contents]

In general, according to the Wittig reaction or the Horner reaction, an unsaturated acetate residue is introduced. For this reason, when introducing an unsaturated acetic acid residue, the carboxylic acid moiety of triphenylphosphorane, triphenylphosphonium salt and phosphonate ester is protected with an appropriate protecting group.
A Wittig reaction or a Horner reaction is performed, and after the reaction, a method of removing a protecting group to obtain an unsaturated acetic acid residue can be employed. Alternatively, it may be introduced once as an unsaturated acetic acid ester residue, and after the introduction, the unsaturated acetic acid ester residue may be converted into an unsaturated acetic acid residue. Unsaturated acid ester residue or, et al
Conversion to saturated acid residues, an unsaturated acetic ester residue after reduced to the saturated acid ester residue can be carried out by converting the saturated acid residues. The conversion of a saturated acetic acid ester residue to a saturated acetic acid residue is carried out by the following reaction (iii) by substituting a substituent -CO-CH = CH-Z
(Z is the same as described above).

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0064

[Correction method] Change

[Correction contents]

[R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an acyl group, or a lower alkyl group which may be branched. ]. Y ₁ and Y ₂ are the same-
_{C (R 5 R 6) -C} (R 7 R 8) n-COR 9 ( wherein, R _5, R _6,
R ₇ and R ₈ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ₉ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or Represents a lower dialkylamino group which may be substituted. n is 1. (I) The starting material (III) can be obtained, for example, from Chemistry an Industry (London).
d Industry (London), p. 1652 (1965), Journal of the Chemical Society Parkin Transaction 1 (Journal of the Chemical Society, P.
erkin Transactions 1), 1531, pp. (1974), or the chemical heterocyclic Konpaunzu (English translation)
(Chemical Heterocyclic Compounds (English Translat
ion)), vol. 13, p. 1224 (1977) and the like.

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0065

[Correction method] Change

[Correction contents]

(Ii) First, in the presence of sodium ethoxide, potassium tert-butoxide, sodium, sodium hydride, preferably sodium ethoxide, potassium tert-butoxide, an excess, preferably twice, By reacting the above-mentioned acrylate, the same substituent represented by Y ₁ and Y ₂ at the 3-position of the heterocyclic ring —C (R ₅ R ₆ ) —C (R ₇ R ₈ ) n-COR ₉ (where
R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as described above. ) Is introduced to give an intermediate (XI).

[Procedure amendment 6]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

(V) Further, R ₉ in the Y ₁ and Y ₂ groups is a hydroxyl group, an amino group, a lower alkylamino group which may be branched or a lower dialkylamino group which may be branched .
When producing compound and (I-4) by known methods from intermediates (XI) is a substituted lower alkoxy group R ₉ is branched, R ₉ is a hydroxyl group, an amino group, it may be branched Intermediate (XI), which is a lower alkylamino group or a lower dialkylamino group which may be branched, is produced, and the substituent -CO-CH = CH-Z is prepared by the method described above.
(Z is the same as described above.), Whereby the corresponding compound (I-4) of the present invention can be obtained. Also, Y
Intermediate with ₁ and Y ₂ R ₉ is an amino group in the group, a branched optionally a lower alkyl amino group or a branched optionally lower dialkylamino group of (XI), intermediate R ₉ has a hydroxyl group ( XI) by a known method, whereby the corresponding compound (I-4) of the present invention can be obtained.

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0073

[Correction method] Change

[Correction contents]

Wherein R ₁ , A, B, D and E are the same as above. R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms,
Trifluoromethyl group, hydroxyl group, optionally branched lower alkoxy group, optionally branched lower alkylthio group, amino group, optionally branched lower alkylamino group, optionally branched lower dialkylamino group or nitro group It is.
Y ₁ and Y ₂ are the same or different and are each a hydrogen atom or-
C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ ,
R ₆ , R ₇ and R ₈ are the same or different and each represents a hydrogen atom or a lower alkyl group; R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched; Or a lower dialkylamino group which may be branched. n is 0 or 1. ) Or
Y ₁ and Y ₂ are both = CR ₁₀ -COR ₁₃ (wherein R ₁₀
Represents a hydrogen atom or a lower alkyl group which may be branched, R ₁₃ represents a hydroxyl group, a lower alkoxy group which may be branched,
Represents an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. ) Is formed. However, when Y ₁ is a hydrogen atom, Y ₂ is not a hydrogen atom. (I) The starting material (IV) is, for example,
KIMICA (Rome) (Ann.Chim. (Rome)) , 57 vol., It can be easily obtained by the method described in 492 pages (1967).

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0075

[Correction method] Change

[Correction contents]

(Iii) The compound (I-5) having a substituent = CR ₁₀ -COR _{13 at the} 3-position obtained above (wherein R ₁₀ and R ₁₃ are as defined above) was prepared by a method of producing the compound (I-5). By reduction with the reducing agent described for A, -C
The compound (I-5) of the present invention into which Y ₁ and a hydrogen atom (Y ₂ ) represented by (R ₅ R ₆ ) —COR ₉ (R ₅ , R ₆ and R ₉ are the same as described above) has been introduced. Obtainable. further,
By the methods described in connection with the production method B, the Y ₂ is -
_{C (R 5 R 6) -} [C (R 7 R 8)] n-COR 9 (R 5, R 6, R
₇ , R ₈ , R ₉ and n are the same as described above. ) (I-5 ) of the present invention.

[Procedure amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0083

[Correction method] Change

[Correction contents]

The cytokine is a general term for a group of humoral factors responsible for the main intercellular communication in the immune system and the hematopoietic system, for example, lymphokine,
Monokine , interferon , interleukin (I
L) , colony stimulating factor (CSF) , tumor necrosis factor (T
NF) , TGF-β , PDGF and the like. Preferably, they are interleukin and tumor necrosis factor, more specifically, IL-1, IL-6 or TNF-α.

[Procedure amendment 10]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

The compound (I) of the present invention has low toxicity and is therefore useful as a cytokine production inhibitor for humans and mammals (eg, mice, rats, rabbits, dogs , cats, etc.).

[Procedure amendment 11]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

Example 28 [(E) -1-phenyl-2]
-Oxindole-3-ylidene] acetic acid (compound 2
8) In Example 9, 5-chloro-1- (using 3,4-dimethoxy cinnamoyl) 1- Feniruisachi down instead of isatin, by reacting (tert- butoxycarbonyl methylene) triphenylphosphorane, tert-butyl [(E) -1-phenyl-2-oxindole-
[3-ylidene] acetate was obtained with a yield of 69%. Then, the tert-butyl group was removed in the same manner as in Example 3,
The crystals were recrystallized from 2-propanol-methanol to give the title compound in a yield of 76%.

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[0147]

Test Examples The following tests were performed to confirm that the compounds of the present invention suppress the production of various cytokines . (1) Measurement of inhibitory action on IL-1 production [Method] Human venous blood was collected and Ficoll-Paque PLUS (Phar
macia) and mononuclear cells were obtained by double layer specific gravity centrifugation. R containing 10% of fetal calf serum (FCS)
It was dispersed in a PMI1640 culture solution. This was seeded at 2 × 10 ⁶ / ml / well in a culture 24-well plate (CORNING).
Thereafter, a DMSO solution containing the compound of the present invention (final concentration of DMSO: 0.1%) and lipopolysaccharide (LPS: DIFCO) (final concentration: 50 ng / ml) were added, and the mixture was added under an atmosphere of 5% CO _2.
C. for 24 hours. Thereafter, the culture supernatant was added to IL-1.
Stored at -80 ° C until production was measured. For the measurement of the amount of IL-1, the diluted mononuclear cell supernatant was used for titerZyme human
The amount of IL-1 was measured using an IL-1 EIA kit (PerseptiveBiosystem), and the amount of IL-1 was calculated from the obtained human IL-1 standard curve to determine the production inhibition rate at a compound concentration of 5 μM and 10 μM of the present invention.

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(5) Cytotoxicity [Method] A part of the mononuclear cell supernatant obtained in (1) was collected and subjected to cytotoxicity measurement. The supernatant was stored at 4 ° C. until cytotoxicity was determined. Cytoto
Xicity Detect used io n Kit (BOEHRINGER MANNHEIM Corp.) the LDH activity of mononuclear cell supernatant fluid was measured to calculate the rate of dead cells in whole cells (%). [Results] Table 8 shows the dead cell rate of the compounds in the examples at 5 μM, but no toxicity to cells was observed at the concentration at which cytokine production was suppressed.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 401/06 209 C07D 401/06 209 471/04 104 471/04 104Z (72) Inventor Eiji Sugiyama Chuodaji Awada, Shimogyo-ku, Kyoto-shi No. 1 Town Science Center Building No. 3 Maruho Co., Ltd. Kyoto Metropolitan Research Institute (72) Inventor Koji Imamura 2763 Takamiyacho, Hikone City Maruho Corporation Hikone Research Institute (72) Inventor Hirokazu Tanaka 2763 Takamiyacho Hikone City Maruho Stock Hikone Research Institute

Claims (10)

[Claims] 1. A compound of the general formula (I) [Wherein R ₁ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group which may be branched, A lower alkylthio group which may be
It represents an amino group, a lower alkylamino group which may be branched, a lower dialkylamino group which may be branched or a nitro group. X is -CO-CH = CH-Z, wherein Z is the following formula: (R ₂ and R ₃ are the same or different and represent a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.)
Represents any of Or the formula: (Wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms,
Trifluoromethyl group, hydroxyl group, optionally branched lower alkoxy group, optionally branched lower alkylthio group, amino group, optionally branched lower alkylamino group, optionally branched lower dialkylamino group or nitro group Represents ) Represents an aryl group. Y ₁ and Y ₂ are the same or different and are each a hydrogen atom or —C (R ₅ R ₆ ) — [C (R
₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R ₈ are
Same or different and represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or a lower dialkylamino group which may be branched. Represents n
Is 0 or 1. ) Or in both Y ₁ and Y ₂ = CR _10- [C (R ₁₁ R ₁₂ )] n-COR ₁₃ (wherein R ₁₀ ,
R ₁₁ and R ₁₂ are the same or different and each represent a hydrogen atom or a lower alkyl group which may be branched, and R ₁₃ represents a hydroxyl group,
It represents a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched. n is 0 or 1. )
Is formed. A, B, D and E are the same or different and represent a nitrogen atom or a carbon atom. Where Y
_{When 1} is a hydrogen atom, Y ₂ is not a hydrogen atom. A 2-oxindole derivative or a salt thereof. 2. X is -CO-CH = CH-Z wherein Z is the following formula: (R ₂ and R ₃ are the same or different and represent a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.)
Represents any of And Y ₁ is -C (R ₅ R ₆ ) -C
OR ₉ (wherein, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower group which may be branched. The 2-oxindole derivative or a salt thereof according to claim 1, wherein Y ₂ represents hydrogen, which represents an alkylamino group or a lower dialkylamino group which may be branched. (3) X is -CO-CH = CH-Z wherein Z is the following formula: (R ₂ and R ₃ are the same or different and represent a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.)
Represents any of And Y ₁ is -C (R ₅ R ₆ ) -C
OR ₉ (wherein, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower group which may be branched. An alkylamino group or a lower dialkylamino group which may be branched), and Y ₂ is —C (R ₅ R ₆ )
-[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₉ is a hydroxyl group, A lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched, or a lower dialkylamino group which may be branched, wherein n is 0 or 1.). Or a salt thereof. 4. X is -CO-CH = CH-Z wherein Z is the following formula: (R ₂ and R ₃ are the same or different and represent a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.)
Represents any of And Y ₁ and Y ₂ are both =
CR ₁₀ -COR ₁₃ (wherein, R ₁₀ represents a hydrogen atom or a lower alkyl group which may be branched, and R ₁₃ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkyl which may be branched. 2. The 2-oxindole derivative or a salt thereof according to claim 1, which represents an amino group or a lower dialkylamino group which may be branched. 5. X is -CO-CH = CH-Z wherein Z is the following formula: (R ₂ and R ₃ are the same or different and represent a hydrogen atom, an acyl group, or a lower alkyl group which may be branched.)
And Y ₁ and Y ₂ are the same as each other with -C (R ₅ R ₆ )-
[C (R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R
₈ is the same or different and represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or a lower alkyl which may be branched. Represents a dialkylamino group. n is 1. The 2-oxindole derivative according to claim 1 or a salt thereof. 6. X is a compound represented by the formula: (Wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms,
Trifluoromethyl group, hydroxyl group, optionally branched lower alkoxy group, optionally branched lower alkylthio group, amino group, optionally branched lower alkylamino group, optionally branched lower dialkylamino group or nitro group Represents And Y ₁ and Y ₂ are the same or different and are each a hydrogen atom or —C (R ₅ R ₆ )-[C (R ₇ R ₈ )] n-COR
₉ (wherein, R ₅ , R ₆ , R ₇ and R ₈ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a branched Represents an optionally substituted lower alkylamino group or an optionally branched lower dialkylamino group, wherein n is 0 or 1. (However, when Y ₁ is a hydrogen atom, Y ₂ is not a hydrogen atom.) ), Y ₁ and Y ₂ are both = CR ₁₀ -CO
R ₁₃ (wherein, R ₁₀ represents a hydrogen atom or a lower alkyl group which may be branched; R ₁₃ represents a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or The 2-oxindole derivative or a salt thereof according to claim 1, wherein the 2-oxindole derivative represents a lower dialkylamino group which may be branched. 7. X is a compound represented by the formula: (Wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be branched, a cycloalkyl group having 3 to 7 carbon atoms,
Trifluoromethyl group, hydroxyl group, optionally branched lower alkoxy group, optionally branched lower alkylthio group, amino group, optionally branched lower alkylamino group, optionally branched lower dialkylamino group or nitro group Represents ) And Y ₁ and Y ₂ are the same as those represented by -C (R ₅ R ₆ )-[C
(R ₇ R ₈ )] n-COR ₉ (wherein R ₅ , R ₆ , R ₇ and R
₈ is the same or different and represents a hydrogen atom or a lower alkyl group, and R ₉ is a hydroxyl group, a lower alkoxy group which may be branched, an amino group, a lower alkylamino group which may be branched or a lower alkyl which may be branched. Represents a dialkylamino group. n is 1. The 2-oxindole derivative according to claim 1 or a salt thereof. 8. A cytokine production inhibitor comprising the 2-oxindole derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient. 9. The method according to claim 9, wherein the cytokine is IL-1, IL-6 and T
The cytokine production inhibitor according to claim 8, which is any one selected from the group consisting of NF-α. 10. The method according to claim 1, wherein
An agent for treating or preventing an autoimmune disease, comprising an oxindole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.