JPH04342577A - Benzothiazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antiallergic agent, an immunological action suppressant and an antiulcer agent. CONSTITUTION:A compound, e.g. 2'-carboxy-4-hydroxy-2H-1,2-benzothiazine-3- carboxyanilide-1,1-oxide expressed by formula I (R<1> is H, halogen, lower alkoxy or lower alkyl; R<2> is H or carboxyl; R<2> is carboxyl when R<1> is H or halogen). Furthermore, the compound expressed by formula I is obtained by reacting a benzothiazine compound expressed by formula II [R<3> is lower alkyl; R<4> is H, (substituted)benzyl or alkoxyalkyl] with an aniline compound expressed by formula III in the presence of an adsorbent such as molecular sieve in an organic solvent such as xylene at 100-150 deg.C temperature.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to benzothiazine derivatives, methods for producing the same, and pharmaceuticals containing benzothiazine derivatives as active ingredients.

0002

BACKGROUND ART There are various benzothiazine derivatives that have biological activities useful as pharmaceuticals. For example, piroxicam has anti-inflammatory effects and has already been put into practical use as an anti-inflammatory agent. Also, Journal of Me
dicinal Chemistry [1971, (14
) 1171, J. G. Lombardino, E. H
．． Wiseman and W. M. Mclamore
] also discloses a benzothiazine derivative represented by the following formula as a benzothiazine derivative having an anti-inflammatory effect.

0003

[C4]

[0004] JP-A-1-228975 discloses a benzothiazine derivative represented by the following formula as a benzothiazine derivative having anti-inflammatory and anti-allergic effects.

[0005]

[C5]

(Formula, Ra is a carboxyl group or a tetrazole group, Rb and Rc are hydrogen, halogen, hydroxyl group, nitro group, cyano group, trifluoromethyl group, thiol group, lower alkyl group, lower alkoxy group, lower (Rb and Rc may be the same or different)

[0007] Incidentally, in recent years, the number of allergic patients has been rapidly increasing, and the contents of the diseases have been diversifying. That is,
Allergic diseases have traditionally been classified into types I to IV, but the number of immunohypersensitive patients who cannot be accurately classified according to this classification method is increasing day by day. On the other hand, existing antiallergic drugs can be broadly classified into those that suppress the release of chemical mediators from mast cells (chemical mediator release inhibitors), antihistamine agents, and corticosteroids. Depending on the difference in pharmacological action and degree of side effects, the indications for this drug are almost limited to allergic diseases of types I to IV.
Use is restricted. For example, chemical mediator release inhibitors such as tranilast are applicable to the treatment of type I allergic diseases, but are not applicable to the treatment of other allergic diseases, especially type IV. In addition, antihistamines such as promethazine hydrochloride, chlorpheniramine maleate, clemastine fumarate, and diphenhydramine are used to treat allergic diseases such as urticaria, atopic dermatitis, and contact dermatitis; It is rarely applied to sexual allergic diseases other than allergic rhinitis. This is because side effects of this drug cause drowsiness, general malaise, peptic ulcers, etc. Corticosteroids have strong anti-inflammatory effects,
Since it also has an immunosuppressive effect, it is considered suitable as a therapeutic agent for type I to IV allergic diseases, but a high dose is required for the expression of the immunosuppressive effect, If administered, peptic ulcers, adrenal insufficiency,
Its use is limited because it causes serious side effects such as worsening of infection.

[0008] As described above, in the present situation where the contents of allergic diseases are diversifying, there are no existing antiallergic drugs that can be safely used for all allergic diseases of types I to IV. There was a problem.

[0009]

OBJECTS OF THE INVENTION The purpose of the present invention is to have antiallergic effects on various types of allergic diseases, inhibit the production of physiologically active substances in the body that are involved in allergic diseases, and prevent tissue damage caused by active oxygen and free radicals. It has an antioxidant effect suitable as a medicinal ingredient in terms of inhibition, and
The object of the present invention is to provide a novel benzothiazine derivative having both immunosuppressive and antiulcer effects, a method for producing the same, and a new medicine using this benzothiazine derivative.

0010

[Means for Solving the Problems] The benzothiazine derivative of the present invention that achieves the above object has the following general formula (I).

00
11]

[C6]

(In the formula, R1 is a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, and R2
is a hydrogen atom or a carboxyl group, and when R1 is a hydrogen atom or a halogen atom, R2 is a carboxyl group) or a salt thereof.

[0013] Furthermore, the method for producing the benzothiazine derivative of the present invention includes the following general formula (II):

[0014]

[C7]

(wherein R3 is a lower alkyl group,
R4 is a hydrogen atom, a benzyl group, a substituted benzyl group, or an alkoxyalkyl group) and a benzothiazine compound represented by the following general formula (III)

[0016]

[Chemical formula 8]

(In the formula, R1 is a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, and R2
is a hydrogen atom or a carboxyl group, and when R1 is a hydrogen atom or a halogen atom, R2 is a carboxyl group).

The novel drug of the present invention has the above general formula (
It is an anti-allergic agent, an immune action suppressant, and an anti-ulcer agent containing the benzothiazine derivative represented by I) as an active ingredient.

The present invention will be explained in detail below. First, to explain the benzothiazine derivative of the present invention, this compound has the above-mentioned general formula (I)

[0020]

[Chemical formula 9]

It is a compound represented by the following or a salt thereof. Here, R1 is a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group. Specific examples of the halogen atom include chlorine, bromine, fluorine, or iodine; specific examples of the lower alkoxy group include methoxy, ethoxy, propoxy, and butoxy groups; specific examples of the lower alkyl group include Examples include a methyl group, an ethyl group, a straight-chain or branched propyl group, a straight-chain or branched butyl group, and the like. Further, R2 is a hydrogen atom or a carboxyl group. However, when R1 is a hydrogen atom or a halogen atom, R2 is a carboxyl group. That is, combinations in which R1 is a hydrogen atom and R2 is also a hydrogen atom, and combinations in which R1 is a halogen atom and R2 is a hydrogen atom are excluded from the benzothiazine derivatives of general formula (I). Examples of the salt of the compound represented by formula (I) include any pharmaceutically acceptable salt such as sodium salt and potassium salt.

The benzothiazine derivative of the present invention, which is composed of the compound represented by the general formula (I) or a salt thereof, has an antiallergic effect against various allergic diseases, and also has an antiallergic effect on in vivo physiologically active substances involved in allergic diseases. It is a compound that has an antioxidant effect suitable as a pharmaceutical ingredient in terms of inhibiting production and suppressing tissue damage caused by active oxygen and free radicals, and also has immunosuppressive and anti-ulcer effects, making it suitable as a pharmaceutical raw material. It is a compound. The antioxidant effect of the benzothiazine derivative of the present invention is stronger than that of the benzothiazine derivative disclosed in JP-A-1-228975. The benzothiazine derivative of the present invention having such characteristics can be synthesized, for example, based on the method for producing a benzothiazine derivative of the present invention described in detail below.

As mentioned above, the method for producing the benzothiazine derivative of the present invention is based on the following general formula (II).

[0024]

[Chemical formula 10]

(wherein R3 is a lower alkyl group,
R4 is a hydrogen atom, a benzyl group, a substituted benzyl group, or an alkoxyalkyl group) and a benzothiazine compound represented by the following general formula (III)

[0026]

[Chemical formula 11]

(In the formula, R1 is a hydrogen atom, a halogen atom, a lower alkoxy group, or a lower alkyl group, and R2
is a hydrogen atom or a carboxyl group, and when R1 is a hydrogen atom or a halogen atom, R2 is a carboxyl group).

As is clear from the explanation of R4 in the general formula (II), in the method for producing a benzothiazine derivative of the present invention, in the benzothiazine compound represented by the general formula (II), R4 is a benzyl group, a substituted benzyl group, or A benzothiazine compound having an alkoxyalkyl group, that is, a compound in which the 2-position of the benzothiazine ring is protected with a predetermined substituent, may be used. Here, specific examples of the substituted benzyl group include 6,4-dimethylcarbamoylbenzyl group, 4-benzyl bromide group, 4-methoxybenzyl group, etc., and specific examples of the alkoxyalkyl group include methoxymethyl group. , ethoxymethyl group, etc. These protecting groups are removed after reaction with the aniline compound of general formula (III). Moreover, the general formula (II
R1 and R2 in general formula (I) are R1 and R2 in general formula (I)
and R2.

The reaction between the benzothiazine compound represented by the above general formula (II) and the aniline compound represented by the above general formula (III) can be carried out using xylene, toluene, DMSO (
It is carried out in an organic solvent such as dimethyl sulfoxide) or DMF (dimethylformamide). The reaction temperature at this time is not particularly limited, but is usually room temperature to 180°C.
selected within the range of 100 to 150℃ from the point of view of efficiency.
is particularly preferred. At this time, an adsorbent such as a molecular sieve may be used for the purpose of removing alcohol by-produced in the reaction system. By reacting the benzothiazine compound of general formula (II) with the aniline compound of general formula (III) as described above, a crude benzothiazine derivative is precipitated in the reaction solution. The benzothiazine derivative of the present invention having the various biological activities described above can be obtained with high purity by a conventional method such as filtering and recrystallizing the precipitate.

[0030] Next, the antiallergic agent, immunosuppressant, and antiulcer agent of the present invention (hereinafter may be collectively referred to as the medicament of the present invention) will be explained. All of the medicaments of the present invention utilize the biologically active effects of the benzothiazine derivatives of the present invention, that is, anti-allergic effects against various allergic diseases, antioxidant effects, immunosuppressive effects, and anti-ulcer effects. The active ingredient is a benzothiazine derivative. In preparing the medicament of the present invention, the benzothiazine derivative of the present invention may be formulated as it is, or may be formulated by a conventional method using a conventional pharmaceutical carrier, regardless of the type of indication. The dosage form at this time is not particularly limited, and includes oral solid preparations such as powders, fine granules, granules, tablets, coated tablets, and capsules, oral liquid preparations such as syrups, and transdermal absorption preparations. It can be made into various dosage forms, such as injections, suppositories, oral preparations, and ophthalmic preparations, depending on the type of indication and use.

The dosage of the medicament of the present invention cannot be specified because it varies depending on the type and severity of the disease, the dosage form, the age and health condition of the patient, etc., but the dose of the benzothiazine derivative of the present invention, which is the effective amount, cannot be specified. The desired effect can be obtained by administering the drug in an amount approximately equal to the following amount. ■Anti-allergic agent 1-3000mg/day ■Immune action suppressant 1-3000mg/day ■Anti-ulcer agent 1-3000mg/day

[0032]

[Examples] Examples of the present invention will be described below. Example 1 2'-carboxy-4-hydroxy-2H-1,2-benzothiazine-3-carboxyanilide-1,1-dioxide [In general formula (I), R1 is a hydrogen atom and R2
is a 2'-carboxyl group] First, as a benzothiazine compound represented by general formula (II), 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide [As shown in Table 1, in general formula (II), R3
is a methyl group and R4 is a hydrogen atom], and anthranilic acid [as shown in Table 1, in the general formula (III), R1 is a hydrogen atom] was used as an aniline compound represented by the general formula (III). 4.3 g of an aniline compound in which R2 is a 2-carboxyl group were mixed in 250 ml of xylene for 24 hours.
The mixture was heated to reflux for an hour. After cooling, the deposited precipitate was collected by filtration,
Recrystallization from a dioxane-water mixture gave 3.2 g of the title compound, which is one of the benzothiazine derivatives of the present invention. Table 1 shows the melting point and elemental analysis results of the obtained compound.

Examples 2 to 5 Same as Example 1 except that the compounds shown in Table 1 were used as the benzothiazine compound of general formula (II) and the aniline compound of general formula (III), respectively. The benzothiazine derivative of the present invention represented by the formula shown in Table 1 was obtained. Table 1 shows the melting point and elemental analysis results of each compound obtained.

[0034]

[Table 1]

Pharmacological test example 1 [Pharmacological effect test on PCA reaction (type I allergic reaction)] Regarding the benzothiazine derivative obtained in Example 1, P
The effect on CA reaction (passive cutaneous anaphylactic reaction) was tested in the following manner. First, the weight is 250-300
Male Wistar rats (5 individuals/group) were sensitized intradermally on the back with 100 μl of rat anti-ovalbumin serum diluted with physiological saline, and after 48 hours, physiological saline containing ovalbumin and Evans blue was sensitized. First, 5 ml of the aqueous solution was administered intravenously (dose of ovalbumin: 25 ml).
mg/kg, Evans blue dosage: 12.5mg/
kg), causing a skin reaction. Thirty minutes after challenge, each individual was killed by exsanguination, the skin was peeled off, and the amount of leaked pigment was measured using the method of Katayama et al. [Microbial. Immunol. ,1
22(2), 89 (1987)]. The results are shown in Table 2. The test substance has the potential to cause skin reactions1.
The amount shown in Table 2 was orally administered before the test. In addition, in the control, 1% NaHC was added instead of the test substance.
O3 solution was administered orally.

[0036]

[Table 2]

As is clear from Table 2, the benzothiazine derivatives of the present invention exhibit an excellent inhibitory effect on the PCA reaction. This shows that the benzothiazine derivative of the present invention is suitable as an effective component of a therapeutic agent for type I allergic diseases.

Pharmacological test example 2 [Pharmacological effect test on picryl chloride contact hypersensitivity reaction (type IV allergic reaction)]
The benzothiazine derivative obtained in Example 1 was tested for its effect on picryl chloride contact hypersensitivity reaction in the following manner. First, approximately 1 cm2 of hair was removed from the abdomen of male ICR mice weighing 30 to 35 g (5 individuals/group), and 7% picryl chloride ethanol solution was added to the hair-removed area.
Sensitization was carried out by applying 1 ml of the solution. Then, on the seventh day after sensitization, 0.02 ml of a 1% chlorinated picryl olive oil solution was applied to the ear pinna of each mouse to induce chlorinated picryl contact hypersensitivity. Next, 24 hours after the induction of hypersensitivity, each individual was killed by exsanguination under anesthesia, and a certain part of the auricle was cut out with a punch and its weight was measured. The results are shown in Table 3. The test substance was orally administered in the amounts shown in Table 3 every day from the day of sensitization to the day before the end of the test. In addition, as a control, a 1% NaHCO3 solution was orally administered in place of the test substance.

[0039]

[Table 3]

As is clear from Table 3, the benzothiazine derivatives of the present invention exhibit an excellent suppressive effect on picrylic chloride contact hypersensitivity reactions. This indicates that the benzothiazine derivative of the present invention is suitable as an effective component of a therapeutic agent for type IV allergic diseases.

Pharmacological test example 3 [mitogen
Pharmacological effect test (immune effect suppression test) on the blastogenesis reaction of lymphocytes caused by n)] Each of the benzothiazine derivatives obtained in Examples 1 to 5 and the benzothiazine derivatives disclosed in JP-A-1-228975. The effect of [Ra = carboxyl group (o-position), Rb = hydrogen, Rc = hydrogen] on the blastogenesis of lymphocytes by mitogens was tested in the following manner. First, splenocytes isolated from ICR mice by a conventional method were placed in RPM containing 5% fetal calf serum (FCS).
I1640 medium (hereinafter referred to as FCS-RPMI medium)
A splenocyte suspension of 1×10 7 cells/ml was prepared. In addition, concanavalin A (
ConA) and lipopolysaccharide (LPS) were added to FCS-RPMI medium, and 10 μg
FCS-RPMI medium containing ConA at a concentration of /ml and FC containing LPS at a concentration of 500 μg/ml.
S-RPMI medium was prepared. Next, one of the following (1) to (2) was dispensed into each well of a microplate (96 wells), and cultured for 48 hours in a CO2 incubator kept at 37°C. ■FCS-RPMI medium, test substance, and splenocyte suspension. (2) FCS-RPMI medium containing ConA, test substance and splenocyte suspension. (2) FCS-RPMI medium containing LPS, test substance, and splenocyte suspension. ■Splenocyte suspension. ■FCS-RPMI medium containing ConA and splenocyte suspension. (2) FCS-RPMI medium containing LPS and splenocyte suspension.

[0042] Judgment as to whether or not the larval development of lymphocytes is enhanced is based on the lymphocytes in the culture in item (2) above, using the lymphocytes in the culture in item (2) as a reference, and using the lymphocytes in the culture in item (2) above as a reference. The lymphocytes in the culture in (2) and the lymphocytes in the culture in (2) above were observed using a microscope using the above (2) as a reference. The results are shown in Table 4. The test substance is
FCS-
It was used after being dissolved in RPMI medium.

[0043]

[Table 4]

[0044] As is clear from Table 4, the benzothiazine derivatives of the present invention are effective for lymphocytes (T cells) induced by ConA.
At low doses, it shows an excellent suppressive effect only on the juvenile rejuvenation reaction. This shows that the benzothiazine derivatives of the present invention have immunosuppressive effects. It is also found that it has an anti-allergic effect against type IV allergies. On the other hand, the benzothiazine derivatives disclosed in JP-A-1-228975 are capable of reacting not only to the blastogenesis of lymphocytes (T cells) induced by ConA but also to the blastogenesis of lymphocytes (B cells) induced by LPS. It also strongly suppresses the blastogenesis of lymphocytes in the absence of mitogens. This indicates that the suppressive action of this compound is non-specific to immunocompetent cells.

Pharmacological Effect Test 4 (Pharmacological Effect Test on Hydrochloric Acid-Ethanol Induced Ulcer) The anti-ulcer effect of the benzothiazine derivative obtained in Example 1 on hydrochloric acid-ethanol induced ulcer was tested in the following manner. As a comparative example, the anti-ulcer effect of isogladine, a typical anti-ulcer agent, was also tested in the same manner. First, SD male rats (5 individuals/group) weighing 180 to 220 g were fasted for 24 hours, and then
Hydrochloric acid-ethanol induced ulcers were induced by orally administering 1 ml of a 60% ethanol solution containing 1 ml of hydrochloric acid. Next, one hour after administration of the hydrochloric acid-ethanol solution, each animal was anesthetized with ether, sacrificed by exsanguination, and the stomach was removed, and 12 ml of 2% formalin was injected into the removed stomach to fix it. After fixation, the length of damage to the gastric mucosal layer was measured under a dissecting microscope, and the average value for the group was calculated to determine the ulcer index (English name: u).
(hereinafter also referred to as UI), and the ulcer inhibition rate was calculated based on the formula below. The results are shown in Table 5. The test substance was 0.5% of the administration of hydrochloric acid-ethanol solution.
the amount shown in Table 5 [however, in the form of a physiological saline solution containing 10% Nikkol (trade name, solubilizing agent manufactured by Nikko Chemical Co., Ltd.)]
was administered orally. In addition, as a control, a physiological saline solution containing 10% Nikkol (trade name, solubilizing agent manufactured by Nikko Chemical Co., Ltd.) was administered instead of the above solution of the test substance.

[0046]

[Table 5]

As is clear from Table 5, hydrochloric acid-ethanol induced ulcers can be significantly inhibited by orally administering the benzothiazine derivative of the present invention at a rate of 10 mg/kg. This indicates that the benzothiazine derivative of the present invention also has antiulcer activity.

Pharmacological Effect Test 6 (Pharmacological Effect Test on Lipid Peroxidation of Rat Liver Microsomes) (1) Preparation of Rat Liver Microsome Suspension First, a 30% liver homogenized solution was obtained from SD male rats by a conventional method. . Next, 8000 g of the obtained homogenized liquid (
g: gravitational acceleration) for 10 minutes, and the resulting supernatant was collected. Then, the supernatant was centrifuged at 105,000 g (g: gravitational acceleration) for 1 hour, and the amount of protein in the resulting precipitate was measured by the Lowry method. 1.1
A liver microsome suspension was prepared by adding 5% KCl.

(2) Pharmacological effect test on lipid peroxidation The effect on lipid peroxidation of each benzothiazine derivative obtained in Examples 1 to 3 was tested in the following manner. First, Tris-HCl buffer (167mM KCl
, 74mM Tris, pH 7.4) to 0.5ml of the above (
1) 0.1 ml of the liver microsome suspension obtained in
ADPH 0.1ml (final concentration 2mM), ADP
0.1 ml (final concentration 10 mM), and 10% DM
0.1 ml of test substance solution prepared in F to the concentration shown in Table 1
was added and heated at 37°C for 5 minutes. Then FeCl
3 Add 0.1 ml (final concentration 0.1 mM) and
It was heated at ℃ for 20 minutes. Next, the reaction solution was cooled on ice, and 0.2 ml of 8.1% SDS solution and 10% of acetic acid buffer (20% acetic acid containing 0.27M HCl) were added to the ice-cooled reaction solution.
Adjusted to pH 3.5 with N NaOH) 1.5m
1 and 1.5 ml of 0.8% thiobarbituric acid were added and heated on a boiling water bath for 20 minutes. After heating, the reaction solution was cooled on ice, and 4 m of a mixture of n-BuOH and pyridine [n-BuOH:pyridine = 15:1 (volume ratio)] was added to the ice-cooled reaction solution.
1 was added and mixed vigorously. After this, the reaction solution was heated to 200%
After centrifugation at 0 rpm for 10 minutes, the resulting supernatant was
The amount of thiobarbituric acid reacted was determined by measuring the absorbance at nm, and the amount of lipid peroxide was determined from the calibration curve of the amount of mandelaldehyde (MDA) created using 1,1,3,3-tetramethoxypropane. It was determined as the amount of MDA produced. As a control, the amount of lipid peroxide was determined using 0.1 ml of a 10% DMF solution instead of the DMF solution of the test substance. Also, in the blank, NADPH 0.1m
l, ADP 0.1 ml, and FeCl3 0.1
The amount of lipid peroxide was determined by using 0.1 ml of water instead of each ml, and using 0.1 ml of a 10% DMF solution instead of the DMF solution of the test substance. Then, the inhibition rate of lipid peroxidation reaction is calculated using the following formula: Inhibition rate (%) = [1-(OD
1-OD3)/(OD2-OD3)]×100
OD1: Absorbance when test substance was added OD2: Absorbance of control OD3: Calculated from absorbance of blank. The results are shown in Table 6.

[0050]

[Table 6]

As is clear from Table 6, the benzothiazine derivatives of the present invention have excellent antioxidant activity (lipid peroxidation inhibiting activity). Therefore, the benzothiazine derivative of the present invention is suitable as an effective component of an anti-allergic agent from the viewpoint of inhibiting the production of physiologically active substances in the body involved in allergic diseases and suppressing tissue damage caused by active oxygen and free radicals. I understand that there is something.

Toxicity test ICR male mice weighing around 30g (10 individuals/group)
500 mg/k of the benzothiazine derivative of Example 1.
The test substance was orally administered repeatedly for 14 days at a rate of g/day, and trends in weight gain and general symptoms were observed during the administration period, and blood was collected on the 15th day for blood biochemical tests. . In addition, in the control, 1% was added instead of the test substance.
NaHCO3 solution was administered orally. As a result, there were no major differences in general symptoms or weight gain between the test group and the control group, and no differences were observed in blood biochemical test results between the two groups.

Formulation Example 1 (Tablet) Compound of Example 1
50g
lactose
10g
corn starch
30g
crystalline cellulose
8g
hydroxypropyl cellulose
1g magnesium stearate
1g

100g [Procedure] Use the compound part of Example 1, lactose, corn starch, and crystalline cellulose in the above amounts and mix them. Add hydroxypropyl cellulose dissolved in 30 ml of water and mix thoroughly. did. This kneaded mixture was passed through a 20-mesh sieve to form granules, and after drying, magnesium stearate was mixed with the resulting granules and the mixture was compressed into 100 mg tablets to obtain tablets. Moreover, the compounds of Examples 2 to 5 were also formed into tablets in the same manner.

Formulation Example 2 (Injection) Compound of Example 1
10mg
sodium chloride
90mg
NaHCO3
100mg
Distilled water for injection
Appropriate amount


10 ml [Operation] Dissolve the prescribed amounts of the compound of Example 1, sodium chloride, and NaHCO3 in distilled water for injection, adjust the pH to around 7.0, fill the resulting 10 ml solution into an ampoule, and seal it. , an injection was obtained. Moreover, the compounds of Examples 2 to 5 were also made into injections in the same manner.

[0055]

Effects of the Invention As explained above, the novel benzothiazine derivatives of the present invention have excellent antiallergic effects against various types of allergic diseases, and also have immunosuppressive effects, antiulcer effects, and antioxidant effects. have. Therefore, by carrying out the present invention, an anti-allergic agent or immunosuppressant that does not cause disorders in the digestive organs such as the stomach and intestines and is useful for various types of allergic diseases, and also has an anti-allergic effect. It becomes possible to provide anti-ulcer agents.

Claims (5)

[Claims] Claim 1: The following general formula (I) [Formula 1] (wherein, R1 is a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, R2 is a hydrogen atom or a carboxyl group, and R1 is A benzothiazine derivative consisting of a compound represented by (when R2 is a carboxyl group, when it is a hydrogen atom or a halogen atom) or a salt thereof. [Claim 2] A benzothiazine represented by the following general formula (II) [Formula 2] (wherein R3 is a lower alkyl group, and R4 is a hydrogen atom, a benzyl group, a substituted benzyl group, or an alkoxyalkyl group) compound and
The following general formula (III) [Formula 3] (wherein, R1 is a hydrogen atom, a halogen atom, a lower alkoxy group, or a lower alkyl group, R2 is a hydrogen atom or a carboxyl group, and R1 is a hydrogen atom or a halogen atom) 2. The method for producing a benzothiazine derivative according to claim 1, further comprising a step of reacting the benzothiazine derivative with an aniline compound represented by (where R2 is a carboxyl group). 3. An antiallergic agent comprising the benzothiazine derivative according to claim 1 as an active ingredient. 4. An immune action suppressant comprising the benzothiazine derivative according to claim 1 as an active ingredient. 5. An antiulcer agent comprising the benzothiazine derivative according to claim 1 as an active ingredient.