KR20100103671A - Pharmaceutical composition for preventing or treating fat metabolism-related diseases containing 2-cyclopentene-1-one oxime derivatives - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing 2-cyclopentene-1-one oxime derivative is provided to promote adipose lysis in adipocytes(3T3-L1) and to prevent and treat lipid metabolic diseases including obesity and diabetes. CONSTITUTION: A pharmaceutical composition for preventing and treating lipid metabolic diseases contains 2-cyclopenten-1-one oxime derivative compound of chemical formula 1 or pharmaceutically acceptable salt thereof as an active ingredient. In chemical formula 1, R1 is linear or branched C1-C10 alkyl group or C3-C7 cycloalkyl group, or phenyl group with or without substituent. The phenyl group is denoted by chemical formula 2. The pharmaceutical composition is used for preventing and treating obesity, diabetes, or dyslipidemia.

Description

PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING FAT METABOLISM-RELATED DISEASES CONTAINING 2-CYCLOPENTENE-1-ONE OXIME DERIVATIVES}

The present invention relates to a pharmaceutical composition for preventing and treating fat metabolism disease, comprising 2-cyclopenten-l-one oxime derivative as an active ingredient.

Fat cells are the main fat store in the body, and store not only extra calories, but also have a variety of functions such as a cushion to protect organs and body temperature.

White adipose tissue (WAT), which plays such a role, synthesizes and stores excess nutrients in the form of triglycerides mainly through the lipoprotein lipase (LPL) in the vessel wall, and exists in fat cells. HSL (Hormone sensitive lipase) breaks down the stored fat and supplies it to each organ that needs energy.

In this fat cell degradation, cyclic adenosine monophosphate (cyclic AMP, hereinafter cAMP) acts as a major factor mediating lipolysis. However, cAMP is very unstable and is converted to AMP by Phosphodiesterase present in the cell, and the reduced cAMP concentration leads to decreased lipolysis. Therefore, the mechanisms involved in increasing cAMP concentration in adipocytes and various mechanisms involved in inhibiting phosphodiesterase activity play a role in promoting lipolysis.

Lipid breakdown accelerators currently being used and used for cosmetic purposes include isoproterenol, a derivative of catecholamine, and xanthine, such as caffeine and theophylline, and thyroid hormone. ), Glucocorticoids, and growth hormone. However, these substances are hormones or hormone derivatives, and their use is limited due to side effects, and opinions on the effects are divided.

Technical challenge

Therefore, the present invention has a sufficient effect in the prevention and treatment of fat metabolism diseases such as obesity, and in developing a lipolysis accelerator that can be used safely, pay attention to the increase in the size of fat cells and fat storage, triglycerides in fat cells In view of the fact that promoting degradation can improve fat metabolism diseases such as obesity, the concentration of cAMP in adipocytes is increased, and as a result, a compound that promotes lipolysis is to be found.

Technical solution

The present inventors have found that 2-cyclopenten-l-one oxime derivatives promote triglyceride degradation and increase fat loss by increasing cAMP concentration in adipocytes. Accordingly, the present invention is to provide a pharmaceutical composition for the prevention and treatment of fat metabolism diseases, such as obesity, dyslipidemia, diabetes, etc. comprising a 2-cyclopenten-l-one oxime derivative as an active ingredient.

Favorable effect

The pharmaceutical composition containing the 2-cyclopenten-l-one oxime derivative compound of the present invention as an active ingredient maintains a high level of cAMP by influencing intracellular cAMP production and degradation in completely differentiated adipocytes. Since it promotes lipolysis through the reaction of, it can be used as a pharmaceutical composition for the prevention or treatment of fat metabolism abnormal diseases such as obesity, dyslipidemia, diabetes and the like.

1 is a graph comparing the rate of lipolysis and cAMP increase in adipocytes of 2-cyclopenten-l-one oxime derivative compounds according to an embodiment of the present invention.

Best Mode for Carrying Out the Invention

The present invention provides a pharmaceutical composition containing a 2-cyclopenten-l-one oxime derivative compound as an active ingredient.

Hereinafter, the present invention will be described in more detail.

The pharmaceutical composition according to one embodiment of the present invention includes a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Formula 1

Where

R ₁ means a linear or branched C ₁ -C ₁₀ alkyl group or C ₃ -C ₇ cycloalkyl group, or a phenyl group with or without a substituent, and R ₂ means an aromatic group with or without a substituent, where aromatic Group refers to an aromatic group selected from phenyl, pyridyl, naphthyl, indolyl, thienyl, benzo [b] thienyl, dibenzofuranyl or thiantrenyl.

The phenyl group is the same as the formula (2),

Formula 2

R ₃ to R ₇ in Formula 2 are each independently hydrido, linear or branched C ₁ -C ₉ alkyl, C ₂ -C ₆ alkenyl, halo C ₁ -C ₆ alkyl, phenyl, halo, nitro, Amino, C ₁ -C ₅ alkylamino, C ₁ -C ₅ alkylamino C ₁ -C ₅ alkyl, methylenedioxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkoxy, benzyloxy, C ₁ -C ₅ alkylthio, C ₁ -C ₅ alkylsulfonyl, C ₁ -C ₅ alkylsulfinyl, cyano, carboxy, C ₁ -C ₅ alkoxycarbonyl, C ₁ -C ₅ alkoxy C ₁ -C ₅ alkyl, hydr Hydroxy, hydroxy C ₁ -C ₅ alkyl, C ₁ -C ₅ carbamoyl, N-hydroxy-imino C ₁ -C ₅ alkyl or N- (N-hydroxy-imino C ₁ -C ₅ alkyl) May be selected from amino.

In addition, as a preferred embodiment of the present invention, R ₁ of Formula 1 means a linear or branched C ₁ -C ₆ alkyl, cyclopentyl or cyclohexyl, R ₂ is an aromatic group with or without a substituent, In this case, the aromatic group means an aromatic group selected from pyridyl, naphthyl, indolyl, thienyl, benzo [b] thienyl, dibenzofuranyl or thiantrenyl, or a phenyl group having a substituent. The phenyl group is as shown in the formula (2).

In addition, as another preferred embodiment of the present invention, R ₁ of Formula 1 means propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl or cyclohexyl, and R ₂ means a phenyl group having a substituent. A phenyl group is as shown in Formula 2, and R ₃ to R ₇ are each independently a hydrido, methyl, ethyl, propyl, butyl, vinyl, trifluoromethyl, phenyl, fluoro, chloro, bromo, Nitro, amino, N, N-dimethylamino, N, N-dimethylaminomethyl, methylenedioxy, methoxy, ethoxy, trifluoromethoxy, benzyloxy, methylthio, methylsulfonyl, methylsulfinyl, cyano , Carboxy, methoxycarbonyl, ethoxycarbonyl, methoxymethyl, hydroxy, hydroxymethyl carbamoyl, N- (hydroxyacetimidoyl) amino, N-hydroxyiminomethyl and 1-N-hydroxy It may be selected from iminoethyl.

As another preferred embodiment of the present invention, at least one of the compounds disclosed in Table 1 or a pharmaceutically acceptable salt thereof may be included as an active ingredient of the pharmaceutical composition.

TABLE 1

Compounds as described above, or pharmaceutically acceptable salts thereof, are effective components of at least one of these compounds, mixed with a suitable pharmaceutically acceptable carrier or excipient according to a conventional method, or diluted with a diluent so as to cause metabolic related diseases. It can be prepared as a pharmaceutical composition that prevents, treats and ameliorates. Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The pharmaceutical composition may further include fillers, anti-coagulants, lubricants, wetting agents, flavors, emulsifiers, preservatives, disintegrants, sweeteners, lubricants, flavoring agents and the like.

The pharmaceutical composition according to an embodiment of the present invention may be used in any form such as an oral or external preparation, and these areas may be applied directly to a topical area with many subcutaneous fat such as the face, abdomen, thighs, buttocks, upper arm, etc. Because it can also reduce the fat locally, it can be prepared and used in various external preparations such as lotions, creams, gels, ointments, aerosols, and patches.

Pharmaceutical compositions according to one embodiment of the invention can be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. The formulations may be in the form of tablets, pills, powders, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders and the like.

The pharmaceutical composition according to one embodiment of the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the typical daily dosage of the active compounds is 0.1 to 100 mg / kg / day, It may be administered once or in divided doses. However, it is to be understood that the actual dosage of the active ingredient should be determined in light of several relevant factors such as the route of administration, the age, sex and weight of the patient, and the severity of the disease, and therefore the dosage should in any way be within the scope of the invention. It is not intended to be limiting.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the following Examples.

Example 1 Evaluation of Triglyceride Efficacy in Adipose Cells

(Step 1) Culture and Differentiation of Fat Cell Lines

Mouse-derived adipocytes, 3T3-L1 cells (rat adipocytes; ATCC ＃ CL-173), were placed in 96-well cell culture plates at 5x10 ⁴ / well and 10% bovine serum (Calf serum, GibcoBRL, ＃ 16170). -078) and 37%, 10% CO ₂ cell incubator on DMEM medium (Dulbecco's modifided Eagle's Medium, hereinafter referred to as DMEM, GibcoBRL, ＃ 11965-084) containing penicillin / streptomycin (GibcoBRL # 10378-016) antibiotics Put and incubated. 10% bovine serum, 0.5 mM 3-isobutyl-1-methylxanthine (IBMX; Sigma VII-7018), 1 μM dexamethasone (Sigma VIID-4902), and the following day to differentiate the cells into adipocytes, and After 48 hours of incubation in a medium containing 167 nM insulin (Bovine Insulin; Sigma I-5500), the medium was exchanged with insulin DMEM medium containing 10% bovine serum and 167 nM insulin for another 72 hours. It was. Then, fully differentiated adipocytes were obtained by further incubating 48 hours in DMEM medium containing only 10% fetal bovine serum (FBS; GibcoBRL10437-028) serum.

(Step 2) Evaluate free glycerin (Glycerol) concentration as a lipolysis product

Discard cultures of fully differentiated 3T3-L1 cells, wash with PBS (-), and then remove DMEM (Low glucose, Without phenolred; WelGene® LM001-04) containing 2% BSA (Free fatty acid; BOVogen ＃BSAS 0.025) ) Incubated at 200 ul / well for 1 hour to 24 μm each compound to give a final 0.5% DMSO for 5 hours. Since only the cell culture supernatant was taken to measure the amount of glycerol produced as a lipolysis product using a free glycerol reagent (Free Glycerol Reagent; Sigma ＃ F6428). At this time, the glycerol content was calculated by the method shown in Equation 1 below, and then promoted lipolysis as a relative value for the case of 100% of the control (well, 0.5% DMSO without addition of the compound) according to Equation 2. The rate was obtained.

Formula 1.Glycerol content = (A _sample -A _blank ) / (A _standard -A _blank ) X concentration of glycerol standard

* A _sample : absorbance of the well sample treated with each compound

* A _blank : Absorbance of well sample without indicator

* A _standard : Glycerol standard absorbance

Formula 2. Lipolysis Acceleration Rate (%) = (Amount of Free Glycerol at Compound Addition / Amount of Free Glycerol at No Compound (0.5% DMSO Control)) X 100

The results are shown in Table 2 below, and it can be seen that all promote excellent fat cell decomposition compared to the fat cell decomposition promoting rate of the control group.

TABLE 2

Example 2: Determination of cAMP concentration in differentiated adipocytes

In the differentiated adipocytes as in step 1 of Example 1, the 2-cyclopenten-l-one oxime derivative compound at the concentration of cAMP induced by forskolin, an adenylate cyclase (AC) promoter The purpose of this study was to evaluate their impact. Discard all supernatant cultures of fully differentiated adipocytes, add DMEM medium containing 10% fetal bovine serum (FBS), and then final concentrations of compounds 3 to 9 and compounds 11, 14 and 17 are 10 uM, 0.5% DMSO. After culturing for 15 minutes in a 37 ° C., 10% CO ₂ cell incubator, the mixture was stimulated with 1 μM forskolin for 10 minutes at 37 ° C. Subsequently, all of the cell culture was discarded, and the cells were lysed. Then, the amount of cAMP in the cells was measured using a cAMP enzyme immunoassay (EIA) system (Amersham Pharmacia Biotech, Kit ＃ RPN225). The effects of cAMP production or degradation on Compounds 3 to 9 and Compounds 11, 14, and 17 were evaluated from the dose response curves by standard cAMP amounts, and treated with only 1 uM forskolin without each compound. Assuming%, the relative values of the samples treated with each of the compounds were determined. The results are shown in Table 3 below. These compounds induced high levels of cAMP in differentiated adipocytes by influencing intracellular cAMP production promotion and inhibition of degradation, which is believed to inhibit fat storage by stimulating HSL to promote lipolysis.

TABLE 3

It is shown in Figure 1 by comparing the rate of lipolysis promotion of Table 2 and the increase rate of cAMP cells in Table 3.

As can be seen from Table 2 and Table 3 and FIG. 1, when the pharmaceutical composition according to an embodiment of the present invention is treated with fully differentiated adipocytes (Differentiated 3T3-L1), lipolysis, in particular, adipocytes It was confirmed that triglyceride breakdown occurred actively, which may be attributed to the increase of cAMP concentration in adipocytes.

Therefore, the pharmaceutical composition according to one embodiment of the present invention may increase the decomposition of accumulated adipose tissue and reduce systemic or local fat, and thus fat such as dyslipidemia such as obesity, diabetes, hyperlipidemia, or high blood pressure. It is very effective in preventing, treating and improving metabolic diseases.

Claims (4)

A pharmaceutical composition for treating and preventing fat metabolism, comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula 1]

(Wherein R ₁ is a linear or branched C ₁ -C ₁₀ alkyl group or C ₃ -C ₇ cycloalkyl group, or a phenyl group with or without a substituent, R ₂ is an aromatic group selected from pyridyl, naphthyl, indolyl, thienyl, benzo [b] thienyl, dibenzofuranyl or thiantrenyl with or without a substituent, or a phenyl group with or without a substituent .) The pharmaceutical composition of claim 1, wherein the phenyl group is a phenyl group represented by the following Formula (2). [Formula 2]

Wherein R ₃ to R ₇ are each independently hydrido, linear or branched C ₁ -C ₉ alkyl, C ₂ -C ₆ alkenyl, halo C ₁ -C ₆ alkyl, phenyl, halo, nitro, amino , C ₁ -C ₅ alkylamino, C ₁ -C ₅ alkylamino C ₁ -C ₅ alkyl, methylenedioxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkoxy, benzyloxy, C ₁ -C ₅ Alkylthio, C ₁ -C ₅ alkylsulfonyl, C ₁ -C ₅ alkylsulfinyl, cyano, carboxy, C ₁ -C ₅ alkoxycarbonyl, C ₁ -C ₅ alkoxy C ₁ -C ₅ alkyl, hydroxy , Hydroxy C ₁ -C ₅ alkyl, C ₁ -C ₅ carbamoyl, N-hydroxy-imino C ₁ -C ₅ alkyl or N- (N-hydroxy-imino C ₁ -C ₅ alkyl) amino Is selected from.) The pharmaceutical composition of claim 1, wherein the pharmaceutical composition promotes lipolysis to cause a decrease in triglycerides. According to claim 1, wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and prevention of obesity, diabetes or dyslipidemia.

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