KR101997516B1 - Synthetic method for nocarbenzoxazoles and their derivatives - Google Patents

Synthetic method for nocarbenzoxazoles and their derivatives Download PDF

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KR101997516B1
KR101997516B1 KR1020180036560A KR20180036560A KR101997516B1 KR 101997516 B1 KR101997516 B1 KR 101997516B1 KR 1020180036560 A KR1020180036560 A KR 1020180036560A KR 20180036560 A KR20180036560 A KR 20180036560A KR 101997516 B1 KR101997516 B1 KR 101997516B1
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benzo
oxazole
ethyl
carboxylate
compound
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KR1020180036560A
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Korean (ko)
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전종갑
박형진
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한림대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

An object of the present invention is to provide an anti-inflammation agent having excellent efficacy and minimized side effects by solving side effects of existing anti-inflammation agents, and to provide a novel nocarbenzoxazole derivative and a synthesis method thereof. By using a POCl_3-mediated ring dehydration reaction using commercially available inexpensive raw materials and selective and/or complete demethylation and a reduction reaction as main reactions, nocarbenzoxazole derivatives are easily synthesized in a 15 to 49% of yield and it is confirmed by testing anti-inflammatory activity of compounds.

Description

노카벤즈옥사졸 및 그 유도체 합성방법 {Synthetic method for nocarbenzoxazoles and their derivatives}Synthetic method for nocarbenzoxazoles and their derivatives}

본 발명은 노카벤즈옥사졸 F 및 노카벤즈옥사졸 유도체를 상업적으로 입수 가능한 경제적인 원료로부터 손쉬운 공정으로 합성하는 방법 및 이 화합물을 함유하는 항염증 약학 조성물에 관한 것이다.The present invention relates to a method for synthesizing nocabenzoxazole F and nocabenzoxazole derivatives from a commercially available economical raw material in an easy process and an anti-inflammatory pharmaceutical composition containing the compound.

염증은 병원체, 감염 또는 질병과 같은 내인성 및 외인성 상해에 대한 신체의 국소적 방어 반응이다. 염증은 급성 또는 만성 염증으로 나눌 수 있다. 비록 이 반응이 신체로 하여금 외상 이후 침입과 손상을 제한하도록 할 수 있지만, 장기 염증은 심혈관 질환, 류마티스 관절염, 암, 기관지염, 당뇨병 및 신경퇴행성 질환과 같은 질명의 유발과 관련되어 있다. 염증 과정은 사이토카인(인터류킨-1β, 인터류킨-6 및 종양괴사인자 α), 케모카인, 히스타민, 프로스타글란딘, 보체 단편 그리고 백혈구에서 배출되는 산화질소와 같은 활성 분자와 같은 다양한 화학적 매개인자의 배출을 포함한다. 이들 중 산화질소(NO)는 세 종류의 유사한 산화질소 합성효소(NOS) 즉, 내피 NOS, 뉴런 NOS 및 유도 NOS에 의해 생성되는 작고 일시적인 프리 라디칼이며, 염증 발병에서 중요한 역할을 한다. 이것은 농도에 따라 "친구와 적" 앙면으로 작용한다. 산화질소는 정상적인 생리 농도 하에서는 항염증 효과를 나타낸다. 그러나 유도 NOS에 의한 산화질소 생성이 여러 병리생리학적 과정에 관여하게 된다. 그리하여 산화질소 생성에 대한 약학적 개입은 염증 기반 질병의 치료에 강한 영향을 줄 것이다.Inflammation is the body's local defense response to endogenous and exogenous injuries such as pathogens, infections or diseases. Inflammation It can be divided into acute or chronic inflammation. Although this reaction can cause the body to limit invasion and damage after trauma, long-term inflammation is associated with the induction of vaginal diseases such as cardiovascular disease, rheumatoid arthritis, cancer, bronchitis, diabetes and neurodegenerative diseases. The inflammatory process involves the release of various chemical mediators such as cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor α), chemokines, histamine, prostaglandins, complement fragments, and active molecules such as nitric oxide released from white blood cells. . Of these, nitric oxide (NO) is a small, temporary free radical produced by three kinds of similar nitric oxide synthase (NOS): endothelial NOS, neuronal NOS and induced NOS, and plays an important role in the development of inflammation. This acts as a "friend and enemy" face depending on concentration. Nitric oxide has an anti-inflammatory effect under normal physiological concentrations. However, nitric oxide production by induced NOS is involved in several pathophysiological processes. Thus, pharmaceutical intervention in nitric oxide production will have a strong impact on the treatment of inflammation based diseases.

아스피린과 이부프로펜, 코르티코스테로이드, 선택적 COX-2 억제제 (COXIBs) 및 항히스타민제와 같이 처방전 없이 살 수 있는 약제를 포함하는 비스테로이드성 항염증제(Non-steroidal anti-inflammatory drugs; NSAIDs)는 통증, 열병 및 염증 치료에 일반적으로 처방되고 있다. 이들은 부상에 대한 숙주의 반응을 일으키는 매개인자의 합성 또는 활성을 차단함으로써 작동한다. 이들 소분자 저해제들은 다양한 염증질환에 대한 주요 처방을 제공하며, 이들의 사용은 위궤양, 관절 파괴, 신장 독성 및 심혈관 질환과 같은 일반적인 부작용으로 인해 제한된다. 결과적으로 이러한 문제들을 해결하기 위하여 효과가 개선되고 부작용을 최소화할 수 있는 새로운 약제 개발이 필요하다.Non-steroidal anti-inflammatory drugs (NSAIDs), including over-the-counter drugs such as aspirin and ibuprofen, corticosteroids, selective COX-2 inhibitors (COXIBs), and antihistamines, are used for pain, fever, and inflammation. It is usually prescribed for treatment. They work by blocking the synthesis or activity of mediators that cause the host's response to injury. These small molecule inhibitors provide major prescriptions for various inflammatory diseases, and their use is limited due to common side effects such as gastric ulcers, joint destruction, kidney toxicity, and cardiovascular disease. As a result, in order to solve these problems, new drugs need to be developed to improve the effects and minimize side effects.

벤즈옥사졸(Benzoxazole)은 벤젠과 융합된 옥사졸 링 구조로서, 중요한 헤테로사이클이다. 수많은 벤즈옥사졸의 유도체들은 생화학 및 약학 분야에서 빌딩블록으로 이용되고 있을 뿐 아니라, 농약, 안료, 섬유조제(textile auxiliaries) 및 플라스틱과 같은 다른 산업분야에도 응용되고 있다. 치환된 벤즈옥사졸은 항생제, 항암제, 항미생물제, 항곰팡이제, 파킨슨병 치료제, 항염증제, 항경련제, 면역억제제, 항바이러스제 및 항기생충제와 같은 폭넓은 생물활성 스펙트럼을 나타낸다(8,9). 또, 어떤 벤즈옥사졸은 효소저해활성을 나타낸다(10). 이뿐만 아니라, 어떤 벤즈옥사졸은 음이온 및 금속 양이온 센서와 같은 형광 프로브에서 중요한 구조체로 인식된다(11).Benzoxazole is an oxazole ring structure fused with benzene and is an important heterocycle. Numerous benzoxazole derivatives are used as building blocks in the biochemical and pharmaceutical fields, as well as in other industries such as pesticides, pigments, textile auxiliaries and plastics. Substituted benzoxazoles exhibit a broad spectrum of bioactivity such as antibiotics, anticancer agents, antimicrobial agents, antifungal agents, Parkinson's disease agents, anti-inflammatory agents, anticonvulsants, immunosuppressants, antiviral agents and antiparasitic agents (8, 9). In addition, some benzoxazoles exhibit enzymatic inhibitory activity (10). In addition, some benzoxazoles are recognized as important structures in fluorescent probes such as anion and metal cation sensors (11).

대한민국 특허 10-1792743호 "신규한 노카벤즈옥사졸 유도체, 이의 제조방법 및 이의 용도"Republic of Korea Patent No. 10-1792743 "Novel benzobenzoxazole derivatives, preparation method thereof and uses thereof"

A. Ortega-Gomez, M. Perretti O. Soehnlein, EMBO Mol. Med. 2013, 5, 661.A. Ortega-Gomez, M. Perretti O. Soehnlein, EMBO Mol. Med. 2013, 5, 661. P. Libby, Nutr. Rev. 2007, 65, 140. P. Libby, Nutr. Rev. 2007, 65, 140. D. W. Gilroy, T. Lawrence, M. Perretti, A. G. Rossi, Nat. Rev. Drug Discov. 2004, 3, 401.D. W. Gilroy, T. Lawrence, M. Perretti, A. G. Rossi, Nat. Rev. Drug Discov. 2004, 3, 401. J. A. McCleverty, Chem. Rev. 2004, 104, 403.J. A. McCleverty, Chem. Rev. 2004, 104, 403. J. Lei, Y. Vodovotz, E. Tzeng, T.R. Billiar, Nitric Oxide 2013, 35, 175. J. Lei, Y. Vodovotz, E. Tzeng, T.R. Billiar, Nitric Oxide 2013, 35, 175. R. J. Flower, Nature Rev. Drug Discov. 2003, 2, 179.R. J. Flower, Nature Rev. Drug Discov. 2003, 2, 179. I. L. Meek, M. A. F. J. van de Laar, H. E. Vonkeman, Pharmaceuticals 2010, 3, 2146.I. L. Meek, M. A. F. J. van de Laar, H. E. Vonkeman, Pharmaceuticals 2010, 3, 2146. B. Maleki, M. Baghayeri, S. M. Vahdat, A. Mohammadzadeh, S. Akhoondic, RSC Adv. 2015, 5, 46545.B. Maleki, M. Baghayeri, S. M. Vahdat, A. Mohammadzadeh, S. Akhoondic, RSC Adv. 2015, 5, 46545. S. Rajasekhar, B. Maiti, K. Chanda, Synlett 2017, 28, 521.S. Rajasekhar, B. Maiti, K. Chanda, Synlett 2017, 28, 521. (a) P. Malapati, V.S. Krishna, R. Nallangi, R. R. Srilakshmi, D. Sriram, Eur. J. Med. Chem. 2018, 145, 23; (b) M. -H. Nam, M. Park, H. Park, Y. Kim, S. Yoon, V. S. Sawant, J. W. Choi, J. -H. Park, K. D. Park, S. -J. Min , C. J. Lee, H. Choo, ACS Chem. Neurosci, 2017, 8 1519. (a) P. Malapati, V.S. Krishna, R. Nallangi, R. R. Srilakshmi, D. Sriram, Eur. J. Med. Chem. 2018, 145, 23; (b) M. -H. Nam, M. Park, H. Park, Y. Kim, S. Yoon, V. S. Sawant, J. W. Choi, J. -H. Park, K. D. Park, S.-J. Min, C. J. Lee, H. Choo, ACS Chem. Neurosci, 2017, 8 1519. M. Taki, J. L. Wolford, T. V. O'Halloran, J. Am. Chem. Soc. 2004, 126, 712.M. Taki, J. L. Wolford, T. V. O'Halloran, J. Am. Chem. Soc. 2004, 126, 712. M. Sun, X. Zhang, H. Hao, W. Li, C. Lu, J. Nat. Prod. 2015, 78, 2123.M. Sun, X. Zhang, H. Hao, W. Li, C. Lu, J. Nat. Prod. 2015, 78, 2123. (a) K. Damodar, J. -K. Kim, J. -G. Jun, Tetrahedron Lett.　2017, 58, 50; (b) H. Y. Jang, H. J. Park, K. Damodar, J. -K. Kim, J. -G. Jun, Bioorg. Med. Chem. Lett., 2016,　26, 5438. (a) K. Damodar, J.-K. Kim, J.-G. Jun, Tetrahedron Lett. 2017, 58, 50; (b) H. Y. Jang, H. J. Park, K. Damodar, J.-K. Kim, J.-G. Jun, Bioorg. Med. Chem. Lett., 2016, @ 26, 5438. (a) H. Ramser, E. Wiberg, Chem. Ber. 1930, 63, 1136; (b) W. Gerrard, M. F. Lappert, J. Chem. Soc. 1952, 1486.(a) H. Ramser, E. Wiberg, Chem. Ber. 1930, 63, 1136; (b) W. Gerrard, M. F. Lappert, J. Chem. Soc. 1952, 1486. (a) D. Tsikas, J. Chromatogr. B, 2007, 851, 51; (b) E. M. Hetrick, M. H. Schoenfisch, Annu. Rev. Anal. Chem. 2009, 2, 409.(a) D. Tsikas, J. Chromatogr. B, 2007, 851, 51; (b) E. M. Hetrick, M. H. Schoenfisch, Annu. Rev. Anal. Chem. 2009, 2, 409. (a) J. D. Laskin, D. E. Heck, D. L. Laskin, Trends Endocrinol. Metab. 1994, 5, 377; (b) D. Schade, J. Kotthaus, B. Clement, Pharmacol. Ther. 2010, 126, 279; (c) C. S. Kim, L. Subedi, J. Oh, S. Y. Kim, S. U. Choi, K. R. Lee, J. Nat. Prod. 2017, 80, 1134.(a) J. D. Laskin, D. E. Heck, D. L. Laskin, Trends Endocrinol. Metab. 1994, 5, 377; (b) D. Schade, J. Kotthaus, B. Clement, Pharmacol. Ther. 2010, 126, 279; (c) C. S. Kim, L. Subedi, J. Oh, S. Y. Kim, S. U. Choi, K. R. Lee, J. Nat. Prod. 2017, 80, 1134. J. Carmichael, A. F. Gazdar, Cancer Res. 1987, 47, 943.J. Carmichael, A. F. Gazdar, Cancer Res. 1987, 47, 943.

본 발명은 종래 항염증제의 부작용을 해결하여 효능이 우수하고 부작용을 최소화한 항염증제를 제공하는 것을 목적으로 한다.An object of the present invention is to provide an anti-inflammatory agent that is excellent in efficacy and minimized side effects by solving the side effects of the conventional anti-inflammatory agent.

또한, 본 발명은 새로운 노카벤즈옥사졸 유도체 및 그 합성방법을 제공하는 것을 목적으로 한다.It is another object of the present invention to provide a novel nocabenzoxazole derivative and its synthesis method.

본 발명자들은 상업적으로 판매하는 저렴한 원료물질을 이용하여 15~49% 수율로 노카벤즈옥사졸 F (화합물 1)와 노카벤즈옥사졸 유도체 (화합물 8)를 손쉽게 합성하였다. The present inventors easily synthesized nocabenzoxazole F (compound 1) and nocabenzoxazole derivative (compound 8) in 15-49% yield using commercially available inexpensive raw materials.

POCl3-매개 원환탈수반응, 선택적 및/또는 완전한 탈메틸화 및 환원반응은 이 합성 경로의 성공에서 주요 단계이다. 또한, 이들 벤즈옥사졸 화합물들은 LPS-유도 RAW264.7 세포에서 눈에 띌 만한 세포독성 없이 농도 의존적으로 온화한 산화질소 생성 저해활성을 나타내었다. 주목할 점은 화합물 8 (53.5% at 10 μM; IC50 = 8.17 μM)이 양성 대조군인 L-NMMA (19.5% at 10 μM; IC50 = 18.77 μM)와 비교할 때 가능성 있는 저해제로 파악되었다는 것이다. 본 발명에서는 벤즈옥사졸 2번 위치의 카테콜의 존재가 산화질소 생성 저해활성에 가장 크게 기여하는 것으로 나타났다.POCl 3 -mediated toroidal dehydration, selective and / or complete demethylation and reduction are key steps in the success of this synthetic route. In addition, these benzoxazole compounds showed mild nitric oxide production inhibitory activity in a concentration-dependent manner without noticeable cytotoxicity in LPS-induced RAW264.7 cells. Note that compound 8 (53.5% at 10 μM; IC 50 = 8.17 μM) was identified as a potential inhibitor when compared to the positive control L-NMMA (19.5% at 10 μM; IC 50 = 18.77 μM). In the present invention, the presence of the catechol at the benzoxazole 2-position was shown to most contribute to the nitric oxide production inhibitory activity.

본 발명의 치환된 벤즈옥사졸 (화합물 1, 8)은 도 1에 도시되어 있다. 화합물 1 (노카벤즈옥사졸 F(nocarbenzoxazoles F)은 호염성인 노카디옵시스 루센텐시스(Nocardiopsis lucentensis) DSM 44048에서 분리한 천연 산물(12)인 반면, 화합물 8은 합성한 유도체이다. 그러나 이들의 항염증 활성에 대한 보고는 없었으며, 화합물 8의 합성방법도 보고된 바 없었다.Substituted benzoxazoles (compounds 1, 8) of the present invention are shown in FIG. Compound 1 (nocarbenzoxazoles F) is a natural product (12) isolated from the basophilic Nocardiopsis lucentensis DSM 44048, while compound 8 is a synthetic derivative. There was no report of inflammatory activity, and no method of synthesizing Compound 8 was reported.

본 발명은The present invention

가) 에틸 3-아미노-4-하이드록시벤조에이트를 무수 1,4-다이옥산에 넣고 교반한 용액에 화학식 14로 표시되는 화합물 14 또는 화합물 17을 상온, 질소 분위기 하에서 가하고 90℃로 가온하고 교반한 다음, POCl3를 적가하고 교반하여 각각 대응하는 에틸 2-(4-메톡시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이메톡시페닐)벤조[d]옥사졸-5-카복실레이트를 얻는 단계;A) Ethyl 3-amino-4-hydroxybenzoate was added to anhydrous 1,4-dioxane, and the compound 14 or compound 17 represented by the formula (14) was added to the stirred solution under normal temperature and nitrogen atmosphere, heated to 90 ° C., and stirred. Next, POCl 3 was added dropwise and stirred to respectively correspond to the corresponding ethyl 2- (4-methoxyphenyl) benzo [ d ] oxazole-5-carboxylate or ethyl 2- (3,4-dimethoxyphenyl) benzo [ d ] Oxazole-5-carboxylate;

나) 에틸 2-(4-메톡시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이메톡시페닐)벤조[d]옥사졸-5-카복실레이트를 무수 CH2Cl2에 넣고 교반한 용액에 BBr3를 0℃, 질소 분위기 하에서 한 방울씩 가한 후, 상온으로 가온하고 교반하여 각각 대응하는 에틸 2-(4-하이드록시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이하이드록시페닐)벤조[d]옥사졸-5-카복실레이트를 얻는 단계; 및B) ethyl 2- (4-methoxyphenyl) benzo [ d ] oxazole-5-carboxylate or ethyl 2- (3,4-dimethoxyphenyl) benzo [ d ] oxazole-5-carboxylate BBr 3 was added dropwise to the stirred solution in CH 2 Cl 2 at 0 ° C. under a nitrogen atmosphere, and then warmed to room temperature and stirred to respectively correspond to ethyl 2- (4-hydroxyphenyl) benzo [ d ] oxazole. Obtaining -5-carboxylate or ethyl 2- (3,4-dihydroxyphenyl) benzo [ d ] oxazole-5-carboxylate; And

다) 에틸 2-(4-하이드록시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이하이드록시페닐)벤조[d]옥사졸-5-카복실레이트를 무수 THF에 넣고 교반한 용액에 LiAlH4 용액을 0℃, 질소 분위기 하에서 한 방울씩 가한 후, 상온으로 가온하고, 교반하여 반응 완료 후 0℃로 냉각하고, 포화 Na2CO3 수용액을 서서히 가하여 과량의 LiAlH4를 퀀칭하고 교반하여 각각 대응하는 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)페놀 또는 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올을 얻는 단계;를 포함하는 노카벤즈옥사졸 또는 그 유도체 합성방법에 관한 것이다.C) ethyl 2- (4-hydroxyphenyl) benzo [ d ] oxazole-5-carboxylate or ethyl 2- (3,4-dihydroxyphenyl) benzo [ d ] oxazole-5-carboxylate LiAlH 4 solution was added dropwise to the stirred solution in THF at 0 ° C. under a nitrogen atmosphere, and then warmed to room temperature, stirred to complete the reaction, cooled to 0 ° C., and saturated Na 2 CO 3 aqueous solution was slowly added to the solution. LiAlH 4 was quenched and stirred to respectively correspond to 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) phenol or 4- (5- (hydroxymethyl) benzo [ d ] oxazole- It relates to a method for synthesizing nocabenzoxazole or a derivative thereof, comprising the step of obtaining 2-yl) benzene-1,2-diol.

<화학식 14><Formula 14>

Figure 112018031374618-pat00001
Figure 112018031374618-pat00001

또한, 본 발명은 신규한 노카벤즈옥사졸 유도체인 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올에 관한 것이다.The present invention also relates to 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) benzene-1,2-diol, which is a novel nocabenzoxazole derivative.

또한, 본 발명은 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)페놀 및 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올 중 1종 이상을 함유하는 항염증 약학 조성물에 관한 것이다. The present invention also provides 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) phenol and 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) benzene An anti-inflammatory pharmaceutical composition containing at least one of -1,2-diol.

본 발명의 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)페놀 및 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올 1종 이상을 유효성분으로 함유하는 약제학적 조성물은 약제학적 분야에서 통상적으로 허용되는 담체와 함께 배합하여 통상적인 방법에 의해 경구 또는 주사 형태로 제형화할 수 있다. 경구용 조성물로는 예를 들면 정제 및 젤라틴 캡슐이 있으며, 이들은 활성 성분 이외에도 희석제(예: 락토스, 덱스트로스, 수크로스, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활탁제(예: 실리카, 탤크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)을 함유하고, 정제는 또한 결합제(예: 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로스, 나트륨 카복시메틸셀룰로스 및/또는 폴리비닐피롤리돈)를 함유하며, 경우에 따라서 붕해제(예: 전분, 한천, 알긴산 또는 그의 나트륨염) 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유하는 것이 바람직하다. 주사용 조성물은 등장성 수용액 또는 현탁액이 바람직하고, 언급한 조성물은 멸균되고/되거나 보조제(예: 방부제, 안정화제, 습윤제 또는 유화제 용액 촉진제, 삼투압 조절을 위함 염/또는 완충제)를 함유한다. 또한, 이들은 기타 치료적으로 유용한 물질을 함유할 수 있다.4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) phenol and 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) benzene-1 of the present invention Pharmaceutical compositions containing at least one, 2-diol as an active ingredient can be formulated in oral or injectable form by conventional methods in combination with a carrier which is conventionally acceptable in the pharmaceutical art. Oral compositions include, for example, tablets and gelatin capsules, which, in addition to the active ingredient, may contain diluents (e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (e.g. silica, talc) , Stearic acid and its magnesium or calcium salts and / or polyethylene glycols, the tablets also contain binders (e.g. magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone). ), And optionally a disintegrant (eg starch, agar, alginic acid or its sodium salt) or boiling mixture and / or absorbent, colorant, flavor and sweetener. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and the compositions mentioned are sterile and / or contain auxiliaries such as preservatives, stabilizers, wetting or emulsifier solution promoters, salts or buffers for controlling osmotic pressure. In addition, they may contain other therapeutically valuable substances.

이와 같이 제조된 약제학적 제제는 목적하는 바에 따라 경구로 투여하거나, 비경구 방식 즉, 정맥 내, 피하, 복강 내 투여 또는 국소적용할 수 있다. 용량은 일일 투여량 0.0001~100㎎/㎏을 1 내지 수회에 나누어 투여할 수 있다. 특정 환자에 대한 투여용량 수준은 환자의 체중, 연령, 성별, 건강상태, 투여시간, 투여방법, 배설율, 질환의 중증도 등에 따라 변화될 수 있다.The pharmaceutical preparations thus prepared can be administered orally as desired, or parenterally, ie, intravenously, subcutaneously, intraperitoneally, or topically. The dose may be administered by dividing the daily dose between 0.0001 and 100 mg / kg in one to several times. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, time of administration, method of administration, rate of excretion, severity of the disease, and the like.

나아가, 본 발명은 상기 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)페놀 및 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올 중 하나 이상을 유효성분으로 하고 약학적으로 허용되는 담체를 포함하는 것을 특징으로 하는, 아토피, 피부소양증과 같은 피부염증을 비롯한 염증질환의 예방과 치료에 유용한 약제학적 조성물을 제공한다.Furthermore, the present invention provides the above 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) phenol and 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) Pharmaceutically useful for the prevention and treatment of inflammatory diseases, including atopic dermatitis, such as atopic dermatitis, characterized in that it comprises at least one of benzene-1,2-diol as an active ingredient and comprises a pharmaceutically acceptable carrier. To provide a composition.

본 발명에서 정의되는 염증질환이란 아토피 피부염을 포함하는 피부염증질환, 신경교종세포 등 신경세포 염증질환, 척추염, 요도염, 방광염, 신염, 신우신염, 혈관염, 비염, 인후염, 편도염, 급성통증 또는 염증성 장질환 등이며, 바람직하게는 피부염증질환, 요도염, 방광염, 신염, 신우신염, 비염, 인후염, 편도염 또는 염증성 장질환이다.Inflammatory diseases as defined in the present invention are dermatitis diseases including atopic dermatitis, neuronal inflammatory diseases such as glioma cells, spondylitis, urethritis, cystitis, nephritis, pyelonephritis, vasculitis, rhinitis, sore throat, tonsillitis, acute pain or inflammatory bowel Diseases, and the like, and are preferably dermatitis diseases, urethritis, cystitis, nephritis, pyelonephritis, rhinitis, sore throat, tonsillitis, or inflammatory bowel disease.

본 발명에 따르면, 상업적으로 판매하는 저렴한 원료물질을 이용하여 15~49% 수율로 노카벤즈옥사졸 F (화합물 1), G (화합물 5) 및 그 유도체들 (화합물 2-4 및 6-8)을 손쉽게 합성할 수 있다. According to the present invention, nocarbenzoxazole F (Compound 1), G (Compound 5) and its derivatives (Compounds 2-4 and 6-8) in 15-49% yield using commercially available inexpensive raw materials Can be easily synthesized.

또한, 본 발명에 따르면, 상기 합성한 노카벤즈옥사졸 F, G 및 그 유도체들 중 1종 이상을 포함하는 항염증 약학 조성물을 제공할 수 있다.In addition, according to the present invention, it is possible to provide an anti-inflammatory pharmaceutical composition comprising at least one of the synthesized nocabenzoxazole F, G and derivatives thereof.

도 1은 노카벤즈옥사졸 F, G 및 그 유도체들의 화학구조를 나타낸다.
도 2는 노카벤즈옥사졸 F, G와 그 유도체들의 합성방법을 나타낸다.Figure 1 shows the chemical structures of nocabenzoxazole F, G and its derivatives.
Figure 2 shows a method for synthesizing nocabenzoxazole F, G and its derivatives.

아래에서는 구체적인 실시예를 들어 본 발명의 구성을 좀 더 자세히 설명한다. 그러나 본 발명의 범위가 실시예의 기재에만 한정되는 것이 아님은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 자명하다.Hereinafter, the configuration of the present invention will be described in more detail with reference to specific embodiments. However, it is obvious to those skilled in the art that the scope of the present invention is not limited only to the description of the embodiments.

모든 화학제품은 특별한 언급이 없는 한 구입한 그대로 정제하지 않고 사용하였다. 반응에 사용한 모든 용매는 질소 분위기 하에서 적절한 탈수제로부터 증류하였다. 크로마토그래피에 사용한 모든 용매는 구입하여 별도의 정제 없이 바로 사용하였다. All chemicals were used without purification as purchased unless otherwise noted. All solvents used for the reaction were distilled from an appropriate dehydrating agent under a nitrogen atmosphere. All solvents used for chromatography were purchased and used directly without further purification.

DC-Plastikfolien 60, F254 (Merck, 층 두께 0.2 mm) 플라스틱 판에 실리카젤을 입힌 플레이트를 이용한 박막 크로마토그래피(TLC)로 모든 반응을 모니터하였고, UV (254 nm)를 이용하여 관찰하거나 또는 p-아니스알데하이드와 포스포몰리브딕산 (PMA)으로 염색하여 관찰하였다. 실리카 젤 60 (230-400 mesh, Merck, Darmstadt, Germany)은 컬럼 크로마토그래피로 얻은 화합물의 정제에 이용하였다. 1H-NMR 스펙트럼은 Varian Mercury-300 MHz FT-NMR (Palo alto, CA, USA) 및 13C에 대해서는 75 MHz로 기록하였고, 화학적 이동 (δ)은 TMS에 대하여 ppm (parts per million)으로 나타내었고, 커플링 상수 (J)는 Hz로 인용하였다. 피크 분할양상은 s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet) 및 m (multiplet)과 같이 약자로 표시하였고, CDCl3/CD3OD/acetone-d 6/DMSO-d 6는 용매 및 내부 스탠다드로 이용하였다. 저해상도 질량 스펙트럼 (전자 이온화, EI)은 Agilent-5977E spectrometer를 이용하여 기록하였고, 고해상도 질량 스펙트럼은 JMS-700 (JEOL, Japan)을 이용하여 기록하였다. 녹는점은 MEL-TEMP Ⅱ 장치에서 측정하고, 보정하지 않았다. All reactions were monitored by thin layer chromatography (TLC) using a plate coated with silica gel on a DC-Plastikfolien 60, F 254 (Merck, 0.2 mm layer) plastic plate and observed using UV (254 nm) or p -Observed by staining with anisaldehyde and phosphomolybdic acid (PMA). Silica gel 60 (230-400 mesh, Merck, Darmstadt, Germany) was used to purify the compound obtained by column chromatography. 1 H-NMR spectra were recorded at 75 MHz for Varian Mercury-300 MHz FT-NMR (Palo alto, CA, USA) and 13 C, and chemical shifts (δ) are expressed in parts per million (ppm) for TMS. Coupling constants ( J ) are quoted in Hz. Peak division patterns are abbreviated as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet) and m (multiplet), and CDCl 3 / CD 3 OD / acetone d 6 / DMSO- d 6 was used as solvent and internal standard. Low resolution mass spectra (electron ionization, EI) were recorded using an Agilent-5977E spectrometer, and high resolution mass spectra were recorded using JMS-700 (JEOL, Japan). Melting points were measured on a MEL-TEMP II instrument and were not corrected.

에틸 3-아미노-4- 하이드록시벤조에이트 (Ethyl 3-amino-4-hydroxybenzoate) (화합물 10): 3-아미노-4-하이드록시벤조산 (화합물 9) (1.0 g, 6.53 mmol)을 EtOH (10 mL)에 넣고 교반한 용액에 0℃, 질소 분위기 하에서 진한 H2SO4 (3.0 mL)를 가하였다. 반응 완료 후, 혼합물을 가온하고 12시간 동안 환류시켰다. 반응 완료 후, 상온으로 냉각시키고, 분쇄된 얼음에 넣고 포화 NaHCO3 수용액으로 중화시켰다. 반응 혼합물을 EtOAc (3 x 45 mL)로 추출하였다. 혼합 유기용매층은 H2O (2 x 20 mL), 식염수 (20 mL)로 세척하고, 무수 Na2SO4로 건조하여, 진공 농축하였다. 컬럼 크로마토그래피 (EtOAc:Hexane=1:2)로 조화합물을 정제하여 연한 오렌지색 고체 화합물 10 (1.01 g, 85 %)을 얻었다. 녹는점 96-98℃; Rf= 0.33 (EtOAc/hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 7.44 (1H, d, J = 1.8 Hz), 7.41 (1H, dd, J = 7.8, 1.8 Hz), 6.75 (1H, d, J = 7.8 Hz), 4.32 (2H, q, J = 7.2 Hz) 1.37 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 167.0, 148.6, 134.1, 123.3, 122.2, 118.2, 114.6, 61.0, 14.7. Ethyl 3-amino-4-hydroxybenzoate (Ethyl 3-amino-4- hydroxybenzoate) ( Compound 10): 3-amino-4-hydroxy-benzoic acid (Compound 9) (1.0 g, 6.53 mmol ) EtOH (10 mL) was added to the stirred solution and concentrated H 2 SO 4 (3.0 mL) was added at 0 ° C. under a nitrogen atmosphere. After the reaction was completed, the mixture was warmed and refluxed for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into crushed ice, and saturated with NaHCO 3. Neutralized with aqueous solution. The reaction mixture was extracted with EtOAc (3 x 45 mL). The mixed organic solvent layer was washed with H 2 O (2 × 20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2) to give a pale orange solid compound 10 (1.01 g, 85%). Melting point 96-98 ° C .; R f = 0.33 (EtOAc / hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 7.44 (1H, d, J = 1.8 Hz), 7.41 (1H, dd, J = 7.8, 1.8 Hz), 6.75 (1H, d, J = 7.8 Hz), 4.32 (2H, q, J = 7.2 Hz) 1.37 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 167.0, 148.6, 134.1, 123.3, 122.2, 118.2, 114.6, 61.0, 14.7.

치치환된Substituted 벤조산 (화합물 11- Benzoic Acid (Compound 11- 13)으로부터From 13) 치환된  Substituted 벤조일Benzoyl 클로라이드 (화합물 14, 16 및 17)를 합성하는 일반적인 절차:  General procedure for the synthesis of chlorides (compounds 14, 16 and 17):

SOCl2 (2 mL)를 치환된 벤조산 (0.55 mmol)에 0℃, 질소 분위기 하에서 가하였다. 혼합물을 60℃에서 2시간 동안 교반하였다. 반응 완료 후 실온으로 냉각시키고, 과량의 SOCl2를 감압하에 제거하였다. 생성된 벤조일 클로라이드를 진공하에 30분 동안 건조하고, 추가 정제 없이 다음 단계에서 사용하였다.SOCl 2 (2 mL) was added to substituted benzoic acid (0.55 mmol) at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 60 ° C. for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and excess SOCl 2 was removed under reduced pressure. The resulting benzoyl chloride was dried under vacuum for 30 minutes and used in the next step without further purification.

2-아릴 2-aryl 벤조[d]옥사졸Benzo [d] oxazole -5--5- 카복실레이트Carboxylate (2-aryl  (2-aryl benzo[benzo [ dd ]oxazole] oxazole -5-carboxylate)의 POCl-5-carboxylate) POCl 33 매개 합성에 대한 일반적인 절차: General procedure for mediated synthesis:

화합물 10 (0.55 mmol)을 무수 1,4-다이옥산 (3 mL)에 넣고 교반한 용액에 치환된 벤조일 클로라이드 (1.1 mmol, 2.0 당량)를 상온, 질소 분위기 하에서 가하였다. 혼합물을 90℃로 가온하고 3시간 동안 교반하였다. 이 단계에서, POCl3 (0.16 mL, 1.65 mmol, 3.0 당량)를 적가하고, 추가로 12시간 동안 교반하였다. 반응 완료 후, 상온으로 냉각하고, 용매 및 POCl3를 감압하에 제거하였다. EtOAc (25mL), H2O (10mL)를 상기 조화합물에 첨가하고 두 개의 층을 분리하였다. 수성층은 EtOAc (2 x 20 mL)로 추출하였다. 혼합 유기용매층은 H2O (2 x 15 mL)와 식염수 (15 mL)로 세척하고, 무수 Na2SO4로 건조하여 진공 농축하였다. 컬럼 크로마토그래피 (EtOAc:Hexane=1:5 - 1:2)로 조화합물을 정제하여 순수한 화합물을 얻었다.Compound 10 (0.55 mmol) was added to anhydrous 1,4-dioxane (3 mL), and substituted benzoyl chloride (1.1 mmol, 2.0 equiv) was added to the stirred solution under normal temperature and nitrogen atmosphere. The mixture was warmed to 90 ° C. and stirred for 3 hours. In this step, POCl 3 (0.16 mL, 1.65 mmol, 3.0 equiv) was added dropwise and stirred for a further 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent and POCl 3 were removed under reduced pressure. EtOAc (25 mL), H 2 O (10 mL) were added to the crude compound and the two layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The mixed organic solvent layer was washed with H 2 O (2 × 15 mL) and brine (15 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 5-1: 2) to give pure compound.

에틸 2-Ethyl 2- (4-메톡시페닐)벤조[(4-methoxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate {Ethyl 2- {Ethyl 2- (4-methoxyphenyl)benzo(4-methoxyphenyl) benzo [[ dd ]oxazole-5-carboxylate} (화합물 18): ] oxazole-5-carboxylate} (Compound 18):

수율: 55%; 회백색 고체; 녹는점 156-158℃; Rf= 0.73 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 8.38 (1H, s), 8.14 (2H, d, J = 8.7 Hz), 8.04 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.4 Hz), 6.99 (2H, d, J = 8.7 Hz), 4.40 (2H, q, J = 7.2 Hz), 3.86 (3H, s), 1.42 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 166.3, 164.3, 162.6, 153.5, 142.4, 129.6, 127.2, 126.6, 121.5, 119.1, 114.5, 110.1, 61.3, 55.6, 14.6.Yield: 55%; Off-white solid; Melting point 156-158 ° C .; R f = 0.73 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 8.38 (1H, s), 8.14 (2H, d, J = 8.7 Hz), 8.04 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.4 Hz), 6.99 (2H, d, J = 8.7 Hz), 4.40 (2H, q, J = 7.2 Hz), 3.86 (3H, s), 1.42 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 166.3, 164.3, 162.6, 153.5, 142.4, 129.6, 127.2, 126.6, 121.5, 119.1, 114.5, 110.1, 61.3, 55.6, 14.6.

에틸 2-Ethyl 2- 페닐벤조[Phenylbenzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate (Ethyl 2-phenylbenzo[ (Ethyl 2-phenylbenzo [ dd ]oxazole-5-carboxylate) (화합물 19):] oxazole-5-carboxylate) (compound 19):

수율: 60%; 회백색 고체; 녹는점 102-104℃; Rf= 0.54 (EtOAc/Hexane=1/3); 1H NMR (300 MHz, CDCl3) δ 8.42 (1H, d, J = 0.9 Hz), 8.22-8.18 (2H, m), 8.06 (1H, dd, J = 8.7, 1.8 Hz), 7.56- 7.48 (4H, m), 4.40 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 166.1, 164.2, 153.6, 142.2, 131.9, 129.0, 127.8, 127.4, 127.0, 126.7, 122.0, 110.3, 61.3, 14.6.Yield: 60%; Off-white solid; Melting point 102-104 ° C; R f = 0.54 (EtOAc / Hexane = 1/3); 1 H NMR (300 MHz, CDCl 3 ) δ 8.42 (1H, d, J = 0.9 Hz), 8.22-8.18 (2H, m), 8.06 (1H, dd, J = 8.7, 1.8 Hz), 7.56- 7.48 ( 4H, m), 4.40 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 166.1, 164.2, 153.6, 142.2, 131.9, 129.0, 127.8, 127.4, 127.0, 126.7, 122.0, 110.3, 61.3, 14.6.

에틸 2- (2,4-다이메톡시페닐)벤조[ d ]옥사졸 -5- 카복실레이트 (Ethyl 2-(2,4-dimethoxyphenyl)benzo[ d ]oxazole-5-carboxylate) (화합물 20): 수율: 48%; 회백색 고체; 녹는점 148-150℃; Rf= 0.61 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 8.45 (1H, s), 8.08 (1H, J = 9.3 Hz), 8.03 (1H, d, J = 9.3 Hz), 7.54 (1H, d, J = 8.7 Hz), 6.60 (1H, d, J = 8.7 Hz), 6.58 (1H, s), 4.40 (2H, q, J = 6.9 Hz), 4.00 (3H, s), 3.87 (3H, s), 1.42 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 166.2, 163.7, 162.8, 159.9, 152.9, 142.2, 132.5, 126.8, 126.2, 121.6, 109.8, 108.4, 105.3, 99.0, 61.0, 56.1, 55.5, 14.4. Ethyl 2- (2,4-dimethoxyphenyl) benzo [d] oxazole-5-carboxylate (Ethyl 2- (2,4-dimethoxyphenyl) benzo [d] oxazole-5-carboxylate) (compound 20): Yield: 48%; Off-white solid; Melting point 148-150 ° C .; R f = 0.61 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (1H, s), 8.08 (1H, J = 9.3 Hz), 8.03 (1H, d, J = 9.3 Hz), 7.54 (1H, d, J = 8.7 Hz ), 6.60 (1H, d, J = 8.7 Hz), 6.58 (1H, s), 4.40 (2H, q, J = 6.9 Hz), 4.00 (3H, s), 3.87 (3H, s), 1.42 (3H , t, J = 6.9 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 166.2, 163.7, 162.8, 159.9, 152.9, 142.2, 132.5, 126.8, 126.2, 121.6, 109.8, 108.4, 105.3, 99.0, 61.0, 56.1, 55.5, 14.4.

에틸 2-Ethyl 2- (3,4-다이메톡시페닐)벤조[(3,4-dimethoxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate (Ethyl 2-(3,4-dimethoxyphenyl)benzo[ (Ethyl 2- (3,4-dimethoxyphenyl) benzo [ dd ]oxazole-5-carboxylate) (화합물 21):] oxazole-5-carboxylate) (Compound 21):

수율: 53%; 회백색 고체; 녹는점 146-148℃; Rf= 0.47 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, d, J = 1.8 Hz), 8.03 (1H, dd, J = 8.7, 1.8 Hz), 7.78 (1H, dd, J = 8.4, 2.1 Hz), 7.67 (1H, d, J = 2.1 Hz),7.50 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 4.39 (2H, q, J = 7.2 Hz), 3.98 (3H, s), 3.94 (3H, s), 1.42 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 166.2, 164.3, 153.5, 152.3, 149.3, 142.3, 127.3, 126.6, 121.5, 121.4, 119.2, 111.1, 110.2, 110.1, 61.3, 56.3, 56.2, 14.6.Yield: 53%; Off-white solid; Melting point 146-148 ° C .; R f = 0.47 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 8.36 (1H, d, J = 1.8 Hz), 8.03 (1H, dd, J = 8.7, 1.8 Hz), 7.78 (1H, dd, J = 8.4, 2.1 Hz) , 7.67 (1H, d, J = 2.1 Hz), 7.50 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 4.39 (2H, q, J = 7.2 Hz), 3.98 (3H, s), 3.94 (3H, s), 1.42 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 166.2, 164.3, 153.5, 152.3, 149.3, 142.3, 127.3, 126.6, 121.5, 121.4, 119.2, 111.1, 110.2, 110.1, 61.3, 56.3, 56.2, 14.6.

BBrBBr 33 를To 이용한 탈 메틸화의 일반적인 절차: General Procedure of Demethylation Using:

에틸 2-아릴 벤조[d]옥사졸-5-카복실레이트 (0.2 mmol)을 무수 CH2Cl2 (4 mL)에 넣고 교반한 용액에 BBr3 (1.0 M in CH2Cl2, 0.3 mL, 1.5 당량)를 0℃, 질소 분위기 하에서 한 방울씩 가하였다. 혼합물을 상온으로 가온하고 3시간 동안 교반하였다. 반응 완료 후 0℃로 냉각하고, 1.0 N HCl (1 mL)을 천천히 가하고 15분 동안 교반하였다. 혼합물을 CH2Cl2 (2 x 20 mL)로 추출하였다. 혼합 유기용매층은 H2O (2 x 10 mL)와 식염수 (10 mL)로 세척하고, 무수 Na2SO4로 건조하여 진공 농축하였다. 컬럼 크로마토그래피 (EtOAc:Hexane=1:2 - 1:1)로 조화합물을 정제하여 순수한 화합물을 얻었다 [주: 화합물 21의 경우에는 3.0 당량의 BBr3를 이용하였다].Ethyl 2-aryl benzo [ d ] oxazole-5-carboxylate (0.2 mmol) was added to anhydrous CH 2 Cl 2 (4 mL) and stirred in BBr 3 (1.0 M in CH 2 Cl 2 , 0.3 mL, 1.5). Equivalent) was added dropwise at 0 ° C. under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to 0 ° C, 1.0 N HCl (1 mL) was slowly added thereto, and stirred for 15 minutes. CH 2 Cl 2 Extracted with (2 x 20 mL). The mixed organic solvent layer was washed with H 2 O (2 × 10 mL) and brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2-1: 1) to obtain a pure compound. [Note: In the case of compound 21, 3.0 equivalents of BBr 3 were used].

에틸 2-Ethyl 2- (4-하이드록시페닐)벤조[(4-hydroxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate (Ethyl 2- (Ethyl 2- (4-hydroxyphenyl)benzo(4-hydroxyphenyl) benzo [[ dd ]oxazole-5-carboxylate) (화합물 22): ] oxazole-5-carboxylate) (compound 22):

수율: 71%; 회백색 고체; 녹는점 210-212℃; Rf= 0.55 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, DMSO-d6) δ 8.26 (1H, d, J = 1.5 Hz), 8.08-8.03 (3H, m), 7.68 (1H, d, J = 8.7 Hz), 6.95 (2H, d, J = 8.4 Hz), 4.38 (2H, q, J = 7.2 Hz), 1.43 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, DMSO-d6) δ 167.5, 166.6, 163.1, 154.8, 143.3, 131.0, 128.6, 127.7, 121.6, 118.4, 117.2, 111.6, 62.6, 14.9.Yield: 71%; Off-white solid; Melting point 210-212 ° C; R f = 0.55 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (1H, d, J = 1.5 Hz), 8.08-8.03 (3H, m), 7.68 (1H, d, J = 8.7 Hz), 6.95 (2H, d , J = 8.4 Hz), 4.38 (2H, q, J = 7.2 Hz), 1.43 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, DMSO-d6) δ 167.5, 166.6, 163.1, 154.8, 143.3, 131.0, 128.6, 127.7, 121.6, 118.4, 117.2, 111.6, 62.6, 14.9.

에틸 2-Ethyl 2- (3,4-다이하이드록시페닐)벤조[(3,4-dihydroxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate (Ethyl 2-(3,4-dihydroxyphenyl)benzo[ (Ethyl 2- (3,4-dihydroxyphenyl) benzo [ dd ]oxazole-5-carboxylate) (화합물 23):] oxazole-5-carboxylate) (Compound 23):

수율: 75%; 회백색 고체; 녹는점 214-216℃; Rf= 0.35 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, DMSO-d6) δ 8.21 (1H, d, J = 1.8 Hz), 7.96 (1H, d, J = 8.4 Hz), 7.81 (1H, dd, J = 8.4, 1.8 Hz), 7.58 (1H, d, J = 2.1 Hz), 7.54 (1H, dd, J = 8.4, 2.1 Hz), 6.92 (1H, d, J = 8.4 Hz), 4.34 (2H, q, J = 7.2 Hz), 1.35 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, DMSO-d6) δ 165.2, 164.1, 152.8, 149.8, 145.6, 141.8, 126.5, 125.9, 120.0, 119.9, 116.6, 116.0, 114.3, 110.6, 60.8, 14.2.Yield: 75%; Off-white solid; Melting point 214-216 ° C .; R f = 0.35 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, DMSO-d6) δ 8.21 (1H, d, J = 1.8 Hz), 7.96 (1H, d, J = 8.4 Hz), 7.81 (1H, dd, J = 8.4, 1.8 Hz), 7.58 (1H, d, J = 2.1 Hz), 7.54 (1H, dd, J = 8.4, 2.1 Hz), 6.92 (1H, d, J = 8.4 Hz), 4.34 (2H, q, J = 7.2 Hz), 1.35 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, DMSO-d6) δ 165.2, 164.1, 152.8, 149.8, 145.6, 141.8, 126.5, 125.9, 120.0, 119.9, 116.6, 116.0, 114.3, 110.6, 60.8, 14.2.

에틸 2-Ethyl 2- (2-하이드록시-4-메톡시페닐)벤조[(2-hydroxy-4-methoxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate {Ethyl 2-(2-hydroxy-4-methoxyphenyl)benzo[ {Ethyl 2- (2-hydroxy-4-methoxyphenyl) benzo [ dd ]oxazole-5-carboxylate} (화합물 24):] oxazole-5-carboxylate} (Compound 24):

화합물 20 (0.09 g, 0.27 mmol)을 무수 CH2Cl2 (4 mL)에 넣고 교반한 용액에 BCl3 (1.0 M in CH2Cl2, 0.28 mL)를 0℃, 질소 분위기 하에서 가하였다. 반응 혼합물을 상온으로 가온하고, 2시간 동안 교반하였다. 반응 완료 후 0 ℃로 냉각하고, 1.0 N HCl (1 mL)을 천천히 가하고, 15분 동안 교반하였다. 혼합물을 CH2Cl2 (2 x 20 mL)로 추출하였다. 혼합 유기용매층은 H2O (2 x 10 mL)와 식염수 (10 mL)로 세척하고, 무수 Na2SO4로 건조하여 진공 농축하였다. 컬럼 크로마토그래피 (EtOAc:Hexane=1:2)로 조화합물을 정제하여 순수한 회백색 고체 화합물 24 (0.08 g, 89%)를 얻었다. 녹는점 154-156℃; Rf= 0.70 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 11.33 (1H, s), 8.31 (1H, d, J = 1.8 Hz), 8.05 (1H, dd, J = 8.4, 1.8 Hz), 7.84 (1H, d, J = 9.0 Hz), 7.54 (1H, d, J = 8.4 Hz), 6.57 (1H, d, J = 2.1 Hz), 6.54 (1H, dd, J = 9.0, 2.1 Hz), 4.41 (2H, q, J = 7.2 Hz), 3.85 (3H, s), 1.44 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 165.8, 164.4, 164.1, 160.8, 151.6, 140.2, 128.2, 127.5, 126.6, 120.4, 110.0, 107.8, 103.1, 101.2, 61.2, 55.5, 14.4.Compound 20 (0.09 g, 0.27 mmol) was added to anhydrous CH 2 Cl 2 (4 mL), and BCl 3 (1.0 M in CH 2 Cl 2 , 0.28 mL) was added to the stirred solution under 0 ° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0 ° C, 1.0 N HCl (1 mL) was added slowly, and stirred for 15 minutes. CH 2 Cl 2 Extracted with (2 x 20 mL). The mixed organic solvent layer was washed with H 2 O (2 × 10 mL) and brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2) to give pure off-white solid compound 24 (0.08 g, 89%). Melting point 154-156 ° C .; R f = 0.70 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 11.33 (1H, s), 8.31 (1H, d, J = 1.8 Hz), 8.05 (1H, dd, J = 8.4, 1.8 Hz), 7.84 (1H, d, J = 9.0 Hz), 7.54 (1H, d, J = 8.4 Hz), 6.57 (1H, d, J = 2.1 Hz), 6.54 (1H, dd, J = 9.0, 2.1 Hz), 4.41 (2H, q, J = 7.2 Hz), 3.85 (3H, s), 1.44 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 165.8, 164.4, 164.1, 160.8, 151.6, 140.2, 128.2, 127.5, 126.6, 120.4, 110.0, 107.8, 103.1, 101.2, 61.2, 55.5, 14.4.

에틸 2-Ethyl 2- (4-하이드록시-2-메톡시페닐)벤조[(4-hydroxy-2-methoxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate {Ethyl 2-(4-hydroxy-2-methoxyphenyl)benzo[ {Ethyl 2- (4-hydroxy-2-methoxyphenyl) benzo [ dd ]oxazole-5-carboxylate} (화합물 25): ] oxazole-5-carboxylate} (Compound 25):

화합물 20 (0.09 g, 0.27 mmol)을 무수 CH2Cl2 (4 mL)에 넣고 교반한 용액에 AlCl3 (0.12 g, 0.92 mmol)를 질소 분위기 하에서 가하였다. 반응 혼합물을 상온에서 48시간 동안 교반하였다. 반응 완료 후 H2O (1 mL)를 천천히 가하고, 15분 동안 교반하였다. 혼합물을 CH2Cl2 (2 x 20 mL)로 추출하였다. 혼합 유기용매층은 H2O (2 x 10 mL)와 식염수 (10 mL)로 세척하고, 무수 Na2SO4로 건조하여 진공 농축하였다. 컬럼 크로마토그래피 (EtOAc:Hexane=1:2)로 조화합물을 정제하여 순수한 회백색 고체의 화합물 25 (0.04 g, 42%)를 얻었다. 녹는점 204-206℃; Rf= 0.22 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CD3COCD3) δ 9.48 (1H, s), 8.29 (1H, s), 8.04 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.7 Hz), 6.68 (1H, s), 6.63 (1H, d, J = 8.4 Hz), 4.38 (2H, q, J = 7.2 Hz), 3.94 (3H, s), 1.40 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CD3COCD3) δ 166.3, 163.2, 161.3, 154.1, 143.1, 133.6, 127.8, 126.8, 121.4, 111.0, 108.8, 106.9, 100.5, 99.7, 61.6, 56.2, 14.7.Compound 20 (0.09 g, 0.27 mmol) was added to anhydrous CH 2 Cl 2 (4 mL) and AlCl 3 (0.12 g, 0.92 mmol) was added to the stirred solution under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, H 2 O (1 mL) was slowly added and stirred for 15 minutes. CH 2 Cl 2 Extracted with (2 x 20 mL). The mixed organic solvent layer was washed with H 2 O (2 × 10 mL) and brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2) to give compound 25 (0.04 g, 42%) as a pure off-white solid. Melting point 204-206 ° C; R f = 0.22 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CD 3 COCD 3 ) δ 9.48 (1H, s), 8.29 (1H, s), 8.04 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 8.4 Hz) , 7.71 (1H, d, J = 8.7 Hz), 6.68 (1H, s), 6.63 (1H, d, J = 8.4 Hz), 4.38 (2H, q, J = 7.2 Hz), 3.94 (3H, s) , 1.40 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CD 3 COCD 3 ) δ 166.3, 163.2, 161.3, 154.1, 143.1, 133.6, 127.8, 126.8, 121.4, 111.0, 108.8, 106.9, 100.5, 99.7, 61.6, 56.2, 14.7.

에틸 2-Ethyl 2- (2,4-다이하이드록시페닐)벤조[(2,4-dihydroxyphenyl) benzo [ dd ]옥사졸] Oxazole -5--5- 카복실레이트Carboxylate {Ethyl 2-(2,4-dihydroxyphenyl)benzo[ {Ethyl 2- (2,4-dihydroxyphenyl) benzo [ dd ]oxazole-5-carboxylate} (화합물 26):] oxazole-5-carboxylate} (Compound 26):

화합물 24 제조에 이용된 절차에 따라, 화합물 25 (0.09g, 0.29mmol)를 BCl3 (1.0M in CH2Cl2, 0.58mL)로 처리하여 회백색 고체 화합물 26 (0.08 g, 97%)을 얻었다. 녹는점 218-220℃; Rf= 0.12 (EtOAc/Hexane=1/1); 1H NMR (300 MHz, CD3COCD3) δ 11.19 (1H, s), 9.53 (1H, s), 8.27 (1H, d, J = 1.2 Hz), 8.06 (1H, dd, J = 8.4, 1.8 Hz), 7.85 (1H, d, J = 9.0 Hz), 7.76 (1H, d, J = 8.4 Hz), 6.59 (1H, dd, J = 9.0, 1.8 Hz), 6.52 (1H, d, J = 1.8 Hz), 4.37 (2H, q, J = 7.2 Hz), 1.40 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CD3COCD3) δ 166.0, 165.4, 163.9, 161.7, 152.4, 141.0, 129.6, 128.5, 127.3, 120.5, 111.2, 109.5, 103.8, 102.9, 61.8, 14.6.According to the procedure used for preparing compound 24, compound 25 (0.09 g, 0.29 mmol) was treated with BCl 3 (1.0 M in CH 2 Cl 2 , 0.58 mL) to give an off-white solid compound 26 (0.08 g, 97%). . Melting point 218-220 ° C .; R f = 0.12 (EtOAc / Hexane = 1/1); 1 H NMR (300 MHz, CD 3 COCD 3 ) δ 11.19 (1H, s), 9.53 (1H, s), 8.27 (1H, d, J = 1.2 Hz), 8.06 (1H, dd, J = 8.4, 1.8 Hz), 7.85 (1H, d, J = 9.0 Hz), 7.76 (1H, d, J = 8.4 Hz), 6.59 (1H, dd, J = 9.0, 1.8 Hz), 6.52 (1H, d, J = 1.8 Hz), 4.37 (2H, q, J = 7.2 Hz), 1.40 (3H, t, J = 7.2 Hz); 13 C NMR (75 MHz, CD 3 COCD 3 ) δ 166.0, 165.4, 163.9, 161.7, 152.4, 141.0, 129.6, 128.5, 127.3, 120.5, 111.2, 109.5, 103.8, 102.9, 61.8, 14.6.

에틸 2-아릴 Ethyl 2-aryl 벤조Benzo [[ dd ]]]] 옥사졸Oxazole -5--5- 카르복실레이트Carboxylate (ethyl 2-aryl benzo[ (ethyl 2-aryl benzo [ dd ]oxazole-5-carboxylate)의 환원에 대한 일반적인 절차:general procedure for the reduction of oxazole-5-carboxylate):

에틸 2-아릴 벤조[d]옥사졸-5-카르복실레이트 (0.17 mmol)를 무수 THF (3 mL)에 넣고 교반한 용액에 LiAlH4 용액 (1.0 M in THF, 0.34 mL, 0.34 mmol, 2.0 equiv.)을 0℃, 질소 분위기 하에서 한 방울씩 가하였다. 혼합물을 상온으로 가온하고, 30분 동안 교반하였다. 반응 완료 후 0℃로 냉각시키고, 포화 Na2CO3 수용액 (1 mL)을 서서히 첨가하여 과량의 LiAlH4를 퀀칭하고 20분 동안 교반하였다. 생성된 현탁액을 여과하고, 에틸 아세테이트 (2 Х 10 mL)로 세적하고, 혼합 유기용매층을 무수 Na2SO4로 건조하여 감압 농축하였다. 컬럼 크로마토그래피 (MeOH/CH2Cl2=1/10)로 조화합물을 정제하여 순수한 화합물을 얻었다 [주: 화합물 2, 3 및 7의 정제에는 EtOAc:Hexane=1:2 - 1:1을 이용하였다].To a stirred solution of ethyl 2-aryl benzo [ d ] oxazole-5-carboxylate (0.17 mmol) in anhydrous THF (3 mL) was added LiAlH 4 solution (1.0 M in THF, 0.34 mL, 0.34 mmol, 2.0 equiv). .) Was added dropwise at 0 ° C. under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 30 minutes. After the reaction was completed, the reaction mixture was cooled to 0 ° C, and saturated Na 2 CO 3 aqueous solution (1 mL) was slowly added to quench excess LiAlH 4 and stirred for 20 minutes. The resulting suspension was filtered, washed with ethyl acetate (2 Х 10 mL), and the mixed organic solvent layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (MeOH / CH 2 Cl 2 = 1/10) to obtain pure compound. [Note: For purification of compounds 2, 3 and 7, EtOAc: Hexane = 1: 2-1: 1 was used. ].

4-(5-4- (5- (하이드록시메틸)벤조[(Hydroxymethyl) benzo [ dd ]옥사졸] Oxazole -2-일)페놀 (-2-yl) phenol ( 노카벤즈옥사졸Nocabenzoxazole F) (4-(5-(Hydroxymethyl)benzo[ F) (4- (5- (Hydroxymethyl) benzo [ dd ]oxazol-2-yl)phenol (] oxazol-2-yl) phenol ( nocarbenzoxazolenocarbenzoxazole F)) (화합물 1):  F)) (Compound 1):

수율: 95%; 담황색 고체; 녹는점 230-232℃; Rf = 0.25 (MeOH/CH2Cl2=1/10); 1H NMR (300 MHz, DMSO-d6) δ 10.36 (1H, s), 8.01 (2H, d, J = 7.5 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.62 (1H, s), 7.29 (1H, d, J = 8.1 Hz), 6.94 (2H, d, J = 7.5 Hz), 5.35 (1H, br s), 4.59 (2H, s); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 160.7, 148.9, 141.6, 139.2, 129.2, 123.3, 117.2, 116.9, 116.0, 109.9, 62.8; EI-MS m/z 241 (M+), 207 (base), 148, 119; HRMS: Calcd for C14H11NO3 (M+): 241.0739, found: 241.0744.Yield: 95%; Pale yellow solid; Melting point 230-232 ° C .; R f = 0.25 (MeOH / CH 2 Cl 2 = 1/10); 1 H NMR (300 MHz, DMSO-d6) δ 10.36 (1H, s), 8.01 (2H, d, J = 7.5 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.62 (1H, s), 7.29 (1H, d, J = 8.1 Hz), 6.94 (2H, d, J = 7.5 Hz), 5.35 (1H, br s), 4.59 (2H, s); 13 C NMR (75 MHz, DMSO-d6) δ 162.8, 160.7, 148.9, 141.6, 139.2, 129.2, 123.3, 117.2, 116.9, 116.0, 109.9, 62.8; EI-MS m / z 241 (M + ), 207 (base), 148, 119; HRMS: Calcd for C 14 H 11 NO 3 (M + ): 241.0739, found: 241.0744.

2-2- 페닐벤조[Phenylbenzo [ dd ]옥사졸] Oxazole -5-일)메탄올 {(2--5-yl) methanol {(2- Phenylbenzo[Phenylbenzo [ dd ]oxazol] oxazol -5-yl)methanol}-5-yl) methanol} (화합물 2): (Compound 2):

수율: 97%; 담황색 고체; 녹는점 146-148℃; Rf = 0.31 (MeOH/CH2Cl2=1/20); 1H NMR (300 MHz, CDCl3) δ 8.24-8.21 (2H, m), 7.73 (1H, s), 7.55-7.50 (4H, m), 7.35 (1H, d, J = 8.4 Hz), 4.80 (2H, s), 2.41 (1H, br s); 13C NMR (75 MHz, CDCl3) δ 163.6, 150.3, 142.3, 137.9, 131.7, 129.0, 127.8, 127.2, 124.5, 118.6, 110.6, 65.5; EI-MS m/z 225 (M+, base), 224 (M-H), 208, 194; HRMS: Calcd for C14H11NO2 (M+): 225.0790, found: 225.0783.Yield: 97%; Pale yellow solid; Melting point 146-148 ° C .; R f = 0.31 (MeOH / CH 2 Cl 2 = 1/20); 1 H NMR (300 MHz, CDCl 3 ) δ 8.24-8.21 (2H, m), 7.73 (1H, s), 7.55-7.50 (4H, m), 7.35 (1H, d, J = 8.4 Hz), 4.80 ( 2H, s), 2.41 (1H, broad singlet); 13 C NMR (75 MHz, CDCl 3 ) δ 163.6, 150.3, 142.3, 137.9, 131.7, 129.0, 127.8, 127.2, 124.5, 118.6, 110.6, 65.5; EI-MS m / z 225 (M + , base), 224 (MH), 208, 194; HRMS: Calcd for C 14 H 11 NO 2 (M + ): 225.0790, found: 225.0783.

2-2- (2,4-다이메톡시페닐)벤조[(2,4-dimethoxyphenyl) benzo [ dd ]옥사졸] Oxazole -5-일)메탄올 {(2--5-yl) methanol {(2- (2,4-Dimethoxyphenyl)(2,4-Dimethoxyphenyl) benzo[benzo [ dd ]oxazol-5-yl)methanol} (화합물 3): ] oxazol-5-yl) methanol} (Compound 3):

수율: 92%; 백색 고체; 녹는점 134-136℃; Rf= 0.3 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 8.05 (1H, d, J = 8.4 Hz), 7.70 (1H, s), 7.45 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.7 Hz), 6.60 (1H, dd, J = 8.7, 2.1 Hz), 6.56 (1H, d, J = 2.1 Hz), 4.75 (2H, s), 3.99 (3H, s), 3.87 (3H, s), 2.62 (1H, br s); 13C NMR (75 MHz, CDCl3) δ 163.6, 162.2, 160.0, 149.6, 142.3, 137.6, 132.5, 123.9, 118.4, 110.2, 109.0, 105.5, 99.2, 65.5, 56.3, 55.8; EI-MS m/z 285 (M+, base), 284 (M-H), 254, 148; HRMS: Calcd for C16H15NO4 (M+): 285.1001, found: 285.1011.Yield: 92%; White solid; Melting point 134-136 ° C .; R f = 0.3 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 8.05 (1H, d, J = 8.4 Hz), 7.70 (1H, s), 7.45 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.7 Hz), 6.60 (1H, dd, J = 8.7, 2.1 Hz), 6.56 (1H, d, J = 2.1 Hz), 4.75 (2H, s), 3.99 (3H, s), 3.87 (3H, s) , 2.62 (1H, broad singlet); 13 C NMR (75 MHz, CDCl 3 ) δ 163.6, 162.2, 160.0, 149.6, 142.3, 137.6, 132.5, 123.9, 118.4, 110.2, 109.0, 105.5, 99.2, 65.5, 56.3, 55.8; EI-MS m / z 285 (M + , base), 284 (MH), 254, 148; HRMS: Calcd for C 16 H 15 NO 4 (M + ): 285.1001, found: 285.1011.

2-(5-2- (5- (하이드록시메틸)벤조[(Hydroxymethyl) benzo [ dd ]옥사졸] Oxazole -2-일)-5-2-yl) -5- 메톡시페놀Methoxyphenol {2-(5-(Hydroxymethyl)benzo[ {2- (5- (Hydroxymethyl) benzo [ dd ]oxazol-2-yl)-5-methoxyphenol} (화합물 4):] oxazol-2-yl) -5-methoxyphenol} (Compound 4):

수율: 93%; 담황색 고체; 녹는점 170-172℃; Rf= 0.30 (MeOH/CH2Cl2=1/15); 1H NMR (300 MHz, CDCl3) δ 7.90 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1.5 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.36 (1H, d, J = 8.4, 1.5 Hz), 6.63 (1H, d, J = 2.4 Hz), 6.59 (1H, dd, J = 8.7, 2.4 Hz), 4.83 (2H,s), 3.88 (3H, s); 13C NMR (75 MHz, CDCl3) δ 164.2, 163.7, 160.8, 148.6, 140.5, 138.1, 128.4, 124.1, 117.4, 110.5, 107.9, 103.8, 101.4, 65.5, 55.8; EI-MS m/z 271 (M+, base), 254, 240, 149; HRMS: Calcd for C15H13NO4 (M+): 271.0845, found: 271.0851.Yield: 93%; Pale yellow solid; Melting point 170-172 ° C .; R f = 0.30 (MeOH / CH 2 Cl 2 = 1/15); 1 H NMR (300 MHz, CDCl 3 ) δ 7.90 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1.5 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.36 (1H , d, J = 8.4, 1.5 Hz), 6.63 (1H, d, J = 2.4 Hz), 6.59 (1H, dd, J = 8.7, 2.4 Hz), 4.83 (2H, s), 3.88 (3H, s) ; 13 C NMR (75 MHz, CDCl 3 ) δ 164.2, 163.7, 160.8, 148.6, 140.5, 138.1, 128.4, 124.1, 117.4, 110.5, 107.9, 103.8, 101.4, 65.5, 55.8; EI-MS m / z 271 (M + , base), 254, 240, 149; HRMS: Calcd for C 15 H 13 NO 4 (M + ): 271.0845, found: 271.0851.

4-(5-4- (5- (하이드록시메틸)벤조[(Hydroxymethyl) benzo [ dd ]옥사졸] Oxazole -2-일)-3--2-yl) -3- 메톡시페놀Methoxyphenol {4-(5-(Hydroxymethyl)benzo[ {4- (5- (Hydroxymethyl) benzo [ dd ]oxazol-2-yl)-3-methoxyphenol} (화합물 5): ] oxazol-2-yl) -3-methoxyphenol} (Compound 5):

수율: 94%; 담황색 고체; 녹는점 214-216℃; Rf= 0.18 (MeOH/CH2Cl2=1/10); 1H NMR (300 MHz, CD3OD) δ 7.93 (1H, d, J = 8.7 Hz), 7.68 (1H, s), 7.56 (1H, d, J = 8.7 Hz), 7.35 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 1.8 Hz), 6.54 (1H, dd, J = 8.4, 1.8 Hz), 4.72 (2H, s), 3.95 (3H, s); 13C NMR (75 MHz, CD3OD) δ 164.1, 161.9, 143.0, 139.8, 133.3, 125.2, 118.3, 111.1, 109.2, 107.8, 107.6, 100.6, 99.7, 65.3, 56.3; EI-MS m/z 271 (M+, base), 254, 240, 149; HRMS: Calcd for C15H13NO4 (M+): 271.0845, found: 271.0834.Yield: 94%; Pale yellow solid; Melting point 214-216 ° C .; R f = 0.18 (MeOH / CH 2 Cl 2 = 1/10); 1 H NMR (300 MHz, CD 3 OD) δ 7.93 (1H, d, J = 8.7 Hz), 7.68 (1H, s), 7.56 (1H, d, J = 8.7 Hz), 7.35 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 1.8 Hz), 6.54 (1H, dd, J = 8.4, 1.8 Hz), 4.72 (2H, s), 3.95 (3H, s); 13 C NMR (75 MHz, CD 3 OD) δ 164.1, 161.9, 143.0, 139.8, 133.3, 125.2, 118.3, 111.1, 109.2, 107.8, 107.6, 100.6, 99.7, 65.3, 56.3; EI-MS m / z 271 (M + , base), 254, 240, 149; HRMS: Calcd for C 15 H 13 NO 4 (M + ): 271.0845, found: 271.0834.

4-(5-4- (5- (하이드록시메틸)벤조[(Hydroxymethyl) benzo [ dd ]옥사졸] Oxazole -2-일)벤젠-1,3--2-yl) benzene-1,3- 다이올Dior {4-(5-(Hydroxymethyl)benzo[ {4- (5- (Hydroxymethyl) benzo [ dd ]oxazol-2-yl)benzene-1,3-diol} (화합물 6): ] oxazol-2-yl) benzene-1,3-diol} (Compound 6):

수율: 92%; 담황색 고체; 녹는점 224-226℃; Rf= 0.21 (MeOH/CH2Cl2=1/10); 1H NMR (300 MHz, CD3OD) δ 11.28 (1H, s), 10.45 (1H, s), 7.81 (1H, dd, J = 8.7, 2.1 Hz), 7.70 (1H, dd, J = 8.4, 1.8 Hz), 7.65 (1H, s), 7.33 (1H, d, J = 8.4 Hz), 6.50 (1H, d, J = 8.7 Hz), 6.45 (1H, s), 5.38 (1H, t, J = 4.5 Hz), 4.60 (2H, d, J = 4.5 Hz); 13C NMR (75 MHz, CD3OD) δ 162.9, 162.6, 159.6, 147.3, 139.8, 139.4, 128.7, 123.5, 116.1, 110.1, 108.7, 102.8, 102.0, 62.7; EI-MS m/z 257 (M+, base), 256 (M-H), 240, 228; HRMS: Calcd for C14H11NO4 (M+): 257.0688, found: 257.0692. Yield: 92%; Pale yellow solid; Melting point 224-226 ° C .; R f = 0.21 (MeOH / CH 2 Cl 2 = 1/10); 1 H NMR (300 MHz, CD 3 OD) δ 11.28 (1H, s), 10.45 (1H, s), 7.81 (1H, dd, J = 8.7, 2.1 Hz), 7.70 (1H, dd, J = 8.4, 1.8 Hz), 7.65 (1H, s), 7.33 (1H, d, J = 8.4 Hz), 6.50 (1H, d, J = 8.7 Hz), 6.45 (1H, s), 5.38 (1H, t, J = 4.5 Hz), 4.60 (2H, d, J = 4.5 Hz); 13 C NMR (75 MHz, CD 3 OD) δ 162.9, 162.6, 159.6, 147.3, 139.8, 139.4, 128.7, 123.5, 116.1, 110.1, 108.7, 102.8, 102.0, 62.7; EI-MS m / z 257 (M + , base), 256 (MH), 240, 228; HRMS: Calcd for C 14 H 11 NO 4 (M + ): 257.0688, found: 257.0692.

(2-(2- (2,4-다이메톡시페닐)벤조[(2,4-dimethoxyphenyl) benzo [ dd ]옥사졸] Oxazole -5-일)메탄올 {(2--5-yl) methanol {(2- (2,4-Dimethoxyphenyl)(2,4-Dimethoxyphenyl) benzo[benzo [ dd ]oxazol-5-yl)methanol} (화합물 7): ] oxazol-5-yl) methanol} (Compound 7):

수율: 95%; 백색 고체; 녹는점 130-132℃; Rf= 0.25 (EtOAc/Hexane=1/2); 1H NMR (300 MHz, CDCl3) δ 7.86 (1H, dd, J = 8.1, 1.5 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.73 (1H, s), 7.54 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.00 (1H, d, J = 8.4 Hz), 4.82 (2H, d, J = 6.0 Hz), 4.03 (3H, s), 3.99 (3H, s), 1.88 (1H, br t, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 162.9, 152.2, 150.4, 149.4, 142.6, 137.8, 124.1, 121.4, 119.9, 118.3, 111.2, 110.5, 110.3, 65.7, 56.4, 56.3; EI-MS m/z 285 (M+, base), 284 (M-H), 268, 163; HRMS: Calcd for C16H15NO4 (M+): 285.1001, found: 285.0983.Yield: 95%; White solid; Melting point 130-132 ° C; R f = 0.25 (EtOAc / Hexane = 1/2); 1 H NMR (300 MHz, CDCl 3 ) δ 7.86 (1H, dd, J = 8.1, 1.5 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.73 (1H, s), 7.54 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.00 (1H, d, J = 8.4 Hz), 4.82 (2H, d, J = 6.0 Hz), 4.03 (3H, s), 3.99 (3H, s), 1.88 (1H, broad singlet, J = 6.0 Hz); 13 C NMR (75 MHz, CDCl 3 ) δ 162.9, 152.2, 150.4, 149.4, 142.6, 137.8, 124.1, 121.4, 119.9, 118.3, 111.2, 110.5, 110.3, 65.7, 56.4, 56.3; EI-MS m / z 285 (M + , base), 284 (MH), 268, 163; HRMS: Calcd for C 16 H 15 NO 4 (M + ): 285.1001, found: 285.0983.

4-(5-4- (5- (하이드록시메틸)벤조[(Hydroxymethyl) benzo [ dd ]옥사졸] Oxazole -2-일)벤젠-1,2--2-yl) benzene-1,2- 다이올Dior {4-(5-(Hydroxymethyl)benzo[ {4- (5- (Hydroxymethyl) benzo [ dd ]oxazol-2-yl)benzene-1,2-diol} (화합물 8):] oxazol-2-yl) benzene-1,2-diol} (Compound 8):

수율: 91%; 담황색 고체; 녹는점 222-224℃; Rf= 0.18 Rf= 0.18 (MeOH/CH2Cl2=1/10); 1H NMR (300 MHz, DMSO-d6) δ 9.80 (1H, s), 9.53 (1H, s), 7.63 (H, d, J = 8.7 Hz), 7.62 (1H, s), 7.56 (1H, d, J = 2.1 Hz), 7.51 (1H, dd, J = 8.4, 2.1 Hz), 7.29 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.4 Hz), 5.30 (1H, t, J = 4.2 Hz), 4.60 (2H, d, J = 4.2 Hz); 13C NMR (75 MHz, DMSO-d6) δ 162.9, 149.2, 148.8, 145.6, 141.6, 139.1, 123.2, 119.4, 117.3, 116.8, 116.0, 114.1, 109.8, 62.8; EI-MS m/z 257 (M+, base), 256 (M-H), 240, 228; HRMS: Calcd for C14H11NO4 (M+): 257.0688, found: 257.0681.Yield: 91%; Pale yellow solid; Melting point 222-224 ° C .; R f = 0.18 R f = 0.18 (MeOH / CH 2 Cl 2 = 1/10); 1 H NMR (300 MHz, DMSO-d6) δ 9.80 (1H, s), 9.53 (1H, s), 7.63 (H, d, J = 8.7 Hz), 7.62 (1H, s), 7.56 (1H, d , J = 2.1 Hz), 7.51 (1H, dd, J = 8.4, 2.1 Hz), 7.29 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.4 Hz), 5.30 (1H, t , J = 4.2 Hz), 4.60 (2H, d, J = 4.2 Hz); 13 C NMR (75 MHz, DMSO-d6) δ 162.9, 149.2, 148.8, 145.6, 141.6, 139.1, 123.2, 119.4, 117.3, 116.8, 116.0, 114.1, 109.8, 62.8; EI-MS m / z 257 (M + , base), 256 (MH), 240, 228; HRMS: Calcd for C 14 H 11 NO 4 (M + ): 257.0688, found: 257.0681.

결과result

본 발명의 합성은 상업적으로 구입 가능한 3-아미노-4-하이드록시벤조익산(화합물 9)의 에스테르화로 시작한다 (도 1). 환류 조건에서 H2SO4 존재하에 에탄올로 화합물 9를 처리하면 치환된 벤조익산 화합물 10이 85% 수율로 얻어졌다. 다음으로, 치환된 벤조산 화합물 11-13을 60℃에서 SOCl2와 반응시키면 각각 대응하는 산염화물 14, 16 및 17이 생성된다. 이것은 정제 없이 다음 단계에서 바로 사용된다. 다음으로, 주요 단편을 손에 쥐고 화합물 10과 14를 모델 기질로 이용하여 주요 원환탈수반응(cyclodehydration reaction)을 연구하였다(표 1). POCl3, PCl5, H2SO4, P2O5, SOCl2, CH3SO3H 및 CF3SO3H는 DMF, 무수 아세트산, 1,4-다이옥산 및 피리딘과 같은 다른 용매에서 원환탈수화제로 스크린되었다. 원환탈수화를 진행하려는 모든 시도들은 실패하거나(표 1의 3, 4 및 7) 또는 낮은 수율로 화합물 18을 얻었다(표 1의 1, 2, 5, 6 및 8-11). 기쁘게도, POCl3는 1,4-다이옥산에서 원환탈수화를 매개하여 화합물 18을 55% 수율로 얻을 수 있었다(표 1의 12). 반응시간을 줄이거나 늘려도 생산물 수율이 좋아지지 않았다(표 1의 13과 14). 이러한 최적화된 조건에 따라, 화합물 10과 치환된 벤조일 클로라이드 화합물 15-17의 반응으로 벤즈옥사졸 화합물 19-21이 각각 얻어졌다. 표 1은 화합물 10과 화합물 14 간의 원환탈수화 반응의 최적 조건을 시험한 결과이다.The synthesis of the present invention begins with the esterification of commercially available 3-amino-4-hydroxybenzoic acid (Compound 9) (FIG. 1). Treatment of compound 9 with ethanol in the presence of H 2 SO 4 at reflux gave a substituted benzoic acid compound 10 in 85% yield. Subsequently, the reaction of substituted benzoic acid compounds 11-13 with SOCl 2 at 60 ° C. yields the corresponding acid chlorides 14, 16 and 17, respectively. It is used directly in the next step without purification. Next, the main cyclodehydration reaction was studied using the main fragments in hand and using compounds 10 and 14 as model substrates (Table 1). POCl 3 , PCl 5 , H 2 SO 4 , P 2 O 5 , SOCl 2 , CH 3 SO 3 H and CF 3 SO 3 H are dehydrated in other solvents such as DMF, acetic anhydride, 1,4-dioxane and pyridine Screened topically. All attempts to proceed to ring dehydration either failed (3, 4 and 7 in Table 1) or yielded compound 18 in low yield (1, 2, 5, 6 and 8-11 in Table 1). Fortunately, POCl 3 was able to obtain compound 18 in 55% yield via mediated ring dehydration in 1,4-dioxane (12 in Table 1). Reducing or increasing the reaction time did not improve product yields (13 and 14 in Table 1). According to these optimized conditions, benzoxazole compound 19-21 was obtained by reaction of compound 10 with substituted benzoyl chloride compound 15-17, respectively. Table 1 shows the results of testing the optimum conditions for the ring dehydration reaction between compound 10 and compound 14.

EntryEntry ReagentReagent SolventSolvent Time (h)Time (h) YieldYield bb ( ( %% )) 1One POCl3 POCl 3 DMFDMF 0.50.5 1515 22 POCl3 POCl 3 1,4-dioxane1,4-dioxane 0.50.5 1515 33 POCl3 POCl 3 PyridinePyridine 0.50.5 N.RN.R 44 H2SO4 H 2 SO 4 Ac2OAc 2 O 1One N.RN.R 55 POCl3 POCl 3 DMFDMF 33 1616 66 POCl3 POCl 3 1,4-dioxane1,4-dioxane 33 2929 77 PCl5 PCl 5 1,4-dioxane1,4-dioxane 33 N.RN.R 88 P2O5 P 2 O 5 1,4-dioxane1,4-dioxane 33 2424 99 SOCl2 SOCl 2 1,4-dioxane1,4-dioxane 33 1717 1010 CH3SO3HCH 3 SO 3 H 1,4-dioxane1,4-dioxane 33 2525 1111 CF3SO3HCF 3 SO 3 H 1,4-dioxane1,4-dioxane 33 2020 1212 POClPOCl 33 1,4-1,4- dioxanedioxane 1515 5555 1313 POCl3 POCl 3 1,4-dioxane1,4-dioxane 1212 4545 1414 POCl3 POCl 3 1,4-dioxane1,4-dioxane 2424 3535

다음으로, 화합물 18 및 21을 BBr3(boron tribromide) 용액(1.0M in CH2Cl2)으로 처리하면 좋은 수율로 화합물 22와 23이 각각 생성되었다. 화합물 20은 BCl3 용액(1.0M in CH2Cl2)과 AlCl3로 선택적 탈메틸화되어 각각 화합물 24와 25가 생성되었다. 벤즈옥사졸 원환의 질소 또는 산소 원자와 킬레이션으로 인해, BCl3 는 4' 위치보다는 2' 위치에서의 탈메틸화에 현저히 효과적이다. BCl3가 분리된 아릴메틸기를 효과적으로 선택적으로 제거하지 못하므로, 본 발명자들은 AlCl3를 이용하여 4' 위치의 탈메틸화에 영향을 주어 어느 정도 성공하였다. 화합물 25는 BCl3로 더 메틸화되어 벤즈옥사졸 화합물 26이 되었다. 최종적으로, 화합물 22, 19, 20, 24-26, 21 및 23은 LiAlH4를 이용하여 에스테르기 환원반응으로 목표로 하는 벤즈옥사졸 화합물 1-8을 각각 높은 수율로 얻었다(91-97%). 모든 목표 화합물 1-8은 NMR (1H- 및 13C-) 및 MS 데이터로 결정되었다. Next, Compounds 18 and 21 were treated with BBr 3 (boron tribromide) solution (1.0 M in CH 2 Cl 2 ) to yield Compounds 22 and 23, respectively. Compound 20 was selectively demethylated with BCl 3 solution (1.0M in CH 2 Cl 2 ) and AlCl 3 to yield compounds 24 and 25, respectively. Due to chelation with nitrogen or oxygen atoms of the benzoxazole ring, BCl 3 is significantly more effective at demethylation at the 2 'position than at the 4' position. Since BCl 3 does not selectively remove the separated arylmethyl groups, the inventors have some success by affecting the demethylation of the 4 ′ position with AlCl 3 . Compound 25 was further methylated with BCl 3 to form benzoxazole compound 26. Finally, Compounds 22, 19, 20, 24-26, 21 and 23 obtained target benzoxazole compounds 1-8 in high yield, respectively, using LiAlH 4 (91-97%). . All target compounds 1-8 were determined by NMR ( 1 H- and 13 C-) and MS data.

산화질소 생성 저해Nitric Oxide Production Inhibition

합성된 벤즈옥사졸 화합물 1-8의 산화질소 생성 저해제로서의 생물학적 활성은 지다당(lipopolysaccharide; LPS)으로 자극한 RAW 264.7 세포에서 항염증 활성의 지시자로서 산화질소의 양을 측정하여 평가하였다. 산화질소의 매우 짧은 생리학적 반감기와 다른 노폐물 제거 분자들의 존재로 인하여 산화질소 수준은 그것의 안정적인 대사산물인 아질산염 및 질산염 농도를 Griess 반응을 이용한 분광학적 방법으로 간접적으로 평가하였다. L-NMMA(N G -Monomethyl-L-arginine acetate)는 양성 대조군으로 이용하였다. 표 2는 노카벤즈옥사졸 F(화합물 1)와 그 유도체들(화합물 2-4 및 6-8)의 산화질소 생성 저해효과를 나타낸다.The biological activity of the synthesized benzoxazole compound 1-8 as an inhibitor of nitric oxide production was evaluated by measuring the amount of nitric oxide as an indicator of anti-inflammatory activity in RAW 264.7 cells stimulated with lipopolysaccharide (LPS). Due to the very short physiological half-life of nitric oxide and the presence of other waste-removing molecules, nitric oxide levels were indirectly assessed by its spectroscopic method using the Griess reaction, its stable metabolites, nitrite and nitrate concentrations. L-NMMA ( N G -Monomethyl-L-arginine acetate) was used as a positive control. Table 2 shows the inhibitory effect of nitric oxide production of nocabenzoxazole F (compound 1) and its derivatives (compounds 2-4 and 6-8).

CompoundCompound NO Production (% inhibition)a,b NO Production (% inhibition) a, b Proliferationa Proliferation a IC50
(μM)IC 50
(μM) 1 μM1 μM 10 μM10 μM 1 μM1 μM 10 μM10 μM LPSLPS 100.0 ± 1.8 (0.0)100.0 ± 1.8 (0.0) 100.0 ± 1.8 (0.0)100.0 ± 1.8 (0.0) 1One 120.6 ± 1.1 (-20.6)**120.6 ± 1.1 (-20.6) ** 97.2 ± 3.9 (2.8)*97.2 ± 3.9 (2.8) * 111.9 ± 2.1*111.9 ± 2.1 * 91.8 ± 4.891.8 ± 4.8 26.2426.24 22 107.7± 2.5 (-7.7)107.7 ± 2.5 (-7.7) 92.2 ± 2.7 (7.8)92.2 ± 2.7 (7.8) 90.2 ± 3.190.2 ± 3.1 84.6 ± 1.4**84.6 ± 1.4 ** 29.1129.11 33 117.7 ± 0.7 (-17.7)**117.7 ± 0.7 (-17.7) ** 92.6 ± 1.7 (7.4)92.6 ± 1.7 (7.4) 92.7 ± 3.892.7 ± 3.8 103.1 ± 1.1103.1 ± 1.1 27.3127.31 44 117.0 ± 2.3 (-17.0)**117.0 ± 2.3 (-17.0) ** 96.6 ± 1.5 (3.4)96.6 ± 1.5 (3.4) 99.2 ± 5.199.2 ± 5.1 98.9 ± 4.198.9 ± 4.1 21.0121.01 66 115.0 ± 1.3 (-15.0)*115.0 ± 1.3 (-15.0) * 87.3 ± 0.7 (12.7)87.3 ± 0.7 (12.7) 104.4 ± 4.1104.4 ± 4.1 98.1 ± 5.198.1 ± 5.1 28.2628.26 77 114.6 ± 4.4 (-14.6)114.6 ± 4.4 (-14.6) 110.4 ± 2.5 (-10.4)110.4 ± 2.5 (-10.4) 97.1 ± 2.097.1 ± 2.0 92.2 ± 4.092.2 ± 4.0 39.9139.91 88 90.6 ± 25.4 (9.4)90.6 ± 25.4 (9.4) 46.5 ± 3.3 (53.5)***46.5 ± 3.3 (53.5) *** 99.9 ± 3.999.9 ± 3.9 90.9 ± 6.290.9 ± 6.2 8.178.17 L-L- NMMANMMA 95.2 ± 1.1 (4.8)95.2 ± 1.1 (4.8) 80.5 ± 2.9 (19.5)**80.5 ± 2.9 (19.5) ** 102.2 ± 2.5102.2 ± 2.5 100.7 ± 1.8100.7 ± 1.8 18.7718.77

a 결과는 세 번의 평균±표준편차로 나타내었다. 통계학적 유의성은 LPS 처리군과의 차이에 바탕을 둔 것이다(*P < 0.05, **P < 0.01, ***P < 0.001). The results are expressed as three means ± standard deviation. Statistical significance was based on differences from LPS treated groups (* P <0.05, ** P <0.01, *** P <0.001).

b % Inhibition은 괄호로 나타내었다. b % Inhibition is shown in parentheses.

유도된 대식세포에 의한 산화질소 저해에 대한 화합물 1-8의 효과를 모니터하였다(표 2). 노카벤즈옥사졸 G(화합물 5)는 매우 불안정하여 24시간 내에 쉽게 분해되었다. 대식세포에서 LPS로 유도된 산화질소 생성은 벤즈옥사졸에 의해 농도 의존적으로 저해되었다. 모든 화합물들은 최저 농도(1 μM)에서는 적게 산화질소 생성을 감소시켰다. 그러나, 화합물 6과 8은 대조군 L-NMMA과 비교하였을 때 최고 농도(10 μM)에서 가장 좋은 저해활성을 나타내었다. 이뿐만 아니라, 산화질소 생성에 대한 저해 효과가 시험 화합물의 세포독성에 의한 것인지를 밝히기 위하여 세포 생존율은 MTT{ 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide}의 테트라졸리움염의 포마잔 결정으로의 환원에 기초하여 평가하였다. 그 결과, 화합물 1-4, 6-8은 평가시 사용한 농도에서는 RAW 264.7 세포에서 현저한 세포독성을 나타내지 않았다. 산화질소 생성을 50% 억제하는 데 필요한 농도 즉, IC50 값은 GraphPad Prism 4.0 소프트웨어로 평가하였고, 각각 26.24, 29.11, 27.31, 21.01, 28.26, 39.91 및 8.17 μM로 나타났다. 이 결과들을 종합하면, 벤즈옥사졸 구조체의 2번 위치에 카테콜이 있는 화합물 8은 양성 대조군인 L-NMMA보다 더 우수한 산화질소 저해효과를 나타내었다.The effect of compound 1-8 on nitric oxide inhibition by induced macrophages was monitored (Table 2). Nocabenzoxazole G (Compound 5) was very unstable and readily degraded within 24 hours. LPS-induced nitric oxide production in macrophages was inhibited concentration-dependently by benzoxazole. All compounds reduced nitric oxide production at the lowest concentration (1 μM). However, compounds 6 and 8 showed the best inhibitory activity at the highest concentration (10 μM) compared to the control L-NMMA. In addition, cell viability was determined by MTT {3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide} to determine whether the inhibitory effect on nitric oxide production was due to the cytotoxicity of the test compound. The evaluation was based on the reduction of the tetrazolium salt to formazan crystals. As a result, Compounds 1-4 and 6-8 did not show significant cytotoxicity in RAW 264.7 cells at the concentrations used for evaluation. The concentrations required to inhibit nitric oxide production 50%, ie IC 50 values, were evaluated with GraphPad Prism 4.0 software and were 26.24, 29.11, 27.31, 21.01, 28.26, 39.91 and 8.17 μM, respectively. Taken together, the compound 8 with catechol at position 2 of the benzoxazole structure showed better nitric oxide inhibitory effect than the positive control L-NMMA.

Claims (3)

가) 에틸 3-아미노-4-하이드록시벤조에이트를 무수 1,4-다이옥산에 넣고 교반한 용액에 화학식 14로 표시되는 화합물 14 또는 화합물 17을 상온, 질소 분위기 하에서 가하고 90℃로 가온하고 교반한 다음, POCl3를 적가하고 교반하여 각각 대응하는 에틸 2-(4-메톡시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이메톡시페닐)벤조[d]옥사졸-5-카복실레이트를 얻는 단계;
나) 에틸 2-(4-메톡시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이메톡시페닐)벤조[d]옥사졸-5-카복실레이트를 무수 CH2Cl2에 넣고 교반한 용액에 BBr3를 0℃, 질소 분위기 하에서 한 방울씩 가한 후, 상온으로 가온하고 교반하여 각각 대응하는 에틸 2-(4-하이드록시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이하이드록시페닐)벤조[d]옥사졸-5-카복실레이트를 얻는 단계; 및
다) 에틸 2-(4-하이드록시페닐)벤조[d]옥사졸-5-카복실레이트 또는 에틸 2-(3,4-다이하이드록시페닐)벤조[d]옥사졸-5-카복실레이트를 무수 THF( tetrahydrofuran)에 넣고 교반한 용액에 LiAlH4 용액을 0℃, 질소 분위기 하에서 한 방울씩 가한 후, 상온으로 가온하고, 교반하여 반응 완료 후 0℃로 냉각하고, 포화 Na2CO3 수용액을 서서히 가하여 과량의 LiAlH4를 퀀칭하고 교반하여 각각 대응하는 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)페놀 또는 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올을 얻는 단계;를 포함하는 노카벤즈옥사졸 또는 그 유도체 제조방법
<화학식 14>
Figure 112019502716443-pat00002

A) Ethyl 3-amino-4-hydroxybenzoate was added to anhydrous 1,4-dioxane, and the compound 14 or compound 17 represented by the formula (14) was added to the stirred solution under normal temperature and nitrogen atmosphere, heated to 90 ° C., and stirred. Next, POCl 3 was added dropwise and stirred to respectively correspond to the corresponding ethyl 2- (4-methoxyphenyl) benzo [ d ] oxazole-5-carboxylate or ethyl 2- (3,4-dimethoxyphenyl) benzo [ d ] Oxazole-5-carboxylate;
B) ethyl 2- (4-methoxyphenyl) benzo [ d ] oxazole-5-carboxylate or ethyl 2- (3,4-dimethoxyphenyl) benzo [ d ] oxazole-5-carboxylate BBr 3 was added dropwise to the stirred solution in CH 2 Cl 2 at 0 ° C. under a nitrogen atmosphere, and then warmed to room temperature and stirred to respectively correspond to ethyl 2- (4-hydroxyphenyl) benzo [ d ] oxazole. Obtaining -5-carboxylate or ethyl 2- (3,4-dihydroxyphenyl) benzo [ d ] oxazole-5-carboxylate; And
C) ethyl 2- (4-hydroxyphenyl) benzo [ d ] oxazole-5-carboxylate or ethyl 2- (3,4-dihydroxyphenyl) benzo [ d ] oxazole-5-carboxylate LiAlH 4 solution was added dropwise to a stirred solution in THF (tetrahydrofuran) at 0 ° C. under a nitrogen atmosphere, and then warmed to room temperature, stirred, cooled to 0 ° C. after completion of the reaction, and the saturated Na 2 CO 3 aqueous solution was slowly The excess LiAlH 4 was quenched and stirred to respectively correspond to the corresponding 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) phenol or 4- (5- (hydroxymethyl) benzo [ d ] A method for preparing nocabenzoxazole or a derivative thereof, comprising the steps of: obtaining oxazol-2-yl) benzene-1,2-diol.
<Formula 14>
Figure 112019502716443-pat00002

 신규한 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올
Novel 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) benzene-1,2-diol
4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)페놀 및 4-(5-(하이드록시메틸)벤조[d]옥사졸-2-일)벤젠-1,2-다이올 중 1종 이상을 함유하는 항염증 약학 조성물
4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) phenol and 4- (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) benzene-1,2- Anti-inflammatory pharmaceutical composition containing one or more of diols
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