JPS62155217A - Cardiac - Google Patents

Abstract

NEW MATERIAL:A thiazolidine derivative shown by formula I (R<1> is phenyl; Q is single bond valence, lower alkylene or lower alkenylene; Alk is lower alkylene; R<2> and R<3> are H, lower alkyl, etc.,; Y and Z are O or S) and its salt. EXAMPLE:(+ or -)-N-Methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazoli dine-3-carboxamide. USE:A cardiac having cardiac action of durability by oral administration and a low side effect. PREPARATION:A compound shown by formula II is reacted with a compound shown by formula III (X<3> is reactive residue) to give a novel thiazolidine shown by formula IV or its salt. Then, the compound shown by formula IV is reacted with a piperazine derivative shown by formula V (X<1> is reactive residue) or its salt to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a cardiotonic agent comprising a novel thiazolidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

(Objective of the Invention) The object of the present invention is to provide a novel cardiotonic agent having excellent cardiotonic action.

(Structure and effects of the present invention) The present invention relates to a cardiotonic agent comprising a novel thiazolidine derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.

Z=C-N<: R3 (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 RZ 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. The phosphoryl group, Y and Z, are the same or different and represent an oxygen atom or a sulfur atom. ) Compound (I) or a pharmacologically acceptable salt thereof, which is the active ingredient of the present invention, has excellent cardiotonic action and duration of action, and has excellent properties as a cardiotonic agent.

For example, when a sample was administered intravenously to dogs to examine its cardiac effect, 9 the active ingredient of the present invention (-)-N-methyl-2
-(2-(2-(4-phenylpiperazin-1-yl)
Ethyloxyphenyl) thiazolidine-3-carboxamide (oxalate) can increase the maximum rate of change in left heart intracardial pressure by 36% upon administration [0,003 μ/kg, and its effect lasts for about 40 minutes. In addition, the inotropic effect was examined using the Langendorff method using isolated guinea pig hearts.1 (+) (or (±)) -
N-Methyl-2-[2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide (oxalate) can increase cardiac contractility at a dose of 34. can.

Furthermore, compound (1) or its pharmacologically acceptable salt, which is the active ingredient of the present invention, has low toxicity.

For example, (±)-N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide (oxalate) was administered to mice (1 group = 5 mice). ) for oral administration (dose: tooo
■/kg) L. When observed for 7 days after administration, no mortality was observed in the mice. Therefore, the cardiotonic agent of the present invention containing compound (1) as an active ingredient has a It can be used to treat, prevent and/or improve congestive heart diseases such as oxygenosis. Also.

The cardiotonic agent of the present invention, which contains Compound (1) or a pharmacologically acceptable salt thereof as an active ingredient, exhibits a sustained cardiotonic effect when administered orally, and has few side effects (e.g., effects on heart rate). Because of these characteristics, it is an excellent cardiotonic agent from this point as well.

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

Examples of pharmacologically acceptable salts of compound (I) include inorganic acid addition salts such as hydrochloride, sulfate, nitrate, phosphate, and hydrobromide.

Acetate, oxalate, fumarate, succinate.

maleate, citrate, lactate, glucuronate,
Examples include organic acid addition salts such as 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 (I) with an acid or alkaline reagent in a conventional manner.

The cardiotonic agent of the present invention containing Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient can be administered either orally or parenterally. However, since the cardiotonic agent of the present invention exhibits an excellent cardiotonic effect even when administered orally, it is particularly preferable to use it orally. In addition, the cardiotonic agent of the present invention can be used in the form of ordinary preparations, such as solid preparations such as tablets, powders, capsules, and granules, and liquid preparations. As the agent, 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 the case of parenteral administration, the cardiotonic agent of the present invention can be used, for example, as an injection or a suppository. Injectables can be used as solutions or suspensions, and are prepared using distilled water.

Essential oils (e.g. peach 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 cardiotonic agent of the present invention varies depending on the administration method, the age and weight of the patient, the condition, and the type of disease, but the dosage of the active ingredient Compound (1) or a pharmacologically acceptable salt thereof Usually about 0.001~10a per day
It is preferable to use it within a range of 0.003 to 5 t/kg, particularly 0.003 to 5 t/kg.

Examples of compounds that are active ingredients of the present invention include:

-i In formula (I), 1171 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,
ethyl, propyl, butyl or pentyl), lower alkylthio (e.g.

Methylthio group, ethylthio group, propylthio group.

butylthio group or pentylthio group), lower alkoxy group (e.g. methoxy group, ethoxy group, propoxy group, butoxy group or pentyloxy group), or phenyl group substituted with nitro group; Q is a single bond, lower alkylene group (e.g., methylene group, ethylene group, trimethylene group, tetramethylene group, or pentamethylene group) or lower alkenylene group (e.g., vinylene group, propenylene group, butenylene group, or pentenylene group), and A
IK is a lower alkylene group (e.g., methylene group, ethylene group, trimethylene group, tetramethylene group, or pentamethylene group); R2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group (e.g., methyl group, ethyl group, 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 (for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group).

butylsulfonyl group or pentylsulfonyl group).

benzoyl group, phenyl group or di(lower alkyl)phosphoryl group (for example, dimethylphosphoryl group, diethylphosphoryl group, dipropylphosphoryl group, dibutylphosphoryl group or diethylphosphoryl group); Y and Z are the same or different and oxygen Examples include compounds that are atoms or sulfur atoms.

Among these, preferable compounds are those in which R1 in the general formula (■) 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, and AIK is a lower alkylene group, and R2 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, or a benzoyl group. group, phenyl group or di(
R3 is a hydrogen atom or a lower alkyl group in a phosphoryl group (lower alkyl), or R2 is a lower alkyl group and R
Examples include compounds in which 3 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. More preferred compounds include those in which R1 in general formula (1) is a phenyl group or a fluorine atom.

is a phenyl group substituted with a chlorine atom, 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 nitro group; Q is a single bond, and Q is a single bond; ~3 alkylene groups or propenylene (-C
H=CH-C1lz-) group; AIK has 2 to 2 carbon atoms
5 alkylene group; R1 is a hydrogen atom, and carbon number is 1 to
4 alkyl group, a cycloalkyl group having 4 to 6 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, a hendiyl group, a phenyl group, or a di(alkyl) group having 2 to 6 carbon atoms. R3 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms in a phosphoryl group, or R2 is an alkyl group having 1 to 4 carbon atoms and R3 is an alkanoyl group or benzoyl group having 2 to 5 carbon atoms; Y and Examples include compounds in which Z is the same or different and is an oxygen atom or a sulfur atom. 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. Yes R3 is a hydrogen atom, methyl group or acetyl group, and Y
and a compound in which Z is the same or different and is 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 the 1st position, a compound in which the group R<-q-C)-AtK-y- is substituted at the 2nd or 4th position on the benzene ring is preferred.

Other more preferable compounds include the general formula (wherein 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, RZ and R3 are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkanoyl group , lower alkoxycarbonyl group, 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. ). More preferred compounds include those in which 1171 in general formula (IA) 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, AI
K is an alkylene group having 2 to 5 carbon atoms; RZ 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 R'' is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R2 has 1 carbon number -4 alkyl group, R2 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. A more preferred compound is one in which R1 is a phenyl group, a fluorophenyl group, a chlorophenyl group, a methylphenyl group, or a methoxyphenyl group in the general formula (1-A); Q is a single bond, and AIK
is an ethylene group or a trimethylene group, RZ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkanoyl group having 2 to 4 carbon atoms; Examples include compounds in which Y and Z are the same or different and are oxygen atoms or sulfur atoms. Other preferred compounds include general formula (I A) in which R1 is a phenyl group, fluorophenyl group or methylphenyl group; Q is a single bond; AIK is an ethylene group; R2 is a hydrogen atom or is a methyl group, R3 is a hydrogen atom, a methyl group or an acetyl group; Y and Z are the same -
Or, compounds that are different from each other include oxygen atoms or sulfur atoms. Even more preferred compounds include -fct
In formula CI A), R1 is a phenyl group, fluorophenyl group or methylphenyl group; Q is a single bond; ^IK is an ethylene group, R2 is a hydrogen atom or a methyl group, and R3 is hydrogen atom, methyl group or acetyl group; 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 R1 is a phenyl group or a fluorophenyl group; Q is a single bond; and AIK is an ethylene group;
I? Examples include compounds in which 2 is a methyl group, R3 is a hydrogen atom or an acetyl group; and Y and Z are oxygen atoms.

Since the compound (1), which is the active ingredient of the present invention, has an asymmetric carbon atom at the 2-position of the tiapridine ring, two types of optical isomers may exist, but in the present invention, these optical isomers and mixtures thereof Any of these can be used as an active ingredient of a cardiotonic agent.

Compound N), which is an active ingredient of the present invention, is a thiazolidine represented by, for example, [Production method (A)] RZ Z=C-N ((However, R2, R', Y and Z have the same meanings as above) Is the derivative or its salt reacted with a piperazine derivative or its salt generally represented by (where χ1 represents a reactive residue, and R', Q and AIK have the same meanings as above)?

[Manufacturing method (B)]

General formula (where y and 2 represent reactive residues, AIK, R
2, R'.

Y and 2 have the same meanings as above. ) A thiazolidine derivative or a salt thereof is reacted with a piperazine derivative or a salt thereof represented by the general formula (wherein R1 and Q have the same meanings as above).

[Manufacturing method (C)]

A thiazolidine derivative or a salt thereof represented by the general formula (wherein R', Q, A]K and Y have the same meanings as above) and the general formula (where X3 represents a reactive residue and R2, R2 and Z are (Has the same meaning as above.) or (Production method (D)
)] (However, X4 represents a reactive residue, R', Q, A
IK.

Y and Z have the same meanings as above. ) or a salt thereof and general (however, R2 and R3
has the same meaning as above. ) or a salt thereof.

Raw material compounds (■n, (IIri), (IV), (V), (V
T), (■) and (IK) can be used in their free form or as their salts. For example, compound (II
As the salts of [), (V), (Vl), (■), and (IX), ordinary acid addition salts such as hydrochloride, hydrobromide, sulfate, and nitrate can be suitably used. Also, as the salts of compounds (n) and (■), alkali metal salts such as sodium salts and potassium salts, organic amine salts, etc. can be suitably used. Starting compound (I [I), (mV
), (■), and (■) reactive residues (groups Xl, X2 .
X3. Preferred examples of and It will be done.

[Production methods (A), (B), (C) and (D)] These reactions are carried out in a suitable solvent (e.g. dimethylformamide, tetrahydrofuran, etc.) in the presence or absence of a deoxidizing agent (e.g. potassium carbonate etc.). Below about 0℃~110
It can be carried out at ℃.

When the compound (I) thus obtained is a racemate,
The racemate can be separated into optical isomers.

For example, in compound (1), a racemic compound in which R2 is a lower alkyl group and R3 is a hydrogen atom has optical activity 1-(
2-naphthylsulfonyl)pyrrolidine-2-carbonyl halide to form a pair of diastereomers.Then, the diastereomers are separated into each by fractional crystallization or column chromatography, and each of the resulting diastereomers is hydrolyzed. By doing so, each optically active form thereof can be obtained.

Raw material compounds (n), (IV), (Vl), and (
■) is a new compound. Among these, compound (n)
can be produced by, for example, reacting a compound represented by the general formula (wherein Y has the same meaning as above) with compound (■).

Compound (rV) is composed of compound (II) and the general formula %() (where X" represents a reactive residue such as a halogen atom, a substituted or unsubstituted phenylsulfonyloxy group, or a lower alkylsulfonyloxy group, and IK and x2 have the same meanings as above.) It can be produced by reacting with the compound shown below.

Compound (Vl) can be produced by subjecting a compound represented by the general formula (R', Q, AIK and Y have the same meanings as above) to a condensation reaction with cysteamine or a salt thereof.

Compound (■) is compound (VI) or its salt and general formula: Z
=C-(X')z(XX) (However, Z and x4 have the same meanings as above.) It can be produced by reacting with a compound represented by:

9 In this specification, a "lower alkyl group" refers to a straight chain or branched alkyl group having 1 to 5 carbon atoms.

A "cycloalkyl group" refers to a cycloalkyl group having 3 to 7 carbon atoms, and a "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 ” represents a straight chain or branched saturated fatty acid having 2 to 6 carbon atoms. Furthermore, "lower alkoxy group" refers to a straight chain or branched alkoxy group having 1 to 5 carbon atoms, and "lower alkoxycarbonyl group" refers to a carbon number 2 to 6 group.
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 Tables 1 and 2 below.

Table 1 R2 Z=C-N< (Part 1) (Q=single bond, Alk= -(CIl□)z,
R2=CH5, R3=H) Second table Z=C-N( (Q=single bond at±CH3, R'=H, Y=
O, Z = S) Experimental Example 2 (Method) The isolated heart of a male guinea pig (body weight: approximately 280.9 mm) 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 3 below.

Table 3 R' (Part 1) (Part 2) (Q=Single bond, R"=CH3, R'=H) (Part 3) (Q=Single bond, R"=CH3, R'=H , Y=O) Production example l N-methyl-2-(2-hydroxyphenyl)thiazolidine-3-carboxamide 2.38L Potassium carbonate 1.
38g, sodium iodide 0.1g.

1-(2-chloroethyl)-4-phenylpiperazine 3
．． 36.9 and dimethylformamide 25. ,! 1 mixture is stirred at 90° C. for 24 hours. After the reaction, the solvent is distilled off under reduced pressure. Water is added to the residual aroma 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 residual aroma was removed by silica gel chromatography (solvent, benzene: ethyl acetate = 1:5).
), N-methyl-2-(2-(2
-(4-phenylpiperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carboxamide 1.8
9: Obtain j.

M, p, 127-129°C (recrystallized from ethyl acetate/n-hexane), 9. 133-135°C (recrystallized from ethyl acetate ether) Oxalate: M, p, 169.5-172.5°C (decomposed) (recrystallized from acetone) 1/2 fumarate: M, p, 169 -170℃ (decomposition) (ethanol/
(recrystallized from ether) 1/2 succinate: M, p, 122-124°C (decomposed) (recrystallized from acetone-ether) Methanesulfonate: M, p, 110-117°C (decomposed) (from acetone) Recrystallization) Hydrochloride: M, p, 195-197℃ (decomposition) (methanol/
(recrystallized from acetone/ether) dihydrochloride: M, p, 206-207°C (decomposition) (methanol/
Recrystallization from ether) Production Examples 2 to 7 In the same manner as in Production Example 1, the compounds listed in Table 4 below are obtained from the corresponding thiazolidine compounds and piperazine compounds.

Production example 8 N-methyl-2-(2-(2-chloroethyloxy)phenyl]thiazolidine-3-carboxamide 1.81,
9. N-phenylpiperazine O0gL? .

Potassium carbonate 0.83g, sodium iodide 0.9
A mixture of 0J and dimethylformamide 25- was heated to 90°C.
Stir for 18 hours. After the reaction, the solvent is distilled off under reduced pressure. Water is added to the residual aroma and the mixture is extracted with ethyl acetate.

After washing the extract with water? The solvent is distilled off under Jji pressure.

The residual aroma was crystallized from isopropyl ether, and the resulting crystals were recrystallized from a mixture of ethyl acetate and n-hexane to obtain N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)). 1.411 of ethyloxy]phenyl)thiazolidine-3-carboxamide is obtained.

The physicochemical properties of the main island matched those of the specimen obtained in Production Example 1.

Production Examples 9 to 55 The compounds listed in Table 5 below are obtained in the same manner as Production Example 8 from the corresponding thiazolidine compounds and piperazine compounds.

Production Example 56 1.66g of potassium carbonate was mixed with 2-(2-(2-(4-(
3-Fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine was added to a solution of 3.09.9 in 40.11' of dimethylformamide, 1.29.9 of dimethylcarbamoyl chloride was added to the solution, and 2 Time 9 Then stir at 50° C. for 5 hours.

Pour the mixture into water and extract the mixture with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. The residual aroma was purified by silica gel chromatography (solvent: benzene: ethyl acetate: methanol = 10:10:0.3) and then recrystallized from isopropyl ether to obtain N,N-dimethyl-2-(2-(2 -(4-(3-
Fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide1.
Get 82#.

M, p, 90.5-93°C Oxalate: M, p, 171-172.5°C (decomposition) (recrystallization from a mixture of acetone, ethanol, and ether) Production example 5
7-59 The compounds shown in Table 6 below are obtained in the same manner as in Production Example 56 from the corresponding thiazolidine compounds and carbamoyl compounds.

Production example 60 2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine 2゜0II
A solution of 30% in tetrahydrofuran was added to 2.15% of 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-
and methylamine 1.61 toluene 30J! After sequentially adding the solutions, stir 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 residual aroma was purified by silica gel chromatography (vehicle, benzene:ethyl acetate = 1:5) and then recrystallized from a mixture of ethyl acetate and n-hexane to give N-methyl-2-(2-( 1.5M of 2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide is obtained.

The physicochemical properties of the main island matched those of the specimen obtained in Production Example 1.

Production Examples 61-62 The compounds listed in Table 7 below are obtained in the same manner as in Production Example 60 from the corresponding thiazolidine compound and thiophosgene.

Production Example 63 (+)-N-Methyl-2-(2-(2-(4-phenypiperazin-1-yl)ethyloxyphphenyl)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 rIg 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 residual fragrance was removed by silica gel chromatography (solvent, chloroform:ethanol =
(+)-N-methyl-2-[2-(2-(4-phenypiperazin-1-yl) ) Ethyloxyphphenyl) thiazolidine-3-carboxamide 350 Akebono is obtained.

M, p, 151-152℃ (α) +152.40 (C=0.210.chloroform) Oxalate 1/3 H2O: M, p, 170-172℃ (decomposition) (recrystallized from acetone) ( α) +88.6° (C=0.102.methanol) Production Examples 64 to 66 In the same manner as in Production Example 63, the compounds listed in Table 8 below are obtained from the corresponding thiazolidine compounds.

Duck mold example 67 Cysteamine hydrochloride 0.5711. Sodium hydroxide 0
．． A mixture of 21.9 and ethanol 20-10 at room temperature
Stir for a minute and add 1.
After adding 55.9, reflux for 1 hour. The mixture is concentrated under reduced pressure to remove the solvent. The remaining amount is ditrahydrofuran 2
0-, and 0.32% of methyl inocyanate was added to the solution.
Add 9 and stir at room temperature for 2 hours. The mixture is concentrated under reduced pressure, the two resulting residues are added, and the mixture is extracted with ethyl acetate.

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

By crystallizing the first sample from a mixture of ethyl acetate and n-hexane, N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethylonicyphenyl)thiazolidine-3-carboxamide was obtained. Obtain 1.70 g.

The physicochemical properties of the main island matched those of the specimen obtained in Production Example 1.

Production Examples 68-122 Production Example 6 from the corresponding cysteamine, benzaldehyde compound and isocyanic acid (isothiocyanic acid) compound
Compounds listed in Tables 9 and 10 below are obtained in the same manner as in 7.

Production example 123 2-[2-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine 3゜69.
9 was dissolved in 40% of tetrahydrofuran, and 0.62II 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 residual aroma, and the precipitate is collected by filtration. N-methyl-2-(2
-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide 3.82# is obtained.

The physicochemical properties of the main island matched those of the specimen obtained in Production Example 1.

Production Examples 124 to 131 The compounds listed in Table 11 below are obtained in the same manner as Production Example 123 from the corresponding thiazolidine compounds and isocyanic acid (or isothiocyanic acid) compounds.

Production example 132 Potassium isocyanate 1.12i water 10a9 and acetic acid 2
A mixture of
Add to Jl solution and stir at room temperature for 2 hours. A mixture of 0.56.9 d of potassium isocyanate and 0.5 d of acetic acid was added to this mixture, and the mixture was stirred at room temperature for 2 hours.

Make the mixture alkaline with sodium bicarbonate.

The solvent is distilled off under reduced pressure. Extract the residual aroma with ethyl acetate,
The extract is washed with saturated brine, dried, and then the solvent is distilled off under reduced pressure. The residual aroma 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-(
2.63 of 3-fluorophenyl)piperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carboxamide are obtained.

Gate, p, 142-143℃ Oxalate: Gate, p, 104-105℃ (decomposition) (recrystallized from methanol/ether) Production example 133 A solution of 1.07# sodium isocyanate in 20% water
- (2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine 3.03.9
of 40% of ethanol, and 2.4% of acetic acid was added to the mixture.
Add #6 and stir at room temperature for 2 hours.

After adding 200 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 residual aroma from ethyl acetate, 2-(2-(
2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide2.
Get 78.9.

M, 9. 137-139°C Oxalate: Gate, p, 146-150.5°C (decomposition) (recrystallized from acetone/methanol) Production Examples 134-135 Produced in the same manner as in Production Example 133 from the corresponding thiazolidine compound and sodium isocyanate. The following compound is obtained.

2-(2-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide, p, 141-143°C (recrystallized from ethyl acetate) oxalate : A, p, 111-115°C (decomposition) (recrystallized from acetone/methanol) 2- (2-(2-(4-phenylpiperazin-1-yl)ethylthio]phenyl)thiazolidine-3-carboxamide M, p , 141-143.5°C (recrystallized from ethyl acetate) Oxalate 1/2 H,O: M, p, 174-177°C (decomposed) (recrystallized from acetone) Production example 136 Penzamide 0.63, 9. After refluxing a mixture of 0.73 # of phosgene and 50 # of methylene chloride for 3 hours.

The solvent is distilled off under reduced pressure. Tetrahydrofuran 30Wt for residual fragrance (i.e. benzoyl isocyanate)! and 1.23 of triethylamine were added, and then 2-(2-(2-
A solution of (4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine 1.5II in tetrahydrofuran is added and stirred 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 residual aroma was purified by silica gel chromatography (solvent: chloroform:ethyl acetate = 7:3) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain N-pesozoyl-2-
(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide 0.87.9 is obtained.

M, p, 125-127°C Sodium salt: M, p, 118-123°C Production example 137 2- (2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl) Add 0.9JF of ethoxycarbonyl isocyanate to a solution of 2.9% of thiazolidine in 30% of tetrahydrofuran and add 1.0% of ethoxycarbonyl isocyanate at room temperature.
Stir for 8 hours. Ethoxylponyl isocyanate (3.1) and IF were added to the mixture, and the mixture was further stirred at room temperature for 2 hours. 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 residual aroma was purified by silica gel chromatography (solvent, benzene:ethyl acetate = 1:1) to produce N-ethoxycarbonyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl). ) ethyloxyphphenyl) thiazolidine-3-carboxamide i, os
Il is obtained as an amorphous powder.

Sodium salt: Base, p, 213-217°C Production example 138 1.91 of 2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine in anhydrous acetone Dissolve.

After adding 0.733 g of methanesulfonyl isocyanate to the solution and stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure.

The residual aroma was filtered, washed with water and ether, and recrystallized from a mixture of acetone and ether to obtain N-methanesulfonyl-2-(2-(2-(4-(3-fluorophenyl)piperazine-1). -yl)ethyloxyphphenyl)thiazolidine-3-carboxamide 1.56.9 is obtained.

A, p, 138-140°C (decomposition) 1/2 oxalate, 1/2 H, 0: M, 9. 171-172℃ (decomposition) Production example 139 2- (2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine 1.23.9 in acetone 20J1f solution with diethyl After adding 0.68.9% of phosphoryl isothiocyanate and stirring for one day, the solvent is distilled off under reduced pressure.The residual aroma is extracted with chloroform, the extract is washed with saturated brine, and after drying, the solvent is distilled off under reduced pressure. The residual aroma 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 1.491 is obtained.

M, 9. 128-129°C Oxalate M, p, 79-81°C (decomposition) (recrystallized from acetone ether) Preparation example 14O N-methyl-2-(2-(2-(4-(3-fluorophenyl) Sodium hydride (60%
Add 0.1.9 of oily dispersion).

Then, a 5-ether solution of 0.191 acetyl chloride was added and stirred at 50°C for 20 hours. The solvent was distilled off from the mixture under reduced pressure, water was added to the residual aroma, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. 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: n, p, 110-117°C (decomposition) (recrystallized from acetone/methanol/n-hexane) Production example 141~
142 The following compound is obtained in the same manner as in Production Example 140 from the corresponding thiazolidine compound and alkanoyl compound.

N-acetyl-N-methyl-2-(2-C2-C4-(
3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide oil Mass (m/e): 502 (M''),
429.386.207 Oxalate: M, 9. 106-109°C (decomposition) (recrystallized from acetone/ether) N-acetyl-N-methyl-2-(2-(3-(4phenylpiperazin-1-yl)propylthio]phenyl)
Thiazolidine-3-carbothioamide oxalate: Table 1, p, 135-142°C (decomposition) (recrystallized from acetone) Production example 143 N-methyl-2-(2-(2-(4-(3-fluorophenyl) ) Piperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carboxamide 2.22L
Propionic acid chloride 1.39.9. A mixture of 2.53.9 liters of triethylamine and 50 tI of toluene is refluxed with stirring for 2.5 days, and then the solvent is distilled off under reduced pressure. Add water to the residual fragrance and extract with ethyl acetate. The extract is washed with saturated hydrogen carbonate solution, IJum water and saturated brine, and after drying, the solvent is distilled off under reduced pressure. The residual fragrance 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)ethyloxy]phenyl)thiazolidine-3-
Carboxamide 0.3M is obtained as an oil.

Mass (ta/e): 500 (M'') Oxalate: M', p, 125-127°C (recrystallized from acetone ether) Production Example 144 Same as Production Example 143 from the corresponding thiazolidine compound and benzoyl compound to obtain the following compound.

N-benzoyl-N-methyl-2-(2-(2-(4-
(3-Fluorophenyl)piperadi-sol-1-yl)ethyloxy]phenyl)thiazolidine-3-carbothioamide M, p, 119-121°C (recrystallized from ethyl acetate-fi-hexane) Oxalate: mon, p, 102-112°C (recrystallized from ethanol/ether) Production example 145 (1) 2-[2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphenyl)
1.08 g of thiazolidine-3-carboxamide is dissolved in 20 g of tetrahydrofuran, and 0.7 i of triethylamine is added to the solution. Add 0.0% acetyl chloride to the mixture.
Add 5M tetrahydrofuran 1-solution and stir at room temperature for 3 days. Add 0.51 F of acetyl chloride and 0.76 # of triethylamine to this mixture, and add an additional 2
After stirring for 4 hours, the solvent was distilled off under reduced pressure. Dissolve the residual aroma in ethyl acetate, wash sequentially with saturated brine, hydrogen carbonate, and brine, dry, and then evaporate the solvent under reduced pressure.

The residual aroma was purified by silica gel chromatography (solvent: chloroform:ethyl acetate = 2:1) and recrystallized from a mixture of chloroform and ether to obtain N,
0-Diacetyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]fenyl)thiazolidine-3-carboximidic acid 0.72
Get #.

M, p, 114-115 °C Oxalate: M, p, 157-158 °C (decomposed) (recrystallized from ethanol) (21N, O-diacetyl-2-(2-(2-(4-(
3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carboximidic acid 0.59.9% in ethanol 1SrI& and tetrahydrofuran 5. 1.34% of 10% sodium hydroxide solution was added to the solution under water cooling, and the mixture was 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 residual aroma is extracted with ethyl acetate, the extract is washed with brine, dried, and the solvent is distilled off under reduced pressure. By recrystallizing the residual aroma from a mixture of ethyl acetate and ether,
N-acetyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carboxamide 0.49.9
get.

M, p, 142-143°C Oxalate: M, p, 165-166°C (decomposition) (recrystallized from ethanol) Production example 146 (1) 2- (2-(2-(4-phenylpiperazine-
1-yl)ethyloxyphphenyl)thiazolidine-3
-Carboxamide 1.49L l-ethylamine 1
．． 27.9 and benzene 60. ! 0.311.9 of acetyl chloride was added to the mixture of I at 50°C, then at 80°C.
Stir for 1.5 hours. Add 0.0% acetyl chloride to the mixture.
Add 563.9 and triethylamine 0.7283 and add 8
Stir at 0°C for 2.5 hours. After washing the mixture with water and drying, the solvent was distilled off under reduced pressure. The residual aroma was purified using silica gel chromadog (solvent, benzene: ethyl acetate = 1:1),
Recrystallization from ether gives N,0-diacetyl-2-(2-(2-(4-phenylpiperazine-1-
1.25# of yl)ethyloxy)phenyl)thiazolidine-3-carboximidic acid is obtained.

Gate, p, 120-123.5℃ (21N, O-diacetyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-calpoimidic acid 1.19L
Ethanol20. R, sodium hydroxide 0.287g,
A mixture of 2.7 ml of water and 201 n2 of tetrahydrofuran is 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 residual aroma was purified by silica gel chromatography (solvent, ethyl acetate:chloroform = 5:1), and recrystallized from a mixture of ethyl acetate and n-hexane.
-Acetyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide 0°7219 is obtained.

A, p, 137-139℃ 1/2 sieate 1/2 II□O=M, p, 1
64-168°C (decomposition) (recrystallized from acetone) Production example 147 N-acetyl-2-(2-(2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxyphphenyl)thiazolidine- 3-carbothioamide 2.87L
10% sodium hydroxide solution 7.3- and ethanol 60-
- After refluxing the mixture for 20 hours, the solvent was distilled off under reduced pressure.

The residual aroma is extracted with ethyl acetate, the extract is washed with saturated brine, dried, and the solvent is distilled off under reduced pressure. The residual aroma was removed by silica gel chromatography (solvent, chloroform: ethyl acetate =
By purifying with 2=1), 2- (2-(2-(
4-(3-fluorophenyl)piperazin-1-yl)
Ethyloxyphphenyl)thiazolidine-3-carbothioamide 2.36.9 is obtained.

M, p, 136-137°C (recrystallized from ether)
1/2 fumarate: M, p, 164-165°C (recrystallized from ethanol/ether) Production example 148 +1) Sodium hydride (50% oily dispersion) O0
(±)-N-Methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3 was added to a suspension of dimethylformamide 55.1 & 64.9 under water cooling. -Carbothioamide 5°333 was added and stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes.To the mixture were added 4.0Q of (-)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride and 9.0Q of dimethylformamide. 40- Add the solution under water cooling and keep it at the same temperature for 30 minutes.
The mixture is further stirred 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 residual aroma was removed by 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)ethyloxyphphenyl)thiazolidine-3-carbothioamide Yield: 1.10.9 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-(
Yield of mixture of 2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide and 2-(2-(4-phenylpiperazin-1-yl)ethyloxybenzaldehyde; 0. 881?, caramel (21'(+)-N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl)-2-(
2-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide 1. Oi with 40% of tetrahydrofuran and 40% of methanol. Dissolved in a mixture of &.

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-C2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-
600 μ of 3-carbothioamide are obtained.

Gate, p, 144-145.5℃ [α) +145.7° (C=0.365.
- 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-■-yl)ethyloxyphenyl)thiazolidine-
0.88.9 of a mixture of 3-carbothioamide and 2-(2-(4-phenylpiperazin-1-yl)ethyloxybenzaldehyde) was dissolved in a mixture of tetrahydrofuran 35 and methanol 35, and added to the solution. A solution of 100 μl of sodium hydroxide in water is added while stirring under water cooling. The mixture is stirred at room temperature for 24 hours, and then the solvent is distilled off under reduced pressure. After adding water to the residual aroma, it is extracted with ethyl acetate, and the extract is washed with water. After drying, the solvent is distilled off under reduced pressure.The residual aroma is 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-C2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide 108 ml is obtained.

Gate, p, 143-145℃ [α) -139,80 (C = 0.265. Chloroform) Production example 149 (1) Sodium hydride (50% oily dispersion) 0゜641 (±) -N-methyl -2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide 5.33.9.
(+)-1-(2-Naphthylsulfonyl)pyrrolidine-2-carbonyl chloride 4.00.9 and dimethylformamide 95- are treated in the same manner as in Production Example 148 (1) to obtain the following compound.

(-)-N-methyl-N-(1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl]-2-(2-C2
-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide Yield: 1. OIM, p, 191-192°C (recrystallized from ethyl acetate/n-hexane) [α) -26,5° (C=0.200, chloroform) N-methyl-N-(1-(2-naphthyl) sulfonyl)pyrrolidine-2-carbonyl)-2-(2-(2
-(4-phenylpiperazin-1-yl)ethyloxyphenyl)thiazolidine-3-carbothioamide and 2
-(2-(4-phenylpiperadisol l-yl)) Mixture yield with ethyloxylabenzaldehyde: 1.0411. Caramel (21(-)-N-methyl-N-(1-(2-naphthylsulfonyl) pyrrolidine-2-carbonyl]-2-(2
-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide 1.05#, tetrahydrofuran 40.9. Methanol 40. ,! ', 120 m of sodium hydroxide and 3 -
By treating in the same manner as in Production Example 148 (2),
600 μl of (-)-N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide are obtained. Yield: 94.2% , p, 144-145°C (recrystallized from ethyl acetate/n-hexane) [α) -145,4° (C=0.216,
Chloroform fumarate 1/2 II□0: M, 9. 138-144.5℃ (decomposition) (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)ethyloxyphphenyl)thiazolidine-3-
Mixture of carbothioamide and 2-(2-(4-phenylpiperazin-1-yl)ethyloxylabenzaldehyde) 1.04.9. 30 J of tetrahydrofuran, 30 J of methanol, 120 J of sodium hydroxide and 3 J of water. By processing in the same manner as in Production Example 148 (3), (
205 mg of -N-methyl-2-(2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carbothioamide are obtained.

M, p, 144-145°C (recrystallized from ethyl acetate-n-hexane)

Claims (1)

[Claims] 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, Al
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 cardiotonic agent containing a thiazolidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.