KR20230132078A - Composition for preventing, improving or treating Sarcopenia comprising novel compound - Google Patents
Composition for preventing, improving or treating Sarcopenia comprising novel compound Download PDFInfo
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/316—Foods, ingredients or supplements having a functional effect on health having an effect on regeneration or building of ligaments or muscles
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
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Abstract
Description
본 발명은 신규 화합물을 포함하는 근감소증의 예방 또는 치료용 약학적 조성물; 근감소증의 예방 또는 개선용 건강기능식품; 근육강화용 조성물; 및 운동수행능력 증진용 조성물을 제공하는 것이다. The present invention provides a pharmaceutical composition for preventing or treating sarcopenia containing a novel compound; Health functional foods for preventing or improving sarcopenia; Composition for muscle strengthening; And to provide a composition for improving exercise performance.
현대에 이르러 과도한 영양 섭취와 불규칙적인 생활로 인한 대사 불균형이 많아지고 비만이 증가하여 당뇨병 발병이 꾸준히 증가하는 추세이다. 또한, 지속적인 비만 인구의 증가 역시 당뇨병의 발병에 매우 중요한 원인 중 하나로 보고되어 있다 (Ogurtsova et al., 2017; 및 West et al., 1966). 당뇨병 환자들에게는 여러 합병증이 발생하는데, 심근경색, 심혈관 질환, 근감소증(또는 근육감소증) 등이 이에 해당된다 (Norhammar et al., 2002; 및 Cohen et al., 2015). 최근 당뇨합병증에 중요한 병증으로 대두되고 있는 근감소증은 근육 감소로 신체적 활동이 어려워지고 삶의 질이 떨어지며, 여러 대사적 질환에 취약해질 수 있다. 또한, 활동 능력의 감소로 인해 생존률이 떨어지고 일상에서 여러 사고의 위험에 노출될 수 있다고 보고된 바 있다 (Lynch et al., 2001). In modern times, metabolic imbalances due to excessive nutritional intake and irregular lifestyles are increasing, obesity is increasing, and the incidence of diabetes is steadily increasing. In addition, the continued increase in the obese population is also reported to be one of the very important causes of diabetes (Ogurtsova et al., 2017; and West et al., 1966). Many complications occur in diabetic patients, including myocardial infarction, cardiovascular disease, and sarcopenia (or sarcopenia) (Norhammar et al., 2002; and Cohen et al., 2015). Sarcopenia, which has recently emerged as an important diabetic complication, can make physical activity difficult due to muscle loss, reduce quality of life, and make people vulnerable to various metabolic diseases. In addition, it has been reported that survival rates decrease due to a decrease in activity ability and that people may be exposed to the risk of various accidents in daily life (Lynch et al., 2001).
근육 조직은 신체 내 혈당의 70%를 흡수하며, 이는 체내 혈당조절에 매우 중요한 역할을 한다. 특히, 근육조직의 절대량은 당뇨병 환자들에게 고혈당을 조절하는데 있어 중요한 역할을 하며, 이러한 근육이 감소하면 당뇨병이 더욱 심각해질 수 있다. 이러한 근감소증은 1989년 Irwin Rosenberg에 의하여 개념이 확립되었다 (Rosenberg et al., 1989). 근감소증의 측정지표는 사지 근육량을 신장의 제곱으로 나눈 값으로 진단하고 있으며, 이 수치가 20~40세 젊은 남녀의 평균값보다 -2 표준편차 미만으로 감소한 경우 근감소증으로 정의한다 (Baumagartner et al., 1998). Muscle tissue absorbs 70% of the body's blood sugar, which plays a very important role in regulating blood sugar in the body. In particular, the absolute amount of muscle tissue plays an important role in controlling high blood sugar in diabetic patients, and if this muscle decreases, diabetes can become more serious. The concept of sarcopenia was established by Irwin Rosenberg in 1989 (Rosenberg et al., 1989). The measurement index of sarcopenia is diagnosed as limb muscle mass divided by the square of height, and sarcopenia is defined when this value decreases by less than -2 standard deviations from the average value of young men and women aged 20 to 40 (Baumagartner et al. , 1998).
근육은 정상적인 상황에서 근육단백질들의 합성과 분해가 균형적으로 조절된다. 그러나, 단백질 합성과 분해의 균형이 깨지면, 단백질 합성의 감소와 단백질 분해의 증가로 인해 골격근에서의 단백질 손실이 발생하게 된다. 즉, 근육 소실은 단백질의 합성 감소 및 분해 증가가 복합적으로 작용하여 발생된다고 보고되었다 (Breen et al., 2011). 근감소증은 단백질 합성과 분해의 균형의 깨어짐에 따라 AKT 경로가 억제되고 합성 기전의 활성이 떨어지고 분해 기전의 활성으로 Caspase, Calpain, 오토파지의 과발현, 프로테아좀의 활성이 유도된다. 이러한 경로로 인해 근육 조직의 세포들의 단백질이 분해되어 근육 소실이 발생한다 (Kim et al., 2019). Muscles regulate the synthesis and decomposition of muscle proteins in a balanced manner under normal circumstances. However, when the balance between protein synthesis and degradation is broken, protein loss occurs in skeletal muscle due to a decrease in protein synthesis and an increase in protein degradation. In other words, it has been reported that muscle loss is caused by a combined effect of decreased protein synthesis and increased degradation (Breen et al., 2011). In sarcopenia, as the balance between protein synthesis and degradation is disrupted, the AKT pathway is inhibited, the activity of the synthesis mechanism decreases, and the activity of the decomposition mechanism induces overexpression of Caspase, Calpain, and autophagy, and the activity of the proteasome. Due to this pathway, proteins in muscle tissue cells are decomposed, resulting in muscle loss (Kim et al., 2019).
근육 감소의 다른 기작은 FoxO의 발현을 통해 E3 ligase 로 알려진 Atrogin-1, MuRF1(muscle RING-finger protein-1)의 발현으로 근섬유 단백질이 분해되어 유도되는 것으로 보고되어 있다 (Gomes et al., 2001; Bodine et al., 2001). Atrogin-1은 ubiquitin-proteasome system의 핵심 인자로 근육 소실 관련 전사 인자인 FoxO1과 FoxO3a에 의해 활성된다 (Mammucari et al., 2008; Sandri et al., 2004; 및 Zhao et al., 2007). 이러한 Foxo의 발현은 당뇨병성 근육 감소증 환자들에게서 확인되었으며, 이러한 기작으로 인해 근감소증이 일어나는 것으로 보고되어 있다 (Perry et al., 2016).Another mechanism of muscle loss is reported to be induced by the decomposition of muscle fiber proteins through the expression of Atrogin-1, known as E3 ligase, and MuRF1 (muscle RING-finger protein-1) through the expression of FoxO (Gomes et al., 2001 ; Bodine et al., 2001). Atrogin-1 is a key factor in the ubiquitin-proteasome system and is activated by the muscle loss-related transcription factors FoxO1 and FoxO3a (Mammucari et al., 2008; Sandri et al., 2004; and Zhao et al., 2007). This expression of Foxo has been confirmed in patients with diabetic sarcopenia, and it is reported that sarcopenia occurs due to this mechanism (Perry et al., 2016).
본 발명의 목적은 하기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근감소증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다:The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating sarcopenia containing a compound represented by the following formula (1) as an active ingredient:
[화합물 1][Compound 1]
. .
본 발명의 다른 목적은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근감소증의 예방 또는 개선용 건강기능식품을 제공하는 것이다. Another object of the present invention is to provide a health functional food for preventing or improving sarcopenia containing the compound represented by Formula 1 above as an active ingredient.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근육강화용 조성물을 제공하는 것이다. Another object of the present invention is to provide a composition for muscle strengthening containing the compound represented by Formula 1 above as an active ingredient.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 운동수행능력 증진용 조성물을 제공하는 것이다. Another object of the present invention is to provide a composition for improving exercise performance containing the compound represented by Formula 1 above as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근감소증의 예방 또는 치료용 약학적 조성물을 제공한다:In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating sarcopenia containing a compound represented by the following formula (1) as an active ingredient:
[화합물 1][Compound 1]
. .
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근감소증의 예방 또는 개선용 건강기능식품을 제공한다. In addition, the present invention provides a health functional food for preventing or improving sarcopenia containing the compound represented by Formula 1 above as an active ingredient.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근육강화용 조성물을 제공한다. Additionally, the present invention provides a composition for muscle strengthening containing the compound represented by Formula 1 above as an active ingredient.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 운동수행능력 증진용 조성물을 제공한다.In addition, the present invention provides a composition for enhancing exercise performance containing the compound represented by Formula 1 above as an active ingredient.
본 발명에 따른 조성물은 근육량을 증가시키고, 근육 손실을 억제하며, 근위축 인자의 발현을 억제하고, 근육 분화 촉진 인자의 발현을 증가시키는 효과가 있어, 근감소증의 예방, 개선 또는 치료에 유용하게 사용될 수 있다. The composition according to the present invention has the effect of increasing muscle mass, suppressing muscle loss, suppressing the expression of muscle atrophy factors, and increasing the expression of muscle differentiation promoting factors, making it useful for preventing, improving or treating sarcopenia. can be used
도 1은 본 발명에 따른 동물실험 디자인을 나타내는 것이다.
도 2는 마우스에 HM2102 약물을 투여한 후, 마우스의 악력(Grip Strength)을 측정한 결과이다 (DB/DB vs. Drug treated groups:*P < 0.05).
도 3은 마우스에 HM2102 약물을 투여한 후, 마우스 뒷다리의 근육을 관찰한 결과이다.
도 4는 마우스에 HM2102 약물을 투여한 후, MRI를 통해 마우스 뒷다리의 근육량을 측정한 결과이다 (DB/DB vs. Drug treated groups:*P < 0.05).
도 5는 마우스에 HM2102 약물을 투여한 후, 비복근(GM) 및 전경골근(TA)의 무게를 측정한 결과이다 (DB/DB vs. Drug treated groups:*P < 0.05).
도 6은 전경골근(TA)의 근육세포 크기를 비교한 결과이다.
도 7은 비복근(GM)의 근육세포 크기를 비교한 결과이다.
도 8은 마우스에 HM2102 약물을 투여한 후, Atrogin-1, MurF-1, Myogenin 및 MyoD의 mRNA 발현량을 분석하기 위해 real-time PCR을 수행한 결과이다.
도 9는 근육조직에 대식세포의 침윤을 조사하기 위하여 대식세포 마커인 F4/80 면역 염색을 수행한 결과이다.
도 10은 염증성 사이토카인인 IL-1β, IL-6, TNF-α 및 Myostatin의 mRNA 발현량을 분석하기 위해 real-time PCR를 수행한 결과이다 (DB/DB vs. Drug treated groups:*P < 0.05).
도 11은 근육조직의 섬유화를 조사하기 위하여 근육조직을 시리우스레드(sirius red) 염색을 수행한 결과이다.
도 12는 인슐린 내성 검사(Insulin Tolerance Test, ITT) 및 포도당 부하 검사(Glucose Tolerance Test, GTT)를 수행한 결과이다. Figure 1 shows the animal test design according to the present invention.
Figure 2 shows the results of measuring the grip strength of mice after administering drug HM2102 to mice (DB/DB vs. Drug treated groups:* P < 0.05).
Figure 3 shows the results of observing the muscles of the mouse's hind limbs after administering the HM2102 drug to the mouse.
Figure 4 shows the results of measuring the muscle mass of the hind limbs of the mouse through MRI after administering the drug HM2102 to the mouse (DB/DB vs. Drug treated groups:* P < 0.05).
Figure 5 shows the results of measuring the weight of the gastrocnemius (GM) and tibialis anterior (TA) muscles after administering the HM2102 drug to mice (DB/DB vs. Drug treated groups:* P < 0.05).
Figure 6 shows the results of comparing the size of muscle cells of the tibialis anterior (TA).
Figure 7 shows the results of comparing the size of muscle cells of the gastrocnemius muscle (GM).
Figure 8 shows the results of real-time PCR to analyze the mRNA expression levels of Atrogin-1, MurF-1, Myogenin, and MyoD after administering the drug HM2102 to mice.
Figure 9 shows the results of F4/80 immunostaining, a macrophage marker, to investigate the infiltration of macrophages into muscle tissue.
Figure 10 shows the results of real-time PCR to analyze the mRNA expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and Myostatin (DB/DB vs. Drug treated groups:* P < 0.05).
Figure 11 shows the results of Sirius red staining of muscle tissue to investigate fibrosis of muscle tissue.
Figure 12 shows the results of an insulin tolerance test (ITT) and a glucose tolerance test (GTT).
이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물(이하, "HM2102" 약물로 기재함)을 유효성분으로 포함하는 근감소증의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating sarcopenia containing a compound represented by the following formula (1) (hereinafter referred to as “HM2102” drug) as an active ingredient.
[화학식 1][Formula 1]
상기 HM2102의 합성 방법은 하기 실시예 1에 기재된 바와 같다. HM2102는 MS-275(entinostat)의 플루오린화 구조유사체(fluorinated analog)로서, 기존 MS-275에 비해 독성이 감소되고, 효과가 개선된 화합물이다. The method for synthesizing HM2102 is as described in Example 1 below. HM2102 is a fluorinated analog of MS-275 (entinostat), and is a compound with reduced toxicity and improved effectiveness compared to the existing MS-275.
본 발명의 일 실시예에 있어서, 상기 조성물은 근육량을 증가시키거나, 근육 손실을 억제하는 것일 수 있다. In one embodiment of the present invention, the composition may increase muscle mass or inhibit muscle loss.
본 발명의 일 실시예에 있어서, 상기 조성물은 근위축 인자의 발현을 억제하거나, 근육 분화 촉진 인자의 발현을 증가시키는 것일 수 있다. 바람직하게는 상기 조성물은 근위축을 야기하는 Atrogin-1 및 MuRF-1(Muscle RING-finger protein-1)의 발현을 억제하는 것일 수 있고, 근육분화를 촉진하는 Mmyogenin 및 MyoD (myoblast determination protein 1)의 발현을 증가시키는 것일 수 있다. In one embodiment of the present invention, the composition may suppress the expression of muscle atrophy factors or increase the expression of muscle differentiation promoting factors. Preferably, the composition may inhibit the expression of Atrogin-1 and MuRF-1 (Muscle RING-finger protein-1), which cause muscle atrophy, and Mmyogenin and MyoD (myoblast determination protein 1), which promote muscle differentiation. It may increase the expression of .
본 발명의 일 실시예에 있어서, 상기 근감소증은 노화, 비만 또는 당뇨병에 의해 유발되는 것일 수 있으나, 이에 한정되는 것은 아니다. In one embodiment of the present invention, the sarcopenia may be caused by aging, obesity, or diabetes, but is not limited thereto.
본 발명의 일 실시예에 있어서, 상기 근감소증은 근위축증, 근무력증, 근이영양증, 근력약화, 근육퇴행위축, 근위축성 측삭 경화증, 척수구근위축 및 중증 근무력증으로 이루어진 군에서 선택되는 것일 수 있으나, 이에 한정되는 것은 아니다. In one embodiment of the present invention, the sarcopenia may be selected from the group consisting of muscular dystrophy, myasthenia gravis, muscular dystrophy, muscle weakness, muscular dystrophy, amyotrophic lateral sclerosis, spinal bulbar muscular atrophy, and myasthenia gravis, but is limited thereto. That is not the case.
본 발명의 약학적 조성물은 약학적으로 허용가능한 담체를 추가로 포함할 수 있다. 본 발명에서 용어, "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제, 기제, 부형제, 윤활제 등 당업계에 공지된 것이라면 제한없이 사용할 수 있다. The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. In the present invention, the term “pharmaceutically acceptable” means that the composition exhibits non-toxic properties to cells or humans exposed to the composition. The carrier may be used without limitation as long as it is known in the art, such as a buffer, preservative, analgesic agent, solubilizer, isotonic agent, stabilizer, base, excipient, lubricant, etc.
또한, 본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 나아가, 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태의 피부 외용제의 형태로 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.In addition, the pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. You can. Furthermore, it can be used in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel, or external skin preparation in the form of a gel. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 싸이코트리아 루브라 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 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, 글리세로제라틴 등이 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the Cycotria rubra extract with at least one excipient, such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "투여"란 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미하며 상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "administration" in the present invention means introducing a predetermined substance into an individual by an appropriate method, and the composition may be administered through any general route as long as it can reach the target tissue. It may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, topically, intranasally, intrapulmonaryly, or rectally, but is not limited thereto.
상기 용어, "개체"란 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 바람직하게는, 인간을 포함한 포유동물일 수 있다.The term "individual" refers to all animals, including rats, mice, and livestock, including humans. Preferably, it may be a mammal, including humans.
상기 용어, "약학적으로 유효한 양"이란 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강 상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다. 투여는 상기 권장 투여량을 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.The above term, "pharmaceutically effective amount" means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment and not cause side effects, and the effective dose level is determined by the patient's gender, age, Factors including body weight, health status, type and severity of the disease, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and excretion rate, duration of treatment, drugs combined or used simultaneously, and other medical fields. It can be readily determined by a person skilled in the art according to well-known factors. The recommended dosage may be administered once a day, or it may be administered several times.
또한, 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 또한, 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다. Additionally, the pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Additionally, it can be administered single or multiple times. It is important to consider all of the above factors and administer the amount that will achieve the maximum effect with the minimum amount without side effects.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근감소증의 예방 또는 개선용 건강기능식품을 제공한다. In addition, the present invention provides a health functional food for preventing or improving sarcopenia containing the compound represented by Formula 1 above as an active ingredient.
본 발명의 건강기능식품은 통상적인 의미의 식품을 모두 포함할 수 있으며, 기능성 식품 등 당업계에 알려진 용어와 혼용 가능하다.The health functional food of the present invention may include all foods in the conventional sense and can be used interchangeably with terms known in the art, such as functional food.
본 발명의 용어, "기능성 식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The term "functional food" in the present invention refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and "functional" refers to food that is useful for the human body. It means ingestion for the purpose of controlling nutrients for structure and function or obtaining useful health effects such as physiological effects.
본 발명의 용어, "건강기능식품"은 건강보조의 목적으로 특정성분을 원료로 하거나 식품 원료에 들어있는 특정성분을 추출, 농축, 정제, 혼합 등의 방법으로 제조, 가공한 식품을 말하며, 상기 성분에 의해 생체방어, 생체리듬의 조절, 질병의 방지와 회복 등 생체조절기능을 생체에 대하여 충분히 발휘할 수 있도록 설계되고 가공된 식품을 말하는 것으로서, 상기 건강식품용 조성물은 질병의 예방 및 질병의 회복 등과 관련된 기능을 수행할 수 있다. The term "health functional food" of the present invention refers to a food manufactured or processed using specific ingredients as raw materials or by extracting, concentrating, refining, or mixing specific ingredients contained in food raw materials for the purpose of health supplementation. It refers to a food designed and processed so that its ingredients can sufficiently exert bioregulatory functions such as biodefense, regulation of biorhythm, prevention and recovery of disease, etc. to the living body. The composition for health food refers to a composition for disease prevention and recovery from disease. It can perform functions related to etc.
본 발명의 조성물이 사용될 수 있는 식품의 종류에는 제한이 없다. 아울러, 본 발명의 조성물은 당업자의 선택에 따라 식품에 포함될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 추출물 및 이의 분획물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.There are no restrictions on the types of food in which the composition of the present invention can be used. In addition, the composition of the present invention can be prepared by mixing known additives with other appropriate auxiliary ingredients that can be included in food according to the selection of a person skilled in the art. Examples of foods that can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and There are vitamin complexes, etc., and they can be prepared by adding the extract and its fraction according to the present invention to juice, tea, jelly, juice, etc.
또한, 본 발명에 적용될 수 있는 식품에는 예컨대, 특수영양식품(예: 조제유류, 영,유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류(예: 라면류, 국수류 등), 건강보조식품, 조미식품(예: 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류(예:스낵류), 유가공품(예: 발효유, 치즈 등), 기타 가공식품, 김치, 절임식품(각종 김치류, 장아찌 등), 음료(예: 과실, 채소류 음료, 두유류, 발효음료류 등), 천연조미료(예, 라면스프 등) 등 모든 식품을 포함할 수 있다.In addition, foods that can be applied to the present invention include, for example, special nutritional foods (e.g., infant formula, infant and toddler food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g., ramen, noodles, etc.), and health supplements. , seasoned foods (e.g. soy sauce, soybean paste, red pepper paste, mixed paste, etc.), sauces, confectionery (e.g. snacks), dairy products (e.g. fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickles, etc.) ), beverages (e.g. fruit, vegetable drinks, soy milk, fermented beverages, etc.), natural seasonings (e.g. ramen soup, etc.), etc.
본 발명의 건강기능식품 조성물이 음료의 형태로 사용될 경우에는 통상의 음료와 같이 여러 가지 감미제, 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.When the health functional food composition of the present invention is used in the form of a beverage, it may contain various sweeteners, flavoring agents, or natural carbohydrates as additional ingredients like ordinary beverages. In addition to the above, the health functional food composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, and glycerin. , alcohol, and carbonating agents used in carbonated beverages. In addition, it may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 근육강화용 조성물을 제공한다. Additionally, the present invention provides a composition for muscle strengthening containing the compound represented by Formula 1 above as an active ingredient.
본 발명의 용어, "근육강화"는 근육의 근력 및/또는 크기를 증가시키는 효과를 의미하며, 근육의 종류를 제한하지 않는다. 바람직하게는 근육량을 증가시키는 효과를 나타내고, 근육 감소를 억제시키는 효과를 나타내는 것을 특징으로 한다.The term “muscle strengthening” of the present invention refers to the effect of increasing muscle strength and/or size, and does not limit the type of muscle. Preferably, it has the effect of increasing muscle mass and has the effect of suppressing muscle loss.
상기 근육량의 증가는 근육의 성능을 향상시키는 것으로, 육체적 운동 및 지구력 향상을 통해 근육량을 증가시킬 수 있고, 근육 증가 효과를 가지는 물질을 체내에 투여하는 방식으로 근육량을 증가시킬 수 있다. 또한 상기 근육 감소는 근육량의 점진적 손실, 근육, 특히 골격근 또는 수의근 및 심장근육의 약화 및 퇴행을 특징으로 하며, 유전적 요인, 후천적 요인. 노화 등이 원인일 수 있다.The increase in muscle mass improves muscle performance, and muscle mass can be increased through physical exercise and improved endurance, and muscle mass can be increased by administering a substance with a muscle-increasing effect into the body. In addition, the above-mentioned muscle loss is characterized by gradual loss of muscle mass, weakness and degeneration of muscles, especially skeletal or voluntary muscles and cardiac muscles, and can be caused by genetic or acquired factors. Aging may be the cause.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 운동수행능력 증진용 조성물을 제공한다. In addition, the present invention provides a composition for enhancing exercise performance containing the compound represented by Formula 1 above as an active ingredient.
본 발명의 용어, "운동수행능력"은 일상생활이나 스포츠에서 볼 수 있는 신체동작을 외형적으로 달리기, 뛰기, 던지기, 헤엄치기 등으로 구분할 때, 상기 동작을 빠르게, 강하게, 정확하게, 오래, 능숙하게 할 수 있는 정도를 나타내는 것으로서, 운동수행능력은 근력, 민첩성 및 지구력 등의 인자로 규정된다. The term "exercise performance" of the present invention refers to physical movements seen in daily life or sports that are externally divided into running, jumping, throwing, swimming, etc., and refers to the movement being performed quickly, strongly, accurately, long, and skillfully. As it indicates the degree to which a person can do something, exercise performance is defined by factors such as strength, agility, and endurance.
본 발명의 용어, "운동수행능력 증진"은 운동수행능력을 개선하거나 향상시키는 것을 말한다. 바람직하게는 상기 조성물은 근력을 증가시키는 효과를 나타내고, 근 지구력을 증가시키는 효과를 나타내는 것을 특징으로 한다.The term "exercise performance enhancement" in the present invention refers to improving or enhancing exercise performance. Preferably, the composition exhibits an effect of increasing muscle strength and increases muscular endurance.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명하기로 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrating the present invention in more detail, and the scope of the present invention is not limited to these examples.
실시예 1. HM2102의 합성Example 1. Synthesis of HM2102
1.1. 분석기기1.1. analysis equipment
본 발명에서 얻은 생성물의 구조 확인을 위해 사용된 기기는 하기와 같다. 핵자기 공명 스펙트럼(1H NMR)은 ADVANCE digital 500, 용매는 CD3OD 또는 DMSO-d6를 사용하였다. The equipment used to confirm the structure of the product obtained in the present invention is as follows. ADVANCE digital 500 was used for nuclear magnetic resonance spectrum ( 1H NMR), and CD 3 OD or DMSO-d 6 was used as a solvent.
1.2. TLC 및 관 크로마토그래피1.2. TLC and tube chromatography
TLC (Thin layer chromatography)는 Merk 사 제품인 실리카겔(Merck F254)을 사용하였으며 관 크로마토그래피(Column chromatography)를 위해서는 실리카(Merck EM9385, 230-400 mesh)를 사용하였다. 또한, TLC 상에서 분리된 물질을 확인하기 위해서 UV 램프(254 nm)를 이용하거나 아니스알데히드(anisaldehyde) 발색시약에 담근 후, 플레이트를 가열하여 확인하였다.For TLC (Thin layer chromatography), silica gel (Merck F254) manufactured by Merk was used, and for column chromatography, silica (Merck EM9385, 230-400 mesh) was used. Additionally, in order to confirm the substances separated on TLC, they were confirmed by using a UV lamp (254 nm) or by heating the plate after immersing it in anisaldehyde color development reagent.
1.3. 사용 시약1.3. reagent used
본 발명에서 사용된 시약은 시그마-알드리치(sigma-aldrich) 및 티시아이(TCI) 제품을 구입하여 사용하였다. 반응 및 정제에 사용된 용매는 ACS 등급의 무수 용매를 구매하거나, 용매정제 장치를 사용하여 무수 용매를 제조하여 사용하였다. Reagents used in the present invention were purchased from Sigma-Aldrich and TCI. The solvent used in the reaction and purification was an ACS grade anhydrous solvent purchased or an anhydrous solvent prepared using a solvent purification device.
1.4.1.4. 합성 과정synthesis process
terttert -Butyl (5-fluoro-2-nitrophenyl)carbamate (2a)-Butyl (5-fluoro-2-nitrophenyl)carbamate (2a)
5-Fluoro-2-nitroaniline 1a (600 mg, 3.8 mmol)의 methylene chloride (66 mL) 용액에 Et3N (0.26 mL, 1.9 mmol)과 DMAP (46 mg, 0.32 mmol)를 넣고, 10 mL의 methylene chloride 에 희석한 917 mg (4.2 mmol)의 Boc2O를 2시간동안 천천히 넣는다. 상온에서 24시간 반응시키고 반응물을 1N HCl 로 산성화하고 ethyl acetate와 물로 추출한 후 brine으로 세척하였다. 유기층을 무수 MgSO4로 건조하고 진공 하에 용매를 제거한 후, 반응 혼합물을 1 : 40 비율의 ethyl acetate와 n-hexane 용매를 이용한 컬럼 크로마토그래피법(실리카겔)으로 정제하여 708 mg (2.8 mmol, 73%)의 화합물 2a를 얻었다. Add Et 3 N (0.26 mL, 1.9 mmol) and DMAP (46 mg, 0.32 mmol) to a solution of 5-Fluoro-2-nitroaniline 1a (600 mg, 3.8 mmol) in methylene chloride (66 mL), and add 10 mL of methylene. Slowly add 917 mg (4.2 mmol) of Boc 2 O diluted in chloride over 2 hours. The reaction was performed at room temperature for 24 hours, and the reactant was acidified with 1N HCl, extracted with ethyl acetate and water, and washed with brine. After drying the organic layer with anhydrous MgSO 4 and removing the solvent under vacuum, the reaction mixture was purified by column chromatography (silica gel) using a 1:40 ratio of ethyl acetate and n-hexane solvent to yield 708 mg (2.8 mmol, 73%). ) Compound 2a was obtained.
1H NMR (500 MHz, MeOD) δ 8.29 (m, 1H), 8.23 (d, J = 11.6 Hz, 1H), 6.93 (m, 1H), 1.55 (s, 3H), 1.55 (s, 3H), 1.55 (s, 3H). 1H NMR (500 MHz, MeOD) δ 8.29 (m, 1H), 8.23 (d, J = 11.6 Hz, 1H), 6.93 (m, 1H), 1.55 (s, 3H), 1.55 (s, 3H), 1.55 (s, 3H).
terttert -Butyl (4-fluoro-2-nitrophenyl)carbamate (2b)-Butyl (4-fluoro-2-nitrophenyl)carbamate (2b)
2a의 합성법을 이용하여 4-fluoro-2-nitroaniline 1b (500 mg, 3.2 mmol)로부터 343 mg (1.33 mmol, 42%)의 화합물 2b를 얻었다. Using the synthesis method of 2a , 343 mg (1.33 mmol, 42%) of compound 2b was obtained from 4-fluoro-2-nitroaniline 1b (500 mg, 3.2 mmol).
1H NMR (500 MHz, MeOD) δ 8.23 (dd, J = 9.1, 5.1 Hz, 1H), 7.90 (dd, J = 8.5, 2.2 Hz, 1H), 7.52 - 7.45 (m, 1H), 1.53 (s, 3H), 1.53 (s, 3H), 1.53 (s, 3H). 1H NMR (500 MHz, MeOD) δ 8.23 (dd, J = 9.1, 5.1 Hz, 1H), 7.90 (dd, J = 8.5, 2.2 Hz, 1H), 7.52 - 7.45 (m, 1H), 1.53 (s) , 3H), 1.53 (s, 3H), 1.53 (s, 3H).
terttert -Butyl (2-amino-5-fluorophenyl)carbamate (3a)-Butyl (2-amino-5-fluorophenyl)carbamate (3a)
658 mg (2.6 mmol)의 화합물 2a의 methanol (100 mL) 용액에 촉매량의 Pd/C를 넣고 수소 기체 하에서 하루 간 반응시켰다. Celite filter로 palladium 촉매를 제거 및 감압농축하여 581 mg (2.6 mmol, 100%)의 화합물 3을 얻었다.A catalytic amount of Pd/C was added to a solution of 658 mg (2.6 mmol) of Compound 2a in methanol (100 mL) and reacted under hydrogen gas for one day. The palladium catalyst was removed using a Celite filter and concentrated under reduced pressure to obtain 581 mg (2.6 mmol, 100%) of Compound 3 .
1H NMR (500 MHz, MeOD) δ 7.10 (d, J = 9.6 Hz, 1H), 6.78 (dd, J = 8.8, 5.6 Hz, 1H), 6.68 (td, J = 8.4, 2.9 Hz, 1H), 4.63 (s, 1H), 1.52 (s, 3H), 1.52 (s, 3H), 1.52 (s, 3H). 1H NMR (500 MHz, MeOD) δ 7.10 (d, J = 9.6 Hz, 1H), 6.78 (dd, J = 8.8, 5.6 Hz, 1H), 6.68 (td, J = 8.4, 2.9 Hz, 1H), 4.63 (s, 1H), 1.52 (s, 3H), 1.52 (s, 3H), 1.52 (s, 3H).
terttert -Butyl (2-amino-4-fluorophenyl)carbamate (3b)-Butyl (2-amino-4-fluorophenyl)carbamate (3b)
3a의 합성법을 이용하여 2b (343 mg, 1.3 mmol)로부터 267 mg (1.2 mmol, 88%)의 화합물 3b를 얻었다. 267 mg (1.2 mmol, 88%) of compound 3b was obtained from 2b (343 mg, 1.3 mmol) using the synthesis method of 3a .
1H NMR (500 MHz, MeOD) δ 7.07 - 7.02 (m, 1H), 6.50 (d, J = 10.6 Hz, 1H), 6.34 (t, J = 8.4 Hz, 1H), 1.50 (s, 3H), 1.50 (s, 3H), 1.50 (s, 3H). 1 H NMR (500 MHz, MeOD) δ 7.07 - 7.02 (m, 1H), 6.50 (d, J = 10.6 Hz, 1H), 6.34 (t, J = 8.4 Hz, 1H), 1.50 (s, 3H), 1.50 (s, 3H), 1.50 (s, 3H).
Pyridin-3-ylmethyl(4-((2-((tert-butoxycarbonyl)amino)-4-fluorophenyl)carbamoyl)benzyl)carbamate (5a)Pyridin-3-ylmethyl(4-((2-((tert-butoxycarbonyl)amino)-4-fluorophenyl)carbamoyl)benzyl)carbamate (5a)
Aniline 3a (267 mg, 1.2 mmol)의 DMF (6 mL) 용액에 문헌(Journal of Medicinal Chemistry, 1999, Vol. 42, No. 15 3001-3003)에 알려진 4-((((pyridin-3-ylmethoxy)carbonyl)amino)methyl)benzoic acid 4 (370 mg, 1.1 mmol)와 EDCI (288 mg, 1.3 mmol) 및 HOBT (203 mg, 1.3 mmol)를 넣었다. 60℃에서 하루 간 반응시킨 후 물을 가하여 반응을 종결하였다. Ethyl acetate로 추출한 후 brine으로 세척하였다. 유기층을 무수 MgSO4로 건조하고 진공 하에 용매를 제거한 후 반응 혼합물을 20 : 1 비율의 methylenechloride 와 methanol 용매를 이용한 컬럼 크로마토그래피법(실리카겔)으로 정제하여 242 mg (0.76 mmol, 42%)의 화합물 5a을 얻었다. 4-((((pyridin-3-ylmethoxy) known from the literature (Journal of Medicinal Chemistry, 1999, Vol. 42, No. 15 3001-3003) was added to a solution of Aniline 3a (267 mg, 1.2 mmol) in DMF (6 mL). )carbonyl)amino)methyl)benzoic acid 4 (370 mg, 1.1 mmol) and EDCI (288 mg, 1.3 mmol) and HOBT (203 mg, 1.3 mmol) were added. After reacting at 60°C for one day, water was added to terminate the reaction. Extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous MgSO 4 , the solvent was removed under vacuum, and the reaction mixture was purified by column chromatography (silica gel) using a 20:1 ratio of methylenechloride and methanol solvent to yield 242 mg (0.76 mmol, 42%) of Compound 5a. got it
1H NMR (500 MHz, DMSO) δ 9.77 (s, 1H), 8.79 (s, 1H), 8.60 (d, J = 1.4 Hz, 1H), 8.54 (dd, J = 4.7, 1.2 Hz, 1H), 8.00 (t, J = 6.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.53 (dd, J = 11.1, 2.8 Hz, 1H), 7.48 - 7.37 (m, 4H), 6.97 (td, J =8.4 Hz, 2.9 Hz, 1H), 5.10 (s, 2H), 4.29 (d, J = 6.3 Hz, 2H), 1.45 (s, 3H), 1.45 (s, 3H), 1.45 (s, 3H). 1H NMR (500 MHz, DMSO) δ 9.77 (s, 1H), 8.79 (s, 1H), 8.60 (d, J = 1.4 Hz, 1H), 8.54 (dd, J = 4.7, 1.2 Hz, 1H), 8.00 (t, J = 6.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.53 (dd, J = 11.1, 2.8 Hz, 1H), 7.48 - 7.37 (m, 4H), 6.97 (td, J =8.4 Hz, 2.9 Hz, 1H), 5.10 (s, 2H), 4.29 (d, J = 6.3 Hz, 2H), 1.45 (s, 3H), 1.45 (s, 3H), 1.45 (s, 3H).
Pyridin-3-ylmethyl(4-((2-((tert-butoxycarbonyl)amino)-5-fluorophenyl)carbamoyl)benzyl)carbamate (5b)Pyridin-3-ylmethyl(4-((2-((tert-butoxycarbonyl)amino)-5-fluorophenyl)carbamoyl)benzyl)carbamate (5b)
5a의 합성법을 이용하여 3b (585 mg, 2.2 mmol)로부터 668 mg (1.35 mmol, 62%)의 화합물 5b를 얻었다. 668 mg (1.35 mmol, 62%) of compound 5b was obtained from 3b (585 mg, 2.2 mmol) using the synthesis method of 5a .
1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 7.96 (t, J = 5.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 10.2 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.41 (d, J = 7.6 Hz, 3H), 7.04 (t, J = 8.15, 1H), 5.10 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 1.44 (s, 3H), 1.44 (s, 3H), 1.44 (s, 3H). 1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 7.96 (t, J = 5.7) Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 10.2 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.41 (d, J = 7.6 Hz, 3H), 7.04 (t, J = 8.15, 1H), 5.10 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 1.44 (s, 3H), 1.44 (s, 3H), 1.44 (s, 3H).
HM2102HM2102
5b (379 mg, 0.77 mmol)의 methylenechloride (5 mL) 용액에 TFA (0.75 mL, 9.7 mmol)를 넣었다. 상온에서 3 시간 동안 반응시키고 반응물을 NaHCO3 용액으로 종결하고 ethyl acetate로 추출하였다. 유기층을 무수 MgSO4로 건조하고 진공 하에 용매를 제거하였다. 잔사를 n-hexane과 methylenechloride로 세척한 후, 건조하여 202 mg (0.96 mmol, 67%)의 화합물 HM2102를 얻었다.TFA (0.75 mL, 9.7 mmol) was added to a solution of 5b (379 mg, 0.77 mmol) in methylenechloride (5 mL). React at room temperature for 3 hours and terminate the reaction with NaHCO 3 solution. Extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO 4 and the solvent was removed under vacuum. The residue was washed with n-hexane and methylenechloride and dried to obtain 202 mg (0.96 mmol, 67%) of compound HM2102 .
1H NMR (500 MHz, DMSO) δ 9.64 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.06 - 7.75 (m, 4H), 7.47 - 7.31 (m, 3H), 7.17 (d, J = 9.3 Hz, 1H), 6.82 (d, J = 6.6 Hz, 1H), 6.78 (d, J = 5.3 Hz, 1H), 5.10 (s, 2H), 4.85 (s, 2H), 4.28 (d, J = 4.6 Hz, 2H). 1 H NMR (500 MHz, DMSO) δ 9.64 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.06 - 7.75 (m, 4H), 7.47 - 7.31 (m, 3H), 7.17 (d, J = 9.3 Hz, 1H), 6.82 (d, J = 6.6 Hz, 1H), 6.78 (d, J = 5.3 Hz, 1H), 5.10 (s, 2H), 4.85 (s, 2H), 4.28 (d, J = 4.6 Hz, 2H).
실시예 2. 동물모델 및 통계분석Example 2. Animal model and statistical analysis
본 발명에서는 당뇨병 및 근감소증 질환 모델인 10주령의 수컷 DB/DB (-/-) 마우스와 수컷 C57BL/6j 마우스로 실험을 수행하였다. 실험군은 다음과 같다: C57BL/6j 마우스: 정상 대조군; DB/DB (-/-) 마우스: 근감소증 질환 마우스; 및 HM2102(화학식 1로 표시되는 화합물) 약물 처리군: 근감소증 질환 마우스에 HM2102 약물을 처리한 마우스.In the present invention, experiments were performed with 10-week-old male DB/DB (-/-) mice and male C57BL/6j mice, which are disease models for diabetes and sarcopenia. The experimental groups were as follows: C57BL/6j mice: normal control; DB/DB (-/-) mice: mice with sarcopenia disease; and HM2102 (compound represented by Formula 1) drug treatment group: mice with sarcopenia disease treated with HM2102 drug.
순화기간 종료 후, 마우스에 4주간 주3회 HM2102 약물을 복강내 투여(Intraperitoneal, IP)한 후, 근육조직의 무게 분석, 뒷다리 MRI 촬영, 조직병리학적 검사 및 면역염색 평가, 포도당 부하 검사(Glucose Tolerance Test, GTT) 및 인슐린 내성 검사(Insulin Tolerance Test, ITT) 등을 수행하였다 (도 1). After the acclimatization period, the drug HM2102 was administered intraperitoneally (IP) three times a week for 4 weeks to mice, followed by muscle tissue weight analysis, hind limb MRI, histopathological examination and immunostaining evaluation, and glucose tolerance test. Tolerance Test (GTT) and insulin tolerance test (ITT) were performed (Figure 1).
각 군간의 비교는 GraphPad Prism 6.0 (GraphPad software, San Diego, CA)를 사용하여 ANOVA 분석을 수행하였으며, 유의성이 인정된 경우에 사후검정은 Bonferroni로 수행하였다. 각 군간을 비교하여 5%의 유의수준에서 유의성을 검증하였다. For comparison between each group, ANOVA analysis was performed using GraphPad Prism 6.0 (GraphPad software, San Diego, CA), and when significance was recognized, a post hoc test was performed using Bonferroni. By comparing each group, significance was verified at a significance level of 5%.
실시예 3. 운동수행능력 증진 효과Example 3. Effect of improving exercise performance
마우스에 HM2102 약물을 4주간 주3회 투여한 후, 마우스의 근육 강도를 측정하기 위해 악력(Grip Strength) 실험을 수행하였다. 그 결과, 질환 모델 마우스인 DB/DB (-/-) 마우스에서는 정상 대조군인 C57BL/6j 마우스에 비해 악력이 현저히 감소한 반면, HM2102 약물 처리군에서는 질환 모델 마우스에 비해 악력(Grip Strength)이 증가 또는 회복되었음을 확인하였다 (도 2). After administering the drug HM2102 to mice three times a week for four weeks, a grip strength experiment was performed to measure the muscle strength of the mice. As a result, in DB/DB (-/-) mice, which are disease model mice, grip strength was significantly reduced compared to C57BL/6j mice, which are normal controls, while in the HM2102 drug treated group, grip strength was increased or increased compared to disease model mice. Recovery was confirmed (Figure 2).
이로써, 본 발명에서는 HM2102 약물이 운동수행능력을 증진시키는 효과가 있음을 확인하였다. As a result, the present invention confirmed that the HM2102 drug has the effect of improving exercise performance.
실시예 4. 근육량(muscle mass) 증가 효과Example 4. Effect of increasing muscle mass
4주간의 약물 투여 후 마우스를 희생시키고, 마우스 뒷다리의 근육을 관찰하는 실험을 수행하였다. 그 결과, HM2102 약물 처리군에서는 DB/DB (-/-) 마우스에서 감소된 근육이 증가 또는 회복되었음을 확인하였다 (도 3). 또한, 마우스 뒷다리의 근육량을 MRI(Magnetic Resonance Imaging)를 이용하여 촬영하고 Image J를 이용하여 마우스 뒷다리(hindlimb)의 근육량을 측정하였다. 그 결과, DB/DB (-/-) 마우스에서는 정상 대조군에 비해 근육량이 현저히 감소한 반면, HM2102 약물 처리군에서는 DB/DB (-/-) 마우스에 비해 근육량이 증가 또는 회복되었음을 확인하였다 (도 4). After 4 weeks of drug administration, the mice were sacrificed, and an experiment was performed to observe the muscles of the mouse's hind limbs. As a result, it was confirmed that in the HM2102 drug treatment group, the muscles decreased in DB/DB (-/-) mice were increased or recovered (FIG. 3). In addition, the muscle mass of the mouse hindlimb was imaged using MRI (Magnetic Resonance Imaging) and the muscle mass of the mouse hindlimb was measured using Image J. As a result, it was confirmed that muscle mass was significantly reduced in DB/DB (-/-) mice compared to the normal control group, while muscle mass was increased or recovered in the HM2102 drug treatment group compared to DB/DB (-/-) mice (Figure 4 ).
또한, 마우스의 비복근(gastrocnemius muscle, GM) 및 전경골근(Tibialis Anterior muscle, TA)의 근육 무게를 측정하는 실험을 수행하였다. 그 결과, DB/DB (-/-) 마우스에서는 정상 대조군에 비해 비복근(GM) 및 전경골근(TA)의 무게가 현저히 감소한 반면, HM2102 약물 처리군에서는 DB/DB (-/-) 마우스에 비해 비복근(GM) 및 전경골근(TA)의 무게가 유의하게 증가 또는 회복되었음을 확인하였다 (도 5). Additionally, an experiment was performed to measure the muscle weight of the gastrocnemius muscle (GM) and tibialis anterior muscle (TA) of mice. As a result, the weight of the gastrocnemius (GM) and tibialis anterior (TA) muscles was significantly reduced in DB/DB (-/-) mice compared to the normal control group, while in the HM2102 drug treatment group compared to DB/DB (-/-) mice. It was confirmed that the weight of the gastrocnemius muscle (GM) and tibialis anterior (TA) significantly increased or recovered (Figure 5).
이후, 마우스의 비복근(GM) 및 전경골근(TA)에서 H&E 염색을 수행하여 근육세포의 크기를 분석하였다. 그 결과, DB/DB (-/-) 마우스에서는 정상 대조군에 비해 근육세포의 크기가 감소한 반면, HM2102 약물 처리군에서는 DB/DB (-/-) 마우스에 비해 비복근(GM) 및 전경골근(TA)의 근육세포 크기가 증가 또는 회복되었음을 확인하였다 (도 6 및 도 7). Afterwards, H&E staining was performed on the gastrocnemius (GM) and tibialis anterior (TA) muscles of mice to analyze the size of muscle cells. As a result, the size of muscle cells was reduced in DB/DB (-/-) mice compared to the normal control group, while the gastrocnemius (GM) and tibialis anterior (TA) muscles were decreased in the HM2102 drug treatment group compared to DB/DB (-/-) mice. ) It was confirmed that the muscle cell size increased or recovered (Figures 6 and 7).
이로써, 본 발명에서는 HM2102 약물이 근육량을 증가시키거나, 근육 손실을 억제하는 효과가 있음을 확인하였다. As a result, the present invention confirmed that the HM2102 drug has the effect of increasing muscle mass or suppressing muscle loss.
실시예 5. 근육 분화 증진 및 근위축 억제 효과Example 5. Effect of promoting muscle differentiation and suppressing muscle atrophy
Atrogin-1 및 MuRF1(muscle RING-finger protein-1)은 근육 단백질을 파괴하여 근위축(atrophy)을 야기하는 것으로 알려진 유전자이며, Myogenin 및 MyoD는 근육 분화를 촉진하는 인자로 알려져 있다. 이에 본 발명자들은 HM2102 약물이 근위축 유전자 및 근육 분화 촉진 유전자의 발현량에 영향을 주는지 확인하기 위해 real-time PCR을 수행하였다. 그 결과, DB/DB (-/-) 마우스에서는 정상 대조군에 비해 근위축 유전자인 MuRF1 및 Atrogin-1의 mRNA 발현량이 증가하였고, 근육 분화 촉진 인자인 Myogenin 및 MyoD의 mRNA 발현량이 감소하였다 (도 8). 그러나, HM2102 약물 처리군에서는 증가된 Atrogin-1의 mRNA 발현량이 유의하게 감소하였고, Myogenin 및 MyoD의 mRNA 발현량이 유의하게 회복하였다 (도 8). Atrogin-1 and MuRF1 (muscle RING-finger protein-1) are genes known to cause muscle atrophy by destroying muscle proteins, and Myogenin and MyoD are known to be factors that promote muscle differentiation. Accordingly, the present inventors performed real-time PCR to determine whether the HM2102 drug affects the expression levels of muscle atrophy genes and muscle differentiation promotion genes. As a result, in DB/DB (-/-) mice, the mRNA expression levels of muscle atrophy genes MuRF1 and Atrogin-1 increased, and the mRNA expression levels of muscle differentiation promoting factors Myogenin and MyoD decreased compared to the normal control group (Figure 8 ). However, in the HM2102 drug treatment group, the increased mRNA expression level of Atrogin-1 was significantly decreased, and the mRNA expression levels of Myogenin and MyoD were significantly recovered (Figure 8).
이로써, 본 발명에서는 HM2102 약물이 근육 분화를 촉진하고, 근위축을 억제하는 효과가 있음을 확인하였다. As a result, the present invention confirmed that the HM2102 drug has the effect of promoting muscle differentiation and suppressing muscle atrophy.
실시예 6. 대식세포의 침윤 감소 및 염증성 사이토카인의 발현 감소 효과Example 6. Effect of reducing macrophage infiltration and expression of inflammatory cytokines
근육조직에 대식세포의 침윤을 조사하기 위하여 대식세포 마커인 F4/80 면역 염색을 수행하였다. 그 결과, DB/DB (-/-) 마우스에서는 대식세포의 침윤이 관찰된 반면, HM2102 약물 처리군에서는 대식세포의 침윤이 현저히 감소하였음을 확인하였다 (도 9). To investigate macrophage infiltration into muscle tissue, F4/80 immunostaining, a macrophage marker, was performed. As a result, while macrophage infiltration was observed in DB/DB (-/-) mice, it was confirmed that macrophage infiltration was significantly reduced in the HM2102 drug treatment group (FIG. 9).
또한, 근육조직에 염증의 유무를 조사하기 위하여 염증성 사이토카인인 IL-1β, IL-6, TNF-α 및 Myostatin의 mRNA 발현량을 real-time PCR을 이용하여 조사하였다. 그 결과, DB/DB (-/-) 마우스에서는 정상 마우스에 비해 염증성 사이토카인의 mRNA 발현량이 현저히 증가한 반면, HM2102 약물 처리군에서는 염증성 사이토카인의 mRNA 발현량이 유의하게 감소하였음을 확인하였다 (도 10).In addition, to investigate the presence or absence of inflammation in muscle tissue, the mRNA expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and Myostatin were examined using real-time PCR. As a result, it was confirmed that the mRNA expression level of inflammatory cytokines was significantly increased in DB/DB (-/-) mice compared to normal mice, while the mRNA expression level of inflammatory cytokines was significantly decreased in the HM2102 drug treatment group (Figure 10 ).
이로써, 본 발명에서는 HM2102 약물이 대식세포의 침윤을 감소시키고, 염증성 사이토카인의 발현을 감소시키는 효과가 있음을 확인하였다. Accordingly, in the present invention, it was confirmed that the HM2102 drug has the effect of reducing the infiltration of macrophages and the expression of inflammatory cytokines.
실시예 7. 근육 섬유화 억제 효과Example 7. Effect of inhibiting muscle fibrosis
근육조직의 섬유화를 조사하기 위하여 근육조직을 시리우스레드(sirius red) 염색을 수행하였다. 그 결과, DB/DB (-/-) 마우스에서는 정상 마우스에 비해 근육조직에서 섬유화가 유발된 반면, HM2102 약물 처리군에서는 근섬유화가 현저히 감소하였음을 확인하였다 (도 11). To investigate fibrosis of muscle tissue, Sirius red staining was performed on the muscle tissue. As a result, it was confirmed that fibrosis was induced in muscle tissue in DB/DB (-/-) mice compared to normal mice, while muscle fibrosis was significantly reduced in the HM2102 drug treatment group (FIG. 11).
실시예 8. 인슐린 내성 검사(Insulin Tolerance Test, ITT) 및 포도당 부하 검사(Glucose Tolerance Test, GTT) 결과Example 8. Results of Insulin Tolerance Test (ITT) and Glucose Tolerance Test (GTT)
인슐린 내성 검사(ITT)는 마우스를 6시간 동안 절식시킨 후 인슐린 (Insulin, 2 U/kg)을 복강내(IP) 투여하여 측정하였다. 포도당 부하 검사(GTT)는 마우스를 20시간 동안 절식시킨 후 포도당(glucose, 0.5 g/kg)을 복강내(IP) 투여하였다. 그 결과, HM2102 약물 처리군에서는 인슐린 저항성을 회복하는 효능이 있음을 확인하였다 (도 12). Insulin tolerance test (ITT) was measured by fasting mice for 6 hours and administering insulin (2 U/kg) intraperitoneally (IP). For the glucose tolerance test (GTT), mice were fasted for 20 hours and then glucose (0.5 g/kg) was administered intraperitoneally (IP). As a result, it was confirmed that the HM2102 drug treatment group was effective in recovering insulin resistance (FIG. 12).
Claims (8)
[화합물 1]
.
A pharmaceutical composition for preventing or treating sarcopenia comprising a compound represented by the following formula (1) as an active ingredient:
[Compound 1]
.
상기 조성물은 근육량을 증가시키거나, 근육 손실을 억제하는 것인, 약학적 조성물.
According to claim 1,
The composition is a pharmaceutical composition that increases muscle mass or inhibits muscle loss.
상기 조성물은 근위축 인자의 발현을 억제하거나, 근육 분화 촉진 인자의 발현을 증가시키는 것인, 약학적 조성물.
According to claim 1,
The composition is a pharmaceutical composition that inhibits the expression of muscle atrophy factors or increases the expression of muscle differentiation promoting factors.
상기 근감소증은 노화, 비만 또는 당뇨병에 의해 유발되는 것인, 약학적 조성물.
According to claim 1,
A pharmaceutical composition wherein the sarcopenia is caused by aging, obesity, or diabetes.
상기 근감소증은 근위축증, 근무력증, 근이영양증, 근력약화, 근육퇴행위축, 근위축성 측삭 경화증, 척수구근위축 및 중증 근무력증으로 이루어진 군에서 선택되는 것인, 약학적 조성물.
According to claim 1,
The sarcopenia is selected from the group consisting of muscular dystrophy, myasthenia gravis, muscular dystrophy, muscle weakness, muscular dystrophy, amyotrophic lateral sclerosis, spinal bulbar muscular atrophy, and myasthenia gravis.
[화합물 1]
.
Health functional food for preventing or improving sarcopenia containing a compound represented by the following formula (1) as an active ingredient:
[Compound 1]
.
[화합물 1]
.
A composition for muscle strengthening containing a compound represented by the following formula (1) as an active ingredient:
[Compound 1]
.
[화합물 1]
.
A composition for enhancing exercise performance comprising a compound represented by the following formula (1) as an active ingredient:
[Compound 1]
.
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