KR100292673B1 - Intermediate Compounds for the Preparation of Water-soluble Phytosterol Derivatives for Lowering Cholesterol Level - Google Patents
Intermediate Compounds for the Preparation of Water-soluble Phytosterol Derivatives for Lowering Cholesterol Level Download PDFInfo
- Publication number
- KR100292673B1 KR100292673B1 KR1019990007975A KR19990007975A KR100292673B1 KR 100292673 B1 KR100292673 B1 KR 100292673B1 KR 1019990007975 A KR1019990007975 A KR 1019990007975A KR 19990007975 A KR19990007975 A KR 19990007975A KR 100292673 B1 KR100292673 B1 KR 100292673B1
- Authority
- KR
- South Korea
- Prior art keywords
- water
- sterol
- cholesterol
- soluble
- phytosterol
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
- A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
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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
-
- 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
- A23V2250/20—Natural extracts
- A23V2250/21—Plant extracts
- A23V2250/2136—Phytosterols, phytostanols
- A23V2250/21368—Phytosterols
Abstract
본 발명은 콜레스테롤 저하효과를 갖는 수용성 스테롤 치환체의 제조를 위한 스테롤 중간체 화합물에 관한 것이다. 본 발명자들은 식물성 스테롤인 피토스테롤이 콜레스테롤과의 구조적 유사성을 통하여 인체내 콜레스테롤 흡수대사를 저해하는 작용기작을 가질 뿐만 아니라, 콜레스테롤 저하제 등의 약품 복용이 초래할 수 있는 부작용을 가지고 있지 않으나, 피토스테롤 그 자체로는 물, 유지 모두에 용해되지 않는 물리적 한계로 인하여 그 제형화에 제한을 받고 있음에 착안하여, 피토스테롤을 수용성 거대분자와 화학적 방법으로 결합시켜, 콜레스테롤 저하효과를 가지면서도 인체에도 안전한, 다양한 수용성 스테롤 치환체를 제조하기 위한 스테롤 중간체 화합물을 제조하였다. 본 발명의 스테롤 중간체는 종래의 지용성 피토스테롤과는 달리 물에 쉽게 용해될 뿐만 아니라, 인체에 해로운 LDL-콜레스테롤의 흡수를 감소시켜 혈중 콜레스테롤치를 저하시키는 반면, 종래의 콜레스테롤 저하제 등의 약품복용시 유발되는 간 기능 장애 등의 부작용이 전혀 수반되지 않는 수용성 스테롤 치환체의 제조에 사용될 수 있다.The present invention relates to a sterol intermediate compound for the preparation of a water-soluble sterol substituent having a cholesterol lowering effect. The inventors of the present invention not only have a mechanism of inhibiting metabolism of cholesterol in the human body through the structural similarity to cholesterol of phytosterol, but also does not have side effects that can be caused by taking drugs such as cholesterol lowering agents, phytosterol itself In view of its limitation in formulation due to physical limitations that are insoluble in both water and fats and oils, phytosterols are combined with water-soluble macromolecules by chemical methods, which are effective in reducing various cholesterol levels and are safe for the human body. Sterol intermediate compounds were prepared to prepare substituents. Unlike the conventional fat-soluble phytosterol, the sterol intermediate of the present invention not only dissolves easily in water, but also reduces absorption of LDL-cholesterol, which is harmful to the human body, and lowers blood cholesterol levels. It can be used for the preparation of water-soluble sterol substituents that do not involve any side effects such as liver dysfunction.
Description
본 발명은 콜레스테롤 저하효과를 갖는 수용성 스테롤 유도체 제조를 위한 중간체 화합물에 관한 것이다. 좀 더 구체적으로, 본 발명은 콜레스테롤 과다증의 치료뿐 아니라, 일부 심장계 질환 및 고혈압 등의 예방에도 이용 가능한 수용성 스테롤 유도체의 제조를 위한 스테롤 중간체 화합물에 관한 것이다.The present invention relates to an intermediate compound for preparing a water-soluble sterol derivative having a cholesterol lowering effect. More specifically, the present invention relates to sterol intermediate compounds for the preparation of water-soluble sterol derivatives that can be used not only for the treatment of hypercholesterolemia but also for the prevention of some cardiovascular diseases and hypertension.
콜레스테롤은 생체막의 구성성분인 동시에, 호르몬 합성의 출발물질로 이용되는 등 인체에 반드시 필요한 영양소이나, 이러한 콜레스테롤도 과다 섭취하게 되면 혈관내에 축적되어 심장계 질환을 유발하는 것으로 알려져 있다. 아직까지는 저콜레스테롤 식이요법 이외에는 이를 예방할 방법이 없으며, 콜레스테롤 저하제 등의 약품 복용이 효과는 있으나, 콜레스테롤 합성효소의 작용억제에 따른 간기능 장애의 부작용을 유발하는 등의 이유로 인하여 극히 제한적으로 밖에 사용되지 못하고 있다.Cholesterol is a nutrient necessary for the human body such as being used as a constituent of a biological membrane and used as a starting material for hormonal synthesis, and when ingested too much cholesterol, it is known to accumulate in blood vessels and cause heart disease. So far, there is no way to prevent this except low-cholesterol diet, and taking drugs such as cholesterol-lowering drugs are effective, but they are only used on a very limited basis for causing side effects of liver dysfunction due to inhibition of cholesterol synthase. I can't.
인체내 혈중 콜레스테롤 저하작용을 하는 것으로 알려진 물질로는 키토산(chitosan), 피토스테롤(phytosterol), 이노시톨(inositol), 펙틴(pectin) 등이 있으나, 피토스테롤을 제외한 물질은 그 효과나 대사기작이 명확히 밝혀져 있지 않다. 식물성 스테롤인 피토스테롤은 장내에서 장벽에 흡착하여, 그 구조적 유사성으로 해로운 저밀도 지질단백질(LDL: low density lipoprotein) 콜레스테롤과의 경쟁을 통하여 인체내 콜레스테롤 흡수대사를 저해하는 작용기작이 이미 밝혀져 있고, 따라서 콜레스테롤 생합성기작에 전혀 영향을 주지 않고 위에 언급한 부작용이 전혀 수반되지 않는 식품첨가물로서 FDA의 승인을 받았다.Chitosan, phytosterol, inositol, and pectin are known substances that lower blood cholesterol in the human body, but substances other than phytosterol have no clear effect or metabolic mechanism. not. Phytosterol, a plant sterol, is known to have a mechanism of action that inhibits the absorption of cholesterol in the body through competition with low density lipoprotein (LDL) cholesterol, which is adsorbed on the intestinal wall and its structural similarity. It is FDA approved as a food additive that does not affect any biosynthetic mechanisms and does not involve any of the side effects mentioned above.
피토스테롤은 고등식물에서 발견되는 스테로이드 구조를 갖는 알코올 화합물을 통칭하는 것으로, 스티그마스테롤(stigmasterol), 스피나스테롤(spinasterol), 캄페스테롤(campesterol) 및 시토스테롤(sitosterol) 등으로 분류할 수 있으며, 예를 들면, 시토스테롤에도 α, β, γ 타입 등이 존재한다. 이와 같이 다양한 피토스테롤 화합물 중에서 가장 대표적인 물질인 β-시토스테롤(24-ethyl-5α-cholestene-3β-ol)의 콜레스테롤 저하효과는 웅성 랫트(male rat) 및 인체를 대상으로 한 실험에서 확인된 바 있다(참조: J. Nutr., 107:2011-2019(1977)). 또한, β-시토스테롤이 지방산에 의하여 치환된 β-시토스테롤 에스테르(β-sitosterol ester) 화합물도 거의 동일한 효과를 나타내는 것으로 보고되었다(참조: J. Nutr., 107:1139-1146(1977)). 예를 들면, 성인 남성에게 매일 2g의 β-시토스테릴 올레이트(β-sitosteryl oleate)를 5일간 투여하였을 때, 혈중 콜레스테롤치가 33% 저하된다는 보고가 있다(참조: Am. J. Clin. Nutr., 35:697-700(1982)).Phytosterol is a generic name for alcohol compounds having a steroid structure found in higher plants, and may be classified into stigmasterol, spinasterol, campesterol and cytosterol, for example. For example, α, β, and γ types also exist in cytosterol. The cholesterol-lowering effect of β-sitosterol (24-ethyl-5α-cholestene-3β-ol), the most representative of the various phytosterol compounds, has been confirmed in experiments in male rats and humans ( See J. Nutr., 107: 2011-2019 (1977). It has also been reported that β-sitosterol ester compounds in which β-sitosterol is substituted by fatty acids have almost the same effect (J. Nutr., 107: 1139-1146 (1977)). For example, an adult male reported that a daily administration of 2 g of β-sitosteryl oleate reduced his blood cholesterol levels by 33% (see Am. J. Clin. Nutr). , 35: 697-700 (1982).
이와 같은 콜레스테롤 저하효과 이외에도, β-시토스테롤은 치주증 및 치은염의 치료제인 ＆Zea mays L＆.의 주요성분으로도 알려져 있다. 그러나, β-시토스테롤 그 자체로는 물, 유지 모두에 용해되지 않는 물리적 한계로 인하여 제형화에 제한을 받고 있으며, 현재 상업화된 것은 영양제 타입의 단순정제 차원에 머물러 있어 식품소재로서의 개발은 미비한 상태이다.In addition to the cholesterol lowering effect, β-sitosterol is also known as a major component of & Zea mays L &. Which is a treatment for periodontal disease and gingivitis. However, β-sitosterol itself is limited in formulating due to physical limitations insoluble in water and fats and oils, and the commercialization is currently limited to simple tablets of nutrient type, and development as a food material is insufficient. .
최근에는, 이와 같은 β-시토스테롤의 단점을 보완하기 위해서, β-시토스테롤의 고형 형태인 β-시토스타놀(24-ethyl-5α-cholestene-3β-ol)을 지방산과 반응시킨 β-시토스타놀 에스테르(β-sitostanol ester) 화합물이 버터, 마아가린 등과 같은 고형 유제품에 첨가제로 사용될 경우, 혈중 콜레스테롤을 낮출 수 있는 것으로 밝혀졌다(WO 92/19640). 그러나, β-시토스타놀 에스테르 화합물은, 비교적 수요가 적은 고형 유제품에만 적용 가능하며, 액상 오일제품에는 용해되지 않는다는 단점을 지니고 있다. 또한, β-시토스테롤을 유기화학적 방법에 의해서 수소화(hydrogenation)시켜 β-시토스타놀을 합성한 다음, 지방산과 반응시켜야 하는 어려움이 있다. 이에, 본 발명자들은 불포화지방산 또는 그의 에스테르 화합물이 포화지방산 또는 그의 에스테르 화합물보다 융점이 현저히 낮고 대부분이 실온에서 액상인 점에 착안하여, β-시토스테롤을 불포화 지방산 메틸 에스테르와 반응시킴으로써, 액상 오일에 용해 가능하다는 것을 확인한 바 있으며, 전기의 피토스테롤 지용성 치환체를 임상실험한 결과, 탁월한 콜레스테롤 저하 효과를 나타내는 것을 알 수 있었으나, 이 지용성 치환체는 활용 범위가 오일형 식품 등으로 한정되어 있었다(참고: 특허출원 제 98-7535호).Recently, in order to compensate for the disadvantage of β-sitosterol, β-sitostanol obtained by reacting β-sitostanol (24-ethyl-5α-cholestene-3β-ol), which is a solid form of β-sitosterol, with a fatty acid It has been found that β-sitostanol ester compounds can lower blood cholesterol when used as additives in solid dairy products such as butter and margarine (WO 92/19640). However, β-cytostanol ester compounds have the disadvantage that they are applicable only to solid dairy products, which are relatively in low demand, and do not dissolve in liquid oil products. In addition, it is difficult to hydrogenate β-sitosterol by an organic chemical method to synthesize β-sitostanol and then react with fatty acids. Therefore, the inventors pay attention to the fact that the unsaturated fatty acid or its ester compound is significantly lower in melting point than the saturated fatty acid or its ester compound and most of them are liquid at room temperature, so that β-sitosterol is reacted with the unsaturated fatty acid methyl ester to be dissolved in liquid oil. As a result of clinical trials of the phytosterol fat-soluble substituents described above, it was found that the cholesterol-lowering effect was excellent. However, the fat-soluble substituents were limited to oil-type foods and the like (reference: Patent Application No. 98). -7535).
따라서, 이 피토스테롤을 수용성으로 변화시켜 식음료에 첨가함으로써, 손쉽게 섭취 가능케 하는 수용성 식품소재를 개발해야 할 필요성이 끊임없이 대두되어 왔다.Therefore, the need to develop a water-soluble food material that can be easily ingested by changing the phytosterol to water-soluble and added to food and beverage has been constantly emerging.
이에, 본 발명자들은 각종 성인병의 주요 유발인자의 하나인 콜레스테롤의 저하효과를 지닌 피토스테롤을 수용성 거대분자와 화학적 방법으로 결합시킨, 인체에 안전한 친수성 고분자 담체를 개발하고자 예의 연구노력한 결과, 피토스테롤을 숙신산 무수물과 반응시켜 반응성이 높은 중간물질로서의 스테롤 중간체를 수득하고, 전기의 중간물질과 식품첨가제로서 사용이 가능하고 인체에 안전한 친수성 고분자 담체를 사용하여 결합반응시켜 피토스테롤의 수용성 치환체를 제조한 후, 전기 치환체의 물에 대한 용해도를 조사한 결과, 온도변화에 관계없이 물에 대한 용해도가 10mg(치환체 중 스테롤 부분의 무게)/ml 이상임을 확인하였음은 물론, 콜레스테롤 저하 효과를 동물실험을 통해 조사한 결과, 피토스테롤과 동등한 효과를 가짐을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors have succinic anhydride as a result of earnest research to develop a hydrophilic polymer carrier that is safe for the human body by combining a phytosterol having a lowering effect of cholesterol, which is one of the main inducers of various adult diseases, with a water-soluble macromolecule and chemical method. And a sterol intermediate as a highly reactive intermediate, which can be used as a food additive as an intermediate, and is combined with a hydrophilic polymer carrier that is safe for the human body to prepare a water-soluble substituent of phytosterol. The solubility of water in water was not less than 10 mg (weight of the sterol part of the substituent) / ml, regardless of temperature change. Make sure they have the same effect It was completed the people.
결국, 본 발명의 주된 목적은 콜레스테롤 과다증의 치료뿐 아니라, 일부 심장계 질환 및 고혈압 등의 예방에도 이용 가능하며 인체에도 안전한 수용성 식품소재로서의 스테롤 치환체의 제조를 위한 스테롤 중간체 화합물을 제공하는 것이다.After all, the main object of the present invention is to provide a sterol intermediate compound for the preparation of a sterol substituent as a water-soluble food material that can be used not only for the treatment of hypercholesterolemia, but also for the prevention of some cardiovascular diseases and hypertension, and also safe for human body.
본 발명에서는 비수용성 스테롤인 피토스테롤에 숙신산 무수물(succinic anhydride) 또는 글루타르산 무수물(glutaric anhydride)을 1:1.0 내지 1:1.3 의 몰비로 첨가하여 톨루엔, 염화메틸렌, 테트라히드로퓨란(tetrahydrofuran), 벤젠 또는 디에틸에테르(diethylether) 등의 비극성 유기용매 내에서 4-디메틸아미노피리딘(DMAP: 4-dimethylaminopyridine), 피리딘 또는 트리에틸아민(TEA: triethylamine)과 같은 염기성 촉매를 이용하여 반응시켜 친수성 고분자 담체에 대해 반응성이 높은 하기 식으로 나타내는 스테롤 중간체 화합물을 수득한다.In the present invention, succinic anhydride or glutaric anhydride is added to phytosterol, a water-insoluble sterol, in a molar ratio of 1: 1.0 to 1: 1.3, toluene, methylene chloride, tetrahydrofuran, benzene. Or a basic catalyst such as 4-dimethylaminopyridine (DMAP: 4-dimethylaminopyridine), pyridine or triethylamine (TEA) in a nonpolar organic solvent such as diethylether to react with a hydrophilic polymer carrier. The sterol intermediate compound represented by the following formula which is highly reactive with respect to is obtained.
상기 식에서,Where
m은 2 또는 3이다.m is 2 or 3.
그런 다음, 친수성 담체와 그에 대해 1 내지 2배의 몰비의 상기에서 제조된 스테롤 중간체 화합물을 염기성 촉매하에 비극성 유기용매 내에서 1,3-디시클로헥실카보디이미드(DCC), 1-에틸-3-(3'-디메틸아미노프로필)카보디이미드(1-ethyl-3-[3'-dimethylaminopropyl]carbodiimide), 옥살릴클로라이드(oxalyl chloride), 카보닐디이미다졸(carbonyl diimidazole), 2-클로로피리디움(2-chloropyridium), 2,2'-디피리딜디설파이드(2,2'-dipyridyl disulfide) 또는 2-이미다조일디설파이드(2-imidazoyl disulfide)와 같은 결합제를 첨가하여 에스테르화 반응시켜 하기 식으로 나타내는 수용성 스테롤 치환체를 제조한다. 이때, 비수용성 스테롤로서 사용하는 피토스테롤은 고등식물에서 발견되는 스테로이드 구조를 갖는 알코올 화합물을 통칭하는 것으로, 전술한 스티그마스테롤(stigmasterol), 스피나스테롤(spinasterol), 캄페스테롤 (campesterol) 및 시토스테롤(sitosterol) 등을 포함하며, 바람직하게는 α, β, γ 타입의 시토스테롤을 포함한다. 또한, 친수성 고분자 담체로서는 폴리에틸렌글리콜(PEG), 잔탄검(xanthan gum), 구아검(guar gum), 소디움 알지네이트, 덱스트린, 올리고당, 키토산 또는 카복시메틸셀룰로스를 사용하며, 특히 폴리에틸렌글리콜은 평균 분자량이 바람직하게는 1,500 내지 4,000, 보다 바람직하게는 2,000 내지 3,000, 가장 바람직하게는 2,000의 것을 이용한다.The hydrophilic carrier and the sterol intermediate compound prepared above at a molar ratio of 1 to 2 times are then subjected to 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3 in a nonpolar organic solvent under a basic catalyst. -(3'-dimethylaminopropyl) carbodiimide (1-ethyl-3- [3'-dimethylaminopropyl] carbodiimide), oxalyl chloride, carbonyl diimidazole, 2-chloropyridium Esterification by addition of a binder such as (2-chloropyridium), 2,2'-dipyridyl disulfide or 2-imidazoyl disulfide The water-soluble sterol substituent shown is manufactured. At this time, the phytosterol used as the water-insoluble sterol is a generic name for the alcohol compound having a steroid structure found in higher plants, the above-described stigmasterol, spinasterol, campesterol and cytosterol And the like, and preferably include α, β, and γ type cytosterols. As the hydrophilic polymer carrier, polyethylene glycol (PEG), xanthan gum, guar gum, sodium alginate, dextrin, oligosaccharide, chitosan or carboxymethyl cellulose are used. Particularly, polyethylene glycol has an average molecular weight. Preferably 1,500 to 4,000, more preferably 2,000 to 3,000, most preferably 2,000.
상기 식에서,Where
R은 -H 또는이고;R is -H or ego;
m은 2 또는 3이며; 및,m is 2 or 3; And,
n은 30 내지 95인 정수이다.n is an integer from 30 to 95.
이하에서는, 본 발명의 식품소재로서의 수용성 스테롤 치환체의 제조방법을, 피토스테롤로서 β-시토스테롤을, 친수성 고분자 담체로서 PEG를 채용한 예를 중심으로 공정별로 나누어, 보다 상세히 설명하고자 한다.Hereinafter, the method for producing a water-soluble sterol substituent as a food material of the present invention will be described in more detail by dividing the process by the step of using β-sitosterol as a phytosterol and PEG as a hydrophilic polymer carrier.
＆제 1공정:＆ 스테롤 중간체(I)의 수득& First step: & Obtaining sterol intermediate (I)
＆제 1-1공정＆: 피토스테롤과 숙신산 무수물의 반응& 1st process-Reaction of phytosterol and succinic anhydride
피토스테롤과 숙신산 무수물의 반응에 의해서 스테롤 중간체(I)을 수득하는 반응은 4-디메틸아미노피리딘(DMAP), 피리딘 또는 트리에틸아민(TEA)와 같은 염기성 촉매를 이용하여 하기의 조건에서 수행된다. 피토스테롤과 숙신산 무수물을 1:1.0 내지 1:1.3의 몰비로, 가장 바람직하게는 1:1.3의 몰비로 첨가하고 톨루엔, 염화메틸렌, 테트라히드로퓨란(tetrahydrofuran), 벤젠 또는 디에틸에테르(diethylether)와 같은 비극성 유기용매에 용해시킨 후, 염기성 촉매를 처리하여 2 내지 30시간, 바람직하게는 4 내지 9시간 동안, 40 내지 150℃, 가장 바람직하게는 사용한 유기용매의 끓는 점으로 가열하여, β-시토스테롤의 -OH 기가 -COOH로 변환되어 반응이 완료되면 유기용매를 휘발시킨다. 남은 고형물을 염화메틸렌에 용해시킨 후, 증류수로 추출한 다음, MgSO4로건조시킨 유기용매 층을 여과하고 냉각하여 미반응 숙신산 무수물을 결정화하여 제거시키고, 유기용매를 증발시켜 스테롤 중간체(I)을 수득한다.The reaction for obtaining the sterol intermediate (I) by the reaction of phytosterol with succinic anhydride is carried out under the following conditions using a basic catalyst such as 4-dimethylaminopyridine (DMAP), pyridine or triethylamine (TEA). Phytosterol and succinic anhydride are added in a molar ratio of 1: 1.0 to 1: 1.3, most preferably in a molar ratio of 1: 1.3, and toluene, methylene chloride, tetrahydrofuran, benzene or diethylether After dissolving in a non-polar organic solvent, the basic catalyst was treated and heated to the boiling point of 40 to 150 DEG C, most preferably the used organic solvent for 2 to 30 hours, preferably 4 to 9 hours, to obtain β-sitosterol. The -OH group is converted to -COOH to volatilize the organic solvent when the reaction is completed. The remaining solid was dissolved in methylene chloride, extracted with distilled water, and then the organic solvent layer dried with MgSO 4 was filtered and cooled to crystallize and remove the unreacted succinic anhydride, and the organic solvent was evaporated to obtain sterol intermediate (I). do.
＆제 1-2공정＆: 피토스테롤과 글루타르산 무수물의 반응& 1st-2nd process &: Reaction of phytosterol and glutaric anhydride
피토스테롤과 글루타르산 무수물의 반응에 의해서 스테롤 중간체(I)을 수득하는 반응은 4-디메틸아미노피리딘(DMAP), 피리딘 또는 트리에틸아민(TEA)와 같은 염기성 촉매를 이용하여 하기의 조건에서 수행된다. 피토스테롤과 글루타르산 무수물을 1:1.0 내지 1:1.3의 몰비로, 가장 바람직하게는 1:1.3의 몰비로 첨가하고 톨루엔, 염화메틸렌, 테트라히드로퓨란(tetrahydrofuran), 벤젠 또는 디에틸에테르(diethylether)와 같은 비극성 유기용매에 용해시킨 후, 염기성 촉매를 처리하여 2 내지 30시간, 바람직하게는 4 내지 12시간 동안, 40 내지 150℃, 가장 바람직하게는 사용한 유기용매의 끓는 점으로 가열하여, β-시토스테롤의 -OH 기가 -COOH로 변환되어 반응이 완료되면 유기용매를 휘발시킨다. 남은 고형물을 염화메틸렌에 용해시킨 후, 증류수로 추출한 다음, MgSO4로건조시킨 유기용매 층을 여과하고 냉각하여 미반응 글루타르산 무수물을 결정화하여 제거시키고, 유기용매를 증발시켜 스테롤 중간체(I)을 수득한다.The reaction for obtaining the sterol intermediate (I) by reaction of phytosterol with glutaric anhydride is carried out under the following conditions using a basic catalyst such as 4-dimethylaminopyridine (DMAP), pyridine or triethylamine (TEA). . Phytosterol and glutaric anhydride are added in a molar ratio of 1: 1.0 to 1: 1.3, most preferably in a molar ratio of 1: 1.3, and toluene, methylene chloride, tetrahydrofuran, benzene or diethylether After dissolving in a non-polar organic solvent such as, the basic catalyst was treated and heated to the boiling point of 40 to 150 ° C., most preferably the used organic solvent for 2 to 30 hours, preferably 4 to 12 hours, and β- The -OH group of the cytosterol is converted to -COOH to volatilize the organic solvent when the reaction is completed. The remaining solid was dissolved in methylene chloride, extracted with distilled water, and then the organic solvent layer dried with MgSO 4 was filtered and cooled to crystallize and remove the unreacted glutaric anhydride, and the organic solvent was evaporated to sterol intermediate (I). To obtain.
＆제 2공정＆: 중간체(I)과 PEG의 결합반응에 의한 수용성 스테롤 치환체(II)의& 2nd process |: of water-soluble sterol substituent (II) by the coupling reaction of intermediate (I) and PEG
제조Produce
제 1공정에서 수득한 비수용성 스테롤 중간체(I)과 친수성 고분자 담체, 바람직하게는 폴리에틸렌글리콜(PEG)을 1:1 내지 2:1의 몰비로 비극성 유기용매에 용해시키고, 실온에서 반응물을 교반하면서 결합제로서 1,3-디시클로헥실카보디이미드(DCC), 1-에틸-3-(3'-디메틸아미노프로필)카보디이미드(1-ethyl-3-[3'-dimethyl -aminopropyl]carbodiimide), 옥살릴클로라이드(oxalyl chloride), 카보닐디이미다졸(carbonyl diimidazole), 2-클로로피리디움(2-chloropyridium), 2,2'-디피리딜디설파이드(2,2'-dipyridyl disulfide) 또는 2-이미다조일디설파이드(2-imidazoyl disulfide)와 염기성 촉매를 첨가하여, 5 내지 15시간 동안 반응을 진행하고, 반응 완료후 반응물을 여과하여 DCC-urea를 제거함으로써 반응을 종료시킨다. 그런 다음, 노르말-헥산(＆n＆-hexane)에 침전시켜 그 침전물을 걸러내고 노르말-헥산으로 충분히 세척하여 수용성 스테롤 치환체(II)를 제조한다.The water-insoluble sterol intermediate (I) obtained in the first step and the hydrophilic polymer carrier, preferably polyethylene glycol (PEG), are dissolved in the nonpolar organic solvent in a molar ratio of 1: 1 to 2: 1, and the reaction is stirred at room temperature. 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (1-ethyl-3- [3'-dimethyl-aminopropyl] carbodiimide) as a binder , Oxalyl chloride, carbonyl diimidazole, 2-chloropyridium, 2,2'-dipyridyl disulfide or 2- The reaction is performed for 5 to 15 hours by adding an imidazoyl disulfide and a basic catalyst. After completion of the reaction, the reaction is filtered to remove DCC-urea to terminate the reaction. Then, precipitate in normal-hexane (& n & -hexane) to filter out the precipitate and wash thoroughly with normal-hexane to prepare a water-soluble sterol substituent (II).
＆수용성 스테롤 치환체(II)＆& Water-soluble sterol substituent (II) &
상기 식에서,Where
R은 -H 또는이고;R is -H or ego;
m은 2 또는 3이며; 및,m is 2 or 3; And,
n은 30 내지 95인 정수이다.n is an integer from 30 to 95.
이하, 실시예에 의하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
＆실시예 1:＆ 스테롤 중간체(I)의 수득& Example 1: Obtaining Sterol Intermediate (I)
＆실시예 1-1:＆& Example 1-1: &
환류관과 Dean-Stark이 부착된 플라스크에서 β-시토스테롤과 숙신산 무수물을 1:1.15의 몰비로 톨루엔에 용해시킨 후, DMAP를 첨가하였다. 9시간 동안 140℃로 가열하며 톨루엔의 환류상태를 유지하고, TLC로 반응의 진행상황을 확인하여 반응이 완료된 후 톨루엔을 휘발시켰다. 고형물을 염화메틸렌에 용해시키고 다시 증발시켜 재결정화함으로써 스테롤 중간체(I)을 수득한 결과, 수율은 70%였다.Β-sitosterol and succinic anhydride were dissolved in toluene in a molar ratio of 1: 1.15 in a flask fitted with a reflux tube and Dean-Stark, and then DMAP was added. The mixture was heated to 140 ° C. for 9 hours to maintain the reflux state of toluene, and toluene was volatilized after completion of the reaction by checking the progress of the reaction by TLC. The solid was dissolved in methylene chloride and evaporated again to recrystallize to afford sterol intermediate (I), with a yield of 70%.
＆실시예 1-2:＆&Amp; Example 1-2: &
β-시토스테롤과 숙신산 무수물을 1:1.20의 몰비로 4시간 동안 반응시키는 것을 제외하고는, 상기 실시예 1-1과 동일한 방법으로 스테롤 중간체(I)을 수득하였으며 수율은 68%였다.A sterol intermediate (I) was obtained in the same manner as in Example 1-1, except that β-sitosterol and succinic anhydride were reacted for 4 hours at a molar ratio of 1: 1.20, and the yield was 68%.
＆실시예 1-3:＆& Example 1-3: &
β-시토스테롤과 글루타르산 무수물을 1:1.20의 몰비로 6시간 동안 반응시키는 것을 제외하고는, 상기 실시예 1-1과 동일한 방법으로 스테롤 중간체(I)을 수득하였으며 수율은 60%였다.A sterol intermediate (I) was obtained in the same manner as in Example 1-1, except that β-sitosterol and glutaric anhydride were reacted for 6 hours at a molar ratio of 1: 1.20, and the yield was 60%.
＆실시예 2:＆ 중간체(I, m=2)와 PEG의 결합반응에 의한 수용성 스테롤 치환체(II)의 제조& Example 2: Preparation of Water-soluble Sterol Substitute (II) by Coupling Reaction of Intermediate (I, m = 2) and PEG
비수용성 스테롤 중간체(I, m=2)와 PEG를 1.5:1의 몰비로 소량의 염화메틸렌에 용해시킨 후, 실온에서 반응물을 교반하면서 결합제로서 DCC와 촉매로서 DMAP를 첨가하였다. 반응의 진행상황을 TLC로 추적하여 10시간이 지나 반응이 완료되면, 반응물을 여과하여 DCC-urea를 제거함으로써 반응을 종료시키고, 여과액을 노르말-헥산에 침전시켰다. 침전물을 여과하여 얻어낸 다음, 노르말-헥산으로 충분히 세척함으로써 최종 생성물인 수용성 스테롤 치환체(II)를 얻고, 전기 물질의 구조를1H-NMR을 통해 확인하였다.The water-insoluble sterol intermediate (I, m = 2) and PEG were dissolved in a small amount of methylene chloride in a molar ratio of 1.5: 1, then DCC as binder and DMAP as catalyst were added while stirring the reaction at room temperature. After the reaction was completed after 10 hours by TLC, the reaction was completed by filtration to remove DCC-urea, and the filtrate was precipitated in normal-hexane. The precipitate was obtained by filtration and then washed thoroughly with normal-hexane to obtain the final product, water-soluble sterol substituent (II), and the structure of the electrical material was confirmed by 1 H-NMR.
＆실시예 3:＆ 수용성 스테롤 치환체(II, m=2) 제조조건의 최적화& Example 3: Optimization of manufacturing conditions of water-soluble sterol substituent (II, m = 2)
＆실시예 3-1:＆ PEG 분자량과 반응성의 관계& Example 3-1: Relationship between PEG molecular weight and reactivity
하기 표 1에 표시된 바와 같이, 스테롤 중간체(I, m=2)와 각각 평균분자량이 다른 PEG를 반응물로 사용하여, 상기 실시예 2에 개시된 방법으로 수용성 스테롤 치환체(II, m=2)를 제조하고, 전기 물질 중의 스테롤의 평균 치환도(DS: degree of substitution)를1H-NMR을 이용하여 측정하였다.As shown in Table 1 below, a sterol intermediate (I, m = 2) and PEG, each having a different average molecular weight, were used as a reactant to prepare a water-soluble sterol substituent (II, m = 2) by the method described in Example 2. In addition, the degree of substitution (DS) of the sterol in the electrical material was measured using 1 H-NMR.
＆[표 1] PEG와 중간체(I)의 반응조건 및 스테롤의 평균 치환도＆& [Table 1] Reaction conditions of PEG and intermediate (I) and average degree of substitution of sterol &
＆*DS(degree of substitution): 수용성 스테롤 치환체(II) 중의 스테롤의 평균 치환도＆& * DS (degree of substitution): Average degree of substitution of sterol in water-soluble sterol substituent (II) &
상기 표 1의 결과에서 보듯이, 수용성 스테롤 치환체(II) 중의 스테롤의 평균 치환도를 통해 확인한 반응성은 PEG의 분자량에 크게 영향을 받지 않음을 알 수 있었다.As shown in the results of Table 1, the reactivity confirmed by the average degree of substitution of the sterol in the water-soluble sterol substituent (II) was found to be not significantly affected by the molecular weight of PEG.
＆실시예 3-2:＆ PEG 분자량과 용해도의 관계& Example 3-2: Relationship between PEG molecular weight and solubility
상기 표 1에 언급된 수용성 스테롤 치환체(II)의 용해도는 각 농도의 시료를 각각의 온도에서 2일간 방치하는 방법으로 조사하였다.The solubility of the water-soluble sterol substituent (II) mentioned in Table 1 above was examined by the method of leaving the samples at each concentration for 2 days at each temperature.
＆[표 2] PEG의 분자량에 따른 수용성 스테롤 치환체(II)의 용해도＆& [Table 2] Solubility of water-soluble sterol substituent (II) according to molecular weight of PEG &
＆*DS(degree of substitution): 수용성 스테롤 치환체(II) 중의 스테롤의 평균 치환도 ＆& * DS (degree of substitution): Average substitution degree of sterol in water-soluble sterol substituent (II)
＆**수율 = 수용성 스테롤 치환체(II)의 몰수 / PEG의 몰수＆& ** Yield = number of moles of water-soluble sterol substituent (II) / number of moles of PEG &
상기 표 2에서 보듯이, 분자량 1,000인 PEG를 이용하여 제조된 스테롤 치환체(II)는 거의 물에 용해되지 않았으며, 분자량 2,000의 PEG로 제조된 스테롤 치환체(II)와 분자량 4,000의 PEG로 제조된 치환체(II)를 서로 비교한 경우 스테롤 치환체(II) 기준으로는 분자량 4,000의 경우에 더 높은 농도까지 용해되었다. 그러나, 스테롤 잔기 기준으로 용해도를 환산한다면 분자량 2,000의 경우의 용해도가 더 우수하므로, 이후의 실시예에서는 담체로서의 PEG의 분자량을 2,000으로 고정하였다.As shown in Table 2, the sterol substituent (II) prepared using PEG with a molecular weight of 1,000 was hardly dissolved in water, and the sterol substituent (II) prepared with PEG having a molecular weight of 2,000 and a PEG having a molecular weight of 4,000. When the substituents (II) were compared with each other, the sterol substituents (II) were dissolved up to a higher concentration for the molecular weight of 4,000. However, the solubility of the molecular weight of 2,000 is better if the solubility is converted based on the sterol residue, so that the molecular weight of PEG as a carrier is fixed to 2,000 in the following examples.
＆실시예 3-3＆: 결합반응의 규모확대에 따른 평균치환도의 변화 측정& Example 3-3 & Measurement of change in average substitution degree due to scale-up of binding reaction
담체로서 사용하는 PEG의 분자량을 2,000으로 고정하고, 상기 실시예 2에 개시된 방법으로 결합반응 규모만을 확대하여, 평균 치환도가 다른 여러종류의 수용성 스테롤 치환체(II)-1,-2,-3,-4를 제조한 다음, 그 합성 결과를 표 3에 정리하였다.The molecular weight of PEG used as a carrier was fixed at 2,000, and the binding reaction scale was expanded by the method described in Example 2, and various kinds of water-soluble sterol substituents (II) -1, -2, -3 having different average substitution degrees , -4 was prepared, and the synthesis results thereof are summarized in Table 3.
＆[표 3] 결합반응의 규모확대에 따른 평균치환도의 변화＆& [Table 3] Change in average substitution degree due to scale-up of binding reaction
＆*DS(degree of substitution): 수용성 스테롤 치환체(II) 중의 스테롤의 평균 치환도＆& * DS (degree of substitution): Average degree of substitution of sterol in water-soluble sterol substituent (II) &
＆**수율 = 수용성 스테롤 치환체(II)의 몰수 / PEG의 몰수＆& ** Yield = number of moles of water-soluble sterol substituent (II) / number of moles of PEG &
상기 표 3에서 알 수 있듯이, 반응 규모확대에 의해 제조되는 수용성 스테롤 치환체(II)의 DS 값은 약간 변화되나, 규모, 반응물의 몰비 및 반응 시간을 일정하게 유지하면 DS 값을 거의 일정하게 유지할 수 있는 것으로 사료되었다.As can be seen in Table 3, the DS value of the water-soluble sterol substituent (II) prepared by the expansion of the reaction is slightly changed, but if the scale, the molar ratio of the reactants and the reaction time are kept constant, the DS value can be kept almost constant. It was considered to be present.
＆실시예 4＆: 수용성 스테롤 치환체(II)의 온도에 따른 용해도 측정& Example 4 & solubility measurement according to the temperature of the water-soluble sterol substituent (II)
본 발명에 의해 제조된 수용성 스테롤 치환체는 식음료에 첨가될 수 있어야 하므로, 일반적 식음료가 냉장상태로 판매된다는 점을 고려하여, 온도변화에 따른 수용성 치환체(II)의 용해도의 변화를 조사하였다.Since the water-soluble sterol substituent prepared by the present invention should be able to be added to food and beverage, the change in solubility of the water-soluble substituent (II) was investigated in accordance with the temperature change in consideration of the fact that general food and beverage is sold in a refrigerated state.
실시예 3-3에서 제조한 수용성 스테롤 치환체(II)-1,-2,-3,-4를 이용해 온도에 따른 용해도를 측정한 결과, 용해도는 일반적으로 소비되는 음료수 1캔 (250ml)에 콜레스테롤을 저하시키는 효과가 있다고 FDA에서 인정한 성인의 1일 섭취량인 2.7g의 스테롤이 포함된 농도인 10mg(수용성 스테롤 치환체(II) 중의 스테롤 부분 무게)/ ml (1 wt%에 해당) 이상에서 충분히 가용이며, 또한 온도의 변화에 따른 용해도의 변화도 적은 것을 확인할 수 있었다(참조: 표 4).As a result of measuring the solubility with temperature using the water-soluble sterol substituent (II) -1, -2, -3, -4 prepared in Example 3-3, the solubility is generally cholesterol in 1 can (250 ml) Sufficiently available at or above 10 mg (partial weight of sterol in water-soluble sterol substituents) / ml (corresponding to 1 wt%), which contains 2.7 g of sterol, the daily intake of adults recognized by the FDA as being effective in lowering In addition, it was confirmed that the change of solubility with the change of temperature was also small (see Table 4).
＆[표 4] 수용성 스테롤 치환체(II)의 물에 대한 용해도＆& [Table 4] Solubility & solubility in water of water-soluble sterol substituent (II)
＆*DS(degree of substitution): 스테롤 치환체 중의 스테롤의 평균 치환도＆& * DS (degree of substitution): Average degree of substitution of sterol in sterol substituent &
＆**농도(wt%) = ( 스테롤 치환체(II)의 g수 / 물의 g수 ) X 100＆& ** Concentration (wt%) = (g number of sterol substituents (II) / g number of water) X 100 &
＆실시예 5＆: 동물 실험을 통한 콜레스테롤 저하 효과의 확인& Example 5 & Confirmation of cholesterol lowering effect through animal experiment
건강한 SD(Sprague-Dawley) 웅성 랫트를 3주 동안 안정화시킨 후, 각 실험군당 4마리의 랫트에게14C-콜레스테롤과 상기 실시예 4의 스테롤 치환체(II)-3를 동시에 3일간 경구 투여하였다.14C-콜레스테롤의 투여량은 하루 0.004 mg (1 X 10-8moles)을 0.5 ml의 옥수수유에 분산시켜 투여하고, 실험군으로는14C-콜레스테롤 투여량의 2배 몰수(2 X 10-8moles)와 15mg의 콜레스테롤에 해당하는 몰수(3.9 X 10-5moles)의 스테롤 치환체(II)-3 수용액을 투여한 것(각각 2군, 3군)과 대조군으로는14C-콜레스테롤만 투여한 것(1군: (-)대조군),14C-콜레스테롤과 함께 피토스테롤을 투여한 것(4군: (+)대조군)을 사용하였다(참조: 표 5).After stabilizing healthy SD (Sprague-Dawley) male rats for three weeks, four rats of each experimental group were orally administered 14 C-cholesterol and the sterol substituent (II) -3 of Example 4 simultaneously for three days. The dose of 14 C-cholesterol was administered by dispersing 0.004 mg (1 X 10 -8 moles) in 0.5 ml of corn oil per day, and in the experimental group, 2 moles (2 X 10 -8 moles) of the 14 C-cholesterol dose. ) And an aqueous solution of sterol substituent (II) -3 in moles (3.9 X 10 -5 moles) corresponding to 15 mg of cholesterol (groups 2 and 3, respectively) and 14 C-cholesterol as a control group. (Group 1: (-) control), the administration of phytosterol with 14 C-cholesterol (Group 4: (+) control) was used (see Table 5).
＆[표 5] 수용성 스테롤 및 피토스테롤의 투여 방법 및 양＆& [Table 5] Administration method and amount of water-soluble sterol and phytosterol
상기의 시료를 3일간 투여한 후, 랫트의 심장으로부터 6 ml의 혈액을 채취하여 3 ml씩 2개로 나누어 각 군당 8개의 표본을 만든 다음, 각각 2 ml의 섬광계측 용액을 혼합하여14C-콜레스테롤의 양을 측정하고, 그 최대치와 최소치를 제외한 6개의 표본수의 평균값과 표준편차를 계산하였다.After administering the sample for 3 days, 6 ml of blood was collected from the rat's heart, divided into 2 each of 3 ml to make 8 samples for each group, and then mixed with 2 ml of scintillation measurement solution and 14 C-cholesterol. The average and standard deviation of the six samples, except for the maximum and minimum values, were calculated.
＆[표 6] 투여 3일 후 각 군의 ＆＆14＆＆C-콜레스테롤의 평균 값 (단위: dpm)＆& [Table 6] Average value of && 14 && C-cholesterol of each group 3 days after administration (unit: dpm) &
＆* ＆＆＆P＆＆＆〈0.01 vs 1군＆& * &&& P &&& <0.01 vs one group &
상기 표 6에서 보듯이, 콜레스테롤 15mg에 해당하는 몰수의 수용성 스테롤 치환체(II)-3를 콜레스테롤과 함께 투여한 3군에서의14C-콜레스테롤 양은 274.7±55.3으로, 콜레스테롤만 투여한 1군((-)대조군)의 460.6±154.9에 비해서 현저하게 저하되는 것을 알 수 있었으며, 콜레스테롤 15mg에 해당하는 몰수의 피토스테롤을 콜레스테롤과 함께 투여한 4군((+)대조군)에서 측정된14C-콜레스테롤의 양 (258.9±33.2)과 비교하여도 그 콜레스테롤 저하 효과가 거의 동일하였다. 즉, 피토스테롤을 수용성 고분자인 PEG에 결합시킨 스테롤 치환체(II)는 피토스테롤과 동등한 콜레스테롤 저하효과를 지니고 있으며, 피토스테롤의 용도 개발에 가장 큰 장애요인으로 작용한 비수용성을 완전히 개선한 것이라 사료되었다.As shown in Table 6 above, the amount of 14 C-cholesterol in group 3 administered with cholesterol plus a mole of water-soluble sterol substituent (II) -3 corresponding to 15 mg of cholesterol was 274.7 ± 55.3. -) Significantly lower than 460.6 ± 154.9 of the control group, and the amount of 14 C-cholesterol measured in the 4 group ((+) control group) in which a mole of phytosterol equivalent to 15 mg of cholesterol was administered together with cholesterol. Compared with (258.9 ± 33.2), the cholesterol lowering effect was almost the same. In other words, the sterol substituent (II) incorporating phytosterol to PEG, which is a water-soluble polymer, has the same cholesterol lowering effect as phytosterol, and is thought to have completely improved the water-insoluble property which acted as the biggest obstacle to the development of phytosterol.
이상에서 상세히 설명하고 입증하였듯이, 본 발명은 콜레스테롤 저하 효과를 갖는 수용성 스테롤 치환체 제조를 위한 스테롤 중간체 화합물을 제공한다. 본 발명의 스테롤 중간체는 종래의 지용성 피토스테롤과는 달리 물에 쉽게 용해될 뿐만 아니라, 인체에 해로운 LDL-콜레스테롤의 흡수를 감소시켜 혈중 콜레스테롤치를 저하시키는 반면, 종래의 콜레스테롤 저하제 등의 약품복용시 유발되는 간 기능 장애 등의 부작용이 전혀 수반되지 않는 수용성 스테롤 치환체의 제조에 널리 사용될 수 있다.As described and demonstrated in detail above, the present invention provides a sterol intermediate compound for preparing a water-soluble sterol substituent having a cholesterol lowering effect. Unlike the conventional fat-soluble phytosterol, the sterol intermediate of the present invention not only dissolves easily in water, but also reduces absorption of LDL-cholesterol, which is harmful to the human body, and lowers blood cholesterol levels. It can be widely used in the preparation of water-soluble sterol substituents that do not involve any side effects such as liver dysfunction.
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| AU29466/00A AU2946600A (en) | 1999-03-04 | 2000-03-03 | Water-soluble sterol derivative for inhibiting cholesterol absorption and process for preparing the same |
| PCT/KR2000/000170 WO2000052029A1 (en) | 1999-03-04 | 2000-03-03 | Water-soluble sterol derivative for inhibiting cholesterol absorption and process for preparing the same |
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