JPH0474121A - Agent for inhibiting production of interleukin 1 - Google Patents

Abstract

PURPOSE:To obtain an interleukin 1 production inhibitor useful for the remedy and prevention of various inflammations and allergic diseases caused by interleukin 1 based on abnormal autoimmunity by using a specific 3- arylisothiazole derivative as an active component. CONSTITUTION:The objective agent contains, as an active component, a com pound of formula I [Ar is pyridyl, thienyl, furyl, naphthyl or group of formula II (R1 to R3 are H, halogen, NO2, OH, 1-4C alkyl, 1-4C halogenated alkyl, 1-4C alkoxy or R1 and R2 together form alkylenedioxy); X is H, halogen, OH, NH2 or 1-4C alkylamino; Y is carboxyl, alkoxycarbonyl or CONR<4>R<5> are H, 1-4C alkyl or together form a 5-7 membered heterocyclic group)] or its salt [e.g. 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid. The daily dose of the compound is preferably about 10-100 mg.

Description

[Detailed description of the invention] <Industrial application field> The present invention relates to an interleukin-1 production inhibitor.

More specifically, the present invention provides an anti-inflammatory agent containing a 3-arylisothiazole derivative as an active ingredient, such as a therapeutic agent for nephritis, a therapeutic agent for hepatitis, and a therapeutic agent for arthritis.

Alternatively, it relates to antiallergic agents, antipyretic agents, etc.

<Prior art> In recent years, it has been reported that cytokines such as interleukin 1 increase in various diseases and that they develop pathological conditions similar to those of the diseases, suggesting a relationship between cytokines and diseases. There is. In other words, interleukin 1 activates white blood cells and increases antibody production.

It is known to induce macrophage cytotoxicity, increased PGE2 production, osteolysis and fever, etc., and is known to induce rheumatoid arthritis, osteoarthritis, osteoporosis, 2 diaphragm rejection, 1 sepsis, 1 septic shock. Endotoxic shock, toxic shock syndrome, adult respiratory disease, various symptoms such as fever due to infection (gastric influenza), chronic nephritis, cachexia secondary to malignant infection, keloid formation, scar formation, It is speculated that Crohn's disease 7 is involved in the onset and progression of ulcerative colitis, multiple sclerosis, adverse reactions to dialysis, etc.

<Purpose of the Invention> As a result of intensive study by the inventors as to the effect of inthiazole derivatives on interleukin-1 production,
It has been found that isothiazole derivatives have a strong inhibitory effect on interleukin-1 production. Furthermore, for the purpose of exploring the possibility of effectiveness against inflammation such as arthritis and nephritis caused by autoimmune abnormalities, we investigated collagen arthritis and M.
The effect on spontaneous nephritis in RL/Q mice was investigated. As a result, it was discovered that inthiazole derivatives are effective against collagen arthritis and spontaneous nephritis in MRL/l) mice, leading to the present invention.

<Configuration and effects of the invention> That is, the present invention provides an interleukin-1 production inhibitor containing the following formula [I] and a pharmaceutically acceptable salt thereof as active ingredients, and a compound represented by the above formula [I] and a salt thereof. It is an anti-inflammatory agent based on the effect of inhibiting interleukin-1 production.

In the above formula [I], Ar is a substituted or unsubstituted pyridyl group, thienyl group, furyl group, naphthyl group, or R1\ mother -C6H2- ゐ/ (However, R1, R2 and the formula each independently represent a hydrogen atom. , halogen atom, nitro group, hydroxy group, C1
-4 alkyl group, C1-a halogenated alkyl group and C1-4 alkoxy group, or together with R1, represents an alkylenedioxy group.

) represents a group represented by

Examples of the substituent for Ar include one or more C1-4 halogenated alkyl groups, halogen atoms, C-4 alkyl groups, and C1-a alkoxy groups.

Among these, preferred are, for example, trifluoromethyl, fluorine atom, chlorine atom, methyl group, methoxy and isopropoxy groups.

When R1 and you together represent a C0-4 alkylenedioxy group, a methylenedioxy group is preferably mentioned, for example.

The isothiazole derivative in the present invention is a 3-aryl-5-thiazolecarboxylic acid derivative,
Specific examples include 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid compound 1).

3-(4-nitrophenyl)-4-amino-raisothiazolecarboxylic acid sodium salt 3-<3-pyridyl)-
4-Hydroxy-isothiazolecarphonic acid 3-(2-thienyl)-4-chloro-5-inthiazo-
Luciferin acid.

3-<3.4-methylenedioxyphenyl)-isothiazolekyl levonate calcium salt.

3-(4-isoproboxyphenyl)-4-fluoro-
5-inchazolecarphonic acid.

3-(3-)lyl)-4-dimethylamino-isothiazolecarboxylic acid ammonium salt 3-(3-trifluoromethylphenyl)-5isothiazolecarboxylic acid compound 2).

3N,5-dichlorophenyl)-4-amino-5-
Intiazolecarphonic acid magnesium salt.

3-<4-hydroxy-3-nitrophenyl>4-chloro-5-isothiazolecarfonic acid.

3-(2-naphthyl)-4-amino-5-isothiazolecarboxylic acid 3-(1-naphthyl)-5-isothiazolecarboxylic acid.

3-(2-furyl)-4-bromo-5-isothiazolecarfonic acid.

3-(3-trifluoromethylphenyl)-4=dimethylreamino-5-isothiazolylboxylic acid.

3-<3-)lifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid ethyl ester.

3-(3-)Lifluoromethylphenyl)-5-inchazo-l-lecar-leboxic acid methyl ester.

N,N-dimethyl-3-(2-thienyl)-4chloro-
5-inchazolecarboxamide.

N-ethyl-3-(2-naphthyl)-4-fluoro-5
-isothiazole carboxamide.

3-<3-chlorophenyl)-4-tnitroxy5-
Isothiazole carboxamide.

Examples include 3-(3,4-dimethoxyphenyl)-5-isothiazo[deg.]-alklebonic acid n-butyl ester. Among them: 3-(3-trifluoromethylphenyl)-4-amino-ra-isothiazolecarboxylic acid (compound 1).

3-(3-trifluoromethylphenyl)-5isothiazolecarbon a<compound 2) is preferred.

The compound represented by the above formula [■] is a known compound, such as Chem, Pharm, Bull,
16148 (1960+ and JP-A-57-8537
Among these documents and patents, JP-A-57-85379 mentions that 3-aryl-5-inthiazole derivatives have xanthine oxidase inhibitory activity. However, there is no mention of the interleukin-1 production inhibitory effect, and in particular, there is no mention of therapeutic agents for nephritis or arthritis.

The interleukin-1 production inhibitor of the present invention can be prepared by preparing the 3-arylisothiazole derivative of the present invention in a soft capsule, a single hard capsule, a syrup, etc. using a known method and appropriate excipients. It can be used as an oral preparation, an injection preparation, or an external preparation.

Such excipients include vegetable oils (e.g. corn oil,
Cottonseed oil, coconut oil, almond oil.

peanut oil, etc., oily esters such as medium-chain fatty acid glycerides, mineral oil, vaseline, animal fats and oils, cellulose derivatives (crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose)
, polyvinylpyrrolidone, dextrin, lactose, mannitol, sorbitol, starch and the like.

The dosage of the active ingredient is usually about 1 to 300 μ/day/person, preferably 10 to 100 μ/day/person, and the frequency of administration (usually 1 to 3 times/day). It is preferable to prepare the formulation so as to satisfy the following.

The interleukin-1 production inhibitor of the present invention can also be used in combination with other therapeutic agents.

Thus, the interleukin-1 production inhibitor of the present invention is provided. The interleukin 1 production inhibitor of the present invention is useful for the treatment and prevention of various inflammatory and allergic diseases caused by interleukin 1, such as arthritis, nephritis, hepatitis 5 fever, asthma, rejection, and shock, based on autoimmune abnormalities. It is.

<Example> Next, the present invention will be explained in detail using Examples.

Example I BAL B/c mice (male, 8 weeks old) were given 5?
1 ml of δ oyster glycogen solution was intraperitoneally administered, and after 4 days, the infiltrated peritoneal exudate cells were attached to a plastic tissue for 3 hours to obtain macrophages. LP31 μg/m to macrophages (1 x 106 cells)
Interleukin 1 released during the 24-hour period was measured by ELISA method.

As shown in Table 1, compounds 1 and 2 are interleukin 1
production was strongly inhibited.

Table 1 Effect on interleukin-1 production The tumor rate was 33% at a dose of 10.50 kg/'kg, respectively.
．． 1%.

21.9% restraint. Furthermore, an inhibitory effect of 30.8% and 25.5% on the anti-collagen antibody titer was observed, respectively.

All of these effects were statistically significant. Note that no side effects were observed during the administration period of Compound 1.

Table 2 Effect on collagen arthritis in rats Example 2 Lewis rats (male, 7 weeks old) were intradermally sensitized with bovine type collagen 2 suspended in complete Freund's adjuvant (FCA) to induce arthritis. did. The drug was orally administered via a sensitization mortar once a day, five times for two weeks. 4 weeks after sensitization,
The constant volume was measured to determine the edema rate, and the serum anti-collagen antibody titer was measured by ELISA.

As shown in Table 2, compound T$A1 was suspended in complete Freund's adjuvant (FCA) intradermally at the base of Example 3 DBA/1 mice (male, 7 weeks old) after 4 weeks of sensitization. The mice were sensitized twice with 100 μg of type II collagen at one week intervals to induce pharyngitis. The drug was orally administered once a day, 5 times for 9 weeks, from the day of sensitization. Four weeks after sensitization, the paw volume was measured to determine the edema rate, and the serum anti-collagen antibody titer was measured by ELISA.

As shown in Table 3, Compound 1 (50 μ/mass) showed an inhibitory effect on the edema rate and serum anti-collagen antibody titer 4 weeks after sensitization. All of these effects were statistically significant.

Table 3 Effect on collagen arthritis in mice Example 4 The drug was administered 101 times to MRL/ρ mice (male, 8 weeks old).
The drugs were orally administered five times a week for 12 weeks, and various serum parameters were measured.

As shown in Table 4, Compound 1 significantly reduced serum BUN and cholesterol at a dose of 10.50 kg/kg, serum DN
There was a tendency to suppress the A antibody titer at 10 μ/kg.

Table 4 car p<0.05. This book p<o, o1 Example 5 Tablets were manufactured, each having the following composition.

Active ingredient (compound 1 or 2) 1 ■ Lactose
280mg potato starch
80 ■Polyvinylpyrrolidone 11■ Mix the above active ingredients, lactose and potato starch, moisten it evenly with a 20% ethanol solution of polyvinylpyrrolidone, pass it through a 2oITIrl+mesh sieve, dry at 45°C, and refill it to 15mm. Through mesh. The granules thus obtained are mixed with magnesium stearate and compressed into tablets.

Claims (3)

[Claims] (1) The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] [In the formula, Ar is a substituted or unsubstituted pyridyl group, thienyl group, furyl group, naphthyl group, or ▲Mathematical formula, chemical formula ,
There are tables, etc.▼ (However, R_1, R_2 and R_3 are each independently a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a C_1_-_4 alkyl group, a C_1_-_4 halogenated alkyl group, and a C_1_-_4 alkoxy group. or R_1 and R_2 together represent an alkylenedioxy group. X is a hydrogen atom, a halogen atom, a hydroxyl amino group,
or C_1_-_4 alkylamino group, Y is carboxyl group, C_1_-_4 alkoxycarbonyl group or -CONR^4R^5 (however, R^4 and R^5 each independently represent a hydrogen atom or a C_1_-_4 alkyl group) or which together form a 5- to 7-membered heterocyclic ring. ] An interleukin-1 production inhibitor comprising a 3-arylisothiazole derivative represented by the following and a pharmaceutically acceptable salt thereof as an active ingredient. (2) Claim (1) wherein the 3-arylisothiazole derivative and its pharmaceutically acceptable salt is 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid or a salt thereof. The interleukin 1 production inhibitor described above. (3) An anti-inflammatory agent containing a 3-arylisothiazole derivative represented by the above formula [I] and a pharmaceutically acceptable salt thereof as an active ingredient.