KR102142112B1 - Compound preventing and treating of bone disease and Use therof - Google Patents
Compound preventing and treating of bone disease and Use therof Download PDFInfo
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- KR102142112B1 KR102142112B1 KR1020170099768A KR20170099768A KR102142112B1 KR 102142112 B1 KR102142112 B1 KR 102142112B1 KR 1020170099768 A KR1020170099768 A KR 1020170099768A KR 20170099768 A KR20170099768 A KR 20170099768A KR 102142112 B1 KR102142112 B1 KR 102142112B1
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Abstract
본 발명은 골 질환 예방 또는 치료용 화합물 및 이의 용도에 대한 것으로, 보다 구체적으로는 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환의 예방 또는 치료용 약학적 조성물에 대한 것이다.
본 발명에 따른 화합물들은 뼈 손실을 야기하는 파골세포에 대하여 강력한 증식 및 분화 억제 활성을 나타내고, 동시에 조골세포 분화 및 활성을 현저하게 증가시키기 때문에 안전하고 효과적인 골다공증 등 골 질환 예방 및 치료제 또는 개선용 의약품 및 식품을 개발하는데 유용하게 이용될 수 있다. The present invention relates to a compound for preventing or treating bone diseases and uses thereof, and more particularly, to a pharmaceutical composition for preventing or treating bone diseases comprising a compound represented by Formula 1 as an active ingredient.
The compounds according to the present invention show potent proliferation and differentiation inhibitory activity against osteoclasts that cause bone loss, and at the same time, significantly increase osteoblast differentiation and activity, and thus prevent and treat or improve bone diseases such as osteoporosis and safe and effective drugs And it can be usefully used to develop food.
Description
본 발명은 골 질환 예방 또는 치료용 화합물 및 이의 용도에 대한 것으로, 보다 구체적으로는 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환의 예방 또는 치료용 약학적 조성물에 대한 것이다. The present invention relates to a compound for preventing or treating bone diseases and uses thereof, and more particularly, to a pharmaceutical composition for preventing or treating bone diseases comprising a compound represented by Formula 1 as an active ingredient.
뼈는 몸의 골격 구조를 형성하고 혈중 칼슘(Ca2+) 수준을 유지하는 데 매우 중요한 역할을 한다. 뼈는 대사적으로 뼈를 흡수하는 파골세포(osteoclast)와 생성하는 조골세포(osteoblast) 간의 뼈 리모델링 순환(bone remodelling cycle)의 균형을 통해 유지된다. 뼈의 흡수와 생성 간의 균형이 파괴되어 흡수량이 생성량보다 많아지면 다양한 뼈 관련 질환이 발생하며, 파골세포의 분화 및 활성화와 관련된 대표적인 질환은 골다공증, 류마티스관절염, 관절통, 파제트 병, 골 전이암 및 골절 등을 들 수 있다.(Kim JH and Kim N, 2016; Shiozawa Y et al., 2011; Singer FR, 2016). Bone plays a very important role in forming the body's skeletal structure and maintaining the level of calcium (Ca 2+ ) in the blood. Bone is maintained through a balance of bone remodeling cycles between metabolically absorbing osteoclasts and producing osteoblasts. When the balance between bone absorption and production is destroyed and absorption is greater than the amount of production, various bone-related diseases occur, and typical diseases related to osteoclast differentiation and activation are osteoporosis, rheumatoid arthritis, joint pain, Paget's disease, bone metastasis cancer, and Fractures, etc. (Kim JH and Kim N, 2016; Shiozawa Y et al ., 2011; Singer FR, 2016).
류마티스 관절염은 자가면역질환인데 자가면역항체가 파골세포 분화를 촉진한다. 그로 인한 과도한 골 흡수는 류마티스관절염을 악화시킨다(Takayanagi H, 2007). 그 기전은 다음과 같다. 파골세포 분화 관련 중추적인 전사인자인 NFAT 전사인자들은(NFATc1/c2/c3/c4) 기본적으로 calcium/calmodulin signaling에 의하여 활성화된다(Takayanagi H et al., 2002). 완전한 활성화를 위해서는 면역조절 단백질들인 DNAX-activating protein 12(DAP12) 및 면역항체 Fc receptor common γ chain(FcRγ)과 같은 tyrosine-based activation motif (ITAM)-bearing molecule들이 면역세포에서 calcium signaling을 자극한다(Pitcher LA and van Oers NS, 2003). 파골세포에서 역시 DAP12와 FcRγ가 calcium signaling을 통하여 NFATc1을 활성화시킨다. 따라서 DAP12 및 FcRγ와 연계된 immunoglobulin-like receptor가 파골세포 분화에서 중요한 역할을 한다(Koga T et al., 2004; MoA et al., 2004). 즉, FcRγ는 파골세포에서 osteoclast-associated receptor(OSCAR) 및 paired immunoglobulin-like receptor(PIR-A)와 상호작용한다. ITAM이 인산화되면 phospholipase C γ(PLCγ)를 활성화하고 이는 세포 내 calcium을 유리하고 이는 calmodulin-dependent phosphatase인 calcineurin을 활성화한다. Calcineurin은 직접 NFATc1의 serine을 탈인산화하여 핵 내로 보내고 활성화시킨다. 결과적으로 면역항체는 파골세포 분화를 촉진하게 되고, 파골세포에 의한 과도한 골 흡수는 류마티스 관절염을 악화시키게 된다. 결국, 류마티스관절염 환자에서 파골세포 분화 억제는 자가면역기전 자체의 이상을 교정하지는 못 해도 그 결과 유발된 골다공증과 통증 등 골격계 증상은 치료할 수 있다. Rheumatoid arthritis is an autoimmune disease, but autoimmune antibodies promote osteoclast differentiation. The resulting excessive bone absorption exacerbates rheumatoid arthritis (Takayanagi H, 2007). The mechanism is as follows. NFAT transcription factors (NFATc1/c2/c3/c4), a central transcription factor related to osteoclast differentiation, are basically activated by calcium/calmodulin signaling (Takayanagi H et al ., 2002). For complete activation, tyrosine-based activation motif (ITAM)-bearing molecules such as the immunomodulatory proteins DNAX-activating protein 12 (DAP12) and the immune antibody Fc receptor common γ chain (FcRγ) stimulate calcium signaling in immune cells ( Pitcher LA and van Oers NS, 2003). In osteoclasts, DAP12 and FcRγ also activate NFATc1 through calcium signaling. Therefore, immunoglobulin-like receptors linked to DAP12 and FcRγ play an important role in osteoclast differentiation (Koga T et al ., 2004; MoA et al ., 2004). That is, FcRγ interacts with osteoclast-associated receptor (OSCAR) and paired immunoglobulin-like receptor (PIR-A) in osteoclasts. When ITAM is phosphorylated, it activates phospholipase C γ (PLCγ), which promotes intracellular calcium, which activates calmodulin-dependent phosphatase, calcineurin. Calcineurin dephosphorylates serine of NFATc1 directly into the nucleus and activates it. As a result, immune antibodies promote osteoclast differentiation, and excessive bone absorption by osteoclasts exacerbates rheumatoid arthritis. Eventually, suppression of osteoclast differentiation in patients with rheumatoid arthritis can treat skeletal symptoms such as osteoporosis and pain caused as a result of not correcting the abnormalities of the autoimmune mechanism itself.
파제트 병(Osteitis deformans) 역시 파골세포의 비정상적 골 흡수가 유발한다(Singer FR, 2016). 그러면 조골세포의 비정상적 골 생성이 진행되고 이 과정이 반복되면서 골의 기형과 그로 인한 통증, 두통, 청력손실 등이 초래된다. 팔, 다리, 골반, 척추, 두개골에 호발한다. 새로 생성된 골은 약하여 골절 빈도가 높다. 고칼슘혈증, 심장마비, 반신불수가 유발될 수 있다(Ralstone SH, 2016). 발병 원인은 밝혀져 있지 않으나 유전적 소인과 어릴 적 바이러스 감염이 그 원인으로 의심된다. 약물치료가 병의 진행을 억제하는데 도움이 된다. 현재 가장 많이 사용하는 치료제는 파골세포 분화 억제제인 Fosamax 및 골 대사를 조절하는 calcitonin이다. 하지만 Fosamax는 부작용으로 일부 환자에서 장기 복용이 제한적이다. 통증이 심하면 Acetaminophen(Tylenol)이나 nonsteroidal anti-inflammatory drugs(NSAIDs)를 사용한다. Osteitis deformans also cause abnormal bone resorption of osteoclasts (Singer FR, 2016). Then, abnormal bone formation of osteoblasts progresses, and this process is repeated, resulting in bone deformity and resulting pain, headache, and hearing loss. It affects the arms, legs, pelvis, spine and skull. The newly created bones are weak and the frequency of fractures is high. Hypercalcemia, heart attack and hemiplegia can be induced (Ralstone SH, 2016). The cause of the outbreak is unknown, but genetic predisposition and childhood viral infections are suspected. Medication can help suppress disease progression. Currently, the most used treatments are Fosamax, an osteoclast differentiation inhibitor, and calcitonin, which regulates bone metabolism. However, Fosamax is a side effect and long-term use is limited in some patients. For severe pain, use Acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (NSAIDs).
파골세포는 또한 고형암(solid tumor)의 골 전이를 촉진한다. 뼈는 암의 전이가 가장 호발하는 부위이다. 뼈에 암이 전이되면 극심한 통증과 함께 뼈가 부서져서 완치 가능성이 현저히 낮아진다(Weilbaecher KN et al., 2011). 전신에 퍼진 암세포들은 골수 내의 혈액 줄기세포 증식 장소에서 발견된다(Shiozawa Y et al., 2013). 암세포는 골수세포로부터 파골세포의 분화를 현저히 촉진하여 골 파괴와 이로 인한 골 전이, 암 성장을 촉진한다. 따라서 파골세포는 암의 골 전이에서 핵심적인 역할을 하여 파골세포 분화를 억제하면 골 전이가 감소한다. 많은 고형암의 전이가 골 전이인데 혈액 줄기세포 증식 장소를 거점으로 혈액 줄기세포를 몰아내고 증식하다가 다시 혈액으로 나와 다른 곳으로 전이하기도 한다. 골 전이가 가장 흔한 암은 전립선암으로서 골 전이가 암을 악화시켜서 완치를 어렵게 하고 사망의 주요 원인이다. 사람 전립선 암세포의 직접적인 주요 표적 역시 혈액 줄기세포 증식 장소로서 전이암의 거점으로 사용한다(Shiozawa Y et al., 2011). 또한 파골세포는 전립선 암 조직 내에 혈관 형성을 촉진하여 암 성장을 촉진한다(Bruni-Cardoso A et al., 2010). 유방암 세포도 파골세포 분화를 촉진하여, 유방 절제술을 시행한 유방암 환자에서 파골세포가 골 전이를 통한 암 재발을 촉진한다(Danilin S et al., 2012; Lu X et al., 2011). Osteoclasts also promote bone metastasis of solid tumors. Bones are the most prone to cancer metastasis. When cancer spreads to the bone, the likelihood of cure is significantly lowered due to severe pain and bone fracture (Weilbaecher KN et al ., 2011). Cancer cells spread throughout the body are found at the site of proliferation of blood stem cells in the bone marrow (Shiozawa Y et al ., 2013). Cancer cells significantly promote the differentiation of osteoclasts from bone marrow cells, thereby promoting bone destruction, resulting bone metastasis, and cancer growth. Therefore, osteoclasts play a key role in bone metastasis of cancer, and when osteoclast differentiation is suppressed, bone metastasis decreases. The metastasis of many solid cancers is bone metastasis, and blood stem cells are driven out from the place where blood stem cells proliferate, and then they are multiplied and then released into the blood before being transferred to other places. The most common cancer of bone metastasis is prostate cancer, and bone metastasis exacerbates cancer, making it difficult to cure and leading to death. The main direct target of human prostate cancer cells is also used as a base for metastatic cancer as a place for proliferation of blood stem cells (Shiozawa Y et al ., 2011). In addition, osteoclasts promote blood vessel formation in prostate cancer tissues, thereby promoting cancer growth (Bruni-Cardoso A et al ., 2010). Breast cancer cells also promote osteoclast differentiation, where osteoclasts promote cancer recurrence through bone metastasis in breast resection patients (Danilin S et al ., 2012; Lu X et al ., 2011).
골 전이암을 예방하기 위한 골 표적 치료제가 현재 임상에서 사용되고 있으며 파골세포가 암 골 전이의 핵심 기전 중 하나이므로 항암 신약개발의 주요 표적이 되고 있다. 이에 따라 파골세포 분화를 억제하기 위한 목적으로 현재 미국 FDA 승인을 받은 유일한 bisphosphonate 계열 약제가 Zoledronic acid이다(El-Amm J et al., 2013). Zoledronic acid는 뼈를 보존하고 생존률을 높인다. 고 위험 비전이 전립선암(high risk nonmetastatic prostate cancer)에서 Zoledronic acid는 골 전이를 크게 감소시켰다(Wirth M et al., 2014). Zoledronic acid를 골 생성 촉진제인 부갑상선호르몬(parathyroid hormone)과 함께 투여하면 골 전이가 더욱 감소하였다(Schneider A et al.,2005). 파골세포 분화의 신호전달물질인 RANKL에 대한 단클론 항체(monoclonal antibody)인 Denosumab 역시 전립선암의 골 전이를 억제하여 파골세포 억제가 암의 골 전이 억제에 중요함이 다시 입증되었다(Smith MR et al., 2012). Multiple myeloma 환자에서도 Zoledronic acid를 투여하면 파골세포 분화가 억제되어 골 전이가 현저히 억제된다(Zhuang J et al., 2012). Bone targeting therapies to prevent bone metastasis are currently being used in clinical trials, and osteoclasts are one of the key mechanisms of cancer metastasis, making them a major target for the development of new anticancer drugs. Accordingly, the only bisphosphonate-based drug currently approved by the United States FDA for the purpose of suppressing osteoclast differentiation is Zoledronic acid (El-Amm J et al ., 2013). Zoledronic acid preserves bones and increases survival. In high risk nonmetastatic prostate cancer, Zoledronic acid significantly reduced bone metastasis (Wirth M et al ., 2014). Bone metastasis was further reduced when zoledronic acid was administered with parathyroid hormone, an agent for promoting bone formation (Schneider A et al ., 2005). Denosumab, a monoclonal antibody against RANKL, a signaling agent for osteoclast differentiation, also inhibited bone metastasis of prostate cancer, and it was again proved that osteoclast suppression is important for suppressing bone metastasis of cancer (Smith MR et al . , 2012). In multiple myeloma patients, administration of Zoledronic acid inhibited osteoclast differentiation, significantly inhibiting bone metastasis (Zhuang J et al ., 2012).
다핵성 파골세포의 골흡수능으로 인해 골용해(osteolysis)가 발생한다. 따라서, 파골세포의 분화를 억제하고, 단핵 파골세포의 융합에 의해 다핵성 파골세포가 형성되는 것을 억제하며, 다핵성 파골세포의 골흡수능도 감소시킴으로써, 이러한 골용해를 효과적으로 억제할 수 있다.Osteolysis occurs due to the ability of multinucleated osteoclasts to absorb bone. Therefore, by suppressing the differentiation of osteoclasts, suppressing the formation of multinucleated osteoclasts by fusion of mononuclear osteoclasts, and also reducing the bone resorption capacity of multinuclear osteoclasts, it is possible to effectively suppress such osteolysis.
치주염은 세균에 의해 발생하는 염증성 질환으로 염증 조건에서 파골세포의 형성이 증가하여 뼈의 파괴가 증가하게 된다. 파골세포의 분화를 억제하고, 단핵 파골세포의 융합에 의해 다핵성 파골 세포가 형성되는 것을 억제하며, 다핵성 파골세포의 골흡수능도 감소시킴으로써, 이러한 치주염을 효과적으로 예방 및 치료할 수 있다.Periodontitis is an inflammatory disease caused by bacteria, and the formation of osteoclasts in inflammatory conditions increases, resulting in increased bone destruction. By inhibiting the differentiation of osteoclasts, inhibiting the formation of multinucleated osteoclasts by fusion of mononuclear osteoclasts, and also reducing the bone resorption capacity of multinuclear osteoclasts, it is possible to effectively prevent and treat such periodontitis.
골다공증은 파골세포의 활성화로 뼈의 흡수와 생성 간의 균형이 파괴되어 흡수량이 생성량보다 많아지면 유발된다. 골다공증은 뼈 실질의 밀도를 감소시켜서 골절 빈도를 증가시킨다. 중년 및 노년 여성 등 호르몬 균형이 무너진 여성에서 가장 빈번하게 발생하며, 골절이나 중증 질환으로 거동을 못하는 환자에서도 발병한다. 최근에는 중장년층 이상의 남성에서도 발생 빈도가 증가하고 있다. Osteoporosis is caused by the activation of osteoclasts and the balance between bone absorption and production is destroyed, and the amount of absorption is greater than the amount of production. Osteoporosis increases the frequency of fractures by reducing the density of the bone parenchyma. It occurs most frequently in women who have a hormonal balance breakdown, such as middle-aged and older women, and also occurs in patients who are unable to behave due to a fracture or severe disease. Recently, the incidence has increased in men over the age of middle-aged.
골수 monocyte/macrophage lineage 세포가 파골세포로 분화하는 분자적 기전에는 먼저 아래 2개의 cytokine이 중요한 역할을 한다(Teitelbaum SL and Ross FP, 2003). (i) Macrophage colony-stimulating factor(M-CSF)가 그 수용체인 c-Fms와 결합하면 파골세포 전구세포들이 증식하고 생존한다. Receptor activator of nuclear factor-κB ligand(RANKL)이 그 수용체인 RANK에 결합하면 파골세포의 분화와 골 흡수 기능을 활성화하고 성숙한 파골세포가 생존하게 한다(Lacey DL et al., 1998; Lum L et al., 1999; Sherr CJ, 1990; Suda T et al., 1999; Wong BR et al., 1999). (ii) M-CSF가 c-Fms의 활성화를 유도하면 파골세포 전구세포가 ERK 및 PI3K/Akt 경로를 통하여 증식하고 생존한다(Mancini et al., 1997). (iii) RANKL(OPGL, ODF, TRANCE)과 RANK 역시 파골세포 형성과 기능을 조절한다(Anderson DM et al., 1997; Dougall WC et al., 1999; Kong YY et al., 1999). RANKL이 RANK에 결합하면 TRAFs 1, 2, 3, 5, 6 등의 TNF receptor-associated factor(TRAF)들이 RANK와 결합한다(Darnay BG et al., 1998; Walsh MC and Choi Y, 2003). 이중 TRAF6가 파골세포 형성과 기능에 가장 중요하다(Lomaga MA et al., 1999; Naito A et al., 1999). TRAF6는 RANKL/RANK 신호를 NF-κB, c-Jun N-terminal kinase(JNK), extracellular signal-regulated kinase(ERK), p38, Akt, Nuclear Factor Of Activated T-Cells 1(NFATc1)에 전달하여 파골세포 증식, 융합, 분화가 이루어진다(Kobayashi N et al., 2001; Lomaga MA et al., 1999; Naito A et al., 1999; Takayanagi H et al., 2002; Wong BR et al., 1998; Wong BR et al., 1999)In the molecular mechanism by which bone marrow monocyte/macrophage lineage cells differentiate into osteoclasts, the following two cytokines play an important role (Teitelbaum SL and Ross FP, 2003). (i) When macrophage colony-stimulating factor (M-CSF) is combined with its receptor, c-Fms, osteoclast progenitor cells proliferate and survive. Receptor activator of nuclear factor-κB ligand (RANKL) binds to its receptor, RANK, which activates osteoclast differentiation and bone resorption and allows mature osteoclasts to survive (Lacey DL et al ., 1998; Lum L et al. ., 1999; Sherr CJ, 1990; Suda T et al ., 1999; Wong BR et al ., 1999). (ii) When M-CSF induces c-Fms activation, osteoclast progenitors proliferate and survive through ERK and PI3K/Akt pathways (Mancini et al ., 1997). (iii) RANKL (OPGL, ODF, TRANCE) and RANK also regulate osteoclast formation and function (Anderson DM et al ., 1997; Dougall WC et al ., 1999; Kong YY et al ., 1999). When RANKL binds to RANK, TNF receptor-associated factors (TRAFs) such as
기존의 골다공증의 치료제 개발 방향은 파골세포의 뼈 흡수를 억제하여 뼈 실질의 손실을 예방할 수 있는 물질을 발굴하는 것이었다. 그 대표적인 약품이 bisphosphonate 계열의 Fosamax이다. 같은 맥락에서 arachidonate 대사 산물이 뼈 조직 대사에 미치는 영향에 대하여서도 많은 연구가 이루어졌다(Lee Sung-eun, 1999). Leukotriene-B4(LTB4)는 arachidonate의 대사 경로인 5-lipoxygenase pathway의 대사 산물 중 하나이다(Ford-Hutchinson, A. W. et al., 1980). Giant cell tumor에서 얻은 간질세포주(interstitial cell)인 C433은 5-lipoxygenase 대사 산물을 증가시켜서 조골세포의 수와 활성을 증가시키는 것으로 보고되었다(Mundy, G. R. et al., 1993). 뼈 조직 배양 과정에서 LTB4를 투여하면, 뼈 흡수가 증가하는 것이 관찰되기도 하였다(Bonewald, L. F. et al., 1996). In vitro와 in vivo 연구에서 LTB4는 파골세포의 생성을 증가시켜서 뼈 흡수를 유도한다는 연구 결과도 있다(Bonewald, L. F. et al., 1996). 이에 따라, LTB4 수용체 억제제(LTB4 receptor antagonist)들이 골다공증 치료를 위하여 많이 개발되었지만, 파골세포의 뼈 실질 흡수를 충분히 억제하는 데는 성공하지 못했다. The existing direction for the development of therapeutic agents for osteoporosis was to discover substances that can prevent bone loss by inhibiting osteoclast bone absorption. The representative drug is bisphosphonate-based Fosamax. In the same vein, many studies have been conducted on the effects of arachidonate metabolites on bone tissue metabolism (Lee Sung-eun, 1999). Leukotriene-B4 (LTB4) is one of the metabolites of the 5-lipoxygenase pathway, a metabolic pathway of arachidonate (Ford-Hutchinson, AW et al ., 1980). C433, an interstitial cell obtained from a giant cell tumor, has been reported to increase the number and activity of osteoblasts by increasing 5-lipoxygenase metabolites (Mundy, GR et al. , 1993). In the course of bone tissue cultivation, it was observed that bone absorption increased when LTB4 was administered (Bonewald, LF et al. , 1996). In vitro and in vivo studies have also shown that LTB4 increases osteoclast production and induces bone resorption (Bonewald, LF et al. , 1996). Accordingly, LTB4 receptor antagonists (LTB4 receptor antagonist) have been developed a lot to treat osteoporosis, but did not succeed in sufficiently suppressing the bone parenchymal absorption of osteoclasts.
뿐만 아니라, 기존 골다공증 치료제의 부작용과 고가의 약값도 환자의 치료에 충분한 용량으로 투여하는데 큰 장애가 되고 있다. Fosamax의 주요 부작용으로는 중증 식도염, 신 손상, 간 손상, 저칼슘혈증, 근육 경련 등이 있고, 로슈(Roche)의 Bonviva는 전신근육통, 몸살 등의 부작용이 있다. 노바티스(Novartis)의 Aclasta(zoledronate)와 일라이 릴리(Eli Lilly)의 anabolic 치료제인 parathyroid hormone인 Forsteo와 Forteo(teriparatide)는 효과는 좋으나 가격이 너무 비싸서 사용이 매우 제한적이다. 특히 Forsteo/Forteo는 약물 과민반응 환자, 임산부, 모유수유, 고칼슘혈증(hypercalcemia), 신부전, 부갑상선 기능항진증(hyperparathyroidism)과 파제트 병(Paget’disease) 등의 대사성 골질환, 원인미상의 알칼리포스파타제 활성 증가(unexplained elevations of alkaline phosphatase), 방사선 치료 환자, 골수암 혹은 골 전이암 환자 등에게는 사용할 수 없기 때문에 적용가능한 환자군이 크지 않다. In addition, the side effects of the existing therapeutic agents for osteoporosis and expensive drug prices have also become a major obstacle to administration in sufficient doses for the treatment of patients. The main side effects of Fosamax are severe esophagitis, kidney damage, liver damage, hypocalcemia, and muscle spasms. Roche's Bonviva has side effects such as generalized muscle pain and body aches. Novartis' Aclasta (zoledronate) and Eli Lilly's anabolic treatments parathyroid hormones Forsteo and Forteo (teriparatide) have good effects, but are too expensive to limit their use. In particular, Forsteo/Forteo is active in metabolic bone diseases such as hypersensitivity patients, pregnant women, breastfeeding, hypercalcemia, renal failure, hyperparathyroidism and Paget'disease, and unknown causes of alkaline phosphatase. It cannot be used in patients with unexplained elevations of alkaline phosphatase, radiation therapy, bone marrow cancer, or bone metastasis, so the applicable patient population is not large.
따라서 보다 효과가 강력하고 부작용 없이 안전하며, 기존 치료제보다 저비용으로 생산가능한 골 관련 질환 치료제 개발이 시급히 요구되고 있다.Therefore, there is an urgent need to develop a bone-related disease treatment that is more effective, safe without side effects, and can be produced at a lower cost than existing treatments.
이에 본 발명자들은 부작용이 적고 안전하며 효과가 뛰어난 골 질환 치료제를 개발하기 위하여, 골 손실 억제 활성이 있는 화합물들을 확인하여 본 발명을 완성하였다. Accordingly, the present inventors completed the present invention by identifying compounds having a bone loss-inhibiting activity in order to develop a therapeutic agent for bone disease with little side effects, safety, and excellent effect.
따라서 본 발명의 목적은 Therefore, the object of the present invention
하기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환 예방 또는 치료용 조성물을 제공하는 것이다.To provide a composition for preventing or treating bone disease comprising the compound represented by the following formula (1) as an active ingredient.
<화학식 1><
R1은 , 및 치환기 R7와 1개 이상의 헤테로원자를 갖는 3-9원자의 헤테로아릴기로 이루어진 군에서 선택된 하나이고, 이 때 헤테로원자는 O, N 및 S로 이루어지며;R1 is , And a substituent R7 and a heteroaryl group of 3-9 atoms having one or more heteroatoms, wherein the heteroatoms consist of O, N and S;
R5, R6는 서로 동일하거나 상이하고, 각각 독립적으로 수소, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기 및 카르복시아미드기로 이루어진 군에서 선택된 하나이고;R5 and R6 are the same or different from each other, and each independently hydrogen, -OH, -SH, C 1-4 linear or branched alkyl group, C 1-4 linear or branched alkoxy group, halogen, allyloxy group (allyloxy) , A carboxylic acid group, a carboxyl ester group and a carboxyamide group;
R7는 -H, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기 및 카르복시아미드기로 이루어진 군에서 선택된 하나이고;R7 is -H, -OH, -SH, C 1-4 linear or branched alkyl group, C 1-4 linear or branched alkoxy group, halogen, allyloxy group (allyloxy), carboxylic acid group, carboxyl ester group and One selected from the group consisting of carboxyamide groups;
R2, R3는 서로 동일하거나 상이하고, 각각 독립적으로 수소 및 C1-4의 직쇄 또는 측쇄 알킬기로 이루어진 군에서 선택된 하나이며; R2 and R3 are the same as or different from each other, and each independently is one selected from the group consisting of hydrogen and C 1-4 straight or branched alkyl groups;
R4은 C1-4의 직쇄 또는 측쇄 알킬기, -NH(R8), -N(R8)2 및 -OH로 이루어진 군에서 선택된 하나이며:R4 is one selected from the group consisting of a C 1-4 straight or branched alkyl group, -NH(R8), -N(R8) 2 and -OH:
R8은 C1-4의 직쇄 또는 측쇄 알킬기이다.R8 is a C 1-4 linear or branched alkyl group.
또한, 본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환 예방 또는 개선용 식품 조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a food composition for preventing or improving bone disease comprising the compound represented by
상기와 같은 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환 예방 또는 치료용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for preventing or treating bone disease comprising the compound represented by
<화학식 1><
R1은 , 및 치환기 R7와 1개 이상의 헤테로원자를 갖는 3-9원자의 헤테로아릴기로 이루어진 군에서 선택된 하나이고, 이 때 헤테로원자는 O, N 및 S로 이루어지며;R1 is , And a substituent R7 and a heteroaryl group of 3-9 atoms having one or more heteroatoms, wherein the heteroatoms consist of O, N and S;
R5, R6는 서로 동일하거나 상이하고, 각각 독립적으로 수소, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기 및 카르복시아미드기로 이루어진 군에서 선택된 하나이고;R5 and R6 are the same or different from each other, and each independently hydrogen, -OH, -SH, C 1-4 linear or branched alkyl group, C 1-4 linear or branched alkoxy group, halogen, allyloxy group (allyloxy) , A carboxylic acid group, a carboxyl ester group and a carboxyamide group;
R7는 -H, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기 및 카르복시아미드기로 이루어진 군에서 선택된 하나이고;R7 is -H, -OH, -SH, C 1-4 linear or branched alkyl group, C 1-4 linear or branched alkoxy group, halogen, allyloxy group (allyloxy), carboxylic acid group, carboxyl ester group and One selected from the group consisting of carboxyamide groups;
R2, R3는 서로 동일하거나 상이하고, 각각 독립적으로 수소 및 C1-4의 직쇄 또는 측쇄 알킬기로 이루어진 군에서 선택된 하나이며; R2 and R3 are the same as or different from each other, and each independently is one selected from the group consisting of hydrogen and C 1-4 straight or branched alkyl groups;
R4은 C1-4의 직쇄 또는 측쇄 알킬기, -NH(R8), -N(R8)2 및 -OH로 이루어진 군에서 선택된 하나이며:R4 is one selected from the group consisting of a C 1-4 straight or branched alkyl group, -NH(R8), -N(R8) 2 and -OH:
R8은 C1-4의 직쇄 또는 측쇄 알킬기이다.R8 is a C 1-4 linear or branched alkyl group.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving bone disease comprising the compound represented by
이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환 예방 또는 치료용 조성물을 제공한다.The present invention provides a composition for preventing or treating bone disease comprising the compound represented by
<화학식 1><
R1은 , 및 치환기 R7와 1개 이상의 헤테로원자를 갖는 3-9원자의 헤테로아릴기로 이루어진 군에서 선택된 하나이고, 이 때 헤테로원자는 O, N 및 S로 이루어지며;R1 is , And a substituent R7 and a heteroaryl group of 3-9 atoms having one or more heteroatoms, wherein the heteroatoms consist of O, N and S;
R5, R6는 서로 동일하거나 상이하고, 각각 독립적으로 수소, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기, 카르복시아미드기로 이루어진 군에서 선택된 하나이고;R5 and R6 are the same or different from each other, and each independently hydrogen, -OH, -SH, C 1-4 linear or branched alkyl group, C 1-4 linear or branched alkoxy group, halogen, allyloxy group (allyloxy) , A carboxylic acid group, a carboxyl ester group, a carboxyamide group;
R7는 -H, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기 및 카르복시아미드기로 이루어진 군에서 선택된 하나이고;R7 is -H, -OH, -SH, C 1-4 linear or branched alkyl group, C 1-4 linear or branched alkoxy group, halogen, allyloxy group (allyloxy), carboxylic acid group, carboxyl ester group and One selected from the group consisting of carboxyamide groups;
R2, R3는 서로 동일하거나 상이하고, 각각 독립적으로 수소 및 C1-4의 직쇄 또는 측쇄 알킬기로 이루어진 군에서 선택된 하나이며; R2 and R3 are the same as or different from each other, and each independently is one selected from the group consisting of hydrogen and C 1-4 straight or branched alkyl groups;
R4은 C1-4의 직쇄 또는 측쇄 알킬기, -NH(R8), -N(R8)2 및 -OH로 이루어진 군에서 선택된 하나이며:R4 is one selected from the group consisting of a C 1-4 straight or branched alkyl group, -NH(R8), -N(R8) 2 and -OH:
R8은 C1-4의 직쇄 또는 측쇄 알킬기이다.R8 is a C 1-4 linear or branched alkyl group.
본 발명에서 사용한 용어 “알킬”은 1 내지 4 탄소수를 함유하는 직쇄 또는 측쇄형 알킬기를 포함하는 기 또는 기의 일부분을 기술하기 위해 사용되며; 이러한 기의 예는 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸, tert 부틸을 포함한다.The term “alkyl” used in the present invention is used to describe a group or part of a group comprising a straight or branched alkyl group containing 1 to 4 carbon atoms; Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl.
본 발명에서 사용한 용어 “알콕시”는 O-알킬을 의미한다.The term "alkoxy" used in the present invention means O-alkyl.
상기 알콕시의 정의에 기재된 “알킬”은 본 발명에서 사용한 “알킬”과 동일하며, 상기 알콕시기는 구체적으로는 메톡시기, 에톡시기, 프로폭시기, 이소프로폭시기, n-부톡시기, 이소부톡시기, t-부톡시기이다.The "alkyl" described in the definition of alkoxy is the same as "alkyl" used in the present invention, and the alkoxy group is specifically a methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group. , t-butoxy group.
본 발명에서 사용된 용어 "아릴"이란 무제한 용어는 일-, 이- 또는 삼-환식 탄소환식 방향족기를 뜻하고, 공유결합에 의하여 직접 연결되는 두개의 일환식 탄소환식 방향족 고리를 갖는 기를 포함한다. 이와 같은 기를 예시하면 페닐, 비페닐과 나프틸이 있다.The term "aryl", as used herein, refers to a mono-, di- or tri-cyclic carbocyclic aromatic group, and includes groups having two monocyclic carbocyclic aromatic rings directly connected by covalent bonds. Examples of such groups are phenyl, biphenyl and naphthyl.
본 발명에서 사용된 용어 "헤테로아릴"이란 무제한 용어는 S, N과 O에서 선택한 하나 또는 그 이상의 헤테로원자를 함유하는 일-, 이- 또는 삼-환식 방향족기를 뜻하고, 공유결합에 의하여 직접 연결되는, 두개의 이러한 일환식고리, 또는 하나의 이러한 일환식고리와 하나의 일환식 아릴고리를 갖는 기를 포함한다. 이와 같은 기를 예시하면 티에닐, 벤즈티에닐, 푸릴, 벤즈푸릴, 피롤일, 이미다졸일, 벤즈이미다졸일, 티아졸일, 벤즈티아졸일, 이소티아졸일, 벤즈이소티아졸일, 피라졸일, 옥사졸일, 벤즈옥사졸일, 이소옥사졸일, 벤즈이소옥사졸일, 이소티아졸일, 트리아졸일, 벤즈트리아졸일, 티아디아졸일, 옥사디아졸일, 피리딘일, 피리다진일, 피리미딘일, 피라진일, 트리아진일, 인돌일과 인다졸일이 있다.The term "heteroaryl" as used in the present invention means an mono-, di- or tri-cyclic aromatic group containing one or more heteroatoms selected from S, N and O, and is directly connected by a covalent bond. It includes a group having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring. Examples of such groups include thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazoleyl, oxazolyl , Benzoxazolyl, isooxazolyl, benzisooxazolyl, isothiazolyl, triazoleyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, There are indolyl and indazolil.
또한, 상기 헤테로아릴기는 치환기로서 하나 또는 그 이상의 치환기가 독립적으로 포함될 수 있다. 이 때 치환기는 구체적으로 -H, -OH, -SH, C1-4의 직쇄 또는 측쇄 알킬기, C1-4의 직쇄 또는 측쇄 알콕시기, 할로겐, 알릴록시기(allyloxy), 카르복실산기, 카르복실에스터기 및 카르복시아미드기를 포함한다. Further, the heteroaryl group may independently include one or more substituents as a substituent. In this case, the substituent is specifically -H, -OH, -SH, C 1-4 straight or branched alkyl group, C 1-4 straight or branched alkoxy group, halogen, allyloxy group (allyloxy), carboxylic acid group, carbox And a carboxyl ester group and a carboxyamide group.
본 발명에서 사용한 용어 ‘카르복실에스터기’는 O-알킬, 또는 O-아릴기가 치환된 에스터를 나타내며, ‘카르복시아미드기’는 N-알킬, N,N-디알킬, N-아릴, N,N-디아릴을 나타낸다.The term'carboxyl group' used in the present invention refers to an ester in which O-alkyl or O-aryl group is substituted, and'carboxyamide group' is N-alkyl, N,N-dialkyl, N-aryl, N, N-diaryl.
본 발명의 “치환기 R7와 1개 이상의 헤테로원자를 갖는 3-9원자의 헤테로아릴기로 이루어진 군에서 선택된 하나이고, 이 때 헤테로원자는 O, N 및 S로 이루어진 군”은 보다 바람직하게는 다음과 같은 구조식을 가진 것일 수 있다. The "substituent group R7 and one selected from the group consisting of 3-9 membered heteroaryl groups having one or more heteroatoms, wherein the heteroatoms consist of O, N and S" are more preferably as follows. It may have the same structural formula.
본 발명에서 사용한 용어 ‘할로겐’은 할로겐족 원자를 나타내며, 불소, 염소, 브롬, 요오드 등을 포함한다.The term'halogen' used in the present invention represents a halogen group atom, and includes fluorine, chlorine, bromine, and iodine.
더욱 바람직하게는, 본 발명의 상기 화학식 1의 유도체는 다음 화합물 중에서 선택된다.More preferably, the derivative of
[화합물 1] [Compound 1]
(E)-4-(4-히드록시-3-메톡시페닐)-3-부텐-2-온((E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one; 흰색 고체; M.W 192.21) (E)-4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one(( E )-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one ; White solid; MW 192.21)
[화합물 2] [Compound 2]
(E)-4-(3-히드록시-4-메톡시페닐)-3-부텐-2-온((E)-4-(3-hydroxy-4-methoxyphenyl)-3-buten-2-one; 황색 고체; M.W 192.21) (E)-4-(3-hydroxy-4-methoxyphenyl)-3-buten-2-one (( E )-4-(3-hydroxy-4-methoxyphenyl)-3-buten-2-one ; Yellow solid; MW 192.21)
[화합물 3] [Compound 3]
(E)-4-(3-플루오로-4-히드록시페닐)-3-부텐-2-온 ((E)-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one; 황색 고체; M.W 180.18) (E)-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one (( E )-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one ; Yellow solid; MW 180.18)
본 발명에 따른 화합물은 천연물로부터 분리할 수도 있으며, 공지된 방법에 의해 합성될 수 있고, 상업적으로도 구입 가능하다. The compounds according to the invention can also be isolated from natural products, can be synthesized by known methods, and are also commercially available.
본 발명의 조성물은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 것을 특징으로 하며, 조골세포의 활성 증가 및 파골세포의 분화 또는 증식을 억제하여 골 질환 예방 및 치료의 효능이 있다. The composition of the present invention is characterized in that it contains the compound represented by the formula (1) as an active ingredient, and is effective in preventing and treating bone diseases by inhibiting the activity of osteoblasts and the differentiation or proliferation of osteoclasts.
골질환이란 뼈와 관련된 질환을 말하며, 예를 들어, 조골세포와 파골세포의 불균형이 원인이 되는 질환일 수 있으며, 바람직하게는 골다공증, 파제트병, 구루병, 골연화증, 골 용해, 신부전 환자의 신성골이영양증, 관절통, 골절, 류머티스성 골질환, 퇴행성 골질환, 골전이암, 원발성으로 뼈에 생성된 종양, 치주질환, 염증성 치조골 흡수질환 및 염증성 뼈 흡수질환일 수 있으며, 바람직하게는 골다공증, 파제트병, 구루병, 관절통, 골절, 류머티스성 골질환, 골전이암일 수 있다. Bone disease refers to a disease related to bone, and may be, for example, a disease caused by an imbalance between osteoblasts and osteoclasts, preferably osteoporosis, Paget's disease, rickets, osteomalacia, osteolysis, renal failure Bone dystrophy, joint pain, fracture, rheumatoid bone disease, degenerative bone disease, bone metastasis, primary tumors generated in bone, periodontal disease, inflammatory alveolar bone resorption disease and inflammatory bone absorption disease, preferably osteoporosis, wave Jet disease, rickets, joint pain, fractures, rheumatoid bone disease, and bone metastasis.
상기 본 발명 화합물들의 효능은 본 발명자들의 실시예에 의해 확인되었다.The efficacy of the compounds of the present invention was confirmed by the examples of the present inventors.
본 발명자들은 일실시예에서 본 발명에 따른 화합물들이 뼈 조직을 파괴하고 재흡수하는 역할을 하는 파골세포(osteoclast)의 분화를 효과적으로 억제하는 것을 확인하였다. 마우스에서 분리한 골수세포에서 파골세포의 줄기세포 전구세포인 단핵구 세포를 분리하여 분화촉진인자인 RANKL과 M-CSF로 자극하고, Benzylideneacetone 유도체들을 처리하여 파골세포의 분화에 미치는 영향을 확인한 결과, 골수세포가 다핵 파골세포로 분화하는 것을 효과적으로 억제하였다. 이에, 본 발명자들은 Benzylideneacetone 유도체들은 양성대조군인 Fosamax보다 IC50가 약 40배 낮아서 현저히 우수한 파골세포 분화 억제 활성을 가지고 있을 뿐만 아니라, 세포독성은 매우 낮아 안전한 것으로 확인하였다. The inventors have confirmed that in one embodiment the compounds according to the invention effectively inhibit the differentiation of osteoclasts, which serve to destroy and reabsorb bone tissue. As a result of separating monocytes, which are stem cell progenitor cells of osteoclasts, from bone marrow cells isolated from mice, stimulating them with differentiation promoting factors RANKL and M-CSF, and treating Benzylideneacetone derivatives to determine the effect on osteoclast differentiation, bone marrow Cells were effectively suppressed from being differentiated into multinuclear osteoclasts. Thus, the present inventors confirmed that Benzylideneacetone derivatives have not only excellent osteoclast differentiation inhibitory activity because IC 50 is about 40 times lower than Fosamax, a positive control, but also have very low cytotoxicity and are safe.
본 발명자들은 다른 일실시예에서 본 발명에 따른 화합물들이 조골세포 활성을 증가시키는 것을 확인하였다. 상기 조골세포란 골아세포라고도 불린다. 조골세포는 세포 밖으로 골질을 분비하고 스스로는 골질에 싸여 골세포로 변한다. 조골세포는 중간엽 줄기세포(mesenchymal stem cell)에서 분화한 것으로, 분열 능력이 크고, 형성 과정에 있는 경골의 표층에 한 층으로 배열되어 수상돌기로 서로 연락하고 있다. 이 세포군의 바깥쪽에는 골막이 있다. 뼈 형성이 끝나도 골막내면에는 조골세포가 존재하지만 노화된 뼈에서는 그 수가 감소한다.The inventors have confirmed that in another embodiment, the compounds according to the invention increase osteoblast activity. The osteoblasts are also called osteoblasts. Osteoblasts secrete bone marrow out of the cells and themselves are wrapped in bone marrow and turn into bone cells. Osteoblasts are differentiated from mesenchymal stem cells, which have a large division ability and are arranged in one layer on the surface layer of the tibia in the process of formation, and are in contact with each other with dendrites. There is a periosteum outside of this cell population. Osteoblasts are present on the inside of the periosteum even after bone formation is over, but the number decreases in aged bones.
본 발명의 일실시예에서는 조골세포의 초기 분화 표지자인 ALP(Alkaline phosphatase, 염기성 인산분해효소) 활성을 확인하는 ALP assay를 실시하여, 본 발명의 화합물들이 대조군에 비해 ALP 활성을 400% 이상 증가시켜서 유의하게 조골세포의 분화를 촉진시키고 활성을 증가시키는 것을 확인하였다.In one embodiment of the present invention, an ALP assay was performed to confirm the activity of ALP (Alkaline phosphatase, basic phosphatase), an early differentiation marker of osteoblasts, so that the compounds of the present invention increased ALP activity by 400% or more compared to the control group. It was confirmed that it significantly promotes osteoblast differentiation and increases activity.
따라서 통상의 기술자는 본 발명자들이 규명한 화합물들의 상기 활성을 이용하여 파골세포에 의한 골 흡수와 조골세포에 의한 새로운 골 기질의 형성 및 이후의 무기질화 과정의 골 대사 과정의 균형이 깨지면서 골밀도와 강도가 감소하여 발생하는 다양한 골 질환에 대한 효과적인 예방, 증상의 개선 또는 치료의 효과를 기대할 수 있음을 이해할 수 있다. Therefore, a person skilled in the art uses the above-mentioned activity of the compounds identified by the present inventors, and the bone density and strength are broken while the balance of bone metabolism by osteoclasts, formation of new bone matrix by osteoblasts, and bone metabolism in the subsequent mineralization process are broken. It is understood that effective prevention, improvement of symptoms, or treatment effects for various bone diseases caused by reduction can be expected.
본 발명의 조성물에 포함되는 화합물들은 그 자체 또는 염, 바람직하게는 "약학적으로 허용되는" 염의 형태로 사용될 수 있다. The compounds included in the composition of the present invention may be used by themselves or in the form of salts, preferably "pharmaceutically acceptable" salts.
본 발명에서 '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 말하며, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하다. 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다. 'Pharmaceutically acceptable' in the present invention refers to a physiologically acceptable, when administered to a human, that usually does not cause an allergic reaction or a similar reaction, and the salt is a pharmaceutically acceptable free acid. The acid addition salt formed by) is preferred. Organic acids and inorganic acids can be used as the free acid. The organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid. In addition, the inorganic acids include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
또한, 상기 약학적으로 허용되는 염은 추가적으로 담체, 부형제 및 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.In addition, the pharmaceutically acceptable salts may additionally include carriers, excipients and diluents. Examples of the carrier, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, And polyvinylpyrrolidone water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 명세서에서 '치료'란 치료되는 개체 또는 세포의 자연적 과정을 변경시키려는 임상적 시술을 의미하며, 임상적 병리의 예방을 위해서도 수행될 수 있다. 치료의 바람직한 효과는 질병의 발생 또는 재발 억제, 증상의 완화, 질병의 임의의 직접 또는 간접적인 병리학적 결과의 감소, 질병 진행 속도의 감소, 질병 상태의 개선, 호전, 완화 또는 개선된 예후 등을 포함한다.'Treatment' as used herein refers to a clinical procedure to alter the natural course of the individual or cell being treated, and may also be performed for the prevention of clinical pathology. Desirable effects of treatment include suppressing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, reducing the rate of disease progression, improving the condition of the disease, improving, alleviating, or improving prognosis. Includes.
또한 용어 '예방'은 질병의 발병을 억제시키거나 진행을 지연시키는 모든 행위를 의미한다.The term'prevention' also means any action that suppresses the onset of disease or delays its progression.
본 발명의 약학적 조성물의 투여량은 투여 경로, 투여 시간, 치료 횟수, 치료 기간, 치료가 필요한 개체의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 약물에 대한 민감도, 식이 및 배설율, 등 다양한 요인을 고려하여 당업자가 상술한 특정 용도에 따른 적절한 유효량을 결정할 수 있다. 상기 “유효량”이란 개체에게 투여하였을 때, 골 질환의 개선, 치료, 예방, 검출 또는 진단 효과를 나타내기에 충분한 양을 말한다. 본 발명의 약학적 조성물의 유효량으로는, 이에 한정되지는 않으나, 0.1~200mg/day/체중kg, 바람직하게는 1~50mg/day/체중kg이다. The dosage of the pharmaceutical composition of the present invention includes the route of administration, the time of administration, the number of treatments, the duration of treatment, the age of the individual in need of treatment, weight, health status, sex, severity of disease, sensitivity to drugs, diet and excretion rate, Considering various factors such as, one of ordinary skill in the art can determine an appropriate effective amount according to the specific use described above. The “effective amount” refers to an amount sufficient to exhibit an improvement, treatment, prevention, detection or diagnosis effect of bone disease when administered to an individual. The effective amount of the pharmaceutical composition of the present invention is not limited to this, but is 0.1 to 200 mg/day/kg body weight, preferably 1 to 50 mg/day/kg body weight.
상기‘개체’란 동물, 바람직하게는 포유동물, 가장 바람직하게는 인간을 포함하는 동물일 수 있으며, 동물에서 유래한 세포, 조직, 기관 등일 수도 있다. 상기 개체는 치료가 필요한 골 질환 환자(patient) 일 수 있다.The "individual" may be an animal, preferably a mammal, most preferably an animal including a human, or may be a cell, tissue, organ, or the like derived from an animal. The subject may be a patient with bone disease in need of treatment.
상기 투여는 하루에 한번 또는 수회 나누어 투여할 수도 있다. 본 발명의 약학 조성물은 단독으로 투여되거나 골 질환의 예방 또는 치료에 효과가 있는 것으로 알려진 다른 치료제와 병용하여 투여될 수 있고, 병용하여 투여할 경우 다른 치료제와 순차적 또는 동시에 투여될 수 있다. 상기 단독 투여 또는 병용 투여시 본 발명의 약학 조성물의 투여량은 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 바람직하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The administration may be administered once or several times a day. The pharmaceutical composition of the present invention may be administered alone or in combination with other therapeutic agents known to be effective in the prevention or treatment of bone diseases, and when administered in combination, may be administered sequentially or simultaneously with other therapeutic agents. When administered alone or in combination, the dosage of the pharmaceutical composition of the present invention is preferably administered in an amount that can obtain the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
투여 경로로는 경구적 또는 비경구적으로 투여될 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장내 투여일 수 있다.The route of administration may be administered orally or parenterally. The parenteral administration method is not limited to this, but intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can.
본 발명의 약학적 조성물을 경구투여하는 경우 본 발명의 약학적 조성물은 적합한 경구투여용 담체와 함께 당업계에 공지된 방법에 따라 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 현탁액, 웨이퍼 등의 형태로 제형화될 수 있다. 적합한 담체의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 히드록시프로필메틸셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다. 나아가, 상기 약학적 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.When the pharmaceutical composition of the present invention is orally administered, the pharmaceutical composition of the present invention is a powder, granules, tablets, pills, dragees, capsules, liquids, gels according to methods known in the art together with a suitable oral administration carrier. , Syrups, suspensions, wafers, and the like. Examples of suitable carriers include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch, potato starch, etc., cellulose, Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like may be included, including methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and the like. In addition, if necessary, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant. Furthermore, the pharmaceutical composition may further include an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative.
또한, 비경구적으로 투여하는 경우 본 발명의 약학적 조성물은 적합한 비경구용 담체와 함께 주사제, 경피투여제 및 비강 흡입제의 형태로 당업계에 공지된 방법에 따라 제형화될 수 있다. 상기 주사제의 경우에는 반드시 멸균되어야 하며 박테리아 및 진균과 같은 미생물의 오염으로부터 보호되어야 한다. 주사제의 경우 적합한 담체의 예로는 이에 한정되지는 않으나, 물, 에탄올, 폴리올(예를 들어, 글리세롤, 프로필렌 글리콜 및 액체 폴리에틸렌 글리콜 등), 이들의 혼합물 및/또는 식물유를 포함하는 용매 또는 분산매질일 수 있다. 보다 바람직하게는, 적합한 담체로는 행크스 용액, 링거 용액, 트리에탄올 아민이 함유된 PBS(phosphate buffered saline) 또는 주사용 멸균수, 10% 에탄올, 40% 프로필렌 글리콜 및 5% 덱스트로즈와 같은 등장 용액 등을 사용할 수 있다. 상기 주사제를 미생물 오염으로부터 보호하기 위해서는 파라벤, 클로로부탄올, 페놀, 소르빈산, 티메로살 등과 같은 다양한 항균제 및 항진균제를 추가로 포함할 수 있다. 또한, 상기 주사제는 대부분의 경우 당 또는 나트륨 클로라이드와 같은 등장화제를 추가로 포함할 수 있다. In addition, when administered parenterally, the pharmaceutical composition of the present invention may be formulated according to methods known in the art in the form of injections, transdermal administrations, and nasal inhalants with suitable parenteral carriers. The injections must be sterile and protected from contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols, etc.), mixtures thereof and/or solvents or vegetable media comprising vegetable oils Can. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with ethanol amine or sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used. In order to protect the injection from microbial contamination, it may further include various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, the injection may additionally include an isotonic agent such as sugar or sodium chloride in most cases.
경피투여제의 경우 연고제, 크림제, 로션제, 겔제, 외용액제, 파스타제, 리니멘트제, 에어롤제 등의 형태가 포함된다. 상기에서 ‘경피투여’는 약학적 조성물을 국소적으로 피부에 투여하여 약학적 조성물에 함유된 유효한 양의 활성성분이 피부 내로 전달되는 것을 의미한다. 예컨대, 본 발명의 약학적 조성물을 주사형 제형으로 제조하여 이를 30게이지의 가는 주사 바늘로 피부를 가볍게 단자(prick)하거나 피부에 직접적으로 도포하는 방법으로 투여될 수 있다. 이들 제형은 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania)에 기술되어 있다. In the case of transdermal administration agents, ointments, creams, lotions, gels, external solutions, pasta, linen, airroll, etc. are included. In the above,'transdermal administration' means that the pharmaceutical composition is topically administered to the skin to deliver an effective amount of the active ingredient contained in the pharmaceutical composition into the skin. For example, the pharmaceutical composition of the present invention may be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin injection needle or directly applying to the skin. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania, a recipe generally known in pharmaceutical chemistry.
흡입투여제의 경우, 본 발명에 따라 사용되는 화합물은 적합한 추진제, 예를 들면, 디클로로플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적합한 기체를 사용하여, 가압 팩 또는 연무기로부터 에어로졸 스프레이 형태로 편리하게 전달할 수 있다. 가압 에어로졸의 경우, 투약 단위는 계량된 양을 전달하는 밸브를 제공하여 결정할 수 있다. 예를 들면, 흡입기 또는 취입기에 사용되는 젤라틴 캡슐 및 카트리지는 화합물 및 락토오즈 또는 전분과 같은 적합한 분말 기제의 분말 혼합물을 함유하도록 제형화할 수 있다.For inhalation dosing agents, the compounds used in accordance with the present invention may be pressurized packs or, using suitable propellants, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from a nebulizer. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in inhalers or insufflators can be formulated to contain a powder mixture of a compound and a suitable powder base such as lactose or starch.
또한, 본 발명의 약학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다.In addition, the pharmaceutical compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
또한, 본 발명에 따른 약학적 조성물은 하나 이상의 완충제(예를 들어, 식염수 또는 PBS), 카보하이트레이트(예를 들어, 글루코스, 만노즈, 슈크로즈 또는 덱스트란), 항산화제, 정균제, 킬레이트화제(예를 들어, EDTA 또는 글루타치온), 아쥬반트(예를 들어, 알루미늄 하이드록사이드), 현탁제, 농후제 및/또는 보존제를 추가로 포함할 수 있다.In addition, the pharmaceutical composition according to the present invention may include one or more buffers (e.g. saline or PBS), carbohydrates (e.g. glucose, mannose, sucrose or dextran), antioxidants, bacteriostatic agents, chelating agents (Eg, EDTA or glutathione), adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents and/or preservatives.
그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).As other pharmaceutically acceptable carriers, reference may be made to those described in the following documents (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).
본 발명의 약학적 조성물은 골질환을 예방 또는 치료하는 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다. 상기 화합물의 예로는, 천연 비타민 D3, 에스트로겐, 알렌드로네이트(alendronate) 및 랄록시펜(raloxifene) 등이 있다.The pharmaceutical composition of the present invention may be administered in parallel with a known compound having an effect of preventing or treating bone disease. Examples of such compounds include natural vitamin D3, estrogen, alendronate, and raloxifene.
또한 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 질환 예방 또는 개선용 식품용 조성물을 제공한다. In addition, the present invention provides a food composition for preventing or improving bone disease comprising the compound represented by
본 발명자들이 규명한 화합물들의 상기 골 질환에 대한 예방 또는 개선의 효과는 본 명세서에서 전술한 바와 같다. The effects of the prevention or improvement of the compounds identified by the present inventors on the bone disease are as described above.
상기 식품용 조성물은 기능성 식품(functional food), 영양보조제(nutritional supplement), 건강식품(health food) 및 식품첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형들은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다.The food composition includes all forms of functional food, nutritional supplement, health food, and food additives. These types can be prepared in various forms according to conventional methods known in the art.
예를 들면, 건강식품으로는 본 발명의 식품용 조성물 자체를 차, 쥬스 및 드링크 등 액제의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한 본 발명의 식품용 조성물은 골 질환 예방 또는 개선의 효과가 있다고 알려진 공지의 물질 또는 활성 성분과 함께 혼합하여 조성물의 형태로 제조할 수 있다.For example, as a health food, the food composition itself of the present invention may be prepared in the form of a liquid such as tea, juice, and drink to be consumed or granulated, encapsulated, and powdered. In addition, the food composition of the present invention can be prepared in the form of a composition by mixing with a known substance or active ingredient known to have an effect of preventing or improving bone disease.
상기 분말은 가루나 결정성 물질을 뭉쳐서 눌러 둥글넓적한 원판이나 원추 모양으로 만든 제형으로 복용하기 쉽고 투여량이 정확하다. 본 발명의 기능성 식품 정제는 이에 제한되지는 아니하나 유당, 전분, 백당, 만니톨, 소르비톨, 무기염 등의 부형제를 포함 할 수 있으며, 마그네슘 알루미늄 실리케이트, 전분페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카르복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다.The powder is easy to take in a dosage form with a rounded disc or cone shape by pressing the powder or crystalline substance together and the dosage is correct. The functional food tablet of the present invention is not limited thereto, but may include excipients such as lactose, starch, white sugar, mannitol, sorbitol, inorganic salts, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, May contain a binder such as sodium carboxymethylcellulose and/or polyvinylpyrrolidine, optionally disintegrating or boiling mixtures such as starch, agar, alginic acid or its sodium salt and/or absorbents, colorants, flavoring agents, And sweeteners. The formulation can be prepared by conventional mixing, granulating or coating methods.
상기 과립은 둥글고 잔 알갱이 모양의 제형을 말하며, 혼합제제의 경우 항상 일정한 비율을 취할 수 있고 복용하기 쉽다. 본 발명의 과립제에는 필요에 따라 착색제, 방향제 등이 첨가 될 수 있으며, 적당한 제피제 등으로 제피를 할 수 있다. 과립제의 과립은 전제의 20%가 355um 이상 1400um이하의 크기를 가지는 것이 바람직하다.The granule refers to a round, fine-grained formulation, and in the case of mixed preparations it can always take a certain proportion and is easy to take. Colorants, fragrances, etc. may be added to the granules of the present invention, if necessary, and can be coated with a suitable coating agent. It is preferable that 20% of the granules of granules have a size of 355 um to 1400 um.
상기 액제는 액체로 된 제형을 말하며, 본 발명의 필요에 따라 안정제, 교미제, 보존제 등이 첨가 될 수 있다. 또한 본 발명의 기능성 음료조성물은 풍미개선을 위해 과실추출물을 추가로 포함할 수 있다. 과실추출물은 풍미개선과 함께 과실이 지니는 각종 유효성분을 함께 이용할 수 있는 장점을 준다. 상기 과실추출물에 사용되는 과실로는 이에 한정되는 것은 아니나 파인애플, 레몬, 감귤, 오렌지, 사과, 배, 그레이프후르츠, 살구, 딸기, 복숭아, 멜론, 구아바, 레몬, 자두에서 선택된 적어도 1종을 포함 할 수 있다. 기타 본 발명의 기능성 음료조성물에는 공지의 첨가물을 포함할 수 있다. 이들 공지의 첨가물로는 비타민류로는 니코틴산아마이드, 비타민 A, B, C, D, E, 엽산 등이 사용 될 수 있고, 아미노산류로는 L-글리신, L-라이신, DL-메치오닌, L-발린, 비오틴, L-시스테인, L-시스틴, L-트립토판, L-트레오닌, L-페닐알라닌 등이 사용 될 수 있고, 생약제제로는 구기자, 오가피, 백출, 백작약, 녹곽, 홍삼, 인삼, 음양곽, 우황, 황정 등이 사용 될 수 있고, 착향제로는 혼합과일향, 사과향, 요구르트향, 드링크향 등이 사용 될 수 있고, 감미제류는 정백당, 포도당, 과당, 프락토올리고당, 이소말토올리고당, 말토올리고당, 키토산올리고당, 키토올리고당, 대두올리고당, 자일로올리고당, 이성화당(고과당), 전화당, 아스파탐, 스테비오사이드, 솔비톨, 만니톨 등이 사용될 수 있고, 산미제로는 구연산, DL-사과산, 호박산 등이 사용 될 수 있고, 안정화제로는 소르베이트류 중 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 80 등이 사용 될 수 있고, 보존제류로는 안식향산 및 그의 유도체, 데히드로초산 및 그의 염류, 소르빈산 및 그의 염류 등이 사용 될 수 있다.The liquid formulation refers to a liquid formulation, and a stabilizer, mating agent, and preservative may be added according to the needs of the present invention. In addition, the functional beverage composition of the present invention may further include a fruit extract for flavor improvement. The fruit extract gives the advantage of using various active ingredients possessed by the fruit together with improving flavor. Fruits used in the fruit extract include, but are not limited to, at least one selected from pineapple, lemon, citrus, orange, apple, pear, grapefruit, apricot, strawberry, peach, melon, guava, lemon, and plum. Can. Other functional beverage compositions of the present invention may include known additives. As these known additives, vitamin amide, vitamin A, B, C, D, E, folic acid, etc. can be used as vitamins, and L-glycine, L-lysine, DL-methionine, and L- as amino acids. Valine, biotin, L-cysteine, L-cystine, L-tryptophan, L-threonine, L-phenylalanine, etc. can be used, and herbal medicines include goji berry, ogapi, baekchul, county green, red ginseng, red ginseng, ginseng, yin and yang, and woowang , Hwangjeong, etc. can be used, mixed fruit flavor, apple flavor, yogurt flavor, drink flavor, etc. can be used. Sweeteners include baekbaek sugar, glucose, fructose, fructooligosaccharide, isomaltoligosaccharide, malto-oligosaccharide, Chitosan oligosaccharides, chito oligosaccharides, soybean oligosaccharides, xyloligosaccharides, isomerized saccharides (high fructose), invert sugar, aspartame, stevioside, sorbitol, mannitol, etc. can be used, citric acid, DL-apple acid, succinic acid, etc. As a stabilizer,
또한, 상기 성분 이외에도 공지의 첨가제로서 미각을 돋우기 위하여 매실, 레몬향, 파인애플향 또는 허브향과 같은 천연향료나 천연과즙, 클로르필린(Chlorophyllin), 플라보노이드(Flovonoid) 등의 천연색소 및 감미 성분인 과당, 벌꿀, 당알코올, 설탕 등과 구연산, 구연산나트륨 같은 산미제를 혼합하여 사용할 수 있다.In addition, in addition to the above components, as a known additive, natural flavors such as plum, lemon, pineapple, or herbal flavors, natural juices, fructose, which is a natural pigment such as chlorophyllin and flavonoids, and sweet components , Honey, sugar alcohol, sugar, citric acid, sodium citrate, and so on.
또한 기능성 식품으로는 정제, 과립제, 음료(알콜성 음료 포함), 과실 및 그의 가공식품 (예를 들어 과일 통조림, 병조림, 잼, 마아말레이드 등), 어류, 육류 및 그 가공식품(예를 들어 햄, 소시지, 콘비이프 등), 빵류 및 면류(예를 들어 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예를 들어 버터, 치이즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예를 들어 된장, 간장, 소스 등) 등에 본 발명의 식품용 조성물을 첨가하여 제조할 수 있다.In addition, functional foods include tablets, granules, beverages (including alcoholic beverages), fruits, and processed foods thereof (for example, canned fruits, canned fruits, jams, marmalades, etc.), fish, meat, and processed foods (e.g. Ham, sausage, corn beef, etc., breads and noodles (e.g. udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), juice, various drinks, cookies, syrup, dairy products (e.g. butter, cheese, etc.), Edible plant oil, margarine, vegetable protein, retort food, frozen food, various seasonings (for example, miso, soy sauce, sauce, etc.) can be prepared by adding the food composition of the present invention.
상기 기능성 식품 제조는 본 발명의 식품 조성물이 포함되는 것 이외 다른 특별한 제한이 없으며, 통상의 식품학적으로 허용 가능한 식품보조첨가제로써 식품별로 필요한 성분을 추가로 함유할 수 있다.The functional food preparation is not particularly limited except that the food composition of the present invention is included, and may contain additional ingredients required for each food as a conventional food-pharmaceutically acceptable food additive.
본 발명에 따른 식품용 조성물의 바람직한 함유량으로는 이에 한정되지 않지만 바람직하게는 최종적으로 제조된 식품 총 중량 중 0.01 내지 50중량%이다. 본 발명의 식품용 조성물을 식품첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.The preferred content of the food composition according to the present invention is not limited to this, but is preferably from 0.01 to 50% by weight of the total weight of the food finally produced. In order to use the food composition of the present invention in the form of a food additive, it may be prepared and used in powder or concentrate form.
도 1은 실시예 1-1에서 합성한 (E)-4-(3-히드록시-4-메톡시페닐)-3-부텐-2-온 (화합물 2)의 NMR 동정 결과이다.
도 2는 실시예 1-2에서 합성한 (E)-4-(3-플루오로-4-히드록시페닐)-3-부텐-2-온 (화합물 3)의 NMR 동정 결과이다.
도 3은 본 발명의 화합물 1 내지 화합물 3과 그의 양성 대조군인 Fosamax 및 Osmundacetone을 포함한 화합물들의 파골세포 분화 및 증식 억제능을 TRAP assay로 측정한 결과이다.
도 4는 본 발명의 화합물 1 내지 화합물 3과 그의 양성 대조군인 Osmundacetone을 포함한 화합물들의 조골세포 분화 및 활성 효과를 ALP assay로 측정한 결과이다.
1 is a result of NMR identification of (E)-4-(3-hydroxy-4-methoxyphenyl)-3-buten-2-one (Compound 2) synthesized in Example 1-1.
2 is a result of NMR identification of (E)-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one (Compound 3) synthesized in Example 1-2.
3 is a result of measuring the osteoclast differentiation and proliferation inhibitory ability of
4 is a result of measuring the osteoblast differentiation and activity effects of
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are only to illustrate the present invention, the content of the present invention is not limited to the following examples.
<실시예 1><Example 1>
<실시예 1-1><Example 1-1>
(E)-4-(3-히드록시-4-메톡시페닐)-3-부텐-2-온 (화합물 2)의 합성Synthesis of (E)-4-(3-hydroxy-4-methoxyphenyl)-3-buten-2-one (Compound 2)
3-히드록시-4-메톡시벤잘데하이드(2d, 152.1mg, 1.0mmol) 및 CuBr2(223.35mg,1mmol)를 실온에서 5mL 아세톤에 용해시켰다. 상기 반응 혼합물을 60 ℃에서 교반하였다. 혼합물을 실온으로 냉각한 6시간 뒤, 셀 라이트로 여과 하였다. 유기층을 진공 농축시키고, 황색 고체인 생성물 (E)-4-(3-히드록시-4-메톡시페닐)-3-부텐-2-온(3d, 47.8%, 92mg)를 용리액으로서 에틸 아세테이트 및 n- 헥산 (1 : 4)을 사용하는 플래시 크로마토그래피로 정제 하였다.3-hydroxy-4-methoxybenzaldehyde (2d, 152.1mg, 1.0mmol) and CuBr 2 (223.35mg,1mmol) were dissolved in 5mL acetone at room temperature. The reaction mixture was stirred at 60 °C. After the mixture was cooled to room temperature, after 6 hours, it was filtered through Celite. The organic layer was concentrated in vacuo, and the yellow solid product (E)-4-(3-hydroxy-4-methoxyphenyl)-3-buten-2-one (3d, 47.8%, 92 mg) was used as eluent as ethyl acetate and Purified by flash chromatography using n-hexane (1:4).
NMR 및 MS 분석 결과는 다음과 같다.(도 1 참조)The NMR and MS analysis results are as follows (see FIG. 1).
1H NMR (400 MHz, DMSO): δ 9.22 (1H, br), 7.48 (1H, d, J = 16.4 Hz), 7.14-7.10 (2H, m), 6.97 (1H, d, J = 8.0 Hz), 6.54 (1H, J = 16.4 Hz), 3.81 (3H, s), 2.29(3H, s); Ms(ESI) m/z: 193.1 [M+H]+; 1 H NMR (400 MHz, DMSO): δ 9.22 (1H, br), 7.48 (1H, d, J = 16.4 Hz), 7.14-7.10 (2H, m), 6.97 (1H, d, J = 8.0 Hz) , 6.54 (1H, J = 16.4 Hz), 3.81 (3H, s), 2.29 (3H, s); Ms(ESI) m/z : 193.1 [M+H] + ;
<실시예 1-2><Example 1-2>
(E)-4-(3-플루오로-4-히드록시페닐)-3-부텐-2-온 (화합물 3)의 합성Synthesis of (E)-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one (Compound 3)
3-플루오로-4-히드록시벤잘데하이드(2e, 140.1mg, 1.0mmol) 및 CuBr2(223.35mg,1mmol)를 실온에서 5mL 아세톤에 용해시켰다. 상기 반응 혼합물을 60 ℃에서 교반하였다. 혼합물을 실온으로 냉각한 6시간 뒤, 셀 라이트로 여과 하였다. 유기층을 진공 농축시키고, 황색 고체인 생성물 (E)-4-(3-플루오로-4-히드록시페닐)-3-부텐-2-온 (3e, 44mg, 24.4%)를 용리액으로서 에틸 아세테이트 및 n- 헥산 (1 : 4)을 사용하는 플래시 크로마토그래피로 정제 하였다.3-Fluoro-4-hydroxybenzaldehyde (2e, 140.1 mg, 1.0 mmol) and CuBr 2 (223.35 mg, 1 mmol) were dissolved in 5 mL acetone at room temperature. The reaction mixture was stirred at 60 °C. After the mixture was cooled to room temperature, after 6 hours, it was filtered through Celite. The organic layer was concentrated in vacuo, and the yellow solid product (E)-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one (3e, 44 mg, 24.4%) was used as eluent as ethyl acetate and Purified by flash chromatography using n-hexane (1:4).
NMR 및 MS 분석 결과는 다음과 같다.(도 2 참조)The NMR and MS analysis results are as follows (see FIG. 2).
1H NMR (400 MHz, DMSO): δ 7.58 (1H, dd, J = 2.0, 2.0 Hz), 7.51 (1H, d, J = 16.4 Hz), 7.35 (1H, dd, J = 1.6, 1.6 Hz), 6.97 (1H, t, J = 8.8 Hz), 6.66 (1H, J = 16.4 Hz), 2.28 (3H, s); Ms(ESI) m/z: 181.1 [M+H]+; 1 H NMR (400 MHz, DMSO): δ 7.58 (1H, dd, J = 2.0, 2.0 Hz), 7.51 (1H, d, J = 16.4 Hz), 7.35 (1H, dd, J = 1.6, 1.6 Hz) , 6.97 (1H, t, J = 8.8 Hz), 6.66 (1H, J = 16.4 Hz), 2.28 (3H, s); Ms(ESI) m/z : 181.1 [M+H] + ;
<실시예 2><Example 2>
MTT 어세이MTT assay
본 발명의 화합물 1 내지 3에 대하여 MTT assay를 이용하여 정상세포에 대한 세포독성을 확인하였다. Cytotoxicity to normal cells was confirmed using MTT assay for
본 발명의 화합물 1은 Sigma-Aldrich(St Louis, MO, USA)의 #306045이며, 화합물 2는 본 발명 실시예 1-1에서 합성한 것이며, 화합물 3은 실시예 1-2에서 합성한 것을 사용하였다.
MTT assay 방법은 다음과 같다.The MTT assay method is as follows.
정상세포(RAW264.7 쥐 마크로파지 세포주(파골세포 전구세포), NIH3T3 쥐 섬유아세포주, 및 HaCAT 인간 피부 세포)를 10% FBS(fetal bovine serum)가 첨가된 DMEM를 포함하는 96웰 플레이트에서 5% CO2, 37℃에서 배양한 후, 화합물 1 내지 3을 10, 100, 1000, 5000μM 농도로 세포배지에 첨가하고 48시간 배양하였다. 그 후 MTT(0.5mg/mL 인산완충식염수) 100μL를 투여한 후, 2시간 배양하였다. 각 well에 100μL의 DMSO를 가하고 10분간 배양 후 마이크로플레이트 리더(microplate reader; SPCTRA MAX 340PC, Molecular Devices, USA)를 이용하여 550nm에서 흡광도를 측정하였다. 흡광도는 생존한 세포의 수를 나타내는 지표로서 하단의 식으로 계산되며, 3회의 실험으로 재현성을 확인하였다.5% in 96-well plates containing DMEM with 10% fetal bovine serum (FBS) in normal cells (RAW264.7 rat macrophage cell line (osteoblast progenitor cell), NIH3T3 rat fibroblast line, and HaCAT human skin cells) After incubation at CO 2 and 37° C., compounds 1 to 3 were added to the cell medium at concentrations of 10, 100, 1000, and 5000 μM and incubated for 48 hours. Then, 100 μL of MTT (0.5 mg/mL phosphate buffered saline) was administered, followed by incubation for 2 hours. After adding 100 μL of DMSO to each well and incubating for 10 minutes, absorbance was measured at 550 nm using a microplate reader (SPCTRA MAX 340PC, Molecular Devices, USA). Absorbance is an index indicating the number of surviving cells, calculated by the formula below, and confirmed reproducibility in 3 experiments.
세포 증식율(%)=OD550(sample)/OD550(control)Cell proliferation rate (%)=OD550(sample)/OD550(control)
표 3에서 확인할 수 있듯이, 화합물 1 내지 3투여 후 세포증식율의 변화에 근거하여 산출된 화합물들의 정상세포에 대한 LD50 측정 결과, 세포 독성이 거의 없음을 확인하였다. 마크로파지(macrophage) 세포주인 RAW264.7의 경우, 화합물 1과 화합물 2가 약한 세포독성을 나타내서 이 화합물들은 약한 면역억제 기능이 있음을 확인하였다. 따라서 전반적으로 정상세포에 대한 낮은 세포독성을 가진 본 발명의 화합물들이 안전하게 약학, 식품 조성물로 사용될 수 있음을 알 수 있다.As can be seen in Table 3 , LD 50 measurement of normal cells of the compounds calculated based on the change in cell proliferation rate after administration of
<실시예 3> <Example 3>
파골세포의 증식 및 분화억제 활성Inhibitory activity of osteoclast proliferation and differentiation
본 발명의 화합물들에 대하여 파골세포 특이적인 염색법인 TRAP assay(tartrate-resistant acid phosphatase)를 이용하여 파골세포에 대한 증식 및 분화억제의 활성을 확인하였다. Using the osteoclast specific staining method TRAP assay (tartrate-resistant acid phosphatase) for the compounds of the present invention was confirmed the activity of proliferation and differentiation inhibition on osteoclasts.
TRAP assay의 구체적인 방법은 다음과 같다. The specific method of the TRAP assay is as follows.
1. 골수세포 배양1. Bone marrow cell culture
6~8주령 수컷 C57BL/6 마우스의 정강이뼈(tibia)와 대퇴골(femur)을 무균적으로 절제하고 골수세포를 syringe(21G, Korea Green Cross)로 무균적으로 채취하였다. 15 골수세포를 10% 소태아혈청(fetal bovine serum, FBS; Capricorn Scientific, Ebsdorfergrund, Germany), 1%(v/v) 항생제(100 U/mL penicillin G, 100 mg/mL streptomycin)을 포함하는 α-MEM 배지(Gibco BRL Co.) 500 μ에 부유하여 48well plate에 분주하고, triplicate으로 assay를 진행하였다. 37oC, 5% CO2에서 배양하며 3일 후 배지를 교환하였다. 파골세포 분화를 촉진하기 위하여 배지에 파골세포 분화인자인 M-CSF(60ng/mL)과 RANKL(150ng/mL) (PeproTech, Seoul, Korea)로 처리하면 파골세포의 전구세포인 단핵구세포가 5~7일 내에 성숙한 파골세포로 분화되었다. The tibia and femur of the male C57BL/6 mice aged 6-8 weeks were aseptically excised, and bone marrow cells were collected aseptically with a syringe (21G, Korea Green Cross). 1 5 bone marrow cells containing 10% fetal bovine serum (FBS; Capricorn Scientific, Ebsdorfergrund, Germany), 1% (v/v) antibiotic (100 U/mL penicillin G, 100 mg/mL streptomycin) Suspended in 500 μ of α-MEM medium (Gibco BRL Co.), dispensed into 48 well plates, and assayed with triplicate. After incubation at 37 o C, 5% CO 2 , the medium was changed after 3 days. In order to promote osteoclast differentiation, monocytes, progenitor cells of osteoclasts, are treated with 5~~ when the medium is treated with M-CSF (60ng/mL) and RANKL (150ng/mL) (PeproTech, Seoul, Korea). It differentiated into mature osteoclasts within 7 days.
2. 파골세포 분화 측정2. Measurement of osteoclast differentiation
1) 시료 준비: 화합물 1 내지 3 (0.05μ0.1μ0.5μ1μ5μ10μ또는 20μOsmundacetone 및 Fosamax(0.5μ1μ5μ또는 10μ등을 각각 적정한 농도로 DMSO(dimethylsulfoxide) 또는 무균 증류수에 용해하였다. 본 발명의 화합물 1은 Sigma-Aldrich(St Louis, MO, USA)의 #306045이며, 화합물 2는 본 발명 실시예 1-1에서 합성한 것이며, 화합물 3은 실시예 1-2에서 합성한 것을 사용하였다.1) Sample preparation:
2) 시료 투여: 시료는 골수세포 배양 첫날부터 1:20(v/v; 배지 500μ당 시료 25μ로 지속적으로 배지에 투여하고, 배지는 3일 간격으로 교체하였다.2) Sample administration: The sample was continuously administered to the medium at the first day of bone marrow cell culture at 1:20 (v/v; 25 μm sample per 500 μ medium), and the medium was replaced every 3 days.
3) 파골세포 분화 측정: 파골세포는 TRAP으로 염색된 TRAP-양성 다핵세포로 정의하였다. TRAP 염색 용액은 기질인 naphthol AS-MS phosphate(Sigma N-4875) 5 mg과 발색시약인 Fast Red Violet LB salt 25mg을 약 0.5 mL의 N,N-dimethylformamide에 녹인 후, 50mM tartaric acid를 포함하는 0.1N NaHC03 buffer solution(50mL)과 혼합하였다. 반응시약은 사용 전까지 냉장고에 보관하였다.3) Measurement of osteoclast differentiation: Osteoblasts were defined as TRAP-positive multinucleated cells stained with TRAP. The TRAP staining solution was dissolved in 5 mg of naphthol AS-MS phosphate (Sigma N-4875) and 25 mg of Fast Red Violet LB salt, a color development reagent, in about 0.5 mL of N,N-dimethylformamide, and 0.1 containing 50 mM tartaric acid. It was mixed with N NaHC0 3 buffer solution (50 mL). Reaction reagents were stored in the refrigerator until use.
골수세포는 분화촉진인자를 포함하는 배지에서 6-7 일간 배양한 후, 배지를 제거하고 PBS로 세척한 후 10% formalin을 포함한 PBS로 2~5분 동안 고정하였다. 이후 ethanol과 acetone의 1:1 혼합용액으로 1분간 고정하고, 건조하였다. 고정된 세포는 TRAP 염색용액으로 빛을 차단한 채 37oC에서 60 분간 처리하고 PBS로 세척한 후 Hematoxylin 염색을 시행하고, 세포의 염색 정도를 현미경으로 관찰하였다.Bone marrow cells were cultured for 6-7 days in a medium containing a differentiation promoting factor, and then the medium was removed, washed with PBS, and fixed with PBS containing 10% formalin for 2-5 minutes. Then, it was fixed for 1 minute with a 1:1 mixed solution of ethanol and acetone, and dried. The immobilized cells were treated with TRAP staining solution for 6 minutes at 37 o C while blocking light, washed with PBS, and then hematoxylin staining was performed, and the degree of staining of the cells was observed under a microscope.
현미경 시야에서 TRAP-양성세포 중, 2개 이상의 핵을 갖는 세포를 파골세포로 판정하고 세포의 수를 측정하였다. 본 발명의 화합물 1, 화합물2 및 화합물3의 파골세포 분화억제 효과는 화합물을 처리하지 않은 대조군 대비 50% 억제 농도를 IC50로 계산하였다.Of the TRAP-positive cells in the microscope field, cells having two or more nuclei were determined as osteoclasts and the number of cells was measured. The osteoclast differentiation inhibitory effect of
도 3에서 확인할 수 있듯이, 화합물들로 처리한 군에서는 양성대조군(배양 배지에 Osmundacetone 또는 Fosamax를 첨가한 군)과 유사하게 다핵세포인 거대한 파골세포 형성이 현저히 억제되었으며, 그 중에서도 osmundacetone의 phenyl ring의 4번 탄소의 hydroxyl 기를 methoxy 기로 치환한 화합물인 화합물 2의 경우, IC50가 0.1μM로서 임상에서 가장 많이 사용되는 골다공증 치료제인 Fsamax(IC50=4μM)의 40배, osmundacetone(IC50=8μM)의 80배 정도 강력한 파골세포 억제활성을 나타냈다. 부가적으로, 파골세포 전구세포의 증식도 현저히 억제되어 파골세포의 분화뿐만 아니라 증식 억제효과도 매우 큰 것으로 관찰되었다.As can be seen in Figure 3, in the group treated with the compounds, the formation of giant osteoclasts, which are multinuclear cells, was significantly suppressed similarly to the positive control group (group to which Osmundacetone or Fosamax was added to the culture medium), and among them, of the phenyl ring of osmundacetone. In the case of
<실시예 4> <Example 4>
조골세포 증식 및 분화 활성Osteoblast proliferation and differentiation activity
화합물 1, 화합물 2 및 화합물 3은 조골세포 활성 측정 방법인 ALP(Alkaline phosphatease) assay를 이용하여 조골세포에 대한 증식 및 분화 활성을 확인하였다. 본 발명의 화합물 1은 Sigma-Aldrich(St Louis, MO, USA)의 #306045이며, 화합물 2는 본 발명 실시예 1-1에서 합성한 것이며, 화합물 3은 실시예 1-2에서 합성한 것을 사용하였다.
조골세포의 세포막에 존재하는 Alkaline phosphatase(ALP)는 조골세포 활성의 표지인자로 알려져 있으며 석회화 과정 동안 무기인산의 운반, 세포 분열이나 분화의 조절자 역할을 한다. 그러므로 본 발명의 화합물들이 조골세포의 활성에 미치는 영향을 알아보기 위해 ALP 활성을 측정하였다. ALP 활성도는 p-nitrophenyl phosphate(pNPP, Sigma, St.Louis, MO, USA)의 가수분해 반응에 ALP가 촉매로 작용하여 생성되는 p-nitrophenol의 양을 405nm 파장에서 microplate reader를 이용하여 측정함으로써 간접적으로 산출해내었다.Alkaline phosphatase (ALP), which is present in the osteoblast cell membrane, is known as a marker of osteoblast activity and serves as a transporter of inorganic phosphoric acid, a regulator of cell division or differentiation during the calcification process. Therefore, ALP activity was measured to find out the effects of the compounds of the present invention on the activity of osteoblasts. ALP activity is indirect by measuring the amount of p-nitrophenol produced by ALP as a catalyst in the hydrolysis reaction of p-nitrophenyl phosphate (pNPP, Sigma, St.Louis, MO, USA) using a microplate reader at a wavelength of 405 nm. Was calculated.
구체적으로, 조골세포(mouse MC3T3-E1)를 96-well plate에 3 ×103 cells/100μ의 농도로 조골세포 분화인자인 ascorbic acid(50 μ와 10 mM β-glycerophosphate를 첨가한 α-MEM 배지에 분주하고, 본 발명의 화합물 1 내지 3과 osmundacetone을 최종농도 10μM 및 50μM로 투여한 후, 72시간마다 배지를 교환하며 14일간 배양하였다. 14일 후, 각각의 well에서 배양액을 제거하고 PBS로 3회 세척 후 0.2% Nonidet P-40/10 mmol/L MgCl2로 세포를 용해한 후 3분간 sonifier cell disrupter(Model W-380, Heat Systems-Ultrasonics, Inc., Farmingdale, NY)로 4°에서 초음파 처리하였다. 세포 분해액을 1500g에서 10분간 원심분리한 후 상층액을 모아 ALP 활성도를 측정하였다. 세포수 차이에 따른 ALP 활성도 변화를 고려하기 위해, 총단백질 양은 bovine serum albumin을 표준 단백질로 bicinchoninic acid(BCA) protein assay kit를 사용하여 측정하였으며 효소 활성은 화합물을 첨가하지 않은 대조군에 대한 백분율로 나타내었다.Specifically, α-MEM medium containing osteoblast differentiation factor ascorbic acid (50 μ and 10 mM β-glycerophosphate) was added to the 96-well plate at a concentration of 3 × 10 3 cells/100 μ of osteoblasts (mouse MC3T3-E1). After dispensing, and administering the
도 4에 나타낸 바와 같이, 화합물 1과 화합물 2는 10μM, 50μM 농도에서 화합물을 첨가하지 않은 대조군보다 높은 ALP 활성을 나타냈으며, 특히 화합물 1 ((E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one)를 50μM 농도로 첨가한 경우, 대조군에 비해 ALP 활성을 400% 이상 증가시켰으며 osmundacetone에 비해서도 1.5배의 조골세포 활성 증가를 보이는 것을 확인하였다. 이는 기존 임상에서 골다공증 치료에 사용 중인 조골세포 활성화제들에 준하는 매우 우수한 결과이다. 반면 화합물 3은 파골세포 분화 억제활성은 매우 우수하였으나(IC50=6μM), 조골세포 활성화 활성은 전혀 없었다.As shown in FIG . 4 ,
본 발명에 따른 화합물들은 뼈 손실을 야기하는 파골세포에 대하여 강력한 증식 및 분화 억제 활성을 나타내고, 조골세포 분화 및 활성을 현저히 증가시키기 때문에 안전하고 효과적인 골다공증 등 골 질환 예방 및 치료제 또는 개선용 식품을 개발하는데 유용하게 이용될 수 있다. The compounds according to the present invention show potent proliferation and differentiation inhibitory activity against osteoclasts causing bone loss and develop safe and effective bone disease prevention and treatment or improvement foods such as osteoporosis because they significantly increase osteoblast differentiation and activity It can be useful to do.
Claims (6)
(E)-4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one, (E)-4-(3-hydroxy-4-methoxyphenyl)-3-butene- Osteoporosis, Paget's disease, rickets disease, comprising a compound selected from the group consisting of 2-one and (E)-4-(3-fluoro-4-hydroxyphenyl)-3-buten-2-one as an active ingredient. , Osteomalacia, osteolysis, renal osteotrophy in patients with renal failure, joint pain, fractures, rheumatoid bone disease, degenerative bone disease, bone metastasis, primary tumors generated in bone, periodontal disease, inflammatory alveolar bone resorption disease and inflammatory bone absorption disease A pharmaceutical composition for preventing or treating bone disease selected from the group consisting of.
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