KR800000060B1 - Method for preparing thienothiazine derivatives - Google Patents

Abstract

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Description

Method for preparing thienothiazine derivatives

The present invention relates to a method for preparing a thienothiazine derivative of the following structural formula (I).

(I)

(I)

In the above structural formula

A together with the two linked carbon atoms forms the following (A) or (B) group,

또는

or

(Ghana )

Dashed line represents a double bond in group

R ₁ is a lower alkyl group,

R ₂ is an aromatic heterocyclic moiety containing 1 to 4 heteroatoms, which may be substituted with one or two lower alkyl groups, or substituted with halogen, hydroxy, lower alkyl, trifluoro methyl or lower alkoxy Represents a phenyl group which may be

R ₃ and R ₄ each represent a hydrogen atom or a lower alkyl group.

As used herein, "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl ethyl, propyl, isopropyl, tertiary butyl and the like. In addition, "lower alkoxy" means hydro carbonoxy containing up to 4 carbon atoms. "Halogen" refers to chlorine, bromine, fluorine and iodine. "Residues of aromatic heterocycles containing 1 to 4 heteroatoms which may be substituted with one or two lower alkyl groups" contain 1 to 4 nitrogen and / or oxygen and / or sulfur atoms and are 2-thiazolyl, 4 -Methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazolyl, 2-pyridinyl, 2-pyrimidinyl, 1,2,4- Triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6 -Methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2, 5-membered which may be substituted with one or two lower alkyl groups, such as 6-dimethyl-4-pyrimidinyl, 6-methyl-2-pyridyl, 1,2,3,4-tetrazol-5-yl and the like It means the residue of a 6-membered aromatic heterocycle.

A preferred group of thienothiazine derivatives of formula (I) is that R ₃ and R ₄ are each hydrogen atoms. R ₁ is preferably a methyl group and R ₂ is preferably a 2-thiazolyl, 5-isooxazolyl or 2-pyridyl group.

Particularly preferred thienothiazine derivatives of formula (I) are 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3 Carboxamide-1,1-dioxide.

The manufacturing method of the thienothiazine derivative according to the present invention is as follows.

A) reacting a compound of formula (II) with an amine of

(Ⅱ)H ₂ NR ₂ (Ⅲ)

(Ⅱ)

(Wherein R is a lower alkyl group and A, R ₁ and R ₂ are the same as described above)

B) ring-closing the reactive functional derivative of the following structural formula (VI)

(Ⅳ)

(Ⅳ)

(Wherein A, R ₁ and R ₂ are the same as described above), the lower alkylated compound of formula (V)

(Ⅴ)

(Ⅴ)

(A and R ₂ in the structural formula is the same as described above)

D) reacting a compound of formula (XX) with an isocyanate of formula (XX) in the presence of a strong base, or

(XIX)

(XIX)

O = C = N -R ₂ (XX)

(A, R ₁ and R ₂ in the structural formula are the same as described above)

E) prepared by hydrolyzing the enamine of the following formula (XXI).

(XXI)

(XXI)

(Wherein A, R ₁ and R ₂ are as defined above and R ₅ and R ₆ each represent a lower alkyl or with a nitrogen atom to which they are attached pyrroline, pyrrolidine, piperidine, morpholine or N -(Lower alkyl)-forms a piperazine ring)

In the method (a) of the present invention, the reaction of the compound of formula (II) with the amine of formula (III) may be carried out in the presence or absence of an inert solvent, and suitable solvents include alcohols (eg ethanol), hydrocarbons (eg Benzene, toluene, xylene, etc.), hydrogen halides (eg chloroform, chlorobenzene, methylene chloride, carbon tetrachloride, etc.), dimethylformamide or dioxane. This reaction is preferably heated to the melting point or reflux temperature of the reaction mixture.

In the process b) of the present invention, the reactive derivative of the structural formula (VI) acid is closed in the presence of a base, preferably in the presence of a solvent, at a reflux temperature of the reaction mixture, preferably from room temperature to 60 ° C. Bases include hydrides, amides or alcohol salts of alkali metals, and suitable solvents include aprotic or pro- al such as alcohols (e.g. methanol or ethanol), ethers (e.g. dioxane) and acid amides (e.g. dimethylformamide). There is a tick solvent. This ring closure reaction is carried out by dissolving the reactive derivative of structural acid (IV) in a solvent, treating the resulting solution with a base, and then leaving the resulting mixture at room temperature for 1 to 4 hours or heating it to a temperature of up to 60 ° C. for 1 to 4 hours. do. Particularly suitable reactive derivatives of the acid of formula IV are lower alkyl esters such as methyl esters.

In the present method c), lower alkylation of the compound of formula (V) is carried out by dissolving the compound of formula (V) in an aprotic solvent (e.g. acetonitrile, dioxane or dimethylformromide) Treatment with metal amides or alkali metal hydrides to form alkali metal salts of the compound of formula (V), followed by treatment of the mixture with a suitable alkylating agent, in particular lower alkyl halides or di (lower alkyl) sulfates, to obtain thienothiazine derivatives of formula (I) To obtain. Although the dhs degree and pressure required for this lower alkylation reaction are not restrict | limited, Usually, it is preferable to carry out at room temperature and atmospheric pressure.

In the process d) of the present invention, the compound of the old tank (XIX) is reacted with the isocyanate of dp structure (XX) in the presence of a strong base. As a strong base, Alkali amide; Alkali and alkaline earth metal hydrides; Alkali and alkaline earth metals are suitable. The reaction is carried out under an inert gas atmosphere (e.g. nitrogen) at an inert polar solvent (e.g. toluene, dioxane, dimethylformromide, dimethylsulfoxide or hexamethylphosphate triamide (HMTP)) at 0 ° to 50 ° C, preferably at room temperature. It is preferable to carry out in the presence. Isocyanates of structural formula (XX) as starting materials are known compounds or can be readily prepared by known methods.

In the method e) of the present invention, the enamine of the structural formula (XXI) is hydrolyzed, and the hydrolysis reaction is carried out at the reflux temperature of the reaction mixture, preferably at the reflux temperature of the reaction mixture, such as hydrogen chloride, hydrogen bromide, hydrogen iodide and sulfuric acid. Preference is given to carrying out with an aqueous inorganic acid or trifluoro-acetic acid. The acid used for this hydrolysis also acts as a solvent.

The compound of formula (II) used as starting material in the method a) of the present invention is prepared according to the following scheme (I), wherein A, R and R ₁ are the same as described above and Hal is a halogen atom.

Scheme (Ⅰ)

Compounds of the structural formulas (XlX) and (XXI) used as starting materials in the process of the present invention) and e) are prepared according to the following scheme (II), wherein A, R, R ₁ , R ₂ , R ₅ And R ₆ is the same as described above, and Hal is a halogen atom.

Scheme (II)

Among the compounds of formula (VI), 3-chloro-thiophene-2-carboxylic acid and 4-bromo-thiophene-3-carboxylic acid are known compounds and the former have been prepared in a relatively complex manner. A more convenient process for the preparation of 3-chloro-thiophene-2-carboxylic acid is to prepare known compound 3-hydroxy-thiophene-2-carboxylic acid methyl ester in a boiling insoluble solvent such as chloroform or dioxane. Is converted to 3-chloro-thiophene-2-carboxylic acid chloride in the presence of a chloroating agent (e.g. phosphorus pentachloride) and hydrolyzed to the corresponding acid.

In a similar manner, it is also possible to prepare compounds of the formula (VI) in which Hal is a chlorine atom and A and the two carbon atoms to which they are attached, i.e. substituted 3-chloro-thiophene-2-carboxylic acid.

Wherein R ₃ and / or R ₄ are other than a hydrogen atom

In the preparation of structural compounds, bromo compounds (eg known 4-bromo-thiophene-3-carboxylic acids) can be used in principle, but the corresponding chloro compounds are preferred. 4-Chloro-thiophene-3-carboxylic acids not known in the literature are known as 4-chloro-thiophene-3-carboxylic acids using known 3-keto-thiophene-4-carboxylic acid methyl esters with phosphorus pentachloride with fragrance. Conversion to chloride and hydrolysis of this acid chloride to the corresponding acid. In a similar manner, a substituted 4-chloro-thiophene-3-carboxylic acid can be prepared in which Hal is a chlorine atom and A and two carbon atoms to which they are attached and a structural compound forming the following group.

Wherein R ₃ and / or R ₄ are other than a hydrogen atom

The method for converting the halothiophenecarboxylic acid of formula (VI) to the potassium salt of sulfothiophenecarboxylic acid of formula (VII) is carried out by reacting with sodium hydrogen sulfide in the presence of a cuprous salt catalyst, particularly copper chloride, and reacting the product with potassium chloride. do. The reaction with sodium hydrogen sulfide should be carried out at 143 ° C. to obtain optimum yields.

The method for converting the compound of formula IV to the free acid of formula IV is carried out using a known method, for example, a strong ion exchanger.

The process of esterifying an acid of formula (VII) to an ester of formula (XI) is carried out autocatalytically (in the presence of a sulfone group) in a mixture of alcohol / chloroform. To make the methyl ester the acid is dissolved in methanol / chloroform and the resulting mixture is heated to the boiling point of the ternary azeotrope (methanol / chloroform / half).

The conversion of the compound of formula (XI) to the acid halide of formula (X) is carried out in a known manner using halogenating agents, in particular chlorinating agents such as thionyl chloride or phosphorus pentachloride.

Chlorination reaction with thionyl chloride is carried out by heating until reflux in the absence of solvent. The chlorination reaction using phosphorus pentachloride is carried out between 50 ° C. and the reflux temperature of the mixture in the presence of an inert solvent (chloroform, carbon tetrachloride or dioxane).

However, the compound of formula (X) can also be prepared from the potassium salt of sulfothiophenecarboxylic acid of formula (XI) via the compound of formula (XI). In this method the potassium salt is reacted with 2 moles of phosphorus pentachloride at the boiling point of 30 ° C. to phosphorus oxychloride in the presence of phosphorus oxychloride as solvent.

However, inert organic solvents such as dioxane, chloroform, carbon tetrachloride, benzene, toluene, etc. may be used instead of phosphorus ox chloride.

The process for esterifying the compound of formula (XI) to produce the ester of formula (X) is carried out at room temperature to the reflux temperature of the mixture with a suitable alcohol, in particular methanol. As the solvent, an alcohol or an inert solvent such as chloroform, carbon tetrachloride, dioxane or benzene can be used.

The starting material of formula (II) is obtained from the compound of formula (X) in two ways: the first method via the compounds of formulas (XII) and (XIII), the second method is formula (XV) and in particular formula (XIV) Through the compound.

According to this first method, the compound of formula (X) is reacted with glycinealkylester hydrochloride, preferably glycineethylester hydrochloride in a known manner. This reaction is carried out at room temperature in the presence of an inert solvent such as pyridine, chloroform, dioxane, methylene chloride, benzene or carbon tetrachloride. The compound of formula (XII) thus obtained is closed by reacting with alkali metal ethyl salt or alkaline earth metal ethyl salt, especially sodium ethyl salt, in an ethanol at a temperature of 40 ° to 65 ° C. to give a compound of formula (XIII) wherein R is an ethyl group. Get

The alkylation reaction to obtain the starting material of formula (II) is carried out in a known manner with alkyl halides or dialkyl sulfates at 0 ° C. to room temperature in the presence of polar aprotic solvents such as dimethylformamide, dimethylsulfoxide or hexametaple. It is carried out using the same alkylating agent.

According to the second method, the compound of formula (X) is amino alkylated to obtain a compound of formula (XIV) and converted into a compound of formula (XV) or a compound of formula (X) directly into a compound of formula (XV). In both cases, the obtained compound of formula (II) is closed by ring closure.

Aminoalkylation of the compound of formula (X) is carried out by reaction with alkylamine in the presence of an inert organic solvent (e.g. chloroform, methylene chloride, carbon tetrachloride, benzene or dioxane) at room temperature in a known manner.

The obtained structural formula (XIV) is reacted with the following structural formula (XVI) compound in the presence of a polar aprotic solvent (e.g., dimethylformamide, dimethyl sulfoxide or hexametaple) by a known method. To obtain.

X-CH ₂ -COO-R (XVI)

Where R is as described above and X is a halogen atom

This reaction is typically carried out at 0 ° C. to room temperature.

In addition, the compound of formula (XV) is obtained by reacting the compound of formula (X) with a compound of formula (XVII) or an acid addition salt thereof by a known method.

(XVII)

(XVII)

Wherein R and R ₁ are the same as described above

This reaction is carried out at room temperature and is conveniently carried out in pyridine when using acid addition salts of formula (XVII). Instead of acid addition salts, two moles of free amines can be used, preferably in dioxane, methylene chloride, benzene or carbon tetrachloride.

The reaction for preparing the starting material of formula (II) by ring closing the compound of formula (XV) is usually carried out at room temperature to 65 ° C. using an alkali metal or alkaline earth metal methyl salt or ethyl salt in the presence of methanol or ethanol.

Structural (XVI) and (XVII) compounds are known or can be prepared by known methods.

The lower alkyl ester of the structural formula (IV) acid used as a starting material in the method of the present invention is produced by reacting the amine of the structural formula (III) with chloro acetyl chloride, and then converts the compound of the structural formula (XVIII) It can be obtained by reaction.

(XVIII)

(XVIII)

Where R ₂ is the same as described above

Other reactive derivatives of the structural formula (XI) acids can be prepared from known esters by known methods.

Compounds of formula (V) used as starting materials in process c) of the present invention may be obtained by reacting compounds of formula (XIII) with amines of formula (III).

The compounds of formulas (II), (VI) and (II) to (XV) are novel compounds and these compounds and their preparation are part of the present invention.

The thienothiazine derivatives obtained according to the present invention have anti-inflammatory, analgesic and antirheumatic effects. These beneficial pharmacological properties can be measured by standard tests; For example, kaolin edema test in rats. In this study, 0.1 ml of a 10% kaolin suspension was injected epidermally into the rat's right foot, causing acute local inflammation and oral administration of the test substance.

1. Measure the diameter of the sole in mm (degree of inflammation)

2. Measure the pressure on the sole of the foot in grams (pain threshold measurement)

The test drug is administered 30 minutes before and 3.5 hours after the kaolin injection, and the above is measured 4 hours after the kaolin injection.

It indicates the effect of suppressing edema of the test drug based on the difference in the degree of edema of the treated and untreated animals in%, and shows the anti-hazardous water solubility as an increase rate of the pain threshold.

In the electronic test, 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide 1,1- Dioxide (oral LD ₅₀ in mice was about 900 mg / kg) increased oral administration by 27% at 4 mg / kg and 3% / pain threshold at 43 mg / kg. 23% more pain relief.

The thienothiazine derivatives according to the present invention have a similar action to phenylbutazone, which is known for its therapeutic use and properties.

Thienothiazine derivatives according to the invention can be used as medicaments; For example, it may be used in the form of a pharmaceutical preparation in combination with a nontoxic pharmaceutical tint. Carrier materials include organic, inorganic inert carriers suitable for oral and parenteral administration, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, petroleum jelly, etc. . Pharmaceutical preparations may be solid (eg, stagnation, dragees, suppositories, capsules, etc.), semi-solids (eg ointments), or liquids (eg, liquids, suspensions, emulsions, etc.). The pharmaceutical preparations may be sterile or may contain auxiliaries such as preservatives or stabilizers, emulsions, salts and buffers for changing the osmotic pressure. Pharmaceutical formulations may also contain other therapeutically valuable substances in addition to thienothiazines according to the invention.

The following examples illustrate the method according to the invention.

Example 1

52.1 g of phosphorus pentachloride was dissolved in 600 ml of anhydrous carbon tetrachloride and heated until boiling, followed by a solution of 15.8 g of 3-hydroxy-2-methoxycarbonylthiophene in 200 ml of carbon tetrachloride for 3 hours. Add it down. The mixture is boiled for 13 hours to reflux, carbon tetrachloride is distilled off and the mixture is evaporated to dryness in vacuo.

450 ml of water is added dropwise with cooling and the mixture is heated to boiling and then cooled again. The resulting precipitate is filtered off with suction and boiled with a solution of 10 g of activated carbon dissolved in 25 g of sodium bicarbonate solution. The activated carbon is filtered off with suction and the cooled solution is acidified with hydrochloric acid to yield 3-chlorothiophene-2-carboxylic acid having a melting point of 185 to 186 ° C.

In a glass autoclave, 8.6 g of 3-chlorothiophene-2-carboxylic acid was dissolved in 23 ml of water containing 2.1 g of sodium hydroxide, and 5.6 g of sodium bisulfite was added to 16 ml of water. Alkaline with sodium hydroxide solution. The mixture is treated with 0.43 g of cuprous chloride and heated at 143 ° C. for 16 hours. After cooling, the red copper oxide was suction filtered and the filtrate was acidified with 7 ml of concentrated hydrochloric acid to precipitate unreacted starting material. The precipitate is removed by shaking with methylene chloride. The acidic solution was treated with 12 g of potassium chloride while warming, cooled to 0 ° C., and the potassium salt of 3-sulfothiophene-2-carboxylic acid of colorless crystals was separated.

8.2 g of potassium salt of 3-sulfothiophene-2-carboxylic acid are dissolved in 50 m of water. The solution is passed through a proton-filled ion exchange column and the column is rinsed in water until the solution has a pH of 5. The solution is evaporated to dryness in vacuo and the crystalline residue is recrystallized from a small amount of water to give pure 3-sulfothiophene-2-carboxylic acid.

7.6 g of 3-sulfothiophene-2-carboxylic acid is dissolved in 140 ml of anhydrous methanol and 65 ml of anhydrous chloroform and boiled to reflux. The reaction water is distilled off in a sealed column as a ternary azeotrope (chloroform, methanol, water). This mixture is evaporated in vacuo. The residue is treated with 100 ml of chloroform to remove the methanol and the resulting mixture is evaporated at atmospheric pressure. The remaining brown oil consists of 3-sulfothiophene-2-carboxylic acid methyl ester and crystallizes shortly after cooling. However, crystals are hygroscopic and deliquescent in the atmosphere.

7.4 g of 3-sulfothiophene-2'-carboxylic acid methyl ester is dissolved in 50 ml of thionyl chloride and heated to reflux for 16 hours. The mixture is evaporated to dryness in vacuo and the remaining yellow oil is crystallized with petroleum ether to afford 3-chlorosulfonylthiophene-2-carboxylic acid ethyl ester.

20 g of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester are dissolved in anhydrous chloroform and 21 g of sacosine ethyl ester is added dropwise for 10 minutes. At this time, the temperature of the mixture is raised to 50 ℃. After 20 minutes the mixture is cooled, shaken once with water, 0.5-N hydrochloric acid and sodium bicarbonate solution, respectively, and evaporated to dryness. The residual oil is crystallized with ethanol to give 3- (N-carboethoxymethyl-N-methyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester having a melting point of 84 to 85 ° C.

13.2 g of 3- (N-carboethoxymethyl-N-methyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester are suspended in 43 ml of cooled 1-N methanolic sodium methylate solution under nitrogen flow. . Stirring for 15 minutes gives a clear solution which is heated to reflux for 20 minutes, cooled, neutralized and evaporated in vacuo. The residue is dissolved in methylene chloride, shaken once with water and sodium bicarbonate solution, and evaporated to dryness. The residue was crystallized with methanol to give 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine l, 1- with a melting point of 193 to l95 ° C. Dioxide is obtained.

1.9 g 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno- [2,3-e] -1,2-thiazine 1,1-dioxide to 0.9 g 2-aminothia It is suspended in 250 ml of anhydrous xylene with a sol, heated to reflux for 7 hours, and then 150 ml of xylene is slowly distilled off. The remaining xylenes are evaporated in vacuo. The crystalline residue was recrystallized from ethanol to give 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2-thia with a melting point of 217 ° C. (decomposition). Obtain true-3-carboxamide 1,1-dioxide.

Example 2

50 g (0.203 mole) of monopotassium salt of 3-sulfothiophene-2-carboxylic acid is suspended in 250 ml of phosphorus oxychloride, and 85 g (0.406 mole) of phosphorus pentachloride is added with stirring (hydrogen chloride is released vigorously). The mixture is heated in a water bath with stirring for 90 minutes and cooled to room temperature. The inorganic salts are suction filtered and distilled off under phosphorus oxychloride 릍 vacuum. To completely remove the inorganic salts, the oily residue is dissolved in 400 ml of anhydrous chloroform, filtered and evaporated. The oil residue is crystallized during cooling and consists of 3-chlorosulfonylthiophene-2-carboxylic acid chloride.

48 g (0.196 mol) of 3-chlorosulfonylthiophene-2-carboxylic acid chloride obtained are dissolved in 500 ml of anhydrous chloroform, 9.6 g (0.3 mol) of anhydrous ethanol are added, and the mixture is heated to reflux for 3 hours (hydrogen chloride Until no longer released). The mixture is evaporated to dryness in vacuo and the residue is crystallized to give pure 3-chlorosulfonyldiophen-2-carboxylic acid methyl ester. 43.5 g (0.18 mole) of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester obtained is dissolved in 450 ml of anhydrous chloroform, and anhydrous methylamine is added to this solution at 10 DEG C until pH paper shows alkalinity. The mixture is allowed to react for another 2 hours at room temperature and the solution remains alkaline. Shake the solution in 500 ml of water and 500 ml of 5% bicarbonate solution (extract the aqueous layer once with chloroform). The combined organic phases are dehydrated over sodium sulfate and evaporated. Purification of the crystalline residue with ether gives 3-methylsulfamoylthiophene-2-carboxylic acid methyl ester having a melting point of 115 to 122 ° C.

43.5 g (0.184 mole) of 3-methylsulfamoylthiophene-2-carboxylic acid methyl ester obtained was dissolved in 400 ml of anhydrous dimethylformamide, and 50 g of 4.5 g (0.187 mole) of sodium hydride was dissolved in 400 ml of anhydrous dimethylformamide for 1 hour. It is added dropwise to the suspension dissolved in anhydrous dimethylformamide. 40 g (0.187 mole) of iodoacetic acid ethyl ester dissolved in 50 ml of anhydrous dimethylformamide was added dropwise for 2 hours while cooling to 0 ° to 5 ° C. and the mixture was further added for 1 hour (until the pH test paper showed pH 7 to 8). React. The mixture is evaporated in vacuo and the residue is taken up in 300 ml of 0.5-N hydrochloric acid and 300 ml of methylene chloride. The organic layer is separated and the aqueous layer is extracted twice with a small amount of methylene chloride and the combined organic layers are shaken twice each time with 100 ml of 5% sodium bicarbonate solution each time (the aqueous layer is extracted once again with a small amount of methylene chloride). The organic layer was dehydrated over sodium sulfate and evaporated. Purification of the crystalline residue by treatment with a small amount of cold ethanol yielded 3- (N-carboethoxymethyl-N-methyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester having a melting point of 83 to 85 ° C. do.

13.2 g (0.041 mol) of 3- (N-carboethoxymethyl-methyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester obtained in 42 ml of 1-N-methanol sodium methylate solution under nitrogen atmosphere. Suspend and dissolve after stirring for 15 minutes. The solution is heated to reflux for 25 minutes, cooled, neutralized with concentrated hydrochloric acid and evaporated in vacuo. The residue is dissolved in methylene chloride and evaporated to dryness by shaking once with water and 5% sodium bicarbonate solution, respectively.

The crystalline residue was purified by treatment with a small amount of methanol to give 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [2,3-e] -1,2- with a melting point of 193 to 195 ° C. A thiazine 1,1-dioxide is obtained, which is reacted with 2-aminothiazole in a similar manner as described later in Example 1 to 4-hydroxy-2-methyl-N having a melting point of 217 ° C. (decomposition). -(2-thiazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide.

Example 3

50 g (0.203 mol) of monopotassium salt of 3-sulfothiophene-2-carboxylic acid are suspended in 250 ml of phosphorus oxychloride and 85 g (0.406 mol) of phosphorus pentachloride is added with stirring (hydrogen chloride is vigorously released). The mixture is heated and stirred for 90 minutes in a water bath and cooled to room temperature. The inorganic salts are suction filtered and the phosphorus oxychloride is distilled off in vacuo as possible. The oily residue is dissolved in 400 ml of chloroform and filtered evaporated to remove the remaining inorganic salts. On cooling the oily residue crystallizes and consists of 3-chlorosulfonylthiophene-2-carboxylic acid chloride.

48 g (0.196 mol) of 3-chlorosulfonylthiophene-2-carboxylic acid chloride obtained are dissolved in 500 ml of anhydrous chloroform, 9.6 g (0.3 mol) of anhydrous methane are added, and the solution is heated to reflux for 3 hours (hydrogen chloride further Until no longer released). The mixture is evaporated to dryness in vacuo and the residue is crystallized to give pure 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.

241 g (0.010 mol) of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester obtained are dispersed together with 1.53 g of sacosinethyl ester hydrochloride in 10 ml of anhydrous pyridine and stirred at room temperature. After 2 hours the mixture is poured into 50 ml ice-cold 2-N hydrochloric acid and extracted five times with 20 ml of methylene chloride each time. The combined organic layers are dehydrated over sodium sulfate and filtered and evaporated. Crystalline residue is leached with a small amount of ice cold ethanol.

13.2 g (0.041 mole) of 3- (N-carboethoxymethyl-N-methyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester obtained was obtained by 42 ml of 1-N methanolic sodium methylate at low temperature under a nitrogen atmosphere. Suspension in solution and stirred for 15 minutes to dissolve all. The solution is heated to reflux for 25 minutes, cooled, neutralized with concentrated hydrochloric acid and evaporated in vacuo. The residue is taken up in methylene chloride and shaken once with water and 5% sodium bicarbonate each time once and evaporated to dryness. Purification of the crystalline residue by leaching in a small amount of methanol to purify 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [2,3-e] -1 having a melting point of 193 to 195 ° C. , 2-thiazine 1, l-dioxide is obtained, which is reacted with 2-aminothiazole using a method as described later in Example 1 to 4-hydroxy-2-methyl having a melting point of 217 ° C. (decomposition). -N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide.

Example 4

12.03 g (0.05 mole) of 3-chlorosulfonylthiophene-2-carboxylic acid betyl ester and 7 g (0.05 mole) of glycineethyl ester hydrochloride are dissolved in 50 ml of anhydrous pyridine and dissolved within 30 minutes. The solution is stirred for another 5 hours at room temperature and the pyridine is distilled off. The residue is dissolved in 50 ml of 2-N hydrochloric acid and 5 ml of methylene chloride, the organic layer is separated, and the aqueous layer is extracted four times with a small amount of methylene chloride. The combined organic phases are washed with water and activated carbon is added to dehydrate over sodium sulfate.

After filtration the filtrate is evaporated. The oily residue consists of 3- (N-carboethoxymethyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester.

9.38 g (0.03 mol) of the obtained 3- (N-carboethoxymethyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester in 10 ml of ethanol was dissolved in 1.38 g (0.06 mol) of sodium at 40 ° C. To the solution dissolved in 20 ml of anhydrous ethanol is added to heat the mixture to 60-65 ° C. The mixture is stirred for another 2 hours at this temperature, then poured into 100 ml of ice-cold 2-N hydrochloric acid and shaken several times with a small amount of methylene chloride. The combined organic extracts were shaken twice with 20 ml of 5% sodium acetate solution each time and shaken four times with 10% sodium carbonate solution. The organic phase is dried and evaporated to recover 2.5 g of starting material. The combined carbonate extract is acidified with hydrochloric acid and shaken with methylene chloride. After dehydration over sodium sulfate, the solvent is distilled off and the crystalline residue is leached with a small amount of ether to give 3-ethoxycarbonylmethyl-4-hydroxy-2H-thieno [2,3-e]-with a melting point of 148 to 150 ° C. Obtain 1,2-thiazine 1,1-dioxide.

1.93 g (7 mmol) of 3-ethoxycarbonylmethyl-4-hydroxy-2H-thieno [2,3-e] -1,2-thiazine 1,1-dioxide in 4 ml of anhydrous dimethylformamide The solution was added dropwise to a suspension suspended in 0.185 g (7.7 mmol) of sodium hydride in 2 ml of anhydrous dimethylformamide at 0 ° C. for 30 minutes. The mixture was stirred for an additional hour at room temperature, first 0.53 ml (1.2 g: 8.45 mmol) of methyl iodide was added and after 30 minutes 0.25 ml (0.565 g: 4 mmol) of methyl iodide was added to allow the mixture to react. Leave for one hour. After distilling off the solvent, the residue is dissolved in 30 ml of 0.5-N hydrochloric acid and 30 ml of methylene chloride, the organic phase is separated, and the aqueous layer is extracted twice with a small amount of methylene chloride. The combined organic extracts are dehydrated on sodium sulfate. The crystalline residue was leached into a small amount of cold ethanol to give 3-ethoxy-carbonylmethyl-4-hydroxy-2-methyl-2H-thieno with a melting point of 161 to 163 ° C. (crystals modified at 151 to 152 ° C.) [ 2,3-e] -1,2-thiazine 1,1-dioxide is obtained.

3-Ethoxycarbonylmethyl-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine 1,1 in a similar manner as described later in Example 1 Dioxide reacts with 2-aminothiazole to 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2 with a decomposition temperature of 217 ° C. Thiazine-3-carboxamide 1,1-dioxide.

Example 5

25 g of 3-keto-thiophene-4-carboxylic acid methyl ester dissolved in a small amount of anhydrous carbon tetrachloride are added dropwise to a boiling solution by dissolving 100 g of phosphorus pentachloride in 250 ml of anhydrous carbon tetrachloride for two hours. The mixture is heated to reflux for another 15 hours until the end of hydrogen chloride release and then evaporated in vacuo to remove phosphorus chloride.

Ice water is added to the residue, the mixture is stirred for 1 hour, the organic layer is separated, and the aqueous layer is shaken once more with methylene chloride. The combined organic layers are dehydrated over sodium sulfate and evaporated. The remaining brown oil is 4-chlorothiophene-3-carboxylic acid chloride. The oil is heated to 50 ° C. with 2-N aqueous sodium hydroxide solution to form a uniform brown solution. It is shaken once with methylene chloride and acidified with concentrated hydrochloric acid. Aspiration filtration of the precipitated crystals gives ÷ 4-chlorothiophene-3-carboxylic acid. This crystal is dissolved in sodium bicarbonate solution and purified by reprecipitation with concentrated hydrochloric acid. Melting Point 154 ℃ (Recrystallized from Water)

In a free autoclave, 8.6 g of 4-chlorothiophene-3-carboxylic acid was dissolved in 23 ml of water containing 2. lg sodium hydroxide, and a solution of 5.6 g of sodium bisulfite was added to 16 ml of water, and the solution was dissolved in 30% sodium hydroxide. Alkali as. This solution is treated with 0.43 g of cuprous chloride and heated to 143 ° C. for 16 hours. After cooling, the red copper oxide was suction filtered. The filtrate is acidified with 7 ml of concentrated hydrochloric acid and the unreacted starting material is precipitated and then removed by shaking with ether. The acidic solution was treated with 12 g of potassium chloride while warming, cooled to 0 ° C., and the potassium salt of 4-sulfothiophene-3-carboxylic acid was separated into colorless crystals. The crystals are dissolved in 50 ml of water and the solution is passed through an ion exchange column filled with protons and the column is rinsed with water until the pH of the effluent is 5. This eluate was evaporated to dryness in vacuo to give 4-sulfothiophene-3-carboxylic acid having a melting point of l54 ° C. (recrystallized from water) as a crystalline residue.

7.6 g of 4-sulfothiophene-3-carboxylic acid is dissolved in 140 ml of anhydrous metalol and 65 ml of anhydrous chloroform and heated to reflux. The reaction water is distilled into a sealed column (1 m) as a ternary azeotrope (chloroform, methanol, water). This mixture is evaporated in vacuo. To remove the methanol, the residue is treated with 100 ml of chloroform and the solution is evaporated at atmospheric pressure. Cooling immediately crystallizes the brown oil of the residue, which consists of 4-sulfothiophene-3carboxylic acid ethyl ester (hygroscopic crystals which are deliquescent in the atmosphere).

7.4 g of 4-sulfothiophene-3-carboxylic acid methyl ester is dissolved in 50 ml of thionyl chloride and heated to reflux for 16 hours. The mixture is evaporated to dryness in vacuo and the remaining tan oil is crystallized with petroleum ether to give 4-chlorosulfonyl thiophene-3-carboxylic acid methyl ester (recrystallized from petroleum ether) having a melting point of 71 ° C.

50 g of 4-chlorosulfonylthiophene-3-carboxylic acid methyl ester are dissolved in 500 ml of anhydrous chloroform. Anhydrous methylamine is passed through the solution while cooling until the indicator paper shows a basic reaction with a persistent group. The precipitated methylammonium chloride is removed by shaking with water. The organic layer is evaporated to dryness. The yellow oil of the bottom oil immediately crystallized to give 4- (N-methyl-sulfamoyl) -thiophene-carboxylic acid methyl ester having a melting point of 14 ° C.

46 g of 4- (N-methyl-sulfamoyl) -thiophene-3-carboxylic acid, methyl ester are dissolved in 450 ml of diphenylformamide. The solution is cooled to 0 ° C. and treated with 7 g (> 20%) sodium hydroxide to release hydrogen. The solution is slowly heated to room temperature and subsequently treated with 32.6 g of potassium iodide and 21.3 g of ethyl chloroacetate. The temperature rises to 45 ° C. and the white precipitate is separated. When dimethylformamide is evaporated, the yellow oil of the bottoms is partitioned between 0.5-N hydrochloric acid and hydrochloric acid. The organic layer is shaken with sodium bicarbonate and evaporated to dryness. The yellow oil of the bottom oil immediately crystallized to give 4- (N-methoxycarbonylethyl-N-methyl-sulfamoyl) -thiophene-3-carboxylic acid methyl ester (recrystallized from ethanol) having a melting point of 124 ° C.

41.6 g of 4- (N-methoxycarbonylmethyl-N-methyl-sulfamoyl) -thiophene-3-carboxylic acid methyl ester is taken up in 140 ml of 1-N sodium methylate solution and dissolved under heating under reflux. This solution rapidly turns yellow and turns deep red; After 20 minutes the solution is cloudy with a precipitate forming. The mixture is cooled, oxidized and evaporated in vacuo. The residue is dissolved in methylene chloride and water, the organic layer is shaken with sodium bicarbonate solution and water, and then extracted with a finally cooled 0.5-N sodium hydroxide solution. By acidifying the sodium hydroxide solution, 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [3,4-e] -1,2-thiazine 1,1-dioxide has a melting point of 190 캜. Obtained in the form of phosphorus colorless crystals (recrystallized from methanol).

0.9 g of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [3,4-e] -1,2-thiazine-1,1-dioxide to 0.4 g of 2-amino Suspension in lOOml of anhydrous xylene with terazole, heated to reflux for 4 hours and slowly distill 70ml of xylene. The crystalline precipitate was separated from the cooling solution by suction filtration and 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno with a melting point of 243-245 ° C. (decomposition) [3,4-e] -1,2-thiazine-3-carboxamide 1,1-dioxide is obtained.

Example 6

94.6 g (0.384 mole) of monopotassium salt of 4-sulfothiophene-3-carboxylic acid is suspended in 390 ml of phosphorus oxychloride and 160.8 g (0.768 mole) of phosphorus pentachloride is added with stirring (hydrogen chloride released vigorously). . The mixture is heated in a water bath for 3 hours with stirring and cooled to room temperature. The inorganic salts are filtered off and the phosphorusoxy chloride is distilled off in vacuo as much as possible. The residue is dissolved in 400 ml of anhydrous chloroform and filtered evaporated to remove the remaining inorganic salts. The residue is crystallized on cooling and consists of 4-chlorosulphylthiophene-3-carboxylic acid chloride.

44.1 g (0.18 mol) of 4-chlorosulphylthiophene-3-carboxylic acid chloride obtained are dissolved in 450 ml of anhydrous chloroform, 9.6 g (0.3 mol) of anhydrous methanol is added, and the solution is heated to reflux for 9 hours. Until the end of the release). The mixture was evaporated to dryness in vacuo and the residue was crystallized to yield 4-chlorosulfonyl thiophene-3-carboxylic acid methyl ester, which was prepared in a similar manner as described later in Example 5 to 4-hydroxy-2-methyl-. N- (2-thiazolyl) -2H-thieno [3,4-e] -1,2-thiazine-3-carboxamide 1,1-dioxide can be converted.

Example 7

3-amino-5-methyl-isoxazole and ε-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine 1,2-dioxide 4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno [2,3- with a decomposition temperature of 239 to 243 ° C. in a reaction similar to Example 1 for 7 hours. e] -1,2-thiazine-3-carboxamide 1,1-dioxide is obtained.

Example 8

Aniline and 3-carbomethoxy-4-hydroxy-2-methylthieno [2,3-e] -1,2-thiazine 1,1-dioxide for 7 hours in the same manner as described in Example 1 Reaction to obtain 4-hydroxy-2-methyl-2-thieno [2,3-e] -1,2-thiazine-3-carboxycyanide 1,1-dioxide having a decomposition temperature of 248 to 251 ° C. (Recrystallized from xylene).

Example 9

2-pyridylamine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine 1 for 7 hours in a similar manner as described in Example 1 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno [2,3-e] -1,2-thia having a decomposition temperature of 209 to 213 캜 by reacting 1,1-dioxide. Obtain true-3-carboxamide 1,1-dioxide (recrystallized from xylene).

Example 10

3-pyridylamine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine 1 for 7 hours in a similar manner as described in Example 1 4-hydroxy-2-methyl-N- (3-pyridyl) -2H-thieno [2,3-e] -1,2-thia with a decomposition temperature of 241 to 244 ° C by reacting 1,1-dioxide Obtain true-3-carboxamide 1,1-dioxide (recrystallized from pyridine).

Example 11

4-pyridylamine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thia for 7 hours in a similar manner to that described in Example 1 4-hydroxy-2-methyl-N- (4-pyridyl) -2H-thieno [2,3-e] -1 having a decomposition temperature of 263 to 267 ° C. by reacting jin-1,1-dioxide. 2-thiazine-3-carboxamide 1,1-dioxide is obtained (recrystallized from dimethylformamide).

[12]

4-hydroxy aniline was reacted with 3-carboethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine for 7 hours in a similar manner as described in Example 1. 1,1-dioxide reacts to 4,4'-dihydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3- with a decomposition temperature of 287 to 290 ° C. Carboxanilide 1,1-dioxide is obtained (recrystallized from dioxane).

Example 13

In a similar manner as described in Example 1, 3-methylaniline and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine 1, 4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxy-m-tolui having a decomposition temperature of 197-199 ° C. by reacting 1-dioxide Mid 1,1-dioxide is obtained. (Recrystallized from benzene: crystal change temperature of 185 to 188 ° C.)

Example 14

In a similar manner as described in Example 1, 3-chloro aniline and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine 1, 3'-Chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-car having a decomposition temperature of 241 to 243 ° C by reacting 1-dioxide Obtain voxanilide 1,1-dioxide (recrystallized from xylene).

Example 15

Aminopyrazine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine 1,1 for 7 hours in a similar manner as described in Example 1 4-hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -1,2-thiazine-3-caroxy having a decomposition temperature of 245 to 248 ° C. by reacting the dioxide. Obtained amide 1,1-dioxide. (Recrystallized from Xylene)

Example 16

5-amino-3,4-dimethyl-isoxazole and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e for 14 hours in a similar manner as described in Example 1 ] -1,2-thiazine-1,1-dioxide reacts with N- (3,4-dimethyl-5-isoxazolyl) -4-hydroxy-2-methyl- with a decomposition temperature of 206-208 ° C. 2H-thieno [2,3-e] -1,2-thiazine-3-caroxamide 1,1-dioxide is obtained (recrystallized from benzene).

Example 17

In a manner similar to that described in Example 1, 4-amino-2,6-dimethyl-pyrimidine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] for 7 hours. N- (2,6-dimethyl-4-pyrimidinyl) -4-hydroxy-2-methyl-2H- having a decomposition temperature of 270 to 271 ° C by reacting -1,2-thiazine 1,1-dioxide. Thieno [2.3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide is obtained (recrystallized from xylene).

Example 18

2-amino-6-methyl-pyridine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2 for 7 hours in a similar manner as described in Example 1 -Tyazine 1,1-dioxide reacted to yield 4-hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-thieno [2,3- with decomposition temperature of 216-218 ° C. e] -1,2-thiazine-3-carboxamide 1,1-dioxide is obtained (recrystallized from benzene)

Example 19

5-amino-1,2,3,4-tetrazole and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3- for 14 hours in a similar manner as described in Example 1 e] -hydroxy-2-methyl-N- (1,2,3,4-detrazol-5-yl having a decomposition temperature of 22 캜 by reacting 1,2-thiazine 1,1-dioxide ) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide is obtained (recrystallized from ethanol).

Example 20

2-amino-pyrimidine and 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] 1,2-thiazine for 18 hours in a similar manner as described in Example 1 4-hydroxy-2-methyl-N- (2-pyrimidinyl) -2H-thieno [2,3-e] -1,2 having a decomposition temperature of 221 to 223 캜 by reacting 1,1-dioxide -Thiazine-3-carboxamide 1,1-dioxide is obtained (recrystallized from ethanol).

Example 21

0.82 g (0.003 mol) of 3-ethoxycarbonyl-4-hydroxy-2H-thieno [2,3-e] -1,2-thiazine 1,1-dioxide 0.4 g (0.004 mol)- Suspend in 100 ml of anhydrous xylene with aminothiazole and heat the mixture until boiling. 50 ml of solvent is slowly azeotropically distilled with the resulting ethanol for 7 hours. After 2 hours 4-hydroxy-N- (2-diazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide begins to crystallize do. After cooling, the crystals are filtered off, washed with petroleum ether and recrystallized with xylene or dioxane if necessary. Melting Point 289-290 ° C (Decomposition)

0.329 g (1 mmol) 4-hydroxy-N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide Was dissolved in 2 ml of anhydrous dimethylformamide and 0.026 g (1.1 mmol) of sodium hydride was suspended in 1 ml of anhydrous dimethylformamide at 0 ° C. and added to the stirred suspension. The mixture is stirred for another 1 hour at room temperature. 0.1 ml (0.226 g: 1.6 mmol) of methyl iodide is added to a sodium salt solution and allowed to react for another hour. After distillation of the solvent, the residue is dissolved in 200 ml of methylene chloride and 10 ml of 0.5-N hydrochloric acid. The organic phase is separated and shaken with 50 ml of 0.5% sodium bicarbonate solution. The aqueous layer containing the desired product is extracted several times with methylene chloride and acidified with hydrochloric acid. The acidic aqueous layer is extracted with methylene chloride and the combined organic extracts are dehydrated over sodium sulfate and then evaporated. The crystalline residue was purified by leaching with a small amount of cold ethanol to afford 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno- [2,3-e] with a melting point of 217 ° C. (decomposition). -1,2-thiazine-3-carboxamide 1,1-dioxide is obtained.

Example 22

40 g (0.4 mol) of 2-aminothiazole are dissolved in 400 ml of dioxane anhydride and treated with 100 g of pyrogenated potassium carbonate. When 95 ml of chloroacetyl chloride is added dropwise, the temperature is raised to 70 ° C. The mixture is stirred for 90 minutes and 150 g of potassium carbonate is dissolved in 4,000 ml of water and poured into a cooled solution to precipitate 2-chloroacetylaminothiazole. The mixture is stirred for another hour and filtered in vacuo. The residue is washed well with water and recrystallized from ethanol. Melting Point 176-177 ° C

0.5 g (2.2 moles) of methylsulfamoyl-thiophene-2-carboxylic acid methyl ester was dissolved in 8 ml of anhydrous dimethylformamide, and 0.06 g of sodium hydride was suspended in 2 ml of anhydrous diethylformamide at 0 ° C and stirred. To the suspension. The mixture is stirred for another 1 hour at room temperature. 0.38 g (2.13 mmol) of 2-chloroacetylamino thiazole obtained and 0.36 g (2.17 mmol) of potassium iodide are added to a sodium solution and the mixture is further stirred for 2 hours. After distilling off the solvent, the residue is dissolved in 20 ml of 0.5-N hydrochloric acid and 50 ml of methylene chloride, and the aqueous layer is shaken several times with methylene chloride. The combined organic layers were washed with water, dehydrated over sodium sulfate and filtered and evaporated to afford 3- [N- (2-thiazolylcarbamoyl-methyl) -N-methyl) -sulfamoyl-thiophene-2-carboxylic acid methyl ester. .

0.1 g (0.27 mmol) of 3- [N- (2-thiazolyl-carbamoyl-methyl) -N-methyl] -sulfamoyl-thiophene-2-carboxylic acid methyl ester is dissolved in 5 ml of anhydrous dimethylformamide. Treated with 0.0 lg of sodium hydride. After stirring for 2 hours, the desired 4-hydroxy-2-metal-N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2-diazine-3-cartide was purified by thin layer chromatography. Voxamide 1,1-dioxide is detected.

Example 23

23.5 g (0.1 mole) of 3-methylsulfamoyl thiophene-2-carboxylic acid methyl ester is dissolved in 50 ml of ethanol while warming.

The mixture is treated with 50 ml of 3N calcium hydroxide solution and hung under reflux for 3 hours. The mixture is cooled, diluted with water and extracted with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted several times with 50 ml of ether.

Dehydration over sodium sulfate followed by evaporation of the solvent affords 3-methyl-sulfamoyl-thiophene-carboxylic acid as colorless crystals, which are pure enough for the next reaction but can be recrystallized from water. Melting Point: 182 ~ 184 ℃

11.06 g (0.05 mole) of 3-methyl-sulfamoyl-thiophene-carboxylic acid and 11.5 g (0.055 mole) of phosphorus pentachloride are suspended in 150 ml of anhydrous chloroform and the mixture is heated at 40 ° C. for 30 minutes, and then half of the solvent. It is evaporated under vacuum without warming. The solution of the residual oil containing acid chloride was added dropwise to a solution (prepared from 34 g of nitrozomethylurea) which was cooled to -20 DEG C in diazomethane in ether over 60 minutes. The reaction mixture was allowed to come to room temperature and after 1 hour, 80 ml of concentrated hydrochloric acid was carefully added, and the mixture was heated to reflux for 1 hour. After extraction with water and ether again extraction, the combined organic phases are dehydrated over sodium sulfate and filtered and evaporated. The crystals thus obtained are slurried with a small amount of ether to give 3-methylsulfamoyl-2-chloro acetyl-thiophene, which is pure enough to be used for the next reaction but may be recrystallized from benzene. Melting Point: 98 ~ 100 ℃

2.53 g (0.01 mol) of 3-methylsulfamoyl-2-chloroacetyl-thiophene was dissolved in 20 ml of anhydrous dimethylformamide and the solution was dissolved in 5 ml of 0.27 g sodium hydride over 20 minutes at 0 ° C. under nitrogen atmosphere. It is added dropwise to a solution dissolved in anhydrous dimethylformamide. The initial brightly colored solution is blackened and the pH drops to 7.5. After 10 minutes the mixture is acidified with hydrochloric acid and the solvent is evaporated. The oily residue is partitioned between 2N hydrochloric acid and methylene chloride. The phases are separated and the aqueous phase is extracted several times with methylene chloride. The combined organic layer is dehydrated over sodium sulfate and evaporated. The crystalline residue was slurried with a small amount of cold ethanol to give 3,4-dihydro-2-methyl-3-oxo-2H-thieno [2,3-e] -1,2-thia with a melting point of 130 to 131 ° C. Obtain true-1,1-dioxide.

0.99 g (4.1 mmol) of 3,4-dihydro-2-methyl-4-oxo-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide and 0.49 g ( 4.1 mmol) of phenylisocyanate is dissolved in 9 ml of anhydrous dimethylformamide and the solution is added dropwise to 0.11 g of sodium hydride suspension over 10 minutes under a nitrogen atmosphere. After 15 minutes, the black solution is poured into 50 ml of ice-cold 3N hydrochloric acid to precipitate a yellow solid. The aqueous layer is extracted several times with methylene chloride and the combined organic phases are extracted with sodium carbonate solution, the carbonate solution is acidified with hydrochloric acid and extracted with methylene chloride. The organic phase is dehydrated over sodium sulfate, treated with activated charcoal and then filtered and evaporated. The oily residue is crystallized from benzene and recrystallized from benzene to give 4-hydroxy-2-methyl-3- (phenyl-carbamoyl) -2H-thieno [2,3-e] with a melting point of 248 to 251 ° C. (decomposition). -1,2-thiazine-1,1-dioxide is obtained.

Example 24

1.1 g (5 mmol) of 3,4-dihydroxy-2-methyl-4-oxo-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide 0,75 g of distilled pyrrolidine is dissolved in 45 ml of anhydrous benzene and the mixture is hung until reflux for 72 hours using a water collector. The solvent was distilled off and the crystalline residue was dried in vacuo to give 2-methyl-4- (1-pyrrolidinino) -2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide This product is pure enough to be used for the next reaction but can be recrystallized from benzene / ether (1: 9).

Melting Point: 183 ~ 184 ℃

1.2 g (4.4 mmol) of 2-methyl-4- (1-pyrrolidino) -2H-thieno [2,3-e] -I, 2-thiazine-1,1-dioxide in 20 ml of anhydrous tetra Suspended in hydrofuran, 5 ml of anhydrous benzene and 0.8 ml of triethylamine and 0.5 g (5 mmol) of phosgene is slowly added dropwise to a solution of 5.5 ml of anhydrous benzene and 3 ml of anhydrous tetrahydrofuran at -10 ° C. The resulting brown solution is warmed to room temperature and stirred for 3 hours. A solution of 0.68 g of 2-aminothiazole and 0.8 ml of triethylamine in 5 ml of anhydrous tetrahydrobutane was added dropwise over 30 minutes, and the reaction mixture was heated to reflux for 10 hours. The mixture is poured into cold water and extracted with methylene chloride. The extract is dehydrated over sodium sulfate, filtered and concentrated to a volume of 30 ml. The mother liquor is evaporated where the yellow solid precipitates as a by-product (melting point 319 to 321 ° C). The oily residue is separated by column gromatography [60 g of silica gel, cone size: 0.068 to 0.2 mm, eluent benzene / ethanol (9: 1)]. Combine the clearest fractions and evaporate. The residue is naturally crystallized to give 2-methyl-4- (1-pyrrolidino) -3- (2-thiazolyl-carbamoyl) -2H-thieno [2, 3-e] -1,2-thiazine -, 1-dioxide (melting point: 177 to 179 ° C) which can be used directly for the next reaction.

0.6 g (1.5 mmol) 2-methyl-4- (1-pyrrolidino) -3- (2-thiazolylcarbamoyl) -2H-thieno [2,3-e] -1,2-thiazine Dissolve -1,1-oxide in 20 ml of 3N hydrochloric acid and heat under reflux for 1 hour. The mixture is cooled and then extracted several times with methylene chloride. The combined organic phases are extracted with sodium carbonate solution. The resulting 4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide 1,1-dioxide Acidify, liberate and dissolve in methylene chloride. Dehydrate on sodium sulfate, evaporate the solvent and recrystallize with ethanol to give the pure product with melting point 225 ° C. (decomposition).

The following formulation describes a pharmaceutical formulation containing thienothiazine according to the present invention.

[Prescription 1]

In the usual manner, suppositories containing the following compositions are prepared.

4-hydroxy-2-methyl-N- (2-thiazolyl)-

2H-thieno [2,3-e] -1,2-thiazine-

3-carboxamide 1,1-dioxide 0.025 g

1.230 g hydrogenated coconut oil

Carnauba Wax 0.045g

[Prescription 2]

In a conventional manner, a tablet containing the following composition is prepared.

4-hydroxy-2-methyl-N- (2-thiazolyl)-

-2H-thieno [2,3-e] -1,2-thiazine-3-

Carboxamide 1,1-Dioxide 25.00mg

Lactose 64.50mg

Corn Starch 10.00mg

Magnesium Stearate 0.50mg

Gross weight 100.00mg

[Prescription 3]

In a conventional manner, a capsule containing the following composition is prepared.

4-hydroxy-2-methyl-N- (2-thiazolyl)-

2H-thieno [2,3-e] -1,2-thiazine-3-

Carboxamide 1,1-dioxide 50mg

Lactose 125mg

Corn Starch 30mg

Talc 5mg

210 mg gross weight

Claims (1)

Reacting a compound of formula (II) with an amine of formula (III), or closing a reactive agonist of formula (IV), lower alkylating a compound of formula (V), or a strong base of a compound of formula (XIX) Reacting with isocyaneno of formula (XX) or hydrolyzing enamine of formula (XXI), to prepare a thienothiazine derivative of formula (I).

(Ⅰ)

(Ⅱ) H ₂ N-R ₂ (III)

(Ⅳ)

(Ⅴ)

(XIX) O = C = N-R ₂ (XX)

(XXI) In the above structural formula A forms the following (A) or (B) group with the two carbon atoms connected

or

(Ghana) The dotted line represents the double bond present in the group R is a lower alkyl group, R ₁ is a lower alkyl group, R ₂ represents an aromatic heterocyclic moiety containing 1 to 4 heteroatoms (which may be substituted with one or two alkyl groups) or a phenyl group (halogen, hydroxy, lower alkyl, trifluoromethyl or lower alkoxy) May be substituted by R ₃ and R ₄ are each a hydrogen atom or a lower alkyl group, R ₅ and R ₆ each represent a lower alkyl or together with the nitrogen atom to which they are attached form a pyrroline, pyrrolidine, piperidine, morpholine or N- (lower alkyl) -piperazin ring.