JP3029768B2 - Cachexia improver - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a cachexia improver containing a thiazolidine derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Patients with cancer and chronic sexually transmitted diseases are often accompanied by symptoms such as significant weight loss, anorexia, anemia, asthenia and nausea (Lawson DH et al., Ann. Rev. Nutr., 2
277-301 (1982); Starin AJ, Invest. C
ell. Pathol., 2: 181-193 (1979); Theolog
ides A., Cancer, 43, 2004-2012 (1979
Year)).

[0003] A series of these symptoms accompanied by general weakness is called cachexia. For example, cancer cachexia, infectious cachexia, thyroid cachexia, cachexia due to parasitic infection, inflammatory cachexia, cachexia due to acquired immunodeficiency (AIDS), and the like are known. These cachexia conditions, for example, increase acute mortality and reduce the durability of cancer to chemotherapy, radiation therapy, and surgery (Dewys WD et al., Am.
J. Med., 69, 491-497 (1980); Dwyer J.
T., Cancer, 43, 2077-2086 (1979); Don.
aldson SS et al., Cancer, 43, 2036-2052 (197
9 years)).

[0004] Therefore, in order to improve these cachexia, attempts have been made, for example, to give a high-fat diet or a high-carbohydrate diet or to give a high-calorie infusion to patients with terminal cancer. Liquid quality has not yet been resolved (Br
enann MP, Cancer Res., 37, 2359-2364 (1977
Year); Young VR, Cancer Res., 37, 2336-2347
(1979)).

[0005] Under the circumstances described above, it is difficult to improve or treat cachexia at this stage, and researches on ameliorating drugs effective for cachexia have been carried out for many years at various places. There has been no complete success yet.

[0006] There are various reports on the causes of cachexia. For example, it has been pointed out that cytokines including TNF (tumor necrosis factor) / cachectin are involved in nitrogen consumption associated with cancer cachexia (Warren RS,
Arch.Surg., 122, 1396-1400 (1987); Starn
es HF et al., J. Clin. Invest., 82, 1321-1325.
(1988)). It is also known that injection of TNFα into animals causes septic shock, causes intestinal necrosis and acute lung injury, and promotes catabolism of muscle proteins (Tracey KJ and Cerami A., Ann. Re.
v. Cell Biol., 9, 317-343 (1993)). Among such symptoms called cachexia, particularly remarkable weight loss is considered to be caused by abnormally enhanced protein catabolism in muscles and the like (Argiles JM
Med.Res.review, 12, 637-652 (1992)
). Under such a condition, not only TNF production is enhanced but also TNF response is enhanced (Haung ZB et al., Chest., 104, 751-755 (1993).
Year); Antinori A. et al., Allegol. Immunopathol. Madr.,
20, 249-254 (1992)). Therefore, suppression of TNF production, suppression of TNF response, and suppression of increase in protein catabolism, which are observed in cachexia, lead to improvement of cachexia and, consequently, treatment of patients. It is expected not only to improve the durability at the time, but also to improve the quality of life of the patient and lead to the prolongation of the patient's life.

[0007]

SUMMARY OF THE INVENTION The present inventors have studied for the purpose of improving cachexia, and as a result, have found that thiazolidine derivatives have
Inhibition of NF production, suppression of TNF response, and protein catabolism, i.e., the effect of significantly improving nitrogen balance excluding urinary nitrogen excretion from urinary excretion rate and nitrogen intake. The present invention has been completed, and the present invention has been completed.

[0008]

According to the present invention, there is provided a compound of the general formula

[0009]

Embedded image

(Wherein 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 is a hydrogen atom, an aliphatic acyl group, A thiazolidine derivative having an aromatic acyl group or a lower alkoxycarbonyl group) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the above formula (I), when R ¹ represents a lower alkyl group, the alkyl group may be, for example, a linear or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl. Having 1 to 5 carbon atoms, preferably 1 to 4, most preferably methyl,
Can be given.

When R ² and R ⁵ represent a lower alkyl group, the alkyl group may be, for example, a linear or branched C ¹ -carbon such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl. -5, preferably 1-3, optimally methyl.

When R ³ represents an aliphatic acyl group, the acyl group may be, for example, a linear or branched C 1 -carbon atom such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl. -7, preferably 1-4, most preferably acetyl.

When R ³ represents an aromatic acyl group which may have a substituent, examples of the acyl group include benzoyl, 4-nitrobenzoyl, 3-fluorobenzoyl,
2-chlorobenzoyl, 3,4-dichlorobenzoyl,
1 to 3 nitro, amino, alkyl as substituents such as 4-aminobenzoyl, 3-dimethylaminobenzoyl, 2-methoxybenzoyl, 3,5-di-t-butyl-4-hydroxybenzoyl, 1-naphthoyl An amino, dialkylamino, alkoxy, halo, alkyl, hydroxy-containing aromatic acyl group having 7 to 11 carbon atoms, preferably an aromatic acyl group having 7 to 11 carbon atoms having no substituent An acyl group, optimally benzoyl, can be mentioned.

When R ³ represents a lower alkoxycarbonyl group, the alkoxycarbonyl group may be a straight-chain or branched chain such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl. And 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, most preferably ethoxycarbonyl.

When R ⁴ represents a lower alkyl group, examples of the alkyl group include straight or branched carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl. 1 to 5,
Preferably 1 to 4, most preferably methyl, t-butyl, especially methyl, can be mentioned.

The compound having the 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. Further, when the compound having the general formula (I) has a basic group, it can be used in the form of a pharmaceutically acceptable non-toxic acid addition 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, malic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, methanesulfonic acid And organic acids; and salts thereof.

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

[0019] In compounds wherein having the general formula (I) of the present invention, preferably R ¹ is a lower alkyl group having 1 to 4 carbon atoms of straight or branched chain; R ²
Represents a hydrogen atom or a straight-chain or branched lower alkyl group having 1 to 3 carbon atoms; R ³ has a hydrogen atom, a straight-chain or branched carbon atom having 1 to 4 carbon atoms Aliphatic acyl group, unsubstituted carbon number of 7 to 11
An aromatic acyl group or a linear or branched lower alkoxycarbonyl group having 2 to 4 carbon atoms with a number; R ⁴ is C 1 -C linear or branched
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 is a linear or branched lower alkyl group having 1 to 4 carbon atoms;
R ² represents a lower alkyl group having 1 to 3 carbon atoms in hydrogen atom or a straight-chain or branched; R ³ represents a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group; R ⁴ is R ⁵ 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. Show.

[0021] In the compounds 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.

[0023]

[Table 1] Example Compound No. R ¹ R ² R ³ R ⁴ R ⁵ ───────────────────────────────── 1 Me Me H Me Me 2 H Me H Me Me 3 Me HHHH 4 Me HH 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 11 Me H Ac Me H 12 Me HH Me H 13 Me Me Byr Me Me ─────────────────────────────────.

In the table, Me = methyl, Et = ethyl, iBu
= Isobutyl, tBu = tertiary butyl, Pn = pentyl, Ac = acetyl, Byr = butyryl, Bz = benzoyl, EtC = ethoxycarbonyl.

In the compound having the general formula (I) of the present invention, exemplified compound numbers 1, 4, 5,
6, 8, 10 compounds, more preferably 1,
4, 10 compounds, and particularly preferably 1 compound.

The compound having the general formula (I) of the present invention is a known compound, for example, a compound described in JP-A-60-511189.
No. 4,572,912, and European Patent No. 0139421.

The compound of the present invention having the above general formula (I) 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 a cachexia improving effect can be measured by the following method.

The effect of suppressing TNF production is measured by the following method. That is, the method of Daniel-Issakani et al. (J. Biol. Chem., 264, 20240-20247 (1989)
Year)), human monocyte cells U937 are induced to differentiate, and the amount of TNF produced by simultaneous addition of LPS (Lipopolysaccharide) (LPS-treated control cells) and drug is measured. The value obtained by subtracting the amount of production in the LPS-untreated cells from the amount of production in the LPS-treated control cells is defined as 0% inhibition rate.
The inhibition rate is calculated from a value obtained by subtracting the production amount in the LPS-untreated cells from the production amount in the drug-treated cells.

Next, the effect of suppressing the TNF response is measured by the following method. That is, the human immunodeficiency virus (HIV) promoter region, HIV-LTR, is added to human breast cancer strain MCF-7 cells (TNF hypersensitive cells).
Expression vector (HIV) in which a luciferase gene is connected downstream of (long-terminal repeat).
-LTR-luciferase) was introduced as a TNF reporter gene (D. Weissmann et al., Proc. Natl.
Acad. Sci. USA, 90, 2537-2541 (1993)), T
HIV by adding NF (human recombinant TNFα)
-The luciferase activity is measured by a chemiluminescence method by replacing the transient expression induction of LTR with the expression of luciferase gene.

Next, the anti-catabolic effect of the protein is measured by the following method. That is, since the accumulated protein in the living body is excreted in the urine as urea nitrogen when decomposed, the amount of excreted nitrogen in the urine is used as an indicator of protein degradation (Flores EA. Et al., J. Clin. In
vest. 83, 1614-1622 (1989)). Therefore, for example, Wistar Imado rats are arbitrarily divided into a control group and a drug-administered group, the control group is further divided into a normal control group not administered with TNF and a TNF-administered control group administered with TNF, and the drug-administered group is administered with TNF. Oral administration at the beginning, measuring food intake and urine output after a certain period of time, subtracting urinary nitrogen excretion from ingested food nitrogen content and calculating nitrogen balance, anti-catabolic effect of protein Can be seen.

[0032]

The compound of the present invention having the above general formula (I) or a pharmacologically acceptable salt thereof is useful for improving cachexia, especially for cancer cachexia, infectious cachexia, thyroid cachexia, and parasitic infection. It is useful for improving cachexia, inflammatory cachexia, and cachexia due to acquired immunodeficiency disorder (AIDS).

The compound having the general formula (I) or a pharmaceutically acceptable salt thereof 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. . These various preparations are commonly used in the field of pharmaceutical preparation technology such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, dissolution aids, suspensions, coatings, etc., in accordance with the usual methods for the main drug. It can be formulated using known adjuvants. Its usage depends on symptoms,
Although it varies depending on age, body weight, administration method, dosage form and the like, usually, an adult can be administered 50 mg to 5000 mg daily.

[0034]

EXAMPLES The following examples, test examples and formulation examples are given.
The present invention will be described more specifically. Embodiment 1 FIG. TNFα production inhibitory action Induction of differentiation of human monocyte cell line U937 was carried out by Daniel-I
Sassani et al., J. Biol. Chem., 264, 2
0240-20247 (1989))
Was. That is, human monocyte cell line U937 was added at 30 ng / ml.
Incubate for 72 hours in culture medium supplemented with TPA to induce differentiation
I let it. Next, the culture supernatant was removed, and LPS (Lipopoly
A culture solution containing 10 ng / ml was added.
(Hereinafter referred to as "LPS-treated cells"). LPS unprocessed fine
The same volume of culture was added to the cells. Furthermore, LPS processing details
In the vesicle, Exemplified Compound No. 1. Compound of 10^-FiveM (4.4
μg / ml) dissolved in the culture solution and added simultaneously with LPS
(Hereinafter, referred to as “Compound 1. Treated cells”). Compound 1.
The same volume of culture solution was added to the control cells of the treated cells (hereinafter referred to as “control cells”).
Below, "LPS-treated control cells"). From LPS addition
After 6 hours, the amount of TNFα produced was determined by ELISA kit.
(Manufactured by ENDOGEN). The measured value is flat
Mean ± standard error.

From the amount of LPS-treated control cells, LPS
The value obtained by subtracting the production amount in untreated cells was defined as the inhibition rate of 0%. It was calculated from the value obtained by subtracting the amount of production in the LPS-untreated cells from the amount of production in the treated cells.

Table 2 shows the results.

[0037]

[Table 2] TNFα (per 10 ^-5 pg cells) Inhibition rate (%) ────────────────────────────────── LPS-untreated cells 54.8 ± 21 LPS-treated control cells 545 ± 370 Compound 1. Treated cells 333 ± 29 ^* 43 中 In the above table, * indicates p <0 0.01 (t-test, control cells treated with LPS) As can be seen from Table 2, Exemplified Compound No. 1. Is L
PS treatment significantly reduced TNFα production. That is, Exemplified Compound No. 1. Inhibited the production of TNFα, one of the causative agents of cachexia. Embodiment 2. FIG. Effect of suppressing TNF response response The effect of suppressing TNF response response is described in Weissman
Acad. Sci. (D. Weissmann et al., Proc. Natl. Acad. Sci.
USA, 90, 2537-2541 (1993)).

That is, human breast cancer strain MCF-7 cells (2.5
× 10 ⁴ ) with a final concentration of 10% fetal calf serum (FCS) and 100 U / ml penicillin and 100 μg / m
RPMI1640 medium containing 1 streptomycin (hereinafter referred to as “10% FCS / RPMI1640”)
, And added to a 24-well microculture plate in a total volume of 0.5 ml so that the number of cells becomes 2.5 × 10 ⁴ cells per well, followed by culturing at 37 ° C. for 2 days in a carbon dioxide incubator. After the culture, the cells were washed twice with RPMI1640 medium containing no 10% FCS. Then, HIV-LTR (long-ter) which is a promoter region of human immunodeficiency virus (HIV) was used.
An expression vector (HIV-LTR-luc) in which a luciferase gene is connected downstream of a Minor repeat.
0.75 μg / well, D
EAE-dextran was added in an amount of 80 μg per well to a total of 0.2 ml of RPMI164 without 10% FCS.
0 medium and 37 in a carbon dioxide incubator.
C. for 3 hours. Next, 10% FCS / RPMI
1640 was added in an amount of 0.5 ml per well, and 3
After stirring for 0 minutes, all the medium was removed. Then 10
% FCS / RPMI 1640 0.5 / well
ml, and cultured at 37 ° C. for 24 hours in a carbon dioxide incubator. Then, TNF (human recombinant TNFα; manufactured by Genzyme) was added to a final concentration of 30Un.
10% FCS / RPMI16 to make it / ml
The mixture was adjusted at 40 (total amount: 1 ml / well), and further cultured in a carbon dioxide incubator at 37 ° C. for 24 hours.
Exemplary Compound No. 1. Is a final concentration of 0.1 μg / m
1, 0.3 μg / ml, 1 μg / ml, 3 μg / ml and 10 μg / ml were added simultaneously with the addition of TNF (total amount 1 ml / well). After the culture, TN
The transient induction of HIV-LTR expression induced by the addition of F was replaced with the expression of a luciferase gene (reporter gene), and a measurement kit (New Reporter Gene) was used.
Luciferase Assay System Luciferase activity was measured with a chemiluminescence measuring device (Lab System Co., Ltd.) using Picker Gene (trade name, manufactured by Toyo Ink Mfg. Co., Ltd.). In addition, the result was shown by the average value +/- standard error. The significance test was performed by a t-test, and p <0.05 was determined to be significant.

Table 3 shows the results of the TNF response reaction inhibitory action.

In the table, the inhibition rate (%) due to luciferase activity was calculated from the following equation.

[0041] The concentration at which the luciferase activity induced by the addition of TNF was inhibited by 50% was determined by a conventional method.

[0042]

[Table 3] ─────────────────────────────────── Concentration of luciferase activity inhibition (%) (μg / ml) ─────────────────────────────────── untreated control group 3.9 ± 0.5-TNF Treatment control group 35.9 ± 2.2 0.0 (TNF concentration: 30 V / ml) Exemplified Compound No. 1. 0.1 30.0 ± 1.8 18.4 Compound treated group 0.3 24.1 ± 1.4 ^* 36.9 1 26.0 ± 1.6 ^* 30.9 32.0 ± 2. 1 ^* 40.3 10 14.5 ± 1.7 ^** 66.9──────────────────────────────── * In the above table, * indicates p <0.05 (vs. TNF-treated control group) ** indicates p <0.01 (vs. TNF-treated control group).

As is clear from Table 3, Exemplified Compound No. 1.
Compound (4) dose-dependently suppressed luciferase activity (induction of TNF reporter gene expression) transiently induced by TNF treatment. That is, Exemplified Compound No. 1. Compound dose-dependently suppressed the response to TNF, which is thought to be one of the causative agents of cachexia. The concentration that suppresses the TNF response reaction by 50% is 4.
It was 7 μg / ml (10.7 μM).

Embodiment 3 FIG . Urinary nitrogen excretion rate and nitrogen balance
Improving action Using 8-week-old male Wistar Imado rats (about 250 g), TNFα dissolved in phosphate buffer-saline was used.
1 μg / ml was continuously infused at a flow rate of 1 μg / hour / kg for 24 hours from a catheter placed in the jugular vein two days ago.
A normal control group (hereinafter referred to as “normal control group”) was continuously infused with the same amount of phosphate buffer-saline.

Further, in the TNF-administered group, Exemplified Compound No. 1. Was suspended in 0.5% carboxymethylcellulose (CMC), and 100 mg / kg was orally administered immediately after the start of TNFα injection (hereinafter, referred to as “compound administration group of Exemplified Compound No. 1.”).
The same amount of a 0.5% carboxymethylcellulose (CMC) solution was administered to a control group to which TNF was administered (hereinafter referred to as “TN
F administration control group). 24 from the start of TNFα injection
Food consumption and urine output over time were measured. Urine urea nitrogen was measured by "urea nitrogen test Wako" (manufactured by Wako Pure Chemical Industries, Ltd.). The value obtained by subtracting the amount of urinary nitrogen excretion from the nitrogen content in the feed (crude protein content × nitrogen content in protein) was defined as a nitrogen balance (Nitrogen Balance).

The measured values are shown as mean ± standard error.

Table 4 shows the results.

From the results, it was found that the TNF-administered control group and Exemplified Compound No. 1. And p <0.05 was determined to be significant by t-test.

[0049]

[Table 4] 数 Number of cases Urinary nitrogen excretion rate Nitrogen balance (mg / 100g body weight) (mg / 100g body weight) 正常 Normal control group 5 86.5 ± 3.0 59.0 ± 14.7 ^** TNF administration control group 5 78.6 ± 3.9 -35.8 ± 10.2 Exemplified Compound No.1. Compound administration group 5 65.3 ± 4.3 ^* 17.0 ± 9.6 ^** ─────────────────────────────────── In the table, ^* indicates p <0.05 (vs. TNF administration control group), and ^** indicates p <0.01 (vs. TNF administration control group).

As is clear from Table 4, Exemplified Compound No. 1.
Compound (1) significantly improved the urinary nitrogen excretion rate shown during the administration of TNF, and showed that the nitrogen balance that became negative by the administration of TNF corrected for food intake and the like turned to the positive side. That is, Exemplified Compound No. 1. Compound suppressed the catabolism of protein caused by TNF administration, which is considered to be one of the causative agents of cachexia.

Test Example 1 Acute toxicity Acute toxicity was measured according to a conventional method. That is, three ddy mice (male) were used. These are exemplified compound Nos. Was orally administered at a dose of 300 mg / kg and observed for 5 days, all of which survived.

Similarly, for example, exemplified compound numbers 2, 3,
The acute toxicity of any of the compounds 4 and 10 was oral
It was 300 mg / kg or more.

Formulation Example 1 Capsule Exemplified Compound No. 1. 100 mg lactose 168.3 mg corn starch 70 mg magnesium stearate 1.7 mg ─── Total amount: 340.0 mg The powder of the above formulation was mixed and passed through a 20-mesh sieve, and 340 mg of this powder was placed in a No. 2 gelatin capsule to prepare a capsule.

[0054]

The compound having the general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention is produced by suppressing the production of TNF, suppressing the TNF response, and administering TNF. It exhibited excellent improving effects such as suppressing the catabolism of proteins. Therefore, the compound having the general formula (I) or a pharmacologically acceptable salt thereof of the present invention is useful as an agent for improving various cachexia caused by cancer, infectious disease and the like. It increases the durability of chemotherapy, radiation therapy, surgery, etc., improves the quality of life of patients, and reduces mortality.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI A61P 35/00 A61P 35/00 43/00 43/00 // C07D 417/12 C07D 417/12 (72) Inventor Tomoo Kobayashi Tokyo 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Jun Osumi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Munehiro Teranishi Horikoshi, Fukuroi-shi, Shizuoka 717 Sankyo Co., Ltd. (72) Inventor Takao Yoshioka 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Shinichi Kurata 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock In-company (72) Inventor, Mr. Tatsuta, 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References JP-A-62-234085 (JP, A) JP-A-61-36284 (JP, A) JP-A-62-5980 (JP, A) JP-A-7-188006 (JP, A) JP-A-2-229168 (JP, A) JP-A-64-45344 (JP, A) JP-A-61-100555 (JP, A) JP-A-59-232069 (JP, A) JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 417/12 CA (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] 1. A compound of the general formula (Wherein, 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 represents a hydrogen atom, an aliphatic acyl group, or an optionally substituted aromatic A cachexia improving agent comprising a thiazolidine derivative having an aromatic acyl group or a lower alkoxycarbonyl group) or a pharmacologically acceptable salt thereof as an active ingredient. 2. The compound according to claim 1, wherein R ¹ is a linear or branched lower alkyl group having 1 to 4 carbon atoms; R ² is a hydrogen atom or a linear alkyl group. Or R ³ is a hydrogen atom, a linear or branched aliphatic acyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted lower alkyl group having 1 to 3 carbon atoms. R ⁴ represents a straight-chain or branched-chain aromatic acyl group having 7 to 11 carbon atoms or a straight-chain or branched-chain lower alkoxycarbonyl group having 2 to 4 carbon atoms; R ⁵ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 3 carbon atoms; R ⁵ represents a lower alkyl group having 1 to 3 carbon atoms; A cachexia containing an acceptable salt as the active ingredient Improving agent. 3. The compound according to claim 1, wherein R ¹ is a linear or branched lower alkyl group having 1 to 4 carbon atoms; R ² is a hydrogen atom or a linear alkyl group. Or a 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 chain A 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 a pharmaceutically acceptable salt thereof Cachexia improver containing a salt to be used as an active ingredient. 4. The compound according to claim 1, 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; ⁴ represents a methyl group or a t-butyl group; R ⁵ represents a hydrogen atom or a methyl group; a cachexia improving agent comprising a thiazolidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 5. The compound according to claim 1, wherein 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4 -Dione, 2) 5- [4- (6-hydroxy-2-methyl-7-tert-butylchroman-2-methoxy) benzyl]
Thiazolidine-2,4-dione, 3) 5- [4- (6-hydroxy-2-ethyl-5,
7,8-trimethylchroman-2-methoxy) benzyl] thiazolidine-2,4-dione 4) 5- [4- (6-hydroxy-2-isobutyl-
5,7,8-trimethylchroman-2-methoxy) benzyl] thiazolidine-2,4-dione 5) 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-methoxy) ) Benzyl] thiazolidine-2,4-dione, 6) 5- [4- (6-ethoxycarbonyloxy-2,
5,7,8-Tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof as an active ingredient. 6. The compound according to claim 1, 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4 -Dione, 2) 5- [4- (6-hydroxy-2-methyl-7-tert-butylchroman-2-methoxy) benzyl]
Thiazolidine-2,4-dione, 3) 5- [4- (6-ethoxycarbonyloxy-2,
5,7,8-Tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof as an active ingredient. 7. The compound according to claim 1, wherein 1) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy) benzyl] thiazolidine-2,4 -A cachexia improving agent containing dione or a pharmacologically acceptable salt thereof as an active ingredient. 8. The cachexia improving agent according to any one of claims 1 to 7, wherein the cachexia is cancer cachexia. 9. The cachexia improving agent according to any one of claims 1 to 7, wherein the cachexia is infectious cachexia. 10. The cachexia improving agent according to any one of claims 1 to 7, wherein the cachexia is thyroid cachexia. 11. The cachexia improving agent according to any one of claims 1 to 7, wherein the cachexia is cachexia due to parasitic infection. 12. The cachexia improving agent according to any one of claims 1 to 7, wherein the cachexia is inflammatory cachexia. 13. The cachexia improving agent according to any one of claims 1 to 7, wherein the cachexia is cachexia due to acquired immunodeficiency.