WO1994019347A1 - Arteriosclerosis remedy - Google Patents

Abstract

An arteriosclerosis preventive and/or remedy containing a thiazolidine derivative represented by general formula (I) or a pharmacologically acceptable salt thereof as the active ingredient, wherein R?1, R2, R4 and R5¿ represent each independently hydrogen or lower alkyl; and R3 represents hydrogen, aliphatic acyl, optionally substituted aromatic acyl or lower alkoxycarbonyl. This compound is useful as an arteriosclerosis preventive and/or remedy.

Description

 Specification

 Atherosclerosis treatment

 [Technical field]

 The present invention relates to an agent for preventing and / or treating arteriosclerosis containing a thiazolidine derivative as an active ingredient.

 [Background technology]

 Arteriosclerosis is roughly classified into atherosclerosis (atherosclerosis), Monkeberg-type arteriosclerosis (media sclerosis), and atherosclerosis, and of these, atherosclerosis (atherosclerosis) in particular. Sclerosis occupies an important place. Atherosclerosis (porgy) arteriosclerosis mainly involves the accumulation of plaques called atheroma on the inner wall of the heart artery or the lining of the blood vessels, resulting in hardening and weakening of the aorta, and eventually bleeding due to destruction of blood vessels. To death. It is called atherosclerosis or atherosclerosis because the inner wall of blood vessels becomes plaque. As long ago, Glavind et al. (Acta Pattiol. Microbiol. Scand., Vol. 20, p. 1 (1952)) reported that there is a proportional relationship between the severity of arteriosclerosis and the mass of lipid peroxide in atheroma. The causal relationship between oxidation and arteriosclerosis has been actively discussed.

 In addition, there has recently been a review by Peter A. McCarth describing the relationship between various compounds and atherosclerosis (Medicinal Research Reviews, Vol. 13, No. 2, pp. 139-159 (1993)). ).

Yoshioka et al., For example, have shown that substituted phenols and thiazolidine derivatives have a blood glucose lowering effect and a serum lipid and serum lipid peroxide lowering effect, and describe the relationship between the effects of atherosclerosis (Yoshioka Et al., J. Med. Chem., 32, 421 (1989)). Recently, Goldstein et al. (丄 Cell Biol., 82, 597 (1979); Sci. Am., 251, 52 (1984)) and Steinberg 6 (New Engl. J. ed., 320, Pp. 5 (1989)), oxidized low-density lipoprotein (hereinafter referred to as “LDL”) is taken up by macrophages, and macrophages become foam cells and form atheroma. The elucidation of the preservation revealed the etiology of atherosclerosis and established that oxidative peroxidation of LDL was the direct cause of atherosclerosis. Therefore, it is expected that a compound having an effect of suppressing the oxidation and / or peroxidation of LDL can be a prophylactic and / or therapeutic agent for arteriosclerosis. However, in practice, no prophylactic and / or therapeutic agent for arteriosclerosis that can be put to practical use has been found.

 [Disclosure of the Invention]

 The present inventors have studied for the purpose of preventing and / or treating arteriosclerosis, and as a result, have found a thiazolidine derivative as a compound that inhibits oxidative peroxidation of LDL, and furthermore, the derivative has an excellent effect in animal tests. And completed the present invention.

 The present invention has the general formula

(In the formula, R ¹ , R ² , R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group. R ³ has a hydrogen atom, a fatty acid group, a substituted group, The present invention relates to a prophylactic and / or therapeutic agent for arteriosclerosis comprising as an active ingredient a thiazolidine derivative or a pharmacologically acceptable salt thereof having an aromatic acyl group or a lower alkoxycarbonyl group.

 In the general formula (I),

When R ¹ represents a lower alkyl group, the alkyl group may be, for example, a straight chain such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, and pentyl; | a dog or branched carbon number. 1 to 5, preferably 1 to 4, most preferably methyl.

When R ² and R ⁵ represent a lower alkyl group, examples of the alkyl group include linear or branched carbon atoms having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl. , Preferably 1 to 3, most preferably methyl. When R ³ represents an aliphatic acryl group, examples of the acryl group include linear or branched carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, bentanoyl, hexanoyl, and heptanyl. To 7, preferably 1 to 4, most preferably acetyl.

When an aromatic acyl group optionally having ⁵ R ³ substituents is shown, examples of the acyl group include benzoyl, 4-122 benzoyl, 3-fluorobenzoyl, and 2-fluorobenzoyl. Black benzoyl, 3, 4-dicyclo benzoyl, 4-amino benzoyl, 3-dimethylamino benzoyl, 2-methoxy benzoyl, 3, 5-di-t-butyl, 1-hydroxy benzoyl, 1-naphthoyl Aromatic acyl having 7 to 11 carbon atoms optionally having 1 to 3 nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, hydroxy, etc. Groups, preferably an aromatic acyl group having 7 to 11 carbon atoms having no substituent, and most preferably benzoyl.

When R ³ represents a lower alkoxycarbonyl group, examples of the alkoxycarbonyl group include straight-chains such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl. Examples thereof include linear or branched carbon atoms having 2 to 7, preferably 2 to 4, and most preferably ethoxycarbonyl.

When R ⁴ represents a lower alkyl group, examples of the alkyl group include linear or branched carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and pentyl. From 5 to 5, from i to 4, most preferably methyl, t-butyl, especially methyl.

The compound having the above general formula (I) of the present invention can be used in the form of a pharmaceutically acceptable non-toxic salt. Examples of such salts include salts with alkali metals such as sodium and potassium; alkaline earth metals such as calcium; basic amino acids such as lysine and arginine. When the compound having the general formula (I) has a basic group, it can be used in the form of a pharmacologically acceptable non-toxic acid-containing caro salt. Examples of such salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, succinic acid, maleic acid, fumaric acid, apple And organic acids such as acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, and methanesulfonic acid.

 In the compound having the general formula (I) of the present invention, the carbon atoms at the 2-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms, and the stereoisomers based on these are also the present invention. Included in the compound of

 In the compound of the present invention having the general formula (I), preferably

R ¹ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ² represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

R ³ is a hydrogen atom, a linear or branched aliphatic acyl group having 1 to 4 carbon atoms, an aromatic acyl group having 7 to 11 carbon atoms having no substitution, or linear Or a branched lower alkoxycarbonyl group having 2 to 4 carbon atoms;

 R "represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms.

 In the compound having the general formula (I) of the present invention, more preferably,

R ¹ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ² represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group;

R ⁴ represents a linear or branched lower alkyl group having 1 carbon atom;

R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms. In the compound having the general formula (I) of the present invention, particularly preferably

R ¹ represents a methyl group;

R ² represents a hydrogen atom or a methyl group;

R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group;

R ⁴ represents a methyl group or a t-butyl group;

R ⁵ represents a hydrogen atom or a methyl group.

 Specific examples of the compound having the general formula (I) of the present invention include compounds having a structural formula as shown in Table 1.

1] Exemplary compound number R ¹ R ² R ³ R ⁴ R ⁵

1 Me Me H Me Me

2 H Me H Me Me

3 Me H H H H

4 Me H H tBu H

5 Et Me H Me Me

6 iBu Me H Me Me

7 Pn Me H Me Me

8 Me Me Ac Me Me

9 Me Me Bz Me Me

10 Me Me EtC Me Me

1 1 Me H Ac Me H

12 Me H H Me H

13 Me Me Byr Me Me

Me; Methyl, Et;; Ethyl, iBu;; Isobutyl,

 tBu; tert-butyl, Pn; pentyl, Ac; acetyl

Byr; butyryl, Bz; benzoyl, EtC; ethoxycarbonyl. Among the compounds having the general formula (I) of the present invention, preferred are compounds of Exemplified Compound Nos. 1, 4, 5, 6, 8, and 10, and more preferred are compounds of 1, 4, 10 Preferably it is one compound.

 The compound having the general formula (I) of the present invention is a known compound and described in, for example, JP-A-60-51189, US Pat. No. 4,572,912, and European Patent 0139421.

 The compound having the above general formula (I) of the present invention is used as it is or in the form of a pharmaceutically acceptable salt thereof.

 The fact that the compound having the above general formula (I) of the present invention has the effect of inhibiting the oxidation and peroxidation of LDL can be measured by the following method.

That is, human LDL is prepared by a conventional ultracentrifugation method (丄 L. Goldstein et al., Methods in Enzraolog, 98, 241 (1983)). That is, the human blood is allowed to stand for a certain period of time, and then subjected to centrifugation at a low temperature and a low rotation speed for a certain period of time to obtain a serum. Add a specific gravity such as sodium chloride or sodium bromide to the obtained serum, and subject it to ultra-high-speed centrifugation at low temperature and high rpm for a certain period of time. Then, the lower layer of serum and high-density riboprotein (hereinafter referred to as “HDL”) are separated. Next, the specific gravity of the obtained LDL and HDL is adjusted again with a specific gravity adjusting agent such as potassium bromide or sodium bromide. Then, it is subjected to ultra-high-speed centrifugation for a certain period of time under low temperature and high rotation speed conditions, and the LDL of the upper layer of the obtained serum is collected. Next, the dialysate is dialyzed for a certain period of time against a saline solution containing a chelating agent such as ethylenediamine disodium salt (EDTA-2Na) and a physiological saline solution containing a δ ペ ^ substance such as penicillin and streptomycin. Prepare an LDL sample for the experiment. Next, a low-concentration solution of the test drug is prepared and then evaporated to dryness to form a film-like drug layer. To this, add the above-mentioned experimental human LDL sample, and solubilize the test drug in LDL using an ultrasonic cleaner. This is subjected to an oxidation reaction using an oxidizing agent such as Cu "or Fe ^3+, and the T BARS (thiobarbituric acid reaction positive substance) value after the reaction is determined by a photometric method (Yagi et al., Vitamin, Volume 37, 105). Page (1968) Furthermore, heme with a high-performance liquid chromatograph (High Performance Liquid Chroraatograph) is used. , Lipid peroxide research, 16 Vol. 1, No. 23, p. 23 (1992)). The test drug is incorporated into the LDL, for example, by extracting the drug with an organic solvent such as black form and confirming it by high performance liquid chromatography. For example, the fact that LDL is not denatured by the drug solubilization operation is determined by electrophoresis (FT Hatch et al., Adv. Lip. Res., 6, 1 (196S)), gel filtration chromatography (FTHatch Adv. Lip. Res., Vol. 6, p. 1 (1968)).

(4) The preparation of Egret LDL is performed in accordance with the preparation of the human LDL described above, and an experimental Egret LDL sample is prepared. Next, solutions of various concentrations of the test drug are prepared, and this is added to the WH ^ 1 cattle sample. This is subjected to an oxidation reaction using an oxidizing agent such as Cu ²⁺ , Fe ^3t, etc., and the T BARS (thiobarbituric acid reaction positive substance) value after the reaction is measured by a fluorescence method (Yagi et al., Vitamin, 37, 105 pages) (1968))

Next, the effect of suppressing macrophage foaming is measured by the following method. That is, intraperitoneal macrophages were detected from ddy mice (Edeison et al., In Vitro Methods in Cell-Mediated & Tumor Immunity, eds. Bloon, BR & David, 丄 R. (Academic, New York), p. 333 (1976 ))) Add the oxidatively modified LDL and ¹⁴ C monoleic acid, and measure the amount of “C-cholesteryl ester produced in the cells.

 Next, in animal tests, it can be measured according to, for example, the method of Y. Watanabe et al. (Biochiraica et Biophysica Acta, 960, 294-302 (1988)). That is, for example, WHHL rabbits are arbitrarily divided into a control group and a treatment group, and a standard feed is administered to the control group, and a mixed feed containing a drug is administered to the treatment group for a certain period. After a certain period of time i, the animals in the control group and the administration group are sacrificed, the aorta from the bow to the abdomen is taken, and the ratio of the total area of arteriosclerosis in the control group and the administration group is determined, and the anti-arterial effect can be observed.

 [Industrial applicability]

 The compound of the present invention having the above general formula (I) or the drug S ± acceptable salt thereof has an excellent action of suppressing the oxidation of LDL and Z or peroxidation, and is actually effective in animal tests. Atherosclerosis was shown. Moreover, it is a compound having low toxicity.

Therefore, the compound of the present invention having the general formula (I) or a pharmaceutically acceptable compound thereof Salts are useful as prophylactic and therapeutic agents for or against atherosclerosis, especially atherosclerosis.

 The compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is administered in various forms. Examples of the administration form include oral administration by t¾, capsule, granule, powder, syrup, etc. or parenteral administration by injection (intravenous, intramuscular, subcutaneous), drip, suppository, etc. Can be. These various preparations are commonly used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, turbidity agents, coating agents, etc. in the main drug according to the usual method. It can be formulated using known adjuvants. The amount used depends on the symptoms, age, body weight, administration method and dosage form, but usually 50 to 500 mg / day can be administered to an adult.

 [Best Mode for Carrying Out the Invention]

 Hereinafter, the present invention will be described more specifically with reference to Examples and Preparation Examples.

Example 1 · Oxidation of human L D L Z Inhibition of peroxidation

 The preparation of human LDL is separated by ultracentrifugation using a conventional method, J.L. Goldstein et al. (J.L. Goldstein et al., Methods in Enz molog, 98, 241 (1983)). That is, 180 ml of human blood was allowed to stand for 2 hours, and then centrifuged at 4 and 3000 rpm for 15 minutes to obtain serum. The resulting serum was adjusted to a specific gravity of 1.019 by adding a bromide reamer, and then subjected to ultracentrifugation at 4, 39,000 rpm for 20 hours. After the completion of the ultracentrifugation operation, LDL and HDL in the lower layer of the obtained serum were collected. The obtained LDL and HDL were added with potassium bromide again to adjust the specific gravity to 1.063, and then subjected to ultra-high-speed centrifugation at 4, 39, 000 rpm for 24 hours. Next, the LDL of the upper layer of the obtained serum was collected. Then, ethylenediamine 'disodium salt

Experimental human LDL samples were prepared by dialysis for 24 hours using a dialysate consisting of (EDTA-2Na) and a saline solution containing benicillin and streptomycin. Next, the test drug was dissolved in acetonitrile solution that was muted to a final drug concentration of 0.3 mM.

(Example compound No. 1 compound (= CS-045), 123.8M1; ciglitazone ¹ ', 102.0 ^ 1) is evaporated to dryness under a nitrogen stream to form a film-like drug layer. Created. Add 1.0 ml of the experimental human LDL sample to the film-like drug layer described above. The test drug was solubilized in the above-mentioned LDL sample by ultrasonic dispersion at 20 ° C. for 10 minutes using a water tank type ultrasonic cleaner (Bransonic 220, manufactured by Daiwa Kagaku Co., Ltd.). Next, 1.0 ml of a 10 mM concentration solution of copper sulfate was added to the obtained solubilized product and subjected to an oxidation reaction with Cu ²⁺ , and the T BARS (thiobarbituric acid reaction positive substance) value after the reaction was added. Was measured by the Yagi et al. Spectrophotometric method (Yagi et al., Vitamin, Vol. 37, p. 105, 1968), and chemiluminescence catalyzed by a heme equipped with a high-performance liquid chromatograph (High Performance Liquid Chromatograph). Measuring device (825-C

Lipid peroxide value was measured by Iwaoka et al. (Iwaoka et al., Lipid Peroxide Research, Vol. 16, No. 1, p. 23 (1992)). That is, reversed-phase high-performance liquid chromatography (separation column: octadecylsilylated silica gel (0DS), eluent: methanol / butanol (1: 1), flow rate: l ml / min) and normal-phase high-performance liquid chromatography (Separation column: silica gel, eluent: methanol / acetonitrile water (45: 50: 5), flow rate: 1 ml, min) and quantification was performed. The incorporation of the test drug into the LDL is first determined by the gel-based chromatographic method of FTHatch et al. (FT Hatch et al., Adv. Lip. Res., Vol. 6, p. 1 (1968)). Isolated. That is, the gel was simply subjected to gel chromatography (gel-based column: Superrose 6, eluent: 0.15N aqueous sodium chloride solution containing 0.01% ethylenediamine-disodium salt and 0.02% sodium azide). Released. Next, the drug was extracted from the obtained LDL using a chromate form and confirmed by high performance liquid chromatography. That is, the drug was detected by reverse phase high performance liquid chromatography (separation column: octadecylsilylated silica gel (0DS), eluent: methanol, 1 ml / min). In addition, it was confirmed by the electrophoresis method of FTHatch et al. (FTHatch et al., Adv. Lip. Res., Vol. 6, p. 1 (1968)) that LDL was not denatured by the drug solubilization operation. That is, a single band was confirmed by agarose gel electrophoresis using an agarose gel as a base material. Furthermore, it was confirmed by the gel permeation chromatography method of FTHatch et al. (FTHatch et al., Adv. Res., Vol. 6, p. 1 (1968)). Immediately, the gel was chromatographed (gel-based column: Superrose 6, eluent: 0.15N aqueous sodium chloride solution containing 0.01% ethylenediamine disodium salt and 0.02% sodium azide). The peak was 5HS. The value of the 1 ^ 5 value is the oxidation index of the leaf, and the value of the lipid peroxide is the index of LDL lipid peroxidation (Naito, Atherosclerosis, Vol. 18, No. 1, p. 33 (1990)).

 Table 2 shows the results of the inhibitory action on LDL oxidation / peroxidation.

 In the table, the inhibition rate (%) by the T BARS value and the inhibition rate (%) by the lipid peroxide value were calculated from the following equations, respectively.

 Inhibition rate by T BARS value (%) = {(T BARS value in the absence of drug-T BARS value in the presence of drug) Z TBARS value in the absence of drug} x 100

 Inhibition rate by lipid peroxide level (%) = {(lipid peroxide value in the absence of drug-lipid peroxide value in the presence of drug) lipid peroxide value in the absence of drug} X 100

 [Table 2] Inhibition of human L D L oxidation Z peroxidation

TB ARS value Inhibition rate by lipid peroxide value (%) Inhibition rate by% (%) Compound of Exemplified Compound No. 1. (= CS-045)

1) See Yoshioka et al., J. Med. Chem., 32, 421 (1989).

As is clear from Table 2, the compound of Exemplified Compound No. 1 (= CS-045) inhibited the peroxidation of Z 2 oxide induced by Cu ²⁺ by 100% and inhibited ^ of the oxidized LDL. Then, it was restored to the same state as LDL without addition of Cu ²⁺ . However, ciglitazone did not inhibit Cu-induced peroxidation at all and produced oxidized LDL.

Example 2. Inhibition rate of human LDL oxidation reaction by drugs

 Human LDL was prepared by a conventional method, ultracentrifugation by J.L. Goldstein et al. (Pashi Goldstein et al., Methods in Enzymology, 98, 241 (1983)). That is, it was prepared and prepared in the same manner as in Example 1.

Next, the test drug is treated with an acetate solution or a solution prepared at a final drug concentration of 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, 30.0, 100.0, 300.0 "M. The evening solution was evaporated to dryness under a stream of nitrogen to form a film-like drug layer on the vessel wall. After infiltration with ethanol (final content 1%), 200 PI of 0.9% saline (Otsuka Pharmaceutical Co., Ltd.) was added and shaken to confirm that there was no drug layer on the vessel wall. To this, 0.5 mg protein / ml human LDL 400 "1 was added, and the mixture was subjected to ultrasonic treatment at about 20 ° C for 10 minutes to solubilize the drug in LDL. Next, the drug was solubilized. 400 ul of 37.5 uM copper sulfate aqueous solution was added to 600 ul of human LDL and oxidized by incubation at 37 ° C for 2 hours at 37 ° C. Using this sample, TBA reaction (Naito method, Japanese Journal of Geriatrics, 15 Vol., Pp. 187-191 (1978)) TBARS value was determined.The concentration that inhibits the generation of T BARS by 50% was determined by a conventional method.

 The TBARS value is an index of oxidation of LDL, and the lipid peroxide value is an index of oxidation of LDL lipid (Naito, Atherosclerosis, Vol. 18, No. 1, p. 33 (1990)).

 Table 3 shows the results of the action of suppressing LDL oxidation / peroxidation.

 [Table 3] Inhibition of human L D L oxidation Z peroxidation

The concentration that suppresses T BARS generation by 50% M) Compound of Exemplified Compound No. 1. (= CS-045) 2.0

Vitamin E 23.6

Englitazone ² '' sodium salt ＞> 300

Pioglitazone ³⁾ 156

2) See David A. Clark et al., 丄 ed. Chem., 34, 31_9 (1989).

 3) T. Sohda et al., Arzneimittel-Forschung Drug Research, vol. 40, ref. 37, good As shown in Table 3, the compound of Exemplified Compound No. 1 (= CS-045) has superior oxidation inhibition compared to other drugs. The effect was shown.

Example 3. Oxidation of egret LDL Z Inhibition of peroxidation

The preparation of ^ 1 ^ 1 Egret 0 was performed by the method of FTHatch et al. (FTHatch et al., Adv. Li _P. Res., Vol. 6, p. 1 (1968)). That is, blood was collected from WH HL ゥ herons using EDTA at a final concentration of 5 mM as an anticoagulant to obtain plasma. Obtained The plasma thus obtained was adjusted to a specific gravity of 1.019 by adding a sodium bromide solution, and then subjected to ultracentrifugation at 39,000 rpm for 1 hour at 39,000 rpm. After the completion of the ultracentrifugation operation, the lower LDL and HDL fractions were collected. A sodium bromide solution was added thereto to adjust the specific gravity to 1.063. C, subjected to ultracentrifugation at 39,000 rpm for 24 hours. After the completion of the ultracentrifugation operation, the upper LDL fraction was collected. Next, dialysis was performed at 4 ° C. using 10 mM phosphate buffer (pH 7.5) containing 150 m of sodium chloride to prepare an experimental WHH L ゥ egret LDL sample.

Next, the test drug was dissolved in ethanol to obtain various final drug concentrations. Next, 2 mg of WHHL ゥ Sagi LDL, the test drug dissolved in ethanol, and copper sulfate (final concentration 0.5 or 5 wM) in 1 ml PBS (-) (phosphate buffered saline: Nissui Pharmaceutical Co., Ltd.) dissolved in, the C0 _{2/0 2} incubator one

Incubated at 37 for 24 hours. Then, it is subjected to the oxidation reaction induced by Cu ²⁺ , and the TBARS (thiobarbituric acid reaction positive substance) value after the reaction is determined by the fluorescence method of Yagi et al. (Yagi et al., Vitamin, Vol. 37, p. 105 (1968) Year))

The degree of inhibition of T BARS formation by 50% was determined by a conventional method.

 The TB ARS value is an index of oxidation of LDL as described above (Naito, Atherosclerosis, Vol. 18, No. 1, p. 33 (1990)).

 Table 4 shows the results of the inhibitory action on LDL oxidation.

 [Table 4] Inhibitory effect on oxidation of \ ^ 11 ^ 1 squirrel egret 1 ^^

Concentration that suppresses T BARS ^ by 50% (M)

Cii ² concentration 0.5 uM 5 MM Compound of Exemplified Compound No. 1. (= CS-045) 2.9 17.'Probucol ⁴¹ 6.3> 100

4) See Yoshioka et al., J. Med. Chem., 32, 421 (1989).

As is clear from Table 4, the compound of Exemplified Compound No. 1 (= CS-045) was 0.5 M And 5 wM Cu ²⁺ inhibited LDL-induced oxidation in a dose-dependent manner. Its effect was stronger than probucol.

Example 4 Effect of suppressing foaming of macrophages

Macrophages were collected by the method of Edelson et al. (In Vitro Methods in Cell-Mediated & Tumor Immunity, eds. Bloon, BR David, JR (Academic, New York), p. 333 (1976)). That is, about 10 ml of a physiological saline solution containing heparin dissolved to a final concentration of 1 M / ml was injected into the peritoneal cavity of female ddy mice, and collected together with intraperitoneal macrophages. After physiological saline containing macrophages obtained from 20 to 40 mice was pooled, it was centrifuged at 400 xg, 4 ° C for 10 minutes. This was suspended in Dulbece's modified Eagle's medium (DMEM) containing a final concentration of 10% Fetal Calf Serum (FCS) and 100 li / ml of benicillin and streptomycin. Were then incubated for 2 hours at 35X10 mm Petri dish 1 well Ah or 3 XL0 ^e number of 37 Ri by the C0 ₂ incubator one that was added to a cell number. After culturing, which was washed 2 times with DM EM containing no 10% FCS, followed by the addition of DMEM C 0 by ₂ incubator one by culturing 37 for 18 hours with 10% FCS. After culturing, DMEM containing 10% riboprotein-deficient serum was added to this and used for experiments.

The effect of suppressing macrophage foaming was measured by an improved method of Kita et al. (Kita et al., Proc. Natl. Sci. USA, vol. 84, p. 592δ (1987)). That, 100 ug petri dish oxide per LD L, the © shea serum albumin at ^l4 C one year old maleic acid and a final concentration of 0.2 mM in the final饞度2.4 mg / nd added, with C 0 ₂ incubator one by 37 6 Cultured for hours. After washing the cells three times with PBS, lipids in the cells were extracted with a solvent of hexane: isopropyl alcohol = 3: 2. After extraction, it was evaporated to dryness under a stream of nitrogen. After evaporating to dryness, dissolve the residue in a small amount of chloroform.

1) Thin-layer chromatography using the developing solvent

The ( ^14C- CE) fraction was separated.

 Table 4 shows the results of the action of suppressing foaming of macrophages.

In the table, the inhibition rate (%) of macrophage foaming was calculated from the following equation. Inhibition rate of foam macrophages (%) = ^{(14 C at a drug non-coexistence - CE generation amount - ¹⁴ under drug coexistence C - CE generation amount) / drug ¹⁴ C one CE formation in the non-coexistence Amount}

 [Table 5] Inhibition of foaming of macrophages Inhibition rate of foaming (%)

Cu ²⁺ concentration 0.5 uM 5 μΜ Compound of Exemplified Compound No. 1. (= CS-045) 85.9 71.5

 (Addition amount: 30 μΜ)

Probucol 74.1 1.1

(Addition amount: 30 μΜ) As is clear from Table 5, by adding 30 MM of the compound of Exemplified Compound No. 1 (= CS-045), 0.5 μΜ and 5% of Cu ²⁺ induced by the addition of Compound 2 LDL with suppressed denaturation suppressed the production of ¹⁴ C-CE in macrophages. The effect was stronger than 30 μΜ blobcol.

Example 5. Inhibition of arterial stiffness in WHHL rabbits

 The effect of inhibiting arteriosclerosis in WHHL rabbits was performed according to the method of Y. Watanabe et al. (Biochimica et Biophysica Acta, 960, 294-302 (1988)). That is, 13 rabbits (female, 11 months old) were arbitrarily divided into 6 birds in a group and 7 birds in a treatment group, and only standard feed (Standard Diet RC4, manufactured by Oriental Yeast Co., Ltd.) was used in the control group. The same diet containing 0.2% of the compound of Exemplified Compound No. 1 (= CS-045) was administered to the administration group every day at 80 mg each. Six months after administration, all animals were sacrificed and the major artery was removed. In each case, the aorta was divided into 10 sections from the aortic arch to the abdominal aorta. The intima area and the media area where atheroma mainly existed were measured, and the ratio between them, that is, the area ratio of atherosclerotic lesions was determined.

As a result, as a mean of all pieces, the intimal area of the group to which the feed containing the compound of Exemplified Compound No. 1 (= CS-045) was administered was 10.4% significantly higher than that of the control group. Showed a decrease. In addition, the calculated intima / media area ratio ([intimal area / media area] of the target group) and the [intima / media] area of the control group to which the feed containing the compound of Exemplified Compound No. Example 6: Acute toxicity

 Acute toxicity was measured according to standard methods.

 That is, three ddy mice (male) were used. The compound of Exemplified Compound No. 1 was orally administered to these at 300 mg / kgl and observed for 5 days, but all of them survived.

 Similarly, for example, the acute toxicity of the exemplified compounds Nos. 2, 3, 4, and 10 was 300 mg / kg or more in all cases after oral administration.

Formulation Example 1. Cabcell

 100 g of compound of Exemplified Compound No. 1.

 Lactose 168.3 rag

 Corn starch 70 mg

 Magnesium stearate 1.7 mg Total 340.0 mg

 The powder of the above formulation was mixed and passed through a 20-mesh sieve. Then, 340 mg of this powder was placed in a No. 2 gelatin capsule to prepare a capsule.

Claims

The scope of the claims

 1.

 General formula

(Wherein, R ¹ , R ² , IT and R ^s are the same or different and each represent a hydrogen atom or a lower alkyl group. R ³ represents a hydrogen atom, an aliphatic acyl group, or an optionally substituted aromatic group. A thiazolidine derivative or a pharmacologically acceptable salt thereof having an aromatic group or a lower alkoxycarbonyl group as an active ingredient;

 2. The compound according to claim 1,

R ¹ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ² represents a hydrogen atom or a lower alkyl group having i to 3 linear or branched carbon atoms.

R ³ is a hydrogen atom, a straight-chain or branched-chain aliphatic acyl group having 1.7 to 4 carbon atoms, an unsubstituted aromatic acyl group having 7 to 11 carbon atoms, or A chain or branched lower alkoxycarbonyl group having 2 to 4 carbon atoms;

R ⁴ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

A thiazolidine derivative or its pharmacology. A prophylactic and / or therapeutic agent for arteriosclerosis, which comprises an acceptable salt as an active ingredient.

3. The compound according to claim 1, R ¹ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ² represents a carbon atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group;

R ⁴ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

A prophylactic and / or therapeutic agent for arteriosclerosis comprising a thiazolidine derivative or a drug thereof, which is an acceptable salt.

 4. The compound according to claim 1,

R ¹ represents a methyl group;

R ² represents a hydrogen atom or a methyl group;

R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group;

R ⁴ represents a methyl group or t-butyl group;

R ⁵ represents a hydrogen atom or a methyl group;

A preventive and / or therapeutic agent for arteriosclerosis comprising a thiazolidine derivative or a drug thereof, an SLL-acceptable salt as a component I.

 5. The compound according to claim 1, wherein

 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-1-methoxy) benzyl] thiazolidine-1,4-dione,

 2) 5— [4- (6-Hydroxy-2-methyl-7—tert-butylchroman-2-methoxy) benzyl] thiazolidine-1,2, dione,

 3) 5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchroman-2-methoxy) benzyl] thiazolidine-1,4 dione,

 4) 5-[4- (6-Hydroxy-2- ^ Tsobutyl-5,7,8-trimethylchroman-2-methoxy) benzyl] thiazolidine-1,4 dione

7 5) 5-[4- (6-acetoxy-1,2,5,7,8-tetramethylchroman-12-methoxy) benzyl] thiazolidine-1, 4-dione,

 6) 5-[4- (6-ethoxycarbonyloxy 2, 5, 7, 8-tetramethyl chroman-2-methoxy) benzyl] thiazolidine 1, 4-dione or a pharmaceutically acceptable salt thereof A prophylactic and / or therapeutic agent for arteriosclerosis comprising:

 6. The compound of claim 1,

 1) 5-[4- (6-hydroxy-2,5,7,8-tetramethylchroman-12-methoxy) benzyl] thiazolidine-1, 4-dione,

 2) 5— [4- (6-hydroxy-2-methyl-17-tert-butylchroman-2-methoxy) benzyl] thiazolidine-1,2-dione,

 3) 5— [4- (6-ethoxycarbonyloxy 2,5,7,8-tetramethyl chroman-2-methoxy) benzyl] thiazolidine-1,4-dione, masuko is pharmacologically acceptable A prophylactic and / or therapeutic agent for arteriosclerosis containing a salt as a main component.

 7. The compound according to claim 1,

 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-1-methoxy) benzyl] thiazolidine-2,4-dione,

Alternatively, a prophylactic and / or therapeutic agent for arteriosclerosis containing a pharmacologically acceptable salt thereof as an active ingredient.

8. The prophylactic agent and Z or the therapeutic agent according to claim 1, wherein the arteriosclerosis is atherosclerosis.

9

 General formula

(Wherein, R ¹ , R ² , R "and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group. R ³ may have a hydrogen atom, an aliphatic acyl group, or a substituent (Aromatic acyl group or lower alkoxycarbonyl group.)) Prevention and / or treatment of arteriosclerosis characterized by administering to a mammal a thiazolidine derivative or a drug ± an acceptable salt thereof having Method.

 10. The compound according to claim 9, wherein

R ¹ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ² represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

R ³ is a hydrogen atom, a linear or branched aliphatic acyl group having 1 to 4 carbon atoms, an aromatic acyl group having 7 to 11 carbon atoms having no substitution or a straight chain Or a branched lower alkoxy group having 2 to 4 carbon atoms;

R ⁴ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

A method for preventing and / or treating arteriosclerosis, which comprises administering a thiazolidine derivative or a pharmaceutically acceptable salt thereof to a mammal.

 11. The compound according to claim 9, wherein

R ¹ is a linear or branched lower alkyl group having 1 to 4 carbon atoms

9 Show;

R ^{2 represents a} hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group;

R ⁴ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms;

R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms;

A method for preventing and / or treating arteriosclerosis, which comprises administering a thiazolidine derivative or a drug S ± acceptable salt thereof to a mammal.

 12. The compound according to claim 9, wherein

R ¹ represents a methyl group;

R ² represents a hydrogen atom or a methyl group;

R ³ represents a hydrogen atom, an acetyl group or an ethoxycarbonyl group;

R ⁴ represents a methyl group or a t-butyl group;

R ⁵ represents hydrogen ^ · ^{: a} child or a methyl group;

Thiazolidine A method for preventing and / or treating arteriosclerosis comprising administering to a mammal a plant or a drug S ± acceptable salt thereof.

 13. The compound according to claim 9, wherein

 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-1-methoxy) benzyl] thiazolidine-1,4-dione,

 2) 5-[4- (6-Hydroxy-2-methyl-7-tert-butylchroman-l- 2-methoxy) benzyl] thiazolidine-l, 4-dione,

 3) 5- [4- (6-hydroxy-2-ethyl-5,7,8-trimethylchromane-12-methoxy) benzyl] thiazolidine-12,4-dione,

 4) 5- [4- (6-Hydroxy-2-isobutyl-5,7,8-trimethylchroman-12-methoxy) benzyl] thiazolidine-1,4 dione,

5) 5— [4— (6-acetoxy-1, 2, 5, 7, 8—tetramethylchroman 1 -Methoxy) benzyl] thiazolidine-1,2-dione,

6) 5-[4- (6-ethoxycarbonyloxy 2,5,7,8-tetramethylchroman-1-methoxy) benzyl thiazolidine-12,4-dione or a pharmacologically acceptable salt thereof A method for preventing and / or treating arteriosclerosis, which is administered to an animal.

 14. The compound according to claim 9, wherein

 1) 5— [4 -— (6-hydroxy-2,5,7,8-tetramethylchroman-1-methoxy) benzyl] thiazolidine-1,4-dione,

 2) 5- [4- (6-hydroxy-2-methyl-17-tert-butylchroman-2-methoxy) benzyl] thiazolidine-1,2-dione,

 3) 5- [4- (6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-1-methoxy) benzyl] thiazolidine-12,4-dione or a pharmaceutically acceptable salt thereof A method for preventing and / or treating arteriosclerosis, which is administered to an animal.

 1 5. The compound according to claim 9, wherein

 1) 5— [4- (6-hydroxy-2,5,7,8-tetramethylchroman-1-methoxy) benzyl] thiazolidine-1,4-dione,

Or a method for preventing and / or treating arteriosclerosis, which comprises administering a pharmacologically acceptable salt thereof to a mammal.

 1 6. The method according to claims 9 to 15, wherein the arteriosclerosis is atherosclerosis.