JPH07258238A - New thiazine or thiomorpholine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound having a combination of excellent lipid peroxide formation-inhibitory activity and protein-stabilizing activity, thus useful as a therapeutic agent for cataract. CONSTITUTION:The objective compound is expressed by formula I {R<1> is (protected) OH; R<2> is a lower alkyl; R<3> is H, a [(protected) OH- or (protected) (lower alkyl)amino-substituted] lower alkyl- or (protected) lower alkoxyl; R<4> is a (ester- or amide-converted) carboxyl, tetrazol-yl, (ester- or amide-converted) phosphone, etc.; A is an alkylene; B is C=O, C=S or CH2} or a salt thereof, e.g. 2-(3,5-di-t-butyl-4-hydroxybenzylidene)-4-phosphonomethylthiomorpholin -3-one. The compound of formula I (where, R<1> is OH; R<4> is carboxyl) is obtained by the following processes: a compound of formul.a II is reacted with a compound of formula III in the presence of a base to form a compound of formula IV followed by protecting its OH group and then reaction with a compound of formula, VY-A-R<4> (Y is a halogen, etc.) in the presence of a base followed by eliminating the OH-protecting group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 1,4-thiazine or thiomorpholine derivative having a protein stabilizing action and a lipid peroxide production inhibiting action and useful as a medicine such as a cataract treating agent.

[0002]

2. Description of the Related Art 1,4-the basic skeleton of compounds of the present invention
A compound having a benzylidene group at the 2-position of thiazine or thiomorpholine has an antiallergic action, a tyrosine kinase inhibitory action (Japanese Patent Laid-Open No. 62-29570) and an ultraviolet absorbing action (Japanese Patent Laid-Open Nos. 50-126676 and 50-1).
26677 et al.). However, in any of the compounds described in these reports, the nitrogen atom, that is, the 4-position of 1,4-thiazine or thiomorpholine skeleton is not substituted, or substituted with an alkyl group or an aralkyl group. It was a thing. Further, these reports do not describe any protein stabilizing action or lipid peroxide production inhibiting 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 production inhibiting action. It has been reported (Japanese Patent Laid-Open No. 1-287077).

[0004]

Cataract is an intractable eye disease in which the crystalline lens becomes cloudy and loses visual acuity. Although various factors have been studied for a long time about the factors causing cataracts, the mechanism, and the treatment methods thereof, the number of effective drugs is very small at present.

It is said that the increase of peroxide in the lens is related to the development of cataract, and it has been reported that a compound having a lipid peroxide production inhibitory effect is effective for cataract (Current Eye Res., 5 , 37 (1986)). In addition, it has been reported that proteins in the lens are denatured in patients with cataract (Ophthalmology 19, 1283 (1977)).

From the above, it is considered that a compound having both lipid peroxide production inhibitory action and protein stabilizing action is particularly useful for cataract. However, research on a compound having both of these two actions has not yet been conducted, and development of such a compound has been desired.

[0007]

Therefore, the present inventors
Based on the information that a 3-oxo-1,4-benzothiazine derivative in which a benzylidene group is substituted at the position has a lipid peroxide production inhibitory action (JP-A-1-287077), the skeleton is 1,4-thiazine or thiol. We changed to morpholine and conducted diligent studies to solve the above problems.

First, the present inventors have found that the hydroxy group and tert.-
We paid attention to the fact 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 lipid peroxides, various substituents such as alkyl groups and hydroxy groups are introduced into the phenyl ring of the benzylidene group, and the role of the substituents on the lipid peroxide formation suppressing effect. Was examined. 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 inhibitory action on lipid peroxide formation can be obtained.

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

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 was 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 lipid peroxide production inhibitory action and protein stabilizing action.

Further, aldose reductase inhibitors have recently been attracting attention as a therapeutic agent for cataracts, but the compound of the present invention also has an aldose reductase inhibitory action and is extremely useful as a therapeutic agent for cataracts.

[0012]

DISCLOSURE OF THE INVENTION The present invention provides 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]. The present invention relates to a body (hereinafter referred to as an intermediate of the present invention).

[0013]

[Chemical 10] [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 which may be protected by a protecting group or a lower alkoxy group, and the lower alkyl group may be a hydroxy group which may be protected by a protecting group or an amino group. Alternatively, it may be substituted with a lower alkylamino group.

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

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. same as below. ]

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

Lower alkyl means 1 to 6 such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and the like.
It represents a straight-chain or branched alkyl having 4 carbon atoms.

Lower alkoxy is methoxy, ethoxy,
Propoxy, hexyloxy, isopropoxy, tert.-
A linear or branched alkoxy having 1 to 6 carbon atoms such as butoxy is shown.

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

The 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. Indicates.

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, benzoyl. , Tetrahydropyranyl, benzyloxymethyl, trimethylsilyl and the like, which are commonly used as a protective group for a hydroxy group, are shown.

The ester means 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.

The amides are 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 represents an aromatic such as phenyl, naphthyl and pyridyl. Those aromatic groups 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, ammonium salts, salts with organic amines such as diethylamine and triethanolamine salts. Further, salts with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid are also included.

Typical synthetic methods of the compound of the present invention are shown in 1) to 4) below.

1) Compounds in which R ⁴ is a carboxyl group which may be converted into an ester or an amide

[Chemical 11] [In the formula, 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
The compound represented by the formula [V] is obtained by reacting the compound represented by the formula [V] in the presence of a base. Then the formula
The hydroxy group of the compound represented by [V] is protected by a commonly used method to obtain the compound represented by the formula [VI], and then the compound represented by the formula [VI] and the compound represented by the formula [VI]
The compound represented by the formula [IX] is obtained by reacting the compound represented by the formula [I] in the presence of a base, and then removing the hydroxy-protecting group using a commonly used method. Further, dehydration of the compound represented by the formula [V] gives a compound represented by the formula [VIII].
The compound of the formula [IX] can also be obtained by reacting the compound of the formula [VIII] with the compound of the formula [VII] in the presence of a base. The formula [V
The compound represented by III] can also be synthesized according to the method described in JP-A-62-29570.

2) Compounds in which R ⁴ is a tetrazolyl group

[Chemical 12] The compound represented by formula [XI] is obtained by reacting the compound represented by formula [VI] with the compound represented by formula [X] in the presence of a base. Then the expression [X
The compound of the present invention (formula [XII]) in which R ⁴ is a tetrazolyl group is obtained by reacting the compound represented by the formula [I] with sodium azide. Further, the compound represented by the formula [VIII] is reacted with the compound represented by the formula [X] in the presence of a base to obtain a compound represented by the formula [XIII]. The compound of the present invention (formula [XII]) can also be obtained by reacting with. The compounds represented by the formula [XI] and the formula [XIII] are R
It is a novel compound that is particularly useful as a synthetic intermediate for introducing a tetrazolyl group into ⁴ .

3) A compound in which R ⁴ is a phosphonic acid group which may be converted into an ester or an amide.

[Chemical 13] [In the formula, 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, a compound of the formula [XV]
A compound represented by If necessary, the hydroxy-protecting group can be removed using a general-purpose method to give a compound of the formula [XV
The compound of the present invention (formula [XVII]) can be obtained by reacting the compound represented by the formula [I] with trimethylsilyl halide, and then reacting with trialkylphosphite and the like. The compound of the present invention (formula [XVII]) can also be obtained by reacting the compound of formula [VIII] with the compound of formula [XVIII] in the presence of a base.

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

4) A compound in which R ⁴ is a sulfonic acid group which may be converted into an ester or an amide.

[Chemical 14] [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 the 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 of which B is C = O can be obtained by reacting with Lawesson's reagent.
= S, or 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 commonly used method before or after the reaction, and the protecting group should be eliminated by a commonly used method. You can

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 by using a commonly used method. Similarly, a phosphonic acid group or a sulfonic acid group can be converted into an ester or an amide by using a commonly used method.

On the contrary, the ester or amide can be hydrolyzed into a carboxylic acid, a phosphonic acid or a sulfonic acid by using a commonly used method.

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

The compounds of the present invention or the intermediates of the present invention include stereoisomers and optically active compounds, 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, Z-form and E-form
Although the body exists, the present invention includes them all.

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

A compound having both lipid peroxide production inhibitory action and protein stabilizing action is considered to be particularly useful for cataracts, but no studies have been conducted on compounds having both of these actions, and The development of such compounds has been desired.

Therefore, as a result of diligent investigations by the present inventors, the 4-position of 1,4-thiazine or thiomorpholine was substituted with an acidic group such as carboxyl group, tetrazolyl group, phosphonic acid or sulfonic acid. It has been found that a compound in which the phenyl ring of the benzylidene group is substituted with a hydroxy group and a lower alkyl group has an action of suppressing lipid peroxide formation and a protein stabilizing action.

The present invention is mainly composed of the novel compound having the above-mentioned chemical structure, but it goes without saying that the hydroxy group may be protected by a protecting group which is widely used as a protecting group for the hydroxy group, and a carboxyl group, The phosphonic acid group and the sulfonic acid group may be converted into an ester or amide form, or may be introduced into a salt.

These protecting groups and derivatives are used according to various purposes such as synthetic means, compound stabilization, and prodrug formation.

The structural characteristics of the compound of the present invention are as described above. When R ¹ is a hydroxy group protected by a protecting group, the group is 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 methyl group, isopropyl group or te
rt.-butyl group is preferable, isopropyl group or tert.-
A butyl group is 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. Of these, an isopropyl group or a tert.-butyl group is particularly preferable. R ⁴ is more preferably a carboxyl group, a tetrazolyl group or a phosphonic acid group, but a preferable example in the case where the carboxyl group or the phosphonic acid group is converted into an ester or an amide includes a lower alkyl ester in the case of an ester. 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.
The alkylene group of 6 is preferable, and a methylene group or an ethylene group is more preferable.

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

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

[In the general formula [I], 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, tetrahydro. A pyranyloxy group or a trimethylsilyloxy group is shown.

R ² represents a lower alkyl group.

R ³ is hydrogen atom, lower alkyl group, hydroxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydropyrani Is a hydroxy group, a lower alkanoyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, a benzyloxy group. 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 into an ester with lower alkyl or aryl lower alkyl; a carboxyl group which may be converted into an amide with ammonia, lower alkylamine or aryl lower amine; tetrazolyl group; Phosphonic acid group which may be converted to ester with lower alkyl or aryl lower alkyl; Phosphonic acid group which may be converted to amide with ammonia, lower alkylamine or aryl lower amine; Lower alkyl or aryl lower alkyl Or a sulfonic acid group which may be converted to an ester thereof; or 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.

---- represents a single bond or a double bond. ]
The compound [Ia] represented by or a salt thereof.

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 lower alkyl; a carboxyl group which may be converted to an amide with ammonia or a lower alkylamine; a tetrazolyl group; Optionally a phosphonic acid group; or a sulfonic acid group optionally converted to an ester with lower alkyl.

B represents C = O, C = S or CH ₂ .

A represents an alkylene group.

---- represents a single bond or a double bond. ]
A compound represented by 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 a lower alkyl; a carboxyl group which may be converted to an amide with ammonia or a lower alkylamine; a tetrazolyl group; or an ester with a lower alkyl B, which represents an optionally substituted phosphonic acid group, represents C = O, C = S or CH ₂ .

A represents an alkylene group.

---- represents a single bond or a double bond. ]
The compound [Ib] represented by or a salt thereof.

In the above compound [Ib], R ¹ is hydroxy group or acetyloxy group; R ² is methyl group, isopropyl group or t-butyl group; R ³ is hydrogen atom, methyl group, isopropyl group, t- A butyl group or a methoxy group; a carboxyl group in which R ⁴ may be converted into a methyl or ethyl ester; a tetrazolyl group; a phosphonic acid group in which R ⁴ may be converted into an ethyl ester; B is C =
O, C = S or CH ₂ , especially C = O; A is a methylene group or an ethylene group, especially a methylene group; ---- is preferably a single bond, and 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; R ⁴ is converted to an amide with ammonia or methylamine 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.

Among the compounds of the present invention, R ¹ is a hydroxy group; R ² is a lower alkyl group; R ³ is a lower alkyl group; R
⁴ is a carboxyl group, tetrazolyl group or phosphonic acid group; B is C = O; A is an alkylene group; ---- is a compound having a single bond or a double bond, especially R ¹ is a hydroxy group; R ² is t- Butyl group; R ³ is t-butyl group; R ⁴ is carboxyl group, tetrazolyl group or phosphonic acid group;
A compound in which B is C = O; A is a methylene group; ---- is a single bond or a double bond is preferable.

Of 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.

Further, among the above compounds [Ia], R ⁴
A carboxyl group which may be converted into an ester with lower alkyl; a carboxyl group which may be converted into an amide with ammonia or a lower alkylamine; a tetrazolyl group; a phosphone which may be converted into 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 A carboxyl group which may be converted; a tetrazolyl group; a phosphonic acid group which may be converted to an ethyl ester is more preferable,
It is particularly preferable that R ⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group.

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 preferable.

More specifically, in the above compound [Ia], R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group; R ² is a lower alkyl group; R ³
Is a hydrogen atom, a lower alkyl group or a lower alkoxy group, the lower alkyl group is preferably a hydroxy group, a tetrahydropyranyloxy group, an amino group or a group which may be substituted with a lower alkylamino group,
More preferably, R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group; R ² is a lower alkyl group; R ³ is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ¹ is a hydroxy group or acetyloxy. Group; R ² is a methyl group, an isopropyl group or t
-Butyl group; 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; R
Most preferably, ³ is a t-butyl group.

Examples of the intermediate of the present invention include [in the general formula [II],
R ¹ represents a hydroxy group, a lower alkanoyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, a benzyloxymethyloxy group, a tetrahydropyranyloxy group or a trimethylsilyloxy group.

R ² represents a lower alkyl group.

R ³ is hydrogen atom, lower alkyl group, hydroxy group, lower alkanoyloxy group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkoxymethyloxy group, benzoyloxy group, benzyloxymethyloxy group, tetrahydropyrani Is a hydroxy group, a lower alkanoyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkoxymethyloxy group, a benzoyloxy group, a benzyloxy group. 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. ]
The compound represented by or a salt thereof is preferable, and 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. ]
More preferably a compound represented by or a salt thereof,
[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. ]
The compound represented by or a salt thereof is particularly preferable.

As the intermediate of the present invention, R ¹ is a hydroxy group, an acetyloxy group or a methoxymethoxy group; R ²
Is a methyl group, an isopropyl group or a t-butyl group; R ³
Is most preferably 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 investigate the action and effect of the compound of the present invention, first, an experiment was conducted to examine the protein stabilizing action using bovine serum albumin.

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

Next, in order to examine the inhibitory effect of the compound 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 inhibitory effect on lipid peroxide production.

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

Further, the compounds of the present invention are described in Kato et al. (Ch
As a result of an experiment according to em. Pharm. Bull., 33 , 74-83 (1985)), it was found that it also has an aldose reductase inhibitory action. This finding further supports that the compound of the present invention is excellent as a therapeutic agent for cataracts, and also shows that it is expected as a therapeutic agent for diabetic complications.

Also, it has been reported that a compound having a protein stabilizing action and a lipid peroxide production inhibiting action is an anti-inflammatory agent (Lancet, 1, 169 (1965); Biochem Biophys.
Acta.489, 163 (1977)), the compound of the present invention is expected to be useful as an anti-inflammatory agent. The compound of the present invention is orally
It can also be administered parenterally. As the dosage form,
Tablets, capsules, granules, powders, injections, eye drops and the like can be mentioned, and they can be formulated using a commonly used technique. For example, oral preparations such as tablets, capsules, soft capsules and granules may be supplemented with lactose, starch, crystalline cellulose, extenders such as vegetable oil, lubricants such as magnesium stearate and talc, hydroxypropyl, etc. It can be formulated using a binder such as cellulose or polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose calcium, a coating agent such as hydroxypropylmethylcellulose, or the like. If it is an eye drop,
It can be formulated using an isotonicity agent such as sodium chloride, a buffering agent such as sodium phosphate, a solubilizing agent such as polysorbate 80, a preservative such as benzalkonium chloride and the like.

The dose may be appropriately selected depending on the symptoms, age, dosage form, etc., but usually 1 to 5000 m / day for oral preparations.
g, preferably 1-1000 mg, can be administered once or in several divided doses. If it is an eye drop, 0.0
01% to 10%, preferably 0.01 to 5%
It may be applied once to several times a day.

The production examples and formulation examples of the compound of the present invention are shown below, but these examples are for the purpose of 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)

[Chemical 15] A solution of diisopropylamine (24.3 ml) in tetrahydrofuran (120 ml) was placed in a nitrogen atmosphere at -70 ° C.
Then, a solution of n-butyllithium in n-hexane (1.6
M, 95 ml) is added dropwise. After stirring at −70 ° C. for 1 hour, 1,4-thiazin-3-one (5.0 g) was added to the reaction solution.
Tetrahydrofuran solution (20 ml) was added dropwise, and the mixture was stirred at the same temperature for an additional 1 hour, and then 3,5-di-tert.-butyl-
A solution of 4-hydroxybenzaldehyde (10.2 g) in tetrahydrofuran (20 ml) -hexamethylphosphoric triamide (100 ml) mixed solution is added dropwise. -70 °
After stirring at 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 brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 7.6 g of the title compound.
(50%) is obtained.

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

By using the same method as in Reference Example 1, the following compounds are 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)

[Chemical 16] In a solution of diisopropylamine (71.8 ml) in tetrahydrofuran (400 ml), in a nitrogen atmosphere at -70 ° C.
Then, a solution of n-butyllithium in n-hexane (1.6
M, 320 ml) is added dropwise. After stirring at -70 ° C for 50 minutes, thiomorpholin-3-one (20.0
A solution of g) in tetrahydrofuran (200 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour, and then 3,5-di-tert.-.
Butyl-4-hydroxybenzaldehyde (40.0
A solution of a mixture of g) of tetrahydrofuran (50 ml) -hexamethylphosphoric triamide (200 ml) is added dropwise. After stirring at -70 ° C for 2 hours, diluted hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 24.17 g (40%) of an erythro compound and 2.84 g (5%) of a threo compound of the title 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

Threo Form 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

By using the same method as in Reference Example 2, the following compounds are obtained.

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

Threo body 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 form m.p. 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

Threo Form 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 derivative IR (KBr, cm ⁻¹ ): 3494, 3360 , 298
6,1670,1644,1613,1466,130
2,1221,1090,852,677

Threo Form m. p. 173.0 to 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)

[Chemical 17] 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 To a mixed solution of (5 ml), triethylamine (0.24 ml) and methanesulfonic acid chloride (0.07 ml) were added under ice cooling. After stirring for 15 minutes under ice-cooling, diluted hydrochloric acid is added to the reaction solution, and extracted with chloroform. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oily substance was purified by silica gel column chromatography to give 0.19 g (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 and the same method as in Reference Example 3, the following compounds are obtained.

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)

[Chemical 18] 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) thiomorpholin-3-one erythro derivative (reference compound 2-1, 10.0 g) methylene chloride (4
(0 ml) -tetrahydrofuran (40 ml) mixed solution was added with triethylamine (11.9 ml) and methanesulfonic acid chloride (3.3 ml) under ice cooling. After stirring under ice-cooling for 1 hour, diluted hydrochloric acid was added to the reaction solution and extracted with chloroform. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 8.13 g (87%) of the title compound. m. p. 192-196 ° 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 starting materials and the same method as in Reference Example 4, the following compounds are obtained.

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)

[Chemical 19] 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 placed under a nitrogen atmosphere. , 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 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily substance obtained is 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
0,2965,2872,1757,1725,167
2,1631, 1457, 1372, 1335, 131
9,1306,1244,1213

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

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)

[Chemical 20] 2- (α, 4-dihydroxy-3,5-diisopropylbenzyl) thiomorpholin-3-one (reference compound 2
Pyridine (15.00 ml) is added to a suspension of −2,2.00 g) in methylene chloride (20 ml), and the mixture is stirred at 40 ° C. for 8 hours. The reaction solution is poured into IN hydrochloric acid under ice cooling and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.99 g of the title compound (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 starting materials and the same method as in Reference Example 6, the following compounds are obtained.

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. 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. 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)

[Chemical 21] Aluminum chloride (0.34 g) is added to a suspension of lithium aluminum hydride (0.29 g) in diethyl ether (8 ml) 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 brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance 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)

[Chemical formula 22] A suspension of sodium hydride (60% mineral oil suspension, 0.96 g) in tetrahydrofuran (20 ml) was added to 2- (3,5-di-te) under ice-sodium chloride cooling under a nitrogen atmosphere.
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) was added to the reaction solution. After stirring at room temperature for 3 hours, water was added to the reaction solution,
Extract with ethyl acetate. The organic layer was washed with saturated saline,
After drying over anhydrous magnesium sulfate, it is concentrated under reduced pressure. The resulting oily matter 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 Reference Compound 4-2 as a starting material and the same method as in Example 1, the following compound is obtained.

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)

[Chemical formula 23] 2- (3,5-di-ter) was added to a suspension of sodium hydride (60% mineral oil suspension, 0.06 g) in tetrahydrofuran (2 ml) under ice-sodium chloride cooling under a nitrogen atmosphere.
t.-Butyl-4-hydroxybenzylidene) -1,4-
Thiazin-3-one (reference compound 3-1 and 0.23 g)
Tetrahydrofuran solution (5 ml) of is added dropwise. After stirring at room temperature for 10 minutes, a solution of methoxymethyl chloride (0.1 ml) in tetrahydrofuran (1 ml) was 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Using Reference Compound 3-2 as a starting material and the same method as in Example 2, the following compounds are obtained.

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)

[Chemical formula 24] 2- (α, 4-diacetoxy-3,5-diisopropyl) was added to a suspension of sodium hydride (60% mineral oil suspension, 0.14 g) in tetrahydrofuran (3 ml) under ice-sodium chloride cooling under a nitrogen atmosphere. 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Using the reference compounds 6-2 to 6-6 as starting materials and the same method as in Example 3, the following compounds can be obtained.

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)

[Chemical 25] 2- (α, 4-diacetoxy-3,5-diisopropyl) was added to a suspension of sodium hydride (60% mineral oil suspension, 0.16 g) in tetrahydrofuran (3 ml) under cooling with ice-sodium chloride in a nitrogen atmosphere. 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) was 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Using the reference compounds 5-2 to 5-6 as starting materials and the same method as in Example 4, the following compounds can be obtained.

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)

[Chemical formula 26] 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxymethylthiomorpholine-3-
To a solution of on (compound 3-1, 0.83 g) in tetrahydrofuran (18 ml), an aqueous solution (14 ml) of lithium hydroxide monohydrate (0.89 g) was added dropwise under ice cooling. 1
After stirring for an hour, hydrochloric acid is added to the reaction solution to make it acidic, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Using the compounds 3-3 to 3-6 as starting materials and the same method as in Example 5, the following compounds can be obtained.

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)

[Chemical 27] 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxymethyl-1,4-thiazine-3
An aqueous solution (11 ml) of lithium hydroxide monohydrate (0.45 g) was added dropwise to a tetrahydrofuran (14 ml) solution of -one (compound 4-1, 0.42 g) under ice cooling.
After stirring for 1 hour, hydrochloric acid is added to the reaction solution to make it acidic, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Using the compounds 4-3 to 4-6 as starting materials and the same method as in Example 6, the following compounds can be obtained.

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)

[Chemical 28] 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 cooling with sodium chloride,
Trimethylsilyl iodide (1.9
7 g) is added dropwise. After stirring for 15 minutes, triethylphosphite (5.4 ml) is added dropwise to the reaction solution. After stirring for 10 minutes, water is added to the reaction solution and extracted with chloroform.
The organic layer is washed with saturated brine, 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. 159.3-162.0 ° C IR (KBr, cm ^-1 ): 3120, 2952, 163
6,1572,1472,1437,1340,126
3,1203,1013

Using the compounds 5-1, 5-2, 5-3, 5-5 as starting materials and the same method as in Example 7, the following compounds can be obtained.

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 )

[Chemical 29] Sodium hydride (60% mineral oil suspension, 0.026g)
In a tetrahydrofuran (1 ml) suspension of 2- (3,5-di-te in a nitrogen atmosphere under ice-sodium chloride cooling.
rt.-Butyl-4-hydroxybenzylidene) -1,4-
Thiazin-3-one (reference compound 3-1, 0.099
A solution of g) in tetrahydrofuran (1.4 ml) is added dropwise. After stirring at room temperature for 20 minutes, a solution of 2-bromoethylphosphoric acid diethyl ester (0.096 g) in tetrahydrofuran (1 ml) was added to the reaction solution. After stirring at room temperature for 4 hours, an aqueous solution of ammonium chloride is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to give the title compound (0.
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 starting materials, the following compounds can be 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)

[Chemical 30] 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 5.8N hydrochloric acid (28 ml). After stirring at room temperature for 1 hour, the reaction solution is poured into diluted hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate,
Concentrate under reduced pressure. The obtained oily substance 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
Four

Using the compounds 7-2 to 7-5 as starting materials and the same method as in Example 9, the following compounds can be obtained.

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)

[Chemical 31] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1 was added to a suspension of sodium hydride (60% mineral oil suspension, 0.19 g) in tetrahydrofuran (5 ml) under a nitrogen atmosphere. , 4-thiazin-3-one (reference compound 3-1, 0.80 g) in tetrahydrofuran (15
ml) solution is added. After stirring at room temperature for 20 minutes, bromoacetonitrile (0.34 ml) is added to the reaction solution. After stirring for 15 hours at room temperature, 1N hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily substance obtained is 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 starting materials and the same method as in Example 10, the following compounds can be obtained.

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)

[Chemical 32] 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 in a nitrogen atmosphere under nitrogen.
-Butyllithium (1.6M, 3.74ml) 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance 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

By using the reference compounds 4-1 to 4-3 as starting materials and the same method as in Example 11, the following compounds can be obtained.

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)

[Chemical 33] 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) -in a tetrahydrofuran (2 ml) suspension of sodium hydride (60% mineral oil suspension, 0.12 g) in a nitrogen atmosphere under ice cooling. A solution of 1,4-thiazin-3-one (reference compound 5-1 and 1.00 g) in tetrahydrofuran (12 ml) is added dropwise. After stirring for 15 minutes at room temperature, 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. The organic layer was washed with saturated saline,
After drying over anhydrous magnesium sulfate, it is concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.70 g (74%) of the title compound.

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

By using the reference compounds 5-2 to 5-6 as starting materials and the same method as in Example 12, the following compounds are obtained.

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)

[Chemical 34] 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) thiomorpholine-3 was added to a suspension of sodium hydride (60% mineral oil suspension, 0.32 g) in tetrahydrofuran (15 ml) under a nitrogen atmosphere. Tetrahydrofuran (15 m) of -one (reference compound 6-1, 1.50 g)
l) Add the solution dropwise. After stirring at room temperature for 1 hour, bromoacetonitrile (0.52 ml) was added to the reaction solution and the mixture was stirred at 60 ° C for 2 hours. The reaction solution is cooled, poured into a dilute salt, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance 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, 2253, 1759, 1641, 1
590, 1573, 1470, 1435, 1421, 1
385,1370

By using the reference compounds 6-2 to 6-6 as starting materials and the same method as in Example 13, the following compounds can be obtained.

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. 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. 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)

[Chemical 35] 4-Cyanomethyl-2- (3,5-di-tert.-butyl-
4-hydroxybenzylidene) -1,4-thiazine-3
Sodium azide (0.1 ml) was added to dimethylformamide (10 ml) solution of -one (compound 10-1, 0.40 g).
4 g) and ammonium chloride (0.12 g) are added. After stirring at 110 ° C for 2 hours, saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 0.22 g of the title compound.
(49%) is obtained.

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
Two

Compounds 10-2, 10-5, 10-6, 1
Using 2-1 to 12-6 and 29-1 as raw materials and the same method as in Example 14, the following compound can be obtained.

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)

[Chemical 36] 4-Cyanomethyl-2- (3,5-di-tert.-butyl-
4-Hydroxybenzylidene) thiomorpholine-3-
Sodium azide (73 mg) was added to a solution of one (compound 11-1, 0.29 g) in dimethylformamide (7 ml).
And ammonium chloride (60 mg) are added. 110
After stirring at ° C for 8 hours, saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to obtain 0.14 g (41.4 g) of the title compound.
%).

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
Four

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

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. p. 197.3-198.5 ° 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 higher 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
Four

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)

[Chemical 37] 2- (3,5-di-tert.-butyl-4-hydroxy) was added to a suspension of sodium hydride (60% mineral oil suspension, 0.05 g) in tetrahydrofuran (2 ml) under ice cooling under a nitrogen atmosphere. 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) was added to the reaction solution. 6
After stirring at 0 ° C for 2 days, diluted hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance 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

By using the same method as in Example 16, the following compound is 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)

[Chemical 38] 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl)-in a tetrahydrofuran (3 ml) suspension of sodium hydride (60% mineral oil suspension, 0.12 g) in a nitrogen atmosphere under ice cooling. A solution of 1,4-thiazin-3-one (reference compound 5-1 and 1.00 g) in tetrahydrofuran (10 ml) is added dropwise. After stirring at room temperature for 10 minutes, methyl bromoacetate (0.23 ml) was added to the reaction solution. After stirring at room temperature for 1 hour, diluted hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to obtain 0.95 g (92%) of the title compound. m. p. 126.4-133.5 ° 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
Four

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

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)

[Chemical Formula 39] 2- (α, 4-diacetoxy-3,5-diisopropylbenzyl) thiomorpholine-3 was added to a suspension of sodium hydride (60% mineral oil suspension, 0.15 g) in tetrahydrofuran (5 ml) under a nitrogen atmosphere. Tetrahydrofuran of 12-one (reference compound 6-1, 0.70 g) (12 m
l) Add the solution dropwise. After stirring at room temperature for 40 minutes, methyl bromoacetate (0.18 ml) was added to the reaction solution, and the mixture was stirred at 60 ° C for 3 days. The reaction solution is cooled, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.65 g, 90%).

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
Three

By using the reference compounds 6-1 to 6-6 as starting materials and in the same manner as in Example 18, the following compounds are obtained.

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)

[Chemical 40] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1 was added to a suspension of sodium hydride (60% mineral oil suspension, 0.53 g) in tetrahydrofuran (10 ml) under a nitrogen atmosphere. , 4-thiazin-3-one (reference compound 3-1, 2.00 g) in tetrahydrofuran (25
ml) solution is added dropwise. After stirring for 40 minutes at room temperature, ethyl bromoacetate (0.74 ml) is added to the reaction solution. After stirring for 15 minutes at room temperature, diluted hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is dissolved in tetrahydrofuran (10 ml), and after cooling to 0 ° C., 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily substance 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

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

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)

[Chemical 41] 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.
Aqueous solution (10 ml) is added dropwise. After stirring for 2 hours, hydrochloric acid is added to the reaction solution to make it acidic, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.62 g, 81%).

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 compounds 17-4 to 17-8 as starting materials and the same method as in Example 20, the following compounds can be obtained.

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)

[Chemical 42] 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 with ice. An aqueous solution (2 ml) of lithium hydroxide monohydrate (0.76 g) was added dropwise under cooling. After stirring for 1 hour, hydrochloric acid is added to the reaction solution to make it acidic, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.56 g, 79%).

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 raw 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. p. 151.7-152.8 ° 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. 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)

[Chemical 43] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethylthiomorpholin-3-one (Compound 16-1, 0.69 g) in toluene (40 ml) was added to Lawson's reagent. (1.38g)
Add. After refluxing for 15 hours, the reaction solution is concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.25 g (35%) of the title compound.

M. p. 136.4 to 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
Three

Using the compounds 18-1, 18-4 to 18-8 as starting materials and the same method as in Example 22, the following compounds can be obtained.

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)

[Chemical 44] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-methoxycarbonylmethyl-3-thioxothiomorpholine (Compound 22-1, 0.16 g)
In tetrahydrofuran (5 ml) of water under ice-cooling, lithium hydroxide monohydrate (0.16 g) in water (4 ml)
And methanol (3 ml) are added. After stirring for 15 minutes at room temperature, 6N hydrochloric acid is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.12 g, 77).
%).

M. p. 200-208 ° 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 and the same method as in Example 23, the following compounds can be obtained.

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)

[Chemical formula 45] 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. , 4-thiazin-3-one (reference compound 3-1, 0.20 g) in dimethylformamide (2
ml) solution is added dropwise. After stirring at room temperature for 10 minutes, a solution of chloromethanesulfonic acid (0.20 g) in dimethylformamide (1 ml) was added to the reaction solution. After stirring overnight at 50 ° C, 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Example 24 Using Reference Compound 4-1 as a Starting Material
The following compounds are obtained using a method similar to.

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)

[Chemical formula 46] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) thiomorpholine (reference compound 7-1,0.
To a solution of dimethylformamide (8 ml) in 60 g) potassium carbonate (0.26 g) and methyl bromoacetate (0.
20 ml) is added. 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 brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 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)

[Chemical 47] 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 with water under ice cooling. Lithium oxide 1
An aqueous solution of the hydrate (1.98 g) (13 ml) and methanol (3 ml) are added. After stirring for 15 minutes at room temperature, 6N hydrochloric acid is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.25 g, 35%).

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)

[Chemical 48] 2- (4-acetoxy-3,5-diisopropylbenzylidene) -4-methoxycarbonylmethyl-1,4-thiazin-3-one (Compound 17-1, 0.1 g) was added to a solution of ammonia in methanol (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 solution is concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained oily substance 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 Using a method similar to that in Example 27, the following compound is obtained.

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)

[Chemical 49] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -4- (2-phosphonoethyl) -1,4-thiazin-3-one diethyl ester (Compound 8-1,
5.8N to a solution of 0.50g) in dioxane (20ml).
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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain the title compound.

Using the compounds 8-2 to 8-9 as starting materials and the same method as in Example 28, the following compounds can be obtained.

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)

[Chemical 50] 2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -1 was added to a suspension of sodium hydride (60% mineral oil suspension, 0.24 g) in tetrahydrofuran (5 ml) under a nitrogen atmosphere. , 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 0.76 g of the title compound.
(66%).

M. p. 160.5-164.8 ° 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)

[Chemical 51] 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) were added,
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 brine and dried over anhydrous magnesium sulfate,
Concentrate under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.56 g (72%) of the title compound. m. p. 101.7-102.6 ° 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)

[Chemical 52] 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) solution under ice-cooling lithium hydroxide monohydrate (0.50 g) in water (8 m).
l) Add solution and methanol (1 ml) and stir for 50 minutes. Dilute hydrochloric acid is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily substance was purified by silica gel column chromatography to give 0.37 g (7%) of the title compound.
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 Example] The following is an example of the formulation of the compound of the present invention.

[0360]

[0361]

[0362]

(Ophthalmic Solution) Formulation 1 In 100 ml The compound of the present invention 0.5 g Concentrated glycerin 1.5 g Polyoxyethylene hydrogenated castor oil 1.0 g Benzalkonium chloride 0.005 g Sodium edetate 0.01 g Dilute hydrochloric acid Adequate amount Sodium hydroxide Adequate amount Sterile purified water

Formulation 2 In 100 ml 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 Appropriate sodium hydroxide Appropriate sterile purified water Appropriate amount

Formulation 3 In 100 ml 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 Sodium hydroxide qs Sterile purified water qs

(Eye ointment) In 100 g 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 action and a lipid peroxide production inhibiting action were examined.

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

Therefore, the protein-stabilizing action of the compound of the present invention was examined according to the method described in the above literature.

(Experimental method) 0.2% bovine serum albumin (manufactured by Sigma) was added to a concentration of 0.75% under ice cooling.
It was dissolved in M potassium phosphate buffer (pH 5.3).
To 2.7 ml of this albumin solution was added 0.3 ml of a dimethyl sulfoxide solution in which the test compound was dissolved, and the mixture was stirred and allowed to stand for about 15 minutes to return to room temperature. After reacting the solution in a water bath at 67 ° C for 2 minutes with shaking,
The reaction was stopped by cooling with ice. After returning the reaction solution to room temperature, the absorbance caused by the cloudiness 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 without addition of test compound A ₁ : Absorbance with addition of test compound

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

[0373]

[Table 1] The compound of the present invention obviously suppresses thermal aggregation of protein,
It showed an excellent protein stabilizing effect.

2. Lipid peroxide production inhibitory effect (experimental method) 0.04M Tris buffer containing a test compound (containing 0.09M 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) and reacted at 37 ° C for 15 minutes, and the produced lipid peroxide was quantified by the TBA method (Biochem. Med., 15, 212 (1976)).

(Results) The obtained results are shown in Table 2.

[0376]

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

As shown by the results of the above pharmacological tests, the compound of the present invention has a protein stabilizing action and a lipid peroxide production inhibiting action, and is expected to be an excellent therapeutic agent for cataract. .

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C07F 9/6544 9155-4H

Claims (39)

[Claims] 1. A compound represented by the following general formula [I] or a salt thereof. [Chemical 1] [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 which may be protected by a protecting group or a lower alkoxy group, wherein the lower alkyl group may be a hydroxy group which may be protected by a protecting group, an amino group or a lower alkyl group. It may be substituted with an amino group. R ⁴ represents a carboxyl group which may be converted into an ester or amide; a tetrazolyl group; a phosphonic acid group which may be converted into an ester or amide; or a sulfonic acid group which may be converted into an ester or amide. B is C = O, C = S or C
Indicates H ₂ . A represents an alkylene group. ---- represents a single bond or a double bond. ] 2. A compound represented by the following general formula [I] or a salt thereof. [Chemical 2] [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. Indicates 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 into an ester with lower alkyl or aryl lower alkyl; a carboxyl group which may be converted into an amide with ammonia, lower alkylamine or aryl lower amine; tetrazolyl group; lower alkyl or aryl Phosphonic acid group optionally converted to ester with lower alkyl; Phosphonic acid group optionally converted to amide with ammonia, lower alkylamine or aryl lower amine; Converted to ester with lower alkyl or aryl lower alkyl A sulfonic acid group which may be converted; or 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. ---- represents a single bond or a double bond. ] 3. A compound represented by the following general formula [I] or a salt thereof. [Chemical 3] [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 a lower alkyl; a carboxyl group which may be converted to an amide with ammonia or a lower alkylamine; a tetrazolyl group; which may be converted to an ester with a lower alkyl A good phosphonic acid group; or a sulfonic acid group which may be converted into an ester with a lower alkyl. B is C
═O, C═S or CH ₂ . A represents an alkylene group. ---- represents a single bond or a double bond. ] 4. A compound represented by the following general formula [I] or a salt thereof. [Chemical 4] [In the formula, 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 a carboxyl group which is converted to an ester with lower alkyl B which represents a good phosphonic acid group is C =
Indicates O, C = S or CH ₂ . A represents an alkylene group. ---- represents a single bond or a double bond. ] 5. R ¹ is a hydroxy group or acetyloxy group; R ² is a methyl group, isopropyl group or t-butyl group; R ³ is a hydrogen atom, methyl group, isopropyl group, t-
A butyl group or a methoxy group; a carboxyl group in which R ⁴ may be converted into a methyl or ethyl ester; a tetrazolyl group; a phosphonic acid group in which R ⁴ may be converted into an ethyl ester; B is C═O, C═S or CH _2. A compound or a salt thereof according to claim 4, wherein A is a methylene group or an ethylene group; and ---- is a single bond. 6. R ¹ is a hydroxy group or an acetyloxy group; R ² is a methyl group, isopropyl group or t-butyl group; R ³ is a hydrogen atom, a methyl group, an isopropyl group, t-
A butyl group or a methoxy group; a carboxyl group in which R ⁴ may be converted into a methyl or ethyl ester; a tetrazolyl group; a phosphonic acid group in which R ⁴ may be converted into an ethyl ester; B is C═O; A is a methylene group; The compound or salt thereof according to claim 4, wherein ---- is a single bond. 7. 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; and R ⁴ is a methyl or ethyl ester. Good carboxyl group; carboxyl group which may be converted to amide with ammonia or methylamine; tetrazolyl group;
A phosphonic acid group which may be converted to an ethyl ester;
The compound or salt thereof according to claim 4, wherein B is C = O; A is a methylene or ethylene group; and ---- 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; A is The compound or salt thereof according to claim 4, wherein the methylene group; ---- is a single bond. 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 ; A is methylene. The compound or salt thereof according to claim 4, wherein the group; ---- is a single bond. 10. A compound represented by the following general formula [I] or a salt thereof. [Chemical 5] [In the formula, 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; A is a methylene group. ; ---- is a single bond or a double bond.
The compound of 0 or its salt. 12. The compound or a salt thereof according to claim 2, wherein R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group. 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 or a salt thereof according to claim 2, wherein R ¹ is a hydroxy group or an acetyloxy group. 15. The compound or a salt thereof according to claim 2, wherein R ¹ is a hydroxy group. 16. A carboxyl group in which R ⁴ may be converted into an ester with lower alkyl; a carboxyl group which may be converted into an amide with ammonia or a lower alkylamine; a tetrazolyl group; The compound or salt thereof 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 a lower alkyl. 17. A carboxyl group 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; which may be converted to an ethyl ester. The compound or salt thereof according to claim 2, which has a good phosphonic acid group. 18. The compound or a salt thereof according to claim 2, wherein R ⁴ is a carboxyl group, a tetrazolyl group or a phosphonic acid group. 19. The compound according to claim 2, wherein B is C═O, or a salt thereof. 20. The compound or salt thereof according to claim 2, wherein ---- is a single bond. 21. The compound or salt thereof according to claim 2, wherein ---- is a double bond. 22. R ¹ is a hydroxy group, a lower alkanoyloxy group or a benzoyloxy group; R ² is a lower alkyl group; R ³ is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the lower alkyl group is a hydroxy group. The compound according to claim 2, which is a group which may be 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 group or acetyloxy group; R ² is methyl group, isopropyl group or t-butyl group; R ³ is hydrogen atom, methyl group, isopropyl group, t
-The compound or salt thereof according to claim 2, which is a butyl group or a methoxy group. 25. The compound according to claim 2, wherein R ¹ is a hydroxy group; R ² is a t-butyl group; R ³ is a t-butyl group, or a salt thereof. 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. [Chemical 6] [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 which may be protected by a protecting group or a lower alkoxy group, wherein the lower alkyl group may be a hydroxy group which may be protected by a protecting group, an amino group or a lower alkyl group. It may be substituted with an amino 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. ] 33. A compound represented by the following general formula [II] or a salt thereof. [Chemical 7] [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. Indicates 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 =
Indicates O, C = S or CH ₂ . A represents an alkylene group. ---- represents a single bond or a double bond. ] 34. A compound represented by the following general formula [II] or a salt thereof. [Chemical 8] [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. ---- represents a single bond or a double bond. ] 35. A compound represented by the following general formula [II] or a salt thereof. [Chemical 9] [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.
---- represents a single bond or a double bond. ] 36. R ¹ is a hydroxy group, acetyloxy group or methoxymethoxy group; R ² is a methyl group, isopropyl group or t-butyl group; R ³ is a hydrogen atom, methyl group, isopropyl group or t-butyl group; The compound or salt thereof according to claim 35, wherein R ⁵ is a cyano group or a methoxy group; A is a methylene or ethylene 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.