KR101101011B1 - A composition comprising novel +-decursin-structural isomer synthesis derivative for treating and preventing atopic dermatitis disease - Google Patents
A composition comprising novel +-decursin-structural isomer synthesis derivative for treating and preventing atopic dermatitis disease Download PDFInfo
- Publication number
- KR101101011B1 KR101101011B1 KR1020090035688A KR20090035688A KR101101011B1 KR 101101011 B1 KR101101011 B1 KR 101101011B1 KR 1020090035688 A KR1020090035688 A KR 1020090035688A KR 20090035688 A KR20090035688 A KR 20090035688A KR 101101011 B1 KR101101011 B1 KR 101101011B1
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- KR
- South Korea
- Prior art keywords
- group
- dimethyl
- substituent
- substituted
- hydroxy
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- 201000008937 atopic dermatitis Diseases 0.000 title claims abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 14
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)의 구조이성체인 (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린((8s)-8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin)과 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노[3,2-f]쿠마린((6s)-6-hydroxy-7,7-dimethyl-5,6-dihydropyrano[3,2-f]coumarin)을 제조 및 합성한 후 이를 다시 전구체로 한 신규 구조의 (+)-데쿠르신-구조이성체 합성 유도체 화합물들은 EoL-1 세포에서 진드기에 의해 유도된 아토피성 피부염증 반응을 나타내는 MCP-1, IL-6 및 IL-8의 분비량을 효과적으로 억제함을 확인함으로써, 이를 포함하는 조성물은 아토피성 피부염 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품으로 유용하게 이용될 수 있다.The present invention relates to (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano, which is a structural isomer of (+)-decursinol isolated from Angelica gigas [2,3- g] coumarin ((8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin) and (6s) -6-hydroxy-7,7-dimethyl-5, 6-dihydropyrano [3,2-f] coumarin ((6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin) was prepared and synthesized. Newly constructed (+)-decursin-structural isomeric derivative compounds, which are precursors, secrete MCP-1, IL-6 and IL-8, which show an atopic dermatitis response induced by ticks in EoL-1 cells. By effectively inhibiting the composition, the composition comprising the same can be usefully used as a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis diseases.
참당귀, (+)-데쿠르시놀(decursinol), 아토피성 피부염 Angelica gigas, (+)-decursinol, atopic dermatitis
Description
본 발명은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)의 구조이성체인 (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린((8s)-8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin)과 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노[3,2-f]쿠마린((6s)-6-hydroxy-7,7-dimethyl-5,6-dihydropyrano[3,2-f]coumarin)을 제조 및 합성한 후 이를 다시 전구체로 한 신규 구조의 (+)-데쿠르신-구조이성체 합성 유도체 화합물들을 유효성분으로 포함하는 조성물에 관한 것이다. The present invention relates to (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano, which is a structural isomer of (+)-decursinol isolated from Angelica gigas [2,3- g] coumarin ((8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin) and (6s) -6-hydroxy-7,7-dimethyl-5, 6-dihydropyrano [3,2-f] coumarin ((6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin) was prepared and synthesized. The present invention relates to a composition comprising, as an active ingredient, (+)-decurin-structure isomer derivative compounds having a novel structure as precursors.
[문헌 1] Hanifin JM et al., Guidelines of care for atopic dermatitis. J. Am Acad. Dermatol., 50, pp391-404, 2004.[1] Hanifin JM et al., Guidelines of care for atopic dermatitis. J. Am Acad. Dermatol., 50, pp 391-404, 2004.
[문헌 2] Williams HC., Clinical practice. Atopic dermatitis. N. Engl. J. Med., 352, pp2314-24, 2005.[2] Williams HC., Clinical practice. Atopic dermatitis. N. Engl. J. Med., 352 , pp 2314-24, 2005.
[문헌 3] Oh JW et al., Nationwide study for epidemiological change of atopic dermatitis in school aged children between 1995 and 2000 and kindergarten aged children in 2003 in Korea, Pediatr. Allergy Respir. Dis., 13, pp227-237, 2003.Oh JW et al., Nationwide study for epidemiological change of atopic dermatitis in school aged children between 1995 and 2000 and kindergarten aged children in 2003 in Korea, Pediatr. Allergy Respir. Dis., 13 , pp 227-237, 2003.
[문헌 4] Colloff MJ., Exposure to house dust mites in homes of people with atopic dermatitis. Br. J. Dermatol., 127, pp322-327, 1992.Colloff MJ., Exposure to house dust mites in homes of people with atopic dermatitis. Br. J. Dermatol., 127 , pp 322-327, 1992.
[문헌 5] Jeon SY et al., Correlation between house dust mite allergen concentrations in scalp dander and clinical severity of atopic dermatitis in children. Pediatr. Allergy Respir. Dis., 9, pp32-40, 1999.Jeon SY et al., Correlation between house dust mite allergen concentrations in scalp dander and clinical severity of atopic dermatitis in children. Pediatr. Allergy Respir. Dis., 9 , pp 32-40, 1999.
[문헌 6] Kino T et al., Tissue-specific glucocorticoid resistance hypersensitivity syndromes: multifactorial states of clinical importance. J. Allergy Clin. Immunol., 109, pp609-613, 2002.Kino T et al., Tissue-specific glucocorticoid resistance hypersensitivity syndromes: multifactorial states of clinical importance. J. Allergy Clin. Immunol., 109 , pp 609-613, 2002.
[문헌 7] Lu B et al., Abnorm alities in monocyte recruitment and cytokine expression in monocyt e chemoattractant protein 1- deficient mice. J. Exp. Med., 187, pp601-608, 1998.Lu B et al., Abnorm alities in monocyte recruitment and cytokine expression in monocyt e chemoattractant protein 1-deficient mice. J. Exp. Med., 187 , pp 601-608, 1998.
[문헌 8] Karpus WJ et al., MIP-1 alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1/Th2 lymphocyte differentiation. J. Leukoc. Biol., 62, pp681-687, 1997.Karpus WJ et al., MIP-1 alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1 / Th2 lymphocyte differentiation. J. Leukoc. Biol., 62 , pp 681-687, 1997.
[문헌 9] Harada A et al., Essential involvement of interleukin-8 (IL-8) in acute inflammation. J, Leukoc, Biol,, 56, pp559-564, 1994.9 Harada A et al., Essential involvement of interleukin-8 (IL-8) in acute inflammation. J, Leukoc, Biol ,, 56 , pp 559-564, 1994.
[문헌 10] Fujimura M et al., Role of leukotriene B4 in bronchial hyperresponsiveness induced by interleukin 8. Eur. Respir. J., 11, pp306-311, 1998 [10] Fujimura M et al., Role of leukotriene B4 in bronchial hyperresponsiveness induced by interleukin 8. Eur. Respir. J., 11 , pp306-311, 1998
[문헌 11] Kurashima K et al., Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks. J. Leukoc. Biol., 59, pp313-316, 1996Kurashima K et al., Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks. J. Leukoc. Biol., 59 , pp313-316, 1996
[문헌 12] Chi, H. J and Kim H. S. : Studies on the components of Umbelliferae Plants in Korea. Kor. J. Pharmacogn., 1, pp.25, 1970.12, Chi, H. J and Kim HS: Studies on the components of Umbelliferae Plants in Korea. Kor. J. Pharmacogn ., 1 , pp. 25, 1970.
[문헌 13] Bae, E. A. et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull. 21, pp.990, 1998.[13] Bae, EA et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull . 21 , pp. 990, 1998.
[문헌 14] Kim J. H et al., Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-k B activation in macrophages. Molecular Pharmacology, 69(6), pp1783-1790, 2006.Kim J. H et al., Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-k B activation in macrophages. Molecular Pharmacology, 69 (6) , pp 1783-1790, 2006.
[문헌 15] 한국등록특허 : 10-2007-18057 [Document 15] Korean Registered Patent: 10-2007-18057
아토피성 피부염은 소양증, 건조증, 습진성 병변, 그리고 각질 등이 특징으로 만성 재발성 결과를 보이는 만성염증성 피부질환이다(Hanifin JM et al., Guidelines of care for atopic dermatitis. J. Am Acad. Dermatol., 50, pp391-404, 2004). 최근 우리나라를 포함하여 세계적으로 아토피성 피부염의 발병률이 급격하게 증가하고 있는 추세이나, 아직 근본적으로 질병의 경과를 바꿀 수 있는 치료법이 개발되지 못하여 대중적인 약물 치료만이 시행되고 있는 상태이다(Williams HC., Clinical practice. Atopic dermatitis. N. Engl. J. Med., 352, pp2314-24, 2005). Atopic dermatitis is a chronic inflammatory skin disease with chronic recurrences, characterized by pruritus, dryness, eczema, and keratin (Hanifin JM et al., Guidelines of care for atopic dermatitis. J. Am Acad. Dermatol. , 50, pp 391-404, 2004). Recently, the incidence of atopic dermatitis has been increasing rapidly in Korea and around the world. However, only the most popular drug treatments have been carried out since no treatment has been developed to fundamentally change the course of the disease (Williams HC). ., Clinical practice.Atopic dermatitis.N. Engl. J. Med., 352 , pp2314-24, 2005).
아토피성 피부염의 병인기전은 아직 완전하게 밝혀지지 않았지만 환경 내에 흔한 물질(알레르겐)에 대한 과민한 면역반응(알레르기반응)으로 피부에 만성적인 염증반응을 유발시켜 아토피성 피부염이 발생하는 것으로 알려져 왔다(Oh JW et al., Nationwide study for epidemiological change of atopic dermatitis in school aged children between 1995 and 2000 and kindergarten aged children in 2003 in Korea. Pediatr. Allergy Respir. Dis., 13, pp227-237, 2003). 특히 그 근거로 집먼지 진드기에 노출된 양에 비례하여 아토피성 피부염의 발병 빈도 (Colloff MJ., Exposure to house dust mites in homes of people with atopic dermatitis. Br. J. Dermatol., 127, pp322-327, 1992)과 아토피성 피부염의 중증도간의 유의한 상관성을 들 수 있다(Jeon SY et al., Correlation between house dust mite allergen concentrations in scalp dander and clinical severity of atopic dermatitis in children. Pediatr. Allergy Respir. Dis., 9, pp32-40, 1999). 또한 환경 내에서 집먼지 진드기에 대한 노출을 줄임으로써 아토피성 피부염의 중증도를 감소시킬 수 있다고 알려져 있다. The pathogenesis of atopic dermatitis is not yet fully understood, but it has been known that atopic dermatitis is caused by a chronic inflammatory response to the skin due to a sensitive immune response (allergic reaction) to a substance (allergen) common in the environment ( Oh JW et al., Nationwide study for epidemiological change of atopic dermatitis in school aged children between 1995 and 2000 and kindergarten aged children in 2003 in Korea.Pediatr.Allergy Respir.Dis ., 13 , pp227-237, 2003). In particular, the incidence of atopic dermatitis in proportion to the amount exposed to house dust mites (Colloff MJ., Exposure to house dust mites in homes of people with atopic dermatitis.Br . J. Dermatol., 127 , pp322-327, (1992) and significant severity of atopic dermatitis (Jeon SY et al., Correlation between house dust mite allergen concentrations in scalp dander and clinical severity of atopic dermatitis in children.Peatr . Allergy Respir. Dis., 9 , pp 32-40, 1999). It is also known to reduce the severity of atopic dermatitis by reducing exposure to house dust mites in the environment.
스테로이드는 기관지천식 등의 염증성 질환에서 가장 널리 사용되는 효과적인 치료제이다. 최근 스테로이드에 대한 기전이 많이 밝혀지고 있으나, 아직은 그 기전을 완전히 이해하지 못한 상태이며 기관지 천식이나 류마티스 관절염 등의 환자들 중 일부는 스테로이드에 반응하지 않는 스테로이드 저항성을 보인다. 이러한 스테로이드 저항성을 보이는 환자들이 많지는 않으나 대개가 중증이고, 치료에 의한 합병증에 시달리며 치료비도 많이 들어 스테로이드 저항성의 기전을 밝히는 것은 조속히 해결해야 할 숙제이다(Kino T et al., Tissue-specific glucocorticoid resistance hypersensitivity syndromes: multifactorial states of clinical importance. J. Allergy Clin. Immunol., 109, pp609-613, 2002). Steroids are the most widely used and effective treatments for inflammatory diseases such as bronchial asthma. Recently, many mechanisms for steroids have been elucidated, but the mechanisms have not yet been fully understood, and some patients with bronchial asthma or rheumatoid arthritis show steroid resistance that does not respond to steroids. Although there are not many patients showing this steroid resistance, it is usually a serious problem, a complication caused by treatment, and a high cost of treatment, and it is a task to identify the mechanism of steroid resistance as soon as possible (Kino T et al., Tissue-specific glucocorticoid resistance). hypersensitivity syndromes: multifactorial states of clinical importance.J. Allergy Clin.Imunmun ., 109 , pp 609-613, 2002).
만성 염증성 반응에서는 많은 세포를 통해 섬유화에 관련된 종양성장인자(Tumor growth factor-β, TGF-β), IL-4 및 IL-13 등의 다양한 사이토카인이 분비된다. 사이토카인은 섬유모세포(fibroblast)를 활성화시키는 IL-6의 분비를 증가시킴으로써 많은 섬유모세포의 분화 및 증식을 일으키고 세포외기질(extra cellular matrix)을 과생산하여 세포 및 조직의 변형과 섬유화를 야기시킨다. In chronic inflammatory reactions, many cells secrete various cytokines such as tumor growth factor-β (TGF-β), IL-4 and IL-13, which are involved in fibrosis. Cytokines increase the secretion of IL-6, which activates fibroblasts, resulting in differentiation and proliferation of many fibroblasts and overproduction of extracellular matrix, resulting in cell and tissue deformation and fibrosis .
아토피 피부염이 스테로이드 계통의 약제를 통해 치료가 되나, 만성화되면서 위와 같은 조직의 변형 및 섬유화로 인해 스테로이드 제재에 대한 내성을 보이게 하는 이유이다. 단핵구 화학유인물질 단백질-1(Monocyte Chemoattractant Protein-1;이하MCP-1)은 케모카인 수용체(Chemokine receptor;이하CCR2)에 결합하며, MCP-1유전자가 제거된 생쥐는 단핵구(monocytes)에 대한 화학주성이 손상을 받고 특정 균의 감염에 대하여 저항성이 약화되는것이 관찰되었으며(Lu B et al., Abnorm alities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J. Exp. Med., 187, pp601-608, 1998), 이러한 현상은 CCR2 유전자가 제거된 동물에서 관찰되는 증상과 유사하였다. 이 밖에도 MCP-1은 시험관에서 헬퍼T전구세포(Th0 cells)를 헬퍼T세포 싸이토카인(Th2 cytokines)을 분비하는 세포로 전환시킨다는 보고가 있다(Karpus WJ et al., MIP-1 alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1/Th2 lymphocyte differentiation. J. Leukoc. Biol., 62, pp681-687, 1997). 그리고 MCP-1을 정맥주사 하였을 때 IL-12의 생성은 감소되고 IL-4의 생성이 증가한다. 이는 간접적으로 IgE-의존적 알레르기 염증을 악화시킬 수 있음을 의미한다. Atopic dermatitis is treated with steroid-based drugs, but as it becomes chronic, it is a reason to show resistance to steroid agents due to the deformation and fibrosis of the above tissues. Monocyte Chemoattractant Protein-1 (MCP-1) binds to the chemokine receptor (CCR2), and mice with the MCP-1 gene removed are chemotactic for monocytes. This damage and weakened resistance to infection of certain bacteria were observed (Lu B et al., Abnorm alities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J. Exp. Med., 187 , pp601-608, 1998), this phenomenon was similar to the symptoms observed in animals with the CCR2 gene removed. In addition, MCP-1 has been reported to convert helper T progenitor cells (Th0 cells) into cells that secrete helper T cell cytokines (Karpus WJ et al., MIP-1 alpha and MCP-1) in vitro. differentially regulate acute and relapsing autoimmune encephalomy elitis asell as Th1 / Th2 lymphocyte differentiation.J. Leukoc. Biol., 62 , pp681-687, 1997). Intravenous injection of MCP-1 decreased IL-12 production and increased IL-4 production. This indirectly means that IgE-dependent allergic inflammation can be exacerbated.
초기염증반응에 중요한 IL-8은 기도상피세포에서 분비되는 중요한 염증성 케모카인으로써(Harada A et al., Essential involvement of interleukin-8 (IL-8) in acute inflammation. J, Leukoc, Biol,, 56, pp559-564, 1994), IL-8에 의해 기관지과민성이 유발되고 알레르기비염이나 기관지천식 질환에서 증가되어 나타나며(Fujimura M et al., Role of leukotriene B4 in bronchial hyperresponsiveness induced by interleukin 8. Eur. Respir. J., 11, pp306-311, 1998 ; Kurashima K et al., Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks. J. Leukoc. Biol., 59, pp313-316, 1996) 스테로이드에 의해 억제된다. IL-8, which is important for early inflammatory responses, is an important inflammatory chemokine secreted from airway epithelial cells (Harada A et al., Essential involvement of interleukin-8 (IL-8) in acute inflammation. J, Leukoc, Biol ,, 56 , pp559-564, 1994), induced bronchial hypersensitivity by IL-8 and increased in allergic rhinitis or bronchial asthma disease (Fujimura M et al., Role of leukotriene B4 in bronchial hyperresponsiveness induced by interleukin 8. Eur.Respir. J., 11 , pp306-311, 1998; Kurashima K et al., Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks.J. Leukoc. Biol., 59 , pp313-316, 1996) .
(+)-데쿠르신(decursin)은 참당귀에서 분리된 물질로써 최근에 항암활성을 비롯하여 여러 가지 활성을 나타내어 주목 받고 있는 물질이다. (+)-Decursin (decursin) is a substance that has been attracting attention since it exhibits various activities including anticancer activity recently.
참당귀(Angelica gigas)는 미나리과(umbelliferae)의 식물로써 한국산 당귀를 말하며, 어린순은 나물로 식용하고 뿌리는 진통효과, 신장독성 경감효과, 당뇨성 고혈압 치료 등 여러 가지 질환에 대한 약제로 사용하고 있다(Chi, H. J and Kim H. S. : Studies on the components of Umbelliferae Plants in Korea. Kor. J. Pharmacogn., 1, pp.25, 1970). 이러한 여러 가지 활성을 나타내는 주요한 성분은 디하이드로피라노쿠마린(dihydropyranocoumarin) 계열의 물질인 (+)-데쿠르신(decursin), (+)-데쿠르시놀 안젤레이트(decursinol angelate)와 같이 (+)-데쿠르시놀(decursinol)[7-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrano (3,2-g)chromen-2-one]의 2차 알코올(secondary alcohol)기가 에스터화된 물질들이다(Bae, E. A. et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull. 21, pp.990, 1998). Angelica gigas is an umbelliferae plant and refers to Korean donkeys. Young shoots are used as medicinal agents for various diseases such as edible and rooted analgesic effect, relieving kidney toxicity, and treating diabetic hypertension. (Chi, H. J and Kim HS: Studies on the components of Umbelliferae Plants in Korea.Kor . J. Pharmacogn ., 1 , pp. 25, 1970). The main components exhibiting these different activities are (+)-such as (+)-decursin and (+)-decursinol angelate, which are dihydropyranocoumarin-based substances. Secondary alcohol group esters of decursinol [7-hydroxy-8,8-dimethyl-7,8-dihydro- 6H- pyrano (3,2-g) chromen-2-one] (Bae, EA et al., Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull . 21 , pp. 990, 1998).
최근에는 (+)-데쿠르신이 염증반응을 매개하는 세포인 대식세포(macrophage)에서 NF-kB를 억제함으로써 염증반응을 유도하는 싸이토카인인 IL-8, MCP-1, TNF-a을 억제한다고 밝혀진 바 있다(Kim J. H et al., Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-k B activation in macrophages. Molecular Pharmacology, 69(6), pp1783-1790, 2006). Recently, (+)-decursin has been shown to inhibit IL-8, MCP-1, and TNF-a, which are cytokines that induce inflammatory responses by inhibiting NF-kB in macrophage, an inflammatory mediator. Kim J. H et al., Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-k B activation in macrophages.Molecular Pharmacology, 69 (6) , pp 1783-1790, 2006).
또한, 본 발명자에 의해 (+)-데쿠르시놀(decursinol)을 출발물질로 하여 당귀에 존재하지 않는 다양한 구조의 에스터(ester) 형태의 새로운 (+)-데쿠르신(decusrin) 유도체들을 합성하고 그들의 항아토피효과를 측정한 결과, 우수한 아토피 억제 효과를 확인함으로써 아토피성 피부염 치료제로 사용 가능성을 확인하여 특허결정을 통고받은 바 있다(한국등록특허 : 10-2007-18057).In addition, the inventors have synthesized novel (+)-decusrin derivatives of ester forms of various structures that do not exist in Angelica vulgaris using (+)-decursinol as a starting material and their As a result of measuring the anti-atopic effect, it was confirmed that the use as atopic dermatitis treatment by confirming the excellent atopic inhibitory effect has been notified a patent decision (Korea Patent Registration: 10-2007-18057).
따라서 본 발명자는 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)의 구조이성체인 (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린((8s)-8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin)과 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노[3,2-f]쿠마린((6s)-6-hydroxy-7,7-dimethyl-5,6-dihydropyrano[3,2-f]coumarin)을 제조 및 합성한 후 이를 다시 전구체로 한 신규 구조의 (+)-데쿠르신-구조이성체 합성 유도체 화합물들은 EoL-1 세포에서 진드기에 의해 유도된 아토피성 피부염증 반응을 나타내는 MCP-1, IL-6 및 IL-8의 분비량을 측정한 결과, 탁월한 아토피 억제 효과를 확인함으로써 본 발명을 완성하게 되었다.Thus, the present inventors found that (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3], which is a structural isomer of (+)-decursinol isolated from Angelica gigas -g] coumarin ((8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin) and (6s) -6-hydroxy-7,7-dimethyl-5 , 6-6-dihydropyrano [3,2-f] coumarin ((6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin) was prepared and synthesized. The novel (+)-decursin-structure isomer derivative compounds, which are used as precursors, of MCP-1, IL-6 and IL-8 exhibiting atopic dermatitis response induced by ticks in EoL-1 cells. As a result of measuring the amount of secretion, the present invention was completed by confirming an excellent atopy inhibitory effect.
상기 목적을 달성하기 위하여, (+)-데쿠르시놀의 구조이성체를 전구체로 하여 합성된 하기 일반식 (I)로 표기되는 신규 구조의 (+)-데쿠르신-구조이성체 합성 유도체(decursin-structural isomer synthesis derivative) 화합물 또는 이의 약학 적으로 허용가능한 염:In order to achieve the above object, a (+)-decursin-structural isomer synthetic derivative of a novel structure represented by the following general formula (I) synthesized using the structural isomer of (+)-decursinol as a precursor (decursin-structural isomer synthesis derivative) or a pharmaceutically acceptable salt thereof:
상기식에서,In this formula,
R1은 하나이상의 R′로 치환되거나 비치환된 C1 내지 C20 알킬기, C2 내지 C20 알켄일기, C2 내지 C20 알키닐기 및 A 치환기로 구성되는 군으로부터 선택된 하나이상의 치환기이며, 여기에서 R′는 할로겐원자, 니트로기, 아민기 또는 C1 내지 C4 저급 알킬기로부터 선택된 치환기이고;R 1 is one or more substituents selected from the group consisting of C 1 to C 20 alkyl groups, C 2 to C 20 alkenyl groups, C 2 to C 20 alkynyl groups and A substituents unsubstituted or substituted with one or more R ′, wherein R ′ is a substituent selected from a halogen atom, a nitro group, an amine group or a C 1 to C 4 lower alkyl group;
여기에서 A 치환기는 Where A substituent is
이며, 여기에서 R''는 o, m, p 위치에 임의로 치환 가능한 하나 이상의 치환기이고, 수소원자, 히드록시기, 아세테이트기, 할로겐원자, C1 내지 C4 저급 알킬기, C1 내지 C4 저급 알콕시기, C1 내지 C4 저급 알킬 에스테르 및 C1 내지 C4 저급 알킬 카 르복시기로부터 구성되는 군으로부터 선택된 하나 이상의 치환기이고; Wherein R '' is one or more substituents optionally substituted at o, m, and p positions, and hydrogen atom, hydroxy group, acetate group, halogen atom, C 1 to C 4 lower alkyl group, C 1 to C 4 lower alkoxy group At least one substituent selected from the group consisting of C 1 to C 4 lower alkyl esters and C 1 to C 4 lower alkyl carboxy groups;
n은 0 내지 4의 정수이며, ( ) 은 이중결합 또는 단일결합을 의미한다. n is an integer from 0 to 4, ( ) Means a double bond or a single bond.
상기 일반식 (I) 화합물의 바람직한 화합물군으로는 R1은 할로겐원자 또는 C1 내지 C4 저급 알킬기로 치환되거나 비치환된 C1 내지 C10 알킬기, C2 내지 C10 알켄일기, C2 내지 C10 알키닐기 및 A 치환기로 구성되는 군으로부터 선택된 치환기이며, 여기에서 A 치환기의 R''는 o, m, p 위치에 치환된 수소원자, 히드록시기, 아민기, 할로겐원자, 메틸기, 에틸기, 메톡시기, 에톡시기, 니트로기 또는 아세틸기로부터 선택된 하나 이상의 치환기이고; n은 o 또는 1의 정수인 화합물군들이며, 보다 바람직하게는 R1가 o, m, p 위치에 치환된 수소원자, 히드록시기, 메틸기, 에틸기, 메톡시기, 에톡시기 또는 아세틸기로부터 선택된 하나 이상의 치환기로 치환되거나 비치환된 A 치환기이고; n은 o 또는 1의 정수인 화합물군들이다.In a preferred group of compounds of the formula (I) compounds R 1 is a halogen atom or a C 1 to C 4 lower substituted with an alkyl group or an unsubstituted C 1 to C 10 alkyl group, C 2 to C 10 alkenyl, C 2 to A substituent selected from the group consisting of a C 10 alkynyl group and an A substituent, wherein R '' of the A substituent is a hydrogen atom, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, or a methoxy group substituted at o, m, and p positions At least one substituent selected from a period, an ethoxy group, a nitro group or an acetyl group; n is a group of compounds having an integer of o or 1, more preferably R 1 is at least one substituent selected from a hydrogen atom, a hydroxy group, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an acetyl group substituted in the o, m, p position Substituted or unsubstituted A substituent; n is a group of compounds that is an integer of o or 1;
또한, 상기 목적을 달성하기 위하여, (+)-데쿠르시놀의 구조이성체를 전구체로 하여 합성된 하기 일반식 (Ⅱ)로 표기되는 신규 구조의 (+)-데쿠르신-구조이성체 합성 유도체(decursin-structural isomer synthesis derivative) 화합물 또는 이의 약학적으로 허용가능한 염:In addition, in order to achieve the above object, (+)-decursin-structural isomer synthetic derivative of a novel structure represented by the following general formula (II) synthesized using the structural isomer of (+)-decursinol as a precursor (decursin) -structural isomer synthesis derivative) or a pharmaceutically acceptable salt thereof:
상기식에서,In this formula,
R2은 하나이상의 R′로 치환되거나 비치환된 C1 내지 C20 알킬기, C2 내지 C20 알켄일기, C2 내지 C20 알키닐기 및 A 치환기로 구성되는 군으로부터 선택된 하나이상의 치환기이며, 여기에서 R′는 할로겐원자, 니트로기, 아민기 또는 C1 내지 C4 저급 알킬기로부터 선택된 치환기이고;R 2 is one or more substituents selected from the group consisting of C 1 to C 20 alkyl groups, C 2 to C 20 alkenyl groups, C 2 to C 20 alkynyl groups and A substituents unsubstituted or substituted with one or more R ′, wherein R ′ is a substituent selected from a halogen atom, a nitro group, an amine group or a C 1 to C 4 lower alkyl group;
여기에서 A 치환기는 Where A substituent is
이며, 여기에서 R''는 o, m, p 위치에 임의로 치환 가능한 하나 이상의 치환기이고, 수소원자, 히드록시기, 아세테이트기, 할로겐원자, C1 내지 C4 저급 알킬기, C1 내지 C4 저급 알콕시기, C1 내지 C4 저급 알킬 에스테르 및 C1 내지 C4 저급 알킬 카르복시기로부터 구성되는 군으로부터 선택된 하나 이상의 치환기이고; Wherein R '' is one or more substituents optionally substituted at o, m, and p positions, and hydrogen atom, hydroxy group, acetate group, halogen atom, C 1 to C 4 lower alkyl group, C 1 to C 4 lower alkoxy group At least one substituent selected from the group consisting of C 1 to C 4 lower alkyl esters and C 1 to C 4 lower alkyl carboxyl groups;
n은 0 내지 4의 정수이며, ( ) 은 이중결합 또는 단일결합을 의미한다. n is an integer from 0 to 4, ( ) Means a double bond or a single bond.
상기 일반식 (Ⅱ) 화합물의 바람직한 화합물군으로는 R2은 할로겐원자 또는 C1 내지 C4 저급 알킬기로 치환되거나 비치환된 C1 내지 C10 알킬기, C2 내지 C10 알켄일기, C2 내지 C10 알키닐기 및 A 치환기로 구성되는 군으로부터 선택된 치환기이며, 여기에서 A 치환기의 R''는 o, m, p 위치에 치환된 수소원자, 히드록시기, 아민기, 할로겐원자, 메틸기, 에틸기, 메톡시기, 에톡시기, 니트로기 또는 아세틸기로부터 선택된 하나 이상의 치환기이고; n은 o 또는 1의 정수인 화합물군들이며, 보다 바람직하게는 R2가 o, m, p 위치에 치환된 수소원자, 히드록시기, 메틸기, 에틸기, 메톡시기, 에톡시기 또는 아세틸기로부터 선택된 하나 이상의 치환기로 치환되거나 비치환된 A 치환기이고; n은 o 또는 1의 정수인 화합물군들이다.In a preferred group of compounds of the general formula (Ⅱ) compound is R 2 is a halogen atom or a C 1 to C 4 lower substituted with an alkyl group or an unsubstituted C 1 to C 10 alkyl group, C 2 to C 10 alkenyl, C 2 to A substituent selected from the group consisting of a C 10 alkynyl group and an A substituent, wherein R '' of the A substituent is a hydrogen atom, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, or a methoxy group substituted at o, m, and p positions At least one substituent selected from a period, an ethoxy group, a nitro group or an acetyl group; n is a group of compounds having an integer of o or 1, and more preferably, R 2 is one or more substituents selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy or acetyl group substituted at o, m and p positions. Substituted or unsubstituted A substituent; n is a group of compounds that is an integer of o or 1;
가장 바람직하게는 일반식 (Ⅰ) 또는 (Ⅱ) 화합물로는 하기와 같은 화합물들을 들 수 있으며, 본 발명은 발명의 범위를 이에 제한하고자 함이 아니다.Most preferably, the compounds of the general formula (I) or (II) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.
(3s)-3-메틸-부-2테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터 (LM-1), (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터 (LM-2), (3s)-3-(3,4-디메톡시-페닐)-아크릴산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터 (LM-3), (3s)-3-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (LS-1) 또는 (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (LS-2).(3s) -3-methyl-but-2tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (LM-1), (3s) -2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chrome Men-3-yl-ester (LM-2), (3s) -3- (3,4-dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H- Pyrano [2,3-g] chromen-3-yl-ester (LM-3), (3s) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3, 4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester (LS-1) or (3s) -2-methyl-but-2-tenophosphoric acid-2,2- Dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester (LS-2).
상기 일반식 (Ⅰ) 또는 (Ⅱ)로 표시되는 본 발명의 화합물들은 당해 기술분 야에서 통상적인 방법에 따라 약학적으로 허용가능한 염으로 제조될 수 있다. The compounds of the present invention represented by the general formula (I) or (II) may be prepared as pharmaceutically acceptable salts according to conventional methods in the art.
염으로는 약학적으로 허용가능한 유리산 (free acid)에 의해 형성된 산부가염이 유용하다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동몰량의 화합물 및 물 중의 산 또는 알코올 (예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산 (maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 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, 히드로 아이오딕산 등을 사용할 수 있다.In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이 때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염 (예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
상기의 일반식 (Ⅰ) 또는 (Ⅱ) 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 일반식 (Ⅰ) 또는 (Ⅱ) 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염이 포함되며, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포네이트 (메실레이트) 및 p-톨루엔설포네이트 (토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the above compounds of formula (I) or (II) include salts of acidic or basic groups which may be present in compounds of formula (I) or (II) unless otherwise indicated. . For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, which are known in the art. It can be prepared through.
본 발명의 다른 목적은 상기 일반식 (Ⅰ) 또는 (Ⅱ) 화합물의 제조방법을 제공하는 것으로, 하기의 반응식들에 도시된 방법에 의해 화학적으로 합성될 수 있지만, 이들 예로만 한정되는 것은 아니다. Another object of the present invention is to provide a method for preparing the compound of Formula (I) or (II), which may be chemically synthesized by the method shown in Schemes below, but is not limited thereto.
하기의 반응식들은 본 발명의 대표적인 화합물들의 제조방법을 제조 단계별로 나타내는 것으로 본 발명의 여러 화합물들은 반응식 1 내지 반응식 5의 합성과정에서 사용되는 시약, 용매 및 반응 순서를 바꾸는 등의 작은 변경으로 제조될 수 있다. 본 발명의 몇몇 화합물들은 반응식 1 내지 반응식 5의 범주에 포함되지 않는 과정에 따라 합성되었으며, 이러한 화합물들에 대한 상세한 합성 과정은 이들 각각의 실시예에 설명되어 있다.The following reaction schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 5. Can be. Some compounds of the present invention were synthesized according to procedures not included in the scope of Schemes 1-5, and detailed synthesis procedures for these compounds are described in their respective examples.
반응식 1은 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 5단계 제조 과정을 나타낸다.Scheme 1 represents a five step preparation process for preparing commercial compounds or compounds synthesized by known methods.
제 1단계에서는 하이드로퀴논(hydroquinone)을 85%의 포름산에 용해시키고 2-메틸-3-부텐-2-올을 넣고 70 내지 130℃정도, 바람직하게는 90 내지 110℃에서 가열환류 시키면서 반응을 수행한다. 반응 시간은 1 내지 10시간동안 수행할 수 있고 바람직하게는 2 내지 6시간 동안 교반한 후 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 6-하이드록시-2,2-디메틸 크로멘 (2)을 제조할 수 있다. 제 2단계에서는 6-하이드록시-2,2-디메틸 크로멘 (2)을 에틸 프로피오레이트(ethyl propiolate)에 용해시키고 여기에 염화아연(zinc chloride)을 넣고 약 90 내지 150℃, 바람직하게는 100 내지 120℃ 정도에서 가열환류 시키면서 반응을 수행한다. 1 내지 5시간, 바람직하게는 2 내지 4시간 정도 교반 하면서 반응을 진행시켜 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 각각 7,7-디메틸-8,9-디하이드로-7H-피라노 [2,3-g] 크로멘-2-온 (3a)과 7,7-디메틸-5,6-디하이드로-7H-피라노 [3,2-f] 크로멘-2-온 (3b)을 제조할 수 있다. 제 3단계에서는 7,7-디메틸-8,9-디하이드로-7H-피라노 [2,3-g]크로멘-2-온 (3a)을 벤젠에 용해시켜 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)을 넣고 가열환류 하면서 반응을 수행한다. 반응시간은 40 내지 160시간은 교반시켜야 하며 바람직하게는 60 내지 120시간 동안 교반한 후 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 7,7-디메틸-7H-피라노 [2,3-g]크로멘-2-온 (4)를 제조할 수 있다. 제 4단계에서는 7,7-디메틸-7H-피라노 [2,3-g]크로멘-2-온 (4)을 아세토니트릴 용액에 용해시키고 (S, S)-(+), N, N’-비스(3,5-디-테트 부틸 살리 시리딘)-1,2-시클로헥산디아미노 망간네스(Ⅲ) 클로라이드 ((S, S)-(+),N,N’-Bis(3,5-di-tert- butyl-salicylidene)-1,2-cyclohexane-diaminomanganese(Ⅲ) chloride)촉매를 넣고 다음 소듐 테트라보레이트 데카하이드레이트(sodium tetraborate decahydrate)가 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(ethylene diamine tetraacetic acid disodium salt solution)에 있는 완충용액에 테트라 부틸 암모늄 비스술페이트(tetra butylammonium bisulfate)를 용해시켜 넣어준다. 이 혼합물을 -20 내지 0℃, 바람직하게는 0℃까지 온도를 낮춰준 후 1,1,1-트라이플루오로아세톤(1,1,1-trifluoro acetone)을 넣어주고 옥손이 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(ethylene diamine tetraacetic acid disodium salt solution)에 용해되여 있는 용액과 나트륨 바이카보네이트 수용액을 교반하면서 천천히 넣어준 다음 -20 내지 0℃, 바람직하게는 0℃에서 반응을 수행한다. 반응시간 은 1 내지 2시간, 바람직하게는 약 1시간 동안 교반시킨 후 반응액을 물로 처리하고 에틸 에테르로 추출하여 유기층을 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 (8s, 9s)-8,9-에폭시-7,7-디메틸-8,9-디하이드로-7H-피라노[2,3g]크로멘-온 (5)을 제조할 수 있다. 제 4단계의 생성물이 불안정하므로 바로 그 다음 단계로 반응을 진행한다. 제 5단계에서는 (8s, 9s)-8,9-에폭시-7,7-디메틸-8,9-디하이드로-7H-피라노[2,3g]크로멘-온 (5)을 테트라하이드로 푸란에 용해시켜 나트륨 시아노브롬하이드리드(sodium cyanoborohydride)와 보론트리플루오라이드 디에틸이써레이트(boron trifluoride diethyl etherate)를 넣고 -20 내지 30℃, 바람직하게는 0℃에서 반응을 수행하다가 상온에서 수행한다. 반응시간은 0℃에서 0.5 내지 5시간, 바람직하게는 0.5 내지 1.5시간 동안 교반시키고 상온에서는 0 내지 5시간, 바람직하게는 1 내지 2시간 동안 교반하여 반응액을 수포화 탄산수소나트륨으로 처리후 초산에틸로 추출하여 유기층을 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린 (1) 을 제조할 수 있다.In the first step, hydroquinone is dissolved in 85% formic acid, 2-methyl-3-butene-2-ol is added, and the reaction is performed by heating and refluxing at about 70 to 130 ° C., preferably at 90 to 110 ° C. do. The reaction time may be carried out for 1 to 10 hours, preferably after stirring for 2 to 6 hours, the reaction solution is cooled to room temperature, and then concentrated to obtain a residue obtained by silica gel column separation through 6-hydroxy-2,2-. Dimethyl chromen (2) can be prepared. In the second step, 6-hydroxy-2,2-dimethyl chromen (2) is dissolved in ethyl propiolate, and zinc chloride is added thereto, about 90 to 150 캜, preferably The reaction is carried out while heating to reflux at about 100 to 120 ℃. After stirring for 1 to 5 hours, preferably 2 to 4 hours, the reaction mixture was cooled to room temperature, and the residue obtained by concentrating the residue was purified by silica gel column separation to obtain 7,7-dimethyl-8,9-dihydro, respectively. -7H-pyrano [2,3-g] chromen-2-one (3a) and 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2 -On (3b) can be prepared. In the third step, 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one (3a) is dissolved in benzene to give 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was added thereto, followed by heating under reflux to carry out the reaction. The reaction time should be stirred for 40 to 160 hours, preferably after stirring for 60 to 120 hours, the reaction solution is cooled to room temperature and concentrated to obtain the residue obtained by silica gel column separation 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4) can be prepared. In the fourth step, 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4) is dissolved in acetonitrile solution (S, S)-(+), N, N '-Bis (3,5-di-tet butyl salicyridine) -1,2-cyclohexanediamino manganese (III) chloride ((S, S)-(+), N, N'-Bis (3 , 5-di-tert-butyl-salicylidene) -1,2-cyclohexane-diaminomanganese (III) chloride, and then sodium tetraborate decahydrate was added to 0.4 mM ethylene diamine tetrasodium disodium salt solution. Dissolve tetra butylammonium bisulfate in buffer in (ethylene diamine tetraacetic acid disodium salt solution). The mixture was cooled to -20 to 0 ° C, preferably 0 ° C, and then 1,1,1-trifluoroacetone was added and oxone was 0.4 mM ethylene diamine. The solution dissolved in ethylene diamine tetraacetic acid disodium salt solution and sodium bicarbonate solution are slowly added while stirring, and then the reaction is performed at -20 to 0 ° C, preferably 0 ° C. The reaction time is stirred for 1 to 2 hours, preferably about 1 hour, the reaction solution is treated with water and extracted with ethyl ether to concentrate the residue obtained by silica gel column separation (8s, 9s) -8,9 Epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3 g] chromen-one (5) can be prepared. Since the product of the fourth stage is unstable, the reaction proceeds to the next stage. In the fifth step, (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3g] chromen-one (5) was added to tetrahydrofuran. After dissolution, sodium cyanoborohydride and boron trifluoride diethyl etherate were added thereto, and the reaction was performed at -20 to 30 ° C, preferably 0 ° C, and then at room temperature. . The reaction time is stirred at 0 ° C. for 0.5 to 5 hours, preferably 0.5 to 1.5 hours, and at room temperature for 0 to 5 hours, preferably 1 to 2 hours, and then the reaction solution is treated with saturated sodium hydrogencarbonate and then acetic acid. The residue obtained by extracting with ethyl and concentrating the organic layer was purified by silica gel column separation (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) Can be prepared.
반응식 2는 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 1단계의 제조과정을 나타낸다.Scheme 2 shows a one step process for preparing a commercial compound or a compound synthesized by known methods.
제 1단계에서는 3,3-디메틸아크릴산과 엔젤산을 각각 디클로로메탄으로 용해시키고 1,3-디사이클로헥실카보디이미드(DCC) 및 4-디메틸아미노피리딘(DMAP(8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린(1) 을 넣고 반응을 수행한다. 반응 온도는 특별히 제한되지 않지만 10 내지 50℃, 바람직하게 30 내지 45℃, 반응시간은 30 내지 70 시간, 바람직하게는 40 내지 60시간 정도 교반한다. 여액은 감압농축 하였으며 얻은 잔사를 실리카겔 컬럼 분리를 통해 각각 (3s)-3-메틸-부-2테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(LM-1)와 (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(LM-2) 를 제조할 수 있다. In the first step, 3,3-dimethylacrylic acid and angelic acid were dissolved in dichloromethane, respectively, 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP (8s) -8-hydroxy- The reaction is carried out with 7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) The reaction temperature is not particularly limited but is 10 to 50 ° C, preferably 30 to 45 ° C. The reaction time was stirred for 30 to 70 hours, preferably 40 to 60 hours, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by silica gel column separation (3s) -3-methyl-but-2tenophosphate-2. , 2-Dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (LM-1) and (3s) -2-methyl-part- 2-Tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (LM-2) may be prepared. have.
반응식 3은 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 1단계의 제조과정을 나타낸다. Scheme 3 shows a one-step process for preparing a commercial compound or a compound synthesized by known methods.
제 1 단계에서는 3,4-디메톡시신남산을 디클로로메탄으로 용해시키고 1,3-디 사이클로 헥실카보디이미드(DCC) 및 4-디메틸아미노피리딘(DMAP), (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린(1)을 넣고 반응을 수행한다. 반응 온도는 특별히 제한되지 않지만 20 내지 40℃, 바람직하게는 상온 또는 40℃으로, 반응시간은 10 내지 48시간, 바람직하게는 20 내지 40시간정도 교반한다. 여액은 감압농축 하였으며 얻은 잔사를 실리카겔 컬럼 분리를 통해 (3s)-3-(3,4-디메톡시-페닐)-아크릴산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(LM-3)를 제조할 수 있다.In the first step, 3,4-dimethoxycinnamic acid is dissolved in dichloromethane and 1,3-dicyclo hexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), (8s) -8-hydroxy- 7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) was added thereto and the reaction was carried out. Although reaction temperature is not specifically limited, 20-40 degreeC, Preferably it is normal temperature or 40 degreeC, The reaction time is stirred for 10 to 48 hours, Preferably it is about 20 to 40 hours. The filtrate was concentrated under reduced pressure and the obtained residue was purified by (3s) -3- (3,4-dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H- by silica gel column separation. Pyrano [2,3-g] chromen-3-yl-ester (LM-3) can be prepared.
반응식 4은 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 5단계 제조 과정을 나타낸다.Scheme 4 represents a five step preparation process for preparing commercial compounds or compounds synthesized by known methods.
제 1단계에서는 하이드로퀴논(hydroquinone)을 85%의 포름산에 용해시키고 2-메틸-3-부텐-2-올을 넣고 70 내지 130℃정도, 바람직하게는 90 내지 110℃에서 가열환류 시키면서 반응을 수행한다. 반응 시간은 1 내지 10시간동안 수행할 수 있고 바람직하게는 2 내지 6시간 동안 교반한 후 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 6-하이드록시-2,2-디메틸 크로멘 (2)을 제조할 수 있다. 제 2단계에서는 6-하이드록시-2,2-디메틸 크로멘 (2)을 에틸 프로피오레이트(ethyl propiolate)에 용해시키고 여기에 염화아연(zinc chloride)을 넣고 약 90 내지 150℃, 바람직하게는 100 내지 120℃ 정도에서 가열환류 시키면서 반응을 수행한다. 1 내지 5시간, 바람직하게는 2 내지 4시간 정도 교반 하면서 반응을 진행시켜 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 각각 7,7-디메틸-8,9-디하이드로-7H-피라노 [2,3-g]크로멘-2-온 (3a)과 7,7-디메틸-5,6-디하이드로-7H-피라노 [3,2-f] 크로멘-2-온 (3b)을 제조할 수 있다. 제 3단계에서는 7,7-디메틸-5,6-디하이드로-7H-피라노 [3,2-f] 크로멘-2-온 (3b)을 벤젠에 용해시켜 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)을 넣고 가열환류 하면서 반응을 수행한다. 반응시간은 40 내지 160시간, 바람직하게는 60 내지 120시간 동안 교반한 후 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 각각 7,7-디메틸-7H-피라노 [3,2-f]크로멘-2-온 (9)를 제조할 수 있다. 제 4단계에서는 7-디메틸-7H-피라노 [3,2-f]크로멘-2-온 (9)을 아세토니트릴 용액에 용해시키고 (S, S)-(+), N, N’-비스(3,5-디-테트 부틸 살리 시리딘)-1,2-시클로헥산 디아미노 망간네스(Ⅲ) 클로라이드 ((S,S)-(+),N,N'-Bis(3,5-di-tert-butyl- salicylidene)-1,2-cyclohexane-diaminomanganese(Ⅲ) chloride) 촉매를 넣고 다음 소듐 테트라보레이트 데카하이드레이트(sodium tetraborate decahydrate)가 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(ethylene diamine tetraacetic acid disodium salt solution)에 있는 완충용액에 테트라 부틸 암모늄 비스술페이트(tetra butylammonium bisulfate)를 용해시켜 넣어준다. 이 혼합물을 -20 내지 0℃, 바람직하게는 0℃로 온도를 낮춘 후, 1,1,1-트라이플루오로아세톤(1,1,1-trifluoro acetone)을 넣어주고 따라서 옥손이 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(ethylene diamine tetraacetic acid disodium salt solution)에 용해되여 있는 용액과 나트륨 바이카보네이트 수용액을 교반하면서 천천히 넣어주고 -20 내지 0℃, 바람직하게는 0℃에서, 반응시간은 0.5 내지 5시간, 바람직하게는 1 내지 2시간 동안 교반시킨 후 반응액을 물로 처리하고 에틸 에테르로 추출하여 유기층을 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 (5s, 6s)-5,6-에폭시-7,7-디메틸-5,6-디하이드로-7H-피라노[3,2-f]크로멘-온 (10)을 제조할 수 있다. 제 4단계의 생성물이 불안정하므로 바로 그 다음 단계로 반응을 진행시켰다. 제 5단계에서는 (5s, 6s)-5,6-에폭시-7,7-디메틸-5,6-디하이드로-7H-피라노[3,2-f]크로멘-온 (10) 을 테트라하이드로 푸란에 용해시켜 나트륨 시아노브롬하이드리드(sodium cyanoborohydride)와 보론트리플루 오라이드 디에틸이써레이트(boron trifluoride diethyl etherate)를 넣고 -20 내지 30℃, 바람직하게는 0℃에서 반응을 수행하다가 상온에서 수행한다. 반응시간은 0℃에서 0.5 내지 5시간, 바람직하게는 0.5 내 지 1.5시간 동안 교반시키고 상온에서는 0 내지 2시간, 바람직하게는 1 내지 2시간 동안 교반하여 반응액을 수포화 탄산수소나트륨으로 처리후 초산에틸로 추출하여 유기층을 농축하여 얻은 잔사를실리카겔 컬럼분리를 통해 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠마린 (11) 을 제조할 수 있다.In the first step, hydroquinone is dissolved in 85% formic acid, 2-methyl-3-butene-2-ol is added, and the reaction is performed by heating and refluxing at about 70 to 130 ° C., preferably at 90 to 110 ° C. do. The reaction time may be carried out for 1 to 10 hours, preferably after stirring for 2 to 6 hours, the reaction solution is cooled to room temperature, and then concentrated to obtain a residue obtained by silica gel column separation through 6-hydroxy-2,2-. Dimethyl chromen (2) can be prepared. In the second step, 6-hydroxy-2,2-dimethyl chromen (2) is dissolved in ethyl propiolate, and zinc chloride is added thereto, about 90 to 150 캜, preferably The reaction is carried out while heating to reflux at about 100 to 120 ℃. After stirring for 1 to 5 hours, preferably 2 to 4 hours, the reaction mixture was cooled to room temperature, and the residue obtained by concentrating the residue was purified by silica gel column separation to obtain 7,7-dimethyl-8,9-dihydro, respectively. -7H-pyrano [2,3-g] chromen-2-one (3a) and 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2 -On (3b) can be prepared. In the third step, 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b) is dissolved in benzene to give 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was added thereto, followed by heating under reflux to carry out the reaction. The reaction time is stirred for 40 to 160 hours, preferably 60 to 120 hours, the reaction solution is cooled to room temperature and concentrated to obtain the residue obtained by silica gel column separation, respectively 7,7-dimethyl-7H-pyrano [3 , 2-f] chromen-2-one (9) can be prepared. In the fourth step, 7-dimethyl-7H-pyrano [3,2-f] chromen-2-one (9) is dissolved in acetonitrile solution and (S, S)-(+), N, N'- Bis (3,5-di-tet butyl salicyridine) -1,2-cyclohexane diamino manganese (III) chloride ((S, S)-(+), N, N'-Bis (3,5 -di-tert-butyl- salicylidene) -1,2-cyclohexane-diaminomanganese (III) chloride, followed by a sodium tetraborate decahydrate solution of 0.4 mM ethylene diamine tetrasodium disodium salt (ethylene Dissolve tetra butylammonium bisulfate in buffer in diamine tetraacetic acid disodium salt solution. The mixture was lowered to -20 to 0 ° C., preferably 0 ° C., and then 1,1,1-trifluoroacetone was added so that oxone was 0.4 mM of ethylene. Slowly add the solution dissolved in ethylene diamine tetraacetic acid disodium salt solution and sodium bicarbonate solution while stirring, and at -20 to 0 ℃, preferably 0 ℃, the reaction time is 0.5 to After stirring for 5 hours, preferably 1 to 2 hours, the reaction solution was treated with water, extracted with ethyl ether, and the residue obtained by concentrating the organic layer was separated through silica gel column separation (5s, 6s) -5,6-epoxy-7. , 7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-one (10) can be prepared. Since the product of the fourth stage is unstable, the reaction proceeds to the next stage. In the fifth step, (5s, 6s) -5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-one (10) was converted to tetrahydro After dissolving in furan, sodium cyanoborohydride and boron trifluoride diethyl etherate were added thereto, and the reaction was performed at -20 to 30 ° C, preferably 0 ° C. Perform on The reaction time is stirred at 0 ° C. for 0.5 to 5 hours, preferably 0.5 to 1.5 hours, and at room temperature for 0 to 2 hours, preferably 1 to 2 hours, after treating the reaction solution with saturated sodium hydrogencarbonate. The residue obtained by extracting with ethyl acetate and concentrating the organic layer was purified by silica gel column separation (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin (11 ) Can be prepared.
반응식 5는 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 1단계의 제조과정을 나타낸다.Scheme 5 shows a one-step process for preparing a commercial compound or a compound synthesized by known methods.
제 1단계에서는 3,3-디메틸아크릴산과 엔젤산을 각각 디클로로메탄으로 용해시키고 N-(3-디메틸아미노프로필)-N’-에틸카프보이아마이드 하이드로클로라이드 (EDC) 및 4-디메틸아미노피리딘(DMAP), (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠마린 (11)을 넣고 반응을 수행한다. 반응 온도는 특별히 제한되지 않지만 10 내지 40℃, 바람직하게 20 내지 40℃, 반응시간은 30 내지 70 시간, 바람직하게는 40 내지 60시간 정도 교반하였다. 여액은 감압농축 하였으며 얻은 잔사를 실리카겔 컬럼 분리를 통해 (3s)-3-메틸-부-2-테노인산-2,2-디메틸-7옥 소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (LS-1)와 (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (LS-2)를 제조할 수 있다.In the first step, 3,3-dimethylacrylic acid and angelic acid were dissolved in dichloromethane, respectively, and N- (3-dimethylaminopropyl) -N'-ethylcarbovoamide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP). ), (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] coumarin (11) is added and the reaction is carried out. Although reaction temperature is not specifically limited, 10-40 degreeC, Preferably it is 20-40 degreeC, The reaction time was stirred for 30 to 70 hours, Preferably it is about 40 to 60 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column separation to obtain (3s) -3-methyl-but-2-tenophosphate-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano. [3,2-f] chromen-3-yl-ester (LS-1) and (3s) -2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4- Dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester (LS-2) can be prepared.
상기 제조방법으로 얻어진 일반식 (Ⅰ) 또는 (Ⅱ) 을 유효성분으로 함유하는 조성물은 진드기에 의해 유도된 MCP-1, IL-6, IL-8의 분비 억제 효과를 확인함으로써, 아토피성 피부염 질환의 예방 및 치료에 효과적인 약학 조성물 및 건강기능식품으로 유용하게 이용될 수 있다. The composition containing the general formula (I) or (II) obtained by the above production method as an active ingredient, atopic dermatitis disease by confirming the inhibitory effect of MCP-1, IL-6, IL-8 induced by ticks It can be usefully used as a pharmaceutical composition and health functional food effective for the prevention and treatment of.
따라서, 본 발명은 상기 일반식 (Ⅰ) 또는 (Ⅱ) 로 표기되는 신규구조의 (+)-데쿠르신-구조이성체 합성 유도체(decursin-structural isomer synthesis derivative) 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아토피성 피부염 질환의 예방 및 치료를 위한 약학조성물을 제공한다.Accordingly, the present invention provides a (+)-decursin-structural isomer synthesis derivative of the novel structure represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof It provides a pharmaceutical composition for the prevention and treatment of atopic dermatitis diseases containing as an active ingredient.
본 발명의 상기 일반식 (Ⅰ) 또는 (Ⅱ) 화합물을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. The composition comprising the compound of formula (I) or (II) of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.
본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, 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 and mineral oil.
본 발명의 화합물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과 립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. The compositions comprising the compounds of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods. Can be used.
상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose, etc. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물은 0.0001 ~ 100 mg/kg으 로, 바람직하게는 0.001 ~ 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 조성물에서 본 발명의 화합물은 전체 조성물 총 중량에 대하여 0.0001 ~ 50 중량%의 함량으로 배합될 수 있다.Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably 0.001 ~ 100 mg / kg divided once to several times daily. The compound of the present invention in the composition may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the total composition.
또한, 본 발명의 화합물의 약학적 투여 형태는 이들의 약학적 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
본 발명의 약학 조성물은 쥐, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
본 발명은 상기 일반식 (Ⅰ) 또는 (Ⅱ)로 표기되는 신규구조의 (+)-데쿠르신-구조이성체 합성 유도체(decursin-structural isomer synthesis derivative) 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아토피성 피부염 질환의 예방 및 치료를 위한 개선용 건강기능식품을 제공한다.The present invention relates to a (+)-decursin-structural isomer synthesis derivative compound of the novel structure represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof. It provides a health functional food for improvement for the prevention and treatment of atopic dermatitis disease.
본 발명의 화합물은 아토피성 피부염 질환의 예방 및 개선을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The compounds of the present invention can be used in various ways, such as drugs, foods and beverages for the prevention and improvement of atopic dermatitis diseases. Examples of the food to which the compound of the present invention may be added include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and may be used in the form of powders, granules, tablets, capsules, or beverages. have.
본 발명의 화합물은 독성 및 부작용은 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있는 약제이다. Since the compound of the present invention has little toxicity and side effects, it is a drug that can be used safely even for long-term administration for the purpose of prevention.
본 발명의 상기 화합물은 아토피성 피부염 질환의 예방 및 치료를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 화합물의 양은 일반적으로 본 발명의 건강식품 조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 30 g, 바람직하게는 0.3 내지 10 g의 비율로 가할 수 있다. The compound of the present invention may be added to food or beverage for the purpose of preventing and treating atopic dermatitis diseases. At this time, the amount of the compound in the food or beverage is generally added to the health food composition of the present invention to 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 30 g based on 100 ml, preferably Can be added in a ratio of 0.3 to 10 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 것 외에 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health beverage composition of the present invention, in addition to containing the compound as an essential ingredient in the indicated proportions, has no particular limitation on the liquid component and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrin, cyclodextrin and the like Sugar, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 화합물은 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제(치즈, 초콜릿 등), 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. 그 밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the compounds of the present invention, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. In addition, the compositions of the present invention may contain fruit flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
상기와 같이 본 발명의 (+)-데쿠르신-구조이성체 합성 유도체(decursin-structural isomer synthesis derivative) 화합물들은 EoL-1 세포에서 진드기에 의해 유도된 아토피성 피부염증 반응을 나타내는 MCP-1, IL-6 및 IL-8의 분비량을 효과적으로 억제하므로 아토피성 피부염 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품을 제공할 수 있다.As described above, the (+)-decursin-structural isomer synthesis derivative compounds of the present invention are MCP-1, IL- showing an atopic dermatitis response induced by ticks in EoL-1 cells. 6 and effectively inhibit the amount of IL-8 can provide a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis diseases.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다. Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.
참조예 1. 시약 및 기기Reference Example 1. Reagents and Instruments
분석기기로는 1H-NMR (400MHz) 스펙트로미터(spectrometer, JNM-AL 400, JEOL Ltd., 일본), 멜팅 포인터(Melting pointer, Yamako, MD-S3, 일본), 질량분석기(MS, PE SCIX API 2000 MS/MS, 캐나다), 광학 측정기(Polarimeter, JASCO DIP-370, 일본)를 사용하였다. 각종 시약들은 알드리치사(Aldrich Chemical Co.)의 제품을 사용하였으며 기타 용매는 1급 이상의 시약을 정제하지 않고 사용하였다. 합성한 물질들의 정제를 위하여 실리카겔(Silica gel, Merck, 230-400 mesh)을 사용하였다.As an analyzer, 1 H-NMR (400 MHz) spectrometer (JNM-AL 400, JEOL Ltd., Japan), melting pointer (Melting pointer, Yamako, MD-S3, Japan), mass spectrometer (MS, PE SCIX API) 2000 MS / MS, Canada), an optical meter (Polarimeter, JASCO DIP-370, Japan) was used. Various reagents were used by Aldrich Chemical Co., and other solvents were used without purification of the first or higher reagents. Silica gel (Silica gel, Merck, 230-400 mesh) was used for the purification of the synthesized materials.
참조예 2. EoL-1 배양Reference Example 2 EoL-1 Culture
사람의 호산구(eosinophil)인 EoL-1 (eosinophilic leukemia cell, 일본세포주은행) 세포를 2.0 x 105/m로 RPMI 1640 배지, 항생물질 (페니실린 104 U/㎖, 스트렙토마이신 10 mg/㎖, 암포테리신 B 25 ㎍/㎖)과 10% FBS를 넣고, 37℃ CO2 배양기에서 3일간 배양하였다.Human eosinophil EoL-1 (eosinophilic leukemia cell) cells at 2.0 x 10 5 / m RPMI 1640 medium, antibiotics (penicillin 10 4 U / ml, streptomycin 10 mg / ml, cancer cells 25 μg / ml erysine B) and 10% FBS were added thereto, followed by incubation for 3 days in a 37 ° C. CO 2 incubator.
실시예 1. (3s)-3-메틸-부-2테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(6)((3s)-3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano[2,3-g]chromen-3-yl-ester)의 제조Example 1. (3s) -3-Methyl-but-2tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3 -Yl-ester (6) ((3s) -3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3 -yl-ester)
1-1. 6-하이드록시-2,2-디메틸 크로멘 (2)(6-hydroxy-2,2-dimethyl chroman)중간체의 제조1-1. Preparation of 6-hydroxy-2,2-dimethyl chroman (2) (6-hydroxy-2,2-dimethyl chroman) intermediate
상기반응식에서 나타난 바와 같이 라운드 플라스크에 하이드로퀴논(hydroquinone, 220g, 1.998mol)을 85%의 포름산에 500ml에 용해시키고 2-메틸-3-부텐-2-올(109ml, 1.043mol)을 넣고 100℃정도에서 4시간동안 교반하면서 환류 시켰다. 반응용액을 냉각 시키고 2000ml의 물에 넣은후 NaHCO3로 PH 7-8로 중화시키고 800ml의 아세트산 에틸로 3번 추출하여 무수 황산나트륨으로 탈수 시킨 후 감압농축하여 실리카겔 컬럼 분리를 통해 물성치를 갖는 6-하이드록시-2,2-디메틸 크로멘 (2)61.33g을 얻었다.As shown in the reaction scheme, hydroquinone (hydroquinone, 220 g, 1.998 mol) was dissolved in 500 ml of 85% formic acid in a round flask, 2-methyl-3-butene-2-ol (109 ml, 1.043 mol) was added thereto, and then 100 ° C. It was refluxed while stirring for about 4 hours. The reaction solution was cooled, poured into 2000 ml of water, neutralized with NaHCO 3 to PH 7-8, extracted three times with 800 ml of ethyl acetate, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-hydride with silica gel column separation. 61.33 g of oxy-2,2-dimethyl chromen (2) was obtained.
수율: 33%;Yield: 33%;
적갈색의 결정;Reddish brown crystals;
Rf=0.50(n-Hexane:ethylacetate=2:1);R f = 0.50 (n-Hexane: ethylacetate = 2: 1);
mp=72-73℃;mp = 72-73 ° C .;
1H NMR(CDCl3,400MHz):δppm 6.645-6.555 (m, 3H), 6.352 (s, OH), 2.654 (t, J=6.8, 2H), 1.736 (t, J=6.8, 2H), 1.29 7(s, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 6.645-6.555 (m, 3H), 6.352 (s, OH), 2.654 (t, J = 6.8, 2H), 1.736 (t, J = 6.8, 2H), 1.29 7 (s, 6H);
MS(m/z)179.4(M+H)+.MS ( m / z ) 179.4 (M + H) + .
1-2. 7,7-디메틸-8,9-디하이드로-7H-피라노[2,3-g]크로멘-2-온 (3a) (7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g]chromen-2-one)과 7,7-디메틸-5.6-디하이드로-7H-피라노[3,2-f]크로멘-2-온(3b)(7,7-dimethyl-5,6- dihydro-7H-pyrano [3,2-f]chromen-2-one)중간체의 제조1-2. 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one (3a) (7,7-dimethyl-8,9-dihydro-7H-pyrano [ 2,3-g] chromen-2-one) and 7,7-dimethyl-5.6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b) (7,7-dimethyl Preparation of -5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one) intermediates
상기 반응식에서 나타난 바와 같이 실시예 1-1의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 6-하이드록시-2,2-이메틸 크로멘 (2) (50g, 0.281mol)를 넣고 에틸 프로피오레이트(ethyl propiolate, 42.8ml, 0.421mol)에 용해시킨 후 여기에 염화아연(38.5g, 0.282mol)을 넣고 110℃ 1.5시간 교반하면서 환류 시켰다. 반응 용액에 5% 염화수소 수용액을 넣고 아세트산 에틸로 추출하고 감압농축하여 실리카겔 컬럼 분리를 통하여 물성치를 갖는 7,7-디메틸-8,9-디하이드로-7H-피라노 [2,3-g] 크로멘-2-온 (3a) 8.41g과 7,7-디메틸-5,6-디하이드로-7H-피라노 [3,2-f] 크로멘-2-온 (3b) 17.5g을 얻었다.As shown in the reaction scheme, 6-hydroxy-2,2-methylchrome (2) (50 g, 0.281 mol) was added to an intermediate compound prepared in the same manner as in Example 1-1 in a round flask. After dissolving in the pilate (ethyl propiolate, 42.8ml, 0.421mol), zinc chloride (38.5g, 0.282mol) was added thereto, and the mixture was refluxed while stirring at 110 ° C for 1.5 hours. 5% aqueous hydrogen chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and concentrated under reduced pressure to obtain 7,7-dimethyl-8,9-dihydro-7H-pyranochrome [2,3-g] with physical properties through silica gel column separation. 8.41 g of men-2-one (3a) and 17.5 g of 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b) were obtained.
화합물: 7,7-디메틸-8,9-디하이드로-7H-피라노 [2,3-g] 크로멘-2-온 (3a) Compound: 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one (3a)
수율: 13%;Yield: 13%;
백색고체상(solid);White solid;
Rf=0.46(n-Hexane:ethylacetate=3:2);R f = 0.46 (n-Hexane: ethylacetate = 3: 2);
mp= 138-139℃;mp = 138-139 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.594 (d, J=9.52 1H), 7.052 (s, 1H), 6.850 (s, 1H), 6.356 (d, J=9.52, 1H), 2.885 (t, J=6.70 2H), 1.845 (t, J=6.70, 2H), 1.3489(s, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.594 (d, J = 9.52 1H), 7.052 (s, 1H), 6.850 (s, 1H), 6.356 (d, J = 9.52, 1H), 2.885 (t, J = 6.70 2H), 1.845 (t, J = 6.70, 2H), 1.3489 (s, 6H);
MS(m/z)231.4(M+H)+.MS ( m / z ) 231.4 (M + H) + .
화합물: 7,7-디메틸-5,6-디하이드로-7H-피라노 [3,2-f] 크로멘-2-온 (3b)Compound: 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one (3b)
수율: 27.1%;Yield: 27.1%;
연한 황색 고체상(solid);Light yellow solid;
Rf=0.33(n-Hexane:ethylacetate=3:2);R f = 0.33 (n-Hexane: ethylacetate = 3: 2);
mp= 135.5-136.5℃;mp = 135.5-136.5 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.860 (d, J=9.76 1H), 7.120 (d, J=9.00 1H), 6.991 (d, J=9.04 1H), 6.442 (d, J=9.76, 1H), 2.905 (t, J=6.82 2H), 1.895 (t, J=6.84, 2H), 1.350(s, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.860 (d, J = 9.76 1H), 7.120 (d, J = 9.00 1H), 6.991 (d, J = 9.04 1H), 6.442 (d, J = 9.76, 1H ), 2.905 (t, J = 6.82 2H), 1.895 (t, J = 6.84, 2H), 1.350 (s, 6H);
MS(m/z)231.4(M+H)+.MS ( m / z ) 231.4 (M + H) + .
1-3. 7,7-디메틸-7H-피라노 [2,3-g]크로멘-2-온 (4)(7,7-dimethyl- 7H- pyrano [2,3-g]chromen-2-one)중간체의 제조1-3. 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4) (7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one) intermediate Manufacture
상기 반응식에서 나타난 바와 같이 실시예 1-2의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 7,7-디메틸-8,9-디하이드로-7H-피라노 [2,3-g]크로멘-2-온(3a)(5.5g, 23.8mmol)을 넣고 500ml의 벤젠에 용해시킨 후 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(10.9g, 48.0mmol)을 넣고 80시간동안 교반하면서 환류시켰다. 반응 용액을 수포화 NaHSO3로 처리한 후 디에틸에테르로 추출한후 무수황산나트륨으로 탈수시킨 후 감압 농축하여 실리카겔 컬럼분리를 통하여 물성치를 갖는 7,7-디메틸-7H-피라노 [2,3-g]크로멘-2-온 (4)를 4.7g을 얻었다.As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 1-2 was placed in a round flask with 7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen. 2-one (3a) (5.5 g, 23.8 mmol) was added to dissolve in 500 ml of benzene, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.9 g, 48.0 mmol) was added. It was refluxed while stirring for 80 hours. The reaction solution was treated with saturated NaHSO 3 , extracted with diethyl ether, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column separation to obtain 7,7-dimethyl-7H-pyrano [2,3-g]. ] 4.7 g of chroman-2-one (4) was obtained.
수율: 86.5%;Yield: 86.5%;
연한 황색 고체성(solid);Light yellow solid;
Rf=0.49(n-Hexane:ethylacetate=3:2);R f = 0.49 (n-Hexane: ethylacetate = 3: 2);
mp= 124-125℃;mp = 124-125 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.578 (d, J=9.60, 1H), 6.947 (s, 1H), 6.832 (s, 1H), 6.371 (t, J=10.2, 2H), 5.840 (d, J=10.00 1H), 1.451 (s, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.578 (d, J = 9.60, 1H), 6.947 (s, 1H), 6.832 (s, 1H), 6.371 (t, J = 10.2, 2H), 5.840 (d , J = 10.00 1H), 1.451 (s, 6H);
MS(m/z)229.3(M+H)+.MS ( m / z ) 229.3 (M + H) + .
1-4. (8s, 9s)-8,9-에폭시-7,7-디메틸-8,9-디하이드로-7H-피라노[2,3g]크로멘-온(5)((8s,9s)-8,9-epoxy-7,7-dimethyl-8,9- dihydro-7H-pyrano [2,3-g]chromen-2-one)중간체의 제조1-4. (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3g] chromen-one (5) ((8s, 9s) -8, Preparation of 9-epoxy-7,7-dimethyl-8,9-dihydro-7H-pyrano [2,3-g] chromen-2-one) intermediate
상기 반응식에서 나타난 바와 같이 실시예 1-3의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 7,7-디메틸-7H-피라노 [2,3-g]크로멘-2-온 (4) (987.9mg, 4.33mmol)을 넣고 아세토니트릴 용액 50ml에 용해시킨후 상온에서 (S, S)-(+), N, N’-비스(3,5-디-테트 부틸 살리 시리딘)-1,2-시클로헥산디아미노 망간네스(Ⅲ) 클로라이드(57mg, 0.09mmol)를 넣고 다음 소듐 테트라보레이트 데카하이드레이트(sodium tetraborate decahydrate)가 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(ethylene diamine tetraacetic acid disodium salt solution)에 있는 완충용액에 테트라 부틸 암모늄 비스술페이트(tetra butylammonium bisulfate)를 용해시킨 용액 35ml을 넣어준다. 이 혼합물을 0℃까지 냉각시킨 후 1,1,1-트라이플루오로아세톤(0.5ml)을 넣어주고 따라서 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(50ml)에 옥손(10.25g, 16.61mmol)을 첨가한 용액과 나트륨 바이카보네 이트(3g, 35.7mmol) 수용액 50ml을 교반하면서 천천히 넣어주고 0℃에 1시간 동안 교반하면서 반응을 시킨다. 반응 혼합액을 물로 처리하고 디에틸에테르로 추출하고 유기층을 무수황산나트륨으로 탈수 시킨 후 감압농축하여 실리카걸 컬럼 분리를 통해 물성치를 갖는 (8s, 9s)-8,9-에폭시-7,7-디메틸-8,9-디하이드로-7H-피라노[2,3g]크로멘-온 (5) 545.7mg을 얻었다. As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 1-3 was placed in a round flask with 7,7-dimethyl-7H-pyrano [2,3-g] chromen-2-one (4). (987.9 mg, 4.33 mmol) was added and dissolved in 50 ml of acetonitrile solution, and then (S, S)-(+), N, N'-bis (3,5-di-tet butyl salicyridine) -1 at room temperature. , 2-cyclohexanediamino manganese (III) chloride (57mg, 0.09mmol) was added, and then sodium tetraborate decahydrate was added to 0.4mM ethylene diamine tetraacetic acid disodium solution. 35 ml of a solution of tetra butylammonium bisulfate was added to the buffer solution in salt solution. After cooling the mixture to 0 ° C., 1,1,1-trifluoroacetone (0.5 ml) was added, and thus oxone (10.25 g, 16.61 mmol) in 0.4 mM ethylene diamine tetraacid disodium salt solution (50 ml). The solution to which the solution was added and 50 ml of sodium bicarbonate (3 g, 35.7 mmol) aqueous solution were slowly added while stirring, and the reaction was stirred at 0 ° C. for 1 hour. The reaction mixture was treated with water, extracted with diethyl ether, the organic layer was dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (8s, 9s) -8,9-epoxy-7,7-dimethyl- having physical properties through separation of a silica girl column. 545.7 mg of 8,9-dihydro-7H-pyrano [2,3g] chromen-one (5) was obtained.
수율: 51.6%;Yield: 51.6%;
연한황색의 고체상(solid);Light yellow solid;
Rf=0.31(n-Hexane:ethylacetate=3:2);R f = 0.31 (n-Hexane: ethylacetate = 3: 2);
mp=120-121;mp = 120-121;
1H NMR(CDCl3,400MHz):δppm 7.606 (d, J=9.52, 1H), 7.344 (s, 1H), 6.902 (s, 1H), 6.417 (d, J=9.52, 1H), 3.966 (d, J=4.4, 1H), 3.553 (d, J=4.4 1H), 1.600 (s, 3H), 1.260 (s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.606 (d, J = 9.52, 1H), 7.344 (s, 1H), 6.902 (s, 1H), 6.417 (d, J = 9.52, 1H), 3.966 (d , J = 4.4, 1H), 3.553 (d, J = 4.4 1H), 1.600 (s, 3H), 1.260 (s, 3H);
MS(m/z)245.2(M+H)+;MS ( m / z ) 245.2 (M + H) + ;
[α]D 25=11.2 (c 3, CHCl3).[a] D 25 = 11.2 (c 3, CHCl 3 ).
1-5. (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린(1)((8s)-8-hydroxy-7,7-dimethyl-8,9-dihydropyrano[2,3-g] coumarin)중간체의 제조1-5. (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] coumarin (1) ((8s) -8-hydroxy-7,7-dimethyl-8 , 9-dihydropyrano [2,3-g] coumarin)
상기 반응식에서 나타난 바와 같이 실시예 1-4의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 (8s, 9s)-8,9-에폭시-7,7-디메틸-8,9-디하이드로-6H-피라노[2,3g]크로멘-온(5) (420.3mg, 1.72mmol)을 넣고 테트라히드로 푸란(90ml)에 용해시켜 나트륨 시아노브롬하이드리드(132mg, 2.1mmol)와 보론트리플루오라이드 디에틸이써레이트(216mg, 1.52mmol)를 넣고 0℃에서 반응을 수행하다가 상온에서 0.5시간 교반한다. 반응 혼합물을 수포화 NaHCO3로 처리하고 아세트산 에틸로 추출하여 유기층을 감압농축하여 실리카겔 컬럼분리를 통하여 물성치를 (8s)-8-hydroxy-7,7-dimethyl-8,9-dihydropyrano[2,3-g]coumarin(1) 315.3mg 얻었다. As shown in the scheme, the intermediate compound prepared in the same manner as in Example 1-4 was placed in a round flask with (8s, 9s) -8,9-epoxy-7,7-dimethyl-8,9-dihydro-6H. -Pyrano [2,3g] chromen-on (5) (420.3mg, 1.72mmol) was added and dissolved in tetrahydrofuran (90ml), sodium cyanobromide hydride (132mg, 2.1mmol) and borontrifluoride Diethyl acrylate (216 mg, 1.52 mmol) was added thereto, the reaction was performed at 0 ° C., and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was treated with saturated NaHCO 3 , extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, and the physical properties were determined by silica gel column separation (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3]. 315.3 mg of -g] coumarin (1) was obtained.
수율: 74.4%;Yield: 74.4%;
백색의 고체상(solid)White solid
Rf=0.26(n-Hexane:ethylacetate=1:1);R f = 0.26 (n-Hexane: ethylacetate = 1: 1);
mp= 161.5-162.5℃;mp = 161.5-162.5 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.587 (d, J=9.60, 1H), 7.043 (s, 1H), 6.898 (s, 1H), 6.341 (d, J=9.60, 1H), 3.868 (t, J=5.2, 1H), 3.163 (dd, J=4.8, 11.2, 1H), 2.891 (dd, J=5.6, 11.6, 1H), 1.381 (s, 3H), 1.335 (s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.587 (d, J = 9.60, 1H), 7.043 (s, 1H), 6.898 (s, 1H), 6.341 (d, J = 9.60, 1H), 3.868 (t , J = 5.2, 1H), 3.163 (dd, J = 4.8, 11.2, 1H), 2.891 (dd, J = 5.6, 11.6, 1H), 1.381 (s, 3H), 1.335 (s, 3H);
MS(m/z)247.4(M+H)+;MS ( m / z ) 247.4 (M + H) + ;
[α]D 25=30.2 (c 0.5, CHCl3).[a] D 25 = 30.2 (c 0.5, CHCl 3 ).
1-6. (3s)-3-메틸-부-2테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라 노[2,3-g]크로멘-3-일-에스터(6)((3s)-3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano[2,3-g]chromen-3-yl-ester)의 제조1-6. (3s) -3-methyl-but-2tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester (6) ((3s) -3methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3-g] chromen-3-yl-ester Manufacturing
상기 반응식에서 나타난 바와 같이 실시예 1-5의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 3,3-디메틸아크릴산(34mg, 0.34mmol)을 넣고 10ml의 디클로로메탄으로 용해시키고 1,3-디사이클로헥실카보디이미드(101mg, 0.49mmol) 및 4-디메틸아미노피리딘(30mg, 0.246mmol)과 (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린(1) (60.5mg, 0.265mmol)을 넣고 38℃에서 48시간동안 교반하면서 환류시킨다. 반응 혼합액을 감압농축하여 실리카겔 컬럼을 통하여 물성치를 갖는 (3s)-3-메틸-부-2테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(LM-1) 57.7mg을 얻어 실험예의 시료로 사용하였다. As shown in the scheme, 3,3-dimethylacrylic acid (34 mg, 0.34 mmol) was added to a round flask with the intermediate compound prepared in the same manner as in Example 1-5, and dissolved with 10 ml of dichloromethane. Cyclohexylcarbodiimide (101 mg, 0.49 mmol) and 4-dimethylaminopyridine (30 mg, 0.246 mmol) and (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2, 3-g] Coumarin (1) (60.5 mg, 0.265 mmol) was added and refluxed with stirring at 38 ° C. for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain (3s) -3-methyl-but-2tenophosphate-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2] having physical properties through a silica gel column. 57.7 mg of, 3-g] chromen-3-yl-ester (LM-1) was used as a sample for the experimental example.
수율: 66.3%;Yield: 66.3%;
백색의 고체상(solid)White solid
Rf=0.49(n-Hexane:ethylacetate=2:1);R f = 0.49 (n-Hexane: ethylacetate = 2: 1);
mp= 117-118℃;mp = 117-118 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.605 (d, J=9.60, 1H), 7.034 (s, 1H), 6.920 (s, 1H), 6.365 (d, J=9.60, 1H), 5.665 (s, 1H), 5.078 (t, J=5.00, 1H), 3.25 (dd, J=6, 18.0, 1H), 2.897 (dd, J=4.4, 18.0, 1H), 2.154 (s, 3H), 1.881 (s, 3H), 1.548 (s, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.605 (d, J = 9.60, 1H), 7.034 (s, 1H), 6.920 (s, 1H), 6.365 (d, J = 9.60, 1H), 5.665 (s , 1H), 5.078 (t, J = 5.00, 1H), 3.25 (dd, J = 6, 18.0, 1H), 2.897 (dd, J = 4.4, 18.0, 1H), 2.154 (s, 3H), 1.881 (s, 3H), 1.548 (s, 6H);
MS(m/z)329.3(M+H)+;MS ( m / z ) 329.3 (M + H) + ;
[α]D 25=12.1 (c 3, CHCl3).[a] D 25 = 12.1 (c 3, CHCl 3 ).
실시예 2. (3s)-시스-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(7)((3s)-2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano[2,3-g]chromen-3-yl-ester)의 제조Example 2. (3s) -cis-2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] chrome Men-3-yl-ester (7) ((3s) -2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [2,3- g] chromen-3-yl-ester)
상기 반응식에서 나타난 바와 같이 실시예 1-5의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 엔젤산 (25mg, 0.25 mmol)을 넣고 10ml의 디클로로메탄으로 용해시키고 1,3-디사이클로헥실카보디이미드(49mg, 0.237mmol) 및 4-디메틸아미노피리딘(17mg, 0.139mmol)과 (8s)-8-히드록시-7,7-디메틸-8,9-디히드로피라노 [2,3-g] 쿠마린(1) (28.8mg, 0.117mmol)을 넣고 38℃에서 58시간동안 교반하면서 환류시킨다. 반응 혼합액을 감압농축하여 실리카겔 컬럼을 통하여 물성치를 갖는 (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(LM-2) 26.4mg을 얻어 실험예의 시료로 사용하였다. As shown in the reaction scheme, the intermediate compound prepared in the same manner as in Example 1-5 was added angelic acid (25 mg, 0.25 mmol) to a round flask, dissolved in 10 ml of dichloromethane, and then 1,3-dicyclohexylcarbodie. Mead (49 mg, 0.237 mmol) and 4-dimethylaminopyridine (17 mg, 0.139 mmol) with (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydropyrano [2,3-g] Add coumarin (1) (28.8 mg, 0.117 mmol) and reflux with stirring at 38 ° C. for 58 hours. The reaction mixture was concentrated under reduced pressure and (3s) -2-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [ 26.4 mg of 2,3-g] chromen-3-yl-ester (LM-2) was obtained and used as a sample for the experimental example.
수율: 68.7%;Yield: 68.7%;
백색의 고체상(solid)White solid
Rf=0.50(n-Hexane:ethylacetate=2:1);R f = 0.50 (n-Hexane: ethylacetate = 2: 1);
mp= 106-107℃;mp = 106-107 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.610 (d, J=9.60, 1H), 7.034 (s, 1H), 6.930 (s, 1H), 6.82 (g, J=4.2, 1H), 6.371 (d, J=9.60, 1H), 5.086 (t, J=5.2, 1H), 3.267 (dd, J=4.8, 18.4, 1H), 2.914 (dd, J=5.4, 18.2, 1H), 1.766 (d, J=7.2 3H), 1.588 (s, 3H), 1.356 (d, J=6.4, 6H). 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.610 (d, J = 9.60, 1H), 7.034 (s, 1H), 6.930 (s, 1H), 6.82 (g, J = 4.2, 1H), 6.371 (d , J = 9.60, 1H), 5.086 (t, J = 5.2, 1H), 3.267 (dd, J = 4.8, 18.4, 1H), 2.914 (dd, J = 5.4, 18.2, 1H), 1.766 (d, J = 7.2 3H), 1.588 (s, 3H), 1.356 (d, J = 6.4, 6H).
MS(m/z)329.3(M+H)+;MS ( m / z ) 329.3 (M + H) + ;
[α]D 25=8.7 (c 1, CHCl3).[a] D 25 = 8.7 (c 1, CHCl 3 ).
실시예 3. (3s)-3-(3,4-디메톡시-페닐)-아크릴산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(8)((3s)-3- (3,4-dimethoxy-phenyl)-acrylicacid-2,2-dimethyl-7-oxo-3,4- dihydro-2H-pyrano[2,3-g]chromen-3-yl-ester)의 제조Example 3. (3s) -3- (3,4-Dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [2,3-g] Chromen-3-yl-ester (8) ((3s) -3- (3,4-dimethoxy-phenyl) -acrylicacid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [ 2,3-g] chromen-3-yl-ester)
상기 반응식에서 나타난 바와 같이 실시예 1-5의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 3,4-디메톡시신남산(208mg, 0.999 mmol)을 넣고 20ml의 디클로로메탄으로 용해시키고 1,3-디사이클로헥실카보디이미드(289.2mg, 0.1.402mmol) 및 4-디메틸아미노피리딘(57.4mg, 0.47mmol)과 (8s)-8-하이드록시-7,7-디메틸-8,9-디하이드로피라노 [2,3-g] 쿠마린(1) (150.3mg, 0.659mmol)을 넣고 상온에서 24시간 교반시켰다. 반응 혼합액을 감압농축하여 실리카겔 컬럼을 통하여 물성치를 갖는 ((3s)-3-(3,4-디메톡시-페닐)-아크릴산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[2,3-g]크로멘-3-일-에스터(LM-3) 235.6mg을 얻어 실험예의 시료로 사용하였다. As shown in the scheme, 3,4-dimethoxycinnamic acid (208mg, 0.999 mmol) was added to a round flask with the intermediate compound prepared in the same manner as in Example 1-5, and dissolved in 20ml of dichloromethane. Dicyclohexylcarbodiimide (289.2 mg, 0.1.402 mmol) and 4-dimethylaminopyridine (57.4 mg, 0.47 mmol) and (8s) -8-hydroxy-7,7-dimethyl-8,9-dihydro Pyrano [2,3-g] coumarin (1) (150.3 mg, 0.659 mmol) was added thereto and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain ((3s) -3- (3,4-dimethoxy-phenyl) -acrylic acid-2,2-dimethyl-7oxo-3,4-dihydro-2H having physical properties through a silica gel column. 235.6 mg of pyrano [2,3-g] chromen-3-yl-ester (LM-3) was obtained and used as a sample for the experimental example.
수율: 81.9%;Yield: 81.9%;
백색의 고체상(solid);White solid;
Rf=0.42(n-Hexane:ethylacetate=3:2);R f = 0.42 (n-Hexane: ethylacetate = 3: 2);
mp= 182-183℃;mp = 182-183 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.641 (d, J=9.2, 1H), 7.609 (d, J=2.8, 1H), 7.081 (dd, J=1.8, 5.2, 1H), 7.062 (s, 1H), 7.020 (d, J=1.6, 1H), 6.958 (s, 1H), 6.848 (d, J=8.4, 1H), 6.376 (d, J=9.2, 1H), 6.292 (d, J=15.6, 1H), 5.20. (t, J=4.8, 1H), 3.899 (d, J=6.0 6H), 3.304 (dd, J=5.2, 18.0, 1H), 2.980 (dd, J=4.4, 18.0, 1H), 1.419 (s, 3H), 1.370 (s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.641 (d, J = 9.2, 1H), 7.609 (d, J = 2.8, 1H), 7.081 (dd, J = 1.8, 5.2, 1H), 7.062 (s, 1H), 7.020 (d, J = 1.6, 1H), 6.958 (s, 1H), 6.848 (d, J = 8.4, 1H), 6.376 (d, J = 9.2, 1H), 6.292 (d, J = 15.6 , 1H), 5.20. (t, J = 4.8, 1H), 3.899 (d, J = 6.0 6H), 3.304 (dd, J = 5.2, 18.0, 1H), 2.980 (dd, J = 4.4, 18.0, 1H), 1.419 (s, 3H), 1.370 (s, 3H);
MS(m/z)436.9(M+H)+;MS ( m / z ) 436.9 (M + H) + ;
[α]D 25=37.9 (c 2, CHCl3).[a] D 25 = 37.9 (c 2, CHCl 3 ).
실시예 4. (3s)-3-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터(12)((3S)-3-methyl-but-2-enoic acid-2,2- dimethyl-7-oxo-3,4-dihydro-2H-pyrano[3,2-f]chromen-3-yl-ester)의 제조Example 4 (3s) -3-Methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen- 3-yl-ester (12) ((3S) -3-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester)
4-1. 7,7-디메틸-7H-피라노 [3,2-f]크로멘-2-온 (9)(7,7-dimethyl- 7H-pyrano[3,2-f]chromen-2-one)중간체의 제조4-1. 7,7-dimethyl-7H-pyrano [3,2-f] chromen-2-one (9) (7,7-dimethyl-7H-pyrano [3,2-f] chromen-2-one) intermediate Manufacture
상기 반응식에서 나타난 바와 같이 실시예 1-2의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 7,7-디메틸-5,6-디하이드로-7H-피라노 [3,2-f] 크로멘-2-온 (3b) (9.44g, 50.0mmol)을 넣고 500ml의 벤젠에 용해시킨 후 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(24.1g, 106.2mmol)을 넣고 5일 동안 교반하면서 환류시켰다. 반응 용액을 수포화 NaHSO3로 처리한 후 디에틸에테르로 추출한후 무수황산나트륨으로 탈수시킨 후 감압 농축하여 실리카겔 컬럼분리를 통하여 물성치를 갖는 7,7-디메틸-7H-피라노 [3,2-f]크로멘-2-온 (9)를 4.44g을 얻었다.As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 1-2 was placed in a round flask with 7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen. 2-one (3b) (9.44 g, 50.0 mmol) was added to dissolve in 500 ml of benzene, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (24.1 g, 106.2 mmol) was added. It was refluxed with stirring for 5 days. The reaction solution was treated with saturated NaHSO 3 , extracted with diethyl ether, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7,7-dimethyl-7H-pyrano [3,2-f] having physical properties through silica gel column separation. ] 4.44 g of chroman-2-one (9) was obtained.
수율: 47.5%;Yield: 47.5%;
연한 황색 고체성(solid);Light yellow solid;
Rf=0.452(n-Hexane:ethylacetate=3:2);R f = 0.452 (n-Hexane: ethylacetate = 3: 2);
mp= 118-119℃;mp = 118-119 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.910 (d, J=9.76, 1H), 7.103 (d, J=9.04, 1H), 6.986 (d, J=9.00, 1H ), 6.683 (d, J=10.04, 1H ), 6.439 (d, J=9.76, 1H ), 5.839 (d, J=10.00, 1H ), 1.456 (s, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.910 (d, J = 9.76, 1H), 7.103 (d, J = 9.04, 1H), 6.986 (d, J = 9.00, 1H), 6.683 (d, J = 10.04, 1H), 6.439 (d, J = 9.76, 1H), 5.839 (d, J = 10.00, 1H), 1.456 (s, 6H);
MS(m/z)229.3(M+H)+.MS ( m / z ) 229.3 (M + H) + .
4-2. (5s,6s)-5,6-에폭시-7,7-디메틸-5,6-디하이드로-7H-피라노[3,2-f] 크로멘-온 (10) ((5s,6s)-5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H- pyrano [3,2-f]chromen-2-one)중간체의 제조4-2. (5s, 6s) -5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-on (10) ((5s, 6s)- Preparation of 5,6-epoxy-7,7-dimethyl-5,6-dihydro-7H-pyrano [3,2-f] chromen-2-one) intermediate
상기 반응식에서 나타난 바와 같이 실시예 4-1의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 7-디메틸-7H-피라노 [3,2-f]크로멘-2-온 (9) (1.01g, 4.425mmol)을 넣고 아세토니트릴 용액 50ml에 용해시킨후 상온에서 (S, S)-(+), N, N’-비스(3,5-디-테트 부틸 살리 시리딘)-1,2-시클로헥산디아미노 망간네스(Ⅲ) 클로라이드(320.1mg, 0.504mmol)를 넣고 다음 소듐 테트라보레이트 데카하이드레이트(sodium tetraborate decahydrate)가 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(ethylene diamine tetraacetic acid disodium salt solution)에 있는 완충용액에 테트라 부틸 암모늄 비스술페이트(tetra butylammonium bisulfate)를 용해시킨 용액 35ml을 넣어준다. 이 혼합물을 0℃까지 냉각시킨 후 1,1,1-트라이플루오로아세톤(0.5ml)을 넣어주고 따라서 0.4mM의 에틸렌 디아민 테트라산 디나트륨염 용액(50ml)에 옥손(15g, 24.3mmol)을 첨가한 용액과 나트륨 바이카보네이트(3g, 35.7mmol) 수용액 50ml을 교반하면서 천천히 넣어주고 0℃에 1.5시간 동안 교반하면서 반응을 시킨다. 반응 혼합액을 물로 처리하고 디에틸에테르로 추출하고 유기층을 무수황산나트륨으로 탈수 시킨 후 감압농축하여 실리카걸 컬럼 분리를 통해 물성치를 갖는 (5s, 6s)-5,6-에폭시-7,7-디메틸-5,6-디하이드로-7H-피라노[3,2-f]크로멘-온 (10) 549mg 얻었다. As shown in the above scheme, the intermediate compound prepared in the same manner as in Example 4-1 was placed in a round flask with 7-dimethyl-7H-pyrano [3,2-f] chromen-2-one (9) (1.01). g, 4.425 mmol), dissolved in 50 ml of acetonitrile solution, and then (S, S)-(+), N, N'-bis (3,5-di-tet butyl salicyridine) -1,2 at room temperature. Add cyclohexanediamino manganese (III) chloride (320.1mg, 0.504mmol), and then add sodium tetraborate decahydrate to 0.4mM ethylene diamine tetraacetic acid disodium salt. 35 ml of a solution of tetra butylammonium bisulfate was added to the buffer solution. After the mixture was cooled to 0 ° C., 1,1,1-trifluoroacetone (0.5 ml) was added thereto, and oxone (15 g, 24.3 mmol) was added to 0.4 mM ethylene diamine tetrasodium disodium salt solution (50 ml). Slowly add the added solution and 50 ml of sodium bicarbonate (3 g, 35.7 mmol) aqueous solution with stirring, and react with stirring at 0 ° C. for 1.5 hours. The reaction mixture was treated with water, extracted with diethyl ether, the organic layer was dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (5s, 6s) -5,6-epoxy-7,7-dimethyl- having physical properties through separation of a silica gal column. 549 mg of 5,6-dihydro-7H-pyrano [3,2-f] chromen-one (10) was obtained.
수율: 50.8%;Yield: 50.8%;
연한황색의 반고체;Light yellow semisolid;
Rf=0.21(n-Hexane:ethylacetate=3:2);R f = 0.21 (n-Hexane: ethylacetate = 3: 2);
1H NMR(CDCl3,400MHz):δppm 8.069 (d, J=10.00, 1H), 7.230 (d, J=9.04, 1H), 7.017 ((d, J=9.00, 1H), 6.522 (d, J=9.76, 1H), 4.273 (d, J=4.36, 1H), 3.594 (d, J=4.36, 1H), 1.606 (s, 3H), 1.292 (s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 8.069 (d, J = 10.00, 1H), 7.230 (d, J = 9.04, 1H), 7.017 ((d, J = 9.00, 1H), 6.522 (d, J = 9.76, 1H), 4.273 (d, J = 4.36, 1H), 3.594 (d, J = 4.36, 1H), 1.606 (s, 3H), 1.292 (s, 3H);
MS(m/z)245.2(M+H)+;MS ( m / z ) 245.2 (M + H) + ;
[α]D 25=5.5 (c 6, CHCl3).[a] D 25 = 5.5 (c 6, CHCl 3 ).
4-3. (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠린(11)((6s)-6-hydroxy-7,7-dimethyl-5,6-dihydropyrano[3,2-f] coumarin) 중간체의 제조4-3. (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2-f] curin (11) ((6s) -6-hydroxy-7,7-dimethyl-5 , 6-dihydropyrano [3,2-f] coumarin) intermediates
상기 반응식에서 나타난 바와 같이 실시예 4-2의 방법과 동일하게 제조한 중간체 화합물를 라운드 플라스크에 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠마린 (11) (549mg, 2.25mmol)을 넣고 테트라하이드로 푸란(100ml)에 용해시켜 나트륨 시아노브롬하이드리드(183mg, 2.91mmol)와 보론트리플루오라이드 디에틸이써레이트(320mg, 2.26mmol)를 넣고 0℃에서 반응을 수행하다가 상온에서 2시간 교반한다. 반응 혼합물을 수포화 NaHCO3로 처리하고 아세트산 에틸로 추출하여 유기층을 감압농축하여 실리카겔 컬럼분리를 통하여 물성치를 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠마린 (11) 455.2mg 얻어 실험예의 시료로 사용하였다. As shown in the reaction scheme, the intermediate compound prepared in the same manner as in Example 4-2 was placed in a round flask with (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano [3,2]. -f] Add coumarin (11) (549 mg, 2.25 mmol) and dissolve in tetrahydrofuran (100 ml) to dissolve sodium cyanobromide (183 mg, 2.91 mmol) and borontrifluoride diethyl etherate (320 mg, 2.26). mmol) and the reaction was carried out at 0 ° C., followed by stirring at room temperature for 2 hours. The reaction mixture was treated with saturated NaHCO 3 , extracted with ethyl acetate, the organic layer was concentrated under reduced pressure, and the physical properties were determined by (6s) -6-hydroxy-7,7-dimethyl-5,6-dihydropyrano using silica gel column separation. 455.2 mg of [3,2-f] coumarin (11) was obtained and used as a sample for the experimental example.
수율: 82.2%;Yield: 82.2%;
백색의 고체상(solid)White solid
Rf=0.23(n-Hexane:ethylacetate=1:1);R f = 0.23 (n-Hexane: ethylacetate = 1: 1);
mp=167-168℃;mp = 167-168 ° C .;
1H NMR(CDCl3,400MHz):δppm 7.798 (d, J=9.76, 1H), 7.128 (d, J=9.04, 1H), 7.034 (d, J=9.00, 1H), 6.427 (d, J=9.76, 1H), 3.924 (s, 1H), 3.150 (dd, J=5.12, 16.84, 1H), 2.920 (dd, J=5.64, 17.08, 1H), 1.379 (s, 3H), 1.340 (s, 3H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.798 (d, J = 9.76, 1H), 7.128 (d, J = 9.04, 1H), 7.034 (d, J = 9.00, 1H), 6.427 (d, J = 9.76, 1H), 3.924 (s, 1H), 3.150 (dd, J = 5.12, 16.84, 1H), 2.920 (dd, J = 5.64, 17.08, 1H), 1.379 (s, 3H), 1.340 (s, 3H );
MS(m/z)247.4(M+H)+;MS ( m / z ) 247.4 (M + H) + ;
[α]D 25=3.9 (c 5, CHCl3).[a] D 25 = 3.9 (c 5, CHCl 3 ).
4-4. (3s)-3-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라 노[3,2-f]크로멘-3-일-에스터 (12) ((3S)-3-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano[3,2-f]chromen-3-yl-ester)의 제조4-4. (3s) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl- Ester (12) ((3S) -3-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3- yl-ester)
상기 반응식에서 나타난 바와 같이 실시예 4-3의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 3,3-디메틸아크릴산(69mg, 0.69mmol)을 넣고 10ml의 디클로로메탄으로 용해시키고 N-(3-디메틸아미노프로필)-N’-에틸카프보이아마이드 하이드로클로라이드 (EDC) (151mg, 1.01mmol) 및 4-디메틸아미노피리딘(26.3mg, 0.215mmol)과 (6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠마린 (11) (50.8mg, 0.206mmol)을 넣고 상온에서 48시간동안 교반하면서 반응을 진행시켰다. 반응 혼합액을 감압농축하여 실리카겔 컬럼을 통하여 물성치를 갖는 (3s)-3-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (LS-1) 36.7mg을 얻어 실험예의 시료로 사용하였다. As shown in the scheme, 3,3-dimethylacrylic acid (69 mg, 0.69 mmol) was added to a round flask in the same manner as in Example 4-3, and dissolved in 10 ml of dichloromethane. Dimethylaminopropyl) -N'-ethylcarbodiamide hydrochloride (EDC) (151 mg, 1.01 mmol) and 4-dimethylaminopyridine (26.3 mg, 0.215 mmol) and (6s) -6-hydroxy-7,7- Dimethyl-5,6-dihydropyrano [3,2-f] coumarin (11) (50.8 mg, 0.206 mmol) was added thereto, and the reaction proceeded while stirring at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and (3s) -3-methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [ 36.7 mg of 3,2-f] chromen-3-yl-ester (LS-1) was obtained and used as a sample for the experimental example.
수율: 66.3%;Yield: 66.3%;
무색의 반고체상Colorless semisolid
Rf=0.38(n-Hexane:ethylacetate=2:1);R f = 0.38 (n-Hexane: ethylacetate = 2: 1);
1H NMR(CDCl3,400MHz):δppm 7.769 (d, J=9.76, 1H), 7.151 (d, J=9.04, 1H), 7.048 (d, J=9.28, 1H), 6.435 (d, J=9.76, 1H), 5.687 (s, 1H), 5.114 (t, J=5.4, 1H), 3.257 (dd, J=5.36, 17.32, 1H), 2.930 (dd, J=5.12, 17.32, 1H), 2.168 (s, 3H), 1.892 (s, 3H), 1.352 (d, J=8.04, 6H); 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.769 (d, J = 9.76, 1H), 7.151 (d, J = 9.04, 1H), 7.048 (d, J = 9.28, 1H), 6.435 (d, J = 9.76, 1H), 5.687 (s, 1H), 5.114 (t, J = 5.4, 1H), 3.257 (dd, J = 5.36, 17.32, 1H), 2.930 (dd, J = 5.12, 17.32, 1H), 2.168 (s, 3H), 1.892 (s, 3H), 1.352 (d, J = 8.04, 6H);
MS(m/z)329.3(M+H)+;MS ( m / z ) 329.3 (M + H) + ;
[α]D 25=18.3 (c 3, CHCl3).[a] D 25 = 18.3 (c 3, CHCl 3 ).
실시예 5. (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (13) ((3S)-2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano[3,2-f]chromen-3-yl-ester)의 제조Example 5. (3s) -2-Methyl-but-2-tenophosphoric acid-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen- 3-yl-ester (13) ((3S) -2-methyl-but-2-enoic acid-2,2-dimethyl-7-oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl-ester)
상기 반응식에서 나타난 바와 같이 실시예 4-3의 방법과 동일하게 제조한 중간체 화합물을 라운드 플라스크에 엔젤산 (150.9mg, 1.507 mmol)을 넣고 15ml의 디클로로메탄으로 용해시키고 N-(3-디메틸아미노프로필)-N’-에틸카프보이아마이드 하이드로클로라이드 (EDC) (250mg, 1.304mmol) 및 4-디메틸아미노피리딘(50.7mg, 0.415mmol)과 ((6s)-6-하이드록시-7,7-디메틸-5,6-디하이드로피라노 [3,2-f] 쿠마린 (11) (106mg, 0.43mmol)을 넣고 상온에서 72시간동안 교반하면서 환류시킨다. 반응 혼합액을 감압농축하여 실리카겔 컬럼을 통하여 물성치를 갖는 (3s)-2-메틸-부-2-테노인산-2,2-디메틸-7옥소-3,4-디하이드로-2H-피라노[3,2-f]크로멘-3-일-에스터 (LS-2) 87mg을 얻어 실험예의 시료로 사용하였다. As shown in the reaction scheme, the intermediate compound prepared in the same manner as in Example 4-3 was added angelic acid (150.9 mg, 1.507 mmol) to a round flask, dissolved in 15 ml of dichloromethane, and then N- (3-dimethylaminopropyl). ) -N'-ethylcarbodiamide hydrochloride (EDC) (250 mg, 1.304 mmol) and 4-dimethylaminopyridine (50.7 mg, 0.415 mmol) and ((6s) -6-hydroxy-7,7-dimethyl- 5,6-Dihydropyrano [3,2-f] coumarin (11) (106 mg, 0.43 mmol) was added thereto, and the mixture was refluxed under stirring at room temperature for 72 hours.The reaction mixture was concentrated under reduced pressure to obtain physical properties through a silica gel column. (3s) -2-Methyl-but-2-tenophosphate-2,2-dimethyl-7oxo-3,4-dihydro-2H-pyrano [3,2-f] chromen-3-yl- 87 mg of ester (LS-2) was obtained and used as a sample of an experiment example.
수율: 61%;Yield: 61%;
무색의 반고체상Colorless semisolid
Rf=0.357 (n-Hexane:ethyl acetate=2:1);R f = 0.357 (n-Hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3, 400MHz): δppm 7.774 (d, J=9.76, 1H), 7.149 (d, J=9.00, 1H), 7.056 (d, J=9.04, 1H), 6.854 (q, J=7.04, 1H), 6.434 (d, J=10.0, 1H), 5.120 (t, J=5.4, 1H), 3.291 (dd, J=5.36, 17.32, 1H), 2.943 (dd, J=5.38, 17.34, 1H), 1.824 (s, 3H), 1.784 (d, J=7.08, 3H), 1.367 (d, J=6.12, 6H) 1 H NMR (CDCl 3 , 400 MHz): δ ppm 7.774 (d, J = 9.76, 1H), 7.149 (d, J = 9.00, 1H), 7.056 (d, J = 9.04, 1H), 6.854 (q, J = 7.04, 1H), 6.434 (d, J = 10.0, 1H), 5.120 (t, J = 5.4, 1H), 3.291 (dd, J = 5.36, 17.32, 1H), 2.943 (dd, J = 5.38, 17.34, 1H), 1.824 (s, 3H), 1.784 (d, J = 7.08, 3H), 1.367 (d, J = 6.12, 6H)
MS(m/z) 329.3 (M+H)+ MS ( m / z ) 329.3 (M + H) +
[α]D 25=25.8 (c 5, CHCl3).[a] D 25 = 25.8 (c 5, CHCl 3 ).
실험예 1. EoL-1에서 mite에 의해 유도된 MCP-1/IL-6/IL-8분비에 미치는 (+)-데쿠르신-에테르 유도체의 영향 측정Experimental Example 1. Determination of the effect of (+)-decurin-ether derivatives on mite-induced MCP-1 / IL-6 / IL-8 secretion in EoL-1
일본세포주은행에서 구입한 인간 호산구(eosinophil)인 EoL-1 (eosinophilic leukemia cell, 일본세포주은행(RCB 0641)) 세포를 이용하여 상기 실시예에서 합성한 데쿠르신-에테르 유도체들의 ELISA를 측정하기 위하여 하기와 같이 실험을 수행하였다.In order to measure the ELISA of the decursin-ether derivatives synthesized in the above Example using EoL-1 (eosinophilic leukemia cell (RCB 0641)) cells, which are human eosinophils purchased from Nippon Cell Line Bank, The experiment was performed as follows.
상기 참조예 1 에서 배양시킨 EoL-1 세포를 0.5% FBS 및 항생제(100 U/㎖ penicillin, 100㎍/㎖ streptomycin)가 든 RPMI(Life Technologies Inc.)에 2.0 x 106/m로 24 웰 플레이트에 분주한 후 배양기 (37℃, 5% CO2)에서 1시간 배양하였다. 배양 후 실시예 1 내지 3의 (+)-데쿠르신-구조이성체 합성 유도체들(10 ㎍/㎖)을 각각 1시간 동안 처리한 후 진드기 항원 (mite) (1㎍/㎖)를 각각 24시간 동안 처리한 다음, 엘리사 키트(ELISA kit)를 이용하여 상층액에서 단핵구 화학유인물질 단백질-1 (monocyte chemoattractant protein-1, MCP-1), IL-6, IL-8의 양을 측정하였고, 실험결과를 하기 표 2에 나타내었다.EoL-1 cells incubated in Reference Example 1 were plated at 24 × well plates at 2.0 × 10 6 / m in RPMI (Life Technologies Inc.) containing 0.5% FBS and antibiotics (100 U / ml penicillin, 100 μg / ml streptomycin). After aliquoting, the cells were incubated for 1 hour in an incubator (37 ° C., 5% CO 2 ). After incubation, the (+)-decursin-structure isomeric synthetic derivatives (10 μg / ml) of Examples 1 to 3 were treated for 1 hour, and then the mite (1 μg / ml) was treated for 24 hours, respectively. After treatment, the amount of monocyte chemoattractant protein-1 (MCP-1), IL-6, and IL-8 was measured in the supernatant using an ELISA kit. Is shown in Table 2 below.
(pg/ml)(pg / ml)
(pg/ml)(pg / ml)
실험결과, EoL-1 세포의 정상군에서의 MCP-1, IL-6 및 IL-8의 양은 19.50, 15.55 및 15.52 pg/ml인데 반해, 항원인 진드기를 처리하면 MCP-1, IL-6 및 IL-8의 양이 236.77, 39.50 및 23.64 pg/ml으로 증가됨을 확인할 수 있었다. 이렇게 진드기에 의해서 증가된 상태에서 양성대조군인 덱사메타손을 처리하면 MCP-1, IL-6 및 IL-8의 양은 94.50, 8.32 및 5.52 pg/ml으로 나타났으며, 이를 화합물과 비교해 보면 먼저, 화합물 LM-1의 경우는 22.68, 23.71 및 6.61 pg/ml로 나타났고, 화합물 LM-2의 경우는 0.86, 4.37 및 15.20 pg/ml로 나타났으며, 화합물 LM-3의 경우는 19.50, 15.55 및 10.36으로 확인되어 양성대조군으로 사용한 덱사메타손과 동등한 수준의 효과를 나타냄을 확인할 수 있다(표 1 참조). 또한, MTT assay를 통한 독성은 확인되지 않았다. Experimental results show that the amounts of MCP-1, IL-6 and IL-8 in the normal group of EoL-1 cells are 19.50, 15.55 and 15.52 pg / ml, whereas MCP-1, IL-6 and The amount of IL-8 was confirmed to increase to 236.77, 39.50 and 23.64 pg / ml. Treatment of dexamethasone, a positive control in the increased state by ticks, resulted in 94.50, 8.32 and 5.52 pg / ml of MCP-1, IL-6 and IL-8. -1 for 22.68, 23.71 and 6.61 pg / ml, for compound LM-2 0.86, 4.37 and 15.20 pg / ml, for compound LM-3 19.50, 15.55 and 10.36 It can be confirmed that the same effect as the dexamethasone used as a positive control group (see Table 1). In addition, no toxicity was confirmed through the MTT assay.
하기에 상기 조성물의 제제예를 설명하나, 이는 본 발명을 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Examples of the formulation of the composition are described below, but are not intended to limit the present invention but to explain in detail only.
제제예 1. 산제의 제조 Formulation Example 1 Preparation of Powder
(+)-데쿠르신-구조이성체 합성 유도체 (LM-1) 20 mg(+)-Decursin-structural isomer synthetic derivative (LM-1) 20 mg
유당 100 mgLactose 100 mg
탈크 10 mgTalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
(+)-데쿠르신-구조이성체 합성 유도체 (LM-2) 10 mg(+)-Decursin-structural isomer synthetic derivative (LM-2) 10 mg
옥수수전분 100 mgCorn starch 100 mg
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예 3. 캅셀제의 제조Formulation Example 3 Preparation of Capsule
(+)-데쿠르신-구조이성체 합성 유도체 (LM-3) 10 mg(+)-Decursin-structural isomer synthetic derivative (LM-3) 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
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 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
(+)-데쿠르신-구조이성체 합성 유도체 (LS-1) 10 mg(+)-Decursin-structural isomer synthetic derivative (LS-1) 10 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO412H2O 26 mgNa2HPO412H2O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예 5. 액제의 제조Formulation Example 5 Preparation of Liquid
(+)-데쿠르신-구조이성체 합성 유도체 (LS-2) 20 mg(+)-Decursin-structural isomer synthetic derivative (LS-2) 20 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to the conventional method for preparing a liquid, each component is added and dissolved in purified water, lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. The solution is prepared by sterilization.
제제예 6. 건강 식품의 제조Formulation Example 6 Preparation of Healthy Food
(+)-데쿠르신-구조이성체 합성 유도체 (LM-1) 1000 ㎎(+)-Decursin-structural Isomer Synthetic Derivative (LM-1) 1000 mg
비타민 혼합물 적량Vitamin mixture proper amount
비타민 A 아세테이트 70 ㎍70 μg of vitamin A acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 ㎎Vitamin C 10 mg
비오틴 10 ㎍10 μg biotin
니코틴산아미드 1.7 ㎎Nicotinic Acid 1.7 mg
엽산 50 ㎍50 μg folic acid
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture
황산제1철 1.75 ㎎Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎Dibasic calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium Citrate 90 mg
탄산칼슘 100 ㎎Calcium Carbonate 100 mg
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
제제예 7. 건강 음료의 제조Formulation Example 7 Preparation of Healthy Drink
(+)-데쿠르신-구조이성체 합성 유도체 (LM-2) 1000 ㎎(+)-Decursin-Somer Isomer Synthesis Derivative (LM-2) 1000 mg
구연산 1000 ㎎Citric acid 1000 mg
올리고당 100 g100 g oligosaccharides
매실농축액 2 gPlum concentrate 2 g
타우린 1 g1 g of taurine
정제수를 가하여 전체 900 ㎖Add 900 ml of purified water
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above components according to a conventional healthy beverage production method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained by sterilization in a sterilized 2 L container, sealed sterilized and then stored in the present invention For the preparation of healthy beverage compositions.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용 용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is mixed with a relatively suitable component in a preferred embodiment in a preferred embodiment, the compounding ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.
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