A method for the prophylaxis and treatment of diseases induced by accelerated INF-.alpha. secretion, such as rheumatoid arthritis, endotoxin shock, adult respiratory distress syndrome, thermal burn, asthma, myocardial infarction, acute phase of viral myocardiosis, etc. which comprises administering a carbostyril compound of the formula: ##STR1## wherein R.sup.1 is H or lower alkyl, and R.sup.2 is phenyl(lower)alkyl having optionally 1 to 3 lower alkoxy substituents on the phenyl ring, or a pharmaceutically acceptable salt thereof to a subject.

FIELD OF THE INVENTION 
This invention relates to an inhibitor of production or secretion of tumor 
necrosis factor-.alpha. (TNF-.alpha.), which comprises as an active 
ingredient a carbostyril compound or a pharmaceutically acceptable salt 
thereof. 
BACKGROUND OF THE INVENTION 
There have been found various cytokines which are a protein inhibiting 
manifectation of biofunctions such as immunoresponse, inflammatory 
reaction and hemopoietic function in biobody, and the structures and 
activities thereof have gradually been clarified. With such clarification, 
it has also been made clear that they are effective not only onto the 
immune system but also onto various biofunctions and have much relevance 
to generation of biobody, differentiation, homeostasis, and pathological 
physiology. 
Among the cytokines, TNF has been found as an antitumor cytokine and has 
been expected to be useful as an antitumor agent. However, later on it was 
found that it is identical with cachectin which is a cachexy-inducing 
factor. It is reported that TNF has an activity of stimulating production 
of other cytokines such as IL-1, etc., proliferative activity of 
fibroblast, endotoxin shock-inducing activity, an activity of promoting 
the adhesion of leukocytes to endothelium by increasing intercellular 
adhesion molecules (ICAM-1, ICAM-2) or endothelial leukocyte adhesion 
molecule-i (ELAM-1), an activity of bone absorption, and an activity of 
inducing arthritis (e.g. cartilage decomposing activity) cf. Beutler, B., 
et al., Nature, 316, 552-554 (1985); Peetre, C., et al., J. Clin. Invest., 
78, 1694-1700 (1986); Kurt-Jones, E. A., et al., J. Immunol., 139, 
2317-2324 (1987); Bevilacqua, M. P., et al., Science, 241, 1160-1165 
(1989); Akatu, K. & Suda, T., Medical Practice, 8 (9), 1393-1396 (1991)!. 
Moreover, it is reported that in bacterial or parasitic infectious 
diseases, TNF is contained in a higher concentration in blood and 
cerebrospinal fluid cf. Mituyama, M., IGAKU-NO-AYUMI, 159 (8), 467-470 
(1991); and Nakao, M., IGAKU-NO-AYUMI, 159 (8), 471-474 (1991)!. It is 
also reported that in rheumatoid arthritis, the joint fluid and blood 
serum have TNF-.alpha. activity cf. Saxne, T., et al., Arthritis Rheum., 
31, 1041 (1988); Chu, C. Q., et al., Arthritis Rheum., 34, 1125-1132 
(1991); Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990); 
Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992); and Brennan, F. 
M., et al., Bri. J. Rheum., 31, 293-298 (1992)!. 
It is further reported that in patients suffered from a severe respiratory 
diseases: adult respiratory distress syndrome (ARDS), the phlegm of the 
patients contain an increased TNF cf. Millar, A. B., et al., Nature, 324, 
73 (1986)!, and that TNF participates also in the severity of virus 
hepatitis cf. Muto, Y. et al., Lancet, ii, 72-74 (1986)!. 
It is also reported that the blood concentration of TNF-.alpha. raises in 
case of myocardial ischemia (e.g. acute myocardial infarction) cf. 
Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994)!, and it is 
suggested that TNF-.alpha. will participate in such diseases cf. Lefer, 
A. M., et al, Science, 249, 61-64 (1990)!. It is recently reported that 
TNF-.alpha. inhibits myocardial contraction cf. Finkel, M. S., et al., 
Science, 257, 387-389 (1992); and Pagani, D. F., et al., J. Clin. Invest., 
90, 389-398 (1992)!. 
However, there have never been developed a chemo-therapeutic drug which 
exhibits satisfactory effects on the above-mentioned various diseases such 
as rheumatoid arthritis, endotoxin shock, or ARDS, and there have merely 
been used some steroids, antiinflammatory agents, platelet agglutination 
inhibitors, antibiotics from the nostropic viewpoint. Since it has been 
suggested the correlation between these diseases and the raising of 
concentration and activity of TNF-.alpha., it has recently been tried to 
employ an antibody of TNF-.alpha. in the treatment of these diseases, but 
it did not give satisfactory result. Thus, it has been desired to find and 
develop a new type drug for the treatment of these diseases by a new 
mechanism to inhibit the accelerated production or secretion of 
TNF-.alpha.. 
By the way, the carbostyril compounds of the formula I! as shown 
hereinafter are disclosed in U.S. Pat. No. 5,053,514 as a cardiotonic 
agent, wherein the processes for the preparation thereof are also 
disclosed. It is also known that these compounds have myocardial contract 
increasing activity (i.e. positive inotropic activity), coronary blood 
flow increasing activity, hypotensive activity, an activity of inhibiting 
blood vessel contract induced by norepinephrine, and antiinflammatory 
activity (cf. the above U.S. Patent as well as U.S. Pat. Nos. 5,266,577 
and 5,385,914), and are useful as a thrombosis treating agent, 
phosphodiesterase inhibitor, cerebral circulatory improving agent (cf. 
U.S. Pat. No. 5,401,754), as an antiarrhythmic agent (cf. WO 94/06427), 
and as an anti-histaminic agent (cf. Japanese Patent First Publication 
(Kokai) No. 56-8319). It is also reported that a compound inclusive in the 
carbostyril compounds of the formula I!: i.e. 
6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril has 
hemodynamic effects in patients with advanced heart failure (cf. Journal 
of Cardiac Failure, Vol. 1 No. 1 pp. 57-62, Oct. 1994). However, these 
literatures do not teach or even suggest that the carbostyril compounds 
have the activities of inhibiting production or secretion of TNF-.alpha.. 
DISCLOSURE OF THE INVENTION 
The present inventors have studied to develop a new TNF-.alpha. inhibitor 
having the desired activities and being suitable for the treatment of the 
above-mentioned diseases and have found that the carbostyril compounds of 
the formula I! as shown below, 
particularly6-3-(3,4-dimethoxybenzyl)amino-2-hydroxypropoxy!carbostyril 
or a pharmaceutically acceptable salt thereof are useful as a TNF-.alpha. 
inhibitor. 
##STR2## 
wherein R.sup.1 is hydrogen atom or a lower alkyl, and R.sup.2 is a 
phenyl(lower)alkyl group having optionally 1 to 3 lower alkoxy 
substituents on the phenyl ring. 
An object of the invention is to provide a novel TNF-.alpha. inhibitor. 
Another object of the invention is to provide a new use of the known 
carbostyril compounds of the formula (I) and their pharmaceutically 
acceptable salts as a TNF-.alpha. inhibitor. A further object is to 
provide a method for the prophylaxis and treatment of various diseases 
induced by accelerated production or secretion of TNF-.alpha. by 
administering an effective amount of the carbostyril compounds (I) or a 
pharmaceutically acceptable salt thereof to the subject suffering from 
such diseases in human being and other animals. 
The TNF-.alpha. inhibitor of the present invention is used for the 
prophylaxis and treatment of various diseases accompanied by the 
accelerated production or secretion of TNF-.alpha., particularly 
rheumatoid arthritis, endotoxin shock, adult respiratory distress syndrome 
(ARDS), thermal burn, asthma, myocardial infarction which is a syndrome of 
myocardial ischemia, the acute phase of viral myocardiosis, idiopatic 
dilated cardiomyopathy. It is also used in the coronary artery bypass 
grafting (CABG) and in the use of artificial heart or lung. 
The each group in the formula (I) denotes as follows. 
The "lower alkyl group" denotes a straight chain or branched chain alkyl 
group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 
isopropyl, butyl, tert-butyl, pentyl, hexyl, and the like. 
The "lower alkoxy group" denotes a straight chain or branched chain alkoxy 
group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. 
The "phenyl(lower)alkyl group having optionally 1 to 3 lower alkoxy 
substituents on the phenyl ring" denotes a phenylalkyl group wherein the 
alkyl moiety is a straight chain or branched chain alkyl group having 1 to 
6 carbon atoms and it has 1 to 3 substituents of a straight chain or 
branched chain alkoxy group having 1 to 6 carbon atoms on the phenyl ring, 
for example, 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, 2,5-dimethoxybenzyl, and the 
like. 
The compounds of the present invention include the compounds of the formula 
I! wherein R.sup.1 is hydrogen atom and R.sup.2 is a phenyl(lower)alkyl 
group having optionally 1 to 3 lower alkoxy substituents on the phenyl 
ring, and the compounds of the formula I! wherein R.sup.1 is a lower 
alkyl group and R.sup.2 is a phenyl(lower)alkyl group having optionally 1 
to 3 lower alkoxy substituents on the phenyl ring. 
Among the carbostyril compounds of the formula (I), basic compounds can 
easily form a salt with conventional pharmaceutically acceptable acids. 
These acids include, for example, inorganic acids such as sulfuric acid, 
nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, etc., 
and organic acids such as acetic acid, p-toluenesulfonic acid, 
ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, 
tartaric acid, citric acid, succinic acid, benzolic acid, etc. Besides, 
among the carbostyril compounds of the formula (I), acidic compounds can 
easily form a salt with conventional pharmaceutically acceptable basic 
compounds. These basic compounds include, for example, metal hydroxides 
such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc., 
alkali metal carbonates or hydrogen carbonates such as sodium carbonate, 
potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The 
compounds of the present invention include also their optical isomers. 
The compounds of the formula (I) and their salts of this invention are used 
in the form of a conventional pharmaceutical preparation in human being 
and other animals. The preparation is prepared by using conventional 
diluents or carriers such as fillers, thickening agents, binders, wetting 
gents, disintegrators, surfactants, lubricants, and the like. The 
pharmaceutical preparations may be selected from various forms in 
accordance with the desired utilities, and the representative forms are 
tablets, pills, powders, solutions, suspensions, emulsions, granules, 
capsules, suppositories, injections (solutions, emulsion, suspensions, 
etc.), and the like. In order to form in tablets, there are used 
conventional carriers such as vehicles (e.g. lactose, white sugar, sodium 
chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline 
cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, 
simple syrup, glucose solution, starch solution, gelatin solution, 
carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, 
polyvinyl-pyrrolidone, etc.), disintegrators (e.g. dry starch, sodium 
arginate, agar powder, laminaran powder, sodium hydrogen carbonate, 
calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium 
laurylsulfate, stearic monoglyceride, starches, lactose, etc.), 
disintegration inhibitors (e.g. white sugar, stearin, cacao butter, 
hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium 
base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, 
starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, 
colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, 
boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the 
tablets may also be in the form of a conventional coated tablet, such as 
sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film 
coating tablets, or double or multiple layer tablets. 
In the preparation of pills, the carriers include any conventional 
carriers, for example, vehicles (e.g. glucose, lactose, starches, cacao 
butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. 
gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), 
disintegrators (e.g. laminaran, agar, etc.), and the like. In the 
preparation of suppositories, the carriers include any conventional 
carriers, for example, polyethylene glycol, cacao butter, higher alcohols, 
higher alcohol esters, gelatin, semi-synthetic glycerides, and the like. 
Capsules can be prepared by charging a mixture of the compound of this 
invention with the above carriers into hard gelatin capsules or soft 
capsules in a usual manner. 
In the preparation of injections, the solutions, emulsions or suspensions 
are sterilized and are preferably made isotonic with the blood. In the 
preparation of these solutions, emulsions and suspensions, there are used 
conventional diluents, such as water, ethyl alcohol, macrogol, propylene 
glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, 
polyoxyethylene sorbitan fatty acid esters, and the like. In this case, 
the pharmaceutical preparations may also be incorporated with sodium 
chloride, glucose or glycerin in an amount sufficient to make them 
isotonic, and may also be incorporated with conventional solubilizers, 
buffers, anesthetizing agents. Besides, the pharmaceutical preparations 
may optionally be incorporated with coloring agents, preservatives, 
perfumes, flavors, sweetening agents, and other medicaments, if desired. 
The amount of the active compound to be incorporated into the 
pharmaceutical composition of this invention is not specified but may be 
selected from a broad range, but it is usually in the range of 1 to 70% by 
weight, preferably about 1 to 30% by weight based on the weight of the 
composition. 
The pharmacetuical composition of this invention may be administered in any 
method, and suitable method for administration may be determined in 
accordance with various forms of preparation, ages, sexes and other 
conditions of the patients, the degree of severity of diseases, and the 
like. For example, tablets, pills, solutions, suspensions, emulsion, 
granules and capsules are administered orally. The injections are 
intraveneously administered alone or together with a conventional 
auxiliary liquid (e.g. glucose, amino acid solutions), and further are 
optionally administered alone in intramuscular, intracutaneous, 
subcutaneous, or intraperitoneal route, if desired. Suppositories are 
administered in intrarectal route. 
The dosage of the pharmaceutical composition of this invention may be 
selected in accordance with the usage, ages, sexes and other conditions of 
the patients, the degree of severity of the diseases, and the like, but is 
usually in the range of about 0.1 to 10 mg of the active compound of this 
invention per 1 kg of body weight of the patient per day. The daily dosage 
may be administered dividedly in one to four times in a day. The active 
compound is preferably contained in an amount of about 1 to about 200 mg 
per the dosage unit.

BEST MODE FOR CARRYING OUT THE INVENTION 
The present invention is illustrated by the following pharmacological 
experiments and preparations. 
Pharmacological Experiment 
By using 6-3-(3,4-dimethoxybenzyl)amino-2-hydroxy-propoxy!carbostyril 
(hereinafter, referred to as "Compound 1") as a test compound, the 
following experiment was done. 
A 10% heparinized peripheral blood from healthy volunteer, a test compound 
(30 .mu.g/ml) and lipopolysaccharide (LPS, 3.3 .mu.g/ml) were added to 
RPMI-1640 medium (supplemented with penicillin 100 units/ml and 
streptomycin 0.1 .mu.g/ml), and the mixture was incubated in a 5% CO.sub.2 
atmosphere at 37.degree. C. for 18-24 hours. The supernatant of the 
culture was collected by centrifugation. This supernatant was used as a 
test sample. 
The TNF-.alpha. was measured by an enzyme immunoassay (EIA) method. The 
amount of TNF-.alpha. in the test sample was determined based upon the 
standard curve. The detection limit was 20 pg/ml. The results are shown in 
the following table. 
______________________________________ 
Concentration of TNF-.alpha. (pg/ml) 
______________________________________ 
Group without 
1211 
addition of test 
compound 
Group added with 
472 
Test Compound 1 
______________________________________ 
PREATION 1 
Tablets are prepared from the following components. 
______________________________________ 
Components Amount 
______________________________________ 
6-3-(3,4-Dimethoxybenzyl)amino-2-hydroxy- 
5 mg 
propoxy!carbostyril 
Starch 132 mg 
Magnesium stearate 18 mg 
Lactose 45 mg 
Totally 200 mg 
______________________________________ 
According to a conventional method, there are prepared tablets which 
contain the above components in the above-mentioned amounts in each 
tablet. 
PREATION 2 
Injections are prepared from the following components. 
______________________________________ 
Components Amount 
______________________________________ 
6-3-(3,4-Dimethoxybenzyl)amino-2-hydroxy- 
500 mg 
propoxy!carbostyril 
Polyethylene glycol (molecular weight: 4000) 
0.3 g 
Sodium chloride 0.9 g 
Polyoxyethylene sorbitane monooleate 
0.4 g 
Sodium metabisulfite 0.1 g 
Methylparaben 0.18 g 
Propylparaben 0.02 g 
Distilled water for injecton 
100 ml 
______________________________________ 
The above parabens, sodium metabisulfite and sodium chloride are dissoved 
in the above distilled water with stirring at 80.degree. C., The resulting 
solution is cooled to 40.degree. C., and therein are dissolved succesively 
the active compound of this invention, polyethylene glycol and 
polyoxyethylene sorbitan monooleate, and thereto is added the distilled 
water for injection so as to adjust the final volume. The solution is 
sterilized by filtration with a filter paper and each 1 ml of the solution 
is poured into an ampoule to give the desired injection. 
INDUSTRIAL APPLICATION 
The INF-.alpha. inhibitor of this invention is useful for the prophylaxis 
and treatment of various diseases induced by accelerated production or 
secretion of TNF-.alpha., such as rheumatoid arthritis, endotoxin shock, 
adult respiratory distress syndrome, thermal burn, asthma, and further 
myocardial infarction, acute phase of viral myocardiosis, etc.