MXPA97005144A - Use of a compound of carbohestiril to prepare an inhibitor of the production or secretion of tumor necrosis delfactor a - Google Patents

Abstract

The present invention relates to the use of a carbostyril compound of the formula (I), wherein R 1 is H or a lower alkyl, and R 2 is a phenyl (lower) alkyl group optionally having 1 to 3 lower alkoxy substituents on the the phenyl ring, or a pharmaceutically acceptable salt thereof, for the preparation of an inhibitor of the production or secretion of TNF-alpha, for the prophylaxis and treatment of diseases induced by accelerated secretion of TNF-alpha, such as rheumatoid arthritis, endotoxin shock, respiratory distress syndrome in adults, thermal burn, asthma, myocardial infarction, acute phase of viral myocardiosis, and

Description

USE OF A COMPOSITE COMPOUND FOR PREPARING AN INHIBITOR FOR THE PRODUCTION OR SECRETION OF THE NECROSIS FACTOR TUMORRL RLFfl FIELD OF INVENTION This invention relates to an inhibitor of production or secretion of tumor necrosis factor alpha (TNF-a), which comprises as an active ingredient a carbostyril compound or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION Several cytokines have been found that are a protein that inhibits the manifestation of biological functions such as the immune response, inflammatory reaction and hernatopoietic function in the biological body, and the structures and activities of these have been gradually clarified. With this clarification, it has also become clear that they are effective not only on the immune system but also on several biological functions that have great relevance for the generation of biological bodies, differentiation, homeostasis and physiopathology. Among the cytokines, TNF has been found as an antitumor cytokine and has been expected to be useful as an anti-tumor agent. However, it was later found to be identical to cachectin, which is a caquexia inducing factor. It is reported that FNT has a stimulatory production activity of other cytokines such as IL-1, etc., proliferative activity of fibroblasts, endotoxic shock-inducing activity, an activity promoting the adhesion of leukocytes to the endothelium by increasing intercellular adhesion molecules. (ICAM-1, ICRM-2) or encephalum leukocyte adhesion molecule-1 (ELAM-1), bone absorption activity, and arthritis induction activity (e.g., cartilage decomposition activity) [see Beutler, B., et al., Nature, 316, 552-554 (1985); Peetre, C, and others, 3. Clin. Invest., 78, 1694-1700 (1986); Hurte-Jones, E.A., et al., 3. Immunol., 139, 2317-2324 (1987); Bevilacqua, n.P., et al., Science, 241, 1160-1165 (1989); Akatu, K. & Suda, T., Medical Practice, £ (9), 1393-1396 (1991)]. In addition, it has been reported that in bacterial or parasitic infectious diseases, TNF is present in a higher concentration in the blood and cerebrospinal fluid Cvease Mituyama, M-, IGRKU-NO-AYUrlI, 159 (8), 467-470 (1991 ); and Nakao, M., IGAKU-NO-AYUMI, 259 (8), 471-474 (1991)]. It is also reported that in rheumatoid arthritis, the fluid of the icicles and the blood serum have TNF-α activity [see Saxne, T., et al., Arthritis Reurnatoid, 3_1, 1041 (1988); Chu, C.Q., et al., Rheumatoid Arthritis, 34_, 1125-1132 (1991); Macnaul, K.L., et al., 3. Trnmunol., 145, 4154-4166 (1990); Brennan, F.M. , and others, 1.

Irnrnunol., 22, 1907-1912 (1992); and Brennan, F.M., and others, Bri. 3. Rheurn., 31., 293-298 (1992)]. In addition it has been reported that in patients suffering from severe respiratory diseases, respiratory distress syndrome in adults (ARDS), the phlegm of patients contains an increased FNT [see Millar, A.B., and others, Nature, 32, 73 (1986)], and that TNF also participates in the severity of viral hepatitis [see Muto, Y. et al., Lancet, ii, 72-74 (1986)]. It is also reported that the blood concentration of TNF-a increases the case of myocardial ischemia (eg, acute myocardial infarction) [see Latini, R., et al., 3., Cardiovascular Drug, 23_, 1-6 (1994)], and it is suggested that TNF-a participates in these diseases [see Lefer, RM., et al., Science, 249, 61-64 (1990)]. Recently it was reported that FNT-a shows contraction of myocardium [see Finkel, M.S., et al., Science, 257, 387-389 (1992); and Pagani, D.F., and others, 3. Clin. Invest., 90, 389-398 (1992). However, a quiniotherapeutic drug that shows satisfactory effects on the various aforementioned diseases such as reurnatoid arthritis, endotoxin shock, or ARDS has never been developed, and some steroids, anti-inflammatory agents have simply been used., inhibitors of platelet agglutination, antibiotics from the nostropic point of view. Since the correlation between these diseases and the increased concentration and activity of TNF-c has been suggested, it has recently been attempted to employ an antibody to TNF-a in the treatment of these diseases, but it did not give a satisfactory result. Therefore, it has been desired to find and develop a new type of drug for the treatment of these diseases by a new mechanism to inhibit the accelerated production or secretion of TNT-. By the way, two carbetyl compounds of the formula [I], as shown below, is described in the U.S. patent. 5,053,514 as a cardiotoxic agent, wherein the procedures for the preparation thereof are also described. It is also known that these compounds have increased myocardial contraction activity (i.e., positive inotropic activity), increased coronary blood flow activity, hypotensive activity, an inhibitory activity of blood vessel contraction induced by noremetry, and anti-inflammatory amatory activity ( see the above US patent as well as US patents 5,266,577 and 5,385,914), and are useful as a thrombosis treatment agent, phosphodiesterase inhibitor, brain circulation enhancing agent (see US patent 5,401,754), as an antiarrhythmic agent ( see WO 94/06427), and as an anhistamine agent (see Japanese Patent First Publication (Kokai) No. 56-8319). It is also reported that a compound that is included in the carboetipiplo compounds of the formula I I z z that is 6- [3- (3,4-d? Methox? Benz? L) ammo-2-hydroxyproxylcarbostyril has hemodynamic effects in patients with advanced heart failure (see Journal of Cardiac Failure, Vol. 1 No. 1 pp. 57-62, Oct. 1994). However, these citations do not teach or even suggest that the carbostyril compounds have the activities of inhibiting the production or secretion of TNF-a.

DESCRIPTION OF LR INVENTION The inventors of the present invention have studied the development of a new inhibitor of TNF-α having the desired activities and which is suitable for the treatment of the aforementioned diseases and have found that the carbostyril compounds of the formula [I] as shown below, particularly 6- [3- (3,4-dirnetoxybenzyl) arnino-2-hydroxypropoxycarboestir.yl or a pharmaceutically acceptable salt thereof are useful as an inhibitor of TNF-a. wherein R * is a hydrogen atom or a lower alkyl, and R2 is a phenylalkyl (lower) group optionally having 1 to 3 alkoxy substituents on the phenyl ring. An object of the invention is to provide a novel TNF-a inhibitor. Another object of the invention is to provide a new use of the known carbostyril compounds of the formula Cl] and their pharmaceutically acceptable salts as an inhibitor of TNF-a. A further object is to provide a method for the prophylaxis and treatment of various diseases induced by the production or accelerated secretion of TNF-a by the administration of an effective amount of carbostyril compounds [I] or a pharmaceutically acceptable salt thereof. Subject suffering from these diseases in humans and other animals. The TNF-a inhibitor of the present invention is used for the prophylaxis and treatment of various diseases accompanied by the production or accelerated secretion of TNF-a, particularly reurnatoid arthritis, endotoxin shock, adult respiratory distress syndrome (ARDS), thermal burn, asthma, myocardial infarction that is a syndrome of myocardial ischemia, the acute phase of viral rniocardiosis, idiopathic dilated cardiorniopathy. It is also used in coronary artery bypass graft (CABG) and in the use of heart or artificial lung. Each group in formula (I) denotes the following. The "lower alkyl group" denotes a straight chain or branched chain alkyl group having from 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 from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. The "enylaxy (lower) group having optionally 1 to 3 lower alkoxy substituents on the phenyl ring" denotes a phenylaikyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and has 1 to 3 substituents of a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms on the femloy ring, eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1, l-dirnethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-rnethyl-3-phenylpyrol, 2- (3-N-phenyl-phenyl), 1- (4-phenoxyphenyl) ) ethyl, 2-methox-benzyl, 3- (2-ethoxy-fem) -α, 4 (3-ethoxy-phenyl), 1, 1-d-rnetyl-2- (4-ethoxyphenyl) ethyl , 5- (4-isopropox? Phenyl) pentyl, 6- (4-hexyloxyphenyl) halo, 3,4-dimethoxybenzyl, 3,4,5-t-prethoxy-benzyl, 2,5-dimethoxybenzyl, and the like. Compounds of the present invention include the compounds of the formula [I] wherein Ri is a hydrogen atom and R 2 is a phenyl lower alkyl group having optionally 1 to 3 lower alkoxy substituents on the femloy ring, and the compounds of the formula [I] wherein R is a lower alkyl group and R 2 is a phenylalkyl lower group having optionally 1 to 3 substituent and alkoxy. lower on the phenyl ring. Among the carbostyril compounds of the formula (I), the basic compounds can be easily formed on a salt with conventional pharmaceutically acceptable acids. These acids include, for example, organic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid., hydrobromic acid, etc., and organic acids such as acetic acid, p-toluensulonic acid, ethanesulfonic acid, oxalic acid, rnaleic acid, fumaric acid, rnálico acid, tartaric acid, citric acid, succinic acid, benzolic acid, etc. In addition, among the carbostyril compounds of the formula (I), the 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 bicarbonates such as sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. . The compounds of the present invention also include 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 humans and other animals. The preparation is prepared using conventional diluents or carriers such as fillers, thickeners, binders, wetting agents, disintegrators, surfactants, lubricants and the like. The pharmaceutical preparations can be selected in various ways in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, emulsions, suspensions, etc.). ), and the like. To form tablets, conventional carriers such as carriers (e.g., lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.) are used, binders, (e.g., water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxy ethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.) disintegrators (e.g., dry starch, sodium arginate, agar powder, laminating powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium lauryl sulfate, stearic rnonoglyceride, starches, lactose, etc. ) disintegration inhibitors (e.g., white sugar, stearin, cocoa butter, hydrogenated oils, etc.), absorption promoters (eg, quaternary ammonium base, sodium lauryl sulfate, etc.), wetting agents (e.g., glycerin, starches, etc.), absorbent (e.g. starches, lactose, kaolin, beto a, colloidal silicates, etc.) lubricants (e.g., purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. In addition, 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, eg, vehicles, (eg, glucose, lactose, starches, cocoa butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (v. gr., gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g., laminating, agar, etc.), and the like. In the preparation of suppositories, the vehicles include any conventional carriers, for example, polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. Capsules can be prepared by loading a mixture of the compound of this invention with the above carriers into hard gelatin capsules or soft capsules in the usual manner. In the preparation of injections, the solutions, emulsions or suspensions are sterilized and preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions, conventional diluents, such as water, are used, ethyl alcohol, acrogol, propylene glycol, ethoxylated iso-ethereal alcohol, propoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations can also be incorporated with sodium chloride, glucose or glycerin in an amount sufficient to make them isotonic, and they can also be incorporated with conventional solubilizers, pH regulators, anesthetic agents. In addition, pharmaceutical preparations may optionally be incorporated with color-before agents, preservatives, perfumes, sabotagers, sweetening agents and other medicaments, if desired. The amount of the active compound to be incorporated in the pharmaceutical composition of this invention is not specific but can be selected from a wide range, but is generally in the range of 70% by weight, preferably from about 1. at 30% by weight based on the weight of the composition The pharmaceutical composition of this invention can be administered in any method, and the method suitable for administration can be determined according to various forms of preparation, and ages, sexes and other conditions of the patients, the degree of severity of the diseases and the like For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.The injections are administered intravenously alone or together with a liquid or conventional auxiliary (e.g., glucose, amino acid solutions), and are also optionally administered alone intramuscularly, incutaneously, subcutaneously ea or intraperitoneal, if desired. Suppositories are administered intra-rectally. The dosage of the pharmaceutical composition of this invention can be selected according to the use, ages, sex and other conditions of the patients, the degree of severity of these diseases and the like but generally on the scale of about 0.1 to 10 rng of the active compound of this invention per 1 kg body weight of the patient per day. The daily dose can be administered in divided form in one or four times a day. The active compound is preferably contained in an amount of about 1 to about 200 mg per unit dose.

BEST WAY TO PROMOTE THE INVENTION The present invention is illustrated by the following pharmacological experiments and preparations.

PHARMACOLOGICAL EXPERIMENT Using 6 ~ [3- (3,4-dirnetoxybenzyl) mino-2-hydroxy-propoxylcarbostyril (hereinafter referred to as "compound 1") as the test compound, the following experiment was made.

Peripheral blood heparinized at 10% of a healthy volunteer, a test compound (30 μg / ml) and 1 ipopolysaccharide (LPS, 3.3 μg / ml) were added to a medium of RPMT-1640 (supplemented with 100 units / ml of penicillin and 0.1 μg / ml streptomycin), and the mixture was incubated in a 5% CO2 atmosphere at 37 ° C for 18-24 hours. The supernatant of the culture was collected by centrifugation. This supernatant was used as a test sample. The TNF-or was measured by an enzyme in-assay (EIA) method. The amount of TNF-a in the test sample was determined based on the normal curve. The limit of detection was 20 pg / ml. The results are shown in the following table.

PREPARATION 1 Tablets are prepared from the following components.

Components Quantity 6- [3- (3,4-Dimethoxybenzyl) amino-2-hydroxy-propoxy i. ] carboesti ri 1o 5 r g starch 132 mg magnesium stearate 28 rng lactose 45 rng total 200 g In accordance with a conventional method, tablets containing the above components are prepared in the aforementioned amounts in each tablet.

PREPARATION 2 Injections are prepared from the following components.

Components Quantity 6- [3- (3,4-Dirnetoxybenzyl) amino-2-hydroxy propoxycarbostyril 500 mg Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan mono-oleate 0.4 g sodium tetabisulfite 0.1 g Methylparaben 0.18 g Propylparaben 0.02 g Distilled water for injection 100 ml The parabens, sodium rnatabisulite and sodium chlorine above are dissolved in the distilled water above with stirring at 80 ° C, the resulting solution is cooled to 40 ° C and the compound is dissolved in succession active ingredient of this invention, polyethylene glycol and polyoxyethylene sorbitan rnonooleate, and distilled water for injection is added thereto to adjust to the final volume. The solution is sterilized by filtration with a filter paper and each 1 ml of the solution is emptied into an ampoule to give the desired injection.

INDUSTRIAL APPLICATION The inhibitor of TNF-a. of this invention is useful for the prophylaxis and treatment of various diseases induced by the production or accelerated secretion of TNF-a, such as rheumatoid arthritis, endotoxin shock, respiratory distress syndrome in adults, thermal burn, asthma and myocardial infarction, acute phase of viral iocardiosis, etc.

Claims (4)

1. NOVELTY OF THE INVENTION CLAIMS I. The use of a carbostyril compound of the formula: wherein R1 is a hydrogen atom or a lower alkyl, and R2 is a phenylaikyl group (lower) having optionally 1 to 3 lower alkoxy substituents on the phenyl ring, or a pharmaceutically acceptable salt thereof for the preparation of a inhibitor of the production or secretion of TNF-a for the treatment of diseases induced by the accelerated secretion of TNF-a.
2. 2. The use according to claim 1, further characterized in that the disease induced by accelerated secretion of TNF-a is a disease selected from rheumatoid arthritis, endotoxin shock, respiratory distress syndrome in adults, thermal burn and as a.
3. 3. The use according to claim 1, further characterized in that the disease induced by accelerated secretion of TNF-a is a disease selected from myocardial infarction or an acute phase of viral iocardiosis.
4. 4. The use according to claims 2 and 3, further characterized in that the active ingredient is 6- [3- (3,4-d? Methox? Benc? L) am? No-2-h? Droxipropoxy] carboest or a pharmaceutically acceptable salt thereof.