KR20080072579A - Medicine for prevention and/or treatment of obesity - Google Patents

Abstract

A composition comprising an amino alkoxy non-benzyl is provided to be useful for preventing and treating obesity, thereby being used as a therapeutic medicine for diseases caused by the obesity such as diabetes mellitus, hypercholesterinemia, hypertriglyceridemia, hypo-HDL cholesterolemia, hypertension, angina pectoris, myocardial infarction or chronic artery occlusion. A composition for preventing and treating obesity comprises an amino alkoxy non-benzyl represented by a formula(1), a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof as an effective ingredient. In the formula(1), R^1 is H, halogen, C1-5 alkoxy, or C2-6 dialkylamino; R^2 is H, halogen or C1-5 alkoxy; R^3 is H, hydroxyl, O(CH2)nCOOH(wherein n is an integer from 1 to 5) or OCO(CH2)lCOOH(wherein l is an integer from 1 to 3); R^4 is N(R^5)(R^6)(wherein each R^5 and R^6 is independently H or C1-8 alkyl) or a group(1)(wherein A is C3-5 alkylene which is substituted by carboxyl); and m is an integer from 0 to 5.

Description

Obesity prevention and / or treatment {MEDICINE FOR PREVENTION AND / OR TREATMENT OF OBESITY}

The present invention relates to a prophylactic and / or therapeutic drug for obesity, comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyls, pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof.

Obesity has been the basis for the development of various diseases and has been elucidated by epidemiological investigations, rapid advances in local science and related brain science. It is also known that diabetes, hypertension, and hyperlipidemia, together with obesity, accumulate together in one individual, which is a very dangerous cause in the development of atherosclerotic disease. Such a condition is currently attracting attention from home and abroad as a metabolic syndrome (Non-Patent Document 1).

The Metabolic Syndrome Diagnosis Criteria Review Committee, which consists of eight members of the Japanese Society of Internal Medicine, published in April 2005, `` Definition and Diagnosis Criteria of Metabolic Syndrome, '' the accumulation of visceral fat plays a major role in the metabolic syndrome. It is in charge and it becomes an essential item in this diagnostic standard (nonpatent literature 2). This is caused by a multiplicity of risk factors such as hypertension, hypertriglyceridemia, hypo-HDL cholesterol, and hyperglycemia due to abnormal hyperactivity of bioactive substances secreted from visceral fat and lowering of adiponectin. This is because it is demonstrated by domestic and international clinical trials. From a preventive medical point of view, it is suggested to focus on treatments targeting visceral fat accumulation.

In addition, Japanese obesity differs from the West in terms of frequency and pathological significance. In Japan, the incidence of obesity with a body mass index (BMI) of more than 30 kg / m ² is less than 3% of the total population, and one digit less than in the West. On the other hand, the incidence of diabetes and hyperlipidemia due to obesity is comparable to that of Gumi, and does not match the number less than 3% already described. In view of these epidemiological facts, it is clear that in order to make obesity a medically correct treatment target, it is necessary to include refreshments of visceral fat accumulation (Non-Patent Document 1).

Aminoalkoxybibenzyl having a specific structure represented by safoglylate hydrochloride represented by the following formula (2) is 5HT ₂ It is reported that it exhibits high selectivity to the receptor and hardly affects blood pressure, and has little side effects of intoxication and is a drug showing high safety. It is known that hydrochloric acid safoglylate is effective for improving various microcirculation disorders based on thrombus formation and vasoconstriction in diseases such as cerebral circulation disorder, ischemic heart disease, peripheral circulation disorder and the like (Patent Document 1).

In recent years, it has been reported that safoglycerate hydrochloride improves insulin resistance in diabetic rats, lowers blood sugar levels, and reduces body weight (Non-Patent Document 3). However, it is not known that hydrochloride safoglylate is useful as a prophylactic and / or therapeutic drug for obesity.

[Patent Document 1] Japanese Patent Application Laid-Open No. 2-304022

[Non-Patent Document 1] Japanese Journal of Obesity Vol. 12, No.1 Extraordinary Paper, 2006: p1-3

[Non-Patent Document 2] Japanese Society of Internal Medicine, Vol. 94, No. 4, 2005: p188-203

[Non-Patent Document 3] J Cardiovasc Pharmacol 43 (2), 2004: p266-270

An object of the present invention is to provide a novel use of substances selected from the group consisting of aminoalkoxybibenzyls, pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the present inventors discovered that aminoalkoxy bibenzyl was useful as a preventive and / or therapeutic agent for obesity. The present invention has been completed based on the above facts.

That is, the summary of this invention is as follows.

[1] prevention and / or obesity comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyl represented by the following formula (1), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof Remedy.

<Formula 1>

(식 중, A는 카르복실기로 치환될 수도 있는 C₃ 내지 C₅의 알킬렌기를 나타냄)를 나타내고, m은 0 내지 5의 정수를 나타낸다.In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkoxy group of C ₁ to C ₅ or a dialkylamino group of C ₂ to C ₆ , and R ² represents a hydrogen atom, a halogen atom or an alkoxy of C ₁ to C ₅ represents a group, R ³ is a hydrogen atom, a hydroxyl _{group, -O- (CH 2) n -COOH} ( wherein, n represents an integer of 1 to 5) or _{-O-CO- (CH 2) l} - COOH (wherein l represents an integer of 1 to 3), and R ⁴ is —N (R ⁵ ) (R ⁶ ), wherein R ⁵ and R ⁶ are each independently a hydrogen atom or C ₁ to It represents an alkyl group of C _8), or

(Wherein A represents an alkylene group of C ₃ to C ₅ which may be substituted with a carboxyl group), and m represents an integer of 0 to 5.

[2] prevention and / or obesity comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyls represented by the following formula (2), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof Remedy.

<Formula 2>

[3] prevention and / or obesity comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyl represented by the following formula (3), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof Remedy.

[4] The prophylactic and / or therapeutic drug according to the above [2] or [3], which is in the form of a hydrochloride salt.

[5] The prophylactic and / or therapeutic drug according to any one of [1] to [4], wherein obesity is accompanied by an increase in visceral fat.

[6] The prophylactic and / or therapeutic drug according to any one of [1] to [5], wherein obesity involves metabolic syndrome.

[7] The prophylactic and / or therapeutic drug according to [6], wherein obesity is accompanied by visceral fat syndrome or metabolic syndrome.

[8] any one of the above [1] to [5], wherein obesity is accompanied by diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hypoHDLemia, hypertension, angina pectoris, myocardial infarction, or chronic arterial occlusion Prophylactic and / or therapeutic drug for obesity.

[9] The preventive and / or therapeutic drug for obesity according to [8], wherein the chronic arterial occlusion is obstructive atherosclerosis or burger disease.

[10] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (1), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof for the manufacture of drugs for the prevention and / or treatment of obesity The use of.

[11] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (2), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof for the manufacture of drugs for the prevention and / or treatment of obesity. The use of.

[12] Substances selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (3), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof for the manufacture of drugs for the prevention and / or treatment of obesity The use of.

[13] Use according to the above [11] or [12], which is in the form of a hydrochloride salt.

[14] The use according to any one of [10] to [13], wherein obesity is accompanied by an increase in visceral fat.

[15] The use according to any one of [10] to [14], wherein obesity involves metabolic syndrome.

[16] The use according to the above [15], wherein obesity involves visceral fat syndrome or metabolic syndrome.

[17] The method of any one of [10] to [14], wherein obesity is accompanied by diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hypoHDLemia, hypertension, angina pectoris, myocardial infarction, or chronic arterial obstruction. Use made with.

[18] The use according to the above [17], wherein the chronic atherosclerosis is obstructive atherosclerosis or a burger disease.

According to the present invention, a prophylactic and / or therapeutic drug for obesity can be provided. Moreover, according to this invention, the prophylactic and / or therapeutic drug of the disease accompanying obesity can be provided.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail. The prophylactic and / or therapeutic drug of the present invention comprises a substance selected from the group consisting of aminoalkoxybibenzyl represented by the formula (1), pharmaceutically acceptable salts thereof, esters thereof, and solvates thereof and hydrates thereof as an active ingredient. Include.

R ¹ is a hydrogen atom; Halogen atoms such as chlorine atom and fluorine atom; An alkoxy group of C ₁ to C ₅ such as a methoxy group, an ethoxy group, a butoxy group; Dimethylamino group, diethylamino group, represents a dialkylamino group of C ₂ to C ₆ such as methyl ethyl amino group. R ² is a hydrogen atom; Halogen atoms such as chlorine atom and fluorine atom; Methoxy, represents an alkoxy group of C ₁ to C _5, such as an ethoxy group, a butoxy group. R ³ is a hydrogen atom; Hydroxyl group; _{-O- (CH 2) 2 -COOH,} -O- (CH 2) 3 -O- (CH 2) n -COOH , such as -COOH (, wherein n is an integer of 1 to 5); _{-O-CO- (CH 2) 2} -COOH, -O-CO- (CH 2) 3 -O-CO- (CH 2) l -COOH ( wherein, l, such as -COOH is an integer from 1 to 3 Indicates a). R ⁴ represents an amino group or an amino group having 1 to 2 carbon atoms such as methylamino group, ethylamino group, butylamino group, hexylamino group, heptylamino group, dimethylamino group, diethylamino group, methylethylamino group, etc. Or a 4-6 membered polymethyleneamino group in which a carboxyl group may be substituted on a ring such as trimethyleneamino group, pentamethyleneamino group, or 3-carboxypentamethyleneamino group.

Among the compounds contained in the above Formula 1, some of the compounds preferably used in the present invention are shown in Tables 1 and 2 below.

Among these is an amino alkoxy group, ^{_{-OCH 2 C (R 3) H-}} (CH 2) m -R 4 is compound bonded to the 2-position of the phenyl group are preferred. R ¹ is preferably a hydrogen atom, an alkoxy group of C ₁ to C ₅ , or a dialkylamino group of C ₂ to C ₆ , R ² is preferably a hydrogen atom, and R ⁴ is one or more C ₁ to C ₈ It is preferable that it is the 4-6 membered polymethyleneamino group which has an amino group or trimethylene group or pentamethylene group which has an alkyl group of, and it is preferable that m is an integer of 0-2. Particularly preferred are compounds of No. 15 in which R ¹ is a methoxy group, R ² is a hydrogen atom, R ³ is a hydroxyl group, R ⁴ is a dimethylamino group, and m is 1 (hereinafter, referred to as (Also referred to as "M-1") and its succinic acid ester.

Examples of the acid that forms a pharmaceutically acceptable salt of the compound represented by Formula 1 include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, Organic acids such as maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid and methanesulfonic acid. In addition, solvates or hydrates of the compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or an ester thereof may also be used. Particularly preferred among them is (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propylhydrogensuccin represented by the following general formula (4). Hydrochloride of a nate (hereinafter, in this specification, this substance is also called "hydrochloride safoglylate").

The aminoalkoxy bibenzyl represented by the above formula (1), pharmaceutically acceptable salts thereof and esters thereof are well known and can be easily synthesized by the method described in Japanese Patent Application Laid-open No. 58-32847 or a method similar thereto. Can be. In addition, hydrochloric acid safoglylate represented by the above formula (4) is commercially available as "Anflag (registered trademark)" from Tanabe Mitsubishi Seyaku Kabukishi Co., and in the present invention, it is also possible to use commercially available "Anflag" as it is. Do.

In the present invention, obesity means that the body mass index (BMI) is 25 kg / m ² or more and is determined to be visceral fat type obesity. Here, BMI is calculated by BMI = weight (kg) ÷ height (m) ÷ height (m). In addition, visceral fat is considered to be more accurate by X-ray computed tomography (CT scan), and visceral fat type obesity is determined when visceral fat area in the cross section of the navel is 100 cm ² or more. However, the method of using a CT scan can be replaced by measuring waist diameter because of the time and cost of going to the hospital. Visceral fat area 100 cm ² if the waist circumference is more than 85 cm for men and more than 90 cm for women It seems to correspond to the above (refer to Japanese obesity journal Vol.12 temporary extra care issue, 2006 "obesity treatment guidelines 2006").

To reduce visceral fat in the present invention means to reduce visceral fat area or to reduce the diameter around the waist.

The prophylactic and / or therapeutic drug of obesity in the present invention is useful as a medicine for the prophylaxis and / or treatment of a disease involving obesity. As such a disease, metabolic syndrome (visceral fat syndrome, metabolic syndrome, etc.) is mentioned, for example. In addition, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hypoHDLemia, hypertension, angina (preferably chronic stable angina and unstable angina, etc.), myocardial infarction and chronic arterial obstruction (preferably obstructive atherosclerosis and burger disease) Although it is mentioned, it is not limited to these.

The administration method in the case of using the preventive and / or therapeutic drug of obesity of the present invention as a medicine can be appropriately selected by those skilled in the art. For example, any administration route of parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or oral administration can be selected. The dosage can be appropriately determined according to the conditions of the patient's age, health condition, weight, etc., if there is a medicine to be administered at the same time, the condition such as the type or frequency of administration, or the nature of the desired effect. Generally, the daily dose of the active ingredient is 0.5 to 50 mg / kg body weight, usually 1 to 30 mg / kg body weight, and may be administered once or more per day.

When using the preventive and / or therapeutic drug of obesity of this invention as a medicine, it is preferable to manufacture and administer the pharmaceutical composition containing the said active ingredient and the additive for 1 type, or 2 or more types of preparations. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, solutions, elixirs, and the like. Pharmaceutical compositions suitable for parenteral administration include, for example, sterilized liquid forms such as liquids or suspending agents. The pharmaceutical composition of can be illustrated.

The kind of the additive for preparation used in the preparation of the pharmaceutical composition is not particularly limited, and it is possible to select an appropriate preparation for the preparation according to various forms of the pharmaceutical composition. The additive for preparation may be either solid or liquid, and for example, a solid carrier or a liquid carrier may be used. As an example of the solid carrier, conventional gelatinous capsules can be used. In addition, for example, the active ingredient may be tableted together with one or two or more additives for the preparation, or without using the additive for the preparation, or may be prepared and packaged as a powder. These capsules, tablets, powders may generally comprise from 5 to 95% by weight, preferably from 5 to 90% by weight of the active ingredient with respect to the total weight of the formulation, the dosage unit form is from 5 to 500 mg, preferably Preferably 25 to 250 mg of active ingredient. As the liquid carrier, water or oils of animal or plant origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil or the like is used. In general, glycols such as physiological saline solution, dextrol or similar sucrose solution, ethylene glycol, propylene glycol and polyethylene glycol are preferable as liquid carriers, and in particular, in the case of injection solution using physiological saline solution, usually 0.5 to 20%, preferably Preferably it can be prepared to contain 1 to 10% by weight of the active ingredient.

<Example>

Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In addition, what was synthesize | combined according to the description of Unexamined-Japanese-Patent No. 58-32847 was used for the saponacrylate hydrochloride used below.

<Example 1>

Eight-week-old C57BL / 6 mice were divided into high-fat diet (HFD) and normal diet (NC) groups and reared for 4 weeks. Thereafter, each group was divided into four groups, and sapoglychloride hydrochloride was administered orally for 4 weeks, 0, 3, 10, 30 mg / kg / day. After 4 weeks, body weight, mesenteric fat weight / body weight and mesenteric fat weight / body weight and subcutaneous fat weight / body weight were measured. Each result is shown in FIGS. In the high-fat diet group administered with 10 and 30 mg / kg / day hydrochloric acid safoglylate, a significant decrease in mesenteric fat percentage was observed.

From these results, it was found that hydrochloride safograte is effective for the prevention and / or treatment of obesity.

According to the present invention, a novel drug for preventing and / or treating obesity can be provided. Moreover, according to this invention, the prophylactic and / or therapeutic drug of the disease resulting from obesity can be provided.

1 is a diagram showing the body weight of each group after 4 weeks.

2 is a diagram showing the mesenteric fat weight (Body weight) of each group after 4 weeks.

3 is a diagram showing the subcutaneous fat weight (Body weight) of each group after 4 weeks.

Claims (10)

A prophylactic and / or therapeutic drug for obesity, comprising as an active ingredient an aminoalkoxybibenzyl represented by the following formula (1), a pharmaceutically acceptable salt thereof, an ester thereof, and a solvate thereof and a hydrate thereof. <Formula 1>

In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkoxy group of C ₁ to C ₅ or a dialkylamino group of C ₂ to C ₆ , and R ² represents a hydrogen atom, a halogen atom or an alkoxy group of C ₁ to C ₅ R ³ represents a hydrogen atom, a hydroxyl group, -O- (CH ₂ ) _n -COOH (wherein n represents an integer of 1 to 5) or -O-CO- (CH ₂ ) ₁ -COOH ( In the formula, l represents an integer of 1 to 3, and R ⁴ represents -N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom or C ₁ to C ₈ Represents an alkyl group of) or

(Wherein A represents an alkylene group of C ₃ to C ₅ which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. A prophylactic and / or therapeutic drug for obesity, comprising as an active ingredient an aminoalkoxybibenzyl represented by the following formula (2), a pharmaceutically acceptable salt thereof, an ester thereof, and a solvate thereof and a hydrate thereof. <Formula 2>

A prophylactic and / or therapeutic drug for obesity, comprising as an active ingredient an aminoalkoxybibenzyl represented by the following formula (3), a pharmaceutically acceptable salt thereof, an ester thereof, and a solvate thereof and a hydrate thereof. <Formula 3>

The prophylactic and / or therapeutic drug for obesity according to claim 2, which is in the form of hydrochloride. The prophylactic and / or therapeutic agent for obesity according to claim 3, which is in the form of hydrochloride. The obesity prevention and / or treatment drug according to any one of claims 1 to 5, wherein obesity is accompanied by an increase in visceral fat. The obesity prevention and / or treatment drug according to any one of claims 1 to 5, wherein obesity involves metabolic syndrome. The obesity prevention and / or treatment drug according to any one of claims 1 to 5, wherein obesity involves visceral fat syndrome or metabolic syndrome. The obesity according to any one of claims 1 to 5, characterized in that obesity is accompanied by diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hypoHDLemia, hypertension, angina pectoris, myocardial infarction, or chronic arterial obstruction. Prophylactic and / or therapeutic drugs. The obesity prophylactic and / or therapeutic drug according to claim 9, wherein the chronic arterial occlusion is obstructive atherosclerosis or Burger's disease.

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