JPH0812573A - Free fatty acid reducing agent - Google Patents

Abstract

PURPOSE:To obtain the subject new medicine, containing a specific pyrrole derivative as an active ingredient, excellent in reducing activities of free fatty acids in portal or peripheral bloods, useful in prevention and treatment of diseases caused by high FFA blood such as obesity, diabetes and insulin-resistant disease. CONSTITUTION:This free fatty acid reducing agent comprises a pyrrole derivative of the formula (R<1> is a 10-16C alkyl or a 10-16C alkenyl; R<2> is H, phenyl or a 1-4C alkyl) or its pharmaceutically permissible salt as an active ingredient. Furthermore, it is preferable that R<1> and CO2R<2> in the formula are not substituted at adjacent positions, and the compounds of which R<1> is selected from dodecyl, tridecyl tetradecyl, etc., and R2 is selected from H, methyl and ethyl, are preferable. One example is 4-dodecylpyrrole-2-carboxylic acid. The medicine is preferably administated orally, and the daily dose thereof is preferably 1mg to 1g, more preferably 1-100mg administrated dividedly 2-3 times.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a free fatty acid lowering agent, and more particularly to a drug for improving portal vein and peripheral hyperfree fatty acidemia.

[0002]

2. Description of the Related Art Obesity is a state in which the ratio of body fat is increased, and generally + 20% or more of standard body weight is defined as obesity. The causes of obesity are considered to be complicatedly involved in overeating, lack of exercise, heredity, and dietary patterns. Vague reported that upper body obesity is more likely to cause diabetes, hypertension and hyperlipidemia than lower body obesity (Am. J. Cli.
n. Nutr. 4:20 1956). Then Kiss
ebah et al. have reported that those with a high waist / hip ratio (WHR) are prone to these metabolic disorders (Diabetes / Metab. Rev. 5: 831).
989). Although WHR is used as a parameter for upper body obesity and lower body obesity, it has been reported to have a strong correlation with intraperitoneal fat. (Am. J. Cli
n. Nuty. 48: 1351 1988). For example, C
The results using T-scan also show that visceral fat-type obesity, which has a high ratio of abdominal fat to subcutaneous abdominal fat (V / S ratio), is likely to be associated with abnormal glucose metabolism and hyperlipidemia. (M
etabolism 36:57 1987). Thus, it is considered that the abdominal fat accumulation has a great influence on the development of insulin resistance, diabetes and arteriosclerosis.

On the other hand, as a mechanism by which fat accumulation in the abdominal cavity causes insulin resistance, hyperglycemia and hyperlipidemia,
Attention has been focused on the involvement of high free fatty acid (hereinafter, "free fatty acid" is abbreviated as "FFA") blood disease (Chronic
Disease 4: 547 1991). In visceral fat obesity, a large amount of FFA flows into the liver via the portal vein by various mechanisms. When FFA is excessively supplied to the liver, the synthesis and secretion of ultra-light density lipoprotein in the liver are promoted to cause hyperlipidemia. Also, gluconeogenesis in the liver is increased, and a hyperglycemic state appears. Furthermore, in visceral fat type obesity, peripheral F
FA is also elevated, causing insulin resistance. Then, in the insulin overproduction state thus generated, fat synthesis is increased and obesity is promoted.

Therefore, a drug that suppresses the elevation of FFA in the portal vein and the peripheral region is expected to have anti-obesity action, anti-diabetic action, insulin resistance-improving action, etc. Not found.

[0005]

Means for Solving the Problems The present inventor has conducted repeated searches for the purpose of providing a drug capable of solving the above problems, and as a result, a specific pyrrole derivative has a portal blood FFA lowering effect, Furthermore, the inventors have for the first time found that the compound also has a peripheral blood FFA lowering action, and have completed the present invention.

That is, the gist of the present invention resides in a free fatty acid lowering agent containing a pyrrole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0007]

Embedded image

(In the formula, R ¹ represents a C ₁₀ -C ₁₆ alkyl group or a C ₁₀ -C ₁₆ alkenyl group, and R ² represents a hydrogen atom, a phenyl group or a C ₁ -C ₄ alkyl group. Hereinafter, the present invention will be described in detail. The general formula (I)
All of the pyrrole derivatives represented by are known compounds described in European Patent Publication No. 347902, and are known to have an effect of potently lowering blood triglyceride and cholesterol at the same time. Therefore, the compound of formula (I) can be easily synthesized according to the method described in the publication.

In the present invention, among the pyrrole derivatives represented by the general formula (I), compounds in which R ¹ and CO ₂ R ² are not adjacently substituted on the pyrrole ring are preferred, and further substitution of R ¹ More preferred is a compound in which the group is selected from dodecyl group, tridecyl group, tetradecyl group, 1-tridecenyl group, 1-tetradecenyl group and 1-pentadecenyl group, and the substituent of R ² is selected from hydrogen atom, methyl group and ethyl group. .

The pyrrole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is administered to humans as an FFA lowering agent, preferably by oral administration. As the dosage form for oral administration, tablets, granules, powders, capsules, syrups, and other forms are used, and these compounds have the usual additives such as glucose, lactose, corn starch, and mannitol. It can be manufactured by adding a shaping agent, a binder such as hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC), a disintegrating agent such as starch and gelatin powder, and a lubricant such as talc and magnesium stearate. In the case of oral administration, the dose of the compound is 1 mg to 1 day for an adult.
It is 1 g, more preferably 1 mg to 100 mg, which can be administered at once or in 2 to 3 divided doses.

[0011]

The FFA lowering agent of the present invention lowers FFA concentrations in portal blood and peripheral blood. Therefore, the FFA-lowering agent of the present invention has a preventive or therapeutic effect on diseases such as obesity, diabetes, insulin resistance (diabetes, hypertension, reduction of tyrosine kinase activity, etc.) and the like, which are considered to be caused by hyper-FFA. Is expected to have.

[0012]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the invention is not limited thereto unless it exceeds the gist. <Synthesis Example> 4-Dodecylpyrrole-2-carboxylic acid (hereinafter simply referred to as "the present compound") was synthesized according to the method described in European Patent Publication 347902. m. p. : 150-151 ° C IR (KBr) cm ^-1 : 3390, 2960, 292
5,2860,1685,1495,1440,128
0, 1130, 1120 ¹ H NMR (DMSO-d ₆ , 250 MHz) δ: 0.84 (3 H, t, J = 6.5 Hz), 1.22
(20H, broad, s), 1.40-1.52 (2
H, m), 2.35 (2H, t, J = 7.4Hz),
6.53 (1H, s), 6.71 (1H, s).

Example 1 Male Wistar 6 Rats
The compound or cholestyramine was administered by diet at the age of week. As a powder feed for rats, Oriental Yeast Co. (MF) was used. The dose of this compound is 10, 30, 100 mg /
Equivalent to kg, the dose of cholestyramine was 2% in the diet. After 10 days, the rats were sacrificed under pentobarbital anesthesia, and the FFA concentrations in portal blood and peripheral blood were measured by an enzymatic method (Daiichi Pure Chemicals; Enzabai 2). Three rats in each group were used in the experiment. The results are shown in FIGS. 1 and 2. In the compound-administered group, a decrease in FFA in portal blood and peripheral blood was observed in a dose-dependent manner.

Example 2 Male Wistar 6 Rats
The compound or bezafibrate was orally administered by gavage at the age of week. As a rat feed, a solid feed (MF) manufactured by Oriental Yeast Co. was used. The dose of this compound is 3, 10, 30
Equivalent to mg / kg, the dose of bezafibrate is 30 mg
/ Kg. The drug was prepared in an aqueous solution containing 0.05% Tween80. Five hours after the final drug administration 5 days later, the rats were sacrificed under pentobarbital anesthesia, and the FFA concentrations in portal blood and peripheral blood were measured by an enzyme method (Daiichi Pure Chemicals; Enzabai 2). The rats of each group were used in the experiment, 8 in the control group and 6 in the drug administration group.
The results are shown in FIGS. 3 and 4. In the compound-administered group, a decrease in FFA in portal blood and peripheral blood was observed in a dose-dependent manner.

Example 3 Wistar Male Rat 6
The compound or bezafibrate was orally administered by gavage at the age of week. Rat feed is 2% cholesterol, 0.2%
Cholic acid-containing solid yeast (MF) manufactured by Oriental Yeast Co. was used. The dose of this compound is 3,10,30 mg / kg
Correspondingly, the dose of bezafibrate was set to 30 mg / kg. The drug was prepared in an aqueous solution containing 0.05% Tween80. Five hours after the final drug administration 5 days later, the rats were sacrificed under pentobarbital anesthesia, and the FFA concentrations in portal blood and peripheral blood were measured by an enzyme method (Daiichi Pure Chemicals; Enzabai 2). The rats of each group were used in the experiment, 8 in the control group and 6 in the drug administration group. The results are shown in FIGS. 5 and 6. In the compound-administered group, a decrease in FFA in portal blood and peripheral blood was observed in a dose-dependent manner.

[Brief description of drawings]

FIG. 1 is a drawing showing FFA concentration in portal blood after drug treatment in Example 1 of the present invention.

FIG. 2 is a drawing showing FFA concentration in peripheral blood after drug treatment in Example 1 of the present invention.

FIG. 3 is a drawing showing FFA concentration in portal blood after drug treatment in Example 2 of the present invention.

FIG. 4 is a drawing showing FFA concentration in peripheral blood after drug treatment in Example 2 of the present invention.

FIG. 5 is a drawing showing FFA concentration in portal blood after drug treatment in Example 3 of the present invention.

FIG. 6 is a view showing FFA concentration in peripheral blood after drug treatment in Example 3 of the present invention.

Claims (7)

[Claims] 1. A free fatty acid lowering agent comprising a pyrrole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Embedded image (In the formula, R ¹ is a C ₁₀ -C ₁₆ alkyl group or C ₁₀ -C
₁₆ represents an alkenyl group, R ² represents a hydrogen atom, a phenyl group or a C ₁ -C ₄ alkyl group. ) 2. In a pyrrole derivative, R ¹ and CO ₂
The R ² and the R ² are not adjacently substituted with each other.
The free fatty acid lowering agent described. 3. R ¹ represents a dodecyl group, a tridecyl group, a tetradecyl group, a 1-tridecenyl group, a 1-tetradecenyl group or a 1-pentadecenyl group, and R ² represents a hydrogen atom, a methyl group or an ethyl group. The free fatty acid lowering agent according to claim 1 or 2. 4. The free fatty acid reducing agent according to claim 1, wherein the pyrrole derivative is 4-dodecylpyrrole-2-carboxylic acid. 5. The agent for lowering free fatty acid according to claim 1, which is a preventive or therapeutic agent for obesity. 6. The agent for lowering free fatty acid according to claim 1, which is a preventive or therapeutic agent for diabetes. 7. The free fatty acid lowering agent according to any one of claims 1 to 4, which is an insulin sensitizer.