JP3058287B2 - Thiazolidine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel thiazolidine compound having an action as a diabetic or diabetic complication.

[0002]

BACKGROUND OF THE INVENTION Thiazolidine derivatives having a hypoglycemic action include, for example, JP-A-55-22636 (JP-B-62-42903), JP-A-60-51189, JP-A-61-36284, and JP-A-61-36284. No. 62-5980, Y.
KAWAMATSU et al., Chem. Pharm. Bull., Volume 30, pages 3580-3600.
(1982).

[0003]

As a result of various studies on thiazolidine compounds, the present inventors have found that novel thiazolidine compounds have excellent actions as diabetic drugs and diabetic complications, and completed the present invention. .

[0004]

SUMMARY OF THE INVENTION The present invention provides

[0005]

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[Where the A is

[0007]

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[0008] W is a methylene group, a carbonyl group or a group represented by the formula: ＣC = N-OV (wherein, V represents a hydrogen atom, a sulfo group, an acyl group, or an alkyl group which may have a substituent). Is shown. U represents a methylene group. Alternatively, W and U may together form a double bond. R ¹ is a hydrogen atom or C 1-8
Represents a linear or branched alkyl group having a single bond. R ² and R ⁴ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms. R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms. Y ¹ and Y ² are the same or different and each represent a hydrogen atom or a hydroxyl-protecting group. n represents an integer of 1 to 3. Or a salt thereof.

When R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like. sec-butyl, pentyl, isopentyl, hexyl, 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethylhexyl, having 1 to 8 carbon atoms, preferably 1 to 4, and most preferably methyl And a linear or branched alkyl group having the formula:

When R ³ represents a linear or branched alkyl group having 1 to 10 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethylhexyl,
1,1,3,3-tetramethylbutyl, such as decyl, having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, most preferably methyl,
Mention may be made of linear or branched alkyl groups having t-butyl, especially methyl.

When R ² and R ⁴ are the same or different and each represent a linear or branched alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl,
1 to 8 carbon atoms such as 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethylhexyl,
A straight-chain or branched alkyl group having preferably 1 to 3, most preferably methyl, may be mentioned.

When V represents an acyl group, examples of the acyl group include acetyl, propionyl, butyryl, n-
A linear or branched aliphatic acyl group having 2 to 6, preferably 2 to 4, optimally acetyl, such as hexanoyl; benzoyl, naphthoyl,
3-methylbenzoyl, 2,4-dimethylbenzoyl, 4-ethylbenzoyl, 4-butylbenzoyl, p-anisoyl, 4-
Ethoxybenzoyl, 4-butoxybenzoyl, 3-chlorobenzoyl, 2-bromobenzoyl, 4-fluorobenzoyl, 4-trifluoromethylbenzoyl, 3-nitrobenzoyl, 2,4-dinitrobenzoyl, salicyloyl, 4-hydroxybenzoyl such 1 to 3 C ₁ - ₅ alkyl, C ₁ - ₅ alkoxy, halogen, trifluoromethyl, nitro, an aromatic acyl group optionally having a hydroxy as a substituent, preferably a benzoyl, Unsubstituted aromatic acyl groups such as naphthoyl; 2-thenoyl, 3-furoyl, picolinoyl, 2-pyridinecarbonyl, nicotinoyl, isonicotinoyl, 4-isoxazolecarbonyl, 1- (1,2,3-triazolyl) carbonyl, Nitrogen and oxygen atoms in the ring such as piperidinylcarbonyl and 1-pyrrolidinylcarbonyl A 5- or 6-membered member containing one or two or more identical or different hetero atoms such as a sulfur atom, and preferably one containing one or more identical or different two or more nitrogen atoms and / or oxygen atoms in a ring; And 6-membered heterocyclic acyl groups.

When V represents an alkyl group which may have a substituent, examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sebutyl.
1 to 8, preferably 1 to 4 carbon atoms, such as c-butyl, pentyl, isopentyl, hexyl, 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethylhexyl, most preferably methyl And a linear or branched alkyl group having the formula: If V is an alkyl group having substituents, Examples of the substituents such as phenyl, p- methylphenyl, m- chlorophenyl, o- methoxy C ₁ such as phenyl - ₅ alkoxy - ₅ alkyl, halogen, C ₁ which may have aryl; carboxyl; ethoxycarbonyl, C _2, such as a t- butoxycarbonyl - ₆ alkoxycarbonyl, preferably may be mentioned carboxyl and.

When Y ¹ and Y ² are the same or different and each represent a hydroxyl-protecting group, the protecting group is a protecting group in a reaction and is easily hydrolyzed in a living body for forming a prodrug when administered to a living body. There is no particular limitation as long as it is a protecting group. For example, formyl, acetyl, propionyl,
C ₁ such as pentanoyl - ₅ alkylcarbonyl; chloroacetyl, trichloroacetyl, halides such as trifluoroacetyl C ₂ - ₆ alkylcarbonyl;
Such as methoxyacetyl C ₁ - ₅ alkoxy of C ₂ -
Aliphatic acyl groups having 1 to 6 carbon atoms such as _6- alkylcarbonyl; arylcarbonyl such as benzoyl and α-naphthoyl; halogenated arylcarbonyl such as 2-bromobenzoyl and 4-chlorobenzoyl;
C such as 2,4,6-trimethylbenzoyl, 4-toluoyl
₁ - ₅ alkylated arylcarbonyl; 4-anisoyl like C ₁ - ₅ alkoxy arylcarbonyl; 4-nitrobenzoyl, nitrated arylcarbonyl such as 2-nitrobenzoyl; 2- (methoxycarbonyl) such as benzoyl C ₂ - ₆ alkoxycarbonyl arylcarbonyl; p-phenyl arylation arylcarbonyl such as benzoyl; and aromatic acyl groups: tetrahydropyran-2-yl, 3-bromo-tetrahydropyran -2
-Tetrahydropyranyl, such as yl, 4-methoxytetrahydropyran-4-yl; tetrahydrothiopyran-2-
Yl, tetrahydrothiopyranyl such as 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2
-Tetrahydrofuranyl, such as yl; tetrahydrothiofuranyl, such as tetrahydrothiofuran-2-yl;
Heterocyclic groups such as: tri-C _1- such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, and triisopropylsilyl
₅ alkylsilyl; diphenylmethylsilyl, diphenyl-butylsilyl, C ₁ substituted with 1 or two aryl such as diphenyl triisopropylsilyl - ₅ alkylsilyl; silyl groups such as methoxymethyl, 1,1-dimethyl-1 - Tokishimechiru, ethoxymethyl, propoxymethyl, iso-propoxymethyl, butoxymethyl, C ₁ such as t- butoxymethyl - ₅ alkoxy methyl; such as 2-methoxyethoxymethyl C ₁ - ₅ alkoxy of C
₁ - ₅ alkoxy methyl; trichloroethoxymethyl, bis (2-chloroethoxy) halides, such as methyl C ₁ - ₅ alkoxy methyl; 1-ethoxyethyl, 1-methyl-1-methoxy ethyl, 1- (isopropoxy) C _1, such as ethyl - ₅ alkoxylated ethyl; such alkoxyalkyl groups: benzyl, phenethyl, 3-
Phenylpropyl, alpha-naphthylmethyl, diphenylmethyl, C ₁ substituted with 1 to 3 aryl such as triphenylmethyl - ₅ alkyl; 4-methylbenzyl,
2,4,6-trimethyl benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-chlorobenzyl, 4-bromo-C _1, such as benzyl - ₅ alkyl, C ₁ - ₅ alkoxy, nitro, aryl ring by halogen substituted with 1 to 3 aryl substituted C ₁ - ₅ alkyl; and aralkyl group: methoxycarbonyl, ethoxycarbonyl, C _2, such as isobutoxycarbonyl - ₆ alkoxycarbonyl; 2,2,2 ethoxycarbonyl, 2-trimethylsilyl-ethoxy halogen or tri C ₁ such as carbonyl - ₅ alkylsilyl with substituted C ₂ - ₆ alkoxycarbonyl; etc. alkoxycarbonyl group having 2 to 6 carbon atoms: sulfo group: a is Preferably an aliphatic acyl group having 1 to 6 carbon atoms, an aromatic acyl group, or a sulfo group, more preferably Aliphatic acyl group having 2 to 4 carbon atoms, an unsubstituted aromatic acyl group,
And a sulfo group, most preferably an aliphatic acyl group having 2 to 4 carbon atoms, especially an acetyl group.

The target compound having the general formula (I) of the present invention can be converted into a salt according to a conventional method. Such salts include, for example, when the 3-position of the thiazolidine ring and Y ¹ and / or Y ² are hydrogen atoms, for example, salts of alkali metals such as lithium, sodium and potassium; alkaline earths such as calcium and barium Metal salts; aluminum salts; and salts of basic amino acids such as lysine and arginine. When the salt indicates, for example, a salt of an alkali metal, it can be in the form of its mono, di or tri salt. Alternatively, when W is of the formula = C = N-OH, mineral acids such as hydrobromic acid, hydrohalic acid such as hydrochloric acid, nitric acid and sulfuric acid; alkyl such as methanesulfonic acid and trifluoromethanesulfonic acid Sulfonic acid; benzenesulfonic acid,
Aromatic sulfonic acids such as p-toluenesulfonic acid; organic carboxylic acids such as acetic acid and oxalic acid; and salts of acidic amino acids such as glutamic acid and aspartic acid. Preferably, it is a pharmacologically acceptable salt.

In the compound having the general formula (I), when the carbon atom at the 5-position of the thiazolidine ring and R ¹ are an alkyl group, the carbon atom to which R ¹ is bonded is an asymmetric carbon atom. And each isomer based thereon is also encompassed in the compounds of the present invention.

Further, as for the thiazolidine moiety in the formula (I), the following tautomers can be considered, all of which are represented by a single formula (I).

[0018]

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In the compound having the general formula (I), A is preferably

[0020]

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Is shown.

W is a methylene group, a carbonyl group or a group represented by the formula
= C = N-OV (wherein V is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and the alkyl group is substituted by C ₁ −
₅ alkyl which may have aryl; carboxyl; C ₂ - ₆ alkoxycarbonyl; may have. ). U represents a methylene group. R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R ² and R ⁴ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms. R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Y ¹ and Y ² are the same or different and each represent a hydrogen atom, an aliphatic acyl group having 1 to 6 carbon atoms, an aromatic acyl group or a sulfo group. n
Represents 1 or 2.

In the compound having the general formula (I), more preferably, A is

[0024]

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Is shown. W is a methylene group or a formula = C =
A group represented by N-OV (wherein V is a hydrogen atom,
A linear or branched alkyl group having from 4 to 4 carbon atoms, and the alkyl group may have carboxyl as a substituent. ). U represents a methylene group. R
¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R ² and R ⁴ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms. R
³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Y ¹ and Y ² are the same or different and each represent a hydrogen atom, an aliphatic acyl group having 2 to 4 carbon atoms, an unsubstituted aromatic acyl group or a sulfo group. n represents 1 or 2.

In the compound having the general formula (I), A is most preferably

[0027]

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And especially

[0029]

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Is shown. W is a methylene group or a formula = C =
And a group represented by N-OV (wherein V represents a hydrogen atom, a carboxymethyl group or a 1-carboxy-1-methylethyl group, particularly a hydrogen atom), and particularly a methylene group. U represents a methylene group. R ¹ represents a methyl group.
R ² and R ⁴ are the same or different and each represent a hydrogen atom or a methyl group. R ³ represents a methyl group or a t-butyl group, particularly a methyl group. Y ¹ and Y ² are the same and represent a hydrogen atom or an aliphatic acyl group having 2 to 4 carbon atoms, particularly a hydrogen atom or an acetyl group. n
Indicates 1.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in the following table.

[0032]

[Table 1]

[0033]

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────────────────────────────────── Compound R ¹ R ² R ³ R ⁴ W n number ─ ───────────────────────────────── 1-1 Me Me Me Me CH ₂ 1 2 Me Me Me Me CH ₂ 2 3 Me Me Me Me C = O 14 Me Me Me Me C = NOH 15 Me Me Me Me C = NOCOMe 16 Me Me Me Me C = NOCOPh 17 Me Me Me Me C = NOMe 18 Me Me Me Me C = NOCH ₂ Ph 1 9 Me Me Me Me C = NOCH ₂ C ₆ H ₄ Me (P) 1 10 Me Me Me Me C = NOCH ₂ COOH 1 11 Me Me Me Me C = NOCH ₂ COOEt 1 12 Me Me Me Me C = NOCMe ₂ COOH 1 13 Me H tBu H CH ₂ 1 14 Me H tBu H CH ₂ 2 15 Me H tBu HC = O 1 16 Me H tBu HC = NOH 1 17 Et Me Me Me CH ₂ 1 18 iBu Me Me Me CH ₂ 1 19 iBu Me Me Me C = O 1 20 Pn Me Me Me CH ₂ 1 21 H Me Me Me CH ₂ 1 22 Me H iPr H CH ₂ 1 23 iBu H tBu H CH ₂ 1 24 Oc Me Me Me CH ₂ 1 25 Oc Me Me Me C = O 1 26 Me H TMB H CH ₂ 1 27 Me H TMB H CH ₂ 2 28 Me H TMB HC = O 1 29 Me H TMB HC = NOH 1 30 iBu H TMB HC = NOCH ₂ COOH 1 31 Oc H TMB HC = NOCH ₂ COOE t 1 ──────────────────────────────────

[0035]

[Table 2]

[0036]

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────────────────────────────────── Compound Y ¹ Y ² R ¹ R ² R ³ R ⁴ W n number ────────────────────────────────── 2- 1 HH Me Me Me Me CH ₂ 1 2 HH Me Me Me Me CH ₂ 2 3 HH Me Me Me Me C = O 1 4 HH Me Me Me Me C = NOH 15 HH Me Me Me Me C = NOMe 16 HH Me Me Me Me C = NOCH ₂ COOH 1 7 HH Me Me Me Me C = NOC (Me) ₂ COOH 18 HH Et Me Me Me CH ₂ 19 HH Me H tBu H CH ₂ 1 10 HHHHHH CH ₂ 1 11 HH iBu HHHC = O 1 12 Ac Ac Me Me Me Me CH ₂ 1 13 Ac Ac Me Me Me Me CH ₂ 2 14 Ac Ac Me Me Me Me C = O 1 15 Ac Ac Et Me Me Me C = NOH 1 16 Ac H Me Me Me Me CH ₂ 1 17 Su H Me Me Me Me CH ₂ 1 18 H Ac Me Me Me Me CH ₂ 1 19 H Su Me Me Me Me CH ₂ 1 20 Su Su Me Me Me Me CH ₂ 1 21 Bz Bz Me Me Me Me CH ₂ 1 ──── ────────────────────────────── In Tables 1 and 2, Me = methyl; Et = ethyl iPr = isopropyl; iBu
= Isobutyl; tBu = Tertiary butyl; Pn = Pentyl; Oc = Octyl; TMB = 1,1,3,3-tetramethylbutyl; Ph = Phenyl;
Ac = acetyl; Su = sulfo; Bz = benzoyl; Among the compounds having the general formula (I) of the present invention, preferably, the compound numbers 1-1, 1-2 and 1-4 in Table 1 and the compound numbers 2-1, 2-4 and 2 in Table 2
-12, 2-13, 2-17 and 2-19, more preferably compound No. 1-1 in Table 1 and compound Nos. 2-1 and 2-12 in Table 2; Is the compound number 1-1.

In the compound of the present invention having the general formula (I), the compound wherein the reaction (1) A is the formula (III) is described in, for example, JP-A-60-51.
Nos. 189, 61-36284 and 62-598
A known general formula described in No. 0

[0039]

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Where R ¹ , R ² , R ³ , R ⁴ , W, U
And n have the same meaning as described above. ) Is subjected to an oxidation reaction. The reaction is carried out by converting the raw material compound to a trivalent iron salt such as ferric chloride, ferric bromide, or ferric sulfate; a divalent salt such as copper sulfate, cupric chloride, or cupric acetate. Copper salts; organic free represented by N-oxyl such as 2,2,6,6-tetramethylpiperidine-1-oxyl and 2,2,6,6-tetramethyl-4-oxopiperidin-1-oxyl The reaction is performed by contact with radicals. Usually, an oxidizing agent is used for 1 mole of the starting compound
It is preferred to use 0.5 to 15 moles, preferably 2 to 8 moles. The reaction is carried out in the presence of ketones such as acetone and methyl ethyl ketone; alcohols such as methanol and ethanol; or a mixed solvent of these organic solvents and water. The reaction temperature is not particularly limited, but is usually 0 to 50 ° C, preferably 15 to 30 ° C. The reaction time varies depending on the reaction temperature, the starting compound used, the reaction reagent and the like, but is usually from several minutes to 30 hours, preferably from 3 minutes to 20 hours.

Reaction (2) Next, a compound in which A is the formula (II) and Y ¹ and Y ² are hydrogen atoms is obtained by subjecting the compound obtained in the above reaction (1) to a reduction reaction. Obtained by The reaction is carried out by bringing the compound obtained in the above reaction (1) into contact with a metal borohydride compound such as sodium borohydride or potassium borohydride. Usually, a reducing agent is added to 1 mole of the compound obtained in the above reaction (1).
It is preferred to use 1 to 20 moles, preferably a large excess. The reaction is usually performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in this reaction,
For example, alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol monomethyl ether; ethers such as tetrahydrofuran and dioxane are preferable. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds, reaction reagents, solvents, and the like.
30 hours.

Reaction (3) In the above reaction (2), when W is a carbonyl group, the carbonyl group may be used as it is, but it is preferable that the carbonyl group is protected and subjected to a reduction reaction. It is not particularly limited as long as it is not affected by the reduction reaction as a protecting group for a carbonyl group, for example, ethylenedioxy, trimethylenedioxy, ethylenedithio, an expression such as trimethylene dithio -X - (CH ₂₎ and p-X- (wherein, X represents an oxygen atom or a sulfur atom, and p represents an integer of 2 or 3). Such protecting groups can be obtained by contacting corresponding glycols such as ethylene glycol, trimethylene glycol, ethylenedithioglycol, trimethylenedithioglycol in the presence of an acid catalyst such as hydrochloric acid and sulfuric acid. After protecting the carbonyl group in this way, the compound is subjected to a reduction reaction, and then the protecting group is removed by a conventional method to obtain the desired compound.

Reaction (4) Further, W is a group represented by the formula ＣCＣNOV (where V is
Has the same meaning as described above. )), The target compound can be obtained by subjecting the group as it is to the reduction reaction of the above reaction (2). However, preferably, the compound in which W is a carbonyl group obtained in the above reaction (3) is converted to a conventional oximinating agent, for example, a compound of the formula H ₂ N-OV (wherein V has the same meaning as described above). )) Or an inorganic or organic acid salt thereof. The reaction is carried out according to the method described in JP-A-62-5980. That is, a compound in which W obtained in the above reaction (3) is a carbonyl group and a hydroxylamine represented by, for example, a formula H ₂ N-OV (wherein V has the same meaning as described above) In the reaction, the molar ratio used is not particularly limited, but it is usually preferable to use the latter in equimolar to large excess with respect to the former,
Preferably it is 1 to 50 mol. Formula H ₂ N-OV
(In the formula, V has the same meaning as described above.) When the hydroxylamine represented by the formula is a salt with an inorganic acid, a deoxidizing agent may be used in the reaction. As such a deoxidizing agent, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal carbonate such as sodium carbonate or potassium carbonate is suitable. The molar ratio of the deacidifying agent to the inorganic acid salts may be not more than equimolar. The reaction is usually performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the present reaction. Examples thereof include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether; ethers such as tetrahydrofuran and dioxane; dimethylformamide, dimethyl Examples include amides such as acetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; organic bases such as triethylamine and pyridine; or water; or a mixed solvent thereof. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds, reaction reagents, solvents and the like, but are usually 0 to 100 ° C. and several minutes to about 10 days.

Reaction (5) or a compound wherein W is a carbonyl group has the formula:
It can be obtained by treating a compound having a group represented by = N-OV (wherein V has the same meaning as described above) with an acid, if desired. As the acid used, for example, inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are suitable. The reaction is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction. For example, methanol, ethanol, propanol,
Alcohols such as butanol and ethylene glycol monomethyl ether; ethers such as tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; triethylamine and pyridine Organic bases such as;
Or water; or a mixed solvent thereof. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds, reaction reagents, solvents and the like, but are usually 20 to 100 ° C. and several minutes to several days.

Reaction (6) Next, the reaction of protecting a compound in which Y ¹ and Y ² are hydrogen atoms with a protecting group for a hydroxyl group is carried out according to a conventional method. That is, when the protecting group of the hydroxyl group is an aliphatic acyl group or an aromatic acyl group, the reaction is carried out by reacting with an acylating agent. The reaction is carried out according to the method described in JP-A-62-5980. That is, the reaction is performed using an organic acid corresponding to the acyl group or a reactive derivative of the organic acid such as an acid anhydride or an acid halide as the acylating agent.
The ratio between the starting compound and the acylating agent is not particularly limited,
It is preferable to use an acylating agent in excess of equimolar with respect to 1 mol of the starting compound, and preferably 1 to 10 mol of the acylating agent per 1 mol of the starting compound. The reaction is usually performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; hexane, cyclohexane, Aliphatic hydrocarbons such as heptane; halogenated hydrocarbons such as dichloromethane and chloroform; organic bases such as pyridine and triethylamine; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide. Sulfones such as sulfolane; or water; or a mixed solvent thereof. The reaction conditions such as reaction temperature and reaction time vary depending on the used starting compounds, reaction reagents, solvents and the like, but are usually 0 to 100 ° C., several minutes to about 20 minutes.
Time.

A protecting group for a hydroxyl group is tetrahydropyranyl,
In the case of a heterocyclic group such as tetrahydrothiopyranyl, tetrahydrofuranyl, or tetrahydrothiofuranyl, the reaction is performed with dihydropyran, dihydrothiopyran, dihydrothiophene, or 4-methoxy-5,6-dihydro (2H) pyran. This is performed using a heterocyclic compound. The reaction is carried out in the presence of small amounts of acids, for example inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorus oxychloride, and organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, picric acid, benzenesulfonic acid. . The reaction is preferably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as tetrahydrofuran; nitriles such as acetonitrile; halogenated hydrocarbons such as chloroform and methylene chloride; and dimethylformamide. Such dialkylformamides. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds, reaction reagents, solvents and the like, but are usually about 0 ° C. to room temperature and 30 minutes to about 8 hours.

When the protecting group of the hydroxyl group is a silyl group, the reaction is carried out using a silyl compound such as trimethylsilyl chloride, dimethyl-t-butylsilyl chloride or diphenyl-t-butylsilyl chloride. The reaction is carried out in the presence of an organic base such as triethylamine, dimethylaminopyridine, imidazole, pyridine or a sulfide compound such as lithium sulfide. The reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as tetrahydrofuran; nitriles such as acetonitrile; halogenated hydrocarbons such as chloroform and methylene chloride; and dimethylformamide. Such as dialkylformamides; and organic bases such as triethylamine and pyridine. Reaction conditions such as reaction temperature and reaction time vary depending on the starting compound used, reaction reagents, solvents, etc.
0 ° C to room temperature, 30 minutes to about 8 hours.

When the protecting group for the hydroxyl group is an alkoxyalkyl group or an aralkyl group, the reaction is carried out by reacting with an alkoxyalkylating agent or an aralkylating agent. The reaction is carried out according to the method described in JP-A-62-5980. That is, the reaction is performed using an alkoxyalkyl halide (preferably bromide) such as chloromethyl methyl ether as the alkoxyalkylating agent. As the aralkylating agent, for example, aralkyl halide (preferably bromide) such as benzyl chloride or benzyl bromide is used. The ratio between the starting compound and the alkoxyalkylating agent or aralkylating agent is not particularly limited, but it is preferable to use an equimolar excess of the alkoxyalkylating agent or aralkylating agent with respect to 1 mole of the starting compound, and preferably Alkoxyalkylating or aralkylating agent per mole of compound
1 to 10 moles. The reaction is performed in the presence of a base. Examples of the base to be used include alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides and alkalis such as sodium hydroxide, potassium hydroxide and calcium hydroxide Earth metal; sodium hydride, alkali metal hydride such as potassium hydride; sodium methoxide, sodium ethoxide, potassium tert
-Alkali metal alkoxides such as butoxide; organic lithium compounds such as butyllithium and tert-butyllithium; lithium dialkylamides such as lithium diisopropylamide and lithium dicyclohexylamide; organic bases such as pyridine and triethylamine; It is an alkali metal carbonate such as potassium carbonate. The ratio of the starting compound to the base is 1 to 10 mol of the base per 1 mol of the starting compound. The reaction is usually performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as ethyl ether, tetrahydrofuran and dioxane; aliphatic hydrocarbons such as hexane, heptane and cyclohexane; benzene, toluene and xylene. Aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as methanol, ethanol and tert-butanol; ketones such as acetone and methyl ethyl ketone;
Organic bases such as triethylamine; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; or water; or a mixed solvent thereof. The reaction conditions such as the reaction temperature and reaction time vary depending on the used starting compounds, reaction reagents, solvents and the like, but are usually -10 to 100 ° C and several minutes to several days.

When the protecting group of the hydroxyl group is an alkoxycarbonyl group, the reaction is carried out by reacting with an alkoxycarbonyl halide such as alkoxycarbonyl chloride. The reaction is trimethylamine, triethylamine,
The reaction is performed in the presence of a base such as an organic base such as pyridine. The reaction is usually performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction,
For example, ethers such as ethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane, heptane and cyclohexane; organic bases such as pyridine and triethylamine. Amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; and the like. Reaction conditions such as reaction temperature and reaction time vary depending on the starting compound used, reaction reagents, solvents, etc.
At 0 to 50 ° C, it takes several minutes to several days.

When the protecting group for the hydroxyl group is a sulfo group, the reaction is carried out by reacting with a sulfonating agent. The reaction is carried out according to the method described in JP-A-62-123186. That is, it is performed by contacting with chlorosulfonic acid in the presence of an organic base such as pyridine, picoline, lutidine, and triethylamine. The ratio of the starting compound and chlorosulfonic acid is not particularly limited, but is 0.5 to 10 mol of chlorosulfonic acid per 1 mol of the starting compound. The reaction is suitably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene;
Esters such as ethyl acetate; nitriles such as acetonitrile; or a mixed solvent thereof.
Reaction conditions such as reaction temperature and reaction time vary depending on the starting compounds used, reaction reagents, solvents, etc.
At 100 to 100 ° C for 10 minutes to 2 hours.

Alternatively, it may be produced by an esterification reaction with a raw material compound and sulfuric acid in the presence of a dehydrating agent. N, N, -dicyclohexylcarbodiimide (DCC) as a dehydrating agent,
Carbodiimides exemplified by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or a mineral acid salt such as hydrochloride thereof include, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Hydrochloride is preferred. In the esterification reaction, the molar ratio of the raw material compound to sulfuric acid was 1 to 5 mol of sulfuric acid to 1 mol of the raw material compound.
Mole, preferably 1 to 2 moles. The molar ratio of the starting compound to the dehydrating agent is 1 to 10 mol, preferably 3 to 6 mol, of the dehydrating agent to 1 mol of the starting compound.
Is a mole. The reaction is usually performed in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; halogenated carbons such as dichloromethane and chloroform. Hydrogen; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; or water; or a mixed solvent thereof. Amides are preferred. The reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds, reaction reagents, solvents and the like, but are usually 0 to 50 ° C., preferably around room temperature, about 10 minutes to 2 days, preferably 1 to 1 day. 3 hours.

After completion of the reaction, the target compound of each reaction can be purified, if necessary, by a conventional method, for example, column chromatography, recrystallization, reprecipitation, or the like. For example, a solvent is added to the reaction mixture for extraction, and the solvent is distilled off from the extract. The obtained residue is purified by subjecting it to column chromatography using silica gel or the like, whereby a pure product of the target compound can be obtained. In particular, the isomers can be separated at an appropriate time by a conventional separation and purification means.

[0053]

The thiazolidine compound of the present invention showed a hypoglycemic effect in a test system using genetically hyperglycemic animals. Varma et al. [SDVarma and JHKinoshit
a, Biochem. Pharmac., 25, 2505 (1976)], showed an aldose reductase inhibitory effect. Therefore, it is expected to be useful for treating human hyperlipidemia, diabetes and their complications such as diabetic cataract and diabetic neuropathy.

The compound having the general formula (I) of the present invention is administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, powders, syrups and the like, and parenteral administration by injections (intravenous, intramuscular, subcutaneous), drops, suppositories and the like. For ocular mucosal administration, eye drops and eye ointments are preferred. These various preparations are commonly used in the field of pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, flavoring agents, dissolution aids, dissolution aids, suspensions, coatings, etc. in the main drug in accordance with ordinary methods. It can be formulated using known adjuvants.
The dosage varies depending on symptoms, age, body weight, administration method and dosage form. For example, when used as a therapeutic agent for hyperlipidemia and / or diabetes and their complications, the dosage is usually 1 day for adults. 5 mg to 5000 mg can be administered.

[0055]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Embodiment 1 FIG. 5- {4- [2-methyl-2-hydroxy-4- (3,5,6-trimethyl-
1,4-benzoquinone-2-yl) butoxy] benzyl} -2,4
-Dioxothiazolidine 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2
-Ylmethoxy) benzyl] -2,4-dioxothiazolidine
The 6.3 g was dissolved in acetone 50 ml, and then hydrochloric acid aqueous solution of ferric chloride with stirring under ice cooling (FeCl ₃ · 6H ₂ O
(About 65 wt% as concentrated hydrochloric acid and about 35 wt% as concentrated hydrochloric acid), and left overnight at room temperature. After completion of the reaction, the reaction mixture was diluted by adding 500 ml of water, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the resulting residue was purified by silica gel column chromatography (eluent; benzene: ethyl acetate = 5: 1) to give a yellow powder having a softening point of 55-65 ° C. Compound
4.2 g were obtained. Nuclear magnetic resonance spectrum (δppm,
Heavy acetone) 1.35 (3H, s), 1.5-1.85 (2H, m), 1.97 (6H, s), 2.05 (3H, s)
s), 2.4-2.9 (2H, nd), 3.11 (1H, dd, J = 9 and 15Hz), 3.45
(1H, dd, J = 3 and 15Hz), 3.85 (2H, br.), 4.80 (1H, dd, J = 3
And 9Hz), 6.90 (2H, d, J = 9Hz), 7.25 (2H, d, J = 9Hz).

Embodiment 2 FIG. 5- {4- [2-hydroxy-4-hydroxyimino-2-methyl-4
-(3,5,6-trimethyl-1,4-benzoquinone-2-yl) butoxy] benzyl} -2,4-dioxothiazolidine 5- [4- (6-hydroxy-4-hydroxyimino-2,5 , 7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-
Dioxothiazolidin 2 g, acetone 15 ml and acidified with hydrochloric acid aqueous solution of ferric chloride (about 65wt as FeCl ₃ · 6H ₂ O
%, About 35 wt% as concentrated hydrochloric acid). As a result, 0.74 g of the target compound was obtained as a yellow powder having a softening point of 80-85 ° C. Nuclear magnetic resonance spectrum (δppm, DMSO-d ₆ ) 1.19 (3H, s), 1.79 (3H, br.s), 1.84 (3H, br.s), 1.97 (3H,
s), 2.8-3.0 (2H, m), 3.03 (1H, dd, J = 9 and 14Hz), 3.25-
3.4 (1H, nd), 3.53 (1H, d, J = 9Hz), 3.62 (1H, d, J = 9Hz), 4.7
-4.85 (1H, br, disappeared by adding heavy water), 4.85 (1H, dd, J = 4 and 9
Hz), 6.71 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 11.41 (1
H, s, disappeared by adding heavy water), 11.99 (1H, s, disappeared by adding heavy water)
.

Embodiment 3 FIG. 5- {4- [4- (2,5-dihydroxy-3,4,6-trimethylphenyl) -2-hydroxy-2-methylbutoxy] benzyl} -2,4-
Dioxothiazolidine 5- [4- (2-hydroxy-2-methyl-4- (3,5,6-trimethyl-
1,4-benzoquinone-2-yl) butoxy] benzyl} -2,4-
1 g of dioxothiazolidine was dissolved in 10 ml of ethanol, and then 165 mg of sodium borohydride was added with stirring under ice-cooling, followed by stirring at room temperature for 30 minutes. After the reaction is completed, the reaction mixture is mixed with 100 ml of ice water and 35% hydrochloric acid.
When added to 0.6 ml of the mixture, white crystals precipitated. The crystals are collected by filtration and dried under reduced pressure over phosphorus pentoxide, melting point 84-88 ℃
0.9 g of the target compound was obtained as a yellow powder having the formula: Nuclear magnetic resonance spectrum (δppm, DMSO-d ₆ ) 1.24 (3H, s), 1.5-1.65 (2H, m), 2.03 (6H, s), 2.05 (3H,
s), 2.58-2.65 (2H, m), 3.05 (1H, dd, J = 9 and 14Hz), 3.2
5-3.35 (1H, nd), 3.74 and 3.78 (2H, AB type, J = 9Hz), 4.66
(1H, s, disappeared by adding heavy water), 4.86 (1H, dd, J = 4 and 9Hz),
6.88 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz), 7.24 (1H, s, disappeared by adding heavy water), 7.26 (1H, s, disappeared by adding heavy water), 11.98 (1H, b
rs, disappeared by adding heavy water).

Embodiment 4 FIG. 5- {4- [4- (2,5-diacetoxy-3,4,6-trimethylphenyl) -2-hydroxy-2-methylbutoxy] benzyl} -2,4-
Dioxothiazolidine 5- {4- [4- (2,5-dihydroxy-3,4,6-trimethylphenyl) -2-hydroxy-2-methylbutoxy] benzyl} -2,4-
0.8 g of acetic anhydride was added to a mixture of 0.9 g of dioxothiazolidine and 7 ml of pyridine, and the mixture was allowed to stand at room temperature for 3 days.
After completion of the reaction, the reaction mixture was added to 50 ml of water, and then extracted with ethyl acetate. The extract was washed with 0.1N hydrochloric acid and then with saturated saline, and then dried over anhydrous sodium sulfate.
The solvent was distilled off from the extract, and the obtained residue was purified by silica gel column chromatography (eluent; benzene: ethyl acetate = 7: 3) to give a white powder having a softening point of 94-97 ° C. 0.3 g of compound was obtained. Nuclear magnetic resonance spectrum _{(δppm, DMSO-d 6)} 1.23 (3H, s), 1.4-1.7 (2H, br.), 1.95 (3H, s), 1.98 (3H,
s), 1.99 (3H, s), 2.22 (3H, s), 2.3-2.7 (2H, nd), 2.34 (3
H, s), 3.05 (1H, dd, J = 9 and 14Hz), 3.2-3.4 (1H, nd),
3.72 (1H, d, J = 9Hz), 3.79 (1H, d, J = 9Hz), 4.72 (1H, s), 4.8
6 (1H, dd, J = 4 and 9Hz), 6.91 (2H, d, J = 9Hz), 7.15 (2H,
d, J = 9 Hz), 11.98 (1H, br.s).

Embodiment 5 FIG. Monopotassium salt of 5- {4- [4- (2-hydroxy-5-sulfoxy-3,4,6-trimethylphenyl) -2-hydroxy-2-methylbutoxy] benzyl} -2,4-dioxothiazolidine ( A) and 5- {4- [4- (5-hydroxy-2-sulfoxy-
3,4,6-trimethylphenyl) -2-hydroxy-2-methylbutoxy] benzyl} -2,4-dioxothiazolidine monopotassium salt (B) 5- {4- [4- (2,5-dihydroxy- 3,4,6-Trimethylphenyl) -2-hydroxy-2-methylbutoxy] benzyl} -2,4-dioxothiazolidine 1.0 g, pyridine 0.35 g and acetonitrile 10 ml
After adding 0.26 g, the mixture was heated at 80 ° C for 3 hours. After the completion of the reaction, the reaction mixture was cooled, and the supernatant was removed by decantation. Then, the residual oily substance was extracted with ethyl acetate 10
Washed with ml. 5 ml of water was added to the obtained oil, and then about 2N aqueous potassium hydroxide solution was added to adjust the pH to about 6.
And 5. Ethyl acetate was added to this to remove the soluble portion. The obtained aqueous layer was freeze-dried to obtain a crude product as a white powder. The resulting crude product was purified by applying it to an ion exchange resin (eluent; water: acetonitrile = 85: 15) using Diaion HP-20 (trade name, manufactured by Mitsubishi Kasei Corporation). The target compound was obtained as a white powder from the fractions. Mass spectrometry spectrum (m / e, NEG.FAB using metanitrobenzyl alcohol for matrix)
Measured by the method: M indicates the molecular weight of the target compound. (M−H) ⁻ = 576, (M−K) ⁻ = 538 Nuclear magnetic resonance spectrum (δ ppm, DMSO-d ₆ ) The nuclear magnetic resonance spectrum measured at 270 MHz is 4.80 (1H, q), 4.67 (0.5 H, s) and 4.05 (0.5H, s) showed specific peaks. From these peaks, the constitutional ratio of the target compounds (A) and (B) was about 1: 1.

Test Example 1 Aldose reductase inhibitory method [S. Hayman and JH Kinoshita, J.
According to Biol. Chem., 240, 877, (1965)], the aldose reductase of the rat lens was adjusted and Va was used.
rma et al. [SDVarma and JHKinoshita, Bioc
hem. Pharmac., 25, 2505 (1976)], and the aldose reductase activity of the test compound was measured.
Table 3 shows the results. In Table 3, the aldose reductase inhibitory activity is indicated by IC ₅₀ .

[0061]

[Table 3] Aldose reductase inhibitory activity {Compound IC ₅₀ (μM)}化合物 Compound of Example 1 0.82 Control compound * 2.07 ─────────────────────── * 5- [4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (Compound of Example 1 in JP-B-2-1079) As shown in Table 3, the compound of Example 1 of the present invention exhibited about 2.5 times the aldose reductase inhibitory activity as compared with the control compound.

[0062]

The thiazolidine compound of the present invention is expected to be useful for treating human hyperlipidemia, diabetes and their complications, such as diabetic cataract and diabetic neuropathy.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI C12N 9/99 C12N 9/99 (72) Inventor Wanichi Nakamura 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Daigo Minakoshi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kunihiro Sasahara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Takeshi Kinoshita 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 277/34-277/54 A61K 31/425-31/427 A61K 31/47 C07D 417/12 A61P 3/10 A61P 5/46 C12N 9/99 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (4)

(57) [Claims] 1. A compound of the general formula Wherein A is Is shown. W is a methylene group, a carbonyl group or a formula =
And a group represented by C = N-OV (wherein, V represents a hydrogen atom, a sulfo group, an acyl group, or an alkyl group which may have a substituent). U represents a methylene group. Alternatively, W and U may together form a double bond. R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms. R ² and R ⁴ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms. R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms. Y ¹ and Y ² are the same or different and each represent a hydrogen atom or a hydroxyl-protecting group. n represents an integer of 1 to 3. Or a salt thereof. 2. The method according to claim 1, wherein A is W is a methylene group, a carbonyl group or a formula: ＝ CＣN-O
A group represented by V (wherein V is a hydrogen atom and has 1 to 4 carbon atoms)
A straight-chain or branched-chain alkyl group having at least _one C _1-5 alkyl as a substituent; carboxyl;
C ₂ - ₆ alkoxycarbonyl; may have. U represents a methylene group, R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ² and R ⁴ are the same or different and represent hydrogen. R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, wherein R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; Wherein Y ¹ and Y ² are the same or different and each represent a hydrogen atom, an aliphatic acyl group having 1 to 6 carbon atoms, an aromatic acyl group or a sulfo group, and n represents 1 or 2; Or its salt. 3. The method according to claim 1, wherein A is Wherein W is a methylene group or a group represented by the formula: ＣC = N-OV (where V is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, The alkyl group may have a carboxyl as a substituent), U represents a methylene group, and R ¹ represents a hydrogen atom or a linear or branched chain having 1 to 4 carbon atoms. R ² and R ⁴ are the same or different and each represent a hydrogen atom or a linear or branched alkyl group having 1 to ³ carbon atoms, and R ³ represents a hydrogen atom or 1 to ³ carbon atoms. A linear or branched alkyl group having 4 groups, wherein Y ¹ and Y ² are the same or different and each are a hydrogen atom, an aliphatic acyl group having 2 to 4 carbon atoms, an unsubstituted aromatic acyl group Or a sulfo group, and n represents 1 or 2. ; Thiazolidine compound or its salt is. 4. The method according to claim 1, wherein A is W represents a methylene group or a group represented by the formula: ＣC = N-OV (where V represents a hydrogen atom, a carboxymethyl group or a 1-carboxy-1-methylethyl group), and U represents shows for methylene group, R ¹ represents a methyl group, R ² and R ⁴ are the same or different and represent a hydrogen atom or a methyl group, R ³ represents a methyl group or a t- butyl group, Y ¹ and Y ² Identical, hydrogen atom or carbon number 2
A thiazolidine compound or a salt thereof, which represents an aliphatic acyl group having from 1 to 4; and n represents 1.