JPH0557988B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiazolidine derivatives that have an effect of improving blood lipid metabolism, that is, lowering blood peroxide lipids, lowering blood triglycerides, and lowering blood cholesterol, and which have extremely low toxicity. More specifically, the present invention relates to the general formula [In the formula (), R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ and R ³ ', which will be described later, are the same or different and represent a hydrogen atom,
Aliphatic lower acyl group, alicyclic acyl group, aromatic acyl group that may have a substituent, heterocyclic acyl group, aromatic aliphatic acyl group that may have a substituent, lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group, n is an integer of 1 to 3,
W is a carbonyl group or a formula CH-OR ³ ' [wherein,
R ³ ′ has the same meaning as described above. ], Y represents an oxygen atom or an imino group, and Z represents an oxygen atom or an imino group. Regarding the thiazolidine derivative represented by [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n
has the same meaning as described above, X represents a halogen atom, A represents a cyano group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, or the formula -
Represents a group represented by COOM (M represents an equivalent cation). A general formula characterized by reacting a compound represented by ] with thiourea [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and Y have the same meanings as described above. A method for producing a thiazolidine derivative represented by the general formula (2); a method for producing a thiazolidine derivative represented by the general formula (2); [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n
has the same meaning as above. A method for producing a thiazolidine derivative represented by the general formula (2); a method for producing a thiazolidine derivative represented by the general formula (2), which is characterized by reacting a compound represented by the general formula (2) with a reducing agent. [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and Y have the same meanings as described above. A method for producing a thiazolidine derivative represented by the general formula (2); a method for producing a thiazolidine derivative represented by the general formula (2), which is characterized by reacting a compound represented by the general formula (2) with a reducing agent. [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n
has the same meaning as above. A method for producing a thiazolidine derivative represented by the general formula (2); a method for producing a thiazolidine derivative represented by the general formula (2), which comprises reacting a compound represented by the general formula (2) with an acylating agent. [In formula (), R ³ ′ _a represents an acyl group having the same meaning as in R ³ ′ except for the hydrogen atom, and R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , n and Y have the same meanings as described above. ] A method for producing a thiazolidine derivative represented by; and a general formula characterized by reacting a compound represented by the general formula () with an acylating agent. [In formula (), R ¹ , R ² , R ³ , R ³ ' _a , R ⁴ , R ⁵ and n have the same meanings as described above. ] The present invention relates to a method for producing a thiazolidine derivative represented by the following. In the general formula (), when R ¹ and R ² represent a lower alkyl group, R ¹ and R ² are the same or different and are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Examples include linear or branched chain carbon atoms having 1 to 5 carbon atoms, such as n-pentyl, isopentyl, 2-methylbutyl, and 2,2-dimethylpropyl. When R ³ and R ³ ′ described below represent an acyl group,
R ³ and R ³ ′ are the same or different and are formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyl,
Aliphatic acyl groups having 1 to 6 carbon atoms which may have an unsaturated bond such as methacryloyl and crotonoyl, alicyclic acyl groups such as cyclopentanecarbonyl, cyclohexanecarbonyl and cycloheptanecarbonyl, benzoyl, p- Nitrobenzoyl, m-fluorobenzoyl, o-chlorobenzoyl, p-aminobenzoyl, m-dimethylaminobenzoyl, o-methoxybenzoyl,
3,4-dichlorobenzoyl, 3,5-di-t-
Aromatic acyl groups such as butyl-4-hydroxybenzoyl, 1-naphthoyl, 2-furoyl, 3
- Heterocyclic acyl groups such as thenoyl, 3-pyridinecarbonyl, 4-pyridinecarbonyl, phenylacetyl, p-chlorophenylacetyl, phenylpropionyl, cinnamoyl, and unsaturated Examples thereof include an aromatic aliphatic acyl group which may have a bond, and a lower alkoxy or aralkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl. When R ⁴ and R ⁵ represent an alkyl group, R ⁴ and R ⁵ are the same or different and are methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and other linear or branched chain carbon atoms having 1 to 5 carbon atoms are mentioned. When R ⁴ and R ⁵ represent an alkoxy group, R ⁴ and R ⁵ may be the same or different and include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. Also, adjacent R ⁴ and R ⁵
may also represent a lower alkylenedioxy group such as methylenedioxy or ethylenedioxy taken together. W is a carbonyl group or has the formula CH-OR ³ ′ [wherein R ³ ′ has the same meaning as above,
And, it may be the same as or different from R ³ at the 6-position of the chroman ring. ] Examples include groups represented by the following. Y may be an oxygen atom or an imino group, and Z may be an oxygen atom or an imino group. The target compound of the present invention represented by the above general formula () can be converted into a pharmacologically acceptable non-toxic salt according to a conventional method. Examples include salts and salts of alkaline earth metals such as calcium. It has been reported in Japanese Patent Application Laid-open No. 55-22636 and Chem.Pharm.Bull that thiazolidine derivatives have blood lipid and sugar lowering effects and are said to have low toxicity. 30 ,
3580 (1982). However, the present inventors are currently actively researching derivatives having the general formula (), and have found that the compound () has a high antioxidant effect on unsaturated fatty acids such as linoleic acid and ethyl linoleate, and their esters. Therefore, it is expected that oxidation of phospholipids, which have a high proportion of unsaturated fatty acids, can be prevented in vivo; Biochem・Biophys.Res.Commun.95,
734-737 (1980), rat liver microsomal lipid peroxidation inhibition test showed that it not only had a strong lipid peroxide-lowering effect, but also had a strong effect on blood peroxidation in mice with experimental hyperlipidemia induced by alloxan. Exhibits extremely excellent pharmacological effects in lowering lipid peroxides, triglycerides, and cholesterol; Regarding toxicity, it has extremely low anorectic effects, suppressive effects on weight gain, and especially hepatomegaly effects in experimental animals such as rats. These findings led to the completion of the present invention. From the results of the above tests, it is expected that the thiazolidine derivatives (2) of the present invention are useful for treating hyperlipidemia, diabetes, and their complications in humans.
Administration methods include tablets, capsules, powders,
In addition to being used orally as granules, it can also be administered parenterally as injections, suppositories, and the like. The dosage varies depending on the symptoms, age, etc., but for example, when used as a therapeutic agent for hyperlipidemia and/or diabetes and their complications, the dose for adults is usually 50 mg to 5 g per day orally or parenterally. It can be administered separately. Specific examples of the thiazolidine derivatives () of the present invention include compounds having the structural formulas shown in the following table.

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[Table] Furthermore, in the compound () of the present invention, preferred compounds include R ¹ being lower alkyl, furthermore isobutyl, methyl, especially methyl; ^R2 being hydrogen atom or lower alkyl, furthermore hydrogen atom or methyl, isopropyl, especially methyl; R ³ is a hydrogen atom or aliphatic lower acyl;
aromatic acyl, also hydrogen atom, acetyl, benzoyl, especially hydrogen atom; R ⁴ is hydrogen atom,
lower alkyl or lower alkoxy, further methyl, isopropyl, tert-butyl, methoxy, more preferably methyl, tert-butyl, especially methyl; R ⁵ is a hydrogen atom, lower alkyl, lower alkoxy, further a hydrogen atom, methyl, methoxy , especially methyl; n is 1 or 2, especially 1; W is a carbonyl group; Y is an oxygen atom; Z is an oxygen atom or an imino group, especially an oxygen atom. . The thiazolidine derivative () of the present invention can be produced, for example, as follows. That is, a compound () in which W is a carbonyl group and Z is an imino group has the general formula () It can be obtained by reacting the compound represented by with thiourea. In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and Y
has the same meaning as above, A is a cyano group,
Carboxy groups, e.g. alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, carbamoyl groups or groups of the formula -COOM, where M is e.g. sodium, potassium, calcium, represents a metal atom such as aluminum or an equivalent cation such as ammonium group), and X represents, for example, chlorine,
Represents a halogen atom such as bromine or iodine. Note that although compound () may have tautomers as shown below, these are simply expressed as formula () for convenience. When Y is an oxygen atom, When Y is an imino group, The reaction between compound () and thiourea is usually carried out in a solvent. Examples of the solvent include methanol, ethanol, propanol, butanol,
Examples include alcohols such as ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, acetone, dimethyl sulfoxide, sulfolane, and dimethylformamide. Although the molar ratio of compound () and thiourea to be used is not particularly limited, it is preferable to use thiourea in a slightly excess amount of equimolar to compound (). Preferably 1 to 1 mole of compound ()
It is 2 moles. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, but
The reaction usually takes place at the boiling point of the solvent or at 80 to 150°C.
It lasts from one hour to more than ten hours. In formula (), W is a carbonyl group, Y and Z
The compound () of the present invention in which both are oxygen atoms,
It can be produced by hydrolyzing the compound () without isolation or isolation. The hydrolysis step is to dissolve the compound () in a suitable solvent (e.g. sulfolane, methanol, ethanol,
ethylene glycol monomethyl ether, etc.),
It is carried out by heating in the presence of water, an organic acid such as acetic acid, or a mineral acid such as sulfuric acid or hydrochloric acid. The amount of acid added is usually 0.1 to 10 mol, preferably 0.2 to 3 mol, per 1 mol of compound (), and the amount of water or aqueous solvent added is usually in large excess to 1 mol of compound (). The reaction temperature is usually 50 to 100°C, and the heating time is usually several hours to more than ten hours. After this hydrolysis step, R ³ in the compound () usually represents a hydrogen atom [() in which R ³ is a hydrogen atom is particularly indicated by ( _H ). ], but it is also possible to leave an acyl group by selecting the reaction conditions. The thiazolidine derivative () obtained in this step can be treated with various metals such as alkali metals such as sodium and potassium; alkaline earth metals such as calcium; or trivalent metals such as aluminum, by a conventional method. ; Preferably, it can form a salt with an alkali metal such as sodium or potassium; an alkaline earth metal such as calcium; more preferably a salt with an alkali metal such as sodium or potassium. Furthermore, in the case of a thiazolidine derivative having a phenolic hydroxyl group, a monosalt or a di-salt can be formed as necessary, for example, with respect to a monovalent metal such as sodium or potassium. ( _H ) can also be used with acylating agents such as acid halides and acid anhydrides, or organic acids such as aromatic carboxylic acids and aliphatic carboxylic acids, mineral acids such as hydrochloric acid and sulfuric acid, and para-toluenesulfonic acid. The desired esters can be converted by using a dehydrating agent or a dehydrating catalyst consisting of an organic acid such as. The reaction is usually carried out in a solvent. Solvents used include ether, tetrahydrofuran, ethers such as dioxane, benzene,
Aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptatane, halogenated hydrocarbons such as dichloromethane, chloroform, ketones such as acetone, methyl ethyl ketone, dimethyl Examples include amides such as formamide and dimethylacetamide, organic bases such as pyridine and triethylamine, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, and water. Although the ratio of the compound ( _H ) and the acylating agent is not particularly limited, it is preferable to use the acylating agent in a slightly excess amount of equimolar to the compound ( _H ). Preferably, per mol of compound ( _H ),
1 to 2 moles of acylating agent. Reaction conditions such as reaction temperature and reaction time vary depending on the type of raw materials and solvent used, but are usually at 0°C to 100°C and for several minutes to more than ten hours. A compound () in which W is a hydroxymethylene group and Z is an imino group is a compound represented by the general formula () and a reducing agent such as sodium borohydride or K-selectride, especially hydrogen. Obtained by reacting sodium boronate. In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and Y
has the same meaning as above. Note that although compound () may have tautomers as shown below, these are simply expressed as formula () for convenience. When Y is an oxygen atom When Y is an imino group, The reaction between compound () and sodium borohydride is usually carried out in a solvent. As the solvent,
Examples include alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol monomethyl ether, and ethers such as tetrahydrofuran and dioxane. The molar ratio of compound () and sodium borohydride used is not particularly limited, but compound ()
It is better to use an excess of sodium borohydride. Preferably, the amount is 1 to 20 mol per 1 mol of compound (). Although reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, the reaction is usually carried out at 0 to 100° C. for one hour to more than ten hours. A compound () in which W is a hydroxymethylene group and Y and Z are both oxygen atoms
can be obtained by reacting the compound represented by the general formula () with a reducing agent such as sodium borohydride or K-selectride, especially sodium borohydride. In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above. In addition, the compound ()
As shown below, tautomers are possible, but for convenience, these are simply expressed as formula (). The reaction between compound () and sodium borohydride is usually carried out in a solvent. As the solvent,
Examples include alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol monomethyl ether, and ethers such as tetrahydrofuran and dioxane. The molar ratio of compound () and sodium borohydride used is not particularly limited, but compound ()
It is better to use an excess of sodium borohydride. Preferably, the amount is 1 to 20 mol per 1 mol of compound (). Although reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, the reaction is usually carried out at 0 to 100° C. for one hour to more than ten hours. Furthermore, the compound () can be converted into the desired acylated compound () by reacting with an acylating agent such as an acid halide or an acid anhydride. In the above formula, R ¹ , R ² , R ³ , R ³ ' _a , R ⁴ , R ⁵ , n and Y have the same meanings as described above. Note that compound () may have tautomers as shown below, but for convenience, these are simply expressed as formula ().
Expressed as When Y is an oxygen atom When Y is an imino group The reaction is usually carried out in a solvent. The solvents used include ethers such as ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, and aliphatic hydrocarbons such as n-hexane, cyclohexane, and n-heptane. Examples include halogenated hydrocarbons such as dichloromethane and chloroform, organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfones such as sulfolane. It will be done. Although the ratio of the compound () to the acylating agent is not particularly limited, it is preferable to use the acylating agent in a slightly excess amount of equimolar to the compound (). Preferably, the amount of the acylating agent is 1 to 2 mol per 1 mol of the compound (). Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and type of solvent used, but
Usually, the temperature is 0 to 100°C for several minutes to more than ten hours. Furthermore, the compound () can be converted into the desired acylated compound () by reacting with an acylating agent such as an acid halide or an acid anhydride. In the above formula, R ¹ , R ² , R ³ , R ³ ′ _a R ⁴ , R ⁵ and n
has the same meaning as above. Note that the compound () may have tautomers as shown below, but for convenience, these are simply expressed as the formula (). The reaction is usually carried out in a solvent. Examples of solvents used include ethers such as ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, and aliphatic hydrocarbons such as n-hexane, cyclohexane, and n-heptane. Examples include halogenated hydrocarbons such as dichloromethane and chloroform, organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfones such as sulfolane. It will be done. Although the ratio of the compound () to the acylating agent is not particularly limited, it is preferable to use the acylating agent in a slightly excess amount of equimolar to the compound (). Preferably, 1 mol of the compound () is used as an acylating agent.
~2 moles. Reaction conditions such as reaction temperature and reaction time vary depending on the type of raw materials and solvent used, but are usually at 0 to 100°C and for several minutes to more than ten hours. Compounds obtained in this way (), (),
() or () is sodium,
Salts can be formed with alkali metals such as potassium, alkaline earth metals such as calcium, or trivalent metal ions such as aluminum. In the general formula (), when W is a carbonyl group, the carbon atoms at the 2-position of the chroman ring and the 5-position of the thiazolidine ring in the thiazolidine derivative represented by the formula () are asymmetric carbon atoms, respectively. Each isomer based on is also included in the compounds of the present invention. Further, in formula (), W represents the formula CH-OR ³ ′ [R ³ ′ has the same meaning as described above. ], in the thiazolidine derivative represented by formula (), the carbon atoms at the 2nd and 4th positions of the chroman ring and the 5th position of the thiazolidine ring are asymmetric carbon atoms, and each isomer based on them is also an asymmetric carbon atom. Also included in the compounds of the present invention. The thiazolidine derivative () obtained by the above reaction is subjected to known separation and purification methods such as concentration, vacuum concentration, solvent extraction, crystallization recrystallization, dissolution, chromatography, and optical resolution method. It is possible to isolate and purify it. α-halogenocarboxylic acids ( ), which are raw material compounds for producing the target compound represented by the general formula ( ) of the present invention, can be produced, for example, by the following reaction route. In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n, X and A have the same meanings as described above. 1st step First starting material, chroman-4-ones (XI)
is an acetophenone analogue () described, for example, in Chem. Berichte, Vol. 95 , pp. 1413 et seq.
and, for example, J.Med.Chem, Vol. 21 , p. 386 (1978) or J.Am.Chem.Soc., Vol. 99 ,
The p-nitrophenoxyalkyl alkyl ketones () described on page 7653 (1977) and after are prepared by the method described in JP-A-52-19670, that is, in the presence of a secondary amine. It can be produced by the reaction method described below. The solvent used in the above reaction is not particularly limited as long as it is inert to the raw materials and the target product, but examples include aliphatic solvents such as petroleum ether, benzene, toluene, xylene, n-hexane, and cyclohexane. or aromatic hydrocarbons, aliphatic or aromatic halogenated hydrocarbons such as carbon tetrachloride, dichloromethane, chloroform, chlorobenzene, dichlorobenzene, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethyl Amides such as acetamide and N-methylpyrrolidone, alcohols such as methanol, ethanol, and ethylene glycol monomethyl ether, esters such as ethyl acetate, nitriles such as acetonitrile, and sulfoxides such as dimethyl sulfoxide. can give. The secondary amine used in the above reaction has the formula R ⁶ -NH-R ⁷ [wherein R ⁶ and R ⁷ represent an alkyl group,
These can be combined with a nitrogen atom to form a heterocycle. ]. for example,
Diethylamine, dimethylamine, N-methylpiperazine, pyrrolidine, piperidine, morpholine, preferably pyrrolidine. The ratio of compound () to compound () is not particularly limited, but it is usually preferable to use equimolar amounts.
Generally, secondary amines are 0.05 to 1.5 mol per 1 mol of compound () or compound (),
Preferably 0.1 to 1 mol is used. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, but are usually -30 to +150°C, preferably 10 to 120°C, for 0.5 hours to 3 days. Second step The nitro compound (XI) thus obtained is reduced to the amino compound (XII). Examples of the reduction method include catalytic reduction or using a metal such as zinc or iron with an acid (for example, a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid), but catalytic reduction is preferably used. Examples of the catalyst used in the catalytic reduction include palladium-carbon, Raney nickel, and platinum oxide, but palladium-carbon is preferable.
The hydrogen pressure is from 1 atm to 100 atm, preferably from 1 atm to 6 atm. Examples of the solvent include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, organic acids such as acetic acid, water, and mixtures thereof. The reaction temperature and reaction time vary depending on the raw materials and solvent used, but are usually at room temperature to 50°C for several minutes to more than ten hours. Third step The 2-(4-aminophenoxyalkyl)chroman-4-ones (XII) thus obtained are diazotized and then subjected to Meerwein Arylation, whereby the Production of α-halogenocarboxylic acids ( ), which is a raw material for the target compound ( ), is achieved. The reaction involves diazotization with nitrites such as nitrite sozo in the presence of hydrochloric acid, hydrobromic acid, etc., followed by diazotization with acrylic acid, methyl acrylate,
By reacting a catalytic amount of cuprous salts such as cuprous chloride and cuprous oxide in the presence of acrylic acid esters such as ethyl acrylate, acrylonitrile, and acrylic acid derivatives such as acrylamide. and start. As the acrylic acid derivative, acrylic esters are preferred, and as the cuprous salt, cuprous oxide is preferred. Examples of the solvent for the reaction include alcohols such as methanol and ethanol, acetone, ketones such as methyl ethyl ketone, water, and mixtures thereof. The ratio of the amino compound (XII) to the acrylic acid derivative is 1 to 15 mol, preferably 5 to 10 mol, per 1 mol of compound (XII). The ratio of the compound (XII) to the cuprous salt is 0.01 to 1 mol, preferably 0.03 to 0.3 mol, per 1 mol of the compound (XII). The reaction temperature and reaction time vary depending on the raw materials, solvent, etc. used, but are usually at room temperature to 100°C for a dozen minutes to a dozen hours, preferably at 30 to 60°C for 30 minutes to two hours. The thus obtained α-halogenocarboxylic acids () having a chroman ring can be converted into various hydrolyzed products, transesterified products, or metal salts such as sodium, potassium, calcium, aluminum, etc., as desired. Or conversely, esters from metal salts or from free phenols and/or free carboxylic acids,
It can be converted into an amide form, etc. In particular, when α-halogenocarboxylic acids () are introduced into various desired hydrolyzed products, the production of the products can be accomplished, for example, as follows. Compounds in which R ³ is a hydrogen atom and A is a carboxyl group include compounds () in which R ³ is an acyl group and A is an alkoxycarbonyl group, an alkali metal carbonate such as sodium carbonate, potassium carbonate, water Hydrolysis in the presence of inorganic bases such as alkali metal hydroxide bases such as sodium oxide, potassium hydroxide, or bases such as alkali metal alcoholates such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide. It can be obtained by carrying out a reaction. Examples of the solvent include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water, and mixed solvents thereof. The ratio of the compound () to the inorganic base or the base is 1 to 5 mol, preferably 2 to 3 mol, per 1 mol of the compound (). Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials, base, solvent, etc. used, but the reaction temperature is usually -10 to 30°C, preferably 0 to 10°C, and the reaction time is several minutes to several tens of hours. be. In the compound where R ³ is a hydrogen atom and A is an alkoxycarbonyl group, R ³ is, for example, an acyl group,
Compounds in which A is an alkoxycarbonyl group ()
can be obtained by conducting a solvolysis reaction in the presence of a base such as an alkali metal alcoholate such as sodium methoxide, sodium ethoxide, or potassium tertiary butoxide. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, and t-butyl alcohol, ethers such as tetrahydrofuran and dioxane, and mixed solvents thereof. In particular, when it is desired to retain the alkoxycarbonyl group shown in Group A of the raw material as it is, it is necessary to select an alkali metal alcoholate corresponding to the alkoxy group and to use an alcohol corresponding to the alkoxy group as a solvent. It is desirable to select. Furthermore, if desired, the alkoxycarbonyl group in the raw material can be replaced with a desired alkoxycarbonyl group by selecting an arbitrary alkali metal alcoholate and an alcohol as a solvent. The ratio of the raw material compound () and the base is as follows:
The amount is 1 to 3 mol, preferably 1 to 2 mol.
Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials, base, solvent, etc. used, but the reaction temperature is usually -10 to 30°C, preferably 0 to 10°C,
The reaction time is from several minutes to several tens of hours. Compounds in which R ³ is an acyl group and A is a carboxyl group include, for example, compounds in which R ³ is an acyl group and A is an alkoxycarbonyl group, an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal carbonate such as sodium carbonate, potassium carbonate, water Hydrolysis in the presence of inorganic bases such as alkali metal hydroxide bases such as sodium oxide, potassium hydroxide, or bases such as alkali metal alcoholates such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide. It can be obtained by carrying out a reaction. Examples of the solvent include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water, and mixed solvents thereof. The ratio of the compound () to the inorganic base or the base is 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound (). Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials, base, solvent, etc. used, but the reaction temperature is usually -10 to 30°C, preferably 0 to 10°C, and the reaction time is several minutes to several tens of hours. be. In the α-halogenocarboxylic acids represented by formula (), the carbon atoms at the 2-position of the chroman ring and the α-position of the substituent A are each asymmetric carbon atoms,
Each isomer based thereon is also included in the compound (). It should be noted that the α-halogenocarboxylic acids () obtained in this way are also recognized to have not only a blood peroxidized lipid-lowering effect but also a blood triglyceride and cholesterol-lowering effect. It is useful as a therapeutic agent for bloodemia. Suitable compounds represented by the formula () that exhibit the above pharmacological activity include the compounds shown in the following table.

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[Table] The present invention will be explained in more detail with reference to Examples and Reference Examples below. Example 1 Ethyl 3-[4-(6-acetoxy-2,5,
7,8-tetramethylchroman-4-one-2-
A mixture of 1.3 g of methoxy)phenyl]-2-chloropropionate, 0.4 g of thiourea, and 2 g of sulfolane is heated at 120-130° C. for 4 hours under a nitrogen stream. Then, 15 ml of ethylene glycol monomethyl ether, 4 ml of water, and 2 ml of concentrated hydrochloric acid were added to the reaction mixture.
Heat at ~90 °C for an additional 2.5 days. Add water to the reaction mixture and extract with benzene. The extract is washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off benzene was subjected to silica gel column chromatography (eluent; n-hexane:ethyl acetate = 5:3) to obtain 5-[4-(6-hydroxy-2,5,7 ,8-tetramethylchroman-
4-one-2-methoxy)benzyl]thiazolidine-2,4-dione was obtained. Softening point: 79-83°C NMR spectrum (δ _ppn , _CDCl3 ): 1.50 (3H, s), 2.11 (3H, s), 2.22 (3H,
s), 2.56 (3H, s), 2.66 (1H, d, J=15
Hz), 3.05 (1H, d, J = 15Hz), 3.05 (1H,
dd, J = 9 and 15Hz), 3.42 (1H, dd, J
= 4 and 15Hz), 3.95 (1H, d, J = 10
Hz), 4.07 (1H, d, J = 10Hz), 4.46 (1H,
dd, J=4 and 9Hz), 4.5-5.2 (1H, br,
s), 6.84 (2H, d, J=9Hz), 7.13 (2H,
d, J=9Hz) Example 2 5-[4-(6-hydroxy-2,5,7,8-
Tetramethylchroman-4-one-2-methoxy)benzylthiazolidine-2,4-dione
Add 450 mg of sodium borohydride to a mixture of 278 mg and 9 ml of methyl alcohol, and stir at room temperature for 2 hours. After adding a 1% acetic acid aqueous solution to the reaction mixture, the mixture was neutralized with a potassium carbonate aqueous solution and extracted with ethyl acetate. After washing the ethyl acetate solution with water, it is dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent; n-hexane:ethyl acetate = 5:3) to obtain 5-[4-(4,6-dihydroxy -2,5,7,8-tetramethylchroman-
2-methoxy)benzyl]thiazolidine-2,4
-Dione was obtained. Melting point: 102-118℃ NMR spectrum (δ _ppn , acetone- _d6 and
D ₂ O): 1.52 (3H, s), 2.01 (3H, s), 2.13 (3H,
s), 2.29 (3H, s), 1.9-2.5 (1H min, nd),
2.9~3.6 (2H, m), 4.03 (2H, s), 3.9~4.5
(1H min, nd), 4.6-5.1 (2H, m), 6.7-7.4
(4H minutes) nd: Indicates indistinguishability due to overlap with other signals. Example 3 According to Example 1, ethyl 3-[4-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)phenyl]-2
- 291 mg of chloropropionate, 64 mg of thiourea,
5-[4-(7-tert-butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy)benzyl] prepared from 1 ml sulfolane, 5 ml ethylene glycol monomethyl ether, 1 ml concentrated hydrochloric acid, and 2 ml water. Thiazolidine-2,4-
Dione has the following physical properties. Softening point: 95-107℃ NMR spectrum (δ _ppn , heavy acetone) 1.40 (9H, s), 1.48 (3H, s), 2.65 (1H,
d, J = 16.5Hz), 3.05 (1H, d, J = 16.5
Hz), 3.08 (1H, dd, J=9 and 14Hz),
3.42 (1H, dd, J = 4.5 and 14Hz), 4.14
(2H, s), 4.74 (1H, dd, J = 4.5 and 9
Hz), 6.83 (1H, s), 6.92 (2H, d, J=9
Hz), 7.23 (1H, s), 7.24 (2H, d, J=9
Hz), 7.5−9.4 (1H, br. disappears with addition of heavy water). Example 4 Ethyl 3-[4-(6-acetoxy-2,5,
7,8-tetramethyl-4-oxochroman-2
-ylmethoxy)phenyl]-2-chloropropionate, 0.62 g of thiourea, and 3.1 g of sulfolane at 120-125°C in a nitrogen stream.
Heat for an hour. Benzene is added to the reaction mixture, insoluble materials are removed, and the solvent is distilled off. After washing the oily residue with water, silica gel column chromatography (eluent: (1) hexane: ethyl acetate = 2:1,
(2) Ethyl acetate, (3) Ethyl acetate:ethanol = 1:
1), 5-[4-(6-acetoxy-2,
5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one was obtained. Melting point: 218-222°C NMR spectrum (δ _ppn , DMSO-d ₆ ): 1.43 (3H, s), 2.04 (6H, s), 2.32 (3H,
s), 2.35 (3H, s), 2.4−3.5 (4H, nd),
4.13 (2H, s), 4.56 (1H, dd, J = 4 and 9Hz), 6.85 (2H, d, J = 9Hz), 7.14 (2H,
d, J = 9Hz). Reference example 1 2,5-dihydroxy-3,4,6-trimethylacetophenone 3.9g, 4-nitrophenoxyacetone 3.9g, pyrrolidine 2.0g and toluene
After leaving 15 g at room temperature for 2 days, dilute hydrochloric acid was added to the reaction mixture and extracted with ether. The aqueous phase is further extracted with ethyl acetate, combined with the ether extract and dried over anhydrous sodium sulfate. The solvent is distilled off, n-hexane is added to the resulting residue, and the precipitated crystals are collected. After further subjecting to silica gel column chromatography (eluent: n-hexane: ethyl acetate: = 5:1), it was recrystallized from ethyl acetate, and 6-hydroxy-2-(4
-nitrophenoxy)methyl-2,5,7,8-
Tetramethylchroman-4-one was obtained. melting point
199-204℃ NMR spectrum (δ _ppn , DMSO- _d6 ): 1.43 (3H, s), 2.01 (3H, s), 2.14 (3H,
s), 2.46 (3H, s), 2.67 (1H, d, J=16
Hz), 3.03 (1H, d, J = 16Hz), 4.31 (2H,
s), 7.19 (2H, d, J=9Hz), 7.92 (1H,
s), 8.21 (2H, d, J = 9Hz) Reference example 2 5-acetoxy-2-hydroxy-3,4,6
- After leaving a mixture of 17.7 g of trimethylacetophenone, 14.6 g of 4-nitrophenoxyacetone, 7.5 g of pyrrolidine and 60 ml of benzene at room temperature for 1 day,
The mixture was heated under reflux for 7 hours using a water separator. Water and ethyl acetate were added to the reaction mixture, and the organic phase was separated and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (eluent: n-hexane:ethyl acetate = 2:1) to obtain 6-acetoxy-2-(4-
Nitrophenoxy)methyl-2,5,7,8-tetramethylchroman-4-one was obtained. Rf value by thin layer chromatography: 0.17 (silica gel;
Developing solvent; n-hexane: ethyl acetate = 3:1) NMR spectrum (δ _ppn , CDCl ₃ ): 1.56 (3H, s), 2.10 (6H, s), 2.36 (3H,
s), 2.43 (3H, s), 2.70 (1H, d, J=15
Hz), 3.06 (1H, d, J = 15Hz), 4.11 (1H,
d, J = 10Hz), 4.24 (1H, d, J = 10Hz),
6.98 (2H, d, J = 9Hz), 8.20 (2H, d, J
=9Hz) Reference example 3 6-acetoxy-2-(4-nitrophenoxy)
at room temperature in a mixture of 3.6 g of methyl-2,5,7,8-tetramethylchroman-4-one, 1 g of 10% palladium-carbon and 100 ml of methyl alcohol.
Pass hydrogen under atmospheric pressure for 2 hours. The catalyst is removed and the liquid is concentrated. The obtained residue was subjected to silica gel column chromatography (eluent; n-hexane:ethyl acetate = 2:1), and then recrystallized from acetone to obtain 6-acetoxy-2-(4-aminophenoxy)methyl-2 , 5,7,8-tetramethylchroman-4-one was obtained. Melting point 177-178
°C NMR spectrum (δ _ppn , CDCl ₃ ): 1.49 (3H, s), 2.09 (3H, s), 2.12 (3H,
s), 2.33 (3H, s), 2.42 (3H, s), 2.65
(1H, d, J = 15Hz), 3.07 (1H, d, J =
15Hz), 3.2-3.6 (2H, br.s), 3.91 (1H, d,
J=10Hz), 4.06 (1H, d, J=10Hz), 6.60
(2H, d, J=9Hz), 6.75 (2H, d, J=
9Hz) Reference example 4 6-acetoxy-2-(4-aminophenoxy)
To a mixture of 2.1 g of methyl-2,5,7,8-tetramethylchroman-4-one and 26 ml of acetone, 3 ml of concentrated hydrochloric acid was added dropwise under ice cooling, followed by 1.1 ml of an aqueous solution of 700 mg of sodium nitrite, and the mixture was heated at the same temperature. After stirring for 30 minutes,
After adding 7 g of ethyl acrylate, the reaction temperature was increased to 30
Cuprous oxide is gradually added while maintaining the temperature at ~35°C, followed by stirring at room temperature for 1 hour. Water and benzene are added to the reaction mixture, and the benzene layer is separated, washed with water, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off benzene was subjected to silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to obtain ethyl 3-[4-(6-acetoxy-2,5, 7,8-tetramethylchroman-
4-one-2-methoxy)phenyl]-2-chloropropionate was obtained. Rf value by thin layer chromatography: 0.21 [silica gel; developing solvent; n
-hexane:ethyl acetate = 3:1] NMR spectrum (δ _ppn , CDCl ₃ ): 1.24 (3H, t, J = 7Hz), 1.51 (3H, s),
2.10 (3H, s), 2.12 (3H, s), 2.34 (3H,
s), 2.43 (3H, s), 2.67 (1H, d, J=15
Hz), 3.07 (1H, dd, J=7.5 and 15Hz),
3.10 (1H, d, J = 15Hz), 3.32 (1H, dd, J
=7.5 and 15Hz), 4.06 (2H, s), 4.18
(2H, q, J=7Hz), 3.9~4.5 (1H, nd),
6.84 (2H, d, J = 9Hz), 7.15 (2H, d, J
=9Hz) Reference Example 5 According to Reference Example 1, 4-t-butyl-2,5-
7-tert-butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxyacetone) prepared from 2.0 g dihydroxyacetophenone, 1.9 g 4-nitrophenoxyacetone, 1.0 g pyrrolidine, and 10 ml benzene. (dimethyl)chroman-4-one has the following physical properties. Melting point: 205-209℃ NMR spectrum (δ _ppn , deuterated acetone): 1.39 (3H, s), 1.53 (9H, s), 2.70 (1H,
d, J = 16.5Hz), 3.05 (1H, d, J = 16.5
Hz), 4.37 (2H, s), 6.80 (1H, s), 7.18
(2H, d, J=10Hz), 7.22 (1H, s), 8.22
(2H, d, J = 10Hz), 8.31 (1H, s, disappears with addition of heavy water). Reference Example 6 A mixture of 1.7 g of 7-t-butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one, 1 ml of acetic anhydride, and 10 ml of pyridine was heated at room temperature for 1 day. put. The reaction mixture was poured into ice water, stirred for 2 hours, and then extracted with benzene. The organic layer is washed successively with 3N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was mixed with benzene-ethyl acetate (approximately 10:1).
Recrystallization from 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one was obtained. Melting point: 82-84℃ NMR spectrum (δ _ppn , heavy acetone): 1.33 (9H, s), 1.57 (H, s), 2.33 (3H, s), 2.82 (1H, d, J = 16.5Hz), 3.13 (1H, d,
J=16.5Hz), 4.42 (2H, s), 6.93 (1H,
s), 7.25 (2H, d, J=9Hz), 7.44 (1H,
s), 8.22 (2H, d, J = 9Hz). Reference Example 7 According to Reference Example 3, 6-acetoxy-7-t-
6-acetoxy-2- prepared by catalytic reduction using 0.9 g of butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one, 0.4 g of 10% palladium on carbon, and 20 ml of acetic acid. (4
-aminophenoxymethyl)-7-t-butyl-
2-Methylchroman-4-one has the following physical properties. R _f by silica gel thin layer chromatography
Value = 0.24 [Developing solvent; benzene: ethyl acetate =
5:1] NMR spectrum (δ _ppn , CDCl ₃ ): 1.35 (9H, s), 1.52 (3H, s), 2.30 (3H,
s), 2.67 (1H, d, J=16.5Hz), 3.07 (1H,
d, J = 16.5Hz), 3.2-3.6 (2H, br, disappeared by adding heavy water), 3.92 (1H, d, J = 10.5Hz),
4.07 (1H, d, J = 10.5Hz), 6.58 (2H, d,
J=10Hz), 6.75 (2H, d, J=10Hz), 6.98
(1H, s), 7.49 (1H, s). Reference Example 8 According to Example 4, 6-acetoxy-2-(4
-aminophenoxymethyl)-7-t-butyl-
Ethyl 3-[4 prepared from 0.42 g of 2-methylchroman-4-one, 0.09 g of sodium nitrite, 1.1 g of ethyl acrylate, 16 mg of cuprous oxide, 0.2 ml of concentrated hydrochloric acid, 0.5 ml of water, and 5 ml of acetone. -(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)phenyl]-
2-chloropropionate has the following physical properties. R _f by silica gel thin layer chromatography
Value = 0.61 [Developing solvent; benzene: ethyl acetate =
5:1] NMR spectrum (δ _ppn , CDCl ₃ ): 1.25 (3H, t, J = 7Hz), 1.35 (9H, s),
1.55 (3H, s), 2.32 (3H, s), 2.70 (1H,
d, J=16.5Hz), 2.95−3.5 (3H, m), 3.9−
4.5 (5H, m), 6.87 (2H, d, J=9Hz),
7.00 (1H, s), 7.17 (2H, d, J=9Hz),
7.50 (1H, s).

Claims (1)

[Claims] 1. General formula [In the formula (), R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ and R ³ ', which will be described later, are the same or different and represent a hydrogen atom,
Aliphatic lower acyl group, alicyclic acyl group, aromatic acyl group that may have a substituent, heterocyclic acyl group, aromatic aliphatic acyl group that may have a substituent, lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group, n is an integer of 1 to 3,
W is a carbonyl group or [Formula] [In the formula, R ³ ' has the same meaning as described above. ]
In the group represented by, Y represents an oxygen atom or an imino group, and Z represents an oxygen atom or an imino group. ]
A thiazolidine derivative represented by and a pharmacologically acceptable salt thereof. 2 General formula [In formula (), R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group,
An aromatic acyl group which may have a substituent, a heterocyclic acyl group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ⁴ and R ⁵
are the same or different, and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group, n is an integer of 1 to 3, X is a halogen atom, and A is a cyano group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, or It represents a group represented by the formula -COOM (in the formula, M represents an equivalent cation). A general formula characterized by reacting a compound represented by ] with thiourea [In formula (), Y represents an oxygen atom or an imino group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as above. ] A method for producing a thiazolidine derivative and a pharmacologically acceptable salt thereof. 3 General formula [In formula (), R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group,
An aromatic acyl group which may have a substituent, a heterocyclic acyl group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ⁴ and R ⁵
are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group, n represents an integer of 1 to 3, and Y represents an oxygen atom or an imino group. ]
A general formula characterized by hydrolyzing a compound represented by [In formula (), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n
indicates the same meaning as above. ] A method for producing a thiazolidine derivative and a pharmacologically acceptable salt thereof.