JPH01146875A - Benzothiazole derivative and antirheumatic agent containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:2-(2-Methylphenyl)-4-hydroxybenzothiazole of formula I. USE:An anti-rheumatic agent having immuno-regulating action as the action mechanism. PREPARATION:The compound of formula I can be produced e.g., by (1) reacting 2-methyl-2'-methyl-2'-methoxybenzanilide of formula II with Lowessons reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide] to obtain 2-methyl-2'methoxybenzothioanilide of formula III, (2) reacting the product with potassium ferricyanide in the presence of potassium hydroxide and (3) reacting the resultant compound of formula IV with aluminum iodide in the presence of a catalytic amount of tetra-n-butyl ammonium iodide.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial 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 11A has mainly been symptomatic therapy that suppresses inflammation using non-steroidal anti-inflammatory drugs, etc., but recently attention has been focused on therapies that approach the cause of the disease by improving immune abnormalities based on immunomodulatory effects. An example of this type of drug is wapenzarit disodium [Progre
ss in Drug Research, 24, 18
5-186゜Ern5t Jucker Ji, Birk
h; see 1user Verlag publication (1980)]
.

Lobenzaricitonisodium J, Med, Chem, 198&, 29,820-
825 includes 2-(4-methylphenyl)-5-hydroxybenzothiazole, 2-(4-methylphenyl)-6
-Hydroxybenzothiazole and 2-(4-methylphenyl)-7-hydroxybenzothiazole are described, but there is no description of pharmacological action.

(Problems to be Solved by the Invention) Various studies were conducted with the aim of developing a new type of anti-rheumatic agent whose mechanism of action is immunomodulation 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, for example, by the following method.

(That is, Compound (II) is mixed with Lawesso's reagent [Lawesso
-n's Reagent; 2,4-bis(4-
methoxyphenyl)-1,3-dithia-2,4-defosphethane-2,4-disulfide] to obtain compound (m), and then reacted with potassium ferricyanide in the presence of potassium hydroxide to obtain compound (IV). . Next, the compound (I) of the present invention can be produced by reacting aluminum iodide with compound (IV) in the presence of a catalytic amount of tetra-n-butylammonium iodide.

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 (1) 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 adjuvant 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 enhanced 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] Fischer male rats (8 weeks old, weight 120-1
80g) 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 1z gum arabic solution and orally administered once a day, 6 days a week, for 3 weeks from the day of the adjuvant injection. To the control group, 1z gum arabic solution was administered instead of the test compound. The volume (ml) of the adjuvant-treated paw (right hindlimb) and non-stirrup paw (left hindlimb) was orally measured by the water displacement method, and the paw edema suppression rate was determined by the following formula.

Book: 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.

*: Foot volume after adjuvant treatment Book *: Fixed volume before adjuvant treatment [test results] Paw edema of each compound 21 days after adjuvant injection Table 1 Umbrella: 4 out of 16 cases died during the test and were therefore excluded.

As is clear from Table 1, the compound (I) of the present invention exhibits a clear suppressive effect on edema in both adjuvant-treated and non-adjuvant-treated feet, and this effect is more pronounced than that of lobenzarit disodium. It was strong.

Test example 2 Effect on delayed 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 x 10' cells/ml) into the tail vein. Three days after sensitization, sheep red blood cell suspension (8X109
A dose of 0.05 ml (200 mg/ml) was injected into the right hind paw skin to induce a delayed allergic reaction. After 24 hours, the thickness of the foot pedal (mm) was measured using a dial thickness gauge (dial).
The difference between this thickening value and the thickening value before sensitization was defined as foot edema (mm), 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 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.

*: Average foot edema of the test compound administration group *: Average foot edema of the control group [Test results] As is clear from Table 2, the compound (I) of the present invention is similar to lobenzarit disodium. Furthermore, it was found that neither dose suppressed paw edema nor affected delayed allergic reactions in a normal immune state.

(B) Effect on normal immune 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, 0.00 mg/ml of sheep red blood cell suspension (5 x 10' cells/ml) was administered into the tail vein. 2ml
sensitized by injecting Three days after sensitization, sheep red blood cell suspension (8
A dose of 0.05 ml (x109 cells/ml) was injected into the right hind paw skin to induce a delayed allergic reaction. 24 hours later,
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. To the control group, 1z gum arabic solution was administered instead of the test compound. In addition, a group in which physiological saline was administered in place of cyclophosphamide and 1z gum arabic solution 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 of normal group [Test results] See Table 3: There was a significant difference with p < o, os compared to the control group.

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

As is clear from Table 3, it was found that the compound (I) of the present invention, like lobenzarit disodium, significantly suppressed paw edema and suppressed delayed allergic reactions in immunohyperactive states.

Test example 3 m: [Test compound] Same as in Test Example 1.

[Test method] ddY male mice (body weight around 123 g) were fasted overnight,
The test compound was dissolved or suspended in a 1% gum arabic solution and administered orally. The LDso value was calculated from the number of deaths one week later using the Probit method.

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

Table 4 (Examples) Below, the present invention will be explained in more detail with reference to Examples.

Example 1 2-(2-methylphenyl)-4-hydroxybenzothiazole: (1) 2-Methyl-2'-methoxybenzthioanilide: 2-methyl-2'-methoxybenzanilide (Japanese Patent Application Laid-Open No. 1989-1993)
0-83339)) 20.0g toluene 100m
1, 18.5 g of Lawson's reagent was added thereto, and the mixture was refluxed for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [eluting with cyclohexane-ethyl acetate (20:1.v/v)] to obtain 2-methyl-2'-methoxybenzthioanilide 18. .3g was obtained.

Note that a portion of this was recrystallized from n-hexane, and the mp was 86.0-88.0°C.

(2) 2-(2-methylphenyl)-4-methoxybenzothiazole: 13.1 g of potassium hydroxide and 3 potassium ferricyanide
2-methyl-2'-methoxybenzthioanilide 1 obtained by dissolving 8.4 g in 750 ml of water and stirring (1)
5.0 g was added and stirred at room temperature for 44 hours. After the reaction, the crystals were collected by filtration, washed with water, dried, and subjected to silica gel column chromatography [cyclohexane-ethyl acetate (10:1).
, v/v) and then recrystallized from n-hexane to give 2-(2-methylphenyl)-
4.8 g of 4-methoxybenzothiazole was obtained.

mp 117.5-119.5°C (3) 2-(2-methylphenyl)-4-hydroxybenzothiazole: 52 mg of powdered aluminum and 3.9 g of iodine were added to 20 ml of benzene, and the color of the iodine disappeared under a nitrogen stream. It was refluxed until To this, 4.5 g of 2-(2-methylphenyl)-4-methoxybenzothiazole obtained in (2)
A solution of 12 mg of tetra-n-butylammonium iodide in 30 ml of benzene was added dropwise under reflux. After further refluxing for 1 hour, it was poured into 60ml of water and diluted with ethyl acetate for 3 hours.
Extracted twice. After drying the extract with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure and recrystallized from n-hexane to obtain 3.0 g of 2-(2-methylphenyl)-4-hydroxybenzothiazole. .

mp 58.0-60.0°C NMR (CDCI:s, δppm): 2.62 (3H,
s), 6.9-7.1 (2H.

m), 7.2-7.5 (5H, m), 7.6-7.8 (
IH, m).

Elemental analysis value (as C14H, NO3): Calculated value ($
) C, 69,68; H, 4,59; N, 5.80 Actual value (X) C, 69,65; H, 4,47; N, 5.8
6 Example 2 Manufacturing Example Tablet L: [Formulation] (Compound of Example 1) 500 Lactose 700 Crystalline cellulose 400 Carboxymethyl cellulose calcium 150 Hydroxypropyl cellulose 30 Magnesium stearate 20 Total 1800 [Operation] Compound of Example 1 , 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 (2mm screen), and then passed through a fluidized bed granulator (8mm screen).
0°C) for 20 minutes. The obtained granules were sieved through 20 meshes, and then crystalline cellulose, calcium carboxymethyl cellulose and magnesium stearate were added and mixed, and then tableted to form tablets containing 50 mg of the compound of Example 1 (180+ng). Lock, diameter 8m
m) was produced.

Example 3 Formulation example (powder): [Formulation] Lactose 600 Corn starch 290 Magnesium stearate 10 Total 1000 [Operation] The above components were thoroughly mixed to form a uniform mixed powder, and 1 g contained the active ingredients of Example 1. A powder containing 100 mg of the compound was obtained.

Example 4 Rikaden” granule top = [Formulation] Milk tli 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 (80° C.). 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 Pierre Legend's left-hand medicine 1: [Formulation] Lactose 970 Crystalline cellulose 600 Corn starch 400 Magnesium stearate
30 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 each 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. ▼.