JPH07215954A - New benzothiadiazine compound - Google Patents

Abstract

PURPOSE:To obtain a new compound useful for treating hyperglycemia. CONSTITUTION:The objective compound of formula I [R<1> to R<3> each is a lower alkyl; R<4> is H, a lower alkyl, a nitrogen-contg. unsaturated heterocycle or a (substituted) aryl; X and Y each is a lower alkylene; n is 0 or 1], e.g. 2-(4- bromophenyl)-6-(2-hydroxy-2-methylpropoxy)-4-methyl-1,1-dioxo-4H-benzo [e][1,2,4 ]thiadiazin-3-one. The compound of formula I can be obtained by reaction of a compound of formula II with a compound of formula R<2>MG-A (A is halogen). The raw material compound of formula II, which is also a new material, can be obtained by starting from reaction of a compound of formula III (R<6> is a lower alkoxyl) with a compound of formula H2N-(Y)n-R<4>.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzothiadiazine compound having hypoglycemic activity and a pharmaceutically acceptable salt thereof, which is used in the medical field.

[0002]

Many benzothiadiazine compounds are known, but no benzothiadiazine compound represented by the following general formula (I) of the present invention is known.

[0003]

A large number of compounds having hypoglycemic activity are known, but the present invention was made with the intention of developing more excellent pharmaceutical products.

[0004]

The benzothiadiazine compound of the present invention is novel and can be represented by the following general formula [I].

[Chemical 2] [Wherein R ¹ is a lower alkyl group, R ² is a lower alkyl group, R ³ is a lower alkyl group, R ⁴ is hydrogen, a lower alkyl group, a nitrogen-containing unsaturated heterocyclic group, or a halogen or a lower alkyl group. Group, an nitro group or an aryl group which may be substituted with an aryloxy group, X represents a lower alkylene group, Y represents a lower alkylene group, and n represents an integer of 0 or 1] [I] can be produced by the following production methods.

Manufacturing method 1

[Chemical 3]

Manufacturing method 2

[Chemical 4]

Manufacturing method 3

[Chemical 5]

(In the above formulas, R ¹ , R ² , R ³ , R ⁴ , X,
Y and n are respectively as defined above, R ⁵ is a nitrogen-containing unsaturated heterocyclic group, or an aryl group optionally substituted with a halogen, a lower alkyl group, a nitro group or an aryloxy group, and A is Halogen and Z are leaving groups, respectively. ) The raw material compound [II] is novel and can be produced by the following production method.

Manufacturing method A

[Chemical 6]

Manufacturing method B

[Chemical 7]

Manufacturing method C

[Chemical 8]

Manufacturing method D

[Chemical 9]

Manufacturing method E

[Chemical 10]

Manufacturing method F

[Chemical 11]

(In the above formulas, R ¹ , R ² , R ³ , R ⁴ , X,
Y, Z and n are each as defined above, and R
⁶ represents a lower alkoxy group, and R ⁷ and R ⁸ represent a halogen, a lower alkoxy group or an imidazolyl group, respectively. )

In the above and subsequent description of this specification, preferred and illustrative examples of the various definitions within the scope of this invention are described in detail below. “Lower” means 1 to 6 carbon atoms unless otherwise specified. The number of substituents of the aryl group of R ⁴ is 1 to 3, preferably 1
Or 2. Preferable examples of the lower alkyl group include:
Linear or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like can be mentioned.
Preferred examples of the lower alkylene group include linear or branched ones such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylethylene, ethylethylene, propylethylene, isopropylethylene, methylpenta. Methylene etc. can be mentioned. Preferable examples of “halogen” include chlorine, bromine, iodine and fluorine. Preferable examples of "lower alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy and the like. Preferable examples of “aryl group” include phenyl, tolyl, xylyl, cumenyl, naphthyl and the like. Preferable examples of "aryloxy group" include:
Phenoxy, tolyloxy, naphthyloxy and the like can be mentioned. Suitable "leaving group" may include hydroxy group and acid residue, and suitable examples of "acid residue" include halogen (eg chlorine, bromine, iodine or fluorine), sulfonyloxy (eg Methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, etc.) and the like, and more preferable examples include halogen.

Suitable "nitrogen-containing unsaturated heterocyclic group" is one containing at least one nitrogen atom, and examples thereof include monocyclic or polycyclic heterocyclic groups, and more preferable heterocyclic group. A 3- to 6-membered unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4- Triazolyl, 1H-
1,2,3-triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl and the like), etc .; unsaturated condensed heterocyclic group having 1 to 5 nitrogen atoms, for example Indolyl, isoindolyl, indoridinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl, etc.); 1 or 2 oxygen atoms and nitrogen atom A 3- to 6-membered unsaturated heteromonocyclic group having 1 to 3 groups, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc. )Such;
Unsaturated condensed heterocyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (for example, benzoxazolyl, benzooxadiazolyl, etc.); 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms A 3- to 6-membered unsaturated heteromonocyclic group having, for example, thiazolyl, thiadiazolyl (eg 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl etc.) and the like; unsaturated condensed heterocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg benzothiazolyl, benzothiadiazolyl etc.) And so on. The above-mentioned "heterocyclic group" may have 1 to 4 substituents such as the lower alkyl groups exemplified above.

Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts, which are organic acid salts [eg formate, acetate, trifluoroacetate, maleate, tartaric acid]. Salts, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], inorganic acid salts [eg hydrochloride, hydrobromide, sulfate, phosphate etc.], salts with amino acids [eg arginine salt, Ornithine salt, etc.], a salt with a base such as alkali metal salt [eg sodium salt, potassium salt etc.], alkaline earth metal salt [eg calcium salt, magnesium salt etc.] and the like. In this regard, compounds [Ia] to [Ic] are included within the scope of compound [I],
As suitable salts of these compounds [Ia] to [Ic], those exemplified above for the target compound [I] can be referred to. Each of the target compound [I] contains at least one stereoisomer based on an asymmetric carbon atom in the molecule, and all such isomers of the compound [I] are included in the scope of the present invention. The method for producing the object compound [I] or a salt thereof will be described in detail below.

Production Method 1 The object compound [I] or its salt can be produced by reacting the compound [II] or its salt with the compound [III]. Compound [III] is called a Grignard reagent, and suitable Grignard reagents include halogens such as methyl magnesium bromide, ethyl magnesium bromide, methyl magnesium iodide, ethyl magnesium iodide, ethyl magnesium chloride and n-butyl magnesium chloride. Mention may be made of alkylmagnesium chloride. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as methanol, ethanol, propanol, tetralin, tetrahydrofuran, dioxane,
It is performed in chloroform, toluene, N, N-dimethylformamide, dimethylsulfoxide or other organic solvent. The reaction temperature is not particularly limited and is usually performed under cooling or at room temperature.

Production Method 2 The object compound [Ib] or its salt can be produced by subjecting the compound [Ia] or its salt to catalytic reduction. The catalytic reduction is carried out in the presence of Pearlman's catalyst, ie palladium hydroxide charcoal. The reaction is usually performed in a solvent. Suitable solvents used include water,
Mention may be made of alcohols such as methanol, ethanol, propanol, acetonitrile, or other conventional organic solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof. The reaction is preferably carried out under cooling, at room temperature or under heating.

Production Method 3 The object compound [Ic] or its salt can be produced by reacting the compound [Ib] or its salt with the compound [IV]. This reaction is preferably carried out in the presence of a base such as an inorganic or organic base. Suitable organic or inorganic bases include alkali metal hydrides [eg sodium hydride, potassium hydride, etc.],
Alkaline earth metal hydride [eg calcium hydride, magnesium hydride etc.], alkali metal hydroxide [eg sodium hydroxide, potassium hydroxide etc.],
Alkali metal carbonate [eg sodium carbonate, potassium carbonate etc.], alkali metal bicarbonate [eg sodium bicarbonate, potassium bicarbonate etc.], alkali metal fluoride [eg potassium fluoride, cesium fluoride etc.], alkali metal alkoxide [Eg sodium methoxide, sodium ethoxide, potassium tertiary butoxide etc.], trialkylamine [eg trimethylamine, triethylamine etc.], picoline, 1,
5-diazabicyclo [4,3,0] non-5-ene,
1,4-diazabicyclo [2,2,2] octane, 1,
5-diazabicyclo [5,4,0] undecene-5 and the like can be mentioned. This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, such as water, methanol,
Ethanol, propanol, tetralin, tetrahydrofuran, dioxane, chloroform, toluene, N, N
-Done in dimethylformamide, dimethylsulfoxide or other organic solvent. The reaction temperature is not particularly limited and is usually under cooling, at room temperature or under heating. The method for producing the starting compound [II] or a salt thereof will be described in detail below.

Production Method A Compound [VII] or its salt is prepared by reacting compound [V] or its reactive derivative at its sulfo group or its salt with compound [VI] or its reactive derivative at its amino group or its salt. It can be produced by reacting. Suitable examples of the reactive derivative at the sulfo group may include conventional ones such as acid halides (eg acid chlorides, acid bromides, etc.), acid anhydrides, active esters or amides. Suitable reactive derivative at the amino group of compound [VI] is, for example, a Schiff base type imino produced by reacting compound [VI] with a carbonyl compound or a tautomeric enamine type isomer thereof, compound [VI]. Is used for amination of silyl derivatives formed by reacting trimethylsilylacetamide, bis (trimethylsilyl) acetamide and the like with silyl compounds, and compounds [VI] formed by reacting with phosphorus trichloride or phosgene. The conventional one can be mentioned. This reaction is preferably performed in the presence of an organic or inorganic base as described in Production method 3. The reaction is usually performed in a solvent. Suitable solvents used include water, alcohols [eg methanol, ethanol, propanol etc.], acetonitrile or other conventional organic solvents such as methylene chloride, diethyl ether, dioxane, tetrahydrofuran etc. or mixtures thereof. be able to. Furthermore, the liquid bases mentioned above can also be used as solvents. The reaction is preferably carried out under cooling or heating.

Production Method B Compound [VIII] or a salt thereof is compound [VII]
Alternatively, it can be produced by reducing the salt. The reaction may include chemical reduction and catalytic reduction carried out in conventional manner. Suitable reducing agents used in the chemical reduction include metals [eg tin, zinc, iron etc.], the metals and / or metal compounds mentioned above [eg chromium chloride, chromium acetate etc.] and organic or inorganic acids [eg formic acid]. , Acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.], a metal and / or metal compound as described above and a base [eg ammonia, ammonium chloride,
Hydrogen such as aluminum hydride compound [eg, lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-tertiary butoxyaluminum hydride, etc.] Metal compounds, borohydride compounds [eg sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, borane,
Diborane, etc.] and phosphorus compounds [eg phosphorus trichloride, phosphorus tribromide, triphenylphosphine, triethylphosphine, etc.]. Suitable catalysts used in the catalytic reduction include conventional catalysts such as platinum catalysts [eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [eg palladium sponge, palladium black , Palladium oxide, palladium charcoal, colloidal palladium, palladium-barium sulfate,
Palladium-barium carbonate etc.], nickel catalyst [eg reduced nickel, nickel oxide, Raney nickel etc.], cobalt catalyst [eg reduced cobalt, Raney cobalt etc.], iron catalyst [eg reduced iron, Raney iron etc.], copper catalyst [eg reduced copper. , Raney copper, Ullmann copper, etc.] and the like. The reaction is usually performed in a solvent. Suitable solvents used may include water, alcohols [eg methanol, ethanol, propanol etc.], acetonitrile or other conventional organic solvents such as diethyl ether, dioxane, tetrahydrofuran etc. or mixtures thereof. . The reaction is preferably carried out under heating or heating.

Production Method C Compound [X] or a salt thereof can be produced by reacting compound [VIII] or a reactive derivative at the amino group thereof or a salt thereof with compound [IX]. Preferable examples of the reactive derivative at the amino group include those described in the above production method A. The reaction is usually performed in a conventional solvent that does not adversely influence the reaction, such as tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, dimethylformamide, dimethylsulfoxide, or other organic solvent. The reaction temperature is not particularly limited, and the reaction is carried out under cooling or heating.

Production Method D Compound [XI] or a salt thereof can be produced by subjecting compound [X] or a salt thereof to a reaction for introducing a substituent of a nitrogen atom. This introduction reaction is performed using compound [X]
Alternatively, a salt thereof may be represented by the formula: R ³ -Z (wherein R ³ and Z are
Each of them is as defined above). In this introduction reaction, compound [X] or a salt thereof is converted into a di (lower) alkyl sulfate salt [eg, dimethyl sulfate, diethyl sulfate, etc.],
It can also be carried out by reacting with a diazo (lower) alkane [eg diazomethane, diazoethane, etc.]. Di (lower) alkyl sulfate or formula: R ³
The reaction with the compound of -Z is usually carried out in a solvent that does not adversely influence the reaction, for example, water, acetone, ethanol, ether, N, N-dimethylformamide or other solvent. This reaction is preferably carried out in the presence of a base such as an inorganic or organic base as described in production method 3. The reaction temperature is not particularly limited, and it is usually performed under cooling or heating. The reaction using diazoalkane is usually carried out in a solvent such as ether or tetrahydrofuran. The reaction temperature is not particularly limited and is usually performed under cooling or at room temperature.

Production Method E Compound [XII] or a salt thereof can be produced by subjecting compound [XI] or a salt thereof to a reaction for eliminating a substituent of an oxygen atom. This reaction is preferably carried out in the presence of a Lewis acid such as boron halide (eg boron trichloride, boron tribromide), hydrohalic acid (eg hydrobromic acid, hydroiodic acid etc.) and the like. . The reaction is usually performed without using a solvent or in a solvent that does not adversely influence the reaction, for example, a solvent such as chloroform, methylene chloride, carbon tetrachloride and the like. The reaction temperature is not particularly limited, and it is usually performed under cooling or heating.

Production Method F Compound [II] or a salt thereof can be produced by reacting compound [XII] or a salt thereof with compound [XIII]. This reaction is preferably carried out in the presence of a base such as an inorganic or organic base as described in Production method 3. This reaction is usually carried out in a solvent that does not adversely influence the reaction, such as water, methanol, ethanol, propanol, tetralin, tetrahydrofuran,
It is carried out in dioxane, chloroform, toluene, N, N-dimethylformamide, dimethylsulfoxide or other organic solvent. The reaction temperature is not particularly limited, and is usually
It is carried out under cooling, at room temperature or under heating.

Processes 1 to 3 and Processes A to F
The compounds obtained by can be converted into their pharmaceutically acceptable salts as described above by a conventional method. The object compound [I] and a pharmaceutically acceptable salt thereof have, for example, hypoglycemic activity, and have type II diabetes,
It is effective for treating hyperglycemia characterized by abnormal glucose metabolism such as obesity, hyperlipidemia, hypertension, atherosclerosis, cardiovascular disease and eating disorders.

In order to show the effectiveness of the target compound [I],
The pharmacological test data of a representative compound of the compound [I] is shown below. (1) Hypoglycemic activity test method Male db / db mice (Jackson Laboratories, USA) aged 7 weeks were fed with CE-2 diet (CLEA Japan, Japan) containing the test compound for 2 weeks. Both the db / db control mice and the + / + normal control mice had CE-
Two diets were fed for 2 weeks. Blood was collected from the eyes using heparinized capillaries without anesthesia. Glucose in plasma was measured using a glucose assay kit based on the glucose oxidase method (Glucose C-II test, Wako, Japan). The inhibitory potency of the test compounds was evaluated by percent inhibition as described below.

[Table 1] Results of glucose concentration (mg / dl) test in plasma of db / db control mouse (A), + / + normal control mouse (B) and drug-treated db / db mouse (C)

[Table 2]

For treatment, the compounds of the invention [I]
And a pharmaceutically acceptable salt thereof, with one of the compounds as an active ingredient, and a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral and parenteral and external use. Can be used in the form of a pharmaceutical preparation containing The pharmaceutical preparation may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions and the like. If necessary, auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers, and other commonly used additives may be added to the above-mentioned preparation. The dose of the compound [I] varies depending on the age and condition of the patient, but the average single dose of the compound [I] is about 0.1 mg, 1 mg, 10 mg, 50
mg, 100 mg, 250 mg, 500 mg, 1000
As mg, it can be effectively used for the treatment of the above-mentioned diseases. Generally, 0.1 mg to about 100 per day
An amount in the range of 0 mg may be administered per patient.
The following Production Examples and Examples are provided to illustrate the present invention.

Production Example 1 4-Bromoaniline (17.2 g) and 4-methoxy-2
-Nitrobenzene to a mixture of sulfonyl chloride (25.2 g), aqueous sodium hydroxide solution (0.7 N, 143 m
1) is added dropwise at 80 ° C. over 30 minutes. After the dropping, the mixture is stirred at the same temperature for 3 hours. The cooled mixture is diluted with 1N hydrochloric acid. The oil that separates is extracted with ethyl acetate. The extract is washed with water and brine and concentrated under reduced pressure.
Crystallize a yellow oil from isopropyl ether,
4-Methoxy-2-nitro-N- (4-bromophenyl) benzenesulfonamide (20.7 g) is obtained. mp: 103-106 ° C NMR (CDCl ₃ , δ): 3.90 (3H, s), 7.00 (1H, d, J = 10H
z), 7.08 (2H, d, J = 8Hz), 7.15 (1H, br s), 7.32 (1H,
s), 7.40 (2H, d, J = 8Hz), 7.75 (1H, d, J = 10Hz)

Production Example 2 The following compounds are obtained in the same manner as in Production Example 1. (1) 4-methoxy-2-nitro-N- (4-iodophenyl) benzenesulfonamide mp: 115-118 ° C NMR (CDCl ₃ , δ): 3.97 (3H, s), 6.93-7.03 (3H, m ),
7.17 (1H, br s), 7.31 (1H, s), 7.58 (2H, d, J = 10H
z), 7.75 (1H, d, J = 10Hz) (2) 4-methoxy-2-nitro-N- (3-bromophenyl) benzenesulfonamide mp: 138-141 ° C NMR (CDCl ₃ , δ): 3.91 (3H, s), 7.02 (1H, d, J = 10H
z), 7.12-7.20 (3H, m), 7.25-7.35 (2H, m), 7.40 (1H,
s), 7.80 (1H, d, J = 10Hz) (3) 4-methoxy-2-nitro-N- (4-bromo-2-fluorophenyl) benzenesulfonamide mp: 58-60 ° C NMR (CDCl ₃ , δ): 3.90 (3H, s), 7.01 (1H, d, J = 10H
z), 7.15 (1H, d, J = 10Hz), 7.30 (1H, d, J = 10Hz), 7.4
0 (1H, s), 7.48-7.58 (2H, m), 7.77 (1H, d, J = 10Hz) (4) 4-methoxy-2-nitro-N- (butyl) benzenesulfonamide (oil) NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7.5Hz), 1.35 (2H,
m), 1.51 (2H, m), 3.07 (2H, q, J = 7.5Hz), 3.90 (3H,
s), 5.15 (1H, t, J = 7.5Hz), 7.17 (1H, dd, J = 7.5, 2H
z), 7.34 (1H, d, J = 1.5Hz), 8.03 (1H, d, J = 7.5Hz) (5) 4-methoxy-2-nitro-N- (4-propylphenyl) benzenesulfonamide (solid NMR) (CDCl ₃ , δ): 0.91 (3H, t, J = 7.5Hz), 1.59 (2H,
m), 2.52 (2H, t, J = 7.5Hz), 3.90 (3H, s), 6.98 (1H,
dd, J = 10, 2Hz), 7.09 (4H, s), 7.33 (1H, d, J = 2Hz),
7.72 (1H, d, J = 10Hz) (6) 4-methoxy-2-nitro-N- (4-tertiarybutylphenyl) benzenesulfonamide mp: 136-138 ° C NMR (CDCl ₃ , δ): 1.25 (9H, s), 3.90 (3H, s), 6.99
(1H, dd, J = 10, 2Hz), 7.11 (2H, d, J = 10Hz), 7.27 (2
H, d, J = 10Hz), 7.34 (1H, d, J = 2Hz), 7.25 (1H, d, J =
10Hz) (7) 4-methoxy-N- (1-naphthyl) -2-nitrobenzenesulfonamide mp: 145-148 ° C NMR (CDCl ₃ , δ): 3.92 (3H, s), 6.88 (1H, dd, J = 1
0,2Hz), 7.33-7.50 (6H, m), 7.57 (1H, d, J = 10Hz), 7.
77 (1H, d, J = 8Hz), 7.80-7.86 (1H, m), 8.10-8.17 (1
H, m) (8) 4-methoxy-N- (2-naphthyl) -2-nitrobenzenesulfonamide mp: 100-103 ° C NMR (CDCl ₃ , δ): 3.88 (3H, s), 6.89 (1H, dd , J = 1
0,2Hz), 7.32-7.37 (3H, m), 7.40-7.52 (2H, m), 7.65
(1H, s), 7.73-7.80 (4H, m)

Preparative Example 3 4-Methoxy-2-nitrobenzene To a solution of sulfonyl chloride (20.08g) in dry methylene chloride (200ml) was added benzylamine (21.40g) in methylene chloride (5ml) at 5 ° C. Add. Mix the mixture at the same temperature 1
Stir for half an hour. The reaction mixture is poured into 1N hydrochloric acid. The mixture is extracted with methylene chloride. The extract is washed with water and brine and concentrated under reduced pressure. The yellow oil was crystallized from isopropyl ether to give 4-methoxy-2-nitro-N- (benzyl) benzenesulfonamide (24.3
0 g) is obtained. mp: 107-109 ° C NMR (CDCl ₃ , δ): 3.91 (3H, s), 4.25 (2H, d, J = 5H
z), 5.58 (1H, t, J = 5Hz), 7.06 (1H, dd, J = 7.5,1.5H
z), 7.20-7.32 (6H, m), 7.94 (1H, d, J = 7.5Hz)

Preparation Example 4 4-Methoxy-2-nitro-N- (4-bromophenyl) benzenesulfonamide (20.6 g) in a solution mixture of ethanol (114 ml) and acetic acid (114 ml).
To, add iron (7.46 g). The reaction mixture is refluxed for 2 hours. The cooled mixture was sodium carbonate (209 g)
And a solution of water (1.5 l). The mixture is extracted twice with ethyl acetate. The extracts are washed with brine, dried and concentrated. The yellow oil was crystallized from isopropyl ether to give 2-amino-4-methoxy-N- (4-
Bromophenyl) benzenesulfonamide (11.7
g) is obtained. mp: 93-95 ° C NMR (CDCl ₃ , δ): 3.75 (3H, s), 6.18 (1H, s), 6.22
(1H, d, J = 10Hz), 6.72 (1H, br s), 6.92 (2H, d, J = 10
Hz), 7.32 (2H, d, J = 10Hz), 7.40 (1H, d, J = 10Hz)

Production Example 5 The following compounds are obtained in the same manner as in Production Example 4. (1) 2-Amino-4-methoxy-N- (4-iodophenyl) benzenesulfonamide mp: 60-63 ° C NMR (CDCl ₃ , δ): 3.75 (3H, s), 4.85 (2H, br s) ,
6.17 (1H, s), 6.22 (1H, d, J = 10Hz), 6.71 (1H, br
s), 6.80 (2H, d, J = 10Hz), 7.41 (1H, d, J = 10Hz), 7.5
1 (2H, d, J = 10Hz) (2) 2-amino-4-methoxy-N- (3-bromophenyl) benzenesulfonamide mp: 129-131 ° C NMR (CDCl ₃ , δ): 3.25 (3H, s), 4.88 (2H, br s),
6.20 (1H, s), 6.25 (1H, d, J = 10Hz), 6.75 (1H, br
s), 6.95-7.12 (2H, m), 7.20-7.25 (2H, m), 7.46 (1H,
d, J = 10Hz) (3) 2-amino-4-methoxy-N- (4-bromo-2-fluorophenyl) benzenesulfonamide mp: 117-120 ° C NMR (CDCl ₃ , δ): 3.75 (3H, s), 4.92 (2H, br s),
6.18 (1H, s), 6.22 (1H, d, J = 10Hz), 6.91 (1H, br
s), 7.10-7.21 (2H, m), 7.35-7.46 (2H, m) (4) 2-amino-4-methoxy-N- (butyl) benzenesulfonamide (oil) NMR (CDCl ₃ , δ) : 0.85 (3H, t, J = 7.5Hz), 1.20-1.49
(4H, m), 2.87 (2H, q, J = 7.5Hz), 3.81 (3H, s), 4.55
(1H, t, J = 7.5Hz), 4.88 (2H, s), 6.24 (1H, d, J = 1.5H
z), 6.47 (1H, dd, J = 7.5, 1.5Hz), 7.54 (1H, d, J = 7.5
Hz) (5) 2-amino-4-methoxy-N- (benzyl)
Benzenesulfonamide mp: 93-97 ° C NMR (CDCl ₃ , δ): 3.82 (3H, s), 4.03 (2H, d, J = 5H
z), 4.91 (2H, t, J = 5Hz), 6.23 (1H, d, J = 2Hz), 6.87
(1H, dd, J = 10, 2Hz), 7.18-7.34 (5H, m), 7.67 (1H,
d, J = 10Hz) (6) 2-amino-4-methoxy-N- (1-naphthyl) benzenesulfonamide mp: 106-110 ° C NMR (CDCl ₃ , δ): 3.72 (3H, s), 4.96 ( 2H, br s), 6.
09-6.15 (2H, m), 6.97 (1H, br s), 7.24-7.35 (3H,
m), 7.42-7.46 (2H, m), 7.70 (1H, d, J = 8Hz), 7.73-7.
82 (1H, m), 8.02-8.10 (1H, m) (7) 2-amino-4-methoxy-N- (2-naphthyl) benzenesulfonamide mp: 113-116 ° C NMR (CDCl ₃ , δ): 3.72 (3H, s), 4.92 (2H, s),
6.14 (1H, d, J = 8Hz), 6.18 (1H, s), 6.92 (1H, br s),
7.19 (1H, d, J = 8Hz), 7.38-7.47 (3H, m), 7.51 (1H,
s), 7.68-7.78 (3H, m)

Production Example 6 4-Methoxy-2-nitro-N- (4-propylphenyl) benzenesulfonamide (10.40 g), ferric chloride hexahydrate (312 mg) and activated carbon powder (312).
To a mixture of (mg) in 80% aqueous methanol (150 ml) is added hydrazine monohydrate (5.94 g) at 60 ° C over 20 minutes. The reaction mixture is stirred at 60 ° C. for 2.5 hours and the hot mixture is filtered. The solvent is distilled off from the filtrate under reduced pressure and the residue is extracted with ethyl acetate. The extracts are washed with water and concentrated to give the crude product. This was purified by silica gel column chromatography (eluted with ethyl acetate and hexane 1: 2) to give 2-amino-4-.
Methoxy-N- (4-propylphenyl) benzenesulfonamide (9.50 g) is obtained. (Oil) NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7.5Hz), 1.57 (2H,
m), 2.50 (2H, t, J = 7.5Hz), 3.74 (3H, s), 4.87 (2H,
s), 6.16-6.22 (2H, m), 6.63 (1H, s), 6.94 (2H, d, J
= 10Hz), 7.02 (2H, d, J = 10Hz), 7.39 (1H, d, J = 10Hz)

Production Example 7 The following compounds are obtained in the same manner as in Production Example 6. 2-Amino-4-methoxy-N- (4-tert-butylphenyl) benzenesulfonamide mp: 90-95 ° C NMR (CDCl ₃ , δ): 1.25 (9H, s), 3.78 (3H, s), 4.89
(2H, br s), 6.20-6.26 (2H, m), 6.64 (1H, br s), 6.9
6 (2H, d, J = 10Hz), 7.23 (2H, d, J = 10Hz), 7.44 (1H,
d, J = 10Hz)

Production Example 8 2-Amino-4-methoxy-N- (4-bromophenyl) benzenesulfonamide (9.59 g) and 1,1 '
A mixture of carbonyldiimidazole (13.1 g) in dry dioxane (150 ml) is refluxed for 6 hours. Pour the cooled solution into ice water. Collect the separated solids,
Wash with water and diethyl ether, dry and wash with 2- (4-
Bromophenyl) -6-methoxy-1,1-dioxo-
4H-benzo [e] [1,2,4] thiadiazine-3-
Obtained on (9.90 g). mp: 244-246 ° C NMR (DMSO-d ₆ , δ): 3.85 (3H, s), 6.81 (1H, s), 6.
92 (1H, d, J = 10Hz), 7.37 (2H, d, J = 10Hz), 7.73 (2H,
d, J = 10Hz), 7.82 (1H, d, J = 10Hz)

Production Example 9 The following compounds are obtained in the same manner as in Production Example 8. (1) 2- (4-iodophenyl) -6-methoxy-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 263-266 ° C NMR (DMSO-d ₆ , δ): 3.83 (3H, s), 6.71 (1H, s), 6.
92 (1H, d, J = 10Hz), 7.20 (2H, d, J = 10Hz), 7.82 (1H,
d, J = 10Hz), 7.90 (2H, d, J = 10Hz) (2) 2- (3-bromophenyl) -6-methoxy-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 203-205 ° C NMR (DMSO-d ₆ , δ): 3.88 (3H, s), 6.82 (1H, s), 6.
93 (1H, d, J = 10Hz), 7.43-7.57 (2H, m), 7.65 (1H, s),
7.78 (1H, d, J = 8Hz), 7.83 (1H, d, J = 10Hz) (3) 2- (4-bromo-2-fluorophenyl)-
6-methoxy-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 264-266 ° C NMR (DMSO-d ₆ , δ): 3.87 (3H, s), 6.82 (1H, s), 6.
92 (1H, d, J = 10Hz), 7.48-7.62 (2H, m), 7.87 (2H, d,
J = 10 Hz) (4) 2-Butyl-6-methoxy-1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazine-3
-ON (solid) NMR (CDCl ₃ , δ): 0.97 (3H, t, J = 7.5Hz), 1.41 (2H,
m), 1.78 (2H, m), 3.88 (3H, s), 3.93 (2H, t, J = 7.5H
z), 6.55 (1H, d, J = 1.5Hz), 6.80 (1H, dd, J = 7.5, 1.5
Hz), 7.75 (1H, d, J = 7.5Hz), 9.65 (1H, br s) (5) 2-benzyl-6-methoxy-1,1-dioxo-4H-benzo [e] [1,2, 4] Thiadiagin
3-one mp: 177-180 ° C NMR (CDCl ₃ , δ): 3.85 (3H, s), 5.06 (2H, s), 6.47
(1H, d, J = 1.5Hz), 6.80 (1H, dd, J = 10, 1.5Hz), 7.22-
7.47 (3H, m), 7.44-7.52 (2H, m), 7.79 (1H, d, J = 10H
z), 8.85 (1H, br s) (6) 6-methoxy-2- (4-propylphenyl)
-1,1-dioxo-4H-benzo [e] [1,2,
4] thiadiazin-3-one mp: 170-172 ° C NMR (DMSO-d ₆ , δ): 0.97 (3H, t, J = 7.5Hz), 1.65 (2
H, m), 2.67 (2H, t, J = 7.5Hz), 3.89 (3H, s), 6.84 (1
H, d, J = 2Hz), 6.95 (1H, dd, J = 10, 2Hz), 7.80 (2H,
d, J = 10Hz), 7.84 (1H, d, J = 10Hz), 7.88 (2H, d, J = 10
Hz) (7) 6-methoxy-2- (4-tert-butylphenyl) -1,1-dioxo-4H-benzo [e] [1,
2,4] thiadiazin-3-one mp: 250-252 ° C NMR (DMSO-d ₆ , δ): 1.35 (9H, s), 3.37 (1H, br s),
3.88 (3H, s), 6.81 (1H, d, J = 2Hz), 6.94 (1H, dd, J =
10, 2Hz), 7.32 (2H, d, J = 10Hz), 7.56 (2H, d, J = 10H
z), 7.83 (1H, d, J = 10Hz) (8) 6-methoxy-2- (1-naphthyl) -1,1
- dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one mp: 253-256 ℃ NMR (DMSO- d 6, δ): 3.90 (3H, s), 6.89 (1H, s) , 6.
94 (1H, d, J = 10Hz), 7.52-7.70 (5H, m), 7.86 (1H, d,
J = 10Hz), 8.06 (1H, d, J = 10Hz), 8.12 (1H, dd, J = 10,
2Hz) (9) 6-methoxy-2- (2-naphthyl) -1,1
- dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one mp: 275-277 ℃ NMR (DMSO- d 6, δ): 3.87 (3H, s), 6.87 (1H, d, J = 2H
z), 6.95 (1H, dd, J = 10, 2Hz), 7.48 (1H, d, J = 10Hz),
7.58-7.68 (2H, m), 7.85 (1H, d, J = 10Hz), 8.02-8.11
(4H, m)

Production Example 10 2- (4-Bromophenyl) -6-methoxy-1,1-
To a solution of dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one (9.90 g) in dry dimethylformamide (100 ml) was added sodium hydride (6
0% dispersion in oil) (1.24 g) is added in one portion at 5 ° C. The suspension is stirred for 15 minutes at the same temperature, then methyl iodide (4.40 g) is added. The reaction mixture is warmed to room temperature and stirred for 1 hour. The reaction mixture is poured into water. The separated solid was collected, washed with water and diethyl ether, dried and 2- (4-bromophenyl) -6-methoxy-
4-methyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one (9.39 g)
To get mp: 146-148 ° C NMR (DMSO-d ₆ , δ): 3.50 (3H, s), 3.95 (3H, s), 7.
01 (1H, d, J = 10Hz), 7.07 (1H, s), 7.35 (2H, d, J = 10H
z), 7.73 (2H, d, J = 10Hz), 7.90 (1H, d, J = 10Hz)

Production Example 11 The following compound is obtained in the same manner as in Production Example 10. (1) 2- (4-iodophenyl) -6-methoxy-
4-methyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 163-166 ° C NMR (CDCl ₃ , δ): 3.55 (3H, s), 3.76 (3H, s), 6.78
(1H, s), 6.85 (1H, d, J = 10Hz), 7.15 (2H, d, J = 10H
z), 7.82 (2H, d, J = 10Hz), 7.87 (1H, d, J = 10Hz) (2) 2- (3-bromophenyl) -6-methoxy-
4-methyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 164-168 ° C NMR (DMSO-d ₆ , δ): 3.52 (3H, s), 3.98 (3H, s), 7.
02 (1H, d, J = 10Hz), 7.07 (1H, s), 7.40-7.55 (2H, m),
7.62 (1H, s), 7.75 (1H, d, J = 8Hz), 7.90 (1H, d, J =
10Hz) (3) 2- (4-bromo-2-fluorophenyl)-
6-methoxy-4-methyl-1,1-dioxo-4H-
Benzo [e] [1,2,4] thiadiazin-3-one mp: 206-208 ° C NMR (DMSO-d ₆ , δ): 3.53 (3H, s), 3.95 (3H, s), 7.
03 (1H, d, J = 10Hz), 7.09 (1H, s), 7.45-7.62 (2H, m),
7.37 (1H, d, J = 10Hz), 7.40 (1H, d, J = 10Hz) (4) 2- (4-bromophenyl) -4-ethyl-6
-Methoxy-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 154-156 ° C NMR (CDCl ₃ , δ): 1.44 (3H, t, J = 7.5Hz), 3.94 (3H,
s), 4.13 (2H, q, J = 7.5Hz), 6.81-6.88 (2H, m), 7.32
(2H, d, J = 10Hz), 7.64 (2H, d, J = 10Hz), 7.88 (1H, d,
J = 10Hz) (5) 2- (4-bromophenyl) -6-methoxy-
4-Propyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 120-121 ° C NMR (CDCl ₃ , δ): 1.04 (3H, t, J = 7.5Hz), 1.85 (2H,
m), 3.95 (3H, s), 4.04 (2H, q, J = 7.5Hz), 6.79 (1H,
d, J = 2Hz), 6.85 (1H, dd, J = 10, 2Hz), 7.32 (2H, d, J
= 10Hz), 7.63 (2H, d, J = 10Hz), 7.87 (1H, d, J = 10Hz) (6) 2-butyl-6-methoxy-4-methyl-1,
1-Dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one (solid) NMR (CDCl ₃ , δ): 0.95 (3H, t, J = 7.5Hz), 1.38 (2H,
m), 1.73 (2H, m), 3.49 (3H, s), 3.88 (2H, t, J = 7.5H
z), 3.92 (3H, s), 6.69 (1H, d, J = 1.5Hz), 6.81 (1H,
dd, J = 7.5, 1.5Hz), 7.80 (1H, d, J = 7.5Hz) (7) 2-benzyl-6-methoxy-4-methyl-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 92-97 ° C NMR (CDCl ₃ , δ): 3.47 (3H, s), 3.89 (3H, s), 5.06
(2H, s), 6.68 (1H, d, J = 1.5Hz), 6.81 (1H, dd, J = 9,
1.5Hz), 7.25-7.36 (3H, m), 7.42-7.48 (2H, m), 7.84
(1H, d, J = 9Hz) (8) 6-methoxy-4-methyl-2- (4-propylphenyl) -1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 158-160 ° C NMR (CDCl ₃ , δ): 0.98 (3H, t, J = 7.5Hz), 1.68 (2H,
m), 2.64 (2H, t, J = 7.5Hz), 3.54 (3H, s), 3.93 (3H,
s), 6.77 (1H, d, J = 2Hz), 6.85 (1H, dd, J = 10, 2Hz),
7.30 (4H, s), 7.87 (1H, d, J = 10Hz) (9) 6-methoxy-4-methyl-2- (4-tertiarybutylphenyl) -1,1-dioxo-4H-benzo [ e] [1,2,4] thiadiazin-3-one mp: 175-177 ° C NMR (CDCl ₃ , δ): 1.33 (9H, s), 3.53 (3H, s), 3.92
(3H, s), 6.76 (1H, d, J = 2Hz), 6.83 (1H, dd, J = 10,2
Hz), 7.32 (2H, d, J = 10Hz), 7.49 (2H, d, J = 10Hz), 7.
86 (1H, d, J = 10Hz) (10) 4-Ethyl-2- (4-iodophenyl)-
6-methoxy-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 125-129 ° C NMR (CDCl ₃ , δ): 1.41 (3H, t, J = 8Hz), 3.95 (3H,
s), 4.11 (2H, q, J = 8Hz), 6.80 (1H, s), 6.83 (1H, d,
J = 8Hz), 7.65 (2H, d, J = 8Hz), 7.82 (2H, d, J = 8Hz),
7.85 (1H, d, J = 8Hz) (11) 6-methoxy-4-methyl-2- (1-naphthyl) -1,1-dioxo-4H-benzo [e] [1,
2,4] Thiadiazin-3-one mp: 206-210 ° C NMR (CDCl ₃ , δ): 3.56 (3H, s), 3.92 (3H, s), 6.83
(1H, d, J = 2Hz), 6.87 (1H, dd, J = 10, 2Hz), 7.43-7.52
(2H, m), 7.55 (1H, t, J = 10Hz), 7.70 (2H, t, J = 10H
z), 7.89 (2H, d, J = 10Hz), 7.98 (1H, d, J = 10Hz) (12) 6-methoxy-4-methyl-2- (2-naphthyl) -1,1-dioxo-4H -Benzo [e] [1,
2,4] Thiadiazin-3-one mp: 205-208 ° C NMR (DMSO-d ₆ , δ): 3.55 (3H, s), 3.99 (3H, s), 7.
02 (1H, d, J = 8Hz), 7.10 (1H, s), 7.43 (1H, d, J = 8H
z), 7.60-7.67 (2H, m), 7.92 (1H, d, J = 8Hz), 8.02-8.
09 (4H, m)

Production Example 12 2- (4-Bromophenyl) -6-methoxy-1,1-
Dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one (3.00 g), potassium carbonate (3.
A suspension of 24 g) and 2-iodopropane (4.00 g) in N, N-dimethylformamide (30 ml) is stirred at 80 ° C. for 1.5 hours. The reaction mixture is poured into ice water. The mixture is extracted with ethyl acetate. The extract is washed with water and brine and concentrated to give the crude product. This was purified by silica gel column chromatography (eluted with hexane and ethyl acetate 5: 1) to give 2- (4-bromophenyl) -4-isopropyl-6-methoxy-1,
1-Dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one (1.49 g) is obtained as white crystals. mp: 160-162 ° C NMR (CDCl ₃ , δ): 1.65 (6H, d, J = 8Hz), 3.91 (3H,
s), 4.41-4.56 (1H, m), 6.82 (1H, d, J = 10Hz), 6.88 (1
H, s), 7.27 (2H, d, J = 10Hz), 7.60 (2H, d, J = 10Hz),
7.81 (1H, d, J = 10Hz)

Production Example 13 2- (4-Bromophenyl) -6-methoxy-4-methyl-1,1-dioxo-4H-benzo [e] [1,2,
4] To a solution of thiadiazin-3-one (5.00 g) in methylene chloride (30 ml) was added methylene chloride (20 m
Bromotribromide (5.99 g) in 1) is added at room temperature. The mixture is refluxed for one and a half hours and cooled to room temperature.
The reaction mixture is poured into ice water. The separated solid was collected by filtration, washed with water and diethyl ether, dried and
2- (4-Bromophenyl) -6-hydroxy-4-methyl-1,1-dioxo-4H-benzo [e] [1,
2,4] thiadiazin-3-one (4.45 g) is obtained. mp: 301-303 ° C NMR (DMSO-d ₆ , δ): 3.45 (3H, s), 6.82 (1H, d, J = 10)
Hz), 6.90 (1H, s), 7.32 (2H, d, J = 10Hz), 7.72 (2H,
d, J = 10Hz), 7.79 (1H, d, J = 10Hz)

Production Example 14 The following compound was obtained in the same manner as in Production Example 13. (1) 2- (4-iodophenyl) -6-hydroxy-4-methyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 288-291 ° C NMR (DMSO-d ₆ , δ): 3.45 (3H, s), 6.82 (1H, d, J = 10)
Hz), 6.87 (1H, s), 7.18 (2H, d, J = 10Hz), 7.76 (1H,
d, J = 10Hz), 7.89 (2H, d, J = 10Hz) (2) 2- (3-bromophenyl) -6-hydroxy-4-methyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 242-245 ° C NMR (DMSO-d ₆ , δ): 3.47 (3H, s), 6.82 (1H, d, J = 10)
Hz), 6.90 (1H, s), 7.40-7.53 (2H, m), 7.60 (1H, s),
7.70-7.80 (2H, m) (3) 2- (4-bromo-2-fluorophenyl)-
6-hydroxy-4-methyl-1,1-dioxo-4H
- benzo [e] [1,2,4] thiadiazine-3-one mp: 232-236 ℃ NMR (DMSO- d 6, δ): 3.46 (3H, s), 6.82 (1H, d, J = 10
Hz), 6.91 (1H, s), 7.42-7.62 (2H, m), 7.80 (1H, d,
J = 10Hz), 7.86 (1H, d, J = 10Hz) (4) 2- (4-bromophenyl) -4-ethyl-6
-Hydroxy-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp:> 250 ° C NMR (DMSO-d ₆ , δ): 1.29 (3H, t, J = 7.5Hz), 4.06 (2
H, q, J = 7.5Hz), 6.82 (1H, dd, J = 10, 2Hz), 6.96 (1H,
d, J = 2Hz), 7.36 (2H, d, J = 10Hz), 7.73 (2H, d, J = 10H
z), 7.80 (1H, d, J = 10Hz) (5) 2- (4-bromophenyl) -6-hydroxy-4-propyl-1,1-dioxo-4H-benzo [e] [1,2, 4] thiadiazin-3-one mp: 222-224 ° C NMR (DMSO-d ₆ , δ): 0.94 (3H, t, J = 7.5Hz), 1.70 (2
H, m), 4.03 (2H, q, J = 7.5Hz), 6.82 (1H, dd, J = 10,2H
z), 6.96 (1H, d, J = 2Hz), 7.35 (2H, d, J = 10Hz), 7.74
(2H, d, J = 10Hz), 7.81 (1H, d, J = 10Hz) (6) 2-butyl-6-hydroxy-4-methyl-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 105-107 ° C NMR (CDCl ₃ , δ): 0.94 (3H, t, J = 7.5Hz), 1.37 (2H,
m), 1.74 (2H, m), 3.47 (3H, s), 3.88 (2H, t, J = 7.5H
z), 6.45 (1H, br s), 6.68 (1H, d, J = 2Hz), 6.74 (1H,
dd, J = 10, 2Hz), 7.74 (1H, d, J = 10Hz) (7) 2-benzyl-6-hydroxy-4-methyl-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 210-212 ° C NMR (DMSO-d ₆ , δ): 3.40 (3H, s), 5.44 (2H, s), 6.
75-6.81 (2H, m), 7.25-7.35 (5H, m), 7.77 (1H, d, J
= 9Hz) (8) 6-hydroxy-4-methyl-2- (4-propylphenyl) -1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 253 -254 ° C NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7.5Hz), 1.63 (2
H, m), 2.62 (2H, t, J = 7.5Hz), 3.44 (3H, s), 6.81 (1
H, dd, J = 10, 2Hz), 6.88 (1H, d, J = 2Hz), 7.25 (2H,
d, J = 10Hz), 7.35 (2H, d, J = 10Hz), 7.76 (1H, d, J = 10
Hz) (9) 6-hydroxy-4-methyl-2- (4-tert-butylphenyl) -1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp :> 260 ° C NMR (DMSO-d ₆ , δ): 1.31 (9H, s), 3.43 (3H, s), 6.
82 (1H, dd, J = 10, 2Hz), 6.88 (1H, d, J = 2Hz), 7.27 (2
H, d, J = 10Hz), 7.54 (2H, d, J = 10Hz), 7.78 (1H, d, J
= 10 Hz) (10) 2- (4-bromophenyl) -6-hydroxy-4-isopropyl-1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 205 -207 ° C NMR (DMSO-d ₆ , δ): 1.52 (6H, d, J = 5Hz), 4.45-4.60
(1H, m), 6.81 (1H, d, J = 10Hz), 6.97 (1H, s), 7.30
(2H, d, J = 10Hz), 7.71 (3H, d, J = 10Hz) (11) 4-Ethyl-6-hydroxy-2- (4-iodophenyl) -1,1-dioxo-4H-benzo [ e] [1,2,4] thiadiazin-3-one mp: 227-230 ° C NMR (DMSO-d ₆ , δ): 1.30 (3H, t, J = 8Hz), 4.05 (2H,
q, J = 8Hz), 6.81 (1H, d, J = 8Hz), 6.97 (1H, s), 7.18
(2H, d, J = 8Hz), 7.78 (1H, d, J = 8Hz), 7.90 (2H, d, J
= 8Hz) (12) 6-hydroxy-4-methyl-2- (1-naphthyl) -1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 299-301 ° C NMR (DMSO-d ₆ , δ): 3.45 (3H, s), 6.85 (1H, dd, J =
10,2Hz), 6.96 (1H, d, J = 2Hz), 7.51-7.68 (5H, m), 7.
78 (1H, d, J = 10Hz), 8.03 (1H, d, J = 10Hz), 8.11 (1H,
dd, J = 10,2Hz) (13) 6-hydroxy-4-methyl-2- (2-naphthyl) -1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one mp: 304-306 ° C NMR (DMSO-d ₆ , δ): 3.50 (3H, s), 7.83 (1H, d, J = 8H
z), 6.96 (1H, s), 7.43 (1H, d, J = 8Hz), 7.60-7.70
(2H, m), 7.81 (1H, d, J = 8Hz), 8.03-8.10 (4H, m)

Production Example 15 2- (4-Bromophenyl) -6-hydroxy-4-methyl-1,1-dioxo-4H-benzo [e] [1,
2,4] Thiadiazin-3-one (2.73 g), potassium carbonate (2.95 g) and chloroacetone (990
A suspension of mg) in N, N-dimethylformamide (27 ml) is stirred at 80 ° C. for 1 hour. The reaction mixture is poured into ice water. The mixture is extracted twice with ethyl acetate. The extract is washed with water and brine and concentrated. A yellow oil was crystallized from isopropyl ether and isopropyl alcohol to give 2- (4-bromophenyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one (2.20 g) is obtained. mp: 186-190 ° C NMR (CDCl ₃ , δ): 2.32 (3H, s), 3.53 (3H, s), 4.70
(2H, s), 6.75 (1H, d, J = 10Hz), 6.83 (1H, s), 7.28
(2H, d, J = 10Hz), 7.61 (2H, d, J = 10Hz), 7.88 (1H, d,
(J = 10Hz)

Production Example 16 The following compound is obtained in the same manner as in Production Example 15. (1) 2- (4-fluorophenyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 113-115 ° C NMR (CDCl ₃ , δ): 2.30 (3H, s), 2.53 (3H, s), 4.70
(2H, s), 6.75 (1H, d, J = 10Hz), 6.83 (1H, s), 7.15-
7.20 (2H, m), 7.38-7.42 (2H, m), 7.87 (1H, d, J = 10H
z) (2) 2- (4-iodophenyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 211-215 ° C NMR (CDCl ₃ , δ): 2.31 (3H, s), 3.55 (3H, s), 4.71
(2H, s), 6.73 (1H, d, J = 8Hz), 6.82 (1H, s), 7.13 (2
H, d, J = 8Hz), 7.82 (2H, d, J = 8Hz), 7.87 (1H, d, J = 8
Hz) (3) 2- (4-chlorophenyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 157-159 ° C NMR (CDCl ₃ , δ): 2.34 (3H, s), 3.57 (3H, s), 4.72
(2H, s), 6.77 (1H, dd, J = 8.5, 2Hz), 6.86 (1H, d, J =
2Hz), 7.36 (2H, d, J = 8.5Hz), 7.49 (2H, d, J = 8.5Hz),
7.89 (1H, d, J = 8.5Hz) (4) 2- (3-chlorophenyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 185-188 ° C NMR (CDCl ₃ , δ): 2.30 (3H, s), 3.55 (3H, s), 4.70
(2H, s), 6.75 (1H, d, J = 10Hz), 6.83 (1H, s), 7.51-
7.80 (4H, m), 7.88 (1H, d, J = 10Hz) (5) 2- (3-bromophenyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 173-176 ° C NMR (CDCl ₃ , δ): 2.32 (3H, s), 3.52 (3H, s), 4.72
(2H, s), 6.75 (1H, d, J = 10Hz), 6.85 (1H, s), 7.35
7.41 (2H, m), 7.55-7.65 (2H, m), 7.87 (1H, d, J = 10H
z) (6) 2- (4-bromo-2-fluorophenyl)-
4-Methyl-1,1-dioxo-6- (2-oxopropoxy) -4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 168-172 ° C NMR (CDCl ₃ , δ) : 2.32 (3H, s), 3.52 (3H, s), 4.70
(2H, s), 6.75 (1H, d, J = 10Hz), 6.85 (1H, s), 7.35
7.45 (3H, m), 7.85 (1H, d, J = 10Hz) (7) 2- (4-bromophenyl) -4-ethyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 185-188 ° C NMR (DMSO-d ₆ , δ): 1.27 (3H, t, J = 7.5Hz), 2.19 (3
H, s), 4.15 (2H, q, J = 7.5Hz), 5.12 (2H, s), 6.96 (1
H, dd, J = 10, 2Hz), 7.06 (1H, d, J = 2Hz), 7.36 (2H,
d, J = 10Hz), 7.73 (2H, d, J = 10Hz), 7.87 (1H, d, J = 10
Hz) (8) 4-methyl-2- (4-phenoxyphenyl)
-1,1-dioxo-6- (2-oxopropoxy)-
4H-benzo [e] [1,2,4] thiadiazine-3-
On mp: 152-154 ° C NMR (CDCl ₃ , δ): 2.34 (3H, s), 3.56 (3H, s), 4.72
(2H, s), 6.76 (1H, dd, J = 10, 2Hz), 6.86 (1H, d, J = 2
Hz), 7.03- 7.22 (5H, m), 7.31-7.45 (4H, m), 7.89 (1
H, d, J = 10Hz) (9) 2- (4-bromophenyl) -4-propyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 149-150 ° C NMR (CDCl ₃ , δ): 1.03 (3H, t, J = 7.5Hz), 1.82 (2H,
m), 2.33 (3H, s), 4.01 (2H, q, J = 7.5Hz), 4.70 (3H,
s), 6.73 (1H, dd, J = 10, 2Hz), 6.85 (1H, d, J = 2Hz),
7.29 (2H, d, J = 10Hz), 7.62 (2H, d, J = 10Hz), 7.86 (1
(H, d, J = 10 Hz) (10) 2-butyl-4-methyl-1,1-dioxo-6- (2-oxopropoxy) -4H-benzo [e]
[1,2,4] thiadiazin-3-one (oil) NMR (CDCl ₃ , δ): 0.96 (3H, t, J = 7.5Hz), 1.39 (2H,
m), 1.74 (2H, m), 2.32 (3H, s), 3.50 (3H, s), 3.91
(2H, t, J = 7.5Hz), 4.69 (2H, s), 6.69-6.78 (2H, m),
7.82 (1H, d, J = 7.5Hz) (11) 2- (3,4-dichlorophenyl) -4-methyl-1,1-dioxo-6- (2-oxopropoxy) -4H-benzo [e] [ 1,2,4] thiadiazin-3-one mp: 163-164 ° C NMR (CDCl ₃ , δ): 2.32 (3H, s), 3.55 (3H, s), 4.72
(2H, s), 6.76 (1H, dd, J = 10, 2Hz), 6.85 (1H, d, J = 2
Hz), 7.29 (1H, dd, J = 10, 2Hz), 7.53-7.58 (2H, m),
7.86 (1H, d, J = 10Hz) (12) 2- (4-chlorobenzyl) -4-methyl-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 164-167 ° C NMR (CDCl ₃ , δ): 2.30 (3H, s), 3.48 (3H, s), 4.67
(2H, s), 4.99 (2H, s), 6.72 (1H, dd, J = 10,2Hz), 6.
76 (1H, d, J = 2Hz), 7.27 (2H, d, J = 10Hz), 7.40 (2H,
d, J = 10Hz), 7.84 (1H, d, J = 10Hz) (13) 2-benzyl-4-methyl-1,1-dioxo-6- (2-oxopropoxy) -4H-benzo [e] [ 1,2,4] thiadiazin-3-one mp: 128-131 ° C NMR (CDCl ₃ , δ): 2.30 (3H, s), 3.45 (3H, s), 4.67
(2H, s), 5.02 (2H, s), 6.
70 (1H, d, J = 10 Hz), 6.72
(1H, s), 7.22-7.33 (3H,
m), 7.40-7.48 (2H, m), 7.8
5 (1H, d, J = 10 Hz) (14) 4-methyl-2- (4-propylphenyl)
-1,1-dioxo-6- (2-oxopropoxy)-
4H-benzo [e] [1,2,4] thiadiazine-3-
On mp: 153-154 ℃ NMR (CDCl ₃ , δ): 0.98 (3H, t, J = 7.5Hz), 1.69 (2H,
m), 2.32 (3H, s), 2.65 (2H, t, J = 7.5Hz), 3.54 (3H,
s), 4.70 (2H, s), 6.75 (1H, dd, J = 10,2Hz), 6.85 (1
H, d, J = 2Hz), 7.31 (4H, s), 7.88 (1H, d, J = 10Hz) (15) 4-methyl-2- (4-tert-butylphenyl) -1,1-dioxo -6- (2-oxopropoxy) -4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 166-169 ° C NMR (CDCl ₃ , δ): 1.34 (9H, s), 2.32 (3H, s), 3.55
(3H, s), 4.72 (2H, s), 6.75 (1H, dd, J = 10,2Hz), 6.
85 (1H, d, J = 2Hz), 7.32 (2H, d, J = 10Hz), 7.50 (2H,
d, J = 10Hz), 7.86 (1H, d, J = 10Hz) (16) 2- (4-bromophenyl) -4-isopropyl-1,1-dioxo-6- (2-oxopropoxy) -4H- Benzo [e] [1,2,4] thiadiazin-3-one mp: 155-158 ° C NMR (CDCl ₃ , δ): 1.65 (6H, d, J = 5Hz), 2.32 (3H,
s), 4.39-4.53 (1H, m), 4.71 (2H, s), 6.73 (1H, d, J =
10Hz), 6.93 (1H, s), 7.28 (2H, d, J = 10Hz), 7.62 (2
H, d, J = 10Hz), 7.81 (1H, d, J = 10Hz) (17) 2- (4-chlorophenyl) -4-methyl-
1,1-dioxo-6- (2-oxobutoxy) -4H
-Benzo [e] [1,2,4] thiadiazin-3-one mp: 142-144 ° C NMR (CDCl ₃ , δ): 1.15 (3H, t, J = 8Hz), 2.63 (2H,
q, J = 8Hz), 3.53 (3H, s), 4.71 (2H, s), 6.75 (1H, d,
J = 10Hz), 6.83 (1H, s), 7.35 (2H, d, J = 10Hz), 7.46
(2H, d, J = 10Hz), 7.85 (1H, d, J = 10Hz) (18) 4-ethyl-2- (4-iodophenyl)-
1,1-dioxo-6- (2-oxopropoxy) -4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 182-188 ° C NMR (DMSO-d ₆ , δ): 1.27 (3H, t, J = 8Hz), 2.21 (3H,
s), 4.13 (2H, q, J = 8Hz), 5.13 (2H, s), 6.98 (1H, d,
J = 8Hz), 7.08 (1H, s), 7.21 (2H, d, J = 8Hz), 7.87 (1
H, d, J = 8Hz), 7.90 (2H, d, J = 8Hz) (19) 4-methyl-2- (1-naphthyl) -1,1
- dioxo-6- (2-oxopropoxy) -4H- benzo [e] [1,2,4] thiadiazine-3-one _{mp: 207-210 ℃ NMR (CDCl 3} , δ): 2.34 (3H, s) , 3.58 (3H, s), 4.68
(2H, s), 6.78 (1H, dd, J = 10, 2Hz), 6.90 (1H, d, J = 2
Hz), 7.44-7.52 (2H, m), 7.59 (1H, t, J = 10Hz), 7.71
(2H, d, J = 10Hz), 7.87-7.93 (2H, m), 8.00 (1H, d, J =
10Hz) (20) 4-methyl-2- (2-naphthyl) -1,1
- dioxo-6- (2-oxopropoxy) -4H- benzo [e] [1,2,4] thiadiazine-3-one _{mp: 160-164 ℃ NMR (CDCl 3} , δ): 2.34 (3H, s) , 3.55 (3H, s), 4.72
(2H, s), 6.77 (1H, d, J = 10Hz), 6.88 (1H, d, J = 2Hz),
7.43 (1H, d, J = 10Hz), 7.50-7.58 (2H, m), 7.85-7.96
(5H, m)

Example 1 2- (4-Bromophenyl) -4-methyl-1,1-dioxo-6- (2-oxopropoxy) -4H-benzo [e] [1,2,4] thiadiazine-3 -ON (2.2
0 g) in tetrahydrofuran (60 ml),
Methyl magnesium bromide (0.
96N solution, 5.70 ml) is added at -78 ° C. The mixture is stirred at −78 ° C. for 1 hour then warmed to room temperature.
The reaction mixture is quenched with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The extract is washed with water and brine and concentrated to give the crude product. This is purified by silica gel column chromatography (eluted with chloroform) to give 2- (4-bromophenyl).
-6- (2-hydroxy-2-methylpropoxy) -4
-Methyl-1,1-dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one (707 mg)
To get mp: 181-185 ° C NMR (CDCl ₃ , δ): 1.40 (6H, s), 2.04 (1H, s), 3.58
(3H, s), 3.92 (2H, s), 6.82 (1H, s), 6.86 (1H, d, J
= 10Hz), 7.28 (2H, d, J = 10Hz), 7.62 (2H, d, J = 10Hz),
7.85 (1H, d, J = 10Hz)

Example 2 The following compound is obtained as in Example 1. (1) 2- (4-fluorophenyl) -6- (2-hydroxy-2-methylpropoxy) -4-methyl-1,
1-dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one _{mp: 158-161 ℃ NMR (CDCl 3} , δ): 1.40 (6H, s), 2.05 (1H, s), 3.55
(3H, s), 3.92 (2H, s), 6.80 (1H, s), 6.87 (1H, d, J
= 10Hz), 7.13-7.18 (2H, m), 7.37-7.42 (2H, m), 7.85
(1H, d, J = 10Hz) (2) 6- (2-hydroxy-2-methylpropoxy) -2- (4-iodophenyl) -4-methyl-1,
1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 183-186 ° C NMR (CDCl ₃ , δ): 1.38 (6H, s), 2.02 (1H, s), 3.54
(3H, s), 3.88 (2H, s), 6.80 (1H, s), 6.85 (1H, d, J
= 10Hz), 7.15 (2H, d, J = 10Hz), 7.82 (2H, d, J = 10Hz),
7.85 (1H, d, J = 10Hz) (3) 2- (4-chlorophenyl) -6- (2-hydroxy-2-methylpropoxy) -4-methyl-1,1
- dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one _{mp: 173-176 ℃ NMR (CDCl 3} , δ): 1.41 (6H, s), 3.57 (3H, s), 3.92
(2H, s), 6.83-6.91 (2H, m), 7.36 (2H, d, J = 8Hz), 7.
48 (2H, d, J = 8Hz), 7.88 (1H, d, J = 8Hz) (4) 2- (3-chlorophenyl) -6- (2-hydroxy-2-methylpropoxy) -4-methyl-1 , 1
- dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one _{mp: 163-166 ℃ NMR (CDCl 3} , δ): 1.38 (6H, s), 2.04 (1H, s), 3.53
(3H, s), 3.92 (2H, s), 6.82 (1H, s), 6.87 (1H, d, J
= 10Hz), 7.30-7.51 (4H, m), 7.86 (1H, d, J = 10Hz) (5) 2- (3-bromophenyl) -6- (2-hydroxy-2-methylpropoxy) -4- Methyl-1,1
- dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one _{mp: 161-163 ℃ NMR (CDCl 3} , δ): 1.38 (6H, s), 2.05 (1H, s), 3.57
(3H, s), 3.93 (2H, s), 6.84 (1H, s), 6.87 (1H, d, J
= 10Hz), 7.35-7.42 (2H, m), 7.58-7.67 (2H, m), 7.87
(1H, d, J = 10Hz) (6) 2- (4-bromo-2-fluorophenyl)-
6- (2-hydroxy-2-methylpropoxy) -4-
Methyl-1,1-dioxo-4H-benzo [e] [1,
2,4] Thiadiazin-3-one mp: 171-173 ° C NMR (CDCl ₃ , δ): 1.41 (6H, s), 2.05 (1H, s), 3.55
(3H, s), 3.92 (2H, s), 6.85 (1H, s), 6.87 (1H, d, J
= 10Hz), 7.38-7.45 (3H, m), 7.85 (1H, d, J = 10Hz) (7) 2- (4-bromophenyl) -4-ethyl-6
-(2-hydroxy-2-methylpropoxy) -1,1
- dioxo -4H- benzo [e] [1,2,4] thiadiazine-3-one mp: 148-150 ℃ NMR (DMSO- d 6, δ): 1.25 (6H, s), 1.30 (3H, t, J = 7.
5Hz), 3.95 (2H, s), 4.16 (2H, q, J = 7.5Hz), 4.76 (1
H, s), 7.03 (1H, dd, J = 10, 2Hz), 7.12 (1H, d, J = 2H
z), 7.36 (2H, d, J = 10Hz), 7.75 (2H, d, J = 10Hz), 7.8
9 (1H, d, J = 10Hz) (8) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (4-phenoxyphenyl)-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 164-166 ° C NMR (CDCl ₃ , δ): 1.38 (6H, s), 3.55 (3H, s), 3.92
(2H, s), 6.82 (1H, d, J = 2Hz), 6.86 (1H, dd, J = 10,2
Hz), 7.01-7.20 (5H, m), 7.31-7.43 (4H, m), 7.88 (1
H, d, J = 10 Hz) (9) 2- (4-bromophenyl) -6- (2-hydroxy-2-methylpropoxy) -4-propyl-1,
1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 113-117 ° C NMR (CDCl ₃ , δ): 1.05 (3H, t, J = 7.5Hz), 1.41 ( 6H,
s), 1.85 (2H, m), 2.08 (1H, s), 3.91 (2H, s), 4.05
(2H, q, J = 7.5Hz), 6.84 (1H, d, J = 2Hz), 6.86 (1H, d
d, J = 10, 2Hz), 7.30 (2H, d, J = 10Hz), 7.63 (2H, d, J
= 10Hz), 7.87 (1H, d, J = 10Hz) (10) 2-butyl-6- (2-hydroxy-2-methylpropoxy) -4-methyl-1,1-dioxo-4
H-benzo [e] [1,2,4] thiadiazin-3-one mp: 66-70 ° C NMR (CDCl ₃ , δ): 0.94 (3H, t, J = 7.5Hz), 1.37 (2H,
m), 1.39 (6H, m), 1.73 (2H, m), 3.51 (3H, s), 3.87
(2H, t, J = 7.5Hz), 3.88 (2H, s), 6.73 (1H, d, J = 2H
z), 6.82 (1H, dd, J = 10, 2Hz), 7.79 (1H, d, J = 10Hz) (11) 2- (3,4-dichlorophenyl) -6-
(2-Hydroxy-2-methylpropoxy) -4-methyl-1,1-dioxo-4H-benzo [e] [1,2,
4] thiadiazin-3-one mp: 199-204 ° C NMR (DMSO-d ₆ , δ): 1.26 (6H, s), 3.52 (3H, s), 3.
95 (2H, s), 4.78 (1H, s), 7.04 (1H, dd, J = 10,2Hz),
7.10 (1H, d, J = 2Hz), 7.46 (1H, dd, J = 10,2Hz), 7.75
(1H, d, J = 2Hz), 7.83 (1H, d, J = 10Hz), 7.87 (1H, d,
J = 10Hz) (12) 2- (4-chlorobenzyl) -6- (2-hydroxy-2-methylpropoxy) -4-methyl-1,
1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 115-117 ° C NMR (CDCl ₃ , δ): 1.39 (6H, s), 3.49 (3H, s), 3.87
(2H, s), 4.99 (2H, s), 6.73 (1H, d, J = 2Hz), 6.85 (1
H, dd, J = 10, 2Hz), 7.27 (2H, d, J = 10Hz), 7.40 (2H,
d, J = 10Hz), 7.84 (1H, d, J = 10Hz) (13) 2-benzyl-6- (2-hydroxy-2-
Methylpropoxy) -4-methyl-1,1-dioxo-
4H-benzo [e] [1,2,4] thiadiazine-3-
On mp: 147-149 ° C NMR (CDCl ₃ , δ): 1.40 (6H, s), 2.05 (1H, s), 3.48
(3H, s), 3.87 (2H, s), 5.03 (2H, s), 6.70 (1H, s),
6.82 (1H, d, J = 10Hz), 7.22-7.35 (3H, m), 7.40-7.48
(2H, m), 7.83 (1H, d, J = 10Hz) (14) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (4-propylphenyl)-
1,1-dioxo-4H-benzo [e] [1,2,4]
Thiadiazin-3-one mp: 163-165 ° C NMR (CDCl ₃ , δ): 0.98 (3H, t, J = 7.5Hz), 1.41 (6H, 6H,
s), 1.69 (2H, m), 2.65 (2H, t, J = 7.5Hz), 3.56 (3H,
s), 3.92 (2H, s), 6.80-6.88 (2H, m), 7.31 (4H, s),
7.86 (1H, d, J = 10Hz) (15) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (4-tert-butylphenyl)
-1,1-dioxo-4H-benzo [e] [1,2,
4] thiadiazin-3-one mp: 214-215 ° C NMR (CDCl ₃ , δ): 1.34 (9H, s), 1.40 (6H, s), 3.56
(3H, s), 3.91 (2H, s), 6.82 (1H, d, J = 2Hz), 6.87 (1
H, dd, J = 10, 2Hz), 7.33 (2H, d, J = 10Hz), 7.50 (2H,
d, J = 10Hz), 7.87 (1H, d, J = 10Hz) (16) 2- (4-bromophenyl) -6- (2-hydroxy-2-methylpropoxy) -4-isopropyl-1,1- Dioxo-4H-benzo [e] [1,2,
4] thiadiazin-3-one mp: 148-152 ° C NMR (CDCl ₃ , δ): 1.40 (6H, s), 1.65 (6H, d, J = 5H
z), 2.03 (1H, s), 3.89 (2H, s), 4.42-4.52 (1H, m),
6.85 (1H, d, J = 10Hz), 6.92 (1H, s), 7.27 (2H, d, J =
10Hz), 7.60 (2H, d, J = 10Hz), 7.81 (1H, d, J = 10Hz) (17) 2- (4-chlorophenyl) -6- (2-ethyl-2-hydroxybutoxy) -4- Methyl-1,1
-Dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 107-110 ° C NMR (CDCl ₃ , δ): 0.93 (6H, t, J = 8Hz), 1.68 (4H,
q, J = 8Hz), 1.82 (1H, s), 3.55 (3H, s), 3.93 (2H, s),
6.80 (1H, s), 6.87 (1H, d, J = 10Hz), 7.35 (2H, d, J
= 10Hz), 7.45 (2H, d, J = 10Hz), 7.85 (1H, d, J = 10Hz) (18) 4-Ethyl-6- (2-hydroxy-2-methylpropoxy) -2- (4- Iodophenyl) -1,
1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 123-128 ° C NMR (CDCl ₃ , δ): 1.40 (6H, s), 1.43 (3H, t, J = 8H
z), 2.05 (1H, br s), 3.93 (2H, s), 4.12 (2H, q, J = 8H
z), 6.82-6.86 (2H, m), 7.16 (2H, d, J = 10Hz), 7.82
(2H, d, J = 10Hz), 7.85 (1H, d, J = 10Hz) (19) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (1-naphthyl) -1, 1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 195-198 ° C NMR (CDCl ₃ , δ): 1.47 (6H, s), 2.08 (1H, s), 3.58
(3H, s), 3.96 (2H, s), 6.90 (1H, dd, J = 8,2Hz), 6.9
2 (1H, d, J = 2Hz), 7.43-7.52 (2H, m), 7.58 (1H, t, J
= 8Hz), 7.72 (2H, t, J = 8Hz), 7.90 (2H, dd, J = 8, 2H
z), 7.99 (1H, d, J = 8Hz) (20) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (2-naphthyl) -1,1-dioxo-4H-benzo [E] [1,2,4] Thiadiazin-3-one mp: 198-202 ° C NMR (CDCl ₃ , δ): 1.41 (6H, s), 2.10 (1H, s), 3.58
(3H, s), 3.94 (2H, s), 6.86 (1H, s), 6.88 (1H, d, J
= 10Hz), 7.43 (1H, d, J = 10Hz), 7.50-7.58 (2H, m), 7.
87-7.98 (5H, m)

Example 3 Ethanol (50 ml) and tetrahydrofuran (5
2-benzyl-6- (2-hydroxy-2 in 0 ml)
-Methylpropoxy) -4-methyl-1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazine-3
The-one is treated with 20% Pearlman's catalyst (6.12 g) and hydrogen (60 PSI). After 1 hour, filter through cellulose powder, concentrate and dry. Crystallize the oil from ethyl acetate and isopropyl ether to give 6-
(2-Hydroxy-2-methylpropoxy) -4-methyl-1,1-dioxo-4H-benzo [e] [1,2,
4] Thiadiazin-3-one (4.01 g) is obtained. mp: 163-166 ° C NMR (CDCl ₃ , δ): 1.40 (6H, s), 3.49 (3H, s), 3.88
(2H, s), 6.76 (1H, s), 6.82 (1H, d, J = 8Hz), 7.82 (1
(H, d, J = 8Hz)

Example 4 6- (2-Hydroxy-2-methylpropoxy) -4-
Methyl-1,1-dioxo-4H-benzo [e] [1,
2,4] Thiadiazin-3-one (900 mg), potassium carbonate (1.24 g) and 4-nitrobenzyl bromide (778 mg) in N, N-dimethylformamide (1
The suspension in 5 ml) is stirred at 70 ° C. for 1 hour. The reaction mixture is poured into ice water. The mixture is extracted with methylene chloride. The extract is washed with water and brine and concentrated to give the crude product. This was purified by silica gel column chromatography (eluted with ethyl acetate and hexane 3: 2) to give 6- (2-hydroxy-2-methylpropoxy)-.
4-Methyl-2- (4-nitrobenzyl) -1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one (1.13 g) is obtained. mp: 125-128 ° C NMR (CDCl ₃ , δ): 1.42 (6H, s), 3.50 (3H, s), 3.90
(2H, s), 5.12 (2H, s), 6.77 (1H, d, J = 2Hz), 6.87 (1
H, dd, J = 10, 2Hz), 7.62 (2H, d, J = 10Hz), 7.86 (1H,
d, J = 10Hz), 8.18 (2H, d, J = 10Hz)

Example 5 The following compound is obtained as in Example 4. (1) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (2-picolyl) -1,1-dioxo-4H-benzo [e] [1,2,4] thiadiazine-3 -ON mp: 104-107 ° C NMR (CDCl ₃ , δ): 1.40 (6H, s), 2.18 (1H, s), 3.51
(3H, s), 3.90 (2H, s), 5.20 (2H, s), 6.76 (1H, d, J
= 2Hz), 6.84 (1H, dd, J = 10, 2Hz), 7.16 (1H, dd, J = 7.
5, 5Hz), 7.35 (1H, d, J = 7.5Hz), 7.64 (1H, t, J = 7.5H)
z), 7.83 (1H, d, J = 10Hz), 8.53 (1H, d, J = 5Hz) (2) 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (2-naphthyl) Methyl) -1,
1-dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 145-146.5 ° C NMR (CDCl ₃ , δ): 1.35 (6H, s), 3.46 (3H, s), 3.86
(2H, s), 5.20 (2H, s), 6.71 (1H, d, J = 2Hz), 6.83 (1
H, dd, J = 10, 2Hz), 7.42-7.48 (2H, m), 7.56 (1H, d,
J = 10Hz), 7.74-7.92 (5H, m) (3) 2- (5-bromo-2-naphthylmethyl) -6
-(2-Hydroxy-2-methylpropoxy) -4-methyl-1,1-dioxo-4H-benzo [e] [1,
2,4] Thiadiazin-3-one mp: 137-140 ° C NMR (CDCl ₃ , δ): 1.33 (6H, s), 2.02 (1H, s), 3.47
(3H, s), 3.87 (2H, s), 5.21 (2H, s), 6.71 (1H, s),
6.83 (1H, d, J = 8Hz), 7.29 (1H, t, J = 8Hz), 7.65 (1H,
d, J = 8Hz), 7.72 (1H, d, J = 8Hz), 7.78 (1H, d, J = 8H
z), 7.85 (1H, d, J = 8Hz), 7.90 (1H, s), 8.17 (1H, d,
(J = 8Hz)

Example 6 6- (2-Hydroxy-2-methylpropoxy) -4-
Methyl-1,1-dioxo-4H-benzo [e] [1,
To a solution of 2,4] thiadiazin-3-one (900 mg) in dry dimethylformamide (15 ml) was added sodium hydride (60% dispersion in oil) (280 mg) at 5 ° C.
Add at once. The suspension is stirred for 30 minutes at the same temperature, then 4-picolyl chloride hydrochloride (590 mg) is added. The reaction mixture is warmed to 70 ° C. and stirred for 3 hours. Pour the cooled mixture into ice water. The mixture is extracted with water and brine and concentrated to give the crude product. This was purified by silica gel column chromatography (eluted with 1% methanol in methylene chloride) to give 6- (2-hydroxy-2-methylpropoxy) -4-methyl-2- (4-picolyl) -1,1. -Dioxo-4H-benzo [e]
[1,2,4] thiadiazin-3-one (410 mg)
To get mp: 172.5-174 ° C NMR (CDCl ₃ , δ): 1.31 (6H, s), 3.52 (3H, s), 3.91
(2H, s), 5.04 (2H, s), 6.77 (1H, d, J = 2Hz), 6.86 (1
H, dd, J = 10, 2Hz), 7.32 (2H, d, J = 7.5Hz), 7.85 (1H,
d, J = 10Hz), 8.56 (2H, d, J = 7.5Hz)

Example 7 The following compound is obtained as in Example 6. 2- (2,6-dichlorobenzyl) -6- (2-hydroxy-2-methylpropoxy) -4-methyl-1,1-
Dioxo-4H-benzo [e] [1,2,4] thiadiazin-3-one mp: 148-153 ° C NMR (CDCl ₃ , δ): 1.38 (6H, s), 3.49 (3H, s), 3.87
(2H, s), 5.37 (2H, s), 6.73 (1H, d, J = 2Hz), 6.80 (1
H, dd, J = 10Hz, 2Hz), 7.14 (1H, t, J = 10Hz), 7.27 (2
H, d, J = 10Hz), 7.74 (1H, d, J = 10Hz)

Claims (4)

[Claims] 1. A general formula: [Wherein R ¹ is a lower alkyl group, R ² is a lower alkyl group, R ³ is a lower alkyl group, R ⁴ is hydrogen, a lower alkyl group, a nitrogen-containing unsaturated heterocyclic group, or a halogen or a lower alkyl group. Group, an aryl group which may be substituted with a nitro group or an aryloxy group, X represents a lower alkylene group, Y represents a lower alkylene group, and n represents an integer of 0 or 1, and A pharmaceutically acceptable salt thereof. 2. R ⁴ is hydrogen; lower alkyl group; nitrogen atom 1
A 3 to 6 membered unsaturated heteromonocyclic group having 4 to 4;
Alternatively, the compound according to claim 1, which is a phenyl group or a naphthyl group which may be substituted with a halogen, a lower alkyl group, a nitro group or a phenoxy group. 3. R ⁴ is hydrogen; lower alkyl group; pyrrolyl group; pyrrolinyl group; imidazolyl group; pyrazolyl group; pyridyl group; pyrimidinyl group; pyrazinyl group; pyridazinyl group; triazolyl group; tetrazolyl group; Or a phenyl group which may be substituted with a halogen, a lower alkyl group, a nitro group or a phenoxy group. 4. The compound according to claim 3, wherein R ⁴ is a phenyl group which may be substituted with a halogen, a lower alkyl group, a nitro group or a phenoxy group, and n is 0.