JPH10147531A - Tnf-alpha production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject production inhibitor useful as a preventive and a therapeutic agent for chromic rheumatoid arthritis, burn, myocardial infarction, etc., comprising a specific tetrazolylalkoxycarbostyril derivative (salt) as an active ingredient. SOLUTION: At least one of a tetrazolylalkoxycarbostyril derivative (salt) of the formula (R is a cycloalkyl; A is a lower alkylene; the bond between the 3-position and the 4-position of carbostyril skeleton is a single bond or a double bond) is contained as an active ingredient to give a TNF(Tumor Necrosis Factor)-α production inhibitor. The compound of the formula is made into a dosage form such as tablet or injection by optionally using a conventional preparation carrier and administered. A dose is 100-400mg/day in adult (50kg weight) and preferably administered by dividing into once to several times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a TNF-α production inhibitor, and more particularly, to a compound of formula (I):

Embedded image [Wherein, R represents a cycloalkyl group, A represents a lower alkylene group, and the bond between the 3-position and the 4-position of the carbostyril skeleton is 1
TNF comprising at least one selected from the group consisting of a tetrazolylalkoxycarbostyril derivative represented by the following formula:
An α-production inhibitor.

[0002]

2. Description of the Related Art Numerous cytokines have been discovered as protein factors that suppress the development of biological functions such as immune responses, inflammatory responses, and hematopoietic responses in living organisms.
As the structure and action are elucidated, it is clear that the action of the cytokine affects not only the immune system but also various functions of the living body, and is closely related to the development, differentiation, homeostasis and pathophysiology of the living body. Is being done.

[0003] Among the above cytokines, TNF (Tumor Ne
crosis Factor (tumor necrosis factor) was discovered as an antitumor cytokine and expected as an anticancer drug, but was later found to be identical to cachexin, which is a cachexia-inducing factor, and other IL-1 and other proteins were used. Stimulation of cytokine production, proliferation of fibroblasts, endotoxin shock induction, endothelial cell leukocyte adhesion protein IC
AM-1, ICAM-2 (Intercellular adhesion mol
eculas), ELAM (Endothelial Leukocyteadhesion)
The effect of increasing leukocyte adhesion to endothelial cells by increasing molecule-1) and the like, bone resorption, cartilage destruction and other arthritic effects have been reported. (Beutler, B.,
et al., Nature, 316 , 552-554 (1985); Peetre, C.,
et al., J. Clin.Invest., 78 , 1694-1700 (1986); Ku
rt-Jones, EA, et al., J. Immunol., 139 , 2317-232
4 (1987); Bevilacqua, MP, et al., Science, 241 ,
1160-1165 (1989); Akatu, K. & Suda, T., Medical P
practice, 8 (9) 1393-1396 (1991)].

[0004] Furthermore, it has been reported that the concentration of TNF in blood or bone marrow fluid increases in bacterial and parasite infections [Mitsuyama, M., History of Medicine, 159 (8) 467-470].
(1991); Nakao, M., History of Medicine, 159 (8) 471-474
(1991)].

In addition, 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 , 104.
1 (1988); Chu, CQ, et al., Arthritis Rheum., 3
4 , 1125-1132 (1991); Macnaul, KL, et al., J. Im.
munol. 145 , 4154-4166 (1990); Brennan, FM, et a
l., J. Immunol., 22 , 1907-1912 (1992); Brennan, F.
M., et al., Bri.J.Rheum., 31 , 293-298 (199
2)].

[0006] ARDS is a serious respiratory disease.
(Adult Respiratory Distress Syndrom: Adult respiratory distress syndrome) It has been reported that TNF levels are also increased in sputum of patients [Millar, AB et al., Nature, 324 , 7
3 (1986)], and TNF has also been implicated in the fulminancy of viral hepatitis [Muto, Y., et al., Lancet, ii, 72.
-74 (1986)].

In addition, it has been reported that the concentration of TNF-α in blood increases during myocardial ischemia such as acute myocardial infarction [Latini, R., et al., J. Cardiovasc.
rmacol., 23 , 1-6 (1994)], and the involvement of TNF-α in such pathologies has been suggested [Lefer, AM, et al.
al., Science 249 , 61-64 (1990)]. More recently, TN
F-α has been reported to suppress myocardial contractile force [Finkel, MS, et al., Science, 257 , 387-389 (19
92); Pagani, DF, et al., J, Clin. Invest., 90 ,
389-398 (1992)].

However, at present, the above rheumatoid arthritis,
Chemotherapeutic agents that produce satisfactory results for diseases such as endotoxin shock and ARDS have not been developed yet, and steroids, anti-inflammatory agents, platelet aggregation inhibitors,
Antibiotics are only applied symptomatically.
In addition, as described above, it has been suggested that each of these diseases is closely associated with an increase in the concentration and activity of TNF-α, and application of TNF-α antibodies and the like to the treatment of these diseases has recently been attempted. However, these methods have not yet yielded satisfactory results, and the development of drugs for the treatment of such diseases, particularly with a new mechanism of action capable of suppressing overproduction of TNF-α, is needed. It is in the current situation demanded by the industry.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel TNF-α production inhibitor which suppresses abnormal production of TNF-α which meets the above-mentioned demands and can treat the above-mentioned diseases. Is to do.

As a result of intensive studies, the present inventors have found that carbostyril derivatives represented by the following general formula (I) and salts thereof, especially 6- [4- (1-cyclohexyl-1H-
The present inventors have found that tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof is effective as a TNF-α production inhibitor having a new mechanism of action which meets the above-mentioned object, and the present invention relates to the present invention. Was completed.

The tetrazolylalkoxycarbostyril compounds represented by the above (I) used in the present invention are disclosed in JP-B-63-20235. It is described that it is useful as an agent, a cerebral circulation improving agent, an anti-inflammatory agent, an anti-ulcer agent, an antihypertensive agent, an anti-asthmatic agent, a phosphodiesterase inhibitor and the like.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a method for inhibiting the production of TNF-α containing as an active ingredient at least one selected from the group consisting of the tetrazolylalkoxycarbostyril derivative represented by the formula (I) and a salt thereof. The agent is provided. In the formula (I), examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., and cyclohexyl is particularly preferred. Examples of the lower alkylene group include methylene, ethylene, propylene, butylene, and the like, with butylene being particularly preferred. A particularly preferred compound is 6- [4- (1-cyclohexyl-1).
H-tetrazol-5-yl) butoxy] -3,4-dihydrocartostyryl. It is already marketed as a vasodilator under the trade name cilostazol.
These compounds are easily produced by the method described in JP-B-63-20235.

[0013] The TNF-α production inhibitor of the present invention comprises
-Various diseases associated with abnormal α production, especially rheumatoid arthritis,
Chronic heart failure such as endotoxin shock, ARDS, burns, asthma, pulmonary fibrosis, etc., myocardial infarction which is a condition of myocardial ischemia, acute phase of viral myocarditis, idiopathic dilated cardiomyopathy, ischemic cardiomyopathy As a prophylactic or therapeutic agent, etc., and during coronary artery bypass surgery (CABG) or when using artificial heart and lung,
It can be suitably used. The compound of the formula (I) used in the present invention can be administered as it is or together with a conventional pharmaceutical carrier. The dosage unit form is not particularly limited, and may be appropriately selected and used as needed. Examples of such dosage unit forms include oral preparations such as tablets, capsules, granules and various oral liquids, and parenteral preparations such as injections and suppositories. The amount of the active ingredient to be administered is not particularly limited and may be appropriately selected from a wide range.
It is preferable to administer the drug at a dose of 400 mg / day in one or several divided doses. Further, the active ingredient may be contained in a dosage unit form in an amount of 50 to 100.
It is better to include mg.

In the present invention, oral preparations such as tablets, capsules and oral liquid preparations are produced according to a conventional method. That is, tablets are formed by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc and acacia. For capsules, the compound of the present invention is mixed with an inert filler or diluent and filled into hard gelatin capsules, soft capsules and the like. Syrups and elixirs for oral solution are prepared by mixing the compound of the present invention with a sweetening agent such as sucrose, a preservative such as methylparaben and propylparaben, a coloring agent and a seasoning. Parenteral preparations are produced by a conventional method, for example, by dissolving the compound of the present invention in a sterilized liquid carrier. Preferred carriers are water or saline.
Solutions having the desired clarity, stability and suitability for parenteral use are prepared by dissolving about 50-100 mg of the active ingredient in water and organic solvents and further dissolving in polyethylene glycol having a molecular weight of 200-5000. It is preferable that a lubricant such as sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or polyvinylalcohol is blended in such a liquid. Furthermore, the above-mentioned liquid preparation contains bactericides and fungicides such as benzyl alcohol, phenol and thimerosal, and, if necessary, isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, buffers and the like. May be. In addition, from the viewpoint of its stability, the drug for parenteral administration is frozen after filling into a capsule or the like, and water is removed by a normal freeze-drying technique.
Solutions can be reconstituted from lyophilized powder immediately before use.

Pharmacological test The inhibitory effect of TNF-α production was tested in guinea pigs. In other words, lipopolysaccharide (lipopoly
TNF produced by inhaling saccharide (LPS) was examined by the TNF production inhibitory effect of the administration of the test compound. Hartley male guinea pigs (Japan SLC) weighing 300-480 g were used, and methopirone (metopirone) 5, an endogenous corticoid synthesis inhibitor.
After intravenous administration of 0 mg / kg, 0.01% LPS (Escherichia coli Serotype 055:
B5, Sigma) for 30 minutes. Two hours after LPS inhalation, the animals were anesthetized, and 10 ml of a saline solution containing 0.1% bovine serum albumin (BSA) was injected into the trachea to wash the airway three times, and bronchoalveolar lavage fluid (BALF)
Was recovered. The amount of TNF-α of the recovered BALF was measured in a bioassay system using L929 cells treated with actinomycin D. That is, a BALF supernatant sample sterilized by filtration through a filter (0.2 μl) and a 640 μ / ml murine recombinant TNF-α (mr TNF-α) were used as a standard in a 96-well plate.
α) 50 μl of a two-fold dilution series was added. Then 10%
50 μl of 1 × 10 ⁶ cell / ml L929 cells cultured in Eagle MEM medium containing fetal calf serum (FCS) were added,
5% for 24 hours in the presence of actinomycin D 1 μl / ml
Cultured at 37 ° C. in CO ₂ . And Alamar Blue (A
lamar Blue) solution, and after further culturing for 4 hours, the fluorescence intensity at an excitation wavelength of 560 nm and a fluorescence wavelength of 590 mn was measured with a fluorometer (Cyfofluor, Millipore-Wafer).
s). The amount of TNF-α was calculated from the detection line of mr TNF-α. The test compound (6) was added to the experimental animal.
-[4- (1-cyclohexyl-1H-tetrazole-5
-Yl) butoxy] -3,4-dihydrocarbostyril)
50 mg / kg was orally administered 1 hour before the start of LPS inhalation, and TNF activity was compared with that when LPS was inhaled without administration of the test compound. Table 1 shows the results. In addition,
As a control, the TNF activity when physiological saline was inhaled instead of LPS inhalation was examined, and the results are shown in Table 1.

[0016]

[Table 1] Group TNF activity (U / ml in BALF) Number of patients Inhalation of physiological saline 0.00 ± 0.008 Inhalation of LPS 6404.51 ± 1397.26 9 Inhalation of LPS + 50 mg / kg of test compound 1883.11 ± 459.42 ** 8 Mean ± SE, ** p <0.01 As is clear from the above results, TNF due to LPS inhalation
Production was significantly suppressed by administration of the compound of the present invention.

[Preparation Example] Preparation of tablets Compounding amount (g) 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 100 lactose (Japanese Pharmacopoeia) 40) Corn starch (Japanese Pharmacopoeia) 20 Microcrystalline cellulose (Japanese Pharmacopoeia) 20 Hydroxypropylcellulose (Japanese Pharmacopoeia) 4 Magnesium stearate (Japanese Pharmacopoeia) 2 Compound of the present invention, lactose, corn starch and The crystalline cellulose was thoroughly mixed, granulated with a 5% aqueous solution of hydroxypropylcellulose, carefully dried through a 200-mesh sieve, and compressed into tablets by a conventional method.
Prepare 00 tablets.

Claims (2)

[Claims] 1. A compound of the formula (I): [Wherein, R represents a cycloalkyl group, A represents a lower alkylene group, and the bond between the 3-position and the 4-position of the carbostyril skeleton is 1
TNF comprising at least one selected from the group consisting of a tetrazolylalkoxycarbostyril derivative represented by the following formula:
-Α production inhibitors. 2. The method according to claim 1, wherein the active ingredient is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,
The T of claim 1 which is 4-dihydrocarbostyril.
An NF-α production inhibitor.