JPH092954A - Suppressant for production of both il-8 and mcaf - Google Patents

Abstract

PURPOSE: To obtain a suppressant, containing a carbostyril derivative represented by a specific formula and/or its salt as an active ingredient and capable of suppressing abnormal production of both interleukin 8 (IL-8) and a monocyte chemotactic and activating factor (MCAF) and effective in preventing and treating psoriasis, etc. CONSTITUTION: This suppressant contains a carbostyril derivative represented by the formula (R is brenzoyl which may have a lower alkoxyl on the phenyl ring; the carbon bond between the 3- and the 4-positions of the carbostyril skeleton is a single or a double bond) and/or its salt, e.g. 6-[4-(3,4- dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril as an active ingredient. Furthermore, the content of the compound of the formula is preferably about 1-30wt.% in the composition and the daily dose thereof is preferably about 0.5-30mg based on 1kg body weight.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an IL-8 production inhibitor and MCA containing a pharmaceutically useful carbostyril derivative represented by the following general formula (1) and / or a salt thereof as an active ingredient.
It relates to an F production inhibitor.

[0002]

2. Description of the Related Art Inflammation is a biological defense reaction that occurs in order to maintain homeostasis of a living body in tissue damage caused by various stimuli (physical / chemical, microbial, etc.). The inflammation has multiple phases such as enhancement of vascular permeability, infiltration of inflammatory cells such as neutrophils and macrophages, infiltration of lymphocytes as an immune response, and tissue repair. A variety of cells such as various cells that make up the field of inflammation and leukocytes that infiltrate the inflammatory lesion via blood vessels are involved in this inflammation.

Polypeptide-type active factors produced by these cells and involved in the formation of a complex inflammatory response are called inflammatory cytokines. Among these cytokines, many cytokines having leukocyte chemotactic ability have been discovered in recent years, and their structures and functions have been elucidated.
The above cytokines are collectively referred to as chemokines.
Ines) and has been found to play an important role in leukocyte infiltration in inflammation.

The above-mentioned name of chemokine was given to a polypeptide factor having chemotactic activity specifically in leukocytes at the 1992 International Leukocyte Chemotaxis Symposium. These factors are highly homologous in amino acid sequence, structurally have four cystine residues, and have a common feature of a molecular weight of about 10,000. Due to this cystine (Cys) binding mode, chemokines are currently classified into two subfamilies, Cys-X-Cys and Cys-Cys, and IL-8 (Int.
erleukin-8) is the former MCAF (Mono).
cyto Chemotactic and Acti
vating Factor): Another name MCP-1 (Mo
nocyte Chemattractant Pr
Protein-1) is a typical cytokine of the latter.

Both of these cytokines are said to bind to hormone type receptors. IL of these
-8 is a polypeptide having a molecular weight of 8 KDa and is composed of 72 amino acids.

IL-8 (aka NAP-1: Neutro)
phil Activating Peptide-1)
Was isolated and purified as neutrophil chemotactic factor (NCF) from LPS-stimulated human peripheral blood mononuclear cell culture supernatant in 1987 [Yoshimura, T. et al. , Et al. , P
rc. Natl. Acad. Sci. , USA, 8
4 , 9233 (1987)], and then the chemotactic factor (TCF) of T lymphocytes was similarly isolated and purified [Lase].
n, C.I. G. FIG. , Et al. , Science, 24
3, 1983 (1989)], and it became clear that they were the same factor, and it was named IL-8.

The IL-8 induces neutrophil migration and activates neutrophils. As the action of IL-8, not only the enhancement of neutrophil chemotaxis but also the action of promoting degranulation and the production of superoxide, the action of enhancing lysosomal enzyme release, the action of promoting LTB ₄ , 5HETE production, the adhesion molecule (C
D11abc, CD18) expression-enhancing action, CR-1 expression-enhancing action, non-stimulated vascular endothelial cell adhesion-promoting action, cytokine-stimulated vascular endothelial cell adhesion-inhibiting action, Candida albicans growth inhibitory action, T cell and basophil The chemotactic activity of erythrocytes has been reported, and the release of histamine and leukotriene from basophils, and angiogenic activity on vascular endothelial cells have also been reported.

The diseases in which IL-8 may be involved include skin psoriasis, rheumatoid arthritis, bronchial asthma, acute myocardial infarction, adult respiratory distress syndrome (ARDS), sepsis, vascular inflammation, hepatitis and the like. [Masafumi Takahashi, Clinician, 19 (9), 42-45 (1993)].

On the other hand, MCAF is 1 as a monocyte chemotactic factor.
Isolated and purified in 989 [Yoshimura,
T. , Et al, J .; Exp. Med. , 169 , 1
449 (1989)], the MCAF is produced by various cells such as LPS-stimulated monocytes and vascular endothelial cells, fibroblasts, vascular smooth muscle cells stimulated by inflammatory cytokines such as IL-1 and TNF. It has been reported that they have a monocyte chemotactic and activating effect, and further have an enhancing effect on the chemotactic ability of T lymphocytes and basophils. In addition, MCAF promotes superoxide production, lysosomal enzyme release enhancement, antitumor activity enhancement, cytokine production enhancement, adhesion molecule (CD11bc) expression enhancement, histamine release from basophils, etc. Has been reported. The diseases in which the MCAF is involved include arteriosclerosis, rheumatoid arthritis, pulmonary fibrosis, malignant glioma, melanoma, fibrosarcoma, malignant fibrous histiocytoma [Takahashi, Clinician, 19 (9), 42. -45 (199
3)] is considered.

From the relationship between each of the above diseases and IL-8 and MCAF, a drug having a function of suppressing overproduction of IL-8 and MCAF in vivo is effective for the prevention and treatment of each of the above diseases. Therefore, development of such a drug is desired in the art.

[0011]

The present invention provides the above IL-8.
Suppression of abnormal production and / or suppression of abnormal production of MCAF,
Alternatively, a new IL-8 production inhibitor and MCAF production inhibitor capable of treating various diseases caused by the abnormal production of IL-8 and / or MCAF by simultaneously suppressing the abnormal production of IL-8 and MCAF Is in the point of providing.

The inventors of the present invention have conducted extensive studies for the above purpose, and as a result, have developed a carbostyril derivative represented by the following general formula (1) and // which was previously developed as an active ingredient for cardiotonic agents.
Or a salt thereof was found to have a desired IL-8 production inhibitory action that meets the above objectives, and also has an MCAF production inhibitory action, and was found to be effective as a drug that meets the above objectives. The present invention has been completed.

That is, the present invention has the general formula

[0014]

Embedded image

[In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. The carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton indicates a single bond or a double bond. ] It is related with the IL-8 production inhibitor and MCAF production inhibitor which have the carbostyril derivative and / or its salt represented by these as an active ingredient.

The carbostyril derivative used as the active ingredient of the present invention is already known to be useful as a cardiotonic agent, as described in, for example, Japanese Patent Publication No. 1-43747 and US Pat. No. 4,415,572. Also, one of the carbostyril derivatives and / or salts thereof has been shown to improve hemodynamic indices and exercise tolerance in patients with congestive heart failure [Inou.
e et al. , Heart Vessels, 2 ,
166-171 (1986); Sasaymaet a.
l. , Heart Vessels, 2 , 23-28.
(1986); Feldman et al. , Am.
Heart J. , 116 , 771-777 (198
8)].

The mechanism associated with the inotropic effect of the above carbostyril derivative is a decrease in potassium current [Iijima].
et al. , J. et al. Pharmacol. Exp. T
her. , 240 , 657-662 (1987)], including mild inhibition of phosphodiesterase and increased inward flow of calcium current [Yataniet.
al. , J. et al. Cardiovasc. Pharmac
ol. , 13 , 812-819 (1989); Tair.
a et al. , Arznemittelfors
hung, 34 , 347-355 (1984)].

The above-mentioned carbostyril derivative is TNF-α, IL-6, IL-1 produced by lipopolysaccharide (LPS) -stimulated peripheral blood mononuclear cell (PBMC) cells.
It has been reported to suppress the production of various cytokines including β, IL-2 and IFN-γ [Busch,
F. et al. , Eur. J. Clin. Pharm
acol. , 42 , 629-634 (1992); Ma.
ruyama et al. , Biochem. Bio
phys. Res. Commu. , 195 , 1264-
1271 (1993); Shioi, T .; et a
l. , Life Sciences, 54 (1), PL
11-16 (1994); Matsumori, A .; e
t al. , Circulation, 89 (3), 9
55-958 (1994)].

Furthermore, it has been reported that the above carbostyril derivative has an effect of improving virus-induced myocardial injury and an inhibitory effect on natural killer cells (NK Cell) at the time of improving the myocardial injury [Matsui].
S. , Et al. , J. et al. Clin. Invest. ,
94 , 1212-1217 (1994)].

In addition to the above-mentioned actions, it has been reported that the carbostyril derivative has an apoptosis-regulating action, and based on this action, it is useful for treating cancer and suppressing cancer metastasis, autoimmune disease, viral disease and the like. Reported [European Patent Publication EP 0552373; Nakai et.
al. , Jpn. J. Cancer Res. , Ab
struct, and Proc. Jpn. Cance
r Assoc. , 581 (1993); Maruya.
ma et al. , Biochem. Biophy
s. Res. Commun. , 195 , 1264-12
71 (1993)].

However, there is no report that the carbostyril derivative represented by the general formula (1) and / or its salt has the IL-8 production inhibitory action and the MCAF production inhibitory action as described above.

IL-8 production inhibitor of the present invention and MCAF
In the production inhibitor, the above-mentioned carbostyril derivative as a particularly preferable active ingredient compound is 6- [4-
Examples include (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl.

More specifically, each group represented by the above general formula (1), which represents a carbostyril derivative as an active ingredient of the drug of the present invention, includes the following groups.

That is, as the lower alkoxy group, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. Can be illustrated.

The benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring includes, for example, benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl and 3-ethoxybenzoyl. , 4-ethoxybenzoyl, 3-isopropoxybenzoyl, 4-butoxybenzoyl, 2-pentyloxybenzoyl, 3-hexyloxybenzoyl, 3,4-dimethoxybenzoyl,
Having 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent on the phenyl ring, such as 2,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzoyl groups. And a benzoyl group having

The salt of the carbostyril derivative represented by the above general formula (1) includes a pharmaceutically acceptable acid addition salt. Specific examples of the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. An organic acid such as an acid can be exemplified.

The general formula (1) which is an active ingredient of the drug of the present invention
The carbostyril derivative represented by and / or a salt thereof is usually used in the form of a general pharmaceutical preparation. Such a preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules,
Examples include capsules, suppositories, injections (solutions, suspensions, etc.), eye drops and the like.

In the case of forming into a tablet form, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,
Binders such as potassium phosphate and polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, humectants such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, purified talc, stearates, boric acid powders, lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multi-layer tablet.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like, Arabic. A rubber powder, a tragacanth powder, a binder such as gelatin or ethanol, a disintegrating agent such as laminaranthanthene, or the like can be used.

In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like can be used.

When prepared as an injection, a liquid preparation,
Emulsions, suspensions and the like are preferably sterilized and isotonic with blood, and when molding these solutions, emulsions, suspensions and the like, those conventionally used in this field as diluents should be used. All can be used. Examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose, or glucose to prepare an isotonic solution,
Glycerin and the like may be contained in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents and the like may be added. If necessary, coloring agents, preservatives, fragrances, flavors,
Sweeteners and other pharmaceutical agents may be included in the pharmaceutical preparation.

The amount of the compound of the general formula (1) contained as an active ingredient in the drug of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually about 1 to 70% by weight in the whole composition,
It is suitable to set the range of about 1 to 30% by weight.

The administration method of the pharmaceutical preparation of the present invention thus obtained is not particularly limited, and it is determined according to various preparation forms, age and sex of patients, other conditions, and degree of disease. For example, a pharmaceutical preparation in the form of an injection may be administered by intravenous, intramuscular, subcutaneous, intracutaneous, intravaginal administration, etc., which may be mixed with a normal replenishing solution such as glucose or amino acid, if necessary. It can also be administered internally. The pharmaceutical preparation of the present invention in a solid dosage form such as tablets, pills, granules and capsules, or a liquid dosage form for oral administration can be administered orally or enterally. Suppositories can be administered rectally. Also, eye drops can be applied to the eye.

The dose of the drug of the present invention can be appropriately selected from a wide range and is not particularly limited. In general clinical use, the carbostyril derivative of the general formula (1) (and its salt) is usually About 0.1 kg / kg body weight per day.
The amount is preferably selected from the range of about 5 to 30 mg, and the active ingredient in the dosage unit form is about 1 to 100 mg.
It is suitable to contain 0 mg. The administration of the drug of the present invention can be divided into once a day or 3 to 4 times a day.

[0035]

EFFECT OF THE INVENTION IL-8 production inhibitor and MCA of the present invention
The F production inhibitor suppresses abnormal production of IL-8 and MCAF, and is effective in preventing and treating diseases caused by these abnormal production, such as psoriasis of the skin, vasculitis, pulmonary fibrosis and the like.

[0036]

The present invention will be described in more detail with reference to Formulation Examples and Pharmacological Test Examples.

[0037]

[Formulation Example 1] 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets were produced.

[0038]

[Formulation Example 2] 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40 g After mixing and polishing the above active ingredient compounds, Avicel, corn starch and magnesium stearate, sugar coating R10 mm
Tablet with kine. The obtained tablets were treated with hydroxypropyl methylcellulose, polyethylene glycol-600.
0, coating with a film coating agent consisting of castor oil and methanol to produce film coated tablets.

[0039]

[Formulation Example 3] 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 150.0 g Citric acid 1.0 g Lactose 33.5 g Nicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium lauryl sulfate 3.0 g Dry Magnesium starate 3.0 g Ethanol Appropriate amount The above active ingredient compounds, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture was added to No. 60 screen, polyvinyl pyrrolidone, carbowax 1500
And wet granulation with an alcoholic solution containing Carbowax 6000. If necessary, alcohol is added to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. No. Pass through 10 screens, place in trays and dry in oven at 100 ° C. for 12-14 hours. The dried particles were no. Sift through 16 screen, add dry sodium lauryl sulphate and dry magnesium stearate, mix and compression mold to desired shape in tablet press.

The core is treated with a varnish and talc is sprinkled to prevent moisture absorption. An undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. An additional subbing layer and smooth coating are applied to make the tablet completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished to prepare tablets of uniform gloss.

[0042]

[Pharmacological Test Example 1] 6- [4- (3,4
-Dimethoxybenzoyl) -1-piperazinyl] -3,
4-Dihydrocarbostyril (hereinafter referred to as "Compound 1") was used to test the production inhibitory effect of the test compound on IL-8 production and MCAF production as follows.

(1) Human peripheral blood mononuclear cells (PBMC) were isolated from healthy adults by a sucrose density gradient centrifugation method using a separator (Pharmacia), and the obtained cells were phosphate-buffered. After washing with saline (PBS) three times, finally, 10% heat-inactivated fetal bovine serum (FBS: manufactured by Gibco), 100 units / ml penicillin, 100 μg / m.
l streptomycin (manufactured by Gibco) and 50 μM 2−
The cells were resuspended in RPMI-1640 medium (manufactured by Gibco) containing mercaptoethanol and cultured at 37 ° C. under 5% CO ₂ .

Compound 1 was dissolved in 1N hydrochloric acid and mixed with FBS to give 1
It was diluted to a concentration of mg / ml and stored at -20 ° C.

The stock solution was further diluted with a medium to prepare 1N NaO.
The pH was adjusted to 7.0 with H.

Lipopolysaccharide (LPS: manufactured by Difco) was prepared in PBS as a 3 mg / ml stock solution.

PMA (Porbol 12-myri)
state 13-acetate (manufactured by Sigma) was prepared as a 1 mg / ml stock solution in dimethyl sulfoxide.

(2) Production and measurement of cytokine PBMC (2 × 10 ⁶ cells / ml) were stimulated with 10 μg / ml LPS and 10 ng / ml PMA. In the test, 5 μM and 15 μM concentrations of Compound 1 were added at the same time as LPS stimulation. After incubation for 24 hours, the supernatant was obtained and stored at -20 ° C until measurement of cytokine. The culture was performed twice and a total of 10 samples were measured. A well stimulated without addition of Compound 1 was used as a control.

Next, IL-8 and M produced by stimulation
The CAF amount was measured using commercially available IL-8 and MCAF measurement kits (both manufactured by Toray Industries, Inc.).

IL-8 and MCAF were measured according to the measurement procedure attached to the kit, the absorbance at 450 nm was measured, and a calibration curve obtained from the measured values of both standard solutions was prepared to prepare human IL-8 in each sample. And the concentration of MCAF was read.

The above results are shown in FIGS. 1 and 2.

In FIG. 1, the vertical axis represents control (LPS stimulation only, shown as LPS), when compound 1 was added at 5 μM (shown as Ves-5) and when added at 15 μM (Ves).
(Shown as −3 × 5) of each MCAF (pg / ml).

In FIG. 2, the vertical axis represents control (LPS stimulation only, shown as LPS), addition of 5 μM of compound 1 (shown as Ves-5) and addition of 15 μM (Ves).
(Shown as −3 × 5) of each human IL-8 (pg / ml).

From the above results, it is clear that Compound 1 suppresses the production of MCAF and IL-8 produced by LPS stimulation of PBMC.

[0055]

[Pharmacological test example 2] (1) Culturing of human endothelial cells Human umbilical vein endothelial cells (HUVEC) were cultured in Gimbrone.
Et al. [Gimbrone M. A. et al. ,
J. Cell Biol. , 60 , 673-684 (1
974)], and a 199 medium (Sigma) containing 20% fetal calf serum (FCS), 30 μg / ml endothelial cell growth promoter (ECGS; Sigma) and 90 μg / ml heparin. The culture was performed as follows using a medium (manufactured by the company).

That is, the umbilical vein was extracted and a 0.05% collagenase solution (Washington Biochemical Corporation: Worthington Biochem) was used.
and was incubated at 37 ° C. for 20 minutes. The contents were poured into a conical tube containing medium and centrifuged. Pellet cells on a tissue culture plastic plate precoated with gelatin and culture,
Maintenance culture was carried out in a tissue culture incubator at 37 ° C. under 5% CO ₂ . HUVE used in this test
C included 3 to 5 levels.

Compound 1 was dissolved in hydrochloric acid, and 1 mg was obtained with FBS.
It was diluted to a concentration of / ml and stored at -20 ° C. The stock solution was further diluted with medium and the pH was adjusted to 7.0 with 1N NaOH. IL-1 (manufactured by Genzyme) and TNF
-Α (manufactured by R & D Systems) was diluted with the above culture solution and adjusted to have a concentration of 10 ng / ml.

(2) Production and measurement of cytokines HUVE prepared in the above medium on a 24-well plate
C (2 × 10 ⁵ cells / ml) at 10 ng / ml IL-
They were stimulated with 1 and 10 ng / ml TNF-α, respectively.
In the test, 2.6 μM and 26 μM concentrations of Compound 1 were added, followed by the stimulant. After incubation at 37 ° C for 24 hours, the supernatant was obtained and stored at -20 ° C until the measurement of cytokine.

Three samples of each group name were measured. A well stimulated without addition of Compound 1 was used as a control.

Next, IL-8 and M produced by stimulation
The amount of CAF was measured by the same method as in Pharmacological Test Example 1 above.

The above results are shown in FIGS.

In FIG. 3, the vertical axis represents control (no stimulation, −
), Compound 1 alone (shown as V26), IL-1 stimulation only (shown as IL-1), TN
F-α stimulation only (shown as TNF), the amount of each IL-8 produced when 2.6 μM of each stimulant plus compound 1 was added (each shown as + V2.6) and when 26 μM was added (each shown as + V26). (100 pg / m
1) is shown.

In FIG. 4, the vertical axis represents control (no stimulation, −
), Compound 1 alone (shown as V26), IL-1 stimulation only (shown as IL-1), TN
F-α stimulation only (shown as TNF), production of each MCAF (100 pg) when 2.6 μM of each stimulant plus compound 1 was added (each shown as + V2.6) and when 26 μM was added (each shown as + V26). / M
1) is shown.

From the above results, Compound 1 was identified as HUVEC.
Produced by IL-1 and TNF stimulation in I
It is clear that it suppresses the production of L-8.

[Brief description of drawings]

FIG. 1 is a graph showing the results of tests according to Pharmacological Test Example 1.

FIG. 2 is a graph showing the results of the test according to Pharmacological Test Example 1.

FIG. 3 is a graph showing the results of the test according to Pharmacological Test Example 2.

FIG. 4 is a graph showing the results of the test according to Pharmacological Test Example 2.

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Claims (2)

[Claims] 1. A compound of the general formula [In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. Carbostyril skeleton 3
The carbon-carbon bond between the 4-position and the 4-position indicates a single bond or a double bond. ] The IL-8 production inhibitor which uses the carbostyril derivative and / or its salt represented by these as an active ingredient. 2. A compound of the general formula [In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. Carbostyril skeleton 3
The carbon-carbon bond between the 4-position and the 4-position indicates a single bond or a double bond. ] The MCAF production inhibitor which uses the carbostyril derivative and / or its salt represented by these as an active ingredient.