JPH1129473A - Medicine for preventing and/or treating hepar adiposum - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine having effect to lower lipid (triglyceride) content in liver and capable of preventing and/or treating hepar adiposum by including a pyrrolecarboxylic acid-derivative as an active ingredient. SOLUTION: This medicine contains a pyrrolecarboxylic acid-derivative shown by the formula [R<1> is H, a 5-25C alkyl or alkenyl; R<2> is H, phenyl, or a 1-10C (substituted) alkyl; R<3> is H, a 5-25C alkyl or alkenyl] (e.g. 4- tridecylpyrrole-2-carboxylic acid), a salt thereof, hydrates of these, or solvates of these, as an active ingredient. The medicine can be prepared for oral and non-oral administration. In the case of oral administration for adult, it is preferable to administered in a dose of 0.01-1000 mg in one or more portions per day. Such administration allows prevention/treatment of diseases such as hepar adiposum, liver fibrosis, and cirrhosis, all of which are considered to be caused by accumulation of lipid in the liver.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a preventive and / or therapeutic agent for fatty liver, and more particularly to a preventive and / or therapeutic agent for fatty liver containing a pyrrolecarboxylic acid derivative having a specific chemical structure as an active ingredient. .

[0002]

BACKGROUND OF THE INVENTION Fatty liver is a state in which triglycerides have accumulated in hepatocytes beyond the physiological range. There are various causes of fatty liver such as obesity, diabetes, and chronic alcohol intake, and the mechanism of its onset is not uniform. However, hepatic steatosis involves triglyceride synthesis and VLDL (ultra low density lipoprotein) synthesis in the liver.
It is thought to develop when damage occurs during any of the secretory processes. As the onset mechanism of fatty liver, specifically,
Promotion of fatty acid synthesis in the liver, increased fatty acid mobilization from peripheral adipose tissue to the liver, decreased fatty acid oxidizing ability in the liver, decreased lipoprotein synthesis and secretion in the liver, and the like are considered.

[0003] The frequency of fatty liver is estimated to be around 15% when the results of the dissection, the results of the dissection at the time of the traffic accident death and the results of the diagnosis at the medical checkup are combined.
The number is increasing due to recent overnutrition, increase in alcohol consumption, progress in diagnostic imaging, particularly in ultrasound, workplace medical examination, and the spread of liver function tests using a health checkup. Conventionally, the diagnosis of fatty liver was made based on histological biopsy tissue findings or morphological laparoscopic observations. Recently, however, such as abdominal ultrasound (echo) examination and abdominal CT examination, etc. The noninvasive method has made it possible to easily and accurately diagnose fatty liver. Abdominal ultrasonography, in particular, has a short examination time, and the presence of fatty liver can be diagnosed with a mass examination or a health checkup with a probability of 80% or more.

[0004] In general, fatty liver has been regarded as a benign disease having a good prognosis.
cys) may be broken and progress to fatty cirrhosis, and sinusoida disorders of the central vein (sinusoida)
It has been pointed out that impairment of local hepatic blood flow due to l block) may lead to progression to fatty cirrhosis. The frequency of transition to cirrhosis is not always high, at most a few percent, but its prevalence is a serious problem. Recently, animal experiments have reported that hepatic steatosis had already caused an increase in fibrous components, and that obese people without alcohol history had a high rate of histology that could not be distinguished from alcoholic hepatitis or alcoholic cirrhosis Some reports, such as reports, emphasize the role of pre cirrhosis. Therefore, recently, it has been emphasized that not only the necessity of life guidance but also appropriate treatment is given to fatty liver. However, lipid metabolism-improving drugs such as multivitamin drugs, pantethine, polyenphosphatidylcholine, and vitamin E, which are used as pharmacotherapy, are only adjuvant treatments, and no suitable drug has been found. Therefore, a drug that suppresses lipid accumulation in the liver is expected to have an effect of improving fatty liver and is considered to be a very promising drug.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted repeated searches for the purpose of providing a drug capable of solving the above-mentioned problems, and as a result, a pyrrole carboxylic acid derivative having a specific chemical structure was found to be a lipid in liver. It has been found for the first time that it has an effect of lowering the (triglyceride) content and has an effect of improving fatty liver, and has completed the present invention. That is,
The gist of the present invention is the following general formula (I)

[0006]

Embedded image

(Wherein R ¹ is a hydrogen atom, having 5 to 25 carbon atoms)
R ² represents a hydrogen atom, a phenyl group, or an alkyl group having 1 to 10 carbon atoms which may have a substituent, R ³ represents a hydrogen atom,
Represents an alkyl group or an alkenyl group having 5 to 25 carbon atoms. A) a pyrrolecarboxylic acid derivative represented by the formula:
The present invention relates to a preventive and / or therapeutic agent for fatty liver containing a hydrate or a solvate thereof as an active ingredient.

According to a preferred embodiment of the present invention, in the above general formula (I), the substituent in the alkyl group of R ² is a halogen atom, a hydroxyl group, an amino group, and a group having 1 carbon atom.
-5 alkylamino groups, dialkylamino groups having 2-6 carbon atoms, carbamoyl groups, alkylcarbonylamino groups having 1-5 carbon atoms, alkylthio groups having 1-5 carbon atoms, mercapto groups, 1 carbon atoms to five preventing the fatty liver alkylcarbonyl group or aminocarbonyl group, and / or therapeutic agents; R ¹ is 10 carbon atoms
To 16 of the aforementioned fatty liver is an alkyl or alkenyl group of prophylactic and / or therapeutic agents; R ² is a hydrogen atom, the phenyl group or have a substituent group having 1 to 4 carbon atoms which may alkyl group A preventive and / or therapeutic agent for fatty liver; the above preventive and / or therapeutic agent for fatty liver, wherein R ³ is a hydrogen atom. As a further preferred embodiment, there is provided a preventive and / or therapeutic agent for fatty liver, comprising 4-tridecylpyrrole-2-carboxylic acid, a salt thereof, a hydrate or a solvate thereof as an active ingredient.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. In the above general formula (I), the alkyl group represented by R ¹ and R ³ is a linear, branched or cyclic alkyl group having 5 to 25 carbon atoms, preferably 10 to 25 carbon atoms.
There are 16 alkyl groups. Further, as the alkenyl group, an alkenyl group having 5 to 25 carbon atoms having one or more vinyl groups in the molecule, preferably having 10 to 10 carbon atoms.
Sixteen alkenyl groups are included.

In the formula, as the alkyl group represented by R ² , an alkyl group having 1 to 10 carbon atoms, in particular, an alkyl group having 1 to 10 carbon atoms
Four alkyl groups are included. Examples of the substituent which may be substituted on such an alkyl group include a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a C1-5
Alkylamino group, dialkylamino group having 2 to 6 carbon atoms, alkylcarbonylamino group having 1 to 5 carbon atoms, alkylthio group having 1 to 5 carbon atoms, mercapto group,
Examples thereof include an alkylcarbonyloxy group having 1 to 5 carbon atoms and an aminocarbonyloxy group.

R ¹ is preferably an alkyl group or alkenyl group having 10 to 16 carbon atoms, and R ² is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a substituent. A group is preferable, and R ³ is preferably a hydrogen atom. In the present invention, a compound in which the substituent R ¹ and —CO ₂ R ² are substituted at positions that are not adjacent to each other on a pyrrole ring is preferable from the viewpoint of activity. Specifically, a compound in which —CO ₂ R ² (where R ² is preferably a hydrogen atom) is substituted at the 3-position of the pyrrole ring and R ¹ is substituted at the 5-position, or a pyrrole ring A compound in which —CO ₂ R ² (where R ² is preferably a hydrogen atom) is substituted at the 2-position and R ¹ is substituted at the 4- or 5-position is preferred. Further, R ¹ , R ² or R ³
The compound in which any one of is a hydrogen atom is preferred.

Most preferably, R ¹ is CH
₃ (CH ₂ ) ₁₂ , R ² and R ^{3 each} represent a hydrogen atom, and R ¹ and —CO _{2 at} the 2- and 4-positions of the pyrrole ring
Compounds in which R ² is substituted, that is, 4-tridecylpyrrole-2-carboxylic acid, can be mentioned. Hereinafter, this compound may be referred to as MKC-121 as a particularly preferred active ingredient of the present invention. The compound included in the general formula (I) is itself a compound of Japanese Patent Publication No. 6-1.
It is a known compound disclosed in Japanese Patent Publication No. 04658 and Japanese Patent Publication No. 6-37390, can be easily synthesized by the method described in the publication, and is a compound readily available to those skilled in the art. Hereinafter, compounds suitable as active ingredients of the medicament of the present invention will be exemplified, but the active ingredients of the medicament of the present invention are not limited to the following compounds.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

[0016]

[Table 4]

[0017]

[Table 5]

[0018]

[Table 6]

[0019]

[Table 7]

[0020]

[Table 8]

[0021]

[Table 9]

[0022]

[Table 10]

The pharmaceutically acceptable salts of the above pyrrolecarboxylic acid derivatives include, for example, salts of inorganic metals such as sodium, potassium, calcium and magnesium; ammonium or triethylammonium salts; cyclohexylammonium salts; Organic amine salts. In the above formula (I), when R ² contains an amino group, an inorganic acid salt such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid salt such as maleic acid, succinic acid or citric acid is exemplified. be able to.

Further, in addition to the salts and free-form compounds as described above, any hydrate or solvate thereof may be used as an active ingredient of the medicament of the present invention. Tokuhei 6-10
No. 4658 and Japanese Patent Publication No. 6-37390 describe that a certain pyrrole carboxylic acid has a lowering effect on triglyceride and cholesterol in blood, which is a pharmaceutical component of the present invention. There is no description or suggestion that the compound reduces the triglyceride content in the liver.

The above compound, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof which is an active ingredient of the medicament of the present invention may be administered to a patient as a medicament itself. In general, it is preferable to prepare and administer a pharmaceutical composition containing one or more of these active ingredients to a patient. As such a pharmaceutical composition, tablets,
Capsules, fine granules, powders, pills, troches, sublinguals,
Or, preparations for oral administration such as liquid preparations and preparations for parenteral administration such as injections, suppositories, ointments and patches can be exemplified.

Tablets or capsules for oral administration are usually presented as unit dosages, containing binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. It can be produced by adding such ordinary carriers for pharmaceuticals. Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrrolidone, a starch derivative, or Disintegrants such as sodium starch glycolate; lubricants such as magnesium stearate;
It may be manufactured using a wetting agent such as sodium lauryl sulfate.

Liquid preparations for oral administration are provided, for example, as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as dry preparations which can be redissolved with water or a suitable vehicle before use. . Such solutions include conventional additives such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, precipitation inhibitors such as aluminum stearate gel or hydrogenated edible fat, lecithin, sorbitan monooleate, and arabic. Emulsifiers such as gums, almond oil, rectified coconut oil, non-aqueous media (including edible oils) such as oily esters (e.g. esters of glycerin), propylene glycol, ethyl alcohol, methyl p-hydroxybenzoate Preservatives such as esters, ethyl esters, or propyl esters, or sorbic acid, and if desired, conventional flavoring or coloring agents can be included.

Preparations for oral administration can be produced by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive blending operation. Formulations for parenteral administration are generally provided as liquid unit dosage formulations containing the compound, the active ingredient, and a sterile vehicle. Solutions for parenteral administration are usually prepared by dissolving the compound in a vehicle, sterile-filtering and then filling suitable vials or ampoules and sealing. To enhance stability, the composition may be filled into vials after freezing and the water removed under vacuum. Parenteral suspensions are prepared substantially in the same manner as for parenteral solutions, but can be suitably prepared by suspending the active ingredient in a vehicle and sterilizing the suspension with ethylene oxide or the like. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution. The dose of the compound as an active ingredient may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the patient's symptoms, weight, age, sex, etc. In addition, about 0.01 mg to 1,000 mg can be administered orally per day for an adult. Such dosages can be reduced to
It is desirable to administer in several divided doses.

[0029]

The present invention will be described in more detail with reference to the following Examples, which do not limit the scope of the present invention. Synthesis Example 1 4-tridecylpyrrole-2-carboxylic acid
Synthesis of (MKC-121) 102.9 g (0.48 mol) of tridecanoic acid was dissolved in 480 ml of methylene chloride, and 52.6 of thionyl chloride was added thereto.
ml (0.72 mol) and 0.2 ml of N, N-dimethylformamide were added and left overnight. This is concentrated under reduced pressure,
The remaining oil is 106.6 g of anhydrous aluminum chloride.
(0.8 mol) in 400 ml of methylene chloride. To this pyrrole-2-carboxylic acid methyl ester,
200 ml of 50.05 g (0.4 mol) methylene chloride
Was added dropwise at 3-9 ° C over about 40 minutes. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. Add methylene chloride 100
0 ml was added to dissolve all the crystals, separated, and the organic layer was washed with water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was treated with 400 ml of ethyl acetate and 400 ml of hexane.
Recrystallization from the resulting mixture gave 107.2 g of methyl 4-tridecanoylpyrrole-2-carboxylate as almost white crystals. Yield 83% m. p. : 92-93 ° C

IR (KBr) cm ^-1 : 3270, 2920, 2855, 1690, 166
0,1565,1455,1385,1290,1215 ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.6Hz), 1.15-1.38 (18H, m), 1.65-1.75
(2H, m), 2.75 (2H, t, J = 7.5Hz), 3.89 (3H, s), 7.28-7.30 (1H,
m), 7.53-7.55 (1H, m), 9.52 (1H, broad s)

18.29 g of methyl 4-tridecanoylpyrrole-2-carboxylate obtained here (5.
6.9 mmol) was dissolved in 140 ml of acetic acid, and 14.0 ml (167 mmol) of 1,2-ethanediol and 14 ml of boron trifluoride / diethyl ether complex were added thereto.
And the mixture was stirred overnight under water cooling. This was concentrated under reduced pressure, 100 ml of water was added to the residue, and 200 ml of ethyl acetate (100 m
1 × 2). The extracts were combined, washed with a 5% aqueous sodium hydroxide solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain methyl 4-tridecanoylpyrrole-2-carboxylate dithioethylene ketal. The mother liquor is subjected to silica gel column chromatography (eluent: ethyl acetate / hexane / = 1).
/ 6) to obtain 4-tridecanoylpyrrole-2-carboxylic acid methyl ester dithioethylene ketal remaining in the recrystallization solvent. 15.44 g total yield, 68 yield
%, M. p. : 77-78 ° C

IR (KBr) cm ^-1 : 3360,2940,2860,1705,144
0,1385,1265,1210,1120 ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.6 Hz), 1.20-1.40 (20H, m), 2.22-2.28
(2H, m), 3.25-3.41 (4H, m), 3.84 (3H, s), 6.92 (1H, s), 7.05-
7.07 (1H, m), 9.08 (1H, broad s)

Further, 15.06 g (37.9 mmol) of 4-tridecanoylpyrrole-2-carboxylic acid methyl ester dithioethylene ketal thus obtained was added to water,
Then, 150 ml of Raney nickel (activated type, manufactured by Aldrich) washed with ethanol, ethanol 75
The mixture was added to 0 ml of the mixed solution, and heated under reflux for 30 minutes. After cooling to about 30 ° C., Raney nickel was removed by filtration, and the filtrate was concentrated under reduced pressure. 10. recrystallization of the residue from ethanol
70 g of 4-tridecylpyrrole-2-carboxylic acid methyl ester were obtained as white crystals. Yield 91.8
%, M. p. : 80-82 ° C

IR (KBr) cm ^-1 : 3340,2920,2850,1690,144
5,1390,1265,1205,1130 ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.6 Hz), 1.20-1.40 (20H, m), 1.49-1.62
(2H, m), 2.45 (2H, t, J = 7.6Hz), 3.83 (3H, s), 6.72-6.75 (2H,
m), 8.88 (1H, broad s)

Then, 10.01 g of 4-tridecylpyrrole-2-carboxylic acid methyl ester thus obtained was obtained.
(32.6 mmol) in 200 ml of ethanol and 80 in water
ml and 5.5 g (131 mmol) of 95% sodium hydroxide were added, and the mixture was heated under reflux for 1 hour. Water 100 after cooling
The mixture was acidified with hydrochloric acid, and ethyl ether 400 m
l, ethyl acetate 100 ml and tetrahydrofuran 3
The mixture was extracted with 00 ml of the mixed solvent. The aqueous layer was extracted again with 100 ml of ethyl acetate, and the extracts were combined, washed with saturated saline and dried over anhydrous magnesium sulfate. This was concentrated under reduced pressure, and then recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain 7.55 g of 4-tridecylpyrrole-2-carboxylic acid as white crystals. m. p. : 150-15
1 ℃

IR (KBr) cm ^-1 : 3390,2960,2925,2860,168
5,1495,1440,1280,1130,1120 ¹ H NMR (DMSO-d ₆ ) δ: 0.84 (3H, t, J = 6.5 Hz), 1.22 (20H, broad s), 1.40-1.52
(2H, m), 2.35 (2H, t, J = 7.4Hz), 6.53 (1H, s), 6.71 (1H, s)

Example 1 Liver of fructose-loaded rat
Effect on triglyceride content in Wistar male rats at 7 weeks of age
KC-121 was suspended in an aqueous solution containing 0.05% Tween 80 and adjusted, and a predetermined amount was orally administered once a day for 5 days. The fructose-containing diet for rats is fructose 56%, casein 22%, vitamins and minerals 22
% Bait was prepared by Oriental Yeast. MKC-1
The patient was fasted for 2 days after the start of administration of No. 21 and had free access to a fructose diet from the third day. Dissection was performed 2 hours after the administration on the final 5th day, and the liver was collected. The lipid in the liver was extracted, and the triglyceride concentration in the liver was measured using a neutral fat measuring reagent (New Clintech TG Jatron) to determine the amount of triglyceride per unit liver weight. The rats in each group were subjected to the experiment in 6 cases in the control group and 6 cases in each of the MKC-121 groups. The results are shown in FIG. In the MKC-121 group, a decrease in triglyceride content in the liver was observed in a dose-dependent manner.

Example 2 Cholesterol-Loaded Hamster
Of Trichocerin on Liver Triglyceride Content At the age of 6 weeks of age, the MKC-121 obtained above was suspended in an aqueous solution containing 0.05% Tween 80 and adjusted. Gavage was administered for one day. Hamster feed is 0.5% cholic acid, 1
Using a solid feed (MF) manufactured by Oriental Yeast Co., Ltd. containing 5% cholesterol, a cholesterol diet was freely taken for 5 days simultaneously with the administration of MKC-121. Five days later, 2.5 hours after the last drug administration, the liver was dissected and the liver was collected. The lipid in the liver was extracted, and the triglyceride concentration in the liver was measured using a neutral fat measuring reagent (New Clintech TG Jatron) to determine the amount of triglyceride per unit liver weight.
The hamsters in each group consisted of 7 control groups and MKC-12.
5 to 6 cases of each group were subjected to the experiment. The results are shown in FIG. M
In the KC-121 group, a decrease in triglyceride content in the liver was observed in a dose-dependent manner.

Example 3 Rabbit Liver Containing Triglyceride
Effect on Amount A New Zealand white male rabbit was challenged with a cholesterol diet for 11 weeks. After breeding on a normal diet for one week,
From there, MKC-121 was administered as a diet for 12 weeks. Rabbit feed is 0.5% cholesterol or MKC-
Oriental Yeast Inc. containing solid feed (RC
4) was used. Twenty-four weeks after the start of the test, the liver was dissected and the lipid in the liver was extracted. The triglyceride concentration in the liver was measured with a neutral fat measuring reagent (New Clintech TG Jatron), and the amount of triglyceride per unit liver weight was determined.
The rabbits in each group were subjected to 9 cases in each group. The results are shown in FIG. In the MKC-121 group, a decrease in triglyceride content in the liver was observed in a dose-dependent manner. The dose shown in FIG.
It is the dose converted from feeding.

[0040]

The preventive and / or therapeutic agent for fatty liver according to the present invention lowers the lipid (triglyceride) content in the liver, so that fatty liver, hepatic fibrosis, It is expected to have a preventive or therapeutic effect on diseases such as cirrhosis.

[Brief description of the drawings]

FIG. 1 shows the effect of MKC-121 on triglyceride content in the liver of fructose-loaded rats.

FIG. 2 is a graph showing the effect of MKC-121 on the liver triglyceride content of cholesterol-loaded hamsters.

FIG. 3 shows the effect of MKC-121 on triglyceride content in the liver of rabbits after cholesterol loading.

Claims (6)

[Claims] 1. A compound represented by the following general formula (I) (Wherein, R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group having 5 to 25 carbon atoms, and R ² represents a hydrogen atom, a phenyl group, or an optionally substituted 1 to 10 carbon atoms.
R ³ represents a hydrogen atom, having 5 to 2 carbon atoms.
Represents 5 alkyl groups or alkenyl groups. ) A prophylactic and / or therapeutic agent for fatty liver, comprising a pyrrolecarboxylic acid derivative, a salt thereof, a hydrate or a solvate thereof as an active ingredient. 2. The substituent in the alkyl group of R ² is a halogen atom, a hydroxyl group, an amino group, an alkylamino group having 1 to 5 carbon atoms, a dialkylamino group having 2 to 6 carbon atoms, a carbamoyl group, and a carbon atom. The prevention of fatty liver according to claim 1, which is an alkylcarbonylamino group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a mercapto group, an alkylcarbonyloxy group having 1 to 5 carbon atoms or an aminocarbonyloxy group. And / or therapeutic agents. 3. The preventive and / or therapeutic agent for fatty liver according to claim 1, wherein R ¹ is an alkyl or alkenyl group having 10 to 16 carbon atoms. 4. The prevention and / or prevention of fatty liver according to claim 1, wherein R ² is a hydrogen atom, a phenyl group or an alkyl group having 1 to 4 carbon atoms which may have a substituent. Therapeutic agent. 5. The preventive and / or therapeutic agent for fatty liver according to claim 1, wherein R ³ is a hydrogen atom. 6. A preventive and / or therapeutic agent for fatty liver containing 4-tridecylpyrrole-2-carboxylic acid, a salt thereof, a hydrate or a solvate thereof as an active ingredient.