JPH08245391A - Tnf-alpha production suppressing agent - Google Patents

Abstract

PURPOSE: To obtain a TNF-α production suppressing agent containing a specific carbostyril derivative (salt), useful for the prevention and treatment of chronic rheumatoid arthritis, endotoxin shock, adult respiratory distress syndrome, thermal burn, asthma and myocardial infarction. CONSTITUTION: This TNF-α production suppressing agent contains approximately 1-70wt.% (preferably approximately 1-30wt.%) one or more kinds of a carbostyril derivative (salt) of the formula (R1 is H or a lower alkyl; R2 is a phenyl lower alkyl which may have 1-3 lower alkoxy groups as substituents on the phenyl ring) e.g.; 6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy] carbostyril}. The dosage is approximately 0.1-10mg/kg body weight daily based on the active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a TNF-α production inhibitor.

[0002]

A number of cytokines have been discovered as protein factors that suppress the expression of biological functions such as immune response, inflammatory response, and hematopoietic response in the living body, and as their structure and action have been elucidated, the cytokines have been elucidated. It has been clarified that the action of is not limited to the immune system and affects various functions of the living body, and is closely related to the development, differentiation, homeostasis maintenance and pathophysiology of the living body.

Among the above cytokines, TNF (Tumor Neural
was found as an anti-tumor cytokine and was expected as an anti-cancer agent, but it was later found to be the same as cachexin-inducing factor cachectin and other IL-1 and the like. ICA which is a leukocyte adhesion protein of endothelial cells, stimulating the production of cytokines, proliferative effect on fibroblasts, inducing endotoxin shock
M-1, ICAM-2 (Intercellular adhesion molec
ulas), ELAM (Endothelial Leukocyte adhesion m
olecule-1) and other factors that promote leukocyte attachment to endothelial cells, bone resorption, cartilage destruction, and other arthritis-causing effects [Beutler, B., et.
al., Nature, 316 , 552-554 (1985): Peetre, C., et a
l., J.Clin.Invest., 78 , 1694-1700 (1986): Kurt-Jon
es, EA, et al., J. Immunol., 139 , 2317-2324 (1987)
: Bevilacqua, MP, et al., Science, 241 , 1160-116
5 (1989): Akatu, K. & Suda, T., Medical Practice, 8
(9) 1393-1396 (1991)].

Furthermore, it has been reported that the concentration of TNF in blood or cerebrospinal fluid is increased in bacterial or parasitic infections [Mituyama, M., Ayumi of Medicine, 159 (8) 467-470 (1991). )
: Nakao, M., History of Medicine, 159 (8) 471-474 (1991)
].

In addition, chronic rheumatoid arthritis (Rheumatoid Art
hritis; RA), TNF activity was observed in synovial fluid and serum, and this activity was reported to be TNF-α activity [Saxne, T., et al., Arthritis Rheum., 31 , 1041].
(1988): Chu, CQ, et al., Arthritis Rheum., 34 , 112.
5-1132 (1991): Macnaul, KL, et al., J.Immunol., 1
45 , 4154-4166 (1990): Brennan, FM, et al., J. Immu
nol., 22 , 1907-1912 (1992): Brennan, FM, et al., B
ri.J.Rheum., 31 , 293-298 (1992)].

ARDS, which is a serious respiratory disease
(Adult Respiratory Distress Syndrom: Adult respiratory distress syndrome) It has been reported that TNF concentration is increased even in sputum of patients [Millar, AB, et al., Nature, 324 , 73].
(1986)], TNF is also involved in fulminant viral hepatitis [Muto, Y., et al., Lancet, ii, 72-74].
(1986)].

Further, it has been reported that the concentration of TNF-α in blood is high during myocardial ischemia such as acute myocardial infarction [Latini, R., et.al., J. Cardiovasc. Pharmaco.
L., 23 , 1-6 (1994)], TNF-
It has been suggested that α is involved [Lefer, AM, et.al., Scienc
e, 249 , 61-64 (1990)]. More recently, it has been reported that TNF-α suppresses myocardial contractile force [Finkel, MS, e.
t.al., Science, 257 , 387-389 (1992); Pagani, DF, et.a
L., J. Clin. Invest., 90 , 389-398 (1992)].

However, at present, the above-mentioned rheumatoid arthritis,
Chemotherapeutic agents that produce satisfactory results for each disease such as endotoxin shock and ARDS have not been developed yet, and steroid agents, anti-inflammatory agents, platelet aggregation inhibitors, antibiotics, etc. are applied symptomatically. It's just that. Further, as described above, it has been suggested that each of these diseases and the increase in the concentration and activity of TNF-α are closely related, and recently, the treatment of these diseases such as TNF-α antibody has been suggested. Although application has been attempted, the results have not yet been obtained, and a novel mechanism of action for the treatment of each of these diseases, in particular, capable of suppressing overproduction of TNF-α, has been proposed. There is a current need for drug development in the industry.

[0009]

The object of the present invention is to provide a novel TNF-α which can treat the above-mentioned various diseases by suppressing the abnormal production of TNF-α which meets the above-mentioned demands of the industry.
The point is to provide a production inhibitor of

As a result of intensive studies conducted by the present inventors for the purpose described above, the carbostyril derivatives represented by the following general formula (1) and salts thereof, which were previously developed by the present inventors as an active ingredient for cardiotonic agents, were identified as above. We have found the fact that it is effective as a TNF-α production inhibitor with a new mechanism of action that matches the purpose, and completed the present invention here.

That is, according to the present invention, TNF-containing at least one selected from the group consisting of carbostyril derivatives represented by the following general formula (1) and salts thereof as an active ingredient.
An α production inhibitor is provided.

[0012]

Embedded image

[In the formula, R ₁ represents a hydrogen atom or a lower alkyl group. R ₂ represents a phenyl lower alkyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring. Further, according to the present invention, in particular, the above carbostyril derivative is 6- [3- (3,4-dimethoxybenzyl) amino-2.
The above-mentioned TNF-α production inhibitor which is -hydroxypropoxy] carbostyril and / or a salt thereof is provided.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the inhibitor of the present invention, the carbostyril derivative represented by the general formula (1) as an active ingredient, a salt thereof, and the production method thereof are described in, for example, EP Patent Publication No. 355583. It is known that the carbostyril derivative is useful as a cardiotonic agent. However, the TNF-α production inhibitory effect according to the present invention is not related to the cardiotonic action of the above carbostyril derivative, and, of course, cannot be predicted from the cardiotonic action.

The TNF-α production inhibitor of the present invention is TNF-α.
-Various diseases associated with abnormal α production, especially rheumatoid arthritis,
Prevention of various diseases such as endotoxin shock, ARDS, burns, asthma, myocardial infarction which is a condition of myocardial ischemia, acute phase of viral myocarditis, idiopathic dilated cardiomyopathy, chronic heart failure such as ischemic cardiomyopathy, and the like. It can be suitably used as a therapeutic agent, or during coronary artery bypass surgery (CABG) or when using artificial heart-lung machine.

More specifically, each group represented by the above general formula (1) is as follows.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy. be able to.

Examples of the phenyl lower alkyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring include benzyl, 2-phenylethyl, 1
-Phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5
-Phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2- (3-methoxyphenyl) ethyl, 1- (4-methoxyphenyl) ethyl, 2
-Methoxybenzyl, 3- (2-ethoxyphenyl) propyl, 4- (3-ethoxyphenyl) butyl, 1,1
-Dimethyl-2- (4-ethoxyphenyl) ethyl, 5
-(4-isopropoxyphenyl) pentyl, 6- (4
-Hexyloxyphenyl) hexyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl,
A linear or branched alkyl group having a carbon number of 1 to 6 in the alkyl moiety such as a 2,5-dimethoxybenzyl group and a linear or branched alkoxy group having a carbon number of 1 to 6 on the phenyl ring. There may be mentioned 1 to 3 phenylalkyl groups.

In the compound of the present invention, R ₁ is a hydrogen atom and R _{2 is}
Is a lower alkoxy group as a substituent on the phenyl ring.
A compound which is a phenyl lower alkyl group which may have 3; a compound wherein R ₁ is a lower alkyl group and R ₂ is a phenyl lower alkyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring. Is included.

Among the carbostyril derivatives represented by the general formula (1) of the present invention, the compound having a basic group can easily form a salt with a usual pharmacologically acceptable acid. Examples of such an acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid. Examples thereof include organic acids such as citric acid, succinic acid, and benzoic acid.

Of the carbostyril derivatives represented by the general formula (1) of the present invention, the compound having an acidic group can be easily formed into a salt by reacting a pharmaceutically acceptable basic compound. . Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The present invention naturally includes optical isomers.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The 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 can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). When molding into tablets, various carriers well known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose, silicic acid, water, ethanol,
Propanol, 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, lauryl Disintegrating agents such as sodium sulfate, stearic acid monoglyceride, starch, lactose, sucrose,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbents, purified talc, stearates, boric acid powders, lubricants such as polyethylene glycol, etc. can be used. In addition, tablets are tablets with a normal coating, if necessary,
For example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet can be used. In the case of molding in the form of pills, widely known carriers in this field can be used as carriers. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc., gum arabic powder, tragacanth powder, gelatin, binders such as ethanol,
A disintegrating agent such as laminaran or agar can be used. In the case of molding in the form of suppositories, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. Capsules are usually prepared by mixing the active ingredient compound with various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood,
When molding into these forms, all those conventionally used in the art as diluents can be used, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, poly Oxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected from a wide range, but it is usually about 1 to 70% by weight, preferably about 10% by weight in the pharmaceutical composition. It is preferably 1 to 30% by weight.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and various preparation forms, patient age, sex and other conditions,
It is administered by a method depending on the degree of disease and the like. Tablets, for example
In the case of pills, solutions, suspensions, emulsions, granules and capsules, it is orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally alone if necessary. In the case of suppositories, they are administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected according to the usage, the age of the patient, the sex and other conditions, the degree of disease and the like. Usually, the amount of the active ingredient compound is about 1 kg / day body weight. It is preferable to set the amount to about 0.1 to 10 mg.
Further, the active ingredient compound is contained in the dosage unit form in an amount of about 1 to
It is desirable that the content is 200 mg.

[0028]

[Examples] The results of pharmacological tests and formulation examples are listed below.

Pharmacological test The following test was carried out using 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril (hereinafter referred to as "compound 1") as a test compound.

RPMI-1640 medium (penicillin 10
0 unit / ml, including streptomycin 0.1 μg / ml) 10% healthy human peripheral blood (with heparin added), test compound (30 μg / ml) and lipopolysaccharide (LPS, 3.3 μg / ml) Incubate at 37 ° C. for 18 to 24 hours in a 5% CO ₂ incubator,
The culture supernatant was collected by centrifugation and used as a culture supernatant sample (Sup).

TNF-α is measured by enzyme immunoassay (E
IA) was used. The amount of TNF-α in the sample was determined from the standard curve of TNF-α. Measurement detection limit is 20 pg /
It was ml.

[0032]

[Table 1]

Formulation Example 1 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg According to a conventional method, the above composition was prepared in one tablet. A tablet containing was produced.

Formulation Example 2 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 500 mg Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 100 ml While stirring the above-mentioned parapens, sodium metabisulfite and sodium chloride, the above distilled water was added at 80 ° C. Dissolved. The obtained solution is cooled to 40 ° C.,
Polyethylene glycol and polyoxyethylene sorbitan monooleate are sequentially dissolved, then distilled water for injection is added to the solution to adjust the final volume, sterile filtration is performed using an appropriate filter paper, and 1 ml aliquots are dispensed into ampoules. , An injection was prepared.

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Claims (4)

[Claims] 1. A compound of the general formula [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group. R ₂ is a lower alkoxy group having 1 to 3 substituents on the phenyl ring.
Represents a phenyl lower alkyl group which may be present. ]
A TNF-α production inhibitor containing at least one selected from the group consisting of a carbostyril derivative represented by and a salt thereof. 2. The carbostyril derivative is 6- [3-
The TNF-α production inhibitor according to claim 1, which is (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril. 3. Prevention and / or rheumatoid arthritis, endotoxin shock, adult respiratory distress syndrome, burns or asthma.
Alternatively, the T according to claim 1 or 2 used for treatment.
NF-α production inhibitor. 4. The TNF-α production inhibitor according to claim 1 or 2, which is used in the prevention and / or treatment of myocardial infarction or in the acute stage of viral myocarditis.