JP2840800B2 - 1,4-benzothiazine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 1,4-benzothiazine derivative having a lipid peroxide production inhibitory action and an intermediate for synthesizing the same.

[0002]

2. Description of the Related Art As a compound having a benzylidene group at the 2-position of a 1,4-benzothiazine derivative, a compound intended for a herbicide (US Pat. No. 3,923,709) and a compound intended for a tranquilizer (Japanese Patent Publication No. 49-1067)
1) and those which are intermediates for the synthesis of benzothiazepine derivatives (JP-A-60-72875) have been reported.

[0003] However, these patents do not disclose a compound having an inhibitory action on lipid peroxide production, which is the object of the present invention.

[0004] On the other hand, Japanese Patent Application Laid-Open No. 1-287077 also discloses a compound having an action of inhibiting the production of lipid peroxide. However, the compound described in this patent has no substituted or lower nitrogen atom of benzothiazine. It is substituted with an alkyl group and has a different structure from the compound of the present invention.

[0005]

SUMMARY OF THE INVENTION The present inventors are ranked 3rd and 5th.
Attention was paid to the fact that toluene derivatives having a tert.-butyl group at the 4-position and a hydroxy group at the 4-position have an antioxidant effect. Because antioxidants have the effect of suppressing the production of lipid peroxides,
The phenyl ring of the benzylidene group is substituted with a tert.-butyl group and a hydroxy group as substituents of this compound, and various novel 1,4-benzothiazine derivatives having the benzylidene group at the 2-position are synthesized to obtain excellent lipid peroxidation. The present inventors have conducted intensive studies in order to find a compound having a product formation inhibitory action.

[0006]

As a result, the 3- and 5-positions of the phenyl ring of the benzylidene group are tert.-butyl groups and the 4-position is a hydroxy group, and the nitrogen atom of the benzothiazine derivative is substituted with an acyl group or the like. It has been found that the obtained compound has an excellent lipid peroxide production inhibitory action.

[0007]

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

[0008]

Embedded image [Wherein, R ¹ represents a hydroxy group or a hydroxy group having a protecting group.

R ² represents an acyl group or -AR ³ .

R ³ is a hydroxy group, a lower alkoxy group,
It represents an amino group, a lower alkylamino group or a tetrahydropyranyloxy group.

A represents a linear or branched lower alkylene group. ]

Embedded image [Wherein, R ¹ represents a hydroxy group or a hydroxy group having a protecting group.

R ² represents an acyl group or -AR ³ .

R ³ is a hydroxy group, a lower alkoxy group,
It represents an amino group, a lower alkylamino group or a tetrahydropyranyloxy group.

A represents a linear or branched lower alkylene group. When the groups defined above are described in more detail,
Lower alkyl refers to alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, tert.-butyl and hexyl, and lower alkoxy refers to carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and hexyloxy. 1 to 6 alkoxy groups, wherein the acyl group is acetyl, propanoyl, isopropanoyl, pivaloyl,
A lower alkylcarbonyl having 2 to 6 carbon atoms such as hexanoyl or an arylcarbonyl such as phenylcarbonyl; a linear or branched lower alkylene is methylene, ethylene, propylene, tetramethylene, hexamethylene, (dimethyl) methylene, It represents an alkylene group having 1 to 6 carbon atoms such as (diethyl) methylene.

The protecting group for the hydroxy group represented by R ¹ includes lower alkylsulfonyl such as methanesulfonyl, arylsulfonyl such as benzenesulfonyl and p-toluenesulfonyl, lower alkanoyl such as acetyl and propionyl, methoxymethyl and methoxyethoxymethyl. And benzoyl, benzyloxymethyl, trimethylsilyl and the like which are commonly used as protecting groups for phenolic hydroxy groups.

The compounds of the present invention can also form salts with acids. Examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as lactic acid, maleic acid, fumaric acid, and oxalic acid.

A typical method for synthesizing the compound of the present invention is as follows:
The following are mentioned.

1)

Embedded image [Wherein, R1 and R2 have the same meaning as described above. By reacting the compound represented by the formula [III] with the compound represented by the formula [IV], a synthetic intermediate represented by the formula [II] is obtained. Next, the compound of the present invention represented by the general formula [I] can be obtained by dehydrating this compound. The compound represented by the formula [III] can be synthesized according to the method described in JP-A-48-34874.

2)

Embedded image [In the formula, X represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group. , R1 and R2 have the same meaning as described above. By reacting the compound represented by the formula [V] with the compound represented by the formula [VI] in the presence of a base, the compound of the present invention represented by the general formula [I] can be obtained. The compound represented by the formula [V] can be synthesized according to the method described in JP-A-1-287077.

The hydroxy group represented by R ¹ may be protected by the above-mentioned protecting group according to a method generally used before or after the reaction, and the protecting group can be eliminated by a widely used method.

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

The compounds of the present invention include stereoisomers and optically active forms, all of which are included in the present invention.

The present inventors have paid attention to the fact that a toluene derivative having a tert.-butyl group at the 3-position and 5-position and a hydroxy group at the 4-position has an antioxidant effect. To introduce a tert.-butyl group and a hydroxy group, and to synthesize various novel 1,4-benzothiazine derivatives having this benzylidene group at the 2-position, to find a compound having an excellent lipid peroxide production inhibitory action. We worked diligently.

As a result, the 2-position of 3-oxo-1,4-benzothiazine is substituted with a benzylidene group, the 3- and 5-positions of the phenyl ring of the benzylidene group are substituted with a tert.-butyl group, and the 4-position is further substituted. Has a basic structure in which is substituted with a hydroxy group, and the novel compound in which the 4-position of benzothiazine is substituted with an acyl group or the like has been found to have an excellent inhibitory action on lipid peroxide production.

The present invention is mainly composed of a novel compound having the above-mentioned basic structure. Naturally, the hydroxy group may be protected by a protecting group widely used as a protecting group for a hydroxy group. This protecting group is used for various purposes such as synthetic means, compound stabilization, and prodrug.

In order to examine the inhibitory effect of the compounds of the present invention on lipid peroxide production, an experiment was conducted using rat liver microsomes. As a result, it was found that the compound of the present invention has an excellent lipid peroxide production inhibitory action. It has been reported that compounds having a lipid peroxide production inhibitory action are useful for cataracts, inflammation, circulatory diseases, etc. (Cu
rrent Eye Res., 5, 37 (1986), Modern Medicine 39, 1368 (1
984)), it was found that the compound of the present invention can be used as these therapeutic agents.

The compound of the present invention can be administered orally or parenterally. Dosage forms include tablets, capsules, granules, powders, injections, eye drops and the like, and can be formulated using commonly used techniques. For example, oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in lactose, starch, crystalline cellulose, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, and hydroxypropyl. It can be formulated using a binder such as cellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose calcium, and a coating agent such as hydroxypropylmethylcellulose. In the case of eye drops, it may be formulated using an isotonic 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. Can be.

The dose can be appropriately selected depending on the symptoms, age, dosage form, etc., and if it is an oral preparation, it is usually 1 to 5000 mg per day.
Can be administered once or in several divided doses. Also,
In the case of eye drops, 0.001% to 5% may be instilled once or several times a day.

[0029]

【Example】

Example 1 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) -3,4-dihydro-4- [3- (N, N
-Dimethylamino) propyl] -3-oxo-2H-
Synthesis of 1,4-benzothiazine (compound 1-1)

Embedded image A solution of diisopropylamine (2.44 ml) in tetrahydrofuran (15 ml cooled with dry ice-methanol)
ml) in n-hexane solution of n-butyllithium (1.
6M, 10.9 ml) was added dropwise with stirring under a nitrogen atmosphere, and the solution was stirred at 0-10 ° C for 20 minutes.
Again under dry ice-methanol cooling,
4-dihydro-4- [3- (N, N-dimethylamino)
Propyl] -3-oxo-2H-1,4-benzothiazine (2.18 g) in tetrahydrofuran (15 m
1) is added dropwise with stirring, and the mixture is further stirred for 30 minutes.
To this solution, a solution of 3,5-di-tert.-butyl-4-hydroxybenzaldehyde (2.04 g) in tetrahydrofuran (30 ml) is added, and the mixture is stirred at room temperature overnight. The reaction solution is put in a saturated saline solution and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oily residue is purified by silica gel column chromatography to obtain 1.64 g (38.8%) of an erythro form and 1.22 g (28.9%) of a threo form of the title compound.

Physical Properties of Erythro Body m. p. 186-187 ° C (benzene-ethyl acetate) IR (KBr, cmｃｍ): 3356, 2958, 286
8,1656,1585,1448,1436,138
0, 1360, 1207, 1078, 753 TLC (silica gel): Rf 0.34 (chloroform-
Methanol = 5: 1)

Physical Properties of Threo Form IR (Film, cm -1): 3638, 3409, 295
8,1652,1585,1435,1386,121
6,1158,1120,762,666 TLC (silica gel): Rf 0.45 (chloroform-
Methanol = 5: 1)

The following compounds are obtained in the same manner as in Example 1.

2- (3,5-di-tert.-butyl-α,
4-dihydroxybenzyl) -3,4-dihydro-4-
[2- (N, N-dimethylamino) ethyl] -3-oxo-2H-1,4-benzothiazine (compound 1-2)

2- (3,5-di-tert.-butyl-α,
4-dihydroxybenzyl) -3,4-dihydro-4-
(3-methoxypropyl) -3-oxo-2H-1,4
-Benzothiazine (compound 1-3)

2-[(3,5-di-tert.-butyl-4)
-Trimethylsilyloxy) -α-hydroxybenzyl] -3,4-dihydro-4- [3- (N, N-dimethylamino) propyl] -3-oxo-2H-1,4-benzothiazine (compounds 1-4)

2-[(3,5-di-tert.-butyl-4)
-Methoxymethoxy) -α-hydroxybenzyl]-
3,4-dihydro-4- [3- (N, N-dimethylamino) propyl] -3-oxo-2H-1,4-benzothiazine (compound 1-5)

Example 2 (Z) -2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- [3-
(N, N-dimethylamino) propyl] -3-oxo-
Synthesis of 2H-1,4-benzothiazine (compound 2-1)

Embedded image 2- (3,5-di-tert.-butyl-α, 4-dihydroxybenzyl) -3,4-dihydro-4- [3- (N, N
-Dimethylamino) propyl] -3-oxo-2H-
Methanesulfonyl chloride (0.21 ml) was added to a solution of 1,4-benzothiazine (compound 1-1) in erythro form (0.88 g) and triethylamine (0.76 ml) in methylene chloride (10 ml) under a nitrogen atmosphere and ice-cooling. ) Is added with stirring. The reaction solution is put into a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.25 g (29.5%) of the title compound.

M. p. 130-132 ° C (diisopropyl ether) IR (KBr, cm-1): 3616, 3298, 295
8, 1619, 1587, 1485, 1435, 136
1,1282,1202,1169,744

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

(Z) -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- [2- (N, N-dimethylamino) ethyl]- 3
-Oxo-2H-1,4-benzothiazine (compound 2-
2)

(Z) -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (3-methoxypropyl) -3-oxo-2H-
1,4-benzothiazine (compound 2-3)

Example 3 (Z) -4-acetyl-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-oxo-2H-1,4- Benzothiazine (compound 3-1) and (Z) -2- (4-acetoxy-3,5
-Di-tert.-butylbenzylidene) -4-acetyl-
Synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Compound 3-2)

Embedded image (Z) -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-oxo-
To a solution of 2H-1,4-benzothiazine (0.2 g) in tetrahydrofuran (2 ml) was added a n-hexane solution of n-butyllithium (1.6 M, 0.33 ml) in a nitrogen atmosphere under ice-sodium chloride cooling. Add dropwise with stirring. To this solution is added dropwise a solution of acetyl chloride (0.66 g) in tetrahydrofuran (1 ml), and the mixture is stirred at room temperature overnight. The reaction solution is placed in a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to obtain 0.02 g of compound 3-1.
(9.0%) and 0.03 g of compound 3-2 (13.5%).
%)obtain.

Physical Properties of Compound 3-1 m. p. 173-175 ° C IR (KBr, cm -1): 3568,2955,168
9, 1584, 1562, 1476, 1422, 136
9,1268,1182,1116,924,746

Physical Properties of Compound 3-2 IR (Film, cm-1): 2966, 1765, 169
4,1589,1377,1368,1267,118
4,1110,910,731

The following compounds are obtained in the same manner as in Example 3.

(Z) -4-benzoyl-2- (3,5
-Di-tert.-butyl-4-hydroxybenzylidene)-
3,4-dihydro-3-oxo-2H-1,4-benzothiazine (compound 3-3)

(Z) -4-benzoyl-2- (4-benzoyloxy-3,5-di-tert.-butylbenzylidene) -3,4-dihydro-3-oxo-2H-1,4-
Benzothiazine (Compound 3-4)

Example 4 (Z) -2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-oxo-
4- [2- (tetrahydropyran-2-yl) oxyethyl] -2H-1,4-benzothiazine (compound 4-
Synthesis of 1)

Embedded image To a suspension of sodium hydride (0.08 g) in dimethyl sulfoxide (2 ml) was added 2- (3,5-di-
tert.-butyl-4-hydroxybenzylidene) -3,4
A solution of -dihydro-3-oxo-2H-1,4-benzothiazine (0.4 g) in dimethyl sulfoxide (2 ml) is added dropwise with stirring at room temperature under a nitrogen atmosphere. After stirring for 10 minutes, 2- (2-bromoethoxy) tetrahydropyran (0.3 g) in dimethyl sulfoxide (2 m
l) The solution is added dropwise. After stirring overnight at room temperature, the reaction is poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give 0.06 g of the title compound (1
1.8%).

TLC (silica gel): Rf 0.44 (n
-Hexane-ethyl acetate = 2: 1)

Example 5 (Z) -2- (3,5-Di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (2-hydroxyethyl) -3-oxo-2H Synthesis of -1,4-benzothiazine (compound 5-1)

Embedded image (Z) -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-3-oxo-
4- [2- (tetrahydropyran-2-yl) oxyethyl] -2H-1,4-benzothiazine (compound 4-
P-toluenesulfonic acid monohydrate (0.002 g) was added to a methanol solution (3 ml) of
Stir for hours. The reaction solution is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (0.02 g).
(48.3%).

M. p. 164 to 165 ° C (diisopropyl ether) IR (KBr, cm -1): 3600, 3474, 296
0, 1621, 1587, 1485, 1446, 142
1,1367,1260,1214,1044,754

Example 6 (Z) -2- (4-benzoyloxy-3,5-di-te
rt.-butylbenzylidene) -3,4-dihydro-4-
[2- (N, N-dimethylamino) propyl] -3-oxo-2H-1,4-benzothiazine (compound 6-1)
Synthesis of

Embedded image (Z) -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- [3-
(N, N-dimethylamino) propyl] -3-oxo-
2H-1,4-benzothiazine (compounds 2-1 and 0.2
Triethylamine (1.1 ml) is added to 5 g) and benzoic anhydride (6.06 g), and the mixture is stirred at 90 ° C. for 2 days. After adding water to the reaction solution, extraction is performed with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Example 7 (Z) -2- (3,5-Di-tert.-butyl-4-trimethylsilyloxybenzylidene) -3,4-dihydro-
4- (3-methoxypropyl) -3-oxo-2H-
Synthesis of 1,4-benzothiazine (Compound 7-1)

Embedded image (Z) -2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (3-methoxypropyl) -3-oxo-2H-1,4-benzothiazine 1,1,1,3,3,3-Hexamethyldisilazane (1.5 ml) and chlorotrimethylsilane (1.3 ml) were added to a solution of (compound 2-3, 0.48 g) in dimethylformamide (7 ml). Reflux for 4 days. After adding water to the reaction solution, the mixture is extracted with ether. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

Example 8 (Z) -2- (3,5-Di-tert.-butyl-4-methoxymethoxybenzylidene) -3,4-dihydro-4-
(3-methoxypropyl) -3-oxo-2H-1,4
Synthesis of benzothiazine (compound 8-1)

Embedded image A suspension of 60% sodium hydride in mineral oil (0.03 g) was suspended in dimethylformamide (0.5 ml) and (Z)
-2- (3,5-di-tert.-butyl-4-hydroxybenzylidene) -3,4-dihydro-4- (3-methoxypropyl) -3-oxo-2H-1,4-benzothiazine (compound 2 -3, 0.30 g) in dimethylformamide (2 ml) is added. After stirring at room temperature for 10 minutes, chloromethyl methyl ether (0.1 ml) is added, and the mixture is stirred at 60 ° C for 2 hours. After adding saturated saline to the reaction mixture, the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound.

The following compounds are obtained in the same manner as in Example 8.

(Z) -2- [3,5-Di-tert.-butyl-4-[(2-methoxyethoxy) methoxy] benzylidene] -3,4-dihydro-4- (3-methoxypropyl)- 3-oxo-2H-1,4-benzothiazine (compound 8-2)

Example 9 (Z) -2- (3,5-Di-tert.-butyl-4-methanesulfonyloxybenzylidene) -3,4-dihydro-
4- (3-methoxypropyl) -3-oxo-2H-
Synthesis of 1,4-benzothiazine (compound 9-1)

Embedded image Ice-cooled (Z) -2- (3,5-di-tert.-butyl-4)
-Hydroxybenzylidene) -3,4-dihydro-4-
(3-methoxypropyl) -3-oxo-2H-1,4
Under a nitrogen atmosphere, methanesulfonyl chloride (0.07 ml) and triethylamine (0.09 ml) are added to a solution of benzothiazine (compound 2-3, 0.14 g) in methylene chloride (3 ml), and the mixture is stirred at room temperature overnight. After adding water to the reaction solution, extraction is performed with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound. The following compounds are obtained in the same manner as in Example 9.

(Z) -2- [3,5-di-tert.-butyl-4- (p-toluenesulfonyloxy) benzylidene] -3,4-dihydro-4- (3-methoxypropyl) -3 -Oxo-2H-1,4-benzothiazine (compound 9-2)

[0059]

【The invention's effect】

"Pharmacological test" In order to examine the effect of the compound of the present invention, the inhibitory effect on lipid peroxide production was examined.

(Experimental method) 0.0% containing test compound
4M Tris buffer (containing 0.09M potassium chloride,
Rat liver microsomes were converted to ADP (1
3.2 mM), Fe 2+ (0.9 mM) and ascorbic acid (0.5 mM) at 37 ° C. for 15 minutes, and the resulting lipid peroxide was subjected to the TBA method (Yagi et al., Biochem. Med.,
15, 212 (1976)).

As test compounds, compounds 2-1 and 3-1
And 5-1 were used.

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

[0063]

[Table 1] As shown in Table 1, each of the compounds of the present invention had an excellent lipid peroxide production inhibitory effect.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-1-287077 (JP, A) JP-A-60-72875 (JP, A) JP-A-60-72876 (JP, A) (58) Field (Int.Cl. ⁶ , DB name) C07D 279/00-279/36 A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ represents a hydroxy group or a hydroxy group having a protecting group. R ² represents an acyl group or -A-R ^3. R ³ represents a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group or a tetrahydropyranyloxy group. A represents a linear or branched lower alkylene group. ] 2. A compound represented by the following general formula [II] or a salt thereof. Embedded image [Wherein, R ¹ represents a hydroxy group or a hydroxy group having a protecting group. R ² represents an acyl group or -A-R ^3. R ³ represents a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group or a tetrahydropyranyloxy group. A represents a linear or branched lower alkylene group. ]