JPH01143863A - Benzothiazole derivative and antirheumatic agent containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:4-Acetoxy-2-(3-methylphenyl)benzothiazole of formula I. USE:An antirheumatic agent having immune action as the mechanism. PREPARATION:The objective compound of formula I is produced by reacting a novel compound of formula II with an acetylation agent such as acetic anhydride or acetyl chloride. The novel compound of formula II used as a starting material can be produced e.g., by converting m-methylbenzoic acid of formula III to acid chloride, reacting with o-anisidine to obtain a compound of formula IV, reacting with Lowessons reagent, converting the resultant compound of formula V to a compound of formula VI with potassium ferrocyanide and reacting the compound with boron tribromide.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel benzothiazole derivative and an antirheumatic agent containing the compound as an active ingredient.

More specifically, the present invention relates to a benzothiazole derivative represented by the following formula (I) and an antirheumatic agent containing the compound as an active ingredient.

(Prior Art) Rheumatoid arthritis (hereinafter referred to as RA) is a systemic inflammatory disease characterized by chronically destructive, degenerative, and non-purulent joint lesions. Regarding the onset mechanism of RA, it is thought that genetic and environmental factors are at the root of the disease, and that RA is triggered by viral infection and develops through immune abnormalities. Conventionally, the treatment of RA has mainly been symptomatic therapy that suppresses inflammation using non-steroidal anti-inflammatory drugs, but recently, therapy that approaches the cause of the disease by improving immune abnormalities based on immunomodulatory effects has been attracting attention. An example of this type of drug is lobenzarit disodium [Progres
s in Drug Research, 24,185
-186゜Ern5t Juckeril Ji, Bir
See khSiuser Verlag (1980)].

Lobenzarit disodium J, Med, Chem, 1986, 29.82
0-825 includes 5-acetoxy-2-(4-methylphenyl)benzothiazole, 6-acetoxy-2-(4
-methylphenyl)benzothiazole and 7-acetoxy-2-(4-methylphenyl)benzothiazole, but there is no description of their pharmacological action.

[Problem that the invention seeks to solve]

Various studies were conducted with the aim of developing a new type of anti-rheumatic agent that has an immunomodulatory effect as a therapeutic agent for RA.

[Means for solving problems]

As a result of repeated studies, the present inventors discovered that the novel benzothiazole derivative represented by the above formula (I) satisfies such requirements, and completed the present invention.

Compound (I) of the present invention can be produced by reacting a compound represented by the following formula (II) with an acetylating agent such as acetic anhydride, acetyl chloride, etc. according to a conventional method.

That is, compound (II) contains 1.
0 equivalent to an excess amount of the acetylating agent is added without solvent or in an inert organic solvent such as pyridine or dichloromethane, optionally in the presence of a base such as pyridine or 4-dimethylaminopyridine, under reflux conditions from room temperature 1-3. Compound (I) of the present invention can be produced by reacting for a period of time.

Compound (II
) is a new compound and can be produced, for example, by the method below.

That is, first, compound (m) is reacted with thionyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) to form an acid chloride, and this is reacted with 0-anisidine to obtain compound (IV). Next, Lawesson's Reagent; 2,
4-bis(4-methoxyphenyl)-1,3-dithia-
2,4-defosphethane-2,4-disulfide] to obtain compound (V), and then reacted with potassium ferricyanide in the presence of potassium hydroxide to obtain compound (Vl). Furthermore, compound (II) can be produced by reacting compound (VI) with boron tribromide.

As described below, the compound (I) of the present invention strongly suppresses rat adjuvant arthritis, which is a pathological model of RA, based on its immunomodulatory effect, and is also useful as an antirheumatic agent because it has low toxicity and high safety.

When using the compound (I) of the present invention for the treatment of RA, it is usually used as an orally administered agent.

Dosage forms for oral administration include solid preparations such as tablets, granules, powders, and capsules, as well as liquid preparations such as syrups. Such preparations are prepared by conventional methods, and solid preparations are formulated using conventional pharmaceutical additives such as lactose, corn starch, crystalline cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, magnesium stearate, etc. . Capsules can be obtained by filling the granules, powders, etc. thus prepared into suitable capsules. Further, a syrup can be obtained by dissolving or suspending the compound (I) of the present invention in an aqueous solution containing sucrose, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like.

The dosage of the compound (I) of the present invention varies depending on symptoms, age, etc., but is usually 0.1 to 15.0 m/day for adults.
g/kg, which is administered at once or in 2 to 3 divided doses.

(Actions and Effects of the Invention) The compound (I) of the present invention can be used in rats, which is a pathological model of RA.
It showed a clearly stronger inhibitory effect on najuvant arthritis than lobenzarit disodium (see Test Example 1).

The inhibitory effect of the compound (I) of the present invention on adjuvant arthritis is considered to be based on an immunomodulatory effect rather than an anti-inflammatory effect from the following points (i) and (it).

(i) Compound (I) of the present invention, like lobenzarit disodium, does not show any effect on rat carrageenan paw edema, which is an acute inflammation model, and rat mustard paw edema, which is a subacute inflammatory model (neither In this case, there was no effect at a dose of 100 mg/kg).

(ii) Regarding the effect on cell-mediated immunity, we investigated the effect on delayed allergic reactions as an indicator and found that the compound (I) of the present invention, like lobenzarit disodium, has no effect on abnormally light immune reactions. However, it has no effect on normal immune reactions (see Test Example 2).

Furthermore, the compound (I) of the present invention had lower toxicity than lobenzarit disodium (see Test Example 3).

Therefore, the compound (I) of the present invention strongly suppresses adjuvant arthritis based on its immunomodulatory effect, has low toxicity and high safety, and is useful as an antirheumatic agent.

Test Example 1 Adjuvant arthritis suppressive effect: [Test compound] (1) Compound of the present invention (1) (compound of Example 1) (2)
Lobenzarit disodium (comparative compound) [Test method] F 1scher male rats (8 weeks old, weight 120-
180g) were divided into groups so that the average weight of each group was approximately the same, and the complete adjuvant [Mycobacterium butyricum (Difc.

Laboratories) suspended in liquid paraffin to a concentration of 6 mg/ml. ] 00.1 m was injected into the right hind paw skin.

The test compound was dissolved or suspended in a 1% gum arabic solution and orally administered once a day, 6 days a week, for 3 weeks from the day of the adjuvant injection. A 1% gum arabic solution was administered to the control group instead of the test compound. The volume (ml) of the adjuvant-treated paw (right hindlimb) and non-treated paw (left hindlimb) was measured daily by the water displacement method, and the paw edema suppression rate was determined by the following formula.

*: Paw edema rate of rats administered with test compound *Book: Average paw edema rate of control group However, the paw edema rate was calculated using the following formula.

*: Fixed volume after adjuvant treatment * Book: Paw volume before adjuvant treatment [Test results] As is clear from Table 1, the paw edema of each compound 21 days after the adjuvant injection, the compound (I) of the present invention showed a clear inhibitory effect on edema in both adjuvant-treated and non-adjuvant-treated legs, and this effect was clearly stronger than that of lobenzarit disodium.

Test example 2 Effect on slow 1 allergic reaction: (A) Effect on normal immune state: [Test compound] Same as in Test Example 1.

[Test Method] BALB/c male mice (8 weeks old) were sensitized by injecting 0.2 ml of a sheep red blood cell suspension (5×10 6 cells/ml) into the tail vein. Three days after sensitization, sheep red blood cell suspension (8X10
9 pieces/m1) 0.05ml was injected into the right hind paw skin,
It caused a delayed allergic reaction. After 24 hours, the thickness of the foot pedal (mm) was measured using a dial thickness gauge (dialt).
foot edema (mm), and the difference between this thickening value and the thickening value before sensitization is defined as foot edema (mm).
The foot edema suppression rate was calculated using the following formula.

The test compound was dissolved or suspended in a 1% gum arabic solution and administered orally once a day for 7 days starting 4 days before sensitization. A 1% gum arabic solution was administered to the control group instead of the test compound.

N: Average foot edema of the test compound administration group**: Average foot edema of the control group [Test results] The results are shown in Table 2.

(Margin below) Table 2 As is clear from Table 2, the compound (I) of the present invention, like lobenzarit disodium, does not suppress foot edema at any dose and delays the normal immune state. It was found that this type of allergic reaction had no effect.

(B) Effect on immunohyperactive state: [Test compound] Same as in Test Example 1.

[Test method] 75 mg/kg of cyclophosphamide was intraperitoneally administered to BALB/c male mice (8 weeks old), and 4 days later, 0.2 m of sheep red blood cell suspension (5 x 10 cells/ml) was injected into the tail vein.
sensitized by injecting L. Three days after sensitization, sheep red blood cell suspension (
0.05 ml of axio (9 pieces/ml) was injected into the right hind paw skin to induce a delayed allergic reaction. After 24 hours, the foot edema (mm) was measured in the same manner as in (A) above, and the foot edema suppression rate was determined by the following formula.

The test compound was dissolved or suspended in a 1% gum arabic solution, and 1 day before sensitization (immediately after administration of cyclophosphamide).
The drug was administered orally once a day for 7 days. A 1% gum arabic solution was administered to the control group instead of the test compound. In addition, a group in which physiological saline was administered instead of cyclophosphamide and a 1% gum arabic solution was administered in place of the test compound was defined as a normal group.

*: Mean foot edema of control group**: Mean foot edema of test compound administration group***:
Average foot edema in normal group [Test results] Table 3 Umbrella: Significant difference (I) <0.05 compared to control group.

◆◆Monkey: P <0.001 compared to control group by test
There is a significant difference.

As is clear from Table 3, the present striking compound (1) was found to significantly suppress foot edema and suppress delayed allergic reactions in the immunophotopathic state, similar to lobenzarit disodium. .

Test example 3 Acute toxicity: [Test compound Same as in Test Example 1.

[Test method] ddY male mice (body weight around 23 g) were fasted overnight,
The test compound was dissolved or suspended in a 1% gum arabic solution and administered orally. LDs from the number of deaths after one week. Values were calculated using the Probit method.

[Test results] The results are shown in Table 4.

Table 4 [Examples] The present invention will be explained in more detail below with reference to Production Examples and Examples.

Production Example 1 4-hydroxy-2-(3-methylphenyl)benzothiazole: (1) 3-methyl-2'-methoxybenzanilide: m
-Methylbenzoic acid25. A catalytic amount of about 0.5 ml of DMF was added to a mixture of Og and 40 ml of thionyl chloride, and the mixture was refluxed for 3 hours. After the reaction, the mixture was dried under reduced pressure, and the residue was dissolved in 30 ml of tetrahydrofuran and added dropwise to a solution of 22.6 g of O-anisidine in 150 ml of pyridine at 5-10°C. After stirring at room temperature for 3 hours, it was poured into 1.81 g of water. The precipitated crystals were collected by filtration, washed with water, and then dried to obtain 42.7 g of 3-methyl-2'-methoxybenzanilide.

In addition, a part of this was recrystallized from n-hexane, and the mp was 62.0-64.0°C.

(2) 3-Methyl-2'-methoxybenzthioanilide: 40.0 g of 3-methyl-2'-methoxybenzthioanilide obtained in (1) was dissolved in 200 ml of toluene, and 36.9 g of Lawesson's reagent was added. It was refluxed for 2.5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [cyclohexane-ethyl acetate (10:
1. v/v) to obtain 34.2 g of 3-methyl-2'-methoxybenzthioanilide.

A portion of this was recrystallized from n-hexane-ethyl acetate and had a mp of 66.5-68.5°C.

(3) 2-(3-methylphenyl)-4-methoxybenzothiazole: 29.6 g of potassium hydroxide and 8 potassium ferricyanide
3-Methyl-2'-methoxybenzthioanilide 34 obtained by dissolving 6.9 g in 1.71 water and stirring (2)
．． 0 g was added and stirred at room temperature for 2 days. After the reaction, the crystals were collected by filtration, washed with water, dried, and then subjected to silica gel column chromatography [cyclohexane-ethyl acetate (10:1.v
/v)] and then recrystallized from cyclohexane to give 2-(3-methylphenyl)-4-
11.4 g of methoxybenzothiazole was obtained.

mp 83.0-85.0°C (4) 4-hydroxy-2-(3-methylphenyl)benzothiazole: 2-(3-methylphenyl)-4-methoxybenzothiazole obtained in (3)6. 7g dichloromethane 70
A solution of 7.2 g of boron tribromide in 30 ml of dichloromethane was added dropwise thereto. After stirring at room temperature for 4.5 hours, the mixture was poured into 200 ml of ice water and extracted three times with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. By subjecting the residue to silica gel column chromatography [elution with chloroform], 4
3.4 g of -hydroxy-2-(3-methylphenyl)benzothiazole was obtained.

A portion of this was recrystallized from cyclohexane and had a mp of 110. '5-112.5°C.

Example 1 4-acetoxy-2-(3-methylphenyl)benzothiazole: 3.0 g of 4-hydroxy-2-(3-methylphenyl)benzothiazole obtained in Production Example 1 was mixed with 30 m of acetic anhydride.
1 and refluxed for 1 hour. After the reaction, the resulting residue was dried under reduced pressure, washed with a small amount of cyclohexane, and then recrystallized from cyclohexane to give 4-acetoxy-2-
2.5 g of (3-methylphenyl)benzothiazole was obtained.

mp 88.0-90.0°C NMR (CDC13, δppm): 2.42 (3H,
s), 2.50 (3H, s).

7.1-7.5 (4H, m), 7.6-8.0 (3H
, m).

Elemental analysis value (as C16H□3NO□S): Calculated value (
%') C, 67,82; H, 4,62; N, 4.94
Actual value (%”) C, 67,90; H, 4,53; N,
4.90 Example 2 Formulation example (tablet): [Formulation] (Compound of Example 1) 500 Lactose 700 Crystalline cellulose 400 Carboxymethyl cellulose calcium 150 Hydroxypropyl cellulose 30 Magnesium stearate 20 Total 1800 [Operation] Example 1 The compound, lactose and crystalline cellulose were mixed uniformly. Hydroxypropylcellulose is purified with water (6
00g), added to the above mixture, kneaded, passed through a crushing granulator i (2mm screen), and passed through a fluidized bed granulator (
80°C) for 20 minutes. The obtained granules were sieved through 20 meshes, and then crystalline cellulose, carboxymethyl cellulose calcium and magnesium stearate were added and mixed, and then tableted to form tablets (180 mg) containing 50 mg of the compound of Example 1 in the tablets. Lock, diameter 8m
m) was produced.

Example 3 Formulation example (powder): [Formulation] Component Amount (g) 4-acetoxy-2-(3-methyl lactose 600 Corn starch 290 Magnesium stearate 10 Total 1000 [Operation] Thoroughly mix each of the above ingredients. A uniform mixed powder was prepared, and a powder containing 100 mg of the compound of Example 1 as an active ingredient in 1 g was obtained.

Example 4 Formulation example (granules): [Formulation] Lactose 400 Corn starch 280 Crystalline cellulose
200 hydroxypropylcellulose
20 total 1000 [Operation] The compound of Example 1, lactose, corn starch and crystalline cellulose were mixed uniformly. Hydroxypropyl cellulose was dissolved in purified water (400 g), added to the above mixture, kneaded, passed through an extrusion granulator (0.8 mm screen), and dried for 20 minutes in a fluidized bed granulator (8°C). did. The obtained granules were passed through a 14-mesh sieve to obtain granules containing 100 mg of the compound of Example 1 in 1 g.

Example 5 釦哩■叉目■4m= [Formula (compound of Example 1) 500 lactose
970 crystalline cellulose
600 corn starch
400 Magnesium Stearate 3
0 Total 2500 [Operation] The above ingredients were thoroughly mixed and filled into hard capsules (No. 3) to obtain capsules containing 50 mg of the compound of Example 1 as an active ingredient in 1 capsule (250 mg).

Claims (2)

[Claims] (1) Below formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A benzothiazole derivative represented by (2) An anti-rheumatic agent whose active ingredient is a benzothiazole derivative represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼.