JP2964382B2 - New thiazine or thiomorpholine derivatives - 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 1,4-thiazine or thiomorpholine derivative which has a protein stabilizing effect and a lipid peroxide production suppressing effect and is useful as a medicament such as a therapeutic agent for cataract.

[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 thiazine or thiomorpholine have antiallergic activity, tyrosine kinase inhibitory activity (JP-A-62-29570), and ultraviolet-absorbing activity (JP-A-50-126676, JP-A-50-1).
26677 et al.). However, in all of the compounds described in these reports, the nitrogen atom, that is, the 4-position of the 1,4-thiazine or thiomorpholine skeleton is not substituted, or substituted with an alkyl group or an aralkyl group. Was something. Further, these reports do not describe any protein stabilizing action or lipid peroxide production suppressing action.

On the other hand, a compound having a benzylidene group at the 2-position of a 3-oxo-1,4-benzothiazine derivative having a skeleton in which a phenyl ring is condensed with a thiazine ring has an active oxygen scavenging action and a lipid peroxide formation inhibitory action. (Japanese Patent Laid-Open No. 1-287077).

[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 involved in the development 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 (1986)). It has also been reported that cataract patients show denaturation of protein in the lens (Ophthalmology 19, 1283 (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 Therefore, the present inventors have made the following
Based on the information that a 3-oxo-1,4-benzothiazine derivative substituted with a benzylidene group at the position has a lipid peroxide production inhibitory action (JP-A-1-287770). Instead of morpholine, intensive studies were made to solve the above problems.

First, the present inventors have proposed that a hydroxy group and tert.-
We focused on that a toluene derivative having a butyl group as a substituent has an antioxidant effect. Since antioxidants have the effect of suppressing the production of peroxides in lipids, various substituents such as alkyl and hydroxy groups are introduced into the phenyl ring of the benzylidene group, and the role of the substituents on the effect of suppressing lipid peroxide production is introduced. Was considered. As a result, it was found that by introducing a hydroxy group and a lower alkyl group into the phenyl ring of the benzylidene group, a compound having an excellent lipid peroxide production inhibitory action was obtained.

Next, a novel compound having a basic skeleton of 1,4-thiazine or thiomorpholine having a benzylidene group at the 2-position into which a hydroxy group and a lower alkyl group are introduced, and having various substituents at the 4-position is synthesized. As a result of studying to find a compound having a protein stabilizing action, the introduction of an alkyl group substituted with an acidic group such as a carboxyl group, a tetrazolyl group, a phosphonic acid group or a sulfonic acid group into a nitrogen atom shows a protein stabilizing action. I found something.

From these findings, the 4-position of 1,4-thiazine or thiomorpholine is substituted with an alkyl group substituted with an acidic group such as a carboxyl group, a tetrazolyl group, a phosphonic acid group or a sulfonic acid group, and further, benzylidene. It has been found that a compound in which the phenyl ring of the group is substituted with a hydroxy group and a lower alkyl group has both a lipid peroxide production inhibitory action and a protein stabilizing action.

In recent years, aldose reductase inhibitors have attracted attention as therapeutic agents for cataracts. However, the compounds of the present invention also have an aldose reductase inhibitory activity and are very useful as therapeutic agents for cataracts.

[0012]

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 of the present invention), its pharmaceutical use as a therapeutic agent for cataract, and a synthetic intermediate represented by the general formula [II] (Hereinafter referred to as the intermediate of the present invention).

[0013]

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 or an amino group which may be protected with a protecting group. Alternatively, it may be substituted with a lower alkylamino group.

R ⁴ is a carboxyl group which may be converted to an ester or an amide; a tetrazolyl group; a phosphonic acid group which may be converted to an ester or an amide, ie, a phosphono group [—P (＝ O) (OH) ₂ ];
Or a sulfonic acid group which may be converted to an ester or an amide.

R ⁵ represents a cyano group or a lower alkoxy group.

B represents C ＝ O, C ＝ S or CH ₂ .

A represents an alkylene group. ---- indicates a single bond or a double bond. same as below. ]

The groups used in the present invention are described in more detail below.

Lower alkyl means 1 to 6 such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and the like.
Represents a straight or branched alkyl having three carbon atoms.

Lower alkoxy means methoxy, ethoxy,
Propoxy, hexyloxy, isopropoxy, tert.-
Shows straight-chain or branched alkoxy having 1 to 6 carbon atoms such as butoxy.

The lower alkanoyl is a straight or branched alkanoyl having 2 to 6 carbon atoms such as acetyl, propionyl, pivaloyl and the like.

Alkylene is a linear or branched alkylene having 1 to 10 carbon atoms such as methylene, ethylene, propylene, tetramethylene, hexamethylene, heptamethylene, decamethylene, (dimethyl) methylene, (diethyl) methylene and the like. Is shown.

The hydroxy-protecting group includes lower alkylsulfonyl such as methanesulfonyl, arylsulfonyl such as phenylsulfonyl and p-toluenesulfonyl, lower alkanoyl such as acetyl, propionyl and pivaloyl, lower alkoxymethyl such as methoxymethyl and benzoyl. And those commonly used as hydroxy-protecting groups such as, for example, tetrahydropyranyl, benzyloxymethyl or trimethylsilyl.

Esters are those commonly used as esters, 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.

Amides include those commonly used as amides 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.

Aryl refers to aromatics such as phenyl, naphthyl and pyridyl. Those aromatics may have a substituent such as a lower alkyl group.

In the present invention, examples of pharmaceutically acceptable salts include salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium, and salts with organic amines such as ammonium salt, diethylamine and triethanolamine salt. And salts with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid.

Representative synthetic methods of the compound of the present invention are shown in the following 1) to 4).

1) A compound wherein R ⁴ is a carboxyl group which may be converted to an ester or an amide

Embedded image [Wherein, R ⁶ represents a lower alkanoyl group or a benzoyl group, and Y represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group. ]

The compound represented by the above formula [III] and the compound represented by the formula [I
When the compound represented by the formula [V] is reacted in the presence of a base, the compound represented by the formula [V] is obtained. Then the formula
The compound represented by the formula [VI] is obtained by protecting the hydroxy group of the compound represented by the formula [V] using a commonly used method, and then the compound represented by the formula [VI] and the compound [VI]
The compound of the present invention represented by the formula [IX] is obtained by reacting the compound of the formula [IX] with a compound of the formula [IX] in the presence of a base and then removing the protecting group for the hydroxy group using a commonly used method. When the compound represented by the formula [V] is dehydrated, a compound represented by the formula [VIII] is obtained.
The compound of the present invention represented by the formula [IX] can also be obtained by reacting the compound represented by the formula [VIII] with the compound represented by the formula [VII] in the presence of a base. Note that the expression [V
The compound represented by the formula [III] can also be synthesized according to the method described in JP-A-62-29570.

2) Compound wherein R ⁴ is a tetrazolyl group

Embedded image By reacting the compound represented by the formula [VI] and the compound represented by the formula [X] in the presence of a base, a compound represented by the formula [XI] is obtained. Then, the formula [X
By reacting the compound represented by formula [I] with sodium azide, the compound of the present invention (formula [XII]) wherein R ⁴ is a tetrazolyl group can be obtained. Further, by reacting a compound represented by the formula [VIII] with a compound represented by the formula [X] in the presence of a base, a compound represented by the formula [XIII] is obtained. And the compound of the present invention (formula [XII]). The compounds represented by the formulas [XI] and [XIII] are represented by R
It is a novel compound particularly useful as a synthetic intermediate for introducing a tetrazolyl group into ⁴ .

3) Compounds wherein R ⁴ is a phosphonic acid group which may be converted to an ester or an amide

Embedded image [Wherein, R ⁷ represents a lower alkoxy group.

R ⁸ and R ⁹ are the same or different and each represents a hydroxy group, an ester residue or an amide residue. ]

By reacting the above formula [VI] with the compound represented by the formula [XIV] in the presence of a base, the compound of the formula [XV]
Is obtained. If necessary, the protecting group for the hydroxy group is removed using a commonly used method, and the compound of the formula [XV
The compound of the present invention (formula [XVII]) can be obtained by reacting this compound with a trimethylsilyl halide and then reacting it with a trialkyl phosphite or the like. The compound of the present invention (Formula [XVII]) can also be obtained by reacting a compound represented by the formula [VIII] with a compound represented by the formula [XVIII] in the presence of a base.

The compounds represented by the formulas [XV] and [XVI] are novel compounds particularly useful as synthetic intermediates for introducing a phosphonic acid group into R ⁴ .

4) A compound wherein R ⁴ is a sulfonic acid group which may be converted to an ester or an amide

Embedded image [In the formula, R ¹⁰ represents a hydroxy group, an ester residue or an amide residue. ]

The compound of the present invention (formula [XXI]) can be obtained by reacting the above formula [XIX] with the compound represented by formula [XX] in the presence of a base.

As described above, the compound of the present invention has the above-mentioned 1)
4), the compound in which B is CＯO is reacted with a Lawesson reagent to obtain B
= S, and by reducing with a reducing agent such as lithium aluminum hydride-aluminum chloride, a compound in which B is CH ₂ can be obtained.

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 may be removed by a generally used method. Can be.

The carboxyl group substituted at the 4-position of 1,4-thiazine or thiomorpholine can be converted into an ester or an amide before or after the reaction using a commonly used method. Similarly, a phosphonic acid group or a sulfonic acid group can be converted into an ester or an amide using a commonly used method.

Conversely, esters and amides can be hydrolyzed into carboxylic acids, phosphonic acids, and sulfonic acids using commonly used methods.

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

The compounds of the present invention or intermediates of the present invention also include stereoisomers and optically active forms, all of which are included in the present invention. For example, since the compound of the present invention or the intermediate of the present invention has a benzylidene group, the Z-form and the E-form
There are bodies, but the invention embraces them all.

The compound of the present invention or the intermediate of the present invention may be in the form of a hydrate.

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 inventors of the present invention have conducted intensive studies on this problem, and as a result, the 4-position of 1,4-thiazine or thiomorpholine was substituted with a carboxyl group, tetrazolyl group, phosphonic acid or sulfonic acid which is an acidic group. It has been found that a compound substituted with an alkyl group and further substituted on the phenyl ring of the benzylidene group with a hydroxy group and a lower alkyl group has both a lipid peroxide production inhibitory action and a protein stabilizing action.

The present invention is based on a novel compound having the above-mentioned chemical structure. Naturally, the hydroxy group may be protected with a protecting group generally used as a protecting group for a hydroxy group, and a carboxyl group, The phosphonic acid group and the sulfonic acid group may be converted to an ester or amide form, or may be converted to a salt.

These protecting groups and derivatives are used for various purposes such as synthetic means, stabilization of compounds, and prodrug formation.

The structural features of the compound of the present invention are as described above. In the case where the hydroxy group in R ¹ is protected by a protecting group, the group may be a lower alkanoyloxy group or a lower alkoxymethyloxy group. Alternatively, a benzoyloxy group is preferable, a lower alkanoyloxy group or a benzoyloxy group is more preferable, and a lower alkanoyloxy group represented by an acetyloxy group is particularly preferable. R ² is a methyl group, an isopropyl group or a te
rt.-butyl group is preferred, isopropyl group or tert.-
Butyl groups are more preferred. R ³ is preferably a hydrogen atom, a lower alkoxy group, or a lower alkyl group which may be substituted with a hydroxy group, a tetrahydropyranyloxy group, an amino group or a lower alkylamino group,
A hydrogen atom, a lower alkoxy group or a lower alkyl group is more preferable, and a lower alkyl group is particularly preferable. Among them, an isopropyl group or a tert.-butyl group is particularly preferred. As R ⁴ , a carboxyl group, a tetrazolyl group or a phosphonic acid group is more preferable, but a preferable example in a case where the carboxyl group or the phosphonic acid group is converted to an ester or an amide is, Particularly, methyl or ethyl ester is preferable, and in the case of amide, amide with ammonia or lower alkylamine is preferable. Also, B
Is preferably a compound of C ＝ O, and A has 1 to 1 carbon atoms.
6 alkylene groups are preferred, and a methylene group or an ethylene group is more preferred.

Next, preferred examples of the position of the substituent on the phenyl ring of the benzylidene group will be described. The hydroxy group is preferably located at the 4-position, and at least one lower alkyl group is substituted at the position adjacent to the hydroxy group. It is preferred that That is, a compound in which the lower alkyl group is substituted at the 3-position or both 3- and 5-positions is preferable.

More specific examples of the compound of the present invention include:
The following are mentioned.

[In the general formula [I], R ¹ is a hydroxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydro Represents a pyranyloxy group or a trimethylsilyloxy group.

R ² represents a lower alkyl group.

R ³ is a hydrogen atom, lower alkyl group, hydroxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydropyrani A loweroxy 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, or benzyloxy. It may be substituted with a methyloxy group, a tetrahydropyranyloxy group, a trimethylsilyloxy group, an amino group or a lower alkylamino group.

R ⁴ is a carboxyl group which may be converted to an ester with lower alkyl or aryl lower alkyl; a carboxyl group which may be converted to amide with ammonia, lower alkylamine or aryl lower amine; tetrazolyl group; A phosphonic acid group which may be converted into an ester with lower alkyl or aryl lower alkyl; a phosphonic acid group which may be converted into an amide with ammonia, lower alkylamine or aryl lower amine; A sulfonic acid group which may be converted to an amide with ammonia, a lower alkylamine or an aryl lower amine.

B represents C ＝ O, C ＝ S or CH ₂ .

A represents an alkylene group.

---- indicates a single bond or a double bond. ]
[Ia] or a salt thereof represented by the following formula:

More preferably, in the general formula [I], R ¹ represents a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group.

R ² represents a lower alkyl group.

R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the lower alkyl group may be substituted with a hydroxy group, a tetrahydropyranyloxy group, an amino group or a lower alkylamino group.

R ⁴ is a carboxyl group which may be converted to an ester with a lower alkyl; a carboxyl group which may be converted to an amide with ammonia or a lower alkylamine; a tetrazolyl group; A sulfonic acid group which may be converted to an ester with a lower alkyl;

B represents C ＝ O, C ＝ S or CH ₂ .

A represents an alkylene group.

---- indicates a single bond or a double bond. ]
Or a salt thereof.

More preferably, in the general formula [I], R ¹
Represents a hydroxy group or a lower alkanoyloxy group.

R ² represents a lower alkyl group.

R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group.

R ⁴ is a carboxyl group which may be converted to an ester with lower alkyl; a carboxyl group which may be converted to an amide with ammonia or lower alkylamine; a tetrazolyl group; or an ester with lower alkyl. B showing a better phosphonic acid group be show a C = O, C = S or CH _2.

A represents an alkylene group.

---- indicates a single bond or a double bond. ]
[Ib] or a salt thereof represented by the following formula:

In the above compound [Ib], R ¹ is a hydroxy group or an acetyloxy group; R ² is a methyl group, an isopropyl group or a t-butyl group; R ³ is a hydrogen atom, a methyl group, an isopropyl group or a t-butyl group. A butyl group or a methoxy group; a carboxyl group wherein R ⁴ may be converted to a methyl or ethyl ester; a tetrazolyl group; a phosphonic acid group which may be converted to an ethyl ester;
O, C ＝ S or CH ₂ , especially C ＝ O; A is preferably a methylene group or an ethylene group, particularly a methylene group; ---- is preferably a single bond, R ¹ is a hydroxy group or an acetyloxy group; R ² is an isopropyl group or a t-butyl group; R ³ is an isopropyl group or a t-butyl group; R ⁴ is a carboxyl group which may be converted to a methyl or ethyl ester; methylene or ethylene group a;; is B C = O; good phosphonic acid group be converted into ethyl ester; which may carboxyl group; a tetrazolyl group are more preferable ---- is a double bond, R ¹ is a hydroxyl group; a carboxyl group which may R ⁴ has not been converted to the methyl ester;; R ² is t- butyl group; R ³ is t- butyl group B is C = S also CH _2; A is a methylene group; those wherein ---- is single bond are particularly preferred.

R ¹ is a hydroxy group; R ² is a lower alkyl group; R ³ is a lower alkyl group;
⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group; B is C = O; A is an alkylene group; ---- is a compound showing a single bond or a double bond, especially R ¹ is a hydroxy group; R ² is t- A butyl group; R ³ is a t-butyl group; R ⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group;
B is preferably C = O; A is a methylene group; ---- is a compound showing a single bond or a double bond.

Among the above compounds [Ia], those in which R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group are preferred, and R ¹ is a hydroxy group or a lower alkanoyloxy group, specifically an acetyloxy group. Some are particularly preferred.

In the above compound [Ia], R ⁴
A carboxyl group which may be converted to an ester with lower alkyl; a carboxyl group which may be converted to an amide with ammonia or lower alkylamine; a tetrazolyl group; a phosphon which may be converted to an ester with lower alkyl An acid group; or a sulfonic acid group which may be converted to an ester with lower alkyl, and a carboxyl group in which R ⁴ may be converted to a methyl or ethyl ester; an amide with ammonia or methylamine; More preferably a carboxyl group which may be converted; a tetrazolyl group; a phosphonic acid group which may be converted to an ethyl ester,
Those in which R ⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group are particularly preferred.

Of the above compounds [Ia], those in which B is C ＝ O, those in which ---- is a single bond, and those in which ---- are double bonds are preferred.

More specifically, in the above compound [Ia], R ¹ is a hydroxy group, lower alkanoyloxy group or benzoyloxy group; R ² is a lower alkyl group; R ³
Represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the lower alkyl group is preferably a group which may be substituted with a hydroxy group, a tetrahydropyranyloxy group, an amino group or a lower alkylamino group,
R ¹ is a hydroxy group, lower alkanoyloxy group or benzoyloxy group; R ² is a lower alkyl group; R ³ is more preferably a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ¹ is a hydroxy group or an acetyloxy group. group; R ² is a methyl group, an isopropyl group or t
R ³ is particularly preferably a hydrogen atom, a methyl group, an isopropyl group, a t-butyl group or a methoxy group; R ¹ is a hydroxy group; R ² is a t-butyl group;
Those in which ³ is a t-butyl group are most preferred.

The intermediates of the present invention include those represented by the following general formula [II]:
R ¹ represents a hydroxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydropyranyloxy group or trimethylsilyloxy group.

R ² represents a lower alkyl group.

R ³ is a hydrogen atom, lower alkyl group, hydroxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydropyrani A loweroxy 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, or benzyloxy. It may be substituted with a methyloxy group, a tetrahydropyranyloxy group, a trimethylsilyloxy group, an amino group or a lower alkylamino group.

R ⁵ represents a cyano group or a lower alkoxy group.

B represents C ＝ O, C ＝ S or CH ₂ .

A represents an alkylene group.

---- represents a single bond or a double bond. ]
Or a salt thereof is preferable. [In the general formula [II], R ¹ represents a hydroxy group, a lower alkanoyloxy group, a lower alkoxymethyloxy group or a benzoyloxy group.

R ² represents a lower alkyl group.

R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the lower alkyl group may be substituted with a hydroxy group, a tetrahydropyranyloxy group, an amino group or a lower alkylamino group.

R ⁵ represents a cyano group or a lower alkoxy group.

B indicates C = O.

A represents an alkylene group.

---- represents a single bond or a double bond. ]
A compound represented by or a salt thereof is more preferable,
[In the general formula [II], R ¹ represents a hydroxy group, a lower alkanoyloxy group or a lower alkoxymethyloxy group.

R ² represents a lower alkyl group.

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁵ represents a cyano group or a lower alkoxy group.

B represents C = O.

A represents an alkylene group.

---- represents a single bond or a double bond. ]
Or a salt thereof is particularly preferred.

[0099] As the present invention intermediates, R ¹ is hydroxy group, an acetyloxy group or a methoxy methoxy group; R ²
Is a methyl, isopropyl or t-butyl group; R ³
Is a hydrogen atom, a methyl group, an isopropyl group or a t-butyl group; R ⁵ is a cyano group or a methoxy group; and A is a methylene or ethylene group.

In order to examine the effect of the compound of the present invention, first, an experiment was conducted to examine the protein stabilizing effect using bovine serum albumin.

The details will be described in the section of pharmacological test, but the compound of the present invention has an excellent protein stabilizing effect.

Next, in order to examine the inhibitory effect of the compounds of the present invention on lipid peroxide production, an experiment was conducted using rat liver microsomes. As a result, it was found that the compound of the present invention has an excellent lipid peroxide production inhibitory action.

From these results, it was found that the compound of the present invention has both a lipid peroxide production inhibitory action and a protein stabilizing action, and is useful as an anticataract agent.

Further, the compounds of the present invention are described in Kato et al.
As a result of conducting an experiment according to em. Pharm. Bull., 33 , 74-83 (1985)), it was found that the compound also had an aldose reductase inhibitory action. 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 used as a therapeutic agent for diabetic complications.

It has also been reported that compounds having a protein stabilizing action or a lipid peroxide production inhibiting action can be anti-inflammatory agents (Lancet, 1, 169 (1965); Biochem Biophys.
Acta. 489, 163 (1977)), and the compound of the present invention is expected to be useful also as an anti-inflammatory agent. The compound of the present invention can be administered orally,
It can also be administered parenterally. As a dosage form,
Examples include tablets, capsules, granules, powders, injections, eye drops, and the like, and can be formulated using commonly used techniques. For example, oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in lactose, starch, crystalline cellulose, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, and hydroxypropyl. It can be formulated using a binder such as cellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose calcium, and a coating agent such as hydroxypropylmethylcellulose. Also, if it is an eye drop,
Formulations can be made using isotonic agents such as sodium chloride, buffering agents such as sodium phosphate, solubilizing agents such as polysorbate 80, preservatives such as benzalkonium chloride, and the like.

The dose can be appropriately selected depending on the symptoms, age, dosage form and the like.
g, preferably 1 to 1000 mg, can be administered once or several times. In the case of eye drops, 0.0
01% to 10%, preferably 0.01 to 5%
It may be administered once or several times a day.

Hereinafter, Production Examples and Preparation Examples of the compound of the present invention are shown, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[0108]

【Example】

Reference Example 1 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) -1,4-thiazin-3-one (Reference compound 1-1)

Embedded image A solution of diisopropylamine (24.3 ml) in tetrahydrofuran (120 ml) was placed in a nitrogen atmosphere at -70 ° C.
In n-butyllithium n-hexane solution (1.6
M, 95 ml) are added dropwise. After stirring at -70 ° C for 1 hour, 1,4-thiazin-3-one (5.0 g) was added to the reaction solution.
Of tetrahydrofuran (20 ml) was added dropwise, and the mixture was further stirred at the same temperature for 1 hour, and then treated with 3,5-di-tert.-butyl-.
A solution of a mixture of 4-hydroxybenzaldehyde (10.2 g) in tetrahydrofuran (20 ml) -hexamethylphosphoric triamide (100 ml) is added dropwise. -70 °
After stirring at C for 2 hours, dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give 7.6 g of the title compound.
(50%).

M. p. 216.7-218.7 ° C IR (KBr, cm ^-1 ): 3637, 3347, 295
6,1655,1623,1442,1400,137
2,1331,1308,1237,1214,118
7

Using the same method as in Reference Example 1, the following compound is obtained.

.2- (α, 4-dihydroxy-3,5-
Diisopropylbenzyl) -1,4-thiazin-3-one (Reference compound 1-2) m. p. 166.2 to 167.8 ° C IR (KBr, cm ^-1 ): 3598, 3318, 307
7, 2963, 2870, 1651, 1447, 137
6,1309,1278,1260,1189,117
6,1148,1125

2- (3-tert.-butyl-α, 4-dihydroxybenzyl) -1,4-thiazin-3-one (Reference compound 1-3)

.2- (α, 4-dihydroxy-3,5-
Dimethylbenzyl) -1,4-thiazin-3-one (Reference compound 1-4)

2- (α, 4-dihydroxy-3-methoxy-5-methylbenzyl) -1,4-thiazine-3-
ON (Reference compound 1-5)

2- (5-tert.-butyl-α, 4-dihydroxy-3-dimethylaminomethylbenzyl) -1,
4-thiazin-3-one (Reference compound 1-6)

2- [5-tert.-butyl-α, 4-dihydroxy-3- [1,1-dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] benzyl] -1,
4-thiazin-3-one (reference compound 1-7)

2- (3,5-di-tert.-butyl-α-
(Hydroxy-4-methoxymethoxybenzyl) -1,4
-Thiazin-3-one (Reference compound 1-8)

Reference Example 2 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) thiomorpholin-3-one (Reference compound 2-1)

Embedded image A solution of diisopropylamine (71.8 ml) in tetrahydrofuran (400 ml) was placed in a nitrogen atmosphere at -70 ° C.
In n-butyllithium n-hexane solution (1.6
M, 320 ml) are added dropwise. After stirring at -70 ° C for 50 minutes, thiomorpholin-3-one (20.0
g) in tetrahydrofuran (200 ml) was added dropwise, and the mixture was further stirred at the same temperature for 1 hour.
Butyl-4-hydroxybenzaldehyde (40.0
g) A solution of a mixture of tetrahydrofuran (50 ml) and hexamethylphosphoric triamide (200 ml) is added dropwise. After stirring at -70 ° C for 2 hours, dilute hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to obtain 24.17 g (40%) of the title compound and 2.84 g (5%) of a threo compound.

Erythro body m. p. 178.5-179.8 ° C IR (KBr, cm ^-1 ): 3638, 3306, 310
7, 2955, 1659, 1480, 1439, 140
0, 1363, 1319, 1271

Threobody m. p. 167.7-168.3 ° C IR (KBr, cm ^-1 ): 3640, 3558, 334
4,2952,2917,2883,1670,165
1,1486,1468,1435,1412,139
0,1374

Using the same method as in Reference Example 2, the following compound is obtained.

.2- (α, 4-dihydroxy-3,5-
Diisopropylbenzyl) thiomorpholin-3-one (Reference compound 2-2) Erythro m. p. 85.5-86.7 ° C IR (KBr, cm ^-1 ): 3304,2962,286
9,1657,1470,1362,1342,128
4,1200,1153,1123,1032,936

Threo form IR (KBr, cm ^-1 ): 3348, 2961, 165
1,1471,1286,1202,1153,112
1,936,881,816,755,665

2- (3-tert.-butyl-α, 4-dihydroxybenzyl) thiomorpholin-3-one (Reference compound 2-3) Erythro compound m. p. 163.5 to 165.8 ° C (decomposition) IR (KBr, cm ^-1 ): 3387,3188,293
5,1647,1382,1206,1010,83
4,619

Threobody IR (KBr, cm ^-1 ): 3306, 2954, 165
2,1483,1424,1343,1260,120
2,1085,820

.2- (α, 4-dihydroxy-3,5-
Dimethylbenzyl) thiomorpholin-3-one (Reference compound 2-4) Erythro compound m. p. 177.7-179.1 ° C IR (KBr, cm ^-1 ): 3358, 3011, 291
4,1626,1485,1442,1382,134
5,1293,1218,1150,1111,104
6,1023,997,964,954

Threobody m. p. 178.7-180.0 ° C IR (KBr, cm ^-1 ): 3365, 2918, 287
5,1634,1605,1480,1448,138
4,1345,1303,1275,1186,114
4,1109,1076,1015

2- (α, 4-dihydroxy-3-methoxy-5-methylbenzyl) thiomorpholin-3-one (Reference Compound 2-5) Erythro IR (KBr, cm ⁻¹ ): 3494,3360 , 298
6,1670,1644,1613,1466,130
2,1221,1090,852,677

Threobody m. p. 173.0-174.8 ° C (decomposition) IR (KBr, cm ^-1 ): 3375, 3184, 304
2,2917,1654,1645,1487,142
9,1319,1075,828,704 2- [5-tert.-butyl-α, 4-dihydroxy-3
-Dimethylaminomethylbenzyl) thiomorpholine-
3-one (Reference compound 2-6)

2- [5-tert.-butyl-α, 4-dihydroxy-3- [1,1-dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] benzyl] thiomorpholin-3-one (Reference compound 2-7)

.2- (3,5-di-tert.-butyl-α-
(Hydroxy-4-methoxymethoxybenzyl) thiomorpholin-3-one (Reference compound 2-8)

Reference Example 3 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (Reference compound 3-1)

Embedded image 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) -1,4-thiazin-3-one (Reference compound 1-1, 0.20 g) in methylene chloride (5 ml) -tetrahydrofuran (5 ml) Triethylamine (0.24 ml) and methanesulfonic acid chloride (0.07 ml) were added to the mixed solution under ice cooling. After stirring for 15 minutes under ice cooling, dilute hydrochloric acid is added to the reaction solution, and the mixture is extracted with chloroform. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give 0.19 g of the title compound (1
00%).

M. p. 208.7-210.6 ° C IR (KBr, cm ^-1 ): 3630, 3374, 319
5,3068,2962,1658,1625,157
4,1481,1434,1418,1381,133
1

Using the reference compounds 1-7 to 1-8 as starting materials, the following compounds are obtained in the same manner as in Reference Example 3.

2- [5-tert.-butyl-3- [1,1
-Dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-hydroxybenzylidene] -1,4
-Thiazin-3-one (reference compound 3-2)

.2- (3,5-di-tert.-butyl-4-)
Methoxymethoxybenzylidene) -1,4-thiazine-
3-one (Reference compound 3-3)

Reference Example 4 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one (Reference Compound 4)
-1)

Embedded image The erythro form of 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) thiomorpholin-3-one (reference compound 2-1 and 10.0 g) in methylene chloride (4
To a solution of a mixture of 0 ml) and tetrahydrofuran (40 ml) were added triethylamine (11.9 ml) and methanesulfonic acid chloride (3.3 ml) under ice cooling. After stirring for 1 hour under ice cooling, dilute hydrochloric acid is added to the reaction solution, and the mixture is extracted with chloroform. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 8.13 g (87%) of the title compound. m. p. 192 to 196 ° C IR (KBr, cm ^-1 ): 3616,3168,296
0, 1640, 1580, 1472, 1418, 139
0, 1362, 1339, 1290, 1262, 119
7,1120

Using the reference compounds 2-7 to 2-8 as raw materials, the following compounds are obtained in the same manner as in Reference Example 4.

2- [5-tert.-butyl-3- [1,1
-Dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-hydroxybenzylidene] thiomorpholin-3-one (Reference compound 4-2)

.2- (3,5-di-tert.-butyl-4-)
Methoxymethoxybenzylidene) thiomorpholine-3
-One (Reference compound 4-3)

Reference Example 5 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) -1,4-thiazin-3-one (Reference compound 5-1)

Embedded image Under a nitrogen atmosphere, a solution of 2- (α, 4-dihydroxy-3,5-diisopropylbenzyl) -1,4-thiazin-3-one (reference compound 1-2, 3.43 g) in pyridine (17.3 ml) was added. , Acetic anhydride (10.1 ml) is added. After stirring at room temperature for 24 hours, the reaction solution is ice-cooled, 1N hydrochloric acid is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with a 1N aqueous solution of sodium hydroxide and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound 3.2
6 g (75%) are obtained.

M. p. 206.8-208.4 ° C IR (KBr, cm ^-1 ): 3359, 3084, 303
0,2965,2872,1557,1725,167
2,1631,1457,1372,1335,131
9,1306,1244,1213

Using the reference compounds 1-2 to 1-6 as starting materials, the following compounds are obtained in the same manner as in Reference Example 5.

.2- (α, 4-dibenzoyloxy-
3,5-diisopropylbenzyl) -1,4-thiazin-3-one (Reference compound 5-2)

2- (3-tert.-butyl-α, 4-diacetoxybenzyl) -1,4-thiazin-3-one (Reference compound 5-3)

.2- (α, 4-diacetoxy-3,5-
Dimethylbenzyl) -1,4-thiazin-3-one (Reference compound 5-4)

.2- (α, 4-diacetoxy-5-methoxy-3-methylbenzyl) -1,4-thiazine-3-
ON (Reference compound 5-5)

2- (5-tert.-butyl-α, 4-diacetoxy-3-dimethylaminomethylbenzyl) -1,
4-thiazin-3-one (reference compound 5-6)

Reference Example 6 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) thiomorpholin-3-one (Reference compound 6
-1)

Embedded image 2- (α, 4-dihydroxy-3,5-diisopropylbenzyl) thiomorpholin-3-one (Reference compound 2
Pyridine (15.00 ml) was added to a suspension of methylene chloride (20 ml) of -2,2.00 g), and the mixture was stirred at 40 ° C for 8 hours. The reaction solution is put in IN hydrochloric acid under ice cooling, and extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.99 g (79
%).

M. p. 159.3-160.1 ° C IR (KBr, cm ^-1 ): 3180, 3043, 296
1,1768,1749,1664,1488,147
1,1429,1368,1346,1302,127
7,1233,1213

Using the reference compounds 2-2 to 2-6 as raw materials, the following compounds are obtained in the same manner as in Reference Example 6.

.2- (α, 4-dibenzoyloxy-
3,5-diisopropylbenzyl) thiomorpholine-
3-one (Reference compound 6-2)

2- (3-tert.-butyl-α, 4-diacetoxybenzyl) thiomorpholin-3-one (Reference compound 6-3) m. p. 170.5 to 174 ° C (decomposition) IR (KBr, cm ^-1 ): 3204, 2980, 175
1,1728,1652,1489,1370,125
0,1214,1028,828

.2- (α, 4-diacetoxy-3,5-
Dimethylbenzyl) thiomorpholin-3-one (Reference compound 6-4) m. p. 175.6-184.2 ° C IR (KBr, cm ^-1 ): 3204, 3087, 293
2,2888,1753,1680,1611,148
4,1411

2- (α, 4-diacetoxy-5-methoxy-3-methylbenzyl) thiomorpholin-3-one (Reference compound 6-5) m. p. 144.5 to 147.6 ° C (decomposition) IR (KBr, cm ^-1 ): 3375, 3184, 304
2,2917,1654,1645,1487,142
9,1319,1075,828,704

2- (5-tert.-butyl-α, 4-diacetoxy-3-dimethylaminomethylbenzyl) thiomorpholin-3-one (Reference compound 6-6)

Reference Example 7 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholine (Reference compound 7-1)

Embedded image To a suspension of lithium aluminum hydride (0.29 g) in diethyl ether (8 ml) is added aluminum chloride (0.34 g) under a nitrogen atmosphere. After stirring at room temperature for 15 minutes, 2- (3,5-di-tert.-butyl-
4-hydroxybenzylidene) -1,4-thiazine-3
A solution of a mixture of -one (Reference compound 3-1, 0.50 g) in diethyl ether (2 ml) -tetrahydrofuran (6 ml) is added. After stirring at room temperature for 30 minutes, water is added to the reaction solution, and the mixture is extracted 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 0.26 g (54%) of the title compound.

M. p. 150.5 to 151.7 ° C IR (KBr, cm ^-1 ): 3315, 2947, 161
4,1596,1570,1483,1430,139
7, 1372, 1352, 1340, 1319, 129
0,1270,1235

Example 1 2- (3,5-di-tert.-butyl-4-methoxymethoxybenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 1-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.96 g) in tetrahydrofuran (20 ml) was added 2- (3,5-di-te) in a nitrogen atmosphere under ice-sodium chloride cooling.
A solution of (rt.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one (Reference compound 4-1, 4.00 g) in tetrahydrofuran (50 ml) is added dropwise. After stirring at room temperature for 30 minutes, a solution of methoxymethyl chloride (1.82 ml) in tetrahydrofuran (10 ml) is added to the reaction solution. After stirring at room temperature for 3 hours, water was added to the reaction solution,
Extract with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture is concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 2.33 g (46%) of the title compound.

IR (Film, cm ^-1 ): 2957, ¹
644, 1574, 1469, 1430, 1390, 1
189,1166,1111,1081,964

Using the reference compound 4-2 as a raw material, the following compound is obtained in the same manner as in Example 1.

2- [5-tert.-butyl-3- [1,1
-Dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-methoxymethoxybenzylidene]-
4-methoxymethylthiomorpholin-3-one (compound 1-2)

Example 2 2- (3,5-di-tert.-butyl-4-methoxymethoxybenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 2-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.06 g) in tetrahydrofuran (2 ml) was added 2- (3,5-di-ter-
t-butyl-4-hydroxybenzylidene) -1,4-
Thiazin-3-one (Reference compound 3-1, 0.23 g)
Of tetrahydrofuran (5 ml) is added dropwise. After stirring at room temperature for 10 minutes, a solution of methoxymethyl chloride (0.1 ml) in tetrahydrofuran (1 ml) is added to the reaction solution. After stirring at room temperature for 2 hours, water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Using the reference compound 3-2 as a starting material, the following compound is obtained in the same manner as in Example 2.

2- [5-tert.-butyl-3- [1,1
-Dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-methoxymethoxybenzylidene]-
4-methoxymethyl-1,4-thiazin-3-one (compound 2-2)

Example 3 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxymethylthiomorpholine-3-
ON (Compound 3-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.14 g) in tetrahydrofuran (3 ml) was added 2- (α, 4-diacetoxy-3,5-diisopropyl) in a nitrogen atmosphere under ice-sodium chloride cooling. A solution of (benzyl) thiomorpholin-3-one (Reference compound 6-1, 1.21 g) in tetrahydrofuran (8 ml) is added dropwise. 3 at room temperature
After stirring for 0 minutes, a solution of methoxymethyl chloride (0.3 ml) in tetrahydrofuran (2 ml) is added to the reaction solution. After stirring at room temperature for 3 hours, water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium 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 by using the reference compounds 6-1 to 6-6 as raw materials and using the same method as in Example 3.

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-methoxymethylthiomorpholin-3-one (Compound 3-2)

2- (4-acetoxy-3-tert.-butylbenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 3-3)

2- (4-acetoxy-3,5-dimethylbenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 3-4)

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 3-5)

2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 3-
6)

Example 4 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxymethyl-1,4-thiazine-3
-One (compound 4-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.16 g) in tetrahydrofuran (3 ml) was added 2- (α, 4-diacetoxy-3,5-diisopropyl) in a nitrogen atmosphere under ice-sodium chloride cooling. A solution of (benzyl) -1,4-thiazin-3-one (reference compound 5-1 and 1.35 g) in tetrahydrofuran (8 ml) is added dropwise. After stirring at room temperature for 15 minutes, a solution of methoxymethyl chloride (0.3 ml) in tetrahydrofuran (2 ml) is added to the reaction solution. After stirring at room temperature for 3 hours, water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Using the reference compounds 5-2 to 5-6 as raw materials, the following compounds are obtained in the same manner as in Example 4.

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-methoxymethyl-
1,4-thiazin-3-one (compound 4-2)

2- (4-acetoxy-3-tert.-butylbenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 4-3)

2- (4-acetoxy-3,5-dimethylbenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 4-4)

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4-methoxymethyl-1,
4-thiazin-3-one (compound 4-5)

2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 4
-6)

Example 5 2- (3,5-diisopropyl-4-hydroxybenzylidene) -4-methoxymethylthiomorpholine-3-
ON (Compound 5-1)

Embedded image 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxymethylthiomorpholine-3-
An aqueous solution (14 ml) of lithium hydroxide monohydrate (0.89 g) was added dropwise to a solution of ON (compound 3-1 and 0.83 g) in tetrahydrofuran (18 ml) under ice cooling. 1
After stirring for an hour, the reaction solution is made acidic by adding hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Using the compounds 3-3 to 3-6 as raw materials, the following compounds are obtained in the same manner as in Example 5.

2- (3-tert.-butyl-4-hydroxybenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 5-2)

2- (3,5-dimethyl-4-hydroxybenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 5-3)

.2- (4-hydroxy-5-methoxy-)
3-methylbenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 5-4)

2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 5-
5)

Example 6 2- (3,5-diisopropyl-4-hydroxybenzylidene) -4-methoxymethyl-1,4-thiazine-3
-One (compound 6-1)

Embedded image 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxymethyl-1,4-thiazine-3
To a solution of -one (compound 4-1 and 0.42 g) in tetrahydrofuran (14 ml) was added dropwise an aqueous solution (11 ml) of lithium hydroxide monohydrate (0.45 g) under ice-cooling.
After stirring for 1 hour, the reaction solution is acidified by adding hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Using compounds 4-3 to 4-6 as starting materials, the following compounds are obtained in the same manner as in Example 6.

2- (3-tert.-butyl-4-hydroxybenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 6-2)

2- (3,5-dimethyl-4-hydroxybenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 6-3)

.2- (4-hydroxy-5-methoxy-)
3-methylbenzylidene) -4-methoxymethyl-1,
4-thiazin-3-one (compound 6-4)

2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-methoxymethyl-1,4-thiazin-3-one (compound 6
-5)

Example 7 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholine-3
-One diethyl ester (compound 7-1)

Embedded image A solution of 2- (3,5-di-tert.-butyl-4-methoxymethoxybenzylidene) -4-methoxymethylthiomorpholin-3-one (compound 1-1, 2.33 g) in chloroform (55 ml) was added with ice. -Under sodium chloride cooling
Trimethylsilyl iodide (1.9 in a nitrogen atmosphere)
7 g) are added dropwise. After stirring for 15 minutes, triethyl phosphite (5.4 ml) is added dropwise to the reaction solution. After stirring for 10 minutes, water is added to the reaction solution, and the mixture is extracted with chloroform.
The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give 1.40 g (56%) of the title compound.
%).

M. p. 159.3 to 162.0 ° C IR (KBr, cm ^-1 ): 3120, 2952, 163
6,1572,1472,1437,1340,126
3,1203,1013

The following compounds are obtained in the same manner as in Example 7 by using Compounds 5-1, 5-2, 5-3, and 5-5 as raw materials.

4-phosphonomethyl-2- (3,5-diisopropyl-4-hydroxybenzylidene) thiomorpholin-3-one diethyl ester (compound 7-
2)

2- (3-tert.-butyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one diethyl ester (compound 7-3)

4-phosphonomethyl-2- (3,5-dimethyl-4-hydroxybenzylidene) thiomorpholin-3-one diethyl ester (compound 7-4)

2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one diethyl ester (compound 7-5)

Example 8 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (compound 8-1) )

Embedded image Sodium hydride (60% mineral oil suspension, 0.026 g)
To a suspension of tetrahydrofuran (1 ml) in a nitrogen atmosphere under cooling with ice-sodium chloride.
rt.-butyl-4-hydroxybenzylidene) -1,4-
Thiazin-3-one (Reference compound 3-1,0.099
g) in tetrahydrofuran (1.4 ml) is added dropwise. After stirring at room temperature for 20 minutes, a solution of 2-bromoethyl phosphoric acid diethyl ester (0.096 g) in tetrahydrofuran (1 ml) is added to the reaction solution. After stirring at room temperature for 4 hours, an aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound 0.1.
11 g (75%) are obtained.

IR (film, cm ^-1 ): 3440, 2
958, 1737, 1644, 1568, 1435, 1
421, 1393, 1359, 1248, 1027, 9
70

Using the reference compounds 3-2, 5-1 to 5-6 as raw materials, the following compounds are obtained in the same manner as in Example 8.

• 2- [5-tert.-butyl-3- [1,1
-Dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-hydroxybenzylidene] -4-
(2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (compound 8-2)

.2- (4-acetoxy-3,5-diisopropylbenzylidene) -4- (2-phosphonoethyl)
-1,4-thiazin-3-one diethyl ester (compound 8-3)

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (Compound 8-4)

2- (4-acetoxy-3-tert.-butylbenzylidene) -4- (2-phosphonoethyl) -1,
4-thiazin-3-one diethyl ester (compound 8
-5)

2- (4-acetoxy-3,5-dimethylbenzylidene) -4- (2-phosphonoethyl) -1,
4-thiazin-3-one diethyl ester (compound 8
-6)

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (compound 8-7)

.2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-
(2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (compound 8-8)

-2- (3,5-di-tert.-butyl-4-
(Hydroxybenzylidene) -4- (7-phosphonoheptyl) -1,4-thiazin-3-one diethyl ester (compound 8-9)

Example 9 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholine-3
-One (compound 9-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholine-3
-One diethyl ester (compound 7-1, 1.00
To a solution of g) in dioxane (38 ml) is added 5.8 N hydrochloric acid (28 ml). After stirring at room temperature for 1 hour, the reaction solution is poured into dilute hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
Concentrate under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.17 g (19.2%) of the title compound.

IR (KBr, cm ^-1 ): 3626, 29
58, 1608, 1564, 1476, 1438, 14
21, 1343, 1209, 1156, 1008, 75
4

Using the compounds 7-2 to 7-5 as raw materials, the following compounds were obtained in the same manner as in Example 9.

• 2- (3,5-diisopropyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one (compound 9-2)

• 2- (3-tert.-butyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one (compound 9-3)

2- (3,5-dimethyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one (compound 9-4)

2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one (compound 9-
5)

Example 10 4-cyanomethyl-2- (3,5-di-tert.-butyl-
4-hydroxybenzylidene) -1,4-thiazine-3
-One (compound 10-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.19 g) in tetrahydrofuran (5 ml) was added 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1 under a nitrogen atmosphere. Of 4,4-thiazin-3-one (Reference compound 3-1, 0.80 g) in tetrahydrofuran (15
ml) Add the solution. After stirring at room temperature for 20 minutes, bromoacetonitrile (0.34 ml) is added to the reaction solution. After stirring at room temperature for 15 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound 0.4
5 g (50%) are obtained.

M. p. 158.9-160.5 ° C IR (KBr, cm ^-1 ): 3625, 3082, 295
6,2365,1636,1582,1557,143
8,1420,1386,1362

Using the reference compounds 3-1 to 3-3 as raw materials, the following compounds are obtained in the same manner as in Example 10.

• 4- (3-cyanopropyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 10-
2)

4-cyanomethyl-2- [5-tert.-butyl-3- [1,1-dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-hydroxybenzylidene] -1,4- Thiazin-3-one (Compound 10
-3)

• 4-cyanomethyl-2- (3,5-di-
tert.-butyl-4-methoxymethoxybenzylidene)-
1,4-thiazin-3-one (compound 10-4)

• 4- (7-cyanoheptyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 10-
5)

.4- (6-cyanohexyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 10-
6)

Example 11 4-cyanomethyl-2- (3,5-di-tert.-butyl-
4-hydroxybenzylidene) thiomorpholine-3-
ON (Compound 11-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one (Reference compound 4
-1,1.00 g) of tetrahydrofuran (20 ml)
The solution was cooled in ice-sodium chloride under a nitrogen atmosphere.
-Butyllithium (1.6 M, 3.74 ml) is added dropwise. After stirring for 30 minutes, a solution of bromoacetonitrile (0.44 ml) in tetrahydrofuran (10 ml) is added dropwise to the reaction solution. After stirring at room temperature for 18 hours, water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.35 g (31.4%) of the title compound.

M. p. 172.8-173.7 ° C IR (KBr, cm ^-1 ): 3627, 2958, 173
6,1629,1561,1482,1436,133
7, 1237, 1209, 1160, 1094, 90
4,737

Using the reference compounds 4-1 to 4-3 as raw materials, the following compounds are obtained in the same manner as in Example 11.

• 4- (3-cyanopropyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one (compound 11-2)

4-cyanomethyl-2- [5-tert.-butyl-3- [1,1-dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-hydroxybenzylidene] thiomorpholine-3 -One (compound 11-
3)

.4-cyanomethyl-2- (3,5-di-
tert.-butyl-4-methoxymethoxybenzylidene) thiomorpholin-3-one (compound 11-4)

Example 12 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-cyanomethyl-1,4-thiazine-3-
ON (Compound 12-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.12 g) in tetrahydrofuran (2 ml) was added 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl)-under a nitrogen atmosphere under ice cooling. A solution of 1,4-thiazin-3-one (Reference compound 5-1, 1.00 g) in tetrahydrofuran (12 ml) is added dropwise. After stirring at room temperature for 15 minutes, bromoacetonitrile (0.19 ml) is added dropwise to the reaction solution. After stirring at room temperature for 1 hour, hydrochloric acid was added to the reaction solution,
Extract with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture is concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give 0.70 g (74%) of the title compound.

M. p. 181 to 185 ° C IR (KBr, cm ⁻¹ ): 3075, 2966, 287
0,2241,1763,1652,1593,157
5,1470,1420,1385,1368,135
3,1310,1267,1218

Using the reference compounds 5-2 to 5-6 as raw materials, the following compounds are obtained in the same manner as in Example 12.

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-cyanomethyl-
1,4-thiazin-3-one (compound 12-2)

-2- (4-acetoxy-3-tert.-butylbenzylidene) -4-cyanomethyl-1,4-thiazin-3-one (compound 12-3)

.2- (4-acetoxy-3,5-dimethylbenzylidene) -4-cyanomethyl-1,4-thiazin-3-one (compound 12-4)

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4-cyanomethyl-1,4
-Thiazin-3-one (compound 12-5)

2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-cyanomethyl-1,4-thiazin-3-one (compound 12
-6)

Example 13 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-cyanomethylthiomorpholin-3-one (compound 13-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.32 g) in tetrahydrofuran (15 ml) was added 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) thiomorpholine-3 under a nitrogen atmosphere. -One (Reference compound 6-1, 1.50 g) in tetrahydrofuran (15 m
l) The solution is added dropwise. After stirring at room temperature for 1 hour, bromoacetonitrile (0.52 ml) is added to the reaction solution, and the mixture is stirred at 60 ° C for 2 hours. After cooling, the reaction mixture is poured into a diluted salt and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.67 g (47%) of the title compound.

IR (Fi1m, cm ^-1 ): 2964,2
930, 2871, 2553, 1759, 1641, 1
590, 1573, 1470, 1435, 1421, 1
385,1370

The following compounds were obtained using Reference Compounds 6-2 to 6-6 as raw materials and in the same manner as in Example 13.

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-cyanomethylthiomorpholin-3-one (Compound 13-2)

-2- (4-acetoxy-3-tert.-butylbenzylidene) -4-cyanomethylthiomorpholin-3-one (Compound 13-3) m. p. 126.5-128.0 ° C IR (KBr, cm ^-1 ): 1703, 1674, 149
0, 1375, 1330, 1254, 1234, 118
8,1167,1134,1094

2- (4-acetoxy-3,5-dimethylbenzylidene) -4-cyanomethylthiomorpholin-3-one (Compound 13-4) m. p. 141.5-144.5 ° C IR (KBr, cm ^-1 ): 2990, 2950, 291
6,2246,1748,1629,1601,157
0, 1484, 1442, 1423, 1411

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4-cyanomethylthiomorpholin-3-one (compound 13-5)

2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-cyanomethylthiomorpholin-3-one (compound 13-
6)

Example 14 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) -1,4-thiazin-3-one (Compound 14) -1)

Embedded image 4-cyanomethyl-2- (3,5-di-tert.-butyl-
4-hydroxybenzylidene) -1,4-thiazine-3
To a solution of -one (compound 10-1, 0.40 g) in dimethylformamide (10 ml) was added sodium azide (0.1
4 g) and ammonium chloride (0.12 g). After stirring at 110 ° C. for 2 hours, a saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give 0.22 g of the title compound.
(49%).

M. p. 183.8-186.2 ° C. (hexane-ethyl acetate) IR (KBr, cm ⁻¹ ): 3627, 3090, 295
6,1651,1612,1560,1541,143
8,1422,1392,1352,1316,128
2

Compounds 10-2, 10-5, 10-6, 1
Using 2-1 to 12-6 and 29-1 as raw materials, the following compounds are obtained in the same manner as in Example 14.

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- [3- (1H-tetrazol-5-yl) propyl] -1,4-thiazine-3
-One (compound 14-2)

• 2- (3,5-diisopropyl-4-hydroxybenzylidene) -4- (1H-tetrazole-
5-ylmethyl) -1,4-thiazin-3-one (Compound 14-3) m. p. 177.4-178.6 ° C. (hexane-ethyl acetate) IR (KBr, cm ⁻¹ ): 3212, 2964, 161
7, 1584, 1561, 1536, 1470, 142
7, 1395, 1356, 1294, 1271, 124
1,1202,1176

2- (3-tert.-butyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) -1,4-thiazin-3-one (compound 14
-4)

2- (3,5-dimethyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) -1,4-thiazin-3-one (compound 14
-5)

.2- (4-hydroxy-5-methoxy-)
3-methylbenzylidene) -4- (1H-tetrazol-5-ylmethyl) -1,4-thiazin-3-one (compound 14-6)

.2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-
(1H-tetrazol-5-ylmethyl) -1,4-thiazin-3-one (compound 14-7)

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- [7- (1H-tetrazol-5-yl) heptyl] -1,4-thiazine-3
-One (compound 14-8)

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- [2- (1H-tetrazol-5-yl) ethyl] -1,4-thiazine-3-
ON (Compound 14-9) m. p. Around 235 ° C IR (KBr, cm ^-1 ): 3611, 3124, 308
5,2950,2897,1649,1604,157
9, 1554, 1440, 1418, 1365, 131
0,1288,1257

.2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- [6- (1H-tetrazol-5-yl) hexyl] -1,4-thiazine-3
-One (compound 14-10)

Example 15 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) thiomorpholin-3-one (Compound 15-1)

Embedded image 4-cyanomethyl-2- (3,5-di-tert.-butyl-
4-hydroxybenzylidene) thiomorpholine-3-
Sodium azide (73 mg) was added to a solution of ON (compound 11-1, 0.29 g) in dimethylformamide (7 ml).
And ammonium chloride (60 mg) are added. 110
After stirring at 8 ° C for 8 hours, a saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (0.14 g, 41.4).
%).

M. p. 229.2-230.1 ° C (n
-Hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3618, 2956, 160
7,1563,1536,1482,1438,142
0, 1316, 1267, 1209, 1148, 108
4

Using the compounds 11-2 and 13-1 to 13-6 as starting materials, the following compounds are obtained in the same manner as in Example 15.

.2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- [3- (1H-tetrazol-5-yl) propyl] thiomorpholine-3-
On (compound 15-2) 2- (3,5-diisopropyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) thiomorpholin-3-one (compound 15-3) m. p. 197.3 to 198.5 ° C (hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3281, 2963, 161
3,1567,1534,1470,1427,137
4,1360,1344,1306,1274,123
7, 1208, 1175, 1156

• 2- (3-tert.-butyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) thiomorpholin-3-one (compound 15-
4) m. p. 250 ° C or more IR (KBr, cm ⁻¹ ): 3315, 1631, 158
5,1557,1341,1228,1096,105
7,907,833

2- (3,5-dimethyl-4-hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) thiomorpholin-3-one (compound 15-
5) m. p. 225.0-229.0 ° C (ethyl acetate-ethanol) IR (KBr, cm ^-1 ): 3299,2981,290
7,2768,2640,1605,1589,155
4

.2- (4-hydroxy-5-methoxy-)
3-methylbenzylidene) -4- (1H-tetrazol-5-ylmethyl) thiomorpholin-3-one (compound 15-6)

.2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-
(1H-tetrazol-5-ylmethyl) thiomorpholin-3-one (compound 15-7)

Example 16 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (Compound 16-1)

Embedded image A suspension of sodium hydride (60% mineral oil suspension, 0.05 g) in tetrahydrofuran (2 ml) was added to a suspension of 2- (3,5-di-tert.-butyl-4-hydroxy) in a nitrogen atmosphere under ice-cooling. A solution of (benzylidene) thiomorpholin-3-one (Reference compound 4-1, 0.20 g) in tetrahydrofuran (2 ml) is added dropwise. After stirring at room temperature for 30 minutes, methyl bromoacetate (0.06 ml) is added to the reaction solution. 6
After stirring at 0 ° C. for 2 days, dilute hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.24 g (99%) of the title compound. m. p. 159.3-163.9 ° C IR (KBr, cm ^-1 ): 3358, 2998, 295
5,2870,1748,1615,1567,147
3,1436,1418,1364,1343,130
9

Using the same method as in Example 16, the following compound was obtained.

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4-ethoxycarbonylmethylthiomorpholin-3-one (compound 16-2)

.2- (3,5-di-tert.-butyl-4-)
Hydroxybenzylidene) -4- (3-methoxycarbonylpropyl) thiomorpholin-3-one (Compound 1
6-3)

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- (7-methoxycarbonylheptyl) thiomorpholin-3-one (compound 1
6-4)

.2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- (6-methoxycarbonylhexyl) thiomorpholin-3-one (compound 1
6-5)

Example 17 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.12 g) in tetrahydrofuran (3 ml) was added 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl)-under a nitrogen atmosphere under ice cooling. A solution of 1,4-thiazin-3-one (Reference compound 5-1, 1.00 g) in tetrahydrofuran (10 ml) is added dropwise. After stirring at room temperature for 10 minutes, methyl bromoacetate (0.23 ml) is added to the reaction solution. After stirring at room temperature for 1 hour, dilute hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.95 g (92%) of the title compound. m. p. 126.4 to 133.5 ° C IR (KBr, cm ⁻¹ ): 3077, 3024, 296
5,2934,2871,1760,1654,159
3,1573,1468,1455,1436,141
8,1381,1335,1283,1270,124
4

Using the reference compounds 5-1 to 5-6 as starting materials, the following compounds are obtained in the same manner as in Example 17.

.2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-ethoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-2)

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-ethoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-
3)

• 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4- (3-methoxycarbonylpropyl) -1,4-thiazin-3-one (compound 1
7-4)

• 2- (4-acetoxy-3-tert.-butylbenzylidene) -4-methoxycarbonylmethyl-
1,4-thiazin-3-one (compound 17-5)

• 2- (4-acetoxy-3,5-dimethylbenzylidene) -4-methoxycarbonylmethyl-
1,4-thiazin-3-one (compound 17-6)

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4-methoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-7)

.2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-methoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-8)

Example 18 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 18-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.15 g) in tetrahydrofuran (5 ml) was added 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) thiomorpholine-3 under a nitrogen atmosphere. -One (Reference compound 6-1, 0.70 g) in tetrahydrofuran (12 m
l) The solution is added dropwise. After stirring at room temperature for 40 minutes, methyl bromoacetate (0.18 ml) is added to the reaction solution, and the mixture is stirred at 60 ° C. for 3 days. After cooling, the reaction mixture is poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.65 g (90%) of the title compound.

M. p. 148.7-149.9 ° C IR (KBr, cm ^-1 ): 2957, 2936, 287
0, 1765, 1741, 1641, 1589, 157
0,1469,1438,1421,1405,137
3

Using the reference compounds 6-1 to 6-6 as raw materials, the following compounds are obtained in the same manner as in Example 18.

• 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-ethoxycarbonylmethylthiomorpholin-3-one (compound 18-2)

• 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4- (3-methoxycarbonylpropyl) thiomorpholin-3-one (compound 18)
-3)

.2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 18-
4)

• 2- (4-acetoxy-3-tert.-butylbenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 18-5)

.2- (4-acetoxy-3,5-dimethylbenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 18-6)

.2- (4-acetoxy-5-methoxy-)
3-Methylbenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (Compound 18-7) m. p. 110.0-113.5 ° C IR (KBr, cm ^-1 ): 2939, 1759, 173
7, 1627, 1589, 1206, 1149, 110
1,1011,909,844,742

• 2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 18-8)

Example 19 4-Carboxymethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (Compound 19-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.53 g) in tetrahydrofuran (10 ml) was added 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1 under a nitrogen atmosphere. Of 4,4-thiazin-3-one (Reference compound 3-1, 2.00 g) in tetrahydrofuran (25
ml) The solution is added dropwise. After stirring at room temperature for 40 minutes, ethyl bromoacetate (0.74 ml) is added to the reaction solution. After stirring at room temperature for 15 minutes, dilute hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is dissolved in tetrahydrofuran (10 ml), cooled to 0 ° C, and an aqueous solution (10 ml) of lithium hydroxide monohydrate (2.53 g) is added. After stirring at 0 ° C for 30 minutes, hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.76 g (63%) of the title compound.

M. p. 207.7-209.2 ° C (hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3624, 3078, 295
6,1737,1642,1563,1438,142
1,1244,1212,1160

Using the reference compounds 3-1 and 3-2 as raw materials, the following compounds are obtained in the same manner as in Example 19.

• 4- (3-carboxypropyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 19-
2)

.2- [5-tert.-butyl-3- [1,1
-Dimethyl-2- (tetrahydropyran-2-yloxy) ethyl] -4-carboxymethyl-4-hydroxybenzylidene] -1,4-thiazin-3-one (compound 19-3)

• 4- (7-carboxyheptyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 19-
4)

Example 20 4-Carboxymethyl-2- (3,5-diisopropyl-4-hydroxybenzylidene) -1,4-thiazine-
3-one (compound 20-1)

Embedded image 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-1, 0.89 g) in tetrahydrofuran (10 ml) -methanol (4 ml)
Lithium hydroxide monohydrate (0.89 g) was added to the mixed solution.
(10 ml) is added dropwise. After stirring for 2 hours, the reaction solution is acidified by adding hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.62 g (81%) of the title compound.

M. p. 121.8-123.7 ° C (hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3410, 2964, 172
8, 1634, 1596, 1561, 1469, 142
9, 1407, 1379, 1362, 1339, 127
0,1195

Using the compounds 17-4 to 17-8 as raw materials, the following compounds are obtained in the same manner as in Example 20.

• 4- (3-carboxypropyl) -2-
(3,5-diisopropyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 20-2)

.2- (3-tert.-butyl-4-hydroxybenzylidene) -4-carboxymethyl-1,4-thiazin-3-one (compound 20-3)

• 4-carboxymethyl-2- (3,5-
Dimethyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 20-4)

• 4-carboxymethyl-2- (4-hydroxy-5-methoxy-3-methylbenzylidene)-
1,4-thiazin-3-one (compound 20-5)

• 2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-carboxymethyl-1,4-thiazin-3-one (compound 20-6)

Example 21 4-Carboxymethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholine-
3-one (Compound 21-1)

Embedded image To a solution of 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 16-1, 0.73 g) in tetrahydrofuran (3 ml) was added ice. Under cooling, an aqueous solution (2 ml) of lithium hydroxide monohydrate (0.76 g) was added dropwise. After stirring for 1 hour, the reaction solution is acidified by adding hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.56 g (79%) of the title compound.

M. p. 212.2-218.5 ° C (hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3618, 3580, 295
7, 1736, 1607, 1558, 1479, 144
0,1421,1397,1374,13591338

Compounds 16-3, 16-4, 18-1 to 1
Using 8-8 as a starting material and the same method as in Example 21, the following compound is obtained.

• 4- (3-carboxypropyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one (compound 21-2)

• 4- (7-carboxyheptyl) -2-
(3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one (compound 21-3)

• 4-carboxymethyl-2- (3,5-
Diisopropyl-4-hydroxybenzylidene) thiomorpholin-3-one (Compound 21-4) m. p. 151.7 to 152.8 ° C (n-hexane-
Ethyl acetate) IR (KBr, cm ^-1 ): 3322, 2960, 172
0, 1623, 1598, 1562, 1469, 143
7, 1391, 1345, 1308, 1273, 125
3,1198

• 4- (3-carboxypropyl) -2-
(3,5-diisopropyl-4-hydroxybenzylidene) thiomorpholin-3-one (compound 21-5)

• 2- (3-tert.-butyl-4-hydroxybenzylidene) -4-carboxymethylthiomorpholin-3-one (compound 21-6)

• 4-carboxymethyl-2- (3,5-
Dimethyl-4-hydroxybenzylidene) thiomorpholin-3-one (Compound 21-7)

• 4-carboxymethyl-2- (4-hydroxy-5-methoxy-3-methylbenzylidene) thiomorpholin-3-one (Compound 21-8) m. p. 205.5-208.5 ° C (ethyl acetate, decomposition) IR (KBr, cm ^-1 ): 3552, 2964, 171
9, 1607, 1479, 1309, 1220, 115
9,1089,835,620

2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-carboxymethylthiomorpholin-3-one (compound 2
1-9)

Example 22 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (Compound 22-1)

Embedded image Lawson's reagent was added to a solution of 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (compound 16-1, 0.69 g) in toluene (40 ml). (1.38g)
Add. After refluxing for 15 hours, the reaction solution is concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.25 g (35%) of the title compound.

M. p. 136.4-138.4 ° C (hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3587, 2959, 174
2,1583,1494,1439,1420,139
2,1376,1362,1343,1317,128
3

The following compounds are obtained by using the compounds 18-1, 18-4 to 18-8 as starting materials and using the same method as in Example 22.

• 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (compound 22-2)

• 2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (compound 22
-3)

-2- (4-acetoxy-3-tert.-butylbenzylidene) -4-methoxycarbonylmethyl-3
-Thioxothiomorpholine (Compound 22-4)

• 2- (4-acetoxy-3,5-dimethylbenzylidene) -4-methoxycarbonylmethyl-3
-Thioxothiomorpholine (compound 22-5)

• 2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (compound 22-
6)

• 2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (compound 22-7)

Example 23 4-Carboxymethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3-thioxothiomorpholine (Compound 23-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (compound 22-1, 0.16 g)
Aqueous solution (4 ml) of lithium hydroxide monohydrate (0.16 g) in a tetrahydrofuran (5 ml) solution of
And methanol (3 ml). After stirring at room temperature for 15 minutes, 6N hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.12 g, 77%).
%).

M. p. 200 to 208 ° C (hexane-
Ethyl acetate) IR (KBr, cm ^-1 ): 3627,2951,173
9, 1585, 1567, 1506, 1436, 141
9,1391,1358,1348,1316,128
2,1266,1238

Using the compounds 22-1 to 22-7 as starting materials, the following compounds are obtained in the same manner as in Example 23.

.4-carboxymethyl-2- (3,5-
Diisopropyl-4-hydroxybenzylidene) -3-
Thioxothiomorpholine (Compound 23-2)

• 2- (3-tert.-butyl-4-hydroxybenzylidene) -4-carboxymethyl-3-thioxothiomorpholine (compound 23-3)

.4-carboxymethyl-2- (3,5-
Dimethyl-4-hydroxybenzylidene) -3-thioxothiomorpholine (Compound 23-4)

• 4-carboxymethyl-2- (4-hydroxy-5-methoxy-3-methylbenzylidene) -3
-Thioxothiomorpholine (Compound 23-5)

• 2- (5-tert.-butyl-3-dimethylaminomethyl-4-hydroxybenzylidene) -4-carboxymethyl-3-thioxothiomorpholine (compound 23-6)

Example 24 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -4-sulfomethyl-1,4-thiazine-
3-one (compound 24-1)

Embedded image 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -1 was added to a suspension of sodium hydride (60% mineral oil suspension, 0.10 g) in tetrahydrofuran (2 ml) under a nitrogen atmosphere. Dimethylformamide (2,4-thiazin-3-one (Reference compound 3-1, 0.20 g))
ml) The solution is added dropwise. After stirring at room temperature for 10 minutes, a solution of chloromethanesulfonic acid (0.20 g) in dimethylformamide (1 ml) is added to the reaction solution. After stirring at 50 ° C. overnight, a saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Example 24 was prepared using Reference Compound 4-1 as a raw material.
The following compounds are obtained by using the same method as in the above.

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4-sulfomethyl-thiomorpholin-3-one (Compound 24-2)

Example 25 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethylthiomorpholine (Compound 25-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholine (Reference compound 7-1,0.
Potassium carbonate (0.26 g) and methyl bromoacetate (0. 60 g) in a dimethylformamide (8 ml) solution.
20 ml). After stirring at room temperature for 1 hour, water is added to the reaction solution, and the mixture is extracted with diethyl ether. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give 0.76 g (100%) of the title compound.

IR (Film, cm ^-1 ): 3635, 2
954,2872,1747,1517,1435,1
392,1361,1309,1202,1155,1
120, 1023

Example 26 4-Carboxymethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholine (Compound 26-1)

Embedded image To a solution of 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethylthiomorpholine (compound 25-1, 0.74 g) in tetrahydrofuran (10 ml) was added water under ice-cooling. Lithium oxide 1
An aqueous solution (13 ml) of hydrate (1.98 g) and methanol (3 ml) are added. After stirring at room temperature for 15 minutes, 6N hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.25 g (35%) of the title compound.

IR (KBr, cm ^-1 ): 3632, 34
18, 2955, 1633, 1437, 1340, 13
18, 1239, 1214, 1160, 1119, 10
25,890,811,792

Example 27 4-carbamoylmethyl-2- (3,5-diisopropyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (compound 27-1)

Embedded image 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxycarbonylmethyl-1,4-thiazin-3-one (compound 17-1, 0.1 g) was added to a methanol solution of ammonia (17.85N, 10 ml), 0.1N hydrochloric acid in methanol (2 ml) is added, and the mixture is stirred in a sealed tube at 80 ° C for 3 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.

IR (film, cm ^-1 ): 3337,3
080, 2961, 2926, 2869, 1682, 1
634,1557,1302,1075,992,95
8 The following compound was obtained using a method similar to that in Example 27.

-2- (3,5-diisopropyl-4-hydroxybenzylidene) -4- (N-methylcarbamoylmethyl) -1,4-thiazin-3-one (compound 27)
-2) IR (Film, cm ^-1 ): 3336,296
2,2870,1682,1622,1563,147
0,1441

Example 28 • 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4- (2-phosphonoethyl) -1,4-
Thiazin-3-one (Compound 28-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (compound 8-1,
0.50 g) in dioxane (20 ml)
Hydrochloric acid (14 ml) is added. After stirring for 1 hour at room temperature,
The reaction solution is poured into diluted hydrochloric acid and extracted with diethyl ether.
The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Using the compounds 8-2 to 8-9 as starting materials, the following compounds are obtained in the same manner as in Example 28.

• 2- [5-tert.-butyl-3- (1,1
-Dimethyl-2-hydroxyethyl) -4-hydroxybenzylidene] -4- (2-phosphonoethyl) -1,4
-Thiazin-3-one (compound 28-2)

• 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4- (2-phosphonoethyl)
-1,4-thiazin-3-one (compound 28-3)

• 2- (4-benzoyloxy-3,5-
Diisopropylbenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one (compound 28-
4)

• 2- (4-acetoxy-3-tert.-butylbenzylidene) -4- (2-phosphonoethyl) -1,
4-thiazin-3-one (compound 28-5)

• 2- (4-acetoxy-3,5-dimethylbenzylidene) -4- (2-phosphonoethyl) -1,
4-thiazin-3-one (compound 28-6)

.2- (4-acetoxy-5-methoxy-)
3-methylbenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one (compound 28-7)

• 2- (4-acetoxy-5-tert.-butyl-3-dimethylaminomethylbenzylidene) -4-
(2-phosphonoethyl) -1,4-thiazin-3-one (compound 28-8)

-2- (3,5-di-tert.-butyl-4-)
(Hydroxybenzylidene) -4- (7-phosphonoheptyl) -1,4-thiazin-3-one (compound 28-9)

Example 29 4- (2-cyanoethyl) -2- (3,5-di-tert.-
(Butyl-4-hydroxybenzylidene) -1,4-thiazin-5-one (compound 29-1)

Embedded image To a suspension of sodium hydride (60% mineral oil suspension, 0.24 g) in tetrahydrofuran (5 ml) was added 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1 under a nitrogen atmosphere. 4,4-thiazin-3-one (Reference compound 3-1, 1.00 g) in tetrahydrofuran (8 m
l) Add the solution. After stirring at room temperature for 20 minutes, acrylonitrile (0.50 ml) is added to the reaction solution, and the mixture is stirred at room temperature for 3 hours. The reaction solution is poured into IN hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (0.76 g).
(66%).

M. p. 160.5 to 164.8 ° C IR (KBr, cm ⁻¹ ): 3628, 3564, 308
4,2959,2252,1638,1586,156
4,1438,1420,1393,1359,132
8,1308,1289

Example 30 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4- (2-ethoxycarbonylethyl)-
1,4-thiazin-3-one (compound 30-1)

Embedded image 2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -1,4-thiazin-3-one (Reference compound 3-1; 0.60 g) in dimethylformamide (13 m
l) in a solution of potassium carbonate (0.50
g) and ethyl acrylate (0.49 ml)
Stir at 110 ° C. for 1 hour. After cooling the reaction solution to room temperature,
Pour into diluted hydrochloric acid and extract with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
Concentrate under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.56 g (72%) of the title compound. m. p. 101.7 to 102.6 ° C IR (KBr, cm ^-1 ): 3614, 2959, 172
7, 1630, 1586, 1567, 1435, 139
2,1364,1321,1294,1255,118
3,1145

Example 31 4- (2-carboxyethyl) -2- (3,5-di-te
rt.-butyl-4-hydroxybenzylidene) -1,4-
Thiazin-5-one (Compound 31-1)

Embedded image 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4- (2-ethoxycarbonylethyl)-
1,4-thiazin-3-one (compound 30-1, 0.5
1 g) in tetrahydrofuran (8 ml) was added to a solution of lithium hydroxide monohydrate (0.50 g) in water (8 m
l) Add the solution and methanol (1 ml) and stir for 50 minutes. Dilute hydrochloric acid is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give 0.37 g of the title compound (7
7%).

M. p. 200.6 to 201.5 ° C (n
-Hexane-ethyl acetate) IR (KBr, cm ^-1 ): 3620, 3207, 295
6,1732,1650,1617,1584,155
9,1434,1401,1362,1333,128
2,1263,1149,1120

[Formulation Examples] Examples of the formulation of the compound of the present invention are shown below.

[0360]

[0361]

[0362]

(Ophthalmic solution) Formulation 1 In 100 ml of the compound of the present invention 0.5 g Condensed glycerin 1.5 g Polyoxyethylene hydrogenated castor oil 1.0 g Benzalkonium chloride 0.005 g Sodium edetate 0.01 g Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Appropriate amount of sterilized purified water

Formulation 2 In 100 ml of the compound of the present invention 3.0 g Concentrated glycerin 1.0 g Polysorbate 80 7.0 g Benzalkonium chloride 0.005 g Sodium edetate 0.01 g Dilute hydrochloric acid qs Sodium hydroxide qs Sterile purified water qs

Formulation 3 In 100 ml of the compound of the present invention 0.01 g concentrated glycerin 2.0 g polysorbate 80 0.5 g benzalkonium chloride 0.005 g sodium edetate 0.01 g dilute hydrochloric acid qs sterile purified water qs

(Eye ointment) In 100 g of the compound of the present invention 1.0 g Liquid paraffin 10.0 g White petrolatum 89.0 g

[0367]

【The invention's effect】

[Pharmacological test] In order to examine the usefulness of the compound of the present invention, a protein stabilizing effect and a lipid peroxide production suppressing effect were examined.

[0368] 1. Protein stabilizing action As a method for examining the protein stabilizing action of a compound, a method of measuring the stabilizing effect of bovine serum albumin on thermal aggregation is known (Lancet, 1, 169 (1965)).

Thus, the protein stabilizing effect of the compound of the present invention was examined according to the method described in the above literature.

(Experimental method) Under ice-cooling, 0.2% of bovine serum albumin (manufactured by Sigma) was added to a concentration of 0.75%.
M potassium phosphate buffer (pH 5.3).
To 2.7 ml of this albumin solution, 0.3 ml of a dimethyl sulfoxide solution in which a test compound was dissolved was added, and the mixture was stirred, and then allowed to stand for about 15 minutes to return to room temperature. After reacting this solution for 2 minutes in a water bath at 67 ° C. while shaking,
The reaction was stopped by cooling on ice. After the temperature of the reaction solution was returned to room temperature, the absorbance caused by clouding of the water-soluble protein due to thermal aggregation was measured at a wavelength of 660 nm, and the protein stabilizing effect of the compound of the present invention was determined using the following formula 1.

[0371]

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

(Results) The results obtained are shown in Table 1.

[0373]

[Table 1] The compound of the present invention clearly suppresses thermal aggregation of the protein,
Excellent protein stabilizing effect was shown.

[0374] 2. Lipid peroxide production inhibitory effect (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) The results obtained are shown in Table 2.

[0376]

[Table 2] As shown in Table 2, the compound of the present invention had an excellent lipid peroxide production inhibitory effect.

As shown by the results of the above pharmacological tests, the compound 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. .

────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification symbol FI C07F 9/6544 C07F 9/6544 (56) References JP-A-7-138241 (JP, A) JP-A-7-138242 (JP) , A) JP-A-6-73033 (JP, A) JP-A-1-87077 (JP, A) WO 94/05647 (WO, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) ) C07D 279/00-279/36 A61K 31/00-31/80 C07D 417/00-417/14 CA (STN) REGISTRY (STN)

Claims (39)

(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, wherein 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 tetrazolyl group; a phosphonic acid group which may be converted to an ester or an amide; or a sulfonic acid group which may be converted to an ester or an amide. B is C = O, C = S or C
Shows the H _2. A represents an alkylene group. ---- indicates a single bond or a double bond. ] 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 which may be converted to an ester with lower alkyl or aryl lower alkyl; a carboxyl group which may be converted to an amide with ammonia, lower alkylamine or aryl lower amine; tetrazolyl group; lower alkyl or aryl Phosphonic acid group which may be converted to an ester with lower alkyl; phosphonic acid group which may be converted to amide with ammonia, lower alkylamine or aryl lower amine; conversion to ester with lower alkyl or aryl lower alkyl A sulfonic acid group which may be converted to an amide with ammonia, lower alkylamine or aryl lower amine. B represents a C = O, C = S or CH _2. A represents an alkylene group. ---- indicates a single bond or a double bond. ] 3. A compound represented by the following general formula [I] or a salt thereof. Embedded image [In the formula, R ¹ represents a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group. R ² represents a lower alkyl group. R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the lower alkyl group may be substituted with a hydroxy group, a tetrahydropyranyloxy group, an amino group or a lower alkylamino group. R ⁴ is a carboxyl group which may be converted to an ester with lower alkyl; a carboxyl group which may be converted to amide with ammonia or lower alkylamine; a tetrazolyl group; which may be converted to an ester with lower alkyl. A good phosphonic acid group; or a sulfonic acid group which may be converted to an ester with lower alkyl. B is C
ＯO, C ＝ S or CH ₂ . A represents an alkylene group. ---- indicates a single bond or a double bond. ] 4. A compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ represents a hydroxy group or a lower alkanoyloxy group. R ² represents a lower alkyl group. R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group. R ⁴ is a carboxyl group which may be converted to an ester with lower alkyl; a carboxyl group which may be converted to amide with ammonia or lower alkylamine; a tetrazolyl group; or a carboxyl group which is converted to an ester with lower alkyl. B which represents a good phosphonic acid group is represented by C =
O, C = S or CH ₂ is shown. A represents an alkylene group. ---- indicates a single bond or a double bond. ] 5. R ¹ is hydroxy or acetyloxy; R ² is methyl, isopropyl or t-butyl; R ³ is hydrogen, methyl, isopropyl or t-butyl.
A butyl group or a methoxy group; a carboxyl group wherein R ⁴ may be converted to a methyl or ethyl ester; a tetrazolyl group; a phosphonic acid group which may be converted to an ethyl ester; B is C ＝ O, C ＝ S or CH _2; a is a methylene group or an ethylene group; a compound or salt thereof according to claim 4, wherein ---- is a single bond. 6. R ¹ is hydroxy or acetyloxy; R ² is methyl, isopropyl or t-butyl; R ³ is hydrogen, methyl, isopropyl or t-butyl.
A butyl group or a methoxy group; a carboxyl group wherein R ⁴ may be converted to a methyl or ethyl ester; a tetrazolyl group; a phosphonic acid group which may be converted to an ethyl ester; B is C ＝ O; The compound according to claim 4, wherein ---- is a single bond, or a salt thereof. 7. R ¹ is hydroxy or acetyloxy; R ² is isopropyl or t-butyl; R ³ is isopropyl or t-butyl; and R ⁴ is methyl or ethyl ester. A good carboxyl group; a carboxyl group which may be converted to an amide with ammonia or methylamine; a tetrazolyl group;
A phosphonic acid group which may have been converted to an ethyl ester;
The compound or a salt thereof according to claim 4, wherein B is C = O; A is a methylene or ethylene group; ---- is a double bond. 8. R ¹ is a hydroxy group; R ² is a t-butyl group; R ³ is a t-butyl group; R ⁴ is a carboxyl group which may be converted to a methyl ester; B is C = S; 5. The compound according to claim 4, wherein methylene group; ---- is a single bond, or a salt thereof. 9. R ¹ is a hydroxy group; R ² is a t-butyl group; R ³ is a t-butyl group; R ⁴ is a carboxyl group which may be converted to a methyl ester; B is CH ₂ ; 5. The compound according to claim 4, wherein the group is a single bond, or a salt thereof. 10. A compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ represents a hydroxy group. R ² represents a lower alkyl group. R ³ represents a lower alkyl group. R ⁴ represents a carboxyl group, a tetrazolyl group or a phosphonic acid group. B indicates C = O. A represents an alkylene group. ----
Represents a single bond or a double bond. ] 11. R ¹ is a hydroxy group; R ² is a t-butyl group; R ³ is a t-butyl group; R ⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group; B is C ＝ O; Wherein ---- is a single bond or a double bond.
0 or a salt thereof. 12. The compound according to claim 2, wherein R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group, or a salt thereof. 13. The compound according to claim 2, wherein R ¹ is a hydroxy group or a lower alkanoyloxy group, or a salt thereof. 14. The compound according to claim 2, wherein R ¹ is a hydroxy group or an acetyloxy group, or a salt thereof. 15. The compound according to claim 2, wherein R ¹ is a hydroxy group, or a salt thereof. 16. A carboxyl group wherein R ⁴ may be converted to an ester with lower alkyl; a carboxyl group which may be converted to amide with ammonia or lower alkylamine; a tetrazolyl group; The compound according to claim 2, which is a phosphonic acid group which may be converted; or a sulfonic acid group which may be converted to an ester with lower alkyl, or a salt thereof. 17. A carboxyl group in which R ⁴ may be converted to a methyl or ethyl ester; a carboxyl group which may be converted to an amide with ammonia or methylamine; a tetrazolyl group; 3. The compound according to claim 2, which is a good phosphonic acid group, or a salt thereof. 18. The compound according to claim 2, wherein R ⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group, or a salt thereof. 19. The compound according to claim 2, wherein B is C ＝ O, or a salt thereof. 20. The compound according to claim 2, wherein ---- is a single bond, or a salt thereof. 21. The compound according to claim 2, wherein ---- is a double bond, or a salt thereof. 22. R ¹ is a hydroxy group, lower alkanoyloxy group or benzoyloxy group; R ² is a lower alkyl group; R ³ is a hydrogen atom, a lower alkyl group or a lower alkoxy group, wherein the lower alkyl group is a hydroxy group The compound according to claim 2, which is optionally substituted with a tetrahydropyranyloxy group, an amino group or a lower alkylamino group, or a salt thereof. 23. The compound according to claim 2, wherein R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group; R ² is a lower alkyl group; and R ³ is a hydrogen atom, a lower alkyl group or a lower alkoxy group. salts. 24. R ¹ is hydroxy or acetyloxy; R ² is methyl, isopropyl or t-butyl; R ³ is hydrogen, methyl, isopropyl, t
The compound according to claim 2, which is a -butyl group or a methoxy group, or a salt thereof. 25. The compound according to claim 2, wherein R ¹ is a hydroxy group; R ² is a t-butyl group; and R ³ is a t-butyl group. 26. 2- (3,5-di-tert.-butyl-4)
-Hydroxybenzylidene) -4-phosphonomethylthiomorpholin-3-one. 27. 2- (3,5-di-tert.-butyl-4)
-Hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) -1,4-thiazin-3-one. 28. 2- (3,5-di-tert.-butyl-4)
-Hydroxybenzylidene) -4- (1H-tetrazol-5-ylmethyl) thiomorpholin-3-one. 29. 4-carboxymethyl-2- (3,5
-Di-tert.-butyl-4-hydroxybenzylidene)-
1,4-thiazin-3-one. 30. 4-carboxymethyl-2- (3,5
-Di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one. 31. A therapeutic agent for cataract, comprising the compound according to claim 1 or a salt thereof as an active ingredient. 32. 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, wherein 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 ⁵ represents a cyano group or a lower alkoxy group. B represents a C = O, C = S or CH _2. A represents an alkylene group. ---- indicates a single bond or a double bond. ] 33. 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. R
⁵ represents a cyano group or a lower alkoxy group. B is C =
O, C = S or CH ₂ is shown. A represents an alkylene group. ---- indicates a single bond or a double bond. ] 34. A compound represented by the following general formula [II] or a salt thereof. Embedded image [In the formula, R ¹ represents a hydroxy group, a lower alkanoyloxy group, a lower alkoxymethyloxy group or a benzoyloxy group. R ² represents a lower alkyl group. R ³ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the lower alkyl group may be substituted with a hydroxy group, a tetrahydropyranyloxy group, an amino group or a lower alkylamino group. R ⁵ represents a cyano group or a lower alkoxy group. B indicates C = O. A represents an alkylene group. ---- indicates a single bond or a double bond. ] 35. A compound represented by the following general formula [II] or a salt thereof. Embedded image [In the formula, R ¹ represents a hydroxy group, a lower alkanoyloxy group or a lower alkoxymethyloxy group. R ² represents a lower alkyl group. R ³ represents a hydrogen atom or a lower alkyl group. R ⁵ represents a cyano group or a lower alkoxy group. B indicates C = O. A represents an alkylene group.
---- indicates a single bond or a double bond. ] 36. R ¹ is hydroxy, acetyloxy or methoxymethoxy; R ² is methyl, isopropyl or t-butyl; R ³ is hydrogen, methyl, isopropyl or t-butyl; compounds or salts thereof according to claim 35 wherein a is a methylene or ethylene group; R ⁵ is a cyano group or a methoxy group. 37. 2- (3,5-di-tert.-butyl-4)
-Methoxymethoxybenzylidene) -4-methoxymethylthiomorpholin-3-one. 38. 4-cyanomethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1,
4-thiazin-3-one. 39. 4-cyanomethyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholin-3-one.