JPS62116568A - Thiazolidine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A thiazolidine derivative shown by formula I (R<1> is phenyl; Alk is alkylene; R<2> is alkyl; one of R<3> and R<4> is halogen, alkyl, alkoxy, OH, nitro or amino and the other is H, halogen or alkoxy; Z is 0 or S) or its salt. EXAMPLE:N-Methyl-2-{4-chloro-2-[4-phenylpiperazin-1-yl)ethyloxy]phenyl }thiazo lidine-3-carboxamide. USE:A cardiac. PREPARATION:For example, an alkoxyphenylthiazolidine derivative shown by formula II (one of R<31> and R<41> is halogen, alkyl, alkoxy or nitro and the other is H, halogen, alkoxy; X<1> is reactive residue) or its salt is reacted with a piperazine compound shown by formula III or its salt to give a compound shown by formula I wherein R<3> and R<4> are R<31> and R<41>.

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 method for producing the same.

(Structure and Effects of the Invention) The novel thiazolidine derivative of the present invention is represented by the following general formula (1).

(However, R1 is a substituted or unsubstituted phenyl group, Alk is a lower alkylene group, R2 is a lower alkyl group, R3 and R4
is a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group or an amino group,
The other one is a hydrogen atom, a halogen atom, or a lower alkoxy group, and 2 represents an oxygen atom or a sulfur atom. ) The thiazolidine derivative (I) or a salt thereof of the present invention is a pharmaceutical compound useful as a cardiotonic agent.

For example, when a sample was administered intravenously to dogs to examine its inotropic effect, it was found that the N-methyl-2-[4-chloro-2-(
2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carboxamide (oxalate) can increase the maximum rate of change in left cardiac pressure by 24% at a dose of 0.03 mg/kg. The effect lasts for about 34 minutes. In addition, when the inotropic effect of the present invention was investigated by Langendorff method using isolated guinea pig hearts, it was found that the N-methyl-2-(5-methyl-2-(2-(4-(3)
-Fluorophenyl)piperazin-1yl)ethyloxy)phenyl)thiazolidine-3-carboxamide (oxalate) can increase cardiac contractility at a dose of 3 μm.

Examples of the thiazolidine derivatives of the present invention include the general formula (1
), R1 is a phenyl group or a halogen atom (e.g. fluorine atom, chlorine atom or bromine atom)
, a phenyl group substituted with a lower alkyl group (e.g., methyl group, ethyl group, propyl group, or butyl group) or a lower alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, or butoxy group), and Alk is a lower is an alkylene group (e.g., methylene group, ethylene group, trimethylene group, or tetramethylene group); R2 is a lower alkyl group (e.g., methyl group, ethyl group, propyl group, or butyl group); either R3 or R4 One side is a halogen atom (e.g., fluorine, chlorine, or bromine atom), a lower alkyl group (e.g., methyl, ethyl, propyl, or butyl), or a lower alkoxy group (e.g., methoxy, ethoxy, propoxy). or butoxy group), hydroxyl group, nitro group, or amino group, and the other side is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), or a lower alkoxy group (e.g., a methoxy, ethoxy, propoxy, or butoxy group) Z is an oxygen atom or a sulfur atom. Among these, preferred compounds include R1 being a phenyl group, fluorophenyl group, methylphenyl group, or methoxyphenyl group; A1k being an ethylene group;
R2 is a methyl group; one of R3 and R4 is a chlorine atom, methyl group, methoxy group, hydroxyl group, nitro group, or amino group; the other is a hydrogen atom, a chlorine atom, or a methoxy group; Z is an oxygen atom or Examples include compounds that are sulfur atoms. More preferred compounds include R1 being a phenyl group or fluorophenyl group, ^1k being an ethylene group, R2 being a methyl group, and R3 being a chlorine atom, methyl group, methoxy group, water R%, nitro or amino group, R4 is a hydrogen atom, and Z is an oxygen atom or a sulfur atom.

Other preferred compounds include the general formula % (where R1 is a substituted or unsubstituted phenyl group, Alk is a lower alkylene group, R2 is a lower alkyl group, R3 and R4
is a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group or an amine group,
The other one is a hydrogen atom, a halogen atom, or a lower alkoxy group, and Z represents an oxygen atom or a sulfur atom. ). More preferred compounds include general formula (IA), in which R1 is a phenyl group, fluorophenyl group, methylphenyl group, or methoxyphenyl group, and Alk is an ethylene group; R2
is a methyl group; one of R3 and R4 is a chlorine atom, methyl group, methoxy group, hydroxyl group, nitro group, or amino group; the other is a hydrogen atom, a chlorine atom, or a methoxy group; Z is an oxygen atom or sulfur Examples include compounds that are atoms. An even more preferable compound is the general formula (1-
In A), R1 is a phenyl group or a fluorophenyl group, Alk is an ethylene group, R2 is a methyl group, and R:l is a chlorine atom, a methyl group, a methoxy group, a hydroxyl group, a nitro group, or an amino group. Examples include compounds in which R4 is a hydrogen atom and Z is an oxygen atom or a sulfur atom. Other more preferable compounds include the general formula (1-
In A), R1 is a phenyl group or a fluorophenyl group, Alk is an ethylene group, R2 is a methyl group, R'' is a chlorine atom, methyl group or methoxy group, and R4 is a hydrogen atom, Examples include compounds in which Z is an oxygen atom.Particularly preferred compounds include compounds in which R1 is a phenyl group in the general formula (IA), and Al
k is an ethylene group, R2 is a methyl group, R'3
is a chlorine atom or a methoxy group, R4 is a hydrogen atom, and Z is an oxygen atom.

Since the thiazolidine derivative (1) of the present invention has an asymmetric carbon atom at the 2-position of the thiazolidine ring, two types of optical isomers may exist, but the present invention does not include any of these optical isomers and their racemic forms. It is inclusive.

According to the present invention, the thiazolidine derivative (1) has the general formula (wherein, one of R3' and R'' is a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group, and the other is a hydrogen atom or a halogen atom. ) or a salt thereof is reacted with a piperazine compound or a salt thereof represented by the general formula (wherein R1 has the same meaning as above) to form the compound having the general formula % formula %. (a) In the thiazolidine derivative (I-a), one of R3' and R'' is a lower alkoxy group and the other is a hydrogen atom. In some cases, if desired, the lower alkoxy group is dealkylated to form a hydroxyl group; (b) In the thiazolidine derivative 4 (I-a), when R'' is a nitro group, the nitro group is optionally reduced. It can be produced by using an amino group.

Raw material compound alkoxyphenylthiazolidine fb
NL form (II) and piperazine compound (I[I) can be used as free forms or as salts thereof.

For example, as the salt of compound (n), alkali metal salts such as sodium salt and potassium salt, organic amine salts, etc. can be preferably used, and as the salt of compound (III), hydrochloride, hydrobromic acid salt, etc. Common acid addition salts such as salts, sulfates and nitrates can be suitably used. Furthermore, when the thiazolidine derivative (I-a) of the present invention is used in the above reaction, it can be used either as a free form or as a salt thereof, such as hydrochloride, hydrobromide, etc. , acid addition salts such as sulfates and nitrates, alkali metal salts such as sodium salts and potassium salts, organic amine salts, etc. can be used as appropriate. Further, preferable examples of the reactive residue (Xl) of the starting compound (II) include halogen atoms such as chlorine atom and bromine atom, substituted or unsubstituted phenylsulfonyloxy group such as tosyloxy group, and methanesulfonyloxy group. Examples include lower alkylsulfonyloxy groups such as.

The reaction between the alkoxyphenylthiazolidine derivative (II) and the piperazine compound (III) can be carried out in an appropriate solvent in the presence or absence of a deoxidizing agent. Examples of deoxidizing agents include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., potassium carbonate, sodium carbonate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate), ), organic bases such as triethylamine, N-methylmorpholine, pyridine, diisopropylethylamine, etc. can be suitably used. Preferred examples of the reaction solvent include dimethylformamide, dimethylsulfoxide, acetonitrile, dioxane, tetrahydrofuran, acetone, methanol, and ethanol. The reaction is preferably carried out at a temperature of about 50°C to 110°C, especially about 60°C to 100°C.

In the thiazolidine derivative (I-a) of the present invention, R”
and R41 is a lower alkoxy group and the other is a hydrogen atom, the dealkylation reaction of the lower alkoxy group can be carried out by treating the compound <1-a) with a dealkylating agent in an appropriate solvent. It can be implemented. Preferred examples of the dealkylating agent include boron tribromide, trimethylsilyl halide (eg, trimethylsilyl iodide), and a combination of trimethylsilyl chloride and sodium iodide. As the solvent, for example, methylene chloride, chloroform, acetonitrile, sulfolane, etc. can be suitably used. This reaction is preferably carried out at -80°C to 60°C, particularly at -50°C to 30°C.

In addition, in the thiazolidine derivative (I-a), when R'' is a nitro group, the reduction reaction of the acid nitro group to the amino group involves catalytic reduction of the compound (1-a) in the presence of a catalyst in a hydrogen gas stream. Preferred catalysts include palladium on carbon, palladium black, Raney nickel, etc. The reduction reaction can be carried out using a suitable reducing agent (for example, sodium borohydride and nickel chloride or These reduction reactions can also be carried out in the presence of ferrous iron (in combination with ferrous iron).These reduction reactions are preferably carried out in a suitable solvent at room temperature or under pressure at 10°C to 60°C, particularly 20°C to 40°C.As a solvent For example, alkanol (
For example, methanol, ethanol, propatool), tetrahydrofuran, dioxane, etc. can be suitably used.

The alkoxyphenylthiazolidine derivative (n), which is the raw material compound of the present invention, is a new compound, and can be produced, for example, by the method shown in the reaction formula below.

(In the above formula, X2 represents a reactive residue, Alk, R
2. R"% R" and Z have the same meanings as above. )
That is, compound (II) is a hydroxy compound (TV)
and a di-substituted alkane compound (V) at about 0°C to 100°C in the presence of a deoxidizing agent (e.g., potassium carbonate) in a suitable solvent (e.g., dimethylformamide) to form an alkoxy compound (VI), Compound (VI) and cysteamine or a salt thereof (e.g., hydrochloride) are combined in a suitable solvent (e.g., ethanol) in the presence or absence of a deoxidizing agent (e.g., sodium hydroxide) at about 25°C to 100°C. It can be produced by conducting a condensation reaction to obtain an alkoxythiazolidine compound (■), and then subjecting the compound (■) and an isocyanate compound (■) to a condensation reaction at 25°C to 100°C in a suitable solvent (e.g., tetrahydrofuran). can. As the reactive residue (X2) of the di-substituted alkane compound (V),
Examples include the reactive residues exemplified in compound (II).

The thiazolidine derivative (I-a) of the present invention can also be produced by the method shown by the following reaction formula, and the raw material compounds for these reactions can be produced according to the method described in Japanese Patent Application No. 141409/1982. I can do it.

(In the above formula, X3, X4 and XS represent reactive residues,
R', Alk, R", R"SR" and Z have the same meanings as above.) That is, the reaction of compound (IX) with compound (X), the reaction of compound (XI) with compound (XI[) and the reaction between compound (X In) and compound (XIV) are both carried out using a deoxidizing agent (e.g., hydroxyl It can be carried out at 0°C to 110°C in the presence or absence of an alkali metal, an alkali metal carbonate, an alkali metal hydrogen carbonate, triethylamine, N-methylmorpholine, pyridine, diisopropylethylamine), and the compound (XI) and the compound The reaction with (■) is carried out using an appropriate solvent (
For example, it can be carried out at 25°C to 100°C in methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile).

Examples of the reactive residues (X', X4, X') of compounds (X), (XII) and (XI[[) include the reactive residues exemplified for compound (II).

Compound (I) of the present invention can be used as a medicament either in free form or in the form of a salt.

Examples of pharmacologically acceptable salts of compound (1) include inorganic acid addition salts such as hydrochloride, sulfate, nitrate, phosphate, and hydrobromide, acetate, oxalate, and fumarate. organic acid addition salts, sodium salts, such as succinate, maleate, citrate, lactate, glucuronate, sulfamate, pyruvate, tartrate, benzenesulfonate, methanesulfonate, Examples include alkali metal salts such as potassium salts. These salts can be easily obtained by treating free compound (1) with an acid or alkaline reagent in a conventional manner.

Compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibits excellent cardiac inotropy and long-lasting action, and is useful for 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 (1) of the present invention or a pharmacologically acceptable salt thereof does not substantially exhibit an adrenergic β-receptor stimulating effect, and therefore,
It has the characteristics of selectively activating the myocardium and having few side effects (for example, effects on heart rate).

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

The compound (1) of the present invention or a salt thereof can be used in conventional preparations, such as solid preparations such as tablets, powders, capsules, and granules.
It can be used in any form of liquid formulation, but when used as a solid formulation, excipients include calcium carbonate, calcium phosphate, corn starch, potato starch, sucrose, lactose, talc, magnesium stearate, etc. can be used as appropriate. In addition, when using a liquid agent, for example, water-based or oil-based: B? The compound (I) of the present invention or a salt thereof can be used parenterally, for example, in the form of an injection or a suppository. Injections can be used as solutions or QJ liquids, and when formulated, distilled water, essential oils (e.g., peanut oil, corn oil), hydrophobic solvents (e.g., polyethylene glycol, polypropylene glycol, lanolin, (coconut oil) etc. may be used as appropriate.Furthermore, the above preparation 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 varies depending on the administration method, age, weight, condition, and type of disease of the patient, but is usually about 0.00% per day.
, 0 O3~30mg/kg, especially 0.01~
The amount is preferably about 20 mg/kg.

In this specification, "lower alkyl group" refers to a straight chain or branched alkyl group having 1 to 4 carbon atoms, and "lower alkoxy group" refers to a straight chain or branched alkoxy group having 1 to 4 carbon atoms. "Lower alkylene group" represents a straight chain or branched alkylene group having 1 to 4 carbon atoms.

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

Table 1. Represents the substitution position on the benzene ring of R3.

Experimental Example 2 (Method) The isolated heart of a male guinea pig (weight: approximately 280 g) was
Rock Ringer containing 2% rabbit defibrinated blood - 1 night (30
°C) was used as portal flow, and perfused with Langendorff flow. Cardiac contractility was measured by Transgenisa. The specimen was dissolved in physiological saline and administered into an aortic tube. 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=C-NH-122 (Note 1): Same meaning as (Note 1) in Table 1.

Example l N-methyl-2-[4-chloro-2-(2-chloroethyloxy)phenyl]thiazolidine-3-carboxamide 1.95 g, N-phenylpiperazine 1.13 g, potassium carbonate 0.96 g, sodium iodide A mixture of 0.87 g and 30n+1 dimethylformamide is stirred at 90° C. for 18 hours. After the reaction, 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, the solvent is distilled off under reduced pressure. N-methyl-2-(4-chloro-
1.43 g of 2-C2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl)thiazolidine-3-carboxamide are obtained. Yield: 53.4% M, p, 108-112°C Oxalate: M, 9.184-185°C (decomposition) (recrystallized from acetone) Examples 2-22 From the corresponding thiazolidine compound and piperazine compound In the same manner as in Example 1, the compounds listed in Table 3 below are obtained.

j Vision e Example 23 N-methyl-2-(4-methoxy-2-('2-(4-
Phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamidro, 5.37 m boron tribromide in a solution of 48 g in 100 ml methylene chloride
After adding a solution of 1 in 15 ml of methylene chloride at -60 to -50°C, the mixture is gradually warmed to room temperature and stirred at room temperature for 6 hours. The mixture is poured into 150 ml of 10% aqueous sodium hydroxide and washed with methylene chloride. Cool the aqueous layer with water for 10 minutes.
Neutralize with % hydrochloric acid, add ethyl acetate and sodium hydrogen carbonate, and stir. The ethyl acetate solution is separated, washed with saturated brine, dried, and the solvent is distilled off under reduced pressure. N-methyl-2-
1.61 g of (4-hydroxy-2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide are obtained.

M, p, 177-179°C (decomposed) (recrystallized from ethyl acetate methanol ether) Oxalate: M, p, 132-135°C (decomposed) (recrystallized from acetone ether) Example 24 N- 3.21 g of methyl-2-(5-methoxy-2-(2-(4-phenylpiperazin-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide, 2.66 ml of boron tribromide and 60 ml of methylene chloride. By treating in the same manner as in Example 23, N-methyl-2-
1.68 g of (5-hydroxy-2-(2-(4-phenylpiperazisol-1-yl)ethyloxyphphenyl)thiazolidine-3-carboxamide is obtained as a colorless caramel. Yield: 54% r Rv (cm -'): 3420, 1630,
1595,1490,760 oxalate: M, p, 130-135°C (decomposed) (recrystallized from acetone ether) Example 25 N-Methyl-2-(5-nitro-2-(2-(4- phenylpiperazin-1-yl)ethyloxyphphenyl)
0.24 g of 10% palladium on carbon was added to a mixture of 0.24 g of thiazolidine-3-carboxamide, 10 ml of ethanol, and 10 ml of tetrahydrofuran, and the mixture was heated at room temperature.
Catalytic reduction is carried out in a hydrogen gas stream under normal pressure. Filter off the catalyst;
The solvent of the filtrate is distilled off under reduced pressure. The residual fragrance was removed by silica gel chromatography (solvent, chloroform:methanol = 3
N-methyl-2-(5
-Amino-2-(2-(4-phenylpiperazine-1-
0.18 g of ethyloxyphenyl)thiazolidine-3-carboxamide is obtained. Yield: 80% M, p, 80-83°C (recrystallized from ether) 2 oxalate 1/2H20: M, p, 105-110°C (decomposed) (recrystallized from acetone-ether) [ Preparation of raw material compound] Production example 1 7.8 g of 3-chloro-2-hydroxybenzaldehyde
, 11.7 g of 1-chloro-2-tosyloxyethane, 6.9 g of potassium carbonate, and 60 ml of dimethylformamide are stirred under an argon atmosphere at room temperature for 6 days and at 70° C. for 1 day. After the reaction, dimethylformamide is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The ethyl acetate solution is washed with diluted sodium hydroxide solution and water, and after drying, the solvent is distilled off under reduced pressure. The residue is distilled under reduced pressure to obtain 7.5 g of 3-chloro-2-(2-chloroethyloxy)benzaldehyde.

B, 9.115-123°C (0.5 mmHg) The compounds listed in Table 4 below are obtained from the corresponding starting compounds in the same manner as above.

Table 4 (Vl-A) (Note 3): The substitution position of R" and R" is the carbon atom of the benzene ring substituted by the formyl group as the 1st position, and the group CI CH
It represents the substitution positions of the groups R3+ and R41 on the benzene ring when the carbon atom of the benzene ring substituted by zCHzO- is set at the 2-position.

Production example 2 Cysteamine hydrochloride 2.28 g ethanol 50ml
Add 0.80 g of powdered sodium hydroxide to the 1 solution under an argon atmosphere and reflux for 15 minutes. To the mixture, add a solution of 4.0 Og of 3-chloro-2-(2-chloroethyloxy)benzaldehyde in 20 ml of ethanol. Reflux for .5 hours. The solvent of the mixture was distilled off under reduced pressure, and the residue was dissolved in 60 ml of tetrahydrofuran. Add 1.36 g of methyl isocyanate to this solution and reflux for 2 hours. The solvent was distilled off from the mixture under reduced pressure, and the residue was dissolved in ethyl acetate. After washing the ethyl acetate solution with water and drying, the solvent was distilled off under reduced pressure. N-methyl-2-
[3.67 g of 3-chloro-2-(2-chloroethyloxy)phenylphthiazolidine-3-carboxamide is obtained.

M, 9.140-143°C Compounds listed in Table 5 below are obtained from the corresponding starting compounds in the same manner as above.

Table 5 (VI-A)
H0=C-NH-CH:1 (n-A) (Note 4): The substitution position of R" and R" is the carbon atom of the benzene ring substituted by the thiazolyl group is the 1st position, and the group CI
2 carbon atoms in the benzene ring to be substituted in CHzCH20-
represents the group R" and the ヱsubstituted position (■) on the benzene ring of R41.

Production example 3 Cysteamine hydrochloride 2.08 g ethanol 60ml
1. Add 0.73 g of powdered sodium hydroxide to the solution under argon atmosphere and reflux for 15 minutes. Add 2-(2
A solution of 3.30 g of -chloroethyloxy)-5-methylbenzaldehyde in 10 ml of ethanol was added and the mixture was refluxed for 2 hours, and then a solution of 1.46 g of methyl isothiocyanate in 10 ml of ethanol was added and the mixture was refluxed for 2 hours. The solvent was distilled off from the mixture under reduced pressure, and the residue was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. N-methyl-
3.0 g of 2-(2-(2-chloroethyloxy)-5-methylphenyl)thiazolidine-3-carbothioamide
get.

M, p, 154-155°C (recrystallized from ethyl acetate/n-hexane) The following compound is obtained from the corresponding raw material compound in the same manner as above.

N-Methyl-2-C3-chloro-2-(2-chloroethyloxy)phenyl]thiazolidine-3-carbothioamide M, p, 176-178°C (decomposition) (ethyl acetate n-
(Recrystallized from hexane) Agent: Tadashi Nakajima, Patent Attorney, Voluntary Procedural Amendment, April 1, 1985, 1, Indication of the Case, Showa Do O, Patent Application No. 257(c)9, 2, Name of Invention゛N story specialist\Lty←Ranniji 93, Supplement 1 [
Relationship with the case of a person who does
295) M-be Pharmaceutical Co., Ltd. Representative Matsubara - Department 4, Agent 3-16-89 Kashima, Yodogawa-ku, Osaka-shi, Osaka Prefecture (532
) 5. Number of inventions increased by amendment Contents of amendment 1. "It is preferable to practice." in the 8th line from the bottom of page 15 of the specification is corrected to "It is preferable to practice."

2. In the reaction formula in Table 3, page 30 of the same Z, C-NH-R2J Z=C-NO-R"　Corrected to J.

3, 4 in the column of Example 20 in Table 3, page 35 of the same, No. 40 of the same
5 in the reaction formula in Table 4 on page 4. In the physical property value column of the fourth compound in Table 4 on page 41 of the same

Claims (1)

[Claims] 1. General formula▲ Numerical formulas, chemical formulas, tables, etc.▼(I) (However, R^1 is a substituted or unsubstituted phenyl group, Alk is a lower alkylene group, and R^2 is a lower alkyl group. , R^3 and R^4 represent that either one is a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, or an amino group, and the other is a hydrogen atom, a halogen atom, or a lower alkoxy group. , Z represents an oxygen atom or a sulfur atom) or a salt thereof. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (However, Alk is a lower alkylene group, R^2 is a lower alkyl group, and one of R^3^1 and R^4^1 is It represents a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group, and the other is a hydrogen atom, a halogen atom, or a lower alkoxy group, Z represents an oxygen atom or a sulfur atom, and X' represents a reactive residue. ) and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (However, R^1 represents a substituted or unsubstituted phenyl group.)
The general formula ▲ has mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1, Alk, R^2, R^3^1, R^4)
^1 and Z have the same meanings as above. ) A thiazolidine derivative represented by (a) In the thiazolidine derivative (I-a),
When either one of R^3^1 and R^4^1 is a lower alkoxy group and the other is a hydrogen atom, the lower alkoxy group is optionally dealkylated to a hydroxyl group, and (b) the thiazolidine derivative ( In I-a),
When R^3^1 is a nitro group, the nitro group is optionally reduced to an amino group, and if necessary, the compound (I-a) or (a) or (b
) A general formula characterized by using the compound obtained in the process as its salt ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (However, R^3 and R^4 are either a halogen atom or a lower R^1, A
lk, R^2 and Z have the same meanings as above. ) A method for producing a thiazolidine derivative or a salt thereof.