WO2007060976A1

WO2007060976A1 - Novel ascochlorin derivative compounds and medicinal compositions containing the same

Info

Publication number: WO2007060976A1
Application number: PCT/JP2006/323285
Authority: WO
Inventors: Hisao Kondo; Hidenori Watanabe; Junji Magae; Tatsuo Hoshino; Hirohiko Shimizu; Kunio Ando
Original assignee: Yokohama Tlo Company, Ltd.
Priority date: 2005-11-25
Filing date: 2006-11-22
Publication date: 2007-05-31
Also published as: JP2009051731A

Abstract

It is intended to provide an ascochlorin-related compound which is useful as a PPARϜ activator or a medicinal composition, in particular, a medicinal composition for preventing or treating life style-related diseases or preliminarily conditions thereof or a medicinal composition comparable to pioglitazone in preventing or treating type II diabetes, and the effective concentration of which in blood can be sustained for a certain period of time or longer but does not increase to the level of exerting toxicity; and a method of producing the same. Namely, an ascochlorin derivative compound represented by the general formula (I): [Chemical formula 10] (I) wherein R1 represents a hydrogen atom or -CnH2n+1 (wherein n is an integer of from 1 to 5); and R2 represents a hydrogen atom, -CnH2n+1 (wherein n is an integer of from 1 to 5), -CnH2nCOOR’ (wherein n is an integer of from 1 to 5; and R’ represents a hydrogen atom or a C1-3 alkyl group), or -COR” (wherein R” represents a pyridyl group, an amino group substituted by a C1-3 alkyl group, a phenoxyalkyl group having a halogen atom in its nucleus, a phenyl group having a C1-3 alkoxy group in its nucleus or a phenyl group having a C1-3 alkoxycarbonyl group in its nucleus); a pharmacologically acceptable salt thereof or a prodrug of the same.

Description

Specification

Novel ascochlorin derivative compound and pharmaceutical composition containing the same

[0001] The present invention relates to a novel ascochlorin derivative compound, and a preventive and therapeutic agent for lifestyle-related diseases containing the same.

Background art

[0002] Lifestyle-related diseases such as ischemic heart disease (hypercholesterolemia), type II diabetes, hypertension (cerebrovascular disorder) and fattening are serious problems, especially in developed countries and developing countries including Japan. is there.

[0003] The risk factors or preliminary symptoms of these lifestyle-related diseases are common to each other, and dietary therapy, exercise therapy, drug therapy, etc. have been proposed for the prevention and treatment of these lifestyle-related diseases. .

[0004] Pioglitazone (Patent Document 1) has been used as a drug for improving insulin resistance in type II diabetes, but has recently been shown to induce heart failure due to rapid water retention.

[0005] One of the ascochlorin derivatives, the hydrogen at the 4-position hydroxyl group of CHACO

2

4-O-Carboxymethylascochlorin (AS-6) substituted with OH improves glucose metabolism in hereditary obese diabetic mouse, C57BL ksj (db / db), a model animal of type II diabetes, And it is known that this improvement in glucose metabolism is caused by the reduction of insulin resistance in white adipose tissue (Non-patent Document 1).

[0006] However, AS-6 is rapidly absorbed when administered orally because at least 6% of the pH of the small intestine (7.2 to 7.4) is soluble in water. As a result, the blood concentration exceeded the effective concentration and increased to the toxic expression concentration, and there was a problem that toxicity to the liver was easily developed in humans and animals. In addition, ascochlorin compounds such as AS-6 have a strong effect on time-dependent medicinal effects, and the effective blood concentration to show medicinal effects lasts for a certain period of time. As an absolute condition, AS-6 has a medicinal effect due to its rapid excretion, short duration of effective concentration, and rapid oxidization of aldehyde groups to carboxylic acids. However, there are drawbacks such as a significant drop.

[0007] In addition, an ascochlorin derivative (4-O-alkylascochlorin) that was developed prior to AS-6 and alkylated at the 4-position hydroxyl group, such as 4-O-methylascochlorin (MAC), Solubility in water is 0.7 gZml, it is extremely insoluble in water, and it is difficult to express its medicinal properties because it is slow to absorb from the gastrointestinal tract where the dissolution rate of single molecules dissolved in water is slow. Met. Moreover, in addition to low bioavailability, gastrointestinal absorption varies depending on whether or not food is consumed, so that reproducibility in animal experiments is poor, impeding practical application. Furthermore, since the effective blood concentration is short-lived and the blood concentration peak is low, the effectiveness of the drug, for example, the rate of decrease in serum total cholesterol, blood glucose, blood pressure, etc. is low.

[0008] Peroxisome · Proreferencer ^ ~ · End Activator ~ · Receptor ^ ~ · Gamma (PPAR

Ύ) is a transcription factor belonging to the nuclear receptor family involved in the differentiation of adipocytes, and the ability of knock-out mice to demonstrate that TZD compounds that release insulin resistance have potent agonist activity. It has been suggested that it is deeply involved in the onset of diabetes, and it is known that the presence or absence of PPARγ activation correlates with the presence or absence of diabetes suppression. However, almost no activation effect of PPAR y was observed in MAC, and AS-6 was much lower than piodaritazone, showing only an activation effect! 2).

Therefore, conventional ascochlorin compounds such as MAC and AS-6 are inferior to pioglitazone in terms of practicality and effectiveness.

Patent Document 1: Japanese Patent Laid-Open No. 5-86057

Patent Document 2: Japanese Patent Fair 1-41624

Patent Document 3: Japanese Patent Publication 8-16057

Patent Document 4: JP-A-2005-53780

Patent Document 5: JP-A-6-305959

Patent Document 6: WO2003Z63849

Patent Document 7: WOOOZ53563

Non-Patent Literature l: Hosokawa, Ando and Tamura; Diabetes, vol. 34, pp. 267-274 (19

85) Non-Patent Document 2: M. Togashi, S. Ozawa, S. Abe, T. Nishimura, M. Tsuruga, K. Ando, G. Tamura, S. Kuwahara, M. Ubukata, and J. Magae; Ascochlorin derivatives as li gands for nuclear hormone receptors. J. Med. Chem. 46, 4113-4123 (2003) Disclosure of the Invention

Problems to be solved by the invention

[0011] The present invention is an ascochlorin compound, wherein the effective blood concentration is maintained for a certain time or more.

In addition, one object is to provide a derivative whose blood concentration does not increase to the level of toxicity and a method for producing the same. The present invention also provides a PPAR y activator, a pharmaceutical composition, particularly a pharmaceutical composition for preventing or treating lifestyle-related diseases and their preliminary symptoms, and further, hypercholesterolemia, hypertension, II with a single drug. Another object of the present invention is to provide a pharmaceutical composition that can improve a plurality of symptoms in type 2 diabetes and obesity. Another object of the present invention is to provide a pharmaceutical composition useful for the prevention or treatment of type II diabetes, which exhibits efficacy comparable to pioglitazone.

Means for solving the problem

[0012] For these purposes, the present inventors have conducted research focusing on the acetoxymethylene derivative of the aromatic aldehyde group of the ascochlorin compound and its derivatives. As a result, specific new ascochlorin derivatives have been found. The present invention was completed by finding out that it had the desired excellent characteristics.

[0013] That is, the present invention provides

(1) General formula (I):

[0014] [Chemical 1]

[In the formula, R represents a hydrogen atom or C H (n represents an integer of 1 to 5); R represents hydrogen.

1 n 2n + l 2

Atom, —CH (n represents an integer of 1 to 5), —CH COOR, (n is an integer of 1 to 5, R, n 2n + ln 2n Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or COR "(R" is a pyridyl group, an amino group substituted with an alkyl group having 1 to 3 carbon atoms, or a phenoxyalkyl group having a halogen atom in the nucleus. Represents a furyl group having an alkoxy group having 1 to 3 carbon atoms in the nucleus, or a furyl group having an alkoxycarbonyl group having 1 to 3 carbon atoms in the nucleus). A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof;

[2] The ascochlorin derivative compound of the above-mentioned [1], a pharmacologically acceptable salt thereof, or a prodrug thereof, which is an R-catyl group in the general formula (I);

[3] The ascochlorine according to the above [1], wherein in the general formula (I), R is -CHCOOH.

twenty two

Derivative compounds, pharmacologically acceptable salts thereof, or prodrugs thereof;

(4) General formula (Π):

[Chemical 2]

1- (2 acetylethyl) -2-0-methyl-4-0 carboxymethyl 1-deformylascochlorin, a pharmacologically acceptable salt thereof, or a prodrug thereof;

[5] The ascochlorin derivative compound according to any one of [1] to [4] above, a pharmacologically acceptable salt thereof, or a PPARy activator that also has a prodrug ability thereof;

[6] The ascochlorin derivative compound according to any one of [1] to [4], a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient. A pharmaceutical composition;

[7] The pharmaceutical composition according to the above [6], which is for prevention or treatment of lifestyle-related diseases; [8] the pharmaceutical composition according to the above [7], wherein the lifestyle-related disease is diabetes;

(9) General formula (III): [0018] [Chemical 3]

1 n 2n + l 2 atom, —C H (n represents an integer from 1 to 5), -C H COOR, (n is an integer from 1 to 5, R, n 2n + l n 2n

Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or COR "(R" is a pyridyl group, an amino group substituted with an alkyl group having 1 to 3 carbon atoms, or a phenoxyalkyl group having a halogen atom in the nucleus. Or a vinyl group having an alkoxy group having 1 to 3 carbon atoms in the nucleus, or a furyl group having an alkoxy carbonyl group having 1 to 3 carbon atoms in the nucleus) A method for producing an ascochlorin derivative compound according to the above [1], comprising reacting a derivative compound with a reagent having a acetylmethylene group.

The invention's effect

[0020] According to the present invention, the drug efficacy comparable to or superior to that of pioglitazone (for example, anti-diabetic action in vivo, in vitro PPAR y activity, which is not possible with conventional ascochlorin compounds) And a useful compound that exhibits an effect coefficient and the like. The compound of the present invention shows excellent effects such as improvement of obvious symptoms of diabetes, that is, reduction of blood glucose level, reduction of urine sugar level, reduction of drinking water, in experiments using dbZdb mice which are diabetes model animals. . In addition, the compounds of the present invention are effective for hypertension and hypercholesterolemia based on the results of thorough examination of AS-6 and MAC, and are considered to be effective for general lifestyle-related diseases including obesity. It is done. Therefore, using the compounds of the present invention, novel PPAR y activators, pharmaceutical compositions, particularly pharmaceutical compositions for preventing or treating lifestyle-related diseases or their preliminary symptoms are provided.

Furthermore, according to this invention, the manufacturing method of such a novel useful compound is also provided. Brief Description of Drawings [0021] FIG. 1 is a diagram showing the structure and production process of ASK-9-ACT and its intermediate (or prodrug).

[FIG. 2] is a diagram showing a comparison of PPAR y activation effects of ASK-9-ACT and pioglitazone.

FIG. 3 is a diagram showing a comparison of cell growth inhibitory effects of ASK-9 ACT and pioglitazone.

BEST MODE FOR CARRYING OUT THE INVENTION

[0022] General formula (I) of the present invention:

[0023] [Chemical 4]

[0024] All the acetoxoxymethylene derivatives of ascochlorin represented by the formula:

In the ascochlorin derivative represented by the general formula (I) of the present invention, R is a hydrogen atom or —CH 2 (n represents an integer of 1 to 5). Preferably, R is an al n 2n + l 1 having 1 to 3 carbon atoms.

A kill group, most preferably a methyl group.

[0026] R is a hydrogen atom, C H (n represents an integer of 1 to 5), C H COOR '(n is 1 to 5

2 n 2n + l n 2n

An integer of 5, R ′ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or COR ”(R ′ ′ is a pyridyl group, an amino group substituted with an alkyl group having 1 to 3 carbon atoms, A phenylalkyl group having a halogen atom, a phenol group having a C 1-3 alkoxy group in the nucleus, or a phenol group having a C 1-3 alkoxycarbo group in the nucleus; Preferably, R is CH COOH (n is an integer from 1 to 3), most preferably —CH 2 C

2 n 2n 2

OOH.

Therefore, preferred specific examples of the compound of the present invention include: 1- (2-acetylethyl) -2-O-methyl 4-O-methoxycarboromethyl 1-deformylascochlor Phosphorus (ASK—9—me—ACT), 1— (2 acetylethyl) 2—O Methyl 4—O—Carboxymethyl—1-Deformylascochlorin (ASK—9—ACT), 1— (2—acetylyl) -2-0-Methyl 4— O—Ethoxycarboromethyl 1 Deformylmuscochlorin (ASK—9— et—ACT), 1— (2 Acetylectur) 4— O —Carboxymethyl— 1—Deformylusco Examples include chlorin (AS-6-ACT), 1- (2-acetyl chloro) 4-O methyl 1 deformyl scochlorin (MAC-ACT), and the like. Most preferred is ASK-9-ACT, ie, in vivo anti-diabetic action and in vitro PPAR y activity.

[0028] [Chemical 5]

[0029]

[0030] The compound of the present invention has a basic skeleton in common with AS-6 and MAC, and is effective for hypertension, hypercholesterolemia, obesity and the like known for AS-6 and MAC. It is considered effective for all lifestyle-related diseases.

[0031] The compound of the present invention can be easily synthesized from ascochlorin or a derivative thereof in a high yield by a known general synthesis technique. Specifically, for example, the general formula (III):

[0032] [Chemical 6]

2n + l

Atoms, C H (n represents an integer of 1 to 5), C H COOR, (n is an integer of 1 to 5, R

2n + l 2n

Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or COR "(R" is a pyridyl group) An amino group substituted with an alkyl group having 1 to 3 carbon atoms, a phenoxyalkyl group having a halogen atom in the nucleus, a furan group having an alkoxy group having 1 to 3 carbon atoms in the nucleus, or a carbon number in the nucleus 1 to (Representing a furyl group having 3 alkoxycarbonyl groups)) and reacting a compound having a acetylmethylene group with an ascochlorin represented by the following formula: The compound of the present invention is obtained by changing the CHO (aldehyde) group bonded to the atom to —CH = CH—COCH (2-acetylethyl) group.

Three

You can get things. The reagent having a acetylmethylene group is not particularly limited as long as it is a Wittig reagent generally having a acetylmethylene group, and examples thereof include commercially available (acetylmethylene) triphenylphosphorane. A specific example of the production of the compound of the present invention is shown in Example 1 and FIG.

[0034] The compound of the present invention may be in the form of a pharmacologically acceptable salt, ester or prodrug. The pharmacologically acceptable salt is not particularly limited, but for example, hydrochloride, nitrate, hydrobromide, ptoluenesulfonate, methanesulfonate, fumarate, succinate, lactate Etc. The compound of the present invention or a salt thereof may be in the form of a solvate such as a hydrate. Similarly, there is no particular limitation on the ester. Examples of prodrugs include those that can be hydrolyzed in vivo to ASK-9-ACT, such as ASK-9-me-ACT. Thus, ASK-9 me-ACT is itself a compound of the present invention, but is also a prodrug of ASK-9 ACT.

Since the compound of the present invention has a PPARγ activation activity, it can be used as a PPARγ activator for various purposes such as medical purposes and research purposes in vivo or in vitro.

[0036] The compound of the present invention can be administered to humans or animals by any route of administration. For example, it can be administered orally, intranasally, parenterally or topically, preferably in a suitable unit dosage form that can be administered in a precise volume at one time. The compound of the present invention may be administered in a pure form, but may be used as an appropriate pharmaceutical composition so that the dosage can be selected to be adjustable depending on the degree of the disease. It is preferable to formulate.

[0037] Examples of the dosage form of the pharmaceutical composition include tablets, granules, suppositories, pills, capsules, powders, and the like. Solid, semi-solid, lyophilized powder or liquid dosage forms such as agents, sustained release formulations, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments, gelling agents and the like. This composition contains a general usual pharmaceutical carrier or excipient suitable for such various desired dosage forms and the compound of the present invention, as well as other medicaments, binders, disintegrants, bulking agents, It may contain additives such as coating agents and absorption aids.

[0038] Specifically, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate, 2-calcium phosphate, gum arabic, polybule Examples of additives include pyrrolidone, surfactants, fat-soluble additives, bile acids, and phospholipids. Aliphatic synthesis It is particularly preferred to contain a surfactant or a polymer auxiliary soluble in organic solvents. Examples of these include gum arabic, sodium alginate, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, bentonite, sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl stearate 40, etc. .

[0039] In general, a pharmaceutically acceptable pharmaceutical composition contains about 1 to 99% (by weight) of the compound of the present invention, depending on the dosage form to be administered, and contains an appropriate pharmaceutical and Z or an additive. Contains 99 to 1%. Preferably, the pharmaceutical composition of the present invention contains about 5 to 75% of the compound of the present invention as an active ingredient, and the rest contains a suitable pharmaceutical excipient.

[0040] When the compound of the present invention is used as a pharmaceutical composition, the dosage is appropriately selected depending on various factors such as the type and symptoms of the disease, the body weight, age, sex, and administration route of the administration target. The effective daily dose to improve lifestyle-related diseases or their preliminary symptoms is 0.01 to: LOOmgZkg per kg body weight for adults, preferably 0.1 to LOmgZkg. is there.

Hereinafter, the present invention will be described in more detail based on examples.

Example

[0041] ¾ Example ί: Production of a compound of the present invention

A. Methylation and methyl esterification of AS-6 (synthesis of ASK-9-me)

4-Carboxymethylascoclodine (AS-6) (1.50 g, 3.24 mmol) was added to THF (˜70 To this, powdered anhydrous potassium carbonate (6 g) and methyl iodide (6 ml) were added, heated under reflux (reflux) for 3 hours, and cooled. After filtration, the glass filter was washed with THF, and the solvent was distilled off from the THF solution under reduced pressure using an evaporator.

The residue was purified by column chromatography on silica gel (carrier = silica gel (neutral, ˜80 g), eluent = ethyl acetate: hexane (1: 2)), dried and 1.59 g of 2-O— Methyl-4-O methoxycarbomethylmethylascochlorin (ASK-9-me) was obtained as a colorless viscous oil (yield: 99.6%).

NMR (CDC1, 300Mhz): 0.69 (3H, s), 0.78

3 to 0.82 (6H, dd), 1.53 to 1

68 (1H, m) l. 89 ~: L 95 (5H, m), 2. 32 ~ 2. 47 (3H, m), 2. 61 (3H, s), 3. 81 (3H, s) 3.82 (3H, s), 4.61 (2H, s), 5.36 to 5.46 (2H, dd), 5.88 (1 H, d, 16.2Hz), 10.40 ( 1H, s)

[0042] B. ASK-9-me acetylylmethyleneation (synthesis of ASK-9-me-ACT)

ASK—9—me (l. 59 g, 3.23 mmol), (acetylylmethylene) triphenyl-phosphorane (1.08 g, 3.40 mmol) to tonoleene (~ 30! ^), Calo-free, 120. In C, it was full of calo heat all day and night. The solvent was distilled off with an evaporator, and the residue was purified by column chromatography on silica gel (carrier = silica gel (neutral, ~ 80g), eluent = ethyl acetate: hexane (1: 2)) and dried. 1. 59 g of 1— (2 acetylethyl) — 2—O-methyl—4-—O-methoxymethyl 1 deformylmuscochlorin (ASK—9—me—ACT) as colorless viscous oil (Yield: 92.7%) ₀

NMR (CDC1, 300Mhz): 0.69 (3H, s), 0.78

3 to 0.83 (6H, dd), 1.57 to 1

70 (1H, m) l. 81 ~: L 96 (5H, m), 2. 36 ~ 2. 48 (8H, m), 3. 59 ~ 3.66 (5 H, bs), 3. 81 (3H, s), 4.61 (2H, s), 5.35 to 5.47 (2H, dd), 5.88 (1H, d, 16.5Hz), 6.67 (1H, d, 16 5Hz) 7. 61 (1H, d, 16.5Hz)

[0043] C. ASK 9 me— Hydrolysis of ACT (Synthesis of ASK— 9 ACT)

ASK-9-me-ACT (1.59g, 3.OOmmol), 20% potassium carbonate aqueous solution (6ml), methanol (~ 6 (^ 1) solution was heated to reflux for 1 hour. Acidified with 3N hydrochloric acid aqueous solution Extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate, filtered the desiccant, washed the filtrate well with ethyl acetate, and evaporated the solvent with an evaporator. Purified by ram chromatography (carrier = silica gel (neutral, ~ 80g), eluent = ethyl acetate: methanol (6: 1)) and dried to give 1.42g 1- (2 acetylethyl) — 2—O -Methyl 4-O carboxymethyl 1 formylmuscochlorin (ASK-9-ACT) was obtained as yellow crystals (yield: 91.2%).

NMR (CDC1, 300Mhz): 0.70 (3H, s), 0.80-0.85 (6H, dd), 1.57-1

Three

70 (1H, m) l. 93 to: L 96 (5H, m), 2.40 to 2.52 (8H, m), 3.58 (2H, d), 3.63 (3H, s) 4.61 (2H, s), 5.35-5.47 (2H, dd), 5.87 (1H, d, 16.5Hz), 6.69 (1H, d, 16.2Hz) 7. 63 (1H, d, 16. 2Hz)

An outline of these syntheses is shown in FIG.

Test, Example 1: PP AR v activation effect of ASK-9 ACT and pioglitazone ¾ and 谐包 ¾ 制 m.

A. For PPAR v activity W

U20S cells (1 X 10 ⁵ Zml) are cultured overnight in medium (DMEM supplemented with 5% FBS, 50 μg Zml kanamycin, 8 μg / ml Tymus); 1 μg total containing 10: 2: 1 Gal4 reporter plasmid pSV-GAL4-luc, Gal4-PPAR y fusion protein expression plasmid pCMV—Gal4-PPAR y, β-galactosidase expression plasmid ρ CMV-β-Gal DNA was introduced into the cells by the ribosome method (Fugene, Roch e Diagnosis). -After sputum culture, the cells are removed with trypsin solution (0.25% trypsin, 5 mM EDTA, in PBS), suspended in 2 ml of medium, and 0.1 ml is mixed with medium containing 0.1 ml of drug. The cells were cultured for 20 hours on a flat bottom microplate. As the drug, ί, PI GLITA: / NON ίMA ASK-9-ACT (0.001, 0.01, 0.1, 1.0, 10 or 100 M, respectively) was used.

After incubation, the medium was removed, cells were lysed in passive lysis buffer (Promega Corp. than available) 20 mu 1, luciferase activity and - a Garatatoshidaze activity, Haka疋³ r Tsu City of巿販using chemiluminescence ( " Bnght- (JIO Luciferase Assay ¾ystem ”, Promega Chito: ^; and“ Luminescent β-Galactosidase Reporter System ”, manufactured by Clontech) Dividing the frequency of luminescence by noluciferase by the frequency of luminescence by j8-galactosidase, The standardized relutive luciferase unit (RLU) is used, and the RLU in the drug group is the RLU in the control (no drug) group. The PPAR y activation effect was evaluated by the value divided by (stimulation index).

[0045] The results are shown in FIG. Data are shown as the average of three independent culture strength values. In the figure, 參 = pioglitazone, ○ = ASK—9—ACT. From these results, it was revealed that ASK-9-A CT is effective at a lower concentration than pioglitazone, and shows an action comparable to pioglitazone at a concentration of about 1Z10 of pioglitazone.

[0046] B. Growth inhibitory action

U20S cells (1 X loVmDO. 1 ml and 0.1 ml of medium containing the drug (same as above) were mixed and cultured for 20 hours in a flat bottom microplate. [ ³ H] thymidine was collected in 0.5 CiZwell, After further incubation for 4 hours, the medium was removed, the cells were peeled off with trypsin solution 50 μ1, trapped on a glass filter with a harvester, and the incorporated radioactivity was measured.Control (no drug added) group Cell proliferation was evaluated by the percentage of radioactivity taken up in the drug-added group when the radioactivity taken up was taken as 100%.

The results are shown in Figure 3. The data is the average of the values obtained for three independent culture forces. In the figure, 參 = pioglitazone, ○ = ASK—9—ACT. From these results, it was found that ASK-9-ACT has the same or slightly lower inhibitory effect on cell proliferation than pioglitazone.

[0047] Test Example 2: Comparison of the efficacy of ASK-9 ACT and pioglitazone

PPARγ activation and growth inhibitory effects were evaluated by the method shown in Test Example 1, and the efficacy of ASK-9—ACT and pioglitazone was compared. Compared to the control (no drug added) group, the concentration of the drug required to activate PPA 150-fold (ie, the stimulation index is 150) is the ED value, and [¾] thymidine incorporation is inhibited by 50% The concentration of the drug required to

150

I c , .

50 ic 50 ZED was used as the effect factor

150

The results are shown in Table 1.

[0048] [Table 1]

A S K— 9— Comparison of the efficacy of A C T and pioglitazone

Drug ED _I50 (jt M) IC ₅₀ ( _Efficacy factor

ASK-9-ACT 0. 185 1 3. 6 73.5 Pioglitazone 1. 28 32. 1 25. 1 [0049] From this result, it was found that ASK-9-ACT has a value of about three times higher than that of pioglitazone.

[0050] Test example 3: ASK-9 9 Comparison of ACT and pioglitazone against diabetes

Each group of three 7-week-old female dbZdb mice was given ip each of the drugs shown in Table 2 on the 0th, 2nd, and 4th days. On the 7th day, blood was collected from the orbital venous plexus, and blood glucose level and urine sugar level in plasma were measured using a commercially available measurement kit (Kainos). The drug was dissolved in DMSO, diluted 10-fold with 0.5% Tween 80ZPBS, and administered in an amount of 0.3 ml (dose shown in Table 2). The amount of water consumed was calculated by calculating the average value per animal per day for the 8th to 10th days. The frequency of urinary glucose exceeding lOOOmgZdl was considered as the onset of diabetes and the frequency of onset was determined. For comparison, the same measurement was performed on animals not receiving the drug (untreated group).

The results are shown in Table 2.

[0051] [Table 2]

A S K— 9— Comparison of A C T and pioglitazone against diabetes

* p <0. 05 (doub l e s i de t-test)

[0052] As can be seen from these results, ASK-9-ACT exhibited a blood glucose level-lowering action equivalent to or better than pioglitazone (PG) even in vivo.

Column 1

In the same manner as in Test Example 3, the effect of suppressing diabetes was compared using pioglitazone and AS-6 as drugs.

The results are shown in Table 3.

[0053] [Table 3] Table 3 Comparison of anti-diabetic effects of AS-6 and pioglitazone

* poku 0. Οΰ (doub l e s i de t one test)

[0054] While pioglitazone had a significant effect, AS-6 did not show a significant effect even when used at the highest concentration (25 mgZkg) that did not cause toxicity compared to the untreated group. .

[0055] Comparative Example 2

In the same manner as in Test Example 3, the effect of suppressing diabetes was compared using pioglitazone and MAC as drugs.

The results are shown in Table 4.

[0056] [Table 4]

Comparison of anti-diabetic effects of MAC and pioglitazone

* p <0. 05 (doub l e s i de t one test)

[0057] While pioglitazone had a significant effect, MAC did not show a significant effect when compared to the untreated group when used at the highest concentration that did not show toxicity (25 mgZkg).

[0058] This application is based on Japanese Patent Application No. 2005-339624 filed on November 25, 2005. The contents described in the specification and claims of Japanese Patent Application No. 2005-339624 are as follows: Are all encompassed in this application.

Claims

The scope of the claims

[1] General formula (I)

[Chemical 7]

[Wherein, R represents a hydrogen atom or C H (n represents an integer of 1 to 5);

1 n 2n + l 2

Atom, —C H (n represents an integer of 1 to 5), -C H COOR, (n is an integer of 1 to 5, R, n 2n + l n 2n

Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or COR "(R" is a pyridyl group, an amino group substituted with an alkyl group having 1 to 3 carbon atoms, or a phenoxyalkyl group having a halogen atom in the nucleus. Represents a furyl group having an alkoxy group having 1 to 3 carbon atoms in the nucleus, or a furyl group having an alkoxycarbonyl group having 1 to 3 carbon atoms in the nucleus). Compound, pharmacologically acceptable salt thereof, or prodrug thereof.

[2] The ascochlorin derivative compound according to claim 1 or a pharmacologically acceptable salt thereof, or a prodrug thereof, which is an R cation group in the general formula (I).

[3] The ascochlorine according to claim 1, wherein in the general formula (I), R is —CH 2 COOH.

twenty two

Derivative compounds, pharmacologically acceptable salts thereof, or prodrugs thereof.

[4] General formula (Π):

[Chemical 8]

1- (2 acetylethyl) -2-0-methyl-4-0 carboxymethyl 1-deformylascochlorin, a pharmacologically acceptable salt thereof, or a prodra thereof G.

[5] A PPAR y activator which also has the ascochlorin derivative compound according to any one of claims 1 to 4, a pharmacologically acceptable salt thereof, or a prodrug force thereof.

[6] A pharmaceutical comprising the ascochlorin derivative compound according to any one of claims 1 to 4, a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient Composition.

[7] The pharmaceutical composition according to claim 6, which is used for prevention or treatment of lifestyle-related diseases.

[8] The pharmaceutical composition according to claim 7, wherein the lifestyle-related disease is diabetes.

[9] General formula (III):

[Chemical 9]

1 n 2n + l 2

Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), or COR "(R" is a pyridyl group)

An amino group substituted with an alkyl group having 1 to 3 carbon atoms, a phenoxyalkyl group having a halogen atom in the nucleus, a furan group having an alkoxy group having 1 to 3 carbon atoms in the nucleus, or a carbon number in the nucleus 1 to And a derivative thereof, which comprises reacting a reagent having a acetylmethylmethylene group with a reagent having a acetylmethylene group. A process for producing the ascochlorin derivative compound according to 1.