JPS61158972A - Thiazolidine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is (substitute) phenyl, Q is single bond, alkylene, or alkenylene; Alk is alkylene; R<2> and R<3> are H, alkyl, cycloalkyl, alkanoyl, alkoxycarbonyl, alkylsulfonyl, benzoyl, phenyl, or di(alkyl)phosphoryl; Y and Z are O, or S] or its salt. EXAMPLE:N-Methyl-2-{2-[-(4-phenylpiperazin-1-yl)ethyloxy]phenyl} thiazolidine-3- carboxamide. USE:A cardiac having improved cardiac action and prolonged action, and useful for remedying and preventing congestive heart diseases. PREPARATION:A thiazolidine derivative shown by the formula II or its salt is reacted with a piperazine derivative shown by the formula III (X<1> is reactive residue) or its salt in a solvent at 50-110 deg.C to give a compound shown by the formula I. The compound shown by the formula II is obtained by reacting a compound shown by the formula IV with a compound shown by the formula V at 0-80 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel thiazolidine derivative and a method for producing the same.

(Objective of the Invention) The object of the present invention is to provide a novel thiazolidine derivative having excellent cardiotonic action and a synthetic intermediate thereof. Another object is to provide a method for preparing the thiazolidine derivatives.

(-1# Structure and effects of the invention) The novel thiazolidine derivative of the present invention has the following general formula % (where R1 is a substituted or unsubstituted phenyl group, Q is a single bond, a lower alkylene group or a lower alkenylene group, A
IK is a lower alkylene group, R1 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group, a phenyl group, or a di(lower alkyl group). ) Phosphoryl group, Y and 2 are the same or different and represent an oxygen atom or a sulfur atom. ) Compound (1) of the present invention or a salt thereof is a pharmaceutical compound useful as a cardiotonic agent.

For example, when a sample was intravenously administered to dogs to examine its inotropic effect, 9 the (-)-N-methyl-2-(2-(2-
(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide (oxalate) decreased left ventricular contractility by 3 at a dose of 0.003 μ/kg.
It can be increased by 6% and the effect lasts for about 40 minutes. Also.

The inotropic effect was investigated using the Langendorff method using isolated guinea pig hearts.2 (+) (or (±))-N- of the present invention
Methyl-2-(2-(2-(4-phenylpiperazine-
1-yl)ethyloxyphphenyl)thiazolidine-3
- Carboxamide (oxalate) can increase cardiac contractility at a dose of 34.

As an example of the compound of the present invention, in general formula (1),
11 is a phenyl group, or a halogen atom (for example, a fluorine atom, a chlorine atom, or a bromine atom), a lower alkyl group (for example, a methyl group, an ethyl group, a propyl group, a butyl group, or a pentyl group), a lower alkylthio group ( for example,
Methylthio group.

ethylthio, propylthio, butylthio or pentylthio), lower alkoxy (e.g.

Q is a single bond, a lower alkylene group (e.g., methylene group, ethylene group, trimethylene group, tetra methylene group or pentamethylene group) or lower alkenylene group (e.g.

and dirun group, propenylene group, butenylene group or hapentenylene group); atg is a lower alkylene group (for example, methylene group, ethylene group, trimethylene group, tetramethylene group or pentamethylene group); R2 and R3
are the same or different hydrogen atoms.

Lower alkyl groups (e.g. methyl, ethyl).

propyl group, butyl group or pentyl group), cycloalkyl group (e.g. cyclopropyl group, cyclobutyl group,
Cyclopentyl group, cyclohexyl group.

or cycloheptyl group), lower alkanoyl group (e.g. acetyl group, propionyl group, butyryl group, valeryl group or hexanoyl group), lower alkoxycarbonyl group (e.g. methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group) or pentyloxycarbonyl group), lower alkylsulfonyl group (e.g. methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group or pentylsulfonyl group), benzoyl group, phenyl group or di(lower alkyl)phosphoryl group (e.g. , dimethylphosphoryl group, diethylphosphoryl group, dipropylphosphoryl group, dibutylphosphoryl group, or diethylphosphoryl group); and compounds in which Y and Z are the same or different and are an oxygen atom or a sulfur atom. Among these, preferable compounds include those represented by general formula (1).
R1 is a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkylthio group, a lower alkoxy group, or a nitro group; Q is a single bond, a lower alkylene group, or a lower alkenylene group; ; AIK is a lower alkylene group, and RZ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxysulfonyl M, a-class alkylsulfonyl group, a benzoyl group, a phenyl group, or a di(lower alkyl)phosphoryl group; Examples include compounds in which R3 is a hydrogen atom or a lower alkyl group, or R2 is a lower alkyl group and R3 is a lower alkanoyl group or a benzoyl group; Y and Z are the same or different and are an oxygen atom or a sulfur atom. It will be done. More preferable compounds include general formula 〇)
In, R1 is a phenyl group, or a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms, or a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms,
3 is an alkoxy group, an alkylthio group having 1 to 3 carbon atoms, or a phenyl group substituted with a nitro group; Q is a single bond, an alkylene group having 1 to 3 carbon atoms, or a propenylene group (
-CH=CH-CHz-) group and i AIK is an alkylene group having 2 to 5 carbon atoms; R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, a carbon Alkanoyl group having 2 to 5 carbon atoms, alkoxycarbonyl group having 2 to 4 carbon atoms, and benzoyl group.

A phenyl group or a di(alkyl)phosphoryl group having 2 to 6 carbon atoms, and R'' is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R2 is an alkyl group having 1 to 4 carbon atoms, and R3
is an alkanoyl group or a benzoyl group having 2 to 5 carbon atoms; and compounds in which Y and Z are the same or different and are an oxygen atom or a sulfur atom are exemplified. Other preferred compounds include those in general formula (1) in which R1 is a phenyl group, fluorophenyl group or methylphenyl group, Q is a single bond, AIK is an ethylene group, and R2 is a hydrogen atom or a methyl group. Examples include compounds in which R3 is a hydrogen atom, a methyl group, or an acetyl group, and Y and Z are the same or different and are an oxygen atom or a sulfur atom.

Furthermore, in general formula (I), when the carbon atom of the benzene ring substituted by the thiazolidyl group is set at the 1st position.

Compounds in which the group Rl-a-fl-AIK-Y- is substituted at the 2- or 4-position on the benzene ring are preferred. Other more preferred compounds include the general formula (where R1 is a substituted or unsubstituted phenyl group, Q is a single bond, a lower alkylene group or a lower alkenylene group, AIK is a lower alkylene group, Hl and R3 are the same or different) Hydrogen atom, lower alkyl group, cycloalkyl group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfonyl group, benzoyl group, phenyl group or di(lower alkyl)phosphoryl group, Y and 2 are the same or different and are oxygen atoms or representing a sulfur atom). More preferred compounds include those in which 1171 in general formula (1-A) is a phenyl group, or a chlorine atom or a fluorine atom.

is an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, or a phenyl group substituted with a nitro group; Q is a single bond, and Q is a single bond;
~3 alkylene group or propenylene group; AIK
is an alkylene group having 2 to 5 carbon atoms; HE is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms, and 2 carbon atoms;
~4 alkoxycarbonyl group, benzoyl group, phenyl group, or di(alkyl)phosphoryl group having 2 to 6 carbon atoms, and R3 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R8 is a carbon number 1 to 4 alkyl group, R3 is an alkanoyl group or benzoyl group having 2 to 5 carbon atoms; Y
and a compound in which Z is the same or different and is an oxygen atom or a sulfur atom. More preferred compounds include general formula (1-A) in which R1 is a phenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, or methoxyphenyl group; Q is a single bond; AI
K is an ethylene group or a trimethylene group; Hl is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkanoyl group having 2 to 4 carbon atoms; ; Compounds in which Y and 2 are the same or different and are an oxygen atom or a sulfur atom are mentioned. Other preferred compounds include R' in general formula (I-A)
is a phenyl group, a fluorophenyl group or a methylphenyl group; Q is a single bond; AIK is an ethylene group; HX is a hydrogen atom or a methyl group; R3 is a hydrogen atom, a methyl group or an acetyl group; Yes; Compounds in which Y and 2 are the same or different and are an oxygen atom or a sulfur atom are included. A further more preferred compound is one in which R+ is a phenyl group, fluorophenyl group or methylphenyl group; Q is a single bond; AIK is an ethylene group; and HR is a hydrogen atom in the general formula (IA). or a methyl group; R3 is a hydrogen atom, a methyl group or an acetyl group; and Y is an oxygen atom.

Examples include compounds in which Z is an oxygen atom or a sulfur atom.

Particularly preferred compounds include those in the general formula (1-A) in which 1llI is a phenyl group or a fluorophenyl group; Q is a single bond; AIK is an ethylene group; R2 is a methyl group, and R3 is a Examples include compounds in which the compound is a hydrogen atom or an acetyl group; Y and Z are oxygen atoms.

Since the compound (I) of the present invention has an asymmetric carbon atom at the 2-position of the thiazolidine ring, two types of optical isomers may exist; however, the present invention encompasses both of these optical isomers and their ceramiforms. It is something to do.

According to the invention, compound (I) is.

[Manufacturing method (A)]

R2 Z=C-N ((However, R", R', Y and Z have the same meanings as above.) Thiazolidine derivatives or salts thereof and general (However, XI represents a reactive residue, R ', Q and AIK have the same meanings as above.) or a salt thereof.

[Manufacturing method (B)] General formula (where XZ represents a reactive residue, AIK, R”
, R3゜Y and Z have the same meanings as above. ) A thiazolidine derivative or its salt represented by the general formula (however, 1171 and Q have the same meanings as above)
or a piperazine derivative represented by or a salt thereof.

[Manufacturing method (C)]

Thiazolidine derivatives or salts thereof represented by the general formula (wherein R', Q, AIK and Y have the same meanings as above) and the general formula (wherein, X3 represents a reactive residue, Hl, R3 and Z have the same meanings as above) (has the same meaning as
)] Z=C-X' (However, 14 represents a reactive residue l R'I Ql^I
K.

Y and Z have the same meanings as above. ) or a salt thereof and general (however, Bt and R3
has the same meaning as above. ) or a salt thereof.

Further, in compound (I), Z is an oxygen atom (i.e., thiazolidine derivative (1-a)).

[Manufacturing method (E)]

A thiazolidine derivative or a salt thereof represented by the general formula % formula % ((However, R', Q, Al is 17!, R3 and Y have the same meanings as above) and the general formula % formula % () (However, +R ' represents a lower alkyl group or a substituted or unsubstituted phenyl group; R% represents a lower alkyl group).

The compound (1) in which R3 is a hydrogen atom (that is, the thiazolidine derivative (I-c)) is as follows.

[Manufacturing method (F)]

Thiazolidine derivative (Vl) or its salt and general formula % formula %
() (However, +R" and Z have the same meanings as above).

Further, in compound (1), R2 is a lower alkyl group and +R'' is a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group, or a phenyl group (i.e., thiazolidine Derivative (1-d)) is.

[Manufacturing method (G)]

General formula % Formula % (However, R1+ represents a lower alkyl group, R', Q
, AI) [.

Y and 2 have the same meanings as above. ) and a thiazolidine derivative or its salt represented by the general formula % () (where R31 is a lower alkyl group, a cycloalkyl group,
It can also be produced by reacting with a compound represented by a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group, or a phenyl group, xS represents a reactive residue.

Furthermore, a compound (i.e., thiazolidine derivative (1-f)) in which R1 is a lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfonyl group, or benzoyl group and R2 is a hydrogen atom in compound (I) is as follows.

[Manufacturing method (H)]

Shown by the general formula % formula % (where Bit represents a lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfonyl group, or benzoyl group, and R', Q, AIK, Y and Z have the same meanings as above) It can also be produced by hydrolyzing a thiazolidine derivative or a salt thereof.

Furthermore, compounds in which H2 and R3 are hydrogen atoms in compound (I) (i.e., thiazolidine derivatives (1-g
))teeth.

[Production method (I)]

It can also be produced by hydrolyzing the thiazolidine derivative (I-f).

Raw material compound (II), (m), (!V), (V), (V
I), (■).

(IX) and 01) can be used as free forms or as salts thereof. For example, compound (■).

(V), (Vl), (■), (IX) and (XI)
As the salt of compound (n) and (I'/), common acid addition salts such as hydrochloride, hydrobromide, sulfate, and nitrate can be suitably used, and as the salt of compound (n) and (I'/), sodium salt,
Alkali metal salts such as potassium salts, organic amine salts, etc. can be suitably used. In addition, two compounds of the present invention (I
-b), (I-e) and (1-f) can also be used in the above reaction either in their free form or as their salts, such as hydrochloride, bromide, etc. Acid addition salts such as hydroxide salts, sulfates, and nitrates, alkali metal salts such as sodium salts and potassium salts, organic amine salts, and the like can be used as appropriate. Furthermore, the raw material compound (III)
, (IV), (■).

(■) and Oa) reactive residues (groups X'+X''+X3J
' and X') are preferably 1, for example, a chlorine atom,
Examples include halogen atoms such as bromine atoms, substituted or unsubstituted phenylsulfonyloxy groups such as tosyloxy groups, lower alkylsulfonyloxy groups such as methanesulfonyloxy groups, and hydroxyl groups.

Furthermore, when the group represented by the symbol R31 is a lower alkanoyl group, the compound (XI) also contains a lower saturated fatty acid or its anhydride.

(Can be carried out in the absence of the deoxidizing agent.9) Examples of deoxidizers include alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide), alkali metal carbonates (eg, potassium carbonate, sodium carbonate).

Alkali metal bicarbonate (e.g. sodium bicarbonate,
Inorganic bases such as potassium bicarbonate), triethylamine, N-methylmorpholine, pyridine.

Any organic base such as diisopropylethylamine can be suitably used. Manufacturing method (A) and (B)
Preferred reaction solvents include dimethylformamide, dimethylsulfoxide, acetonitrile, dioxane, tetrahydrofuran, acetone, methanol, ethanol, and the like.

Preferably, the reaction solvent for production method (C) is 1, for example, tetrahydrofuran, dioxane, pyridine, dimethylformamide, etc., while the solvent for production method (D) is 2
For example, tetrahydrofuran, toluene, acetonitrile, dioxane, etc. are preferred, and the temperature for manufacturing methods (A) and (B) is about 50-110°C.

It is particularly preferable to carry out the process at about 60 to 80°C, and the production method (C) is preferably carried out at about 0 to 80°C, particularly preferably about 25 to 60°C. It is particularly preferred to carry out the reaction at a temperature of about 10 to 50°C.

[Manufacturing method (E)]

The reaction between compound (1-b) or a salt thereof and compound (X) can be carried out in a suitable solvent.

Examples of the group R4 in compound (X) include lower alkyl groups such as methyl, ethyl, propyl, butyl, or substituted or unsubstituted phenyl, methylphenyl, methoxyphenyl, and ethoxyphenyl groups. Examples include phenyl group.

Examples of the group R5 include 9 such as methyl group, ethyl group,
Examples include lower alkyl groups such as propyl and butyl groups. Compound (X) has cis and trans isomers, but the single reaction can be carried out using either isomer. Examples of the solvent include methanol, ethanol, lower alkanols such as propatool, and tetrahydrofuran.

The reaction, which preferably uses dioxane, benzene, etc., is preferably carried out at a temperature of about 40 to 100°C, particularly about 60 to 80°C.

[Production method (F)] The condensation reaction between compound (Vl) or a salt thereof and compound (XI) can be carried out in a suitable solvent.

Examples of solvents include methanol and ethanol.

Preferably, tetrahydrofuran, dioxane, acetonitrile, etc. are used. This reaction is preferably carried out at about 25-100°C, especially about 60-80°C. In addition, when R2 is a hydrogen atom in compound (1-c), the production method (
F) is compound (VI) or a salt thereof and compound (XI)
It also includes a method of reacting an alkali metal salt of (R".H) with an alkali metal salt in an appropriate solvent in the presence of an acid. Examples of the alkali metal salt of compound (XI) (R"=H) include 1, for example. Potassium isocyanate, sodium isocyanate,
Preferred examples include potassium isothiocyanate and sodium isothiocyanate. Examples of acids include acetic acid,
Hydrochloric acid, sulfuric acid, etc. can be suitably used. Examples of solvents include water, tetrahydrofuran, dioxane,
Lower alkanols (e.g. methanol).

It is preferable to use ethanol, propatool) or a mixed solvent thereof. This reaction is carried out at approximately 0 to 60°C.

It is particularly preferred to carry out the reaction at a temperature of about 10 to 25°C.

[Manufacturing method (G)]

The reaction between compound (1-e) or a salt thereof and compound Oa) can be carried out by a conventional method. For example, compound (I
-e) or a salt thereof and compound (XI) (X'/hydroxyl group) can be reacted in a suitable solvent with a dehydrating agent (for example).

The reaction can be carried out in the presence of carbonyldiimidazole, dicyclohexylcarbodiimide).

On the other hand, compound (I-e) or its salt and compound 0a) (X
' - Reactive residues other than hydroxyl groups (including cases where compound (XI) is a lower fatty acid anhydride) are carried out in an appropriate solvent in the presence of a deoxidizing agent as exemplified in production methods (A) to (D). Alternatively, preferred solvents used in the zero reaction which can be carried out in the absence thereof include tetrahydrofuran, dioxane, benzene, toluene and the like. This reaction is about 0~
80℃.

Special, about. 5-6o17 implementation tao ka 3 is good.
[tau] [Production methods (H) and (■)] Hydrolysis of compound (XI) or CI-f) can be carried out according to a conventional method, for example, by treatment with a base in an appropriate solvent. As the base, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide can be suitably used. As the solvent, the solvents exemplified in production method CF) can be used, and this reaction
Preferably it is carried out at 100°C.

When the target compound (1) thus obtained is a racemate, the racemate can be separated into optical isomers. For example, a racemic compound in which R2 is a lower alkyl group and R3 is a hydrogen atom in compound (1) has an optical activity of 1
-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl halide to form a pair of diastereomers 2 Then, after separating the diastereomers into each by fractional crystallization or column chromatography, each diastereomer obtained is separated into a pair of diastereomers. Each optically active form thereof can be obtained by hydrolysis.

Raw material compounds (If), (rV), (Vl), (
■) and (XI) are new compounds. Of these,
Compound (It) can be prepared by reacting a compound represented by the general formula (wherein, Y has the same meaning as above) and compound (■) under the same conditions as explained in production method (C). can be manufactured. Further, in compound (II), R3 is di(lower alkyl)
Compounds other than phosphoryl groups can be prepared by reacting compound (ff) and compound (X[) under the same conditions as explained in production method (F). , Y and 2 have the same meanings as above), and optionally produced by reacting this compound with compound (X[) under the same conditions as explained in production method (G). be able to.

Compound (rt/) is compound (If) and general formula X''-AI
K-X' (Xi) (where y and b represent a reactive residue such as a halogen atom, a substituted or unsubstituted phenylsulfonyloxy group, or a lower alkylsulfonyloxy group, and AIK and xz have the same meanings as above.

) can be produced by reacting the compound shown in the formula (A) to (D) at about 0 to 100°C in the presence of a deoxidizer as exemplified in production methods (A) to (D). In addition, compound (■) is a compound represented by the general formula (however, AIK, Y, and xz have the same meanings as above) and compound (■) under the same conditions as explained in production method (C). It can also be produced by reaction. Furthermore, a compound in which H3 is other than a di(lower alkyl)phosphoryl group in compound (IV) can be prepared by reacting compound (m) and compound OG) under the same conditions as explained in production method (F). A compound represented by the formula % (wherein R2, ^IK, Y, Z and X2 have the same meanings as above), and if desired, the compound and the compound (
It can also be produced by reacting XI) under the same conditions as explained in production method (G).

Compound (Vl) is prepared by combining a compound represented by the general formula (where R', Q, AlK and Y have the same meanings as above) and cysteamine or a salt thereof using the manufacturing method (
It can be produced by carrying out a condensation reaction at about 25 to 100°C in the presence or absence of the deoxidizing agent exemplified in A) to (D).

Compound (■) is compound (W) or its salt and general formula: Z=
Compound (XI) can be produced by reacting C-(X')z(XX) (where Z and x4 have the same meanings as above), and compound (XI) can be produced by reacting with compound (1 -g) or a salt thereof and the general formula: Rt2X' (
Produced by reacting with a compound represented by XX[) (where X? represents a halogen atom, a substituted or unsubstituted phenylsulfonyloxy group, or a lower alkylsulfonyloxy group, and Rzz has the same meaning as above) be able to. These reactions can be carried out at about 0 to 80° C. in the presence or absence of a deoxidizing agent as exemplified in production methods (A) to (D).

Compounds (II), (IV), (V
I), (■).

(XI), (1-b), (I-e), (1-f), and (1-g) can be isolated and purified, but they are isolated from one reaction solution.

It can also be subjected to the reaction of the present invention without purification.

Compound (1,) of the present invention can be used as a medicine either in free form or in the form of a salt.

As a pharmacologically acceptable salt of compound (1).

Inorganic acid addition salts such as hydrochlorides, sulfates, nitrates, phosphates, hydrobromides, acetates, oxalates, fumarates, succinates, maleates, citrates, lactates ,
Examples include organic acid addition salts such as glucuronate, sulfamate, pyruvate, tartrate, benzenesulfonate, methanesulfonate, and alkali metal salts such as sodium salt and potassium salt. These salts can be easily obtained by treating free compound (1) with an acid or alkaline reagent in a conventional manner.

Compound (1) of the present invention or a pharmacologically acceptable salt thereof exhibits excellent cardiac inotropy and long-lasting action.

It is useful in the treatment and prevention of congestive heart disease. For example, compound (1) or a salt thereof can be used to treat, prevent, and/or improve various symptoms of heart disease, such as edema, dyspnea, cyanosis, and hypoxia. Furthermore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof does not substantially exhibit an adrenergic β-receptor stimulating effect, and therefore selectively activates the myocardium and has side effects.
For example, it has a characteristic that it has little effect on heart rate).

Compound (I) of the present invention or a salt thereof can be administered orally or parenterally. However, since compound (1) or a salt thereof exhibits an excellent cardiotonic effect even when administered orally, it is particularly preferable to use it orally.

Compound (I) of the present invention or a salt thereof can be used in conventional formulations such as tablets and powders.

It can be used as either a solid preparation such as a capsule or a granule, or a liquid preparation, but in the case of a solid preparation, the excipient is calcium carbonate.

Calcium phosphate, corn starch, potato starch, sucrose, lactose, talc, magnesium stearate, etc. can be used as appropriate. In the case of a liquid formulation, it can be used in the form of, for example, an aqueous or oily suspension, solution, syrup, or elixir. In addition, in the case of parenteral administration, the compound (1) of the present invention 9
Alternatively, its salts can be used, for example, as injections or suppositories. Injectables can be used as solutions or suspensions, and are prepared using distilled water.

Essential oils (e.g. peanut oil, corn oil).

Hydrophobic solvents (e.g. polyethylene glycol).

polypropylene glycol, lanolin, coconut oil)
etc. can be used as appropriate. Furthermore, the formulation may be sterilized and may contain other additives such as preservatives, stabilizers, etc.

The dosage of the compound (1) of the present invention or a pharmacologically acceptable salt thereof depends on the administration method and the age of the patient.

It also depends on your weight, condition, and type of disease.

Usually about 0.001 to 10 kg/day,
In particular, it is preferably about 0.003 to 5 .mu./kg.

9 In this specification, "lower alkyl group" refers to a straight or branched alkyl group having 1 to 5 carbon atoms, f"
The term "cycloalkyl group" refers to a cycloalkyl group having 3 to 7 carbon atoms, and the term ``lower alkylene group'' refers to a linear or branched alkylene group having 1 to 5 carbon atoms.

In addition, "lower alkenylene group" is a straight chain or branched alkenylene group having 2 to 6 carbon atoms, "lower alkanoyl group" is a straight chain or branched alkanoyl group having 2 to 6 carbon atoms, "lower saturated fatty acid ” refers to a straight chain or branched saturated fatty acid having 2 to 6 carbon atoms, and “lower alkoxy group” refers to a straight chain or branched alkoxy group having 1 to 5 carbon atoms, “lower alkoxycarbonyl group” means carbon number 2-6
represents a straight-chain or branched alkoxycarbonyl group.

Experimental Example 1 (Method) A male mongrel dog (body weight: 10-20 kg) was anesthetized with bendoparbital sodium (30 μg/kg, intravenous administration), and an incision was made in the left fourth intercostal space under one artificial respiration. The left heart pressure was measured using a pressure transducer.

The maximum rate of change in left heart pressure was determined. The specimen was dissolved in a 5% glucose solution and administered intravenously. The inotropic effect of the specimen was determined as the rate of increase in the maximum rate of change in left heart intracardial pressure.

(Result) The results are shown in Table 1 below.

Experimental Example 2 (Method) The isolated heart of a male guinea pig (weight: approximately 280 II) was
Lock-Ringer solution containing 2% rabbit defibrinated blood (30°C)
) was used as the perfusate and perfused using the Langendorff method.

Cardiac contractility was measured by a transducer. The specimen was dissolved in physiological saline and administered into the aortic cannula. The inotropic effect of the sample was determined as the minimum dose required to increase the cardiac contractile force of isolated guinea pig hearts.

(Result) The results are shown in Table 2 below.

Table 2 Z, CN (Example I N-methyl-2-(2-hydroxyphenyl)thiazolidine-3-carboxamide 2.38L Potassium carbonate 1.
38.9. Sodium iodide 0.7i 1-(2-chloroethyl)-4-phenylpiperazine 3.36.9 and dimethylformamide 25. ,! l mixture at 90℃
Stir for 24 hours. After the reaction, the solvent is distilled off under reduced pressure. Water is added to the residue and the mixture is extracted with ethyl acetate.

After washing the extract with dilute aqueous sodium hydroxide and water, the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent, benzene:ethyl acetate = 1:5) to obtain N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl). )
1.89 g of thiazolidine-3-carboxamide are obtained.

M, p, 127 129°C (recrystallized from ethyl acetate/n-hexane) M, p, 133-135°C (recrystallized from ethyl acetate/ether) Silica salt: M, p, 169.5-172 .5℃ (decomposed) (recrystallized from acetone) 1/2 fumarate: M, p, 169-170℃ (decomposed) (ethanol/
(recrystallized from ether) 1/2 succinate: M, p, 122-124°C (decomposed) (recrystallized from acetone-ether) Methanesulfonate: M, p, 110-117°C (decomposed) (recrystallized from acetone) Recrystallization) Hydrochloride: A, p, 195-197℃ (decomposition) (methanol/
(recrystallized from acetone/ether) dihydrochloride: M, p, 206-207°C (decomposition) (methanol/
(recrystallized from ether) Examples 2-7 Corresponding thiazolidine compounds and piperazine compounds.

The compounds listed in Table 3 below are obtained in the same manner as in Example 1.

Example 8 N-methyl-2-(2-(2-chloroethyloxy)phenyl]thiapridine-3-carboxamide 1.81,
9. N-phenylpiperazine 0.97J.

Potassium carbonate 0.83,9. Sodium iodide 0.
A mixture of 903 and dimethylformamide 25-90
Stir at ℃ for 18 hours. After the reaction, the solvent is distilled off under reduced pressure. Water is added to the residue and the mixture is extracted with ethyl acetate. After washing the extract with water, the solvent is distilled off under reduced pressure. The residue was crystallized from isopropyl ether, and the resulting crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give N-methyl-2-[2-(2-(4-phenylpiperazin-1-yl) ) ethyloxy]phenyl)thiazolidine-3-carboxamide 1.48 lI are obtained. Yield: 57.8% The physicochemical properties of the main island matched those of the specimen obtained in Example 1.

Examples 9 to 55 Compounds listed in Table 4 below are obtained in the same manner as in Example 8 from the corresponding thiazolidine compounds and piperazine compounds.

Example 56 1.66.9 potassium carbonate was converted into 2-(2-(2-(4-
(3-Fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine was added to a solution of 3.09 J in dimethylformamide, and 1.29.9 J of dimethylcarbamoyl chloride was added to the solution for 2 hours at room temperature. Then, stir at 50°C for 5 hours.

The mixture is poured into water and the mixture is extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: benzene:ethyl acetate:methanol=10:10:0.3) and then recrystallized from isopropyl ether to give N,N-dimethyl-2-(2-( 2-(4-(3-
Fluorophenyl)pisafuran-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide1.
82Ii is obtained.

M, p, 90.5-93°C Recrystallization from a mixture of ethanol and ether) Example 57
~59 The compounds listed in Table 5 below are obtained in the same manner as in Example 56 from the corresponding thiazolidine compounds and carbamoyl compounds.

Example 60 2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine 2゜0II
A solution of 30% in tetrahydrofuran was added to 2%, 15% phosgene.
After the mixture was added dropwise to a 30% toluene solution of 9, the solvent was distilled off from the mixture under reduced pressure. Tetrahydrofuran 50- for the balance
and a solution of 1.63% of methylamine in 30% of toluene were sequentially added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the mixture, the mixture was washed with water, and after drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: benzene:ethyl acetate = 1:5) and then recrystallized from a mixture of ethyl acetate and n-hexane to give N-methyl-2-(2-(2-( 1.508% of 4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide is obtained.Yield: 65%.

Examples 61-62 The compounds listed in Table 6 below are obtained in the same manner as in Example 60 from the corresponding thiazolidine compound and thiophosgene.

Example 63 (+)-N-Methyl-2-(2-C2-(4-phenypiperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carbothioamide 480■ and trans-
339 μl of 3-(4-methoxyphenyl) glycidic acid methyl ester was dissolved in 40 μl of ethanol, and the solution was diluted with 1
Heat to reflux for 1 hour.

After adding 339 μl of trans-3-(4-methoxyphenyl)glycidic acid methyl ester to the mixture and refluxing for 3 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (solvent, chloroform; ethanol = 40
(+)-N-methyl-
2-(2-(2-(4-phenypiperazin-1-yl)
350 ml of ethyloxy[phenyl)thiazolidine-3-carboxamide are obtained. Yield near 5.7% M, p,
151-152℃ [α) +152.4° (C=0.210.Chloroform) Shellate, 1/3 H,0: K, p, 170-172℃ (decomposition) (recrystallized from acetone) [α ) +88.6° (C=0.102.methanol) Examples 64 to 66 In the same manner as in Example 63, the compounds listed in Table 7 below are obtained from the corresponding thiazolidine compounds.

Example 67 Cysteamine hydrochloride 0.57L Sodium hydroxide 0.2
A mixture of 11I and 20- ethanol was stirred at room temperature for 10 minutes, and 1.5
After adding 5.9, reflux for 1 hour. The mixture is concentrated under reduced pressure to remove the solvent. The remaining amount is 20% tetrahydrofuran.
- 0.32 g of methyl isocyanate in the solution
and stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure, water is added to the resulting residue, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying, the solvent was distilled off under reduced pressure.

The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide. 1.70II is obtained. Yield is near 9.8% The physicochemical properties of this product are as shown in Example 1.
It matched the specimen obtained in .

Examples 68-122 Example 6 from the corresponding cysteamine, benzaldehyde compound and isocyanic acid (isothiocyanic acid) compound
Compounds listed in Tables 8 and 9 below are obtained in the same manner as in 7.

Example 123 2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine 3°69.
9 to tetrahydrofuran 40. ．． 19, and 0.628 g of methyl isocyanate was added to the solution at room temperature.

Stir at the same temperature for 2 hours. The solvent is distilled off from the mixture under reduced pressure, water is added to the residue, and the precipitated pores are filtered. N-methyl-2-(2
-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide 3.82.9 is obtained. Yield: 89.7% The physicochemical properties of the main island matched those of the specimen obtained in Example 1.

Examples 124-131 Corresponding thiazolidine compounds and isocyanic acid Example 1
32 Potassium Isocyanate 1.12.9. A mixture of 10- water and 2- acetic acid was added to 20-
Add to the solution and stir at room temperature for 2 hours. A mixture of 0.5 i potassium isocyanate and 0.5 i acetic acid was added to this mixture and stirred at room temperature for 2 hours.

Make the mixture alkaline with sodium bicarbonate.

The solvent is distilled off under reduced pressure. The residue was extracted with ethyl acetate,
The extract is washed with saturated brine, dried, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: ethyl acetate) and recrystallized from a mixture of ethyl acetate and ether to give 2-(2-(2-(4-(
3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide 2.6.9 is obtained.

M, 9. 142-143℃ Oxalate: M, p, 104-105℃ (decomposition) (methanol/
(Recrystallized from ether) Example 133 A solution of 1.07# sodium isocyanate in 20ml of water
- (2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine 3,0311
of 40% of ethanol, and 2.4% of acetic acid was added to the mixture.
Add 6.9 and stir at room temperature for 2 hours.

After adding 20 g of water to the mixture, the mixture was made alkaline with potassium carbonate and extracted with ethyl acetate and chloroform. The extracts are combined, washed with water and dried, and then the solvent is distilled off under reduced pressure. By recrystallizing the residue from ethyl acetate, 2-(2-(
2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide2.
Get 78#. Yield: 82.2% M, p, 137-139°C Oxalate: M, p, 146-150.5°C (decomposition) (recrystallized from acetone/methanol) Examples 134-135 With the corresponding thiazolidine compound The following compound is obtained from sodium isocyanate in the same manner as in Example 133.

2-(2-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide yield near 0.4%, p, 141-143°C (ethyl acetate 2-(2-(2-(4-phenylpiperazin-1-yl)ethylthio]phenyl)thiazolidine -3-Carboxamide yield: 5B, 4% M, p, 141-143.5°C (recrystallized from ethyl acetate) oxalate l/2 HzO: 1, p, 174-177°C (decomposed) (acetone Example 136 After refluxing a mixture of 0.63 J penzamide, 0.73 J! phosgene and 50 rIj! methylene chloride for 3 hours.

The solvent is distilled off under reduced pressure. Tetrahydrofuran 3 or! & and add 1.23 of triethylamine 2 then 1.5 of 2-lysine
．． 9. Tetrahydrofuran 10. Add the solution and stir at room temperature for 18 hours. Ethyl acetate was added to the mixture, the mixture was washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform:ethyl acetate = 773) and recrystallized from a mixture of ethyl acetate and n-hexane to give N-pesozoyl-2-(2-(2-(4-( 0.8711 of 3-fluorophenyl)piperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide is obtained.

A, p, 125-127°C Sodium salt: M, p, 118-123°C Example 137 2- (2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphenyl) To a solution of 2 g of thiazolidine in 30% of tetrahydrofuran was added 0.9.9% of ethoxycarbonyl isocyanate, and the solution was heated to 18% at room temperature.
Stir for an hour. Add 3.1 # of ethoxycarbonyl isocyanate to the mixture and stir for an additional 2 hours at room temperature. After adding water to the mixture, it is made alkaline with potassium carbonate and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off under reduced pressure.

The residue was purified by silica gel chromatography (solvent, benzene:ethyl acetate = 1:1) to give N-ethoxycarbonyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl). ) ethyloxyphenyl) thiazolidine-3-carboxamide 1.05
II is obtained by grinding into an amorphous powder.

Sodium salt: M, 9. 213-217°C Example 138 2- (2-(2-<4- (3-fluorophenyl)
Piperazin-1-yl)ethyloxyphenyl)thiazolidine 1.94.9 was dissolved in anhydrous acetone.

After adding 0.73 J of methanesulfonyl isocyanate to the solution and stirring at room temperature for 30 minutes, the solvent was distilled off under positive pressure. The residue was collected by filtration, washed with water and ether, and recrystallized from a mixture of acetone and ether to give N-methanesulfonyl-2-(2-(2-(4-(3-fluorophenyl)piperazine-1). -yl)ethyloxyphenyl)thiazolidine-3-carboxamide 1.56y is obtained.

M, p, 138-140℃ (decomposition) 1/2 oxalate 1/2H! 8: Gate, p, 171-172 °C (decomposition) Example 139 2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine 1.23 Fl Add 0.68 g of diethylphosphoryl isothiocyanate to the acetone 20W solution and stir for 1 day, then evaporate the solvent under reduced pressure. Extract the residue with chloroform, wash the extract with saturated brine, dry, and remove the solvent under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform:methanol = 40:1) and recrystallized from a mixture of ethyl acetate and ether.

N-diethylphosphoryl-2-(2-(2-(4-(3
-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide 1.49.9 is obtained. Yield: 81% M, p, 128
129°C Oxalate M, p, 79-81°C (decomposed) (recrystallized from acetone ether) Example 14O N-Methyl-2-(2-(2-(4-(3-fluorophenyl)piperazine- 0.1 J of sodium hydride (60% oily dispersion) was added to a solution of 1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide 13 in dimethylformamide.

Then the ether 5- of acetyl chloride 0.19 II
Add the solution and stir at 50°C for 20 hours. The solvent was distilled off from the mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By purifying the residue with silica gel chromatography (solvent, ethyl acetate: n-hexane = 4 = 1),
N-acetyl-N-methyl-2-(2-(2-(4-(
3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide 0°323 is obtained as an oil.

Mass (m/e): 486. 386 oxalate: A, p, 110-117°C (decomposition) (recrystallized from acetone/methanol/n-hexane) Example 141~
142 The following compound is obtained in the same manner as in Example 140 from the corresponding thiazolidine compound and alkanoyl compound.

N-acetyl-N-methyl-2-(2-(2-(4-(
3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide Yield near 7.2% Oil Mass (a+/e): 502 (M'')
, 429.386. ．． 207 Oxalate: ? 1.9. 106-109℃ (decomposition) (acetone/
recrystallized from ether) N-acetyl-N-methyl-2-(2-[3-(4phenylpiperazin-1-yl)propylthio]phenyl)
Thiazolidine-3-carbothioamide yield: S2. O% oxalate: Lp, 135-142°C (decomposed) (recrystallized from acetone) Example 143 N-Methyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl) ) ethyloxyphphenyl) thiazolidine-3-carboxamide 2.22.9.
Propionic acid chloride 1.39.9. A mixture of 2.53 # of triethylamine and 50 # of toluene was refluxed with stirring for 2.5 days, and then the solvent was distilled off under reduced pressure.

Add water to the residue and extract with ethyl acetate. The extract is washed with saturated aqueous sodium bicarbonate and saturated brine, dried, and the solvent is distilled off under reduced pressure. The remainder was removed by silica gel chromatography (solvent).

By purifying with chloroform:ethyl acetate=3:1), N-methyl-N-propionyl-2-(2-
(2-(4-(3-fluorophenyl)piperazine-1
-yl)ethyloxyphphenyl)thiazolidine-3-
0.3011 of carboxamide is obtained as oily sauce.

Mass (m/e): 500 (M'') Oxalate: M, p, 125-127℃ (7 cells): / ・x-
Example 144 The following compound is obtained in the same manner as in Example 143 from the corresponding thiazolidine compound and benzoyl compound.

N-benzoyl-N-methyl-2-(2-(2-(4-
(3-Fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide Yield: St, S% M, 9. 119-121°C (recrystallized from ethyl acetate-fi-hexane) Oxalate: M+p, 102-112°C (recrystallized from ethanol ether) Example 145 (112-(2-(2-(4-(3) 1.081 of -fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide is dissolved in 20- of tetrahydrofuran and 0.7i of triethylamine is added to the solution.0.59 of acetyl chloride is added to the mixture.
．． 9 Tetrahydrofuran 1rI! 1 solution and stirred at room temperature for 3 days. Add 0.5 acetyl chloride to this mixture.
9II and 0.76.9% of triethylamine were added, and after stirring at room temperature for an additional 24 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with saturated brine, sodium bicarbonate water and brine, dried, and the solvent was distilled off under reduced pressure.

The remaining amount is 1. Ka,,-7,,wa7. Guu, ee, solvent,
N,0-diacetyl-2-(2-(2-(4
-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3 to carpoimidisocnic acid 0.72.9 is obtained. Yield: 56% River, ρ, 114-115°C Oxalate: M, 9. 157-158℃ (decomposition) (recrystallized from ethanol) (2) N,O-diacetyl-2-(2-(27(4-()
3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboimidifukuic acid 0.59. ? ethanol 15. The mixture is dissolved in a mixture of il and tetrahydrofuran, 1.34% of a 10% sodium hydroxide solution is added to the solution under water cooling, and the mixture is stirred at the same temperature for 15 minutes. The mixture was neutralized with 10% hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with brine, dried, and the solvent was distilled off under reduced pressure. By recrystallizing the residue from a mixture of ethyl acetate and ether,
N-acetyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide 0°493 is obtained. Yield: 90% ?1 .p, 142-143°C Oxalate: M, 9. 165-166°C (decomposed) (recrystallized from ethanol) Example 146 (1) 2- (2-(2-(4-phenylpiperazine-
1-inoC)ethyloxyphphenyl)thiazolidine-
3-carboxamide 1.49.9! , Add 0.311 # of acetyl chloride to a mixture of 1.27 F of triethylamine and 60 °C of benzene at 50°C, and stir at 80°C for 1.5 hours. Add 0.5 acetyl chloride to the mixture
Add 63JF and triethylamine 0.7283 and add 80
Stir at ℃ for 2.5 hours. After washing the mixture with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: benzene; ethyl acetate = 1:1) and recrystallized from ether to give N,0-diacetyl-2-(2-(2-(4-phenylpiperazine-1).
-yl)ethyloxyphenyl)thiazolidine-3-
1.25# of calpoimidic acid is obtained. Yield near 0%M
, p, 120-123.5°C (2) N,O-diacetyl-2-(2-(2-(4
-phenylpiperazine-■-yl)ethyloxyphenyl)thiazolidine-3-carboimidic acid i, i9
y, ethanol 20-9 sodium hydroxide 0.2871
? A mixture of 2.7 W, water and 20 W& of tetrahydrofuran was stirred for 1.5 hours under water cooling, and then neutralized with 10% hydrochloric acid. The mixture was extracted with ethyl acetate, the extract was washed with water, dried, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel chromatography (solvent: ethyl acetate:chloroform = 5:1) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain N.
-Acetyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide 0°72.9 is obtained. Yield: 66
．． 1%, p, 137-139°C 1/2 oxalate, 1/2 H, 0: M, p. 164-168°C (decomposition) (recrystallized from acetone) Example 147 N-acetyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphenyl)thiazolidine- 3-carbothioamide 2.87.
9.10% sodium hydroxide water 7.3- and ethanol 60.1! After refluxing the mixture for 20 hours, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent, chloroform:ethyl acetate = 2:1) to obtain 2-(2
-(2-(4-(3-fluorophenyl)piperazine-
1-yl)ethyloxyphenyl)thiazolidine-3
-carbothioamide 2.36.9 is obtained. Yield: 90% M, p, 136-137°C (recrystallized from ether)
1/2 Fumarate: M, p, 164-165°C (recrystallized from ethanol-ether) Example 148 (1) Sodium hydride (50% oily dispersion) Suspension of 0°643 in dimethylformamide 55- Add (±)-N-methyl-2-(2-C2-<4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide 5°3319 to the liquid under water cooling and stir at the same temperature for 10 minutes. , and further stirred for 30 minutes at room temperature. (-)-1-(2-naphthylsulfonyl)pyrrolidine-
A solution of 4.00 # of 2-carbonyl chloride in dimethylformamide was added under water cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. After adding ice water to the mixture, it is extracted with ethyl acetate, and the extract is washed with saturated sodium bicarbonate water and water, dried, and then the solvent is distilled off under reduced pressure. The remaining residue was subjected to silica gel column chromatography (solvent.

The following compound is obtained by treatment with benzene:ethyl acetate=3:2).

(+)-N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl]-2-(2-[2
-(4-phenylpiperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carbothioamide Yield: 1.1 (NF M, p, 191-192°C (recrystallized from ethyl acetate/n-hexane) [α) +27.2' (C=0.206.chloroform)N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl)-2-(2-(2
-(4-phenylpiperazin-1-yl)ethyloxyphenyl)≠azolidine-3-carbothioamide and 2
- Yield of mixture with (2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde: o, say, caramel (21(+)-N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine- 2-carbonyl]-2-(2
-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide 1.06II was dissolved in a mixture of tetrahydrofuran 40- and methanol 40-.

To this solution is added a solution of 120 μm of sodium hydroxide in 3 parts of water while stirring under water cooling. After stirring the mixture at room temperature for 16 hours, the solvent was distilled off under reduced pressure. After adding water to the residual aroma, it is extracted with methylene chloride, the extract is washed with water, dried, and the solvent is distilled off under reduced pressure.

The residual aroma was purified by silica gel chromatography (solvent: benzene: ethyl acetate = 3:2) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain (+)-N
-Methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-
600 μ of 3-carbothioamide are obtained. Yield: 93.3
% M, p, 144-145.5°C [α) +145.7° (C=0.365.chloroform) fumarate 1/2 H,0: M, p, 13B-144°C (decomposed) ( acetone n
- recrystallized from hexane) [α) +65.0° (C=0.150, methanol) (3) N-methyl-N-(
1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl]-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-
0.88 g of a mixture of 3-carbothioamide and 2-(2-(4-phenylpiperazin-1-yl)ethyloxyfubenzaldehyde) was dissolved in a mixture of tetrahydrofuran 35- and methanol 35-, and hydroxylated in the solution. A 3-solution of 100 μm of sodium in water is added under water cooling and stirring. The mixture is stirred at room temperature for 24 hours and the solvent is distilled off under reduced pressure.

After adding water to the residual aroma, it is extracted with ethyl acetate, the extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The residual aroma was purified by silica gel chromatography (ml benzene:ethyl acetate = 12) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain (-)-N-methyl-
108 ml of 2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide are obtained.

M, p, 143-145°C [α) -139,8° (C=0.265, chloroform) Example 149 (1) Sodium hydride (50% oily dispersion) 0°641 (±) -N- Methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide 5.331 (
+)-1-(2-naphthylsulfonyl)pyrrolidine-2
-Carbonyl chloride 4.00# and dimethylformamide 95- are treated in the same manner as in Example 148 (1) to obtain the following compound.

(-)-N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl)-2-(2-(2
-(4-Phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide Yield: 1.0B, 9M, p, 191-192°C (recrystallized from ethyl acetate/n-hexane) (α ) -26,5° (C=0.200, chloroform)N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl)-2-(2-(2
-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide and 2
Yield of mixture with -(2-(4-phenylpiperazin-1-yl)ethyloxyfubenzaldehyde: 1°04', 9. Caramel (2) (-)-N-methyl-N-(1-(2- naphthylsulfonyl)pyrrolidine-2-carbonyl]-2-
(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide 1.051 Tetrahydrofuran 40-9, methanol 40-9 Sodium hydroxide 120 ■ and water 3- By processing in the same manner as (2) of 148, (-
)-N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide 6QO■ is obtained. Yield: 9
4.2% Lp, 144-145°C (ethyl acetate-n
- recrystallized from hexane) [α) -145,4' (C=0.216.chloroform) fumarate 1/2 H,0: M, p, 13B-144,5℃ (decomposed) (acetone・Recrystallized from n-hexane) [α]-67,3' (C=0.110, methanol) (3) N-methyl-N-(1-(
2-naphthylsulfonyl)pyrrolidine-2-carbonyl) -2-(2-(2-(4-phenylpiperazine-1)
-yl)ethyloxyphenyl)thiazolidine-3-
A mixture of carbothioamide and 2-(2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde (1.04 L) was prepared from Example 148 ( By processing in the same way as 3), (+)
-N-Methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide 205 ml is obtained.

Lp, 144-145℃ (ethyacetate) L/・n −
Recrystallized from hexane) [α) +141.7° (C = 0.206.Chloroform) [Preparation of raw material compound] Production example 1 (However, H2 and 2 have the same meanings as above.) Compound (XXn) and cysteamine The reaction between compound (XIX) and cysteamine or its salt can be carried out in the same manner as the reaction between compound (XIX) and cysteamine or its salt, and the reaction between 4* compound (ff-a) and compound Oa) can be carried out according to production method (F). It can be implemented similarly.

Specific examples of the above reaction are as follows.

Cysteamine Hydrochloride 5.65.9. Sodium hydroxide 2
A mixture of Ii and ethanol 150- is refluxed for 15 minutes to salicylaldehyde 6,1,! F ethanol 30.
1? Add the solution and reflux for an additional 2 hours. The solvent of the mixture was distilled off under reduced pressure, and after benzene was added to the residue, the solvent was distilled off under reduced pressure. Add 120% of tetrahydrofuran to the residue and stir at room temperature for 1.5 hours.

Add 3.5 g of methyl isocyanate to the mixture and stir at room temperature for 30 minutes.
After stirring for a minute, the mixture is refluxed for an additional hour. The solvent was distilled off from the mixture under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration. Wash the crystals with water and ethyl acetate.

After drying, recrystallization from ethanol yields N-methyl-2-(2-hydroxyphenyl)thiazolidine-3.
- carboxamide 8.97II is obtained.

186-188°C (decomposition) In the same manner as above, the compounds listed in Table 11 below are obtained from the corresponding starting compounds.

Table 11: Substitution position of the group HO- on the benzene ring when the carbon atom is in the 1st position.

Production Example 2 (However, AIK, be able to.

Specific examples of the above reaction are as follows.

2-Hydroxybenzaldehyde 40.0.9.1-Chloro-2-tosyloxyethane 843 and 50 Il of potassium carbonate are added to dimethylformamide 270 and stirred at room temperature for 3 days. The solvent of the mixture was distilled off under reduced pressure to reduce the volume to half, and about 600W of water was added to the residual aroma, and the mixture was extracted with ether. The extract was washed with 10% aqueous sodium hydroxide and water, dried, and then the solvent was distilled off under reduced pressure. By distilling the residual aroma under reduced pressure.

2-(2-chloroethyloxy)penaldehyde51.
9 g are obtained as a colorless oil.

B, p, 116-118℃ (0,2-0,3 Tsuru Hg
) The physicochemical properties of the main island are described in The Journal of Organic Chemistry (J, Org, Che Intestine,
) Volume 18, pages 1380-1402 (1953).

From the corresponding raw material compounds, the following No. 12 is prepared in the same manner as above.
The compounds listed in the table are obtained.

Table 12 In the above table, compounds N11.2.3 and 5 are raw material compound X
"-AIK-X', where Xh is Br, fish 4 is the group X when X6 is the elementary atom at the 1st position"-AIK-0-
substitution position on the benzene ring.

Production Example 3] (However, R2, ^IK, Z and x2 have the same meanings as above.) The reaction between compound (XXI) and cysteamine or its salt is the same as the reaction between compound (XIX) and cysteamine or its salt. Compound (Xll-a) which can be carried out similarly and follows
The reaction between compound (XI) and compound (XI) can be carried out in the same manner as in production method (F).

A mixture of 111I, 6.81 J of cysteamine hydrochloride, 2.43 J of sodium hydroxide and 60 J of ethanol was stirred at room temperature for 5 hours, and then the solvent was distilled off under reduced pressure. Dissolve the residual fragrance in 60% of tetrahydrofuran.

Add 3.42.9 g of methyl isocyanate to the solution and stir at room temperature for 15 hours. The solvent was distilled off from the mixture under reduced pressure, water was added to the residual aroma, and the precipitated crystals were collected by filtration. By washing the crystals with water and recrystallizing them from ethanol, N-methyl-2-
(2-(2-chloroethyloxy)phenyl)thiazolidine-3-carboxamide 12.68.9 is obtained.

M, p, 166-167°C From the corresponding raw material compound, the following 13th
The compounds listed in the table are obtained.

Table 13 (Note 4): Substitution position on the benzene ring of the group X"-AIK-0- when the carbon atom of the benzene ring substituted by the thiazolidyl group is the 1st position.

Production example 4 N-methyl-2-(4-hydroxyphenyl)thiazolidine-3-carbothioamide 5,9.1-chloro-2-
Tosyloxyethane 4.63 potassium carbonate! A mixture of ram 4.9 and dimethylformamide 20 was stirred at room temperature for 2 days and then at 50°C for 20 hours.

The solvent is then distilled off under reduced pressure. Add water to the residue and extract with ethyl acetate. The extract is washed with 10% sodium hydroxide solution and water, and after drying, the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: ethyl acetate:chloroform = 2:8) and recrystallized from ethanol.

N-Methyl-2-(4-(2-chloroethyloxy)phenyl)thiazolidine-3-carbothioamide 3.0?
, we get 9.

M-p, 114-116°C From the corresponding raw material compound, the following 14th
The compounds listed in the table are obtained.

Table 14 (Note 5): Substitution position on the benzene ring of the group X''-AIK-Y- when the carbon atom of the benzene ring substituted by the thiazolidyl group is the 1st position.

Production Example 5 (However, AlK, xl and X6 have the same meanings as above.) This reaction can be carried out in the same manner as Production Example 2.

Specific examples of the above reaction are as follows.

2-(Hydroxymethyl)thiophenol 11.9Ll
A mixture of 35.44 i of -bromo-3-chloropropane, 11.58 # of potassium carbonate, and 150 # of dimethylformamide is stirred at room temperature for 2 hours, insoluble matter is filtered off, and the solvent is distilled off from the liquid under reduced pressure. Add water to the residue and extract with ethyl acetate. Wash the extract with water.

After drying, the solvent is distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 2-(3-chloropropylthio)benzyl alcohol16. Obtain IF.

B, p, 14B-159℃(0,25flHg)2
-(Hydroxymethyl)thiophenol 303 and 1-
Bromo-2-chloroethane 76.8 #t - By treating in the same manner as above, 2- (2-chloroethylthio)
Benzyl alcohol 32. Obtained as an Elt-8 colored oil.

B, p, 143-148°C (0.6 mHg) Production Example 6 (However, R6 represents a lower alkyl group, AIK,
and X6 have the same meanings as above. ) Compound (XX■) is obtained by reducing compound (XXVI) from 0 to 10% using a reducing agent such as sodium borohydride or zinc and acetic acid.
By reducing at 0°C, the subsequent reaction between compound (XX■) and compound (XXVI) can be carried out in the same manner as in Production Example 2. Reduction of compound (XX■) can be carried out by treatment with a reducing agent such as lithium aluminum hydride or lithium borohydride at 0 to 30°C.

Specific examples of the above reaction are as follows.

33.4 g of bis(4-methoxycarbonylphenyl) disulfide is suspended in a mixture of 200 mm of dioxane and 120 mm of methanol, and 5.1 g of sodium borohydride is added to the suspension while stirring under water cooling. Sodium hydride (60% oily dispersion) 6I2 then 1-
- Bromo-3-chloropropane 37.83 dioxane 120 nJ! Add the solution, stir at room temperature for 1 hour, and reflux for an additional hour. Sodium borohydride 411.
Add 4 g of sodium hydride (50% oily dispersion) and 811 l of 1-bromo-3-chloropropane and reflux for 30 minutes.

The mixture was poured into water and extracted with chloroform.

After washing the extract with water and drying, the solvent is distilled off under reduced pressure, and the residual aroma is distilled off under reduced pressure to obtain 31.93 ml of 4-(3-chloropropylthio)benzoic acid methyl ester as a pale yellow oil.

B, p, 155-164°C (0,3+mf 1g) Lithium aluminum hydride 53 is suspended in 200% of tetrahydrofuran, and the suspension is added with 4-(3-chloropropylthio)benzoic acid methyl ester 31.9.9 in tetrahydrofuran. 200. & Add the solution at 5-15°C and stir at room temperature for 45 minutes. Water is added to the mixture at a temperature below 20°C, and insoluble matter is filtered off.

The solvent of the filtrate was distilled off under reduced pressure, and the residual aroma was distilled off under reduced pressure to obtain 24.1 g of 4-(3-chloropropylthio)benzyl alcohol as an oil.

B, p, at 144-154°C (0,35 mHg))
Bis(4-methoxycarbonylphenyl) disulfide 40.11.1-bromo-2-chloroethano 38J,
Sodium borohydride 13.9° Sodium hydride (
60% oily dispersion) 13.6 L of methanol (100) and dioxane (320 rI&) are treated in the same manner as in (a) above to obtain 36 g of 4-(2-chloroethylthio)benzoic acid methyl ester as a crude product. This crude product (36,9) was converted into 4.63 liters of lithium aluminum hydride.
4-(2-chloroethylthio) by treatment with g
Benzyl alcohol 16.3# is obtained as a crude product. This crude product 16.3.9. A mixture of 10% hydrochloric acid and 100% ethanol was stirred at 50° C. for 1.5 hours, and then the solvent was distilled off under reduced pressure. Add water to the residual fragrance and extract with ethyl acetate. Wash the extract with sodium bicarbonate water and water,
After drying, the solvent is distilled off under reduced pressure.

The residual aroma is purified by silica gel chromatography (solvent: chloroform) to obtain 4-(2-chloroethylthio)benzyl alcohol 1019 as an oil.

Mass (m/e): 202.204.15
3.123.107 Manufacturing Example 7 (However, AIK and xZ have the same meaning as above)
This oxidation reaction was carried out using dimethyl sulfoxide and oxalyl chloride in the presence of a tertiary amine.
This can be carried out by treatment at ~30° C. or by treating the compound with manganese dioxide.

Specific examples of the above reaction are as follows.

Dimethyl sulfoxide 27.8. ? methylene chloride 50
- Prepare the solution of 22.6# oxalyl chloride in methylene chloride 4
5. Add 2-(2-chloroethylthio)benzyl alcohol 3 to the solution over 1 hour at 60°C.
Add 50 J of methylene chloride solution of 2.7.9 and stir for 15 minutes. Triethylamine in the mixture? Add 50 J of methylene chloride solution of 1.8.9 at -60°C and stir at the same temperature for 5 minutes and then at room temperature for 1 hour. Add water to the mixture and separate the methylene chloride layer. After washing the methylene chloride solution with water and drying, the solvent is distilled off under reduced pressure, and the residual aroma is distilled off under reduced pressure.

2-(2-chloroethylthio)benzaldehyde29.
7.9 is obtained as an oil.

B, p, 135-140°C (0,4 Hg) Compounds listed in Table 15 below are obtained from the corresponding starting compounds in the same manner as above.

Table 15 (Note 6): Substitution position on the benzene ring of the group X''-AIK-S- when the carbon atom of the benzene ring substituted by the formyl group is set as the 1st position.

Production Example 8 (XVI-b) (However, R2, ^IK, Z and X2 have the same meanings as above.) The reaction between compound (XXIX) and cysteamine or its salt is the reaction between compound (X It can be carried out similarly to the reaction with salt, followed by compound (Xll-b)
The reaction between and compound Oa) can be carried out in the same manner as in production method (F).

Specific examples of the above reaction are as follows.

Sodium hydroxide 3.34g and cysteamine hydrochloride 9
．． 211I was added to a solution of 14.8 J of 2-(2-chloroethylthio)benzaldehyde in 300 g of ethanol, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off from the mixture under reduced pressure.
To the remaining residue, 300% of tetrahydrofuran and 5.04% of methyl isocyanate were added, and the mixture was stirred at room temperature for 20 hours. The solvent of the mixture was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform.

After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (solvent, chloroform:ethanol = 50:1) to obtain N-methyl-2-(2-(2-chloro Ethylthio)phenylftiapridine-3-carboxamide 11.3, # is obtained.

M, p, 123-125°C From the corresponding raw material compound, in the same manner as above, the above No. L6
The compounds listed in the table are obtained.

Table 16 (X”=CH, R”=CH3) (Note 7): When the carbon atom of the benzene ring □ substituted by the thiazolidyl group is set as the 1st position, the Replacement position.

Production Example 9 (However, R', Q, 'AIK and ) is obtained.

Specific examples of the above reaction are as follows.

2-Hydroxybenzaldehyde sodium salt 3.8
B, 9.1-(3-chloropropyl)-4-phenylpiperazine dihydrochloride? , OO#, potassium carbonate 6.8
A mixture of 1 and 50 d of dimethylformamide is stirred at 60 to 70° C. under a nitrogen gas stream for 15 hours, and then the solvent is distilled off under reduced pressure to bring the total amount to 25. Water is added to the residual aroma and extracted with ether. After washing the extract with water and drying, the solvent is distilled off under reduced pressure.

By purifying the residual aroma with silica gel chromatography (solvent, chloroform: methanol = 99:1),
5.42 # of 2-(3-(4-phenylpiperazin-1-yl)propyloxy)benzaldehyde is obtained as an oil.

The physicochemical properties of ice crystals are described in Indian Journal of Chemistry Section B (Indian.

J, Chen+, 5ect B),, 21 B,
It corresponded to the specimen described on pages 435-439 (1982).

From the corresponding raw material compound, the following No. 17 is prepared in the same manner as above.
The compounds listed in the table are obtained.

Table 17 (Q=single bond, AIK=-(CHz)s-, X'=
CI) (Note 8): Group substitution position when the carbon atom of the benzene ring to which the formyl group is substituted is the 1st position.

(However, AIK and x2 have the same meaning as above.

) This reaction is carried out in the presence of an acid such as phosphoric acid or hydrochloric acid.
It can be carried out at 0°C.

Specific examples of the above reaction are as follows.

2-(2-chloroethyloxy)benzaldehyde 46
．． 85% phosphoric acid (0.5) is added to a solution of 5II and ethylene glycol 33.2.9 in benzene, and refluxed for about 18 hours with stirring while removing the water produced. After the reaction, the mixture is cooled with ice and made alkaline with saturated aqueous sodium bicarbonate. Separate the benzene layer, wash with saturated saline,
After drying, the solvent is distilled off under reduced pressure. By distilling the residual aroma under reduced pressure, 56.9 g of 2-(2-chloroethyloxy)benzaldehyde ethylene acecool is obtained as a colorless oil.

B, 9. 130-135°C (0.3w*Hg) Compounds listed in Table 18 below are obtained from the corresponding starting compounds in the same manner as above.

Table 18 (Note 9): Substitution position on the benzene ring of the group X"-AIK-0- when the carbon atom of the benzene ring to which the acetal group is substituted is the 1st position.

Production Example 11 (However, R', Q, AIK and G have the same meanings as above.) The reaction between compound (X
It can be carried out in the same manner as B), and then the compound (XXX
The acid treatment of I) can be carried out using an acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid at 0 to 100°C, and thus the compound (
XIX-a) is obtained.

Specific examples of the above reaction are as follows.

2-(2-chloroethyloxy)benzaldehyde ethylene acetal 2.29I1. A suspension of 1.73 L of N-phenylpiperazine and 1.50.9 L of anhydrous potassium carbonate and 15-dimethylformamide was heated under a stream of argon gas for 70 minutes.
After stirring at ~80°C for about 18 hours.

The solvent is distilled off under reduced pressure. Add water to the residual fragrance and extract with ether. After washing the extract with water and drying, the solvent is distilled off under reduced pressure.

Dissolve the residual aroma in methanol lO-.

Add 10% hydrochloric acid to the solution and heat at 60 to 70°C for 10 to 20 minutes. The mixture is made alkaline with 10% aqueous sodium hydroxide and extracted with ether.

After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residual aroma was purified by silica gel chromatography (solvent: ethyl acetate:chloroform-2=8) to obtain 2- (2-
(4-phenylpiperazin-1-yl)ethyloxy]
1.33 J of benzaldehyde are obtained as a colorless oil.

From the corresponding raw material compound, the following No. 19 is prepared in the same manner as above.
The compounds listed in the table are obtained.

Table 19 (Part 1) [Q-Single bond, ^1)k-(CHz)t-2 substitution position (Note 8): 2nd position] (Part 2) (Q=Single bond, AIK= -(CHz)+-1 Substitution position (Note 8) = 2nd position] (Part 3) [Substitution position (Note 8) = 2nd position] (Note 8); The substitution position is as in (Note 8) in Table 17. Represents the same meaning.

Production Example 12 (However, R', Q, AIK and XI have the same meanings as above.) This reaction can be carried out in the same manner as Production Method (A).

Specific examples of the above reaction are as follows.

2-(hydroxymethyl)thiophenol 1.56y,
A mixture of 3.77 L of 1-(3-chloropropyl)-4-phenylpiperazine dihydrochloride, 5.02 J of potassium carbonate, and 40 J of dimethylformamide was stirred at 50°C for 6 hours, and after removing insoluble matter by filtration, the filtrate was The solvent is distilled off under reduced pressure.

Add water to the residual fragrance and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residual aroma was crystallized with n-hexane and collected by filtration to obtain 2-(3-(4-phenylpiperazin-I-yl)propylthio]benzyl alcohol3. Get 42.9.

H3P, 99-103°C (isopropyl ether,
(Recrystallization from ethyl acetate) Production Example 13 (However, R', Q, AIK and X2 have the same meanings as above.) This reaction can be carried out in the same manner as Production Method (B).

Specific examples of the above reaction are as follows.

2-(3-chloropropylthio)benzyl alcohol 2
．． A mixture of 6g of N-phenylpiperazine, 1.95.9° of potassium carbonate, 1.66Il of potassium carbonate, and 30° of dimethylformamide was stirred at 50°C for 7 hours, and 0.39# of N-phenylpiperazine was added thereto, and the mixture was further stirred at 60°C for 15 hours. Stir at ℃ for 4 hours. Filter off insoluble matter.

The solvent of the filtrate is distilled off under reduced pressure. Water is added to the residue, extracted with ethyl acetate, the extract is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (solvent: chloroform:methanol-20:1) to obtain 2-(3-(4-phenylpiperazin-1-yl)propylthio]benzyl alcohol 2.4.9.

M, 9. 99-103°C (recrystallized from isopropyl ether/ethyl acetate) 2-(2-chloroethylthio)benzyl alcohol 12
．． 16.9. By treating N-phenylpiperazine 9.73i potassium carbonate 9.12.9 and dimethylformamide 80 in the same manner as above, 2-(2-(4-phenylpiperazin-1-yl)ethylthio]benzyl alcohol 6, Get 03.9.

M, p, 72-74°C (recrystallized from isopropyl ether) Production Example 14 (However, R', Q and AIK have the same meanings as above.) This oxidation reaction is carried out in the same manner as Production Example 7. I can do it.

Specific examples of the above reaction are as follows.

Dimethyl sulfoxide 1.1.9 in methylene chloride 5 - solution of oxalyl chloride 0.894.9 in methylene chloride 2
〇- Add to the solution at -50℃ and add 2- (3-(
A solution of 2.19.9 of 4-phenylpiperazin-1-yl)propylthio]benzyl alcohol in 10-methylene chloride was added at -50°C, and the mixture was stirred at the same temperature for 15 minutes. 3.24 ml of triethylamine was added to the mixture, and the mixture was stirred at -50°C for 5 minutes and then at room temperature for 1 hour. The mixture was poured into water and extracted with methylene chloride. After washing the extract with water and drying, the solvent was distilled off under reduced pressure.

The residue was purified by silica gel chromatography (solvent, ethyl acetate:chloroform = 1:6) to obtain 2.
- 1.973 of (3-(4-phenylpiperazin-1-yl)propylthio]benzaldehyde are obtained as an oil.

2- (2-(4-phenylpiperazin-1-yl)ethylthio]benzyl alcohol 6, OL oxalic acid chloride 2.60.9. Dimethyl sulfoxide 3.2
By treating I and triethylamine 9.3.9 as above, 2-(2-(4-phenylpiperazin-1-yl)ethylthio]benzaldehyde 5.55
．． Get 9.

M, p, 73-76°C Production example 15 Cysteamine hydrochloride 5.75Ii in ethanol 200-
2.21.9 of sodium hydroxide was added to the solution and the mixture was
A solution of 14.283 ethyloxybenzaldehyde in 100% ethanol was added and stirred at room temperature for 2 hours. The solvent was distilled off from the mixture under reduced pressure, and the residue was dissolved in ethyl acetate. After washing and drying the ethyl acetate solution, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ether to give 2- (2-
(2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl)thiazolidine 15.54.9 is obtained.

M, p, 77-86℃ from the corresponding starting compound in the same manner as above.

The compounds listed in Table 20 below are obtained.

Table 20 (Q=single bond, AIK=-(CHz) !-) (Note 10): Group RI-q-N'' when the carbon atom of the benzene ring substituted by the thiazolidyl group is the 1st position)v Substitution position on the benzene ring of -Atx-y-.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, a lower alkylene group, or a lower alkenylene group , A.I.
K is a lower alkylene group, R^2 and R^3 are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group,
A lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group, a phenyl group or a di(lower alkyl)phosphoryl group, Y and Z are the same or different and represent an oxygen atom or a sulfur atom. ) A thiazolidine derivative or a salt thereof. 2. (A) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (However, R^2 and R^3 are the same or different and are hydrogen atom, lower alkyl group, cycloalkyl group, lower alkanoyl group, A thiazolidine derivative represented by a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group, a phenyl group or a di(lower alkyl)phosphoryl group, Y and Z are the same or different and represent an oxygen atom or a sulfur atom) or a salt thereof. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K represents a lower alkylene group, and X^1 represents a reactive residue. ) (B) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (However, X^2 represents a reactive residue, AIK, R ^2,
R^3, Y and Z have the same meanings as above. ) Thiazolidine derivatives or their salts represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (V) (However, R^1 and Q have the same meanings as above.) Piperazine derivatives or their salts (C) A thiazolidine derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VI) (However, R^1, Q, AIK and Y have the same meanings as above.) or its salt and general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VII) (However, X^3 represents a reactive residue, and R^2, R^3 and Z have the same meanings as above. ) or (D) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIII) (However, X^4 represents a reactive residue, R^1, Q, AI
K, Y and Z have the same meanings as above. ) Thiazolidine derivatives or salts thereof and amine compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IX) (However, R^2 and R^3 have the same meanings as above.) There are general formulas ▲mathematical formulas, chemical formulas, tables, etc.▼(I) (However, R^1, Q, AIK, R ^2, R^3, Y and Z have the same meanings as above.) A method for producing a thiazolidine derivative or a salt thereof. 3. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1-b) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K is a lower alkylene group, Y is an oxygen atom or a sulfur atom, R
^2 and R^3 are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group,
Represents a benzoyl group, a phenyl group, or a di(lower alkyl)phosphoryl group. ) and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (X) (However, R^4 is a lower alkyl group or a substituted or unsubstituted phenyl group, and R^5 is a lower alkyl group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1-a) (However, R^1, Q, AIK, Y, R^2 and R^3 have the same meanings as above.) A method for producing a thiazolidine derivative or a salt thereof. 4. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VI) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K represents a lower alkylene group, and Y represents an oxygen atom or a sulfur atom. ) Thiazolidine derivatives or salts thereof and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (X I ) (However, R^2 is a hydrogen atom, lower alkyl group, cycloalkyl group, lower alkanoyl group, lower alkoxy carbonyl group, lower alkylsulfonyl group, benzoyl group, phenyl group, or di(lower alkyl)phosphoryl group, Z represents an oxygen atom or a sulfur atom), and if necessary, convert the product into its salt. There are general formulas characterized by the following: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1-c) (However, R^1, Q, AIK, Y, R^2 and Z have the same meanings as above. ) A method for producing a thiazolidine derivative or a salt thereof. 5. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1-e) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K is a lower alkylene group, R^2^1 is a lower alkyl group,
Y and Z are the same or different and represent an oxygen atom or a sulfur atom. ) A thiazolidine derivative or its salt represented by the general formula R^3^1X^5 (XII) (However, R^3^1 is a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkyl group) sulfonyl group, benzoyl group or phenyl group, R^5 represents a reactive residue), and if necessary, the product is converted into a salt thereof. There are chemical formulas, tables, etc.▼(1-d) (However, R^1, Q, AIK, R^2^1, R^3^1
, Y and Z have the same meanings as above. ) A method for producing a thiazolidine derivative or a salt thereof. 6. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (XIII) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K is a lower alkylene group, R^2^2 is a lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfonyl group or benzoyl group, and Y and Z are the same or different and represent an oxygen atom or a sulfur atom. ) is a general formula characterized by hydrolyzing a thiazolidine derivative or its salt, and if necessary converting the product into its salt.There are mathematical formulas, chemical formulas, tables, etc.▼(1-f) (However, R ^1, Q, AIK, R^2^2, Y and Z have the same meanings as above.) A method for producing a thiazolidine derivative or a salt thereof. 7. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1-f) (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K is a lower alkylene group, R^2^2 is a lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfonyl group or benzoyl group, and Y and Z are the same or different and represent an oxygen atom or a sulfur atom. ) is a general formula characterized by hydrolyzing a thiazolidine derivative or its salt and, if necessary, converting the product into its salt.There are mathematical formulas, chemical formulas, tables, etc.▼(1-g) (However, R ^1, Q, AIK, Y and Z have the same meanings as above.) A method for producing a thiazolidine derivative or a salt thereof. 8. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (However, R^2 and R^3 are the same or different and are a hydrogen atom, lower alkyl group, cycloalkyl group, lower alkanoyl group, lower alkoxycarbonyl , lower alkylsulfonyl group, benzoyl group, phenyl group or di(lower alkyl)phosphoryl group, Y and Z are the same or different and represent an oxygen atom or a sulfur atom) or a salt thereof. 9. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, AIK is a lower alkylene group, R^2 and R^3
are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a benzoyl group,
a phenyl group or a di(lower alkyl)phosphoryl group, Y and Z are the same or different and represent an oxygen atom or a sulfur atom,
X^2 represents a reactive residue. ) Thiazolidine derivatives or salts thereof. 10. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a substituted or unsubstituted phenyl group, Q is a single bond, lower alkylene group or lower alkenylene group, AI
K represents a lower alkylene group, and Y represents an oxygen atom or a sulfur atom. ) A thiazolidine derivative or a salt thereof.