WO1995013269A1 - 1,4-benzothiazine derivative - Google Patents

Abstract

A compound represented by general formula (I) or a salt thereof and an intermediate for synthesizing the same wherein R1 represents optionally protected hydroxy; R2 represents lower alkyl; R3 represents hydrogen, lower alkyl, optionally protected hydroxy or lower alkoxy, wherein the lower alkyl group may be substituted by optionally protected hydroxy, amino or lower alkylamino; R4 represents carboxyl which may be in the form of an ester or amide; A represents alkylene; and B represents -CH¿2?- or >C=S. This compound has the activities of stabilizing proteins and inhibiting lipid peroxide formation, and is promising as an excellent cataract remedy.

Description

 Description Name of Invention 1, 4 Benzothiazine derivative Technical field

 TECHNICAL FIELD The present invention relates to a novel 1,4-benzothiazine derivative having a protein stabilizing action and an action of suppressing lipid peroxide production and useful as a drug such as a therapeutic agent for cataract, and a synthetic intermediate thereof. Background art

 Cataract is an intractable eye disease in which the lens becomes cloudy and loses vision. Although various factors have been studied for a long time for the onset factor, mechanism, and treatment of cataracts, there are very few effective drugs at present.

 It is said that an increase in peroxide in the lens is related to the onset of cataract, and it has been reported that compounds having an inhibitory effect on lipid peroxide production are effective for cataract (Current Eye Res., 5). , 37-40 (1986)). It has also been reported that cataract patients show denaturation of protein in the lens (Ophthalmology, 11, 1283-1296 (1977)).

From these facts, it is considered that a compound having both a lipid peroxide production inhibitory action and a protein stabilizing action is particularly useful for cataract. However, research on compounds having both these effects has not been conducted yet, and The development of a compound was desired.

 Compounds having a benzylidene group at the 2-position of the 1,4-benzothiazine derivative, which is the basic skeleton of the compound of the present invention, include a herbicide (Amerili Patent No. 3923379), a tranquilizer (specifically) It has been reported that it can be used as an intermediate for synthesizing a benzothiazepine derivative (Japanese Patent Application Laid-Open No. 60-72875). However, the compounds disclosed in these known documents have an oxo group at the 3-position of the benzothiazine ring, and have a different skeleton chemical structure from the compound of the present invention. Further, no information has been reported on the protein stabilizing action or the lipid peroxide production inhibiting action, which are the characteristics of the effect of the compound of the present invention.

 In addition, Japanese Patent Application Laid-Open No. 1-28707 discloses a 2-benzylidene-3-oxo-1,4-benzothiazine derivative having an active oxygen scavenging action and a lipid peroxide production inhibitory action. However, it is a matter of course that the compounds disclosed in this publication and the compound of the present invention have different skeleton chemical structures, and there is no description of a protein stabilizing effect in this publication. .

 In addition, an aldose reductase inhibitor has recently attracted attention as a cataract therapeutic agent, but the compound of the present invention also has an aldose reductase inhibitory effect, and its usefulness as a cataract therapeutic agent is extremely high. Is expensive. Disclosure of the invention

The present inventors have conducted intensive studies to find a compound having both a lipid peroxide production inhibitory action and a protein stabilizing action. A benzylidene group wherein the 2-position is substituted with a benzylidene group and the 4-position is substituted with a carboxyalkyl group, respectively, and the 3-position is a thioxo or unsubstituted 3,4-dihydro-1,4-benzothiazine compound; It has been found that a compound in which the phenyl ring is further substituted with a hydroxy group and a lower alkyl group has both effects of inhibiting lipid peroxide production and stabilizing a protein.

 The present invention relates to a compound represented by the following general formula [Π or a salt thereof (hereinafter, referred to as the present compound [1]) and a synthetic intermediate of the present compound [I] represented by the following general formula [Π] or a salt thereof: (Hereinafter referred to as the intermediate [II] of the present invention).

[Wherein, R ¹ represents a hydroxy group which may be protected by a protecting group. 2 represents a lower alkyl group. ^{ 3 ^} represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group which may be protected with a protecting group, and the lower alkyl group is a hydroxy group or an amino group which may be protected with a protecting group. Or a lower alkylamino group. R ⁴ represents a carboxyl group which may be converted to an ester or an amide. A represents an alkylene group. B indicates one CH _n — or ≧ C = S. same as below. ] To explain the groups defined above in more detail, lower alkyl groups are defined as 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and (dimethyl) ethyl. A straight-chain or branched alkyl group having an atom. The lower alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy and the like. An alkylene group is a linear or branched alkylene group having 1 to 10 carbon atoms, such as methylene, ethylene, propylene, tetramethylene, heptamethylene, decamethylene, (dimethyl) methylene, and (getyl) methylene. Show. The protecting group for the hydroxy group includes lower alkylsulfonyl such as methanesulfonyl, phenylsulfonyl, lower alkanol such as arylsulfonyl such as P-toluenesulfonyl, acetyl, propionyl, and vivaloyl, and methoxy. Examples include those commonly used as protecting groups for hydroxy groups, such as lower alkoxymethyl such as methyl, benzoyl, benzyloxymethyl, tetrahydrobiranyl, and trimethylsilyl. Esters are those commonly used as esters of carboxylic acids such as lower alkyl esters such as methyl ester, ethyl ester, isopropyl ester, butyl ester and hexyl ester, and aryl lower alkyl esters such as benzyl ester. Show. Amides are amides with ammonia, amides with lower alkylamines such as methylamine, dimethylamineethylamine, and aryl lower alkylamines such as benzylamine. Amide with Examples of carboxylic acid amides are shown below. The compound [I] of the present invention and the intermediate [II] of the present invention may be in the form of a pharmaceutically acceptable salt. Examples of such salts include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium, etc., ammonium salts, getylamine, triethanolamine. Salts with organic amines such as salts and salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid and the like can be mentioned.

 Representative synthetic methods of the compound of the present invention [Π] are as shown in the following 1) and 2).

1) Synthesis of compounds in which B is —CH ₂ —

 [I]

[In the formula, X represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group. same as below. ]

The intermediate [II] of the present invention represented by the formula [IV] can be obtained by treating the compound represented by the formula [IH] with a reducing agent. Next, the intermediate [H] of the present invention and a compound represented by the formula [V] Is reacted in the presence of a base to obtain a compound [I] of the present invention represented by the formula [I].

 2) Synthesis of compounds where B> C = S

 [I]

The present invention intermediate [H] represented by the formula [VI] can be obtained by treating the compound represented by the formula [III] with a mouth reagent or phosphorus pentasulfide or the like. Then, the intermediate [[] of the present invention is reacted with the compound represented by the formula [VII] in the presence of a base to obtain the compound [1] of the present invention represented by the formula Π]. The compound represented by the formula [111] can be synthesized by the method described in Japanese Patent Application Laid-Open No. 1-28707, and a typical synthesis method is shown below.

[III] The hydroxy group substituted on the phenyl ring of the benzylidene group may be protected by the above-mentioned protecting group according to a commonly used method before or after the reaction, and the protecting group may be removed by a commonly used method. Can be.

 In the compound [I] of the present invention, the carboxyl group substituted at the 4-position of benzothiazine can be converted into an ester or amide before or after the reaction using a commonly used method. Conversely, esters and amides can be hydrolyzed to carboxylic acids using commonly used methods.

 The compound obtained by the above method may be converted into a salt as described above by a conventional method.

 The compound [1] of the present invention and the intermediate [11] of the present invention also include stereoisomers and optically active forms, all of which are included in the present invention. For example, the compound [I] of the present invention and the intermediate 本 of the present invention have a benzylidene group and thus have a Z-form and an E-form. However, the present invention includes all of them.

 Compounds that have both a lipid peroxide production inhibitory effect and a protein stabilizing effect are considered to be particularly useful for cataracts.However, studies on compounds that have both of these two effects have not been conducted. The development of compounds has been desired.

The present inventors have reported that a 1,4-monobenzothiazine derivative having a benzylidene group introduced at the 2-position and an oxo group introduced at the 3-position has a lipid peroxide production-suppressing action (Japanese Patent Application Laid-Open No. Hei 12-287007). Based on 7), a study was conducted to solve the above-mentioned problems by using 1,4-benzothiazine as the skeleton. As a result, 2 — benzylidene 3, A compound in which the 3-position of 4-dihydro 1,4-benzothiazine derivative is in the form of a deoxy and a compound converted to a thioxo compound have both a lipid peroxide production inhibitory effect and a protein stabilizing effect. However, they were found to be useful as anticataract agents. The basic constitutional requirement of the compound [I] of the present invention is that the 4-position of 3,4-dihydro-11,4-benzothiazine is substituted with a carboxyalkyl group and the 3-position is thioxo or unsubstituted. Position is substituted by a benzylidene group, and the phenyl ring of the benzylidene group has at least one hydroxy group and one lower alkyl group. By the way, compounds used as pharmaceuticals include carbohydrates for the purpose of prodrugation for the purpose of promoting absorption in the living body and improving sustainability, and stabilizing the formulation. Techniques such as esterification of acids and protection of hydroxy groups with appropriate protecting groups are widely used, and techniques for using these derivatives as production means, that is, synthetic intermediates are also commonly used. Have been. Therefore, in the present invention, the hydroxy group may be protected with a protecting group that is widely used as a protecting group for the hydroxy group, and the carboxyl group of the carboxyalkyl group is a general-purpose derivative of carboxylic acid. It may be converted to a certain ester or amide form. .

The structural features of the compound of the present invention [1] are as described above. Among them, preferred examples of the substituent of the benzyl ring of the benzylidene group are described, and the hydroxy group is preferably located at the 4-position. Preferably, a lower alkyl group is substituted at a position adjacent to the hydroxy group. That is, the lower alkyl group Compounds substituted at both the 3- and 5-positions are preferred. Further, as the lower alkyl group, a tert.-butyl group is a more preferable example.

 The intermediate [II] of the present invention, which is a stage before the introduction of the carboxyalkyl group into the compound [1] of the present invention, is a novel substance particularly useful as an intermediate for the synthesis of the compound [I] of the present invention.

 It has also been reported that compounds having a protein stabilizing effect or an inhibitory effect on lipid peroxide production act as anti-inflammatory agents (Lancet, 1_169-Π0 (1965), Biochem. Biophys. Act a, 4E9, 163-172 (1977)), and the compound [I] of the present invention is expected to be useful also as an anti-inflammatory agent.

 Furthermore, the compound of the present invention was found to have an inhibitory activity on aldose reductase as a result of an experiment conducted according to the literature by Kato et al. (Chem. Pharm. Bui I., 11 (1) 74-83 (1985)). I'm sorry. This finding further supports that the compound of the present invention is excellent as a therapeutic agent for cataract, and indicates that it is expected to be a therapeutic agent for diabetic complications.

The compound [I] of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, eye drops and the like, and can be formulated using widely used techniques. For example, for systemic preparations such as tablets, capsules, granules and powders, bulking agents such as lactose, crystalline cellulose, starch, etc., lubricants such as magnesium stearate, talc, hydroxypropyl pilsenolerose, polyvinylpyrrole Binders such as lidon, carboxymethylcellulose calcium A disintegrating agent such as low-substituted hydroxypropylmethylcellulose and a coating agent such as hydroxypropylmethylcellulose, macrogol, and silicon resin may be added as needed. In the case of eye drops, isotonic agents such as sodium chloride, chlorinated potassium and concentrated glycerin, and buffering agents such as sodium phosphate, boric acid, and monoamine amide. Stabilizers such as edetate sodium, preservatives such as benzalkonium chloride and paraoxybenzoate, polysorbate 80, surfactants such as polyoxyethylene hydrogenated castor oil, diluted hydrochloric acid, and hydroxylated A pH adjuster such as sodium may be added as needed.

 The dose of the compound [I] of the present invention can be appropriately selected depending on the symptom, age, dosage form, and the like. In the case of an oral preparation, it is usually 0.1 to 500 mg / day, preferably 1 to 100 mg / day. mg may be administered once or in several divided doses. In the case of eye drops, a concentration of 0.001% to 10%, preferably a concentration of 0.1% to 3% may be instilled once or several times a day.

 The production examples and preparation examples of the compound [1] of the present invention and the intermediate 中間 of the present invention are shown below, but these examples are for better understanding of the present invention and limit the scope of the present invention. is not. BEST MODE FOR CARRYING OUT THE INVENTION

Example 1

2— (3,5-di-tert.-butyl-4-hydroxybenzylidene) 1 3,4-dihydro 2H—1,4—benzothiazi (Compounds 1-1)

水素化リ チウムアルミ ニウム （ 0. 6 6 g ) のジェチルェ 一テル （ 9 m 1 ) 懸濁液に、 室温下、 アルゴン雰囲気中で塩 化アルミ ニウム （ 0, 7 7 g) のジェチルエーテル （6 m l ) 懸濁液を加え 1 5分間撹拌する。 室温下、 反応液に 2— （ 3， 5—ジ -tert. - プチルー 4ー ヒ ドロキシベンジ リ デン） 一 3， 4ージヒ ドロ一 3—ォキソ一 2 H— 1 , 4一べンゾチ ァジン （1. 0 0 g) のジェチルェ一テル （ 1 5 m l ) —テ トラ ヒ ドロフラ ン （6 m l ) 溶液を滴下した後、 室温で 4. 5時間撹拌する。 反応液に飽和食塩水を加え、 酢酸ェチルで 抽出する。 有機層を無水硫酸ナ ト リ ゥムで乾燥後、 減圧濃縮 し、 得られた固形物をへキサンージイソプロ ピルエーテル混 液で再結晶して標記化合物 0. 5 1 g (5 3. 3 %) を得る ο

A suspension of lithium aluminum hydride (0.66 g) in ethyl acetate (9 ml) was added to a suspension of aluminum hydride (0.777 g) in ethyl acetate (0.67 g) at room temperature in an argon atmosphere. ml) Add the suspension and stir for 15 minutes. At room temperature, the reaction mixture was treated with 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -13,4-dihydroxy-13-oxo-1 2H—1,4,1-benzothiazine (1. A solution of 0. 0 g) in getyl ether (15 ml) -tetrahydrofuran (6 ml) was added dropwise, and the mixture was stirred at room temperature for 4.5 hours. Saturated saline solution is added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting solid was recrystallized from a mixture of hexanediisopropyl ether to give 0.51 g (53.3 %) Get ο

 m.p.l 59-167. C

IR (KB r, cm— ¹ ): 3 6 3 3,3 3 7 3,2 9 5 2, 16 1 1,1 5 8 9,1 4 7 5,1 4 3 6,1 2 9 9, 1 2 3 7, 1 12 0, 890, 743 The following compound is obtained using the same method as in Example 1. • 2- (3-tert.-butyl-4-hydroxy-5-methylbenzylidene) -1,3,4-dihydro-2H—1,4—benzothiazine (compounds 1-2)

 • 2-(3-tert.-Butyl-4-hydroxybenzylidene) 1, 3, 4 dihydro 2 H-1, 4 benzothiazine (compound 13)

 • 3,4—Dihydro 2— (3,5—Dimethyl 4-Hydroxybenzylidene) 1 2H—1,4 Benzothiazine (Compound 1—4)

 • 3,4—Dihydro 2— (4-Hydroxy 3—Methylbenzylidene) 1-2H—1,4 Benzothiazine (Compounds 15)

 • 2-(3-tert.-Butynolee 5-dimethylaminomethyl-4-hydroxybenzylidene) 1, 3, 4-dihydro 2H-1, 4-benzothiazine (compound 16) Example 2

 2 — (3, 5 — di_tert. -Butyl 4-hydroxybenzylidene) 1, 3, 4 — dihydro 1 4 1 ethoxycarbonylmethyl 2 H— 1, 4 — benzothiazine (compound 2 — 1)

CH ₂ COOEt 2 — (3, 5 — di-tert.-butyl-1-hydroxybenzylidene) 1-3, 4 — dihydro 2 H— 1, 4- benzothiazine (compound 11, 0.45 g) To a solution of ethyl acetate and ethyl acetate (0.15 ml) in N, N-dimethylformamide (3 ml) was added potassium carbonate (0.17 g) and sodium iodide (0.2). 0 g), and the mixture is stirred at 50-60 in a nitrogen atmosphere. To the reaction solution is added a saturated saline solution, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.52 g (93.6%) of the title compound.

IR (Fi 1 m, cm— ¹ ): 3632, 2958, 1738, 1616, 1586, 1487, 1436, 119 8, 10 24, 909, 733 Using the same method as in Example 2, the following compounds are obtained.

• 2-(3, 5-di-1 e rt.-Butyl-4-hydroxybenzylidene) 1, 3-4-dihydroxy 4-methoxycarbonylmethyl-1H-1, 4-benzothiazine (compound 2) — 2)

• 4-butoxycarbonylmethyl 2- (3, ji-1 ert.-Butyl 4-hydroxybenzylidene) 1,3,4-dihydroxy 2Η-1,4 benzothiazine (compounds 2 to 3) ) • 2 — (3, 5 — di-tert. -Butyl 4-hydroxybenzylidene) 1, 3, 4 — dihydroxy 1-4 (3-ethoxycarbonylpropyl) 1 2 H — 1, 4 — benzothiazine '(Compound 2-4) • 2— (3,5-di-1 ert · -butyl-1-4—hydroxybenzylidene) 1,3,4-dihydroxy 4— (7-ethoxycarbenylheptyl) 1-2H—1,4,1-benzothiazine ( Compound 2-5)

 • 2- (3-tert.-Butyl-4-hydroxy-5-methylbenzylidene) -1,3,4-dihydro41-ethoxycarbonylmethyl-1H-2,4-benzothiazine (Compound 2— 6)

• 2— (3—tert.-butyl-4—hydroxybenzylidene) — 3,4-dihydroxy 4-1-ethoxycarbonylmethyl 2-H-1,1,4-benzothiazine (compounds 2—7)

 • 3,4-dihydroxy-1— (3,5-dimethyl-4—hydroxybenzylidene) -14-ethoxycarbenylmethyl-2H_1,4-benzothiazine (compounds 2-8)

 • 3,4—dihydroxy 4-ethoxycarbonylmethyl-2- (4-hydroxy-13-methylbenzylidene) 1-2H—1,

4 Benzothiazine (Compound 2-9)

 • 2-(3-tert. -Butyl-5-dimethylaminomethyl-4-hydroxybenzylidene)-1, 3, 4-dihydroxy-4- ethoxycarbonylmethyl-2 H-1, 4- Nzothiazine (Compound 2-10) Example 3

4-carboxymethyl 2- (3,5-di-1eM.-butyl-1-4-hydroxybenzylidene) -1,3,4-dihydro 2H—1,4-benzothiazine (compound 3-1) S, 'CH

CH ₂ COOEt

2- (3,5—di-1 ert .-butyl-4 4-hydroxybenzylidene) 1,3,4—dihydro 4-1-ethoxycarbonylmethyl 2H—1,4 benzothiazine (compound 2—1,0 0.55 g) was dissolved in a mixture of tetrahydrofuran (2 ml) and methanol (1 ml), and lithium hydroxide monohydrate (cooled under ice-cooled sodium chloride). An aqueous solution (2 O ml) of 0.132 2) is added dropwise with stirring. After stirring at 55 ° C. for 30 minutes, the reaction solution is acidified by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.051 g (98.8%) of the title compound.

 m. p. 173.4-174.9. C (decomposition)

IR (KB r, cm): 33382, 304, 295, 178, 3, 166, 158, 148, 149, 426, 13 0 3, 1 2 0 5, 1 1 3 4, 7 4 3 Using the same method as in Example 3, the following compounds are obtained. • 4— (3-carboxypropyl) -1-2— (3,5-di-tert.-butyl-1-4-hydroxybenzylidene) 1-3,4-dihi Draw 2H—1,4—benzothiazine (compound 3—2)

• 2 — (3 — tert.-butyl-1-hydroxy 5 —methylbenzylidene) 1-4-carboxymethyl-3,4 dihydro-1 2H-1, 4-benzothiazine (compound 3-3)

 • 2-(3-tert.-Butyl-4-hydroxybenzylidene) 1-3, 4-dihydroxy 4-carboxymethyl-2H-1, 4-benzothiazine (compound 3-4)

 • 2 — (3 — tert.—Pininole 1 5 —Dimethyltinole 1 4 —Hydroxybenzylidene) 1 4-Carboxymethyl 3, 4 —Dihydro 2 H— 1, 4 1 Benzothiazine ( Compound 3-5) Example 4

 4 One-stroke rubamoylme chiru 2 — (3, 5 — di-t er-peti-lu 4-hydroxybenzylidene) 1 3, 4 — dihydro 1 2

H—1, 4-benzothiazine (compound 4-1)

CH ₂ COOEt CH ₂ CONH ₂

2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) 1,3,4-dihydro 4-1-ethoxycarbonylmethyl 2H-1,4-benzothiazine (compound 2-1,0 4 g) in a methanol solution of ammonia (17.85 N, 15 m Dissolve in 1), add 0.1 N hydrochloric acid in methanol (3 ml), and stir in a sealed tube at 80 ° C for 4 days. The reaction mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give the title compound. Using the same method as in Example 4, the following compound is obtained. • 2— (3,5-di-tert.-butyl-1-4-hydroxybenzylidene) 1,3,4-dihydro-14-1 (N-methylcarbamoylmethyl) 1-2H—1,4-benzothiazine (Compound 4-1 2

)

 • 2— (3,5-di-tert.-butynole-1-hydroxybenzylidene) _3,4-dihydroxy-4— (N, N-dimethylcarbamoylmethyl) 1-2H—1,4 Nzothiazine (compounds 4-3)-

• 4- (N-benzylcarbamoynomethyl) 1 2- (3,5-di-tert.-butynole 4-hydroxybenzylidene) 1,3,4-dihydro-1 2H—1,4-benzothiazine (Compound 4-4) Example 5

水素化ナ ト リ ウムの 6 0 %鉱油懸濁物 （ 0. 0 3 g) をジ メチルホルムア ミ ド （ 1 m l ) に懸濁させた後、 2 — （ 3， 5—ジ- tert. - プチルー 4—ヒ ドロキシベンジリデン） 一 3 , 4ージヒ ドロー 4一エ トキンカルボ二ルメ チルー 2 H— 1 , 4 一べンゾチアジン （化合物 2 — 1， 0. 3 5 g) のジメ チルホルムア ミ ド （ 3 m l ) 溶液を撹拌しながら加える。 窒 素雰囲気下で 1 0分間撹拌した後、 ク ロロメチルメチルエー テル （ 0. 3 m l ) のジメチルホルムア ミ ド （ 1 m l ) 溶液 を加える。 5 0 °Cで 4時間撹拌した後、 反応液に精製水を加 え、 酢酸ェチルで抽出する。 有機層を無水硫酸ナ ト リ ウムで 乾燥後、 減圧濃縮する。 得られる油状物をシリ カゲルカラム ク ロマ トで精製し、 標記化合物を得る。 実施例 6 2- (3,5-di-tert.-butyl- 4-methoxyethoxybenzylidene) 1-3,4-dihydroxy 4-ethoxycarboxymethyl-2H—1,4-benzothiazine (compound 5-1)

A 60% mineral oil suspension of sodium hydride (0.03 g) was suspended in dimethylformamide (1 ml), and then suspended in 2-(3, 5-di-tert.- Dimethyl 4- (hydroxybenzylidene) 1-3,4-dihydroxy 4-ethylquinylmethyl 2H-1, 4 benzothiazine (compound 2-1, 0.35 g) dimethylformamide (3 ml) ) Add the solution with stirring. After stirring for 10 minutes in a nitrogen atmosphere, a solution of chloromethyl methyl ether (0.3 ml) in dimethylformamide (1 ml) is added. After stirring at 50 ° C for 4 hours, add purified water to the reaction solution, and extract with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give the title compound. Example 6

2 — (4-Acetoxy-1,3,5-di-tert.-butylbenzylidene) _ 3,4-Dihydro 4-1-ethoxycarbonylmethyl 2H—1,4 Benzothiazine (Compound 6—1)

CH ₂ COOEt CH ₂ COOEt

2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) 1,3,4-dihydroxy 4 _ethoxycarbonylmethyl 2H—1,4-benzothiazine (Compound 2—1,0 Acetic anhydride (5.8 ml) and triethylamine (2.1 ml) were added to .80), and the mixture was refluxed overnight. After adding dilute hydrochloric acid to the reaction mixture, extract with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give the title compound. The following compounds were obtained using the same method as in Example 6. • 2- (3,5-Di-rt.-butyl-4-prono, ⁰ -yloxy benzylidene) 1-3,4—dihidro 4-ethoxycarbonylmethylmethyl 2H—1,4-benzothiazine (compound 6 — 2) Example 7

2- (3,5-Di-1ert.-butyl-1-4-hydroxybenzylidene) 1-3,4-Dihydroxy-13-thioxo-1 2H—1,4 1-benzothiazine (Compound 7—1)

2-toluene solution of 2- (3,5-di-tert.-butyl-4, hydroxybenzylidene) -1,3,4-dihydroxy-3-oxo-1 2H—1,4—benzothiazine (1.19 g) in toluene ( To 40 ml), add Lawson's reagent (3.74 g) and reflux for 21 hours. The reaction solution is cooled to 0 ° C, the precipitated crystals are removed by filtration, and the filtrate is concentrated under reduced pressure. The oil obtained is purified by silica gel column chromatography to give 0.85 g (69.4%) of the title compound m.p. 171.1-175.9 ° C (decomposition)

IR (KB r, cm ^-1 ): ³⁶ 14, 3 16 8, 3 11 0, 29 6 1, 15 89, 15 36, 1 48 0, 1 4 38 1 4 1 7, 1 3 6 7, 1 3 2 4, 1 2 6 3, 1 2 4 1, 1 2 0 9, 1 1 4 4 Using the same method as in Example 7, the following compounds are obtained. .

• 2— (3-tert.-butyl 4-hydroxy-5-methylbenzylidene) 1,3,4-dihydro 3-thioxo 2H—1,4 monobenzothiazine (compound 7-2)

• 2- (3-tert.-butyl-4-hydroxybenzylidene) — 3,4-dihydroxy 3-thioxo 2H—1,4—benzo Thiazine (compound 7-3)

 • 3,4-Dihydro 2— (3,5-Dimethyl 4-Hydroxybenzylidene) 1-3-Thioxo 1 2H—1,4 Benzothiazine (Compounds 7-4)

 • 3,4-dihydro-2- (4-hydroxy-3-methylbenzylidene) -1,3-thioxo2H-1,4-benzothiazine (compound 7-5)

 • 2- (3-tert.-butyl-5-dimethylaminomethyl-4-hydroxybenzylidene) -1,3,4-dihydroxy-3-thioxo 2H-1,4, -benzothiazine (compound 7 — 6) Example 8

 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) 1,3,4-dihydroxy 4-ethoxycarbonylmethyl 3-H-oxo-2H-1,4-benzothiazine (compound 8 -1)

To a suspension of sodium hydride (0.08 g) in anhydrous tetrahydrofuran (2.5 ml) was added 2- (3,5-di-tert.-butyl) -4-hydroxybenzylidene. 1,3,4-dihydro-3-thioxo 2H—1,4—benzothiazine (compound 7-1, Add 0.41 g) of anhydrous tetrahydrofuran (8 ml) and stir at room temperature for 15 minutes. Ethyl bromoacetate (

Add 0.13 ml) and stir at room temperature for 30 minutes. Add 1N hydrochloric acid to the reaction solution and extract with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.40 g (80.3%) of the title compound.

IR (F i 1 m, cm " ¹ ): 3 6 2 5, 2 9 6 0, 1 7 3 2, 1 5 9 2, 1 5 6 7, 1 5 4 2, 1 4 6 2, 1 4 4 0,

1 4 2 1, 1 3 9 2, 1 3 6 6, 1 2 9 6, 1 2 5 8, 1 2 1 2, 1 1 4 1, 1 1 1 9 Using the same method as in Example 8, Is obtained. • 2— (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,3,4-dihydroxy_4-methoxyethoxycarbonyl methyl 3-thioxo 2H—1,4-benzothiazine (compound 8-2)

 • 4-butoxycarbonylmethyl 2- (3,5-di-1 ert.-butyl-4-hydroxybenzylidene) 1-3,4-dihydro mouth 1-3-thioxo 2 H—1,4-1 Benzothiazine (compounds 8-3)

• 2— (3,5-di-1ert.-butyl-1-4—hydroxybenzylidene) -1,3,4-dihydro4— (3-ethoxycarbonylpropyl) 1-3—Thioxo 2H—1,4 Benzothiazine (compounds 8-4) • 2— (3,5—di-1 ert.-butyl- 4—hydroxybenzylidene) 1,3,4 dihidro 4—1 (7—ethoxycarbyl heptyl) 1—3—thoxoxo 2 H—1,4—benzothiazidi (Compounds 8-5)

 · 2-(3-tert.-Butyl-4-hydroxy 5-methylbenzylidene) 1, 3, 4-dihydro 1-4-ethoxycarbonylmethyl 1-3-thioxo 2 H-1, 4- Benzothiazine (compound 8-6)

 • 2 — (3 — tert. -Pininole 4 — Hydroxybenzylidene) — 3,4-Dihydro 4 — Ethoxycarbenylmethyl 3 — Toxoxo 2 H—1, 4 — Benzothiazine (Compounds 8 — 7) • 3, 4 —Dihydro 2 — (3,5 —dimethyl-4-hydroxybenzylidene) 1 4 —ethoxycarbonylmethyl 1 3 —thioxo 2 H—1,4 —benzothiazine (compounds 8 — 8) · 3,4-dihydroxy-4—ethoxycarbonyl-2-yl-2- (4-hydroxy-3-3-methylbenzylidene) -13—thioxo2H-1,4-benzothiazine (compounds 8-9)

• 2 — (3 — tert. _Butyl-5-dimethylaminomethyl 4- 4-hydroxybenzylidene) 1, 3,4 dihydro 1 4 —ethoxycarbonemethyl 3 —thioxo 2 H— 1, 4—ben Zothiazine (Compounds 8-10) Example 9

4 1-Carboxymethyl 1 2 — (3,5—di-1 ert. -Butyl) 4- 3, hydroxybenzylidene 1 3,4—Dihidro 3 Thioxo- 1 2 H— 1, 4-Benzothiazine (Compound 9-1 1)

CH ₂ COOEt CH ₂ COOH

2- (3,5-di-1ert.-butyl-4-4-hydroxybenzylidene) 1,3,4-dihydroxy-1-4-ethoxycarbonylmethyl 3-H-1oxo-2H-1, 4-benzothiazine (compound To a solution of 2-1, 0.37 g) in tetrahydrofuran (7 ml) was stirred an aqueous solution (6 ml) of lithium hydroxide monohydrate (1.60 g) under ice-cooling. While dripping. Add methanol (3 ml) and stir at 0 ° C for 30 minutes. The reaction mixture is acidified by adding 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting solid was recrystallized from a mixture of hexane and diisopropyl ether to obtain 0.24 g of the title compound (69%). 3%)

 m. p. 17 3 ~ 1 74 ° C (decomposition)

IR (KB r, cm " ¹ ): 3 6 1 5, 2 9 6 0, 2 9 0 9, 1 7 1 6, 1 5 9 2, 1 5 6 6, 1 5 4 4, 1 4 6 1, 1 4 3 9, 1 4 1 8, 1 3 9 2, 1 3 6 6, 1 3 1 0, 1 2 5 7, 1 2 3 9, 1 2 1 1 Using the same method as in Example 9, Is obtained. • 4- (3-carboxypropyl) -1 2 — (3,5-di-tert.-butyl-4-hydroxybenzylidene) 1-3,4-dihydroxy-1 3-thioxo 2H—1,4 —Benzothiazine (compound 9-2)

 • 2 — (3 — tert. -Butyl 4-hydroxy 5-methylbenzylidene) 1-4-carboxymethyl-1, 3-4-dihydro 3-thioxo 2 H-1, 4-benzothiazine (compound 9-1 3)

 • 2- (3-rt.-butyl-4-hydroxybenzylidene) -1,3,4-dihydro-4-carboxymethyl-3 -thioxo-1 2H-1,4-benzothiazine (compound 9-4)

 • 2- (3-tert.-Butyl-5-dimethylaminomethyl-1-4-hydroxybenzylidene) -14-carboxymethyl-3,4 dihidro 3—Thixo 2H—1,4-benzothiazine ( Compound 9-1 5) Example 10

 4 One-piece rubamoylmethyl 2 — (3,5-di-tert.-petiru 4 — hydroxybenzylidene) 1, 3,4-dihydro-1-3-thioxo 2 H—1,4 1-benzothiazine (compound 10 0 — 1 )

CH ₂ COOEt 2- (3,5-di-tert.-butyl-1-hydroxy-4-benzylidene) 1,3,4-dihydroxy 4-ethoxycarbonylmethyl 3-thioxo 2H—1,4-benzothiazine (compound 8 — 1, 0.4 g) is dissolved in ammonia in methanol (17.85 N, 15 ml), 0.1 N hydrochloric acid in methanol (3 ml) is added and sealed. Stir in a tube at 80 ° C for 4 days. The reaction mixture is concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound. The following compounds were obtained using the same method as in Example 10.

 • 2-(3, 5-di-1 ert ·-butyl-4-hydroxybenzylidene) 1-3, 4- dihydro-4-1 (N-methylcarbamoylmethyl) 1-3-thioxo 2 H-1, 4—Venzothiazine

(Compound 10-2)

 • 2- (3,5-di-tert.-butyl-1-hydroxy-4-benzylidene) 1-3,4-dihydro-4- (N, N-dimethylcarbamoylmethyl) 1-3-thioxo 2H—1, (4) Benzothiazine (Compound 10-3)

• 4- (N-benzylzirubarubylmethyl) 1 2- (3,5-di-1 ert.-Butyl 4-hydroxybenzylidene) 1,3,4-dihydroxy 3-thioxo 1 2H— 1, 4 Benzothiazine (Compound 10-4) Example 1 1

 2- (3,5-di-tert.-butyl 4-methoxyethoxybenzylidene) 1,3,4-dihydro 41-ethoxycarboxymethyl-13-thioxo 2 H—1,4,1-benzothiazine Compound 1 1— 1)

A 60% mineral oil suspension of sodium hydride (0.03 g) was suspended in dimethylformamide (1 ml), and then suspended in 2- (3,5-di-tert.- Dimethylforma of 1,4-dihydroxy-4-ethylethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 8-1,0.35 g) Add the mid (3 ml) solution with stirring. After stirring for 10 minutes under a nitrogen atmosphere, a solution of chloromethyl methyl ether (0.3 ml) in dimethylformamide (1 ml) is added. After stirring at 50 ° C for 4 hours, purified water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give the title compound. The following compounds were obtained using the same method as in Example. • 2- (4-benzyloxymethoxy-3,5-di-tert.-butylbenzylidene) _3,4-dihydro-4-ethoxyethoxyloxymethyl-3—thioxo 2H—1,4—benzothiazine (compound 1 1 1 2 ) Example 1 2

 2- (4-acetoxy-1,3,5-di-tert.-butylbenzylidene) -1,3,4-dihydro-4, -ethoxycarbonylmethyl-3, -thioxo-2H—1,4,1-benzothiazine (compound 1 twenty one )

Ch ^ COOEt CH ₂ C〇OEt

2-(3, 5-di-tert.-Butyl-4-hydroxybenzylidene) 1-3, 4-dihydro 4-1-ethoxycarbonylmethyl 3-thioxo 2 H-1, 4-benzothiazine (compound 8-1 , 0.80 g), acetic anhydride (5.8 ml) and triethylamine (2.1 ml) were added, and the mixture was refluxed overnight. After adding dilute hydrochloric acid to the reaction mixture, extract with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give the title compound. The following compounds were obtained using the same method as in Example 12.

• 2— (3,5-di-tert.-butyl 4-prono, ⁰ -yloxy-sibenzi-redene) 1, 3,4-dihydro 1- 4-ethoxycarbone 2-methyl-3- 3-oxo-1 2H—1,4— Benzothiazine (Compound 1 2— 2)

 • 2- (4-benzoyloxy-1,3,5-di-1 ert.-butylbenzylidene) -1,3,4-dihydro4,1-ethoxycarbonyl 2-methyl-1,3-thioxo-2H-1,4 Nzothiazine (Compound 12-3)

[Formulation example]

 Examples of general preparations of an oral preparation and eye drops of the compound [I] of the present invention are shown below.

1) tablets

 Formula 1 1 100 mg in

Compound of the present invention [1] lmg lactose 66.4 mg corn starch 20 mg carboxymethylcellulose calcium 6 mg hydroxypropisolatecellulose 4 mg magnesium stearate 0.6 mg Tinting agents (for example, hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) Coating with 2 mg (normal coating agent) to obtain the target tablet (the same applies to tablets with the following formula). Formula 2 in 100 mg

 Compound of the present invention [I] 5 mg Lactose 62.4 mg Corn starch 20 mg Carboxymethyl cellulose calcium 6 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 0.6 mg Coating agent 2 mg Formulation 3 In 100 mg

Compound of the present invention [I] 20 mg Lactose 5 1 mg Corn starch 15 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 1 mg Talc 1 mg Coating agent 2 mg Formula 4 in 100 mg

 Compound of the present invention [I] 40 mg Lactose 34 mg Corn starch 10 mg Carboxymethyl cellulose Calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 2 mg Talc 2 mg Coating agent 2 mg Formulation 5 2 In 20 mg

Compound of the present invention [I] 100 mg Lactose 67 mg Corn starch 20 mg Carboxymethylcellulose Calcium 10 mg Hydroxypropylcellulose 10 mg Magnesium stearate 4 mg Talc 4 mg Coating agent 5 mg ) Eye drops

Formula 1 1 0 0 m 1 Medium

Compound of the present invention [I] 0.5 g concentrated glycerin 1.5 g polyoxyethylene hydrogenated castor oil 1.0 g Benzalkonium chloride 0.0 5 g Sodium edetate 0.0 1 g Dilute hydrochloric acid

 Sodium hydroxide

 Sterile purified water Formulation 2 100 m1 Medium

 Compound of the present invention [I] 30 g concentrated glycerin 30 g polysorbate 800 7 0 g methyl parahydroxybenzoate 0 26 g g propyl paraoxybenzoate 0 14 g dilute hydrochloric acid

Sodium hydroxide

Sterile purified water Formulation 3 100 m1 Medium

Compound [I] of the present invention 0 1 g Concentrated glycerin 20 g Polyoxyethylene hydrogenated castor oil 08 g Benzalkonidum chloride 0.055 g Sodium edetate 0.01 g Dilute hydrochloric acid.

Sodium hydroxide

Sterile purified water 3) Eye ointment

 Formula 1 1 in 100 g

 Compound of the present invention Π] 0 g Liquid paraffin 10 g White petrolatum 89 g Formulation 2 In 100 g

 Compound of the present invention Π] 2.0 g Liquid paraffin 10 g White petrolatum 88 g Effect of the invention

 [Pharmacological test]

 In order to investigate the usefulness of the compound [1] of the present invention, a protein stabilizing action and a lipid peroxide production inhibitory action were examined.

 1) Protein stabilization

 As a method for examining the protein stabilizing effect of a compound, a method for measuring the stabilizing effect of bovine serum albumin on thermal aggregation (Lancet, L_169-170 (1965)) is known and described in this document. The study was conducted according to the proposed method.

 (experimental method)

Under ice cooling, bovine serum alpinin (Sigma) was dissolved in 0.2 M phosphate buffer (pH 5.3) to a concentration of 0.75%. . To this albumin solution, add 0.3 ml of a dimethyl sulfoxide solution in which the test compound is dissolved in 2.7 ml. After the addition and stirring, the mixture was left for about 15 minutes to return to room temperature. After reacting the solution in a water bath at 67 ° C for 2 minutes while shaking, the reaction was stopped by ice cooling. After the temperature of the reaction solution was returned to room temperature, the absorbance caused by the cloudiness of the water-soluble protein due to heat aggregation was measured at a wavelength of 660 nm, and the protein stabilizing effect of the test compound was determined using the following equation. .

A

 Protein stabilizing effect (%) = X 0 0

 A

 0

 A Absorbance without test compound added

 A

 1 Absorbance when test compound is added

(Result)

As an example of the experimental results, compound 3-1 and compound ^9-1 clearly inhibited the thermal aggregation of protein, and showed an excellent protein stabilizing effect of ⁹⁸ % or more at a concentration of ^10-4 M. .

2) Lipid peroxide production inhibitory action

 (experimental method)

Rat liver microsomes were purified from ADP (13 M) in 0.04 M Tris buffer (0.09 M potassium chloride, pH 7.4) containing the test compound. 2 mM), Fe ²⁺ (0.9 mM) and ascorbic acid (0.5 mM) at 37 ° C for 15 minutes, and the resulting lipid peroxide was analyzed by TBA method (Biochem. Med. , J_ 5, 212 (1976)). . (Result)

As an example of the experimental results, Compound ^3-1 and Compound ^9-1 showed an excellent lipid peroxide production inhibitory effect with an inhibition rate of ^9.9 % or more at a concentration of 10 ^_DM .

 From the results of the above pharmacological tests 1) and 2), compound [I] of the present invention has a protein stabilizing effect and an inhibitory effect on lipid peroxide production, and is expected to be an excellent therapeutic agent for cataract. . Industrial applicability

 The compound [I] of the present invention has a protein stabilizing effect and a lipid peroxide production suppressing effect, and is expected to be an excellent therapeutic agent for cataract.

Claims

The scope of the claims  A compound represented by the following general formula [1] or a salt thereof

[Wherein, R ¹ represents a hydroxy group which may be protected by a protecting group. R ² represents a lower alkyl group. ^Ύ 3 represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group which may be protected with a protecting group, and the lower alkyl group is a hydroxy group or an amino group which may be protected with a protecting group. Or a lower alkylamino group. R ⁴ represents a carboxyl group which may be converted to an ester or an amide. A represents an alkylene group. B is one CH  2 or  > Shows C = S. ]  2. The compound represented by the following general formula [I] or a compound thereof

[Wherein, R ¹ is a hydroxy group and a lower alkyl group A lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, a benzyloxymethyloxy group, a tetrahydrohydranyloxy group or a trimethylsilyloxy group. R ² represents a lower alkyl group. R ³ is a hydrogen atom, a lower alkyl group, a hydroxy group, a lower alkanoyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, a benzyloxymethyloxy group, Represents a hydrobilanyloxy group, a trimethylsilyloxy group or a lower alkoxy group, wherein the lower alkyl group is a hydroxy group, a lower alkyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, or a lower group; Even when substituted with an alkoxymethyloxy group, a benzoyloxy group, a benzyloxymethyloxy group, a tetrahydrobilanyloxy group, a trimethylsilyloxy group, an amino group or a lower alkylamino group. Good. R ⁴ represents a carboxyl group, lower alkoxycarbonyl group, § Li Ichiru lower Arukokishika carbonyl group, a force Rubamoiru group, a lower alkyl force Rubamoiru group or § Li Lumpur lower alkyl force Rubamoiru group. A represents an alkylene group. ] 3. The compound according to claim 2, wherein R ¹ is a hydroxy group or a lower alkanoyloxy group, and R ⁴ is a carboxyl group or a lower alkoxycarbonyl group, or a salt thereof. 4. R ¹ is a hydroxy or lower alkoxy group, R ^a is a hydrogen atom or a lower alkyl group, and R ⁴ is The compound according to claim 2, which is a carboxyl group or a lower alkoxycarbonyl group, or a salt thereof. 5.R ¹ is a hydroxy or acetyl group, R ² is a methyl group or a tert.-butyl group, R ³ is a hydrogen atom, a methyl group or a tert.-butyl group, R ⁴ is a carboxyl group, 3. The compound according to claim 2, wherein the compound is a methoxycarbonyl group or an ethoxycarbonyl group, and A is a methylene group or a propylene group, or a salt thereof. 6. R ¹ is hydroxy, R ² is methyl or tert.-butyl, R ³ is hydrogen, methyl or tert.-butyl, R is carboxyl, A is methylene Or the compound according to claim 2, which is a propylene group, or a salt thereof.  7. 4-carboxymethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) 1,3,4-dihydro2H-1,4 benzothiazine.  8. 4-Carboxymethyl-2 — (3,5-di-tert.-butyl 4-hydroxybenzylidene) 1-3,4-dihydro-3- 3 -Toxoxo 2 H— 1,4 Benzothiazine.  9. A therapeutic agent for cataract containing the compound according to claim 1 or a salt thereof as an active ingredient. 1 0. Compounds represented by the following general formula [Π] or m's thereof o

 II] [Wherein, R ¹ represents a hydroxy group which may be protected by a protecting group. R ² represents a lower alkyl group. R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group which may be protected with a protecting group, and the lower alkyl group is a hydroxy group or an amino group which may be protected with a protecting group. Or a lower alkylamino group. B is -Indicates C H 0 or> C = S. ]  1 A compound represented by the following general formula [II] or a salt thereof,

 [II] [Wherein, R ¹ represents a hydroxy group, a lower alkanoyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, a benzyloxymethyloxy group, a tetrahydro group. It represents a bilanyloxy group or a trimethylsilyloxy group. R ² represents a lower alkyl group. R ³ is a hydrogen atom, a lower alkyl group, Droxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydrovinyliloxy group, trimethylsilyloxy group Or a lower alkoxy group, wherein the lower alkyl group is a hydroxy group, a lower alkanoyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, It may be substituted with a benzyloxymethyloxy group, a tetrahydrobilanyloxy group, a trimethylsilyloxy group, an amino group or a lower alkylamino group. B indicates one CH ₂ — or> C = S. ] 1 2. R ¹ is a hydroxy group or a lower alkanoyloxy group; Or a salt thereof according to claim 10, wherein is a hydrogen atom or a lower alkyl group.  1 3.2 — (3,5-di-tert._butyl 4-hydroxybenzylidene) 1,3,4-dihydroxy 2 H—1,4-benzothiazine.  1 4.2 — (3, 5 — di-tert. -Butyl 4-hydroxybenzylidene) 1, 3, 4 — dihidro 3 — thioxo 2 H-1, 4 — benzothiazine.