JPH02275869A - 1,4-thiazine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [A is N or NR<2> (R<2> is H or aliphatic hydrocarbon group); B is pyrrolyl, amino or alkylthio when A=N; or B is oxo, thioxo, hydrazino, imino or alkylidene when A=NR<2>; R<1> is H, alkoxy, acyloxy, alkylthio, aromatic hydrocarbon group or aromatic heterocyclic ring group; R<3> is aliphatic or aromatic hydrocarbon group or carboxyl; R<4> is H or aliphatic or aromatic hydrocarbon group] or a salt thereof. EXAMPLE:5-Phenyl-2H-1,4-thiazine-3(4H)-one. USE:A medicine such as phospholipase A2, lipoxygenase or cycloxygenase, having an enzyme-inhibiting action, a lipidperoxide production-inhibiting action and an anti-hypoxia action. PREPARATION:For example, a compound of formula II (X is halogen) is reacted with a compound of formula III to prepare a compound of formula IV corresponding to the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel 1,4-thiazine derivatives useful as pharmaceuticals.

Prior Art 1. Synthesis method of 4-thiazine derivative is Il, 5okol
etc.

J, A+++, Chen, Soc,, 70. 351
7 (1948), G.D.

5tevens et al., J.Am.Chem.Soc.
80. 5198 (1958), G, S, 5ki
Nner et al., J,^m,Chem,Soc,, 82, 3756 (1959), C,R,Johnso
n et al., J. l1etero, Chem., 6
.

247 (1969), G. V. Rao et al., 5y
nthesis, l 972°136, M, tlo
Jo et al., 5ynthesis, l 979. 2
72, M, l1ojo et al., J, Org, Chem
,, 53. 2209 (+988), Japanese Patent Application Publication No. 1983-
301876, JP 61-225174. Unexamined Japanese Patent Publication 1986
-18776 etc., but if 5oko
1st place, J, Am, Chem, Soc,, 70+
3517 (194g) states that 1°4-thiazine derivatives having a phenyl substituent at the 5-position cannot be synthesized, and G. S. Skinner et al., J.
Am, Chem, Soc, , 81.

3756 (1959) with disubstituted 5-phenyl-1 at the 2-position
゜The synthesis of only the 4-thiazine derivative has been reported, and the 5-phenyl-1,4-thiazin-3-one derivative (1a) used as one of the synthetic raw materials in the present invention has been reported in the literature. This is a new compound that has not been previously reported.

On the other hand, regarding the pharmacological effects of 1,4-thiazine derivatives in sandals, JP-A No. 63-301876 shows anti-endotoxin action, JP-A No. 61-225174 shows inotropic action, and JP-A No. 61-18776 shows anti-rheumatic action. Effects have been reported.

Problems to be Solved by the Invention The present invention provides a novel compound 1, which has an enzyme inhibitory effect such as phospholipase Ay, lipoxygenase, and cyclooxygenase, an inhibitory effect on lipid peroxide production, and an antihypoxia effect.
4-thiazine derivatives are provided.

The present invention relates to the formula [wherein A represents -N-, B represents an optionally substituted pyrrolyl group, an optionally substituted amide group, or an alkylthio group, and A or -NR' (in the formula , R'' represents hydrogen or an optionally substituted aliphatic hydrocarbon group), B is oxo.

Thioxo, optionally substituted hydrazo7 group, optionally substituted imino group or alkylidene group R
+ is hydrogen, an alkoxy group, an alkyloxy group, an alkylthio group, an optionally substituted amide group, an optionally substituted aromatic hydrocarbon group, or an optionally substituted aromatic heterocyclic ring R3 represents an optionally substituted aliphatic or aromatic hydrocarbon group or an optionally esterified or amidated carboxyl group, R4
indicates hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon group, and a broken line indicates that one of the bonds is a double bond] or a salt thereof.

, L - Regarding the soft formula (+), the optionally substituted amine 7 group represented by R1 includes, for example, an unsubstituted amine 7 group, an alkyl group having about 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl, etc.), alkenyl groups having about 2 to 8 carbon atoms (L vinyl, allyl).

1,-7'robenyl, i-propenyl, 2-butenyl.

1.3-butadienyl, 2-pentenyl, ■-hexenyl, l-hebutenyl, ■-octenylnato), carbon number 7
~1O of optionally substituted aralkyl groups (e.g.
Halogen, nitro, amino + C1゜alkyl + Cl-4
Benzyl which may be substituted on the benzene ring with an alkoxy group, etc.)5. (untyl, phenylpropyl, phenylbutyl groups).

Preferably substituted aryl groups (e.g.), rogens.

Nitro amino + Cl-4 alkyl, C, -, alcoquine + C! -6 alkoxycarbonyl, a phenyl group which may have one or two substituents such as hydroxy)
, an acyl group derived from a carbonic acid having about 2 to 7 carbon atoms (e.g.
having one or two substituents such as acetyl, propionyl, butyryl i-butyryl, hexanoyl, optionally substituted benzoyl, trifluoroacetyl, etc.), amine group, C7-, alkylcarbamoyl, C alkylthiocarbamoyl, etc. 7 groups, an alkyl group with about 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, etc.) or an alkanoyl group with about 2 to 4 carbon atoms (e.g., acetyl, propionyl, phthyryl, i- butyryl, etc.), an optionally substituted hydrazino group, an optionally substituted alicyclic amino group (e.g., piperidino,
piperazinyl, morpholino, N-phenylpiperazino,
Azetidinyl.

phloridinil, etc.).

The alkoxy group represented by R1 has, for example, a carbon number of 1
-4 (eg, methoxy, ethoxy, propoxy, i-propoxy, butoxyri-butoxy, allyloxy, etc.).

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

Examples of the acyloxy group represented by R1 include acyl derived from a carboxylic acid having about 2 to 7 carbon atoms. Examples of the acyloxy group represented by R1 include acetyloxy, propionyloxy, butyryloxy,
i-Butyryloxy.

Examples include hexanoyloxy, optionally substituted penzoyloxy, trifluoroacetyloxy, and the like.

The optionally substituted aromatic hydrocarbon group represented by R1 includes, for example, 1 to 2 hydroxys at the ortho, meta, and para positions, Cl-5 alkoxycarbonyl, Cl-4 alkoxy+Cl-4 alkyl, nitro, Amine + Cl-
Examples include phenyl which may have a substituent such as 4-furkylamino, di-C1-4 alkylamino, and halogen.

The optionally substituted aromatic heterocyclic ring represented by R1 may have, for example, 1 to 2 substituents such as hydroxy, methyl, methyl, amine, dimethylamino, and halogen. 5-8 containing ~2 heteroatoms
Examples include membered aromatic heterocyclic rings (eg, furyl, thienyl, pyrrolinyl, etc.).

R1 is hydrogen, a primary or secondary ami7 group substituted with an alkyl having about 1 to 3 carbon atoms, an alkoxy group having about 1 to 3 carbon atoms, and ortho and meta.

Preferred is phenyl having 1 to 2 substituents such as hydroxy + Cl-4 alkoxy at the para position, and further hydrogen,
Methylamino, methoxy and ortho.

Phenyl having 1 to 2 hydroxys at the meta and para positions is preferred.

Regarding the above soft formula (1), the optionally substituted amine group represented by B includes the same ones as the optionally substituted amino group represented by R1 above,
Among them, an unsubstituted amine group or a primary amine group (-N
HRa is preferred, and the substituent R5 of the primary amine 7 group is, for example, lower alkyl having about 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl, i-propyl, phthyl, i-7
'chill, etc.), alkali/yl having about 2 to 4 carbon atoms (e.g.,
acetyl, propionyl, butyryl, trifluoroacetyl, etc.), optionally substituted benzoyl, optionally substituted aromatic hydrocarbon groups (e.g., ortho, meta 2
1 to 2 halogens, nitro, amino + Cl- in the rose position
4 alkyl + Cl-4 alkoxy.

Ct-s alkoxycarbonyl, phenyl which may have a substituent such as hydroxy, etc.).

Examples of the optionally substituted hydrazino group represented by B include a group represented by the formula =N-N[(R@, where R@ is an alkanoyl group having about 2 to 4 carbon atoms (e.g. , acetyl, propionyl.

butyryl, trifluoroacetyl, etc.), carbon number 2-5
thiocarbamoyl optionally substituted with alkoxycarbonyl (e.g., metquin carbonyl, ethoxycarbonyl, etc.) or alkyl having about 1 to 4 carbon atoms (e.g., methylthiocarbamoyl).

ethylthiocarbamoyl, etc.).

Examples of the optionally substituted alkylidene group represented by B include a group represented by the formula =C<,
R7 and R@ may be the same or different, R',
For example, cyano is used as “R”.

Examples include carbamoyl, alkoxycarbonyl having about 2 to 5 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.), and optionally substituted aromatic hydrocarbon groups (N, phenyl, p-chlorophenyl, etc.).

The optionally substituted pyrrolyl group represented by B is, for example, 2-pyrrolyl which may be substituted with the same group as the substituent of the optionally substituted aromatic hydrocarbon group represented by R1 above. or 3-pyrrolyl.

The alkylthio group represented by B has, for example, a carbon number of 1
- about 4 alkylthio groups (eg, methylthio, etc.).

The optionally substituted imino group represented by B is
For example, a group represented by the formula 2N-R16 may be mentioned, and R'' in the above formula may be, for example, hydrogen or an optionally substituted aromatic hydrocarbon group (eg, ortho).

Halogen, nitro, ami71 C1-4 at meta and para positions
Examples include alkyl + Cl-4 alkoxy + CR-5 alkoxycarbonyl, phenyl which may have one or two substituents such as hydroxy, and the like.

As B, oxo, thioxo, alkylthio, and optionally substituted amine groups are preferable, and among them, halogen + Cl-4 alkyl + Cl-4 at the oxo and para positions
Phenyl-substituted amino groups with i substituted i such as alkoxy are preferred.

Regarding the above soft formula (1), the optionally substituted aliphatic hydrocarbon group represented by Rz or R'' includes hydroxy, halogen, cyano, CI-, alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.) , an optionally substituted aromatic hydrocarbon group (e.g., halokene, nitro, amine + Cl- at the ortho, meta, and para positions)
4 alkyl + Cl-4 alkoxy, Ct-s alkoxycarbonyl, phenyl which may have one or two substituents such as hydroxy), etc., an alkyl group having about 1 to 4 carbon atoms ( Examples include methyl, ethyl, propyl, butyl, etc.).

As for eight, -N= and -N)(- are preferred.

Regarding the above soft formula (1), the optionally substituted aliphatic hydrocarbon group represented by R3 is the same group as the substituent of the optionally substituted aliphatic hydrocarbon group represented by R'' above. An alkyl group having about 4 to 8 carbon atoms that may be substituted with (eg, butyl).

pentyl, hexyl, heptyl, octyl, etc.).

The optionally substituted aromatic hydrocarbon group represented by R3 or R4 includes halogen at the ortho, meta, and para positions (e.g., F, Cρ, Br, .1, etc.), C,-4 alkoxy (L methoxy), , ethoxy, propoxy, butyloxy, etc.), cm-=alkoxycarbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, etc.)
Ct-, alkanoyloxy (e.g., acetyloxy, propionyloxy, butyriroquine, trifluoroacetyloxy, etc.), CI-, alkyl (e.g., methyl, ethyl, propyl, i~propyl, butyl, i-butyl)
, nitro, amino, Ct-a acylamino (e.g., acetylamino, propionylamino, butyrylamino, octylamino.

cyclohexylamino, benzoylamino, etc.).

Examples include phenyl which may have one or two substituents such as hydroxy.

The esterified carboxyl group represented by R3 is, for example, alkoxycarbonyl having about 2 to 5 carbon atoms (
Examples include methoxycarbonyl, ethoxycarbonyl, etc.

Amidated carboxyl group represented by R3 and R
IO is hydrogen, alkyl having about 1 to 18 carbon atoms, and
It represents an alkoxycarbonyl group having about 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), a phenyl group that may be substituted with halogen, etc., and R8
and Rlo together represent an alicyclic amine group (e.g., piperidino, piperazinyl, morpholino, N-phenylpiperazino, azetidinyl, pyrrolidinyl group, etc. which may be substituted with phenyl or halogen, etc.) Examples include groups such as

R3 is preferably an optionally substituted phenyl group or an amidated carboxyl group, and R' may further have 1 to 2 substituents such as halogen or hydroxy at the ortho, meta, or para positions. 1 phenyl group and the formula -CON (R1゜ [wherein, R11
and RIG each represent a phenyl group which may be substituted with hydrogen or a halogen, etc.], and particularly those having 1 to 2 substituents such as halogen, hydroxy, etc. at the ortho, meta, and para positions are preferable. An optionally phenyl group is preferred.

As R4, hydrogen and an optionally substituted aliphatic hydrocarbon group are preferred, and hydrogen and methyl are more preferred.

Among the compounds represented by the above general formula (I) [compound (■)], when A represents -N-, B is phenyl having a substituent such as halogen + Cl-4 alkyl + Cl-4 alkoxy at the para position. indicates a primary amine 7 group substituted with A
When represents -NH-, B represents oxo, R1 is hydrogen,
Primary or secondary substituted with alkyl having about 1 to 3 carbon atoms
class amino, alkoxy having about 1 to 3 carbon atoms, or phenyl which may have 1 to 2 substituents such as hydroxy + Cl-4 alkoxy at the ortho, meta, or para position, and R3 is ortho, meta, 1-2 halogens in the para position,
R8 and R may have substituents such as hydroxy
IG represents a group represented by phenyl which may be substituted with hydrogen or halogen, respectively, and R
More preferred is a compound (bi) in which 4 represents hydrogen or methyl.

Among the above compounds (1), for example, there are compounds in which R3 is etobyldicarbonylmethyl, and there are tautomeric isomers and the same meanings. ) and tautomeric isomers are also included in the present invention.

Examples of the salt of compound (1) include acid addition salts such as hydrochloride;
Inorganic acid salts such as hydrobromides, sulfates, nitrates, phosphates, such as acetates, tartrates, citrates, furalates. Examples include pharmacologically acceptable salts such as organic acid salts such as maleate.

In the above compound (1), when 8 is -N=, the nitrogen atom in the formula may be quaternized, and is represented by ], and in the compound (1), the inorganic acid as A or It may form a salt with an anion (We) of an organic acid, and the salt of compound (I') can be treated with a base (e.g., potassium L-butoxy, sodium hydride, etc.) to form the following Compound (r'') can be derived according to the reaction formula.

group, optionally substituted amide group, or alkylthio group, and other symbols have the same meanings as above] Compound (f'), salt of compound (■'), and compound (i''' ) can be derived more easily than compound (1), and these compounds are also included in the present invention.

Production method The compound of general formula (i) above can be produced, for example, by the method shown below.

Process (a) [In the formula, We represents an anion of the inorganic acid or organic acid, and R1 is optionally substituted pyrrolyl [In the formula, R'
, R' has the same meaning as above. X represents halogen. ] Process (b) Process (e) (XV) [In the formula, R' and R' have the same meanings as above. ] Process (C) (IV) [In the formula, R1, Rff and R4 have the same meanings as above. Coprocess (f) [In the formula, R', R'' and R4 have the same meanings as above.] Process (d) [In the formula, R', R'3 and R4 have the same meanings as above.] Process (g) [In the formula, RI, R!, R3 and R4 have the same meanings as above.][
In the formula, A.

B.

R3 and R4 have the same meanings as above. ] Process (h) [wherein B, R' and R4 have the same meanings as above. ] Process (i) (IVa) (IVb) [In the formula, R11 is a lower alkyl group, Re and RIG
indicates the same meaning as above. Coprocess (j) (■a) (■b) [In the formula, R3 and R4 have the same meanings as above. R14 represents an acyl group. ] The process (a) is a method of directly obtaining compound (IV) by reacting compound ([1) and compound (III) in the presence of a base.

For 1 mol of compound (■), 1 mol of base, compound (n
) is used in excess of 1 mole, for example, about 1.2 to 1.5 moles. As the base, an organic base such as a trialkylamine such as triethylamine or an inorganic base such as potassium carbonate or sodium carbonate is used, and as a solvent, methanol, ethanol, acetone, methyl ethyl ketone, acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, etc. are used. The reaction is carried out using the following solvent.

The reaction conditions were as follows: compound ([) and an appropriate base were dissolved in a solvent, a solution of the same solvent in which compound (III) had been dissolved was added dropwise under water cooling to room temperature over a period of about 30 minutes to 1 hour, and then the solvent was removed. Raise the temperature to the boiling point and keep at 80°C for about 20 to 30 hours.
It is preferable to heat to reflux at a temperature of about 120°C. When benzene, toluene, xylene, etc. are used as a solvent, it is more preferable to carry out the reaction while removing water generated during the reaction.

After the reaction, the reaction product obtained as described above is
When the target product (■) is precipitated as crystals in the reaction solution, it is taken out in a furnace, the solution is concentrated to dryness, and the obtained reaction product is purified using the usual purification method, that is, alcohol.

It can be easily obtained by recrystallization from a solvent such as acetone or ether. In some cases, it can be easily obtained as crystals by conventional isolation and purification methods such as column chromatography. In process (a), the compound <U
Depending on the reactivity of > and the stability of the reaction product (■), the reaction may be completed without the presence of a base.The reaction conditions at that time should be almost the same as those described above. It is preferred that the target compound be isolated and purified in the same manner.

Process (b) is to obtain compound (iV) from the reaction intermediate (XV) produced in process (a) by dehydration ring closure reaction under acidic conditions. Compound (■) and compound (III)
Compound (XV), which can be easily obtained from , is dissolved in a suitable solvent and heated under reflux while removing water produced in the presence of the acid of catalyst (1). As the solvent, it is preferable to use a water-immiscible solvent such as Hensen, toluene and xylene. However, if compound (XV) is insoluble by itself, it is preferable to add dimethylacetamide, dimethylformamide, etc. to about 115 to 1/1O of the above solvent to form a solution. As the acid to be added, it is preferable to use a mineral acid such as sulfuric acid or an organic acid such as p-h luenesulfonic acid in a catalytic amount. The reaction conditions were a reaction temperature of 100
Preferably, the mixture is heated to reflux at a temperature of about 120° C. for a reaction time of about 10 to 50 hours. It is preferable to carry out the reaction while separating water produced during the reaction using a water separator, and the completion of the reaction can be determined by the amount of water separated. Obtained compound (■)
can be easily obtained as a crystal by a method similar to that shown in process (a).

Process (c) involves reacting compound () with m-chloroperbenzoic acid to obtain 2-0-benzoate (■). 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 (■). Dissolving compound (V) in a suitable solvent,
A m-chloroperbenzoic acid solution dissolved in the same solvent is added little by little at a reaction temperature ranging from water cooling to room temperature. After that, it is preferable to react at about 20 to 30°C for about L to 5 hours. As the reaction solvent used at this time, it is preferable to use halogenated hydrocarbons such as chloroform, methylene chloride, and dichloroethane.

The reaction product obtained in the above manner is removed by distilling off the solvent.
After that, the resulting crude product can be recrystallized from a suitable solvent. Compound (Vl) can also be easily purified and isolated by column chromatography.

Process (d) involves reacting compound (Vl) with various nucleophiles to obtain the 2-substituted compound (■).

The reaction is carried out using about 2 to 5 moles of the nucleophile per 1 mole of compound (Vl). The reaction is carried out using commonly used organic solvents,
For example, chloroform, methylene chloride.

The reaction is preferably carried out using dichloroethane, acetone, methyl ethyl ketone, etc., but in order to improve the solubility of the compound (V[) and the nucleophile, an appropriate amount of methanol or ethanol may be added to carry out the reaction as a mixed solvent. Reaction conditions vary depending on the nucleophile used, but usually aliphatic 1
secondary amines (methylamine, ethylamine, propylamine, butylamine, benzylamine, etc.), aliphatic secondary amines (methylamine, diethylamine, etc.), alicyclic amines (piperidine, morpholine, piperazine, etc.).

Aromatic amines (aniline, substituted anilines, etc.).

hydrazines (hydrazine, methylhydrazine, etc.),
When using nucleophiles such as aliphatic alcohols (methanol, ethanol) and mercaptans (methyl mercaptan, phenyl mercaptan, etc.), the reaction temperature is 10-30'.
It is preferable to carry out the reaction at a temperature of about C and a reaction time of about 1 to 30 hours. In addition, when the reaction is carried out using a nucleophile as a salt to promote the reaction (CH5SNa and Ph5Na, etc.)
There is also.

Furthermore, in order to improve the reaction time, yield, etc., the compound (■) may be obtained in a short time and in good yield if the reaction is carried out under reflux.

The reaction product obtained as described above can be easily obtained by distilling off the solvent and then recrystallizing the resulting crude product from an appropriate solvent.

Compound (■) can also be easily obtained using separation means such as column chromatography.

Furthermore, when crystallizing amine-substituted products, etc., they can be isolated as hydrochloride or oxalate.

Process (e) is to react the compound (■) with an alkylating agent to obtain the 4-alkyl compound (V).

The alkylating agent is added in an amount of 1 to 1 mole of compound (IV).
Approximately 5 moles are used. The reaction is acetone.

Descending using acetonitrile, dimethylformamide, etc. in the presence of a suitable base (eg, potassium carbonate, sodium carbonate, toluethylamine, etc.) is preferred. As the alkylating agent, an alkyl halide or an aralkyl halide is used, and the reaction conditions are preferably room temperature to 150°C for about 10 to 40 hours.

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

Process (f) is the reaction of compound (V) with a sulfiding agent to produce 3-
A thioketone body (■) is obtained.

As the sulfurizing agent, phosphorus trisulfide, Lawson's reagent, etc. can be used, and the amount is 0.5 per mol of compound (V).
This is carried out using about 1.0 mol.

Solvents normally used in sulfurization reactions as reaction solvents, namely benzene, toluene, xylene, dioxane, pyridine, hexamethylphosphoric triamide (HMPT)
The reaction is preferably carried out using Lawesson's reagent in a solvent such as toluene. The reaction conditions vary depending on the sulfurizing agent used, but the reaction temperature is 50 to 150℃.
It is preferable to carry out the reaction at a temperature of about 15°C for 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 sulfurizing agent, heating the reaction solution, concentrating the reaction solution, and purifying the resulting residue using conventional purification methods such as solvent extraction, recrystallization, column chromatography, etc. Compound (■) can be easily obtained by the method.

Process (g) is a compound (
(2) After methylating a) to obtain compound (IX), compound (IX) is treated with various nucleophiles such as amines (ammonia, methylamine) using a suitable reaction promoter.

(optionally substituted benzylamine, optionally substituted aniline derivatives, etc.), hydrazines, active methylene compounds (malonitrile, cyanoacetamide, @
Compound (X) is obtained by a substitution reaction with (optionally substituted phenylacetonitrile, etc.).

The methylation reaction of compound (■a) is carried out in the presence of an appropriate base (e.g., sodium carbonate, potassium carbonate, etc.).
Compound (IX) is obtained by allowing 1 to 5 moles of methyl iodide per mole of H in a solvent such as acetonitrile, dimethylformamide, acetone, methyl ethyl ketone or the like at room temperature for about 5 to 30 hours.

Compound (IX) can be easily obtained by conventional isolation and purification methods, such as solvent extraction, recrystallization, and column chromatography.

In the reaction to obtain compound (X) from compound (IX), the reaction solvent, reaction accelerator or base, reaction time, reaction temperature, etc. may vary depending on the nucleophile used.

When using amines and hydrazines as a nucleophile, the amount of nucleophile is 2 to 1 O per 1 mole of compound (rX).
Using molarity, ethers such as dioxane and tetrahydrofuran are used as reaction solvents.

It is preferable to use alcohols such as methanol and ethanol. In addition, as a reaction accelerator, salts of mineral acids corresponding to each nucleophile (e.g., HC1tfl, HBr salt, etc.), triethylamine hydrochloride, iodine, trimethylsilyl chloride, etc. are used per mole of compound (IX). It is preferable to coexist the catalyst in an amount of about 5 moles. The reaction conditions vary considerably depending on the combination of compound (IK) and reaction promoter, but the reaction temperature is room temperature to about 100°C, and the reaction time is 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 per mol of the compound (IXN), and dimethylformamide is used as the reaction solvent.

It is preferable to use dimethylacetamide or the like, and optionally a mixed solvent of these solvents and ethers (ethyl ether, isopropyl ether, etc.). In addition, as the base used at this time, sodium hydride, potassium monobutoxide, etc. are preferably used in an amount of about 2 to 5 mol per mol of IXH.The reaction temperature is room temperature to about 80°C, and the reaction time is 8 to 80°C. It is best to do this in about 24 hours.

Compound (X) can be isolated and purified easily by concentrating the reaction solution to dryness, treating the residue with water and acid, and then using conventional purification methods such as solvent extraction, recrystallization, column chromatography, etc. X) can be obtained. In addition, when the target compound (X) is formed as a salt in the reaction solution, it is preferable to isolate it as is, and any isolation method may be used to convert compound (X) into a salt such as a hydrohalide or oxalate. You can get it.

Process (h) is a compound obtained by process (f) (
■b) is methylated in the same manner as in process (g) to form the compound (
Xl[) and then treated with a base to form compound (XIII)
shall be. Furthermore, the compound (XIII) is reacted with a nucleophile by a method similar to that described in process (g) to obtain the target compound (XIV).

Methylation of compound (■b) is carried out by adding about 1 to 5 moles of methyl iodide to 1 mole of compound (■b) in acetonitrile, dimethylformamide, or acetone in the presence of a base (e.g., sodium carbonate, potassium carbonate, etc.). The compound (
■).

Next, the compound (Xll) obtained here was added to a base (for example,
The compound (Xll
l) is obtained. Compound (XIII) thus obtained
In the substitution reaction of nucleophiles (e.g. aniline derivatives,
Substituted hydrazine, etc.) is used in equal weight with respect to 1 mole of compound (X[II), dioxane, tetrahydrofuran, ethanol, methanol, acetonitrile, etc. are used as the reaction solvent, the reaction temperature is about 10 to 30'C, and the reaction temperature is about 0.5 to 24 It is preferable to do this in about an hour. The reaction product (XIV) can be easily obtained by conventional isolation and purification methods such as solvent extraction, recrystallization, column chromatography, etc.

Process (i) is a compound obtained in process (a) (■
a) from a primary amine or a secondary amine and trimethylaluminum by the method described in the literature [A, Ba5ha et al.

TeLrahedron LetL, , 48,
4171 (1977)] to obtain compound (IVb).

The dimethylamide compound is first synthesized using amines (e.g., alkylamines, arylamines, morpholines).

piperidine, N-phenylpiperazine, etc.) in a solvent I such as methylene chloride, chloroform, dichloroethane, etc., and a hexane solution of trimethylaluminum under a nitrogen stream to generate a dimethylaluminum amide compound. Next, the compound (IVa) obtained in process (a) was added under water cooling at about room temperature, stirred and reacted for 10 to 30 hours, and then
~3 hours.

It is preferable to carry out the reaction by heating at about 60 to 100°C.

Process (j) is a compound obtained in process (d) (■
Compound (■b) is obtained by acylating a).

Acylating agent (e.g., fatty acid anhydride, acid) 10-genide, etc.) is used as a compound (■a about 1 to 3 moles per mole of N),
This is carried out in the presence of pyridine or triethylamine using pyridine, chloroform, methylene chloride, or the like as a solvent. The reaction conditions are preferably room temperature to about 50° C. for about 10 to 30 hours.

Compounds (1'/b) and (■b) can be isolated and purified easily by concentrating the reaction solution to dryness and using the residue by conventional purification methods such as solvent extraction, recrystallization, column chromatography, etc. lVb) and (■b) can be obtained.

During the process (a) to process (b) described above,
The raw material compound (n) is V, I, Forgo, etc., Phar
n+, Acta.

He1v,, 45. 207 (1970), W.
D.Lang! ey, Org.

5ynth,, Co11. Vol, I, 127
(1941), A.W., Wilds et al., J.Am.
,Chem,Soc,,68. 86 (1946) or similar methods or processes (
It is easily synthesized by the method shown in k).

Process (k) (■) [Wherein, X, R' and R4 have the same meanings as above. Compound (II) can also be H, 5okol, etc., J, Am, Che
m,Soc,.

70, 3517 (194g) or the like or according to the method described therein.

The novel 1,4-thiazine derivative (1) of the present invention and its salt can be used for the enzyme phospholipase A1. Inhibits lipoxygenase and cyclooxygenase as well as lipid peroxide production.

Phospholipase A liberates arachidonic acid from phospholipids, which is converted to prostaglandins and leukotrienes by an eicosanoid cascade. That is, phospholipase A f+ lipoxygenase and cyclooxygenase are 5-HETE, I
, T, B, , PGE, , TXA, etc., mediators that have various biological effects and are important in disease states.
It produces.

The compounds of the present invention that inhibit two or more of these enzymes can be used to treat diseases said to be associated with these mediators, such as bronchial asthma and allergic rhinitis.

Human or other conditions such as rheumatoid arthritis, gout, psoriasis, drug allergies, hives, dermatitis, and various other autoimmune diseases, adult respiratory syndrome, Crohn's disease, endotoxic shock, and ischemia caused by myocardial damage. applied to the treatment of diseases in mammals. In addition, the cytotoxicity and tissue damage of reactive oxygen species generated from oxygen, which is essential for living organisms, are deeply related to aging, arteriosclerosis, ischemic heart disease, cerebrovascular disorders, diabetes, and digestive diseases, and this book has a lipid peroxide suppressing effect. The scavenging action of active oxygen species by the compounds of the invention can be applied to the treatment of the above-mentioned diseases. It is thought that the compounds of the present invention can be more effectively applied to the above-mentioned diseases by having both the above-mentioned enzyme-inhibiting action and lipid peroxide-suppressing action.

In addition, compound (r) has low toxicity, and when compound (1) is used as such a medicine, it can be used alone or mixed with an appropriate pharmacologically acceptable carrier, excipient, diluent, powder, granule, etc. It can be safely administered orally or parenterally in dosage forms such as tablets, capsules, injections, suppositories, and ointments. The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but for example, when orally administered to adult patients with rheumatoid arthritis or liver disorders, it is usually the case that the medicinal active ingredient [Compound (1) , 1 mg/
kg to 30 mg/kg body weight, preferably 0,5
mg/kg ~ 10 mg/kg body weight once a day ~
Advantageously, it is administered in about three doses.

EXAMPLES The present invention will be explained in more detail with reference to Examples, Formulation Examples, and Experimental Examples, but it goes without saying that the present invention is not limited thereto.

The abbreviations used in this specification will be explained below.

AC=Acetyl Me: Methyl E [: Ethyl Pr: Propyl Bu Nibutyl Ph; Phenyl HETE: Hydroxyheifsatetraenoic acid bisaccharide icotriene: Brostaglandin: Thromboxane: 12-hydroxyheptadecatrienoic acid; Multiplet: quartet TG

Measurements were made using TMS in DMSO as internal standard.

Further, the chemical shift is expressed in units of ppm.

Example 1 5-phenyl-28-1,4-thiazine-3(41-1
)-onthioglycolic acid amide (22,5 g) and triethylamine (25,3 g) were dissolved in methyl ethyl ketone (250 g).
Phenacylbromide (49,0
The methyl ethyl ketone solution (250 tJ) of g) was added dropwise. The reaction solution was heated to reflux for 40 hours. During this time phenacylbromide (6 g) was added. After cooling, the precipitated crystals were collected in a furnace, the liquid was concentrated to dryness, and the resulting residue and crystals were combined and recrystallized from alcohol to obtain plate crystals (32,
0 g, 50%).

Melting point 157158°C Elemental analysis value C,, +I, C (%)I as NOS
4 (%) N (%) Calculated value 62.80, 4.74; 7.32
Actual value: 62.75; 4.76, 7.54
Example 2 5-(3,4-dihydroxyphenyl)-2H1,4-
Thiazine-3(4)1)-one thioglycolic acid amide (12,2 g) and triethylamine (13,5 g)
was suspended in methyl ethyl ketone (400 d), and 3,4-hydroxy-7-phenacyl bromide (25.0 g) was added under water cooling.
A methyl ethyl ketone solution (200d) of ) was added dropwise.

The reaction solution was heated under reflux for 20 hours. The crystals precipitated after being left to cool were separated, washed with water, dried, and then dissolved in dimethylacetamide (100 AM) and toluene (500+-12 AM). Add a catalytic amount of p-1 luenesulfonic acid,
The mixture was heated under reflux for 0 hours. The reaction solution was concentrated to dryness, and the resulting residue was washed with 6 L of water and then recrystallized from ethanol to give colorless crystals (
6.3 g, 39%) was obtained.

Melting point 23+-232°C Elemental analysis value C, C as oH9NO3S (%)
H (%) N (%) Calculated value 53.80: 4.06; 6.2
7 Actual value 53.60, 4,20; 6.0
7 In the same manner as in Examples 1 and 2, the following compounds were obtained.

Table-1 Example 17 N-butyl (3-oxo-2,3-dihydro 4H-1
, 4-thiazin-5-yl)carboxamidobutylamine (0.3 g) is dissolved in methylene chloride (15 rotations), and 1 ffl (2 d) of 15% trimethylaluminum in hexane is added at room temperature while thoroughly stirring in a nitrogen stream. . After stirring for 15 minutes, a methylene chloride solution (10 rotations) of ethyl (3-oxo-2,3-dihydro-/II-1-1,4thiazin-5-yl)carphocyflate (075 g) was added dropwise. did.

The reaction solution was left stirring at room temperature for 24 hours. The deposited precipitate was collected in a furnace, dissolved in ethyl acetate (food), and diluted with 0.5
After washing with N-HC, water, drying, and concentration to dryness, the obtained silica was recrystallized from hexane-ether to obtain colorless needles (0.35 g, 42%).

Melting point: 6-67°C Elemental analysis: C (%) as C, H,, N, O, S
H (%) N (%) Calculated value: 50.45, 6.59; 13.
07 actual measurement value: 50.68; 6.58;
1.2.93H-NMR(d,-DMSO)δ:
0.87 (3H, L), 1.101, 65 (411,
m), 3.30 (2tl, s), 3.15 (21
1, t), 6.62 (III, s), 8.18 (
ill, br s) The following compound was obtained in the same manner as in Example 17.

Table-3 Example 22 2-(m-chlorobenzoyloxy)-5-phenyl-
2H-1,4-thiazin-3(4H)-one (2,0g
) was dissolved in methylene chloride (2EM), and while stirring at room temperature, a solution of m-chloroperbenzoic acid (1.7 g) in methylene chloride (25 me) was added dropwise. The mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated. The resulting residue was crystallized from ethyl acetate to give colorless needles (2.45 g, 91%).

Melting point +61-163℃ Elemental analysis value C,71-1,,CQN C as O3S
(%) I (%) N (%) Calculated value: 5
9,05; 3.50: 4.05 Actual value:
59.08; 3.52; 4.04'H
-NMR(CDC123)δ: 5.76(Ill
, d), 6.41 (III, d).

7, 33-7.67 (711, m), 7.73-8.
00 (211, m), 9.48 (IIl, brS) The following compound was obtained in the same manner as in Example 22.

Table 4 Example 33 2-Methylamino-5-phenyl-2H-1゜4-thiazin-3(4H)-one 2-(m-chlorobenzoyloxy)-5-phenyl-
211-1,4-thiazin-3(4H)-one (0,5
g) dissolved in acetonitrile (50 Inl)
, 40% methylamine methanol solution t& (2d) was added, and the mixture was stirred at room temperature for 2 hours. Remove the precipitate,
The reaction solution was concentrated to dryness. The resulting residue was crystallized from methylene chloride to obtain colorless powder crystals (0.31 g, 97%).

Melting point 189-190'C Elemental analysis value C,,1(,,N,C as OS (%)
1-1(%) N(%) Calculated value: 59.9
7; 5.49; 12.72 Actual value: 5
9,94: 5.31: 12.58t (-
NMR(CDC123)δ: 2.43(311,
s), 4.28 (ill, d) 77 (III, d) 7.2 65 (5 tl, m), 9 83 (lit, br s) The following compounds were obtained in the same manner as in Example 33. -4.

(Left below) Example 83 4-Methyl-5-phenyl-2H-1,4-thiazine-
3(4H)-one 5-phenyl-28-1,4-thiazine-3(4H)-
(11.4 g) was dissolved in acetonitrile (300 g), potassium carbonate (12.4 g) and methyl iodide (33.8 g) were added, and the mixture was heated under reflux for 34 hours. The mixture was cooled, the precipitate formed was removed, and the filtrate was concentrated to dryness. The resulting residue was mixed with methylene chloride (200 d) and water (100 d).
The organic layer was concentrated and the resulting silica was crystallized from isopropyl ether to give colorless plate crystals (7.8g
, 64%).

Melting point 95-97°C Elemental analysis value C,, H,, No C as S (%)
H (%) N (%) Calculated value: 64.36; 5.40; 6.
82 actual measurement value: 64.43: 5.39, 6
．． 71'H-NMR(CDC(b>δ: 2.9
9 (311, s), 3.37 (211, s) 5, 93
(III, d), 7.20-7.60 (511, m
) The following compound was obtained in the same manner as in Example 83.

Table-6 Example 88 5-phenyl-2H-1,4-thiazine-3(4[()
-son 5-phenyl-2H-1,4-thiazine-3 (41-t
)-one (J, Og) is dissolved in pyridine (25%),
Add phosphorus pentasulfide (0.58 g) and heat to 50° while stirring.
The mixture was heated and reacted at C for 17 hours. The reaction solution was concentrated to dryness, the resulting residue was crystallized from ethanol, and a prism product (0
, 65g, 60%) was obtained.

Melting point 136-137°C Elemental analysis value C1oHnN C as S- (%)
H (%) N (%) Calculated value: 57.93; 4.38; 6.
76 Actual value: 57.82; 4.44;
6.61H-NMR(CDCQ3)δ:3.81
(2H, s), 6.18 (IH, s).

7, 42 (511, s), 9.23 (III, br
s) The following compound was obtained in the same manner as in Example 88.

Table-7 Example 96 5-(p-')lorophenyl)-3-methylthio-2H
-1,4-thiazin5-(p-talolophenyl)-2H-1,4-thiazin-3(4H)-one (6.5 g) was dissolved in acetonitrile (1
Potassium carbonate (5.6 g) and methyl iodide (11.5 g) were added thereto, and the mixture was left stirring at room temperature for 8 hours. Remove the insoluble matter and remove the furnace liquid.
The residue obtained by drying was partitioned between methylene chloride (200 g) and water (load), the organic layer was dried, and the crude crystals obtained by condensing to dryness were recrystallized from isopropyl ether to give needle-like crystals. Crystals (5.5 g, 80%) were obtained.

Melting point 70~71℃ Elemental analysis value C,, H, oCQN S, C (%
)14(%) N(%) Calculated value: 51,65; 3.94; 5.
48 Actual value: 51.94; 3.91;
5.37H-NMR(CDCi2j)δ: 2.
60 (3!I, s), 3.10 (211, s).

6, 20 (ill, s), 7.30 (21!, d
), 7.67(2)1. d) The following compound was obtained in the same manner as in Example 96.

Example 104 5-phenyl-3-(p-toluidino)-2)[-1,
4-thiaziniumiosito 3-methylthio-5-phenyl-2H-1,4thiazine (6,0 g) was dissolved in dioxane (150d) and p
- Toluidine (4.3 g) was added, and while stirring at room temperature, iodine (6.9 g) was added, and the mixture was left stirring for 4 hours. The precipitated crude crystals were separated, washed with ethyl ether, and then recrystallized from ethanol-ethyl acetate to obtain prismatic crystals (6.94 g, 63%).

Melting point 175-176℃ Table 9 Elemental analysis values C (%) as C,, H, 71N, S
H (%) N (%) Calculated value: 50,00; 4゜20+6.86 Actual value: 50.23; 4.19; 6.90
'H-NMR(da-DMSO)δ: 2.35
(3H, s), 3.87 (211, s), 6.67
(III, s), 7.25-7.65 (9H, m)
The following compound was obtained in the same manner as in Example 104.

(Left below) Example 133 4-Methyl-3-methylthio-5-7 ale 2H-1,
4-thiazinium iosito4-methyl-5-phenyl-28-1,4-thiazine-3(41-1)-thione (
5.0 g) was dissolved in acetone (30 g), methyl iodide was added, and the mixture was heated under reflux for 7 hours. The precipitate that had been left to cool was collected in a furnace and washed with isopropyl ether.
Upon drying, a yellow powder (6.1 g, 74%) was obtained.

Melting point 153-155°C Elemental analysis value C, tH141N S-totite C (%)
H (%) N (%) Calculated value: 39.67; 3.88: 3.86
Actual value: 39,83; 3.83: 3.
95'H-NMR(da-DMSO)δ: 1.
98 (311, s), 2.85 (3tl, s) 3,
40 (211, s), 6.12 (Ill, s),
7.25-8.00 (511, 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 (25d), thi-butquine potassium (0.155 g) was added, and the mixture was stirred at room temperature for 3 hours. Insoluble matters were removed, and the filtrate was concentrated to dryness.

The resulting residue was diluted with methylene chloride (2FM water (10%)).
and Shirabu (0.25g) from the organic layer.

77%).

'H-NMR(CDCQ3)δ: 2.28(3
11,s), 2.97(311,s).

5,07 (1B, s), 5.22 (III, s)
, 7.32(511,s) Example 135 4-Methyl-3-(3,4-methylenedioxyphenyl)imino-5-phenyl-3,4-dihydro-2H-1
, 4-Thiazine The 3-methylthio compound (1,3 g) obtained in Example 134 was dissolved in oxane (25d), and a methanol solution (2FM
was added dropwise at room temperature. After the dropwise addition, methanol (2!M) was added and the mixture was stirred at room temperature for 24 hours.

Insoluble materials were removed, the filtrate solution was concentrated to dryness, and the resulting residue was dissolved in ethyl acetate-ethanol. Oxalic acid (0.5g)
After adding an ethyl acetate solution of
) was obtained.

Melting point 155-160℃ Elemental analysis value C,,1-1,,N,O,S as C(
%) H (%) N (%) Calculated value: 57.96; 4.38; 6.76 Actual value: 57.40; 4.43. 6.69H-N
MR(d,-DMSO)δ: 2.98(3H,s
), 3.42(211,s), 5.95(2H,s
), 6.22 (III, dd), 6.38 (II
I, d), 6.80 (ill.

d), 7.38 (511, s) The following compound was obtained in the same manner as in Example 135.

Table 10 Example 140 2-Acetylamino-5-phenyl-28-1゜4-thiazin-3(4H)-one 2-amino-5-phenyl-2H-1 obtained in Example 34
, 4-thiazin-3(4H)-one (1.5 g) was dissolved in pyridine (25d), acetic anhydride (2 ml) was added, and the mixture was left stirring at room temperature for 26 hours. The crude crystals obtained by condensing the reaction solution to dryness were recrystallized from ethanol-ethyl acetate to yield colorless needles (1.05 g).

58%).

Melting point 207-208°C Elemental analysis value C (%) as C,, H,, N, O, S
H (%) N (%) Calculated value: sg, os; 4.87° 11.28
Actual value: 58.25; 4.92; 11.
28II-NMR (CDC123) δ: 2.03
(311, s), 5.50 (111, d).

5, 92 (IIl, s), 7; 20-7.62 (
511, m), 8.17 (III, d), 9.7
5 (lH+ br s) The following compound was obtained in the same manner as in Example 140.

Table 11 Formulation Examples When the compound of the present invention is used as a therapeutic agent for rheumatoid arthritis, bronchial asthma, allergic diseases, arteriosclerosis, ischemic heart disease, etc., it can be used, for example, in the following formulations.

1. Tablet (1) 3-(4-chloroanilino)-5-(3,4 dihydroxyphenyl)-2H-1,4-thiazine
10mg (2) lactose
35B (3) Cornstarch
150mg (4) Microcrystalline cellulose
30mg (5) Magnesium stearate
5mg30mg 2/3 of (1), (2), (3) and (4) and (
After mixing 1/2 of 5), granulate it. The remaining (4) and (5) are added to the granules and compressed into tablets.

2. Capsule (1) 3-(4-anisidino)-5-phenyl-2H-
1,4-thiazine lOmg (2) Lactose 100mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate lomg 90mg After mixing 1/2 of (1), (2), (3) and (4), granules become The remaining (4) is added to the granules and the whole is encapsulated in a gelatin capsule.

3. Ointment (a) (L) N-(p-chlorophenyl)-[2-(3,4
1.25 g (2) White petrolatum
98.758too, OOg Heat (2), add (1) to it and dissolve. Gradually cool while stirring to form an ointment.

Experimental Example 1 5- Test solution adjusted for inhibition of production of IETE and LTB (final concentration: IOμM, IttM).

RBL-1 cells (consisting of 0.1 HM) were injected into RBL-1 cells (ratbas
ophilic 1eukeIIlia cells)
MCM (mast cell me
dit+m, 0.9 ml) and left at 37°C for 5 minutes. Next, arachidonic acid (50 gg) and A-2318
MCM containing 7 (calcium ionophore) (lμg) (
0,1d) was added, and the reaction was further carried out at 37°C for 5 minutes. After the reaction, ethanol (4 volumes) was added and the mixture was thoroughly shaken, followed by centrifugation at 2000 rpm for 10 minutes at room temperature, and the supernatant was concentrated under reduced pressure.

The residue was dissolved in 60% methanol (0.5d), and this solution M (100 μm2) was taken and subjected to high performance liquid chromatography to obtain 5-HETE (5-hydrox
yeicosa-tetraenoic acid) and LTB4 were quantified. 5- HE T E is 237
nm, or LTB, was measured by measuring absorption at 270 nm using an ultraviolet absorption monitor.

The experimental results are shown in Table-12.

Experimental Example 2 12-HETE and Hl (T production inhibition effect) Using 3.2% sodium citrate (1 volume of sodium citrate solution per 9 volumes of whole blood),
ister (male, 12 to 15 weeks old) was subjected to laparotomy with withdrawal, and 8 volumes of blood were collected from the abdominal aorta. Blood was centrifuged at 80 rpm for 10 minutes at room temperature, and platelet rich plasma (PRP) was collected.
lasma) was collected, and the remaining blood was further added to 3000
rpm, centrifugation for 10 minutes, and platelet poor plasma (P P
P: platelet poor plasma)
get. Measure the mantissa in the dish during PRP, and perform PRP with PPP.
was diluted to adjust the platelet concentration to approximately 1 million/μQ. Arachidonic acid (125 μg) and the test compound (final concentration of 10
0 μM, 10 μM.

1 MM, 0.1 μM) was added, and the reaction was carried out at 37° C. for 15 minutes. After the reaction, ethanol (1, 1d) was added and the mixture was thoroughly shaken, followed by centrifugation at 200 rpm for 0 minutes to separate the supernatant. Water (1
HH
T and 12-HETE were quantified. 12-HETE,
HHT was determined by measuring absorption at 240 μm with an ultraviolet absorption monitor, and r Cs. was calculated.

The experimental results are shown in Table-12.

Experimental Example 3 Phospholipase A, inhibitory effect 1M sodium glycinate mild IQ (pH 8, 4).

50μQ) to 20111M calcium chloride aqueous solution (0,
ld), test solution (final concentration 100 μM, 10 μM.

Consisting of 1MM and 0.1μM. 10μQ), phospholipase At (porcine pancrease,
0.0, 63 ug protein amount, 0.25 pm) was added, and 37
Shake at °C for 10 minutes. Add 0.1M sodium glycine buffer (pH 8,4,0,2yd2) containing cimiristyl-α-choline phosphate (0.1mg),
Shake at 7°C for 10 minutes. After adding butane-IN-sulfuric acid (40:20: t, 2 oz.) to i-propanol, methanol (0.1 g) containing palmitic acid (0.1 g) was added.
2me) solution, then heptane (2d) and H,0(
ld) was added and shaken for 15 minutes. 20-00 rpm
After centrifuging for 5 minutes, the supernatant was separated and silicic acid (
150 mg) was added and shaken for 1 minute. 200Q for 5 minutes
After centrifugation with rpn+, the supernatant (0.5 d) was taken, concentrated to dryness, 0.05% 9-anthranyldiazomethane in methanol (ffi (0.2 d) was added,
The reaction was carried out at 0°C for 300 minutes. Methanol (0.8 am) was added, and the mixture was subjected to high performance liquid chromatography to quantify myristic acid methyl ester and palmitic acid methyl ester. Each methyl ester has 254 runs
The absorption was measured using an ultraviolet absorption monitor. The experimental results are shown in Table-12.

Experimental Example 4 Lipid peroxide production inhibition effect Lipid peroxide production using brain homogenate is 5tock
[J, 5tocks et al., Cl1
n, Sci, Mol.

Med, 47.215-222 (1974)].

Specifically, Wistar rats (male, aged 10 weeks) were taken, brain tissue was removed, and 4 times the volume of phosphate buffered saline (
pH7, 5, 100mM) was added and homogenized. The obtained homogenate was centrifuged (2, 70 rpm,
10 minutes), and the supernatant was diluted 3 times with the same buffer (protein concentration, approximately 50 mg/d). One sample was transferred to a 10-ml test tube, and 10μ of an ethanol solution of the test compound at various concentrations was added, mixed, and incubated for 1 hour at 37°C.The reaction was incubated with 35% perchloric acid (200μQ). )
After centrifugation (3,00 Or
pm, l 0 min) The supernatant lipid peroxide was purified by the method of Ohkawa et al. [11,0hkava et al.

Anal, Biochem, 95.351-358
(1979)]. That is, supernatant 0. ! M
Thiobarbylic acid (0.67%) dissolved in 50% acetic acid
%, 0.5d) and heated at 95°C for 6°O minutes. After cooling in ice water, the absorbance at 532 μm was measured using a spectrophotometer. IC5° was calculated from the absorbance at each concentration of the test substance. The results are shown in Table-12.

Table 12: Cyclooxygenase, lipoxygenase, and phospholipase of 1,4-thiazine derivatives.

Inhibitory effect and lipid peroxide production suppressing effect Experimental example 5 Antihypoxia effect 11 Performed by the ypobaric hypoxia method [+1゜Yasuda et at,, ^rch,
int, Pharmacodyn, 233,13l3
6-144 (197), the experimental equipment is a vacuum pump with 3
Desiccator (chamber A, internal volume: 4
0.2 liters) and a desiccator (chamber B) with an internal volume of 12.6 liters connected to this via a stopcock. By opening the cock between chamber B and chamber A, 208 mmHH of hypoxia can be obtained within 20 seconds. Mouse (ICR/Jet) was used for one experiment.

Eight mice (5-6 weeks old) were used, 4 were in the control group, and the remaining 4 were in the test substance administration group. The test substance was suspended in 5% gum arabic, and 30 minutes after intraperitoneal administration, the animal was placed in chamber B, and the time from when the cock was opened until the animal stopped breathing (survival time) was measured. The control group received 5% gum arabic intraperitoneally.

For animals that did not die after 15 minutes, survival time was calculated as 15 minutes. Evaluation of the test substance was expressed as a relative value when the survival time of animals in the control group was set as 100. The same experiment was repeated twice, and the mean value ± SEX of control group 8 and test substance 'Et administration group 8 was calculated. The experimental results are shown in Table-13.

Table-13 Antihyboxia effect *: Indicates a statistically significant difference (p<o, os).

**: Indicates a statistically significant difference (p<o, ot).

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, when A represents -N=, B is an optionally substituted pyrrolyl group, an optionally substituted amino group, or an alkylthio group. When A represents a ▲numerical formula, chemical formula, table, etc.▼ (in the formula, R^2 represents hydrogen or an optionally substituted aliphatic hydrocarbon group), B represents oxo,
Thioxo, optionally substituted hydrazono group, optionally substituted imino group or alkylidene group,
R^1 represents hydrogen, 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. , R^3 represents an optionally substituted aliphatic or aromatic hydrocarbon group or an optionally esterified or amidated carboxyl group, and R^4 represents hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon group. An aromatic hydrocarbon group, and a broken line indicates that one of the bonds is a double bond] or a salt thereof.