KR20100008808A - A composition comprising novel (+)-decursin-ether derivative for treating and preventing atopic dermatitis disease - Google Patents
A composition comprising novel (+)-decursin-ether derivative for treating and preventing atopic dermatitis disease Download PDFInfo
- Publication number
- KR20100008808A KR20100008808A KR1020080069373A KR20080069373A KR20100008808A KR 20100008808 A KR20100008808 A KR 20100008808A KR 1020080069373 A KR1020080069373 A KR 1020080069373A KR 20080069373 A KR20080069373 A KR 20080069373A KR 20100008808 A KR20100008808 A KR 20100008808A
- Authority
- KR
- South Korea
- Prior art keywords
- group
- dimethyl
- pyrano
- dihydro
- chromen
- Prior art date
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
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- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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- A23L29/035—Organic compounds containing oxygen as heteroatom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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Abstract
Description
본 발명은 참당귀에서 분리된 (+)-데쿠르시놀(decursinol)을 전구체로 기존에 알려진 에스테르 형태의 (+)-데쿠르신 유도체(decursin derivative)보다 안정한 구조인 에테르 형태의 (+)-데쿠르신-에테르 유도체(decursin-ether derivative)를 유효성분으로 함유하는 조성물에 관한 것이다. The present invention is an ether form of (+)-decous, which has a more stable structure than the (+)-decursin derivative of the ester form known as a precursor using (+)-decursinol isolated from Angelica gigas. It relates to a composition containing a decursin-ether derivative as an active ingredient.
[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 2312-24, 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 , pp559-564, 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 , pp 227-237, 2003). In particular incidence (Colloff MJ. Atopic dermatitis in proportion to the amount of exposure to house dust mite as the basis, Exposure to house dust mites in homes of people with atopic dermatitis. Br. J. Dermatol., 127, pp322-327, 1992) and may be a significant correlation between the 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. Pediatr. 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 . Immunol ., 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), bronchial hypersensitivity is induced by IL-8 appears and is increased in the allergic rhinitis or 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, is suppressed by the pp313-316, 1996) steroids .
(+)-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 Angelica gigas ) is a plant of the umbelliferae and refers to Korean Angelica, and young shoots are used as medicines for various diseases such as edible and rooted analgesic effect, renal toxicity alleviation, and diabetic hypertension treatment (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] They are materials (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. there bar (J. Kim 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).
따라서 본 발명자는 (+)-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).Therefore, the present inventors synthesized (+)-decursinol as a starting material and synthesized new (+)-decusrin derivatives of ester forms of various structures that do not exist in Angelica gigas and their anti-atopic dermatitis. As a result of measuring the effect, it was confirmed that the excellent atopic inhibitory effect and confirmed the possibility of use as a therapeutic agent for atopic dermatitis has been notified a patent decision (Korea Patent Registration: 10-2007-18057).
그러나 위와 같은 (+)-데쿠르시놀의 알콜기에 여러 가지 유기산으로 에스터화 한 에스터 형태의 (+)-데쿠르신(decursin) 유도체들은 혈액내에 존재하는 에스테라제(esterase)와 같은 효소에 의해서 (+)-데쿠르시놀로 분해되는 단점을 지니고 있다.However, the ester form of (+)-decursin derivatives esterified with various organic acids in the alcohol group of (+)-decurinol as described above is produced by an enzyme such as esterase present in the blood ( It has the disadvantage of being degraded into +)-decurinol.
따라서 본 발명자는 에스터 형태의 구조보다는 에테르 형태와 같은 보다 안정한 구조인 (+)-데쿠르신-에테르 유도체들(decursin-ether derivatives)을 합성하고 그들의 항아토피효과를 측정한 결과, 우수한 아토피 억제 효과를 확인함으로써 본 발명을 완성하게 되었다.Therefore, the present inventors synthesized (+)-decursin-ether derivatives, which are more stable structures like the ether form, than the ester form, and measured their anti-atopic effects, and thus, showed excellent atopic inhibition effect. The present invention was completed by confirming.
상기 목적을 달성하기 위하여, (+)-데쿠르시놀을 전구체로 하여 합성된 하기 일반식 (I)로 표기되는 신규 구조의 (+)-데쿠르신-에테르 유도체(decursin-ether derivative) 화합물 또는 이의 약학적으로 허용가능한 염:In order to achieve the above object, a (+)-decursin-ether derivative compound of the novel structure represented by the following general formula (I) synthesized using (+)-decursinol as a precursor or its Pharmaceutically acceptable salts:
상기식에서,In the above formula,
R1는 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 a C 1 to C 20 alkyl group unsubstituted or substituted with one or more R ′, C 2 to C 20 Alkenyl groups, C 2 to C 20 At least one substituent selected from the group consisting of an alkynyl group and an A substituent, 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, hydrogen atom, hydroxy group, acetate group, halogen atom, C 1 to C 4 lower alkyl group, C 1 to C 4 Lower alkoxy groups, C 1 to C 4 Lower alkyl esters and C 1 to C 4 At least one substituent selected from the group consisting of 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 R1 은 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.Preferred compound groups of the above general formula (I) compound include R 1 is a C 1 to C 10 alkyl group unsubstituted or substituted with a halogen atom or a C 1 to C 4 lower alkyl group, C 2 to C 10 Alkenyl groups, C 2 to C 10 Alkynyl is a substituent selected from the group and the group A consisting of the substituents, where the A substituent of R '' is o, m, p of the hydrogen atoms substituted at the position, a hydroxy group, an amine group, a halogen atom, a methyl group, an ethyl group, a methoxy group, At least one substituent selected from 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;
가장 바람직하게는 일반식 (I) 화합물로는 하기와 같은 화합물들을 들 수 있으며, 본 발명은 발명의 범위를 이에 제한하고자 함이 아니다.Most preferably, the compounds of the general formula (I) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.
(7S)-7-메톡시-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3a), (7S)-8,8-디메틸-7-(3-메틸-부-2-테닐록시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3b), (7S)-8,8-디메틸-7-(2-메틸-알릴록시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3c),(7S)-8,8-디메틸-7-(3-페닐-프로폭시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3d), (7S)-7-[3-(2-메톡시-페닐)-프로폭시]-8,8-디메 틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7a), (7S)-7-[3-(3-메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7b), (7S)-7-[3-(4-메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7c), (7S)-7-[3-(3,4-디메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7d), (7S)-7-[3-(2,3-디메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7e), (7S)-8,8-디메틸-7-[3-(3,4,5-트리메톡시페닐)-프로폭시)]-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7f), (7S)-8,8-디메틸-7-(3-페닐-알릴록시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(12a) 또는 (7S)-7-[3-(4-메톡시-페닐)-알릴록시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(12b) .(7S) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3a), (7S) -8,8 -Dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3b), (7S)- 8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3c), (7S) -8 , 8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3d), (7S) -7- [3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7a) , (7S) -7- [3- (3-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen- 2-one (7b), (7S) -7- [3- (4-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2 g ] chromen-2-one (7c), (7S) -7- [3- (3,4-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -Pyrano [3,2- g ] chromen-2-one (7d), (7S) -7- [3- (2,3-dimethoxy-phenyl) -propoxy] -8,8-dimethyl -7,8-diha Draw - 6H - pyrano [3,2- g] chromen-2-one (7e), (7S) -8,8- dimethyl-7- [3- (3,4,5-trimethoxyphenyl) -Propoxy)]-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7f), (7S) -8,8-dimethyl-7- (3-phenyl -Allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (12a) or (7S) -7- [3- (4-methoxy-phenyl) -Allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (12b).
상기 일반식 (Ⅰ)로 표시되는 본 발명의 화합물들은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용가능한 염으로 제조될 수 있다. The compounds of the present invention represented by the general formula (I) may be prepared as pharmaceutically acceptable salts according to methods conventional 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.Bases can also 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) 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 일반식 (Ⅰ) 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) include salts of acidic or basic groups which may be present in compounds of formula (I), 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) 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), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.
하기의 반응식들은 본 발명의 대표적인 화합물들의 제조방법을 제조 단계별로 나타내는 것으로 본 발명의 여러 화합물들은 반응식 1 내지 반응식 3의 합성과정에서 사용되는 시약, 용매 및 반응 순서를 바꾸는 등의 작은 변경으로 제조될 수 있다. 본 발명의 몇몇 화합물들은 반응식 1 내지 반응식 3의 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 3. Can be. Some compounds of the present invention have been synthesized according to processes not included in the scope of Schemes 1 through 3, and detailed synthesis procedures for these compounds are described in their respective examples.
반응식 (1)은 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 1단계 제조과정을 나타낸다.Scheme (1) shows a one-step preparation process for preparing a commercial compound or a compound synthesized by known methods.
제 1단계에서는 (+)-데쿠르시놀(Ⅰa)을 무수 N,N-디메틸포름아마이드 드의 용매로 용해시킨 후에 수소화나트륨과 요오드화메탄등의 알칼화제를 넣고 반응시킨 다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 N,N-디메틸포름아마이드 및 디메틸설폭사이드 등을 이용하여 반응을 수행한다. 반응 온도는 일반적으로 -20℃ 내지 -40℃에서 수행할 수 있고, 바람직하게는 -20℃에서 수행한다. 반응 시간은 12시간 내지 48시간동안 수행할 수 있고, 바람직하게는 24시간동안 교반한다. 반응액을 실리카겔 단 컬럼에 여과하여 농축한 후, 농축 플라스크를 90-100℃에서 중탕처리하면서 진공에서 N,N-디메틸포름아마이드등의 잔류용매를 제거한다. 얻은 잔사를 실리카겔 컬럼 분리를 통해 알콕시체(Ⅰb)를 제조할 수 있다.In the first step, (+)-decurinol (Ia) is dissolved in a solvent of anhydrous N, N -dimethylformamide , and then reacted with an alkalizing agent such as sodium hydride and methane iodide. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, such as N, N- dimethylformamide and dimethyl sulfoxide. The reaction temperature can generally be carried out at -20 ° C to -40 ° C, preferably at -20 ° C. The reaction time can be carried out for 12 to 48 hours, preferably for 24 hours. The reaction solution was concentrated by filtration over a silica gel column, followed by removing the residual solvent such as N, N -dimethylformamide under vacuum while concentrating the concentrated flask at 90-100 ° C. The obtained residue can be prepared alkoxyl (Ib) through silica gel column separation.
반응식 (2)는 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 3단계 제조과정을 나타낸다.Scheme (2) shows a three step preparation process for preparing a commercial compound or a compound synthesized by known methods.
제 1단계에서는 R''로 치환된 신남산(Ⅱa') 또는 프로피온산(Ⅱa'')을 무수 테트라하이드로푸란드의 용매로 용해시킨 후에 수소화알루미늄리튬등의 환원제를 넣고 반응시켜 알콜체(Ⅱb)를 제조한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 테트라하이드로푸란, 디에틸에테르, 디클로로메탄 및 클로로포름 등의 용매를 이용하여 반응을 수행하며, 바람직하게는 테트라하이드로푸란을 이용한다. 반응 온도는 일반적으로 상온 내지 0℃로 하며, 바람직하게는 상온에서 수행한다. 반응 시간은 2 시간 내지 24시간동안 수행할 수 있고, 바람직하게는 약 3시간 내지 12시간동안 교반한다. 반응액에 증류수를 서서히 가한 후, 열이 발생하지 않을 때까지 교반한다. 여기에 HCl등의 산을 넣어 pH 1 내지 5가 되게 하고 디클로로메탄등의 유기용매로 추출한다. 여액은 무수망초로 탈수하여 감압농축 하였으며 얻은 잔사를 실리카겔 컬럼분리를 통해 알콜체(Ⅱb)를 제조할 수 있다. In the first step, cinnamic acid (IIa ') or propionic acid (IIa' ') substituted with R' 'is dissolved in a solvent of anhydrous tetrahydrofuran, and then reacted with a reducing agent such as lithium aluminum hydride. To prepare. At this time, the solvent used is a solvent that does not adversely affect the reaction using a solvent such as tetrahydrofuran, diethyl ether, dichloromethane and chloroform, preferably using tetrahydrofuran. The reaction temperature is generally from room temperature to 0 ° C., preferably at room temperature. The reaction time can be carried out for 2 to 24 hours, preferably for about 3 to 12 hours. Distilled water is slowly added to the reaction solution, followed by stirring until no heat is generated. Add an acid such as HCl to pH 1 to 5 and extract with an organic solvent such as dichloromethane. The filtrate was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure, and the obtained residue could be prepared by silica gel column separation to prepare alcohol (IIb).
제 2단계에서는 두 가지 다른 방법으로 1-(3-브로모-프로필)-2-메톡시벤젠 또는 1-(3-아이오도-프로필)-2-메톡시벤젠등의 할로겐화물로 합성하여 다음 반응에 이용할 수 있다. 예를들어, 첫 번째 방법은 1-(3-브로모-프로필)-2-메톡시벤젠을 제조하는 방법으로 3-(2-메톡시페닐)프로판-1-올, 보론 트리브로마이드등의 할로겐화제를 가하여 디클로로메탄등의 용매하에 용해하여 반응시킨다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 톨루엔, 벤젠, 디클로로메탄, 클로로포름, 사염화탄소 등을 이용하여 반응을 수행한다. 반응 온도는 일반적으로 0℃ 내지 상온에서 수행할 수 있으며 바람직하게는 0℃에서 수행한다. 반응시간은 30분 내지 24시간동안 수행할 수 있고 바람직하게는 2시간 내지 12시간 교반한다. 반응액을 감압농축하여 얻은 잔사를 실리카겔 컬럼 분리를 통해 1-(3-브로모-프로필)-2-메톡시벤젠(Ⅱc')을 제조할 수 있다. 두 번째 방법은 1-(3-아이오도-프로필)-2-메톡시벤젠을 제조하는 방법으로 3-(2-메톡시페닐)프로판-1-올, 트리페닐포스핀, 요오드, 이미다졸등의 용매를 톨루엔등의 유기용매로 용해하여 반응시킨다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 톨루엔, 벤젠 등을 이용하여 반응을 수행한다. 반응 온도는 일반적으로 0℃ 내지 상온에서 수행할 수 있으며 바람직하게는 상온에서 수행한다. 반응시간은 30분 내지 24시간동안 수행할 수 있고 바람직하게는 30분 내지 12시간 교반한다. 반응액을 감압농축하여 얻은 잔사를 실리카겔 컬럼 분리를 통해 1-(3-아이오도-프로필)-2-메톡시벤젠(Ⅱc'')을 제조할 수 있다. 본 단계에서는 두 번째 방법을 이용하는 것이 경제적이고 반응 조작에 있어 보다 수월하고 안전하지만 2-메톡시기(6a), 3-메톡시기(6b) 또는 4-메톡시기(6c)가 치환된 물질의 경우 반응에 사용하는 시약인 트리페닐포스핀과 극성(Rf값)이 거의 유사하여 분리, 정제하는 것이 어려우므로 첫 번째 방법을 이용하는 것이 더 바람직하다. 그러나 3,4-디메톡시기(6d), 2,3-디메톡시기(6e) 또는 3,4,5-트리메톡시기(6f)가 치환된 물질의 경우는 두 번째 방법을 이용하는 것이 바람직하다. 제 3단계에서는 상기 반응식 1의 (+)- 데쿠르시놀(Ⅰa)을 무수 N,N-디메틸포름아마이드로 용해시킨 후 수소화나트륨과 1-(3-할로-프로필)-2-메톡시벤젠을 넣고 반응시킨다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 N,N-디메틸포름아마이드, 디메틸설폭사이드 등을 이용하여 반응을 수행한다. 반응 온도는 일반적으로 -20℃ 내지 -40℃에서 수행할 수 있고, 바람직하게는 -20℃에서 수행한다. 반응 시간은 12시간 내지 48시간동안 수행할 수 있고, 바람직하게는 24시간동안 교반한다. 반응액을 실리카겔 단 컬럼에 여과하여 농축한 후, 농축 플라스크를 90-100℃ 중탕처리하면서 진공에서 N,N-디메틸포름아마이드를 제거한다. 얻은 잔사를 실리카겔 컬럼 분 리를 통해 (7S)-7-[3-(2-메톡시페닐)프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(Ⅱd)을 제조할 수 있다.In the second step, two different methods are used to synthesize a halide such as 1- (3-bromo-propyl) -2-methoxybenzene or 1- (3-iodo-propyl) -2-methoxybenzene. It can be used for the reaction. For example, the first method is to prepare 1- (3-bromo-propyl) -2-methoxybenzene and halogen such as 3- (2-methoxyphenyl) propan-1-ol and boron tribromide. An agent is added and dissolved in a solvent such as dichloromethane to react. In this case, the solvent is used toluene, benzene, dichloromethane, chloroform, carbon tetrachloride and the like which do not adversely affect the reaction. The reaction temperature may generally be carried out at 0 ° C to room temperature, preferably at 0 ° C. The reaction time may be carried out for 30 minutes to 24 hours and preferably stirred for 2 hours to 12 hours. The residue obtained by concentrating the reaction solution under reduced pressure may prepare 1- (3-bromo-propyl) -2-methoxybenzene (IIc ') through silica gel column separation. The second method is to prepare 1- (3-iodo-propyl) -2-methoxybenzene, 3- (2-methoxyphenyl) propan-1-ol, triphenylphosphine, iodine, imidazole, etc. Solvent is dissolved in an organic solvent such as toluene and reacted. At this time, the solvent is used toluene, benzene and the like that do not adversely affect the reaction to perform the reaction. The reaction temperature can generally be carried out at 0 ℃ to room temperature, preferably at room temperature. The reaction time can be carried out for 30 minutes to 24 hours and preferably stirred for 30 minutes to 12 hours. The residue obtained by concentrating the reaction solution under reduced pressure can be prepared 1- (3-iodo-propyl) -2-methoxybenzene (IIc '') by silica gel column separation. In this step, the second method is economical and easier and safer to operate, but in the case of a substance substituted with 2-methoxy group (6a), 3-methoxy group (6b) or 4-methoxy group (6c) Since the polarity (R f value) is almost similar to triphenylphosphine, which is a reagent for use, it is difficult to separate and purify. However, in the case of a substance substituted with 3,4-dimethoxy group (6d), 2,3-dimethoxy group (6e) or 3,4,5-trimethoxy group (6f), it is preferable to use the second method. . In the third step, (+)- decursinol (Ia) of Scheme 1 is dissolved with anhydrous N, N -dimethylformamide , and sodium hydride and 1- (3-halo-propyl) -2-methoxybenzene are dissolved. Put and react. At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, N, N- dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature can generally be carried out at -20 ° C to -40 ° C, preferably at -20 ° C. The reaction time can be carried out for 12 to 48 hours, preferably for 24 hours. The reaction solution was concentrated by filtration over a silica gel column, and the concentrated flask was then heated at 90-100 ° C. to remove N, N -dimethylformamide under vacuum. The obtained residue was subjected to (7S) -7- [3- (2-methoxyphenyl) propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2 through silica gel column separation. g ] chromen-2-one (IId) can be prepared.
반응식 (3)은 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물을 제조하기 위한 4단계 제조과정을 나타낸다.Scheme (3) shows a four step preparation process for preparing commercial compounds or compounds synthesized by known methods.
예를 들어, 제 1단계에서는 신남산 유도체(Ⅲa)를 메탄올등의 용매에 용해시킨 후에 농축황산등의 강산을 넣고 가온 환류시킨다. 반응온도는 70℃ 내지 90℃에서 수행하며, 바람직하게는 80℃에서 수행한다. 반응 시간은 12-36시간동안 수행할 수 있고, 바람직하게는 24시간동안 교반한다. 반응액을 상온으로 냉각시킨 후 농축하여 얻은 잔사를 실리카겔 컬럼분리를 통해 3-페닐-아크릴산 메틸에스터(Ⅲb)을 제조할 수 있다. 제 2단계에서는 질소충전된 라운드 플라스크에 3-페닐-아크릴산 메틸에스터(Ⅲb)를 무수 디클로로메탄등의 유기용매에 용해하여 -78℃로 냉각시킨 후, 디이소부틸알루미늄 하이드라이드(DIBAL-H, 1M 용액 in hexane)를 10분 내지 2시간, 바람직하게는 20분 내지 1시간에 걸쳐 적가시킨다. 반응액을 0℃ 내지 25℃, 바람직하게는 0℃ 내지 10℃로 냉각하여 30분 내지 5시간, 바람직하게는 30분 내지 2시간 동안 교반한 후, 메탄올등의 용매을 적가한다. 반응액을 0℃ 내지 50℃, 바람직하게는 상온으로 냉각하여 10분 내지 2시간, 바람직하게는 30분 내지 1시간 교반하고 포화 로셀염(Rochelle's salt)을 가한다. 반응액을 격렬하게 30분 내지 5시간, 바람직하게는 1시간 내지 3시간동안 교반한 뒤 디클로로메탄등의 유기용매로 추출하여 무수망초로 탈수한 후, 감암농축한다. 얻은 잔사를 실리카겔 컬럼분리를 통해 3-페닐-프로-2-펜-1-올(Ⅲc)을 제조할 수 있다. 제 3단계에서는 3-페닐-프로-2-펜-1-올(Ⅲc)에 보론 트리브로마이드(1M 용액 in dichloromethane)등의 브롬화제를 디클로로메탄등의 유기용매에 용해하여 반응시킨다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 톨루엔, 벤젠, 디클로로메탄, 클로로포름, 사염화탄소등의 유기용매를 이용하여 반응을 수행한다. 반응 온도는 일반적으로 -20℃ 내지 50℃에서 수행할 수 있으며 바람직하게는 0℃ 내지 상온에서 수행한다. 반응시간은 30분 내지 24시간동안 수행할 수 있고 바람직하게는 30분 내지 12시간 교반한다. 반응액을 증류수가 담긴 삼각플라스크에 붓고 10분간 교반한다. 반응혼액은 포화탄산수소나트륨과 디에틸에테르등의 유기용매로 분액하였고, 디에틸에테르층은 무수망초로 탈수하여 감압농축한다. 얻은 잔사를 실리카겔 컬럼 분리를 통해 (3-브 로모-프로페닐)-벤젠(Ⅲd)을 제조할 수 있다. 제 4단계에서는 상기 반응식 1의 (+)-데쿠르시놀(Ⅰa)을 무수 N,N-디메틸포름아마이드로 용해시킨 후 수소화나트륨과 (3-브로모-프로페닐)-벤젠(Ⅲd)을 넣고 반응시킨다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 N,N-디메틸포름아마이드, 디메틸설폭사이드 등의 용매를 이용하여 반응을 수행한다. 반응 온도는 일반적으로 -20℃ 내지 -40℃에서 수행할 수 있고, 바람직하게는 -20℃에서 수행한다. 반응 시간은 12시간 내지 48시간동안 수행할 수 있고, 바람직하게는 24시간동안 교반한다. 반응액을 실리카겔 단 컬럼에 여과하여 농축한 후, 농축 플라스크를 90-100℃에서 중탕처리하면서 진공에서 N,N-디메틸포름아마이드를 제거한다. 얻은 잔사를 실리카겔 컬럼 분리를 통해 (7S)-8,8-디메틸-7-(3-페닐-알릴콕시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(Ⅲe)을 제조할 수 있다.For example, in the first step, cinnamic acid derivative (IIIa) is dissolved in a solvent such as methanol, and then a strong acid such as concentrated sulfuric acid is added and heated to reflux. The reaction temperature is carried out at 70 ℃ to 90 ℃, preferably at 80 ℃. The reaction time can be carried out for 12-36 hours, preferably for 24 hours. After cooling the reaction solution to room temperature, the residue obtained by concentrating the silica gel column separation can be prepared through the 3-phenyl- acrylic acid methyl ester (IIIb). In the second step, 3-phenyl-acrylic acid methyl ester (IIIb) was dissolved in an organic solvent such as anhydrous dichloromethane and cooled to -78 ° C in a nitrogen-filled round flask, followed by diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane) is added dropwise over 10 minutes to 2 hours, preferably 20 minutes to 1 hour. The reaction solution is cooled to 0 ° C to 25 ° C, preferably 0 ° C to 10 ° C, stirred for 30 minutes to 5 hours, preferably 30 minutes to 2 hours, and then a solvent such as methanol is added dropwise. The reaction solution is cooled to 0 ° C to 50 ° C, preferably at room temperature, stirred for 10 minutes to 2 hours, preferably 30 minutes to 1 hour, and saturated Rochelle's salt is added. The reaction solution is stirred vigorously for 30 minutes to 5 hours, preferably 1 hour to 3 hours, extracted with an organic solvent such as dichloromethane, dehydrated with anhydrous forget-me-not, and then concentrated in dark and dark. The obtained residue may be produced 3-phenyl-pro-2-phen-1-ol (IIIc) by silica gel column separation. In the third step, a brominating agent such as boron tribromide (1M solution in dichloromethane) is dissolved in an organic solvent such as dichloromethane and reacted with 3-phenyl-pro-2-phen-1-ol (IIIc). At this time, the solvent is used to perform the reaction using an organic solvent such as toluene, benzene, dichloromethane, chloroform, carbon tetrachloride, which does not adversely affect the reaction. The reaction temperature may generally be performed at -20 ° C to 50 ° C, and preferably at 0 ° C to room temperature. The reaction time can be carried out for 30 minutes to 24 hours and preferably stirred for 30 minutes to 12 hours. The reaction solution is poured into a Erlenmeyer flask containing distilled water and stirred for 10 minutes. The reaction mixture was separated with an organic solvent such as saturated sodium hydrogen carbonate and diethyl ether, and the diethyl ether layer was dehydrated with anhydrous manganese and concentrated under reduced pressure. The obtained residue can be produced (3-bromo-propenyl) -benzene (IIId) by silica gel column separation. In the fourth step, (+)-decurinol (Ia) of Scheme 1 was dissolved with anhydrous N, N -dimethylformamide , and sodium hydride and (3-bromo-propenyl) -benzene (IIId) were added thereto. React. The solvent used at this time is carried out using a solvent such as N, N -dimethylformamide, dimethyl sulfoxide, which does not adversely affect the reaction. The reaction temperature can generally be carried out at -20 ° C to -40 ° C, preferably at -20 ° C. The reaction time can be carried out for 12 to 48 hours, preferably for 24 hours . The reaction solution was concentrated by filtration over a silica gel column, and the concentrated flask was then heated at 90-100 ° C. to remove N, N -dimethylformamide under vacuum. The obtained residue was subjected to (7S) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen via silica gel column separation. 2-one (IIIe) can be prepared.
상기 제조방법으로 얻어진 일반식 (I) 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) obtained by the above manufacturing method as an active ingredient, by preventing the secretion inhibitory effect of MCP-1, IL-6, IL-8 induced by ticks, thereby preventing and treating atopic dermatitis diseases It can be usefully used as an effective pharmaceutical composition and health functional food.
따라서, 본 발명은 상기 일반식 (I) 로 표기되는 신규구조의 (+)- 데쿠르신-에테르 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아토피성 피부염 질환의 예방 및 치료를 위한 약학조성물을 제공한다.Accordingly, the present invention provides a method for preventing and treating atopic dermatitis diseases containing a (+)-decursin-ether derivative compound or a pharmaceutically acceptable salt thereof of the novel structure represented by the above general formula (I) as an active ingredient. To provide a pharmaceutical composition for.
본 발명의 상기 일반식 (I) 화합물을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. The composition comprising the compound of formula (I) 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. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 화합물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 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 are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with 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 프로필렌글 리콜 (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.Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, 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, talc can 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 sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters 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/kg으로, 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 in an amount of 0.001 to 100 mg / kg 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 can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명은 상기 일반식 (Ⅰ)로 표기되는 신규구조의 (+)- 데쿠르신-에테르 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 아토피성 피부염 질환의 예방 및 치료를 위한 개선용 건강기능식품을 제공한다.The present invention is an improvement for the prevention and treatment of atopic dermatitis disease containing (+)-decursin-ether derivative compound of the novel structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Provide dietary supplements for health.
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 조성 물 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 are conventional 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. Sugars 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 from 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-에테르 유도체(decursin-ether derivative) 화합물들은 THP-1 또는 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-ether derivative compounds of the present invention are MCP-1, IL- showing an atopic dermatitis response induced by ticks in THP-1 or 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 by 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.
참조예Reference Example 1. 시약 및 기기 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.
참조예Reference Example 2. 2. THPTHP -1 배양-1 culture
사람의 단핵구(monocyte)인 THP-1 (human acute monocytic leukemia cell; 미국세포주은행)를 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 monocyte THP-1 (human acute monocytic leukemia cell) was 2.0 × 10 5 / m RPMI 1640 medium, antibiotics (penicillin 10 4 U / ml, streptomycin 10 mg / ml, Amphotericin B 25 μg / ml) and 10% FBS were added thereto, and then cultured in a 37 ° C. CO 2 incubator for 3 days.
참조예Reference Example 3. 3. EoLEoL -1 배양-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.
실시예Example 1. (7S)-7- (7S) -7- 메톡시Methoxy -8,8-디메틸-7,8--8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(3a)의 제조Preparation of 2-one (3a)
상기반응식에서 나타난 바와 같이 라운드 플라스크에 (+)-데쿠르시놀((+)-decursinol, 1, 100mg, 0.41mmol)을 무수 N,N-디메틸포름아마이드(3ml)로 용해시킨 후 -20℃로 냉각하였다. 반응혼액에 요오드화메탄(2a)(37.91mg, 0.609mmol)을 넣고 -20℃에서 24시간동안 교반하였다. 반응혼액을 실리카겔 단 컬럼에 여과하여 농축한 후, 농축 플라스크를 90-100℃ 중탕처리하면서 진공에서 N,N-디메틸포름아마이드를 제거하였다. 순수한 생성물(3a)을 얻기 위해 농축액은 실리카겔 컬럼 분리를 통해 하기 물성치를 갖는 (7S)-7-메톡시-8,8-디메틸-7,8-디하이드로-6H-피라 노[3,2-g]크로멘-2-온(3a) 61㎎을 얻어 실험예의 시료로 사용하였다. As shown in the reaction scheme, (+)-decursinol ((+)-decursinol, 1 , 100 mg, 0.41 mmol) was dissolved in anhydrous N, N -dimethylformamide (3 ml) in a round flask at -20 ° C. Cooled. Methane iodide (2a) (37.91 mg, 0.609 mmol) was added to the reaction mixture, and the mixture was stirred at -20 ° C for 24 hours. The reaction mixture was concentrated by filtration through a silica gel column, and the concentrated flask was then heated in 90-100 ° C. to remove N, N -dimethylformamide under vacuum. To obtain the pure product (3a), the concentrate was purified by silica gel column separation to obtain (7S) -7-methoxy-8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- having the following physical properties. g ] chromen-2-one (3a) 61 mg was obtained and used as a sample of an experiment example.
수율 : 28.1% ;Yield: 28.1%;
고체상(solid);Solid;
m.p 94℃;m.p 94 ° C .;
Rf= 0.45(n-hexane:ethyl acetate=1:1) ;R f = 0.45 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm δ 7.574(d, J= 9.6Hz, 1H), 7.167(s, 1H), 6.759(s, 1H), 6.207(d, J= 9.6Hz, 1H), 3.447(s, 3H), 3.372(dd, J= 5.2, 7.2Hz, 1H), 3.072(dd, J= 4.8, 16.4Hz, 1H), 2.827(dd, J= 7.2, 16.8Hz, 1H), 1.388(s, 3H), 1.330(s, 3H); 1 H NMR (CDCl 3 ): δ ppm δ 7.574 (d, J = 9.6 Hz, 1 H), 7.167 (s, 1 H), 6.759 (s, 1 H), 6.207 (d, J = 9.6 Hz, 1 H), 3.447 (s, 3H), 3.372 (dd, J = 5.2, 7.2 Hz, 1H), 3.072 (dd, J = 4.8, 16.4 Hz, 1H), 2.827 (dd, J = 7.2, 16.8 Hz, 1H), 1.388 ( s, 3H), 1.330 (s, 3H);
MS(m/z) : 261(M+H)+;MS ( m / z ): 261 (M + H) + ;
+97.2(c=1, CHCl3) +97.2 (c = 1, CHCl 3 )
실시예Example 2. (7S)-8,8-디메틸-7-(3- 2. (7S) -8,8-dimethyl-7- (3- 메틸methyl -부-2-Part-2- 테닐록시Tenyloxy )-7,8-) -7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(3b)의 제조Preparation of 2-one (3b)
상기 실시예 1의 라운드 플라스크에 요오드화메탄(2a) 대신 3,3-디메틸 아릴 브로마이드(2b)로 바꾸는 점만 제외하고는 실시예 1의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-8,8-디메틸-7-(3-메틸-부-2-테닐록시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3b) 23.0㎎을 얻어 실험예의 시료로 사용하였다.The same procedure as in Example 1 was carried out except that the round flask of Example 1 was replaced with 3,3-dimethyl aryl bromide (2b) instead of methane iodide (2a) to have (7S) -8. 23.0 mg of 8-dimethyl-7- (3-methyl-but-2-tenyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3b) Obtained and used as a sample of an experiment example.
수율 : 18.0% ;Yield: 18.0%;
고체상(solid);Solid;
m.p 73℃;m.p 73 ° C .;
Rf= 0.59(n-hexane:ethyl acetate=1:1) ;R f = 0.59 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.571(d, J= 9.6Hz, 1H), 7.156(s, 1H), 6.753(s, 1H), 6.205(d, J= 9.6Hz, 1H), 5.331(t, J= 7.0Hz, 1H), 4.157(dd, J= 6.8, 12.0Hz, 1H), 4.036(dd, J= 7.2, 11.6Hz, 1H), 3.490(dd, J= 5.2, 7.6Hz, 1H), 3.048(dd, J= 4.8, 16.4Hz, 1H), 2.812(dd, J= 7.6, 17.2Hz, 1H), 1.750(s, 3H), 1.673(s, 3H), 1.403(s, 3H), 1.309(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.571 (d, J = 9.6 Hz, 1H), 7.156 (s, 1H), 6.753 (s, 1H), 6.205 (d, J = 9.6 Hz, 1H), 5.331 ( t, J = 7.0 Hz, 1H), 4.157 (dd, J = 6.8, 12.0 Hz, 1H), 4.036 (dd, J = 7.2, 11.6 Hz, 1H), 3.490 (dd, J = 5.2, 7.6 Hz, 1H ), 3.048 (dd, J = 4.8, 16.4 Hz, 1H), 2.812 (dd, J = 7.6, 17.2 Hz, 1H), 1.750 (s, 3H), 1.673 (s, 3H), 1.403 (s, 3H) , 1.309 (s, 3 H);
MS(m/z) : 315(M+H)+;MS ( m / z ): 315 (M + H) + ;
+113.9(c=1, CHCl3) +113.9 (c = 1, CHCl 3 )
실시예Example 3. (7S)-8,8-디메틸-7-(2- 3. (7S) -8,8-Dimethyl-7- (2- 메틸methyl -- 알릴록시Allyloxy )-7,8-) -7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(3c)의 제조Preparation of 2-one (3c)
상기 실시예 1의 라운드 플라스크에 요오드화메탄(2a) 대신 3-브로모-2-메틸프로펜(2c)으로 바꾸는 점만 제외하고는 실시예 1의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-8,8-디메틸-7-(2-메틸-알릴록시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3c) 72㎎을 얻어 실험예의 시료로 사용하였다.The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to 3-bromo-2-methylpropene (2c) instead of methane iodide (2a) to have the following physical properties (7S 72 mg of 8,8-dimethyl-7- (2-methyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3c) was obtained. It used as the sample of an experiment example.
수율 : 59.0% ;Yield: 59.0%;
고체상(solid);Solid;
m.p 81℃;m.p 81 ° C .;
Rf= 0.55(n-hexane:ethyl acetate=1:1) ;R f = 0.55 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.577(d, J= 9.6Hz, 1H), 7.158(s, 1H), 6.760(s, 1H), 6.212(d, J= 9.6Hz, 1H), 4.938(d, J= 26.0Hz, 2H), 4.058(d, J= 12.0Hz, 1H), 3.941(d, J= 12.0Hz, 1H), 3.521(dd, J= 4.8, 7.6Hz, 1H), 3.058(dd, J= 5.2, 16.4Hz, 1H), 2.817(dd, J= 7.6, 16.4Hz, 1H), 1.758(s, 3H), 1.420(s, 3H), 1.331(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.577 (d, J = 9.6 Hz, 1H), 7.158 (s, 1H), 6.760 (s, 1H), 6.212 (d, J = 9.6 Hz, 1H), 4.938 ( d, J = 26.0 Hz, 2H), 4.058 (d, J = 12.0 Hz, 1H), 3.941 (d, J = 12.0 Hz, 1H), 3.521 (dd, J = 4.8, 7.6 Hz, 1H), 3.058 ( dd, J = 5.2, 16.4 Hz, 1H), 2.817 (dd, J = 7.6, 16.4 Hz, 1H), 1.758 (s, 3H), 1.420 (s, 3H), 1.331 (s, 3H);
MS(m/z) : 301(M+H)+;MS ( m / z ): 301 (M + H) + ;
+121.9(c=1, CHCl3) +121.9 (c = 1, CHCl 3 )
실시예Example 4. (7S)-8,8-디메틸-7-(3- 4. (7S) -8,8-Dimethyl-7- (3- 페닐Phenyl -- 프로폭시Propoxy )-7,8-) -7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(3d)의 제조Preparation of 2-one (3d)
상기 실시예 1의 라운드 플라스크에 요오드화메탄(2a) 대신 1-브로모-3-페닐프로판(2d)으로 바꾸는 점만 제외하고는 실시예 1의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-8,8-디메틸-7-(3-페닐-프로폭시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(3d) 48㎎을 얻어 실험예의 시료로 사용하였다.The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to 1-bromo-3-phenylpropane (2d) instead of methane iodide (2a) (7S). 48 mg of -8,8-dimethyl-7- (3-phenyl-propoxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (3d) was obtained to give an experiment. Used as an example sample.
수율 : 32.7% ;Yield: 32.7%;
오일상(oil);Oil phase;
Rf= 0.59(n-hexane:ethyl acetate=1:1) ;R f = 0.59 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.577(d, J= 9.2Hz, 1H), 7.290-7.145(m, 6H), 6.768(s, 1H), 6.215(d, J= 9.2Hz, 1H), 3.655(m, 1H), 3.433(m, 2H), 3.033(dd, J= 4.8, 16.4Hz, 1H), 2.788(dd, J= 7.2, 16.4Hz, 1H), 2.685(t, J= 6.4Hz, 2H), 1.903(q, J= 7.0Hz, 2H), 1.445(s, 3H), 1.371(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.577 (d, J = 9.2 Hz, 1H), 7.290-7.145 (m, 6H), 6.768 (s, 1H), 6.215 (d, J = 9.2 Hz, 1H), 3.655 (m, 1H), 3.433 (m, 2H), 3.033 (dd, J = 4.8, 16.4 Hz, 1H), 2.788 (dd, J = 7.2, 16.4 Hz, 1H), 2.685 (t, J = 6.4 Hz , 2H), 1.903 (q, J = 7.0 Hz, 2H), 1.445 (s, 3H), 1.371 (s, 3H);
MS(m/z) : 365(M+H)+;MS ( m / z ): 365 (M + H) + ;
+33.9(c=0.5, CHCl3) +33.9 (c = 0.5, CHCl 3 )
실시예Example 5. (7 5. (7 SRSR )-7-[3-(2-) -7- [3- (2- 메톡시Methoxy -- 페닐Phenyl )-)- 프로폭시Propoxy ]-8,8-디메틸-7,8-] -8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -피라노[-Pyrano [ 3,2-3,2- gg ]크로멘] Chrome -2-온(7a)의 제조Preparation of 2-one (7a)
단계 1.Step 1.
상기 반응식에서 나타낸 방법은 2가지로 다른 방법으로 합성하였다.The method shown in the scheme was synthesized in two different ways.
첫 번째 방법(단계1-1)은 라운드 플라스크에 2-메톡시신남산(700mg,3.93mmol)을 무수 테트라하이드로푸란으로 용해시킨 후 수소화알루미늄리튬(223mg, 5.89mmol)을 넣고 상온에서 6시간동안 교반하였다. 반응액에 증류수(50ml)를 서서히 가한 후, 열이 발생하지 않을 때까지 교반하였다. 반응혼액에 3N HCl을 넣어 pH 2가 되게 하고 디클로로메탄으로 추출하였으며, 여액은 무수망초로 탈수하여 감압농축 하였다. 농축액은 실리카겔 컬럼 분리를 통해 순수한 생성물 3-(2-메톡시)-프로판-1-올(5a) 200mg을 얻었으며 이를 다음 단계에 적용하였다.In the first method (Step 1-1), 2-methoxycinnamic acid (700 mg, 3.93 mmol) was dissolved in anhydrous tetrahydrofuran in a round flask, and lithium aluminum hydride (223 mg, 5.89 mmol) was added and stirred at room temperature for 6 hours. It was. Distilled water (50 ml) was slowly added to the reaction solution, followed by stirring until no heat was generated. 3N HCl was added to the reaction mixture to pH 2 and extracted with dichloromethane. The filtrate was concentrated under reduced pressure by dehydration with anhydrous forget-me-not. The concentrate was purified by silica gel column separation to obtain 200 mg of pure product 3- (2-methoxy) -propan-1-ol (5a), which was applied to the next step.
두 번째 방법(단계1-2)은 라운드 플라스크에 3-(2-메톡시)프로피온산(500mg, 2.77mmol)을 무수 테트라하이드로푸란으로 용해시킨 후 수소화알루미늄리튬(157mg, 4.16mg)을 넣고 상온에서 6시간동안 교반하였다. 반응액에 증류수(50ml)를 서서히 가한 후, 열이 발생하지 않을 때까지 교반하였다. 반응혼액에 3N HCl을 넣어 pH 2 가 되게 하고 디클로로메탄으로 추출하였으며, 여액은 무수망초로 탈수하여 감압농축 하였다. 농축액은 실리카겔 컬럼 분리를 통해 순수한 생성물 3-(2-메톡시)-프로판-1-올(5a) 466mg을 얻었으며 이를 다음 단계에 적용하였다.In the second method (Step 1-2), 3- (2-methoxy) propionic acid (500 mg, 2.77 mmol) was dissolved in anhydrous tetrahydrofuran in a round flask, and lithium aluminum hydride (157 mg, 4.16 mg) was added at room temperature. Stir for 6 hours. Distilled water (50 ml) was slowly added to the reaction solution, followed by stirring until no heat was generated. 3N HCl was added to the reaction mixture to pH 2 and extracted with dichloromethane. The filtrate was concentrated under reduced pressure by dehydration with anhydrous forget-me-not. The concentrate was subjected to silica gel column separation to obtain 466 mg of pure product 3- (2-methoxy) -propan-1-ol (5a), which was applied to the next step.
단계 2.Step 2.
상기 반응식에서 나타낸 바와 같이 라운드 플라스크에 3-(2-메톡시페닐)-프로판-1-올(5a, 461mg, 2.77mmol)을 넣고 무수 디클로로메탄으로 용해시킨 후, 수증빙용상에서 보론 트리브로마이드(1M 용액 in dichloromethane), (104.6㎕, 1.11mmol) 를 넣고 2시간동안 교반하였다. 반응액은 감압농축한 후, 실리카겔 컬럼 분리를 통해 순수한 생성물 1-(3-브로모-프로필)-2-메톡시-벤젠(6a) 180mg을 얻었으며 이를 다음 단계에 적용하였다.As shown in the reaction scheme, 3- (2-methoxyphenyl) -propan-1-ol (5a, 461mg, 2.77mmol) was added to a round flask and dissolved in anhydrous dichloromethane, followed by boron tribromide (water evaporation). 1M solution in dichloromethane), (104.6 μl, 1.11 mmol) was added and stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, 180 mg of pure product 1- (3-bromo-propyl) -2-methoxy-benzene (6a) was obtained through silica gel column separation, which was applied to the next step.
단계 3.Step 3.
상기 실시예 1의 라운드 플라스크에 요오드화메탄(2a) 대신 1-(3-브로모-프로필)-2-메톡시-벤젠(6a)으로 바꾸는 점만 제외하고는 실시예 1의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-7-[3-(2-메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7a) 13.0㎎을 얻어 실험예의 시료로 사용하였다.The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to 1- (3-bromo-propyl) -2-methoxy-benzene (6a) instead of methane iodide (2a). (7S) -7- [3- (2-methoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g with the following physical properties ] 13.0 mg of chroman-2-one (7a) was obtained and used as a sample of an experiment example.
수율 : 8.1% ;Yield: 8.1%;
오일상(oil);Oil phase;
Rf= 0.56(n-hexane:ethyl acetate=1:1) ;R f = 0.56 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.576(d, J= 9.2Hz, 1H), 7.198-7.148(m, 2H), 7.084(d, J= 7.2Hz, 1H), 6.905-6.832(m, 2H), 6.765(s, 1H), 6.212(d, J= 9.6Hz, 1H), 3.811(s, 3H), 3.665(m, 1H), 3.463(m, 2H), 3.045(dd, J= 4.8, 16.4Hz, 1H), 2.796(dd, J= 7.6, 16.4Hz, 1H), 2.672(t, J= 7.6Hz, 2H), 1.867(q, J= 7.0Hz, 2H), 1.419(s, 3H), 1.334(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.576 (d, J = 9.2 Hz, 1H), 7.198-7.148 (m, 2H), 7.084 (d, J = 7.2 Hz, 1H), 6.905-6.832 (m, 2H ), 6.765 (s, 1H), 6.212 (d, J = 9.6 Hz, 1H), 3.811 (s, 3H), 3.665 (m, 1H), 3.463 (m, 2H), 3.045 (dd, J = 4.8, 16.4 Hz, 1H), 2.796 (dd, J = 7.6, 16.4 Hz, 1H), 2.672 (t, J = 7.6 Hz, 2H), 1.867 (q, J = 7.0 Hz, 2H), 1.419 (s, 3H) , 1.334 (s, 3 H);
MS(m/z) : 395(M+H)+;MS ( m / z ): 395 (M + H) + ;
+77.2(c=1, CHCl3) +77.2 (c = 1, CHCl 3 )
실시예Example 6. (7S)-7-[3-(3- 6. (7S) -7- [3- (3- 메톡시Methoxy -- 페닐Phenyl )-)- 프로폭시Propoxy ]-8,8-디메틸-7,8-] -8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(7b)의 제조Preparation of 2-one (7b)
상기 실시예 5의 제 1단계에서 첫 번째 방법의 라운드 플라스크에 2-메톡시신남산 대신 3-메톡시신남산으로, 두 번째 방법의 라운드 플라스크에 3-(2-메톡시)프로피온산 대신 3-(3-메톡시)프로피온산으로 바꾸는 점만 제외하고는 실시예 5의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-7-[3-(3-메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7b) 8.1㎎을 얻어 실험예의 시료로 사용하였다.In the first step of Example 5, 3-methoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, 3- (3 instead of 3- (2-methoxy) propionic acid in the round flask of the second method (7S) -7- [3- (3-methoxy-phenyl) -propoxy] -8 having the following physical properties by the same process as the reaction of Example 5 except for changing to -methoxy) propionic acid; 8.1 mg of 8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7b) was obtained and used as a sample for the experimental example.
수율 : 5.1% ;Yield: 5.1%;
오일상(oil);Oil phase;
Rf= 0.59(n-hexane:ethyl acetate=1:1) ;R f = 0.59 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.570(d, J= 9.6Hz, 1H), 7.187(t, J= 7.6Hz, 1H), 7.140(s, 1H), 6.763-7.714(m, 4H), 6.210(d, J=9.6Hz, 1H), 3.799(s, 3H), 3.662(m, 1H), 3.442(m, 2H), 3.033(dd, J= 5.2, 17.2Hz, 1H), 2.785(dd, J= 7.2, 16.0Hz, 1H), 2.659(t, J= 6.0Hz, 2H), 1.897(q, J= 6.9Hz, 2H), 1.409(s, 3H), 1.333(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.570 (d, J = 9.6 Hz, 1H), 7.187 (t, J = 7.6 Hz, 1H), 7.140 (s, 1H), 6.763-7.714 (m, 4H), 6.210 (d, J = 9.6 Hz, 1H), 3.799 (s, 3H), 3.662 (m, 1H), 3.442 (m, 2H), 3.033 (dd, J = 5.2, 17.2 Hz, 1H), 2.785 (dd , J = 7.2, 16.0 Hz, 1H), 2.659 (t, J = 6.0 Hz, 2H), 1.897 (q, J = 6.9 Hz, 2H), 1.409 (s, 3H), 1.333 (s, 3H);
MS(m/z) : 395(M+H)+;MS ( m / z ): 395 (M + H) + ;
+24.9(c=0.3, CHCl3) +24.9 (c = 0.3, CHCl 3 )
실시예Example 7. (7S)-7-[3-(4- 7. (7S) -7- [3- (4- 메톡시Methoxy -- 페닐Phenyl )-)- 프로폭시Propoxy ]-8,8-디메틸-7,8-] -8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(7c)의 제조Preparation of 2-one (7c)
상기 실시예 5의 제 1단계에서 첫 번째 방법의 라운드 플라스크에 2-메톡시신남산 대신 4-메톡시신남산으로, 두 번째 방법의 라운드 플라스크에 3-(2-메톡시)프로피온산 대신 3-(4-메톡시)프로피온산으로 바꾸는 점만 제외하고는 실시예 5의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-7-[3-(4-메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7c) 7.8㎎을 얻어 실험예의 시료로 사용하였다.In the first step of Example 5, 4-methoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method, 3- (4 instead of 3- (2-methoxy) propionic acid in the round flask of the second method (7S) -7- [3- (4-methoxy-phenyl) -propoxy] -8 having the following physical properties by the same process as the reaction of Example 5 except for changing to -methoxy) propionic acid; 7.8 mg of 8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7c) was obtained and used as a sample for the experimental example.
수율 : 4.9% ;Yield: 4.9%;
오일상(oil);Oil phase;
Rf= 0.52(n-hexane:ethyl acetate=1:1) ;R f = 0.52 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.574(d, J= 9.6Hz, 1H), 7.143(s, 1H), 7.064(d, J= 8.8Hz, 2H), 6.812(d, J= 8.8Hz, 2H), 6.763(s, 1H), 6.210(d, J= 9.6Hz, 1H), 3.648(m, 1H), 3.427(m, 2H), 3.030(dd, J= 4.8, 16.8Hz, 1H), 2.785(dd, J= 7.6, 16.4Hz, 1H), 2.623(t, J= 6.4Hz, 2H), 1.864(q, J= 6.9Hz, 2H), 1.407(s, 3H), 1.335(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.574 (d, J = 9.6 Hz, 1 H), 7.143 (s, 1 H), 7.064 (d, J = 8.8 Hz, 2H), 6.812 (d, J = 8.8 Hz, 2H), 6.763 (s, 1H), 6.210 (d, J = 9.6 Hz, 1H), 3.648 (m, 1H), 3.427 (m, 2H), 3.030 (dd, J = 4.8, 16.8 Hz, 1H), 2.785 (dd, J = 7.6, 16.4 Hz, 1H), 2.623 (t, J = 6.4 Hz, 2H), 1.864 (q, J = 6.9 Hz, 2H), 1.407 (s, 3H), 1.335 (s, 3H );
MS(m/z) : 395(M+H)+;MS ( m / z ): 395 (M + H) + ;
+79.2(c=1, CHCl3) +79.2 (c = 1, CHCl 3 )
실시예Example 8. (7S)-7-[3-(3,4- 8. (7S) -7- [3- (3,4- 디메톡시Dimethoxy -- 페닐Phenyl )-)- 프로폭시Propoxy ]-8,8-디메틸-7,8-] -8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(7d)의 제조Preparation of 2-one (7d)
단계 1.Step 1.
상기 실시예 5의 제 1단계에서 첫 번째 방법의 라운드 플라스크에 2-메톡시신남산 대신 3,4-디메톡시신남산으로, 두 번째 방법의 라운드 플라스크에 3-(2-메톡시)프로피온산 대신 3-(3,4-디메톡시)프로피온산으로 바꾸는 점만 제외하고는 실시예 5의 제 1단계 반응과 동일한 공정을 수행하여 순수한 생성물 3-(3,4-디메톡 시)-프로판-1-올(5d) 236mg을 얻었으며 이를 다음 단계에 적용하였다.3,4-dimethoxycinnamic acid instead of 2-methoxycinnamic acid in the round flask of the first method in the first step of Example 5, 3 instead of 3- (2-methoxy) propionic acid in the round flask of the second method A pure product 3- (3,4-dimethoxy-)-propan-1-ol was subjected to the same process as in the first step reaction of Example 5 except that it was changed to-(3,4-dimethoxy) propionic acid. 5d) 236 mg were obtained and subjected to the next step.
단계 2.Step 2.
상기 반응식에서 나타낸 바와 같이 라운드 플라스크에 트리페닐포스핀(721mg, 2.75mmol), 요오드(232mg, 1.83mmol), 이미다졸(187mg, 2.75mmol)을 톨루엔으로 용해시킨 후 3-(3,4-디메톡시)-프로판-1-올(5d)(180mg, 0.92mmol)을 넣고 상온에서 2시간동안 교반하였다. 반응액은 감압농축한 후, 실리카겔 컬럼 분리를 통해 순수한 생성물 1-(3-아이오도-프로필)-3,4-디메톡시-벤젠(6d) 234mg을 얻었으며 이를 다음 단계에 적용하였다.As shown in the above scheme, triphenylphosphine (721 mg, 2.75 mmol), iodine (232 mg, 1.83 mmol), and imidazole (187 mg, 2.75 mmol) were dissolved in toluene in a round flask, followed by 3- (3,4-dimethol). Toxy) -propan-1-ol (5d) (180mg, 0.92mmol) was added thereto and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 234 mg of pure product 1- (3-iodo-propyl) -3,4-dimethoxy-benzene (6d) was obtained through silica gel column separation, which was applied to the next step.
단계 3.Step 3.
상기 실시예 1의 라운드 플라스크에 요오드화메탄(2a) 대신 1-(3-아이오도-프로필)-3,4-디메톡시-벤젠(6d)으로 바꾸는 점만 제외하고는 실시예 1의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-7-[3-(3,4-디메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7d) 38㎎을 얻어 실험예의 시료로 사용하였다.The same process as in Example 1 except that the round flask of Example 1 was replaced with 1- (3-iodo-propyl) -3,4-dimethoxy-benzene (6d) instead of methane iodide (2a). (7S) -7- [3- (3,4-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3] having the following physical properties , 2- g ] chromen-2-one (7d) 38 mg was obtained and used as a sample of an experiment example.
수율 : 22.0% ;Yield: 22.0%;
오일상(oil);Oil phase;
Rf= 0.46(n-hexane:ethyl acetate=1:1) ;R f = 0.46 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.566(d, J= 9.2Hz, 1H), 7.138(s, 1H), 6.788-6.760(m, 2H), 6.694-6.681(m, 2H), 6.205(d, J= 9.2Hz, 1H), 3.854(s, 6H), 3.660(m, 1H), 3.446(m, 2H), 3.037(dd, J= 4.8, 16.4Hz, 1H), 2.788(dd, J= 7.6, 16.8Hz, 1H), 2.630(dd, J= 4.8, 7.6Hz, 2H), 1.883(q, J=6.9, 2H), 1.413(s, 3H), 1.339(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.566 (d, J = 9.2 Hz, 1H), 7.138 (s, 1H), 6.788-6.760 (m, 2H), 6.694-6.681 (m, 2H), 6.205 (d , J = 9.2 Hz, 1H), 3.854 (s, 6H), 3.660 (m, 1H), 3.446 (m, 2H), 3.037 (dd, J = 4.8, 16.4 Hz, 1H), 2.788 (dd, J = 7.6, 16.8 Hz, 1H), 2.630 (dd, J = 4.8, 7.6 Hz, 2H), 1.883 (q, J = 6.9, 2H), 1.413 (s, 3H), 1.339 (s, 3H);
MS(m/z) : 425(M+H)+;MS ( m / z ): 425 (M + H) + ;
+131.2(c=2, CHCl3) +131.2 (c = 2, CHCl 3 )
실시예Example 9. (7S)-7-[3-(2,3- 9. (7S) -7- [3- (2,3- 디메톡시Dimethoxy -- 페닐Phenyl )-)- 프로폭시Propoxy ]-8,8-디메틸-7,8-] -8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -피-blood 라노[3,2-Llan [3,2- gg ]크로] Cro 멘-2-온(7e)의 제조Preparation of Men-2-one (7e)
상기 실시예 8의 제 1단계에서 첫 번째 방법의 라운드 플라스크에 3,4-디메톡시신남산 대신 2,3-디메톡시신남산으로, 두 번째 방법의 라운드 플라스크에 3-(3,4-디메톡시)프로피온산 대신 3-(2,3-디메톡시)프로피온산으로 바꾸는 점만 제외하고는 실시예 8의 제 1, 2, 3단계 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-7-[3-(2,3-디메톡시-페닐)-프로폭시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7e) 9.5㎎을 얻어 실험예의 시료로 사용하였다.In the first step of Example 8, 2,3-dimethoxycinnamic acid instead of 3,4-dimethoxycinnamic acid in the round flask of the first method, 3- (3,4-dimethic acid in the round flask of the second method Except for changing to 3- (2,3-dimethoxy) propionic acid instead of oxy) propionic acid, the same process as in the first, second and third steps of Example 8 was carried out to give (7S) -7- [ 3- (2,3-dimethoxy-phenyl) -propoxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (7e) 9.5 mg was obtained and used as a sample of an experiment example.
수율 : 3.4% ;Yield: 3.4%;
오일상(oil);Oil phase;
Rf= 0.50(n-hexane:ethyl acetate=1:1) ;R f = 0.50 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.571(d, J= 9.6Hz, 1H), 7.143(s, 1H), 6.962(t, J= 7.6Hz, 1H), 6.785-6.725(m, 3H), 6.207(d, J= 9.6Hz, 1H), 3.856(s, 3H), 3.801(s, 3H), 3.670(m, 1H), 3.463(m, 2H), 3.043(dd, J= 4.8, 16.4Hz, 1H), 2.796(dd, J= 7.2, 16.0Hz, 1H), 2.690(t, J= 7.2Hz, 2H), 1.873(q, J= 6.9Hz, 2H), 1.412(s, 3H), 1.331(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.571 (d, J = 9.6 Hz, 1H), 7.143 (s, 1H), 6.962 (t, J = 7.6 Hz, 1H), 6.785-6.725 (m, 3H), 6.207 (d, J = 9.6 Hz, 1H), 3.856 (s, 3H), 3.801 (s, 3H), 3.670 (m, 1H), 3.463 (m, 2H), 3.043 (dd, J = 4.8, 16.4 Hz , 1H), 2.796 (dd, J = 7.2, 16.0 Hz, 1H), 2.690 (t, J = 7.2 Hz, 2H), 1.873 (q, J = 6.9 Hz, 2H), 1.412 (s, 3H), 1.331 (s, 3H);
MS(m/z) : 425(M+H)+;MS ( m / z ): 425 (M + H) + ;
+34.6(c=0.5, CHCl3) +34.6 (c = 0.5, CHCl 3 )
실시예Example 10. (7S)-8,8-디메틸-7-[3-(3,4,5- 10. (7S) -8,8-Dimethyl-7- [3- (3,4,5- 트리메톡시Trimethoxy -- 페닐Phenyl )-)- 프로폭시Propoxy ]-7,8-] -7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(7f)의 제조Preparation of 2-one (7f)
상기 실시예 8의 제 1단계에서 첫 번째 방법의 라운드 플라스크에 3,4-디메톡시신남산 대신 3,4,5-트리메톡시신남산으로, 두 번째 방법의 라운드 플라스크에 3-(3,4-디메톡시)프로피온산 대신 3-(3,4,5-트리메톡시)프로피온산으로 바꾸는 점만 제외하고는 실시예 8의 제 1, 2, 3단계 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-8,8-디메틸-7-[3-(3,4,5-트리메톡시-페닐)-프로폭시]-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(7f) 13.6㎎을 얻어 실험예의 시료로 사용하였다.3,4,5-trimethoxycinnamic acid instead of 3,4-dimethoxycinnamic acid in the round flask of the first method in the first step of Example 8, 3- (3,4 in the round flask of the second method Except for changing to 3- (3,4,5-trimethoxy) propionic acid instead of dimethoxy) propionic acid, the same process as in the first, second and third steps of Example 8 was carried out to obtain (7S) ) -8,8-dimethyl-7- [3- (3,4,5-trimethoxy-phenyl) -propoxy] -7,8-dihydro- 6H -pyrano [3,2- g ] chrome 13.6 mg of men-2-one (7f) was obtained and used as a sample in an experimental example.
수율 : 6.9% ;Yield: 6.9%;
오일상(oil);Oil phase;
Rf= 0.33(n-hexane:ethyl acetate=1:1) ;R f = 0.33 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.568(d, J= 9.6Hz, 1H), 7.141(s, 1H), 6.764(s, 1H), 6.383(s, 2H), 6.211(d, J= 9.6Hz, 1H), 3.836(s, 6H), 3.823(s, 3H), 3.682(m, 1H), 3.458(m, 2H), 3.505(dd, J= 5.2, 16.4Hz, 1H), 2.794(dd, J= 7.6, 16.8Hz, 1H), 2.628(td, J= 3.2, 7.2Hz, 2H), 1.899(q, J= 6.9Hz, 2H), 1.417(s, 3H), 1.343(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.568 (d, J = 9.6 Hz, 1H), 7.141 (s, 1H), 6.764 (s, 1H), 6.383 (s, 2H), 6.211 (d, J = 9.6 Hz, 1H), 3.836 (s, 6H), 3.823 (s, 3H), 3.682 (m, 1H), 3.458 (m, 2H), 3.505 (dd, J = 5.2, 16.4 Hz, 1H), 2.794 (dd , J = 7.6, 16.8 Hz, 1H), 2.628 (td, J = 3.2, 7.2 Hz, 2H), 1.899 (q, J = 6.9 Hz, 2H), 1.417 (s, 3H), 1.343 (s, 3H) ;
MS(m/z) : 455(M+H)+;MS ( m / z ): 455 (M + H) + ;
+165.2(c=3, CHCl3) +165.2 (c = 3, CHCl 3 )
실시예Example 11. (7S)-8,8-디메틸-7-(3- 11. (7S) -8,8-Dimethyl-7- (3- 페닐Phenyl -- 알릴록시Allyloxy )-7,8-) -7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크] 로in 멘-2-온(12a)의 제조Preparation of Men-2-one 12a
단계 1.Step 1.
상기 반응식에서 나타난 바와 같이 라운드 플라스크에 신남산(8a)(5g, 33.7mmol)을 메탄올(50ml)로 용해시킨 후, 농축 황산 5방울을 넣고 80℃에서 24시간동안 환류시켰다. 반응액을 상온으로 냉각시킨 후 감압농축하였으며, 농축액은 실리카겔 컬럼 분리를 통해 순수한 생성물 3-페닐-아크릴산 메틸에스터(9a) 5.39g을 얻었으며 이를 다음 단계에 적용하였다. As shown in the reaction scheme, cinnamic acid (8a) (5 g, 33.7 mmol) was dissolved in methanol (50 ml) in a round flask, and 5 drops of concentrated sulfuric acid was added thereto and refluxed at 80 ° C. for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by silica gel column separation to obtain 5.39 g of pure product 3-phenyl-acrylic acid methyl ester (9a), which was then applied to the next step.
단계 2.Step 2.
상기 반응식에서 나타낸 바와 같이 질소기체가 충전된 라운드 플라스크에 3-페닐-아크릴산 메틸에스터(9a)(4g, 24.7mmol)를 넣고 무수 디클로로메탄으로 용해시킨 후, -78℃로 냉각시켰다. 반응액에 디이소부틸알루미늄 하이드라이드(DIBAL-H, 1M 용액 in hexane) (74ml, 74.0mmol)를 30분에 걸쳐 적가시킨 후, 반응액을 0℃로 냉각하여 1시간 동안 교반한 다음 메탄올(22ml)을 적가하였다. 반응액을 상온으로 냉각하여 30분간 교반하고 포화 로셀염(Rochelle's salt, 88ml)을 가한다. 반응혼액을 상온에서 격렬하게 2시간동안 교반하였으며, 디클로로메탄으로 추출하여 무수망초로 탈수한 후, 감암농축하였다. 농축액은 실리카겔 컬럼분리를 통해 순수한 생성물 3-페닐-프로-2-펜-1-올(10a) 4.0g을 얻었으며 이를 다음 단계에 적용하였다. As shown in the reaction scheme, 3-phenyl-acrylic acid methyl ester (9a) (4 g, 24.7 mmol) was added to a round flask filled with nitrogen gas, and then dissolved in anhydrous dichloromethane, and cooled to -78 ° C. Diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane) (74 ml, 74.0 mmol) was added dropwise to the reaction solution over 30 minutes, and the reaction solution was cooled to 0 ° C., stirred for 1 hour, and then methanol ( 22 ml) was added dropwise. The reaction solution was cooled to room temperature, stirred for 30 minutes, and saturated Rochelle's salt (88 ml) was added. The reaction mixture was stirred vigorously at room temperature for 2 hours, extracted with dichloromethane, dehydrated with anhydrous forget-me-not, and concentrated in gamyeo. The concentrate was subjected to silica gel column separation to obtain 4.0 g of pure product 3-phenyl-pro-2-phen-1-ol (10a), which was applied to the next step.
단계 3.Step 3.
상기 반응식에서 나타낸 바와 같이 라운드 플라스크에 3-페닐-프로-2-펜-1-올(10a)(1g, 7.45mmol)을 넣고 무수 디클로로메탄으로 용해시킨 후, 수증빙용상에서 보론 트리브로마이드(1M 용액 in dichloromethane), (253.6㎕, 2.61mmol) 를 넣고 1시간동안 교반하였다. 반응액을 증류수(50ml)가 담신 삼각플라스크에 붓고 10분간 교반시켰다. 반응혼액은 포화 탄산수소나트륨과 디에틸에테르로 분액하였고, 디에틸에테르층은 무수망초로 탈수하여 감압농축하였다. 실리카겔 컬럼 분리를 통 해 순수한 생성물 (3-브로모-프로페닐)-벤젠(11a) 933mg을 얻었으며 이를 다음 단계에 적용하였다. As shown in the above reaction scheme, 3-phenyl-pro-2-phen-1-ol (10a) (1 g, 7.45 mmol) was added to a round flask and dissolved in anhydrous dichloromethane, and boron tribromide (1M) was used for water deposition. Solution in dichloromethane), (253.6 μl, 2.61 mmol) was added and stirred for 1 hour. The reaction solution was poured into a Erlenmeyer flask containing distilled water (50 ml) and stirred for 10 minutes. The reaction mixture was separated with saturated sodium hydrogen carbonate and diethyl ether, and the diethyl ether layer was dehydrated with anhydrous manganese and concentrated under reduced pressure. Silicagel column separation gave 933 mg of pure product (3-bromo-propenyl) -benzene (11a), which was applied to the next step.
단계 4.Step 4.
상기 실시예 1의 라운드 플라스크에 요오드화메탄(2a) 대신 (3-브로모-프로페닐)-벤젠(11a)으로 바꾸는 점만 제외하고는 실시예 1의 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-8,8-디메틸-7-(3-페닐-알릴록시)-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(12a) 48㎎을 얻어 실험예의 시료로 사용하였다.The same procedure as in Example 1 was carried out except that the round flask of Example 1 was changed to (3-bromo-propenyl) -benzene (11a) instead of methane iodide (2a) to have the following physical properties ( 48 mg of 7S) -8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H -pyrano [3,2- g ] chromen-2-one (12a) Obtained and used as a sample of an experiment example.
수율 : 32.7% ;Yield: 32.7%;
고체상(solid);Solid;
m.p 143℃;m.p 143 ° C .;
Rf= 0.39(n-hexane:ethyl acetate=2:1) ;R f = 0.39 ( n- hexane: ethyl acetate = 2: 1);
1H NMR(CDCl3) : δ ppm 7.564(d, J= 9.6Hz, 1H), 7.382-7.231(m, 5H), 7.157(s, 1H), 6.763(s, 1H), 6.590(d, J= 16.0Hz, 1H), 6.308-6.237(m, 1H), 6.202(d, J= 9.6Hz,1H), 4.341(dd, J= 6.0, 12.8Hz, 1H), 4.215(dd, J= 6.0, 12.4Hz, 1H), 3.590(dd, J= 5.2, 7.6Hz, 1H), 3.076(dd, J= 4.8, 16.0Hz, 1H), 2.857(dd, J= 7.2, 16.4Hz, 1H), 1.417(s 3H), 1.360(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.564 (d, J = 9.6 Hz, 1H), 7.382-7.231 (m, 5H), 7.157 (s, 1H), 6.763 (s, 1H), 6.590 (d, J = 16.0 Hz, 1H), 6.308-6.237 (m, 1H), 6.202 (d, J = 9.6 Hz, 1H), 4.341 (dd, J = 6.0, 12.8 Hz, 1H), 4.215 (dd, J = 6.0, 12.4 Hz, 1H), 3.590 (dd, J = 5.2, 7.6 Hz, 1H), 3.076 (dd, J = 4.8, 16.0 Hz, 1H), 2.857 (dd, J = 7.2, 16.4 Hz, 1H), 1.417 ( s 3H), 1.360 (s, 3H);
MS(m/z) : 363(M+H)+;MS ( m / z ): 363 (M + H) + ;
+117.6(c=1, CHCl3) +117.6 (c = 1, CHCl 3 )
실시예Example 12. (7S)-7-[3-(4- 12. (7S) -7- [3- (4- 메톡시Methoxy -- 페닐Phenyl )-)- 알릴록시Allyloxy ]-8,8-디메틸-7,8-] -8,8-dimethyl-7,8- 디하이드로Dehydro -- 6H6H -- 피라노[3,2-Pyrano [3,2- gg ]크로멘] Chrome -2-온(12b)의 제조Preparation of 2-one (12b)
상기 실시예 11의 제 1단계에서 라운드 플라스크에 신남산(8a) 대신 4-메톡시신남산(8b)으로 바꾸는 점만 제외하고는 실시예 11의 제 1, 2, 3, 4단계 반응과 동일한 공정을 수행하여 하기 물성치를 갖는 (7S)-7-[3-(4-메톡시-페닐)-알릴록시]-8,8-디메틸-7,8-디하이드로-6H-피라노[3,2-g]크로멘-2-온(12b) 4㎎을 얻어 실험예의 시료로 사용하였다.The same process as in the first, second, third, and fourth steps of Example 11 was repeated except that the round flask was changed to 4-methoxy cinnamic acid (8b) instead of cinnamic acid (8a) in the first step of Example 11. (7S) -7- [3- (4-methoxy-phenyl) -allyloxy] -8,8-dimethyl-7,8-dihydro- 6H -pyrano [3,2- having the following physical properties g ] 4 mg of chroman-2-one (12b) was obtained and used as a sample of an experiment example.
수율 : 30.2% ;Yield: 30.2%;
오일상(oil);Oil phase;
Rf= 0.49(n-hexane:ethyl acetate=1:1) ;R f = 0.49 ( n- hexane: ethyl acetate = 1: 1);
1H NMR(CDCl3) : δ ppm 7.568(d, J= 9.6Hz, 1H), 7.312(d, J= 8.8Hz, 2H), 7.155(s, 1H), 6.857(d, J= 8.8Hz, 2H), 6.767(s, 1H), 6.530(d, J= 16.4Hz, 1H), 6.211(d, J= 9.6Hz, 1H), 6.153(m, 1H), 4.315(dd, J= 6.4, 12.8Hz, 1H), 4.196(dd, J= 6.4, 12.8Hz, 1H), 3.812(s, 3H), 3.583(dd, J= 4.8, 7.2Hz, 1H), 3.074(dd, J= 4.8, 7.2Hz, 1H), 2.846(dd, J= 7.6, 16.8Hz, 1H), 1.415(s, 3H), 1.349(s, 3H); 1 H NMR (CDCl 3 ): δ ppm 7.568 (d, J = 9.6 Hz, 1H), 7.312 (d, J = 8.8 Hz, 2H), 7.155 (s, 1H), 6.857 (d, J = 8.8 Hz, 2H), 6.767 (s, 1H), 6.530 (d, J = 16.4 Hz, 1H), 6.211 (d, J = 9.6 Hz, 1H), 6.153 (m, 1H), 4.315 (dd, J = 6.4, 12.8 Hz, 1H), 4.196 (dd, J = 6.4, 12.8 Hz, 1H), 3.812 (s, 3H), 3.583 (dd, J = 4.8, 7.2 Hz, 1H), 3.074 (dd, J = 4.8, 7.2 Hz , 1H), 2.846 (dd, J = 7.6, 16.8 Hz, 1H), 1.415 (s, 3H), 1.349 (s, 3H);
MS(m/z) : 393(M+H)+;MS ( m / z ): 393 (M + H) + ;
+7.9(c=0.1, CHCl3) +7.9 (c = 0.1, CHCl 3 )
실험예Experimental Example 1. One. THPTHP -1에서 From -1 mitemite 에 의해 유도된 Induced by MCPMCP -1/-One/ ILIL -6/-6 / ILIL -- 8분비에At eight minutes 미치는 (+)- Mick (+)- 데쿠르신Decursin -에테르 유도체의 영향 측정Measuring the effect of ether derivatives
미국세포주은행에서 구입한 인간 단핵구(Monocyte) 세포주(human acute monocytic leukemia cell line;이하 THP-1)를 이용하여 상기 실시예에서 합성한 데쿠르신-에테르 유도체들의 ELISA를 측정하기 위하여 하기와 같이 실험을 수행하였다.In order to measure the ELISA of the decursine-ether derivatives synthesized in the above example using human acute monocytic leukemia cell line (hereinafter referred to as THP-1) purchased from the American Cell Line Bank, experiments were performed as follows. Was performed.
상기 참조예 1에서 배양시킨 THP-1세포를 0.5%FBS가 든 RPMI에 2.0 x 106/m 로 24 웰 플레이트에 분주한 후 배양기 (37℃, 5% CO2)에서 16시간 배양하였다. 배양 후 데쿠르신 유도체 (10 ㎍/㎖)을 1시간 동안 처리한 후 HDE (1㎍/㎖)를 각각 24시간 동안 처리한 다음, ELISA를 이용하여 상층액에서 단핵구 화학유인물질 단백질-1(monocyte chemoattractant protein-1, MCP-1), IL-6, IL-8의 양을 측정하였고, 실험결과를 하기 표 1에 나타내었다.THP-1 cells cultured in Reference Example 1 were dispensed in a 24 well plate at 2.0 × 10 6 / m in RPMI containing 0.5% FBS and incubated in an incubator (37 ° C., 5% CO 2 ) for 16 hours. After incubation, treatment with decursin derivative (10 ㎍ / mL) for 1 hour followed by HDE (1 ㎍ / mL) for 24 hours, respectively, followed by monocyte chemoattractant protein-1 (monocyte) in supernatant using ELISA. The amount of chemoattractant protein-1, MCP-1), IL-6, IL-8 was measured, and the experimental results are shown in Table 1 below.
그 실험결과, THP-1 세포의 정상군에서의 MCP-1, IL-6 및 IL-8의 양은 33.2, 23.3 및 40.8 pg/ml인데 항원인 진드기를 처리하면 MCP-1, IL-6및 IL-8 의 양이 93.8, 525.3 및 2697.0 pg/ml으로 증가됨을 확인할 수 있었다(표 1). 이렇게 진드기에 의해서 증가된 상태에서 양성대조군인 덱사메타손을 처리하면 MCP-1, IL-6 및 IL-8의 양이 정상군과 거의 동등한 수준인 36.2, 25.3 및 66.9 pg/ml으로 감소됨을 알 수 있다. The results showed that the levels of MCP-1, IL-6 and IL-8 in the normal group of THP-1 cells were 33.2, 23.3 and 40.8 pg / ml. The amount of -8 was found to increase to 93.8, 525.3 and 2697.0 pg / ml (Table 1). Treatment of dexamethasone, a positive control, in the increased state by ticks, reduced the amount of MCP-1, IL-6 and IL-8 to 36.2, 25.3 and 66.9 pg / ml, almost equivalent to that of the normal group. .
한편, 합성한 (+)-데쿠르신-에테르 유도체들 중 3b, 7b, 7d 및 7f번 물질들이 덱사메타손 처리군과 거의 동등한 수준으로 진드기에 의해서 증가된 MCP-1의 양을 감소시켰다. 또한 7a, 7b 및 7e번 물질들은 IL-6의 양을 상당히 감소시켰다. 합성한 (+)-데쿠르신-에테르 유도체들은 전반적으로 IL-8의 양에는 커다란 영향을 미치지 않는 것을 볼 수 있었다.Meanwhile, substances 3b, 7b, 7d and 7f of the synthesized (+)-decurin-ether derivatives reduced the amount of MCP-1 increased by ticks to almost the same level as the dexamethasone treated group. In addition, substances 7a, 7b and 7e significantly reduced the amount of IL-6. The synthesized (+)-decurin-ether derivatives were found to have no significant effect on the amount of IL-8 as a whole.
종합해 볼 때 THP-1 세포에 대해서 합성한 (+)-데쿠르신-에테르 유도체들은 진드기에 의해서 증가된 MCP-1 및 IL-6의 양을 전반적으로 감소시켰으며, 특히 3b, 7b, 7d 및 7f 물질들은 기존의 아토피질환에 사용되고 있는 약물인 덱사메타손과 거의 동등한 수준으로 진드기에 의해서 증가된 MCP-1의 양을 감소시켰다. Taken together, the (+)-decurin-ether derivatives synthesized against THP-1 cells generally reduced the amount of MCP-1 and IL-6 increased by ticks, in particular 3b, 7b, 7d and 7f substances reduced the amount of MCP-1 increased by ticks to nearly the same level as dexamethasone, a drug used in existing atopic diseases.
실험예Experimental Example 2. 2. EoLEoL -1에서 From -1 mitemite 에 의해 유도된 Induced by MCPMCP -1/-One/ ILIL -6/-6 / ILIL -- 8분비에At eight minutes 미치는 (+)- Mick (+)- 데쿠르신Decursin -에테르 유도체의 영향 측정Measuring the effect of ether derivatives
일본세포주은행에서 구입한 인간 호산구(eosinophil)인 EoL-1 (eosinophilic leukemia cell) 세포를 이용하여 상기 실시예에서 합성한 데쿠르신-에테르 유도체들의 ELISA를 측정하기 위하여 하기와 같이 실험을 수행하였다.Experiments were carried out as follows to measure the ELISA of the decursin-ether derivatives synthesized in the above example using human eosinophil EoL-1 (eosinophilic leukemia cell) cells purchased from Bank of Japan.
상기 참조예 2 에서 배양시킨 EoL-1 세포를 0.5%FBS가 든 RPMI에 2.0 x 106/m로 24 웰 플레이트에 분주한 후 배양기 (37℃, 5% CO2)에서 16시간 배양하였다. 배양 후 (+)-데쿠르신-에테르 유도체 (10 ㎍/㎖)을 1시간 동안 처리한 후 HDE (1㎍/㎖)를 각각 24시간 동안 처리한 다음, ELISA를 이용하여 상층액에서 단핵구 화학유인물질 단백질-1 (monocyte chemoattractant protein-1, MCP-1), IL-6, IL-8의 양을 측정하였고, 실험결과를 하기 표 2에 나타내었다.The EoL-1 cells cultured in Reference Example 2 were dispensed into a 24 well plate at 2.0 × 10 6 / m in RPMI containing 0.5% FBS, and then cultured in an incubator (37 ° C., 5% CO 2 ) for 16 hours. After incubation, the (+)-decurin-ether derivative (10 μg / ml) was treated for 1 hour, and HDE (1 μg / ml) was treated for 24 hours, respectively, and then monocyte chemoattractant was induced in the supernatant using ELISA. The amount of substance protein-1 (monocyte chemoattractant protein-1, MCP-1), IL-6, IL-8 was measured, and the experimental results are shown in Table 2 below.
실험결과, EoL-1 세포의 정상군에서의 MCP-1, IL-6 및 IL-8의 양은 43.7, 26.2 및 183.5 pg/ml인데 반해, 항원인 진드기를 처리하면 MCP-1, IL-6 및 IL-8의 양이 236.8, 218.8 및 818.5 pg/ml으로 증가됨을 확인할 수 있었다(표 2). 이렇게 진드기에 의해서 증가된 상태에서 양성대조군인 덱사메타손을 처리하면 MCP-1, IL-6 및 IL-8의 양이 정상군과 거의 동등한 수준인 43.7, 18.8 및 158.5 pg/ml으로 감소됨을 알 수 있다. Experimental results showed that the amount of MCP-1, IL-6 and IL-8 in the normal group of EoL-1 cells was 43.7, 26.2 and 183.5 pg / ml, whereas MCP-1, IL-6 and It was confirmed that the amount of IL-8 was increased to 236.8, 218.8 and 818.5 pg / ml (Table 2). Treatment of dexamethasone, a positive control, in the increased state by ticks, reduced the amount of MCP-1, IL-6, and IL-8 to 43.7, 18.8, and 158.5 pg / ml, almost equivalent to those of the normal group. .
한편, 합성한 (+)-데쿠르신-에테르 유도체들 중 3b, 3c, 3d, 7d 및 7f 물질들이 덱사메타손 처리군과 거의 동등한 수준으로 진드기에 의해서 증가된 MCP-1의 양을 감소시켰다. 또한 3b번 물질이 덱사메타손 처리군과 거의 동등한 수준으로 진드기에 의해서 증가된 IL-6 및 IL-8의 양을 감소시켰다. Meanwhile, 3b, 3c, 3d, 7d and 7f substances in the synthesized (+)-decursin-ether derivatives reduced the amount of MCP-1 increased by ticks to almost the same level as the dexamethasone treated group. In addition, substance 3b reduced the amount of IL-6 and IL-8 increased by ticks to approximately the same level as the dexamethasone treated group.
종합해 볼 때 EoL-1 세포에 대해서 합성한 (+)-데쿠르신-에테르 유도체들은 진드기에 의해서 증가된 MCP-1, IL-6 및 IL-8의 양을 전반적으로 감소시켰으며, 특히 3b, 3c, 3d, 7d 및 7f 물질들은 기존의 아토피질환에 사용되고 있는 약물인 덱사메타손과 거의 동등한 수준으로 진드기에 의해서 증가된 MCP-1 또는 IL-6의 양을 감소시켰다.Taken together, (+)-decurin-ether derivatives synthesized against EoL-1 cells generally reduced the amount of MCP-1, IL-6 and IL-8 increased by ticks, especially 3b, The 3c, 3d, 7d and 7f substances reduced the amount of MCP-1 or IL-6 increased by ticks to nearly the same level as dexamethasone, a drug used in existing atopic diseases.
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.
제제예Formulation example 1. One. 산제의Powder 제조 Produce
(+)-데쿠르신-에테르 유도체 (3b) 20 mg(+)-Decursin-ether derivative (3b) 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.
제제예Formulation example 2. 정제의 제조 2. Preparation of Tablets
(+)-데쿠르신-에테르 유도체 (3c) 10 mg(+)-Decurin-ether derivative (3c) 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.
제제예Formulation example 3. 캅셀제의 제조 3. Manufacture of capsule
(+)-데쿠르신-에테르 유도체 (7a) 10 mg(+)-Decursin-ether derivative (7a) 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.
제제예Formulation example 4. 주사제의 제조 4. Preparation of Injectables
(+)-데쿠르신-에테르 유도체 (7b) 10 mg(+)-Decursin-ether derivatives (7b) 10 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO412H2O 26 mgNa 2 HPO 4 12H 2 O 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).
제제예Formulation example 5. 5. 액제의Liquid 제조 Produce
(+)-데쿠르신-에테르 유도체 (12a) 20 mg(+)-Decurin-ether derivative (12a) 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.
제제예Formulation example 6. 건강 식품의 제조 6. Manufacture of healthy food
(+)-데쿠르신-에테르 유도체 (12b) 1000 ㎎(+)-Decursin-ether derivative (12b) 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 mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.
제제예Formulation example 7. 건강 음료의 제조 7. Manufacture of health drinks
(+)-데쿠르신-에테르 유도체 (3a) 1000 ㎎(+)-Decurin-ether derivative (3a) 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 manufacturing method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized and then refrigerated and 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 a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.
Claims (7)
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WO2018199633A1 (en) * | 2017-04-25 | 2018-11-01 | (주)피알지에스앤텍 | Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredient |
KR20180119490A (en) * | 2017-04-25 | 2018-11-02 | (주)피알지에스앤텍 | Pharmaceutical composition for preventing or treating aging-related diseases comprising decursin derivatives |
KR20200039898A (en) * | 2018-10-05 | 2020-04-17 | (주)피알지에스앤텍 | Pharmaceutical composition for preventing or treating aging-related diseases comprising decursin derivatives |
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WO2018199633A1 (en) * | 2017-04-25 | 2018-11-01 | (주)피알지에스앤텍 | Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredient |
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