WO2008038712A1 - Therapeutic/prophylactic agent for metabolic syndrome - Google Patents

Abstract

Disclosed is a novel therapeutic/prophylactic agent for metabolic syndrome having little adverse side-effects. Specifically disclosed is a therapeutic/prophylactic agent for metabolic syndrome, which comprises geranyl-genanyl-acetone, a salt thereof, or a hydrate or solvate of geranyl-genanyl-acetone or the salt thereof as an active ingredient.

Description

 Specification

 Treatment and prevention of metabolic syndrome

 Technical field

 [0001] The present invention relates to a therapeutic / preventive agent for metabolic syndrome.

 Background art

 [0002] Lifestyle-related diseases include obesity, diabetes, hypertension, and hyperlipidemia. These lifestyle-related diseases are often caused by obesity, which is not an independent disease. Often duplicates. A state in which such lifestyle-related diseases are combined is sometimes referred to as metabolic syndrome. Recently, it has been found that the causes of these lifestyle-related diseases include abnormal sugar metabolism and abnormal lipid metabolism. The provisional diagnostic criteria for metabolic syndrome in Japan is that it has visceral fat type obesity, and in addition to this, it is said that it has two or more of hyperglycemia, hypertension and hyperlipidemia! .

 [0003] With rapid changes in lifestyles in recent years, cases of arteriosclerosis due to metabolic syndrome are increasing. The first cause of death in Japan is malignant neoplasm, the second is heart disease, and the third is cerebrovascular disease. Of these, heart disease and cerebrovascular disease can be regarded as arteriosclerotic diseases. Therefore, the occurrence of arteriosclerosis caused by metabolic syndrome has a great impact on mortality, and prevention and treatment of metabolic syndrome is extremely important. However, there are currently no drugs that comprehensively target various metabolic syndromes of metabolic syndrome.

 [0004] On the other hand, geranylgeranylacetone (GGA) (teprenone; trade name Selbex) is known as a therapeutic agent for gastritis and gastric ulcer (Patent Document 1 and Patent Document 2), and is a highly safe anti-ulcer drug in Japan. Developed and used clinically. There is a report that teprenone contributes to reduction of myocardial ischemia / reperfusion injury and ischemic area of cerebral infarction (Patent Document 3), but there is no known effect on improving insulin resistance or body weight suppression in metabolic syndrome. .

 [0005] Patent Document 1: Japanese Patent Laid-Open No. 53-145922

Patent Document 2: Japanese Patent Application Laid-Open No. 62-10013 Patent Document 3: Japanese Unexamined Patent Publication No. 2003-267863

 Disclosure of the invention

 Problems to be solved by the invention

 [0006] An object of the present invention is to provide a novel therapeutic / prophylactic agent for metabolic syndrome that has few side effects!

 Means for solving the problem

 [0007] The present inventors have intensively studied to solve the above-mentioned problems, and the effect of teprenone (geranyl geranylacetone) on the metabolic syndrome, body weight suppression action, blood sugar lowering action, insulin resistance improving action, and blood adiponectin The effect of increasing the amount was examined. As a result, 200 mg / kg of teprenone was orally administered to mice that induced diabetes with insulin resistance due to high-fat diet loading. 2 days of daily administration suppressed weight gain, improved insulin resistance, and glucose tolerance An improvement in performance was observed. The blood concentration of adiponectin, which improves insulin resistance, also increased. From these results, it was found that teprenone is effective as a therapeutic agent for metabolic syndrome. The present invention has been completed based on these findings.

 [0008] That is, according to the present invention, there is provided a therapeutic / preventive agent for metabolic syndrome containing geranylgeranylacetone, a salt thereof, a hydrate or a solvate thereof as an active ingredient.

 Preferably, the therapeutic / prophylactic agent for metabolic syndrome of the present invention is used for suppressing weight gain, reducing blood glucose, improving insulin resistance, and / or increasing blood adiponectin level.

 [0009] According to another aspect of the present invention, there is provided a weight gain inhibitor containing geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient.

 According to still another aspect of the present invention, there is provided a hypoglycemic agent comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient.

[0010] According to still another aspect of the present invention, there is provided an insulin resistance ameliorating agent containing geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient. According to still another aspect of the present invention, there is provided an agent for increasing the amount of adiponectin in blood containing geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient.

 [0011] According to still another aspect of the present invention, treatment of metabolic syndrome comprising the step of administering an effective amount of geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof to a mammal including a human. · A method of preventing, a method of suppressing weight gain, a method of reducing blood sugar, a method of improving insulin resistance, or a method of increasing blood adiponectin level are provided.

 [0012] According to still another aspect of the present invention, there is provided a therapeutic / preventive agent for metabolic syndrome, a weight gain inhibitor, a hypoglycemic agent, an insulin resistance ameliorating agent, or a blood adiponectin amount increasing agent. , Geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof is provided.

 The invention's effect

 [0013] Metabolic syndrome is attracting attention as a cause of arteriosclerotic diseases, and the presence of insulin resistance due to the accumulation of visceral fat is regarded as important. According to the present invention, a novel therapeutic agent for metabolic syndrome can be provided. Since the high safety of geranylgeranylacetone used as an effective component in the present invention has already been recognized, the present invention can provide a safe therapeutic agent for metabolic syndrome with few side effects. .

 BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be specifically described.

As shown in the following examples, it was found that teprenone (geranylgeranylacetone) has an insulin resistance improving action, a body weight gain inhibiting action, and a serum adiponectin level raising action. From these results, it was shown that teprenone (geranylgeranylacetone) can be an insulin resistance ameliorating agent / weight gain inhibitor. In recent years, metabolic syndrome has been attracting attention as a cause of arteriosclerotic diseases, and the presence of insulin resistance due to the accumulation of visceral fat is regarded as important. In view of its pharmacological effects, teprenone (geranyl geranylacetone) is clinically applied as an early intervention for metabolic syndrome Is possible.

 [0015] The therapeutic agent for metabolic syndrome according to the present invention contains geranylgeranylacetone as an active ingredient. Geranyl geranyl acetone used as an active ingredient in the medicament of the present invention is represented by the following formula (I), and the compound name is 6, 10, 14, 18-tetramethyl 1, 5, 9, 13, 17-nona. Decatetraen 1 2-one compound. Geranylgeranylacetone is generally called teprenone and is also abbreviated as GGA.

 Formula (I): H (-CH C (CH) = CH-CH-) CH C (= 0) CH

 2 3 2 4 2 3

 [0016] Geranylgeranylacetone has various isomers. Any isomer can be used in the present invention. For example, the 5, 9, and 13 positions may be either E-form or Z-form, and one kind of isomer may be used, or a mixture of two kinds of isomers may be used. Preferably, it is possible to use 5E-form, 5Z-form in which the 9th-position and the 13th-position are E-form, or a mixture thereof in any mixing ratio. More preferably, the (5E, 9E, 13E) isomer and the (5Z, 9E, 13E) isomer are a 3: 2 mixture.

 [0017] Geranylgeranylacetone is widely used as a therapeutic agent for gastric ulcer and gastritis, and a pharmaceutical grade is readily available. Moreover, the synthesis method of geranylgeranylacetone is well-known, for example, it can synthesize | combine according to the method disclosed by Unexamined-Japanese-Patent No. 53-145922 or Unexamined-Japanese-Patent No. 6-1992073.

[0018] In the present invention, geranylgeranylacetone may be used as a salt. The salt of geranylgeranylacetone is not particularly limited as long as it is a pharmacologically acceptable salt. The salt of geranylgeranylacetone is preferably a hydrohalide salt (eg hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salt (eg sulfate, nitrate) , Perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (eg, acetate, maleate, tartrate, fumarate, kenate, etc.), organic sulfonates (For example, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartate, glutamate, etc.), quaternary amine salts, Examples thereof include alkali metal salts (for example, sodium salt and potassium salt), alkaline earth metal salts (magnesium salt, calcium salt, etc.) and the like. The salt of geranyl geranylacetone is more preferably a hydrochloride, sulfate, methanesulfonate, or vinegar Acid salt.

 [0019] The geranylgeranylacetone used in the present invention may be any of an anhydride, a hydrate, and a solvate.

 [0020] The preparation form of the therapeutic agent for metabolic syndrome of the present invention is not particularly limited, and an appropriate form most suitable for the purpose of treatment or prevention is selected from the preparation forms for oral administration or parenteral administration. Is possible. Examples of the dosage form suitable for oral administration include tablets, capsules, powders, granules, fine granules, syrups, solutions, emulsions, suspensions, and tuples. Suitable dosage forms for administration include, for example, transdermal forms such as injections (subcutaneous injection, intramuscular injection, intravenous injection, etc.), drops, inhalants, sprays, suppositories, gels or ointments. A force S that can include an absorbent, a transmucosal absorbent, a patch or a transdermal absorbent in the form of a tape, etc., but is not limited thereto.

 [0021] Liquid preparations suitable for oral administration, such as solutions, emulsions or syrups, include water, sorbits, sugars such as fructose, darikols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, It can be manufactured using oils such as bean oil, preservatives such as p-hydroxybenzoates, and flavors such as strawberry flavor and peppermint. For the production of solid preparations such as capsules, tablets, powders or granules, excipients such as lactose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc are used. Agents, binders such as polyvinyl alcohol, hydroxypropyl cellulose, and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin can be used.

[0022] An injectable or infusion preparation suitable for parenteral administration preferably contains the above-mentioned substance as an active ingredient dissolved or suspended in a sterile aqueous medium isotonic with the blood of the recipient. . For example, in the case of an injection, a solution can be prepared using a salt solution or an aqueous medium composed of a mixture of salt water and another solution. Formulations for enteral administration can be prepared, for example, using carriers such as strength cacao butter, hydrogenated fats, or hydrogenated carboxylic acids, and are provided as suppositories. In addition, in the manufacture of sprays, the above-mentioned substances that are active ingredients can be dispersed as fine particles, without irritating the recipient's oral cavity and airway mucosa, A carrier that facilitates absorption of the active ingredient can be used. Specific examples of the carrier include lactose and glycerin. Depending on the substance that is the active ingredient and the nature of the carrier used, formulations in the form of aerosols or dry powders can be prepared. These preparations for parenteral administration include one selected from glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Two or more auxiliary components can also be added.

 [0023] The dose and frequency of administration of the therapeutic agent for metabolic syndrome of the present invention are appropriately determined depending on various factors such as the type and severity of the disease, the dosage form, conditions such as the age and weight of the patient, and the presence or absence of complications. The force S that can be set, generally 200 mg / kg per day as the active ingredient dosage is preferred. Because it is metabolized in the liver and kidneys, it is desirable to reduce the dose in elderly people! The maximum dose is considered to be 500 mg / kg!

 [0024] The therapeutic agent for metabolic syndrome of the present invention can be administered to any mammal including humans, and is preferably administered to humans.

 [0025] The therapeutic agent for metabolic syndrome of the present invention can be used to suppress weight gain, decrease blood glucose, improve insulin resistance, and / or increase blood adiponectin level. According to another aspect of the present invention, a weight gain inhibitor, a hypoglycemic agent, an insulin resistance improver, comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient, In addition, a blood adiponectin amount increasing agent is provided.

 [0026] The therapeutic agent for metabolic syndrome of the present invention can be used as a weight gain inhibitor. Since obesity is closely related to the metabolic syndrome, the metabolic syndrome can be treated and / or prevented by suppressing weight gain using the therapeutic agent for metabolic syndrome of the present invention.

[0027] The therapeutic agent for metabolic syndrome of the present invention can also be used as a hypoglycemic agent. For example, diabetes is a disease based on abnormal glucose metabolism characterized by hyperglycemia, and diabetes can be treated by lowering the blood glucose level of diabetic patients using the metabolic syndrome therapeutic agent of the present invention, Diabetes can also be prevented by controlling blood glucose levels in patients suspected of having diabetes. Furthermore, the metabolism of the present invention The therapeutic agent for cough syndrome can be widely used not only for the prevention and / or treatment of diabetes but also for the reduction of blood glucose. Hyperglycemia may be clinically shown by various diseases other than diabetes, such as organic disorders of the winning tissue, chronic liver disease, endocrine disease, increased brain pressure, obesity, overeating, alcohol overdose, stomach Hyperglycemia can occur due to various factors such as dietary hyperglycemia after resection, febrile illness, carbon monoxide poisoning, and drug-induced blood glucose elevation. The therapeutic agent for metabolic syndrome of the present invention may be used to reduce these hyperglycemia.

 [0028] The therapeutic / preventive agent for metabolic syndrome of the present invention can also be used as an agent for improving insulin resistance. A pathological condition with increased insulin resistance, so-called insulin resistance syndrome, is considered to be a fundamental cause of lifestyle-related diseases (for example, diabetes, hypertension or obesity), and in the treatment or prevention of the above-mentioned lifestyle-related diseases, Improving insulin resistance plays an important role. In other words, by improving the insulin resistance using the metabolic syndrome therapeutic / preventive agent of the present invention, the lifestyle-related diseases caused by the insulin resistance syndrome can be treated or prevented.

[0029] The therapeutic / preventive agent for metabolic syndrome of the present invention can also be used as a calorie increasing agent for blood adiponectin level. Adiponectin is a protein produced and extracted from adipocytes, and is closely involved in sugar and lipid metabolism. In patients with cardiovascular disease, diabetes or obesity, blood adiponectin levels are generally decreased. Therefore, a decrease in blood adiponectin concentration is closely related to lifestyle-related diseases such as hypertension, diabetes or obesity, and is considered to contribute to these lifestyle-related diseases. Therefore, it is possible to treat or prevent the above lifestyle-related diseases caused by hypoadiponectinemia by increasing the blood adiponectin level using the therapeutic / preventive agent for metabolic syndrome of the present invention. Adiponectin is also associated with insulin resistance. In hypoadiponectinemia, insulin resistance is known to increase, and in animal models, it is known to improve adiponectin administration power S, insulin resistance life span, and improve glucose metabolism. Therefore, diabetes or diabetic complications can be treated or prevented by increasing the amount of adiponectin in the blood using the therapeutic / preventive agent for metabolic syndrome of the present invention. [0030] The present invention will be specifically described by the following examples, but the present invention is not limited to the examples.

 Example

 [0031] (1) Experimental method

 Ten 11-week-old C57BL / 6 mice were prepared and divided into a control group (5 mice) and a teprenone group (5 mice). The control group and the teprenone group were loaded with a high fat diet for 1 week, and their body weight and blood glucose level were measured. At 12 weeks of age (1 week after high-fat diet), 0.008% tocopherol (dissolved in Phosphate Buffered Saline) was added to the control group, and 200 mg / kg of teprenone dissolved in 0.008% tocopherol was added to the teprenone group. The dose was orally administered once daily. One week later (13 weeks of age), body weight and blood glucose level were measured, and an insulin tolerance test (0.75 U / kg) was performed. In the insulin tolerance test, insulin (0.75 U / kg) was administered intraperitoneally, and blood glucose levels were measured from 0 to 120 minutes. Three days later, a glucose tolerance test (1 g / kg) was conducted. In the glucose tolerance test, glucose (1 g / kg) was administered intraperitoneally and blood glucose levels were measured from 0 to 120 minutes. Leptin was measured using a mouse leptin kit (Morinaga), and adiponectin was measured using a mouse / rat adiponectin ELISA kit (Otsuka Pharmaceutical).

 [0032] (2) Results

 Fig. 1 shows the measurement results of body weight, Fig. 2 shows the change in blood glucose level in the glucose tolerance test, Fig. 3 shows the change in blood glucose level in the insulin tolerance test, and Fig. 4 shows the measurement results of levtin and adiponectin. .

[0033] (i) In the teprenone administration group, body weight increase due to high-fat diet load was suppressed. That is, the control group was + 1.18 g, whereas the teprenone group was 0.39 g (Fig. 1).

 (ii) The effect of lowering fasting blood glucose levels was observed in the teprenone administration group!

 The control group was 118 mg / dl, while the teprenone group was 96 mg / dl. (See Figure 3: Blood glucose level at 0 minutes)

 (iii) In the teprenone administration group, in the glucose tolerance test, an increase in blood glucose was observed. (Figure 2).

(iv) In the teprenone administration group, the hypoglycemic effect was enhanced in the insulin tolerance test, and improvement in insulin resistance was confirmed. (Figure 3). (v) Increased serum adiponectin levels were observed in the teprenone administration group (Fig. 4). Industrial applicability

[0034] Since the high safety of geranylgeranylacetone used as an active ingredient in the present invention has already been recognized, the present invention provides a safe therapeutic agent for metabolic syndrome with few side effects. it can.

 Brief Description of Drawings

 [0035] FIG. 1 shows the results of measuring changes in body weight. GGA seemed to suppress weight gain.

 FIG. 2 shows changes in blood glucose level in a glucose tolerance test. In the glucose tolerance test, glucose tolerance improved!

 FIG. 3 shows changes in blood glucose level in an insulin tolerance test. In the insulin tolerance test, it seemed that insulin resistance improved! /.

 FIG. 4 shows the measurement results of leptin and adiponectin. Like MET, the leptin level was not different, but the adiponectin level increased!

Claims

The scope of the claims  [1] A treatment for preventing metabolic syndrome, comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient.  [2] The therapeutic / preventive agent for metabolic syndrome according to claim 1, which is used for suppressing weight gain, reducing blood glucose, improving insulin resistance, and / or increasing blood adiponectin level.  [3] A weight gain inhibitor comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient. [4] A hypoglycemic agent comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient. [5] An agent for improving insulin resistance comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient. [6] An agent for increasing the amount of adiponectin in blood, comprising geranylgeranylacetone, a salt thereof, or a hydrate or solvate thereof as an active ingredient.