JP2840808B2 - 3-thioxo-1,4-benzothiazine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 3-thioxo-1,4-benzothiazine derivative which has a protein stabilizing action and a lipid peroxide production inhibitory action and is useful as a drug for treating cataracts. is there.

[0002]

2. Description of the Related Art The basic skeleton of the compound of the present invention, 1,4-
Compounds having a benzylidene group at the 2-position of a benzothiazine derivative are known as herbicides (US Pat. No. 3,923,709).
), A tranquilizer (Japanese Patent Publication No. 49-10671) and a synthetic intermediate of a benzothiazepine derivative (JP-A-60-72875). However, the compounds disclosed in these known documents have an oxo group at the 3-position, and have a different skeleton chemical structure from the compound of the present invention. Furthermore, no information has been reported on the protein stabilizing action or the lipid peroxide production inhibiting action, which is a characteristic feature of the compound of the present invention.

Japanese Patent Application Laid-Open No. 1-287077 discloses a 2-benzylidene-3-oxo-1,4-benzothiazine derivative having an active oxygen scavenging effect and a lipid peroxide production inhibitory effect. It goes without saying that the chemical structure serving as the skeleton differs between the compound disclosed in the publication and the compound of the present invention, and there is no description about the protein stabilizing action in this publication.

[0004]

Cataract is an intractable eye disease in which the lens becomes opaque and causes loss of vision. Although various factors have been studied since ancient times for the onset factor, mechanism, and treatment of cataracts, there are very few effective drugs at present.

[0005] It is said that an increase in peroxide in the lens is related to the onset of cataract, and it has been reported that a compound having a lipid peroxide production inhibitory action is 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, 19 , 1283-1296 (1977)).

[0006] From these facts, it is considered that a compound having both the action of inhibiting the production of lipid peroxide and the action of stabilizing the protein is particularly useful for cataract. However, studies on compounds having both these actions have not been conducted yet, and development of such compounds has been desired.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to find a compound having both a lipid peroxide production inhibitory action and a protein stabilizing action. As a result, a benzylidene group is at the 2-position and a thioxo is at the 2-position. 1,4-benzothiazine compound substituted at the 4-position with a carboxyalkyl group, wherein the phenyl ring of the benzylidene group is further substituted with a hydroxy group and a lower alkyl group to form lipid peroxide They have found that they have both the inhibitory action and the protein stabilizing action.

[0008]

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

[0009]

Embedded image

Embedded image [In the formula, R1 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, an amino group or a lower alkyl group which may be protected with a protecting group; It may be substituted with an amino group. R ⁴ represents a carboxyl group which may be converted to an ester or an amide. A represents an alkylene group. same as below. When the groups defined above are described in more detail, a lower alkyl group is a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl, (dimethyl) ethyl, Shows a branched alkyl group. The lower alkoxy group refers to a linear or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy and the like.
The 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, (diethyl) methylene and the like. The protecting group for the hydroxy group includes lower alkylsulfonyl such as methanesulfonyl, arylsulfonyl such as phenylsulfonyl and p-toluenesulfonyl, acetyl,
Examples include those commonly used as hydroxy-protecting groups such as lower alkanoyl such as propionyl and pivaloyl, lower alkoxymethyl such as methoxymethyl, benzoyl, benzyloxymethyl, tetrahydropyranyl and trimethylsilyl. Esters are methyl esters,
Examples thereof include those commonly used as carboxylic acid esters such as lower alkyl esters such as ethyl ester, isopropyl ester, butyl ester and hexyl ester, and aryl lower alkyl esters such as benzyl ester. Amides are those commonly used as amides of carboxylic acids, such as amides with ammonia, amides with lower alkylamines such as methylamine, dimethylamine and ethylamine, and amides with aryl lower alkylamines such as benzylamine. Show.

The compounds [I] and [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 and calcium, salts with organic amines such as ammonium salts, diethylamine and triethanolamine salts, and hydrochloric acid, nitric acid, And salts with inorganic acids such as sulfuric acid.

A typical method for synthesizing the compound [I] of the present invention is as follows.

Embedded image [In the formula, X represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group. The compound of the present invention represented by the formula [II] [II] is treated by treating the compound represented by the formula [III] with a Lawesson reagent or phosphorus pentasulfide or the like.
Is obtained. Next, the compound [I] of the present invention represented by the formula [I] is obtained by reacting the compound [II] of the present invention with the compound of the formula [IV] in the presence of a base.
The compound represented by the formula [III] is disclosed in JP-A-1-287.
No. 077 can be synthesized, and a typical synthesis method is shown below.

[0012]

Embedded image The hydroxy group substituted on the phenyl ring of the benzylidene group may be protected by the above-mentioned protecting group according to a method generally used before or after the reaction, and the protecting group can be eliminated by a widely used method.

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 an 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 the above-mentioned salts by a conventional method. The compounds [I] and [II] of the present invention also include stereoisomers and optically active forms, both of which are included in the present invention. For example, the compound [I] of the present invention and the compound of the present invention
[II] has a benzylidene group and thus has a Z-form and an E-form, but the present invention includes all of them.

It is considered that a compound having both the action of inhibiting the production of lipid peroxide and the action of stabilizing a protein is particularly useful for cataracts. However, a study on a compound having both these actions has not been conducted yet. The development of such compounds has been desired.

The present inventors have proposed a benzylidene group at the 2-position,
Based on the information that a 1,4-benzothiazine derivative having an oxo group introduced at the 1-position has a lipid peroxide production inhibitory action (Japanese Patent Application Laid-Open No. 1-287077), the above-mentioned problem is solved by using 1,4-benzothiazine as a skeleton. We considered to solve it. As a result, a 2-benzylidene-3-thioxo-1,4-benzothiazine derivative having a benzylidene group at the 2-position and a thioxo group at the 3-position has both a lipid peroxide production inhibitory action and a protein stabilizing action, It was found to be useful as an anti-cataract agent.

The basic constituent requirement of the compound [I] of the present invention is 3
-Thioxo-1,4-benzothiazine is substituted at the 4-position with a carboxyalkyl group, substituted at the 2-position with a benzylidene group, and the phenyl ring of the benzylidene group has at least one hydroxy group and one lower alkyl group. It is in. By the way, compounds used as pharmaceuticals include prodrugs for the purpose of promoting absorption in vivo and improving sustainability, and esterification of carboxylic acids and hydroxy groups for the purpose of stabilizing preparations. Are widely used, and techniques using their derivatives as production means, that is, as synthetic intermediates, are also widely used. Therefore, also in the present invention, the hydroxy group may be protected with a protecting group widely used as a protecting group for the hydroxy group, and the carboxyl group of the carboxyalkyl group may be in the form of an ester or amide which is a general-purpose derivative of carboxylic acid. May be converted to

The structural features of the compound [I] of the present invention are as described above. Among them, preferred examples of the substituent on the phenyl ring of the benzylidene group include a hydroxy group located at the 4-position, Further, it is preferable that a lower alkyl group is substituted at a position adjacent to the hydroxy group. That is, a compound in which a lower alkyl group is substituted at both the 3-position and the 5-position is preferable. Further, as the lower alkyl group, a tert.-butyl group is a more preferable example.

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

It has also been reported that compounds having a protein stabilizing action or a lipid peroxide production inhibitory action can be used as anti-inflammatory agents (Lancet, 1, 169-170 (1965), Biochem. Bio).
phys. Acta , 489, 163-172 (1977)), the compound of the present invention
[I] is expected to be useful as an anti-inflammatory agent.

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,
It can be formulated using a commonly used technique.
For example, tablets, capsules, granules, a systemic agent such as powder, lactose, crystalline cellulose, bulking agents such as starch,
Lubricants such as magnesium stearate and talc; binders such as hydroxypropylcellulose and polyvinylpyrrolidone; disintegrants such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose; coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin May be added as needed. In the case of eye drops, isotonic agents such as sodium chloride, potassium chloride and concentrated glycerin; buffering agents such as sodium phosphate, boric acid and monoethanolamine; stabilizers such as sodium edetate; benzalkonium chloride , Preservatives such as paraoxybenzoate, polysorbate 8
0, surfactants such as polyoxyethylene hydrogenated castor oil,
A pH adjuster such as dilute hydrochloric acid or sodium hydroxide may be added as needed.

The dose of the compound [I] of the present invention depends on symptoms, age,
Although it can be appropriately selected depending on the dosage form and the like, it is usually 0.1 to 5000 mg per day, preferably 1 to 100 mg for an oral preparation.
mg may be administered once or in several divided doses. Also,
In the case of eye drops, those having a concentration of 0.001% to 10%, preferably 0.1% to 3% may be instilled once or several times a day.

The production examples and preparation examples of the compound [I] of the present invention and the compound [II] of the present invention are shown below. These examples are for better understanding of the present invention, and the scope of the present invention is as follows. Is not limited.

[0024]

【Example】

[Production Example] Example 1 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-thioxo-2H-
1,4-benzothiazine (compound 1-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-oxo-2H-
Lawson's reagent (3.74 g) was added to a toluene solution (40 ml) of 1,4-benzothiazine (1.19 g), and 2
Reflux for 1 hour. The reaction solution is cooled to 0 ° C., the precipitated crystals are removed by filtration, and the filtrate is concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.85 g (69.4%) of the title compound.

M. p. 171.1-175.9 ° C (decomposition) IR (KBr, cm ^-1 ): 3614,3168,311
0,2961,1589,1536,1480,143
8,1417,1367,1324,1263,124
1,1209,1144

Using the same method as in Example 1, the following compound is obtained. -2- (3-tert.-butyl-4-hydroxy-5-methylbenzylidene) -3,4-dihydro-3-thioxo-
2H-1,4-benzothiazine (compound 1-2) 2- (3-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-thioxo-2H-1,4
-Benzothiazine (compound 1-3)-3,4-dihydro-2- (3,5-dimethyl-4-hydroxybenzylidene) -3-thioxo-2H-1,4
-Benzothiazine (compound 1-4) · 3,4-dihydro-2- (4-hydroxy-3-methylbenzylidene) -3-thioxo-2H-1,4-benzothiazine (compound 1-5) · 2- (3 -Tert.-butyl-5-dimethylaminomethyl-4-hydroxybenzylidene) -3,4-dihydro-
3-thioxo-2H-1,4-benzothiazine (compound 1-6)

Example 2 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine ( Compound 2-1)

Embedded image A suspension of sodium hydride (0.08 g) in anhydrous tetrahydrofuran (2.5 ml) was added to 2- (3,5-di-tert.-
A solution of (butyl-4-hydroxybenzylidene) -3,4-dihydro-3-thioxo-2H-1,4-benzothiazine (compound 1-1, 0.41 g) in anhydrous tetrahydrofuran (8 ml) was added, and the mixture was stirred at room temperature for 15 minutes. I do. Ethyl bromoacetate (0.13 ml) is added to the reaction solution, and the mixture is further stirred at room temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution,
Extract with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous sodium sulfate, the mixture is 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 (Film, cm ^-1 ): 3625,2
960, 1732, 1592, 1567, 1542, 1
462, 1440, 1421, 1392, 1366, 1
296,1258,1212,1141,1119

The following compounds are obtained using the same method as in Example 2.

.2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -3,4-dihydro-4-methoxycarbonylmethyl-3-thioxo-2H-1,4
-Benzothiazine (compound 2-2) 4-butoxycarbonylmethyl-2- (3,5-di-t
ert.-Butyl-4-hydroxybenzylidene) -3,4
-Dihydro-3-thioxo-2H-1,4-benzothiazine (compound 2-3) 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- ( 3-ethoxycarbonylpropyl) -3-thioxo-2H-1,4-
Benzothiazine (Compound 2-4) 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (7-ethoxycarbonylheptyl) -3-thioxo-2H- 1,4-
Benzothiazine (Compound 2-5) 2- (3-tert.-butyl-4-hydroxy-5-methylbenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4- Benzothiazine (Compound 2-6) 2- (3-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (Compound 2 -7) 3,4-dihydro-2- (3,5-dimethyl-4-hydroxybenzylidene) -4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 2-8) , 4-Dihydro-4-ethoxycarbonylmethyl-
2- (4-hydroxy-3-methylbenzylidene) -3
-Thioxo-2H-1,4-benzothiazine (compound 2
-9) 2- (3-tert.-butyl-5-dimethylaminomethyl-4-hydroxybenzylidene) -3,4-dihydro-
4-ethoxycarbonylmethyl-3-thioxo-2H-
1,4-benzothiazine (compound 2-10)

Example 3 4-Carboxymethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-thioxo-2H-1,4-benzothiazine (compound 3-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 2-1,0 Aqueous solution (6 ml) of lithium hydroxide monohydrate (1.60 g) was added dropwise to a solution of .37 g) in tetrahydrofuran (7 ml) with stirring under ice cooling. Further, methanol (3 ml) was added,
Stir for minutes. The reaction solution is acidified by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained solid was recrystallized from a hexane-diisopropyl ether mixed solution to obtain 0.24 g (69.3%) of the title compound. .

M. p. 173 to 174 ° C (decomposition) IR (KBr, cm ^-1 ): 3615, 2960, 290
9, 1716, 1592, 1566, 1544, 146
1,1439,1418,1392,1366,131
0,1257,1239,1211

Using the same method as in Example 3, the following compound is obtained. -4- (3-carboxypropyl) -2- (3,5-di
-tert.-butyl-4-hydroxybenzylidene) -3,
4-dihydro-3-thioxo-2H-1,4-benzothiazine (compound 3-2) 2- (3-tert.-butyl-4-hydroxy-5-methylbenzylidene) -4-carboxymethyl-3,4 -Dihydro-3-thioxo-2H-1,4-benzothiazine (compound 3-3) 2- (3-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-carboxymethyl-3-
Thioxo-2H-1,4-benzothiazine (compound 3-
4)-2- (3-tert.-butyl-5-dimethylaminomethyl-4-hydroxybenzylidene) -4-carboxymethyl-3,4-dihydro-3-thioxo-2H-1,4-
Benzothiazine (Compound 3-5)

Example 4 4-carbamoylmethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-thioxo-2H-1,4-benzothiazine (compound 4-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 2-1,0 0.4 g) was dissolved in a methanol solution of ammonia (17.85 N, 15 ml).
A methanol solution of hydrochloric acid (3 ml) was added, and 80 ml
Stir at 4 ° 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 are obtained using the same method as in Example 4. -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (N-methylcarbamoylmethyl) -3-thioxo-2H-1,4-benzothiazine (compound 4-2) 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (N, N-dimethylcarbamoylmethyl) -3-thioxo-2H-1 ,
4-benzothiazine (compound 4-3) 4- (N-benzylcarbamoylmethyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-thioxo-2H-1,
4-benzothiazine (compound 4-4)

Example 5 2- (3,5-di-tert.-butyl-4-methoxymethoxybenzylidene) -3,4-dihydro-4-ethoxycarboxymethyl-3-thioxo-2H-1,4-benzothiazine (Compound 5-1)

Embedded image A suspension of 60% sodium hydride in mineral oil (0.03 g) was suspended in dimethylformamide (1 ml),
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (Compound 2-1; 0.35 g ) In dimethylformamide (3 ml) is added 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 obtained oil is purified by silica gel column chromatography to obtain the title compound.

Using the same method as in Example 5, the following compound is obtained.

.2- (4-benzyloxymethoxy-)
3,5-di-tert.-butylbenzylidene) -3,4-dihydro-4-ethoxycarboxymethyl-3-thioxo-2H-1,4-benzothiazine (compound 5-2)

Example 6 2- (4-acetoxy-3,5-di-tert.-butylbenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine ( Compound 6-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 2-1,0 Acetic acid anhydride (5.8 m)
l) and triethylamine (2.1 ml) are added and refluxed overnight. After adding dilute hydrochloric acid to the reaction mixture, the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate and saturated brine, 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.

Using the same method as in Example 6, the following compound is obtained. -2- (3,5-di-tert.-butyl-4-propanoyloxybenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 6- 2)-2- (4-benzoyloxy-3,5-di-tert.-butylbenzylidene) -3,4-dihydro-4-ethoxycarbonylmethyl-3-thioxo-2H-1,4-benzothiazine (compound 6 -3)

[Preparation Examples] General preparation examples of oral preparations and eye drops of the compound of the present invention are shown below.

[0042]

1) Tablet Formulation 1 100 mg of the present compound [I] 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg

The tablets of the above formulation are coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin) to obtain a target tablet (the tablets of the following formulation are also the same). ).

[0044]

Table 2 Formulation 2 In 100 mg Compound of the present invention [I] 5 mg Lactose 62.4 mg Corn starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg Coating agent 2 mg

Table 3 Formulation 3 In 100 mg Compound of the present invention [I] 20 mg Lactose 51 mg Maize starch 15 mg Carboxymethylcellulose Calcium 5 mg Hydroxypropylcellulose 5 mg Magnesium stearate 1 mg Talc 1 mg Coating agent 2 mg

Table 4 Formulation 4 In 100 mg Compound of the present invention [I] 40 mg Lactose 34 mg Maize starch 10 mg Carboxymethylcellulose Calcium 5 mg Hydroxypropylcellulose 5 mg Magnesium stearate 2 mg Talc 2 mg Coating agent 2 mg

Table 5 Formulation 5 220 mg of the present compound [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

2) Eye drops

Table 6 Formulation 1 In 100 ml 0.5 g of the present compound [I] 0.5 g concentrated glycerin 1.5 g polyoxyethylene hydrogenated castor oil 1.0 g benzalkonium chloride 0.005 g sodium edetate 0.01 g diluted hydrochloric acid Sodium hydroxide qs sterile purified water qs

Table 7 Formulation 2 In 100 ml of the present compound [I] 3.0 g concentrated glycerin 3.0 g polysorbate 80 7.0 g methyl parahydroxybenzoate 0.026 g propyl paraoxybenzoate 0.014 g dilute hydrochloric acid qs sodium hydroxide qs Appropriate amount of sterilized purified water

[Table 8] Formulation 3 In 100 ml of the present compound [I] 0.1 g concentrated glycerin 2.0 g polyoxyethylene hydrogenated castor oil 0.8 g benzalkonium chloride 0.005 g sodium edetate 0.01 g diluted hydrochloric acid Sodium hydroxide qs sterile purified water qs

3) Eye ointment

Table 9 Formulation 1 In 100 g, Compound of the present invention [I] 1.0 g Liquid paraffin 10 g White petrolatum 89 g

[Table 10] Formulation 2 In 100 g of the present compound [I] 2.0 g Liquid paraffin 10 g White petrolatum 88 g

[0047]

【The invention's effect】

[Pharmacological test] To examine the usefulness of the compound [I] of the present invention,
The effects of stabilizing proteins and inhibiting the production of lipid peroxides were investigated.

1) Protein stabilizing action As a method for examining the protein stabilizing action of a compound, a method for measuring the stabilizing effect of bovine serum albumin on thermal aggregation (Lancet, 1, 169-170 (1965)) is known. And was studied according to the method described in this document.

(Experimental method) Under ice cooling, bovine serum albumin (manufactured by Sigma) was added at a concentration of 0.75% to a concentration of 0.25%.
M potassium phosphate buffer (pH 5.3).
0.3 ml of a dimethylsulfoxide solution in which a test compound was dissolved was added to 2.7 ml of the albumin solution, and the mixture was stirred and 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 cooling with ice. After the temperature of the reaction solution was returned to room temperature, the absorbance caused by the turbidity of the water-soluble protein due to the thermal aggregation was reduced to 6%.
Measurement was performed at a wavelength of 60 nm, and the protein stabilizing effect of the test compound was determined using the following equation.

[0050]

(Equation 1) A ₀ : Absorbance when test compound is not added A ₁ : Absorbance when test compound is added

(Results) As an example of the experimental results, Compound 3-1 clearly inhibited the thermal aggregation of the protein, and showed an excellent protein stabilizing effect of 98.9% at a concentration of 10 ^-4 M. .

2) Inhibition of lipid peroxide production (Experimental method) 0.04 M Tris buffer containing test compound (containing 0.09 M potassium chloride, pH 7.4)
Rat liver microsomes in ADP (13.2 mM),
Fe ²⁺ (0.9 mM) and ascorbic acid (0.5 m
M) at 37 ° C. for 15 minutes, and the resulting lipid peroxide was quantified by the TBA method (Biochem. Med., 15, 212 (1976)).

(Results) As an example of the experimental results, the compound 3-1 showed an excellent lipid peroxide production inhibitory effect of 100.2% at a concentration of 10 ^-6 M, which was an excellent inhibition rate.

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

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-1-287077 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 279/00-279/36 A61K 31 / 00-31/80 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. A compound represented by the following general formula [I] or a salt thereof. Embedded image [In the formula, 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, an amino group or a lower alkyl group which may be protected with a protecting group; It may be substituted with an amino group. R ⁴ represents a carboxyl group which may be converted to an ester or an amide. A represents an alkylene group. ] 2. A compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ is 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 tetrahydropyranyloxy group or a trimethylsilyloxy group] Represents a 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,
Benzoyloxy group, benzyloxymethyloxy group,
A tetrahydropyranyloxy group, a 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 tetrahydropyranyloxy group, a trimethylsilyloxy group, an amino group or a lower alkylamino group. R
⁴ is a carboxyl group, a lower alkoxycarbonyl group, an aryl lower alkoxycarbonyl group, a carbamoyl group,
It represents a lower alkylcarbamoyl group or an aryl lower alkylcarbamoyl group. A represents an alkylene group. ] 3. The compound or a salt thereof 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. 4. The compound according to claim 2, wherein R ¹ is a hydroxy group or a lower alkanoyloxy group, R ³ is a hydrogen atom or a lower alkyl group, and R ⁴ is a carboxyl group or a lower alkoxycarbonyl group, or a salt thereof. 5. R ¹ is a hydroxy group or an acetoxy 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 methoxycarbonyl group or the ethoxycarbonyl group and A is a methylene group or a propylene group, or a salt thereof. 6. R ¹ is a hydroxy 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 A is a methylene group or a propylene group, or a salt thereof. 7. A method for preparing 4-carboxymethyl-2- (3,5-
Di-tert.-butyl-4-hydroxybenzylidene)-
3,4-dihydro-3-thioxo-2H-1,4-benzothiazine. 8. A therapeutic agent for cataract, comprising the compound according to claim 1 or a salt thereof as an active ingredient. 9. A compound represented by the following general formula [II] or a salt thereof. Embedded image [In the formula, 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, an amino group or a lower alkyl group which may be protected with a protecting group; It may be substituted with an amino group. ] 10. A compound represented by the following general formula [II] or a salt thereof. Embedded image [Wherein, R ¹ is 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 tetrahydropyranyloxy group or a trimethylsilyloxy group] Represents a 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,
Benzoyloxy group, benzyloxymethyloxy group,
A tetrahydropyranyloxy group, a 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 tetrahydropyranyloxy group, a trimethylsilyloxy group, an amino group or a lower alkylamino group. ] 11. The compound or a salt thereof according to claim 10, wherein R ¹ is a hydroxy group or a lower alkanoyloxy group, and R ³ is a hydrogen atom or a lower alkyl group. 12. (2- (3,5-di-tert.-butyl-4)
-Hydroxybenzylidene) -3,4-dihydro-3-
Thioxo-2H-1,4-benzothiazine.