KR20220032874A - Composition for preventing or treating bone disease of 2,4,6-tripehenyl-1-hexene - Google Patents

Abstract

The present invention is for preventing or alleviating bone diseases, comprising 2,4,6-triphenyl-1-hexene or a pharmaceutically acceptable salt thereof as an active component. Since a compound or a pharmaceutically or pharmaceutically acceptable salt thereof exhibits an effect of inhibiting osteoporosis, it can be used to develop an anti-osteoporosis agent for preventing or treating bone diseases.

Description

Composition for preventing or treating bone disease comprising 2,4,6-triphenyl-1-hexene as an active ingredient

The present invention relates to a composition for preventing or treating bone disease comprising 2,4,6-triphenyl-1-hexene as an active ingredient.

Bone repeats a cycle from about 120 to 150 days, including bone resorption by osteoclasts, osteoblast formation and resting period (referred to as remodeling). In healthy adults, bone resorption and bone formation are tightly controlled, and total bone mass hardly changes. However, in diseases related to decreased bone mass, the balance between the two is broken, resulting in a decrease in bone mass and deterioration of bone tissue. The decrease in bone mass reaches 20 to 30%, and it is easy to fracture, and this causes sickness, lying down, body deformity, or even death depending on the fracture site, such as a hip fracture.

Osteoporosis is one of the representative diseases related to bone loss. Osteoporosis is a systemic disease whose main symptoms are loss of bone mass and deterioration of bone tissue.

Osteoporosis is a condition in which the calcification of the bone tissue is reduced and the compactness of the bone is thinned and the bone marrow cavity is widened. Bone mass is affected by several factors, such as genetic factors, nutritional intake, hormonal changes, and differences in exercise and lifestyle. Ovariectomy and the like are known. On the other hand, although there are individual differences, blacks have higher bone mass than whites due to a lower level of bone resorption than whites. In general, bone mass is the highest between the ages of 14 and 18, and decreases by about 1% per year in old age. In particular, in the case of women, bone loss continues to progress after the age of 30, and when they reach menopause, bone loss progresses rapidly due to hormonal changes.

As such, osteoporosis is an unavoidable symptom for the elderly, particularly postmenopausal women, although there is a difference in degree, and interest in osteoporosis and its therapeutic agents is gradually increasing in developed countries as the population ages. In addition, it is known that there is a market of about 130 billion dollars related to the treatment of bone disease worldwide, and it is expected to increase further in the future. .

Bone remains healthy through the process of bone remodeling, which replaces damaged or old bone with new bone. The process of bone remodeling is accomplished by osteoblasts and osteoclasts. Osteoblasts are involved in the process of bone formation to create new bones, and osteoclasts are involved in bone resorption that destroys old bones. However, when a deficiency of female hormones occurs due to menopause, it directly or indirectly affects osteoblasts and osteoclasts involved in this bone remodeling process, leading to bone loss. That is, after menopause, bone remodeling becomes active and the degree of bone resorption is greater than the degree of bone formation, which causes bone loss.

Treatment of osteoporosis includes general therapy and drug therapy. General therapy requires changes in calcium and vitamin D intake, exercise, and lifestyle, and hormone replacement therapy, alendronate, calcitonin, latoxifen, Na-F, calcitriol, and bisphosphonate preparations are administered for malaise therapy. Osteoporosis treatment requires a long-term treatment period, and side effects such as urolithiasis, endometrial cancer, breast cancer, etc. are caused when conventional drugs are taken for a long time, so it is necessary to develop a new therapeutic agent for osteoporosis that does not have side effects in the human body.

Substances currently being used for the treatment of osteoporosis include estrogen, androgenic anabolic steroids, calcium preparations, phosphates, fluoride preparations, ipriflavone, and vitamin D3. In 1995, Merck Corporation of the United States developed aminobisphosphonate, and in 1997, Lilly Corporation of the United States of America developed raloxifene, which acts as a selective estrogen receptor modulator, as a new drug for osteoporosis.

On the other hand, most of the conventional osteoporosis treatment agents are estrogen-based substances, and it is known that side effects such as cancer, gallstones, thrombosis, and the like appear when estrogen-based substances are administered for a long time. However, osteoporosis cannot be treated with only short-term administration of drugs, and long-term administration of drugs is essential. situation.

Under this background, the present inventors found that a pharmaceutical composition comprising 2,4,6-triphenyl-1-hexene or a pharmaceutically acceptable salt thereof as an active ingredient may be used. The present invention was completed by confirming the osteoclast activity inhibitory effect as a result of judging that it was and making diligent efforts to solve the problems of the prior art.

One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of bone diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for preventing or treating bone disease comprising administering the pharmaceutical composition to a subject other than a human.

Another object of the present invention is to provide a health functional food composition for the prevention or improvement of bone disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a feed composition for the prevention or improvement of bone diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by the specific descriptions described below.

A first aspect of the present invention for achieving the above object provides a pharmaceutical composition for the prevention or treatment of bone diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In addition, a second aspect of the present invention provides a method for preventing or treating bone disease comprising administering the pharmaceutical composition to an individual other than a human.

In addition, a third aspect of the present invention provides a health functional food composition for the prevention or improvement of bone disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In addition, a fourth aspect of the present invention provides a feed composition for the prevention or improvement of bone diseases, comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

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

Since the composition of the present invention exhibits an effect of inhibiting bone disease, it can be usefully utilized for the prevention or treatment of bone disease.

As used herein, the term 2,4,6-triphenyl-1-hexene (2,4,6-tripehenyl-1-hexene) compound is a compound having a structure of the following formula (1), which can be obtained from an extract containing the same. And, although not limited thereto, it may be separated from barley or sprouted barley. In addition, the 2,4,6-triphenyl-1-hexene (2,4,6-tripehenyl-1-hexene) compound can be synthesized or purchased by a known method.

[Formula 1]

In addition, the 2,4,6-triphenyl-1-hexene (2,4,6-tripehenyl-1-hexene) compound is 2,4,6-triphenyl-1-hexene (2,4,6-tripehenyl -1-hexene) compounds within the range expected by those skilled in the art may be included, and are included without limitation as long as they have the same effect in the present invention.

The bone disease prevention, treatment or improvement effect of the compound is not known, and was first identified by the present inventors.

As used herein, the term "bone disease" is not particularly limited, but specifically, may be osteoporosis, osteomalacia, rickets, Paget's disease, scoliosis, osteomyelitis, benign bone tumor, or Paget's disease.

The "osteoporosis" is a skeletal disease in which bone strength is weakened and fractures easily. Genetic factors, early menopause, medications (steroids), co-morbidities, smoking, alcohol, rheumatoid arthritis, etc. can be the cause. Most of them have no symptoms, but when a fracture occurs, pain occurs, and various symptoms may appear depending on the fracture site. means there is

The pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient is characterized in that it inhibits bone disease, specifically osteoporosis.

In a specific embodiment of the present invention, the 2,4,6-triphenyl-1-hexene (2,4,6-tripehenyl-1-hexene) compound has the osteoporosis inhibitory ability by confirming the osteoclast differentiation inhibitory effect. did

As used herein, the term "pharmaceutically acceptable salt" refers to a salt in a form that can be used pharmaceutically among salts, which are substances in which a cation and an anion are combined by electrostatic attraction, and is usually a metal salt, an organic base and salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine salts with, etc.; salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; Salts with organic acids may be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; Salts with basic amino acids may be salts with arginine, lysine, ornithine and the like; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid, or the like.

As used herein, the term “prevention” refers to any action that inhibits or delays the onset of bone disease by administration of the pharmaceutical composition according to the present invention.

As used herein, the term “treatment” refers to any action in which the symptoms of a suspected and onset individual of bone disease are improved or beneficially changed by administration of the pharmaceutical composition.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent, wherein the carrier may include a non-naturallyoccuring carrier.

More specifically, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, polycaprolactone, polylactic acid ( Poly Lactic Acid), poly-L-lactic acid (poly-L-lactic acid), mineral oil, and the like. The pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. The form may include various amorphous carriers, microspheres, nanofibers, and the like. In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract and its fractions, for example, starch, calcium carbonate, It may be prepared by mixing sucrose or lactose, gelatin, or the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. The content of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited. Another embodiment of the present invention for achieving the above object provides a health functional food composition for preventing or improving bone disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention for achieving the above object, since the compound represented by Formula 1 according to the present invention exhibits an excellent bone disease inhibitory effect, it may be included in a food composition for the purpose of preventing or improving bone disease, Since the food composition can be consumed on a daily basis, a high effect can be expected for the prevention or improvement of bone diseases.

In this case, the description of the "compound represented by Formula 1 (2,4,6-triphenyl-1-hexene)", "bone disease", and "prevention" is the same as described above. In addition, the "food pharmaceutically acceptable salt" herein is as defined in the above "pharmaceutically acceptable salt".

As used herein, the term “improvement” refers to any action that at least reduces a parameter related to a condition to be treated by administration of the dietary supplement composition according to the present invention, for example, the degree of symptoms.

As used herein, the term “health functional food” refers to food manufactured and processed using raw materials or ingredients useful for the human body in accordance with Act No. 6727 of the Health Functional Food Act, and 'functionality' refers to the structure of the human body. And it means to obtain a useful effect for health use, such as regulating nutrients for function or physiological action. On the other hand, health food means food that has an active health maintenance or promotion effect compared to general food, and health supplement means food for the purpose of health supplementation. In some cases, the terms health functional food, health food and health supplement food can be mixed.

The compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.

The food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art. Specifically, the food composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited and any carrier commonly used in the art may be used. In addition, the food composition contains food additives such as preservatives, disinfectants, antioxidants, colorants, coloring agents, bleaching agents, seasonings, sweeteners, flavoring agents, expanding agents, strengthening agents, emulsifying agents, thickeners, filming agents, gum base agents, foam inhibitors, solvents, and improving agents. may include The additive may be selected according to the type of food and used in an appropriate amount.

In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur when taking the drug for a long period of time using food as a raw material, and it is excellent in portability, so the present invention Foods of can be ingested as an adjuvant to enhance the effect of preventing or improving bone disease.

The compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be included in various weight % in the food composition as long as it can exhibit the effect of preventing or improving bone disease. Specifically, it may be included in an amount of 0.00001 to 100% by weight or 0.01 to 80% by weight relative to the total weight of the food composition, but is not limited thereto. In the case of long-term ingestion for health and hygiene purposes, it may contain an amount below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

Another embodiment of the present invention for achieving the above object provides a feed composition for preventing or improving bone disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. In this case, the descriptions of the "compound represented by Formula 1", "food pharmaceutically acceptable salt", "bone disease", "prevention" and "improvement" are the same as those described above.

Since the compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof exhibits an excellent bone disease inhibitory effect, it may be included in a feed composition for the purpose of preventing or improving bone disease, and the feed composition is Since it can be consumed on a daily basis, a high effect can be expected for the prevention or improvement of bone diseases.

As used herein, the term "feed" means any natural or artificial diet, meal, etc., or a component of said meal, intended for or suitable for being eaten, consumed, and digested by an animal. The type of feed is not particularly limited, and feed commonly used in the art may be used. Non-limiting examples of the feed include plant feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, gourds or grain by-products; and animal feeds such as proteins, inorganic materials, oils and fats, minerals, oils and fats, single cell proteins, zooplankton or food. These may be used alone or in mixture of two or more.

Since the 2,4,6-triphenyl-1-hexene compound of the present invention exhibits an effect of inhibiting bone disease, it can be used to develop a composition for preventing or treating the bone disease.

1 is a photograph showing the osteoclast activity inhibitory effect of 2,4,6-triphenyl-1-hexene of the present invention in a high concentration of osteoclast differentiation-inducing cytokine.
2 is a photograph showing the osteoclast activity inhibitory effect of 2,4,6-triphenyl-1-hexene of the present invention at a low concentration of osteoclast differentiation-inducing cytokine.
3 is a photograph showing the osteoclast differentiation of 2,4,6-triphenyl-1-hexene according to the concentration of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These Examples are for explaining the present invention in more detail, and the scope of the present invention is not limited by these Examples.

Example 1: Confirmation of osteoclast activity inhibition

1 and 2 are diagrams confirming the inhibition of osteoclast activity by adding the compound 2,4,6-triphenyl-1-hexene according to the concentration of the present invention.

Specifically, in order to confirm the osteoporosis inhibitory activity of 2,4,6-triphenyl-1-hexene, macrophage colony-stimulating factor (M-) in osteoclast progenitor cells (about 1x10 ⁴ cells/well) CSF) (about 30 ng/ml) to induce differentiation into macrophages and osteoclast differentiation-inducing cytokine RANKL (about 10 ng/ml) was added to induce differentiation, and 2,4,6-triphenyl-1- Hexene (about 10 μg/mL or 30 μg/mL) was added by concentration, and after 4 days, Tartrate resistant acid phosphatase (TRAP), a molecular marker related to osteoclast differentiation, was stained and photographed under an optical microscope for comparison. was performed by measuring the absorbance at about 405 nm using Tartrate resistant acid phosphatase reagents from Sigma aldrich.

As a result, as shown in FIGS. 1 and 2, inhibition of osteoclast formation was confirmed in 2,4,6-triphenyl-1-hexene when performed at a low concentration (10 μg/mL), and at a high concentration (30 μg/mL) ), the inhibitory effect of 2,4,6-triphenyl-1-hexene on osteoclast formation was confirmed.

Example 2: Efficacy of inhibiting osteoclast differentiation according to concentration

3 confirms the inhibitory efficacy of osteoclast differentiation according to the concentration of the compound of the present invention.

In order to confirm the efficacy of the compound shdehp Ekfms to inhibit osteoclast differentiation, it was carried out in the same manner as in Example 1 at concentrations of 1, 5, 10, and 20 μg/mL.

As a result, the expression and activity of tartrate resistant acid phosphatase (TRAP), which is an indicator enzyme of osteoclasts, was affected by the concentration of 2,4,6-triphenyl-1-hexene. It was confirmed that the inhibition of osteoclast differentiation dependently (FIG. 3).

Combining Examples 1 and 2 of the present invention, the inhibitory effect of the compound 2,4,6-triphenyl-1-hexene of the present invention on osteoclast activity It was confirmed that it was ultimately effective in bone diseases.

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the following claims and their equivalents.

Claims (5)

A pharmaceutical composition for the prevention or treatment of bone diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

.
According to claim 1,
The bone disease is osteoporosis, osteomalacia, rickets, Paget's disease, scoliosis, osteomyelitis, benign bone tumor, or Paget's disease, the pharmaceutical composition.
A method for preventing or treating bone disease comprising administering the pharmaceutical composition of claim 1 to a subject other than a human.
A health functional food composition for the prevention or improvement of bone diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

.
A feed composition for preventing or improving bone disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

.

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