JPS6239583A - Benzodioxazole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is formula II (A<1> and A<2> are C or N; R<3> and R<4> are H, hydroxyl group, lower alkoxy, amino, etc.), formula III (A<3> is O, S or NH), etc.; n is an integer 1-5; R<5> and R<6> are H, hydroxyl group or lower alkoxy] and a salt thereof. EXAMPLE:2-(Piperonylthio)benzodioxazole. USE:A medicine and compound useful for preventing and treating hepatopathy. PREPARATION:A thiol compound expressed by the formula R<1>-SM (M is H or alkali metal) or a thiolate compound which is an alkali metal substitution product thereof is reacted with a (substituted) benzodioxazolyl lower alkyl halide or sulfonate expressed by formula IV (X<1> is halogen or lower alkylsulfonyloxy, etc.) to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to novel benzodioxole derivatives and salts thereof represented by the following general formula (I) useful for medicine, particularly for the prevention and treatment of liver diseases. Regarding their manufacturing method.

“The symbols in the formula have the following meanings.

Integers R2 and R2' from nil to 5; same or different, hydrogen atom, hydroxyl group,
or a lower alkoxy group.

A1 and A2; the same or different, a carbon atom or a nitrogen atom.

R3 and R4; the same or different hydrogen atom, hydroxyl group, lower alkoxy group, amine group, or mono- or di-lower alkylamino group.

A3; oxygen atom, sulfur atom, or imino group (-NH-)
R4, A5 and All; same or different, carbon atom,
Oxygen, sulfur or nitrogen atoms.

R5, R6 and R? Same or different, hydrogen atom, lower alkyl group, hydroxyl group, mercapto group, lower alkylthio group, carboxy lower alkylthio group, lower alkoxycarbonyl lower alkylthio group, benzodioxolyl lower alkylthio group, carboxy group, cyano group.

amine group, mono- or di-lower alkylamino group,
Mono- or diaralkyl Rδ: hydrogen atom or lower alkyl group.

(): A', A5. Depending on the type of A', 0
R6, R7, and RA in the above must not exist.

Dotted ring: presence of double bond in resonance structure.

Alk: lower alkylene group.

R9 and RIO: Same or different, lower alkyl group (However, R9 and RIO may be combined with a nitrogen atom to form a piperidine ring, a pyrrolidine ring, and a morpholine ring).

R■: hydrogen atom or lower alkyl group.

Y: oxygen atom or sulfur atom R12: lower alkyl group, pyridyl group, pyrrolyl group, hydroxyl group, lower alkokene group, mercapto group, or lower alkylthio group. (Background of the Invention) Traditionally, treatment for liver diseases, particularly various acute and subacute (and chronic) liver disorders, has included bed rest, high-protein, high-calorie diet, and discontinuation of medication for the causative drug.

In addition to general treatments such as abstinence from alcohol, sugar solutions and vitamins.

General drug therapy such as hepatic agents, corticosteroids such as prednisolone, and immunostimulants are used.

However, the reality is that there is still no satisfactory therapeutic agent, especially for prolonged or chronic liver disorders. Furthermore, drug therapy using steroids, immunostimulants, etc. has the problem of serious side effects6.

Recently, malotylate and noskabine, which are represented by the following chemical formulas, have been developed as compounds that have liver damage-improving effects, hepatocytes, and liver function activation effects. All compounds having prophylactic and therapeutic activity for diseases, especially liver disorders, are known (Detailed Description of the Invention). As a result of intensive research, a new penzodioxole derivative represented by the general formula (I), which has not been described in any literature, was discovered. Through screening, the present invention was discovered to be useful as a prophylactic and therapeutic agent for liver disease.

An object of the present invention is to provide compounds represented by the general formula (I), salts thereof, and methods for producing them.

In this specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Therefore, the "lower alkyl group" specifically includes, for example, a methyl group, an ethyl group, and a propyl group.

Inglovir group, butyl group, isobutyl group.

5ee-butyl group, tert-butyl group, pentyl group (amyl group), impentyl group, neopentyl group,
tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group.

2-methylpentyl group, 3-methylpentyl group.

1.1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2.3-dimethylbutyl group, 3.3-dimethylbutyl group, 1- Ethylbutyl group, 2-ethylbutyl group +
1+1+2) +) Methylpropyl group.

1.2.2-) Limethylprobyl group, 1-ethyl-1
-Methylpropyl group, 1-ethyl-2-, 'thylpropyl group, and the like.

Moreover, the "lower alkoxy group" specifically includes a methoxy group, an ethoxy group, and a propoxy group.

Impropoxy group, butoxy group, imbutoxy group,
5ee-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group Straight chain or branched alkoxy group having 1 to 6 ring carbon atoms can be mentioned.

"Lower alkylthio group" specifically includes methylthio group, ethylthio group, propylthio group, ingropylthio group, butylthio group, inbutylthio group, 5ec
-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group,
Examples include linear or branched carbon atoms having 1 to 6 carbon atoms such as tert-pentylthio group and hexylthio group.

Furthermore, examples of the "lower alkoxycarbonyl group" include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an impropoxycarbonyl group, and a butoxycarbonyl group.

imbutoxycarbonyl group, 5ec-ptoxycarbonyl tv group, tert-7' toxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, t
Examples include groups formed by forming an ester with a carboxy group and a linear or branched lower alcohol having 1 to 6 carbon atoms, such as ert-hentyloxycarbonyl group and hexyloxycarbonyl group.

r carboxy lower alkylene group J, r lower alkoxy carbonyl lower alkylthio group.

"Benzodioxolyl lower alkylthio group" is.

A hydrogen atom at any position of the specific group of the "lower alkylthio group" exemplified above at °C.

Examples include a phenyl lower alkyl group such as a carboxy group, the above-mentioned lower alkoxycarbonyl group, and a benzodioxolyl group. 'Komata. "Mono- or di-lower alkylamino group" or "mono- or di-lower alkylamino group"
Aralkylamino group.

It means a group in which one or two hydrogen atoms of an amine group are substituted with the above-mentioned "lower alkyl group" or "aralkyl group."

Specifically, methylamine group, ethylamino group, propylamine group, isopropylamine group.

Monoalkylamino group, dimethylamino group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, such as butylamino group, imbutylamino group, pentylamino group, isopentylamino group, hexylamino group, etc. , diethylamine group.

Dipropylamino group, diimpropylamino group.

Or a symmetrical dialkylamino group or ethylmethylamino group di-substituted with a branched alkyl group.

Different alkyl groups among linear or branched alkyl groups having 1 to 6 carbon atoms such as methylglobylamine group, ethylpropylamino group, butylmethylamino group, butylethylamino group, butylpropylamino group, etc. Examples include substituted asymmetric dialkylamine groups.

The same applies to mono- or di-aralkyl amino groups.

The "lower alkylene group" represented by Alk includes methyletrimethylene group, I-propylene group, 2-propylene group,
f tramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, 1-
Ethylethylene group.

Examples include 2-ethylethylene group, pentamethylene group, hexamethylene group, and the like.

Y is a lower acylamide group, an N-lower alkyl lower acylamide group, a pyridine or pyrrolecarboxamide group, an N-lower alkyl-N-pyridine or pyrrolecarbonylamino group.

Carbamide group, 〇-lower alkylcarhamide group (lower alkoxycarbonylamino group), dithiocarbamide group,
N-lower alkyl-lower alkylcarbamide group, S
-lower alkyldithiocarbamide group, N-lower alkyl-S-lower alkyldithiocarbamide group, and the like. Specific examples of the lower acylamide group include an acetamide group, a propionamide group, a butanamide group, a 2-methylpropanamide group, a pentanamide group, and a hexaneamide group.

The N-lower alkyl lower acylamido group is a group in which the hydrogen atom bonded to the nitrogen atom of the lower acylamido group is substituted with the "lower alkyl group" described above. 〇-lower alkylcarbamide group is carno(mi)” group (HOOC-NH-
), the carboxyl group is lower alkyl, N-lower alkyl, 〇-lower alkylcarbamide group, the kyldithiocarbamide group of the above 〇-lower alkylcarpamide group is the hydrogen atom of the mercapto group of the dithiocarbamide group (H83-NH-) is a lower S-butyldithiocarbamide group (CH3(CH2
)3S5NH-).

etc. The N-lower alkyl-S-lower alkyldithiorupamide group is an optionally substituted S-lower phenyl group or a phenyl group (both have 1 nitrogen atom and a total of 1 to 4 heteroatoms). Contains
It is a nitrogen-containing aromatic heterocyclic group which may be fused with a benzene ring, and specifically refers to the following three types of benzene rings and heterocycles.

A specific ring group of this type includes benz.

can be mentioned. i.

Some of the compounds of the present invention form salts. The present invention also includes salts of the compound represented by the above general formula (1), and examples of such salts include alkali dimetals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, and alkali metals such as aluminum. Salts with inorganic bases, ethylamine, propylamine, diethylamine, triethylamine.

Morpholine, piperidine, N-ethylpiperidine.

Salts with organic bases such as jetanolamine and cyclohexylamine, salts with basic amino acids such as lysine and ornithine, ammonium salts, hydrochloric acid, and sulfuric acid.

Mineral acid salts such as phosphoric acid and hydrobromic acid, acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and malic acid.

Examples include salts with fumaric acid, tartaric acid, picric acid, and methanesulfonic acid.

In addition, the compound (1) of the present invention has optical isomers based on the presence of asymmetric carbon atoms, types of heterocycles, oxo groups, hydroxy groups, thioxo groups, and mercapto groups (tautomers). The compounds of the present invention include separated isomers and mixtures thereof.

The compounds of the present invention can be synthesized by nine different methods.

Typical methods are illustrated below.

General synthesis method R2' to 4 (I) means an arylsulfonyloxy group. ) General formula (
The compound represented by I) includes a thiol compound represented by the general formula (III) or a thiolate compound which is an alkali metal substitute thereof, and a substituted or unsubstituted benzodioxolyl lower alkyl halide represented by the general formula (III). Alternatively, examples of the lithium, potassium, and chlorine atoms represented by X with which the sulfonate is reacted include iodine, bromine, and chlorine atoms. In addition, lower alkylsulfonyloxy groups and L-'(il), methylsulfonyl groups, ethylsulfonyloxy groups, etc., and arylsulfonyloxy groups include benzenesulfonyloxy groups, p-toluenesulfonyloxy groups, and toluenesulfonyloxy groups. etc.

The reaction was carried out using approximately equal moles of Compound (Il) and Compound (Irl'), with a slight excess mole of one at a certain °C, and dimethylformamide, dimethylsulfokide, acetone,
Ethyl methyl ketone, methanol, ethanol, chloride, chloroform, ether.

It is carried out in an organic solvent such as tetrahydrofuran or dioxane, water, or a mixed solvent of water and an organic solvent.

When a thiol compound is used as compound (II), it is carried out in the presence of a base, and such bases include sodium hydroxide, potassium hydroxide, sodium hydride,
Sodium carbonate, potassium carbonate.

In addition, R5, (R6) and (R7) in the 9 compounds of the present invention are
A compound that is benzodiquindyl lower alkyl group.

A starting compound (n) in which R1 is a nitrogen-containing 5-membered heterocyclic group substituted with a mercapto group and a chemical equivalent of the compound (III)
It can also be produced by reacting with.

Interconversion method of substituents Among the compounds of the present invention, a compound having a specific substituent can be produced by converting the substituent into a specific substituent using the compound of the present invention having a corresponding substituent as a raw material compound. Typical manufacturing methods are illustrated below. In addition,
On the left side of the reaction formula below, a partial structural formula representing only the substituents is used. The number of substituents in the partial structural formula is not limited to only one, such as R', (R'),
Up to three (R7) may be substituted.

− N < R+4 (“1) +41 − C0OR”. -COOH(
Ih) (Ii) Sexual derivative (In the above reaction formula, yl, Y and M have the same meanings as above, R"&'!, lower a-lower alkyl group, dipyridyl group, lyl group, or lower alkoxy group, R+7 is lower alkyl R18 is a lower alkyl group, RBI is a carboxy group, a lower alkoxycarbonyl group, a benzodiquinolyl group, a di-lower alkylamino group, H.

A lower alkyl group substituted with a veridino group, a pyrrolidino group, or a morpholino group, and X2 means a rogen atom) (1) N-alkylated 2 moieties in the compound of the present invention of structural formula (Ib), (Ic) It can be produced by N-alkylation in which a mono- or di-lower alkyl compound (Ia) represented by (Id) is reacted with a lower alkyl (or aralkyl) halide or a lower alkyl (or aralkyl) sulfonate.

Among the starting compounds (IV) and (V), the reaction using a halide in which Xl is a halogen atom may be carried out without a solvent or with an organic material that does not participate in the reaction, such as benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, or ethanol. It is advantageous to carry out the reaction in a solvent at room temperature or under heating under reflux. During the reaction, a base such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, picoline, N, N-dimethylaniline, etc. In some cases, it is preferable to add .

In addition, in the reaction using a compound in which Xl is a lower alkylsulfonyloxy group or an arylsulfonyloxy group among the starting compounds (IV) and (V), an organic solvent inert to the reaction, such as nityl, methanol, ethanol, etc. , toluene, tetrahydrofuran, etc., under cooling or at room temperature.

The amount of raw material compound (IV) used is determined when the compound (IV) is used as the target product.
When producing Ic), it is appropriate to use at least twice the molar amount of compound (Ia), and when producing compound (Ib) as the target product, it is appropriate to use approximately the same molar amount.

In addition, when producing compound (Ib) as the target product,
to the amine group of compound (Ia) in order to suppress tertiary amination and produce the target product in good yield.

Example: Introducing a protecting group such as evaluenesulfonyl group, acetyl group, phenacylsulfonyl group, )'J fluoromethanesulfonyl group, bisbenzenesulfonyl group, reacting with compound (IV), and removing the protecting group after the reaction. Advantageously, the method is adopted.

The asymmetric di-lower alkyl (or aralkyl) amine compound (Id) can be produced by reacting the mono-lower alkyl (or aralkyl) amine compound thus obtained with the compound (V) in the same manner.

(2) Among the compounds of the present invention, the acylamino compound represented by the nine-part structural formula (Ie) is converted into the corresponding amine compound (Ia) or mono-lower alkylamino compound (Ib).

It is produced by amidation using a carboxylic acid represented by the general formula (Vl) or a reactive derivative thereof.

Examples of the reactive derivative of compound (Vl) include acid halides such as acid chloride and acid bromide; hexamixed acid anhydrides such as acid aninsulfonic acid, and the like.

When a free carboxylic acid is used as compound (Vl), the reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1r1'-carbonyldiimidazole.

The reaction involves compound (Ia) or (Ib) and compound (Vl)
or a reactive derivative thereof in approximately equimolar amounts or in monomers such as pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane.

It is carried out in a solvent such as chloroform, dimethylformamide, ethyl acetate, acetonitrile, etc.

9 reactions depending on the type of reactive derivative.

Triethylamine, pyridine, picoline, lutidine, N
, N-dimethylaniline and potassium carbonate.

Adding a base such as sodium hydroxide may be advantageous in making the reaction proceed smoothly.

The reaction temperature varies depending on the type of 9-reactive derivative and is not particularly limited.

(3) Dithiocarbamide conversion Among the compounds of the present invention, the dithiocarbamide compound represented by the 9-part structural formula (If) is a dithiocarbamide compound represented by the nine-part structural formula (If), which is formed by adding carbon disulfide (
VII) to form a salt, the S-lower alkyldithiocarnocumide compound represented by the partial structural formula (Ig) can be converted into a corresponding amine compound (Ia) or mono-lower alkylamino compound (Ib). Carbon disulfide (
Vll) and a lower alkyl halide represented by the general formula (Vll).

Both reactions involve methanol and ethanol.

Dimethylformamide, dimethyl sulfoxide.

The reaction is carried out in an organic solvent such as ether, tetrahydrofuran, dioxane, water, or a mixed solvent thereof in the presence of a base, usually at room temperature.

The base used is sodium hydroxide.

Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, pyridine, picoline, lutidine.

Organic bases such as N,N-dimethylaniline and N-methylmorpholine are suitable.

The amounts of carbon disulfide and lower alkyl halide used are preferably equimolar to molar excess relative to the starting material compound (Ia) or (Ib).

Since compound (If) has poor stability, it is desirable to isolate it as a salt.

(4) Hydrolysis of Ester The compound of partial structural formula (Ii) in which R1 in the compounds of the present invention is a nitrogen-containing 5-membered heterocyclic group substituted with a carboxy group or a carboxy lower alkylthio group.

It is produced by hydrolysis of the corresponding lower alkyl ester compound (Ih).

The reaction can be carried out according to a conventional method.1 For example, saponification with a base is preferable for relatively short lower alkyl esters such as methyl ester and ethyl ester. Lower alkyl esters are preferably saponified with acid. Examples of the base and acid used in the reaction include potassium hydroxide, sodium hydroxide, hydrochloric acid, and trifluoroacetic acid.

(1) Contrary to the reaction of esterification (8), an ester compound of partial structural formula (Ih) in which R1 in the compound of the present invention is a nitrogen-containing 5-membered heterocyclic group substituted with a lower alkoxycarbonyl lower alkylthio group. is produced by reacting a free carboxylic acid represented by the 9-part structural formula (If) or a reactive derivative thereof with a lower alcohol represented by the general formula (IX) or a reactive derivative of a lower alcohol component such as a lower alkyl halide. can do.

The reaction can be easily accomplished according to conventional methods.

(rl) Ether or thioetherification Among the compounds of the present invention, the ether or sulfide compound represented by the two-part structural formula (Ik) is a hydroxy or thiol compound represented by the two-part structural formula (Ij') or its alkali metal substituted product (alcolade). .

phenolate, thiolate) and a halide or sulfonate represented by the general formula (X).

The reaction is almost the same as the general production method described above.

The salt of the compound of the present invention represented by the general formula (1) is produced by applying a salt formation reaction commonly used in the art.

The compound (1) of the present invention and its salt thus produced are crystallized, extracted, distilled off, and recrystallized.

It is isolated and purified by conventional chemical operations such as column chromatography.

(Effect of the invention) Compound (I) and its salt provided by the present invention are:
As described below, as a result of a pharmacological effect test using a pathological model in which liver damage was artificially created by administering a drug such as carbon tetrachloride, it was confirmed that it has an excellent suppressive effect on liver damage.

Therefore, the two compounds of the present invention are suitable for use in patients with liver diseases, especially acute and subacute liver disorders in which histological findings indicate liver damage.

It is useful as a prophylactic and therapeutic agent for all chronic liver diseases.

Viral hepatitis is one such liver disease.

Centrilobular necrosis and perilobular necrosis in fulminant hepatitis, drug-induced liver damage (including both toxic liver damage and idiosyncratic hypersensitivity liver damage), alcoholic liver damage, etc.

Acute and subacute liver damage accompanied by necrosis such as lobular disseminated coagulative necrosis, which was prolonged from acute liver damage.

Or chronic liver damage that has progressed chronically from the beginning.

Fatty liver or long-term liver disease due to lipid metabolism disorders.

Examples include liver cirrhosis, which has progressed from liver disease.

Among the experiments in which the pharmacological effects of the nine compounds of the present invention were confirmed, a method of testing the pharmacological effects using a hepatitis pathology model with a single administration of carbon tetrachloride and using the serum transaminase activity as an index will be described below.

Namely, when carbon tetrachloride is administered, liver cell membranes.

It damages mitochondrial membranes or microsomal membranes, causes loss of original liver cell function, and causes centrilobular 2 necrosis. When liver cells are damaged in this way, enzymes are released and various enzyme activities appear in the serum. Therefore, it is an appropriate method to measure serum transaminase activity as an indicator of liver damage.

A pharmacological effect test using this pathological model is the most suitable method for screening the pharmacological effect of a test compound on liver damage.

(Test method) Six-week-old male SD rats (body weight around 160 g) were used as animals. Carbon tetrachloride dissolves in olive oil.

A 20% solution was administered orally at 5 rnl/kg (1 ml/kg as carbon tetrachloride).

The test compound was suspended in cremophor//pampher for intraperitoneal administration and in 0.5% methiback cellulose for oral administration, and administered at 5 ml/kg, respectively. The test compound was administered twice, 1 hour before and 3 hours after carbon tetrachloride administration. Twenty-four hours after carbon tetrachloride administration, blood was collected from the abdominal vena cava of the rats under ether anesthesia, and serum GPT was measured.

According to this test method, it was confirmed that one of the compounds of the present invention effectively inhibits GPT activity induced by carbon tetrachloride administration even at an oral dose of 10 mg/kg. Therefore, the compounds of the present invention are useful as therapeutic agents for liver diseases.

A preparation containing one or more compounds represented by the general formula (I) and its salts as an active ingredient.

It is prepared into tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, etc. using commonly used pharmaceutical carriers, excipients, and other additives. Administered orally or parenterally.

Pharmaceutical carriers and excipients include solid or liquid non-toxic pharmaceutical substances. Examples of these include, for example, lactose, magnesium stearate, starch, Merck, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc.
Other commonly used items are exemplified.

The clinical dosage of the compound of the present invention is determined by law as appropriate, taking into account the patient's symptoms, body weight, age, gender, etc., and is usually 10 to 600 mg/kg per adult per oral administration.
This can be administered once or in several doses.

(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.

However, the present invention is not limited to the following examples.

In addition, in the examples, NMR refers to nuclear magnetic resonance spectrum,
Mass means mass spectrum, and Anal means elemental analysis.

Example 1 3.41g (20mM) of delide was added. The mixture was stirred at room temperature for 30 minutes, 200 ml of ether was added thereto, the ether layer was separated, washed with 20 n+l of water and 20+ nt of saturated brine, dried over anhydrous magnesium sulfate, and the ether was distilled off. The obtained yellowish solid was recrystallized from n-hexane to obtain 3.7 g of almost colorless crystals of 2-(piperonylthio)benzoxazole having a melting point of 58-59°C.

NMR (90MHz, DMS OIFa
)4.55(2H,S, -9CH2-), 6.0
0(2H,s, -0CH20-)6.70-7.80
(7H, m, benzene ring proton) Mass (M/z
) 285(M+) 252,135° Example 2° 2-Mercaptobenzothiazole (2
0mM) was reacted with biperonyl chloride, treated in the same manner, and recrystallized from ethyl acetate-〇-hexane, with a melting point of 64-6.
31 g of 2-(piperonylthio)benzothiazole crystals exhibiting a temperature of 5°C were obtained.

NMR (90MHz, DMS O-da) 4.57
(2H,s, 5CH2), 6.00(2H,S,
0CH20-) 6.70-8.10 (7H, m, benzene ring proton) Mass (M/z) 301 (M+), 268.135゜Example 3゜Same as Example 1, 2-mercaptobenzimidazole (
20mM) with piveronyl chloride, treated in the same manner, and recrystallized from acetic acid-ether to give a melting point of 164-165.
2.6 g of crystals of 2-(hyberonylthio)benzimidazole were obtained.

NMR (90MHz, CDCls) 4.48 (2H,S, -8CH2-), 5.92 (
2H,s, -0CH20-)6.60-7.70 (
8H, m, benzene ring proton, -NH-)Mass(
M/z) 284 (M+), 251.135゜Example 4゜1.13 g (10 mM) of 2-amino-5-mercapto-1,3,4-thiadiazole was added to 20 m7 of 0.5N aqueous sodium hydroxide solution. 1.71 g (10 mM) of piveronyl chloride was dissolved in a mixture of 20 ml of acetone and cooled with water.
added. After stirring at room temperature for 30 minutes, the precipitated crystals were collected. After air drying, recrystallize with acetone to obtain a melting point of 159-16.
2-amino-5-(biperonylthio)-1 showing 1°C
, 2.2 g of yellowish crystals of 3,4-thiadiazole were obtained.

NMR (90MHz, DMS O-de) 4.20
(2H,8,-3CH2), 6.00(2H,3,-
0CH20-) 6.80 (2H,s, benzene ring proton), 6.90 (LH,s.

benzene ring proton), 7.24 (2H,3,-NH
,) Mass (M/z) 267 (M+) 234, 192, 135° Anal (
As CloHgNi02St) C (%) H (%)
N (chi) S (%) theoretical value 44.93
3.39 15.72 23.99 Actual value 45.
11 3.33 15.77 23.83 Example 5゜Same as Example 4 3-mercap 1--1.2.4-)
'J azole (10mM) was reacted with piperonyl chloride, treated in the same manner, and recrystallized with methanol water, melting point 12.
3-(biperonylthio)-1,2 exhibiting a temperature of 3 to 124°C
, 1.3 g of colorless crystals of 4-triazole were obtained.

NMR (90MHz, DMS O-da) 4.27
(2H,s, -8CHt-), 5.97(2H,s,
-0CR20-).

6.70-7.00 (3H, m, benzene ring proton), 6.50 (LH, S.

triazole ring proton), 14.04 (LH, -NH
-)Mass(M/Z) 235(M'') 202.135゜Example 6゜Dissolved in a mixture of 2-ethoxycarbonylmethylthio-5-mer ml and piperonyl chloride \1.71 under water cooling.
g (10mM) was added. After stirring at room temperature for 30 minutes,
After adding 100 ml of ether and stirring, the ether layer was separated. Extract the aqueous layer with 100 ml of ether, combine the ether extracts, and add 30 ml of water. After washing with 30 ml of saturated brine and drying over anhydrous magnesium sulfate, the ether was distilled off. The obtained yellowish oil was purified by silica gel column chromatography (eluent: benzene) and recrystallized from ethyl acetate-rehexane to give ethyl [[5-
(piperonylthio)-1,3,4-thiadiazole-
1.4 g of colorless crystals of 2-ylcothiocoacetate were obtained.

NMR (90MHz, CDC6,) 1.26 (3H,t,-CHa), 4.06 (2H
, s, -5CH2CO-).

Mass (M/Z) 370 (M”) 337, 192, 135° Example 7
1.50 g (10 mM) of 1.5 g (10 mmol) was added to 20 ml of IN-sodium hydroxide aqueous solution. Dissolved in a mixture of 20mt of acetone,
Piperonyl chloride 3.41 g (20mM
)'k added.

After stirring at room temperature for 30 minutes, two precipitated crystals were collected.

After air drying, recrystallize with ethyl acetate to obtain a melting point of 117-1.
t2.5-bis(hyberonylthio)-1,3
, 2.5g of 4-thiadiazole crystals were obtained.

NMR (90MHz, CDC1,) 4.40 (4H,s, 5CHz-), 5.92 (4
H, S, -0CH20-).

6.60-7. OO (6H, m, benzene ring proton)
Mass (M/z) 418 (Δ(+) 298.252.192.135
゜Example 8゜2-carboxymethylthio-5-mercapto-1,3,
2.08 g (10 mM) of 4-thiadiazole was dissolved in a mixture of 20 ml of IN-sodium hydroxide aqueous solution and 20 ml of acetone, and 1.71 g (10 ml) of biperonyl chloride was dissolved under water cooling.
0mM) was added. After stirring at room temperature for 15 minutes, the acetone was distilled off, acidified with IN-hydrochloric acid aqueous solution, and ethyl acetate 3
Extracted twice with 0rnl. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. The obtained slightly yellow oil was purified by silica gel column chromatography [eluent: chloroform-methanol (7:3)], and recrystallized from ethyl acetate to give [[5-(piperonylthio)- 2.0 g of colorless crystals of 1,3,4-thiadiazol-2-yl]thiocoacetic acid were obtained.

NMR (90MHz, DMS O-da) 4.12
(2H,!!, -8GHzCO-), 4.42 (2H,
s, -8CHz-).

6.00 (2H,s, -OCH,O”), 6.70
~7.10 (3H, m, benzene ring proton), 3.0
0-5.00 (IH, -COOH) Mass (M/z) 342 (M”), 309,192,135° Example 9 1.11 g (10 mM) of 4-mercaptopyridine was dissolved in IN-sodium hydroxide 10 ml of aqueous solution. Dissolve in a mixture of 10 ml of acetone and add 1 ml of piperonyl chloride under water cooling.
．． 71 g (10 mM) was added. After stirring at room temperature for 30 minutes, the mixture was extracted twice with 30 ml of ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off. The obtained oil was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethyl acetate-n-hexane to obtain 1.4 g of colorless crystals of 4-(piveronylthio)pyridine having a melting point of 77-78°C. Obtained.

NMR (90 MHz, CD (j, n 4.12 (2H, s, 5CH2), 5.94 (2H
,3,-0CH20-).

6.60-7. OO (3H, m, benzene ring proton)
, 7.10 (2H.

pyridine ring proton), 8.37 (2H, m, pyridine ring proton) Mass (M/z) 245 (M”), 135° Example 10° 4-hydroxy-2-mercaptopyrimidine 1.28 g
(10mM) in 0.5N aqueous sodium hydroxide solution 20
mt, dissolved in a mixture of 20 ml of acetone and cooled on ice.

1.71 g (10 mM) of piperonyl chloride was added. After stirring at room temperature for 30 minutes, 20 ml of water was added and a lot of precipitated crystals were collected. 4-Hydroxy-2 having a melting point of 221-222°C after being air-dried and recrystallized from dimethylformamide.
-2.2 g of colorless crystals of (biperonylthio)pyrimidine
Obtained.

NMR (90MHz, Pyridine-d5)
4.56 (2H9s, -3CH, -), 5.94 (2H
9s, 0CH20-).

6.38 (IH, d, pyrimidine ring proton), 6.7
0 to 7.30 (3L m + benzene ring proton), 8
．． 00 (LH, d, pyrimidine ring proton) Mass (M/z) 262 (M"), 229,135゜Example 11゜3-Hydrostrawberry sea 5-mercapto 4-inchazolecarboxylic acid tripotadium salt 5.82 g ( 20mM) in 20ml of water, piperonyl chloride 3.41(
Add a solution of 20m4 of acetone (20mM) and stir at room temperature.
Stir for 0 minutes. 150 m4 of acetone was added and a lot of precipitated crystals were collected. The obtained crystals were dissolved in 150 ml of water, insoluble materials were removed, the solution was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected. After air drying, it was recrystallized from a dimethylformamide-methanol mixture to obtain 1.8 g of crystals of 3-hydroxy-5-(piperonylthio)-4-inchazolecarboxylic acid having a decomposition point of 234 to 235°C.

NMR (90MHz, DMS O-d, )4.2
4(2H,!1.-8CH2-), 6.00(2H,
8,-OCH,O-).

6.7 C1-7,10 (3H, m, benzene ring proton) Mass (M/z) 311 (M”), 293.176, 135° Anal
((as +tHeNOsSz) C(chi) H(@
N (%) S (%) Theoretical value 46.29 2
．． 91 4.50 20.60 Actual value 46.3
4 2.99 4.51 20.69 Example 12
゜3-Hydroxy-5-mercapto-4-inchazole luponitrile dibotadium salt 2.34g (10mM)
Dissolve in 35ml of dimethylformamide.

1.71 g of piveronyl chloride (10 m
M) was added and left at the same temperature overnight. Dimethylformamide was distilled off under reduced pressure, and the residue was dissolved in 40 mt of water.
Shake with 4011It of ethyl acetate, take the aqueous layer, add 10mA of IN-hydrochloric acid aqueous solution to make it acidic, and add 300ml of ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off.

The obtained colorless crystals were recrystallized from ethanol, and the melting point was 205.
Crystals of 3-hydroxy-5-(piperonylthio)-4-inchazolecarbonitrile exhibiting a temperature of ~206°C were
I got 1g.

NMR (9°OMHz, DMSO-ds) 4.40
(2H,s, -5CHt-), 6.00 (2H,s
, -0CHtO-).

6.80-7.10 (3H, m, benzene ring proton) t 13.1 (LH.

-0H) Anal (C, 2H, lN2C, S2 as C(%
) H (chi) N (chi) S (chi) Theoretical value 49.30 2.76 9.58 21.
94 actual measurement value 49.492.66 9.45 2
2.22 Example 13゜2-methoxythiophenol 1.40g (10mM)
to 20ml of 0.5N aqueous sodium hydroxide solution. The mixture was dissolved in a mixture of 20 ml of acetone, and 1.71 g (10 mM) of biveronyl chloride was added thereto while stirring while cooling with water. The mixture was stirred at room temperature for 30 minutes, the acetone was distilled off under reduced pressure, and the aqueous solution was extracted with 100 ml of ethyl acetate. The ethyl acetate solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off. The obtained solid was recrystallized from n-hexane and showed a melting point of 79 to 80°C. 2-(Biberonylthio)
1.9 g of anisole crystals were obtained.

NMR (90MHz, CDCl, )3.88 (3H
,S,-OCH,), 4.00(2H,8,-8CH
,-).

5.9'O(2H,S, -OCH,O-), 6.6
0-7.30 (7H, m, benzene ring proton) Mass (M/z) 274 (M”), 135° Example 14° 3-amino-5-mercapto-1,2,4-) lyazole 1. 16g (10mM) was dissolved in a mixture of 20ml of 0.5N sodium hydroxide solution and 20ml of acetone, and 1.71g (10mM) of piperonyl chloride was added under water cooling.

After stirring at room temperature for 30 minutes, 100 ml of ethyl acetate was added and shaken, and the ethyl acetate layer was taken, washed with water, and dried.

Ethyl acetate was distilled off. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (
3-Amino-5-(
1.0 g of crystals of piveronylthio)-1,2,4-)riazole were obtained.

NMR (90MHz, DMS O-da) 4.13
(2H9s, -5CH2-)16.00 (2H9s
, -□cH20-)y6.40(2H,s, -NH2
), 6.7 (1-7,00 (3H, m, benzene m7
°Loto 7), 11.9 (LH, s, -NH-)Mass
(M/z) 250 (M”), 135° Example 14 4.6-Diami2-mercaptopyrimidine 1.42
g (10 mM) was dissolved in a mixture of 20 ml of 0.5 N aqueous sodium hydroxide solution and 20 rnl of 7 ml of setone, 1.71 g (10 mM) of biveronyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. Add 30 ml of water, collect the precipitated crystals, air dry, and recrystallize from acetone-n-hexane. 2.0 g of 4,6-diami2-2-(piveronylthio)pyrimidine crystals exhibiting a melting point of 166 to 167C.
I got it.

NMR (90MHz, DMSO-d6) 4.16
(2H7s, -8CH2) 5.16(IH,s
, pyrimidine ring proton 6.00C2H,9,-0
CH20-') 6.12(4H,s, -NH2X2
) 6.6C) -7,10 (3H, m, benzene ring proton) Mass (M/Z) 276 (M+), 243. 135 Example 15 2,5-dimercapto-1,3,4-thiadiazole 3
．． 0g (20mM) was dissolved in a mixture of 20mZ of IN-sodium hydroxide aqueous solution and 10ml of 7setone, and a solution of 3.41g (20mM) of biperonyl chloride in 10ml of acetone was added dropwise while cooling with ice water. After stirring for 30 minutes at room temperature, 30 ml of water was added and the precipitated crystals were collected. After air drying and purification with silica gel column chromatography (eluent: chloroform), crystals of 2-mercapto-5-(biperonylthio)-1,3,4-thiadiazole were recrystallized from chloroform-n-hexane and had a melting point of 121-122C. 3.5g was obtained.

NMR (90MHz, DMSO-do) 4.36
(2H,s, -5CH2-), 6.00(2H,s
, -0CH20-)6.80~7.00(3H,m,
Benzene ring proton) Mass (M/z) 284 (M''), 252.135 Example 16 665 ITlg (5mM) in 0.5N-sodium hydroxide solution, 8XJ.

3-methquine-4,5- dissolved at 10mtK and cooled with ice water.
Methylenedioxybenzyl chloride 1.1g (5mM
A solution of Xl, 1) in 15 m of acetone was added dropwise. After cooling to room temperature and stirring for 30 minutes, 5 mt of ice water and 50 ml of ethyl acetate were added and stirred. The organic layer was separated, washed with 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained yellowish crystals were recrystallized from benzene to give an almost colorless 2-amino-5-[[(7-medoxy1,3-benzodioxol-5-yl)methylcothio]-1 having a melting point of 115-116C. , 1.2 g of crystals of 3°4-thiadiazole were obtained.

Anal (as CHHHN303S2) C (porridge H
(H) N (Ya) S (width calculation value 44.43 3
．． 73 14.13 21.57 Actual value 44.53
3.613 14.05 21.45NMR (90MH
z, DMSO-d,)3.76(3H,s,-
0CH3) 4.20 (2H, S, 5CH2)
5.96(2H,s, -OCH,0-)6.60(
2H, dd, benzene ring proton) 7.26 (2H
, s , -NH2)Mass (M/z) 297(M”) 264,222,165 Example 17 2-Mercaptobenzoxazole 7561T]g (
5mM) in 10ml of 0.5N aqueous sodium hydroxide solution.
1.1 g of 3-methoxy-4,5-methylenedioxybenzyl chloride (5mMX 1
．． 1) A solution of 15 nn7 of acetone was added dropwise. After stirring at room temperature for 30 minutes, add 5 m4 of ice water. Acetate ethyl ester 5
0 ml was added and mixed.

The organic layer was separated, washed with 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained oil was subjected to silica gel column chromatography (solution mW: n-
2-
[[(7-medoxy1,3-benzodioxole-5
-yl)methylcothio]benzoxazole crystals 1.
1g was obtained.

Anal (as C16Hl3NO4S)C((6)
H (%) N (Transportation 5 ((6) Calculated value 60.
94 4.16 4.44 10.17 Actual value 6
0,95 4,00 4.27 9.99NMR
(90MHz, DMSO-d6)3.80 (
3H,s + 0CHs)4.52(2H,s,
-8CH2-)5.96(2H,s, 0CH20-
) 6.70-6.90 (2H, d, d, benzene ring proton) 7.20-7.50 (2H, m, benzoxazole ring proton) 7.5 (1-7,80 (2H, m, Benzoxazole ring proton) Mass (M/z) 315 (M”), 282,198,165 Example 18 2-mercapto-5-(piperonylthio) 1°3.
4-thiadiazole (obtained in Example 15)2.
42g (8,5mM), N-(2-chloroethyl)piperidine hydrochloride 1.72g (8,5mM
1.1) Anhydrous potassium carbonate 2.58g (8.5m
MX2.2) was suspended in 50ml of dimethylformamide and stirred for 1 hour while heating at 65-70C.

After cooling, insoluble matter was removed and dimethylformamide was distilled off under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and diluted with 30 ml of water.
1. After washing with 30 ml of saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off. 80% of the obtained crystals
%-2- which recrystallizes from ethanol and shows a melting point of 64-65C
2.9 g of crystals of [(2-piperidinoethyl)thio]-5-(piperonylthio)-1,3,4-thiadiazole
I got it.

Anal (as C,7H21N302S3)C(
@H(-N(CH)S(@ Calculated value 51.62 5.35 10.62 24.3
2 Actual measurement value 51,57 5.22 10.58 24.
2ONMR (90MHz, CDCl3) 1.2
0-1.70 (6H, m, piperidine ring proton)
2.30-2.60 (4H, m, piperidine ring proton) 2.70 (2H, t, NCH2) 3.4
4 (2H, t, 5CH2) 4.40 (2H, S,
-8CH2-) 5.93 (2H,s, -0CH20-) 6.60~
7.00 (3H, m, benzene ring proton) Mas
s (M/z) 395 (M+), 135 Example 19 1.32 g (10 mM) of 2-mercapto-5-methyl-1,3,4-thiadiazole was mixed with IN-aqueous sodium hydroxide solution 10 mA and acetone 10 mt. Dissolve piperonyl chloride 1.71g (10mM) under ice water cooling.
Add.

Stirred at room temperature for 30 minutes. Water 15 mZ, ethyl acetate 5
The organic layer was washed with 20 ml of water and 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: chloroform containing 1% methanol), and the resulting crystals were recrystallized from ethyl acetate-n-hexane to give 2-methyl-
1.1 g of crystals of 5-(biperonylthio)-1,3,4-thiadiazole were obtained.

Anal (as CIl HION202S2)C(
@H(彌N(arrogant) S((trans)calculated value 49.61
3.78 10.52 24.08 Actual value 49.6
6 3.66 10.57 23.96NMR(100
MHz, CDCl, )2.71 (3H,s, -
CF! 3) 4.43(2H,s, -8CH2-)5.93(2
H,s, -0CH20-)6.60~6.90(3H
, m, benzene ring proton) Mass (M/z) 266 (M”), 233.192.135 Example 20 2-amino-5-mercaptotriazole 580 mg
(5mM) in 0.5N aqueous sodium hydroxide solution 11
Dissolve in a mixture of m7 acetone 15mZ 3-methoxy-
4゜5-methylenedioxybenzyl chloride 1.1g
(5mM x 1.1) and stirred at room temperature for 30 minutes. 15 ml of water and 50 ml of ethyl acetate were added and mixed.

The separated organic layer was mixed with 20 ml of water + 20 ml of saturated saline.
After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution number: ethyl acetate) and recrystallized from ethyl acetate-n-hexane to give methylcothio]
1.0 g of colorless crystals of -1,3,4-thiadiazole were obtained.

Anal (as CBH12N403S) C (chi)
H (%) N (Hata 5 ((6) Calculated value 4
7,13 4.32 19.99 11.44 Actual value 47.00 4.11 19.80 11.41N
MR (90MHz, DMS O-do, )3
．． 80 (3H,s, 0CH1) 4.12 (2H
,s, 5CH2)5.93(2H,s, -0C
H20-)6.04 (2H,s, -NH2)6.
50-6.70 (2H, dd, benzene ring proton)
11.90 (IH, s, -NH-) Mass (M/z) + 280 (M+), 24
7,195+ 165 Example 21 Ethyl [(2-mercapto-1,3,4-thiadiazol-5-yl)thio]butyrate 1.32 g (5mM
) in 11 ml of 0.5 N aqueous sodium hydroxide solution and 11 ml of acetone, piperonyl chloride 938111
g (5mM x 1.1) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water 15ml1. Add 50 ml of ethyl acetate, shake, let stand, and mix the separated organic layer with 20 ml of water.
After washing with 20 ml of saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography [eluent: ethyl acetate-n
-hexane (1:3)] to give a colorless oil, 2-[
[3-(Ethoxycarbonyl)propylkothio]-5-
1.3 g of (piveronylthio)-1,3°4-thiadiazole was obtained.

NMR (100MHz, CDCl5) 1°25
(3H, t, -CH,) 1.90-2.30 (2H, m, CH2-) 2.3
0-2.60 (2H, m, -CH2Co-)3.32
(2H,t, -5CH2-)4.13 (2H,q
+ OCR2) 4.42 (2H,s, -8CH
,-)5.96(2H,s,0CH20)6.6
0-7.00 (3H, m, benzene ring proton) Mas
s (M/z) 398 (M+), 353,264,192,135 Example 22 0.89 g of 2-amino-4-methyl-5-mercapto-1°3-thiazole was added to IN-sodium hydroxide aqueous solution 6 Dissolve in a mixture of .74 rnl and acetone 6.74 rnl.

After adding 1.15 g of biveronyl chloride while stirring while cooling with water, stirring was continued for 30 minutes. Add ethyl acetate to the reaction solution,
After stirring, the ethyl acetate layer was separated.

The obtained ethyl acetate layer was washed with saturated saline.

It was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column [eluent: toluene-acetone (3:
1)]. 5 m of the resulting pale yellow syrup
1 of methanol and cooled with water to obtain 0.25 g of colorless crystals of salt/-4-methyl-5-piperonylthio-1,3-thiazole hydrochloride (melting point: 155C decomposition).

NMR (90MHz, DMSO-d6) 1.90 (3
H,s, -CH,) 3.83 (2H,s, -8CH,-)5,0 (2H
,s+0CH20)5.30-5.90(3H,
m, benzene ring proton) Mass (FAB) Calculated value 45,49 4.14 8.84 20.2
4 11.19 Actual value 45.28 4.19 8.
75 20.50 11.27 Example 23 Crystal.

5-mercapto-1-methyltetranyl 1.36g
was dissolved in a mixture of 11.7 ml of IN-sodium hydroxide aqueous solution and 11.7 ml of acetone, and 2.0 g of hyheronyl chloride was added thereto while stirring while cooling with water. Return the reaction solution to room temperature.

After continuing the reaction for 30 minutes, ethyl acetate was added and the mixture was vigorously mixed, and then the ethyl acetate layer was separated. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified with 71 ml of chromatography [eluent: toluxn-2-7'':j'/7 (6:1)] and then recrystallized with methanol.

2.8 g of colorless crystals of 1-methyl-5-(biperonylthio)tetrazole having a melting point of 77-78C were obtained.

NMR (100 MHz, CDCl, )N 3.85 (3H,s, -CH5) 4.48 (2
H, s + S CH2) 5.96 (2H, s,
-0CH20-)6.64~6.96(3H,m,
Benzene ring proton) Mass (M/z) 250 (M”), 189. 135 Anal,
(C16H1 (as IN402S)
(919N (@S (chi) calculated value 47.99 4.03
22.39 12.81 Actual value 48.19 3.8
0 22.40 12.65 Example 24 2-amino-5-(piperonylthio)-1,3,4-
2.0 g of thiadiazole was dissolved in 20 rnl of anhydrous dimethylformamide, 3.1 g of anhydrous potassium carbonate was added, and 1.07 ml of benzyl bromide was added dropwise while stirring under water cooling. The reaction solution was returned to room temperature and stirring was continued for a further 10 hours. After filtering the reaction solution and concentrating the resulting filtrate.

It was dissolved in ethyl acetate and washed twice with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was applied to a silica gel column [toluene-2-butanone (5:1)]
Purification was performed to obtain pale yellow syrup. The obtained syrup was dissolved in 10 mA methanol, and after blowing hydrochloric acid gas into the solution while cooling with water, it was concentrated. The resulting residue is recrystallized from methanol-acetone and exhibits a melting point of 179 C (decomposed).
2-benzylamino-5-(piveronylthio)-1,
0.3 g of colorless crystals of 3,4-thiadiazole hydrochloride
Obtained.

NMR (100MHz, DMSO-da) 4.32
(2H,s, -8CH,-)5.20(2H,s,
-NCH2-)5.99(2H,s, -0CH20-
)7.36 (5Hts+@) Mass (FAB) (M/Z) 358 (M+), 135.91 Ana1. (as C17H16N302S2C1)C
(@H(-N(@S(%I ct(@calculated value 51.
83 4.09 10.67 16.28 9.00 Actual value 51.86 3.90 10.61 16.00
8.91 Example 25 2-amino-5-(biveronylthio)-1,3,4-
4.0 g of thiadiazole was dissolved in 40 ml of anhydrous dimethylformamide, 6.2 g of anhydrous potassium carbonate was added, and 1.4 ml of methyl iodide was added dropwise while stirring under water cooling.

The reaction solution was returned to room temperature, and stirring was continued for an additional 3 hours, and then the reaction solution was filtered. After concentrating the obtained filtrate, ethyl acetate was added to the obtained residue, the precipitated crystals were filtered off, and the obtained filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated.

The obtained residue was dissolved in 20 m of methanol and hydrochloric acid gas was blown into the solution while cooling with water to give 2-methylamino-5-(piperonylthio)-1, which had a melting point of 1951:' (decomposition).
, 0.9 g of colorless crystals of 3,4-thiadiazole hydrochloride
Obtained.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Symbols in the formula have the following meanings. R^1; A group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. n; integers from 1 to 5 R^2 and R^2'; same or different, hydrogen atom, hydroxyl group, or lower alkoxy group; A^1 and A^2; same or different, carbon Atom or nitrogen atom, R^3 and R^4; same or different, hydrogen atom,
Hydroxyl group, lower alkoxy group, amino group, or mono- or di-lower alkylamino group, A^3; oxygen atom, sulfur atom, or imino group (-NH-) A^4,
A^5 and A^6; the same or different, carbon atom, oxygen atom, sulfur atom, or nitrogen atom; R^5, R^6 and R^7; the same or different, hydrogen atom, lower alkyl group , hydroxyl group, mercapto group, lower alkylthio group, carboxy lower alkylthio group, lower alkoxycarbonyl lower alkylthio group, benzodioxolyl lower alkylthio group, carboxy group, cyano group, amino group,
mono- or di-lower alkylamino group, mono- or di-aralkylamino group,
A group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ R^8; Hydrogen atom or lower alkyl group, ( ); A^4, Depending on the type of A^5 and A^6, (
) that R^6, R^7, and R^8 do not exist. Dotted ring; presence of double bond in resonance structure, Alk
; Lower alkylene group, R^9 and R^1^0; Same or different, lower alkyl group (However, R^9 and R^1^0 are combined with a nitrogen atom to form a piperidine ring, a pyrrolidine ring, or a morpholine ring. (may be formed). R^1^1; hydrogen atom or lower alkyl group, Y; oxygen atom or sulfur atom R^1^2; lower alkyl group, pyridyl group, pyrrolyl group, hydroxyl group, lower alkoxy group, mercapto group, or lower alkylthio group. ] Benzodioxole derivative or its salt (2)
General formula R^1-SM [Symbols in the formula have the following meanings. R^1; A group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. M; hydrogen atom or alkali metal atom A^1 and A^2; same or different, carbon atom or nitrogen atom; R^3 and R^4; same or different, hydrogen atom, hydroxyl group, Lower alkoxy group, amino group, or mono- or di-lower alkylamino group, A^3; oxygen atom, sulfur atom, or imino group (-NH-
)A^4, A^5 and A^6; same or different, carbon atom, oxygen atom, sulfur atom or nitrogen atom, R^5, R^6 and R^7; same or different, hydrogen Atom, lower alkyl group, hydroxyl group, mercapto group, lower alkylthio group, carboxy lower alkylthio group, lower alkoxycarbonyl lower alkylthio group, benzodioxolyl lower alkylthio group, carboxy group, cyano group, amino group,
mono- or di-lower alkylamino group, mono- or di-aralkylamino group,
A group represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or a group represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^8: Hydrogen atom or lower alkyl group, ( ); A^4 , A^5, depending on the type of A^6, (
), R^6, R^7, and R^8 are absent, dotted ring; double bond of resonance structure exists, Alk
; Lower alkylene group, R^9 and R^1^0; Same or different, lower alkyl group (However, R^9 and R^1^0 are combined with a nitrogen atom to form a piperidine ring, a pyrrolidine ring, or a morpholine ring. ), R^1^1; hydrogen atom or lower alkyl group, Y; oxygen atom or sulfur atom R^1^2; lower alkyl group, pyridyl group, pyrrolyl group, hydroxyl group, lower alkoxy group, Mercapto group or lower alkylthio group. ] Thiol or its alkali metal substituted product, and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (The symbols in the formula have the following meanings. R^2 and R^2'; Same or different. a hydrogen atom, a hydroxyl group, or a lower alkoxy group; n; an integer of 1 to 5; General formulas characterized by reacting with lylalkyl halide or -sulfonate ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^2' and n have the above meanings. A method for producing a benzodioxole derivative having the following.