KR101072866B1 - Composition for preventing or treating dyslipidemia related diseases comprising 1-(5-isoquinolinesulfonyl)-2-methylpiperazine - Google Patents

Abstract

The present invention relates to a composition for the prevention or treatment of dyslipidemia-related diseases comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, more specifically 1- (5-isoquinolinesulfonyl) A composition for the prevention or treatment of dyslipidemia-related diseases caused by MTP, comprising 2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivatives thereof, and a method for treating dyslipidemia-related diseases using the same It is about. Since the composition has an MTP inhibitory activity, it may be usefully used for the development of a medicament or food for the prevention or treatment of dyslipidemia-related diseases caused by MTP.

1- (5-isoquinolinesulfonyl) -2-methylpiperazine, arteriosclerosis, dyslipidemia, MTP

Description

Composition for preventing or treating dyslipidemia related diseases comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine }

The present invention relates to a composition for the prevention or treatment of dyslipidemia-related diseases comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, more specifically 1- (5-isoquinolinesulfonyl) A composition for the prevention or treatment of dyslipidemia-related diseases caused by MTP, comprising 2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivatives thereof, and a method for treating dyslipidemia-related diseases using the same It is about.

Recently, the incidence of cardiovascular diseases such as hyperlipidemia and arteriosclerosis is increasing due to changes in the health environment such as westernization of lifestyle. Cardiovascular disease is known to occur more often than lipid metabolism, and dyslipidemia caused by abnormal lipid lipoprotein metabolism, which determines blood cholesterol or triglyceride levels, is a major cause of cardiovascular disease. It is pointed out as the cause.

Dyslipidemia is a blood vessel caused by an increase in total cholesterol, low-density lipoprotein-cholesterol (LDL), triglyceride, or high-density lipoprotein (HDL-Cholesterol), such as hyperlipidemia and atherosclerosis. Commonly referred to as a disease, cholesterol is deposited on the inner wall of the artery, the inner surface of the arteries is narrowed, which means symptoms such as blood circulation disorder in the blood supply to various organs and extremities.

Dyslipidemia also causes various diseases due to changes in lipid concentrations in the blood. In particular, the occurrence of atherosclerosis is due to the ideal differentiation of arterial wall cells and has been reported to have a high correlation with blood cholesterol levels [Casteli, WP et. al., JAMA., 256, 2835-2845 (1986). Atherosclerosis is an artery that thickens and hardens, loses its elasticity and weakens, and is one of the major diseases that occur with aging. Atherosclerosis is more likely to occur in the cerebral artery or coronary arteries. In the case of cerebral arteriosclerosis, headache, dizziness, and mental disorders are indicated, and cerebral atherosclerosis is caused. Coronary atherosclerosis causes pain and arrhythmia in the heart, causing angina and myocardial infarction. It is known to become. In addition, this causes high blood pressure, heart disease, cerebral hemorrhage, and diseases caused by arteriosclerosis are emerging as the leading cause of death in modern society, especially among men in their 50s and 60s.

Higher blood cholesterol levels are more likely to cause cardiovascular disease. To reduce blood cholesterol levels, you can suppress the absorption of cholesterol by dieting to reduce cholesterol and fat intake or by inhibiting the action of proteins related to lipid metabolism. have.

The lipoproteins in the blood involved in atherosclerosis are low density lipoproteins (LDLs), which are very low density lipoproteins (TG-rich VLDL) in the liver and are released into the blood by MTPs (microsomal triglyceride transfer protein). It is secreted and degraded and produced by blood lipoprotein lipase (Shelness et al., 1999; Rustaeus et al., 1999; Gordon and Jamil, 2000). Only TG (triglyceride, triglyceride) in TG-rich VLDL secreted from the liver by the promotion of MTP is converted into lipoprotein-rich LDL by lipoproteinase. Promoting MTP activity is associated with increased blood LDL levels and increased risk of atherosclerosis (Teng et al., 1986; Venkatesan et al., 1993). Ultimately, to suppress the risk of atherosclerosis, the activity of MTP, which secretes TG-rich VLDL into the blood, must be suppressed from the liver (Davis et al., 1990; Bonnardel and Davis, 1995; McLeod et al., 1996; Taghibiglou et al., 2000; Cho et al., 2006; Shelness et al., 1999; Rustaeus et al., 1999; Gordon and Jamil, 2000).

Therefore, drugs that inhibit the activity of MTP can be used as a treatment for dyslipidemia including atherosclerosis, and several related compounds have been reported. Current inhibitors of MTP include BMS-200150 from Bristol-Myers-Squibb, CP-1044 from Pfizer, 4'-bromo-3'-methylmetaqualone from Glaxowelcome, and BAY13-9952 (implitapide) from Bayer. .

However, these drugs are very expensive, it is not known how the mechanism works in the cell, there is a problem that does not have a high safety because it may cause other side effects.

Accordingly, the present inventors, while searching for various compounds to develop a novel dyslipidemia-related disease treatment, found that the 1- (5-isoquinolinesulfonyl) -2-methylpiperazine compound inhibits MTP activity. The present invention was completed by revealing that the compound is effective in treating diseases related to dyslipidemia including atherosclerosis and hyperlipidemia.

An object of the present invention is to be induced by the microsomal triglyceride transfer protein (MTP) comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof as an active ingredient Dyslipidemia related diseases, for example, arteriosclerosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, obesity and diabetes, to provide a composition for preventing or treating diseases related to dyslipidemia.

It is another object of the present invention to provide an MTP inhibitor comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof as an active ingredient.

Another object of the present invention relates to dyslipidemia induced by MTP, which comprises administering 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof. It is to provide a method for treating a disease.

Another object of the present invention is to prevent dyslipidemia related diseases caused by MTP, including 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivatives thereof, or It is to provide health functional food for improvement.

In one embodiment, the present invention provides an abnormal lipid induced by MTP comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof as an active ingredient. The present invention relates to a composition for preventing or treating a blood disease.

In another aspect, the present invention relates to an MTP inhibitor comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof as an active ingredient.

Hereinafter, the configuration of the present invention in more detail.

1- (5-isoquinolinesulfonyl) -2-methylpiperazine (1- (5-isoquinolinesulfonyl) -2-methylpiperazine) used in the present invention is a compound of formula C ₁₄ H ₁₇ N ₃ O ₂ S, molecular weight 291.37 As, it may have a structural formula of formula (1).

The 1- (5-isoquinolinesulfonyl) -2-methylpiperazine Compound of the present invention may be directly synthesized through a known synthesis method, or may be commercially available.

In addition, the compounds of the present invention can be used in the form of pharmaceutically acceptable salts or derivatives of the compounds, so long as the compounds do not lose their effective MTP inhibitory activity, and the salts or derivatives of the compounds are conventional in the art. It can be prepared by the method.

In the present invention, "pharmaceutically acceptable salts" of the compounds means salts derived from pharmacologically or physiologically acceptable inorganic acids, organic acids and bases Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, Perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzene Sulfonic acids and the like, and salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, alkaline earth metals such as magnesium, ammonium, and the like.

In the present invention, "MTP (microsomal triglyceride transfer protein)" refers to triglyceride (TG), triglyceride (TG), apo (lipo) lipoprotein (Associated lipoproteins) in the reticulum of hepatocytes and enterocytes to transport it into the blood Refers to the carrier protein. In addition, "MTP inhibition" means that the action of inhibiting MTP (microsomal triglyceride transfer protein) protein activity, that is, the catalytic reaction is inhibited by acting on the protein to interfere with the normal mechanism of the protein.

The 1- (5-isoquinolinesulfonyl) -2-methylpiperazine Compound of the present invention is characterized by having such MTP inhibitory activity.

As mentioned above, since the LDL concentration in the blood is increased due to the promotion of the activity of MTP, which causes dyslipidemia, the compound of the present invention inhibits the MTP activity to prevent or treat dyslipidemia related diseases caused by MTP. It can be usefully used.

In the present invention, "dyslipidemia-related disease caused by MTP" means a disease caused by an increase in LDL concentration in the blood by MTP, arteriosclerosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, Hyperglycemia, obesity, diabetes, and the like.

In 'prevention or treatment' of the present invention, 'prevention' means by MTP by administering a composition comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof. Any action that inhibits or delays the onset of any disease associated with dyslipidemia that is induced. 'Treatment' refers to the improvement or benefit of all diseases associated with dyslipidemia caused by MTP by administering the composition. Means all acts of change.

The composition for preventing or treating dyslipidemia related diseases caused by the MTP of the present invention may further include a known cholesterol and triglyceride lowering agent. Cholesterol and triglyceride lowering agents that may be included in the composition of the present invention include atorvastatin, lovastatin, epstatin, Eptastatin, simvastatin, fluvastatin, davstatin, Dalvastatin, Itavastatin, Rosuvastatin, Pravastatin, Polycosanol, Ciprofibrate, Fenofibrate, Benzabibrate, Clofibrate, Clofibrate Filicol, Gemfibrozil, Benfluorex, Cholestyramine, Phytosterols, Colestilan, Acipimox, Meglutol Meglutol, Niceritrol, Binifibrate, Clinofibrate, Sulodexide, Melinaamide, Etofibrat te), pyrifibrate, Probucol and Sorbinicate, and the like are possible, but are not limited thereto, and these compounds may be used alone or in combination.

Prevention or treatment of dyslipidemia related diseases caused by MTP, comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, pharmaceutically acceptable salts thereof or derivatives thereof of the present invention as an active ingredient The composition for administration may further comprise a pharmaceutically acceptable carrier, and may be formulated with the carrier.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate an organism and does not inhibit the biological activity and properties of the administered compound.

The composition of the present invention may be prepared by filling a capsule containing the compound of the present invention without excipients or uniformly and sufficiently in contact with an atomized solid carrier, liquid carrier or both, and, if necessary, molding the product into a preferred formulation for use. Can be. Examples of suitable carrier excipients include starch, water, saline, ethanol, glycerol, Ringer's solution and dextrose solution, and the like (Remington's Pharmaceutical Science, 19 ^th Ed., 1995, Mack Publishing Company, Easton PA) and the like. As disclosed, it may be formulated into a suitable formulation known in the art.

In this case, the compound of the present invention may be formulated to be included in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight based on the total weight of the total composition.

In addition, the composition of the present invention can be applied to any formulation containing it as an active ingredient, it can be prepared in oral or parenteral formulations. Pharmaceutical formulations of the invention may be oral, rectal, nasal, topical (including the cheek and sublingual), subcutaneous, vaginal or parenteral (intramuscular, subcutaneous). And forms suitable for administration by inhalation or insufflation.

Oral dosage forms containing the composition of the present invention as an active ingredient include, for example, tablets, troches, lozenges, water-soluble or oily suspensions, preparation powders or granules, emulsions, hard or soft capsules, syrups or elixirs. can do. For formulation into tablets and capsules, etc., lactose, saccharose, sorbitol, mannitol, starch, amylopectin, binders such as cellulose or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch or sweet potato starch, stearic acid It may include a lubricating oil such as magnesium, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax, and in the case of a capsule, it may further contain a liquid carrier such as fatty oil in addition to the above-mentioned materials.

Formulations for parenteral administration comprising the composition of the present invention as an active ingredient, for injection, such as subcutaneous injection, intravenous injection or intramuscular injection, a suppository injection method or aerosol for spraying by inhalation through the respiratory system It can be formulated as. To formulate injectable formulations, the compositions of the present invention may be mixed in water with stabilizers or buffers to prepare solutions or suspensions, which may be formulated for unit administration of ampoules or vials. For infusion into suppositories, it may be formulated as a rectal composition such as suppositories or body enema including conventional suppository bases such as cocoa butter or other glycerides. When formulated for spraying such as aerosols, a propellant or the like may be combined with the additives to disperse the dispersed dispersion or wet powder.

In another embodiment, the present invention relates to an abnormal lipid induced by MTP, comprising administering the 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof. The present invention relates to a method for treating a blood related disease.

As used herein, the term "administration" means introducing a pharmaceutical composition of the present invention to a patient in any suitable manner, and the route of administration of the composition of the present invention may be varied orally or parenterally as long as it can reach the desired tissue. Route, and may be administered in a conventional manner, specifically, via oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, nasal, inhalation, intraocular or intradermal routes. have. Preferably oral administration.

The method of treatment of the present invention comprises administering the compound in a pharmaceutically effective amount. Appropriate total daily usage may be determined by the practitioner within the scope of good medical judgment. The specific therapeutically effective amount for a particular patient may be based on the specific composition, including the type and severity of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health, sex and diet of the patient, time of administration, It is desirable to apply differently depending on the route of administration and the rate of release of the composition, the duration of treatment, and the various factors and similar factors well known in the medical arts, including drugs used with or concurrent with the specific composition. Therefore, the preferred dosage of the compound of the present invention can be determined in consideration of the above, and can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg, divided once or several times daily.

In addition, the treatment method of the present invention may include co-administration of the above-mentioned known cholesterol and triglyceride lowering agents in addition to the compound.

Pharmaceutically effective amounts of cholesterol and triglyceride lowering agents are known in the art and can be adjusted by the practitioner in view of the prevailing conditions, such as the severity of symptoms and co-administration with the compound. These cholesterol and triglyceride lowering agents may optionally be formulated in a co-formulation, administered in separate formulations, or administered sequentially at separate time intervals.

In addition, the 1- (5-isoquinolinesulfonyl) -2-methylpiperazine Compounds of the present invention may be used alone or for the prevention and treatment of dyslipidemia-related diseases caused by MTP, surgery, hormone therapy, drugs It can be used in combination with methods of using therapeutic and biological response modifiers.

The method for preventing or treating dyslipidemia related diseases of the present invention is applicable to any animal in which dyslipidemia related diseases can occur, and animals are not only humans and primates but also cows, pigs, sheep, horses, dogs and It includes livestock such as cats.

In another embodiment, the present invention provides dyslipidemia induced by MTP comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a pharmaceutically acceptable salt thereof or derivative thereof as an active ingredient. It relates to a dietary supplement for preventing or ameliorating related diseases.

The compound of the present invention may be added to a dietary supplement for the purpose of preventing or ameliorating dyslipidemia related diseases caused by MTP.

As defined herein, "health functional food" means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to Act No. 6767 of the Health Functional Food Act, and "functional" means It means ingestion for the purpose of obtaining useful effects on health use such as nutrient control or physiological action on structure and function.

The health functional food may be prepared by adding other food materials according to the commerciality and consumer preference of the final product. The effective amount of the compound may be suitably determined according to the purpose of use (prevention, health or therapeutic treatment), and preferably, it may be added in an amount of 10% by weight or less, preferably 1% by weight or less based on the total raw material. have.

There is no particular limitation on the kind of food. Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages, vitamin complexes, and the like, and includes all of the functional foods in a conventional sense. In particular, the compound of the present invention can be prepared as a health functional food in the form of a preparation by further comprising a food additive acceptable food formulation, the form of the preparation can be tablets, capsules, pills, liquids and the like. .

In addition, the health functional food of the present invention is a variety of flavors, natural carbohydrates, sweeteners, vitamins, electrolytes, colorants, pectic acid, alginic acid, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonating agents And the like may be further contained. In particular, the natural carbohydrate can be used sugars such as glucose, monosaccharides such as fructose, maltose, disaccharides such as sucrose, polysaccharides such as dextrin, cyclodextrin, xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as tautin, stevia extract, or synthetic sweeteners such as saccharin or aspartame can be used. The proportion of such additives is not critical but is preferably selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

Since the compound according to the present invention exhibits MTP inhibitory activity, it is possible to reduce the production of dyslipidemia induced by MTP by lowering the blood LDL concentration in the cell. Therefore, the composition containing the compound of the present invention can be usefully used for the development of a medicament or food for the prevention or treatment of dyslipidemia-related diseases caused by MTP.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are provided to help the understanding of the present invention, and the scope of the present invention is not limited to the following examples.

Example  1. Material Preparation

<1-1> animal treatment

Japan SLC Inc. Male C57BL / 6 mice were purchased from Tokyo, Japan and used in this study. The animals were individually housed in a light-environment environment at 12-hour intervals in a place where temperature and humidity were automatically controlled in a plastic cage. Breeding animals were fed free pellets and water. Mice were anesthetized with ether, and blood and livers were collected. These experiments were performed after approval in accordance with the Inje University Animal Care and Use Committee.

<1-2> Compound Preparation

Compound 1- (5-isoquinolinesulfonyl) -2-methylpiperazine of the present invention was purchased from Sigma-Aldrich (Missouri, USA).

<1-3> Hepatocyte Suspension Preparation

All processes were carried out below 4 ° C. Immediately after liver tissue was collected through the <1-1> animal treatment, blood remaining in the liver was washed with an appropriate amount of cold 250 mM sucrose. The liver tissue was then weighed and added twice the amount of buffer of liver cell suspension (50 mM Tris, pH 7.4, 250 mM sucrose, 0.02% sodium azide) and then teflon fitted glass Homogenized with homogenizer. The homogenized hepatocyte suspension was filtered through a cheese cloth that had previously been soaked in buffer and frozen at −70 ° C. until analysis, and used for measurement within one week.

Example  2. According to compound treatment MTP  Active measurement

In order to investigate the effect of the compound of the present invention 1- (5-isoquinolinesulfonyl) -2-methylpiperazine on the MTP activity, after treatment with the compound in the hepatocyte suspension prepared in Example 1, changes in MTP activity Was measured.

MTP activity was measured using the method proposed by Wetterau and Zilversmit (1984). Protein content in hepatocyte suspension was measured using Bradford method (1976), and then TG donor (74 pmol (5,000 cpm) [ ¹⁴ C] -triolein, 148 nmol was added to hepatocyte suspension containing 500 μg of protein. After addition of phosphatidylcholin, 0.74 nmol cardiolipin, 0.1% butylated hydroxytoluene and TG receptor (222 pmol triolein, 444 nmol phosphatidylcholin, 2.22 nmol cardiolipin, 0.1% butylated hydroxytoluene), the compound was added (treated at 6 μM concentration) Immediately after 1 hour of inactivity (control), the same amount of reaction stop buffer (25% DEAE-cellulose / 15 mM tris, pH 7.4, 1 mM EDTA: 0.02% sodium azaid, 1: 1) was added. The reaction was stopped.

[ ¹⁴ C] -radioactivity was measured under a 10 minute maximum counting cycle condition using a Liquid Scintillation counter (Packard), and cpm (counts) using the average quench indicating parameter (QIP) value of the SIS (spectral index of sample). per minute) was calculated as the average value. The measured values were calculated as absolute values based on the amount of protein in the hepatocyte suspension used for the MTP measurement.

Statistical analysis was performed using Microsoft Excel ver. Student's t-test was conducted using 2002 to analyze differences between groups. When the P value is 0.05 or less, it was considered to have a statistically significant difference, and it was indicated by a * mark (FIG. 1).

As shown in Figure 1, compared to the MTP activity of the control group (2812 ± 29 cpm / protein-mg), MTP activity when the compound of the present invention is inhibited by about 71.5% (802 ± 104 cpm / protein- mg).

1 is a graph showing the results of measuring the change in MTP activity after treatment of hepatocyte suspension with 1- (5-isoquinolinesulfonyl) -2-methylpiperazine, a compound of the present invention.

Claims (6)

A composition for preventing or treating dyslipidemia related diseases caused by microsomal triglyceride transfer protein (MTP) comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine as an active ingredient, The dyslipidemia related disease caused by the MTP is characterized in that the disease is selected from the group consisting of arteriosclerosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, obesity and diabetes, A composition for preventing or treating dyslipidemia related diseases. delete According to claim 1, wherein the composition is atorvastatin, lovastatin (Lovastatin), Eptastatin (Eptastatin), Simvastatin (Simvastatin), Fluvastatin (Dalvastatin), Itavastatin (Itavastatin), Rosuvastatin, Pravastatin, Polycosanol, Ciprofibrate, Fenofibrate, Benzafibrate, Clofibrate, Clofibrate, Filicol, gem Gemfibrozil, Benfluorex, Cholestyramine, Phytosterols, Colestilan, Acipimox, Meglutol, Meglutol, Niseriterol (Niceritrol), Binifibrate, Clinofibrate, Sulodexide, Melinaamide, Etofibrate, Pirifibrate, Pirifibrate, Probucol , Le beanie Kate (Sorbinicate) and characterized in that further comprises a cholesterol and triglyceride lowering agent is selected from mixtures thereof, more than caused by the MTP dyslipidemia-related disease preventing or treating composition. According to claim 1, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, a composition for preventing or treating dyslipidemia-related diseases caused by MTP. delete As a health functional food for preventing or ameliorating dyslipidemia related diseases caused by MTP, comprising 1- (5-isoquinolinesulfonyl) -2-methylpiperazine as an active ingredient, The dyslipidemia related disease caused by the MTP is characterized in that the disease is selected from the group consisting of arteriosclerosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, obesity and diabetes, Health functional foods for preventing or improving dyslipidemia-related diseases.

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