JPH0228172A - Remedy for liver disease and piperazine derivative - Google Patents

Abstract

PURPOSE:To obtain a remedy for liver diseases comprising a piperazine derivative including a novel compound or a salt thereof as an active ingredient. CONSTITUTION:A remedy for liver diseases comprising a compound shown by the formula [A is phenyl, p-benzoquinonyl or coumarinyl which may contain halogen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl, acyl, OH, alkoxy, NH2, SH alkylthio, NO2, etc., as substituent group; B is single bond and 1-4C alkylene which may contain alkyl, aryl, aralkyl, OH or oxo as substituent group; R is H, alkaline (earth) metal, alkyl, cycloalkyl, aralkyl or aryl] or a salt thereof such as methyl 4-(3,4,5-trimethoxybenzyl)-1-piperazinecarbothioate as an active ingredient. The compound is useful as a remedy for liver diseases, anti- inflammatory drug, antirheumatic agents and a remedy for diseases of digestive tubes.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of the Invention] The present invention relates to a therapeutic agent for liver diseases and novel perazine derivatives.

[Background of the Invention] The liver is responsible for detoxification, carbohydrate metabolism, lipid metabolism, protein metabolism, production of bile, production of blood coagulation factors, hormone regulation, and production of various biological components such as fat, glycogen, protein, and vitamins. It has the functions of rice plants such as storage. However, these functions can be impaired acutely or chronically due to viruses, drugs, poisons, alcohol, malnutrition, hepatic circulatory system disorders, bile duct obstruction, etc., resulting in viral hepatitis, drug-induced toxic hepatitis, and alcoholic hepatitis. It manifests as diseases such as hepatitis, congestive hepatitis, liver damage due to biliary depression, fatty liver, yellow disease, and finally liver cirrhosis.

As a result of research on therapeutic agents for liver diseases as described above, the present inventors found that the general formula (I); , Asil, and Droxy,
A phenyl group, a p-benzoquinonyl group, or a coumarinyl group, which may have at least one substituent selected from the group consisting of alkoxy, acyloxy, glycodyloxy, amino, alkylamino, mercapto, alkylthio, and nitro. , B represents a straight chain alkylene group having 1 to 4 carbon atoms, which may have a single bond or at least one substituent selected from the group consisting of alkyl, aryl, aralkyl, hydroxy, and oxo. R represents an atom or group selected from the group consisting of hydrogen atom, alkali metal atom, alkaline earth metal atom, alkyl, cycloalkyl, aralkyl, and aryl, and n is 2 or 3] Piperazine derivatives or pharmacologically acceptable salts thereof have been shown to exhibit excellent inhibition of GOT (glutamine-oxaloacetate transaminase) and cpT (glutamine-pyruvate transaminase) deviation in an in vivo carbon tetrachloride acute liver injury model. It has been found that it has an excellent effect of reducing or treating liver damage, or has an excellent protective effect against liver damage, and is useful as a treatment or prevention agent for liver diseases.

Further, the piperazine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof has an excellent effect of inhibiting lipid peroxide production, and further has an active oxygen scavenging effect.

It is known that an increase in lipid peroxide in the living body is closely related to the pathological conditions of various organs. It is also thought to be involved in carcinogenesis.

Substances that suppress the production of these interstitial peroxides in living organisms include not only liver disease therapeutics, but also anti-inflammatory agents, antirheumatic agents, gastrointestinal disease therapeutics, anti-cataract agents, anti-arteriosclerotic agents, and anti-cerebral infarction agents. It is also useful as a therapeutic agent for autoimmune diseases.

Among the piperazine derivatives represented by the above general formula (I), 4-(2-phenylalkyl)-1=piperazinecarbodithioic acid and its alkyl ester are known compounds (AcLa, Pharm.

5uecica, 7 (I), 7-22 (I970
), but this document does not describe at all that these compounds are useful as therapeutic agents for liver diseases.

Further, among the piperazine derivatives represented by the above-mentioned formula (I), -formula (■); [wherein, AI is a substituent such as halogen, alkyl,
fluoroalkyl, formyl, alkoxycarbonyl,
Acyl, hydroxy, alkoxy, acyloxy, glycodyloxy, amino, alkylamino, mercapto,
a phenyl group having at least one substituent selected from the group consisting of alkylthio and nitro, or
represents a p-benzoquinonyl group or a coumarinyl group which may have the above substituents, B is a single bond, or alkyl, aryl, aralkyl,
represents a straight 2n alkylene group having 1 to 4 carbon atoms which may have at least one substituent selected from the group consisting of hydroxy and oxo; R is a hydrogen atom, an alkali metal atom, an alkaline earth metal; represents an atom or group selected from the group consisting of alkyl, cycloalkyl, aralkyl, and aryl, and n is 2 or 3] is a new compound.

A compound similar to the piperazine derivative represented by formula (II) is 4-(6,7-cyhydroxycoumarin-8-yl)methyl-1-piperazineethanol (zh).

0bshch, old 1.33 (3), 793-7 (
I963)); 4- (2-(3,4-dihydroxyphenyl)-2-
oxo)ethyl-1-piperazineethanol (Latv
, PSRZinat, ^kad, Vestis,
kim, ser.

(5), 593-6 (I96B)):4-(2-(
3,4-dihydroxyphenyl)-2-oxo)ethyl-1-methylbiperazine (Arznein, -Fors
ch,, 19 (I0), 1698-1702 (
I969)') etc. are known, but the above formula (II
) is not known regarding the piperazine derivative represented by.

[Structure of the Invention] The present invention resides in a liver disease therapeutic agent containing a piperazine derivative represented by the above formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

Another aspect of the present invention is a novel piperazine derivative represented by the general formula (I1).

[Detailed Description of the Invention] In the above formula (I), A represents a substituent such as halogen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl, acyl, hydroxy, alkoxy, acyloxy, glycozyloxy, amino, alkylamino represents a phenyl group, a p-benzoquinonyl group, or a coumarinyl group, which may have at least one substituent selected from the group consisting of , mercapto, alkylthio, and nitro, and specific examples of the above substituent include: Halogens such as chlorine, bromine, and fluorine: Alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl; 1 carbon number such as trifluoromethyl
~6 fluoroalkyl; alkoxycarbonyl having 2 to 7 carbon atoms such as methoxycarbonyl and ethoxycarbonyl; acyl having 2 to 7 carbon atoms such as acetyl and propionyl;
Alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy; Acyloxy having 2 to 7 carbon atoms such as acetoxy, propionyloxy; Glycofuranosyloxy, glycopyranosyloxy (e.g. α-D-glucopyranosyl Oxy, α-D-galactopyranosyloxy, β-L
- arabinopyranosyloxy, etc.), glycodyloxy such as glycopyranosyloxy; carbon number 1 to 6, including monoalkylamino such as monomethylamino, monoethylamino, and dialkylamino such as dimethylamino, diethylamino, etc. alkylamino; alkylthio having 1 to 6 carbon atoms such as methylthio, ethylthio, and propylthio;

The group represented by A, such as a phenyl group or a p-benzoquinonyl group, may have 1 to 5 of the above substituents, and when it has two or more substituents, the substituents may be the same as each other. Well, they can also be different. Moreover, it is preferable that the substituent of this phenyl group is bonded to the position ortho to the bonding position with B.

Furthermore, when hydroxy is bonded to two adjacent carbon atoms of a phenyl group, those oxygen atoms may be bonded via a methylene group to form a -0-(:112-0- bond. .

In the above formula (I), B is a single bond or alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl; for example, alkyl such as methyl, ethyl, alkoxy such as methoxy, ethoxy, fluoro, chloro , aryl such as phenyl which may have a substituent such as halogen such as bromine; aralkyl such as benzyl which may have a substituent similar to the above aryl substituent on the aromatic ring; hydroxy; and oxo. represents a straight 3n alkylene group having 1 to 4 carbon atoms which may have at least one substituent selected from .

In the present invention, B in formula (I) is a linear alkylene having 1 to 4 carbon atoms which may have at least one substituent selected from the group consisting of phenyl, hensyl, hydroxy, and oxo. Preference is given to piperazine derivatives representing the group.

In the above formula (I), R is a hydrogen atom; or an alkali metal atom such as sodium or potassium; an alkaline earth metal atom such as calcium or magnesium; or a carbon atom having 1 to 6 carbon atoms such as methyl, ethyl, propyl or butyl Alkyl;
Cycloalkyl such as cyclopentyl, cyclohexyl;
Represents an atom or group selected from the group consisting of: aryl groups such as phenyl, tolyl, xylyl; aralkyl groups such as benzyl and henzhydryl. Preferably R is alkyl.

In general formula (I), n is 2 or 3, preferably 2.

In the general formula (■), a phenyl group represented by A1,
Specific examples of the substituents possessed by groups such as the ρ-benzoquinonyl group are the same as the substituents described for A in formula (I) above. Moreover, in formula (I1), the number and substitution positions of the substituents of the phenyl group and other groups represented by A1 are the same as those described for formula (I).

In formula (■), B, R1 and n are the same as described for general formula (I).

In the present invention, - AI in formula (II) has at least one substituent selected from the group consisting of hydroxy, alkoxy, acyloxy, amino, alkylamino, alkylthio, halogen, alkyl, and nitro. When representing the phenyl group, perazine derivatives are preferred.

Further, in the present invention, -A1 in formula (II) has one or more hydroxy or alkoxy as a substituent, and halogen, alkyl, fluoroalkyl,
Particularly preferred are piperazine derivatives representing a phenyl group having at least one substituent selected from the group consisting of formyl, alkoxycarbonyl, acyl, acyloxy, glycodyloxy, amino, alkylamino, mercapto, alkylthio, and nitro.

Further, in the present invention, a piperazine derivative in which AI in Formula 1) represents a p-benzoquinonyl group which may have one or more alkyl or alkoxy as a substituent is preferable.

Further, in the present invention, a piperazine derivative in which 81 in formula (TI) represents a coumarinyl group which may have one or more alkyl or alkoxy as a substituent is preferable.

In the case of compounds in which R in formulas (I) and (n) is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group, acid addition salts thereof are also included in the present invention. The above acid addition salts include hydrochloric acid, hydrobromic acid,
Examples include non-toxic salts with sulfuric acid, fumaric acid, maleic acid, tartaric acid, etc.

The compounds represented by the above general formulas (I) and (n) can be obtained, for example, by the following method.

(rV) (wherein A represents a substituent such as halogen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl, acyl, droxy, alkoxy, acyloxy, glycodyloxy, amino, alkylamino, mercapto, alkylthio, and nitro, and R' is a hydrogen atom, alkyl, cycloalkyl, aralkyl, or aryl, and n is 2 or 3.) The above general formula ([),
The Mannich reaction using general formula (■) and formaldehyde or a formaldehyde donor can be carried out under commonly used conditions.

As the piperazine derivative represented by the general formula (rV) used in the above method, an acid addition salt such as a hydrochloride may be used. As the formaldehyde or formaldehyde donor, an aqueous formalin solution, paraformaldehyde, etc. can be used. The above reaction can be carried out using water, alcohol solvents such as methanol and ethanol, organic acids such as acetic acid, ether solvents such as ether and dioxane, DMF,
This can be carried out in a polar solvent such as acetonitrile at a temperature ranging from 0° C. to the boiling point of the solvent. Furthermore, the general formula (r
An active substance obtained by reacting a piperazine derivative represented by V) with formaldehyde, for example, (wherein Ra and n have the same meanings as above).

), etc., and the compound represented by the general formula (III), the compound represented by the general formula (I) can also be obtained.

(However, in the formula, Ql is a leaving group, and AIB, R1 and n have the same meanings as defined in the surface general formula (II).) A compound represented by the general formula (V) and the general formula ( The reaction with the piperazine derivative represented by VT) is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, or triethylamine, in a solvent that does not participate in the reaction such as ethanol, acetone, methylene chloride, or DMF, starting from 0°C. It can be carried out in a temperature range up to the boiling point of the solvent. Also,
The above reaction can also be carried out without a solvent by direct heating in the temperature range of 50 to 250°C. Furthermore, Ql
Examples of the leaving group represented by include halogen atoms such as chlorine and bromine, and tosyloxy groups.

In the piperazine derivative represented by (V) (Vl) (I+□) (■), a compound in which an alkali metal or an alkaline earth metal is substituted with hydrogen is obtained.

(Vll[) (However, in the formula, M is an alkali metal or alkaline earth metal, and A', B, and n are as defined above.) The above reaction is performed using ether, chloroform, methanol, tetrahydrofuran, etc. In a solvent that does not participate in the reaction, the above -
The piperazine derivative represented by formula (VII) is treated with an alkali metal or alkaline earth metal hydroxide and carbon disulfide, and the temperature is reduced from -10°C to the boiling point of the solvent, preferably from 0 to 0.
It is carried out in a temperature range of 30°C.

In addition, when an alkali metal or alkaline earth metal hydroxide is not used in the above reaction, - formula (wherein, Q2 is a leaving group and Rb is an alkyl, cycloalkyl, aralkyl or aryl (A', B, M, and n have the same meanings as above.) The above reaction is carried out in a solvent that does not participate in the reaction, such as methanol, ethanol, DMF, tetrahydrofuran, chloroform, benzene, etc., from -10 °C to boiling point, preferably 0
It is carried out in a temperature range of ~30°C. Examples of the leaving group represented by Q2 include halogen atoms such as chlorine, bromine, and iodine, p-toluenesulfonyloxy groups, methanesulfonyloxy groups, and the like.

In addition, when using as a starting material a compound in which the alkali metal in the piperazine derivative represented by formula (■) is replaced with hydrogen, the reaction can be carried out in the same manner as described above in the presence of an alkali metal. .

(IX) The above reaction is a reaction in which the piperazine derivative represented by formula (IX) above is reacted with an ether cleavage reagent to convert the alkoxy group substituted into the group represented by A2 into a hydroxy group.

As the ether cleavage reagent, boron tribromide, hydrobromic acid, iodized trimethylsilane, pyridine hydrochloride, etc. can be used, but boron tribromide is preferably used.

When boron tribromide is used in the above reaction, it is placed in a solvent that does not participate in the reaction, preferably a halogenated alkyl solvent such as methylene chloride or chloroform, at a temperature of -70°C to 30°C, preferably -50°C to 0°C. 1 hour to S in temperature range
The reaction is carried out during R1, preferably for 5 hours to 2 days.

(However, in the formula, R1 is alkyl, i is an integer of 1 to 5, A2 represents a group other than a group having alkoxy or alkoxycarbonyl as a substituent among the groups represented by A, and B , R5 and n have the same meanings as above.) The reaction is carried out in the presence of an alkylating agent such as sulfuric acid.

(X) (XI) (wherein, R2 is alkyl or acyl,
Q3 is a leaving group, i is an integer of 1 to 5, A3 represents a group excluding a group having hydroxy as a substituent among the groups represented by A+, and B, R1 and n are the above-mentioned groups. is synonymous with ) The above reaction is a reaction in which the hydroxy group substituted on the group represented by A3 in the piperazine derivative represented by the above formula (X) is alkylated or acylated.

The above reaction involves adding an acylating agent such as acetic anhydride or sialic acid (in the formula, B1
and B2 are each a straight-chain alkylene group having 1 to 3 carbon atoms which may be substituted with an alkyl group, an aryl group, or an aralkyl group but not substituted with a hydroxy group or an oxo group, and further B1 may be a single bond (however, the total number of straight chain alkylene group ρ carbon atoms of B1 and B2 is 4 or less), R3 is a hydroxy group or a hydrogen atom, and A, R1 and n have the same meanings as above. It is.

) The above reaction is a reaction for reducing the >C═O group in the piperazine derivative represented by the above formula (XI).

The above reduction reaction involves the reduction of sodium borohydride, sodium borohydride-aluminum chloride, etc. to the piperazine derivative represented by the formula Oa) in a solvent that can be generally used for reduction, such as methanol, ethanol, THF, etc. This is done by using a drug.

and n have the same meaning as ml. ) The above reaction is a method of hydrophilic condensation of a carboxylic acid represented by the above formula (Xll) with a piperazine derivative.

The -F condensation reaction can be carried out using a general condensing agent such as dicyclohexylcarbodiimide, or a carboxylic acid can be converted into a reactive derivative thereof to be condensed with a piperazine derivative.

Further, a compound represented by general formula (I) can be obtained by the method shown below.

(X[I) (wherein, B3 is a single bond, or a straight chain alkylene group having 1 to 3 carbon atoms which may be substituted with an alkyl group, an aryl group, an aralkyl group, a bitroxy group or an oxo group; , A, Ra, and (Xllll) In the above reaction, the oxidizing agent is F e Cfl 1
In addition, nitric acid, silver oxide, lead tetraacetate, alkali dichromate, lead oxide, etc. can be used.

Next, representative compounds of piperazine derivatives represented by general formula (I) are shown in Tables 1 and 2.

Margin below Table (continued) table Table (continued) No. Table (continued) No. Table (continued) -OCR20- H H OAc　　　OAc OMe OMe H H 14H H OMe OMe Oll 011 OMQ OMQ OMe OMe OMe OMe OII Oll 011 0il OMe OMc OMe OH011 H H C.O. C.O. C.O. C.O. C112CII□ C112CI+2 (:112CIl.

C112CIl.

C1l2CIl.

CIl. C112 (:OCI+2 (:0C112 CIl (011) C1l2 0C112 C++2CO C11□CO (:112GO 112GO No.

R+ H -OCH20- H OMe OMe H OMe OMe -OCH20- H OMe OMe OMe OMe OMe OMe OMc OMe OMe OMe Oll 011 OMQ OMe OMe OMc OMe OMe OMe OMe OMe OMe H OMe OMe B nR C112Co21miL L112GO2Me CIlzCIIz(:l !22 M (NCII2C
IhClh 2 MeC1I□CI+, CO2
Lock C CIIz[:II□C02Me C112CIlzC02Et CIIOHClhCo 2 MeCIl□CI
IzCihC02Me Ct123 Me CIl2 2 Na CIl22 Na C11□ 2K CIl22 8 [1:1122 H H C1+22 15L (:ll□2 1-Pr C1+2 2 Pr (:+12 2 Cyc-flexCH ,2(:
Il□llh Table number! Table (continued) H H H HH H H -ell-C1l(:O,- -CICl1-CIIGO 2-OH 11H CIl, 2 CIIPh 2 (:l-lPh 2 CIIPhCI+2 2 CIl (C+12Ph) 2 ell. 2 CIl22 C11 □ 2 CIl22 No, R' 0) (H I Me H 2Me Me 3 Me Me 4HH 5HH 6Me Me 7 Me Me 8 OMQ OMe 9 OMQ OMe 20 OMQ OMe HCH2 HCH2 HCH2 Me CH2 HC112CIl□ H(:lI□CO Me CH2 Me CH2 Me CH2 Me CH2 CRel12ell□C112 2Me 2 Me 2 Me 2 Me 2 Me 2 Me 3 Me 2 Pr 2 Me 2 (River 21) h 2 Me (Note) In Tables 1 and 2, the meanings of the symbols are It is as follows.

Me: methyl, Et: ethyl, Pr: propyl, Cyc
-Hex dichlorohexyl, Ph: phenyl, AC niacetyl, Glu: glucopyranosyl.

Next, pharmacological experiments of the compound of the present invention to inhibit lipid peroxide production and to inhibit deviation of GOT and GPT in an in vivo acute liver injury model will be shown.

Supportive yin.” The method of Ui et al. (Hiroshi Oka, Rio Ui,
! 2. Released Cells - Experiments and Applications 9.91). For the lipid peroxidation reaction, dead line 1θ, which was stored frozen at −85° C. and thawed before use, was used.

50μt of hepatocyte suspension (protein content 0.5~!, Omg) was placed in a centrifuge tube, 5μk of a DMSO solution of the test compound was added, and then 50μt of 40mmol ADP solution in ti50μ2 and 4 was added.
After adding 50 μm of a millimolar NADPH solution, 350 μm of a 0.5 mol Tris-HCl buffer (pH 7,4) was added and the mixture was shaken at 37° C. for 1 hour. The reaction was stopped by moving the centrifuge tube into ice water, and 0.2 mu of 8.1% SDS solution, BHT
50 ul of ethanol solution (5000 ppm), 1.8 mff of 20% acetic acid (pH 3,5), and 1.5 mQ of 0.8% TBA solution (pH 3,5) were added. Centrifuge tube 95-9
The mixture was transferred to a water bath at 8°C and heated for 1 hour to develop color. The degree of inhibition (%) of the test compound against the lipid peroxidation reaction was determined by the following formula by measuring the absorbance at 530 nm by cold welding and centrifugation.

In addition, the control group received DM instead of the test compound solution.
Only SO was used.

The results are shown in Table 3. Test compound N in Table 3
o indicates the compound number listed in Tables 1 and 2.

Test compound No.

Table 3 Inhibition degree (%) Final test compound concentration 10-’M 10-5M 90.

92.

89.

74.

88.

72.

71° 73.

87.

74.

96.

98.

96.

88.

58° 44.

39.

71.

69.

95.

97.

From Experiment 1, it was revealed that the piperazine derivative compound of the present invention has an excellent inhibitory effect on lipid peroxide production in an in vitro manner.

Inhibition of GOT and GPT deviations in an in vivo CCl1.4 acute liver injury model. 50% CCCCl14 dissolved in olive oil was administered to 170-180 g Wistar male rats fasted for 24 hours.
1/kg was orally administered to induce acute liver damage. The test compound was administered at a dose of 3 omg/kg over a 3-hour period of ccn4 absorption. 1.0 instead of the test compound for the control group.
% methylcellulose (MC) and CCjZ4 for the normal group.
Instead, olive oil was administered orally. CCf1. 24 hours after administration, the rat was anesthetized with ether, blood was collected from the abdominal vena cava, and the collected blood was centrifuged at 3000 r, p, IIl for 10 minutes, and then plasma was collected. GO who is salivating
T and G P T (Karmen method) were measured using an autoanalyzer (■705). The test compound is 1.
It was used after being suspended in a 0% MC solution.

The effect of the test compound in the acute liver injury model was determined by
, was determined based on the GPT increase suppression rate.

The results are shown in Table 4. In Table 4, *** is 9
0% to 100%, ** is 60% to less than 90%, * is 30
% to less than 60% inhibition.

Further, the test compound No. indicates the compound No. listed in Tables 1 and 2.

Incidentally, the increase suppression rate (%) of GOT and GPT was determined by the following formula.

Test compound No.

Table 4 Increase suppression rate (%) GOT GPT * * ＊　＊ ＊＊＊ ＊＊＊ ＊＊＊ ** ** ** ＊＊＊ * ＊＊＊ ＊＊＊ ** ** * ＊　＊ ＊＊＊ ＊＊＊ ＊＊＊ * ＊　＊ * ＊＊＊ * ＊＊＊ ＊＊＊ ＊　＊ ＊　＊ Test compound No.

Table 4 (continued) Increase suppression rate (%) GOT ＊　＊ ＊＊＊ ＊＊＊ ＊　＊ ＊　＊ ＊＊＊ ＊　＊ ＊　＊ ＊　＊ ＊＊＊ ＊＊＊ ＊＊＊ ＊　＊ ＊＊＊ GPT ＊　＊ ＊　＊ ＊＊＊ * ＊　＊ ＊　＊ * ＊　＊ ＊　＊ ＊　＊ ＊　＊ ＊＊＊ ＊＊＊ ＊　＊ ＊＊＊ Test compound No.

Table 4 (continued) Increase suppression rate (%) GOT G PT 67 *
*6B **
**71 **
*73 **
**75
** **93
＊＊＊ ＊＊＊100
*110
＊＊＊ ＊＊＊1
13 ***
**118 **
*CCl1. When liver cells are damaged by administration, enzymes are released and various enzyme activities appear in the serum. Therefore, measuring the activity of serum transaminase as an indicator of liver damage is a behavioral method. It was measured as an index.

As shown in Experiment 2, the piperazine derivative of the present invention inhibits GOT and GPT, which are indicators of liver damage.
It was suppressed to 4-g.

The pharmacological experiments described in F-F showed that the piperazine derivative of the present invention exhibited excellent A-oxidized lipid production inhibiting activity and in vitro
It was found to have the effect of suppressing deviation of GOT and GPT in a model of acute liver injury of VO.

Regarding the toxicity of piperazine derivatives in the present invention, for example, Compound N014 listed in Tables 1 and 2
．． 5.22.23.32.33.38.75, and 11
Compound No. 3 caused no deaths when administered orally at 1600 ng/kg.

The liver disease therapeutic agent of the present invention is usually in the form of a pharmaceutical composition together with a pharmaceutical carrier. As carriers, fillers, binders,
Diluents or excipients such as disintegrants and lubricants are used. In addition, the dosage forms include injections, powders, capsules,
It can be in any form such as granules or tablets. Administration 1
j1 depends on the severity of the patient's symptoms, but usually the piperazine derivative of the present invention is about 10 mg to 1 g.
may be administered to the patient.

As mentioned above, the piperazine derivative of the present invention has excellent lipid peroxide production inhibiting action and in vivo CC, Q4
It has the effect of suppressing the deviation of G OT and G PT in acute liver injury models, and is useful as a therapeutic agent for liver diseases, an anti-inflammatory agent, an anti-rheumatic agent, a therapeutic agent for gastrointestinal tract disorders, and especially a therapeutic agent for liver diseases.

Next, the present invention will be explained in more detail with reference to Examples. In each Example, the compound numbers listed after the compound information are the compound numbers shown in Tables 1 and 2 above.

[Example 1] i) 3.4. 5-t'mexybenzyl chloride 3.4
．． 10 g of 51-rimethoxybenzyl alcohol was dissolved in 40 ml of benzene, and 10 ml of a benzene solution containing 7.6 g of thionyl chloride was added dropwise on a water-cooled solution.
Stir for 5 minutes. The reaction solution was poured into a cooled aqueous potassium carbonate solution, and the benzene layer was separated. After washing the benzene layer with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 11.0 g of the title compound as a yellow solid.

Piperazine 611□04.48g and 1 ethanol
0mfi mixture was heated to 65-70℃ to make a homogeneous solution, and piperazine・211[[・11□04.0
3. Add 9 g and 5 rnfi of ethanol and stir at the same temperature.
5.0 g of 4.5-trimethoxyhensyl chloride and 15 m2 of ethanol were added at once. After further stirring for 30 minutes at 65-70°C, the mixture was cooled on ice. After filtering out the precipitated insoluble matter and concentrating the mother liquor, an ethanol solution of 6N hydrochloric acid 8+nJ2
was added and stirred for 30 minutes under water cooling. The precipitated crystals were collected by filtration, washed with ethanol, and dried to obtain the hydrochloride of the title compound.

This hydrochloride was dissolved in 15 m2 of water, made alkaline with IN sodium hydroxide, and extracted 7 times with chloroform under salting out. After drying the chloroform layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain the title compound as a slightly yellow crystalline powder.4.
93g was obtained.

1 (Compound No. 89) Ether suspension of 4.9 g of 1-(3,4,5-trimethoxybenzyl)piperazine 50 mf1. A solution of 1.01 g of sodium hydroxide in 1.5 ml of water was added to the solution under water cooling.
Ether solution of carbon disulfide 1.818 13mf at the same temperature
t was added dropwise. The mixture was stirred at room temperature overnight, and the precipitated crystals were collected by filtration and washed with ether. Drying under reduced pressure gave the title compound as a white powder 6. 67g was obtained.

m, p, 119-122°C IH-NMR (CD30D) δ: 2.30-2.60 (m, 4H) 3.46 (s, 2H) 3.76 (s, 3H) 3.84 (S, 6H) 4.3-4.6 (m, 4H) 6.64 (s, 2H) IRv:'4x (cm-'): 33B0, 1590, 1460, 1420° 1220.
1130° [Example 2] Thorium 4- (3,4,
5-) Dissolve 6.67 g of piperazine carbodithioate in methanol (&
To 70 ml, add 20 mfi of a methanol solution of 2.6 g of methyl iodide under water cooling over 20 minutes at MFL at the same temperature.
Stir for hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in water and extracted with chloroform. The chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting assembly was purified by silica gel column chromatography to obtain 3.7 g of the title compound as pale rose-colored crystals.

HNMR(CDCl3)δ:2.40-2.
60 (m, 4H) 2.66 (s, 3H) 3.46 (s, 2H) 3.84 (S, 3H) 3.86 (s, 6H) 3.9-4.3 (m, 4H) 6.55 (s, 2H) MS (Ql/e) 356 (I4”), 341,3
09ii) Methyl 4- 3.4°5-trimethoxybe LILM (Compound No. 41) m, p, 212.5-214°C (decomposition) H-NM
R (CD30D) δ: 2.65 (s, 3H) 3.1-3.7 (m, 6H) 3.78 (s, 3H) 3.90 (s, 6H) 4.33 (3,2H) 4.9-5.5 (m, 2H) 6.94 (s, 2H) l Rv2g', (Cm-'): 2400.1590,1460,1420°1325.
1270,1250.1120950.

[Example 3] 2.6 ml of boron tribromide was added to 100 mj2 of methylene chloride and cooled to -40°C. 50ml solution was added dropwise over about 30 minutes. The reaction mixture was gradually warmed up, stirred overnight at room temperature, and then water was added little by little under water cooling. The deposited precipitate was collected by filtration, washed successively with water and acetone, and dried under reduced pressure at room temperature. This was dissolved in a small amount of methanol, water was added, and the precipitate precipitated was collected by filtration and dried under reduced pressure to obtain 450 mg of the hydrobromide salt of the title compound as a pale red powder.

m, p, 158-160℃ (decomposition)'H-NMR
(CDJOD) δ: 2.64 (S, 3H) 3.0-3.7 (m, 6H) 4.16 (s, 2H) 4.8-5.6 (m, 2H) 6.53 (s , 2H) Compound number 40) fRv'4':: (cm-') :3125.
1625. 1545. 1450°1420, 13
40. 1255. 1025° [Example 4] 4-3.4.5-1-rimethoxybenzyl)-1-vivazin (Compound No. 108) 3.4.
1.40 g (4.13 mmol) of 5-1-lyftoxybenzyl-1-piperazine dihydrochloride was dissolved in a 10% aqueous sodium hydroxide solution and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was removed. By distilling off, 933 mg of free amine was obtained as white crystals (yield: 9
0.3%).

Dissolve this in 3 ml of methanol and add 0.25 ml of carbon disulfide.
After adding mfl (4.1 mmol) dropwise, the mixture was stirred at room temperature for 1 hour.

Insoluble matter was filtered off and washed with methanol to obtain a pale yellow powder, which was dried under reduced pressure to obtain 1260 mg of the title compound (yield 98.7%).

m, p, 171-174℃ (decomposition) H-NMR (
DMSO-d6) δ: 2, 9-4. 0
(m, 8H)3, 64. 3. 77 (ea
chs, 9H) 4, 1-4. 6 (m,
2H) 6, 4-6. 8 (m, 2H)8,
2-9. 6 (br, IH)' Rum enemy;
(Cm-'): 3400, 2980. 29
60. 2920°2895, 2820. 2645
．． 2575°2500, 1585. 1495.
1460°1440, 1435. 1420. 13
80°1360, 1350. 1340. 1320
゜1250, 1240. 1230. 1200°1
175, 1150. 1120. 1100°106
0, 1020. 1005. 990°980, 9
60. 940. 915. 835°820.

[Example 5 Comethyl 4-3.4 5-lyacetoxybenzyl
-1-Pivasinolupodithioate (Compound No. 42
) Methyl 4-(3,4,5-trihydroxybenzyl)-1-piperazinecarbodithioate 395mg (
To this suspension was added 0.22 mj2 of acetyl chloride (3,1 mmol) under water cooling.
mmol) and stirred. After stirring at room temperature overnight, water was added and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography and crystallized from ether to obtain 249 mg of white crystals as the title compound (yield 63.4%).

rn, p, 141~b 'H-NMR (CDCM,) δ: 2.27 (s, 9H) 2.35-2.65 (m, 4H) 2.66 (s, 3H) 3.51 (s, 2H) 3, s ~ 4.4 (m, 4H) 7, f O(s, 2.H) IRvUni; 2930° 1495° 1215° 1165° 890.

[Example 6] (cm”'l): 2905, 2800°1470, 1420°1205, 1200°1130, 1045°1775°1360°1180°1000° (Compound No. 21) 4-acetoxyphenol 152 mg, methyl 1- 211 mg of piperazine carbodithioate and 36 mg of paraformaldehyde were added to chloroform 5rnjZ and refluxed for 4 hours. After cooling with water, chloroform was added,
After washing with water and saturated brine, it was dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and ethanol was added to the obtained oil to crystallize it, which was collected by filtration to obtain 224 mg of white crystals as the title compound (yield: 65.9%).

m, p, 124°C 'HNMR (CDCIIs) δ22, 24 (s, 3H) 2, 66 (s, 3H) 2, 3~2. 8 (m, 4H)3, 68
(s, 2H) 4, 0-4. 4 (m, 4H)6, 6~7
．． 0 (m, 3H)IRv'442 (cm-
'): 2810, 1750. 1490. 1425°13
70, 1250. 1230. 1215°1195
, 1145° [Example 7] Compound No. 32) 353 mg (2.0 mmol) of methyl 1-piperazine carbodithioate was added to a mixture of 0.15 ml (2.0 mmol) of 37% formalin and 4 ml of methanol with stirring. 2 mu of methanol solution was added dropwise. After adding 253 mg (2.0 mmol) of pyrogallol to this, the mixture was stirred overnight at room temperature in the dark. The precipitated solid was filtered, the filtrate was collected, and the solvent was distilled off. Add chloroform to the residue,
After removing insoluble matter, the solvent was distilled off. The obtained solid was washed with hot ethanol to obtain 210 mg of the title compound as a light brown powder (yield: 11.1%).

H-NMR (DMSO-d6) δ: 2.49 (S, 4H) 2.56 (s, 3H) 3.51 (s, 2H) 3.7~4.3 (br, 4H) 6.1~ 6.4 (m, 2H) 8.1-8.9 (br, 3H) [Example 8] 4- 3.4.5-Trihydroxybenzyl 1-vivazinylbodithio (Compound No. 109) Under nitrogen atmosphere, 4-(3,4,5-trimethoxybenzyl)-1-
1033 mg (3.02 mmol) of piperazinecarbodithioic acid was suspended in dry methylene chloride and placed on dry ice.
Cool to -78°C in an acetone bath, and add 3 boron tribromide to this.
50 mj2 of a ml methylene chloride solution was added dropwise. The mixture was gradually warmed to room temperature and stirred at room temperature for 5 days. After adding water to the reaction mixture, insoluble matter was filtered, and after washing with water, the obtained yellow solid was dissolved in methanol, and after removing the insoluble matter, the solvent was distilled off. Ether was added to the obtained beef oil, and insoluble matter was filtered off, followed by drying. This was subjected to cellulose column chromatography (Avicel 7' butanol:acetic acid:water = 1
After distilling off the eluate, ether was added and insoluble crystals were filtered to obtain 103 mg of the title compound (yield: 11.4%).

m, ρ, 250°C or higher'H-NMR (DMSO-d6) δ: 2.8 to 4.3
(m, 10H) 6.38 (s, 2H) 8, 0-9. 5 (br, 4H)IRv22
H (cm-') 3400, 3325°2920, 2B40°2550, 1610°1430, 1395°1300, 1235°1150, 1070°940, 860° [Example 9] 3105°2760°1 53 0゜1380゜1190゜103 5゜3000゜2700゜1450゜1330゜1160゜1005゜Compound No. 34) Suspend 50 g of methyl 4-(2,3,4-1-lihydroxybenzyl)-1-piperazine carbodithioate in 520 mA of chloroform. 97.3 g of water-cooled acetic anhydride was added dropwise to the solution over 15 minutes, and then 1
Stir for hours. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. Ethyl acetate 250rr+JZ was added to the residual oil to crystallize it, and after stirring for 1 hour, the crystals were collected by filtration and washed with ethyl acetate to obtain 48.8 g of white crystals of the title compound (yield 69.7). %
).

m, p, 148-150℃ (decomposition)'HNMR (
CDCIs) δ: 2.27 (s, 9H) 2.3-2.6 (m, 4H) 2.65 (s, 3H) 3.44 (s, 2H) 3.8-4.3 (br, 4H) 7.13 (d, IH, J=8.6Hz) 7.28 (
d, IH, J=8.6Hz) I Rv 22w (C
m −' ) '2900.2800.1760,14
50°1420.1360,1260,1210°11
70.1050, 1oio, 910°880.820,
770° [Example 10] i) Benzyl 1-vivadine luposithioate l-
Piperazinecarbodithioic acid 3.0g1. m, methanol 9mff1 and sodium hydroxide 0.8g in water 1.2m
! 1 of the solution was added and stirred for 10 minutes. Methanol and water are distilled off under reduced pressure at below 50°C, and the residue is left with methanol.
9 m IL was added. 3.1 g of benzyl bromide was added dropwise to the solution over 20 minutes while cooling with water, and the mixture was further stirred at room temperature for 15 minutes. Insoluble matter was filtered off, the filtrate was distilled off under reduced pressure, and then extracted with ether. This ether solution was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.13 g of the title compound as a pale yellow oil.
was obtained (yield 67.0%).

' H-NMR (CD CJZ 3 ) δ: 1.7
2 (s, IH) 2.6-3.1 (m, 4H) 4.05 (br, 4H) 4.57 (s, 2H) 6.9-7.6 (m, 5H) I RvQ'5Ht (Cm-'): 2950.2900,1460,1420°1250,
1220. 1130. 1020°980, 75
0. 700° above (compound number 100) 35% formalin 0.51g to ethanol 7.7mJ!
Benzylnipiperazine carbodithioate under water cooling in a solution dissolved in! , 5g dissolved in 7.5mjZ of ethanol was added and stirred at room temperature for 10 minutes, and then 3.7g of pyrogallol was added to the solution under cooling with water and 15.3m of ethanol was added.
The solution dissolved in JZ was added at once and stirred at room temperature for 2.5 hours.

Ethanol was distilled off under reduced pressure, and the residue was extracted with dichloromethane. This dichloromethane solution was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.17 g of the title compound as a pale red powder (yield: 9
2.9%).

m, 9. decomposed at 125-126℃)' H-N M
R(CDCl3)δ:2, 4-2-
8 (m, 4H)3, 64 (s, 2
H) 4, 14 (br, 4H) 4, 52 (s, 2H) 6, 11 (br, 3H) 7, 0-7. 4 (m, 7H) [Example 11
] 4-2.3.4-1 Rimethoxybenzyl-1-vivazine tribodio (Compound No. 93) 985 mg (3.7 mmol) of trimetazidine was dissolved in 10 ml of methanol.
0.23 mf of carbon disulfide was added to the solution under stirring at room temperature.
It was added dropwise in 5 minutes. Further, the mixture was stirred at room temperature for 5 hours. The precipitate was filtered and washed with methanol to yield the title compound 1. zg
(yield 87.4%).

m, p, 148-150°C (decomposition) 'H-NMR (DMSO-d,) δ: 2.2-2.7 (m, 4H) 2.9-4.0 (m, 4H) 3,75 (s, 3H) 3. 78 (s, 3H) 3, 80 (s, 3H) 4, 1-4. 6 (m, 2H) 6.6~7,
1 (m, 2H) 8, 2-9. 4 (br, IH)■ RVr
sL (Cm-'): 2975, 2900.
2810. 2780°2700, 1600. 14
90. 1460°1440, 1410. 1380
．． 1350°1320, 1290. 12B0.
1250°1230, 1200. 11B0. 10
90°1040, 1000. 960. 940°9
20, 890. 850. 800. 780°75
0, 690° [Example 12] Hardware No. 33) Under an atom atmosphere, 2.0 g of 4-(2,3,4-trimethoxybenzyl)-1-piperazinecarbodithioic acid, 0.26 g of granular sodium hydroxide, and methanol 3m
1 liter was mixed and stirred at room temperature until the reaction solution became homogeneous. A solution prepared by dissolving 0.39 ml of methyl iodide in 2.4 mf of methanol was added dropwise to the solution under water cooling. After the dropwise addition was completed, the mixture was stirred at room temperature for 2.5 hours, and the solvent was distilled off under reduced pressure.

Chloroform and water were added to the residue to separate the chloroporm layer, which was washed with saturated brine and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure to obtain 2.0 g of a white powder as the title compound (yield 97.9%).
.

'H-NMR (CDC13') δ: 2.4-2.7 (m, 4H) 2.65 (s, 3H) 3.51 (S, 2H) 3.86 (s, 3H) 3.87 ( s, 6H) 3, 8~4.3 (m, 4H) 6.63 (d, IH, J=8.6Hz) 6, 97
(d, IH, J=8.6Hz) Methyl 4-
After 9 ml of an ethanol solution of IN hydrochloric acid was added dropwise to 1.6 g of (2,3,4-trimethoxybenzyl)-1-piperazine carbodithioate under water cooling, the mixture was stirred at room temperature for 3 hours.

The precipitated crystals were collected by filtration and washed with ethanol to obtain 1.5 g of a white powder as the title compound (yield: 87.3%).

m, p, 182-184℃ (decomposition)' H-N
M R (CD Crt 3 ) δ: 2.65 (s, 3
H) 2.6-3.1 (m, 2H) 3.2-3.8 (m, 2H) 3.87 (s, 3H) 3.88 (S, 3H) 3.95 (s, 3H) 3.9-4.2 (m, 2H) 4, 22 (br, 2)i) 4, 8-5. 4 (rn, 2H)6, 7
(d, IH, J=8Hz) 7, 42 (d
, LH, J=8Hz) IRv'74':: (c
m-'): 2900, 2450. 1600.
1500°1460, 1400. 1300. 12
70°1220, 1120. 1100. 1020
゜960゜, 820゜[Example 13] 1 (Compound No. 96) Sodium 4-(3,4,5-1rimethoxybencyl)-1-biperazine luposithioe-]・364 mg
was suspended in 2 ml of ethanol, and 20 ml of isopropyl iodide was added.
4 mg was added and the resulting homogeneous solution was stirred at room temperature overnight. Ethanol was distilled off under reduced pressure, ether and water were added to the residue, and the ether layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 270 mg of a colorless oil as the title compound (yield 70.3%).
.

'H-NMR (CDCJZ3) δ: 1.41 (d, 6H, J=7Hz) 2.3-2.7 (m, 4H) 3.45 (s, 2H) 3, (3and 3.85 (eachs , 9H)
3.9 to 4.6 (m, 5H) 6.54 (s, 2H) 250 mg of the above compound was dissolved in 2 ml of chloroform, 2 ml of a methanol solution of IN hydrochloric acid was added, and then evaporated under reduced pressure, and the residue was dissolved in ethanol/ The crystals were crystallized from diethyl ether, collected by filtration, and washed with cooled ethanol and diethyl ether to obtain 230 mg of white crystals as the title compound (yield: 84.1%).

m, p, 2 1 0 to 2 1 2°C blind H-
NMR (CDC) fis δ: f, 44
(d, 6H, J=8Hz) 2, 5-3. 1
(m, 2H)3, 3-4. 4 (m, 7
H) 3, 84 and 3. 92 (ea
ch s, 9H) 5, 0-5. 4 (m,
2H) 6, 94 (s, 2H) I RVW'A;(cm-'); 2510,
2410. 1590. 1455°1425, 1
400. 1330. 1275°1255, 112
0. 945° [Example 14] (Compound No. 20) 1.05 g of 37% formalin was added to 20 ml of ethanol, and then methyl ! was added under water cooling. -2.29 g of piperazine carbodithioate was added and stirred at room temperature for 30 minutes. 1.24 g of 4-methoxyphenol was added, and the mixture was heated under reflux overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained oil was crystallized by adding 10 ml of ethanol, collected by filtration, and washed with ethanol to give the title compound as white crystals.
．． 06g (yield 34%) was obtained.

m, p, 112°C' H-NMR (CD CIL3) δ: 2.65
(s, 3H) 2.5-2.8 (m, 4H) 3.68 (s, 2H) 3.73 (s, 3H) 3.9-4.4 (m, 4H) 6.4-6 .9 (m, 3H) 9.5 (br, IH) 'R'm2;(Cm-'); 1490.1420,1255,1225°1210.
1035,995,870°735° [Example 15] (Compound No. 16) Methyl 4-(5-acetoxy-2-hydroxybenzyl)-1-piperazine carbodithioate (compound synthesized in Example 6) 10.6 g was suspended in 38 ml of ethanol, and 53 ml of concentrated hydrochloric acid was added at room temperature under nitrogen. After the crystals were dissolved, insoluble matter was removed by filtration, and after washing the insoluble matter with 4 nnJZ of ethanol, the obtained light brown filtrate and washing liquid were stirred at room temperature for 20 hours. The resulting suspension was stirred at 80°C for 3 hours and further stirred at room temperature for 8 hours. The crystals were collected by filtration and washed with ethanol to give the title compound 6 as a light brown crystalline powder.
．． 34g was obtained.

m, P, 200-202℃ (decomposition) H-NMR (
CD30D) δ: 2.65 (s, 3H) 3.1-3.5 (m, 4H) 4.30 (3,2H) 4, 0-4. 7 (m, 4H)6. 6-6
．． 9 (m, 3H)IRvnyl (cm-')
: 3200, 3000. 2830°2580, 1500. 1450°1415, 13B0. 1335°1260, 1230. 1200°950, 835. 825° [Example 16] 2700° 1435° 1320° 1190° (Compound No. 18) 0.86 g of 35% formalin was dissolved in 10 mfl of ethanol, and 2.35 g of methyl 1-piperazine carbodithioate was added to the solution under water cooling. A solution dissolved in 5 ml of ethanol was added dropwise, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution was added a solution of 124 g of 2-methoxyphenol dissolved in 5 m2 of ethanol under water cooling, and the mixture was heated under reflux overnight. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with 5 mfl of ethanol to give the title compound as a white powder.
4g (yield 45.9%).

m, p, 151-152℃ (decomposition)'H-NMR
(CDCI3') δ: 2.3-2.8 (m, 4) 2.65 (s, 3H) 3.75 (s, 2H) 3.87 (s, 3H) 4.2 (br, 4H ) 6.4~6.9 (m, 3H)! 0 (br, 4H) IRvWaS (cm-'): 3450.2580,1580,1460°1420.
1230.1140,1070゜990.960,83
0,770,730° [Example 17] Perazine carbodithioate (Compound No. 44) 35%
0.86 g (I0 mmol) of formalin aqueous solution was dissolved in 10 mM ethanol, and 1.94 g (I0 mmol) of methyl 1-piperazine carbodithioate was dissolved in a water bath.
A solution of 90.7% purity dissolved in 4 ml of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. A solution prepared by dissolving 2.12 g (I0 mmol) of propyl gallate in 4 mj2 of ethanol was added dropwise to this solution in a water bath, and the mixture was stirred overnight at room temperature and then heated under reflux for 4 hours. After cooling to room temperature, the precipitated crystals were filtered and washed with ethanol to obtain 1.843 g of the title compound as an off-white powder (yield: 31.3%).

m, p, 142-144°C (decomposition) H-NMR (CD CIt3) δ: 0.99
(t, 3H, J=7Hz) 1.5-1.9 (m, 2H) 2.4-2.8 (m, 4H) 2.66 (s, 3H) 3, 9-4.4 (at , 8H) 5.0 to 5.6 (br, 3H) 7.08 (s, IH) IRv redundancy 1460° 1230° [Example 18] (cm-'): 2960, 1700. 1600°1420, 1340. 1260°1100, 980. 780° ester (Compound No. 35) 0.86 g of 35% formalin was dissolved in 10 ml of ethanol, and 235 g of methyl 1-piperazine carbodithioate was added to the solution in 5 ml of ethanol under cooling with water. A solution dissolved in was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution, 1.54% of 2.3-dimethoxyphenol was added under water cooling.
A solution prepared by dissolving 1.g in 5 mL of ethanol was added thereto, and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and after purification by silica gel column chromatography, 10 mB of ethanol was added to crystallize, and the crystals were collected by filtration. Washing with ethanol gave the title compound as pale yellow crystals 1.
76 g was obtained (yield 51.5%).

m, p, 113°C (decomposition) 'H-NMR (CDCffi3) δ: 2, 4
~2. 9 (m, 4H)2, 66 (s,
3H) 3, 69 (s, 2H) 3, 84 (s, 3H) 3, 88 (s, 3H) 4, 2 (br, 4H) 6, 35 (d, IH, J=8H2) 6, 6
4 (d, I H, J = 8Hz) Methyl 4-(
3,4-dimethoxy-2-hydroxybenzyl)-1-
Piperazine carbodithioate o, 5g in chloroform! 1.46 mL of an ether solution of I NHCIt was added dropwise to the solution under water cooling, and the mixture was stirred at room temperature.

The precipitated crystals were collected by filtration and washed with 6 m2 of ether to obtain 0.53 g of white powder as the title compound, yield 95.9.
%).

m, p, 204-205℃ (decomposition)' H-NM
R(CD C11,3/CD30D)δ:2
．． 66 (s, 3H) 2.8-3.2 (m, 2H) 3.4-4.2 (m, 4H) 3.86 (s, 3H) 3.88 (s, 3H) 4.28 ( s, 2H) 4.9-5.4 (m, 2H) 6.55 (d, IH, J=8.8Hz) 7.25 (
d, IH, J=8.8Hz) IFt vW! ! s
(cm-') :3420.2920,2350,16
20゜1510.1480,1420,1280゜12
20.1100,1030,950°790.

[Example 19] 0.86 g of 35% formalin was dissolved in 10 ml of ethanol, and a solution of 2.35 g of methyl 1-piperazine carbodithioate dissolved in 4 ml of ethanol was added dropwise to the solution under water cooling, followed by stirring at room temperature for 30 minutes. did. To this reaction solution, 2.82 g of phenol was added to 4 ml of ethanol under water cooling.
After adding the solution dissolved in 1 liter of water and stirring at room temperature for 3 hours, the mixture was further heated under reflux overnight. After cooling to room temperature, about 5 ml of the solvent was distilled off under reduced pressure, 5 ml of ether was added to the residue, and the precipitated crystals were collected by filtration and washed with 15 ml of ether to obtain 1.63 g of crude crystals of the title compound.

The crude crystals were dissolved in chloroform, ethanol in an amount twice that of chloroform was added to the solution, and the precipitated crystals were collected by filtration to obtain 0.95 g of white crystals as a compound (yield: 33.4%). ).

m・2. 147°C'H-NMR(CDCl3)δ:
2, 5~2.8 (m, 4H) 2, 66 (s, 3H) 3, 73 (S, 2H) 4, 2 (br, 4H) 6.7~7.3 (m, 4H) IRv' 42: (Cm-') :3400.28
20. 1580, 1420° 1270.1250.
1220,980° 920, 750° [Example 20] Product number 15) Catechol 1.10 g, methyl l-piperazine carbodithioate 2.11 g, paraformaldehyde 0.3
6 g and 10 m2 of chloroborum were mixed and heated under reflux overnight. After cooling to room temperature, impurities were removed, and the chloroform layer was washed with water, then with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography, and then crystallized from ethanol. The obtained crystals were 1; 09
g was dissolved in 4 ml of chloroform, 8 ml of ethanol was added, and the precipitated crystals were collected by filtration to obtain 0.94 g of white crystals as the title compound (yield: 34.6%).

Methyl 4-(2,3-dihydroxybenzyl)-1-
250 mg of piperazine carbodithioate in 3 parts of acetone
ml of water, and add 1.0 mL of INHCl to the solution under water cooling. 0.84 ml of an ether solution was added thereto, and the mixture was stirred at room temperature. The solvent was distilled off under reduced pressure, 2 m2 of acetone was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration and washed with 4 mfL of acetone to obtain 213 mg of the title compound as a white powder, yield 76.2. %).

m, p, 187-189℃ (decomposition)'HNMR (
CD3 0D n a: 2, 65 (s,
3H) 3.1-3.6 (br, 6H) 3.8-5.
1 (m, 2H) 4.40 (S, 2H) 6, 6~7.0 (m, 3H) T RVW2S
(cm-'): 3460.3260. 2580. 1600°148
0, 1400. 1280. 1240°1210,
980. 730° [Example 21] Sanji (Compound No. 43) 0.86 g of 35% formalin was dissolved in 10 mL of ethanol, and 2.35 g of methyl 1-piperazine carbodithioate was dissolved in 4 mL of ethanol to the solution under water cooling. The solution was added dropwise and stirred at room temperature for 30 minutes. To this reaction solution was added 1.54 g of 2°6-simethoxyphenol under water cooling.
A solution of g dissolved in 4 ml of ethanol was added, stirred at room temperature for 1 hour, and then heated under reflux for 38 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with ethanol to obtain 1.94 g of white crystals as the title compound (yield: 56
．． 7%).

'H-NMR (CD CIL3) δ: 2.3~
2.7 (m, 4) 1) 2.66 (s, 3H) 3.45 (s, 2H) 3.87 (s, 6H) 4.1 (s, 4H) 5.59 (3, IH) 6.55 (s, 2 summer 1) Methyl 4-(3,5-dimethoxy-4-hydroxybenzyl)-1-piperazinecarbodithioate 500m
Dissolve g in 4 mu of chloroform and add to INHCJ under water cooling.
1.46 mJ2 of an ether solution of Z was added dropwise. The solvent was distilled off under reduced pressure and 8 mf of ethyl acetate was left behind! , and stirred overnight at room temperature. The precipitated crystals were collected by filtration to obtain 529 mg of a white powder as the title compound (yield 95.9%).

m, P, 187-188℃ (decomposition)'H-NMR
(CD300) δ: 2.65 (s, 3H) 2.9-4.1 (m, 4H) 3.89 (s, 6H) 4.29 (S, 2H) 4.1-4.9 (m , 2H) 4.9-5.5 (, m. 2H) 6.87 (s, 2H) rRv'4g;(crn-'); 3400.31
00,2520,1610°1510.1460,14
20,1330°1270.1240,1210,11
10°940.

[Example 22] Dithioate (Compound No. 38) 0.86 g of 35% formalin was dissolved in 10 mL of ethanol, and a solution of 1.94 g of methyl 1-piperazine carbodithioate dissolved in 4 mM of ethanol was added dropwise to the solution under water cooling. and stirred at room temperature for 30 minutes. Add 1.52 g of vanillin to this reaction solution under water cooling and add 4 mj2 of ethanol.
After adding the solution dissolved in and stirring at room temperature for 40 minutes,
The mixture was further heated under reflux for 10 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with ethanol to obtain 2.58 g of white crystals as the title compound (yield: 75.8%).

m, p, 144-145℃ (decomposition) H-N M
R(CD Cl 3 ) δ: 2.4 to 2.8 (m, 4
H) 2.66 (s, 3H) 3.84 (s, 2H) 3- 95 (s, 3H) 3, 9-4. 4 (m, 4H)7, 1~7
．． 4 (m, 2H)9, 78 (s,
IH) I Ru2'42 (Cm-1).

3350, 2800. 1660. 1590°14
90, 1450. 1420. 1300°1240
, 1190. 1140. 1060°990, 9
20. 860. 710 [Example 23] Oate (Compound No. 106) 37% formalin 0.375 in 10 mft of methanol
rnJZ was added, 882 mg (5 mmol) of methyl 1-piperazine carbodithioate was added thereto, then 891 mg (5 mmol) of nisfletin and 5 mfi of methanol were added, and after stirring at room temperature for 2.5 hours, the mixture was further stirred for 18 min.
The mixture was heated to reflux while stirring for an hour. After the reaction was completed, it was cooled, and the precipitate was filtered and washed with methanol, ethanol, and n-hexane to obtain 1.36 g of the title compound (yield: 74.
3%).

'H-NMR (CDCffi3) δ: 2.67 (s, 3H) 2.40-2.90 (m, 4H) 3.90-4.40 (m, 4H) 4.11 (S, 2H) 6 .22 (d, IH) 6.92 (s, IH) 7, 57 (d, IH) s, 17 (5,2H) The above compound was dissolved in a mixture of methanol and chloroform, and a hydrogen chloride gas-methanol solution was added. In addition, the hydrochloride salt was obtained.

m, p, 217-220℃ (decomposition)'H-NMR (
CD, 00) δ: 2.64 (3,3H) 3.00-3.60 (m, 4H) 4.53 (S, 2H) 4.00-4.60 (m, 4H) 6.21 ( d, IH) 7.09 (s, IH) 7.83 (d, IH) IRv'4g;(cm-'): 3600-2300, 1700, 1610° 1570,
1400. 1290. 1260° 1210° [Example 24] Compound No. 107> 10 ml of methanol and 0.375 ml of 37% formalin
0.88 g (5 mmol) of methyl l-piperazine carbodithioate was added to the mixed solution with 12. Next, 1.84 g (5 mmol) of Aesculin, 5 methanol
mj2 was added, and the mixture was heated under reflux for 4 hours while stirring. After the reaction was completed, the mixture was cooled, and the resulting yellow candy and methanol were separated by decantation. Ether was added to the yellow candy to make it powder, and the solvent was filtered off. After washing with ether and n-hexane, 7.7 g of the title compound was obtained.

m, p Approx. 170℃ (decomposition) 'H-NMR (DMSO-d6) δ: 2.56 (s, 3H) 2, 40-2.

3, 00-4.

4, 40-5. 6, 24 (d.

7, 38 (s.

7, 85 (d.

[Example 25] 80 (m, 4H) 40 (m, 12H) 40 (m, 6H) IH) IH) IH) 10% to 0.3 g of the compound obtained in Example 23-i)
4.5 ml of hydrochloric acid was added and heated at 100-110°C for 80 minutes. After distilling off the solvent under reduced pressure, water was added to the residue and insoluble matter was filtered to obtain the same hydrochloride as in Example 23-ii).

[Example 26] Carbodithioate (Compound No. 72) Methyl 1-piperazine carbodithioate 184 mg (I,044
mmol) in 2 ml of ethanol, and 2-
Chloro-3'4'-dihydroxyacetophenone 19
5 mg (I,045 mmol) and 3 ml of ethanol were added. When the water was completely dissolved, 333 m of sodium carbonate
After stirring at room temperature for 1 hour, the mixture was further heated to reflux with stirring for 3 hours. After ethanol was distilled off under reduced pressure, 5 ml of water and 0.4 g of acetic acid were added, and the resulting gum was extracted with chloroform. After drying over anhydrous sodium sulfate, chloroform was distilled off under reduced pressure to obtain 0.3 g of candy. Ethanol was added to this, crystallized, collected by filtration, washed sequentially with ethanol and n-hexane, and combined with eA unundai to give a light brown powder of 0.1
3 g was obtained (yield 42.3%).

m, P, 184-186℃ (decomposition)'H-NMR
(DMSO-d6) δ: 2.40-2.90 (m, 4H) 2.57 (s, 3H) 3.80 (s, 2H) 3.86-4.50 (br, s, 4H) 6 , 79
(d, IH, J=6.8Hz) 7, 10~7
．． 50 (m, 2H)I Ru'4'::
(Cm-'): 3400, 2900. 1660
．． 1600°1500, 1470. 1420.
1380°1340, 1280. 1250. 11
60゜1110゜Dissolve the above compound in ethanol, add hydrogen chloride gas-methanol solution, distill off the methanol under reduced pressure, add ether to the residue, collect the precipitate by filtration, and dissolve with ether and n-hexane. After washing and drying, the title compound was obtained.

m, p, 210°C (decomposition) 'H-NMR (CD, OD) δ: 2.65 (s, 3H) 3.10-3.60 (m, 4H) 4.20-4.60 (m, 4H) 4, 76 (s, 2H) 6. 87 (d, 1N, J=9Hz)7,
20-7. 60 (m, 2H)IRv'4'
j= (cm-'): 3600-2300. 16
60. 1590°1510, 1400. 1330
．． 1280゜tiso, tito, 1010
．． 960° [Example 27] Zine carbodithioate (compound number 73) methyl 4
- (2-(3,4-dihydroxyphenyl)-2-oxo)ethyl-81-piperazinecarbodithioate.
Hydrochloride 1021025rn, 14 mmol) was added with 56 ml of ethanol, THFj, 5 mJ2, and under stirring -1
At 0°C, 1.10 g of sodium borohydride was added over 15 minutes.

After stirring at -10 to θ℃ for 5 hours, acetic acid 1
．． 78 g was added to decompose excess sodium borohydride.

The solvent was distilled off, water was added, and the precipitated gum was extracted with ethyl acetate. After separating the organic layer and washing with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain white crystals.

The mixture was washed with ether and the 5N crystals were filtered. n-
Washing with hexane gave 0.59 g of the title compound (yield 57.2%).

'H-NMR (CD30D) δ: 2.20-2.90 (m, 6H) 2.61 (s, 3H) 3.90-4.30 (m, 4H) 4.67 (t, I H, J=4Hz)6.50~6.
90 (m, 3H)' RvlBen11 (Cm-1):3600~3
000. 1590. 1500°1410, 127
0. 1220° The above compound was dissolved in methanol, hydrogen chloride gas-methanol solution was added, methanol was distilled off under reduced pressure, and the residue was washed with a needle to obtain the title compound.

'H-NMR (CD, OD) δ: 2, 64
(s, 3H) 2, 70-3. 40 (m, 6H) 4, 1
0-4. 50 (m, 4H) 4, 60-5. 0
0 (m, IH) 6, 60-6. 90 (
m, 3H) rRv Nitei 2 (0m month): 3600-2300. 1600. 1510°145
0, 1400. 1270. 1220° [Example 2
8] i) α-Bromo-2,3,4-trimethoxyacetophenone 2. Mix 25 g of 3.4-trimethoxyacetophenone, 600 mf1 of ether, and 240 mfl of chloroform, and add 19.18 g of bromine to the solution and 120 mf of chloroform.
A solution dissolved in JZ was added dropwise over 3.3 hours under ice-salt cooling. The solution was sequentially washed with cold water, cold 5% aqueous sodium hydroxide solution, cold water, and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure at below 50°C to give the title compound as a yellow oil 33. og (yield 91.7%).

'H-NMR (CDCJZ3) δ: 3.86 (s, 3H) 3.92 (s, 3H) 4.05 (s, 3H) 4.56 (s, 2H) 6.73 (d, IH, J =9Hz) 7.60 (d, I H, J=9Hz) I RvQ::
t(Cm-'); 2950.1680, 1490, 1410°1290.
1210, 1100, 1000°810.

Radin lupositoate (compound number 71) α-bromo-2,3,4-1-rimethoxyacetophenone 16g
, methyl 1-piperazine carbodithioate 13.2
5 g of sodium carbonate, 17.6 g of sodium carbonate, and 27.0 ml of ethanol were mixed and heated under reflux for 5.5 hours. 0 while the reaction solution is hot! The mixture was filtered to remove inorganic substances. The inorganic material was washed with chloroform, the washing liquid was combined with the previous filtrate, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crystals of No. 26.5. These crystals were recrystallized from 50 ml of ethanol to obtain 12.68 g of pale brown needle crystals as the title compound (yield 59.7%).

m, p, 96-98°C 'H-NMR (CDCJZ3) δ: 2.5-2.8 (m, 4H) 2.66 (s, 3H) 3.84 (s, 2H3 3,86 (s, 3H) 3.91 (s, 3H) 3, 98 (S, 3H) 4, 22 (br, 4H) 6, 72 (d, IH, J=9Hz) 7.53
(d, IH, J=9H2) IRv Futomi; (
cm-'): 3400, 2900. 2800. 1670.15
90, 1460° 1390. 1290°1220
, 1140. 1090. 1020°1000,
980. 820° [Example 291 Thioate (Compound No. 67) Under nitrogen atmosphere, 5 g of methyl 4-(2-(2,3°4-trimethoxyphenyl)-2-oxo)ethyl-1-piperazine carbodithioate, hydrogenated Mix 2.4 g of sodium boron and 4.7 g of anhydrous aluminum chloride, add 120 mjl of dry tetrahydrofuran,
Stirred for 6 hours.

After cooling, 4 Bml of water was added while cooling with water, and the mixture was extracted with ethyl acetate. The extracted solution was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the precipitated inorganic salt was filtered off. This residue was purified by silica gel column chromatography to obtain 1.18 g of the title compound (yield 24.5%).

'H-NMR(CDCl3)δ:2,4~2
．． 8 (m, 8H) 2,67 (3,3H) 3.84 (s, 3H) 3.86 (s, 3H) 3.88 (S, 3H) 4.07 (br, 4H) 6.59 ( s, IH, J=8.4Hz)6.83 (
s, IH, J=8.4Hz)l Rshi:::t(cm-
'): 2980~2B25, 1730, 1600°1490,
1460. 1410. 1270°1215, 1
130. 1095. 1050°1005, 990
．． 925. 795゜if) Methyl 4- 2- 2
．． 3.4-Trimeth 250 mg of the above compound was dissolved in 2.0 mft of dichloromethane, and 0.67 rnjZ of an ether solution of 1N HCI was added under water cooling. The solvent was distilled off under reduced pressure and 1.6 mJ of ethanol was left behind! was added and the crystals were filtered. The obtained crystals were washed with 2 mj2 of ethanol to obtain 159 mg of a white powder as the title compound (yield: 58.2
%).

m, p, 202-203°C 'H-NMR (CD, OD) δ: 2.87 (s, 3H) 2.6-3.2 (br, 2H) 2.9-3.3 (br, 4H ) 3.3~4.3 (br, 4H) 3.84 (s, 6) () 3.92 (s, 3H) 4.9~5.4 (br, 2H) 6.59 (d, IH , J=8.4Hz)6.92
(d, IH, J=8.4Hz) IRv8 mutual (cm-'
): 3450, 2930. 2530. 2360°16
00, 1490. 1470. 1420°1270
, 1240. 1!90. 1100°1050,
960. 910,800°620.

[Example 30] Thioate (Compound No. 68) Boron tribromide 1 mJZ dried dichloromethane 14 mJZ
9.3m of solution dissolved in! (66 as boron tribromide
5 mmol) was cooled to -50°C under a nitrogen atmosphere, and 0.13 g of methyl 4-(2-(2,3°4-trimethoxyphenyl)ethyl)-1-piperazinecarbodithioate was added to the solution in 25 m2 of dry dichloromethane. was added dropwise over 15 minutes. Thereafter, the temperature was gradually raised to room temperature and stirred overnight. Add 3 ml of water to the reaction solution, and add saturated aqueous sodium hydrogen carbonate solution until the pH of the reaction solution is 8.
I added it until it was. Next, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 205 mg of the title compound as an off-white powder (yield 3!, 5%).
.

m, p, 156-158℃ (decomposition) IH-NMFL
(CD30D) δ: 2.63 (5,3H) 2.5-2.9 (m, 8H) 4.0-4.4 (m, 4H) 6.23 (d, IH, J 8.4Hz )6.33 (
(cm
-') :3400.2900,1630,1460
゜1420.1260,1220,1100゜1040
．． 920,760,610° [Example 31] i) 1-3.4.5-trimethoxyphenyl) bihe 1
Poor λ 3.4.5-1rimethoxyaniline 11.9g, bis-
11.6 g of (2-chloroethyl)amine hydrochloride, 9 g of anhydrous potassium carbonate, and diglyme 48nnjZ were mixed and heated under reflux for 28 hours. After cooling, the reaction solution was poured into 100 mf of water, and concentrated potassium hydroxide solution was added to the solution until the pH reached 12. Next, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.37 g of a brown oil as the title compound.

H-NMR (CD Cl3) δ: 1.72 (
s, IH) 3.06 (s, 8H) 3.78 (s, 3H) 3.84 (s, 6H) 6.12 (S, 2H) Under nitrogen atmosphere,! 1.9 g of -(3,4,5-trimethoxyphenyl)piperazine was dissolved in 10 ml of methanol, and 0.46 ml of carbon disulfide was added dropwise to the solution under water cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were collected by filtration to obtain 1.9 g of a grayish brown powder as the title compound (yield: 77.7%).

m, p, 183-190℃ (decomposition) IH-NMR
(DMSO-d6) δ: 2.9-3.4 (m, 7H
) 3.57 (s, 3H) 3.75 (S, 6H) 4.4 (br, 2H) 6.21 (d, 2H, J=3.3Hz) IRv'4'
A: (am-'): 2930.2820,1580,1510°1450.
1420, 1240, 1210゜1120.1000,
930° [Example 32] Methyl 4- 3.4.5-trimethoxyphenyl =
1-Piperazinecarbodithioate (Compound No. 70) Under nitrogen atmosphere, 1.5g of 4-(3,4,5-trimethoxyphenyl)-1-piperazinecarbodithioic acid (4
, 6 mmol) was suspended in methanol, 0.2 g of granular sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. This solution was cooled with ice-salt, and a solution of 0.29 mJZ of methyl iodide dissolved in 3.7 ml of methanol was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to obtain 0.8 g of a grayish brown powder as the title compound. (Yield 50
．． 8%) m, P, 135-137℃ (decomposition)'H-NMR
(CDCfi3) δ: 2゜69 (s, 3H) 3.1~3.3 (m, 4H) 3.79 (s, 3) 1) 3.85 (s, 6H) 4.31 (br, 4H ) 6.16 (s, 2H) IRv'4gx (Cm-'): 1580, 1
510. 1460. 1420°1270, 122
0. 1110. 980°930, 820. 76
0° [Example 33] No. 110) Methyl 4-(2,5-dihydroxybenzyl)-1-
Piperazine carbodithioate 680mg IN hydrochloric acid 6
．． 8ml! and 01.24 g (5,3
A solution of 4.3 mL of water (mmol) was added dropwise over 15 minutes. Further, 25 mft of methanol was added to make a homogeneous solution, and then a solution of 2 g of FeCl2.6H202 in 10 ml of water was added dropwise. After stirring for 10 minutes, methanol was distilled off under reduced pressure, 50 ml of chloroform was added to the residue, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. Insoluble materials were filtered off, and the organic layer was separated and washed with water and saturated brine.

After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 234 mg of the title compound as a yellow powder (yield: 38.
9%).

m, p, 115-116℃ (decomposition) H-N M
R(CDCl3)δ: 2.3-2.8 (m, 4H
) 2.66 (s, 3H) 3.40 (d, 2H, J=2Hz) β, 9~4.4 (m, 4H) 6.6~6.9 (m, 3H) IRv2'',: (cm-'): 3420.1650,1465,1420°1290.
1230,995,910゜[Example 34] 2.58 g (30 mmol) of 35% formalin was dissolved in 30 ml of ethanol.
A solution prepared by dissolving 5.88 g (30 mmol, purity 90%) of methyl 1-piperazine carbodithioate in 15 rnQ ethanol was added dropwise to this solution under water cooling, and the mixture was stirred at room temperature for 30 minutes. This reaction solution was cooled with water.
2゜3.5-trimethylhydroquinone 4.57g (30
A solution prepared by dissolving 30 mmol of ethanol in 30 mff1 of ethanol was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After heating under reflux for about 35 hours, the solvent was distilled off, ether was added to the residue, and the resulting precipitate was collected by filtration to obtain 3.13 g of the title compound as a light brown powder (
yield 30.6%).

'HNMR (CDCjZ3) δ: 2.15 (s, 9H) 2.40-2.7 (m, 7H) 3.70 (s, 2H) 3, 9-4. 4 (m, 4H) 0.5 g (6.47 mmol) of this above compound was dissolved in chloroform 10
A solution of 1N HCl in ether was added under water cooling.
After adding 47rnJZ, the solvent was distilled off under reduced pressure, and 6mN! of acetone was added to the residue. was added to crystallize and collected by filtration to obtain 0.35 g of the title compound as a white powder (yield 70.0
%),.

m, p, 166-169°C (decomposition) 'HNMR (CD30D/CDCl5=3=1) δ: 2.20 (s, 6H) 2.30 (s, 3H) 2.67 (s, 3H) 3. 1~3.6 (br, 4H) 3.6~4.1 (br, 2H) 4.46 (s, 2H) 4.8~5.3 (br, 2H) IRv nail upper 5 3300° 1605° 1210°1020° (cm-'): 2900, 2600°1455, 1400°1190, 1 1 10°1700°1250°1075° [Example 35] Posithioate (Compound No. 113) Methyl 4-[(2,5 -dihydroxy-3゜4.6-
Trimethyl)penzylco-1-piperazinecarbodithioate (10201020 mmol), IN-hydrochloric acid (100 mmol)
mft, add 16 ml of methanol, and add FeCj under water cooling.
23. A solution of 1.86 g (7.95 mmol) of 6H20 in 6.4 m of water was added dropwise over 5 minutes. Furthermore, FeC
IL3 ・6H201.86g (7.95 mmol)
A solution of 6.4 ml of water was added. After the reaction was completed, methanol was distilled off, 75 ml of chloroform was added, and sodium hydrogen carbonate solution was added for neutralization. The precipitated reddish-brown solid was removed by filtration, and the organic layer was separated. The residue was washed with water and saturated brine, dried with sodium sulfate, and then evaporated under reduced pressure. Ethanol was added to the residue to crystallize it, which was then collected by filtration. 840 mg of orange powder was obtained.

m, p, 133-135°C H-NMR (CD CIt3) δ: 2.03
(S, 6H) 2.13 (s, 3H) 2.4-2.6 (m, 4H) 2.65 (s, 3H) 3.45 (s, 2H) 3.9-4.2 (m , 4H) IRv'4':;(am-') :3400.29
00,2790,1630°1620 (shoulder), 1460
,1420°1365.1280.1255,1220
゜1135.1020,990,950゜9 l 5
.

[Example 36] Under a nitrogen atmosphere, 5 g (29.73 mmol) of 3.4-dimethoxybenzyl alcohol was added to 25 m of dichloromethane.
2.16 mL of thionyl chloride (2.16 mL of thionyl chloride) in a water bath
A solution of 9.74 mmol) dissolved in 5 rrrit of methylene chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure at room temperature to obtain 5.624 g of the title compound as a yellow oil.

'H-NMR (CDCJZ3) δ: 3.86 (s, 3H) 3.88 (s, 3H) 4.57 (s, 2H) 6.7-7.0 (m, 3H) Product number 31) Nitrogen Under atmosphere, 3,4-dimethoxybenzyl chloride 5
．． 615 g (30.08 mmol), 5.57 g (30.08 mmol) of methyl 1-piperazine carbodithioate
mmol, purity 95%), anhydrous sodium carbonate 3.19
g (30.08 mmol) and 50 m2 of ethanol were mixed and heated under reflux for 5.5 hours. The solvent was distilled off under reduced pressure, and 20 ml of dichloromethane and 20 ml of water were added to the residue to separate the layers. After washing the organic layer with 30 ml of 1N hydrochloric acid, a 1N aqueous solution of sodium hydroxide was added to separate the organic layer, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 20 mJZ of ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed with ethanol to give 1.465 g of methyl 4-(3
,4-dimethoxybenzyl)-1-piperazinecarbodithioate was obtained (yield 14.9%).

1 g (3.06 mmol) of the above crystals of Hikiko were mixed with 2 ml of ethanol.
．． Suspended in 5mff1, ethanol solution of 6NHCf
, stg was added dropwise under ice-cooling. The solvent was distilled off under reduced pressure, 3mjZ of ethanol was added, and the precipitated crystals were collected by filtration.180,86
6 g of the title compound was obtained as a white powder (yield 78.1
%).

m, p, 138-140℃ (decomposition)'H-NMR
(CDCM3) δ: 2.65 (s, 3H) 2.6~3゜1 (m, 2H) 3.2~3.7 (m, 2H) 3.89 (S, 3H) 3.97 (s , 3H) 3.9-4.3 (m, 4H) 4.9-5.5 (m, 2H) 6.6-7.1 (m, 2H) 7.3-7.6 (m, IH ) IRv,; (Cm-'): 2920.2520,2440,1630°1590.
1520, 1460, 1410゜1265.1240,
1220,1160゜1140.1110,1020,
950° [Example 37] Mel 4-2-dimelaminobenzyl-1-piperazine carbodithioate (compound number 2-dimethylaminobenzyl chloride hydrochloride 2.06 g (I0 mmol), methyl piperazine carbodithioate 1 .76
g (I0 mmol) and 1.06 g of sodium carbonate
(I0 mmol) was stirred in 20 ml of acetone overnight at room temperature. Acetone was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and saturated brine, and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column and recrystallized from ether to obtain 1.32 g (42.7%) of the title compound as white crystals.

m, p, 90-91°C 'HNMR (CDCui) δ: 2.4-2.8 (m, 4H) 2.64 (S, 3H) 2.68 (s, 6H) 3.62 (s, 2H ) 3.8-4.4 (m, 4H) 6.8-7.5 (m, 4H) IRv'4':: (cm-') :2B20.
1450. 1425. 1265°1230, 11
85. 1135. 1125°1040, 990.
940. 760°720.

[Example 38] i) 2.3-dimethoxybenzyl chloride 2.3-dimethoxybenzyl alcohol 3.3 gg (20 mmol)
was dissolved in 30 m2 of methylene chloride, and 1. ．． 6ml! (22 mmol) of methylene chloride 5 mj
The two solutions were added dropwise over 10 minutes. After stirring for 1 hour at the same temperature and distilling off under reduced pressure, 3.71 g (99, s%) of 2
．． 3-Dimethoxybenzyl chloride was obtained as a brown oil.

Product number 22) 2.3-dimethoxybenzyl chloride 1.0g (536
943 mg (5.36 mmol) of methyl 1-biverazine carbodithioate and 568 mg (5.36 mmol) of sodium carbonate were dissolved in ethanol 2
0ml1. and heated under reflux for 2 hours. Ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with 30 mJ2 of ether. 5 ml of 3N hydrochloric acid was added to the ether layer, the mixture was shaken, and the insoluble oil and aqueous layer were combined, 20 ml of IN-sodium hydroxide was added, and the mixture was extracted with ether. After washing with water and saturated brine, it was dried with mirabilite. The solvent was distilled off under reduced pressure, and ethanol was added to the residue to recrystallize it, yielding 708 mg.
(40.5%) of the title compound was obtained as light brown crystals.

m, p, 110-111°C' H-NMR (CD CfL 3 ) δ: 2.4
~2.7 (m, 4H) 2.64 (s, 3H) 3.59 (s, 2H) 3,82 and 3.86 (eachs, 6H
) 3.9-4.4 (m, 4H) 6.7-7.1 (m, 3H) l R1)'4"A;(Cm-'): 148
0, 1425. 1255. 1225°1135,
1065. 1005. 995°780.

[Example 39] Zine carbodithioate (compound number 47) 2.3-dimethoxy-5-methyl-1,4-benzoquinone 1.82
g (I0 mmol) was dissolved in 28 mJ2 of ethanol, and while stirring at room temperature, 240 mg of sodium borohydride (
6.3 mmol) was added little by little. After stirring for 15 minutes, 3
Add N-hydrochloric acid to make acidic, add 50ml of water, 10ml of ether.
0rnJZ was added and extracted. The ether layer was washed with water and saturated brine, and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and 1
．． 72 g of 2,3-dimethoxy-5-methylhydroquinone was obtained as a yellow oil (yield 93.5%). Furthermore, methyl 1-piperazine carbodithioate 1
．． 65 g (9.3 mmol) and 280 rng (9.3 mmol) of rose formaldehyde were added, and the mixture was heated in 17 ml of chloroform for 6 hours. It refluxed. Water was added, extracted with chloroform, washed with water and saturated brine, and dried with mirabilite. The solvent was distilled off under reduced pressure, the residue was dissolved in 10 mL of ethanol, insoluble matter was filtered off, and ethanol was distilled off under reduced pressure. The residue was purified with a silica gel column to obtain 1.1 g of pale yellow oil (yield 31.8%). The crystals were crystallized from ethanol and collected by filtration to obtain 790 mg of the title compound as yellow crystals.

m, p, 135-136℃'HNMR (CDCffi:+) δ: 2.11 (s
, 3H) 2.66 (s, 3H) 2.5-2.8 (m, 4H) 3.72 (s, 2H) 3,9 and 3.95 (eachs, 6H
)4.0~4.4 (m, 4H) IRv4 wealth; (cm-'): 3450.2950,1465,1420°1380,
1270. 1230. 1190°1120, 1
090. 1055. 1050°985, 965.
920° [Example 40] Zincal dithioate (compound number 118) methyl 4-(2,5-dihydroxy-3° 4-dimethoxy-
To 700 mg (I, 88 mmol) of 6-methylbenzyl)-1-piperazine carbodithioate was added 7 m of IN-hydrochloric acid.
1, add 17 mL of methanol, and add FeCff under water cooling.
136H20f, 76 g (7,52 mmol) of water 5
The mIL solution was added dropwise over 15 minutes. The resulting red homogeneous solution was stirred for 30 minutes, and methanol was distilled off under reduced pressure below 50"C. 50 mL of ethyl acetate was added to the residue, and saturated sodium bicarbonate solution was added little by little to adjust the pH to 10. The precipitated brown red color The solid was removed by filtration, and the organic layer was separated.Washed with water and saturated brine, and dried with mirabilite, the solvent was distilled off under reduced pressure.Ethanol was added to the residue to crystallize it, which was collected by filtration.
mg (77.6%) of the title compound was obtained as an orange-brown crystalline powder.

m, p, 115-116°C 'H-NMR (CDC13) δ: 2.11 (s, 3H) 2.4-2.8 (m, 4H) 2.64 (s, 3H) 3.42 (s , 2H) 3.8-4.3 (m, 4H) 4.00 (s, 6H) IRv2= (am-'): 1670.1640,1615,1410°1260.
1230,1195.1150゜990゜ [Example 41] Dithioate (Compound No. 37) 0.86 g (I0 mmol) of 35% formalin was dissolved in 10 m2 of ethanol, and methyl was added to this solution under water cooling.
A solution of 2.35 g (I0 mmol, purity 75%) of 1-piperazine carbodithioate dissolved in 5 mJZ of ethanol was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Add 1.54 g of 3.5-dimethoxyphenol (I
A solution of 0 mmol) dissolved in 5 mJ2 of ethanol was added dropwise and stirred at room temperature for 30 minutes. The suspension was further heated under reflux for 30 minutes, then the solution was allowed to cool, and the precipitated crystals were collected by filtration, washed with ethanol 20rnJZ, and dried under reduced pressure to obtain 1.345 g of the title compound assembly. . Furthermore, after concentrating the mother liquor, 10 m2 of ethanol was added to the residue to precipitate crystals, which were then washed and dried to yield 1.26 g of two products.
was obtained (yield 76.1%).

'HNMR (CDC13) δ: 2.66 (s, 3H) 2.4-2.8 (m, 4H) 3.73 (s, 3H) 3.76 (s, 5H) 3, 9-4. 4 (m, 4H) 5, 9-6
．． 1 (m, 2H) 0.50 g of this above compound
(I, 46 mmol) was dissolved in 2 ml of chloroform, 1.46 ml of an ether solution of I NHCj2 was added, and then evaporated under reduced pressure. 8 mJZ of acetone was added to the residue to crystallize it, and after filtering, 0.48 g ( The title compound was obtained as white crystals (yield: 86.8%).

m, p, 153-154°C (decomposition) 'H-NMR (CD30D) δ: 2.65 (s, 3H) 3.0-3.6 (m, 6H) 3.78 (s, 3H) 3. 87 (s, 3H) 4.34 (s, 2H) 4.4-5.2 (m, 2H) 6.16 (s, 2H) IRvW:S (am-'): 3070, 2930. 2560. 1620°15
90, 1510. 1460. 1420°1270
, 1220. 1200. 1150°1 1 20
, 1 100. 940. 820° [Example 42] 1) 2-methoxybenzyl chloride 2-methoxybenzyl alcohol 2.0 in nitrogen atmosphere
0g (I4.5 mmol) in dichloromethane 10mf
1.06mM thionyl chloride (I
A solution of 4.6 mmol) dissolved in 2 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure at room temperature to obtain 2.32 g of the title compound as a yellow oil.

'HNMR (CDC13) δ: 3.87 (s, 3H) 4.64 (s, 2H) 6.7-7.4 (m, 4H) ii) Methyl 4-2-methoxybenzyl-1 under nitrogen atmosphere, 2-methoxybenzyl chloride 2.28g (I
4.5 mmol), 2.69 g of methyl 1-doberazinocarbodithioate (I4.5 mmol, purity 94.8%)
), 1.53 g (I4.5 mmol) of anhydrous sodium carbonate, and 15 m2 of ethanol were mixed and heated under reflux for 18 hours. Insoluble materials were filtered off, the solvent was distilled off under reduced pressure, and 15 ml of dichloromethane and 15 ml of water were added to the residue to separate the layers.

The organic layer was washed with 17 m2 of 114-hydrochloric acid and an IN-sodium hydroxide aqueous solution at 20 m°C, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by column, and 1
．． 92 g of methyl 4-(2-methoxybenzyl)-1-
Piperazine carbodithioate was obtained (yield 44.7%)
).

1ii) Methyl 4-2-methoxybenzyl-1-vivazinylpodione- 0.87 g (2.95 mmol) of the above crystals were mixed with 5.0 ml of ethanol. Suspended in El+mQ and diluted with 6N-hydrochloric acid/under water cooling.
0.5 ml of ethanol was added dropwise, and the solvent was distilled off under reduced pressure.
3 mfi of ether was added, and the precipitated crystals were collected by filtration and washed with 5 ml of ether to obtain 0.81 g of the title compound as a white powder (yield: 82.0%).

m, p, 216-217°C (decomposition) 'H-NM Ft (CD30D) δ2.65
(s, 3H) 3.2-4.0 (m, 6H) 3.94 (s, 3H) 4.42 (s, 2H) 4, 8-5. 4 (m, 2 summer)
)6.9~7.6 (m, 4H) I Rv Was (Cm-') '2920.2
510,2450,1605゜1495.1460.1
410, 1250° 1210, 1110. 1040
．． 1020°950, '760° [Example 43] i) 2,5-dimethoxybenzyl chloride 2.00 g of 2,5-dimethoxybenzyl alcohol under nitrogen atmosphere
(I1.9 mmol) was dissolved in dichloromethane 10 mJZ, and under water cooling, thionyl chloride 0.87 mJZ (I2,
A solution of 0 mmol) dissolved in 2 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure at room temperature to obtain 2.22 g of the title compound as a pale yellow oil.

H-NMR (CDCl2) δ: 3.76 (s, 3H) 3.81 (s, 3H) 4.59 (s, 2H) 6.7 to 7.0 (m, 3H) Product number 23) Nitrogen atmosphere Bottom, 2,5-dimethoxybenzyl chloride 2
．． 20 g (I1.8 mmol), methyl! 2.19 g (I 1.8 mmol) of -piperazine carbodithioate, 1.25 g (I 1.8 mmol) anhydrous sodium carbonate, and 15 ml ethanol were mixed and heated under reflux for 18 hours. Insoluble matter was filtered off, the solvent was distilled off under reduced pressure, and 15 ml of dichloromethane and 15+nJZ of water were added to the residue to separate the layers.

The organic layer was washed with 15 mJZ of IN-hydrochloric acid and 18 ml of IN-sodium hydroxide aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column.
1.23 g of methyl 4-(2゜5-dimethoxybenzyl)-1-piperazine 0.76 g of the above crystals
(2,31 mmol) was suspended in 5 mff1 of ethanol, 6N-hydrochloric acid/0.4 m of ethanol, and I2 were added dropwise under water cooling, the solvent was distilled off under reduced pressure, 3 mfi of ether was added, and the precipitated crystals were collected by filtration. Wash with ether 5rr + JZ,
0.53 g of the title compound was obtained as a white powder (yield 6
2.8%).

m, p, 195-197°C (decomposition) H-NMR
(CD 30D) δ:2, 66 (s,
3H) 3, 2-3. 7 (m, 6H)3, 79
(s, 3H) 3, 89 (s, 3H) 4, 39 (s, 2H) 4, 9-5. 4 (m, 2H)7, 0~7
．． 1 (m, 3H)I R1)rmL (C
m-') ;2990, 2950. 2830.
2500°2360, 1500. 1470. 14
05°12B0. 1260. 1225. 1045
゜1020, 960. 805゜[Example 44] i) Mel 4-diphenylmethyl-1-vivazinylpodithioate (Compound No. 102) 5.00 g (I 9.8 mmol) of 1-benzhydrylpiperazine was dissolved in 25 ml of methanol, and dissolved in it. , 1.51 g (I9.8 mmol) of carbon disulfide was added to 5 mL of methanol under water cooling.
A solution dissolved in was added dropwise, and the mixture was stirred for 30 minutes. Under water cooling, add 28% sodium methylate/
A solution prepared by dissolving 3.80 g (I9.8 mmol) of methanol solution in 5 mff1 methanol was added and stirred until the solution became transparent.

A solution of 2.90 g (I9.8 mmol) of 97%-iodomethane dissolved in 5 ml of methanol was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The precipitated crystals were filtered, washed with methanol, and methyl 4 -diphenylmethyl-1-
5.78 g of piperazine carbodithioate was obtained.

0.70 g (2.04 mmol) of the above crystals were dissolved in 1.4 mjZ of chloroform and diluted with INHCl under water cooling.
An ether solution of 2.1 mJ2 and chloroform 2rnIL
was added and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with chloroform-ether (I:1), and
1 g of the title compound was obtained as a white powder (yield 91.7
%).

m, p, 216-218°C (decomposition) 'H-NMR (CD30D) δ: 2.64 (s, 3H) 3.2-3.6 (m, 4H) 3.8-5.2 (m, 4H) 5.46 (s, IH) 7.3-7.9 (m, 10H) IRv varnish; (cm): 2410.1620,1470,1450°1410.
1275, 1225, 1205゜1120.1020,
1000,940° 920.750,700° [Example 45] 2.17 g (I2.3 mmol) of carbothioate and 1.30 g (I2.3 mmol) of sodium carbonate were heated under reflux in 20 mL of ethanol for 2 hours. Ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether.

The ether layer was washed with water and saturated brine, and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column to obtain 1.18 g (31%) of the title compound as a yellow oil.

'H-NMR (CDCI13) δ: 2.44 (s, 3H) 2.4-2.7 (m, 4H) 2.64 (3,38) 3.58 (S, 2H) 3.8-4 .4 (m, 4H) 6.9-7.5 (m, 4H) 2.1 g (I2, 2 mmol) of 2-methylthiobenzyl chloride, methyl 1-piperazine, and methoxychloride 1 mol 6NH (I2) After adding the ethanol solution 2rnjZ of
The residue was distilled off under reduced pressure, and 10 ml of ethyl acetate was added to the residue to crystallize it, which was collected by filtration to obtain 910 mg (74%) of the title compound as a white crystalline powder.

m, p, 204-208°C (decomposition) 'H-NMR (CDCfi3+CD30D=1:4.v
/v) δ: 2.55 (s, 3H) 2.66 (s, 3H) 3.2~3.7 (m, 4H) 3.7~4.2 (m, 2H) 4.56 (s , 2H) 4.8-5.4 (m, 2H) 7.2-7.8 (m, 4H) l Rv 2'! g (Cm-') '2350
．． 1460, 1420, 1270゜1215.1110
, 1035, 1010° 955, 765° [Example 46] 1 (Compound No. 75) 2.3.4-trimethoxyphenylacetic acid 310 mg (I
, 37 mmol) and 289 mg (I, 64 mmol) of methyl 1-piperazinecarbodithioate were dissolved in 6.2 mM of methylene chloride, and 395 mg (I, 92 mmol) of dicyclohexylcarbodiimide was added thereto at room temperature.
Stir for hours. The precipitated solid was filtered off, and methylene chloride and IN-hydrochloric acid were added to the filtrate. The organic layer was separated, washed with saturated brine, and dried with mirabilite. The solvent was distilled off under reduced pressure, the residue was purified with a silica gel column, and ethanol/hexane was added to the obtained oil to crystallize, giving 257 mg (48,
8%) of the title compound as white crystals.

m, p, 119-120°C 'H--N M R (CD CIt 3) δ: 2.65
(s, 3H) 66 (s, 2H) 3-4. 3 (m, 8H) 8-3. 9 (m, 9H) 58 and 6. 88 (eachd
, 2H.

J=9Hz) IRv:':;(cm-') :1630, 1
490. 1460. 1420°1275, 124
0. 1215. 1090°1045, 1010.
950° [Example 47] The organic layer was washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, 40 ml of ether was added to the residue, crystallized, filtered, and washed with ether to give 4.3 g.
(69.1%) of JIA-titled gold compound was obtained as colored crystals.

'HNMR (CDCIs) δ: 2.52 (t, 4H, J=5Hz) 2.64 (s, 3H) 3.83 (s, 2H) 3.9-4.4 (m, 4H) 7.2 ~7.9 (m, 4H) 2-nitrobenzyl chloride 3.43 g (20 mmol), methyl 1-piperazine carbodithioate 3.
52 g (20 mmol) and sodium carbonate 2.12
g (20 mmol) to 30 ml of ethanol,
The mixture was stirred at room temperature for 4 hours and then at 50-60°C overnight. Ethanol was distilled off under reduced pressure, and water and chloroform were added to the residue for extraction.

Further, 500 mg (I, 61 mmol) of the above compound was dissolved in 2 ml of methylene chloride, 2 ml of an ethanol solution of 6NHC1 was added, the solvent was distilled off under reduced pressure, 2 ml of ethyl acetate was added to the residue, crystallized, filtered, and 497 mg
(88.8%) of the title compound was obtained as white crystals.

m, P, 208-211°C (decomposition) 'H-NMR (DMSO-d,) δ: 2. 61
(s, 3H) 3, 0-3. 5 (m, 4H)3, 7~4
．． 9 (m, 4H) 4, 59 (s, 3H) 7, 5-8. 2 (m, 4H)' RvA
2x (Cm-'): 2320, 1520.
1460. 1400°1335, 1270. 11
95. 945° [Example 48] Methyl 4-2-aminobenzyl-1-piverazinecarposithioe- (Compound No. 11) Methyl 4-(2-
622 mg (2.0 mmol) of nitrobenzyl)-1-piperazine carbodithioate was added to a solution of 4 ml of concentrated hydrochloric acid and 5 ml of ethanol, and the solution was mixed with 5 ml of nitrobenzyl)-1-piperazine carbodithioate under stirring under water cooling.
・2H202.7g (I2 mmol) of ethanol 5m
1 solution was added dropwise over 15 minutes. After the dropwise addition, the mixture was further stirred at room temperature for 2 hours, and ethanol was distilled off under reduced pressure. 10ml of water for leftover
, 10 m2 of ethyl acetate were added, and the mixture was made alkaline with saturated sodium bicarbonate solution. The precipitated insoluble matter was filtered off, and the organic layer was washed with saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 436 mg (77.6%) of the title compound as white crystals.

m, p, 110-113.5°C' H-N M R (CD CJZ 3) δ: 2.50
(t, 4H, J=6Hz) 2.65 (s, 3H) 3.53 (s, 2H) 4.10 (br, 4H) 4.54 (br, 2H) 6.5~7.2 (m , 4H) IRv:'j: (cm-'): 3450.3300.2800,1605°1405.
1280, 1260, 1240°1225.1145,
990,925゜740゜ [Example 49] ii) Methyl 4-2,5-diacetoxy-3゜bedinecarpodiaate (Compound No. 48) Under nitrogen atmosphere, methyl 4-(2,5-dihydroxy-3,4 0.50 g (I, 34 mmol) of dimethoxy-6-methylbenzyl)-1-piperazinecarbodithioate was dissolved in 5 mA of dichloromethane, and 0.30 g of triethylamine was dissolved in 5 mA of dichloromethane.
g (2.96 mmol) was added. Add to this solution under water cooling.
A solution of 0.25 g (2.96 mmol) of 95% acetyl chloride dissolved in 3 mJ2 of dichloromethane was added dropwise, and the mixture was stirred for 6 hours. Dichloromethane 10m2
After adding a small amount of saturated aqueous sodium bicarbonate solution and stirring well, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 0.63 g of methyl 4-
(2,5-diacetoxy-3,4-dimethoxy-6-methylbenzyl)-1-piperazine carbodithioate was obtained as an oil.

0.63 g (I, 38 mmol) of this oily substance was dissolved in 10 ml of dichloromethane, and hydrogen chloride gas was blown into the solution under water cooling. The solvent was distilled off under reduced pressure to give 4ml of ether.
, a small amount of acetone and 2 mJ2 of dichloromethane were added, and the precipitated crystals were collected by filtration to obtain 0.54 g of the title compound as a white powder (yield 79.7%).

m, p, 194-195°C (decomposition) 'H-NMR (CDCJI!3) δ: 2.34 (s, 3H) 2.35 (s, 3H) 2.43 (S, 3H) 2.66 ( s, 3H) 2.8-3.6 (m, 4H) 3.84 (s, 3H) 3.8-5.3 (m, 4H) 3.88 (s, 3H) 4, 20 (s, 2H) I R11eaL (Cm −' ) 3000,
2950°1750, 1605°1410, 1370°1250, 1200°1060, 1010°910, 880° [Example 50] 2500, 2420°1475, 1450°1350, 1270°1170, 1105゜950, 940゜Composition number 56) Under nitrogen atmosphere, 2,3.4-1rimethoxybenzoic acid 1.
OOg (4.71 mmol), thionyl chloride 10 m
1 (38 mmol) was added and the mixture was heated under reflux for 2 hours.

The solvent was distilled off under reduced pressure, 10 ml of dry benzene was added, and the operation of distilling off under reduced pressure was repeated twice. At room temperature, methyl! A solution of 0.88 g (4.74 mmol, purity 95%) of -piperazine carbodithioate in 12 mf dichloromethane was added dropwise. On the way, triethylamine 0.48
g (4.74 mmol) and stirred overnight.

The reaction solution was washed with IN-hydrochloric acid and then with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, acetone was added to the residue, the precipitated crystals were collected by filtration, the mother liquor was concentrated, and a small amount of Ethanol was added, and the precipitated crystals were collected by filtration and combined with the previous crystals to obtain 0.90 g of the title compound as white crystals (yield: 51.6%).

m, p, 149-150°C (decomposition) 'H-NMR (CDCffi,) δ: 2.67 (s, 3H) 3.2-l 6 (m, 2H) 3.6-3.9 (m, 2H) 3.88 (s, 9H) 3.9-4.4 (m, 4H) 6.70 (d, IH, J=8.6Hz) 6.98 (
d, IH, J=8.6Hz) I Rv:':: (C
m-'): 2930.2830,1620,1595°1495,
1475. 1450. 1425°1365, 1
280. 1235. 1215°1180, 115
5. 1095. 1040°1000, 925.
900. 820°810, 750. 700° [Example 51] 2-chlorobenzyl chloride 1.61 g (I0 mmol), methyl 1-piperazine carbodithioate 1.
76 g (I0 mmol), and 1.0 sodium carbonate
6 g (I0 mmol) in 16 mf ethanol
The mixture was heated to reflux for an hour. Ethanol was distilled off under reduced pressure, water was added, and the mixture was extracted with 30 ml of ether. Further, the mixture was shaken with 15 mft of 3N hydrochloric acid to separate into three layers, of which an aqueous layer and an oily layer were separated, combined, and made alkaline with IN-sodium hydroxide. After extraction with ether and washing with saturated saline,
Dried mirabilite. The solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column to obtain 1.03 g (34.3%) of methyl 4
-(2-chlorobenzyl)-1-piperazine carbodithioate was obtained as a light brown oil.

'H-NMR (CDCIL3) δ: 2.5-2.8 (m, 4H) 2.66 (s, 3H) 3.64 (s, 2H) 3.9-4.3 (m, 4H) 7 .1 to 7.5 (m, 4H) Furthermore, 0.98 g of the compound obtained above was added to ethyl acetate 2
An ethanol solution of 6NHCλ dissolved in 1.0mff1.
After adding 5rnJZ and stirring, the precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 900 mg of the title compound as pale yellow crystals.

m, p, 235°C (decomposition) 'H-NMR (CDCJZ3 +CD30D=6/1)
δ: 2.63 (s, 3H) 2, 8-4. 2 (m, 6H)4. 47
(s, 2H) 4, 9-5. 5 (m, 2H)7, 2~8
．． 1 (m, 4) ()IRv'4! ! : (
cm-'): 2700-2100. 1465.
1410°1265, 1245. 1215. 11
95° 1 1 10, 955. 745° [Example 52] Methyl 4-4-methoxybenzyl-1-vivazine luposithioate (Compound No. 7) Under nitrogen atmosphere, 4
-Methoxybenzyl alcohol2. OOg (I4,5
1.05 mjL (I4.5 mmol) of thionyl chloride was dissolved in 10 ml of dichloromethane and cooled with water.
A solution of 2 mR of dichloromethane was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure at room temperature, and 2.90 g of methyl l-piperazine carbodithioate was left behind.
(4.5 mmol of I, purity 88.1%), 1.54 g of anhydrous sodium carbonate (4.5 mmol of I), and 25 mL of ethanol were mixed and heated under reflux for 14.5 hours. The solvent was distilled off under reduced pressure, 10 rnJZ of dichloromethane and 10 mL of water were added to the residue to separate the layers, and insoluble materials were filtered off. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column.1.
46g methyl 4-(4-methoxybenzyl)-1-
Piperazine carbodithioate was obtained as a pale yellow oil (yield 33.9%).

1.46 g (2.92 mmol) of this oil was dissolved in 5.8 mIt of dichloromethane, and cooled with INHC under water cooling.
4.92 mj2 of an ether solution of fi was added dropwise, stirred at room temperature, and the precipitated crystals were collected by filtration and washed with 5 ml of ether to obtain 1.43 g of the title compound as a white crystalline powder (yield: 87.4 %).

m, p, 205-206℃ (decomposition) 'H-NMR (CD30D) δ: 2.65 (s, 3H) 3, 0-4. 0 (m.

3, 83 (s, 3H) 4, 34 (s, 2H) 4, 9-5. 6 (m.

7, 02 (d, 2H.

7, 49 (d, 2H.

IRvH2H (cm-') 2900, 2830° 2450, 1610° 1460, 1405° 1250, 1210° 1105, 1025° 820.

[Example 53] 6H) 2H) J=8. 8Hz) J=8, 8Hz) 2650, 2520°1580, 1510°1300, 1270°1175, 1120°945, 845° Under nitrogen atmosphere, 3-methoxybenzyl chloride 1.57
g (I 0.0 mmol), methyl 1-piperazine carbodithioate 2.0 Hg (I 0.0 mmol, purity 8
8.1%), anhydrous sodium carbonate 1.06g (I0,
0 mmol) and 20 mjZ of ethanol were mixed and heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and 15 ml of dichloromethane and 10 m2 of water were added to the residue to separate the layers. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column; 2.
46g methyl 4-(3-methoxybenzyl)-1
- Piperazine carbodithioate was obtained as colorless crystals (yield: 82.8%).

2.31 g (7.79 mmol) of the above crystals were dissolved in 20 mff1 of ethyl acetate, and 2.0 m1 t of an ethanol solution of 6N HCIL was added dropwise under water cooling.

The precipitated crystals were collected by filtration and washed with 10 ml of ethyl acetate.
1.63 g of the title compound was obtained as a white crystalline powder (
yield 62.9%).

m, p, 183-184°C (decomposition) 'HNMR (CDCffi*) δ: 2. 6
5 (s, 3H) 2, 8-3. 7 (m, 4H) 3, 86 (s, 3H) 3, 9-4. 4 (m, 4H) 4, 9-5
．． 5 (m, 2H) 6.8-7. 5 (m
, 4H) IRv:”, :, (cm-') :
3050, 2990. 2910°2660, 2500. 2420°1580, 1490. 1460°1370, 1340. 1295°1250, 1200. 1!90°1120, 1070. 1030°950, 860. 795. 775°690.

[Example 54] 2-methylbenzyl chloride 1°2830°1600°1410°1260°1170°1000°740°405 g (I0 mmol), methyl 1-piperazine carbodithioate 1.76 g (I0 mmol), and carbonic acid 1.06 g (I0 mmol) of sodium in ethanol 14
Heated at reflux in mM for 2.5 hours. Ethanol was distilled off under reduced pressure, water and ether were added to the residue, and the ether layer was separated. 3N-hydrochloric acid f 5ml1. was added, the aqueous layer was separated, and I
After neutralization with N-sodium hydroxide, extraction with ethyl acetate,
Washed with water and saturated saline. After drying Glauber's salt, the solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column to give 790 mg.
(28.2%) of methyl 4-(2-methylbenzyl)-1-piperazine carbodithioate was obtained as a white crystalline powder.

'HNMR (CDCjZ3) δ: 2.36 (s, 3H) 2.51 (t, 4H, J=5Hz) 2.64 (s, 3H) 3.48 (s, 2H) 3.8 to 4.4 (m, 4H) 7.0-7.4 (m, 4H) ii) Mel 4-2-merbenzyl-1 ~ Furthermore, 670 mg (2,39 mmol) of the above compound was dissolved in 7 ml of ethyl acetate, and 68HCj! Ethanol solution 1 of
ml was added and stirred. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 610 mg (80.6%) of the title compound as colorless crystals.

m, p, 214℃ (decomposition) ' HN M R (CD 30 D + CD CJ!
3=3/l) δ: 2.49 (s, 3H) 2.67 (s, 3H) 2.8-4.2 (m, 6H) 4.38 (s, 2H) 4.9-5. 4 (m, 2H) 7.1-7.8 (m, 4H) IRv2: (cm-'): 2700-2200, 1470, 1430° 1400.
1270,1210 1020° 955, 755° [Formulation Example 1] (Powder) Piperazine derivative in the present invention 10 parts Heavy magnesium oxide 10 parts Milk, i*
A o +1 is mixed uniformly into a powder or fine granules to form a powder.

[Formulation Example 2] (Powder) Piperazine derivative in the present invention 10 parts Synthetic aluminum silicate 10 parts Calcium hydrogen phosphate 5 parts Milk W
75 parts are uniformly mixed to form a powder or fine granules to form a powder.

[Formulation Example 3] (Granule) Piperazine derivative in the present invention 50 parts starch 10 parts milk It
15 parts crystalline cellulose
20 parts polyvinyl alcohol
5 parts water
After uniformly mixing and kneading 30 parts, the mixture is crushed, granulated, dried, and sieved to obtain granules.

[Formulation Example 4] (Drug-coated tablets) 99 parts of the granules obtained in Formulation Example 3 are mixed with 1 part of calcium stearate and compressed to form tablets with a diameter of 10 mm.

[Formulation Example 5] (Injection) 0.5 parts of the piperazine derivative of the present invention, 2.5 parts of a nonionic surfactant, and 97 parts of physiological saline are mixed under heating and then sterilized to prepare an injection.

[Formulation Example 6] (Capsule) The powder obtained in Formulation Example 1 is filled into a commercially available capsule container to prepare a capsule.

Patent applicant: Nippon Chemifa Co., Ltd.

Claims (1)

[Claims] 1. General formula (I); ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) [In the formula, A represents a substituent such as halogen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl, acyl, hydroxy, alkoxy , a phenyl group which may have at least one substituent selected from the group consisting of , acyloxy, glycosyloxy, amino, alkylamino, mercapto, alkylthio, and nitro;
represents a p-benzoquinonyl group or a coumarinyl group, B
represents a single bond or a linear alkylene group having 1 to 4 carbon atoms which may have at least one substituent selected from the group consisting of alkyl, aryl, aralkyl, hydroxy, and oxo, and R represents , a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an atom or group selected from the group consisting of alkyl, cycloalkyl, aralkyl, and aryl, and n is 2 or 3] A piperazine derivative represented by or a pharmacologically acceptable salt thereof as an active ingredient. 2. General formula (II); ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) [In the formula, A^1 is a substituent such as halogen, alkyl, fluoroalkyl, formyl, alkoxycarbonyl, acyl, hydroxy , a phenyl group having at least one substituent selected from the group consisting of , alkoxy, acyloxy, glycosyloxy, amino, alkylamino, mercapto, alkylthio, and nitro, or a phenyl group having the above substituent. represents a p-benzoquinonyl group or a coumarinyl group, and B is a single bond, or alkyl, aryl, aralkyl,
represents a linear alkylene group having 1 to 4 carbon atoms which may have at least one substituent selected from the group consisting of hydroxy and oxo, R is a hydrogen atom, an alkali metal atom, an alkaline earth metal an atom or group selected from the group consisting of alkyl, cycloalkyl, aralkyl, and aryl, and n is 2 or 3.