JPH06192272A - New triazolobenzothiadiazine and triazolobenzothiadiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having excellent bone resorption suppressive activity, thus useful as a medicine for osteoporosis. CONSTITUTION:The compound of formula I [R1 is H, OH, lower alkoxy, halogen, (substituted)1-12C alkyl or aralkyl; R2 is H, (substituted)lower alkyl, aralkyl or heteroaryl carbonyl; R3 is H, (substituted)lower alkyl or aralkyl; R4 is H, (substituted)1-12C alkyl or aralkyl; X is SO2, SO or S; (m) is 0 or 1], e.g. 1,4- dimethyl[1,2,4]triazolo[3,4-c][1,2,4]benzothiadiazine 5,5'dioxide. The compound of the formula I can be obtained from a compound of formula II via a compound of formula III, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel triazolobenzothiadiazine and triazolobenzothiadiazepine derivative having a bone resorption inhibitory activity, and is used in the field of medicine.

[0002]

2. Description of the Related Art Osteoporosis is a substance that does not change the chemical composition (ratio of organic substance and inorganic substance) of bone substance itself.
It is a syndrome that refers to a pathological condition in which the amount of bone per unit volume is abnormally reduced, and its physiological characteristic is a decrease in proteins, calcium and phosphorus in the bone. Bone loss as a condition of this condition is accompanied by a decrease in bone amount due to physiological aging.As a definition, bone loss is more prominent than that due to physiological aging. It can be said that the patient exhibited clinical symptoms such as vertebral body deformation. Osteoporosis increases with age and usually affects the spinal cord, causing back pain and shortened height. Especially in advanced cases, long bones are also affected, and sometimes fractures may occur. It is said that most of the causes of femoral fractures in the elderly are due to senile osteoporosis. There are various causes of this osteoporosis such as endocrine abnormalities including menopause, nutritional disorders, etc., but vitamin D preparations, calcium preparations, calcitonin preparations, bisphosphonate preparations, which have been used as therapeutic agents for osteoporosis so far, Targets of isoflavone preparations are limited, and their effects are not certain. Further, with regard to female hormone preparations, serious side effects (genital cancer due to long-term use, etc.) are a problem, although effects can be expected. Therefore, it is strongly desired to develop a therapeutic agent for osteoporosis that is more effective and safe. In recent years, a benzothiadiazine derivative or a benzothiadiazepine derivative having a completely different chemical structure from that of the above-mentioned preparation has been applied as a therapeutic agent for osteoporosis (Japanese Patent Laid-Open Nos. 63-183572 and 1-238).
529, JP-A-2-138272). However, these compounds are still insufficient in terms of activity, and at present, the above demands have not been satisfied.

[0003]

[Means for Solving the Problems] In view of the above problems, the present inventors have conducted diligent research to search for a useful therapeutic drug for osteoporosis. As a result, a benzothiadiazine derivative or a benzothiadiazepine derivative has a triazole ring. It was found that the formation of the compound has a remarkable effect of suppressing bone resorption as compared with the conventional method, and the present invention has been completed. That is, the present invention is
The following general formula [1]

[Chemical 2] (In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen group or an optionally substituted alkyl group or aralkyl group having 1 to 12 carbon atoms, and R ² represents a hydrogen atom or a substituted group. A lower alkyl group, an aralkyl group or a heteroarylcarbonyl group, which may be represented by R ³
Is a hydrogen atom or an optionally substituted lower alkyl group or aralkyl group, R ⁴ is a hydrogen atom or an optionally substituted alkyl group or aralkyl group having 1 to 12 carbon atoms, and X is —SO ₂ -, -SO- or -S-
And m represents 0 or 1. ), A novel triazolobenzothiadiazine and a triazolobenzothiadiazepine derivative or a pharmaceutically acceptable salt thereof, and other objects of the present invention. Is to provide a therapeutic agent for osteoporosis containing the novel triazolobenzothiadiazine and triazolobenzothiadiazepine derivative [1] as an active ingredient.

The meanings of terms used in various definitions in this specification are as follows. The “alkyl group having 1 to 12 carbon atoms” refers to a linear or branched alkyl group containing 1 to 12 carbon atoms, and includes, for example,
Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, ter
t-butyl group, n-pentyl group, 1-methylbutyl group,
2,2-dimethylpropyl group, 2,2-dimethylbutyl group, 2-methylpentyl group, n-hexyl group, 2-methylhexyl group, n-heptyl group, n-octyl group, n-
Nonyl group, n-decyl group, n-undecyl group, n-dodecyl group and the like can be mentioned. Among them, those having 6 to 12 carbon atoms are preferable, and those having 8 to 10 carbon atoms are particularly preferable, for example, n-octyl group, n-nonyl group, n-decyl group and the like. The "lower alkyl group" refers to a linear or branched alkyl group containing 1 to 5 carbon atoms, and includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n- A butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1-methylbutyl group, 2,2-dimethylpropyl group, 2,2-dimethylbutyl group, 2-methylpentyl group, etc. . The “halogen atom” is fluorine, chlorine, bromine or iodine. The "aralkyl group" means an arylalkyl group, and means a benzyl group, a phenethyl group, a 3-phenylpropyl group or the like.

The "lower alkyl group which may be substituted" means the above lower alkyl group substituted with a hydroxyl group, a halogen group, a lower alkoxy group, a nitro group, an amino group, a cyano group or a carboxyl group. . For example, chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, trifluoroethyl group, difluoromethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2,2-dimethoxyethyl group. Group, 2,2-diethoxyethyl group, 2-isopropoxyethyl group, 2-nitroethyl group, 3-nitropropyl group, 2-aminoethyl group, 3-aminopropyl group, 2-
Examples thereof include a cyanoethyl group, a 3-cyanopropyl group, a 2-carboxyethyl group and a 2-methoxybutyl group. The “optionally substituted aralkyl group” means the above aralkyl group substituted with a hydroxyl group, a halogen group, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group or a carboxyl group. For example, 2-hydroxybenzyl group, 4-chlorobenzyl group, 4-ethylbenzyl group, 3,4-dimethoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxyphenethyl group, 4-
Examples thereof include a nitrobenzyl group, a 4-aminophenethyl group, a 4-cyanobenzyl group, a 4-carboxybenzyl group, a 4-isobutylphenethyl group and a 3- (4-isobutylphenyl) propyl group. The "lower alkoxy group" is alkoxylated with the above lower alkyl group, and examples thereof include methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-group. Butoxy group and the like.

The term "heteroarylcarbonyl group" means 2-
Pyridinylcarbonyl group, 3-pyridinylcarbonyl group, 4-pyridinylcarbonyl group, pyrazinylcarbonyl group, 2-pyrimidinylcarbonyl group, 4-pyrimidinylcarbonyl group, 5-pyrimidinylcarbonyl group, 3-
Pyridazinylcarbonyl group, 4-pyridazinylcarbonyl group, 2-furanylcarbonyl group, 3-furanylcarbonyl group, 2-thienylcarbonyl group, 3-thienylcarbonyl group, 2-pyrrolylcarbonyl group, 3 -Pyrrolylcarbonyl group, 3-indolecarbonyl group, 3-thianaphthenecarbonyl group and the like, preferably 2-pyridinylcarbonyl group, 3-pyridinylcarbonyl group, 4-pyridinylcarbonyl group, pyrazini Lecarbonyl group, 3-
It represents an indolecarbonyl group or a 3-thianaphthenecarbonyl group, and particularly preferably a 3-indolecarbonyl group or a 3-thianaphthenecarbonyl group. The "optionally substituted heteroarylcarbonyl group" means that the above heteroarylcarbonyl group is a hydroxyl group, a halogen group, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group,
Means substituted with a cyano group. For example, 6-methyl-2-pyridylcarbonyl group, 5-hydroxy-3-
Examples thereof include an indolylcarbonyl group, a 5-methoxy-3-indolylcarbonyl group, a 5-nitro-2-furanylcarbonyl group and a 3-amino-4-pyrazinylcarbonyl group.

The "optionally substituted C1 to C12 alkyl group" means that the above alkyl group is substituted with a hydroxyl group, a halogen group, a lower alkoxy group, a nitro group, an amino group, a cyano group or a carboxyl group. Means something. For example, chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, trifluoroethyl group, difluoromethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2,2-dimethoxyethyl group. Group, 2,2-diethoxyethyl group, 2-isopropoxyethyl group, 2-nitroethyl group, 3-nitropropyl group, 2-aminoethyl group, 3-aminopropyl group, 2-cyanoethyl group, 3-cyanopropyl group Base, 2-
A carboxyethyl group, a 2-methoxybutyl group, a 5-bromopentyl group, a 6-hydroxyhexyl group, a 7-methoxyheptyl group, an 8-methoxyoctyl group, a 9-methoxynonyl group, a 10-methoxydecyl group and the like. "Pharmaceutically acceptable salts thereof" include various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; acetate, propionate, succinate. , Various organic acids such as glycolate, lactate, malate, tartrate, citric acid, maleate, fumarate, methanesulfonate, p-toluenesulfonate, ascorbate, etc. Addition salts; include salts with various amino acids such as aspartate and glutamate, but are not limited thereto.

The novel compound represented by the general formula [1] according to the present invention can be produced, for example, according to the reaction steps shown below. It goes without saying that the method for producing the compound of the present invention is not limited to the exemplified production method. The flow is shown below and will be described in more detail.

[0009]

[Chemical 3]

[0010]

[Chemical 4]

[0011]

[Chemical 5]

Each of the above reaction steps will be further described. The symbols R ¹ , R ² , R ³ , R ⁴ and X are as defined above, R ⁵ is a hydrogen atom, a nitro group, a lower alkoxy group or a lower alkyl group, and R ⁶ may be substituted. A heteroaryl group, X ¹ is a halogen atom, and R ⁷
Is a carboxyl protecting group such as a methyl group or an ethyl group, and may be any carboxyl protecting group as long as it does not interfere with the reaction.

Production Method A (when m = 0) Production Method 1 First Step By substituting the halogen of o-nitrohalobenzene represented by the general formula [3] with a benzylthio group, the general formula [4] is obtained. Obtain the represented S-benzyl form. Examples of the substitution method include a method of substituting a halogen atom with an S-benzyl group by allowing S-benzylisothiouronium chloride and subsequently an alkaline water such as sodium hydroxide and potassium hydroxide to act.

Second Step The compound of the general formula [4] obtained above is represented by the general formula [5] by blowing chlorine gas in acetic acid in the presence of a suitable solvent, for example, water, and oxidatively cleaving the compound. A sulfonyl chloride form is obtained.

Third Step The compound of the general formula [5] is reacted with an amine derivative represented by R ² NH ₂ to obtain a sulfonamide compound represented by the general formula [6]. Examples of the solvent used include chloroform, ethyl acetate, tetrahydrofuran, pyridine and the like, but the reaction is possible without solvent. When an aqueous solution of an inorganic base such as sodium bicarbonate or sodium hydroxide or an organic base such as triethylamine is added to the reaction solution, the reaction is completed in a shorter time, but the reaction proceeds well even without the above base. The reaction temperature is selected from the range of -20 ° C to 70 ° C. The amount of R ² NH ₂ is appropriately 1 to 10 equivalents, particularly preferably 1 to 2 equivalents based on [5].

Step 4 O-aminobenzenesulfonamide compound represented by the general formula [7] is obtained by reducing the nitro group of the compound represented by the general formula [6] obtained above to an amino group. To get As the reduction method, a catalytic reduction reaction using hydrogen gas in the presence of a metal catalyst such as palladium or platinum oxide, or a method using a metal hydride compound such as lithium aluminum hydride can be applied (Reduct by Milos and Hadricky.
ions in Organic Chemistry John Wiley & Sons page 73
(1984)). A particularly preferred mild method is a method of reducing with iron powder in the presence of ammonium chloride in a mixed solvent of methanol / water.

Step 5 2H represented by the general formula [8] is obtained by introducing a thiocarbonyl group into the compound of the general formula [7] obtained above.
A -1,2,4-benzothiadiazine-3 (4H) -thione-1,1'-dioxide is obtained. For this reaction, a method of reacting with carbon disulfide or thiophosgene in the presence or absence of a base can be applied. Especially 1,1
-Thiocarbonyldiimidazole was used to
A method in which the reaction is carried out in an inert solvent at a temperature in the range of 0 ° C. is suitable.

Step 6 The compound of the general formula [8] obtained above is treated with a suitable solvent (eg, tetrahydrofuran, chloroform, methanol).
1 to 10 equivalents of hydrazine or hydrazine hydrate are added and reacted at a temperature from room temperature to the boiling point of the solvent to give a compound of the general formula

3-hydrazino-2H- represented by [9]
A 1,2,4-benzothiadiazine-1,1-dioxide derivative is obtained. This compound can be purified by silica gel column chromatography or the like, or a crude product just extracted from the reaction solution with an organic solvent (chloroform, methyl chloride, ethyl acetate, etc.) can be used in the next reaction. be able to.

Step 7 General formula obtained in Step 6

The compound of [9] has the general formula R ⁴
2 to 50 equivalents of an ortho ester of a lower fatty acid of C (OR ") ₃ [10] (R ⁴ is the same as above, R" is a lower alkyl group having 1 to 4 carbon atoms) is added, and an inert solvent (eg, In the presence or absence of (toluene), if necessary, a catalyst such as silica gel is added, and when heated in the range from room temperature to the boiling point of the solvent or the orthoester used, it is represented by the general formula [1-a]. [1,2,4] triazolo [3,4-C] [1,2,4] benzothiadiazine-5,5-dioxide compound can be obtained.

Modification of the seventh step The general formula obtained in the sixth step above

The compound represented by [9] has the general formula R ⁴ COX ² [11] (R ⁴ is the same as the above X ²
Is a halogen atom such as chlorine or bromine, or an imidazole group or a pyrazole group which may be substituted with —OCO ₂ R ″ or R ″. Where R ″ is the same as the above), the carboxylic acid reactive derivative is represented by 0 ° C. to 25 ° C. in an inert solvent (tetrahydrofuran, chloroform, etc.) in the presence or absence of an organic base such as pyridine or triethylamine.
When the reaction is carried out within the range of ° C, an acylhydrazino compound represented by the general formula [12] is obtained. This acylhydrazino compound is dissolved in an inert solvent such as toluene, xylene, diglyme, etc., and is heated in the range of 50 ° C. to 200 ° C. in the presence of an acid selected from formic acid, acetic acid, hydrochloric acid and tosylic acid, particularly preferably acetic acid. Then, the compound of the general formula [1-a] is obtained.

Production Method 2 First Step 2H-1, 2, 4 represented by the general formula [13] obtained by a known method (for example, Japanese Patent Laid-Open No. 1-238529).
Benzothiadiazone-3 (4H) -one is oxidized (peracetic acid, potassium permanganate, sodium metaperiodate, peroxide) in a solvent (chloroform, hexane, acetone, etc.) at a temperature from room temperature to the boiling point of the solvent. 2H-1,2,4-benzothiadiazin-3 (4H) -one-represented by the general formula [14] by adding an oxidizing agent such as hydrogen oxide, particularly preferably m-chloroperbenzoic acid). A 1,1 dioxide form can be obtained.

Step 2 The compound of the general formula [14] is dissolved in an inert solvent such as chloroform, tetrahydrofuran, diglyme, toluene or the like to give phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -1, 3-dithia-2,4-diphosphetane-2,4-disulfide (Lawson's reagent, tetrahedron, Vol. 41, p. 5061, 1985) is reacted with the compound of the general formula [from the room temperature to the boiling point of the solvent]. 8H] can be obtained 2H-1,2,4-benzothiadiazine-3 (4H) -thione-1,1 dioxide (the same compound as in the fifth step of Production Method A and Production Method 1). Is obtained).

Production Method 3 (when R ² = H) First Step Debenzylation Reaction (Reductive Removal) The compound of the general formula [1-b] (m = 0, R ² = H) was treated with methanol, A single solvent selected from alcohols such as ethanol, ethers such as 1,4-dioxane and tetrahydrafuran, or esters such as ethyl acetate, or a mixed solvent containing acetic acid, hydrochloric acid, etc. Add an appropriate amount of the selected acid, and in the presence or absence of water, palladium, platinum oxide,
The compound of the general formula [1-c] can be obtained by carrying out the catalytic reduction reaction with hydrogen (normal pressure to 10 atm) in the presence of a metal catalyst selected from nickel and the like. The temperature used can be from room temperature to a high temperature of 80 ° C. The compound [1-b] can be produced according to the above production method 1.

Variant of the first step Debenzylation reaction (under acidic condition) The above reductive debenzylation reaction can be carried out under the following acidic conditions. As the acid to be used, pyridine hydrochloride is particularly preferably selected from pyridine hydrochloride, hydrochloric acid, aluminum chloride, aluminum chloride + sodium iodide, aluminum chloride + ethanethiol and the like. As the solvent, methylene chloride, chloroform, dichloroethane, acetonitrile or the like may be used or may be used without solvent. In the case of pyridine hydrochloride, the reaction temperature is selected from room temperature to a high temperature of about 300 ° C., preferably 140 ° C. to 250 ° C. According to this method, as in Example 7, the alkoxy substituent on the benzene ring was replaced with a hydroxyl group (phenol).
It can be changed at the same time.

Production Method 4 (when R ¹ = OH) First Step Demethylation Reaction As mentioned above, the alkoxy group on the benzene ring can be converted to a hydroxyl group with pyridine hydrochloride, but boron tribromide can be used. With, the ether bond can be cleaved under milder conditions. A compound of the general formula [1-d] (R ¹ = lower alkoxy group such as methoxy and ethoxy) is dissolved in a halogenated solvent such as methylene chloride, chloroform and dichloroethane to prepare 1
To 10 equivalents of boron tribromide is reacted in the temperature range of -40 ° C to 40 ° C to obtain a phenol body represented by the general formula [1-e]. At this time, the optionally substituted benzyl group of R ² is not affected.

Production Method 5 (R ² = Variable Method of Heteroarylcarbonyl Group which may be Substituted) Acylation Reaction Step 1 The compound of the general formula [1-c] obtained in the debenzylation step above is generally used. Formula XCOR ⁶ [15] (X is the same as defined above, R ⁶ is an optionally substituted heteroaryl group),
The title compound [1-d] can be obtained by reacting in an organic solvent such as ethyl acetate, tetrahydrofuran, chloroform or pyridine at a temperature from room temperature to the boiling point of the solvent.

Production Method B (when m = 1) Production Method 1 First Step The compound of the general formula [5] obtained in the second step of the production method 1 in the general production method A is represented by the general formula [16]. The amino acid derivative represented by the above is reacted to obtain a sulfonamide compound represented by the general formula [17]. As the reaction conditions, the same conditions as those in the third step of the production method 1 in the general production method A can be used.

Step 2 The compound of the general formula [17] obtained in the first step is reduced in the same manner as in the fourth step of the production method 1 in the general production method A to give a compound represented by the general formula [17]. The compound can be obtained.

Step 3 (Alkaline hydrolysis of ester) The compound of the general formula [18] is dissolved in a solvent such as alcohols such as methanol and ethanol, acetone or tetrahydrofuran, and sodium hydroxide, A hydrolyzed compound represented by the general formula [19] can be obtained by adding an alkaline aqueous solution of potassium hydroxide or the like (0.2 to 5 N) and reacting at 0 ° C. to 20 ° C.

Fourth Step (Dehydration Condensation Reaction) The compound of the above general formula [19] is treated with tetrahydrofuran, methylene chloride, ethyl acetate, by a conventional peptide synthesis method.
In a solvent such as DMF, DCC (1,3-dicyclohexylcarbodiimide) or WSC.HCl (1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride) is used as a dehydration condensation agent, and 7 members are formed by dehydration condensation reaction in the presence or absence of HOBT (1-hydroxybenzotriazole monohydrate) or HOSUCN (N-hydroxysuccinimide). A compound represented by the general formula [20] having a ring lactam can be obtained.

Fifth Step According to the second step of the production method 2 in the general production method A, the compound of the general formula [20] is reacted with diphosphorus pentasulfide or Lawesson's reagent to give a compound of the general formula [21]. The represented thione form can be obtained.

Step 6 The compound of the general formula [21] is reacted with hydrazine and a lower fatty acid orthoester in order according to the method of the sixth and seventh steps of the production method 1 in the general production method A. A compound represented by [1-g] can be obtained. The compound obtained by the above production method is pulverized, recrystallized,
It can be isolated and purified by a conventional method such as column chromatography, reprecipitation and the like.

The compound represented by the general formula [1] is 0
Individual or one asymmetric carbon and the number of asymmetric carbon is one, a pure optically active substance, a mixture thereof in any ratio,
Alternatively, there may be racemates, racemates or combinations thereof, and mixtures in any ratio. When the compound [1] is used as a pharmaceutical preparation, it is ordinarily known as a pharmacologically acceptable carrier, excipient, diluent,
Extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, flavoring agents, solubilizing agents,
Other additives, specifically water, vegetable oil, ethanol,
Alcohols such as benzyl alcohol or hydroxypropyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, magnesium stearate, talc, lanolin, vaseline, lactose, sucrose, glucose, mannitol, sorbit, crystals Cellulose, gum arabic, dextrin, pullulan, silicic acid, aluminum,
Calcium phosphate, waxes, boric acid, DL-leucine, sodium fatty acid, magnesium lauryl sulfate, dextrin, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, carnauba wax,
Tablets, pills, powders, granules, suppositories mixed with polyoxyethylene, polyoxypropylene, glycol, cocoa butter, lauric acid, lecithin, glycerin, sodium paraoxybenzoate, sodium benzoate, salicylic acid, potassium sorbate, etc. It can be administered orally or parenterally in the form of a preparation, injection, eye drop, liquid, capsule, troche, aerosol, elixir, suspension, emulsion, syrup and the like. The dose may vary depending on the kind and degree of the disease, the compound to be administered and the administration route, the age, sex, weight of the patient, etc., but in the case of oral administration, the compound [1] is usually 0.001-100 per adult per day.
It is preferred to administer 0 mg, especially 0.1-100 mg.

[0034]

EXAMPLES The present invention will be described more specifically below with reference to production examples and examples. The abbreviations used in Production Examples and Examples have the following meanings. NMR nuclear magnetic resonance spectrum FAB fast atom bombardment mass spectrometry AcOEt ethyl acetate n-Hex n-hexane CHCl ₃ chloroform MeOH methanol NH ₄ OH 28% ammonia water AcOH acetic acid Cbz benzyloxycarbonyl DMF N, N-dimethylformamide Boc tert-butoxy. Carbonyl DCC N, N'-dicyclohexylcarbodiimide WSC.HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBT 1-hydroxybenzotriazole monohydrate Lawesson's reagent 2,4-bis (4- Methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,
4-Disulfide HOSU N-Hydroxysuccinimide In the following Examples and Production Examples, preparative thin layer chromatography was performed by Merck's Pre-Coated Silica Gel (Pre-Coated Silica Gel).
SILICA GEL) 60 F-254 (thickness:
Column chromatography was performed using Kieselgel 60 (70.230 mesh) manufactured by Merck.

Production Example 1 2-Methyl-2H-1,2,4-benzothiadiazine-
3 (4H) -one 1,1-dioxide 2-methyl-2H-1,2,4-benzothiadiazin-3 (4H) -one 1 obtained by a known method (Japanese Patent Laid-Open No. 1-238529) 0.000 g of chloroform 20 ml
Was dissolved in the mixture, 2.48 g of m-chloroperbenzoic acid was added, and the mixture was heated under reflux with stirring for 14 hours. After cooling, it was washed with 10% sodium sulfite, saturated sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure gave 1.18 g of the title compound (see Table 1).

Production Example 2 2-Methyl-2H-1,2,4-benzothiadiazine-
3 (4H) -thione 1,1-dioxide 1.00 g of 2-methyl-2H-1,2,4-benzothiadiazin-3 (4H) -one 1,1-dioxide obtained in Production Example 1 was added. It was dissolved in 30 ml of anhydrous toluene, 1.91 g of Lawson's reagent was added, and the mixture was heated under reflux with stirring for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and benzene was added to the residue.
ml was added and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and purified by alumina column chromatography (benzene / ethyl acetate = 90/10) to give the title compound (0.1).
58 g were obtained (see Table 1).

Production Example 3 93.0 g of phosphonium salt obtained from 76.4 ml of 2-chloro-5- (1-decenyl) nitrobenzene n-nonyl bromide and 52.5 g of triphenylphosphine.
Was dissolved in 500 ml of anhydrous tetrahydrofuran and 124 ml of butyllithium (1.6M hexane solution) was added dropwise at 4 ° C. over 1 hour or longer. After the dropping, the reaction solution was stirred at the same temperature for 30 minutes and at room temperature for 1 hour, and a solution of 4-chloro-3-nitrobenzaldehyde in 150 ml of tetrahydrofuran was added dropwise at 4 ° C over 1 hour. The reaction mixture was stirred at room temperature for 12 hours and then filtered, and the residue was washed with ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate = 99/1) to give 51.6 g of the title compound (cis / trans = 7/3).
Was obtained (see Table 1).

Production Example 4 2-chloro-5-decylaniline 2-chloro-5- (1-decenyl) obtained in Production Example 3
A mixture of 9.72 g of nitrobenzene, 100 ml of acetic acid and 1.00 g of palladium black was hydrogenated at 3 to 4 atm at room temperature for 24 hours. The catalyst was exchanged, and the reaction was performed for 15 hours under the same conditions. After removing the catalyst by filtration and concentrating under reduced pressure, the residue was subjected to alumina column chromatography (hexane / ethyl acetate = 9).
6/4) to give 4.69 g of the title compound (see Table 1).

Production Example 5 2-Chloro-5-decylnitrobenzene 2-chloro-5-decylaniline 1 obtained in Production Example 4
5.0 g of the product was dissolved in acetic acid, 43.1 g of sodium perborate tetrahydrate was added with stirring, and the mixture was reacted at 50 ° C. for 2 hours.
After cooling, the precipitated sodium borate was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue and the organic layer was extracted with hexane, washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by alumina column chromatography (hexane / ethyl acetate) and then silica gel column chromatography (hexane / ethyl acetate = 99/1) to give the title compound 2.6.
9 g were obtained (see Table 2).

Production Example 6 2-Benzylthio-5-decylnitrobenzene 0.50 g of 2-chloro-5-decylnitrobenzene obtained in Production Example 5 was dissolved in 2 ml of ethanol, and S-benzylisothiouronium chloride 0 was added under stirring. 0.50 g was added and heated to reflux. 0.235 g of potassium hydroxide
2 ml of ethanol solution was added dropwise and heating under reflux was continued for 2 hours. After cooling to −20 ° C., the precipitated solid was collected by filtration, washed with water, and dried to obtain 0.496 g of the title compound (see Table 2).

Preparation Example 7 2-Benzylthio-4-chloronitrobenzene 48.0 g of 2,4 dichloronitrobenzene was dissolved in 200 ml of ethanol, 50.7 g of S-benzylisothiouronium chloride was added with stirring, and the mixture was heated under reflux. Further, a solution of 38.0 g of potassium hydroxide in ethanol (250 ml) was added dropwise, and the mixture was refluxed for 2 hours. After cooling to -20 ° C, the precipitated solid was collected by filtration and washed with water to obtain 37.6 g of the title compound (see Table 2).

Production Example 8 2-Benzylthio-5-methoxynitrobenzene 27.5 g of 2-chloro-5-methoxynitrobenzene was dissolved in 200 ml of ethanol, 40.5 g of S-benzylisothiouronium chloride was added with stirring, and the mixture was heated. Refluxed. Further, 28.0 g of potassium hydroxide in ethanol solvent (250 ml) was added dropwise, and reflux was continued for 2 hours. -20
After cooling to ° C, the precipitated solid was collected by filtration and washed with water to obtain 33.4 g of the title compound (see Table 2).

Production Example 9 4-decyl-2-nitrobenzenesulfonyl chloride A mixture of 1.00 g of 2-benzylthio-5-decylnitrobenzene obtained in Production Example 6, 70 μl of water and 8 ml of acetic acid was stirred at 17 ° C. to 20 ° C. Then, bubbling chlorine gas for 1 hour. The reaction solution was returned to room temperature, nitrogen was blown into the reaction solution to remove excess chlorine, and the mixture was poured into ice water and extracted with toluene. The extract was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.08 g of the title compound (see Table 3).

Production Example 10 4-Methoxy-2-nitrobenzenezulphonyl chloride 30.0 g of 2-benzylthio-5-methoxynitrobenzene obtained in Production Example 8, 3.6 ml of water, 240 m of acetic acid
Chlorine gas was blown into the mixture (1) with stirring at 17 ° C to 20 ° C for 1.5 hours. After the reaction solution was returned to room temperature and nitrogen was blown to remove excess chlorine, the reaction solution was poured into ice water and extracted with toluene. The extract was washed with water and saturated saline and then dried over anhydrous sodium sulfate. Recrystallization from hexane-ethyl acetate gave 22.4 g of the title compound as pale yellow needle crystals (see Table 3).

Production Example 11 4-decyl-2-nitro-N-benzylbenzenesulfonamide To 1.00 g of 4-decyl-2-nitrobenzenesulfonyl chloride obtained in Production Example 9, 30 μl of benzylamine was added dropwise under ice cooling. After the dropping, 4 ml of a 0.7N sodium hydroxide aqueous solution was dropped at 70 ° C., and the mixture was stirred at the same temperature for 1 hour. After cooling, the pH was adjusted to 3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is chromatographed on silica gel (hexane / ethyl acetate = 90/10).
By purifying in (1), 0.946 g of the title compound was obtained (see Table 3).

Preparation Example 12 2-Nitro-N-benzylbenzenesulfonamide 12.2 ml of benzylamine was added dropwise to 22.2 g of 2-nitrobenzenesulfonyl chloride under ice cooling. After the dropping, 143 ml of 0.7N sodium hydroxide aqueous solution was added dropwise at 70 ° C., and the mixture was stirred at the same temperature for 1 hour. After cooling, the mixture was adjusted to pH 3 with 1N hydrochloric acid and extracted with ether. The extract was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure gave 28.7 g of the title compound (see Table 3).

Production Example 13 4-Methoxy-2-nitro-N-benzylbenzenesulfonamide To 8.00 g of 4-methoxy-2-nitrobenzenesulfonyl chloride obtained in Production Example 10 was added 3.50 ml of benzylamine under ice cooling. Dropped. After the dropping, 45.5 ml of 0.7N sodium hydroxide aqueous solution was added dropwise at 70 ° C., and the mixture was stirred at the same temperature for 1 hour. After cooling, the pH was adjusted to 3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After separation by filtration, the product was concentrated under reduced pressure to obtain 10.1 g of the title compound (see Table 4).

Production Example 14 5-Chloro-2-nitro-N-benzylbenzenesulfonamide A mixture of 30 g of 2-benzylthio-4-chloronitrobenzene obtained in Production Example 7, 3 ml of water and 180 ml of acetic acid was stirred at 17 ° C. Chlorine gas was blown in for 2 hours at -20 ° C. The reaction solution was returned to room temperature, nitrogen was blown into the reaction solution to remove excess chlorine, and the mixture was poured into ice water and extracted with toluene. The extract was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain 27 g of a sulfonyl chloride compound. Benzylamine (4.27 ml) was added dropwise to 10.0 g of the mixture under ice cooling. After dropping, 70 ℃
Then, 56 ml of 0.7N aqueous sodium hydroxide solution was added dropwise. After dropping, the mixture was stirred at the same temperature for 1 hour. After cooling, the pH was adjusted to 3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90/10) to give 3.29 g of the title compound (Table 4).
reference).

Production Example 15 2-Amino-4-decyl-N-benzylbenzenesulfonamide 0.826 g of 4-decyl-2-nitro-N-benzylbenzenesulfonamide obtained in Production Example 11 and methanol 7.
To a suspension of 5 ml, 7.5 ml of water and 1.33 g of ammonium chloride, 1.34 g of iron powder was added over 1 hour at 85 ° C with stirring. The reaction mixture was heated to reflux for 8 hours and filtered hot.
The brown solid was washed with hot methanol and the filtrate was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate and filtering,
It was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 85/15) to obtain 0.666 g of the title compound (see Table 4).

Production Example 16 2-Amino-N-benzylbenzenesulfonamide 2.92 g of 2-nitro-N-benzylbenzenesulfonamide obtained in Production Example 12, 40 ml of methanol, 40 ml of water, 6.95 g of ammonium chloride. 7.05 g of iron powder was added to the above suspension under stirring at 85 ° C. over 1 hour. The reaction mixture was heated to reflux for 8 hours and filtered hot. The brown solid was washed with hot methanol and the filtrate was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.49 g of the title compound (see Table 4).

Preparation Example 17 2-Amino-5-chloro-N-benzylbenzenesulfonamide 3.30 g of 5-chloro-2-nitro-N-benzylbenzenesulfonamide obtained in Preparation Example 14 and methanol 40
To a suspension of 20 ml of water, 40 ml of water, and 7.02 g of ammonium chloride, 7.11 g of iron powder was added over 1 hour at 85 ° C. with stirring. The reaction mixture was heated to reflux for 8 hours and filtered hot. The brown solid was washed with hot methanol and the filtrate was concentrated under reduced pressure.
Water was added to the residue, extracted with ethyl acetate, and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.49 g of the title compound (see Table 5).

Production Example 18 2-Amino-4-methoxy-N-benzylbenzenesulfonamide 4-Methoxy-2-nitro-N-obtained in Production Example 13
Benzylbenzenesulfonamide 9.17 g, methano-
110 ml of water, 110 ml of water, ammonium chloride 19.
20.0 g of iron powder was added to 8 g of the suspension at 85 ° C. with stirring over 1 hour. The reaction mixture was heated to reflux for 8 hours and filtered hot. The brown solid was washed with hot methanol and the filtrate was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and washed with water and saturated brine. 7.66 g of the title compound was obtained by drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure.
Was obtained (see Table 5).

Preparation Example 19 2-Benzyl-6-decyl-2H-1,2,4-benzothiadiazine-3 (4H) -thione 1,1 dioxide 2-amino-4-obtained in Preparation Example 15 Decyl-N-benzylbenzenesulfonamide (0.625 g) was dissolved in anhydrous dioxane (13 ml), 1,1'-thiocarbonyldiimidazole (0.415 g) was added, and the mixture was heated under reflux for 12 hr with stirring. After cooling, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, concentrated under reduced pressure,
The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20). Further, it was recrystallized from hexane-ethyl acetate to obtain 0.541 g of the title compound as white needles (see Table 5).

Production Example 20 2-Benzyl-2H-1,2,4-benzothiadiazine-3 (4H) -thione 1,1-dioxide 2-Amino-N-benzylbenzenesulfone obtained in Production Example 16 2.20 g of amide and 50 ml of anhydrous dioxane
Was dissolved in the solution, 2.24 g of 1,1'-thiocarbonyldiimidazole was added, and the mixture was heated under reflux with stirring for 12 hours. After cooling, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure and recrystallization of the crude product from hexane-ethyl acetate gave 1.94 g of the title compound (see Table 5).

Production Example 21 2-Benzyl-7-chloro-2H-1,2,4-benzothiadiazine-3 (4H) -thione 1,1-dioxide 2-Amino-5 obtained in Production Example 17 2.29 g of -chloro-N-benzylbenzenesulfonamide was dissolved in 50 ml of anhydrous dioxane, 3.44 g of 1,1'-thiocarbonyldiimidazole was added, and the mixture was heated under reflux for 12 hours with stirring. After cooling, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20). Recrystallized from hexane-ethyl acetate to give 2.33 g of the title compound as yellow plate crystals.
Was obtained (see Table 6).

Production Example 22 2-Benzyl-6-methoxy-2H-1,2,4-benzothiadiazine-3 (4H) -thione 1,1-dioxide 2-Amino-4 obtained in Production Example 18 -Methoxy-N-
7.70 g of benzylbenzenesulfonamide was dissolved in 150 ml of anhydrous dioxane, 6.40 g of 1,1′-thiocarbonyldiimidazole was added, and the mixture was heated under reflux for 12 hours with stirring. After cooling, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was recrystallized from hexane-ethyl acetate to obtain 5.78 g of the title compound (see Table 6).

Production Example 23 2-Benzyl-6-decyl-3-hydrazino-2H-
1,2,4-benzothiadiazine 1,1-dioxide 2-benzyl-6-decyl-2H obtained in Preparation Example 19
0.50 g of -1,2,4-benzothiadiazine-3 (4H) -thione 1,1-dioxide was dissolved in 10 ml of tetrahydrofuran, and hydrazine monohydrate 13 was added with stirring.
4 μl was added and the mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, 15 ml of chloroform was added, and the mixture was washed with water. After drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure, silica gel column chromatography (chloroform / methanol =
98/2) to give the title compound 0.144.
g was obtained (see Table 6).

Production Example 24 2-Benzyl-3-hydrazino-2H-1,2,4-benzothiadiazine 1,1-dioxide 2-Benzyl-2H-1,2,4 obtained in Production Example 20
-Benzothiadiazine-3 (4H) -thione 1,1-
Dioxide 7.00 g of tetrahydrofuran 140 ml
Was dissolved in the mixture, and 2.26 ml of hydrazine monohydrate was added with stirring, and the mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, chloroform was added, and the mixture was washed with water. Dried over anhydrous sodium sulfate,
After filtration, concentration under reduced pressure and silica gel chromatography (chloroform / methanol = 99/1) were performed to obtain 1.42 g of the title compound (see Table 6).

Production Example 25 2-Benzyl-3- (2-undecanoylhydrazino)
-2H-1,2,4-benzothiadiazine 1,1-dioxide 2-benzyl-3-hydrazino-obtained in Production Example 24
200 mg of 2H-1,2,4-benzothiadiazine 1,1-dioxide was dissolved in 2 ml of anhydrous tetrahydrofuran, and 165 μl of undecanoyl chloride was added dropwise under cooling. The mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. Chloroform was added to the residue, saturated aqueous sodium hydrogen carbonate solution,
It was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure, silica gel column chromatography (chloroform / methanol = 98/2).
270 mg of the title compound was obtained by purification with (see Table 7).

Production Example 26 N-benzyl-N- {1- (methoxycarbonyl) ethyl} -2-nitrobenzenesulfonamide dl-N-benzylalanine methyl ester 6.0 g and 2-nitrobenzenesulfonyl chloride 9.3 g were added to chloroform. After dissolving, triethylamine 1 under ice cooling
1.7 ml was added dropwise over 30 minutes. After completion of dropping, the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the organic layer was washed with diluted hydrochloric acid and saturated saline and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure and purification by silica gel column chromatography (hexane / ethyl acetate = 95/5) gave 5.6 g of the title compound as a yellow oil (see Table 7).

Production Example 27 2-Amino-N-benzyl-N- {1- (methoxycarbonyl) ethyl} -benzenesulfonamide N-benzyl-N- {1- (methoxycarbonyl) ethyl obtained in Production Example 26 } -Nitrobenzenesulfonamide 5.6g is dissolved in methanol 50ml, 20
% Ammonium chloride aqueous solution 50 ml, and at 70 ° C.,
Add 9.0 g of iron powder over 1.5 hours, add 8 to the reaction mixture.
The mixture was stirred at 0 ° C for 8 hours and filtered through Celite. The filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure gave 4.6 g of the title compound as a yellow oil (Table 7).
reference).

Production Example 28 2-Benzyl-3-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-4-one
1,1-dioxide 2-amino-N-benzyl-N-obtained in Production Example 27
4.4 g of {1- (methoxycarbonyl) ethyl} benzenesulfonamide was dissolved in 30 ml of methanol, and 40 ml of a 1N sodium hydroxide aqueous solution was added under ice cooling. After stirring at room temperature for 3 hours, methanol was distilled off under reduced pressure, the aqueous layer was neutralized (pH = 6) with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the oily substance was dissolved in 30 ml of N, N-dimethylformamide. 1.9 g of 1-hydroxybenzotriazole hydrate was added under ice cooling to give 30
After stirring for a minute, 2.5 g of 1,3-dicyclohexylcarbodiimide was further added. The reaction solution was returned to room temperature, stirred for 3 hours and then filtered through Celite. 40 ml of water was added to the filtrate, extracted with ethyl acetate, and washed with saturated saline. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give 2.6 g of the title compound as white crystals (see Table 7).

Preparation 29 2-Benzyl-3-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-4-thione 1,1-dioxide Obtained in Preparation 28. 2-benzyl-3-methyl-2,
1.0 g of 3,4,5-tetrahydro-1,2,5-benzothiadiazepin-4-one 1,1-dioxide was dissolved in 20 ml of chloroform, and 0.7 g of diphosphorus pentasulfide was added, followed by 3 hours. Heated to reflux. After cooling, add ice water,
Then, it was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, concentrate under reduced pressure and silica gel column chromatography (chloroform / methanol = 99/1).
The title compound 1.0 as pale yellow crystals was obtained after purification by
g was obtained (see Table 7).

Example 1 1,4-Dimethyl [1,2,4] triazolo [3,4-]
c] [1,2,4] benzothiadiazine 5,5′-dioxide 2-methyl-2H-1,2,4-benzothiadiazine-3 (4H) -thione-obtained in Production Example 2 1,1-dioxide (100 mg) was dissolved in tetrahydrofuran (2 ml), and hydrazine monohydrate (46.8 μl) was added with stirring.
The mixture was heated under reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, chloroform was added to the residue, washed with water, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained oily substance is dissolved in 2 ml of toluene, and 160 μl of triethyl orthoacetate is dissolved.
Was added, and the mixture was heated under reflux for 1 hour with stirring. After cooling, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform / methanol = 95/5). Ethyl acetate-
Recrystallized from hexane to give the title compound as a colorless plate crystal 33m
g was obtained (see Table 8).

Example 2 4-Benzyl-8-decyl-1-methyl [1,2,4]
Triazolo [3,4-c] [1,2,4] benzothiadiazine 5,5-dioxide 2-benzyl-6-decyl-3-obtained in Preparation Example 23
Hydrazino-2H-1,2,4-benzodiadiazine
0.140 g of 1,1-dioxide was dissolved in 3 ml of toluene, 116 μl of triethyl orthoacetate was added, and the mixture was heated under reflux for 1 hour with stirring. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 98/2) to obtain 0.134 g of the title compound as a colorless oil (see Table 8).

Example 3 4-Benzyl-1-methyl [1,2,4] triazolo [3,4-c] [1,2,4] benzothiadiazine
5,5-Dioxide 2-benzyl-3-hydrazino-obtained in Production Example 24
1.42 g of 2H-1,2,4-benzothiadiazine 1,1-dioxide was dissolved in 30 ml of toluene, 1.72 ml of triethyl orthoacetate was added, and the mixture was heated under reflux for 1 hour with stirring. After concentration under reduced pressure, the crude product was recrystallized from ethyl acetate-hexane to give 1.34 g of the title compound.
Was obtained (see Table 8).

Example 4 4-Benzyl-7-chloro-1-methyl [1,2,4]
Triazolo [3,4-c] [1,2,4] benzothiadiazine 5,5-dioxide 2-benzyl-7-chloro-2H obtained in Preparation Example 21
1.90 g of -1,2,4-benzothiadiazine-3 (4H) -thione 1,1-dioxide was dissolved in 19 ml of tetrahydrofuran, and hydrazine monohydrate was added to the solution under stirring.
33 ml was added and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure. Chloroform was added to the residue, washed with water,
It was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform / methanol = 96/4). The obtained hydrazino compound (0.181 g) is dissolved in toluene (4 ml), triethyl orthoacetate (0.20 ml) is added, and the mixture is heated under reflux for 1 hr with stirring. After cooling, concentrate under reduced pressure and perform silica gel column chromatography (chloroform / methanol = 96/4).
0.175 g of the title compound was obtained by purification with (see Table 8).

Example 5 4-Benzyl-8-methoxy-1-methyl [1,2,
4] Triazolo [3,4-c] [1,2,4] benzothiadiazine 5,5-dioxide 2-benzyl-6-methoxy-2 obtained in Production Example 22
Dissolve 4.90 g of H-1,2,4-benzothiadiazine-3 (4H) -thione 1,1-dioxide in 50 ml of tetrahydrofuran and add 1.42 ml of hydrazine monohydrate with stirring for 2 hours. Heated to reflux. After cooling, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform / methanol = 98/2). 2.40 g of the obtained hydrazino compound was added to toluene 5
It was dissolved in 0 ml, triethyl orthoacetate (1.92 ml) was added, and the mixture was heated under reflux for 1 hr with stirring. After cooling, concentrate under reduced pressure,
The crude product was recrystallized from ethyl acetate-hexane to obtain 1.52 g of the title compound (see Table 9).

Example 6 4-Benzyl-8-hydroxy-1-methyl [1,2,
4] Triazolo [3,4-c] [1,2,4] benzothiadiazine 5,5-dioxide 4-benzyl-8-methoxy-1-obtained in Example 5
Methyl [1,2,4] triazolo [3,4-c] [1,
2,4] benzothiadiazine 5,5-dioxide 10
0 mg was dissolved in methylene chloride 2 ml and boron tribromide (1 M solution of methylene chloride) 0.84 ml was added at -78 ° C. The mixture was stirred at room temperature for 12 hours, poured into ice water, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure and recrystallized from ethyl acetate-hexane to give 49 mg of the title compound (see Table 9).

Example 7 8-Hydroxy-1-methyl [1,2,4] triazolo [3,4-c] [1,2,4] benzothiadiazine
5,5-Dioxide 4-benzyl-8-methoxy-1-obtained in Example 5
Methyl [1,2,4] triazolo [3,4-c] [1,
2,4] benzothiadiazine 5,5-dioxide 50
A mixture of mg and 1.0 g of pyridine hydrochloride was heated to reflux with stirring for 1 hour. After cooling, water was added, and the precipitated solid was collected by filtration, washed with water, and dried to give 26 mg of the title compound.
Was obtained (see Table 9).

Example 8 1-Methyl [1,2,4] triazolo [3,4-c]
[1,2,4] benzothiadiazine 5,5-dioxide 4-benzyl-1-methyl obtained in Example 3 [1,
A mixture of 0.976 g of 2,4] triazolo [3,4-c] [1,2,4] benzothiadiazine 5,5-dioxide and 20 g of pyridine hydrochloride was heated to reflux with stirring for 1 hour. After cooling, ice water was added, and the precipitated solid was collected by filtration and dried to obtain 0.645 g of the title compound (Table 9).
reference).

Example 9 4- (2-Indolylcarbonyl) -1-methyl [1,
2,4] Triazolo [3,4-c] [1,2,4] benzothiadiazine 5,5-dioxide 42 mg of indole-2-carboxylic acid was added to 2 m of ethyl acetate.
It was dissolved in 1, and catalytic amounts of dimethylformamide and thionyl chloride (37 μl) were added, and the mixture was heated under reflux for 1 hour with stirring.
After cooling, the mixture was concentrated under reduced pressure, 1 ml of pyridine and 5 mg of dimethylaminopyridine were added to the residue at room temperature, and then 1-methyl [1,2,4] triazolo [3,4] obtained in Example 7 was added.
A solution of 50 mg of -c] [1,2,4] benzothiadiazine 5,5-dioxide in 1 ml of pyridine was added and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with ether to give 30 mg of the title compound (see Table 10).

Example 10 2-Benzyl-1-decyl [1,2,4] triazolo [3,4-c] [1,2,4] benzothiadiazine
5,5-Dioxide 2-benzyl-3- (2-undecanoylhydrazino) -2H-1,2,4-benzothiadiazine 1,1-dioxide 172 mg obtained in Production Example 25, toluene 1
A solution of 0 ml and 1 ml of acetic acid was heated to reflux with stirring for 2 hours. After cooling, the mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform / methanol = 98/2) to obtain 142 mg of the title compound (see Table 10).

Example 11 8-decyl-1-methyl [1,2,4] triazolo [3,4-c] [1,2,4] benzothiadiazine
5,5-Dioxide 4-benzyl-8-decyl-1-methyl [1,2,4] triazolo [3,4-c] [1, obtained in Example 2
2,4] benzothiadiazine 5,5-dioxide 30
1 mg of 1N hydrochloric acid and 10% palladium carbon were added to a 0.6 mg solution of methanol in methanol, and the mixture was stirred under a hydrogen atmosphere at 3 atm for 24 hours. The catalyst was filtered off, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The crude crystals were recrystallized from ethanol to obtain 16 mg of the title compound (see Table 10).

Example 12 5-Benzyl-1,4-dimethyl [1,2,4] triazolo [3,4-d] [1,2,5] benzothiadiazepine 6,6-dioxide In Preparation Example 29. The obtained 2-benzyl-3-methyl-2,
3,4,5-Tetrahydro-1,2,5-benzothiadiazepine-4-thione 1,1-dioxide 770 mg
Was dissolved in 10 ml of tetrahydrofuran, and hydrazine 1 was added.
0.12 ml of the hydrate was added, and the mixture was stirred at room temperature for 15 minutes and concentrated under reduced pressure. The obtained oily substance was dissolved in chloroform, washed with ice water, and dried over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure. Purification by silica gel column chromatography (chloroform / methanol = 95/5) gave 620 mg of a yellow oily hydrazino compound. The obtained oil (600 mg) was dissolved in toluene (10 ml), triethyl orthoacetate (0.7 ml) was added, and the mixture was heated under reflux for 3 hr. After cooling, the mixture was concentrated under reduced pressure and recrystallized from ethyl acetate-hexane to give 220 mg of the title compound as white crystals (see Table 10). In the present specification, structural formulas and physical properties of the compounds specifically related to the above-mentioned production examples and examples are shown in Tables 1 to 10.

[0076]

[Table 1]

[0077]

[Table 2]

[0078]

[Table 3]

[0079]

[Table 4]

[0080]

[Table 5]

[0081]

[Table 6]

[0082]

[Table 7]

[0083]

[Table 8]

[0084]

[Table 9]

[0085]

[Table 10]

The present invention is of course not limited to these examples. For example, Tables 11 to 1
The compounds shown in 2 also belong to the present invention.

[Table 11]

[0087]

[Table 12]

Next, the test results of the bone resorption inhibitory effects of the novel triazolobenzothiadiazine and triazolobenzothiadiazepine derivatives represented by the general formula [1] according to the present invention will be shown.

Test Example 1 Bone Resorption Inhibitory Action Basically, the bone resorption inhibitory action was measured by the method of Royce [Journal of Clinical Invest., Vol. 44, p. 103-].
116, 1965]. IC for 1-2 days after birth
⁴⁵ Ca (calcium isotope, CaCl ₂ solution) was intraperitoneally administered to one newborn R-type mouse in an amount of 1.5 μCi, and the parietal bone was aseptically removed the next day. The parietal bone was divided into two along the central suture line, one as a control group and the other as an experimental group.
0.5 ml of BGJb medium (Fitton-Jackson modification, [GIBCO
Laboratories (USA)] bovine serum albumin 1 mg / ml
50 nM after pre-culture at 37 ° C. for 2 days
The culture was continued for another 3 days in the above medium containing hPTH (1-34). After completion of the culture, to measure the radioactivity of ⁴⁵ Ca in the medium and in the bone, according to the following formula, it was released into the medium from the bone ⁴⁵
The ratio (%) of Ca was calculated.

[0090]

[Equation 1]

Bone obtained from the same mouse was treated in the same manner without adding the test compound as a control group, and the ratio (%) to the control group was determined according to the following formula.

[0092]

[Equation 2]

The average value of these values obtained from 4 pairs of bones in each group was determined, and the results are shown in Table 13.

[0094]

[Table 13]

[0095]

INDUSTRIAL APPLICABILITY The novel triazolobenzothiadiazine and triazolobenzothiadiazepine derivatives represented by the above general formula [1] according to the present invention have an excellent bone resorption inhibiting action and low toxicity. is there. From the results of the bone resorption inhibitory effect test, it is also clear that these compounds have an effect of reducing the amount of serum calcium due to bone resorption. Therefore, these compounds are bone resorption associated with diseases such as Paget's disease, hypercalcemia, osteoporosis, or inflammatory joint diseases such as rheumatoid arthritis that are considered to have an important role in the pathological condition of increased bone resorption. Increase (osteoporosis)
It can be used as a drug for effectively suppressing bone resorption, preventing a decrease in bone mass, or preventing or decreasing an increase in serum calcium level due to an increase in bone resorption, with respect to pathological conditions such as.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI technical display location C07D 285: 00 249: 00) (72) Inventor Junichi Hoshi 6 Umegaoka 2 Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Pharmaceutical Research Institute (72) Inventor Junki Shindo 6-6 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Industrial Co. Ltd. Pharmaceutical Research Institute (72) Ino Uchida 6 Umegaoka, Midori-ku Yokohama-shi, Kanagawa 2 Japan Tobacco Inc. Pharmaceutical Research Center

Claims (2)

[Claims] 1. A general formula [1]: (In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen group or an optionally substituted alkyl group or aralkyl group having 1 to 12 carbon atoms, and R ² represents a hydrogen atom or a substituted group. A lower alkyl group, an aralkyl group or a heteroarylcarbonyl group, R ³ is a hydrogen atom or an optionally substituted lower alkyl group or an aralkyl group, and R ⁴ is a hydrogen atom or an optionally substituted carbon atom. A new triazolobenzothiadiazine represented by the formula 1 to 12 alkyl group or aralkyl group, X represents —SO ₂ —, —SO— or —S—, and m represents 0 or 1. Triazolobenzothiadiazepine derivatives or pharmaceutically acceptable salts thereof. 2. The therapeutic agent for osteoporosis according to claim 1, which comprises the compound of the general formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient.