JP2967231B2 - 1,4-thiazine derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel 1,4-thiazine derivative useful as a medicine.

Prior ArtThe synthesis of 1,4-thiazine derivatives is described in H. Sokol et al., J. Am.
em. Soc., 70 , 3517 (1948), GDS Stevens et al., J. Am. Chem. S.
oc., 80 , 5198 (1958), GSSkinner et al., J. Am. Chem. Soc., 8
1 , 3756 (1959), CR Johnson et al., J. Hetero. Chem., 6 , 24.
7 (1969), GVRao et al., Synthesis, 1972 , 136, M. Hojo et al.
Synthesis, 1979 , 272; M. Hojo et al., J. Org. Chem., 53 , 2209.
(1988), JP-A-63-301876, JP-A-61-225174, JP-A-61-225174
61-18776, etc., H. Sokol et al., J. Am. Ch.
em. Soc., 70 , 3517 (1948) states that 1,4-thiazine derivatives having a phenyl substituent at the 5-position cannot be synthesized, and GSSkinner et al., J. Am. Chem. Soc., 81 , 3756 (19
Only the synthesis of disubstituted 5-phenyl-1,4-thiazine derivatives at 2-position is reported in 59), and 5-phenyl-1,5
The 4-thiazin-3-one derivative (Ia) is a novel compound that has not been reported in the literature.

On the other hand, regarding the pharmacological action of a monocyclic 1,4-thiazine derivative, anti-endotoxin action and the like are described in JP-A-63-301876.
JP-A-61-225174 reports an inotropic effect and JP-A-61-18776 reports an anti-rheumatic effect.

DISCLOSURE OF THE INVENTION The present invention provides a novel 1,4-thiazine derivative having an inhibitory action on enzymes such as phospholipase A ₂ , lipoxygenase and cyclooxygenase, an inhibitory action on lipid peroxide production, and an anti-hypoxia action.

Means for Solving the Problems The present invention provides a formula [Wherein, when A represents -N =, B represents an optionally substituted pyrrolyl group, an optionally substituted amino group or an alkylthio group; When R ² represents hydrogen or an optionally substituted aliphatic hydrocarbon group, B represents oxo, thioxo,
Represents an optionally substituted hydrazono group, an optionally substituted imino group or an alkylidene group, wherein R ¹ is hydrogen,
Represents an alkoxy group, an acyloxy group, an alkylthio group, an optionally substituted amino group, an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group, wherein R ³ is substituted Represents an optionally substituted aliphatic or aromatic hydrocarbon group or a carboxyl group which may be esterified or amidated, R ⁴ represents hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon group, The dashed line indicates that one of the bonds is a double bond], or a salt thereof.

In the general formula (I), the optionally substituted amino group represented by R ¹ includes, for example, an unsubstituted amino group,
An alkyl group having about 1 to 8 carbon atoms (eg, methyl, ethyl,
Propyl, i-propyl, butyl, i-butyl, pentyl, i
-Pentyl, hexyl, heptyl, octyl, etc.), an alkenyl group having about 2 to 8 carbon atoms (eg, vinyl, allyl, 1-propenyl, i-propenyl, 2-butenyl,
1,3-butadienyl, 2-pentenyl, 1-hexenyl, 1-
Heptenyl, 1-octenyl, etc.), an optionally substituted aralkyl group having about 7 to 10 carbon atoms (eg, halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy group, etc. on the benzene ring) Optionally substituted benzyl, phenethyl, phenylpropyl, phenylbutyl, etc.), optionally substituted aryl (eg, halogen, nitro,
A phenyl group which may have one or two substituents such as amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, hydroxy, etc., a carboxylic acid having about 2 to 7 carbon atoms Acyl groups derived from acids (eg, acetyl, propionyl, butyryl, i-butyryl, hexanoyl, optionally substituted benzoyl, trifluoroacetyl, etc.),
A primary or secondary amino group having one or two substituents such as an amino group, C _1-4 alkylcarbamoyl, C _1-4 alkylthiocarbamoyl, an alkyl group having about 1 to 3 carbon atoms (eg, A hydrazino group which may be substituted with an alkanoyl group having about 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, i-butyryl, etc.), an optionally substituted alicyclic group Amino group (eg, piperidino, piperazinyl, morpholino, N-phenylpiperazino, azetidinyl, prolidinyl, etc.)
And the like.

As the alkoxy group represented by R ¹ , for example,
And about 4 (eg, methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, allyloxy).

Examples of the alkylthio group represented by R ¹ include those having about 1 to 3 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.).

The acyl of the acyloxy group represented by R ¹ includes, for example, an acyl group derived from a carboxylic acid having about 2 to 7 carbon atoms, and the acyloxy group represented by R ¹ includes, for example, acetyloxy, propionyloxy, butyryloxy, i
-Butyryloxy, hexanoyloxy, optionally substituted benzoyloxy, trifluoroacetyloxy and the like.

Examples of the optionally substituted aromatic hydrocarbon group represented by R ¹ include, for example, 1 to 2 hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C
_1-4 alkyl, nitro, amino, C _1-4 alkylamino, di
And phenyl which may have a substituent such as C _1-4 alkylamino and halogen.

Examples of the optionally substituted aromatic heterocyclic ring represented by R ¹ include, for example, 1 to 2 substituents such as hydroxy, methyl, methoxy, amino, dimethylamino, halogeno and the like. 5 containing two heteroatoms
And an 8-membered aromatic heterocyclic ring (eg, furyl, thienyl, pyrrolinyl, etc.) and the like.

R ¹ is hydrogen, a primary or secondary amino group substituted with alkyl having about 1 to 3 carbon atoms, an alkoxy group having about 1 to 3 carbon atoms, and 1 to 2 hydroxy groups in oct, meta and para positions. , phenyl is preferable to have a substituent such as C _1-4 alkoxy, more hydrogen, methyl, methoxy and ortho, meta, phenyl having one to co hydroxy para position is preferred.

Regarding the general formula (I), examples of the optionally substituted amino group represented by B include the same as the aforementioned optionally substituted amino group represented by R ¹ ,
Among them, an unsubstituted amino group or a primary amino group (-NH
R ⁵ ) is preferable, and as a substituent R ⁵ of a primary amino group,
For example, lower alkyl having about 1 to 4 carbon atoms (eg, methyl,
Ethyl, propyl, i-propyl, butyl, i-butyl, etc., alkanoyl having about 2 to 4 carbon atoms (eg, acetyl, pyropionyl, butyryl, trifluoroacetyl, etc.), optionally substituted benzoyl, substituted Aromatic hydrocarbon groups (eg, ortho, meta, 1-2 halogens in the para position, nitro, amino, C _1-4 alkyl,
Phenyl which may have a substituent such as C _1-4 alkoxy, C _2-5 alkoxycarbonyl, hydroxy, etc.).

The optionally substituted hydrazono group represented by B, for example, include a group represented by the formula = N-NHR ^6, R ⁶
Alkanoyl groups having about 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, trifluoroacetyl, etc.), alkoxycarbonyl having about 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.), carbon atoms of 1 to 4 Thicarbamoyl (eg, methylthiocarbamoyl, ethylthiocarbamoyl, etc.) which may be substituted with a certain amount of alkyl, and the like.

Examples of the optionally substituted alkylidene group represented by B include, for example, In include groups represented, R ⁷ and R ⁸ may be the same or different, as the R ^7, R ⁸ such as cyano, carbamoyl, number 2-5 about alkoxycarbonyl carbon (e.g.,
Methoxycarbonyl, ethoxycarbonyl, etc.), an optionally substituted aromatic hydrocarbon group (eg, phenyl, p-
Chlorophenyl and the like).

Examples of the optionally substituted pyrrolyl group represented by B include, for example, 2-pyrrolyl group which may be substituted with the same substituent as the aforementioned optionally substituted aromatic hydrocarbon group represented by R ^1. Pyrrolyl or 3-pyrrolyl and the like.

Examples of the alkylthio group represented by B include an alkylthio group having about 1 to 4 carbon atoms (eg, methylthio and the like).

Examples of the optionally substituted imino group represented by B include, for example, a group represented by the formula = NR ¹⁵ , wherein R ¹⁵ is, for example, hydrogen or an aromatic hydrocarbon which may be substituted. Hydrogen group (eg, ortho, meta, para-halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C
Phenyl which may have one or two substituents such as _2-5 alkoxycarbonyl, hydroxy and the like.

B is preferably oxo, thioxo, alkylthio or an amino group which may be substituted, and in particular, is substituted with oxo and phenyl having a substituent at the para position such as halogen, C _1-4 alkyl, C _1-4 alkoxy. Amino groups are preferred.

In the general formula (I), examples of the optionally substituted aliphatic hydrocarbon group represented by R ² or R ⁴ include hydroxy, halogen, cyano, C _2-5 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl) Etc.), optionally substituted aromatic hydrocarbon groups (eg, ortho, meta, para-halogen, nitro, amino, C _1-4)
Alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl,
Phenyl optionally having one or two substituents such as hydroxy) and the like.
About 4 alkyl groups (eg, methyl, ethyl, propyl,
Butyl, etc.).

 A is preferably -N = and -NH-.

With respect to the general formula (I), the optionally substituted aliphatic hydrocarbon group represented by R ³ may be the same as the substituent of the optionally substituted aliphatic hydrocarbon group represented by R ² Examples thereof include an alkyl group having about 4 to 8 carbon atoms that may be substituted with a group (eg, butyl, pentyl, hexyl, heptyl, octyl, etc.).

Examples of the optionally substituted aromatic hydrocarbon group represented by R ³ or R ⁴ include halogen (eg, F, C, Br, I, etc.) and C _1-4 alkoxy (eg, oct, meta, para) , Methoxy, ethoxy, propoxy, butyloxy, etc.), C _2-5
Alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _2-5 alkanoyloxy (eg,
Acetyloxy, propylonyloxy, butyryloxy, trifluoroacetyloxy, etc.), C _1-4 alkyl (eg, methyl, ethyl, propyl, i-propyl, butyl, i-butyl), nitro, amino, C _2-8 Examples thereof include phenyl which may have one or two substituents such as acylamino (eg, acetylamino, propionylamino, butyrylamino, octylamino, cyclohexylamino, benzoylamino) and hydroxy.

Examples of the esterified carboxyl group represented by R ³ include alkoxycarbonyl having about 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.)
And the like.

As the amidated carboxyl group represented by R ³ , for example, [Wherein R ⁹ and R ¹⁰ are each substituted with hydrogen, alkyl having about 1 to 18 carbons, alkoxycarbonyl having about 2 to 5 carbons (eg, methoxycarbonyl, ethoxycarbonyl and the like), halogen and the like. A good phenyl group, and R ⁹ and R ^{10 taken} together are an alicyclic amino group (eg, piperidino, piperazinyl, morpholino, N-phenylpiperazino, azetidinyl which may be substituted by phenyl or halogen, etc.) , A pyrrolidinyl group, etc.]].

As R ³ , an optionally substituted phenyl group and an amidated carboxyl group are preferable, and further, phenyl optionally having one or two substituents such as halogen, hydroxy and the like at ortho, meta and para positions. Groups and formulas Wherein R ⁹ and R ¹⁰ each represent a phenyl group which may be substituted with hydrogen, halogen, or the like.
A phenyl group which may have 2 to 2 substituents such as halogen and hydroxy is preferable.

R ⁴ is preferably hydrogen and an optionally substituted aliphatic hydrocarbon group, and more preferably hydrogen and methyl.

Compound represented by the above general formula (I) [Compound (I)]
Among them, when A represents -N =, B represents a primary amino group substituted with phenyl having a substituent at the para position such as halogen, C _1-4 alkyl, C _1-4 alkoxy, and A represents -NH-
B represents oxo, R ¹ is hydrogen, and has 1 to 3 carbon atoms.
Primary or secondary amino substituted with about alkyl, alkoxy having about 1 to 3 carbon atoms or substituents such as 1 to 2 hydroxy, C _1-4 alkoxy in ortho, meta and para positions. be indicated phenyl, R ³ is ortho, meta, para positions 1-2 co halogen, which may have a substituent such as hydroxyphenyl or formula [Wherein R ⁹ and R ¹⁰ each represent hydrogen or phenyl optionally substituted by halogen or the like], and compounds (I ′) in which R ⁴ represents hydrogen or methyl are more preferred.

Among the above compounds (I), for example, a compound wherein R ³ is ethoxycarbonylmethyl [Wherein the symbols are as defined above], isomers having tautomerism [Wherein the symbols have the same meanings as described above], and isomers having tautomerism with compound (I) are also included in the present invention.

Salts of compound (I) include inorganic acid salts such as acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate such as acetate, tartrate, citrate, fumarate, and the like. Pharmacologically acceptable salts such as organic acid salts such as maleate;

 In the above compound (I), when A is -N =,
The nitrogen atom in may be quaternized, in which case A is[Where R^TwoHas the same meaning as defined above].
In (I), -N =-as A isThe compound (I ″) is substituted with the above-mentioned inorganic acid or organic acid
Anin on (W ) May form a salt with
The salt of the compound (I ″) may be a base (eg, t-butoxycaliu)
And sodium hydrite).
Can be converted to compound (I) according to the reaction formula shown below.
Can be.

[Where W Represents an anion of the inorganic or organic acid.
Then R¹Is an optionally substituted pyrrolyl group;
Represents an amino group or an alkylthio group which may be
The other symbols are as defined above.] Compound (I ″), a salt of compound (I ″) and
Compound (I) can be more easily derived than compound (I).
These compounds are also included in the present invention.

Production Method The compound of the above general formula (I) can be produced, for example, by the following method.

Wherein R ³ and R ⁴ are as defined above. Χ represents halogen. ] Wherein R ³ and R ⁴ are as defined above. ] [Wherein, R ² , R ³ and R ⁴ are as defined above. ] [Wherein, R ¹ , R ² , R ³ and R ⁴ are as defined above. ] [Wherein, R ² , R ³ and R ⁴ are as defined above. ] [Wherein, R ² , R ³ and R ⁴ are as defined above. ] Wherein A, B, R ³ and R ⁴ are as defined above. ] Wherein B, R ³ and R ⁴ are as defined above. ] [In the formula, R ¹¹ represents a lower alkyl group, and R ⁹ and R ¹⁰ have the same meaning as described above. ] [Wherein, R ³ and R ⁴ are as defined above. R ¹⁴ represents an acyl group. The process (a) is a method of directly reacting the compound (II) with the compound (III) in the presence of a base to directly obtain the compound (IV).

The reaction is carried out using 1 mol of the base and 1 mol of the compound (II) in excess of 1 mol of the compound (III), for example, about 1.2 to 1.5 mol. Examples of the base include an organic base such as a trialkylamine such as triethylamine and potassium carbonate,
The reaction is performed using an inorganic base such as sodium carbonate or the like and a solvent such as methanol, ethanol, acetone, methyl ethyl ketone, acetonitrile, dioxane, terolahydrofuran, benzene or toluene as a solvent. The reaction conditions are as follows. Compound (II) and a suitable base are dissolved in a solvent, and a solution of the same solvent in which compound (III) is dissolved at room temperature under ice-cooling is added dropwise over 30 minutes to 1 hour. It is preferred to raise the boiling point of the mixture to about 20 to 30 hours, and to heat and reflux at a temperature of about 80 ° C. to 120 ° C. When benzene, toluene, xylene or the like is used as a solvent, it is more preferable to carry out the reaction while removing water generated during the reaction.

After completion of the reaction, the reaction product obtained as described above is collected when the target product (IV) is precipitated as crystals in the reaction solution, and the solution is concentrated to dryness. Can be easily obtained by recrystallization from a conventional purification method, that is, a solvent such as alcohol, acetone or ether. In some cases, it can be easily obtained as crystals by ordinary isolation and purification methods such as column chromatography. In the process (a), the reaction can be completed without the presence of a base depending on the reactivity of the compound (II) and the stability of the reaction product (IV). The reaction is preferably performed under substantially the same conditions as described above. It is also preferable to carry out the isolation and purification of the target compound in the same manner.

In the process (b), the compound (IV) is obtained from the reaction intermediate (ΔV) generated in the process (a) by a dehydration ring closure reaction under acidic conditions. The compound (ΔV) easily obtained from the compound (II) and the compound (III) is dissolved in a suitable solvent, and the mixture is heated under reflux in the presence of a catalytic amount of an acid while removing water generated. As the solvent, it is preferable to use a solvent that does not mix with water, such as benzene, toluene, and xylene. However, when the compound (ΔV) alone is insoluble, it is preferable to add dimethylacetamide, dimethylformamide and the like to about 1/5 to 1/10 of the solvent to form a solution. As the acid to be added, a mineral acid such as sulfuric acid and an organic acid such as p-toluenesulfonic acid are preferably used in a catalytic amount. Regarding the reaction conditions, it is preferable to heat and reflux at a reaction temperature of about 100 to 120 ° C. and about 10 to 50 hours. It is preferable to carry out the water generated during the reaction while separating it with a water separator, and the end of the reaction can be known from the separated water amount. The obtained compound (IV) can be easily obtained as crystals by a method similar to that shown in the process (a).

Process (c) involves reacting compound (V) with m-chloroperbenzoic acid to give 2-O-benzoate (VI). The reaction is carried out using m-chloroperbenzoic acid in excess of 1 mol, for example, about 1.1 to 1.3 mol, per 1 mol of compound (V). Compound (V) is dissolved in an appropriate solvent, and a solution of m-chloroperbenzoic acid dissolved in the same solvent is added little by little at a reaction temperature of about ice-cooling to about room temperature. Then 20
The reaction is preferably performed at about 30 ° C. for about 1 to 5 hours. As the reaction solvent used at this time, it is preferable to use a halogenated hydrocarbon system such as chloroform, methylene chloride and dichloroethane.

The reaction product obtained as described above can be obtained by evaporating the solvent and then recrystallizing the obtained crude product from an appropriate solvent. Compound (VI) can be easily purified and isolated by column chromatography.

Process (d) is a reaction of compound (VI) with various nucleophiles to obtain 2-substituted compound (VII).

The reaction is performed using about 2 to 5 mol of a nucleophile per 1 mol of the compound (VI). The reaction is usually used organic solvent,
For example, the reaction is preferably performed using chloroform, methylene chloride, dichloroethane, acetone, methyl ethyl ketone, etc., but in order to improve the solubility of the compound (VI) and the nucleophile, an appropriate amount of methanol or ethanol is added and the reaction is performed as a mixed solvent. In some cases. The reaction conditions differ depending on the nucleophile used, but are usually aliphatic primary amines (methylamine, ethylamine, propylamine, butylamine, benzylamine, etc.), aliphatic secondary amines (dimethylamine, diethylamine, etc.), alicyclic amines ( Piperidine, morpholine, piperazine, etc.), aromatic amines (aniline, substituted aniline, etc.), hydrazines (hydrazine, methylhydrazine, etc.), aliphatic alcohols (methanol, ethanol), mercaptans (methyl mercaptan, phenyl mercaptan, etc.) When using a nucleophile, at a reaction temperature of about 10 to 30 ° C and a reaction time of 1 to
It is preferably performed in about 30 hours. In some cases, the reaction is carried out using a nucleophile as a salt to promote the reaction (such as CH ₃ SNa and PhSNa).

When the reaction is carried out by heating under reflux in order to improve the reaction time, the yield and the like, the compound (VII) may be obtained in a short time and with high yield.

The reaction product obtained as described above can be easily obtained by distilling off the solvent and recrystallizing the obtained crude product from an appropriate solvent. The compound (VII) can be easily prepared even by using a fractionation means such as column chromatography.
Can be obtained.

In addition, during crystallization of an amine-substituted product or the like, it can be isolated as a hydrochloride or an oxalate.

In the process (e), the compound (IV) is reacted with an alkylating agent to obtain a 4-alkyl compound (V). The reaction is performed using about 1 to 5 mol of an alkylating agent per 1 mol of compound (IV). The reaction is preferably carried out using acetone, acetonitrile, dimethylformamide or the like in the presence of a suitable base (eg, potassium carbonate, sodium carbonate, toluethylamine, etc.). As the alkylating agent, an alkyl halide or an aralkyl halide is preferably used, and the reaction is preferably performed at room temperature to 150 ° C. for about 10 to 40 hours.

The reaction product obtained as described above can be easily obtained by recrystallizing a crude product obtained after distilling off the solvent from an appropriate solvent, or by separation means such as column chromatography. I can do it.

Process (f) comprises reacting compound (V) with a sulfurizing agent to give 3
-To obtain a thioketone (VIII).

Phosphorus pentasulfide and Lawson's reagent can be used as the sulfurizing agent, and 0.5 to 0.5 mol of compound (V) can be used.
It is carried out using about 1.0 mol.

As a reaction solvent, it is preferable to use a solvent which is usually used for a sulfurization reaction, that is, benzene, toluene, xylene, dioxane, pyridine, hexamethylphosphoric triamide (HMPT), etc., using a Lawson reagent in a solvent such as toluene. Is more preferred. The reaction conditions vary depending on the sulphidizing agent to be used, but it is preferable to carry out the reaction at a reaction temperature of about 50 to 150 ° C. and a reaction time of about 15 minutes to 40 hours.

The reaction is carried out by dissolving compound (V) in an appropriate solvent, adding a sulfide agent and reacting by heating, and then concentrating the reaction solution. The obtained residue is subjected to ordinary purification methods, solvent extraction, recrystallization, column chromatography, etc. Compound (VIII) can be easily obtained by the method described above.

In the process (g), after the compound (VIIIa) obtained by the process (f) is methylated to obtain a compound (IΧ), the compound (IΧ) is subjected to various nucleophilic reagents such as an amine using a suitable reaction accelerator. (Ammonia, methylamine, optionally substituted benzylamine, optionally substituted aniline derivatives, etc.), hydrazines, active methylene compounds (malononitrile, cyanoacetamide, optionally substituted phenylacetonitrile, etc.) To give the compound (Χ).

The methylation of compound (VIIIa) is carried out by using a suitable base (eg,
In the presence of sodium carbonate, potassium carbonate, etc.), 1 to 5 mol of methyl iodide is usually added to 1 mol of compound (VIIIa) in a solvent such as acetonitrile, dimethylformamide, acetone, methyl ethyl ketone for about 5 to 30 hours at room temperature. The compound (IΧ) is obtained by the reaction.

Compound (IΧ) can be easily obtained by a conventional isolation and purification method, for example, solvent extraction, recrystallization and column chromatography.

In the reaction for obtaining the compound (Χ) from the compound (IΧ), a reaction solvent, a reaction accelerator or a base, a reaction time, a reaction temperature, and the like may be different depending on a nucleophilic agent used at that time.

When amines and hydrazines are used as nucleophiles, 2 to 10 nucleophiles are used per 1 mol of compound (I).
It is preferable to use about moles and to use ethers such as dioxane and tetrahydrofuran, alcohols such as methanol and ethanol as a reaction solvent. Examples of the reaction accelerator include salts of mineral acids (eg, HCl salt, HBr salt, etc.), triethylamine hydrochloride, iodine, trimethylsilicyl chloride, etc. corresponding to each nucleophile.
Ii) It is preferable that about 5 mol of the catalyst coexist with 1 mol. The reaction conditions vary considerably depending on the combination of the compound (I) and the reaction accelerator, but the reaction is carried out at room temperature to about 100 ° C. for about 1 hour to 3 days.

When an active methylene compound is used as the nucleophile, about 1 to 3 mol of the nucleophile is used with respect to 1 mol of the compound (I 、), and dimethylformamide, dimethylacetamide or the like is used as a reaction solvent. (Ethyl ether, isopropyl ether, etc.)
It is preferred to use a mixed solvent of As the base to be used at this time, sodium hydride, potassium t-butoxide and the like are preferably used in an amount of about 2 to 5 mol per mol of the compound (IΧ). The reaction temperature is from room temperature to about 80 ° C, and the reaction time is from 8 to
It should be done in about 24 hours.

Compound (精製) can be isolated and purified easily by concentrating the reaction solution to dryness, treating the residue with water and an acid, and then using a conventional purification method, that is, solvent extraction, recrystallization, column chromatography, or the like. Χ) can be obtained. When the target compound (Χ) is formed as a salt in the reaction solution, it is preferable to isolate it as it is, and the compound (Χ) can be converted into a salt such as a hydrohalide or an oxalate by any isolation method. Can be obtained.

In the process (h), the compound (VIIIb) obtained by the process (f) is methylated in the same manner as in the process (g) to give a compound (II), and then treated with a base to give the compound (III)
And Further, the compound (III) is reacted with a nucleophile in the same manner as described in the process (g) to obtain the target compound (IV).

The methylation of compound (VIIIb) is carried out in the presence of a base (eg, sodium carbonate, potassium carbonate, etc.) in the presence of compound (VIIIb)
The compound (II) is obtained by reacting about 1 to 5 moles of methyl iodide with respect to 1 mole in a solvent such as asset nitrile, dimethylformamide, acetone or the like at about room temperature for about 5 to 30 hours.

Next, the compound (ΧII) obtained here is dissolved in a solvent such as ethyl ether or tetrahydrofuran in a base (for example,
By reacting with potassium t-butoxide or the like at about room temperature for about 1 to 3 hours, the compound (ΔII
I) is obtained. In the substitution reaction of the compound (III) thus obtained, a nucleophile (eg, an aniline derivative, a substituted hydrazine, etc.) is used in an equivalent amount to 1 mol of the compound (III), and dioxane, tetrahydrofuran, The reaction is preferably carried out using ethanol, methanol, acetonitrile or the like at a reaction temperature of about 10 to 30 ° C. for about 0.5 to 24 hours. The reaction product (ΧIV) can be easily obtained by usual isolation and purification methods such as solvent extraction, recrystallization and column chromatography.

In the process (i), the compound (IVa) obtained in the process (a) is prepared from a primary or secondary amine and trimethylaluminum by a method described in the literature [A. Basha et al., Tetrahedro
n Lett., 48 , 4171 (1977)] to obtain a compound (IVb).

In the synthesis of the dimethyl amide compound, first, an amine (eg, alkylamine, arylamine, morpholine, piperidine, N-phenylpiperazine, etc.) is mixed with a hexane solution of trimethylaluminum in a solvent such as methylene chloride, chloroform, dichloroethane, etc. under a nitrogen stream. In addition, a dimethylaluminum amide is formed. Next, the compound (IVa) obtained in the process (a) is added under ice-cooling at about room temperature, and the mixture is stirred and reacted for about 10 to 30 hours. It is preferred that

Process (j) is carried out by acylating compound (VIIa) obtained in process (d) to give compound (VIIb)
Is what you get.

An acylating agent (eg, fatty acid anhydride, acid halide, etc.) is used in an amount of about 1 to 3 mol per 1 mol of compound (VIIa), and pyridine, chloroform, methylene chloride, or the like is used as a solvent in the presence of pyridine or triethylamine. Perform using The reaction is preferably carried out at room temperature to about 50 ° C. for about 10 to 30 hours.

The compounds (IVb) and (VIIb) can be easily isolated and purified by concentrating the reaction solution to dryness and subjecting the residue to a conventional purification method such as solvent extraction, recrystallization and column chromatography. ) And (VIIb).

Process (a) to process (b) described above
Medium, raw material compound (II) is VIForgo et al., Pharm. Acta.hel
v., 45 , 207 (1970), WDLangley, Org. Synth., Coll. Vol.
I, 127 (1941), AWWilds et al., J. Am. Chem. Soc., 68 , 86 (19
46) or a method analogous thereto, that is, the method shown in the process (k), is easily synthesized.

[Wherein, Χ, R ³ and R ⁴ are as defined above. Compound (III) is disclosed in H. Sokol et al., J. Am. Chem. Soc., 70 , 3517 (1948).
And the like, or can be synthesized according to the method.

Action The novel 1,4-thiazine derivative (I) and a salt thereof of the present invention suppress the enzymes phospholipase A ₂ , lipoxygenase and cyclooxygenase, and also suppress the production of lipid peroxide.

Phospholipase A ₂ is free arachidonic acid from phospholipids, that arachidonic acid is converted to prostaglandins and leukotrienes by eicosanoid cascade. That is, phospholipase A ₂ , lipoxygenase and cyclooxygenase are 5-HETE, LTB ₄ , PGE ₂ , TXA
_It has various biological effects, such as _2, and produces mediators that are important in disease states. Two of these enzymes
Compounds of the present invention that inhibit one or more of these mediators are referred to as diseases involving these mediators, such as bronchial asthma,
Allergic rhinitis, rheumatoid arthritis, ventilation, psoriasis,
Treated for the treatment of human or other mammalian diseases such as drug allergy, urticaria, dermatitis, various other autoimmune diseases, adult respiratory distress syndrome, Crohn's disease, endotoxin shock and ischemia caused by myocardial damage You. In addition, cytotoxicity and tissue damage of reactive oxygen species generated from oxygen essential for living organisms are closely related to aging, arteriosclerosis, ischemic heart disease, active vascular disease, diabetes and digestive diseases, and have lipid peroxide inhibitory action. The scavenging action of reactive oxygen species by the compound of the present invention can be applied to the treatment of the above diseases. It is considered that the compound of the present invention can be more effectively applied to the above-mentioned diseases by having the above-mentioned enzyme inhibitory action and lipid peroxide inhibitory action.

Compound (I) has low toxicity, and when compound (I) is used as such a medicament, it is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent, and powdered, vulcanized. It can be safely orally or parenterally administered in the form of tablets, capsules, injections, suppositories, ointments and the like. The dosage varies depending on the target disease, symptom, administration target, administration method, and the like. For example, in the case of oral administration to an adult patient with rheumatoid arthritis or hepatic impairment, the usual dose of the active ingredient [compound (I)] is usually used as a single dose. 0.1mg / kg-30mg
It is convenient to administer about / kg body weight, preferably about 0.5 mg / kg to 10 mg / kg body weight once to three times a day.

Examples Hereinafter, the present invention is not limited to Examples, Formulation Examples, and Experimental Examples, which will further specifically explain the present invention.

 The abbreviations used in this specification are described below.

Ac: acetyl Me: methyl Et: ethyl Pr: propyl Bu: butyl Ph: phenyl HETE: hydroxyeicosatetraenoic acid LT: leukotriene PG: prostaglandin TΧ: thromboxane HHT: 12-hydroxyheptadecanoenoic acid m: multiplet q: quartet t: triplet d: doublet s: singlet br s: broad singlet Incidentally, in the NMR spectrum CDCl ₃ or d _6-DMSO, TMS
Was used as an internal standard. The chemical shift is shown in ppm.

Example 1 5-Phenyl-2H-1,4-thiazin-3 (4H) -one Thioglycolic acid amide (22.5 g) and triethylamine (25.3 g) were suspended in methyl ethyl ketone (250 ml), and phenacyl was cooled on ice. A solution of bromide (49.0 g) in methyl ethyl ketone (250 ml) was added dropwise. The reaction was heated at reflux for 40 hours. During this time, phenacyl bromide (6 g) was added. After cooling, the precipitated crystals were collected, the liquid was concentrated to dryness, and the obtained residue and the crystals were combined and recrystallized from alcohol to obtain plate crystals (32.0 g, 50%).

Melting point: 157-158 ° C Elemental analysis: as C ₁₀ H ₉ NOS C (%) H (%) N (%) Calculated: 62.85; 4.72; 7.32 Found: 62.75; 4.76; 7.54 Example 25- (3, 4-Dividroxyphenyl) -2H-1,4-thiazin-3 (4H) -one Thioglycolic acid amide (12.2 g) and triethylamine (13.5 g) are suspended in methyl ethyl ketone (400 ml), and the suspension is added under ice cooling. , 4-dihydroxyphenacyl bromide (2
5.0 g) of a methyl ethyl ketone solution (200 ml) was added dropwise. The reaction was heated at reflux for 20 hours. After leaving to cool, the precipitated crystals were collected, washed with water and dried, and then dissolved in dimethylacetamide (100 ml) and toluene (500 ml). A catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 50 hours. The reaction mixture was concentrated to dryness, and the resulting residue was washed with water.
Recrystallization from ethanol gave colorless crystals (6.3 g, 39%).

Melting point: 231-232 ° C Elemental analysis: C (%) as C ₁₀ H ₉ NO ₃ S (%) H (%) N (%) Calculated: 53.80; 4.06; 6.27 Found: 53.60; 4.20; 6.07 Examples 1 and 2 and Similarly, the following compound was obtained.

Example 17 N-butyl (3-oxo-2,3-dihydro-4H-1,4-thiazin-5-yl) carboxamide Butylamine (0.3 g) was dissolved in methylene chloride (15 ml) and sufficiently dissolved in a stream of nitrogen. With stirring, a 15% solution of trimethylaluminum in hexane (2 ml) is added at room temperature. Fifteen
After stirring for minutes, a solution of ethyl (3-oxo-2,3-dihydro-4H-1,4-thiazin-5-yl) carboxylate (0.75 g) in methylene chloride (10 ml) was added dropwise.
The reaction was allowed to stir at room temperature for 24 hours. The precipitated precipitate was taken out, dissolved in ethyl acetate (100 ml), washed with 0.5N-HCl, washed with water, dried and concentrated to dryness. The obtained syrup was recrystallized from hexane-ether to give colorless needles (0.35
g, 42%).

Melting point 66-67 ° C Elemental analysis: C ₉ H ₁₄ N ₂ O ₂ S C (%) H (%) N (%) Calculated: 50.45; 6.59; 13.07 Found: 50.68; 6.58; 12.93 ¹ H-NMR (D ₆ -DMSO) δ: 0.87 (3H, t), 1.10-1.65 (4H,
m), 3.30 (2H, s), 3.15 (2H, t), 6.62 (1H, s), 8.18 (1
H, brs) The following compounds were obtained in the same manner as in Example 17.

Example 22 2- (m-chlorobenzoyloxy) -5-phenyl-
2H-1,4-thiazin-3 (4H) -one (2.0 g) was dissolved in methylene chloride (25 ml), and m-chloroperbenzoic acid (1.7 g) in methylene chloride (25 ml) was stirred at room temperature while stirring. Was added dropwise. Stirred at room temperature for 24 hours. The reaction solution was concentrated to dryness, and the obtained residue was crystallized from ethyl acetate to give colorless needles (2.45 g, 91%).

Mp 161-163 ° C. Elemental analysis C ₁₇ H ₁₂ ClNO ₃ S as C (%) H (%) N (%) Calculated: 59.05; 3.50; 4.05 ^{Found: 59.08; 3.52; 4.04 1 H} -NMR (CDCl ₃ ) δ: 5.76 (1H, d), 6.41 (1H, d), 7.33
-7.67 (7H, m), 7.73-8.00 (2H, m), 9.48 (1H, brs) The following compounds were obtained in the same manner as in Example 22.

Example 33 2-Ethylamino-5-phenyl-2H-1,4-thiazin-3 (4H) -one 2- (m-chlorobenzoyloxy) -5-phenyl-2H-1,4-thiazine-3 ( After 4H) -one (0.5 g) was dissolved in acetonitrile (50 ml), a 40% methylamine methanol solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The deposited precipitate was removed, and the reaction solution was concentrated to dryness. The obtained residue was crystallized from methylene chloride to obtain colorless powdery crystals (0.31 g, 97%).

Melting point: 189-190 ° C Elemental analysis: C (%) H (%) N (%) as C ₁₁ H ₁₂ N ₂ OS Calculated: 59.97; 5.49; 12.72 Found: 59.94; 5.31; 12.58 ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 4.28 (1H, d), 5.77
(1H, d), 7.2-7.65 (5H, m), 9.83 (1H, brs) The following compounds were obtained in the same manner as in Example 33.

Example 83 4-methyl-5-phenyl-2H-1,4-thiazine-3 (4
H) -one 5-Phenyl-2-H-1,4-thiazine-3 (4H)-
Dissolve on (11.4 g) in acetonitrile (300 ml)
Potassium carbonate (12.4 g) and methyl iodide (33.8 g) were added, and the mixture was heated under reflux for 34 hours. Upon cooling, the formed precipitate was removed and the liquid was concentrated to dryness. The obtained residue was partitioned between methylene chloride (200 ml) and water (100 ml), and the organic layer was concentrated, and the resulting syrup was crystallized from isopropyl ether to give colorless plate crystals (7.8 g, 64%). .

Melting point 95-97 ° C Elemental analysis value: C (%) H (%) N (%) as C ₁₁ H ₁₁ NOS Calculated: 64.36; 5.40; 6.82 Found: 64.43; 5.39; 6.71 ¹ H-NMR (CDCl ₃ ) δ: 2.99 (3H, s), 3.37 (2H, s), 5.93
(1H, d), 7.20-7.60 (5H, m) The following compounds were obtained in the same manner as in Example 83.

Example 88 5-Phenyl-2H-1,4-thiazine-3 (4H) -thione 5-Phenyl-2H-1,4-thiazin-3 (4H) -one (1.0 g) is dissolved in pyridine (25 ml). And phosphorus pentasulfide (0.
58 g) was added thereto, and the mixture was heated and reacted at 50 ° C. for 17 hours while stirring. The residue obtained by concentrating and drying the reaction solution was crystallized from ethanol to obtain prism crystals (0.65 g, 60%).

Melting point: 136-137 ° C Elemental analysis: as C ₁₀ H ₉ NS ₂ C (%) H (%) N (%) Calculated: 57.93; 4.38; 6.76 Found: 57.82; 4.44; 6.61 ¹ H-NMR (CDCl ₃ ) Δ: 3.81 (2H, s), 6.18 (1H, s), 7.42
(5H, s), 9.23 (1H, brs) The following compound was obtained in the same manner as in Example 88.

Example 97 5- (p-chlorophenyl) -3-methylthio-2H-1,
4-thiazine 5- (p-chlorophenyl) -2H-1,4-thiazine-
3 (4H) -one (6.5 g) was dissolved in acetonitrile (150 ml), potassium carbonate (5.6 g) and methyl iodide (11.5 g) were added, and the mixture was stirred at room temperature for 8 hours. The insoluble material was removed, the solution was concentrated to dryness, and the residue was partitioned between methylene chloride (200 ml) and water (100 ml). The organic layer was dried and concentrated to dryness. Recrystallization gave needles (5.5 g, 80%).

Melting point 70-71 ° C Elemental analysis value: C (%) H (%) N (%) as C ₁₁ H ₁₀ ClNS ₂ Calculated value: 51.65; 3.94; 5.48 Found: 51.94; 3.91; 5.37 ¹ H-NMR (CDCl ₃ ) Δ: 2.60 (3H, s), 3.10 (2H, s), 6.20
(1H, s), 7.30 (2H, d), 7.67 (2H, d) The following compounds were obtained in the same manner as in Example 96.

Example 104 5-Phenyl-3 (p-triidino) -2H-1,4-thiazinium iodide 3-methylthio-5-phenyl-2H-1,4-thiazine (6.0 g) was added to dioxane (150 ml). After dissolving, p-toluidine (4.3 g) was added, and while stirring at room temperature, iodine (6.9 g) was added, followed by stirring for 4 hours. The precipitated crude crystals were collected, washed with ethyl ether, and recrystallized from ethanol-ethyl acetate to give prism-like crystals (6.94 g, 63
%).

Melting point: 175-176 ° C Elemental analysis: as C ₁₇ H ₁₇ IN ₂ S C (%) H (%) N (%) Calculated: 50.00; 4.20; 6.86 Found: 50.23; 4.19; 6.90 ¹ H-NMR (d _6- DMSO) δ: 2.35 (3H, s), 3.87 (2H, s), 6.
67 (1H, s), 7.25-7.65 (9H, m) The following compound was obtained in the same manner as in Example 104.

Example 133 4-Methyl-3-methylthio-5-phenyl-2H-1,4
-Thiazinium iodide 4-methyl-5-phenyl-2H-1,4-thiazine-3
(4H) -Thion (5.0 g) was dissolved in acetone (30 ml), methyl iodide was added, and the mixture was heated under reflux for 7 hours. The resulting precipitate was collected by cooling, washed with isopropyl ether, and dried to give a yellow powder (6.1 g, 74%).

Melting point: 153-155 ° C Elemental analysis: as C ₁₂ H ₁₄ lNS ₂ C (%) H (%) N (%) Calculated: 39.67; 3.88; 3.86 Found: 39.83; 3.83; 3.95 ¹ H-NMR (d ₆ −DMSO) δ: 1.98 (3H, s), 2.85 (3H, s), 3.
40 (2H, s), 6.12 (1H, s), 7.25-8.00 (5H, m) Example 134 4-Methyl-3-methylthio-5-phenyl-4H-1,4
-Thiazine The thiazinium salt (0.5 g) obtained in Example 133 was suspended in ethyl ether (25 ml), and potassium tert-butoxide (0.
155 g) and stirred at room temperature for 3 hours. Remove insolubles,
The liquid was concentrated to dryness. The residue obtained is methylene chloride (25
ml) and water (10 ml), and syrup (0.
(25 g, 77%). ¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 2.97 (3H, s), 5.07
(1H, s), 5.22 (1H, s), 7.32 (5H, s) Example 135 4-Methyl-3- (3,4-methylenedioxyphenyl)
Imino-5-phenyl-3,4-dihydro-2H-1,4-thiazine The 3-methylthio form (1.3 g) obtained in Example 134 was dissolved in dioxane (25 ml) to give 3,4-methylenedioxyaniline (0.76 g) in methanol (25 ml) was added dropwise at room temperature. After the addition, methanol (25 ml) was added, and the mixture was stirred at room temperature for 24 hours. The insoluble material was removed, the solution was concentrated to dryness, and the obtained residue was dissolved in ethyl acetate-ethanol. A solution of oxalic acid (0.5 g) in ethyl acetate was added, and the precipitated oxalate of aniline was removed. The crude crystal obtained by concentrating the solution was recrystallized from acetone to give colorless prism-like crystals (0.98 g, 43%). )
I got

Mp 155-160 ° C. Elemental analysis _{C 20 H 18 N 2 O 6} S as C (%) H (%) N (%) Calculated: 57.96; 4.38; 6.76 ^{Found: 57.40; 4.43; 6.69 1 H} -NMR (D ₆ -DMSO) δ: 2.98 (3H, s), 3.24 (2H, s), 5.
95 (2H, s), 6.22 (1H, dd), 6.38 (1H, d), 6.80 (1H,
d), 7.38 (5H, s) The following compounds were obtained as in Example 135.

Example 140 2-Acetylamino-5-phenyl-2H-1,4-thiazin-3 (4H) -one 2-amino-5-phenyl-2H-1,4 obtained in Example 34
-Thiazine-3 (4H) -one (1.5 g) was added to pyridine (25 m
l), acetic anhydride (2 ml) was added, and the mixture was stirred at room temperature for 26 hours. The reaction mixture was concentrated to dryness and the resulting crude crystals were recrystallized from ethanol-ethyl acetate to give colorless needles (1.
05g, 58%).

Melting point: 207-208 ° C Elemental analysis: as C ₁₂ H ₁₂ N ₂ O ₂ S C (%) H (%) N (%) Calculated: 58.05; 4.87; 11.28 Found: 58.25; 4.92; 11.28 ¹ H-NMR (CDCl ₃ ) δ: 2.03 (3H, s), 5.50 (1H, d), 5.92
(1H, s), 7.20-7.62 (5H, m), 8.17 (1H, d), 9.75 (1H,
br s) The following compounds were obtained in the same manner as in Example 140.

Formulation Example When the compound of the present invention is used as a therapeutic agent for rheumatoid arthritis, bronchial asthma, allergic disease, arteriosclerosis and ischemic heart disease, it can be used, for example, by the following formulation.

1. Tablets (1) 3- (4-chloroanilino) -5- (3,4-dihydroxyphenyl) -2H-1,4-thiazine 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) microcrystalline cellulose 30mg (5) Magnesium stearate 5mg 230mg (1), (2), 2/3 of (3) and (4) and (5)
After mixing half of the mixture, granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

2. Capsule (1) 3- (4-anisidino) -5-phenyl-2-H
1,4-thiazine 10mg (2) Lactose 100mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10mg 190mg After mixing 1/2 of (1), (2), (3) and (4) Granulate. Add the remaining (4) to the granules,
Enclose the whole in a gelatin capsule.

3. Ointment (a) (1) N- (p-chlorophenyl)-[2- (3,4-dihydroxyphenyl) -3-oxo-3,4-dihydro-2
H-1,4-thiazin-5-yl] carboxamide 1.25 g (2) White petrolatum 98.75 g 100.00 g (2) is heated, and (1) is added and dissolved. It cools gradually with stirring to form an ointment.

Experimental Example 1 5-HETE and the sample liquid produced inhibition adjustment of LTB ₄ (final concentration of 10 [mu] M, 1 [mu] M, from 0.1 [mu] M) in RBL-1 cells (rat basophilic leukemia cell
s) were suspended in MCM (mast cell medium, 0.9ml) containing 10 ^7, and allowed to stand at 37 ° C. 5 min. Next, arachidonic acid (50μ
g) and A-23187 (calcium ionophore) (1 μg)
Was added, and further reacted at 37 ° C. for 5 minutes. After the reaction, ethanol (4 ml) was added, and the mixture was shaken well. The mixture was centrifuged at 2,000 rpm for 10 minutes at room temperature, and the supernatant was concentrated under reduced pressure. The residue was dissolved in 60% methanol (0.5 ml), and this solution (100 µ) was taken and subjected to high performance liquid chromatography to give 5-HETE (5-hydroxy-eicosa-t).
It was quantified etraenoic acid) and LTB _4. 5-HETE is 23
For 7 nm or LTB _4, the absorption at 270 nm was measured with an ultraviolet absorption monitor.

 The experimental results are as shown in Table-12.

Experimental Example 2 Inhibition of 12-HETE and HHT production Using 3.2% sodium citrate (9 volumes of whole blood and 1 volume of sodium citrate solution), rats (Jcl: Wiste) were used.
r, male, 12 to 15 weeks old) was opened under anesthesia, and 8 ml of blood was collected from the abdominal vena cava. Blood is centrifuged at room temperature at 800 rpm for 10 minutes, and platelet-rich plasma (PRP: platelet rich plam
a) is collected, and the remaining blood is further centrifuged at 3000 rpm for 10 minutes to obtain platelet poor plasma (PPP). The number of platelets in PRP was measured, and PRP was diluted with PPP to adjust the platelet concentration to about 1,000,000 / μ. To this PRP (0.25 ml) was added arachidonic acid (125 μg) and a test compound (final concentration: 10 μM, 10 μM, 1 μM, 0.1 μM), and the reaction was carried out at 37 ° C. for 15 minutes. After the reaction, ethanol (1.1 ml) was added, the mixture was shaken well, and then centrifuged at 2000 rpm for 10 minutes to separate the supernatant. Water (1 ml) was added to the supernatant (1 ml) and subjected to high performance liquid chromatography.
HT and 12HETE were quantified. 12-HETE, HHT is the absorption of 240nm measured with a ultraviolet absorbing monitor, to calculate the IC _50. The experimental results are as shown in Table-12.

EXPERIMENTAL EXAMPLE 3 Phospholipase A ₂ Inhibitory Effect 20% of 1M-glycine sodium buffer (pH8.4, 50μ)
mM calcium chloride aqueous solution (0.1 m), test solution (final concentration: 10 μM, 10 μM, 1 μM, 0.1 μM, 10 μl), phospholipase A ₂ (porcine pancrease, 0.63 μg protein, 0.2 μm)
5 ml) and shaken at 37 ° C. for 10 minutes. Dimyristyl
A 0.1 M sodium glycine buffer (pH 8.4, 0.2 ml) containing L-α-choline phosphate (0.1 mg) was added, and the mixture was shaken at 37 ° C for 10 minutes. After addition of i-propanol-heptane-1N-sulfuric acid (40: 20: 1,2 ml), a solution of palmitic acid (0.1 g) in methanol (0.2 ml) and then heptane (2 ml)
And H ₂ O (1 ml) were added and shaken for 15 minutes. After centrifugation at 2000 rpm for 5 minutes, the supernatant was separated and silicic acid (15
0 mg) and shaken for 1 minute. After centrifugation at 200 rpm for 5 minutes, take the supernatant (0.5 ml), concentrate to dryness, and add 0.05%
Methanol solution of 9-anthrenyldiazomethane (0.2m
l) was added and reacted at 40 ° C. for 30 minutes. Methanol (0.8 ml) was added, and the mixture was subjected to high performance liquid chromatography to quantify methyl myristate and methyl palmitate. Each methyl ester
The absorption at 254 nm was measured with an ultraviolet absorption monitor. The experimental results are as shown in Table-12.

Experimental Example 4 Lipid Peroxide Production Inhibition The production of lipid peroxide using a homogenate was carried out by the method of Stocks et al. [J. Stocks et al., Clin, Sci. Mol. Med., 47 , 215-
222 (1974)]. That is, Wistar rats (male, 10 weeks old) were decapitated, and brain tissue was taken out and homogenized by adding 4 volumes of phosphate buffered saline (pH 7.5, 100 mM). The obtained homogenate was centrifuged (2,700 rpm, 10 minutes), and the supernatant was diluted 3-fold with the same buffer (protein concentration, about 50 mg / ml). 1 ml thereof was transferred to a 10 ml test tube, ethanol solutions (10 μ) of test compounds at various concentrations were added, mixed, and incubated at 37 ° C. for 1 hour. The reaction was stopped by adding 35% perchloric acid (200μ), and after centrifugation (3,000 rpm, 10 minutes), the lipid peroxide in the supernatant was removed by a method such as 0hkawa et al. [H. Ohkawa et al., An.
al. Biochem. 95 , 351-358 (1979)].
That is, thiobarbituric acid (0.67%, 0.5 ml) dissolved in 50% acetic acid was added to 0.5 ml of the supernatant, and heated at 95 ° C for 60 minutes.
After cooling in ice water, the absorbance at 532 nm was measured with a spectrophotometer. From the absorbance at each concentration of the test substance,
IC ₅₀ was calculated. The results are as shown in Table-12.

Experimental Example 5 Anti-Hypoxya Effect The test was performed by the Hypobaric hypoxia method [H. Yasuda et al.
al., Arch.int.Pharmacodyn. 233 , 136-144 (1978)].
The experimental apparatus consisted of a desiccator (A room, internal volume: 40.2 liters) depressurized to 35 mmHg by a vacuum pump, and a desiccator (B room) with an internal volume of 12.6 liters connected to this via a stopcock. By opening the cock between room B and room A, a hypoxia of 208 mmHg can be obtained within 20 seconds. Mice (ICR / Jcl, 5-6 weeks old) for one experiment
Eight animals were used, 4 animals were a control group, and the remaining 4 animals were a test substance administration group. The test substance was suspended in 5% gum arabic and the animal was placed in room B 30 minutes after intraperitoneal administration, and the time from when the cock was opened to when the animal stopped breathing (survival time) was measured. The control group received 5% gum arabic intraperitoneally. Animals that did not die after 15 minutes were calculated as having a survival time of 15 minutes. The evaluation of the test substance was expressed as a relative value when the survival time of the animals in the control group was 100. Do the same experiment 2
Repeated times, average ± SE of control group 8 and test substance administration group 8
M was calculated. The experimental results are as shown in Table-13.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI // A61K 31/00 637 A61K 31/00 637E 639 639C 643 643D 31/54 31/54 601 601 C12N 9/99 C12N 9/99 (56) References. Med. Chem. (1988), 31, pages 1575-1579 Chemistry Letters s. (1982), pages 527-528 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 279/00-279/36 C07D 417/00-417/14 A61K 31/00-31/80 CA (STN ) REGISTRY (STN)

Claims (13)

(57) [Claims] (1) Expression [Wherein, when A represents -N =, B is hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C _1-4 alkyl, nitro, amino, C _1-4 alkylamino, diC _{1 -4} pyrrolyl group optionally having 1 to 2 substituents selected from alkylamino and halogen,
(I) an alkyl group having 1 to 8 carbon atoms, (ii) an alkyl group having 2 to 8 carbon atoms
An alkenyl group of (iii) an aralkyl group having 7 to 10 carbon atoms, wherein the benzene ring may be substituted with halogen, nitro, amino, _C1-4 alkyl or _C1-4 alkoxy, (iv)
An aryl group optionally having one or two substituents selected from halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy,
(V) an acyl group derived from a carboxylic acid having 2 to 7 carbon atoms, (v
i) an amino group, (vii) an amino group optionally having 1-2 substituents selected from C _1-4 alkylcarbamoyl and (viii) C _1-4 alkylthiocarbamoyl, and having 1 carbon atom
A represents a hydrazino group, an alicyclic amino group, or an alkylthio group which may be substituted with an alkyl group having 2 to 3 or an alkanoyl group having 2 to 4 carbon atoms; Wherein R ² is hydrogen or (i) hydroxy, (ii)
Selected from halogen, (iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy And B represents oxo, thioxo, or a group represented by an aliphatic hydrocarbon group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may have 1 to 2 substituents. = A group represented by N-NHR ⁶ (R ⁶
Represents an alkanoyl group having 2 to 4 carbon atoms, an alkoxycarbonyl having 2 to 5 carbon atoms or thiocarbamoyl which may be substituted with an alkyl having 1 to 4 carbon atoms), a group represented by the formula: NR ¹⁵ (R ¹⁵ is hydrogen or halogen,
Represents an aromatic hydrocarbon group optionally having 1 to 2 substituents selected from nitro, amino, _C1-4 alkyl, _C1-4 alkoxy, _C2-5 alkoxycarbonyl and hydroxy) or formula Wherein R ⁷ and R ⁸ are the same or different and each represents cyano, carbamoyl, alkoxycarbonyl having 2 to 5 carbon atoms, phenyl or p-chlorophenyl, and R ¹ represents hydrogen, an alkoxy group, An acyloxy group, an alkylthio group, (i) an alkyl group having 1 to 8 carbon atoms,
(Ii) alkenyl group having 2 to 8 carbon atoms, (iii) benzene ring is halogen, nitro, amino, C _1-4 alkyl or C
_1-4 aralkyl group having 7-10 carbon atoms which may be substituted by alkoxy, (iv) halogen, nitro, amino, C _1-4
An aryl group optionally having one or two substituents selected from alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy, (v) an acyl derived from a carboxylic acid having 2 to 7 carbon atoms Group, (vi) amino group, (vii) amino group optionally having 1 to 2 substituents selected from _C1-4 alkylcarbamoyl and (viii) _C1-4 alkylthiocarbamoyl, carbon number 1 Alkyl group of 3 or 2 carbon atoms
A hydrazino group which may be substituted with an alkanoyl group, an alicyclic amino group, hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C _1-4 alkyl, nitro,
Amino, C _1-4 alkylamino, di C _1-4 alkylamino and aromatic optionally having substituent 1-2 selected from halogenated hydrocarbon group or a hydroxy, methyl,
R ³ represents an aromatic heterocyclic group which may have one or two substituents selected from methoxy, amino, dimethylamino and halogeno, and R ³ represents (i) hydroxy, (ii) halogen, (iii) cyano , (Iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy, Aliphatic hydrocarbon group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may have one, halogen, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, C _2-5 Alkanoyloxy, C _1-4 alkyl,
An aromatic hydrocarbon group which may have 1 to 2 substituents selected from nitro, amino, C _2-8 acylamino and hydroxy, or a carboxy group which may be esterified or amidated; ⁴ is hydrogen, (i) hydroxy, (ii) halogen,
(Iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4
An aliphatic hydrocarbon group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may have 1 to 2 substituents selected from alkoxy, C _2-5 alkoxycarbonyl and hydroxy Or halogen, C _1-4 alkoxy,
C _2-5 alkoxycarbonyl, C _2-5 alkanoyloxy, C
_Represents an aromatic hydrocarbon group which may have 1 to 2 substituents selected from _1-4 alkyl, nitro, amino, C _2-8 acylamino and hydroxy; (Wherein A is -NH-, B is oxo, R ¹ is hydrogen, R ³ is methyl or ethoxycarbonyl, R ⁴
Or a salt thereof. (2) [Wherein, when A represents -N =, B is hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C _1-4 alkyl, nitro, amino, C _1-4 alkylamino, diC _{1 -4} pyrrolyl group optionally having 1 to 2 substituents selected from alkylamino and halogen,
(I) an alkyl group having 1 to 8 carbon atoms, (ii) an alkyl group having 2 to 8 carbon atoms
An alkenyl group of (iii) an aralkyl group having 7 to 10 carbon atoms, wherein the benzene ring may be substituted with halogen, nitro, amino, _C1-4 alkyl or _C1-4 alkoxy, (iv)
An aryl group optionally having one or two substituents selected from halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy,
(V) an acyl group derived from a carboxylic acid having 2 to 7 carbon atoms, (v
i) an amino group, (vii) an amino group optionally having 1-2 substituents selected from C _1-4 alkylcarbamoyl and (viii) C _1-4 alkylthiocarbamoyl, and having 1 carbon atom
A represents a hydrazino group, an alicyclic amino group, or an alkylthio group which may be substituted with an alkyl group having 2 to 3 or an alkanoyl group having 2 to 4 carbon atoms; Wherein R ² is hydrogen or (i) hydroxy, (ii)
Selected from halogen, (iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy Represents an aliphatic hydrocarbon group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may have 1 to 2 substituents).
Is an oxo, thioxo, group represented by the formula = N-NHR ⁶ (R ⁶ is an alkanoyl group having 2 to 4 carbon atoms, an alkoxycarbonyl having 2 to 5 carbon atoms or an alkyl having 1 to 4 carbon atoms, Thiocarbamoyl), the formula =
A group represented by N—R ¹⁵ (R ¹⁵ is hydrogen or a substituent selected from halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy; (Indicating an aromatic hydrocarbon group which may have two)
Or expression Wherein R ⁷ and R ⁸ are the same or different and each represents cyano, carbamoyl, alkoxycarbonyl having 2 to 5 carbon atoms, phenyl or p-chlorophenyl, and R ¹ represents hydrogen, an alkoxy group, An acyloxy group, an alkylthio group, (i) an alkyl group having 1 to 8 carbon atoms,
(Ii) alkenyl group having 2 to 8 carbon atoms, (iii) benzene ring is halogen, nitro, amino, C _1-4 alkyl or C
_1-4 aralkyl group having 7-10 carbon atoms which may be substituted by alkoxy, (iv) halogen, nitro, amino, C _1-4
An aryl group optionally having one or two substituents selected from alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy, (v) an acyl derived from a carboxylic acid having 2 to 7 carbon atoms Group, (vi) amino group, (vii) amino group optionally having 1 to 2 substituents selected from _C1-4 alkylcarbamoyl and (viii) _C1-4 alkylthiocarbamoyl, carbon number 1 Alkyl group of 3 or 2 carbon atoms
A hydrazino group which may be substituted with an alkanoyl group, an alicyclic amino group, hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C _1-4 alkyl, nitro,
Amino, C _1-4 alkylamino, di C _1-4 alkylamino and aromatic optionally having substituent 1-2 selected from halogenated hydrocarbon group or a hydroxy, methyl,
R ³ represents (i) hydroxy, (ii) halogen, (iii) an aromatic heterocyclic group which may have one or two substituents selected from methoxy, amino, dimethylamino and halogeno. Substituents selected from cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy are 1 to An aliphatic hydrocarbon group which may be substituted with a substituent selected from two aromatic hydrocarbon groups which may have two, halogen, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, C _{2- 5} alkanoyloxy, C _1-4 alkyl,
An aromatic hydrocarbon group which may have 1 to 2 substituents selected from nitro, amino, C _2-8 acylamino and hydroxy, or a carboxy group which may be esterified or amidated; ⁴ is (i) hydroxy, (ii) halogen, (iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _{2 -5} aliphatic hydrocarbon group or halogen which may be substituted with a substituent selected from an aromatic hydrocarbon group which may have 1 to 2 substituents selected from alkoxycarbonyl and hydroxy, C _It has one or two substituents selected from _1-4 alkoxy, C _2-5 alkoxycarbonyl, C _2-5 alkanoyloxy, C _1-4 alkyl, nitro, amino, C _2-8 acylamino and hydroxy. Aromatic hydrocarbon group Wherein the broken line indicates that one of the bonds is a double bond]. 3. R ⁴ is selected from halogen, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, C _2-5 alkanoyloxy, C _1-4 alkyl, nitro, amino, C _2-8 acylamino and hydroxy. The compound according to claim 2, which is an aromatic hydrocarbon group optionally having 1 to 2 substituents. (4) [Wherein, when A represents -N =, B is hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C _1-4 alkyl, nitro, amino, C _1-4 alkylamino, diC _{1 -4} pyrrolyl group optionally having 1 to 2 substituents selected from alkylamino and halogen,
(I) an alkyl group having 1 to 8 carbon atoms, (ii) an alkyl group having 2 to 8 carbon atoms
An alkenyl group of (iii) an aralkyl group having 7 to 10 carbon atoms, wherein the benzene ring may be substituted with halogen, nitro, amino, _C1-4 alkyl or _C1-4 alkoxy, (iv)
An aryl group optionally having one or two substituents selected from halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy,
(V) an acyl group derived from a carboxylic acid having 2 to 7 carbon atoms, (v
i) an amino group, (vii) an amino group optionally having 1-2 substituents selected from C _1-4 alkylcarbamoyl and (viii) C _1-4 alkylthiocarbamoyl, and having 1 carbon atom
A represents a hydrazino group, an alicyclic amino group, or an alkylthio group which may be substituted with an alkyl group having 2 to 3 or an alkanoyl group having 2 to 4 carbon atoms; Wherein R ² is hydrogen or (i) hydroxy, (ii)
Selected from halogen, (iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy Represents an aliphatic hydrocarbon group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may have 1 to 2 substituents).
Is an oxo, thioxo, group represented by the formula = N-NHR ⁶ (R ⁶ is an alkanoyl group having 2 to 4 carbon atoms, an alkoxycarbonyl having 2 to 5 carbon atoms or an alkyl having 1 to 4 carbon atoms, Thiocarbamoyl), the formula =
A group represented by N—R ¹⁵ (R ¹⁵ is hydrogen or a substituent selected from halogen, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy; (Indicating an aromatic hydrocarbon group which may have two)
Or expression Wherein R ⁷ and R ⁸ are the same or different and each represents cyano, carbamoyl, alkoxycarbonyl having 2 to 5 carbon atoms, phenyl or p-chlorophenyl, and R ¹ represents hydrogen, an alkoxy group, An acyloxy group, an alkylthio group, (i) an alkyl group having 1 to 8 carbon atoms,
(Ii) alkenyl group having 2 to 8 carbon atoms, (iii) benzene ring is halogen, nitro, amino, C _1-4 alkyl or C
_1-4 aralkyl group having 7-10 carbon atoms which may be substituted by alkoxy, (iv) halogen, nitro, amino, C _1-4
An aryl group optionally having one or two substituents selected from alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl and hydroxy, (v) an acyl derived from a carboxylic acid having 2 to 7 carbon atoms Group, (vi) amino group, (vii) amino group optionally having 1 to 2 substituents selected from _C1-4 alkylcarbamoyl and (viii) _C1-4 alkylthiocarbamoyl, carbon number 1 Alkyl group of 3 or 2 carbon atoms
A hydrazino group which may be substituted with an alkanoyl group, an alicyclic amino group, hydroxy, C _2-5 alkoxycarbonyl, C _1-4 alkoxy, C _1-4 alkyl, nitro,
Amino, C _1-4 alkylamino, di C _1-4 alkylamino and aromatic optionally having substituent 1-2 selected from halogenated hydrocarbon group or a hydroxy, methyl,
R ³ represents an aromatic heterocyclic group which may have 1 to 2 substituents selected from methoxy, amino, dimethylamino and halogeno, and R ³ represents (i) halogen, C _1-4 alkoxy, C _{2 A} phenyl group or amide optionally having one or two substituents selected from _-5 alkoxycarbonyl, C _2-5 alkanoyloxy, C _1-4 alkyl, nitro, amino, C _2-8 acylamino and hydroxy R ⁴ represents hydrogen, (i) hydroxy, (ii) halogen,
(Iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C _1-4 alkyl, C _1-4
An aliphatic hydrocarbon group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may have 1 to 2 substituents selected from alkoxy, C _2-5 alkoxycarbonyl and hydroxy Or halogen, C _1-4 alkoxy,
C _2-5 alkoxycarbonyl, C _2-5 alkanoyloxy, C
_Represents an aromatic hydrocarbon group which may have 1 to 2 substituents selected from _1-4 alkyl, nitro, amino, C _2-8 acylamino and hydroxy; Or a salt thereof. Wherein R ¹ is hydrogen, primary or secondary amino group substituted with an alkyl of 1 to 3 carbon atoms, alkoxy groups and ortho having 1 to 3 carbon atoms, meta, para positions 1-2 U The compound according to claim 1, which is a phenyl group having a hydroxy or C _1-4 alkoxy. 6. The compound according to claim 1, wherein A is -N = or -NH-. 7. R ³ is halogen, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, C _2-5 alkanoyloxy, C _1-4 alkyl, selected nitro, amino, a C _2-8 acylamino and hydroxy The compound according to claim 1, which is a phenyl group optionally having 1 to 2 substituents or an amidated carboxyl group. 8. A method according to claim 8, wherein R ⁴ is hydrogen or (i) hydroxy,
(Ii) halogen, (iii) cyano, (iv) C _2-5 alkoxycarbonyl and (v) halogen, nitro, amino, C
_1-4 alkyl, C _1-4 alkoxy, C _2-5 substituted with a substituent selected from aromatic hydrocarbon groups which may have one or two substituents selected from alkoxycarbonyl and hydroxy The compound according to claim 1, which is an aliphatic hydrocarbon group which may be substituted. (9) a 5-phenyl-2H-1,4-thiazine-3 (4
The compound according to claim 1, which is H) -one. 10. A method according to claim 10, wherein 5- (p-methoxyphenyl) -2H-1,
The compound according to claim 1, which is 4-thiazin-3 (4H) -one. (11) 3-methylthio-5-phenyl-2H-1,
The compound according to claim 1, which is 4-thiazine. 12. The compound according to claim 1, which is 5- (p-methoxyphenyl) -3-methylthio-2H-1,4-thiazine. 13. A method for producing 3-methoxycarbonylhydrazono-5.
The compound according to claim 1, which is -phenyl-2H, 4H-1,4-thiazine.