KR101873527B1 - Compound for preventing or treating endometriosis comprising sialic acid derivative - Google Patents
Compound for preventing or treating endometriosis comprising sialic acid derivative Download PDFInfo
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- KR101873527B1 KR101873527B1 KR1020160113436A KR20160113436A KR101873527B1 KR 101873527 B1 KR101873527 B1 KR 101873527B1 KR 1020160113436 A KR1020160113436 A KR 1020160113436A KR 20160113436 A KR20160113436 A KR 20160113436A KR 101873527 B1 KR101873527 B1 KR 101873527B1
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- South Korea
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- sialic acid
- coch
- acid derivative
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- chemical formula
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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
- 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
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 시알산 유도체를 포함하는 자궁내막증 및 이의 합병증 예방 또는 치료용 조성물에 관한 것이다. 본 발명에 따른 시알산 유도체는 자궁내막세포와 복막세포의 부착을 저해함으로써 자궁내막세포의 복막 조직에 대한 유착이 원인이 되어 발생하는 자궁내막증의 예방 또는 치료에 유용하게 사용될 수 있으며, 더 나아가 자궁내막증의 합병증의 예방 또는 치료를 위해 유용하게 사용될 수 있다.The present invention relates to a composition for preventing or treating endometriosis and its complications comprising a sialic acid derivative. The sialic acid derivative according to the present invention can be effectively used for preventing or treating endometriosis caused by adherence of endometrial cells to peritoneal tissue by inhibiting adherence of endometrial cells and peritoneal cells, Can be usefully used for the prevention or treatment of complications of endometriosis.
Description
본 발명은 시알산 유도체를 포함하는 자궁내막증 및 이의 합병증 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating endometriosis and its complications comprising a sialic acid derivative.
시알산은 인간 모유의 천연적으로 존재하는 성분이며, 다양한 올리고사카라이드 및 당단백질과 회합된 상태로 발견된다. 인간 모유가 상당량의 시알산을 함유하지만, 대부분의 유아 제제는 초유 내에 존재하는 시알산의 25% 미만을 함유한다. 또한, 조제유 내의 시알산의 70%는 시알산의 75%가 올리고사카라이드에 결합되어 있는 인간 모유와는 달리 당단백질에 결합되어 있다.Sialic acid is a naturally occurring component of human milk and is found associated with various oligosaccharides and glycoproteins. Although human milk contains a significant amount of sialic acid, most infant formulas contain less than 25% of the sialic acid present in colostrum. In addition, 70% of the sialic acid in the formula is bound to the glycoprotein, unlike human breast milk, where 75% of the sialic acid is bound to the oligosaccharide.
한편, 자궁내막증 세포(endometrial cell)는 그 기원세포인 정상 자궁내막세포(endometrium)와 기능적으로 그리고 분자 기전(molecular mechanism)적으로 매우 다르다. 자궁내막증 세포는 에스트로겐에 대해 반응성(estrogenresponsive)이 있으며, 프로게스테론에 대해서는 비반응성(progesterone-unresponsive)이라고 알려져 있다. 최근, 자궁내막증 세포의 지속적 증식(uncontrolled proliferation), 세포사멸에 대한 저항성(antiapoptosis), 신생혈관생성(angiogenesis), 이동과 침투(migration and invasion), 국소 면역계의 변화(change in local immune system) 등의 특징이 암세포와 매우 유사함을 밝힌 연구결과가 보고된바 있다. 자궁내막증의 대표적인 분자생물학적 특징으로 알려진 것은, 에스트로겐(estrogen), 프로스타그란딘(prostaglandin), 사이토카인(cytokine), 및 단백질분해효소(metalloproteinase) 등의 과발현/과생성이 있다.On the other hand, endometrial cells are functionally and molecular mechanically very different from the endometrium of their origin, the endometrium. Endometriosis cells are estrogenresponsive to estrogen and are known to be progesterone-unresponsive to progesterone. Recently, a number of studies have been carried out on uncontrolled proliferation of endometriotic cells, antiapoptosis, angiogenesis, migration and invasion, and change in local immune system Has been reported to be very similar to cancer cells. Known molecular biologic features of endometriosis include overexpression and overproduction of estrogen, prostaglandin, cytokine, and metalloproteinase.
자궁내막증(endometriosis)은 자궁내막세포가 자궁 이외의 장소에서 증식하여 자라는 병으로 월경통, 만성적인 골반 통증 및 불임까지 유발하는 부인과 질환으로, 이러한 자궁내막증의 유병률은 정상적인 배란주기를 가지는 젊은 여성에서 약 7-10%, 만성적인 골반 통증을 호소하는 여성에서는 약 20-90% 정도에 이르는 것으로 알려져 있다. 이러한 자궁내막증의 치료방법들로는 수술적 치료, 호르몬 치료를 근간으로 하는 약물적 치료, 통증 완화를 목적으로 하는 보존적 치료 등이 있으나, 대부분의 치료가 50%정도의 환자에 대해서만 통증을 경감시키는데 그치며, 지금까지 알려진 어떠한 치료를 하더라도 양측 난소를 모두 제거하지 않는 한 치료 후 5년 내에 약 40-70%의 환자에게서 재발하는 것으로 보고되고 있다. 즉, 지금까지 연구되고 시행되어온 어떠한 치료도 대부분 제한적인 효과에 그치며, 자궁내막증을 완치시킨다기보다는 단순히 자궁내막증의 증상을 억제 또는 완화시키는 수준에 그치는 것들이었다. Endometriosis is a gynecologic disease that causes endometrial cells to proliferate outside the uterus, leading to dysmenorrhoea, chronic pelvic pain and infertility. The prevalence of such endometriosis is lower in young women with normal ovulation cycle 7-10% in women with chronic pelvic pain and 20-90% in women with chronic pelvic pain. These endometriosis treatments include surgical treatment, drug therapy based on hormone therapy, and conservative treatment for pain relief, but most treatments only relieve pain in about 50% of patients , And it has been reported that any treatment so far will recur in about 40-70% of patients within 5 years of treatment, unless both ovaries are removed. In other words, any treatment that has been studied and practiced so far has been mostly limited in its effectiveness, and it is merely a level of inhibiting or alleviating the symptoms of endometriosis rather than curing the endometriosis.
이와 같이, 자궁내막증은 극심한 통증으로 인해 일상생활에 불편함이 있으며, 심한 경우 불임에까지 이르는 질환으로써, 여성의삶의 질'과 임신'의 문제에서 심각하게 인식되어야 하고 반드시 극복해야 할 질병임에도 불구하고 아직까지 이렇다할 예방 및 치료방법이 존재하지 않으며, 이에 대한 연구도 매우 부족하여, 자궁내막증에 대한 새로운 치료방법의 개발이 절실한 실정이다.As such, endometriosis is a discomfort in everyday life due to severe pain, and even severe infertility is a disease that should be seriously recognized in the issue of 'quality of life and pregnancy' of women and should be overcome However, there is no such prophylactic and therapeutic method yet, and there is a lack of research on this, so it is urgent to develop a new treatment method for endometriosis.
특히, 기존 약물연구에서는 자궁내막세포의 세포자멸사 유도, 자궁내막세포의 복막 침윤 억제, 혈관신생의 억제, 염증성 면역 억제 등 다양한 방법으로 자궁내막증 및 이의 합병증 치료에 대한 연구를 진행하여 왔으나 자궁내막증의 근본적 특징 중 하나인 자궁내막세포과 복막조직의 유착을 억제하는 물질 또는 방법에 대한 연구는 거의 이루어지지 않았다.In particular, studies on endometriosis and complications of endometriosis have been conducted by various methods such as induction of apoptosis of endometrial cells, suppression of peritoneal invasion of endometrial cells, inhibition of angiogenesis, and inflammatory immunosuppression. There have been few studies on substances or methods that inhibit adhesion of endometrial cells and peritoneal tissue, one of the fundamental features.
본 발명자들은 상기와 같은 사항을 고려하여, 새로운 자궁내막증 치료제를 개발하기 위해 노력한 결과, 시알산 또는 이의 유도체가 자궁내막세포와 복막조직세포 간의 부착을 억제함으로써 자궁내막증 및 이의 합병증을 예방 및 치료하는 효과가 우수함을 확인하고 본 발명을 완성하였다.The present inventors have made efforts to develop new endometriosis treatment agents in consideration of the above-mentioned problems. As a result, sialic acid or its derivatives inhibit adhesion between endometrial cells and peritoneal tissue cells to prevent and treat endometriosis and its complications And the present invention has been completed.
본 발명의 목적은 시알산 유도체를 포함하는 자궁내막증 또는 이의 합병증의 예방 또는 치료용 조성물을 제공하는 것이다.It is an object of the present invention to provide a composition for preventing or treating endometriosis or complications thereof comprising sialic acid derivatives.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating endometriosis comprising a sialic acid derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or improving endometriosis, which comprises a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 합병증의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating complications of endometriosis comprising a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 합병증의 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or ameliorating complications of endometriosis comprising a sialic acid derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
여기서, R1은 H, 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고, Wherein, R 1 is H, an acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R2는 H, (C1-C6)알킬, (C1-C6)할로알킬, (C1-C6)알콕시, (C1-C6)할로알콕시, 아세틸, 할로아세틸, (C1-C6)알콕시아세틸, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-acetyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이고,R 2 is selected from H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, acetyl, 1 -C 6 ) alkoxyacetyl, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl, GlcNAc), N-acetylgalactosaminyl (GalNAc), N-acetyllactosaminyl, or serine N-acetylgalactosaminyl.
R3는 H 또는 (C1-C6)알킬이다.R 3 is H or (C 1 -C 6 ) alkyl.
본 발명에 따른 시알산 유도체는 자궁내막세포와 복막세포의 부착을 저해함으로써 자궁내막세포의 복막 조직에 대한 유착이 원인이 되어 발생하는 자궁내막증의 예방 또는 치료에 유용하게 사용될 수 있으며, 더 나아가 자궁내막증의 합병증의 예방 또는 치료를 위해 유용하게 사용될 수 있다.The sialic acid derivative according to the present invention can be effectively used for preventing or treating endometriosis caused by adherence of endometrial cells to peritoneal tissue by inhibiting adherence of endometrial cells and peritoneal cells, Can be usefully used for the prevention or treatment of complications of endometriosis.
도 1은 시알산 및 시알산 유도체를 인간 복막세포주인 MeT-5A 세포에 처리하여 MTT 분석법을 통해 세포 독성을 확인한 결과를 나타낸 도이다.
도 2는 시알산을 인간 복막세포주인 MeT-5A 세포에 처리하여 MTT 분석법을 통해 시알산 농도에 따른 세포 독성을 확인한 결과를 나타낸 도이다.
도 3은 TGF-β1을 이용하여 본 발명의 시알산 및 시알산 유도체에 의한 자궁내막 세포와 복막 세포의 부착 억제 효과를 확인하기 위한 실험 방법을 나타낸 도이다.
도 4는 본 발명의 시알산 또는 시알산 유도체에 의한 자궁내막 세포와 복막 세포의 부착 억제 효과를 확인하기 위하여, 형광을 나타내는 HES 세포를 현미경을 통해 관찰한 결과를 나타낸 도이다.
도 5는 본 발명의 시알산 또는 시알산 유도체에 의한 자궁내막 세포와 복막 세포의 부착 억제 효과를 확인하기 위하여, 형광을 나타내는 HES 세포를 계수하여 막대그래프로 나타낸 도이다.
도 6은 본 발명의 시알산 또는 시알산 유도체의 처리에 의한 자궁내막세포와 복막중피세포 간 부착력 감소 비율을 저해율 그래프로 나타낸 도이다.FIG. 1 is a graph showing the cytotoxicity of sialic acid and sialic acid derivatives treated with MeT-5A cells, a human peritoneal cell line, through MTT assay.
FIG. 2 is a graph showing the cytotoxicity of sialic acid to MeT-5A cells treated with human peritoneal cell line and MTT assay according to sialic acid concentration. FIG.
FIG. 3 is a graph showing an experimental method for confirming the inhibitory effect of sialic acid and sialic acid derivatives of the present invention on adhesion of endometrial cells and peritoneal cells using TGF-? 1.
FIG. 4 is a graph showing microscopic observation of HES cells showing fluorescence in order to confirm the inhibitory effect of the sialic acid or sialic acid derivative of the present invention on adhesion of endometrial cells and peritoneal cells.
FIG. 5 is a bar graph showing the HES cells showing fluorescence in order to confirm the inhibitory effect of the sialic acid or sialic acid derivative of the present invention on adhesion of endometrial cells and peritoneal cells.
FIG. 6 is a graph showing the rate of reduction of adherence between endometrial cells and peritoneal cells by treatment with sialic acid or a sialic acid derivative of the present invention.
본 발명은 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 또는 이의 합병증의 예방 또는 치료용 조성물을 제공한다.The present invention provides a composition for preventing or treating endometriosis or a complication thereof comprising a sialic acid derivative or a pharmaceutically acceptable salt thereof.
상기 조성물은 약학적 조성물 또는 식품 조성물을 포함한다.The composition comprises a pharmaceutical composition or a food composition.
이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating endometriosis comprising a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
여기서, R1은 H, 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고, Wherein, R 1 is H, an acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R2는 H, (C1-C6)알킬, (C1-C6 )할로알킬, (C1-C6)알콕시, (C1-C6)할로알콕시, 아세틸, 할로아세틸, (C1-C6)알콕시아세틸, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetyl glucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-ac etyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이고,R 2 is selected from H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, acetyl, 1 -C 6 ) alkoxyacetyl, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetyl glucosaminyl ; GlcNAc), N-acetylgalactosaminyl (GalNAc), N-ac etyllactosaminyl, or serine N-acetylgalactosaminyl.
R3는 H 또는 (C1-C6)알킬이다.R 3 is H or (C 1 -C 6 ) alkyl.
상기 시알산 유도체는 바람직하게는 하기 화학식 2로 표시될 수 있으며, 이에 제한되지 않는다.The sialic acid derivative is preferably represented by the following formula (2), but is not limited thereto.
여기서, R2는 H, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-acetyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이다.Wherein R 2 is selected from the group consisting of H, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl ), N-acetylgalactosaminyl (GalNAc), N-acetyllactosaminyl, or serine N-acetylgalactosaminyl.
본 발명에서 용어 "알킬"은, 선형, 분지형 또는 고리형 부분 또는 이들의 조합물을 갖는 포화된 1가의 탄화수소 라디칼이다. 본 발명에서 용어 "알킬"은 단독으로 또는 접미사나 접두사로서 사용되는데, 특정한 수의 탄소 원자를 갖는 포화 지방족 탄화수소기의 분지쇄 및 직쇄 모두를 포함하는 것으로 의도된다. 예를 들어, "C1-6 알킬"은 1, 2, 3, 4, 5 또는 6 개의 탄소 원자를 갖는 알킬을 나타낸다. 알킬기는 할로겐, 히드록시, 티올, 아미노, 니트로, 시아노, 아실, 아실옥시, 술포닐, 술피닐, 알킬아미노, 카르복시, 에스테르, 에테르, 아미도, 술폰산, 술폰아미드, 알킬술포닐, 아릴술포닐, 알콕시카르보닐, 알킬술피닐, 아릴술피닐, 알킬티오, 아릴티오, 옥시에스테르, 옥시아미도, 헤테로시클로알킬, 헤테로아릴, 비닐, 알콕시, 아릴옥시, 아릴로 이루어지는 군으로부터 독립적으로 선택된 1 내지 5개의 치환기에 의해서 임의적으로 치환될 수 있다. 바람직한 알킬기는 메틸, 에틸, 프로필, 이소프로필, 부틸, i-부틸 또는 t-부틸, 2,2,2-트리메틸에틸, 또는 할로겐, 히드록시, 티올, 아미노, 니트로, 시아노로부터 선택된 하나 이상의 기로 치환된 트리플루오로메틸, 트리클로로메틸, 2,2,2-트리클로로에틸, 1,1-디메틸-2,2-디브로모에틸, 1,1-디메틸-2,2,2-트리클로로에틸과 같은 등가물이 있다. The term "alkyl" as used herein is a saturated monovalent hydrocarbon radical having a linear, branched, or cyclic moiety, or combination thereof. The term "alkyl ", as used herein, alone or as a suffix or prefix, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-6 alkyl" refers to alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group may be substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, 1, independently selected from the group consisting of alkyl, alkoxy, alkoxy, aryloxy, aryl, alkoxy, aryloxy, Lt; / RTI > to 5 substituents. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, i-butyl or t-butyl, 2,2,2-trimethylethyl or one or more groups selected from halogen, hydroxy, thiol, amino, Substituted trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloro There are equivalents such as ethyl.
본 발명에서 용어 "할로"는 플루오로(-F), 클로로(-Cl), 브로모(-Br) 또는 아이오도(-I)를 의미한다.The term "halo " in the present invention means fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).
본 발명에서 용어 "히드록시 아세틸"은 아세트산에서 유도된 1가의 산기에 -OH기가 결합되어 있는 것을 의미한다.The term "hydroxyacetyl" in the present invention means that the -OH group is bonded to the monovalent acid group derived from acetic acid.
본 발명에서 용어 "알콕시"는 -O-알킬기를 포함하는데, 여기에서 알킬기는 상기 정의한 것과 같다. 바람직한 알킬기는 메틸, 에틸, 프로필, 이소프로필, 부틸, i-부틸 또는 t-부틸, 2,2,2-트리메틸에틸, 또는 트리플루오로메틸, 트리클로로메틸, 2,2,2-트리클로로에틸, 1,1-디메틸-2,2-디브로모에틸, 1,1-디메틸-2,2,2-트리클로로에틸과 같은, 하나 이상의 할로기로 치환된 등가물이다.The term "alkoxy" in the present invention includes an -O-alkyl group, wherein the alkyl group is as defined above. Preferred alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, i-butyl or t-butyl, 2,2,2-trimethylethyl, or trifluoromethyl, trichloromethyl, 2,2,2- trichloroethyl , 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
본 발명에서 "치환된"은 해당 기(group), 예를 들어, 알킬기 등이 하나 이상의 치환기를 가질 수 있음을 의미한다. 상기에서 정의한 바와 같은, 알킬, 알콕시, 글리코실 등 및 이들 기를 함유하는 치환기들은 하나 이상의 다른 치환기로 치환되거나 비치환될 수 있다. "치환되거나 치환되지 않은"이란 용어는 특정 기가 비치환되거나 본원에 정의된 바와 같은 하나 이상의 치환기로 치환되는 것을 명백히 나타내는 것이다. 다양한 기들이 나타낸 바와 같이 비치환되거나 치환될 수 있다(즉, 이들은 치환되거나 치환되지 않는다)."Substituted" in the present invention means that the group, for example, the alkyl group, etc., may have one or more substituents. Alkyl, alkoxy, glycosyl, and the like and substituents containing these groups as defined above may be substituted or unsubstituted with one or more other substituents. The term "substituted or unsubstituted" explicitly indicates that the group is unsubstituted or substituted with one or more substituents as defined herein. The various groups may be unsubstituted or substituted as indicated (i.e. they are unsubstituted or substituted).
본 발명에서 용어, "시알산 유도체"는 뉴라민산의 N-아실체(시알산)와 그 유도체를 총칭한다. 상기 시알산 유도체에는 N-아세틸뉴라민산(Neu5Ac)과 N-글리콜뉴라민산(Neu5Gc)이 포함되며 히드록실기가 아세틸기, 황산기, 인산기 등으로 변형된 유도체가 포함된다. 자연계에 존재하는 시알산 유도체는 30종 이상이다.In the present invention, the term "sialic acid derivative" is generically referred to as N-acid (sialic acid) and derivatives thereof of neuraminic acid. The sialic acid derivatives include derivatives in which N-acetylneuraminic acid (Neu5Ac) and N-glycol neuraminic acid (Neu5Gc) are included and the hydroxyl group is modified with an acetyl group, a sulfate group, a phosphoric acid group or the like. There are more than 30 sialic acid derivatives in nature.
본 발명에서 용어, "유도체"는 어떤 화합물의 일부를 화학적으로 변화시켜서 얻어지는 유사한 화합물이다. 보통은 화합물 중의 수소원자 또는 특정 원자단이 다른 원자 또는 원자단에 의하여 치환된 화합물을 말하며, 넓은 의미에서는 첨가 반응 등으로 만들어진 생성물을 유도체라 한다.The term "derivative" in the present invention is a similar compound obtained by chemically changing a part of a compound. Usually refers to a compound in which a hydrogen atom or a specific atomic group in a compound is substituted by another atom or atomic group, and in a broad sense, a product formed by an addition reaction or the like is referred to as a derivative.
본 발명의 시알산 유도체는 "이의 약학적으로 허용가능한 염"의 형태로 사용할 수 있으며, 달리 언급되지 않는 한 시알산 유도체에 존재할 수 있는 통상의 방법에 의해 제조되는 모든 염, 수화물 및 용매화물이 포함된다.The sialic acid derivatives of the present invention can be used in the form of "pharmaceutically acceptable salts thereof ", and all salts, hydrates and solvates prepared by conventional methods which may exist in sialic acid derivatives .
염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가 염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼 화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다. 이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산 (maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산 (fumaric acid), 만데르산, 프로피온산 (propionic acid), 구연산 (citric acid), 젖산 (lactic acid), 글리콜산 (glycollic acid), 글루콘산 (gluconic acid), 갈락투론산, 글루탐산, 글루타르산 (glutaric acid), 글루쿠론산 (glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 히드로아이오딕산 등을 사용할 수 있으며, 이에 제한되지 않는다.As salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. The acid addition salt is prepared in a conventional manner, for example, by dissolving the compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration. As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used. It does not.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is preferable to produce sodium, potassium or calcium salt particularly, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
특히, 본 발명의 "시알산 유도체"는 바람직하게는 α2, 3-시알릴갈락토스(α2, 3-sialylgalactose), α2, 6-시알릴갈락토스(α2, 6-sialylgalactose), α2, 3-시알릴락토스(α2, 3-sialyllactose), α2, 6-시알릴락토스(α2, 6-sialyllactose), α2, 3-시알릴 N-아세틸락토사민(α2, 3-sialyl N-acetyllactosamine), α2, 6-시알릴 N-아세틸락토사민(α2, 6-sialyl N-acetyllactosamine), 다이실릴락토스(Disialyllactose), Stn 에피토프(STn epitope 또는 2-acetamido-6-O-(α-2-N--acetylneuraminyl)-2-deoxyl-α-D-galactopyranosyl serine)를 포함하나, 이에 제한되지 않는다.In particular, the "sialic acid derivative" of the present invention is preferably selected from the group consisting of α2, 3-sialylgalactose, α2,6-sialylgalactose, α2, 3-sialyl 3-sialyllactosamine,? 2, 6-sialyllactose,? 2, 3-sialyl N-acetyllactosamine,? 2, 6- Sialyl N-acetyllactosamine, Disialyllactose, Stn epitope (STn epitope or 2-acetamido-6-O- (α-2-N-acetylneuraminyl) - 2-deoxyl-alpha-D-galactopyranosyl serine).
보다 구체적으로, 본 발명의 시알산 유도체는 하기 화학식 3으로 나타낼 수 있다.More specifically, the sialic acid derivative of the present invention can be represented by the following general formula (3).
또한, 본 발명의 시알산 유도체는 하기 화학식 4 내지 11로 나타낼 수 있다.In addition, the sialic acid derivative of the present invention can be represented by the following formulas (4) to (11).
본 발명에서 용어, "예방"이란 조성물의 투여에 의해 자궁내막증을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.The term "prevention" in the present invention means any action that inhibits endometriosis by administration of the composition or delays the onset of the disease.
본 발명에서 용어, "치료"란 조성물의 투여에 의해 자궁내막증에 의한 증세가 호전되거나 이롭게 변경하는 모든 행위를 의미한다.In the present invention, the term "treatment" means any action that improves or alleviates symptoms due to endometriosis by administering the composition.
본 발명에서 자궁내막증이란 자궁 내에 있어야 할 자궁내막 조직이 자궁 외 골반강인 복막에 자라는 질환으로, 가임기 여성의 약 10~15%에서 발생하며, 골반염, 골반유착, 난소낭종, 자궁근종, 자궁 외 임신 및 불임의 중요한 원인이다. 자궁내막증의 병태생리를 보면 자궁내막 조직이 다른 조직 내로 침윤 또는 본래의 자리를 벗어나 원격 전이를 한다는 면에서 종양 세포와 상당히 유사한 성장, 발달을 한다고 할 수 있다.In the present invention, endometriosis is a disease in which the endometrial tissue that should be in the uterus grows in the peritoneal cavity of the uterine pelvic cavity. It occurs in about 10 to 15% of women in the postpartum period and is associated with pelvic inflammation, pelvic adhesion, ovarian cysts, And is an important cause of infertility. The pathophysiology of endometriosis suggests that endometrial tissues invade or invade other tissues and develop distantly similar to tumor cells in terms of distant metastasis.
자궁내막증 환자의 복강 내에서 다양한 사이토카인의 변화가 관찰되는데, 특히 이 중 TGF-β는 자궁내막증 환자의 복수와 혈청에서 증가되어 있으며, 자궁내막세포와 복막세포 간의 유착의 증가에 관여한다.TGF-beta is elevated in the ascites and serum of patients with endometriosis and is associated with increased adhesion between endometrial cells and peritoneal cells in the peritoneal cavity of patients with endometriosis.
본 발명의 조성물은 자궁 내막세포의 복막 조직에 대한 부착능을 억제할 수 있다. 보다 자세하게 상기 조성물은 TGF-β에 의해 증가된 자궁 내막세포의 복막 조직에 대한 부착능을 억제하는 작용 기전 및 다른 생체 내 물질에 의한 자궁 내막세포의 복막 조직에 대한 부착능 또한 억제시킬 수 있으며, 생체 내 물질의 종류는 제한되지 않는다.The composition of the present invention can inhibit the adherence of endometrial cells to the peritoneal tissue. More specifically, the composition can inhibit the adhesion mechanism of endometrial cells increased by TGF-ss to peritoneal tissue, and the adherence of endometrial cells to peritoneal tissue by other in vivo substances, The kind of the substance in vivo is not limited.
본 발명의 조성물은 시알산 유도체 또는 이의 허용가능한 염과 함께 자궁내막증에 대하여 치료 효과를 갖는 공지의 유효성분을 1종 이상 함유할 수 있다.The composition of the present invention may contain one or more known active ingredients having a therapeutic effect on endometriosis together with a sialic acid derivative or an acceptable salt thereof.
본 발명의 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 내지 90 중량부 포함되는 것이 바람직하나 이에 한정되는 것은 아니다.The composition of the present invention may further comprise a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose Starch glycolate, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, calcium stearate, calcium stearate, White sugar, etc. may be used. The pharmaceutically acceptable additives according to the present invention are preferably included in the composition in an amount of 0.1 to 90 parts by weight, but not limited thereto.
본 발명의 조성물은 실제 임상 투여시에 경구 또는 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있으며, 당해 기술 분야에 알려진 적합한 제제는 문헌 (Remington's Pharmaceutical Science, 최근, Mack Publishing Company, Easton PA)에 개시되어 있는 것을 이용하는 것이 바람직하다. 상기 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등이 있다.The composition of the present invention can be administered orally or parenterally in various clinical formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, And suitable formulations known in the art are preferably those described in Remington ' s Pharmaceutical Science (Mack Publishing Company, Easton PA, recently). Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
상기 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(Calcium carbonate), 수크로스 (Sucrose) 또는 락토오스(Lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 또한, 상기 경구투여를 위한 액상제제로는 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. The solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like May be included.
상기 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 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. 상기 비경구투여는 피부 외용 또는 복강 내 주사, 직장 내 주사, 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 주입방식을 사용하여 이루어질 수 있다.The preparation for parenteral administration includes sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used. The parenteral administration can be carried out using an external or intraperitoneal injection, intramuscular injection, subcutaneous injection, intravenous injection, intramuscular injection or intra-thoracic injection.
상기 본 발명의 조성물은 약학적으로 유효한 양으로 투여될 수 있다.The composition of the present invention may be administered in a pharmaceutically effective amount.
용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 감염된 바이러스 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물은 1일 0.0001 내지 100mg/kg으로, 바람직하게는 0.001 내지 100mg/kg으로 투여하는 것이 좋다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and the effective dosage level will vary depending on the species and severity, age, sex, Activity, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. However, for the desired effect, the compound of the present invention is preferably administered at 0.0001 to 100 mg / kg per day, preferably 0.001 to 100 mg / kg per day. The composition of the present invention may 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. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention may be administered to a subject in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.
본 발명의 약학적 조성물은 자궁내막증의 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the treatment of endometriosis.
또한, 본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or improving endometriosis, which comprises a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
여기서, R1은 H, 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고, Wherein, R 1 is H, an acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R2는 H, (C1-C6)알킬, (C1-C6 )할로알킬, (C1-C6)알콕시, (C1-C6)할로알콕시, 아세틸, 할로아세틸, (C1-C6)알콕시아세틸, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetyl glucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-ac etyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이고,R 2 is selected from H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, acetyl, 1 -C 6 ) alkoxyacetyl, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetyl glucosaminyl ; GlcNAc), N-acetylgalactosaminyl (GalNAc), N-ac etyllactosaminyl, or serine N-acetylgalactosaminyl.
R3는 H 또는 (C1-C6)알킬이다.R 3 is H or (C 1 -C 6 ) alkyl.
본 발명에서, 용어 "식품"은 사람이 일상적으로 섭취하는 음식물을 통틀어 이르는 말로, 건강기능식품을 포함하는 개념이다.In the present invention, the term "food" is a concept including foods that are commonly consumed by people on a daily basis and includes health functional foods.
상기 건강기능식품은 질병의 예방 및 개선, 생체방어, 면역, 병후의 회복, 노화 억제 등 생체조절 기능을 가지는 식품을 말하는 것으로, 장기적으로 복용하였을 때 인체에 무해해야 한다. The health functional food refers to a food having a biological control function such as prevention and improvement of disease, bio-defense, immunity, recovery after disease and aging inhibition, and should be harmless to human body when taken over a long period of time.
본 발명의 시알산 유도체 또는 이의 약학적으로 허용가능한 염은 자궁내막증 예방 또는 개선을 목적으로 식품 조성물에 첨가될 수 있다. 본 발명의 시알산 유도체 또는 이의 허용가능한 염을 식품 첨가물로 사용할 경우, 상기 화합물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 화합물은 원료 조성물 중 0.01 ~ 10 중량%, 바람직하게는 0.05 ~ 1중량%의 양으로 첨가된다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다. The sialic acid derivative of the present invention or a pharmaceutically acceptable salt thereof may be added to a food composition for the purpose of preventing or improving endometriosis. When the sialic acid derivative of the present invention or an acceptable salt thereof is used as a food additive, the compound can be directly added or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). Generally, the compound of the present invention is added in an amount of 0.01 to 10% by weight, preferably 0.05 to 1% by weight, in the raw material composition when the food or drink is prepared. However, in the case of long-term ingestion intended for health and hygiene purposes or for the purpose of controlling health, the amount can also be used below the above-mentioned range.
상기 식품의 종류에 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, and includes foods in a conventional sense.
본 발명의 음료 조성물은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 0.01 ~0.04 g, 바람직하게는 약 0.02 ~ 0.03 g 이다.The beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 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, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다. 그밖에 본 발명의 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 과육의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01 ~ 10 중량부의 범위에서 선택되는 것이 일반적이다. 이들 성분들은 독립적으로 또는 조합하여 사용할 수 있다.In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, A carbonating agent used in a carbonated beverage, and the like. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention. In addition, the composition of the present invention may contain flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. The proportion of such flesh is not critical but is generally selected in the range of 0.01 to 10 parts by weight per 100 parts by weight of the composition of the present invention. These components can be used independently or in combination.
또한, 본 발명은 하기 화학식 1로 표시되는 시알산 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 자궁내막증 합병증의 예방 또는 치료용 조성물을 제공한다.The present invention also provides a composition for preventing or treating complications of endometriosis comprising a sialic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
상기 조성물은 약학적 조성물 또는 식품 조성물을 포함한다.The composition comprises a pharmaceutical composition or a food composition.
[화학식 1][Chemical Formula 1]
여기서, R1은 H, 아세틸(-COCH3) 또 는 히드록시아세틸(-COCH2OH)이고, Wherein, R 1 is H, an acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R2는 H, (C1-C6 )알킬, (C1-C6)할로알킬, (C1-C6)알콕시, (C1 -C6)할로알콕시, 아세틸, 할로아세틸, (C1-C6)알콕시아세틸 , 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl) , N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; G alNAc), N-아세틸락토사미닐(N-acetyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalac tosaminyl)이고,R 2 is selected from H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, acetyl, 1 -C 6 ) alkoxyacetyl, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl, GlcNAc, N-acetylgalactosaminyl, N-acetyllactosaminyl, or serine N-acetylgalac tosaminyl.
R3는 H 또는 (C1-C6)알킬 이다.R 3 is H or (C 1 -C 6 ) alkyl.
본 발명에 있어서, 자궁내막증의 합병증은 골반염, 골반유착, 난소낭종, 자궁근종, 자궁 외 임신 및 불임일 수 있으나 이에 제한되지 않는다.In the present invention, complications of endometriosis include, but are not limited to, pelvic inflammation, pelvic adhesion, ovarian cysts, uterine myoma, extrauterine pregnancy and infertility.
상기 골반염은 골반염이란 자궁내경관에 번식하고 있던 세균이 자궁내막과 나팔관, 혹은 복강까지 퍼지면서 염증을 일으키는 것으로, 자궁내막 조직이 다른 조직 내로 침윤 또는 본래의 자리를 벗어나 원격 전이를 하는 경우 발병할 수 있다.Pelvic inflammation is a condition in which endometrial tissue infiltrates into other tissues or distant from the original site and causes distant metastasis. The pelvic inflammation is caused by the bacteria that have propagated to the endometrium, the fallopian tube, or the abdominal cavity. .
상기 골반유착은 골반 안에서 서로 다른 조직이나 장기가 섬유 조직으로 연결되어서 붙어 있는 상태로, 자궁내막증에 의해 골반 내 유착이 발생하여 발병할 수 있다.The pelvic adhesions may be caused by the adhesion of pelvic endometriosis due to endometriosis with different tissues or organs attached to the fibrous tissue in the pelvis.
상기 난소낭종은 난소에 발생하는 낭성 종양(cystic tumor)으로, 내부가 수액 성분으로 차 있는 물혹을 의미하는데, 자궁내막증은 난소에 낭종을 형성하기도 한다.The ovarian cyst is a cystic tumor that occurs in the ovary. The endometriosis forms a cyst in the ovary.
상기 자궁근종은 자궁을 대부분 이루고 있는 평활근(smooth muscle)에 생기는 종양이며 양성질환으로, 자궁내막증에 의해 자궁내막 조직이 자궁 외에 자라게 되면서 자궁을 이루고 있는 평활근에 종양이 발병할 수 있다.The uterine leiomyoma is a tumor that occurs in the smooth muscle that mostly makes up the uterus. It is a benign disease. The endometrial tissue grows outside the uterus due to endometriosis, and the tumor may develop in the smooth muscle that forms the uterus.
상기 자궁 외 임신은 자궁내막증에 의해 자궁내막 조직이 자궁 외에 자라 수정란이 자궁 외에 착상하는 경우 발병할 수 있다. 이에 따라 궁극적으로는 불임으로 아이를 가지기 어렵게 된다.The ectopic pregnancy may develop when the endometrial tissue grows outside the uterus due to endometriosis and the fertilized egg is implanted outside the uterus. As a result, infertility ultimately makes it difficult to have children.
상기 약학적 조성물 또는 식품 조성물과 관련하여, 앞서 기재한 자궁내막증의 예방 또는 치료용 약학적 조성물 또는 식품 조성물과 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.With respect to the above pharmaceutical composition or food composition, the contents common to the pharmaceutical compositions or food compositions for the prevention or treatment of endometriosis described above are omitted in order to avoid the excessive complexity of the present specification.
이하 본 발명의 이해를 돕기 위하여 바람직한 실시예, 실험예 및 제제예를 제시한다. 그러나 하기 실시예, 실험예 및 제제예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 이에 의해 본 발명의 내용이 한정되는 것은 아니다. 하기 실시예, 실험예 및 제제예의 설명을 위하여 편의상 시알산 유도체를 시알산과 시알산 유도체로 세부적으로 나누어 설명한다.Hereinafter, preferred examples, experimental examples, and formulation examples are provided to facilitate understanding of the present invention. However, the following examples, experimental examples and preparation examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto. For the sake of explanation of the following Examples, Experimental Examples and Preparation Examples, sialic acid derivatives will be described in detail as sialic acid and sialic acid derivatives for convenience.
실시예Example 1. 시알산 및 시알산 유도체의 특정 및 제조 1. Specification and preparation of sialic acid and sialic acid derivatives
본 실험에 사용한 시알산 및 이의 유도체인 α2, 3-시알릴갈락토스, α2, 6-시알릴갈락토스, α2, 3-시알릴락토스, α2, 6-시알릴락토스, α2, 3-시알릴 N-아세틸락토사민, α2, 6-시알릴 N-아세틸락토사민 및 다이실릴락토스는 Carbosynth사(영국)에서 공급받은 것을 사용하였고, STn 에피토프는 Santa Cruz Biotechnology사(미국)에서 공급받은 것을 사용하였다. 그 구체적인 화학 구조를 표 1에 나타내었다.Sialic acid and its derivatives,? 2, 3-sialylgalactose,? 2, 6-sialylgalactose,? 2, 3-sialyllactose,? 2,6-sialyllactose, Acetyllactosamine,? 2, 6-sialyl N-acetyllactosamine and dysylilactose were purchased from Carbosynth (UK), and STn epitope was purchased from Santa Cruz Biotechnology (USA). The specific chemical structures thereof are shown in Table 1.
(α2, 3-sialylgalactose)
(? 2, 3-sialylgalactose)
(α2, 6-sialylgalactose)
(? 2, 6-sialylgalactose)
(α2, 3-sialyllactose)
(? 2, 3-sialyllactose)
(α2, 6-sialyllactose)
(? 2, 6-sialyllactose)
(α2, 3-sialyl N-acetyllactosamine)? 2, 3-sialyl N-acetyllactosamine
(? 2, 3-sialyl N-acetyllactosamine)
(α2, 6-sialyl N-acetyllactosamine)α2, 6-sialyl N-acetyllactosamine
(? 2, 6-sialyl N-acetyllactosamine)
(Disialyllactose)Dyssilyl Lactose
(Disialyllactose)
(STn epitope)
Stn epitope
(STn epitope)
실험예Experimental Example 1. One. MTTMTT 분석을 통한 시알산 및 이의 유도체의 세포독성 확인 Cytotoxicity of sialic acid and its derivatives by analysis
본 발명에 따른 시알산 및 시알산 유도체의 세포독성을 확인하기 위하여 MTT 분석(MTT assay)을 수행하였다. 먼저, 인간 복막세포주인 MeT-5A 세포에 시알산 또는 시알산 유도체를 각각 10 μM 농도로 24시간 동안 처리하였다. 상기 세포를 MTT 용액과 반응 시킨 뒤 각 웰의 샘플들을 마이크로플레이트 리더를 이용하여 540 nm에서 흡광도를 측정하였다. 그 결과는 도 1에 나타내었다.MTT assay (MTT assay) was performed to confirm cytotoxicity of sialic acid and sialic acid derivatives according to the present invention. First, the human peritoneal cell line MeT-5A cells were treated with sialic acid or sialic acid derivatives at a concentration of 10 μM for 24 hours, respectively. The cells were reacted with MTT solution and the absorbance of each well was measured at 540 nm using a microplate reader. The results are shown in Fig.
도 1에 나타낸 바와 같이, 시알산 및 시알산 유도체의 처리에 따라 유의한 세포독성을 확인할 수 없었다. 즉, 시알산 및 시알산 유도체는 10 μM의 농도에서 세포독성을 가지지 않음을 확인하였다.As shown in Fig. 1, significant cytotoxicity could not be confirmed by treatment with sialic acid and sialic acid derivatives. That is, it was confirmed that sialic acid and sialic acid derivatives did not have cytotoxicity at a concentration of 10 μM.
추가적으로 시알산의 농도에 따른 세포 독성을 판단하기 위하여 시알산을 농도별 (0, 5, 10, 20 μM)로 MeT-5A 세포에 24 시간 처리하고 MTT 분석을 수행하였다. 그 결과는 도 2에 나타내었다.In addition, sialic acid was treated with MeOH (5, 10, 20 μM) for 24 h in order to determine the cytotoxicity depending on the sialic acid concentration and MTT analysis was performed. The results are shown in Fig.
도 2에서 나타낸 바와 같이, 시알산의 농도가 20 μM까지 증가하더라도, 유의한 세포독성을 확인할 수 없었다. 즉, 시알산은 고농도에서도 세포 독성을 가지지 않음을 확인하였다.As shown in Fig. 2, even if the concentration of sialic acid was increased to 20 [mu] M, significant cytotoxicity could not be confirmed. That is, it was confirmed that sialic acid does not have cytotoxicity even at a high concentration.
실험예Experimental Example 2. 시알산 및 시알산 유도체에 의한 2. By sialic acid and sialic acid derivatives 자궁내막세포와Endometrial cells 복막세포Peritoneal cell 간 liver 부착능Attachment 억제 효과 확인 Confirmation of inhibition
본 발명에 따른 시알산 및 시알산 유도체의 자궁내막세포와 복막세포 간 부착능을 확인하기 위하여 자궁내막세포의 부착능 증가와 관련된 사이토카인인 TGF-β1을 이용하여 도 3에 나타낸 방법으로 실험을 하였다. 먼저, 자궁내막세포주인 HES 세포에 TGF-β1을 10 ng/mL의 농도로 처리하였다. 복막중피세포주인 MeT-5A 세포를 단일층으로 배양한 후에 실험군에는 세포 부착 시험을 하기 1시간 전에 시알산 또는 시알산 유도체 각각을 10 μM 농도로 처리하고, 대조군에는 시알산 및 시알산 유도체를 처리하지 않았다. 이 후에 TGF-β1 처리 후 24시간이 경과한 후에 HES 세포를 부착시켰다. HES 세포를 형광물질인 CellTracker™ Green CMFDA (5-Chloromethylfluorescein Diacetate)로 표지하여 MeT-5A 세포 위에 추가한 후 20분간 20 rpm의 속도로 교반하여 배양하였다. 이 후에 MeT-5A 세포와 결합하지 않은 HES 세포를 제거하기 위해 인산염완충용액(PBS)로 세척하였고, 형광을 나타내는 HES 세포의 수를 고성능 형광 현미경 (ZEISS HBO100)으로 확인하였다. 형광을 나타내는 HES 세포의 수를 계수하여 그 수의 평균과 표준편차를 막대그래프로 나타내고 통계적인 유의성을 students t-test 방법을 이용하여 확인하였다. 그 결과인 형광을 나타내는 HES 사진은 도 4에 나타내고, 형광을 나타내는 HES 세포의 수를 계수하여 막대그래프로 나타낸 결과는 도 5에 나타내었다. 한편, 상기에 확인한 TGF-β1을 처리한 군의 부착력 증가율을 100%로 잡았을 때 시알산 및 시알산 유도체의 처리에 의한 자궁내막세포주 및 복막중피세포주 간 부착력 감소 비율을 저해율로 표시하였다. 그 결과는 도 6에 나타내었다. In order to confirm the ability of sialic acid and sialic acid derivatives according to the present invention to adhere endometrial cells and peritoneal cells to each other, experiments using the cytokine TGF-β1, which is associated with increased adherence of endometrial cells, Respectively. First, endometrial cell line HES cells were treated with TGF-β1 at a concentration of 10 ng / mL. After the peritoneal cell line MeT-5A cells were cultured in a single layer, each of the sialic acid or sialic acid derivatives was treated with 10 μM of the sialic acid or
도 4 및 5에 나타낸 바와 같이, TGF-β1 처리에 의하여 자궁내막세포와 복막중피세포의 부착력이 증가하고, 증가된 부착력은 시알산 및 시알산 유도체에 의하여 감소됨을 확인하였다. 또한, 도 6에 나타낸 바와 같이, 시알산 처리에 의해 60% 이상의 저해율이 확인되었으며, 시알산 유도체를 처리한 경우에도 시알산과 비슷하거나 더 높은 저해율을 보이는 것이 확인되었다. As shown in FIGS. 4 and 5, the adherence of endometrial cells and adipocytes in peritoneal cells was increased by TGF-β1 treatment, and the increased adherence was reduced by sialic acid and sialic acid derivatives. In addition, as shown in Fig. 6, inhibition rate of 60% or more was confirmed by the sialic acid treatment, and it was confirmed that even when the sialic acid derivative was treated, the inhibition rate was similar to or higher than that of sialic acid.
이를 통하여 시알산 및 이의 유도체가 자궁내막세포와 복막세포의 결합을 저해할 수 있는 중요한 인자로 역할을 함을 알 수 있다. 이는 시알산 및 이의 유도체는 자궁내막세포의 복막 조직에 대한 유착이 원인이 되어 발생하는 자궁내막증 및 이의 합병증인 골반염, 골반유착, 난소낭종, 자궁근종, 자궁 외 임신 또는 불임의 예방 또는 치료에 사용할 수 있음을 시사한다.Through this, it can be seen that sialic acid and its derivatives act as an important factor that can inhibit the binding of endometrial cells to peritoneal cells. It is useful for the prevention or treatment of endometriosis and its complications such as pelvic inflammation, pelvic adhesion, ovarian cysts, uterine myoma, ectopic pregnancy or infertility caused by adhesion to endometrial peritoneal tissue of endometrial cells .
이하 본 발명의 시알산, 시알산 유도체 또는 그의 약학적으로 허용가능한 염을 포함하는 자궁내막증 예방 또는 치료용 약학적 조성물 및 예방 또는 개선용 식품 조성물의 제제예를 설명하나, 본 발명을 한정하고자 함이 아니고 단지 이를 구체적으로 설명하고자 함이다.Hereinafter, the pharmaceutical composition for preventing or treating endometriosis comprising the sialic acid, the sialic acid derivative or the pharmaceutically acceptable salt thereof of the present invention, and the preparation example of the food composition for prevention or improvement will be described, but the present invention is intended to be limited But rather to explain it specifically.
제제예 1. 약학적 제제의 제조Formulation Example 1. Preparation of pharmaceutical preparations
1. 산제의 제조 1. Manufacturing of powder
시알산 또는 이의 유도체 20 mgSialic acid or its derivative 20 mg
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조할 수 있다.The above components can be mixed and filled in an airtight container to prepare powders.
2. 정제의 제조2. Preparation of tablets
시알산 또는 이의 유도체 10 mgSialic acid or its derivative 10 mg
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조할 수 있다.After mixing the above components, tablets may be prepared by tableting according to a conventional method for producing tablets.
3. 캡슐제의 제조3. Preparation of capsules
시알산 또는 이의 유도체 10 mgSialic acid or its derivative 10 mg
결정성 셀룰로오스 3 mg
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조할 수 있다.The above components may be mixed and filled in a gelatin capsule according to a conventional method for preparing a capsule, thereby preparing a capsule.
4. 주사제의 제조4. Preparation of injections
시알산 또는 이의 유도체 10 mgSialic acid or its derivative 10 mg
만니톨 180 mg180 mg mannitol
주사용 멸균 증류수 2974 mgSterile sterilized water for injection 2974 mg
Na2HPO42H2O 26 mgNa 2 HPO 4 2H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2 ml) 상기의 성분 함량으로 제조할 수 있다.(2 ml) per 1 ampoule according to the usual injection preparation method.
5. 액제의 제조5. Manufacture of liquids
시알산 또는 이의 유도체 20 mgSialic acid or its derivative 20 mg
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고, 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 다시 정제수를 가한다. 전체를 정제수로 가한 액제의 약을 전체 100 ml로 조절한 후 갈색병에 충진하여 멸균시켜 최종적으로 액제를 제조할 수 있다.Each component is added to and dissolved in purified water according to a conventional liquid preparation method, and the lemon flavor is added in an appropriate amount, then the above components are mixed, and then purified water is added. The total amount of the liquid agent added to the purified water is adjusted to 100 ml, and the liquid agent can be finally prepared by filling it in a brown bottle and sterilizing it.
제제예 2. 식품 제제의 제조Formulation Example 2. Preparation of food preparation
1. 식품의 제조1. Manufacture of food
시알산 또는 이의 유도체 100 mg100 mg of sialic acid or its derivative
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 g70 g of vitamin A acetate
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 B1 0.13 mgVitamin B1 0.13 mg
비타민 B2 0.15 mg0.15 mg of vitamin B2
비타민 B6 0.5 mgVitamin B6 0.5 mg
비타민 B12 0.2 g0.2 g of vitamin B12
비타민 C 10 mg
비오틴 10 gBiotin 10 g
니코틴산아미드 1.7 mgNicotinic acid amide 1.7 mg
엽산 50 gFolate 50 g
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75 mg1.75 mg of ferrous sulfate
산화아연 0.82 mg0.82 mg of zinc oxide
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mgPotassium monophosphate 15 mg
제2인산칼슘 55 mgSecondary calcium phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mg
염화마그네슘 24.8 mgMagnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a suitable ingredient for the food, it is possible to arbitrarily modify the blending ratio thereof. The above ingredients are mixed according to a conventional food manufacturing method, Can be prepared and used in the manufacture of food compositions according to conventional methods.
2. 음료의 제조2. Manufacturing of beverage
시알산 또는 이의 유도체 100 mg100 mg of sialic acid or its derivative
비타민 C 15 gVitamin C 15 g
비타민 E(분말) 100 gVitamin E (powder) 100 g
젖산철 19.75 g19.75 g of ferrous lactate
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinic acid amide 3.5 g
비타민 A 0.2 gVitamin A 0.2 g
비타민 B1 0.25 gVitamin B1 0.25 g
비타민 B2 0.3gVitamin B2 0.3g
물 정량Water quantification
통상의 음료 제조방법에 따라 상기의 성분을 혼합하고, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 음료 조성물 제조에 사용할 수 있다.The above components were mixed according to a conventional beverage manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The resulting solution was filtered to obtain a sterilized 2L container, sealed sterilized and refrigerated, Can be used for the preparation of a composition.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
Claims (10)
[화학식 1]
여기서, R1은 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고,
R2는 H, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-acetyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이고,
R3는 H이다.A pharmaceutical composition for preventing or treating endometriosis, comprising a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Wherein, R 1 is acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R 2 is selected from the group consisting of H, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl (GlcNAc) N-acetylgalactosaminyl (GalNAc), N-acetyllactosaminyl, or serine N-acetylgalactosaminyl.
R 3 is H.
[화학식 2]
여기서, R2는 H, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-acetyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이다.The pharmaceutical composition for preventing or treating endometriosis according to claim 1, wherein the sialic acid derivative is represented by the following formula (2):
(2)
Wherein R 2 is selected from the group consisting of H, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl ), N-acetylgalactosaminyl (GalNAc), N-acetyllactosaminyl, or serine N-acetylgalactosaminyl.
[화학식 3]
The pharmaceutical composition for preventing or treating endometriosis according to claim 2, wherein the sialic acid derivative is represented by the following formula (3):
(3)
[화학식 4]
[화학식 5]
[화학식 6]
[화학식 7]
[화학식 8]
[화학식 9]
[화학식 10]
[화학식 11]
The pharmaceutical composition for preventing or treating endometriosis according to claim 1, wherein the sialic acid derivative is represented by any one selected from the group consisting of the following Formulas (4) to (11):
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
(7)
[Chemical Formula 8]
[Chemical Formula 9]
[Chemical formula 10]
(11)
[화학식 1]
여기서, R1은 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고,
R2는 H, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc), N-아세틸락토사미닐(N-acetyllactosaminyl) 또는 세린 N-아세틸갈락토사미닐(serine N-acetylgalactosaminyl)이고,
R3는 H이다.A food composition for preventing or improving endometriosis comprising a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Wherein, R 1 is acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R 2 is selected from the group consisting of H, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl (GlcNAc) N-acetylgalactosaminyl (GalNAc), N-acetyllactosaminyl, or serine N-acetylgalactosaminyl.
R 3 is H.
[화학식 1]
R1은 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고,
R2는 H, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc) 또는 N-아세틸락토사미닐(N-acetyllactosaminyl)이고,
R3는 H이다.A prophylactic or therapeutic agent for the treatment of endometriotic complications selected from the group consisting of pelvic inflammatory diseases, ovarian cysts, uterine myoma, ectopic pregnancy and infertility comprising a sialic acid derivative represented by the following formula 1 or a pharmaceutically acceptable salt thereof: Component composition:
[Chemical Formula 1]
R 1 is acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R 2 is selected from the group consisting of H, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl (GlcNAc) N-acetylgalactosaminyl (GalNAc), or N-acetyllactosaminyl,
R 3 is H.
[화학식 1]
R1은 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고,
R2는 H, 글리코실(glycosyl; Glc), 갈락토실(galactosyl; Gal), 락토실(lactosyl), 시알릴락토실(sialyllactosyl), N-아세틸글루코사미닐(N-acetylglucosaminyl; GlcNAc), N-아세틸갈락토사미닐(N-acetylgalactosaminyl; GalNAc) 또는 N-아세틸락토사미닐(N-acetyllactosaminyl)이고,
R3는 H이다.A prophylactic or therapeutic agent for the prevention or amelioration of complications of endometriosis selected from the group consisting of pelvic inflammatory diseases, pelvic inflammatory diseases, ovarian cysts, uterine leiomyomas, ectopic pregnancies and infertility, comprising a sialic acid derivative represented by the following formula 1 or a pharmaceutically acceptable salt thereof Composition:
[Chemical Formula 1]
R 1 is acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R 2 is selected from the group consisting of H, glycosyl (Glc), galactosyl (Gal), lactosyl, sialyllactosyl, N-acetylglucosaminyl (GlcNAc) N-acetylgalactosaminyl (GalNAc), or N-acetyllactosaminyl,
R 3 is H.
[화학식 1]
여기서, R1은 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고,
R2는 세린 N-아세틸락토사미닐(serine N-acetyllactosaminyl)이고,
R3는 H이다.A pharmaceutical composition for the prophylaxis or treatment of endometriotic complications selected from the group consisting of pelvic inflammatory diseases, pelvic inflammatory diseases, ovarian cysts, uterine leiomyomas and extrapelvic pregnancies comprising a sialic acid derivative represented by the following formula 1 or a pharmaceutically acceptable salt thereof :
[Chemical Formula 1]
Wherein, R 1 is acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R 2 is a serine, N- acetyl-galactosyl Sami carbonyl (serine Na cetyllactosaminyl),
R 3 is H.
[화학식 1]
여기서, R1은 아세틸(-COCH3) 또는 히드록시아세틸(-COCH2OH)이고,
R2는 세린 N-아세틸락토사미닐(serine N-acetyllactosaminyl)이고,
R3는 H이다.A food composition for preventing or ameliorating endometriosis complications selected from the group consisting of a pelvic inflammatory disease, a pelvic inflammatory disease, an ovarian cyst, a uterine leiomyoma and an extrauterine pregnancy comprising a sialic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Wherein, R 1 is acetyl (-COCH 3) Or hydroxyacetyl (-COCH 2 OH)
R 2 is a serine, N- acetyl-galactosyl Sami carbonyl (serine Na cetyllactosaminyl),
R 3 is H.
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KR20200092517A (en) | 2019-01-24 | 2020-08-04 | 건양대학교산학협력단 | Development of endometriosis animal model through Ureaplasma urealyticum infection |
KR20220161209A (en) | 2021-05-28 | 2022-12-06 | 연세대학교 산학협력단 | Composition for preventing or treating endometrioma |
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KR20220037373A (en) | 2020-09-17 | 2022-03-24 | 성균관대학교산학협력단 | sialic acid derivatives-conjugated filamentous phage, and use thereof for preventing or treating viral infectious diseases |
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Cited By (2)
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KR20200092517A (en) | 2019-01-24 | 2020-08-04 | 건양대학교산학협력단 | Development of endometriosis animal model through Ureaplasma urealyticum infection |
KR20220161209A (en) | 2021-05-28 | 2022-12-06 | 연세대학교 산학협력단 | Composition for preventing or treating endometrioma |
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