WO1998046229A1

WO1998046229A1 - Il-8 and mcaf production inhibitors

Info

Publication number: WO1998046229A1
Application number: PCT/JP1997/001283
Authority: WO
Inventors: Akira Matsumori
Original assignee: Otsuka Pharmaceutical Co., Ltd.
Priority date: 1995-06-21
Filing date: 1997-04-14
Publication date: 1998-10-22

Abstract

IL-8 and MCAF production inhibitors which inhibit the abnormal production of IL-8 and MCAF and are therefore effective in the prevention and treatment of diseases resulting from the abnormal production, such as psoriasis, angiitis and fibroid lung, which inhibitors contain as the active ingredient carbostyryl derivatives of general formula (1) and/or salts thereof (wherein R is benzolyl which may have lower alkoxy on the phenyl ring; and the linkage between the 3- and 4-position carbon atoms of the carbostyryl skeleton is a single or double bond), and a method for inhibiting IL-8 and MCAF production.

Description

Specification

IL-18 production inhibitor and MCAF production inhibitor

Technical field

The present invention provides a pharmaceutically useful carbostyryl derivative represented by the following general formula (1) and / or a salt thereof as an active ingredient, an IL-8 (Interleukin-8) production inhibitor, and MCAF (Monocyte hemorrhage and The present invention relates to a method for inhibiting the production of IL-18 and a method for inhibiting the production of MCAF using the same.

Background technology

Inflammation is a host defense reaction that occurs to maintain homeostasis in tissue damage caused by various stimuli (physical, chemical, microbial, etc.). The inflammation includes multiple forms such as enhanced vascular permeability, inflammatory cell infiltration of neutrophils and macrophages, lymphocyte infiltration as an immune response, and tissue repair. A variety of cells are involved in this inflammation, such as various cells constituting an inflammation field, and leukocytes infiltrating into an inflammatory focus through blood vessels.

The polypeptide-acting factor produced by these cells and involved in the formation of a complex inflammatory response is called inflammatory cytokin. Of these sites, a number of site kinases with leukocyte chemotaxis have recently been discovered, Their structures and functions have been elucidated. The site cytokines are collectively called chemokines and have been found to play an important role in leukocyte infiltration in inflammation.

The name chemokine was given at the International Leukocyte Chemotactic Factor Symposium in 1992 for polypeptide factors having chemotactic activity specifically for leukocytes. These factors have high amino acid sequence homology, have structurally four cystine residues, and have a common feature of a molecular weight of about 10,000. Chemokines are currently classified into two subfamilies, Cys-X-Cys and Cys-Cys, according to the binding mode of cystine (Cys), and IL-8 (Interleukin-8) is The former, MCAF (Monocyte Chemoattractant Protein-1), also known as MCP-1 (Monocyte Chemoattractant Protein-1), is a typical site-power factor of the latter. It is said that both of these sites bind to hormone-type receptors. Of these, IL-18 is a polypeptide having a molecular weight of 8 KDa and is composed of 72 amino acids.

IL-8 (aka NAP-1: eutrophil Activating Peptide-1) is a human peripheral blood that was stimulated by LPS in 1987. Isolated and purified as neutrophil chemoattractant (NCF) from mononuclear cell culture supernatant [Yoshimura, T., et al., Proc. Natl. Acad. Sci., USA, 84, 9233 ( 1987)], and subsequently the T-lymphocyte chemotactic factor (TCF) was also isolated and purified.

[Lasen, C.G., et al., Science, 243, 1983 (1989)] These were found to be the same factor and were named IL-8.

The IL-8 induces neutrophil migration and activates neutrophils. IL-18 not only enhances neutrophil chemotaxis, but also promotes degranulation and production of peroxide, enhances lysosomal enzyme release,

L T B 4, 5 H E TE production enhancement, adhesion molecule

(CDllabc, CD18) Increases expression, enhances CR-1 expression. Increases adhesion to non-stimulated vascular endothelial cells, inhibits adhesion to vascular endothelial cells, suppresses adhesion to vascular endothelial cells, suppresses Candida * albi-force growth Action, increased chemotactic capacity of T cells and basophils 0, action, etc., and enhanced histamine and leukotriene release from basophils, and also angiogenic action on vascular endothelial cells It has been reported.

Diseases that may involve IL-8 include psoriasis of the skin, rheumatoid arthritis, bronchial asthma, acute myocardial infarction, adult respiratory distress syndrome (ARDS), sepsis, vascular inflammation, and liver Flames have been cited [Masafumi Takahashi, Clinician, 19 (9), 42-45 (1993)].

On the other hand, MCAF was isolated and purified as a monocyte chemotactic factor in 1989 [Yoshimura, T., et al, J. Exp. Med., 169. 1449 (1989)]. Is produced by a variety of cells such as monocytes stimulated by LPS and vascular endothelial cells, fibroblasts, and vascular infiltrating muscle cells stimulated by inflammatory site forces such as IL-1 and TNF. It is reported to have chemotactic and activating effects, and further to enhance the chemotactic ability of T lymphocytes and basophils. In addition, MCAF promotes the production of sono and mono-oxide, enhances the release of lysosomal enzymes, enhances antitumor activity, enhances the production of cytokinin, enhances the expression of adhesion molecules (CD11bc), It has been reported that histamine release from basophils is enhanced. The diseases in which the MCAF is involved include arterial sclerosis, rheumatoid arthritis, pulmonary fibrosis, malignant glioma, melanoma, fibrosarcoma, malignant fibrous histiocytoma [Takahashi Takafumi Clinicians, 19 (9), 42-45 (1993)].

Based on the relationship between each of the above diseases and IL-8 and MCAF, it is considered that a drug having a function of suppressing the overproduction of IL-8 and MCAF in vivo is effective in preventing and treating each of the above diseases. The development of such drugs is desired in the art. ing.

Disclosure of the invention

An object of the present invention is to suppress the abnormal production of IL-8 and / or the abnormal production of MCAF, or to inhibit IL-18.

A new IL-8 production inhibitor which can treat various diseases caused by abnormal production of IL-18 and / or MCAF by simultaneous suppression of abnormal production with MCAF;

An object of the present invention is to provide a MCAF production inhibitor.

The present inventors have conducted intensive studies on the above object. The carbostyril derivative represented by the following general formula (1) and a compound or a salt thereof, which have been previously developed as a cardiotonic active ingredient, are desired. The present inventors have found that it has an inhibitory effect on IL-8 production and also has an inhibitory effect on MCAF production, and is effective as a drug meeting the above-mentioned object, and thus completed the present invention.

That is, according to the present invention,

[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 and the MCAF production inhibitor which contain the carbostyril derivative represented by these formulas and / or its salt as an active ingredient together with a nontoxic pharmaceutical carrier are provided.

Further, according to the present invention, there are also provided a method for suppressing the production of IL-8 and a method for suppressing the production of Z or MCAF using the above-mentioned drug.

The carbostyril derivative used as the active ingredient of the present invention may be, for example, a cardiotonic agent as described in Japanese Patent Publication No. 1443747 and US Patent No.US Pat. It is already known to be useful. In addition, the carbostyril derivative and Z or one of its salts have been demonstrated to improve hemodynamic parameters and exercise tolerance in patients with congestive heart failure [Inoue et al., Heart Vessels, 2, 166-171 (1986); Sasayma et al., Heart Vessels, 2, 23-28 (1986); Feldman et al., Am ..

Heart J., Π6, 771-777 (1988)].

The mechanism related to the inotropic action of the above carbostyril derivative decreases the calcium current [Iijima et al., J.

Pharmacol. Exp. Ther., 24Q, 657-662 (1987)], including mild suppression of phosphodiesterase and increased influx of calcium currents [Yatani et al., J. .. Cardiovasc Pharmacol, 13, 812-819 (1989);. Taira et al, Arzneimittelf orshung, 34. 347-355 (1984)] Q the Karubosuchi Li Le derivative further re POPO Risa' Kalai de (LPS) stimulated peripheral It has been reported to inhibit the production of various cytokines, including TNF- ", IL-6, IL-11 ^ 5, IL-2 and IFN-7 by blood mononuclear cells (PBMC). [Busch, F. et al., Eur. J.

Clin. Pharmacol., 2.629-634 (1992); Maruyama et al., Biochem.Biophys. Res.Commu., 195, 1264-1271 (1993); Shioi, T. et al., Life Sciences, 54 ( 1), PL 11-16 (1994); Matsumori, A. et al., Circulation, 89 (3), 955-958 (1994)].

Furthermore, it has been reported that the above-mentioned carbostyril derivative has an effect of improving virus-induced myocardial injury and an inhibitory effect on natural killer cells (NK cells) during the improvement of myocardial injury [Matsui S., et al. , J. Clin. Invest. 94.

1212-1217 (1994)].

In addition to the above-mentioned effects, it has been reported that the carbostyril derivative has an apoptosis-regulating effect. Based on this effect, treatment of cancer and suppression of cancer metastasis, autoimmune disease, viral disease, etc. Has also been reported [European Patent Publication EP 0 5 52 3 7 3; Nakai et al., Jpn. J. Cancer Res., Abstruct, and Proc. Jpn. Cancer Assoc., 581 (1993); Maruyama et l., Biochem. Biophys. Res.

Commun., 195-1264-1271 (1993)] ₀

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

In the IL-8 production inhibitor and MCAF production inhibitor of the present invention, the above-mentioned rubostyryl derivative as a particularly preferred active ingredient compound is 6- [4- (3,4-dimethoxy). Benzoinole) 1 1 —Piperazinyl] — 3,4 —Dihydrocarbostyril.

Each of the groups represented by the above general formula (1) representing the carbostyril derivative as an active ingredient of the drug of the present invention can be more specifically exemplified by the following groups.

That is, examples of the lower alkoxy group include straight-chain or branched-chain groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. An alkoxy group can be exemplified.

Benzoyl groups which may have a lower alkoxy group as a substituent on the phenyl group include, for example, benzoinole, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoinole, 4-ethoxybenzoinole, 3-isopropoxybenzoyl, 4-butoxyquinyl, 2 1-Pentinoleoxybenzoyl, 3—Hexinoleoxybenzyl, 3,4—Dimethoxybenzoinole, 2,5—Dimethoxybenzoinole, 3,4,5—Trimethoxybenzoyl Examples thereof include benzoyl groups having from 1 to 6 straight or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring, such as a group.

The carbostyril derivative represented by the general formula (1) includes a pharmacologically 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, and lingic acid. And organic acids such as tartaric acid, citric acid and benzoic acid. The carbostyryl derivative represented by the general formula (1), which is an active ingredient of the drug of the present invention, and nose or a salt thereof are usually used in the form of a general pharmaceutical preparation. Such preparations are prepared using commonly used non-toxic preparation carriers, for example, diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants. Is done. As this pharmaceutical preparation Can be selected from various forms according to the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions) , Suspensions and the like), eye drops and the like.

In the form of tablets, any of the above carriers which are conventionally known in the art can be widely used, such as lactose, saccharose, sodium chloride, glucose, urea, starch, canolecum carbonate, and kao. Excipients such as phosphorus, microcrystalline cellulose, gay acid, etc., water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, carboxymethyl phenol resin, cerac, Binders such as methinoresenorelose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, carpet powder, laminarane powder, sodium hydrogencarbonate, carbonate Calcium, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, milk Disintegrators such as sugar, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption promoters such as quaternary ammonium base, sodium lauryl sulfate, glycerin, and den Moisturizers such as starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal gay acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. A powder agent and the like can be exemplified. Further, the tablet can be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.

In the case of molding into pill form, a wide variety of carriers conventionally known in this field can be used as carriers, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and evening oil. Excipients, binders such as arabic gum powder, tragacanth powder, gelatin and ethanol, disintegrants such as lamina lanthanum and the like can be used.

For molding into suppositories, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, and semi-synthetic materials. Glyceride etc. can be used.

When prepared as an injection, liquids, emulsions, suspensions, etc. are preferably sterilized and isotonic with blood, and formed into the form of these liquids, emulsions, suspensions, etc. In this case, any diluent commonly used in this field can be used. Examples include water, ethyl alcohol, propylene glycol, ethoxy diisostearyl alcohol, polyoxylated isostearyl lanolechol, and polyquinethylene sorbitan fatty acid ester. And the like. In this case, the pharmaceutical preparation may contain a sufficient amount of salt, glucose, glycerin, etc. to prepare an isotonic solution, and may use a usual dissolution aid or buffer. Agents, soothing agents and the like may be added. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained 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 may be appropriately selected from a wide range, but is usually about 1 to 70% by weight of the whole composition, preferably It is suitably in 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 is determined according to various preparation forms, the age and sex of the patient, other conditions, and the degree of the disease. For example, a pharmaceutical preparation in the form of an injection can be administered by intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal or intravaginal administration, if necessary. It can also be administered intravenously after mixing with a replacement fluid. The pharmaceutical preparation of the present invention in a solid form such as a tablet, a pill, a granule, a capsule or a liquid form for oral administration can be administered orally or enterally. Suppositories can be administered rectally. Eye drops can also be applied to the eyes.

The dose of the drug of the present invention can be appropriately selected from a wide range, and is not particularly limited. CT / JP97 / 01283

13 is a carbostyryl derivative (and salt thereof) represented by the general formula (1) ^ Usually, an amount selected from the range of about 0.5 to 30 mg per lkg of body weight per day. It is appropriate that the dosage unit form contains about 1 to 100 mg of the active ingredient. The administration of the drug of the present invention can be divided into once a day or 3 to 4 times a day.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a graph showing the results of the test according to Pharmacological Test Example 1.o

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

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

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

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, formulation examples and pharmacological test examples will be given in order to explain the present invention in more detail.

Formulation Example 1

6 — [4 1 (3, 4 — dimethoxybenzoinole) 1 1 — pipera zinyl] 1 3, 4 — dihidrocarbos chirinole

5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg A tablet of the above composition was produced in one tablet.

Formulation Example 2

6-[4 — (3,4-Dimethoxybenzyl) — 1 —Piperazinyl] 1, 3,4-Dihydrocarbostyril

150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl propylmethinoreserulose 10 g Polyethylene glycol corsole 600 0.003 g Castor Oil 40 g Metanole 40. g After mixing and polishing the above active ingredient compound, Avicel, corn starch and magnesium stearate, tablet with sugar coated R10 mm kine. The obtained tablets are treated with hydroxypro pinoleme chinoresenororose, polyethylene glycol, etc.

600, coated with a finolem coating agent consisting of castor oil and methanol, and finolem coated tablets To manufacture.

Formulation Example 3

6 — [4 — (3, 4 — dimethoxybenzoyl) 1 1 1 piperazinyl] 1 3, 4 — dihydrocarbosty

150 000 g Cuenic acid 0 g Lactose 3 35 g Dicalcium phosphate 700 g Pull nick F-680 3Og sodium lauryl sulfate 150 g Polyvinyl alcohol mouth 150 g Polyethylene glycol (Carbox 1500)

4.5 g Polyethylene glycol Cornole (Carbowax 600)

45.0 g Corn starch 30.0.g Dry sodium lauryl sulfate 3.0 g Dry magnesium stearate 3.0 g Ethanol

The above active ingredient compound, citrate, lactose, dicalcium phosphate, pull nick F-68 and sodium lauryl sulfate are mixed. The above mixture is sieved with a No. 60 screen, and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbox 1500 and Carbox 600. . Add alcohol, if necessary, to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. Pass through a No. 10 screen, place in a tray, and dry in an oven at 100 ° C for 12 to 14 hours. The dried particles are sieved with a No. 16 screen, dried sodium lauryl sulfate and dried magnesium stearate are added, mixed, and compression-molded into a desired shape using a tableting machine.

The core is treated with varnish and talc is sprayed to prevent moisture absorption. An undercoat layer is coated around the core. Apply a sufficient number of varnish coats for internal use. In order to make the tablet completely round and smooth, further apply a subbing layer and a smooth coating. The colored coating is applied until the desired shade is obtained. After drying, polish the coating agent to prepare tablets with uniform gloss.

Pharmacological test example 1

Using 6- [4— (3,4-dimethoxybenzoinole) -1-1-piperazinyl] -13,4-dihydroforce rubostyril (hereinafter referred to as “compound 1”) as the test compound, The inhibitory effects of the test compounds on IL-18 production and MCAF production were tested as follows.

(1) Human peripheral blood mononuclear cells (PBMC) were isolated from healthy adults by a sucrose density gradient centrifugation method using a separator (manufactured by Pharmacia), and the obtained cells were washed. After washing three times with acid buffered saline (PBS), finally, 10% heat-inactivated fetal calf serum (FBS _: Gibco), 100 units, Zml penicillin, 100; g / ml RPMI containing Streptomycin (manufactured by Gibco) and 50 M 2 —Mercaptoethanol — resuspended in 1640 medium (manufactured by Gibco) and 5% C 0 _The cells were cultured at 37 ° C under ₂ .

Compound 1 was dissolved in 1N hydrochloric acid, diluted with FBS to a concentration of 1 mg Zml, and stored at 120 ° C.

The stock solution was further diluted with medium and adjusted to pH 7.0 with INNaOH.

Lipoposaccharide (LPS: manufactured by Difco) was prepared in PBS as a 3 mg noml storage solution.

PMA (Phorbol 12-myristate 13-acetate: manufactured by Sigma) was prepared in dimethyl sulfoxide as a 1 mg nom 1 stock solution.

(2) Production and measurement of site kinase

PBMC and (2 xl 0 ⁶ cells Zm l) of l O ^ gZm l Stimulation with LPS and lOng Zml PMA. In the test, 5 M and 15 zM concentrations of Compound 1 were added simultaneously with LPS stimulation. After incubation for 24 hours, the supernatant was obtained and stored at −20 ° C. until measurement of the cytokin. Culture was performed twice, and a total of 10 samples were measured. In addition, the gel stimulated without the addition of Compound 1 was used as a control.

Next, the amount of IL-8 and MCAF produced by the stimulation was measured using a commercially available IL-8 and MCAF measurement kit (both manufactured by Toray Industries, Inc.).

The IL-8 and MCAF measurements were performed according to the measurement procedure attached to the kit, the absorbance at 450 nm was measured, calibration curves were obtained from the measured values of both standard solutions, and the human IL in each sample was measured. One-eight and MC AF concentrations were read.

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

In Fig. 1, the vertical axis indicates the control (only for LPS stimulation,

The amount of MCAF produced (shown as LPS), the amount of MCAF when added (shown as Ves_5), and the amount of MCAF (shown as Ves-3X5) when added (1). pg / m 1).

In FIG. 2, the vertical axis indicates control (only for LPS stimulation,

LPS), with the addition of Compound 1 (shown as V es — 5) and with the addition of 1 (V e 5-3 x 5 The production amount (pg Zm 1) of each human IL-18 is shown.

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

Pharmacological test example 2

(1) Culture of human endothelial cells

Human umbilical vein endothelial cells (HUVEC) were isolated using a method modified from the method of Gimbrone et al. [Gimbrone MA et al., J. Cell Biol., 60, 673-684 (1974)], and 20% Using fetal bovine serum (FCS), an endothelial cell growth promoter (ECGS; Sigma), and a medium of 199 medium (Sigma) containing 90 g nom 1 of heparin Culture was performed as follows.

That is, the umbilical vein was extracted and subjected to a 0.05% collagenase solution (ヮ Sinton 'Nokiochemi Canole' Corporation: Worthington Biochemical Corporation, USA) at 37 ° C. For 20 minutes. The contents were poured into a conical tube containing the medium and centrifuged. Pellet cells were cultured seeded onto tissue culture plastic Kupure preparative you have Pureko bets with gelatin, in 5% C 0 ₂ below, 3 7 ° C in tissue culture Lee Nkyubeta PT / JP9701283

20

-Maintained during culture. The HUVECs used in this study included three to five levels.

Compound 1 was dissolved in hydrochloric acid, diluted with FBS to a concentration of 1 mg no ml, and stored at −20 ° C. The stock solution was further diluted with medium and the pH was adjusted to 7.0 with INNaOH. IL-1 (manufactured by Genzyme) and TNF-a (manufactured by R & D Systems) were diluted with the above culture solution, and adjusted to have a concentration of l Ong Zml.

(2) Production and measurement of site kinase

2 4 Uweru HUVEC adjusted in the culture medium plates of (2 xl 0 ⁵ cells Zm l) was of TNF- Hide each stimulus l O ng Zm l of IL- 1 and 1 0 ng / m 1. In the test, the above stimulants were added after adding 2.6 μM and 26 M concentrations of compound 1. After incubation at 37 ° C for 24 hours, the supernatant was obtained and stored at −20 ° C until measurement of the site force in. Three samples were measured for each group. The wells stimulated without the addition of Compound 1 were closed.

Next, the amounts of IL_8 and MCAF produced by the stimulation were measured in the same manner as in the above-mentioned Pharmacological Test Example 1.

The above results are shown in FIGS.

In Fig. 3, the vertical axis is the control (unstimulated, shown as-), Compound 1 only (shown as V 26), IL-11 stimulation only (shown as IL-1), TNF-α stimulation only

(Shown as TNF) for each stimulant plus compound 1

The amount of IL-8 produced at the addition of 2.6 m (indicated as + V2.6, respectively) and the addition of 26 （(indicated as + V26, respectively) (1 OO pgZm l ).

In FIG. 4, the vertical axis indicates control (no stimulation, shown as —), only compound 1 added (shown as V26), only IL-1 stimulation (shown as IL-1), only TNF-α stimulation

(Shown as TNF) for each stimulant plus compound 1

MCAF production (100 pg / m 1) at 2.6 Μ (each indicated as + V 2.6) and at 26 Μ (each indicated as + V 26) ).

From the above results, it is clear that Compound 1 suppresses the production of IL-11 and IL-18 produced by TNF stimulation in HUVEC.

Industrial applicability

The IL-18 production inhibitor and MCAF production inhibitor of the present invention suppress abnormal production of IL-18 and MCAF, and cause diseases caused by these abnormal production, such as psoriasis of the skin, vasculitis, and pulmonary fibrosis. Effective for prevention and treatment.

Claims

Scope of request

^-

SB Ministry

[In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl group. The carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton indicates a single bond or a double bond. ]

An IL-8 production inhibitor comprising a carbostyril derivative represented by the formula and / or a salt thereof as an active ingredient together with a nontoxic pharmaceutical carrier.

2. General formula

[In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. Carbostyril skeleton The carbon-carbon bond between the 3-position and the 4-position indicates a single bond or a double bond. ]

An agent for inhibiting the production of MCAF, comprising as an active ingredient a carbostyril derivative represented by the formula:

3. The MCAF production inhibitor according to claim 2, which is a therapeutic agent for pulmonary fibrosis.

4. General formula

[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. ]

A method for suppressing IL-18 production, which comprises administering an effective amount of the carbostyril derivative and or a salt thereof represented by the formula (1) to a patient in need of treatment.

5. General formula

A method for suppressing MCAF production, which comprises administering an effective amount of the carbostyril derivative and / or a salt thereof represented by the formula to a patient in need of treatment.

6. The method for suppressing MCAF production according to claim 5, wherein the patient is a patient with pulmonary fibrosis.