WO2022092884A1 - Pharmaceutical composition comprising 13-o-acetylphobol for preventing and treating bone-related diseases and vascular calcification - Google Patents
Pharmaceutical composition comprising 13-o-acetylphobol for preventing and treating bone-related diseases and vascular calcification Download PDFInfo
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- WO2022092884A1 WO2022092884A1 PCT/KR2021/015405 KR2021015405W WO2022092884A1 WO 2022092884 A1 WO2022092884 A1 WO 2022092884A1 KR 2021015405 W KR2021015405 W KR 2021015405W WO 2022092884 A1 WO2022092884 A1 WO 2022092884A1
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- pharmaceutical composition
- bone
- preventing
- acetylphobol
- vascular calcification
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- 238000005406 washing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Definitions
- the present invention relates to a pharmaceutical composition for the prevention or treatment of bone disease and vascular calcification comprising 13-O-acetylphobol as an active ingredient.
- Osteoporosis is a disease in which bone mass is reduced due to the imbalance between bone formation and bone resorption, and the risk of fracture continues to increase due to the degeneration of the microstructure of bone tissue. is the state The gap between the bone microstructures becomes wider and the microstructures become thinner, increasing the risk of easily fractured bones even with a small impact. Old age, lack of exercise, low body weight, smoking, low calcium diet, menopause, and ovarian resection are known causes of osteoporosis.
- vascular calcification increases the stiffness of blood vessels, leading to vascular rupture, and cardiovascular system calcification contributes to exacerbation of hypertension, heart failure, acute coronary syndrome and valvular disease, and various complications (sudden cardiac death, myocardial infarction, angina and ischemic heart failure, etc.).
- the exact mechanism of vascular calcification has not yet been elucidated, and thus a preventive and therapeutic agent for this has not yet been developed.
- the present inventors have completed the present invention by confirming that 13-O-acetylphobol has such an effect as a result of an effort to discover a substance having an effective effect on both osteoporosis and vascular calcification.
- the present inventors have discovered 13-O-acetylphobol as a substance having a therapeutic effect on bone-related diseases, for example, diseases such as osteoporosis.
- diseases such as osteoporosis.
- RANKL receptor activator of NK- ⁇ B ligand
- osteoclast differentiation inducer an osteoclast differentiation inducer
- the 13-O-acetylphobol was also treated with macrophages to convert into osteoclasts. It was found that differentiation was inhibited (FIG. 4).
- the activity of differentiated osteoclasts was also inhibited by 13-O-acetylphobol ( FIG. 4 ).
- one aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases, comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound of Formula 1 is 13-O-acetylphobol (CAS 60857-08-1), also known as prostratin or 12-Deoxyphorbol-13-Acetate.
- the bone disease is osteoporosis, periodontal disease, osteomalacia, osteopenia, bone defect, bone atrophy, osteonecrosis, fracture, osteolysis ( osteolysis), it may be selected from the group consisting of osteoarthritis and osteoporosis imperfecta, preferably osteoporosis.
- osteoporosis refers to a state in which the mineral (especially calcium) and matrix constituting the bone are reduced, and the microstructure of the bone tissue is deteriorated, and as a result, the risk of fractures continuously increases.
- osteoclast activity is increased more than osteoblastic activity, it occurs because the balance of bone remodeling is disturbed, and the causes include calcium malabsorption, vitamin D deficiency, drug side effects, lack of exercise, excessive drinking, menopause, and depression.
- the amount of estrogen secretion decreases after menopause, active oxygen accumulates in the cells and bone loss is triggered.
- the pharmaceutical composition for the prevention or treatment of bone disease may additionally have an inhibitory effect on vascular calcification.
- the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and when formulated, commonly used fillers, extenders, It is prepared using a diluent or excipient such as a binder, a wetting agent, a disintegrant, and a surfactant.
- a diluent or excipient such as a binder, a wetting agent, a disintegrant, and a surfactant.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention and at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin.
- lubricants such as magnesium stearate talc are also used.
- Liquid formulations for oral administration include suspensions, oral solutions, emulsions, or syrups.
- various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.
- Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- injectable esters such as ethyl oleate.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
- the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of an active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination, generally limited thereto
- 0.001 mg to 200 mg preferably 0.01 mg to 100 mg, more preferably 0.2 mg to 50 mg per kg body weight can be administered.
- the dosage is not intended to limit the scope of the present invention in any way.
- Another aspect of the present invention provides a food composition for preventing or improving bone disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the food composition uses the same ingredients as the pharmaceutical composition for the prevention or treatment of bone diseases, overlapping content between the two is omitted to avoid excessive description of the specification.
- the food composition may be provided in the form of powder, granule, tablet, capsule, syrup, beverage or pill, and is used together with other food or food additives in addition to the compound represented by Formula 1 as an active ingredient, a conventional method can be used appropriately.
- the mixing amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.
- the effective dose of the active ingredient contained in the food composition may be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or health control, it may be less than the above range, It is certain that the active ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.
- the food composition includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
- examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides such as conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol and erythritol.
- flavoring agents natural flavoring agents and synthetic flavoring agents can be used.
- citric acid, fructose liquid, sugar, glucose, acetic acid, malic acid, fruit juice, etc. may be additionally included in addition to the active ingredient of the present invention.
- 13-O-acetylphobol also has an inhibitory effect on vascular calcification. Accordingly, another aspect of the present invention provides a pharmaceutical composition for preventing or treating vascular calcification, and a food composition for preventing or improving, comprising the compound of Formula 1 as an active ingredient.
- Vascular calcification is a symptom in which minerals such as calcium phosphate are deposited in the blood vessels and harden the blood vessels, which increases the stiffness of the blood vessels, leading to vascular rupture.
- cardiovascular calcification contributes to the exacerbation of hypertension, heart failure, acute coronary syndrome and valvular disease, leading to various complications (sudden cardiac death, myocardial infarction, angina pectoris and ischemic heart failure, etc.).
- the exact mechanism of vascular calcification has not yet been elucidated, and thus a preventive and therapeutic agent for this has not yet been developed.
- the pharmaceutical composition uses the same components as the pharmaceutical composition for the prevention or treatment of bone diseases, overlapping content between the two is omitted to avoid excessive description of the specification.
- Another aspect of the present invention provides a composition for inhibiting osteoclast differentiation in vitro using the compound represented by Formula 1 above.
- the compound represented by Formula 1 effectively inhibits the differentiation of macrophages into osteoclasts induced by RANKL treatment, and thus can be used for inhibiting osteoclast differentiation.
- 13-O-acetylphobol inhibits the differentiation of macrophages into osteoclasts, inhibits osteoclast activity, and has the effect of inhibiting vascular calcification, thus preventing or treating bone disease and/or vascular calcification It can be usefully used for
- Figure 2 shows the results of quantifying the actual intracellular calcium concentration after treatment with 13-O-acetylphobol while inducing calcification in human arterial smooth muscle cells.
- 3 is a result of TRAP staining after treatment with 13-O-acetylphobol while differentiating macrophages into osteoclasts (A) and the ratio of TRAP+ osteoclasts having 3 or more, or 10 or more nuclei in one cell. It is the result of confirming (B).
- 4 is a result of measuring the activity of osteoclasts after treatment with 13-O-acetylphobol while differentiating macrophages into osteoclasts.
- FIG. 5 shows the results of intracellular calcium staining after treatment with 13-O-acetylphobol or oleic acid while inducing calcification in human arterial smooth muscle cells.
- Example 1 Inhibitory effect of vascular calcification
- Human aortic smooth muscle cells which are vascular cells capable of differentiating into calcified cells by intra-arterial pathological stimulation, were dispensed on the plate and treated with calcified cell differentiation medium (including angiotensin II) for 14 days.
- 13-O-acetylphobol (0.01, 0.05, 0.1, 0.5, 1 and 2 ⁇ g/ml) was treated every 3 days.
- the differentiated cells were fixed with a fixing solution at room temperature for 5 minutes and washed several times with distilled water.
- a substrate solution of sodium tartrate and acid phosphatase was mixed, and the prepared mixture was treated with cells to stain tartrate-resistant acid phosphate (TRAP), an osteoclast differentiation marker. Staining was carried out at 37° C. for 15 to 45 minutes after covering the plate to prevent drying. After that, the dye was discarded and the reaction was stopped by washing with distilled water three times, and after observing it under a microscope, the number of stained cells was counted using the Image J program by taking pictures.
- TRIP stain tartrate-resistant acid phosphate
- the ratio of TRAP + osteoclasts having 3 or more (N ⁇ 3), or 10 or more (N ⁇ 10) nuclei in one cell was calculated.
- the ratio of TRAP + osteoclasts having 3 or more (N ⁇ 3), or 10 or more (N ⁇ 10) nuclei in the 13-O-acetylphobol treatment group was significantly higher in the 13-O-acetylphobol treatment group compared to the control group treated only with RANKL It was confirmed that the decrease (FIG. 3B).
- a bone resorption assay kit (CSR-BRA-48KIT, COSMOBIO) was used. Specifically, RAW264.7 cells were seeded on a culture dish coated with a bone imitation matrix containing a calcium-phosphate layer, and differentiation was induced by treatment with RANKL, an osteoclast differentiation inducer, at a concentration of 40 ng/ml. After that, culture was performed for a total of 4 days while changing the medium every 2 days, and 13-O-acetylphobol was treated together when the medium was replaced. After 6 days, the osteoclasts attached to the culture dish were removed by treatment with 5% sodium hypochlorite for 5 minutes. The culture dish was further washed with water and dried, and after taking a picture of each well, the pit area formed by osteoclasts decomposing the bone imitation matrix was measured as image J. The degradation area is proportional to the activity of osteoclasts.
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Abstract
The present invention relates to a pharmaceutical composition comprising 13-O-acetylphobol as an active ingredient for preventing and treating bone-related diseases and vascular calcification. 13-O-acetylphobol suppresses differentiation of macrophages into osteoclasts, inhibits osteoclast activity, and suppresses vascular calcification, thus 13-O-acetylphobol can be effectively applied to such uses.
Description
본 발명은 13-Ｏ-아세틸포볼을 유효성분으로 포함하는 골 질환 및 혈관 석회화증의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of bone disease and vascular calcification comprising 13-O-acetylphobol as an active ingredient.
골다공증(osteoporosis)은 골 형성과 골 흡수의 평형이 깨져 뼈의 질량이 감소하고 뼈 조직의 미세구조의 퇴화로 골절 위험이 지속적으로 증가하는 질환으로 뼈를 구성하는 미네랄(특히 칼슘)과 기질이 감소한 상태이다. 골 미세구조 사이의 간격이 넓어지고 미세구조가 얇아져 조그만 충격에도 뼈가 쉽게 골절될 위험이 증가한다. 골다공증의 원인으로는 노령, 운동 부족, 저체중, 흡연, 저칼슘 식이, 폐경, 난소 절제 등이 알려져 있는데, 특히 여성은 폐경기에 이르면 호르몬 변화에 의해 골 감소가 급격히 진행된다.Osteoporosis is a disease in which bone mass is reduced due to the imbalance between bone formation and bone resorption, and the risk of fracture continues to increase due to the degeneration of the microstructure of bone tissue. is the state The gap between the bone microstructures becomes wider and the microstructures become thinner, increasing the risk of easily fractured bones even with a small impact. Old age, lack of exercise, low body weight, smoking, low calcium diet, menopause, and ovarian resection are known causes of osteoporosis.
또한, 폐경기 이후의 여성은 골다공증 외에도 혈관에 인산칼슘과 같은 무기질이 침착되어 혈관이 딱딱해지는 혈관 석회화(vascular calcification)가 나타난다. 혈관 석회화는 혈관의 경직도를 증가시켜 혈관 파열을 초래하고, 심혈관계 석회화는 고혈압, 심부전, 급성 관상동맥증후군과 판막 질환의 악화에 기여하며, 이로 인한 여러 가지 합병증(심장 돌연사, 심근 경색, 협심증 및 허혈성 심부전 등)을 유발한다. 하지만, 혈관 석회화의 정확한 기전은 아직까지 밝혀져 있지 않아 이에 대한 예방 및 치료제도 아직 개발되어 있지 않은 실정이다.In addition, in postmenopausal women, in addition to osteoporosis, minerals such as calcium phosphate are deposited in blood vessels and vascular calcification, in which blood vessels are hardened, appears. Vascular calcification increases the stiffness of blood vessels, leading to vascular rupture, and cardiovascular system calcification contributes to exacerbation of hypertension, heart failure, acute coronary syndrome and valvular disease, and various complications (sudden cardiac death, myocardial infarction, angina and ischemic heart failure, etc.). However, the exact mechanism of vascular calcification has not yet been elucidated, and thus a preventive and therapeutic agent for this has not yet been developed.
이에 본 발명자들은 골다공증과 혈관 석회화 모두에 유효한 효과를 나타내는 물질을 발굴하기 위하여 노력한 결과, 13-O-아세틸포볼이 이러한 효과를 갖는 것을 확인하여 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by confirming that 13-O-acetylphobol has such an effect as a result of an effort to discover a substance having an effective effect on both osteoporosis and vascular calcification.
본 발명의 목적은 골다공증과 같은 골 질환 및 혈관 석회화를 같이 치료할 수 있는 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition capable of treating bone diseases such as osteoporosis and vascular calcification together.
상기 목적을 달성하기 위하여, 본 발명자들은 골 관련 질환, 예를 들어 골다공증과 같은 질환에 치료 효과를 갖는 물질로 13-O-아세틸포볼을 발굴하였다. 구체적으로 대식세포에 파골세포 분화 유도물질인 RANKL(receptor activator of NK-κB ligand)을 처리하여 파골세포로의 분화를 유도하면서 상기 13-O-아세틸포볼을 같이 처리하자 대식세포의 파골세포로의 분화가 억제되는 것을 알 수 있었다 (도 4). 또한, 분화된 파골세포의 활성 또한 13-O-아세틸포볼에 의해 억제되었다 (도 4).In order to achieve the above object, the present inventors have discovered 13-O-acetylphobol as a substance having a therapeutic effect on bone-related diseases, for example, diseases such as osteoporosis. Specifically, when macrophages were treated with RANKL (receptor activator of NK-κB ligand), which is an osteoclast differentiation inducer, to induce differentiation into osteoclasts, the 13-O-acetylphobol was also treated with macrophages to convert into osteoclasts. It was found that differentiation was inhibited (FIG. 4). In addition, the activity of differentiated osteoclasts was also inhibited by 13-O-acetylphobol ( FIG. 4 ).
따라서, 본 발명의 일 양상은 하기 화학식 1로 표시되는 화합물 또는 이들의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 골 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, one aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases, comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1의 화합물은 13-O-아세틸포볼(13-O-acetylphobol; CAS 60857-08-1)로 프로스트라틴(prostratin) 또는 12-Deoxyphorbol-13-Acetate로도 알려져 있다.The compound of Formula 1 is 13-O-acetylphobol (CAS 60857-08-1), also known as prostratin or 12-Deoxyphorbol-13-Acetate.
본 발명에서, 상기 골 질환은 골다공증(osteoporosis), 치주 질환(periodontal disease), 골연화증 (osteomalacia), 골감소증(osteopenia), 골결손, 골위축(bone atrophy), 골괴사, 골절(fracture), 골용해(osteolysis), 골관절염(osteoarthritis) 및 골형성 부전증(osteogenesis imperfecta)으로 이루어진 군에서 선택될 수 있으며, 바람직하게는 골다공증일 수 있다.In the present invention, the bone disease is osteoporosis, periodontal disease, osteomalacia, osteopenia, bone defect, bone atrophy, osteonecrosis, fracture, osteolysis ( osteolysis), it may be selected from the group consisting of osteoarthritis and osteoporosis imperfecta, preferably osteoporosis.
본 명세서에 사용된 용어, "골다공증"은 뼈를 구성하는 미네랄(특히 칼슘)과 기질이 감소하여 뼈 조직의 미세구조가 퇴화하고, 결과적으로 골절 위험이 지속적으로 증가하는 상태를 말한다. 파골 작용이 조골 작용보다 증가된 경우 골 재형성의 균형이 깨져서 발생하며, 원인으로는 칼슘 흡수 장애, 비타민 D 결핍, 약물 부작용, 운동 부족, 과음, 폐경, 우울증 등이 있다. 특히 여성의 경우 폐경기 이후 에스트로겐 분비량이 감소하면 활성산소가 세포에 축적되어 골 손실이 촉발되는 것으로 알려져 있다.As used herein, the term "osteoporosis" refers to a state in which the mineral (especially calcium) and matrix constituting the bone are reduced, and the microstructure of the bone tissue is deteriorated, and as a result, the risk of fractures continuously increases. When osteoclast activity is increased more than osteoblastic activity, it occurs because the balance of bone remodeling is disturbed, and the causes include calcium malabsorption, vitamin D deficiency, drug side effects, lack of exercise, excessive drinking, menopause, and depression. In particular, in the case of women, it is known that when the amount of estrogen secretion decreases after menopause, active oxygen accumulates in the cells and bone loss is triggered.
또한, 13-O-아세틸포볼은 파골세포 분화 및 활성화를 억제하는 효과 이외에 혈관 석회화 억제 효과도 나타낸다. 따라서, 상기 골 질환의 예방 또는 치료용 약학적 조성물은 혈관 석회화 억제 효과를 추가로 가질 수 있다.In addition, 13-O-acetylphobol exhibits an inhibitory effect on vascular calcification in addition to the inhibitory effect on osteoclast differentiation and activation. Accordingly, the pharmaceutical composition for the prevention or treatment of bone disease may additionally have an inhibitory effect on vascular calcification.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and when formulated, commonly used fillers, extenders, It is prepared using a diluent or excipient such as a binder, a wetting agent, a disintegrant, and a surfactant.
경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 제조된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용 액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention and at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
또한, 본 발명의 약학 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 이에 제한되는 것은 아니나, 화학식 1의 화합물은 1일 1회 내지 수회 투여 시, 체중 1 ㎏ 당 0.001 ㎎ 내지 200 ㎎, 바람직하게는 0.01 ㎎ 내지 100 ㎎, 보다 바람직하게는 0.2 ㎎ 내지 50 ㎎를 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.In addition, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of an active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination, generally limited thereto However, when the compound of Formula 1 is administered once to several times a day, 0.001 mg to 200 mg, preferably 0.01 mg to 100 mg, more preferably 0.2 mg to 50 mg per kg body weight can be administered. there is. However, since it may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
본 발명의 다른 양상은 상기 화학식 1로 표시되는 화합물 또는 이들의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 골 질환의 예방 또는 개선용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for preventing or improving bone disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 식품 조성물은 골 질환의 예방 또는 치료용 약학적 조성물과 동일한 성분을 사용하므로 이 둘 사이에 중복되는 내용은 명세서의 과도한 기재를 피하기 위하여 생략한다.Since the food composition uses the same ingredients as the pharmaceutical composition for the prevention or treatment of bone diseases, overlapping content between the two is omitted to avoid excessive description of the specification.
본 발명에서, 상기 식품 조성물은 분말, 과립, 정제, 캡슐, 시럽, 음료 또는 환의 형태로 제공될 수 있으며, 유효성분인 화학식 1로 표시되는 화합물 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.In the present invention, the food composition may be provided in the form of powder, granule, tablet, capsule, syrup, beverage or pill, and is used together with other food or food additives in addition to the compound represented by Formula 1 as an active ingredient, a conventional method can be used appropriately. The mixing amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.
상기 식품 조성물에 함유된 유효성분의 유효용량은 상기 약학 조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the active ingredient contained in the food composition may be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or health control, it may be less than the above range, It is certain that the active ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.
상기 식품 조성물은 식품 제조시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로텍스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 및 합성 향미제를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 유효성분 외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙 등을 추가로 포함시킬 수 있다.The food composition includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides such as conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. As flavoring agents, natural flavoring agents and synthetic flavoring agents can be used. For example, when the food composition of the present invention is prepared as a drink, citric acid, fructose liquid, sugar, glucose, acetic acid, malic acid, fruit juice, etc. may be additionally included in addition to the active ingredient of the present invention.
상기 기재한 바와 같이 13-O-아세틸포볼은 혈관 석회화 억제 효과도 가진다. 따라서, 본 발명의 다른 양상은 상기 화학식 1의 화합물을 유효성분으로 포함하는 혈관 석회화증의 예방 또는 치료용 약학적 조성물, 예방 또는 개선용 식품 조성물을 제공한다.As described above, 13-O-acetylphobol also has an inhibitory effect on vascular calcification. Accordingly, another aspect of the present invention provides a pharmaceutical composition for preventing or treating vascular calcification, and a food composition for preventing or improving, comprising the compound of Formula 1 as an active ingredient.
혈관 석회화(vascular calcification)는 혈관에 인산칼슘과 같은 무기질이 침착되어 혈관이 딱딱해지는 증상으로 혈관의 경직도를 증가시켜 혈관 파열을 초래한다. 특히, 심혈관계 석회화는 고혈압, 심부전, 급성 관상동맥증후군과 판막 질환의 악화에 기여하며, 이로 인한 여러 가지 합병증(심장 돌연사, 심근 경색, 협심증 및 허혈성 심부전 등)을 유발한다. 하지만, 혈관 석회화의 정확한 기전은 아직까지 밝혀져 있지 않아 이에 대한 예방 및 치료제도 아직 개발되어 있지 않은 실정이다.Vascular calcification is a symptom in which minerals such as calcium phosphate are deposited in the blood vessels and harden the blood vessels, which increases the stiffness of the blood vessels, leading to vascular rupture. In particular, cardiovascular calcification contributes to the exacerbation of hypertension, heart failure, acute coronary syndrome and valvular disease, leading to various complications (sudden cardiac death, myocardial infarction, angina pectoris and ischemic heart failure, etc.). However, the exact mechanism of vascular calcification has not yet been elucidated, and thus a preventive and therapeutic agent for this has not yet been developed.
상기 약학적 조성물은 골 질환의 예방 또는 치료용 약학적 조성물과 동일한 성분을 사용하므로 이 둘 사이에 중복되는 내용은 명세서의 과도한 기재를 피하기 위하여 생략한다.Since the pharmaceutical composition uses the same components as the pharmaceutical composition for the prevention or treatment of bone diseases, overlapping content between the two is omitted to avoid excessive description of the specification.
본 발명의 또 다른 양상은 상기 화학식 1로 표시되는 화합물을 이용한 시험관내 파골세포 분화 억제용 조성물을 제공한다.Another aspect of the present invention provides a composition for inhibiting osteoclast differentiation in vitro using the compound represented by Formula 1 above.
본 발명의 일 구체예에서, 상기 화학식 1로 표시되는 화합물은 RANKL 처리에 의하여 유도되는 대식세포의 파골세포로의 분화를 효과적으로 억제하였으므로 파골세포 분화 억제 용도로 사용될 수 있다.In one embodiment of the present invention, the compound represented by Formula 1 effectively inhibits the differentiation of macrophages into osteoclasts induced by RANKL treatment, and thus can be used for inhibiting osteoclast differentiation.
본 발명에 따른 13-O-아세틸포볼은 대식세포의 파골세포로의 분화를 억제하고, 파골세포의 활성을 저해하며, 혈관 석회화를 억제하는 효과가 있으므로 골 질환 및/또는 혈관 석회화의 예방 또는 치료 용도로 유용하게 사용될 수 있다.13-O-acetylphobol according to the present invention inhibits the differentiation of macrophages into osteoclasts, inhibits osteoclast activity, and has the effect of inhibiting vascular calcification, thus preventing or treating bone disease and/or vascular calcification It can be usefully used for
도 1은 인간 동맥 평활근 세포에 석회화증을 유도하면서 13-O-아세틸포볼을 같이 처리한 후 세포 내 칼슘을 염색한 결과이다.1 shows the results of intracellular calcium staining after treatment with 13-O-acetylphobol while inducing calcification in human arterial smooth muscle cells.
도 2는 인간 동맥 평활근 세포에 석회화증을 유도하면서 13-O-아세틸포볼을 같이 처리한 후 세포 내 실제 칼슘 농도를 정량한 결과이다.Figure 2 shows the results of quantifying the actual intracellular calcium concentration after treatment with 13-O-acetylphobol while inducing calcification in human arterial smooth muscle cells.
도 3은 대식세포를 파골세포로 분화시키면서 13-O-아세틸포볼을 같이 처리한 후 TRAP을 염색한 결과(A) 및 한 세포에 3개 이상, 또는 10개 이상의 핵을 가지는 TRAP+ 파골세포의 비율(B)을 확인한 결과이다. 3 is a result of TRAP staining after treatment with 13-O-acetylphobol while differentiating macrophages into osteoclasts (A) and the ratio of TRAP+ osteoclasts having 3 or more, or 10 or more nuclei in one cell. It is the result of confirming (B).
도 4는 대식세포를 파골세포로 분화시키면서 13-O-아세틸포볼을 같이 처리한 후 파골세포의 활성을 측정한 결과이다.4 is a result of measuring the activity of osteoclasts after treatment with 13-O-acetylphobol while differentiating macrophages into osteoclasts.
도 5는 인간 동맥 평활근 세포에 석회화증을 유도하면서 13-O-아세틸포볼 또는 올레산을 같이 처리한 후 세포 내 칼슘을 염색한 결과이다. 5 shows the results of intracellular calcium staining after treatment with 13-O-acetylphobol or oleic acid while inducing calcification in human arterial smooth muscle cells.
도 6은 인간 동맥 평활근 세포에 석회화증을 유도하면서 13-O-아세틸포볼 또는 올레산을 같이 처리한 후 세포 내 실제 칼슘 농도를 정량한 결과이다.6 shows the results of quantifying the actual intracellular calcium concentration after treatment with 13-O-acetylphobol or oleic acid while inducing calcification in human arterial smooth muscle cells.
도 7은 도 3은 대식세포를 파골세포로 분화시키면서 13-O-아세틸포볼 또는 올레산을 같이 처리한 후 TRAP을 염색한 결과이다.7 shows the results of TRAP staining after treatment with 13-O-acetylphobol or oleic acid while differentiating macrophages into osteoclasts.
이하 하나 이상의 구체예를 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are for illustrative purposes of one or more embodiments, and the scope of the present invention is not limited to these examples.
실시예 1: 혈관 석회화 억제 효과Example 1: Inhibitory effect of vascular calcification
동맥경화반 내에 존재하는 석회화증을 대상으로 13-O-아세틸포볼 (13-O-acetylphobol, prostratin; CAS 60857-08-1)의 영향을 다음과 같이 확인하였다. 석회화의 증가는 심혈관 질환의 증가와 연관이 있다.The effect of 13-O-acetylphobol (13-O-acetylphobol, prostratin; CAS 60857-08-1) on calcification existing in atherosclerotic plaque was confirmed as follows. An increase in calcification is associated with an increase in cardiovascular disease.
동맥 내 병리학적 자극에 의해 석회화 세포로 분화할 수 있는 혈관세포인 인간 동맥 평활근 세포(human aortic smooth muscle cell)를 플레이트에 분주하고, 석회화 세포 분화배지(angiotensin II 포함)를 14일 동안 처리하였다. 13-O-아세틸포볼(0.01, 0.05, 0.1, 0.5, 1 및 2 ㎍/㎖)은 3일마다 처리하였다.Human aortic smooth muscle cells, which are vascular cells capable of differentiating into calcified cells by intra-arterial pathological stimulation, were dispensed on the plate and treated with calcified cell differentiation medium (including angiotensin II) for 14 days. 13-O-acetylphobol (0.01, 0.05, 0.1, 0.5, 1 and 2 μg/ml) was treated every 3 days.
14일 후 칼슘을 염색할 수 있는 알리자린 레드(alizarin red)로 세포를 염색하여 석회화 정도를 확인하고, 10% 아세트산으로 염색된 알리자린 레드를 추출하여 농도를 측정하였다. 데이터는 평균±표준오차로 나타내었다. 그 결과, 13-O-아세틸포볼을 처리하지 않은 대조군과 비교하여 13-O-아세틸포볼 처리군에서는 처리 농도에 의존적으로 석회화가 억제된 것을 확인할 수 있었다 (도 1).After 14 days, cells were stained with alizarin red, which can stain calcium, to determine the degree of calcification, and alizarin red stained with 10% acetic acid was extracted and the concentration was measured. Data are presented as mean ± standard error. As a result, it was confirmed that calcification was inhibited in a concentration-dependent manner in the 13-O-acetylphobol treated group compared to the 13-O-acetylphobol-treated control group ( FIG. 1 ).
또한, 세포 내 실제 칼슘 농도를 정량한 결과, 대조군과 비교하여 13-O-아세틸포볼 처리군에서는 처리 농도에 의존적으로 세포 내 칼슘 농도가 감소하는 것을 알 수 있었다 (도 2).In addition, as a result of quantifying the actual intracellular calcium concentration, it was found that the 13-O-acetylphobol treated group decreased the intracellular calcium concentration dependently on the treatment concentration as compared to the control group ( FIG. 2 ).
실시예 2: 파골세포 활성화 억제Example 2: Inhibition of osteoclast activation
2-1. TRAP 염색2-1. TRAP staining
48-웰 플레이트에 마우스 대식세포주인 RAW264.7 세포를 각 웰당 3x103개씩 분주하고, 파골세포 분화 유도물질인 RANKL(receptor activator of NK-κB ligand)을 40 ng/㎖ 농도로 처리하여 분화를 유도하였다. 이후 2일마다 배지를 교체하면서 총 4일동안 배양하고, 배지를 교체할 때 13-O-아세틸포볼을 같이 처리하였다.In a 48-well plate, 3x10 3 of RAW264.7 cells, a mouse macrophage cell line, were dispensed into each well, and RANKL (receptor activator of NK-κB ligand), an osteoclast differentiation inducer, was treated at a concentration of 40 ng/ml to induce differentiation. did. After that, culture was performed for a total of 4 days while changing the medium every 2 days, and 13-O-acetylphobol was treated together when the medium was replaced.
4일 후 분화된 세포를 고정액으로 상온에서 5분 동안 고정시키고 증류수로 여러 번 세척하였다. 타타르산 나트륨(sodium tartrate)과 산성 인산분해효소(acid phosphatase)의 기질 용액을 혼합하고, 상기 준비된 혼합액을 세포에 처리하여 파골세포 분화 마커인 TRAP(tartrate-resistant acid phosphate)을 염색하였다. 염색은 건조 방지를 위해 플레이트의 뚜껑을 덮은 뒤 37℃에서 15분 내지 45분 동안 진행하였다. 이후 염색약을 버리고 증류수로 3번 세척하여 반응을 중단시켰으며, 현미경으로 관찰한 뒤 사진을 찍어 이미지 J 프로그램으로 염색된 세포의 수를 계산하였다.After 4 days, the differentiated cells were fixed with a fixing solution at room temperature for 5 minutes and washed several times with distilled water. A substrate solution of sodium tartrate and acid phosphatase was mixed, and the prepared mixture was treated with cells to stain tartrate-resistant acid phosphate (TRAP), an osteoclast differentiation marker. Staining was carried out at 37° C. for 15 to 45 minutes after covering the plate to prevent drying. After that, the dye was discarded and the reaction was stopped by washing with distilled water three times, and after observing it under a microscope, the number of stained cells was counted using the Image J program by taking pictures.
실험 결과, RANKL만 처리한 대조군과 비교하여 13-O-아세틸포볼 처리군에서는 파골세포의 분화가 억제된 것을 알 수 있었다 (도 3의 A). 구체적으로 파골세포의 활성은 뼈의 기질인 칼슘-포스페이트(calcium-phosphate)를 녹이는 것으로 판명하는데, 도 3의 A에서 갈색 중 하얀 구멍들이 파골세포가 활성화되어 기질을 녹여낸 것이다. RANKL 처리에 의해 늘어난 하얀색 구멍의 수 및 평균 면적이 13-O-아세틸포볼의 처리에 의해 감소하고 작아진 것을 알 수 있다.As a result of the experiment, it was found that the differentiation of osteoclasts was inhibited in the 13-O-acetylphobol treated group compared to the control group treated only with RANKL (FIG. 3A). Specifically, the activity of osteoclasts is found to dissolve calcium-phosphate, a bone matrix, and white holes in brown in FIG. 3A indicate that osteoclasts are activated to dissolve the matrix. It can be seen that the number and average area of white pores increased by RANKL treatment decreased and decreased by treatment with 13-O-acetylphobol.
또한, 파골세포는 다수의 핵을 가지는 것이 특징이므로 한 세포에 3개 이상(N≥3), 또는 10개 이상(N≥10)의 핵을 가지는 TRAP+ 파골세포의 비율을 계산하였다. 그 결과, RANKL만 처리한 대조군과 비교하여 13-O-아세틸포볼 처리군에서는 3개 이상(N≥3), 또는 10개 이상(N≥10)의 핵을 가지는 TRAP+ 파골세포의 비율이 현저히 감소하는 것을 확인하였다 (도 3의 B).In addition, since osteoclasts are characterized by having a large number of nuclei, the ratio of TRAP + osteoclasts having 3 or more (N≥3), or 10 or more (N≥10) nuclei in one cell was calculated. As a result, the ratio of TRAP + osteoclasts having 3 or more (N≥3), or 10 or more (N≥10) nuclei in the 13-O-acetylphobol treatment group was significantly higher in the 13-O-acetylphobol treatment group compared to the control group treated only with RANKL It was confirmed that the decrease (FIG. 3B).
2-2. Pit assay2-2. Pit assay
RAW264.7 세포가 RANKL 처리에 의해 파골세포로 분화되었을 때의 활성을 확인하기 위해 Bone resorption assay kit (CSR-BRA-48KIT, COSMOBIO)를 사용하였다. 구체적으로 칼슘-포스페이트 층을 함유한 뼈 모사 매트리스가 도포되어 있는 배양접시 위에 RAW264.7 세포를 분주하고, 파골세포 분화 유도물질인 RANKL을 40 ng/㎖ 농도로 처리하여 분화를 유도하였다. 이후 2일마다 배지를 교체하면서 총 4일동안 배양하고, 배지를 교체할 때 13-O-아세틸포볼을 같이 처리하였다. 6일 후 5% 차아염소산 나트륨(sodium hypochlorite)을 5분 동안 처리하여 배양접시에 붙어 있는 파골세포를 제거하였다. 배양접시는 물로 추가로 세척한 후 건조시키고, 각 웰의 사진을 찍은 후 파골세포가 뼈 모사 매트리스를 분해하여 형성된 분해 면적(pit area)을 이미지 J로 측정하였다. 상기 분해 면적은 파골세포의 활성과 비례한다.To confirm the activity of RAW264.7 cells differentiated into osteoclasts by RANKL treatment, a bone resorption assay kit (CSR-BRA-48KIT, COSMOBIO) was used. Specifically, RAW264.7 cells were seeded on a culture dish coated with a bone imitation matrix containing a calcium-phosphate layer, and differentiation was induced by treatment with RANKL, an osteoclast differentiation inducer, at a concentration of 40 ng/ml. After that, culture was performed for a total of 4 days while changing the medium every 2 days, and 13-O-acetylphobol was treated together when the medium was replaced. After 6 days, the osteoclasts attached to the culture dish were removed by treatment with 5% sodium hypochlorite for 5 minutes. The culture dish was further washed with water and dried, and after taking a picture of each well, the pit area formed by osteoclasts decomposing the bone imitation matrix was measured as image J. The degradation area is proportional to the activity of osteoclasts.
측정 결과, RANKL만 처리한 대조군과 비교하여 13-O-아세틸포볼 처리군에서는 처리 농도 0.5 ㎍/㎖부터 유의미한 분해 면적 감소를 보이는 것을 확인하였다 (도 4).As a result of the measurement, it was confirmed that the 13-O-acetylphobol treated group showed a significant decrease in the decomposition area from the treatment concentration of 0.5 μg/ml compared to the control group treated only with RANKL ( FIG. 4 ).
비교예 1: 파골세포 활성 억제Comparative Example 1: Inhibition of osteoclast activity
13-O-아세틸포볼이 PKC (protein kinase C)의 활성화제로 알려져 있으므로 상기 실시예 1 및 2와 동일한 실험을 진행하여 다른 PKC 활성화제인 올레산(oleic acid)과 효과를 비교하였다.Since 13-O-acetylphobol is known as an activator of PKC (protein kinase C), the same experiment as in Examples 1 and 2 was performed to compare the effect with other PKC activators, oleic acid.
그 결과, 13-O-아세틸포볼은 혈관 석회화를 억제하지만 올레산은 혈관 석회화 억제 효과가 없는 것을 확인할 수 있었다 (도 5). 세포 내 칼슘 농도 또한 올레산 처리에 의해서는 유의미한 변화가 없는 것을 알 수 있었다 (도 6).As a result, it was confirmed that 13-O-acetylphobol inhibited vascular calcification, but oleic acid had no inhibitory effect on vascular calcification ( FIG. 5 ). It was also found that there was no significant change in the intracellular calcium concentration by oleic acid treatment (FIG. 6).
또한, TRAP을 염색하여 파골세포 활성을 확인한 결과 동일한 처리 농도에서 13-O-아세틸포볼은 파골세포의 활성을 억제하지만 올레산은 효과가 없는 것을 확인할 수 있었다 (도 7).In addition, as a result of confirming osteoclast activity by staining TRAP, it was confirmed that 13-O-acetylphobol inhibited osteoclast activity at the same treatment concentration, but oleic acid had no effect (FIG. 7).
Claims (9)
- 하기 화학식 1로 표시되는 화합물 또는 이들의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 골 질환의 예방 또는 치료용 약학적 조성물로서,As a pharmaceutical composition for the prevention or treatment of bone disease comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,상기 골 질환은 골다공증, 치주 질환, 골연화증, 골감소증, 골결손, 골위축, 골괴사, 골절, 골용해, 골관절염 및 골형성 부전증으로 이루어진 군에서 선택되는, 골 질환의 예방 또는 치료용 약학적 조성물.The bone disease is selected from the group consisting of osteoporosis, periodontal disease, osteomalacia, osteopenia, bone defect, bone atrophy, osteonecrosis, fracture, osteolysis, osteoarthritis and osteodystrophy, a pharmaceutical composition for preventing or treating bone disease.[화학식 1][Formula 1]
- 제1항에 있어서, 상기 약학적 조성물은 대식세포의 파골세포로의 분화 또는 파골세포의 활성을 억제하는, 골 질환의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating bone disease according to claim 1, wherein the pharmaceutical composition inhibits the differentiation of macrophages into osteoclasts or the activity of osteoclasts.
- 제1항에 있어서, 상기 약학적 조성물은 혈관 석회화증의 예방 또는 치료 효과를 추가로 나타내는, 골 질환의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating bone disease according to claim 1, wherein the pharmaceutical composition further exhibits an effect of preventing or treating vascular calcification.
- 제1항 내지 제3항 중 어느 한 항에 따른 약학적 조성물을 치료가 필요한 개체에 투여하는 단계를 포함하는 골 질환의 치료 방법으로서,A method for treating bone disease, comprising administering the pharmaceutical composition according to any one of claims 1 to 3 to a subject in need thereof,상기 골 질환은 골 질환은 골다공증, 치주 질환, 골연화증, 골감소증, 골결손, 골위축, 골괴사, 골절, 골용해, 골관절염 및 골형성 부전증으로 이루어진 군에서 선택되는, 골 질환의 치료 방법.The bone disease is a bone disease selected from the group consisting of osteoporosis, periodontal disease, osteomalacia, osteopenia, bone defect, bone atrophy, osteonecrosis, fracture, osteolysis, osteoarthritis and osteodystrophy, a method of treating a bone disease.
- 하기 화학식 1로 표시되는 화합물 또는 이들의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 골 질환의 예방 또는 개선용 식품 조성물로서,As a 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,상기 골 질환은 골다공증, 치주 질환, 골연화증, 골감소증, 골결손, 골위축, 골괴사, 골절, 골용해, 골관절염 및 골형성 부전증으로 이루어진 군에서 선택되는, 골 질환의 예방 또는 개선용 식품 조성물.The bone disease is selected from the group consisting of osteoporosis, periodontal disease, osteomalacia, osteopenia, bone defect, bone atrophy, osteonecrosis, fracture, osteolysis, osteoarthritis and osteodystrophy, a food composition for preventing or improving bone disease.[화학식 1][Formula 1]
- 하기 화학식 1로 표시되는 화합물 또는 이들의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 혈관 석회화증의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating vascular calcification comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.[화학식 1][Formula 1]
- 제5항에 있어서, 상기 약학적 조성물은 혈관 세포 내의 칼슘 농도를 감소시키는, 혈관 석회화증의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating vascular calcification according to claim 5, wherein the pharmaceutical composition reduces the calcium concentration in vascular cells.
- 제6항 또는 제7항의 약학적 조성물을 치료가 필요한 개체에 투여하는 단계를 포함하는 혈관 석회화증의 치료 방법.A method of treating vascular calcification comprising administering the pharmaceutical composition of claim 6 or 7 to a subject in need of treatment.
- 하기 화학식 1로 표시되는 화합물 또는 이들의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 혈관 석회화증의 예방 또는 개선용 식품 조성물.A food composition for preventing or improving vascular calcification comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.[화학식 1][Formula 1]
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