KR101133769B1 - New oxazolidin and indole compounds, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

New oxazolidin and indole compounds, process for the preparation thereof and pharmaceutical composition comprising the same Download PDF

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KR101133769B1
KR101133769B1 KR1020110035774A KR20110035774A KR101133769B1 KR 101133769 B1 KR101133769 B1 KR 101133769B1 KR 1020110035774 A KR1020110035774 A KR 1020110035774A KR 20110035774 A KR20110035774 A KR 20110035774A KR 101133769 B1 KR101133769 B1 KR 101133769B1
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cancer
methyl
hydroxy
tert
methylenenonan
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KR20110047179A (en
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노문철
김영국
최용석
이경
최정호
이우송
이승웅
박수진
장종선
정화영
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한국생명공학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Abstract

본 발명은 신규한 옥사졸리딘계 및 인돌계 화합물, 또는 이의 약학적으로 허용가능한 염, 이의 제조방법, 및 이를 포함하는 약학 조성물에 관한 것이다. 본 발명의 신규 화합물은 염증성 질환 및 암을 유발하는 신호전달과정에서 중요한 매개자로 작용하는 IL-6 또는 IL-11 신호전달 체계를 저해하는 활성이 우수하므로, 항암제 및 항염증제로 유용하게 사용될 수 있다.The present invention relates to novel oxazolidine-based and indole-based compounds, or pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions comprising the same. The novel compounds of the present invention have excellent activity of inhibiting IL-6 or IL-11 signaling system, which acts as an important mediator in inflammatory disease and cancer signaling, and thus can be usefully used as anticancer and anti-inflammatory agents.

Description

신규한 옥사졸리딘계 및 인돌계 화합물, 이의 제조방법 및 이를 포함하는 약학 조성물 {New oxazolidin and indole compounds, process for the preparation thereof and pharmaceutical composition comprising the same}New oxazolidine-based and indole-based compounds, preparation methods thereof, and pharmaceutical compositions comprising the same {New oxazolidin and indole compounds, process for the preparation of honey and pharmaceutical composition comprising the same}

본 발명은 신규 합성 화합물인 옥사졸리딘계 및 인돌계 화합물들, 이들의 합성방법 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항염증 및 항암제에 관한 것이다.The present invention relates to anti-inflammatory and anticancer agents containing oxazolidine-based and indole-based compounds, synthetic methods thereof, or pharmaceutically acceptable salts thereof as an active ingredient.

인터류킨-6 (IL-6) 는 B 세포 자극 인자 2 (BSF2) 또는 인터페론β2 (INF-β2)로도 불리는 사이토카인이다. IL-6는 B 임파구의 활성화에 관여하는 분화인자로서 발견되었다 (Hirano, T. et al., Nature (1986) 324, 73-76). 그 후, 여러 가지 세포의 기능에 영향을 미치는 다기능 사이토카인이라는 것이 밝혀졌다 (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6는 세포막위에 두 종류의 단백질을 매개로 그 생물학적 활성을 전달한다. 하나는 IL-6가 결합하는 단백질인 IL-6 수용체이다. IL-6 수용체는 세포막을 관통하여 발현되어있는 분자량 약 80kD의 막결합형 단백질이다. 다른 하나는, 비리간드 결합성의 시그날 전달에 속하는 분자량 약 130kD의 막단백질 gp130 이다. IL-6와 IL-6 수용체는 IL-6/IL-6 수용체 복합체를 형성하고, 이어서 gp130과 결합한다. (Taga et al., J. Exp. Med. (1987) 166, 967). 리간드와 수용체들의 결합 후, 세포내에서는 Janus Kinases 2 (JAK2)가 인산전이반응(transphosphorylation)에 의해 활성화된다. 활성화된 JAK2에 의해 수용체 세포질 도메인(cytoplasmic domains)의 여러 타이로신 잔기(tyrosine residues)가 인산화 (phosphorylation)되고 이것은 SH2나 다른 인산타이로신 결합 모티프(phosphotyrosine binding motif)를 가지고 있는 STAT3 (signal transducers and activators of transcription 3)와 같은 세포질(cytoplasm) 내 단백질의 docking site 역할을 하게 된다. 수용체의 세포질 도메인(cytoplasmic domain)에 결합한 STAT3는 JAK2에 의해 인산화(phosphorylation)가 된 후 수용체에서 떨어져 나온다. 활성화된 STAT3들은 세포질내에 서로서로 결합하여 호모(homo-) 또는 헤테로다이머(heterodimer)를 이룬 후 핵(nucleus) 내로 들어가 목적 유전자의 인식 서열(recognition sequence)에 결합하여 전사(transcription)을 증가시킨다 (Levy, D.E., 등, Nat Rev Mol Cell Biol, 2002, 3, 651-62, Darnell, J.E., J.r., Science, 1997, 277, 1630-1635). Interleukin-6 (IL-6) is a cytokine, also called B cell stimulating factor 2 (BSF2) or interferonβ2 (INF-β2). IL-6 was found as a differentiation factor involved in the activation of B lymphocytes (Hirano, T. et al., Nature (1986) 324, 73-76). It was subsequently found to be multifunctional cytokines that affect the function of various cells (Akira, S. et al., Adv. In Immunology (1993) 54, 1-78). IL-6 delivers its biological activity through two proteins on the cell membrane. One is the IL-6 receptor, a protein to which IL-6 binds. IL-6 receptor is a membrane-bound protein with molecular weight of about 80 kD expressed through cell membrane. The other is the membrane protein gp130, which has a molecular weight of about 130 kD, which belongs to the signal transfer of nonligand binding. IL-6 and IL-6 receptor form an IL-6 / IL-6 receptor complex, which then binds to gp130. (Taga et al., J. Exp. Med. (1987) 166, 967). After binding of the ligand to the receptor, Janus Kinases 2 (JAK2) is activated by transphosphorylation in the cell. Activated JAK2 phosphorylates several tyrosine residues in the receptor cytoplasmic domains, which are STAT3 (signal transducers and activators of transcription with SH2 or other phosphotyrosine binding motifs). It acts as a docking site for proteins in the cytoplasm such as 3). STAT3 bound to the cytoplasmic domain of the receptor is released from the receptor after phosphorylation by JAK2. Activated STAT3s bind to each other in the cytoplasm to form a homo- or heterodimer and then enter the nucleus to bind to the recognition sequence of the gene of interest to increase transcription ( Levy, DE, et al., Nat Rev Mol Cell Biol, 2002, 3, 651-62, Darnell, JE, Jr, Science, 1997, 277, 1630-1635).

이러한 IL-6에 의해 유도되는 신호전달체계는 염증성 질환 및 여러 암 질환과의 관련이 보고되어 있으며, 따라서 IL-6에 의해 유도되는 신호전달체계의 억제는 치료적으로 유용하다. 현재, IL-6의 신호전달체계의 억제하는 기능에 대한 연구는 항 IL-6 R 항체가 가장 많이 연구되어 있다. 이 항 IL-6 R 항체는 류마티스성 관절염에 대하여 활액 세포 성장 억제제가 보고되었고 (국제특허공개 제98/11020호), 형질구 증가증, 초면역 글로불린 혈증, 빈혈, 신염, 악액질, 류마티스성 관절염, 목축업자 질병, 및 맥관증식신염과 같은 IL-6 산물에 기여하는 질병의 치료에 기술된 바 있다 (국제특허공개 제96/12503호). 다발성 경화증, 포도막염, 만성 갑상선염, 지연과민증, 접촉피부염 및 아토피성 피부염과 같은 민감성 T 세포 관련 질병의 예방/보호제에서도 기술되어있고 (국제특허공개 제98/42377호), 전신성 홍반증의 치료제를 기술하는 특허도 보고 있다 (국제특허공개 제98/42377호). 또한, 크론병의 치료제를 기술하는 보고에서도 (국제특허공개 제99/47170], 이것의 활성성분은 항-IL-6R 항체이었다. 췌장염의 치료제를 기술하고 있는 특허도 활성성분으로 보고되었고 (국제특허공개 제00/10607), 건선의 치료제를 기술하고 있는 특허인 국제특허공개 제02/3492호에서도 활성성분은 항-IL-6R 항체이다. 추가로, 연소성 특발성 위축증의 치료제를 기술하고있는 국제특허공개공보 제02/080969호에서도 이것의 활성성분은 항-IL-6R 항체이다. 그러나, 이들 단백질은 외래 단백질로서 인지되어질 수 있는 에피토프를 가질 수 있으며 치료제로서 사용될 경우 여전히 면역원성일 수 있다. 그러나 단백질이 아닌 작은 분자 화합물(small molecule compound)들은 이러한 면역체계에 인지되지 않아 현재 많은 연구가 이루어지고 있다. The signaling system induced by IL-6 has been reported to be associated with inflammatory diseases and various cancer diseases, and therefore inhibition of the signaling system induced by IL-6 is therapeutically useful. Currently, studies on the inhibitory function of the signaling system of IL-6 have been the most studied anti-IL-6 R antibody. This anti-IL-6 R antibody has been reported as a synovial cell growth inhibitor against rheumatoid arthritis (International Patent Publication No. 98/11020), plasmacytosis, hyperimmunoglobulinemia, anemia, nephritis, cachexia, rheumatoid arthritis, Pastoral disease, and diseases that contribute to IL-6 products, such as vasculitis, have been described (International Publication No. 96/12503). It has also been described in the prevention / protection of susceptible T cell-related diseases such as multiple sclerosis, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis and atopic dermatitis (International Patent Publication No. 98/42377), which describes a therapeutic agent for systemic erythema. It also sees a patent (International Patent Publication No. 98/42377). In addition, in a report describing a therapeutic agent for Crohn's disease (International Patent Publication No. 99/47170), its active ingredient was an anti-IL-6R antibody. A patent describing a therapeutic agent for pancreatitis has also been reported as an active ingredient (International Patent Publication No. 99/47170). Patent Publication No. 00/10607), International Patent Publication No. 02/3492, which describes a therapeutic agent for psoriasis, is also an active ingredient is an anti-IL-6R antibody. Its active ingredient is also an anti-IL-6R antibody in Patent Publication No. 02/080969. However, these proteins may have epitopes that can be recognized as foreign proteins and may still be immunogenic when used as therapeutic agents. Small molecule compounds other than proteins are not recognized by the immune system, and much research is being done.

또한 암과 관련되어 IL-6 신호전달체계는 그 중간 매개인자인 STAT3와 많은 관련이 있다. 이것은 골수종, 유방 암종, 전립선 암, 뇌 종양, 두경부 암종, 흑색종, 백혈병 및 림프종, 특히 만성 골수성 백혈병 및 다발성 골수종을 포함하여 여러 형태의 암에 관여하는 것으로 보고되었다 (Niu, 등, Cancer Res., 1999, 59, 5059-5063). 쥐 및 인간 전립선 암 양쪽에서 유래된 세포들은 구조적으로 활성화된 STAT3을 갖는 것으로 밝혀졌으며, STAT3는 일부 급성 백혈병(Gouilleux-Gruart, V. 등, Leuk.Lymphoma, 1997, 28, 83-88) 및 T 세포 림프종 (Yu,C.L.등, J.Immunol., 1997, 159, 5206-5210) 에서 구조적으로 활성화되는 것으로 밝혀졌다. 흥미롭게도, STAT3은 만성 림프성 백혈병에서 세린 잔기 위에 구조적으로 인산화 되는 것으로 밝혀졌다 (Frank, D.A., 등, J.Clin.Invest., 1997, 100, 3140-3148). STAT3은, 다발성 골수종을 가진 환자로부터의 골수 단핵 세포 및 배양액 양쪽 모두에서, 골수종 종양 세포에서 구조적으로 활성인 것으로 밝혀졌다. 이러한 세포는 Fas-매개 세포고사에 내성이고 높은 수준의 Bcl-xL을 발현한다. STAT3 시그날링은 세포고사에 대한 내성을 부여함으로써 골수종 종양 세포의 생존을 위해 필수적인 것으로 밝혀졌다 (Catlett-Falcone, R. 등, Immunity, 1999, 10, 105-115). 한편, 최근에는 췌장암을 비롯한 Ras 에 의해 유도되는 암 환자군에서 이상적으로 IL-6가 분비되고, IL-6를 제거함으로서 Ras에 의한 종양세포의 성장과 혈관생성이 억제될 뿐 아니라 종양의 크기가 감소됨이 보고되었다 (Brooke Ancrile 등, Gene & Development, 2007, 21, 1714-1719). 또한 EGFR이 변이된 폐 선암(lung adenocarcinoma)에서 IL-6가 과발현됨으로서 STAT3가 활성화됨이 밝혀지면서 IL-6에 의한 gp130/JAK/STAT3 경로가 항암치료에 있어서 새로운 타켓으로 부각되고 있다 (Sizhi Paul Gao 등, J. Clin. Invest. 2007, 117, 38463856).
In addition, the IL-6 signaling system in association with cancer is associated with a number of intermediate mediator STAT3. It has been reported to be involved in several forms of cancer, including myeloma, breast carcinoma, prostate cancer, brain tumors, head and neck carcinoma, melanoma, leukemia and lymphoma, especially chronic myeloid leukemia and multiple myeloma (Niu, et al., Cancer Res. , 1999, 59, 5059-5063). Cells derived from both rat and human prostate cancers have been found to have structurally activated STAT3, which has some acute leukemias (Gouilleux-Gruart, V. et al., Leuk. Lymphoma, 1997, 28, 83-88) and T It has been shown to be structurally activated in cellular lymphomas (Yu, CL et al., J. Immunol., 1997, 159, 5206-5210). Interestingly, STAT3 has been shown to structurally phosphorylate on serine residues in chronic lymphocytic leukemia (Frank, DA, et al., J. Clin. Invest., 1997, 100, 3140-3148). STAT3 has been found to be structurally active in myeloma tumor cells in both myeloid mononuclear cells and cultures from patients with multiple myeloma. These cells are resistant to Fas-mediated apoptosis and express high levels of Bcl-xL. STAT3 signaling has been shown to be essential for the survival of myeloma tumor cells by conferring resistance to apoptosis (Catlett-Falcone, R. et al., Immunity, 1999, 10, 105-115). On the other hand, recently, IL-6 is ideally secreted in a group of cancer patients induced by Ras, including pancreatic cancer, and the removal of IL-6 inhibits tumor cell growth and angiogenesis by Ras as well as reducing tumor size. Has been reported (Brooke Ancrile et al., Gene & Development, 2007, 21, 1714-1719). In addition, the gp130 / JAK / STAT3 pathway caused by IL-6 is emerging as a new target in anti-cancer treatment, as it has been shown that STAT3 is activated by IL-6 overexpression in EGFR-mutated lung adenocarcinoma (Sizhi Paul). Gao et al., J. Clin.Invest. 2007, 117, 38463856).

한편, 인터류킨-11 (IL-11)은 IL-6 family에 속해 있는 염증성 사이토카인으로 IL-6와 거의 같은 신호전달체계를 갖는 것으로 조혈, 면역반응, 염증 및 각종 암세포에서 그 발현이 증가되어 암 진행에 중요한 역할을 하는 것으로 알려지고 있다 (Jackson CB 등 J Pathol 2007, 213, 140-151). 최근 IL-11이 그 수용체인 IL-11Rα와 gp130에 결합하여 위암, 대장암 세포 증식 및 암 침윤을 촉진시키는 작용이 있음이 보고되었고 (Nakayama T 등 Int J Oncol, 2007, 30, 825-833, Yoshizaki A 등, Int J Oncol 2006, 29, 869-876), Ernst 등은 IL-11/Stat3 신호에 의해 smad7이 활성화되고 동시에 TGF β 시그날을 유도하는 smad activator가 차단됨으로서 oncogenic program (antiapoptotic gene, proangiogenic gene, proliferative gene)이 활성화되어 염증관련 위종양이 유도된다고 보고하였다(Ernst 등 J. Clin. Invest 2008, 118(5), 1728-1738). 따라서 IL-11에 의한 gp130/JAK/STAT3 경로가 항암치료에 있어서 새로운 타켓으로 부각되고 있다.
On the other hand, interleukin-11 (IL-11) is an inflammatory cytokine belonging to the IL-6 family and has almost the same signaling system as IL-6, and its expression is increased in hematopoietic, immune response, inflammation and various cancer cells. It is known to play an important role in the process (Jackson CB et al. J Pathol 2007, 213, 140-151). Recently, IL-11 binds to its receptors, IL-11Rα and gp130, and has been reported to promote gastric cancer, colorectal cancer cell proliferation and cancer invasion (Nakayama T et al., Int J Oncol, 2007, 30, 825-833, Yoshizaki A et al., Int J Oncol 2006, 29, 869-876), Ernst et al. Have oncogenic programs (antiapoptotic gene, proangiogenic) by activating smad7 by IL-11 / Stat3 signaling and blocking the smad activator that induces TGF β signal. Gene and proliferative genes have been reported to induce inflammation-related gastric tumors (Ernst et al. J. Clin. Invest 2008, 118 (5), 1728-1738). Thus, the gp130 / JAK / STAT3 pathway by IL-11 is emerging as a new target for chemotherapy.

이에, 본 발명자들은 유기합성 시료로 부터 IL-6 및 IL-11에 의해 유도되는 신호전달체계의 저해제를 탐색한 결과, 신규 합성한 옥사졸리딘계 및 인돌계 화합물들이 IL-6 및 IL-11에 의해 유도되는 신호전달체계를 저해하는 활성이 우수하므로 염증성 질환 및 암 치료제로 유용하다는 것을 규명함으로써 본 발명을 완성하였다.Therefore, the present inventors searched for inhibitors of the signaling system induced by IL-6 and IL-11 from organic synthesis samples, and as a result, newly synthesized oxazolidine-based and indole-based compounds were added to IL-6 and IL-11. The present invention has been completed by elucidating that it is useful as an agent for treating inflammatory diseases and cancer because of its excellent activity of inhibiting the signaling system induced by the present invention.

본 발명의 하나의 목적은 신규한 옥사졸리딘계, 인돌계 화합물, 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다. One object of the present invention is to provide novel oxazolidine-based, indole-based compounds, or pharmaceutically acceptable salts thereof.

본 발명의 또 하나의 목적은 상기 신규 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 염증성 질환 또는 암의 예방 및 치료용 약학 조성물을 제공하는 것이다.It is another object of the present invention to provide a pharmaceutical composition for preventing and treating an inflammatory disease or cancer, comprising the novel compound or a pharmaceutically acceptable salt thereof.

이하, 본 발명을 상세히 설명한다.
Hereinafter, the present invention will be described in detail.

하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 옥사졸리딘계 화합물 또는 이의 약학적으로 허용되는 염에 관한 것이다.As one embodiment, the present invention relates to an oxazolidine-based compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

<화학식 1><Formula 1>

Figure 112011028633390-pat00001
Figure 112011028633390-pat00001

상기에서 R1은 수소 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이고; R2는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬이고; R3는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이고; R4는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이다.R 1 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl; R 2 is hydrogen or C 1-10 straight, branched or cycloalkyl; R 3 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl; R 4 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl.

보다 바람직하게는, 상기 R1은 아이소프로필 또는 벤질이고; R2는 C1-5의 직쇄, 측쇄 또는 사이클로 알킬이고; R3는 수소이고; 및 R4는 C1, C4-7알킬, 아이소프로필, 또는 벤질이다.More preferably, R 1 is isopropyl or benzyl; R 2 is C 1-5 straight, branched or cycloalkyl; R 3 is hydrogen; And R 4 is C 1 , C 4-7 alkyl, isopropyl, or benzyl.

본 발명의 화학식 1의 화합물 중 바람직한 화합물은 구체적으로 하기와 같다:Preferred compounds of the compound of formula 1 of the present invention are specifically as follows:

1) (S)-3-((2S,3S)-3-하이드록시-2,4-디메틸펜트-4-에노일)-4-이소프로필옥사졸리딘-2-온(4a),1) (S) -3-((2S, 3S) -3-hydroxy-2,4-dimethylpent-4-enoyl) -4-isopropyloxazolidin-2-one (4a),

2) (S)-3-((2S,3S)-3-하이드록시-2,5-디메틸-4-메틸렌헥사노일)-4-이소프로필옥사졸리딘-2-온(4b),2) (S) -3-((2S, 3S) -3-hydroxy-2,5-dimethyl-4-methylenehexanoyl) -4-isopropyloxazolidin-2-one (4b),

3) (S)-3-((2S,3S)-3-하이드록시-2-메틸-4-메틸렌옥타노일)-4-이소프로필옥사졸리딘-2-온(4c),3) (S) -3-((2S, 3S) -3-hydroxy-2-methyl-4-methyleneoctanoyl) -4-isopropyloxazolidin-2-one (4c),

4) (S)-3-((2S,3S)-3-하이드록시-2-메틸-4-메틸렌노나노일)-4-이소프로필옥사졸리딘-2-온(4d),4) (S) -3-((2S, 3S) -3-hydroxy-2-methyl-4-methylenenonanoyl) -4-isopropyloxazolidin-2-one (4d),

5) (S)-3-((2S,3S)-3-하이드록시-2-메틸-4-메틸렌데카노일)-4-이소프로필옥사졸리딘-2-온(4e),5) (S) -3-((2S, 3S) -3-hydroxy-2-methyl-4-methylenedecanoyl) -4-isopropyloxazolidin-2-one (4e),

6) (S)-3-((2S,3S)-3-하이드록시-2-메틸-4-메틸렌운데카노일)-4-이소프로필옥사졸리딘-2-온(4f),6) (S) -3-((2S, 3S) -3-hydroxy-2-methyl-4-methyleneundecanoyl) -4-isopropyloxazolidin-2-one (4f),

7) (S)-3-((2S,3S)-4-벤질-3-하이드록시-2-메틸펜트-4-에노일)-4-이소프로필옥사졸리딘-2-온(4g),7) (S) -3-((2S, 3S) -4-benzyl-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (4 g),

8) (S)-3-((2S,3S)-3-사이클로헥세닐-3-하이드록시-2-메틸프로파노일)-4-이소프로필옥사졸리딘-2-온(4h),8) (S) -3-((2S, 3S) -3-cyclohexenyl-3-hydroxy-2-methylpropanoyl) -4-isopropyloxazolidin-2-one (4h),

9) (R)-3-((2R,3R)-3-하이드록시-2-메틸-4-메틸렌노나노일)-4-이소프로필옥사졸리딘-2-온(5),9) (R) -3-((2R, 3R) -3-hydroxy-2-methyl-4-methylenenonanoyl) -4-isopropyloxazolidin-2-one (5),

10) (S)-4-벤질-3-((2S,3S)-3-하이드록시-2-메틸-4-메틸렌노나노일)옥사졸리딘-2-온(7a),10) (S) -4-benzyl-3-((2S, 3S) -3-hydroxy-2-methyl-4-methylenenonanoyl) oxazolidin-2-one (7a),

11) (S)-4-벤질-3-((2R,3S)-3-하이드록시-2-메틸-4-메틸렌노나노일)옥사졸리딘-2-온(7b), 및11) (S) -4-benzyl-3-((2R, 3S) -3-hydroxy-2-methyl-4-methylenenonanoyl) oxazolidin-2-one (7b), and

12) (S)-3-((2S,3R)-3-하이드록시-2-메틸노나노일)-4-이소프로필옥사졸리딘-2-온(9).12) (S) -3-((2S, 3R) -3-hydroxy-2-methylnonanoyl) -4-isopropyloxazolidin-2-one (9).

화합물compound R1R1 R4R4 44 2'2' 3'3 ' 4a4a CH(CH3)2 CH (CH 3 ) 2 CH3 CH 3 SS SS SS 4b4b CH(CH3)2 CH (CH 3 ) 2 CH(CH3)2 CH (CH 3 ) 2 SS SS SS 4c4c CH(CH3)2 CH (CH 3 ) 2 C4H9 C 4 H 9 SS SS SS 4d4d CH(CH3)2 CH (CH 3 ) 2 C5H11 C 5 H 11 SS SS SS 4e4e CH(CH3)2 CH (CH 3 ) 2 C6H13 C 6 H 13 SS SS SS 4f4f CH(CH3)2 CH (CH 3 ) 2 C7H15 C 7 H 15 SS SS SS 4g4 g CH(CH3)2 CH (CH 3 ) 2 benzylbenzyl SS SS SS 4h4h CH(CH3)2 CH (CH 3 ) 2 1-Cyclohexene1-Cyclohexene SS SS SS 55 CH(CH3)2 CH (CH 3 ) 2 CH(CH3)2 CH (CH 3 ) 2 RR RR RR 7a7a benzylbenzyl C5H11 C 5 H 11 SS SS SS 7b7b benzylbenzyl C5H11 C 5 H 11 SS RR SS 99 CH(CH3)2 CH (CH 3 ) 2 C6H15 C 6 H 15 SS SS RR

본 발명의 화학식 1의 옥사졸리딘계 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 통상의 방법에 의해 제조되는 모든 염, 수화물 및 용매화물이 포함된다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 주석산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플루오로아세트산, 메탄술폰산, 벤젠술폰산, 말레인산, 벤조산, 글루콘산, 글리콜산, 숙신산, 4-모폴린에탄술폰산, 캠포술폰산, 4-니트로벤젠술폰산, 히드록시-O-술폰산, 4-톨루엔술폰산, 칼룩투론산, 엠보산, 글루탐산, 아스파르트산 등을 사용할 수 있다.
The oxazolidine-based compound of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and includes all salts, hydrates and solvates prepared by conventional methods. As salts are acid addition salts formed with pharmaceutically acceptable free acids. The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, and trifluoric acid may be used as the organic acid. Roacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, cal Luteuronic acid, emboic acid, glutamic acid, aspartic acid and the like can be used.

또 하나의 양태로서, 본 발명은 하기 화학식 2로 표시되는 인돌계 화합물 또는 이의 약학적으로 허용되는 염에 관한 것이다.As another aspect, the present invention relates to an indole compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

<화학식 2><Formula 2>

Figure 112011028633390-pat00002
Figure 112011028633390-pat00002

상기에서 R1은 수소, 또는 치환 또는 비치환된 C1-10 알킬이고; R2는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬이고; R3는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이고; R4는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이고; X는 수소, 할로겐, 하이드록시, 메톡시, 치환 또는 비치환된 C1-10 알킬이고; Y는 산소이고; Z는 하이드록시, C1-10의 알콕시, -OCOCH3 또는 산소이고; 상기

Figure 112011069568910-pat00003
는 단일 또는 이중 결합이다.R 1 is hydrogen or substituted or unsubstituted C 1-10 alkyl; R 2 is hydrogen or C 1-10 straight, branched or cycloalkyl; R 3 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl; R 4 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl; X is hydrogen, halogen, hydroxy, methoxy, substituted or unsubstituted C 1-10 alkyl; Y is oxygen; Z is hydroxy, C 1-10 alkoxy, —OCOCH 3 or oxygen; remind
Figure 112011069568910-pat00003
Is a single or double bond.

보다 바람직하게는, R1은 하이드록시에틸 또는 터트-부틸디메틸실릴옥시에틸이고; R2는 C1-5의 직쇄, 측쇄 또는 사이클로 알킬이고; R3는 수소이고; R4는 수소 또는 C1-5의 직쇄, 측쇄 또는 사이클로 알킬이고; X는 수소, 할로겐, 하이드록시, 메톡시, 치환 또는 비치환된 C1-10 알킬이고; Y는 산소이고; Z는 하이드록시, C1-5의 알콕시, -OCOCH3 또는 산소이고; 및 상기

Figure 112011069568910-pat00004
는 단일 또는 이중 결합이다.More preferably, R 1 is hydroxyethyl or tert-butyldimethylsilyloxyethyl; R 2 is C 1-5 straight, branched or cycloalkyl; R 3 is hydrogen; R 4 is hydrogen or C 1-5 straight, branched or cycloalkyl; X is hydrogen, halogen, hydroxy, methoxy, substituted or unsubstituted C 1-10 alkyl; Y is oxygen; Z is hydroxy, C 1-5 alkoxy, —OCOCH 3 or oxygen; And
Figure 112011069568910-pat00004
Is a single or double bond.

본 발명의 화학식 2의 화합물 중 바람직한 화합물은 구체적으로 하기와 같다:Preferred compounds among the compounds of formula 2 of the present invention are specifically as follows:

1) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온(13a),1) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -3-hydroxy-2-methyl-4-methylenenonan-1- On (13a),

2) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트(14a),2) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylene-1-oxononane-3- Mono acetate (14a),

3) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트(15a),3) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -2-methyl-4-methylene-1-oxononane- 3-yl acetate (15a),

4) (2S,3S)-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트(15b),4) (2S, 3S) -1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2-methyl-4-methylene-1-oxononan-3-yl acetate (15b ),

5) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온(16a),5) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -3-hydroxy-2-methyl-4-methylenenonan- 1-on 16a,

6) (2S,3S)-3-하이드록시-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-1-온(16b),6) (2S, 3S) -3-hydroxy-1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-1-one (16b) ,

7) (2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-3-올(17a),7) (2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylenenonan-3-ol (17a),

8) (2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-3-올(18a),8) (2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-3-ol (18a ),

9) (2R,3S)-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-3-올(18b),9) (2R, 3S) -1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-3-ol (18b),

10) (2S,3S)-3-하이드록시-1-(3-(2-하이드록시에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-1-온(13b),10) (2S, 3S) -3-hydroxy-1- (3- (2-hydroxyethyl) indolin-1-yl) -2-methyl-4-methylenenonan-1-one (13b),

11) (2S,3S)-1-(3-(2-하이드록시에틸)인돌린-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트(14b) 및11) (2S, 3S) -1- (3- (2-hydroxyethyl) indolin-1-yl) -2-methyl-4-methylene-1-oxononan-3-yl acetate (14b) and

12) (2R,3S)-1-(3-(2-하이드록시에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-3-올(17b).12) (2R, 3S) -1- (3- (2-hydroxyethyl) indolin-1-yl) -2-methyl-4-methylenenonan-3-ol (17b).

화합물compound R1R1 YY ZZ 인돌유도체결합Indole derivatives 13a13a (CH2)2-OTBS(CH 2 ) 2 -OTBS OO HH 단일결합Single bond 14a14a (CH2)2-OTBS(CH 2 ) 2 -OTBS OO OCOCH3 OCOCH 3 단일결합Single bond 15a15a (CH2)2-OTBS(CH 2 ) 2 -OTBS OO OCOCH3 OCOCH 3 이중결합Double bond 15b15b (CH2)2-OH(CH 2 ) 2 -OH OO OCOCH3 OCOCH 3 이중결합Double bond 16a16a (CH2)2-OTBS(CH 2 ) 2 -OTBS OO HH 이중결합Double bond 16b16b (CH2)2-OH(CH 2 ) 2 -OH OO HH 이중결합Double bond 17a17a (CH2)2-OTBS(CH 2 ) 2 -OTBS HH HH 단일결합Single bond 18a18a (CH2)2-OTBS(CH 2 ) 2 -OTBS HH HH 이중결합Double bond 18b18b (CH2)2-OH(CH 2 ) 2 -OH HH HH 이중결합Double bond 13b13b (CH2)2-OH(CH 2 ) 2 -OH OO HH 단일결합Single bond 14b14b (CH2)2-OH(CH 2 ) 2 -OH OO OCOCH3 OCOCH 3 단일결합Single bond 17b17b (CH2)2-OH(CH 2 ) 2 -OH HH HH 단일결합Single bond

본 발명의 화학식 2의 인돌계 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 통상의 방법에 의해 제조되는 모든 염, 수화물 및 용매화물이 포함된다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 주석산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플루오로아세트산, 메탄술폰산, 벤젠술폰산, 말레인산, 벤조산, 글루콘산, 글리콜산, 숙신산, 4-모폴린에탄술폰산, 캠포술폰산, 4-니트로벤젠술폰산, 히드록시-O-술폰산, 4-톨루엔술폰산, 칼룩투론산, 엠보산, 글루탐산, 아스파르트산 등을 사용할 수 있다.
Indole-based compounds of formula (2) of the present invention can be used in the form of pharmaceutically acceptable salts, and include all salts, hydrates and solvates prepared by conventional methods. As salts are acid addition salts formed with pharmaceutically acceptable free acids. The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, and trifluoric acid may be used as the organic acid. Roacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, cal Luteuronic acid, emboic acid, glutamic acid, aspartic acid and the like can be used.

<반응식 1><Scheme 1>

Figure 112011028633390-pat00005

Figure 112011028633390-pat00005

<반응식 2><Scheme 2>

Figure 112011028633390-pat00006

Figure 112011028633390-pat00006

<반응식 3><Scheme 3>

Figure 112011028633390-pat00007

Figure 112011028633390-pat00007

<반응식 4><Scheme 4>

Figure 112011028633390-pat00008

Figure 112011028633390-pat00008

<반응식 5>Scheme 5

Figure 112011028633390-pat00009

Figure 112011028633390-pat00009

<반응식 6><Scheme 6>

Figure 112011028633390-pat00010

Figure 112011028633390-pat00010

<반응식 7><Reaction Scheme 7>

Figure 112011028633390-pat00011

Figure 112011028633390-pat00011

<반응식 8><Reaction Scheme 8>

Figure 112011028633390-pat00012

Figure 112011028633390-pat00012

<반응식 9><Reaction Scheme 9>

Figure 112011028633390-pat00013

Figure 112011028633390-pat00013

<반응식 10><Reaction formula 10>

Figure 112011028633390-pat00014

Figure 112011028633390-pat00014

상기 각 반응 또는 모든 반응이 완결된 후의 생성물은 통상적인 후처리 방법, 예를 들면 크로마토그래피, 재결정화 등의 방법에 의해 분리 및 정제할 수 있다.
After each reaction or all the reactions are completed, the product can be separated and purified by conventional post-treatment methods such as chromatography, recrystallization and the like.

본 발명의 아이소프로필옥사졸리딘계 화합물인 화학식 1과 인돌계 화합물인화학식 2는 합성방법에 의해 합성하여 사용하였으며, 통상적인 모든 방법에 의해 얻을 수 있고, 시판되는 시약을 사용할 수 있다.
The isopropyloxazolidine-based compound of Formula 1 and the indole-based compound of Chemical Formula 2 were synthesized by a synthesis method, can be obtained by all conventional methods, and commercially available reagents can be used.

또 하나의 양태로서, 본 발명은 상기 화학식 1 또는 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 염증성 질환 또는 암의 예방 및 치료용 약학 조성물에 관한 것이다.
As another aspect, the present invention relates to a pharmaceutical composition for the prevention and treatment of inflammatory diseases or cancer, comprising the compound of Formula 1 or Formula 1 or a pharmaceutically acceptable salt thereof.

본 발명에 따른 화합물은 IL-6 또는 IL-11 에 의해 유도되는 신호전달체계를 억제하는 효과가 우수하므로, IL-6 또는 IL-11 에 의해 매개되는 질환, 특히 염증성 질환 또는 암 질환의 치료 또는 예방에 우수한 효과가 있다.
Since the compounds according to the present invention have an excellent effect of inhibiting the signaling system induced by IL-6 or IL-11, the treatment of diseases mediated by IL-6 or IL-11, in particular inflammatory diseases or cancer diseases, or It has an excellent effect on prevention.

상기 염증성 질환은 류마티스 관절염, 골다공증, 형질구 증가증, 초면역 글로불린 혈증, 빈혈, 신염, 악액질, 목축업자 질병, 맥관증식신염, 다발성 경화증, 포도막염, 만성 갑상선염, 지연과민증, 접촉피부염 아토피성 피부염, 전신성 홍반증, 크론병, 췌장염, 건선, 연소성 특발성 위축증, 당뇨병 및 알쯔하이머를 포함하나, 이에 제한되지 않으며, IL-6 또는 IL-11 에 매개되는 모든 염증성 질환을 포함한다. 또한, 상기 암 질환은 췌장암, 유방암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 흑색종, 백혈병, 림프종, 간암, 위암, 결장암, 골암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종 및 중추신경계 종양을 포함하나, 이에 제한되지 않으며, IL-6 또는 IL-11 에 매개되는 모든 암 질환을 포함한다.
The inflammatory diseases include rheumatoid arthritis, osteoporosis, plasmacytosis, hyperimmunoglobulinemia, anemia, nephritis, cachexia, pastoral disease, vasculitis, multiple sclerosis, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis atopic dermatitis, systemic Including, but not limited to, erythema, Crohn's disease, pancreatitis, psoriasis, juvenile idiopathic atrophy, diabetes and Alzheimer's, and all inflammatory diseases mediated by IL-6 or IL-11. In addition, the cancer diseases include pancreatic cancer, breast cancer, prostate cancer, brain tumor, head and neck cancer, melanoma, myeloma, melanoma, leukemia, lymphoma, liver cancer, stomach cancer, colon cancer, bone cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, Including anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer, urinary tract cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor, This includes, but is not limited to, all cancer diseases mediated by IL-6 or IL-11.

본 발명의 약학조성물은, 조성물 총 중량에 대하여 상기 화합물을 0.0001 내지 10 중량%로, 바람직하게는 0.001 내지 1 중량%를 포함할 수 있다.The pharmaceutical composition of the present invention may comprise 0.0001 to 10% by weight of the compound, preferably 0.001 to 1% by weight, based on the total weight of the composition.

또한, 본 발명의 옥사졸리딘계 화합물인 화학식 1과 인돌계 화합물인 화학식 2를 포함하는 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. In addition, the composition comprising the oxazolidine-based compound of Formula 1 and the indole-based compound of Formula 2 of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

또한, 본 발명의 옥사졸리딘계 화합물인 화학식 1과 인돌계 화합물인 화학식 2의 약학적 투여 형태는 이들의 약학적 허용 가능한 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 oxazolidine-based compound of formula 1 and the indole-based compound of formula 2 may also be used in the form of their pharmaceutically acceptable salts, alone or in combination with other pharmaceutically active compounds. As well as can be used as a suitable assembly.

본 발명에 따른 옥사졸리딘계 화합물인 화학식 1과 인돌계 화합물인 화학식 2를 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 추출물을 포함하는 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. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물 또는 분획물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 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, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Compositions comprising formula ( 1 ), which is an oxazolidine-based compound, and formula (2), which are indole-based compounds according to the present invention, are oral forms of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. Formulations, external preparations, suppositories, and sterile injectable solutions can be formulated and used. Carriers, excipients and diluents that may be included in the composition comprising the extract 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. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like in the extract or fraction. (sucrose), lactose (lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

본 발명의 옥사졸리딘계 화합물인 화학식 1과 인돌계 화합물인 화학식 2의 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 추출물 또는 화합물은 1일 0.0001 내지 100 mg/kg으로, 바람직하게는 0.001 내지 100 mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. Preferred dosages of the oxazolidine-based compound of formula 1 and the indole-based compound of formula 2 will vary depending 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, and will be appropriately selected by those skilled in the art. Can be. However, for the desired effect, the extract or compound of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably at 0.001 to 100 mg / kg. Administration may be administered once a day or may be divided several times.

또한, 본 발명의 약학 조성물은 쥐, 생쥐, 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. In addition, the pharmaceutical composition of the present invention can be administered to various mammals such as mice, mice, livestock, humans. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

이상에서 설명한 바와 같이, 본 발명은 IL-6 및 IL-11에 의해 유도되는 신호전달체계의 저해 활성을 가지는 화학식 1 의 옥사졸리딘계 또는 화학식 2의 인돌계 화합물 또는 이의 약학적으로 허용되는 염, 또는 이들을 포함하는 조성물에 관한 것으로, 류마티스 관절염, 골다공증, 형질구 증가증, 초면역 글로불린 혈증, 빈혈, 신염, 악액질, 목축업자 질병, 맥관증식신염, 다발성 경화증, 포도막염, 만성 갑상선염, 지연과민증, 접촉피부염 아토피성 피부염, 전신성 홍반증, 크론병, 췌장염, 건선, 연소성 특발성 위축증, 당뇨병 및 알쯔하이머을 포함하는 염증성 질환, 그리고 췌장암, 유방암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 흑색종, 백혈병, 림프종, 간암, 위암, 결장암, 골암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종 및 중추신경계 종양을 포함하는 암의 예방 및 치료용 의약품으로 유용하게 사용될 수 있다. As described above, the present invention provides an oxazolidine-based or indole-based compound of Formula 2 or a pharmaceutically acceptable salt thereof having the inhibitory activity of the signaling system induced by IL-6 and IL-11, Or to a composition comprising them, rheumatoid arthritis, osteoporosis, plasmacytosis, hyperimmunoglobulinemia, anemia, nephritis, cachexia, cattle breeder disease, vasculitis nephritis, multiple sclerosis, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis Inflammatory diseases including atopic dermatitis, systemic lupus erythematosus, Crohn's disease, pancreatitis, psoriasis, juvenile idiopathic atrophy, diabetes and Alzheimer's disease, and pancreatic cancer, breast cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, melanoma, leukemia, Lymphoma, Liver Cancer, Stomach Cancer, Colon Cancer, Bone Cancer, Uterine Cancer, Ovarian Cancer, Rectal Cancer, Esophageal Cancer, Small Intestine Cancer, Anal Muscle Cancer, Colon Cancer, Fallopian Tube It is a medicine for the prevention and treatment of cancer including endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer, urinary tract cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor. It can be usefully used.

도 1은 아이소프로필옥사졸리딘계 화합물과 인돌계 화합물이 HepG2 세포에서 IL-6로 유도되어지는 루시퍼라제(luciferase)의 발현 저해활성의 IC50을 나타낸 도이다.
도 2는 본 발명에 따른 화학식 4d로 표시되는 아이소프로필옥사졸리딘계 화합물이 HepG2 세포에서 IL-11으로 유도되어지는 luciferase의 발현 저해활성을 나타낸 도이다.
도 3은 본 발명에 따른 화학식 4d로 표시되는 아이소프로필옥사졸리딘계 화합물이 HepG2 세포에서 IL-6 유도 STAT3 인산화 저해 활성을 나타낸 도이다.
도 4는 본 발명에 따른 화학식 4d로 표시되는 아이소프로필옥사졸리딘계 화합물이 U266 세포에서 IL-6 유도 JAK2 와 gp130 인산화 저해 활성을 나타낸 도이다.
도 5는 본 발명에 따른 화학식 4d로 표시되는 아이소프로필옥사졸리딘계 화합물이 3T3L1 세포에서 인슐린 유도 아디포제네시스(adipogenesis)를 저해하는 IL-6 효과를 회복하는 활성을 나타낸 도이다.1 is a diagram showing IC 50 of the expression inhibitory activity of luciferase induced by IL-6 in isopropyloxazolidine compounds and indole compounds in HepG2 cells.
2 is a diagram showing the expression inhibitory activity of luciferase induced by IL-11 in HepG2 cells of the isopropyloxazolidine-based compound represented by Chemical Formula 4d according to the present invention.
Figure 3 is an isopropyl oxazolidine-based compound represented by the formula ( 4d ) according to the invention is a diagram showing the IL-6 induced STAT3 phosphorylation inhibitory activity in HepG2 cells.
4 is a diagram showing isopropyloxazolidine-based compound represented by Formula 4d according to the present invention showing IL-6-induced JAK2 and gp130 phosphorylation inhibitory activity in U266 cells.
5 is a diagram showing the activity of restoring the IL-6 effect of inhibiting insulin-induced adipogenesis in 3T3L1 cells by the isopropyloxazolidine-based compound represented by Chemical Formula 4d according to the present invention.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

실시예Example : 화학식 1과 2로 표시되는 화합물의 합성 Synthesis of Compounds Represented by Chemical Formulas 1 and 2

<< 실시예Example 1> 1>

Figure 112011028633390-pat00015

Figure 112011028633390-pat00015

3-3- 메틸methyl -2--2- 메틸렌부타날의Methylene butanal 제조(2b) Manufacture (2b)

1b 아이소발리알디하이드 (500 mg, 58mmol, 1eq)에 포말알디하이드 수용액 (0.434ml, 58 mmol, 1eq, 37%)과 다이메틸아민하이드로클로라이드 용액을 (440mg, 50mmol, 0.93 eq) 첨가하여 70℃로 48시간 교반 하였다. 반응이 완결된 것을 TLC로 확인하였다. 모든 화합물이 2b가 된 것을 확인한 후에 물을 첨가하여 반응을 정지 시킨 후, 다이에틸이터를 첨가하여 유기층을 분리하였다. 유기층을 무수 황산마그네슘으로 건조시키고, 농축시킨 후, 노란색 액체물질 2b (44-62%)을 얻었다. 컬럼을 하지 않고 바로 다음 반응에 교반시겼다. 1b isovalialdihydride (500 mg, 58mmol, 1eq) was added with aqueous formaldehyde (0.434ml, 58 mmol, 1eq, 37%) and dimethylamine hydrochloride solution (440mg, 50mmol, 0.93 eq). Stirred for 48 hours. TLC confirmed that the reaction was complete. After confirming that all the compounds became 2b , water was added to stop the reaction, and then diethyl ether was added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give a yellow liquid 2b (44-62%). Stirred to next reaction without column.

1H-NMR (CDCl3, 500 MHz) δ 9.52 (1H, s, -CHO), 6.23 (1H, s, -C=CHαHβ), 5.94 (1H, s, -C=CHαHβ), 2.78 (1H, m, -CH(CH3)2), 1.07 (6H, d, J = 6.8Hz, -CH(CH 3)2)
 1 H-NMR (CDCl 3 , 500 MHz) δ 9.52 (1H, s, -C H O), 6.23 (1H, s, -C = C H αHβ), 5.94 (1H, s, -C = CHα H β ), 2.78 (1H, m, -C H (CH 3 ) 2 ), 1.07 (6H, d, J = 6.8 Hz, -CH (C H 3 ) 2 )

2-2- 메틸렌헥사날의Methylene hexanal 제조(2c) Manufacture (2c)

상기의 동일한 방법을 사용하여 노란색 액체물질의 2c (44-62%)를 얻었다.Using the same method as above, 2c (44-62%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 9.53 (1H, s, -CHO), 6.24 (1H, s, -C=CHαHβ), 5.98 (1H, s, -C=CHαHβ), 2.23 (2H, t, J = 7.3 Hz, -CH 2CH2CH2CH3), 1.35-1.30 (4H, m, -CH2CH 2CH 2CH3), 0.90 (3H, t, J = 7.3Hz, -CH2CH2CH2CH 3)
 1 H-NMR (CDCl 3 , 500 MHz) δ 9.53 (1H, s, -C H O), 6.24 (1H, s, -C = C H αHβ), 5.98 (1H, s, -C = CHα H β ), 2.23 (2H, t, J = 7.3 Hz, -C H 2 CH 2 CH 2 CH 3 ), 1.35-1.30 (4H, m, -CH 2 C H 2 C H 2 CH 3 ), 0.90 (3H, t, J = 7.3 Hz, -CH 2 CH 2 CH 2 C H 3 )

2-2- 메틸렌헥타날의Methylene hexanthal 제조(2d) Manufacturing (2d)

상기의 동일한 방법을 사용하여 노란색 액체물질의 2d(44-62%)를 얻었다.Using the same method as above, 2d (44-62%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 9.52 (1H, s, -CHO), 6.23 (1H, s, -C=CHαHβ), 5.97(1H, s, -C=CHαHβ), 2.21 (2H, t, J = 7.8Hz, -CH 2CH2CH2CH2CH3), 1.31-1.25 (6H, m, -CH2CH 2CH 2CH 2CH3), 0.87 (3H, t, J = 6.8Hz, -CH2CH2CH2CH2CH 3)
 1 H-NMR (CDCl 3, 500 MHz) δ 9.52 (1H, s, -C H O), 6.23 (1H, s, -C = C H αHβ), 5.97 (1H, s, -C = CHα H β) , 2.21 (2H, t, J = 7.8 Hz, -C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.31-1.25 (6H, m, -CH 2 C H 2 C H 2 C H 2 CH 3 ), 0.87 (3H, t, J = 6.8 Hz, -CH 2 CH 2 CH 2 CH 2 C H 3 )

2-2- 메틸렌옥타날의Methylene octanal 제조(2e) Manufacture (2e)

상기의 동일한 방법을 사용하여 노란색 액체물질의 2e(65%)를 얻었다.Using the same method as above, 2e (65%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 9.52 (1H, s, -CHO), 6.23 (1H, s, -C=CHαHβ), 5.97 (1H, s, -C=CHαHβ), 2.21 (2H, t, J = 7.8Hz, -CH 2CH2CH2CH2CH2CH3), 1.31-1.25 (8H, m, -CH2CH 2CH 2CH 2CH 2CH3), 0.87 (3H, t, J = 6.8Hz, -CH2CH2CH2CH2CH2CH 3)
 1 H-NMR (CDCl 3, 500 MHz) δ 9.52 (1H, s, -C H O), 6.23 (1H, s, -C = C H αHβ), 5.97 (1H, s, -C = CHα H β) , 2.21 (2H, t, J = 7.8 Hz, -C H 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.31-1.25 (8H, m, -CH 2 C H 2 C H 2 C H 2 C H 2 CH 3 ), 0.87 (3H, t, J = 6.8 Hz, -CH 2 CH 2 CH 2 CH 2 CH 2 C H 3 )

2-2- 메틸렌노네놀의Of methylenenonenol 제조(2f) Manufacture (2f)

상기의 동일한 방법을 사용하여 노란색 액체물질의 2f(44-62%)를 얻었다.Using the same method as above, 2f (44-62%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 9.53 (1H, s, -CHO), 6.24 (1H, s, -C=CHαHβ), 5.98 (1H, s, -C=CHαHβ), 2.22 (2H, t, J = 7.3 Hz, -CH2(CH2)4CH2CH3), 1.43 (2H, m, -CH2(CH2)4CH 2CH3), 1.18-1.30 (8H, m, -CH2(CH 2)4CH2CH3), 0.87 (3H, t, J = 6.8Hz, -CH2(CH2)4CH2CH 3).
 1 H-NMR (CDCl 3, 500 MHz) δ 9.53 (1H, s, -C H O), 6.24 (1H, s, -C = C H αHβ), 5.98 (1H, s, -C = CHα H β) , 2.22 (2H, t, J = 7.3 Hz, -CH 2 (CH 2 ) 4 CH 2 CH 3 ), 1.43 (2H, m, -CH 2 (CH 2 ) 4 C H 2 CH 3 ), 1.18-1.30 (8H, m, -CH 2 (C H 2 ) 4 CH 2 CH 3 ), 0.87 (3H, t, J = 6.8 Hz, -CH 2 (CH 2 ) 4 CH 2 C H 3 ).

2-2- 벤질아크릴알디하이드Benzyl acrylaldehyde (2g)(2 g)

상기의 동일한 방법을 사용하여 노란색 액체물질의 2g (51%)를 얻었다.Using the same method as above, 2 g (51%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 9.56 (1H, s, -CHO), 7.25-7.10 (5H, m, Ar-H), 6.05 (1H, s, -C=CHαHβ), 6.01 (1H, s, -C=CHαHβ), 3.50 (2H, s, Ar-CH 2C=CH2).
 1 H-NMR (CDCl 3 , 500 MHz) δ 9.56 (1H, s, -C H O), 7.25-7.10 (5H, m, Ar- H ), 6.05 (1H, s, -C = C H αHβ) , 6.01 (1H, s, -C = CHα H β), 3.50 (2H, s, Ar-C H 2 C = CH 2 ).

<< 실시예Example 2> 2>

Figure 112011028633390-pat00016

Figure 112011028633390-pat00016

(S)-3-((2S,3S)-3-(S) -3-((2S, 3S) -3- 하이드록시Hydroxy -2,4--2,4- 디메틸펜트Dimethylpent -4--4- 에노일Enoyl )-4-)-4- 이소프로필옥사졸Isopropyl Oxazole 리딘-2-온의 제조(4a)Preparation of Ridin-2-one (4a)

다이클로로메탄 (1.1 ml)에 용해시킨, (R)-(+)4-아이소프로필-3-프로피놀-2-옥사졸리디논 3a (100 mg, 0.541 mmol, 1eq)을 얼음수조에서 빙냉 시킨 후, 1M 다이클로로메탄에 용해되어져 있는 다이부틸보론 트리플로로메탄 썰퍼네이트(596, 0.596 mmo)와 다이아이소프로필에틸아민(90.6, 0.650mmol, 1.2eq)을 천천히 적가하여 같은 온도에서 50분 동안 교반하였다. 교반시킨 반응 혼합물을 영하 78℃에서 10분 동안 냉각시킨 후, 다이클로로메탄 (0.70 ml)에 용해시킨 메틸아크로렌 2a (59.0, 0.704 mmol)를 영하 78℃에서 30분 동안 교반하였다. 그 다음, 다시 얼음수조에서 빙냉 시킨 후 1시간 동안 교반한 후, pH 7.0 포스페이트 (1.2 ml), 메탄올 (1.1 ml), 30%wt 하이드로겐페록싸이드수용액(0.6 ml), 메탄올(1.1 ml)을 차례 대로 첨가하여 반응을 정지시킨다. 다시 얼음수조에서 1시간 더 교반시킨 후 다이클로로메탄과 물을 넣어 분리하여, 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (18 % n-헥산:에틸아세테이트)하여 물질을 분리하고 건조시켜 노란색 액체물질 4a (68mg, 49%)을 얻었다. (R)-(+) 4-isopropyl-3-propynol-2-oxazolidinone 3a (100 mg, 0.541 mmol, 1eq), dissolved in dichloromethane (1.1 ml), was ice-cooled in an ice bath. , Dibutylboron trichloromethane sulfonate (596, 0.596 mmo) and diisopropylethylamine (90.6, 0.650 mmol, 1.2eq) dissolved in 1M dichloromethane were slowly added dropwise and stirred for 50 minutes at the same temperature. It was. The stirred reaction mixture was cooled at minus 78 ° C. for 10 min, then methylacroene 2a (59.0, 0.704 mmol) dissolved in dichloromethane (0.70 ml) was stirred at minus 78 ° C. for 30 min. Then, ice-cold again in an ice bath and stirred for 1 hour, and then pH 7.0 phosphate (1.2 ml), methanol (1.1 ml), 30% wt hydrogen peroxide solution (0.6 ml), and methanol (1.1 ml) were added thereto. Add in order to stop the reaction. After further stirring for 1 hour in an ice bath, dichloromethane and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (18% n-hexane: ethyl acetate) to separate the material and dried to obtain a yellow liquid material 4a (68 mg, 49%).

1H-NMR (CDCl3, 500 MHz) δ 5.12 (1H, s, -C=CHαHβ), 4.97 (1H, s, -C=CHαHβ), 4.48 (1H, m, -OCHαHβCHN), 4.40 (1H, brs, -CH(OH)), 4.30 (1H, dd, J = 17.1, 8.3 Hz, -OCHαHβCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβCHN), 3.97 (1H, dq, J = 7.3, 2.9 Hz, -CH(CH3)CH(OH)-), 3.11 (1H, brs, J = 2.4 Hz, -OH), 2.39-2.32 (1H, m, -CH(CH3)2), 1.72 (s, 3H, -C(=CH)CH 3), 1.18 (3H, d, J = 6.8Hz, -CH(CH 3)CH(OH)-), 0.92 (3H, d, J = 6.8Hz, -CH(CH 3)2), 0.89 (3H, d, J = 6.8Hz, -CH(CH 3)2).
 1 H-NMR (CDCl 3 , 500 MHz) δ 5.12 (1H, s, -C = C H αHβ), 4.97 (1H, s, -C = CHα H β), 4.48 (1H, m, -OC H αHβCHN ), 4.40 (1H, brs, -C H (OH)), 4.30 (1H, dd, J = 17.1, 8.3 Hz, -OCHα H βCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβC H N), 3.97 (1H, dq, J = 7.3, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 3.11 (1H, brs, J = 2.4 Hz, -O H ), 2.39-2.32 (1H, m, -C H (CH 3 ) 2 ), 1.72 (s, 3H, -C (= CH) C H 3 ), 1.18 (3H, d, J = 6.8 Hz, -CH (C H 3 ) CH (OH) —), 0.92 (3H, d, J = 6.8 Hz, —CH (C H 3 ) 2 ), 0.89 (3H, d, J = 6.8 Hz, —CH (C H 3 ) 2 ).

(S)-3-((2S,3S)-3-(S) -3-((2S, 3S) -3- 하이드록시Hydroxy -2,5-디메틸-4--2,5-dimethyl-4- 메틸렌헥사노일Methylenehexanoyl )-4-)-4- 이소프로필옥Isopropyl jade 사졸리딘-2-온의 제조(4b)Preparation of Sazolidin-2-one (4b)

상기의 동일한 방법을 사용하여 노란색 액체물질의 4b (43%)를 얻었다.Using the same method as above, 4b (43%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 5.19 (1H, s, -C=CHαHβ), 5.04 (1H, s, -C=CHαHβ), 4.48 (1H, m, -OCHαHβCHN), 4.46 (1H, brs, -CH(OH)), 4.30 (1H, dd, J = 17.1, 8.3 Hz, -OCHαH βCHN), 4.22 (1H, dd, J = 9.2, 2.9 Hz, -OCHαHβCHN), 3.96 (1H, dq, J = 6.8, 2.9 Hz, -CH(CH3)CH(OH)-), 3.08 (1H, brs, -OH), 2.38-2.32 (1H, m, -CH(CH3)2), 2.18-2.13 (1H, m, -C(=CH)CH(CH3)2), 1.19 (3H, d, J = 6.8Hz, -CH(CH 3)CH(OH)-), 1.09 (3H, d, J = 6.3 Hz, -C(=CH)CH(CH 3)2), 1.05 (3H, d, J = 6.8Hz, -C(=CH)CH(CH 3)2), 0.93 (3H, d, J = 6.8Hz, -CH(CH 3)2), 0.89 (3H, d, J = 7.3Hz, -CH(CH 3)2).
 1 H-NMR (CDCl 3, 500 MHz) δ 5.19 (1H, s, -C = C H αHβ), 5.04 (1H, s, -C = CHα H β), 4.48 (1H, m, -OC H αH β CHN), 4.46 (1H, brs, -C H (OH)), 4.30 (1H, dd, J = 17.1, 8.3 Hz, -OCHα H β CHN), 4.22 (1H, dd, J = 9.2, 2.9 Hz, -OCHαH β C H N), 3.96 (1H, dq, J = 6.8, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 3.08 (1H, brs, -O H ), 2.38-2.32 ( 1H, m, -C H (CH 3 ) 2 ), 2.18-2.13 (1H, m, -C (= CH) C H (CH 3 ) 2 ), 1.19 (3H, d, J = 6.8 Hz, -CH (C H 3 ) CH (OH)-), 1.09 (3H, d, J = 6.3 Hz, -C (= CH) CH (C H 3 ) 2 ), 1.05 (3H, d, J = 6.8 Hz,- C (= CH) CH (C H 3 ) 2 ), 0.93 (3H, d, J = 6.8 Hz, -CH (C H 3 ) 2 ), 0.89 (3H, d, J = 7.3 Hz, -CH (C H 3 ) 2 ).

(S)-3-((2S,3S)-3-(S) -3-((2S, 3S) -3- 하이드록시Hydroxy -2--2- 메틸methyl -4--4- 메틸렌옥타노일Methyleneoctanoyl )-4-)-4- 이소프로필옥사졸Isopropyl Oxazole 리딘-2-온의 제조(4c)Preparation of Ridin-2-one (4c)

상기의 동일한 방법을 사용하여 노란색 액체물질의 4c (16%)를 얻었다.Using the same method as above, 4c (16%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 5.16 (1H, s, -C=CHαHβ), 4.97 (1H, s, -C=CHαH β), 4.46 (1H, m, -OCHαHβCHN), 4.41 (1H, brs, -CH(OH)), 4.28 (1H, dd, J = 17.6, 9.2 Hz, -OCHαH βCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβCHN), 3.95 (1H, dq, J = 6.8, 2.9 Hz, -CH(CH3)CH(OH)-), 3.13 (1H, brs, -OH), 2.38-2.33 (1H, m, -CH(CH3)2), 1.98 (2H, m, -C(=CH)CH 2CH2CH2CH3), 1.46-1.40 (2H, m, -C(=CH)CH2CH 2CH2CH3), 1.35-1.23 (2H, m, -C(=CH)CH2CH2CH 2CH3), 1.17 (3H, d, J = 6.8Hz, -CH(CH 3)CH(OH)-), 0.91 (3H, d, J = 6.8Hz, -CH(CH 3)2), 0.87 (3H, d, J = 7.3Hz, -CH(CH 3)2), 0.86 (3H, d, J = 7.3Hz, -CH(CH 3)2), 0.85 (3H, t, J = 5.6Hz, -C(=CH)CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz) δ 5.16 (1H, s, -C = C H αHβ), 4.97 (1H, s, -C = CHα H β ), 4.46 (1H, m, -OC H αH β CHN), 4.41 (1H, brs, -C H (OH)), 4.28 (1H, dd, J = 17.6, 9.2 Hz, -OCHα H β CHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz , -OCHαH β C H N), 3.95 (1H, dq, J = 6.8, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 3.13 (1H, brs, -O H ), 2.38-2.33 (1H, m, -C H (CH 3 ) 2 ), 1.98 (2H, m, -C (= CH) C H 2 CH 2 CH 2 CH 3 ), 1.46-1.40 (2H, m, -C (= CH) CH 2 C H 2 CH 2 CH 3 ), 1.35-1.23 (2H, m, -C (= CH) CH 2 CH 2 C H 2 CH 3 ), 1.17 (3H, d, J = 6.8 Hz,- CH (C H 3 ) CH (OH)-), 0.91 (3H, d, J = 6.8 Hz, -CH (C H 3 ) 2 ), 0.87 (3H, d, J = 7.3 Hz, -CH (C H 3 ) 2 ), 0.86 (3H, d, J = 7.3 Hz, -CH (C H 3 ) 2 ), 0.85 (3H, t, J = 5.6 Hz, -C (= CH) CH 2 CH 2 CH 2 C H 3 ).

(S)-3-((2S,3S)-3-(S) -3-((2S, 3S) -3- 하이드록시Hydroxy -2--2- 메틸methyl -4--4- 메틸렌노나노일Methylenenonanoyl )-4-)-4- 이소프로필옥사졸Isopropyl Oxazole 리딘-2-온의 제조(4d)Preparation of Ridin-2-one (4d)

상기의 동일한 방법을 사용하여 노란색 액체물질의 4d (84%)를 얻었다.Using the same method as above, 4d (84%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz δ 5.18 (1H, s, -C=CHαHβ), 4.99 (1H, s, -C=CHαHβ), 4.50-4.47 (1H, m, -OCHαHβCHN), 4.42 (1H, brs, -CH(OH)), 4.28 (1H, dd, J = 17.4, 9.0 Hz, -OCHαHβCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβCHN), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -CH(CH3)CH(OH)-), 3.15 (1H, brs, -OH), 2.39-2.33 (1H, m, -CH(CH3)2), 2.04-1.90 (2H, m, -C(=CH)CH 2CH2CH2CH2CH3), 1.49-1.43 (2H, m, -C(=CH)CH2CH 2CH2CH2CH3), 1.34-1.28 (4H, m, -C(=CH)CH2CH2CH 2CH 2CH3), 1.18 (3H, d, J = 7.3Hz, -CH(CH 3)CH(OH)-), 0.93 (3H, d, J = 7.1 Hz, -CH(CH 3)2), 0.88 (3H, d, J = 7.1 Hz, -CH(CH 3)2), 0.88 (3H, t, J = 5.4 Hz, -C(=CH)CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz δ 5.18 (1H, s, -C = C H αHβ), 4.99 (1H, s, -C = CHα H β), 4.50-4.47 (1H, m, -OC H αHβCHN), 4.42 (1H, brs, -C H (OH)), 4.28 (1H, dd, J = 17.4, 9.0 Hz, -OCHα H βCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz,- OCHαH β C H N), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 3.15 (1H, brs, -O H ), 2.39-2.33 (1H , m, -C H (CH 3 ) 2 ), 2.04-1.90 (2H, m, -C (= CH) C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.49-1.43 (2H, m, -C (= CH) CH 2 C H 2 CH 2 CH 2 CH 3 ), 1.34-1.28 (4H, m, -C (= CH) CH 2 CH 2 C H 2 C H 2 CH 3 ), 1.18 (3H, d , J = 7.3 Hz, -CH (C H 3 ) CH (OH)-), 0.93 (3H, d, J = 7.1 Hz, -CH (C H 3 ) 2 ), 0.88 (3H, d, J = 7.1 Hz, -CH (C H 3 ) 2 ), 0.88 (3H, t, J = 5.4 Hz, -C (= CH) CH 2 CH 2 CH 2 CH 2 C H 3 ).

(S)-3-((2S,3S)-3-(S) -3-((2S, 3S) -3- 하이드록시Hydroxy -2--2- 메틸methyl -4--4- 메틸렌데카노일Methylenedecanoyl )-4-)-4- 이소프로필옥사졸Isopropyl Oxazole 리딘-2-온의 제조(4e)Preparation of Ridin-2-one (4e)

상기의 동일한 방법을 사용하여 노란색 액체물질의 4e (87%)를 얻었다.Using the same method as above, 4e (87%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) δ 5.18 (1H, s, -C=CHαHβ), 4.99 (1H, s, -C=CHαHβ), 4.50-4.47 (1H, m, -OCHαHβCHN), 4.42 (1H, brs, -CH(OH)), 4.28 (1H, dd, J = 17.4, 9.0 Hz, -OCHαHβCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβCHN), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -CH(CH3)CH(OH)-), 3.15 (1H, brs, -OH), 2.39-2.33 (1H, m, -CH(CH3)2), 2.04-1.90 (2H, m, -C(=CH)CH 2CH2CH2CH2CH2CH3), 1.49-1.43 (2H, m, -C(=CH)CH2CH 2CH2CH2CH2CH3), 1.34-1.28 (6H, m, -C(=CH)CH2CH2CH 2CH 2CH 2CH3), 1.18 (3H, d, J = 7.3Hz, -CH(CH 3)CH(OH)-), 0.93 (3H, d, J = 7.1 Hz, -CH(CH3)2), 0.88 (3H, d, J = 7.1 Hz, -CH(CH 3)2), 0.88 (3H, t, J = 5.4 Hz, -C(=CH)CH2CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz) δ 5.18 (1H, s, -C = C H αHβ), 4.99 (1H, s, -C = CHα H β), 4.50-4.47 (1H, m, -OC H αHβCHN), 4.42 (1H, brs, -C H (OH)), 4.28 (1H, dd, J = 17.4, 9.0 Hz, -OCHα H βCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαH β C H N), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 3.15 (1H, brs, -O H ), 2.39-2.33 ( 1H, m, -C H (CH 3 ) 2 ), 2.04-1.90 (2H, m, -C (= CH) C H 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.49-1.43 (2H, m , -C (= CH) CH 2 C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.34-1.28 (6H, m, -C (= CH) CH 2 CH 2 C H 2 C H 2 C H 2 CH 3 ), 1.18 (3H, d, J = 7.3 Hz, -CH (C H 3 ) CH (OH)-), 0.93 (3H, d, J = 7.1 Hz, -CH (CH 3 ) 2 ), 0.88 ( 3H, d, J = 7.1 Hz, -CH (C H 3 ) 2 ), 0.88 (3H, t, J = 5.4 Hz, -C (= CH) CH 2 CH 2 CH 2 CH 2 CH 2 C H 3 ) .

(S)-3-((2S,3S)-3-(S) -3-((2S, 3S) -3- 하이드록시Hydroxy -2--2- 메틸methyl -4--4- 메틸렌운데카노일Methylene undecanoyl )-4-)-4- 이소프로필옥사Isopropyloxa 졸리딘-2-온의 제조(4f)Preparation of zolidin-2-one (4f)

상기의 동일한 방법을 사용하여 노란색 액체물질의 4f (41%)를 얻었다.Using the same method as above, 4f (41%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 400 MHz) δ 5.18 (1H, s, -C=CHαHβ), 4.99 (1H, s, -C=CHαHβ), 4.50-4.46 (1H, m, -OCHαHβCHN), 4.42 (1H, brs, -CH(OH)), 4.30 (1H, dd, J = 17.4, 9.1 Hz, -OCHαH βCHN), 4.23 (1H, dd, J = 9.1, 3.1 Hz, -OCHαHβCHN), 3.95 (1H, dq, J = 7.1, 2.8 Hz, -CH(CH3)CH(OH)-), 3.12 (1H, brs, -OH), 2.37-2.33 (1H, m, -CH(CH3)2), 1.95 (2H, m, -C(=CH)CH 2(CH2)5CH3), 1.19-1.26 (10H, m, -C(=CH)CH2(CH 2)5CH3), 1.18 (3H, d, J = 7.1 Hz, -CH(CH 3)CH(OH)-), 0.93 (3H, d, J = 7.0 Hz, -CH(CH 3)2), 0.89 (3H, d, J = 6.72 Hz, -CH(CH 3)2), 0.86 (3H, t, J = 5.8 Hz, -C(=CH)CH2(CH2)5CH 3).
 1 H-NMR (CDCl 3 , 400 MHz) δ 5.18 (1H, s, -C = C H αHβ), 4.99 (1H, s, -C = CHα H β), 4.50-4.46 (1H, m, -OC H αH β CHN), 4.42 (1H, brs, -C H (OH)), 4.30 (1H, dd, J = 17.4, 9.1 Hz, -OCHα H β CHN), 4.23 (1H, dd, J = 9.1, 3.1 Hz, -OCHαH β C H N), 3.95 (1H, dq, J = 7.1, 2.8 Hz, -C H (CH 3 ) CH (OH)-), 3.12 (1H, brs, -O H ), 2.37 -2.33 (1H, m, -CH (CH3) 2), 1.95 (2H, m, -C (= CH) C H 2 (CH 2 ) 5 CH 3 ), 1.19-1.26 (10H, m, -C ( = CH) CH 2 (C H 2 ) 5 CH 3 ), 1.18 (3H, d, J = 7.1 Hz, -CH (C H 3 ) CH (OH)-), 0.93 (3H, d, J = 7.0 Hz , -CH (C H 3 ) 2 ), 0.89 (3H, d, J = 6.72 Hz, -CH (C H 3 ) 2 ), 0.86 (3H, t, J = 5.8 Hz, -C (= CH) CH 2 (CH 2 ) 5 C H 3 ).

(S)-3-((2S,3S)-4-벤질-3-(S) -3-((2S, 3S) -4-benzyl-3- 하이드록시Hydroxy -2--2- 메틸펜트Methylpent -4--4- 에노일Enoyl )-4-)-4- 이소프로필옥Isopropyl jade 사졸리딘-2-온의 제조(4g)Preparation of Sazolidin-2-one (4 g)

상기의 동일한 방법을 사용하여 노란색 액체물질의 4g(72%)를 얻었다.Using the same method as above, 4 g (72%) of a yellow liquid material was obtained.

1H-NMR (CDCl3, 500 MHz) : δ 7.28 ( 5H, m, Ar-H), 5.33 (1H, s, -C=CHαHβ), 4.98 (1H, s, -C=CHαH β), 4.42-4.41 (1H, m, -OCHαHβCHN), 4.39 (1H, d, J=3.3Hz, -CH(OH)), 4.25 (1H, dd, J=9.0,8.3Hz, -OCHαH βCHN), 4.19 (1H,dd,J=9.0,3.2Hz,-OCHαHβCHN), 4.01 (3H, dq, J=7.1,3.0Hz, -CH(CH3)CH(OH)-), 3.44 (1H, d, J=15.4Hz, -C(=CH)CHαHβPh), 3.30 (1H, d, J=15.4Hz, -C(=CH)CHαH βPh), 3.14 (1H, brs, -OH) ,2.35-2.29 (1H, m, -CH(CH3)2), 1.22 (3H, d, J=7.1Hz, -CH(CH 3)CH(OH)-), 0.91(3H, d, J=7.1Hz,-CH(CH 3)2), 0.87 (3H, d, J=6.8Hz, -CH(CH 3)2).
 1 H-NMR (CDCl 3 , 500 MHz): δ 7.28 (5H, m, Ar- H ), 5.33 (1H, s, -C = C H αH β ), 4.98 (1H, s, -C = CHα H β ), 4.42-4.41 (1H, m, -OC H αH β CHN), 4.39 (1H, d, J = 3.3 Hz, -C H (OH)), 4.25 (1H, dd, J = 9.0,8.3 Hz , -OCHα H β CHN), 4.19 (1H, dd, J = 9.0,3.2Hz, -OCHαH β C H N), 4.01 (3H, dq, J = 7.1,3.0Hz, -C H (CH 3 ) CH (OH)-), 3.44 (1H, d, J = 15.4 Hz, -C (= CH) C H αH β Ph), 3.30 (1H, d, J = 15.4 Hz, -C (= CH) CHα H β Ph), 3.14 (1H, brs, -O H ), 2.35-2.29 (1H, m, -C H (CH 3 ) 2 ), 1.22 (3H, d, J = 7.1 Hz, -CH (C H 3 ) CH (OH)-), 0.91 (3H, d, J = 7.1 Hz, -CH (C H 3 ) 2 ), 0.87 (3H, d, J = 6.8 Hz, -CH (C H 3 ) 2 ).

<< 실시예Example 3> 3>

Figure 112011028633390-pat00017

Figure 112011028633390-pat00017

다이클로로메탄 (1.5 ml)에 용해시킨, (R)-(+)4-아이소프로필-3-프로피놀-2-옥사졸리디논 3a (100 mg, 0.541 mmol, 1 eq)을 얼음수조에서 빙냉 시킨 후, 1M 다이클로로메탄에 용해되어져 있는 다이부틸보론 트리플로로메탄 썰퍼네이트 (596 , 0.596 mmo)와 다이아이소프로필에틸아민 (90.6 , 0.650 mmol, 1.2 eq) 을 천천히 적가하여 같은 온도에서 50분 동안 교반하였다. 교반시킨 반응 혼합물을 영하 78℃ 에서 10분 동안 냉각시킨 후, 다이클로로메탄 (0.70 ml)에 용해시킨 1-싸이클로헥센 카복실알디하이드 2h (92.25, 0.81 mmol)를 영하 78℃에서 30분 동안 교반하였다. 그 다음, 다시 얼음수조에서 빙냉 시킨 후 1시간 동안 교반한 후, pH 7.0 포스페이트 (1.2 ml), 메탄올 (1.1 ml), 30%wt 하이드로겐페록싸이드수용액 (0.6 ml), 메탄올(1.1 ml)을 차례대로 첨가하여 반응을 정지시킨다. 다시 얼음수조에서 1시간 더 교반시킨 후 다이클로로메탄과 물을 넣어 분리하여, 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (18 % n-헥산:에틸아세테이트)하여 물질을 분리하고 건조시켜 노란색 액체물질 4h (22.3 mg 14.8 %)를 얻었다.(R)-(+) 4-isopropyl-3-propynol-2-oxazolidinone 3a (100 mg, 0.541 mmol, 1 eq) dissolved in dichloromethane (1.5 ml) was ice-cooled in an ice bath. Then, dibutylboron trichloromethane sulfonate (596, 0.596 mmo) and diisopropylethylamine (90.6, 0.650 mmol, 1.2 eq) dissolved in 1M dichloromethane were slowly added dropwise for 50 minutes at the same temperature. Stirred. The stirred reaction mixture was cooled at minus 78 ° C. for 10 min, then 1-cyclohexene carboxyaldihydride 2h (92.25, 0.81 mmol) dissolved in dichloromethane (0.70 ml) was stirred at minus 78 ° C. for 30 min. . Then, ice-cold again in an ice bath and stirred for 1 hour, and then pH 7.0 phosphate (1.2 ml), methanol (1.1 ml), 30% wt hydrogen peroxide solution (0.6 ml), and methanol (1.1 ml) were added thereto. The reaction is stopped by addition in order. After further stirring for 1 hour in an ice bath, dichloromethane and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (18% n-hexane: ethyl acetate) to separate the material and dried to obtain a yellow liquid 4h (22.3 mg 14.8%).

1H-NMR (CDCl3, 500 MHz) δ 5.81 (1H, t, J = 3. 4 Hz ,Cyclo = (CH2)), 4.50-4.47 (1H, m, -OCHαHβCHN), 4.42 (1H, brs, -CH(OH)), 4.28 (1H, dd, J = 17.4, 9.0 Hz, -OCHαHβCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβCHN), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -CH(CH3)CH(OH)-), 2.93 (1H, brs, -OH), 2.40-2.33 (1H, m, -CH(CH3)2), 2.07-2.05 (2H, m, -Cyclo(CH 2)), 1.927 (2H, t, J = 17.60 Hz, -Cyclo(CH 2)), 1.67-1.55 (4H, m, -Cyclo(CH 2CH 2), 1.18 (3H, d, J = 7.3 Hz, -CH(CH 3)CH(OH)-), 0.93 (3H, d, J = 7.1 Hz, -CH(CH 3)2), 0.88 (3H, d, J = 7.1 Hz, -CH(CH 3)2).
 1 H-NMR (CDCl 3 , 500 MHz) δ 5.81 (1H, t, J = 3. 4 Hz, Cyclo = (CH 2 )), 4.50-4.47 (1H, m, -OC H αHβCHN), 4.42 (1H , brs, -C H (OH)), 4.28 (1H, dd, J = 17.4, 9.0 Hz, -OCHα H βCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαH β C H N) , 3.95 (1H, dq, J = 7.3, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 2.93 (1H, brs, -O H ), 2.40-2.33 (1H, m, -C H (CH 3 ) 2 ), 2.07-2.05 (2H, m, -Cyclo (C H 2 )), 1.927 (2H, t, J = 17.60 Hz, -Cyclo (C H 2 )), 1.67-1.55 (4H, m, -Cyclo (C H 2 C H 2 ), 1.18 (3H, d, J = 7.3 Hz, -CH (C H 3 ) CH (OH)-), 0.93 (3H, d, J = 7.1 Hz,- CH (C H 3 ) 2 ), 0.88 (3H, d, J = 7.1 Hz, -CH (C H 3 ) 2 ).

<< 실시예Example 4> 4>

Figure 112011028633390-pat00018
Figure 112011028633390-pat00018

다이클로로메탄 (2.0 ml)에 용해시킨, (R)-(-)4-아이소프로필-3-프로피놀-2-옥사졸리디논 3b (100 mg, 0.541 mmol, 1 eq)을 얼음수조에서 빙냉 시킨 후, 1M 다이클로로메탄에 용해되어져 있는 다이부틸보론 트리플로로메탄 썰퍼네이트 (596 , 0.596 mmo)와 다이아이소프로필에틸아민 (90.6 , 0.650 mmol, 1.2 eq) 을 천천히 적가하여 같은 온도에서 50분 동안 교반하였다. 교반 시킨 반응 혼합물을 영하 78℃에서 10분 동안 냉각시킨 후, 다이클로로메탄 (0.70 ml)에 용해시킨 2-메틸렌헵탈 2d (68.14 , 1.07 mmol)를 영하 78℃에서 30분 동안 교반하였다. 그 다음, 다시 얼음수조에서 빙냉 시킨 후 1시간 동안 교반한 후, pH 7.0 포스페이트 (0.1 ml), 메탄올 (0.2 ml), 30%wt 하이드로겐페록싸이드수용액(0.2 ml), 메탄올(0.2 ml)을 차례대로 첨가하여 반응을 정지시킨다. 다시 얼음수조에서 1시간 더 교반시킨 후 다이클로로메탄과 물을 넣어 분리하여, 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (15 % n-헥산:에틸아세테이트)하여 물질을 분리하고 건조시켜 노란색 액체물질 5 (146.3 mg 87.2 %)를 얻었다.(R)-(-) 4-isopropyl-3-propynol-2-oxazolidinone 3b (100 mg, 0.541 mmol, 1 eq) dissolved in dichloromethane (2.0 ml) was ice-cooled in an ice bath. Then, dibutylboron trichloromethane sulfonate (596, 0.596 mmo) and diisopropylethylamine (90.6, 0.650 mmol, 1.2 eq) dissolved in 1M dichloromethane were slowly added dropwise for 50 minutes at the same temperature. Stirred. The stirred reaction mixture was cooled at minus 78 ° C. for 10 min, then 2-methyleneheptal 2d (68.14, 1.07 mmol) dissolved in dichloromethane (0.70 ml) was stirred at minus 78 ° C. for 30 min. Then, ice-cold again in an ice bath and stirred for 1 hour, and then pH 7.0 phosphate (0.1 ml), methanol (0.2 ml), 30% wt hydrogen peroxide solution (0.2 ml) and methanol (0.2 ml) were added. The reaction is stopped by addition in order. After further stirring for 1 hour in an ice bath, dichloromethane and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (15% n-hexane: ethyl acetate) to separate the substance and dried to obtain a yellow liquid substance 5 (146.3 mg 87.2%).

1H-NMR (CDCl3, 500 MHz) δ 5.18 (1H, s, -C=CHαHβ), 4.99 (1H, s, -C=CHαHβ), 4.50-4.47 (1H, m, -OCHαHβCHN), 4.42 (1H, brs, -CH(OH)), 4.28(1H, dd, J = 17.4,9.0 Hz, -OCHαHβCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαHβCHN), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -CH(CH3)CH(OH)-), 3.15 (1H, brs, -OH), 2.39-2.33 (1H, m, -CH(CH3)2), 2.04-1.90 (2H, m, -C(=CH)CH 2CH2CH2CH2CH3), 1.49-1.43 (2H, m, -C(=CH)CH2CH 2CH2CH2CH3), 1.34-1.28 (4H, m, -C(=CH)CH2CH2CH 2CH 2CH3), 1.18 (3H, d, J = 7.3Hz, -CH(CH 3)CH(OH)-), 0.93 (3H, d, J = 7.1Hz, -CH(CH3)2), 0.88 (3H, d, J=7.1Hz,-CH(CH 3)2), 0.88 (3H, t, J = 5.4 Hz, -C(=CH)CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz) δ 5.18 (1H, s, -C = C H αHβ), 4.99 (1H, s, -C = CHα H β), 4.50-4.47 (1H, m, -OC H αHβCHN), 4.42 (1H, brs, -C H (OH)), 4.28 (1H, dd, J = 17.4,9.0 Hz, -OCHα H βCHN), 4.22 (1H, dd, J = 9.3, 2.9 Hz, -OCHαH β C H N), 3.95 (1H, dq, J = 7.3, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 3.15 (1H, brs, -O H ), 2.39-2.33 ( 1H, m, -C H (CH 3 ) 2 ), 2.04-1.90 (2H, m, -C (= CH) C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.49-1.43 (2H, m,- C (= CH) CH 2 C H 2 CH 2 CH 2 CH 3 ), 1.34-1.28 (4H, m, -C (= CH) CH 2 CH 2 C H 2 C H 2 CH 3 ), 1.18 (3H, d, J = 7.3 Hz, -CH (C H 3 ) CH (OH)-), 0.93 (3H, d, J = 7.1 Hz, -CH (CH 3 ) 2 ), 0.88 (3H, d, J = 7.1 Hz, -CH (C H 3 ) 2 ), 0.88 (3H, t, J = 5.4 Hz, -C (= CH) CH 2 CH 2 CH 2 CH 2 C H 3 ).

<< 실시예Example 5>  5>

Figure 112011028633390-pat00019
Figure 112011028633390-pat00019

다이클로로메탄 (1.5 ml)에 용해 시킨, (R)-4-벤질-3-프로피오닐옥사졸리딘-2-온 6 (100 mg, 0.43 mmol, 1 eq)을 얼음수조에서 빙냉 시킨 후, 1M 다이클로로메탄에 용해되어져 있는 다이부틸보론 트리플로로메탄 썰퍼네이트 (515 , 0.51 mmol)와 다이아이소프로필에틸아민 (104 , 0.60 mmol, 1.4 eq) 을 천천히 적가 하여 같은 온도에서 50분 동안 교반하였다. 교반 시킨 반응 혼합물을 영하 78℃에서 10분 동안 냉각시킨 후, 다이클로로메탄 (0.70 ml)에 용해시킨 2-메틸렌헵탈 2d (68.14 , 1.07 mmol)를 영하 78℃에서 30분 동안 교반하였다. 그 다음, 다시 얼음수조에서 빙냉 시킨 후 1시간 동안 교반한 후, pH 7.0 포스페이트 (0.1 ml), 메탄올 (0.2 ml), 30%wt 하이드로겐페록싸이드수용액 (0.2 ml), 메탄올 (0.2 ml)을 차례대로 첨가하여 반응을 정지시킨다. 다시 얼음수조에서 1시간 더 교반시킨 후 다이클로로메탄과 물을 넣어 분리하여, 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (18 % n-헥산:에틸아세테이트)하여 물질을 분리여 건조시켜 노란색 액체물질 7a (105mg, 68%)를 얻었다.(R) -4-benzyl-3-propionyloxazolidin-2-one 6 (100 mg, 0.43 mmol, 1 eq) dissolved in dichloromethane (1.5 ml) was ice-cooled in an ice bath, then 1M. Dibutylboron trichloromethane sulfonate (515, 0.51 mmol) and diisopropylethylamine (104, 0.60 mmol, 1.4 eq) dissolved in dichloromethane were slowly added dropwise and stirred at the same temperature for 50 minutes. The stirred reaction mixture was cooled at minus 78 ° C. for 10 min, then 2-methyleneheptal 2d (68.14, 1.07 mmol) dissolved in dichloromethane (0.70 ml) was stirred at minus 78 ° C. for 30 min. Then, ice-cold again in an ice bath and stirred for 1 hour, and then pH 7.0 phosphate (0.1 ml), methanol (0.2 ml), 30% wt hydrogen peroxide solution (0.2 ml) and methanol (0.2 ml) were added. The reaction is stopped by addition in order. After further stirring for 1 hour in an ice bath, dichloromethane and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (18% n-hexane: ethyl acetate) to obtain a yellow liquid material 7a (105 mg, 68%).

1H-NMR (CDCl3, 500 MHz) δ 7.36-7.33 (2H, m, Ar-H), 7.30-7.27 (1H, m, Ar-H), 7.22-7.21 (2H, m, Ar-H), 5.19 (1H, s, -C=CHαHβ), 5.00 (1H, s, -C=CHαH β), 4.74-4.69 (1H, m, -OCHαHβCHN), 4.45 (1H, brs, -CH(OH)), 4.23 (2H, m, PhCH 2-), 3.96 (1H, dd, J = 10.2, 3.4 Hz, -OCHαHβCHN), 3.27 (1H, dd, J = 13.2, 3.4 Hz, -OCHαH βCHN), 3.01 (1H, brs, -OH), 2.81 (1H, dd, J = 13.2, 9.2 Hz, -CH(CH3)CH(OH)-), 2.00 (2H, m, -C(=CH)CH 2(CH2)2CH2CH3), 1.48 (2H, m, -C(=CH)CH2(CH2)2CH 2CH3), 1.32 (4H, m, -C(=CH)CH2(CH 2)2CH2CH3), 1.20 (3H, d, J = 6.8 Hz, -CH(CH 3)CH(OH)-), 0.90 (3H, t, J = 6.8Hz, -C(=CH)CH2(CH2)2CH2CH 3)
 1 H-NMR (CDCl 3 , 500 MHz) δ 7.36-7.33 (2H, m, Ar- H ), 7.30-7.27 (1H, m, Ar- H ), 7.22-7.21 (2H, m, Ar- H ) , 5.19 (1H, s, -C = C H αH β ), 5.00 (1H, s, -C = CHα H β ), 4.74-4.69 (1H, m, -OC H αH β CHN), 4.45 (1H, brs, -C H (OH)), 4.23 (2H, m, PhC H 2- ), 3.96 (1H, dd, J = 10.2, 3.4 Hz, -OCHαH β C H N), 3.27 (1H, dd, J = 13.2, 3.4 Hz, -OCHα H β CHN), 3.01 (1H, brs, -OH), 2.81 (1H, dd, J = 13.2, 9.2 Hz, -C H (CH 3 ) CH (OH)-), 2.00 (2H, m, -C (= CH) C H 2 (CH 2 ) 2 CH 2 CH 3 ), 1.48 (2H, m, -C (= CH) CH 2 (CH 2 ) 2 C H 2 CH 3 ), 1.32 (4H, m, -C (= CH) CH 2 (C H 2 ) 2 CH 2 CH 3 ), 1.20 (3H, d, J = 6.8 Hz, -CH (C H 3 ) CH (OH) -), 0.90 (3H, t, J = 6.8 Hz, -C (= CH) CH 2 (CH 2 ) 2 CH 2 C H 3 )

실시예5에서 얻은 잔사를 실리카켈컬럼크로마토그래피(18 % n-헥산:에틸아세테이트)에서 7a를 얻은 뒤, (12 % n-헥산:에틸아세테이트)에 7b (21mg, 14%)를 얻었다. The residue obtained in Example 5 was obtained 7a by silica gel column chromatography (18% n-hexane: ethyl acetate), and then 7b (21 mg, 14%) was obtained in (12% n-hexane: ethyl acetate).

1H-NMR (CDCl3, 500 MHz) : δ7.36-7.33 (2H, m, Ar-H), 7.30-7.27 (1H, m, Ar-H), 7.22-7.21 (2H, m, Ar-H), 5.19 (1H, s, -C=CHαHβ), 5.00 (1H, s, -C=CHαH β), 4.74-4.69 (1H, m, -OCHαHβCHN), 4.45 (1H, brs, -CH(OH)), 4.26-4.19 (2H, m, PhCH 2-), 3.95 (1H, dd, J=10.2, 3.4 Hz, -OCHαHβCHN), 3.27 (1H, dd, J = 13.7, 3.6 Hz, -OCHαH βCHN), 3.01 (1H, brs, -OH), 2.81 (1H, dd, J=13.2, 9.8 Hz, -CH(CH3)CH(OH)-), 2.00 (2H, m, -C(=CH)CH 2(CH2)2CH2CH3), 1.48 (2H, m, -C(=CH)CH2(CH2)2CH 2CH3), 1.32 (4H, m, -C(=CH)CH2(CH 2)2CH2CH3), 1.20 (3H, d, J = 6.8 Hz, -CH(CH 3)CH(OH)-), 0.90 (3H, t, J = 6.8 Hz, -C(=CH)CH2(CH2)2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ7.36-7.33 (2H, m, Ar- H ), 7.30-7.27 (1H, m, Ar- H ), 7.22-7.21 (2H, m, Ar- H ), 5.19 (1H, s, -C = C H αH β ), 5.00 (1H, s, -C = CHα H β ), 4.74-4.69 (1H, m, -OC H αH β CHN), 4.45 ( 1H, brs, -C H (OH)), 4.26-4.19 (2H, m, PhC H 2- ), 3.95 (1H, dd, J = 10.2, 3.4 Hz, -OCHαH β C H N), 3.27 (1H , dd, J = 13.7, 3.6 Hz, -OCHα H β CHN), 3.01 (1H, brs, -O H ), 2.81 (1H, dd, J = 13.2, 9.8 Hz, -C H (CH 3 ) CH ( OH)-), 2.00 (2H, m, -C (= CH) C H 2 (CH 2 ) 2 CH 2 CH 3 ), 1.48 (2H, m, -C (= CH) CH 2 (CH 2 ) 2 C H 2 CH 3 ), 1.32 (4H, m, -C (= CH) CH 2 (C H 2 ) 2 CH 2 CH 3 ), 1.20 (3H, d, J = 6.8 Hz, -CH (C H 3 ) CH (OH)-), 0.90 (3H, t, J = 6.8 Hz, -C (= CH) CH 2 (CH 2 ) 2 CH 2 C H 3 ).

<< 실시예Example 6>  6>

Figure 112011028633390-pat00020
Figure 112011028633390-pat00020

다이클로로메탄 (1.5 ml)에 용해시킨, (S)-(+)4-아이소프로필-3-프로피놀-2-옥사졸리디논 3a (100 mg, 0.541 mmol, 1 eq)을 얼음수조에서 빙냉시킨 후, 1M 다이클로로메탄에 용해되어져 있는 다이부틸보론 트리플로로메탄 썰퍼네이트 (596 , 0.596 mmol)와 다이아이소프로필에틸아민 (90.6 , 0.650 mmol, 1.2eq) 을 천천히 적가하여 같은 온도에서 50분 동안 교반하였다. 교반 시킨 반응 혼합물을 영하 78°C 에서 10분 동안 냉각시킨 후, 다이클로로메탄 (0.70 ml)에 용해시킨 헥타날 8 (92.25 , 0.81 mmol)를 영하 78℃에서 30분 동안 교반하였다. 그 다음, 다시 얼음수조에서 빙냉 시킨 후 1시간 동안 교반 한 후, pH 7.0 포스페이트 (1.2 ml), 메탄올 (1.1 ml), 30%wt 하이드로겐 페록싸이드수용액 (0.6 ml), 메탄올 (1.1 ml)을 차례대로 첨가하여 반응을 정지시킨다. 다시 얼음수조에서 1시간 더 교반 시킨 후 다이클로로메탄과 물을 넣어 분리하여, 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (18 % n-헥산:에틸아세테이트)하여 물질을 분리하고 건조시켜 노란색 액체물질 9 (22.3 mg, 14.8%)를 얻었다.(S)-(+) 4-isopropyl-3-propynol-2-oxazolidinone 3a (100 mg, 0.541 mmol, 1 eq) dissolved in dichloromethane (1.5 ml) was ice-cooled in an ice bath. Then, dibutylboron trichloromethane sulfonate (596, 0.596 mmol) and diisopropylethylamine (90.6, 0.650 mmol, 1.2eq) dissolved in 1M dichloromethane were slowly added dropwise for 50 minutes at the same temperature. Stirred. The stirred reaction mixture was cooled at minus 78 ° C. for 10 min, then hectal 8 (92.25, 0.81 mmol) dissolved in dichloromethane (0.70 ml) was stirred at minus 78 ° C. for 30 min. Then, ice-cold again in an ice bath and stirred for 1 hour, and then pH 7.0 phosphate (1.2 ml), methanol (1.1 ml), 30% wt hydrogen peroxide solution (0.6 ml), and methanol (1.1 ml) were added thereto. The reaction is stopped by addition in order. After further stirring for 1 hour in an ice bath, dichloromethane and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (18% n-hexane: ethyl acetate) to separate the material and dried to obtain a yellow liquid material 9 (22.3 mg, 14.8%).

1H-NMR (CDCl3, 500 MHz) : δ 5.54 (1H, t, J = 7.3 Hz, -CH(CH3)CH(OH), 4.48 - 4.41 (1H, m, -OCHαHβCHN), 4.39 (1H, brs, -CH(OH)), 4.28 (1H, dd, J = 17.6, 9.3 Hz, -OCHαH βCHN), 4.23 (1H, dd, J = 7.8, 2.9Hz, -OCHαHβCHN), 3.94 (1H, dq, J = 6.8, 2.9 Hz, -CH(CH3)CH(OH)-), 2.38 - 2.33 (1H, m, -CH(CH3)2), 2.10 - 2.01 (3H, m, -CHαHβCH 2(CH2)3CH3), 1.82 - 1.76 (1H, m, -CHαH βCH2(CH2)3CH3), 1.37 - 1.27 (6H, m, -CHαHβCH2(CH 2)3CH3), 1.17 (3H, d, J = 7.3Hz, -CH(CH 3)CH(OH)-), 0.92 (3H, d, J = 6.8 Hz, -CH(CH 3)2), 0.90 (3H, d, J = 7.3 Hz, -CH(CH 3)2), 0.87 (3H, t, J = 5.8 Hz, -CHαHβCH2(CH2)3CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 5.54 (1H, t, J = 7.3 Hz, -CH (CH 3 ) CH (O H ), 4.48-4.41 (1H, m, -OC H αH β CHN ), 4.39 (1H, brs, -C H (OH)), 4.28 (1H, dd, J = 17.6, 9.3 Hz, -OCHα H β CHN), 4.23 (1H, dd, J = 7.8, 2.9 Hz,- OCHαH β C H N), 3.94 (1H, dq, J = 6.8, 2.9 Hz, -C H (CH 3 ) CH (OH)-), 2.38-2.33 (1H, m, -C H (CH 3 ) 2 ), 2.10-2.01 (3H, m, -C H αH β C H 2 (CH 2 ) 3 CH 3 ), 1.82-1.76 (1H, m, -CHα H β CH 2 (CH 2 ) 3 CH 3 ), 1.37-1.27 (6H, m, -CHαH β CH 2 (C H 2 ) 3 CH 3 ), 1.17 (3H, d, J = 7.3 Hz, -CH (C H 3 ) CH (OH)-), 0.92 ( 3H, d, J = 6.8 Hz, -CH (C H 3 ) 2 ), 0.90 (3H, d, J = 7.3 Hz, -CH (C H 3 ) 2 ), 0.87 (3H, t, J = 5.8 Hz , -CHαH β CH 2 (CH 2 ) 3 C H 3 ).

<< 실시예Example 7>  7>

Figure 112011028633390-pat00021
Figure 112011028633390-pat00021

(2S,3S)-3-(2S, 3S) -3- 하이드록시Hydroxy -2--2- 메틸methyl -4--4- 메틸렌노나노익Methylene nonanoic 애시드의Acidic 제조(10d) Manufacture (10d)

실시예 2에서 제조된 (S)-3-((2S,3S)-3-하이드록시-2-메틸-4-메틸렌노나노일)-4-이소프로필옥사졸리딘-2-온 4d( 948 mg, 3.05 mmol)를 테트라하이드로퓨란 : 물 (27 ml : 27 ml)의 혼합물에 용해시키고, 상온에서 리튬히드록사이드(256 mg, 6.10 mmol)를 첨가하였다. 상온에서 12시간 동안 교반하여 반응을 완료시켰다. 감압 하에서 테트라하이드로퓨란을 제거하고 pH 7까지 중화시킨 후 반응혼합물에 에틸아세테이트를 첨가하여 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 액체물질 10d (647 mg, 106.1 %)를 바로 다음 반응에 첨가시켰다. (S) -3-((2S, 3S) -3-hydroxy-2-methyl-4-methylenenonanoyl) -4-isopropyloxazolidin-2-one 4d prepared in Example 2 ( 948) mg, 3.05 mmol) was dissolved in a mixture of tetrahydrofuran: water (27 ml: 27 ml) and lithium hydroxide (256 mg, 6.10 mmol) was added at room temperature. The reaction was completed by stirring at room temperature for 12 hours. Tetrahydrofuran was removed under reduced pressure, neutralized to pH 7, and ethyl acetate was added to the reaction mixture to separate an organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The resulting liquid 10d (647 mg, 106.1%) was added directly to the next reaction.

1H-NMR (CDCl3, 500 MHz) : δ 5.10 (1H, s, -C=CHαHβ), 4.99 (1H, s, -C=CHαHβ), 4.52 (1H, d, J = 3.4 Hz, -CH(CH3)CH-OH), 2.71 (1H, m, -CH(CH3)CH-OH), 2.02-1.93 (2H, m, -CH 2CH2CH2CH2CH3), 1.48 (2H, m, -CH2CH2CH2CH 2CH3), 1.31 (4H, m, -CH2CH 2CH 2CH2CH3), 1.14 (3H, d, J = 37.3 Hz, -CH(CH 3)CH-OH), 0.90 (3H, t, J = 6.8 Hz, -CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 5.10 (1H, s, -C = C H αHβ), 4.99 (1H, s, -C = CHα H β), 4.52 (1H, d, J = 3.4 Hz, -CH (CH 3 ) C H -OH), 2.71 (1H, m, -C H (CH3) CH-OH), 2.02-1.93 (2H, m, -C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.48 (2H, m, -CH 2 CH 2 CH 2 C H 2 CH 3 ), 1.31 (4H, m, -CH 2 C H 2 C H 2 CH 2 CH 3 ), 1.14 (3H, d, J = 37.3 Hz, -CH (C H 3 ) CH-OH), 0.90 (3H, t, J = 6.8 Hz, -CH 2 CH 2 CH 2 CH 2 C H 3 ).

<< 실시예Example 8>  8>

Figure 112011028633390-pat00022
Figure 112011028633390-pat00022

2-(2-( 인돌린Indolin -3-일)에탄올의 제조(11)-3-yl) ethanol (11)

아세틱에시드 (41.5 ml)에 용해 된 2-(3-인돌)-에탄올 (1.2 g, 7.06 mmol)을 얼음 수조에 넣어 빙냉시킨 후 소듐싸이아노보로하이드라이드 (2.2 g, 35.34 mmol)를 첨가하였다. 얼음 수조를 빼고 상온에서 3시간 동안 교반하였다. 반응이 완결된 것을 확인하고, 포화상태의 소듐바이오카보네이트 수용액을 첨가하여 반응을 정지 시켰다. 반응 혼합물을 중화시킨 다음, 에틸아세테를 넣어 유기층을 분리 하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n-헥산 : 에틸아세테이트 = 10 : 1)하여 물질을 분리하고 건조시켜 노란색 액체물질 11 (432 mg 37.4 %)을 얻었다. 2- (3-indole) -ethanol (1.2 g, 7.06 mmol) dissolved in acetic acid (41.5 ml) was added to an ice bath and ice-cooled, followed by addition of sodium thianoborohydride (2.2 g, 35.34 mmol). It was. The ice bath was removed and stirred at room temperature for 3 hours. It was confirmed that the reaction was completed, and the reaction was stopped by adding a saturated aqueous sodium biocarbonate solution. After neutralizing the reaction mixture, ethyl acetate was added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to separate the material and dried to obtain a yellow liquid material 11 (432 mg 37.4%).

1H-NMR(CDCl3, 500 MHz) : δ 7.10 (1H, d, J = 7.9 Hz), 7.06 (1H, dd, J = 7.9, 7.3 Hz), 6.76 (1H, dd, J = 7.6, 7.3 Hz), 6.68 (1H, d, J = 7.6 Hz), 3.74 - 3.55 (3H, m), 3.44 (1H, m), 3.28 (1H, dd, J = 8.6, 5.9 Hz), 3.10 (1H, brs), 2.09 (1H, m), 1.79 (1H, m)
 1 H-NMR (CDCl 3 , 500 MHz): δ 7.10 (1H, d , J = 7.9 Hz), 7.06 (1H, dd, J = 7.9, 7.3 Hz), 6.76 (1H, dd, J = 7.6, 7.3 Hz), 6.68 (1H, d , J = 7.6 Hz), 3.74-3.55 (3H, m), 3.44 (1H, m), 3.28 (1H, dd, J = 8.6, 5.9 Hz), 3.10 (1H, brs ), 2.09 (1H, m), 1.79 (1H, m)

3-(2-(3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸))ethyl) 인돌린의Indolin 제조(12) Manufacture (12)

2-(인돌린-3-일)에탄올 11 (365 mg, 2.23 mmol)을 다이클로로메탄에 녹인 후, 빙냉 시킨 얼음 수조에서 이미다졸 (182.6 mg, 2.68 mmol)과 터셔리-부틸다이메틸실릴 클로라이드 (404.2 mg, 2.68 mmol)를 차례대로 첨가하였다. 상온에서 3시간 동안 교반 시킨 후, 반응이 완결된 것을 확인하였다. 반응 혼합물에 물과 다이클로로메탄에 넣어 반응을 중지시킨 후, 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n-헥산 : 에틸아세테이트 = 20 : 1) 하여 물질을 분리하고 건조시켜 노란색 액체물질 12 (570.5 mg, 92.8 %)를 얻었다.Dissolve 2- (indolin-3-yl) ethanol 11 (365 mg, 2.23 mmol) in dichloromethane, and imidazole (182.6 mg, 2.68 mmol) and tert-butyldimethylsilyl chloride in an ice-cold ice bath. (404.2 mg, 2.68 mmol) was added sequentially. After stirring for 3 hours at room temperature, it was confirmed that the reaction was completed. After the reaction was stopped by adding water and dichloromethane to the reaction mixture, the organic layer was separated. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to separate the material, and dried to obtain a yellow liquid material 12 (570.5 mg, 92.8%).

1H-NMR (CDCl3, 500 MHz) : δ 7.10 (1H, d , J = 7.9 Hz), 7.06 (1H, dd, J = 7.9, 7.3 Hz), 6.76 (1H, dd, J = 7.6, 7.3 Hz), 6.68 (1H, d, J = 7.6 Hz), 3.74 - 3.55 (3H, m), 3.44 (1H, m), 3.28 (1H, dd, J = 8.6, 5.9 Hz), 2.09 (1H, m), 1.79 (1H, m), 0.92 (9H, s, -Si-(CH3)2-(CH 3)3), 0.09 (6H, s, -Si-(CH 3)2-(CH3)3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 7.10 (1H, d , J = 7.9 Hz), 7.06 (1H, dd, J = 7.9, 7.3 Hz), 6.76 (1H, dd, J = 7.6, 7.3 Hz), 6.68 (1H, d , J = 7.6 Hz), 3.74-3.55 (3H, m), 3.44 (1H, m), 3.28 (1H, dd, J = 8.6, 5.9 Hz), 2.09 (1H, m ), 1.79 (1H, m), 0.92 (9H, s, -Si- (CH 3 ) 2- (C H 3 ) 3 ), 0.09 (6H, s, -Si- (C H 3 ) 2- (CH 3 ) 3 ).

<< 실시예Example 9>  9>

Figure 112011028633390-pat00023
Figure 112011028633390-pat00023

(2S,3S)-1-(3-(2-((2S, 3S) -1- (3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸))ethyl) 인돌린Indolin -1-일)-3--1-yl) -3- 하이드록시Hydroxy -2-메틸-4--2-methyl-4- 메틸렌노난Methylenenonane -1-온의 제조(13a)Preparation of -1-one (13a)

3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린 12 (405 mg, 1.45 mmol) ,(2S, 3S)-3-하이드록시-2-메틸-4-메틸레노넥스 에스드 (438 mg, 2.18 mmol) 및 O-(7-아자벤조트리아졸-1-일)-N,N,N`,N`-테트라메틸-우라늄 (832.4 mg, 2.18 mmol) 을 디메틸포름아미드 20.0 ml에 용해시키고, N,N-디이소프로필에틸아민(0.17 ml, 1.0 mmol)을 첨가하였다. 상온에서 교반시키고, 에틸아세테이트 및 염화나트륨 수용액으로 분리시키고, 유기층을 무수 황산마그네슘으로 건조시키고, 농축시킨 후, 실리카겔 칼럼 크로마토그래피(n-헥산 : 에틸아세테이트 = 10 : 1)로 정제하여 목적 화합물1 3 a (404 mg, 60.2 %)를 오일상태로 얻었다.3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin 12 (405 mg, 1.45 mmol), (2S, 3S) -3-hydroxy-2-methyl-4-methylrenonex ed (438 mg, 2.18 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N`, N`-tetramethyl-uranium (832.4 mg, 2.18 mmol) in 20.0 ml of dimethylformamide And N, N-diisopropylethylamine (0.17 ml, 1.0 mmol) were added. The mixture was stirred at room temperature, separated with ethyl acetate and aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography ( n -hexane: ethyl acetate = 10: 1) to obtain the title compound 1 3 a (404 mg, 60.2%) was obtained in the oil state.

1H-NMR (CDCl3, 500 MHz) : δ 8.22 (1H, d, J = 8.3 Hz, Ar-H), 7.22 (2H, m, Ar-H), 7.09 (1H, t, J = 7.3 Hz, Ar-H), 5.27 (1H, s, -C=CHαHβ), 5.02 (1H, s, -C=CHαHβ), 4.50 (1H, brs, HC-OH), 4.27 (1H, t, J = 6.35 Hz, -CHαHβ-OTBS), 3.92 (1H, q, J = 5.86, 4.4 Hz, -CHαHβ-OTBS), 3.87-3.76 (2H, m, -N-CH 2), 3.56 - 3.53 (1H, m, -CO-CH(CH3), 2.80 (1H, m, Ar-CH), 2.01 (2H, m, -CH 2-CH2-OTBS), 2.91 (1H, m, -C=CH-CHαHβ-CH2), 1.82 (1H, m, -C=CH-CHαHβ-CH2), 1.51 (2H, m, -CH 2-CH3), 1.34-1.32 (4H, m, -CH 2CH 2CH2CH3), 1.21 (3H, d, J = 6.84 Hz, C=O-CH(CH 3), 1.19 (3H, t, J = 7.33 Hz, CH2CH 3), 0.90 (9H, s, -Si-(CH3)2-(CH 3)3), 0.09 (6H, s, -Si-(CH 3)2-(CH3)3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.22 (1H, d, J = 8.3 Hz, Ar- H ), 7.22 (2H, m, Ar- H ), 7.09 (1H, t, J = 7.3 Hz , Ar- H) , 5.27 (1H, s, -C = C H αHβ), 5.02 (1H, s, -C = CHα H β), 4.50 (1H, brs, HC-O H ), 4.27 (1H, t, J = 6.35 Hz, -C H αHβ-OTBS), 3.92 (1H, q, J = 5.86, 4.4 Hz, -CHα H β-OTBS), 3.87-3.76 (2H, m, -NC H 2 ), 3.56-3.53 (1H, m, -CO-C H (CH 3 ), 2.80 (1H, m, Ar-C H ), 2.01 (2H, m, -C H 2 -CH 2 -OTBS), 2.91 (1H , m, -C = CH-C H αHβ-CH 2 ), 1.82 (1H, m, -C = CH-CHα H β-CH 2 ), 1.51 (2H, m, -C H 2 -CH 3 ), 1.34-1.32 (4H, m, -C H 2 C H 2 CH 2 CH 3 ), 1.21 (3H, d, J = 6.84 Hz, C = O-CH (C H 3 ), 1.19 (3H, t, J = 7.33 Hz, CH 2 C H 3 ), 0.90 (9H, s, -Si- (CH 3 ) 2- (C H 3 ) 3 ), 0.09 (6H, s, -Si- (C H 3 ) 2- (CH 3 ) 3 ).

(2S,3S)-3-(2S, 3S) -3- 하이드록시Hydroxy -1-(3-(2-하이드록시에틸)-1- (3- (2-hydroxyethyl) 인돌린Indolin -1-일)-2--1-yl) -2- 메틸methyl -4--4- 메틸methyl 렌노난-1-온의 제조(13b)Preparation of lennonan-1-one (13b)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온 13a (54.5 mg, 0.12 mmol)을 테트로하이드로퓨란 (5 ml)에 용해 시킨 후, 테트로하이드로퓨란에 1.0 M로 녹여져 있는 테트라부틸암모니움 플로라이드 (0.15 ml)를 얼음 수조 상태에서 첨가하였다. 상온에서 2시간 동안 교반 한 후, 반응이 완결된 것을 확인하였다. 반응 혼합물에 메탄올을 넣어 반응을 중지 시킨 후, 얻어진 잔사를 바로 실리카겔 컬럼크로마토그래피 ( n-헥산:에틸아세테이트 = 1 : 1)하여 물질을 분리하고 건조시켜 목적화합물 13b (39 mg, 95 %)를 오일상태로 얻었다. (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -3-hydroxy-2-methyl-4-methylenenonan-1-one 13a (54.5 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 ml), and then tetrabutylammonium fluoride (0.15 ml) dissolved in 1.0 M in tetrahydrofuran was added in an ice bath. After stirring for 2 hours at room temperature, it was confirmed that the reaction was completed. After stopping the reaction by adding methanol to the reaction mixture, the obtained residue was immediately purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to separate the material and dried to give the target compound 13b (39 mg, 95%). Obtained in oil state.

1H-NMR (CDCl3, 500 MHz) : δ 8.25 (1H, d, J = 8.3 Hz, Ar-H), 7.25 (2H, m, Ar-H), 7.08 (1H, t, J = 6.8 Hz, Ar-H), 5.27 (1H, s, -C=CHαHβ), 5.02 (1H, s, -C=CHαHβ), 4.50 (1H, brs, HC-OH), 4.49 (2H, s, HC-OH), 4.28 (1H, q, J = 6.35 Hz, -CHαHβ-OH), 3.89 (1H, q, J = 5.86, 4.4 Hz, -CHαHβ-OH), 3.83 - 3.82 (2H, m, -N-CH 2), 3.79 (1H, brs, CH2CH2OH), 3.63 - 3.59 (1H, m, -CO-CH(CH3), 2.78 (1H, m, Ar-CH), 2.06 (2H, m, -CH 2-CH2-OH), 1.88 (1H, m, -C=CH-CHαHβ-CH2), 1.86 (1H, m, -C=CH-CHαHβ-CH2), 1.50 (2H, m, -CH 2-CH3), 1.34-1.32 (4H, m, -CH 2CH 2CH2CH3), 1.21 (3H, d, J = 7.3 Hz, C=O-CH(CH 3), 0.91 (3H, t, J = 6.84 Hz, CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.25 (1H, d, J = 8.3 Hz, Ar- H ), 7.25 (2H, m, Ar- H ), 7.08 (1H, t, J = 6.8 Hz , Ar- H) , 5.27 (1H, s, -C = C H αHβ), 5.02 (1H, s, -C = CHα H β), 4.50 (1H, brs, HC-O H ), 4.49 (2H, s, H C-OH), 4.28 (1H, q, J = 6.35 Hz, -C H αHβ-OH), 3.89 (1H, q, J = 5.86, 4.4 Hz, -CHα H β-OH), 3.83- 3.82 (2H, m, -NC H 2 ), 3.79 (1H, brs, CH 2 CH 2 O H ), 3.63-3.59 (1H, m, -CO-C H (CH 3 ), 2.78 (1H, m, Ar-C H ), 2.06 (2H, m, -C H 2 -CH 2 -OH), 1.88 (1H, m, -C = CH-C H αHβ-CH 2 ), 1.86 (1H, m, -C = CH-CHα H β-CH 2 ), 1.50 (2H, m, -C H 2 -CH 3 ), 1.34-1.32 (4H, m, -C H 2 C H 2 CH 2 CH 3 ), 1.21 (3H , d, J = 7.3 Hz, C = O-CH (C H 3 ), 0.91 (3H, t, J = 6.84 Hz, CH 2 C H 3 ).

(2S,3S)-1-(3-(2-((2S, 3S) -1- (3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸))ethyl) 인돌린Indolin -1-일)-2--1-yl) -2- 메틸methyl -4-메틸렌-1--4-methylene-1- 옥소노난Oxononan -3-일 아세테이트의 제조(14a)Preparation of 3-yl Acetate (14a)

디클로로메탄으로 녹인 (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온 13a (357 mg, 0.77 mmol)에 피리딘 (0.34 ml, 3.88 mmol)을 첨가 한 후, 아세틱언하이드로스를 천천히 적가 하였다. 상온에서 12시간 동안 교반하였는데, 출발물질이 조금 남아 있어 4-다이메틸아미노피리딘 (1 eq) 첨가하여 상온에서 2시간 더 교반하였다. 반응이 완결된 것을 확인하고, 감압기로 피리딘을 제거한 뒤, 에틸아세테이트와 물을 첨가하여 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 20 : 1)하여 물질을 분리하고 건조시켜 목적화합물 14a (570.5 mg, 92.8 %)를 오일상태로 얻었다. (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -3-hydroxy-2-methyl-4-methylenenonane- dissolved in dichloromethane Pyridine (0.34 ml, 3.88 mmol) was added to 1-one 13a (357 mg, 0.77 mmol) followed by the slow dropwise addition of aceticanhydrous. After stirring for 12 hours at room temperature, the starting material remained slightly, 4-dimethylaminopyridine (1 eq) was added and stirred for 2 hours at room temperature. After confirming that the reaction was completed, the pyridine was removed by a pressure reducer, and ethyl acetate and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to separate the substance and dried to obtain the target compound 14a (570.5 mg, 92.8%) as an oil.

1H-NMR (CDCl3, 500 MHz) : δ 8.11 (1H, d, J = 7.8 Hz, Ar-H), 7.10 (2H, m, Ar-H), 6.95 (1H, t, J = 7.3 Hz, Ar-H), 5.42 (1H, d, J = 8.3 Hz, -CHOCOCH3), 5.04 (1H, s, -C=CHαHβ), 4.84 (1H, s, -C=CHαHβ), 4.14 (1H, t, J = 9.2 Hz, -CHαHβ-OTBS), 3.76 - 3.68 (2H, m, -N-CH 2), 3.69 (1H, t, J = 6.3Hz, -CHαHβ-OTBS), 3.44 (1H, m, -CO-CH(CH3), 2.94 (1H, m, Ar-CH), 2.01 (3H, s, CHOCOCH 3), 1.96 (2H, m, -CH 2-CH2-OTBS), 1.66 (1H, m, -C=CH-CHαHβ-CH2), 1.37 (1H, m, -C=CH-CHαHβ-CH2), 1.17 (2H, m, -CH 2-CH3), 0.86 (4H, m, -CH 2CH 2CH2CH3), 0.85 (9H, s, -Si-(CH3)2-(CH 3)3), 0.85 (3H, d, J = 6.84 Hz, C=O-CH(CH 3), 0.76 (3H, t, J = 7.33 Hz, CH2CH 3), 0.01 (6H, s, -Si-(CH 3)2-(CH3)3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.11 (1H, d, J = 7.8 Hz, Ar- H ), 7.10 (2H, m, Ar- H ), 6.95 (1H, t, J = 7.3 Hz , Ar- H) , 5.42 (1H, d, J = 8.3 Hz, -C H OCOCH 3 ), 5.04 (1H, s, -C = C H αHβ), 4.84 (1H, s, -C = CHα H β ), 4.14 (1H, t, J = 9.2 Hz, -C H αHβ-OTBS), 3.76-3.68 (2H, m, -NC H 2 ), 3.69 (1H, t, J = 6.3 Hz, -CHα H β -OTBS), 3.44 (1H, m, -CO-C H (CH 3 ), 2.94 (1H, m, Ar-C H ), 2.01 (3H, s, CHOCOC H 3 ), 1.96 (2H, m,- C H 2 -CH 2 -OTBS), 1.66 (1H, m, -C = CH-C H αHβ-CH 2 ), 1.37 (1H, m, -C = CH-CHα H β-CH 2 ), 1.17 ( 2H, m, -C H 2 -CH 3 ), 0.86 (4H, m, -C H 2 C H 2 CH 2 CH 3 ), 0.85 (9H, s, -Si- (CH 3 ) 2- (C H 3 ) 3 ), 0.85 (3H, d, J = 6.84 Hz, C = O-CH (C H 3 ), 0.76 (3H, t, J = 7.33 Hz, CH 2 C H 3 ), 0.01 (6H, s , -Si- (C H 3 ) 2- (CH 3 ) 3 ).

(2S,3S)-1-(3-(2-하이드록시에틸)(2S, 3S) -1- (3- (2-hydroxyethyl) 인돌린Indolin -1-일)-2--1-yl) -2- 메틸methyl -4-메틸렌-1--4-methylene-1- 옥소노난Oxononan -3-일 아세테이트의 제조(14b)Preparation of 3-yl Acetate (14b)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트 14a (64.4 mg, 0.12 mmol)을 메탄올 (3 ml)에 용해시킨 후, 피리딘 피-톨루엔-썰포네이트를 소량 넣어 준 후 상온에서 2시간 동안 교반하였다. 반응이 완결된 것을 확인한 후, 감압기로 메탄올을 날린 뒤 바로 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 1 : 1)하여 물질을 분리하고 건조시켜 목적화합물 14b (21.3 mg, 42.8 %)를 오일상태로 얻었다. (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylene-1-oxononan-3-yl acetate After dissolving 14a (64.4 mg, 0.12 mmol) in methanol (3 ml), a small amount of pyridine py-toluene-sulfonate was added and stirred at room temperature for 2 hours. After confirming that the reaction was completed, immediately after blowing methanol with a pressure reducer and silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to separate the material and dried to give the target compound 14b (21.3 mg, 42.8%) oil I got in a state.

1H-NMR (CDCl3, 500 MHz) : δ 8.23 (1H, d, J = 7.8 Hz, Ar-H), 7.21 (2H, m, Ar-H), 7.05 (1H, t, J = 7.3 Hz, Ar-H), 5.55( 1H, d, J = 8.3 Hz, -CHOCOCH3), 5.12 (1H, s, -C=CHαHβ), 4.93 (1H, s, -C=CHαHβ), 4.24 (2H, t, J = 9.2 Hz, -CH2CH 2-OH), 3.94 (2H, t, J = 9.2Hz, -CH 2CH2-OH), 3.80 (2H, d, J = 7.3 Hz, -N-CH 2), 3.57 (1H, m, -CO-CH(CH3), 3.04 (1H, t, J = 6.8 Hz, N-CH2CH-C2H4-OH), 2.09 (3H, s, CHOCOCH 3), 1.56 (2H, m, -CH2CH 2CH2CH2CH3), 1.45 (4H, m, -CH2CH2CH 2CH 2CH3), 1.26 (3H, m, CO(CH 3)CH), 0.86 (3H, t, J = 6.3Hz, -CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.23 (1H, d, J = 7.8 Hz, Ar- H ), 7.21 (2H, m, Ar- H ), 7.05 (1H, t, J = 7.3 Hz , Ar- H) , 5.55 (1H, d, J = 8.3 Hz, -C H OCOCH 3 ), 5.12 (1H, s, -C = C H αHβ), 4.93 (1H, s, -C = CHα H β ), 4.24 (2H, t, J = 9.2 Hz, -CH 2 C H 2 -OH), 3.94 (2H, t, J = 9.2 Hz, -C H 2 CH 2 -OH), 3.80 (2H, d, J = 7.3 Hz, -NC H 2 ), 3.57 (1H, m, -CO-C H (CH 3 ), 3.04 (1H, t, J = 6.8 Hz, N-CH 2 C H -C 2 H 4- OH), 2.09 (3H, s, CHOCOC H 3 ), 1.56 (2H, m, -CH 2 C H 2 CH 2 CH 2 CH 3 ), 1.45 (4H, m, -CH 2 CH 2 C H 2 C H 2 CH 3 ), 1.26 (3H, m, CO (C H 3 ) CH), 0.86 (3H, t, J = 6.3 Hz, —CH 2 CH 2 CH 2 CH 2 C H 3 ).

(2S,3S)-1-(3-(2-((2S, 3S) -1- (3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸)-1H-인돌-1-일)-2-) Ethyl) -1H-indol-1-yl) -2- 메틸methyl -4-메틸렌-1--4-methylene-1- 옥소노난Oxononan -3-일 아세테이트의 제조(15a)Preparation of -3-yl acetate (15a)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트 14a (344 mg, 0.68 mmol)를 벤젠 (7 ml)에 용해 시킨 후, 2,3-다이클로로-5,6-다이싸이아노-1,4-벤조큐논 (778.2 mg, 3.42 mmol)을 첨가하여 60℃에서 12시간 동안 교반하였다. 반응이 완결된 것을 확인하고, 에틸아세테이트와 물을 첨가하여 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 7 : 1)하여 물질을 분리하고 건조시켜 목적화합물 15a (85 mg, 24.8 %)를 오일상태로 얻었다. (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylene-1-oxononan-3-yl acetate 14a (344 mg, 0.68 mmol) was dissolved in benzene (7 ml), and then 2,3-dichloro-5,6-diisano-1,4-benzoquinone (778.2 mg, 3.42 mmol) was added to the mixture. Stir at 60 ° C. for 12 h. It was confirmed that the reaction was completed, and ethyl acetate and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to separate the substance and dried to obtain the target compound 15a (85 mg, 24.8%) in an oil state.

1H-NMR (CDCl3, 500 MHz) : δ 8.46 (1H, d, J = 8.3Hz, Ar-H), 7.72 - 7.70 (1H, m, Ar-H), 7.54 - 7.52 (2H, m, Ar-H), 7.37-7.27 (1H, m, Ar-H), 5.66 (1H, d, J = 7.3Hz, -CHOCOCH3), 5.12 (1H, s, -C=CHαHβ), 4.93 (1H, s, -C=CHαHβ), 3.92 (2H, m, -CH 2-OTBS), 3.53 (1H, m, -CO-CH(CH3), 2.93 (2H, m, -CH 2CH2-OTBS), 2.11 (3H, s, CHOCOCH 3), 2.04 (2H, t, J = 7.8 Hz, -CH 2CH2CH2CH2CH3), 1.43 (2H, m, -CH2CH2CH2CH 2CH3), 1.38 (3H, d, J = 7.3 Hz, -CO-CH(CH 3), 1.32 - 1.23 (4H, m, -CH2CH 2CH 2CH2CH3), 0.90 (9H, s, -Si-(CH3)2-(CH 3)3), 0.84 (3H, t, J = 7.3 Hz, -CH2CH2CH2CH2CH 3), 0.04 (6H, d, J = 4.89 Hz, -Si-(CH 3)2-(CH3)3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.46 (1H, d, J = 8.3 Hz, Ar- H ), 7.72-7.70 (1H, m, Ar- H ), 7.54-7.52 (2H, m, Ar- H ), 7.37-7.27 (1H, m, Ar- H ), 5.66 (1H, d, J = 7.3 Hz, -C H OCOCH 3 ), 5.12 (1H, s, -C = C H αHβ), 4.93 (1H, s, -C = CHα H β), 3.92 (2H, m, -C H 2 -OTBS), 3.53 (1H, m, -CO-C H (CH 3 ), 2.93 (2H, m, -C H 2 CH 2 -OTBS), 2.11 (3H, s, CHOCOC H 3 ), 2.04 (2H, t, J = 7.8 Hz, -C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.43 (2H, m, -CH 2 CH 2 CH 2 C H 2 CH 3 ), 1.38 (3H, d, J = 7.3 Hz, -CO-CH (C H 3 ), 1.32-1.23 (4H, m, -CH 2 C H 2 C H 2 CH 2 CH 3 ), 0.90 (9H, s, -Si- (CH 3 ) 2- (C H 3 ) 3 ), 0.84 (3H, t, J = 7.3 Hz, -CH 2 CH 2 CH 2 CH 2 C H 3 ), 0.04 (6H, d, J = 4.89 Hz, -Si- (C H 3 ) 2- (CH 3 ) 3 ).

(2S,3S)-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-(2S, 3S) -1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2- 메틸methyl -4-메틸렌-1--4-methylene-1- 옥소노Oxono 난-3-일 아세테이트의 제조(15b)Preparation of Nan-3-yl Acetate (15b)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트 15a (88.3 mg, 0.17 mmol)을 테트로하이드로퓨란 (5 ml)에 용해 시킨 후, 테트로하이드로퓨란에 1.0 M 로 녹여져 있는 테트라부틸암모니움 플로라이드 (1.76 ml)를 얼음 수조 상태에서 첨가 하였다. 상온에서 2시간 동안 교반한 후, 반응이 완결된 것을 확인하였다. 반응 혼합물에 암모니움 클로라이드 수용액을 넣어 반응을 중지시킨 후, 에틸아세테이트를 넣어 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 1 : 1) 하여 물질을 분리하고 건조시켜 목적화합물 15b (21.3 mg, 31.3 %)를 오일상태로 얻었다. (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -2-methyl-4-methylene-1-oxononane-3- After dissolving 15 acetate (88.3 mg, 0.17 mmol) in tetrahydrofuran (5 ml), tetrabutylammonium fluoride (1.76 ml) dissolved in tetrahydrofuran at 1.0 M in an ice bath. Was added. After stirring for 2 hours at room temperature, it was confirmed that the reaction was completed. Aqueous solution of ammonium chloride was added to the reaction mixture to stop the reaction, and ethyl acetate was added thereto to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to separate the material and dried to obtain the target compound 15b (21.3 mg, 31.3%) in an oily state.

1H-NMR (CDCl3, 500 MHz) : δ 8.47 (1H, d, J = 7.8 Hz, Ar-H), 7.55 (1H, d, J = 6.84 Hz, Ar-H), 7.38 (1H, t, J = 7.3 Hz, Ar-H), 7.37 (1H, s, Ar-H), 7.30(1H, t, J = 7.3 Hz, Ar-H), 5.60 (1H, d, J = 7.3 Hz, -CHOAc), 5.11 (1H, s, -C=CHαHβ), 4.94 (1H, s, -C=CHαHβ), 3.96 (2H, t, J = 6.35 Hz, -CH 2-OTBS), 3.76 - 3.68 (2H, m, -N-CH 2), 3.69 (1H, t, J = 6.3 Hz, -CHαHβOH), 3.56 (1H, m, -CO-CH(CH3), 2.99 (2H, m, CH 2CH2OH), 2.09 (3H, s, CHOCOCH 3), 2.05 (2H, s, CH 2CH2CH2CH2CH3), 1.42 - 1.52 (6H, m, CH2CH 2CH 2CH 2CH3), 0.85 (3H, m, -CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.47 (1H, d, J = 7.8 Hz, Ar- H ), 7.55 (1H, d, J = 6.84 Hz, Ar- H ), 7.38 (1H, t , J = 7.3 Hz, Ar- H ), 7.37 (1H, s, Ar- H ), 7.30 (1H, t, J = 7.3 Hz, Ar- H) , 5.60 (1H, d, J = 7.3 Hz,- C H OAc), 5.11 (1H, s, -C = C H αHβ), 4.94 (1H, s, -C = CHα H β), 3.96 (2H, t, J = 6.35 Hz, -C H 2 -OTBS ), 3.76-3.68 (2H, m, -NC H 2 ), 3.69 (1H, t, J = 6.3 Hz, -CHα H βOH), 3.56 (1H, m, -CO-C H (CH 3 ), 2.99 (2H, m, C H 2 CH 2 OH), 2.09 (3H, s, CHOCOC H 3 ), 2.05 (2H, s, C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.42-1.52 (6H, m , CH 2 C H 2 C H 2 C H 2 CH 3 ), 0.85 (3H, m, -CH 2 C H 3 ).

<< 실시예Example 10>  10>

Figure 112011028633390-pat00024
Figure 112011028633390-pat00024

(2S,3S)-1-(3-(2-((2S, 3S) -1- (3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸)-1H-인돌-1-일)-3-) Ethyl) -1H-indol-1-yl) -3- 하이드록Hydrolock 시-2-Si-2- 메틸methyl -4--4- 메틸렌노난Methylenenonane -1-온의 제조(16a)Preparation of -1-one (16a)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온 13a (156 mg, 0.31 mmol)를 벤젠 (30 ml)에 용해 시킨 후, 2,3-다이클로로-5,6-다이싸이아노-1,4-벤조큐논 (352.8 mg, 1.55 mmol)을 첨가하여 60℃에서 12시간 동안 교반하였다. 반응이 완결된 것을 확인하고, 에틸아세테이트와 물을 첨가하여 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 20 : 1)하여 물질을 분리하고 건조시켜 목적화합물 16a (102 mg, 73.9 %)를 오일상태로 얻었다.(2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -3-hydroxy-2-methyl-4-methylenenonan-1-one 13a (156 mg, 0.31 mmol) was dissolved in benzene (30 ml), followed by addition of 2,3-dichloro-5,6-diisano-1,4-benzoquinone (352.8 mg, 1.55 mmol) to 60 Stir at 12 ° C. for 12 h. It was confirmed that the reaction was completed, and ethyl acetate and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to separate the material and dried to obtain the target compound 16a (102 mg, 73.9%) in an oil state.

1H-NMR (CDCl3, 500 MHz) : δ 8.48 (1H, d, J = 8.3 Hz, Ar-H), 7.55 (1H, d, J = 7.8Hz, Ar-H), 7.38 (1H, t, J = 8.31 Hz, Ar-H), 7.33 (1H, s, Ar-H), 7.3 (1H, t, J = 6.35 Hz, Ar-H), 5.28 (1H, s, -C=CHαHβ), 5.04 (1H, s, -C=CHαHβ), 4.62 (1H, s, -OH), 3.93 (2H, t, J = 6.35 Hz, -CH 2-OTBS), 3.66 (1H, m, -HC-OH), 3.31 - 3.27 (1H, m, -CO-CH(CH3)), 2.94 (1H, t, J = 6.84 Hz, -CHαHβ-OTBS), 2.93 (1H, q, J = 6.35 Hz, -CHαHβ-OTBS), 2.07 (1H, m, -C=CH-CHαHβ-CH2), 1.97 (1H, m, -C=CH-CHαHβ-CH2), 1.50 (2H, m, -CH2CH 2CH2CH2CH3), 1.35 (3H, s, -CO-CH(CH3)), 1.34 (4H, m, -CH2CH2CH 2CH 2CH3), 0.89 (9H, s, -Si-(CH3)2-(CH 3)3), 0.03 (6H, s, -Si-(CH 3)2-(CH3)3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.48 (1H, d, J = 8.3 Hz, Ar- H ), 7.55 (1H, d, J = 7.8 Hz, Ar- H ), 7.38 (1H, t , J = 8.31 Hz, Ar- H ), 7.33 (1H, s, Ar- H ), 7.3 (1H, t, J = 6.35 Hz, Ar- H) , 5.28 (1H, s, -C = C H αHβ ), 5.04 (1H, s, -C = CHα H β), 4.62 (1H, s, -O H ), 3.93 (2H, t, J = 6.35 Hz, -C H 2 -OTBS), 3.66 (1H, m, -H C-OH), 3.31-3.27 (1H, m, -CO-C H (CH 3 )), 2.94 (1H, t, J = 6.84 Hz, -C H αHβ-OTBS), 2.93 (1H , q, J = 6.35 Hz, -CHα H β-OTBS), 2.07 (1H, m, -C = CH-C H αHβ-CH 2 ), 1.97 (1H, m, -C = CH-CHα H β- CH 2 ), 1.50 (2H, m, -CH 2 C H 2 CH 2 CH 2 CH 3 ), 1.35 (3H, s, -CO-CH (CH3)), 1.34 (4H, m, -CH 2 CH 2 C H 2 C H 2 CH 3 ), 0.89 (9H, s, -Si- (CH 3 ) 2- (C H 3 ) 3 ), 0.03 (6H, s, -Si- (C H 3 ) 2- ( CH 3 ) 3 ).

(2S,3S)-3-(2S, 3S) -3- 하이드록시Hydroxy -1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2--1- (3- (2-hydroxyethyl) -1 H-indol-1-yl) -2- 메틸methyl -4--4- 메Me 틸렌노난-1-온의 제조(16b)Preparation of Tylenenonan-1-one (16b)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온 16a (9.9 mg, 0.02 mmol)을 메탄올 (2 ml)에 용해시킨 후, 피리딘 피-톨루엔-썰포네이트를 소량 넣어 준 후 상온에서 2시간 동안 교반하였다. 반응이 완결된 것을 확인한 후, 감압기로 메탄올을 날린 뒤 바로 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 1 : 1)하여 물질을 분리하고 건조시켜 목적화합물 16b (6.9 mg, 94.5 %)를 오일상태로 얻었다.(2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -3-hydroxy-2-methyl-4-methylenenonan-1- After dissolving 16a (9.9 mg, 0.02 mmol) in methanol (2 ml), a small amount of pyridine py-toluene-sulfonate was added and stirred at room temperature for 2 hours. After confirming that the reaction was completed, immediately after blowing methanol with a pressure reducer and silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to separate the material and dried to give the target compound 16b (6.9 mg, 94.5%) oil I got in a state.

1H-NMR (CDCl3, 500 MHz) : δ 8.49 (1H, d, J = 8.3 Hz, Ar-H), 7.57 (1H, d, J = 7.8 Hz, Ar-H), 7.41 - 7.31 (3H, m, Ar-H), 5.27 (1H, s, -C=CHαHβ), 5.04 (1H, s, -C=CHαHβ), 4.61 (1H, s, C=OCH(CH3)CH-OH), 3.98 (2H, t, J = 5.8 Hz, -CH 2-OTBS), 3.51 (1H, brs, CH-OH), 3.34 - 3.29 (1H, m, C=OCH(CH3), 3.00 (2H, t, J = 6.3 Hz, -CH 2CH2-OTBS), 2.12 - 2.06 (1H, m, -C=CHαHβ), 2.00 - 1.94 (1H, m, -C=CHαHβ), 1.60 (1H, brs, CH2CH2-OH), 1.55 - 1.47 (2H, m, -CH2CH 2CH2CH2CH3), 1.36 (3H, d, J = 1.46 Hz, -CO-CH(CH 3)), 1.35 - 1.31 (4H, m, -CH2CH2CH 2CH 2CH3), 0.90 (3H, t, J = 5.8 Hz, CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ 8.49 (1H, d, J = 8.3 Hz, Ar- H ), 7.57 (1H, d, J = 7.8 Hz, Ar- H ), 7.41-7.31 (3H , m, Ar- H ), 5.27 (1H, s, -C = C H αHβ), 5.04 (1H, s, -C = CHα H β), 4.61 (1H, s, C = OCH (CH 3 ) C H -OH), 3.98 (2H, t, J = 5.8 Hz, -C H 2 -OTBS), 3.51 (1H, brs, CH-O H ), 3.34-3.29 (1H, m, C = OC H (CH 3 ), 3.00 (2H, t, J = 6.3 Hz, -C H 2 CH 2 -OTBS), 2.12-2.06 (1H, m, -C = C H αHβ), 2.00-1.94 (1H, m, -C = CHα H β), 1.60 (1H, brs, CH 2 CH 2 -O H ), 1.55-1.47 (2H, m, -CH 2 C H 2 CH 2 CH 2 CH 3 ), 1.36 (3H, d, J = 1.46 Hz, -CO-CH (C H 3 )), 1.35-1.31 (4H, m, -CH 2 CH 2 C H 2 C H 2 CH 3 ), 0.90 (3H, t, J = 5.8 Hz, CH 2 C H 3 ).

(2R,3S)-1-(3-(2-((2R, 3S) -1- (3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸))ethyl) 인돌린Indolin -1-일)-2--1-yl) -2- 메틸methyl -4--4- 메Me 틸렌노난-3-올의 제조(17a)Preparation of Tylenenonan-3-ol (17a)

(2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온 13a (250 mg, 0.54 mmol)를 테트로하이드로퓨란 (15 ml)에 용해 시킨 후, 테트라하이드로퓨란에 2M로 녹여져 있는 보란-다이메틸 썰파이드 (0.5 ml)를 얼음으로 빙냉 시킨 상태에서 첨가하였다. 얼음 수조에서 2시간 동안 교반하여 반응이 완결된 것을 확인한 뒤 메탄올 (1 ml)을 넣어 3시간 동안 더 교반해준다. 반응혼합물을 감압기를 이용하여 날린 후, 바로 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 15 : 1)하여 물질을 분리하고 건조시켜 목적화합물 17a (178 mg, 73.4 %)를 오일상태로 얻었다.(2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -3-hydroxy-2-methyl-4-methylenenonan-1-one 13a After dissolving (250 mg, 0.54 mmol) in tetrahydrofuran (15 ml), borane-dimethyl sulfide (0.5 ml) dissolved in tetrahydrofuran in 2M was added while ice-cooled. After stirring for 2 hours in an ice bath to confirm that the reaction was completed, add methanol (1 ml) and further stirred for 3 hours. After the reaction mixture was blown using a pressure reducer, silica gel column chromatography (n-hexane: ethyl acetate = 15: 1) was used to separate the material and dried to obtain the target compound 17a (178 mg, 73.4%) as an oil.

1H-NMR (CDCl3, 500 MHz) δ 7.07 (2H, t, J = 7.8 Hz, Ar-H), 6.66 (1H, t, J = 7.3 Hz, Ar-H), 6.53 (1H, t, J = 6.8 Hz, Ar-H), 5.08 (1H, s, -C=CHαHβ), 4.95 (1H, s, -C=CHαHβ), 4.25 (1H, d, J = 8.3 Hz, -CH(CH3)CH-OH), 3.75 (2H, d, J = 5.86 Hz, N-CH 2), 3.64 - 3.54 (1H, m, CH2CH 2-OTBS), 3.34 (1H, brs, -OH), 3.29 (1H, q, J = 8.3 Hz, N-CH2CH), 3.16 - 3.07 (1H, m, N-CHαHβ-CH(CH3), 3.08 - 2.98 (1H, m, N-CHαHβ-CH(CH3), 2.84 (1H, m, CH2CH(CH3), 2.05 (2H, q, J = 7.8 Hz, CH 2CH2-OTBS), 1.94 (2H, t, J = 7.3Hz, =C-CH 2), 1.78 (2H, m, -CH2CH2CH2CH 2CH3), 1.47 (2H, m, -CH2CH 2CH2CH2CH3), 1.30 (2H, m, -CH2CH2CH 2CH2CH3), 0.92 (3H, d, J = 7.3 Hz, CH2CH(CH 3)), 0.92 (9H, s, -Si-(CH3)2-(CH 3)3), 0.89 (3H, t, J = 6.8 Hz, -CH2CH2CH2CH2CH 3), 0.09 (6H, s, -Si-(CH 3)2-(CH3)3).
 1 H-NMR (CDCl 3 , 500 MHz) δ 7.07 (2H, t, J = 7.8 Hz, Ar- H ), 6.66 (1H, t, J = 7.3 Hz, Ar- H ), 6.53 (1H, t, J = 6.8 Hz, Ar- H ), 5.08 (1H, s, -C = C H αHβ), 4.95 (1H, s, -C = CHα H β), 4.25 (1H, d, J = 8.3 Hz,- CH (CH 3 ) C H -OH), 3.75 (2H, d, J = 5.86 Hz, NC H 2 ), 3.64-3.54 (1H, m, CH 2 C H 2 -OTBS), 3.34 (1H, brs, -O H ), 3.29 (1H, q, J = 8.3 Hz, N-CH 2 C H ), 3.16-3.07 (1H, m, NC H αHβ-CH (CH 3 ), 3.08-2.98 (1H, m, N-CHα H β-CH (CH 3 ), 2.84 (1H, m, CH 2 C H (CH 3 ), 2.05 (2H, q, J = 7.8 Hz, C H 2 CH 2 -OTBS), 1.94 (2H , t, J = 7.3 Hz, = CC H 2 ), 1.78 (2H, m, -CH 2 CH 2 CH 2 C H 2 CH 3 ), 1.47 (2H, m, -CH 2 C H 2 CH 2 CH 2 CH 2 CH 3 ), 1.30 (2H, m, -CH 2 CH 2 C H 2 CH 2 CH 3 ), 0.92 (3H, d, J = 7.3 Hz, CH 2 CH (C H 3 )), 0.92 (9H, s , -Si- (CH 3 ) 2- (C H 3 ) 3 ), 0.89 (3H, t, J = 6.8 Hz, -CH 2 CH 2 CH 2 CH 2 CH H 3 ), 0.09 (6H, s,- Si- (C H 3 ) 2- (CH 3 ) 3 ).

(2R,3S)-1-(3-(2-하이드록시에틸)(2R, 3S) -1- (3- (2-hydroxyethyl) 인돌린Indolin -1-일)-2--1-yl) -2- 메틸methyl -4--4- 메틸렌노난Methylenenonane -3-올의 제조(17b)Preparation of 3-ol (17b)

(2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-3-올 17a (31 mg, 0.06 mmol)을 메탄올 (1.3 ml)에 용해시킨 후, 피리딘 피-톨루엔-썰포네이트를 소량 넣어 준 후 상온에서 3시간 동안 교반하였다. 반응이 완결 된 것을 확인 한 후, 감압기로 메탄올을 날린 뒤 바로 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 1 : 1)하여 물질을 분리하고 건조시켜 목적화합물 17b (18.4 mg, 79.8 %)를 오일상태로 얻었다. (2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylenenonan-3-ol 17a (31 mg, 0.06 mmol) was dissolved in methanol (1.3 ml), and a small amount of pyridine pi-toluene-sulfonate was added thereto, followed by stirring at room temperature for 3 hours. After confirming that the reaction was completed, immediately after blowing methanol with a pressure reducer, silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to separate the material and dried to give the target compound 17b (18.4 mg, 79.8%). Obtained in oil state.

1H-NMR (CDCl3, 500 MHz) : δ7.09 (2H, m, Ar-H), 6.70 (1H, t, J = 7.3Hz, Ar-H), 6.59 (1H, d, J = 7.8 Hz, Ar-H), 5.09 (1H, s, -C=CHαHβ), 4.96 (1H, s, -C=CHαHβ), 4.23 (1H, d, J = 7.3 Hz, CH(CH3)CH-OH), 3.77 - 3.71 (2H,m, N -CH 2CH(CH3)), 3.58 (1H, t, J = 8.3 Hz, N-CHαHβ-CH(CH3)), 3.52 (1H, t, J = 8.8 Hz, N-CHαHβ-CH(CH3)), 3.40 (1H, q, J = 7.3 Hz, N-CH2CH), 3.20 (2H, m, N-CH 2), 2.92 (1H, m, N-CH2CH(CH3), 2.05 (2H, m, CH 2CH2-OH), 1.83 (2H, m, =C-CH 2CH2CH2CH2CH3), 1.47 (2H, m, -CH2CH2CH2CH 2CH3), 1.31 (4H, m, -CH2CH 2CH 2CH2CH3), 0.91 (3H, s, -CH2CH(CH 3), 0.89 (3H, t, J = 7.3 Hz, -CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ7.09 (2H, m, Ar- H) , 6.70 (1H, t, J = 7.3 Hz, Ar- H ), 6.59 (1H, d, J = 7.8 Hz, Ar- H ), 5.09 (1H, s, -C = C H αHβ), 4.96 (1H, s, -C = CHα H β), 4.23 (1H, d, J = 7.3 Hz, C H (CH 3 ) CH-OH), 3.77-3.71 (2H, m, N-C H 2 CH (CH 3 )), 3.58 (1H, t, J = 8.3 Hz, NC H αHβ-CH (CH 3 )), 3.52 (1H, t, J = 8.8 Hz, NC H αHβ-CH (CH 3 )), 3.40 (1H, q, J = 7.3 Hz, N-CH 2 C H ), 3.20 (2H, m, NC H 2 ) , 2.92 (1H, m, N-CH 2 C H (CH 3 ), 2.05 (2H, m, C H 2 CH 2 -OH), 1.83 (2H, m, = CC H 2 CH 2 CH 2 CH 2 CH 3 ), 1.47 (2H, m, -CH 2 CH 2 CH 2 C H 2 CH 3 ), 1.31 (4H, m, -CH 2 C H 2 C H 2 CH 2 CH 3 ), 0.91 (3H, s, -CH 2 CH (C H 3 ), 0.89 (3H, t, J = 7.3 Hz, -CH 2 CH 2 CH 2 CH 2 C H 3 ).

(2R,3S)-1-(3-(2-((2R, 3S) -1- (3- (2- ( 터트Tert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )에틸)-1H-인돌-1-일)-2-) Ethyl) -1H-indol-1-yl) -2- 메틸methyl -4-메틸렌노난-3-올의 제조(18a)Preparation of 4-methylenenonan-3-ol (18a)

(2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-3-올 17a (87.8 mg, 0.19 mmol)를 벤젠 (18 ml)에 용해 시킨 후, 2,3-다이클로로-5,6-다이싸이아노-1,4-벤조큐논 (89.43 mg, 0.39 mmol)을 첨가하여 60℃에서 12시간 동안 교반하였다. 반응이 완결된 것을 확인하고, 에틸아세테이트와 물을 첨가하여 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 20 : 1)하여 물질을 분리하고 건조시켜 목적화합물 18a (32 mg, 36.6 %)를 오일상태로 얻었다.
(2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylenenonan-3-ol 17a (87.8 mg, 0.19 mmol) was dissolved in benzene (18 ml), then 2,3-dichloro-5,6-diisano-1,4-benzoquinone (89.43 mg, 0.39 mmol) was added for 12 hours at 60 ° C. Stirred. It was confirmed that the reaction was completed, and ethyl acetate and water were added to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to separate the substance and dried to obtain the target compound 18a (32 mg, 36.6%) in an oil state.

1H-NMR (CDCl3, 500 MHz) : δ7.59 (1H, d, J = 7.8 Hz, Ar-H), 7.34 (1H, d, J = 7.3 Hz, Ar-H), 7.18 (1H, t, J = 8.3 Hz, Ar-H), 7.08 (1H, t, J = 7.8 Hz, Ar-H), 6.97 (1H, s, Ar-H), 5.05 (1H, s, -C=CHαHβ), 4.92 (1H, s, -C=CHαHβ), 4.21 (1H, q, J = 8.3 Hz, N-CHαHβCH(CH3)), 3.99 (1H, q, J = 8.3 Hz, N-CHαHβCH(CH3)), 3.86 (2H, t, J = 7.3 Hz, CH2CH 2-OTBS), 3.83 (1H, d, J = 6.3 Hz, CH(CH3)CH-OH), 2.98 (2H, t, J = 7.3 Hz, CH 2CH2-OTBS), 2.26 (1H, m, CH2CH(CH3)), 1.87 (1H, m, =C-CHαHβC4H11), 1.77 (1H, m, =C-CHαHβC4H11), 1.30 - 1.16 (6H, m, -CH2CH 2CH 2CH 2CH3), 0.90 (9H, s, -Si-(CH3)2-(CH 3)3)), 0.84 (3H, s, CH2CH(CH 3), 0.83 (3H, t, J = 7.3Hz, -CH2CH2CH2CH2CH 3), 0.04 (6H, s, -Si-(CH 3)2-(CH3)3)).
 1 H-NMR (CDCl 3 , 500 MHz): δ 7.59 (1H, d, J = 7.8 Hz, Ar- H ), 7.34 (1H, d, J = 7.3 Hz, Ar- H ), 7.18 (1H, t, J = 8.3 Hz, Ar- H ), 7.08 (1H, t, J = 7.8 Hz, Ar- H ), 6.97 (1H, s, Ar- H ), 5.05 (1H, s, -C = C H αHβ), 4.92 (1H, s, -C = CHα H β), 4.21 (1H, q, J = 8.3 Hz, NC H αHβCH (CH 3 )), 3.99 (1H, q, J = 8.3 Hz, N- CHα H βCH (CH 3 )), 3.86 (2H, t, J = 7.3 Hz, CH 2 C H 2 -OTBS), 3.83 (1H, d, J = 6.3 Hz, CH (CH 3 ) C H -OH) , 2.98 (2H, t, J = 7.3 Hz, C H 2 CH 2 -OTBS), 2.26 (1H, m, CH 2 C H (CH 3 )), 1.87 (1H, m, = CC H αHβC 4 H 11 ), 1.77 (1H, m, = C-CHα H βC 4 H 11 ), 1.30-1.16 (6H, m, -CH 2 C H 2 C H 2 C H 2 CH 3 ), 0.90 (9H, s,- Si- (CH 3 ) 2- (C H 3 ) 3 )), 0.84 (3H, s, CH 2 CH (C H 3 ), 0.83 (3H, t, J = 7.3 Hz, -CH 2 CH 2 CH 2 CH 2 C H 3 ), 0.04 (6H, s, -Si- (C H 3 ) 2- (CH 3 ) 3 )).

(2R,3S)-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-(2R, 3S) -1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2- 메틸methyl -4--4- 메틸렌노난Methylenenonane -3-올의 제조(18b)Preparation of 3-ol (18b)

(2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-3-올 18a (35.2 mg, 0.08 mmol)을 테트로하이드로퓨란 (4 ml)에 용해 시킨 후, 테트로하이드로퓨란에 1.0 M로 녹여져 있는 테느라부틸암모니움 플로라이드를 얼음 수조 상태에서 첨가하였다. 상온에서 2시간 동안 교반 한 후, 반응이 완결된 것을 확인하였다. 반응 혼합물에 암모니움 클로라이드 수용액을 넣어 반응을 중지시킨 후, 에틸아세테이트를 넣어 유기층을 분리하였다. 분리한 유기층을 소듐클로라이드 수용액으로 씻어준 후, 무수 황산마그네슘으로 건조시키고, 농축시켰다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 ( n - 헥산 : 에틸아세테이트 = 1 : 1)하여 물질을 분리하고 건조시켜 목적화합물 18b (12.02 mg, 36 %)를 오일상태로 얻었다.(2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-3-ol 18a (35.2 mg , 0.08 mmol) was dissolved in tetrahydrofuran (4 ml), and then tetranefuran ammonium fluoride dissolved in 1.0 M in tetrahydrofuran was added in an ice bath. After stirring for 2 hours at room temperature, it was confirmed that the reaction was completed. Aqueous solution of ammonium chloride was added to the reaction mixture to stop the reaction, and ethyl acetate was added thereto to separate the organic layer. The separated organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to separate the substance and dried to obtain the target compound 18b (12.02 mg, 36%) in an oil state.

1H-NMR (CDCl3, 500 MHz) : δ7.62 (1H, d, J = 7.8Hz, Ar-H), 7.38 (1H, d, J = 8.3 Hz, Ar-H), 7.22 (1H, t, J = 8.3 Hz, Ar-H), 7.11 (1H, t, J = 7.8 Hz, Ar-H), 7.04 (1H, s, Ar-H), 5.07 (1H, s, -C=CHαHβ), 4.94 (1H, s, -C=CHαHβ), 4.23 (1H, q, J = 8.3 Hz, N-CHαHβCH(CH3)), 4.02 (1H, q, J = 7.3Hz, N-CHαHβCH(CH3)), 3.90 (2H, t, J = 6.3 Hz, CH2CH 2-OH), 3.83 (1H, s, -CH2CH(CH3)CH-OH), 3.04 (2H, t, J = 6.3 Hz, CH 2CH2-OH), 2.31 - 2.26 (1H, m, -CH2CH(CH3)), 1.90 (1H, m, =C-CHαHβC4H11), 1.76 (1H, m, =C-CHαHβC4H11), 1.60 (1H, brs, -CH(CH3)CH-OH), 1.30 - 1.17 (6H, m, -CH2CH 2CH 2CH 2CH3), 0.857 (3H, s, CH2CH(CH 3), 0.84 (3H, s, -CH2CH2CH2CH2CH 3).
 1 H-NMR (CDCl 3 , 500 MHz): δ7.62 (1H, d, J = 7.8 Hz, Ar- H ), 7.38 (1H, d, J = 8.3 Hz, Ar- H ), 7.22 (1H, t, J = 8.3 Hz, Ar- H ), 7.11 (1H, t, J = 7.8 Hz, Ar- H ), 7.04 (1H, s, Ar- H ), 5.07 (1H, s, -C = C H αHβ), 4.94 (1H, s, -C = CHα H β), 4.23 (1H, q, J = 8.3 Hz, NC H αHβCH (CH 3 )), 4.02 (1H, q, J = 7.3 Hz, N- CHα H βCH (CH 3 )), 3.90 (2H, t, J = 6.3 Hz, CH 2 C H 2 -OH), 3.83 (1H, s, -CH 2 CH (CH 3 ) C H -OH), 3.04 (2H, t, J = 6.3 Hz, C H 2 CH 2 -OH), 2.31-2.26 (1H, m, -CH 2 C H (CH 3 )), 1.90 (1H, m, = CC H αHβC 4 H 11 ), 1.76 (1H, m, = C-CHα H βC 4 H 11 ), 1.60 (1H, brs, -CH (CH 3 ) CH-O H ), 1.30-1.17 (6H, m, -CH 2 C H 2 C H 2 C H 2 CH 3 ), 0.857 (3H, s, CH 2 CH (C H 3 ), 0.84 (3H, s, —CH 2 CH 2 CH 2 CH 2 C H 3 ).

실험예Experimental Example 1.  One. ILIL -6 -6 매개성Intermediary luciferaseluciferase 저해활성 Inhibitory activity

<1-1> 형질전환체 제조<1-1> Transformant Preparation

96 웰 플레이트에 5×104 세포/웰로 HepG2 세포(ATCC HB-8065)를 분주한 후, 10% FBS(v/v), 60.0 ㎎/ℓ 카나마이신 설페이트(kanamycin sulfate; Gibco., USA) 및 2.0 g/ℓ 탄산수소나트륨(NaHCO3; Sigma, USA)이 포함된 DMEM 배양 배지를 사용하여, 37℃에서 5% CO2의 조건으로 배양접시에 80% 가득찰(confluent) 때까지 배양하였다. 이후 무혈청 배지 50 ㎕로 교환하고, 0.1 ㎍ pSTAT3-TA-Luc (Clontech, CA)와 0.3 ㎕ 리포펙타민 시약(lipofectamin reagent; Invitrogen, USA)의 혼합액을 각 웰에 첨가하여 3시간 반응시킴으로써 pSTAT3-TA-Luc를 형질감염시켰고, 새로 제조한 200 ㎕ DMEM 배양 배지로 바꾸어 추가로 24시간 배양하였다.
Dispense HepG2 cells (ATCC HB-8065) at 5 × 10 4 cells / well in 96 well plates, then 10% FBS (v / v), 60.0 mg / l kanamycin sulfate (Kamyamycin sulfate; Gibco., USA) and 2.0 DMEM culture medium containing g / l sodium hydrogen carbonate (NaHCO 3 ; Sigma, USA) was used to incubate at 37 ° C. with 5% CO 2 until 80% confluent in the culture dish. Subsequently, 50 μl of serum-free medium was exchanged, and a mixture of 0.1 μg pSTAT3-TA-Luc (Clontech, Calif.) And 0.3 μl lipofectamin reagent (Invitrogen, USA) was added to each well and reacted for 3 hours. -TA-Luc was transfected and replaced with freshly prepared 200 μl DMEM culture medium and incubated for an additional 24 hours.

<1-2> <1-2> ILIL -6 및 -6 and ILIL -11 반응성 -11 reactivity STAT3STAT3 리포터 유전자 검사 Reporter Genetic Test

상기 형질감염된 세포를 1% BSA/DMEM으로 무혈청 배양(serum starvation)하고 시료를 하기와 같이 1시간 처리한 후 10 ng/㎖ IL-6(R&D system, USA)를 첨가하여 3시간 동안 배양하였다.The transfected cells were cultured serum-free (serum starvation) with 1% BSA / DMEM, and the samples were treated for 1 hour as follows, followed by incubation for 3 hours with the addition of 10 ng / ml IL-6 (R & D system, USA). .

1: 음성대조군(비처리군);1: negative control group (non-treated group);

2: 양성대조군(IL-6 10 ng/㎖);2: positive control (IL-6 10 ng / ml);

3: 화합물들 (0.3, 1, 3, 10, 30, 100 μM); 및3: compounds (0.3, 1, 3, 10, 30, 100 μΜ); And

4: Madindoline (0.3, 1, 3, 10, 30, 100 μM)4: Madindoline (0.3, 1, 3, 10, 30, 100 μM)

상기 반응한 세포를 PBS로 세척하고 50 ㎕ 용해 완충용액(luciferase assay system, promega, USA)을 넣고 1분간 교반한 후, 30-100 ㎕의 루시퍼라제 기질(luciferase assay system, promega, USA)을 넣고 발색정도를 루미노미터(luminometer; EG&G BERTHOLD, USA)로 5분 안에 측정하였다.The reaction cells were washed with PBS, 50 μl lysis buffer (luciferase assay system, promega, USA) was added thereto, stirred for 1 minute, and then 30-100 μl luciferase substrate (luciferase assay system, promega, USA) was added thereto. The color development was measured within 5 minutes with a luminometer (EG & G BERTHOLD, USA).

각 화합물들의 IL-6 유도 루시퍼라제 저해활성 효과의 IC50 값은 도 1과 같으며 화합물 4d 는 농도의존적으로 IL-11 유도 루시퍼라제 저해활성을 도 2와 같이 나타냈으며 그 IC50 값은 2.1 mM이었다.
IC 50 values of IL-6 induced luciferase inhibitory activity effect of the compounds is the same as Fig. 1 compound 4d is exhibited as shown in Figure 2 the concentration-dependently IL-11 induced luciferase inhibition activity The IC 50 values are 2.1 mM It was.

<1-3> <1-3> ILIL -6에 의해 유도된 Induced by -6 STAT3STAT3 인산화 저해활성 검정 Phosphorylation inhibitory activity assay

6 웰 플레이트에 5×104 세포/웰로 HepG2 세포를 분주하여 배양접시에 80% 가득차게 배양한 후, 무혈청 배지로 교환하여 추가로 6시간 배양하고 하기와 같이 시료를 30분간 처리하였다.HepG2 cells were dispensed at 5 × 10 4 cells / well in 6-well plates and cultured 80% full in a culture dish, then exchanged with serum-free medium for an additional 6 hours, and the samples were treated for 30 minutes as follows.

1: 음성대조군(비처리군);1: negative control group (non-treated group);

2: 양성대조군(IL-6 20 ng/㎖); 및2: positive control (IL-6 20 ng / ml); And

3: 화합물 4d 처리군(1, 3, 0.39, 10, 30 및 100 μM)3: compound 4d treatment group (1, 3, 0.39, 10, 30 and 100 μM)

이후 20 ng/㎖ IL-6를 처리하여 10분간 반응한 뒤 40 ㎕ 용해 완충용액[pH 8, 20 mM Tris-HCl, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM Na3VO4, 2 mM EDTA, 1 mM PMSF, 20 mM 류펩틴(leupeptin), 20 ㎍/㎖ 아포로토닌(aprotonin); Sigma, USA]을 사용하여 세포를 용해시킨 후, 원심분리 (13000g, 15분)하여 단백질이 녹아있는 상등액을 수득하였다. 이때, 시료 및 IL-6을 처리하지 않은 HepG2 세포를 대조군으로 사용하였다. 단백질의 농도는 DC 단백질 검사 키트(Bio-Rad, USA)를 이용하여 정량하였고, 10% SDS 폴리아크릴아마이드 겔(SDS-PAGE)에 단백질을 로딩하여 30 mA에서 2시간 동안 전기영동 하였다. 전기영동이 끝난 후 겔의 단백질을 PVDF 멤브레인(Westran S, pore size 0.2 ㎜; Whatman, USA)으로 90 V에서 90분 동안 전사시켰다. 전사된 멤브레인을 Tris-완충용액(T-TBS; 50 mM Tri-HCl, pH 7.6, 150 mM NaCl, 0.2 % Tween-20, 5% skim milk; Sigma, USA)으로 4℃에서 12시간 차단하고 T-TBS로 5번 세척하였다. 상기 멤브레인에 일차항체로 phospho-STAT3(1:1000 희석)의 다중클론 항체를 2시간 동안 처리하였다. T-TBS로 5번 세척 후 이차항체로 HRP-결합 항-래빗 항체(1:5000 희석)를 1시간 반응시켰다. T-TBS로 세척한 다음 암실에서 ECL 키트(Amersham, USA)를 이용하여 필름을 현상시켰다.After reacting for 10 minutes with 20 ng / ml IL-6, 40 μl lysis buffer [pH 8, 20 mM Tris-HCl, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM Na 3 VO 4 , 2 mM EDTA, 1 mM PMSF, 20 mM leupeptin, 20 μg / ml aprotonin; Sigma, USA] and the cells were lysed and centrifuged (13000 g, 15 minutes) to obtain a supernatant with dissolved protein. At this time, HepG2 cells not treated with the sample and IL-6 were used as a control. Protein concentration was quantified using a DC protein test kit (Bio-Rad, USA), and loaded on a 10% SDS polyacrylamide gel (SDS-PAGE) and electrophoresed at 30 mA for 2 hours. After electrophoresis, the protein of the gel was transferred to a PVDF membrane (Westran S, pore size 0.2 mm; Whatman, USA) at 90 V for 90 minutes. The transcribed membrane was blocked with Tris-buffer (T-TBS; 50 mM Tri-HCl, pH 7.6, 150 mM NaCl, 0.2% Tween-20, 5% skim milk; Sigma, USA) for 12 hours at 4 ° C and T Washed 5 times with TBS. The membrane was treated with polyclonal antibody of phospho-STAT3 (1: 1000 dilution) as a primary antibody for 2 hours. After washing 5 times with T-TBS, HRP-binding anti-rabbit antibody (1: 5000 dilution) was reacted with secondary antibody for 1 hour. After washing with T-TBS the film was developed using an ECL kit (Amersham, USA) in the dark.

그 결과, 도 3에서 나타난 바와 같이 본 발명의 화학식 1 화합물은 IL-6 유도 STAT3 인산화 저해 활성을 나타내었다.
As a result, as shown in Figure 3, the compound of formula 1 of the present invention showed IL-6 induced STAT3 phosphorylation inhibitory activity.

<1-4> <1-4> ILIL -6에 의해 유도된Induced by -6 JAK2JAK2 와 Wow gp130gp130 인산화 저해활성 Phosphorylation inhibitory activity

6 웰 플레이트에 5×104 세포/웰로 HepG2 세포를 분주하여 배양접시에 80% 가득차게 배양한 후, 무혈청 배지로 교환하여 추가로 6시간 배양하고 하기와 같이 시료를 30분간 처리하였다.HepG2 cells were dispensed at 5 × 10 4 cells / well in 6-well plates and cultured 80% full in a culture dish, then exchanged with serum-free medium for an additional 6 hours, and the samples were treated for 30 minutes as follows.

1: 음성대조군(비처리군);1: negative control group (non-treated group);

2: 양성대조군(IL-6 20 ng/㎖); 및2: positive control (IL-6 20 ng / ml); And

3: 화합물 4d 처리군(1, 3, 0.39, 10, 30 및 100 μM)3: compound 4d treatment group (1, 3, 0.39, 10, 30 and 100 μM)

이후 20 ng/㎖ IL-6를 처리하여 10분간 반응한 뒤 40 ㎕ 용해 완충용액[pH 8, 20 mM Tris-HCl, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM Na3VO4, 2 mM EDTA, 1 mM PMSF, 20 mM 류펩틴(leupeptin), 20 ㎍/㎖ 아포로토닌(aprotonin); Sigma, USA]을 사용하여 세포를 용해시킨 후, 원심분리 (13000g, 15분)하여 단백질이 녹아있는 상등액을 수득하였다. 여기에 항-JAK2 항체와 anti-gp130항체(Cell signaling, INC.)를 사용하여 4℃에서 12시간 반응시킨 후, protein A/G plus agarose (Santa Cruz Biotechnology, USA)로 침강시켰다. 원심분리 후 침강물은 완충용액으로 3회 세척 후 전기영동 시료로 사용하였다. 이 때 IL-6 및 시료를 처리하지 않은 HepG2 세포를 대조군으로 사용하였다. 단백질의 농도는 Bio-Rad DC protein assay kit를 이용하여 정량하였고, 8 % SDS-polyacryl-amide gels (SDS-PAGE)에서 단백질을 loading하여 30 mA에서 2시간동안 전기영동 하였다. 전기영동이 끝난 후 gel의 단백질을 PVDF membrane (WeatranS, pore size 0.2 ㎜)으로 90V에서 90분 동안 전사시켰다. 전사된 membrane을 Tris-buffered solution (T-TBS; 50 mM Tri-HCl, pH 7.6, 150 mM NaCl, 0.2 % Tween-20, 5% skim milk)로 4℃에서 12시간 blocking하고 T-TBS로 5번 세척하였다. 이 membranes에 일차항체로 phospho-tyrosine antibody (1:1000 dilutions, respectively)의 polyclonal antibodies를 2시간 동안 처리하였다. T-TBS로 5번 세척 후 이차항체로 HRP-conjucated anti-mouse antibody (1:5000 dilutions)를 1시간 반응시켰다. T-TBS로 세척한 다음 암실에서 ECL을 이용하여 필름을 현상시켰다. 그 결과, 도 4에서 나타난 바와 같이 본 발명의 화학식 1 화합물은 IL-6 유도 JAK2 및 gp130의 인산화 저해 활성을 나타내었다.
After reacting for 10 minutes with 20 ng / ml IL-6, 40 μl lysis buffer [pH 8, 20 mM Tris-HCl, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM Na 3 VO 4 , 2 mM EDTA, 1 mM PMSF, 20 mM leupeptin, 20 μg / ml aprotonin; Sigma, USA] and the cells were lysed and centrifuged (13000 g, 15 minutes) to obtain a supernatant with dissolved protein. It was reacted for 12 hours at 4 ° C using anti-JAK2 antibody and anti-gp130 antibody (Cell signaling, INC.), And then precipitated with protein A / G plus agarose (Santa Cruz Biotechnology, USA). After centrifugation, the precipitate was washed three times with a buffer solution and used as an electrophoretic sample. At this time, HepG2 cells not treated with IL-6 and samples were used as a control. Protein concentration was quantified using a Bio-Rad DC protein assay kit, and electrophoresed at 30 mA for 2 hours by loading proteins in 8% SDS-polyacryl-amide gels (SDS-PAGE). After the electrophoresis, the protein of the gel was transferred to a PVDF membrane (WeatranS, pore size 0.2 mm) at 90V for 90 minutes. The transcribed membrane was blocked with Tris-buffered solution (T-TBS; 50 mM Tri-HCl, pH 7.6, 150 mM NaCl, 0.2% Tween-20, 5% skim milk) at 4 ° C for 12 hours and 5 with T-TBS. Washed twice. The membranes were treated with polyclonal antibodies of phospho-tyrosine antibody (1: 1000 dilutions, respectively) for 2 hours. After washing five times with T-TBS, HRP-conjucated anti-mouse antibody (1: 5000 dilutions) was reacted with a secondary antibody for 1 hour. After washing with T-TBS the film was developed using ECL in the dark. As a result, as shown in Figure 4, the compound of formula 1 of the present invention showed the phosphorylation inhibitory activity of IL-6 induced JAK2 and gp130.

<1-5> <1-5> InsulinInsulin 에 의해 유도된 Induced by adipogenesisadipogenesis 에 대한 화합물 4d의 효과Effect of Compound 4d on

3T3L1 세포를 24 웰 세포 배양 플레이트에 confluence하게 되기 이틀 전에 분화배지(containing 5mg/ml insulin, 1mM dexamethasone, and 0.5 mM IBMX)로 바꾸어주고 8일 동안 2일에 한번 씩 분화배지로 바꾸어주면서 실험을 하였다. 이때 분화용 배지를 사용하지 않거나 분화배지에 IL-6 나 화학식 1 각각 단독으로 혼합하여 처리한 세포 그리고 분화배지에 IL-6와 화학식 1을 함께 혼합하여 처리한 세포를 비교하여 실험하였다. 8일후 세포는 PBS로 세척하고 PBS에 3.7% formaldehyde가 첨가된 용액으로 고정을 시킨 후, Oil Red O dye를 처리하여 1 시간동안 염색을 한다. 그리고 25 % isopropanol을 첨가하여 세척하고 현미경으로 관찰하였다. 그 결과, 도 5에 나타난 바와 같이, 본 발명의 화학식 1의 화합물은 인슐린-유도 아디포제네시스(adipogenesis)를 저해하는 IL-6 효과를 회복하는 활성을 나타내었다.Two days prior to confluence of 3T3L1 cells into a 24-well cell culture plate, the cells were changed to differentiation medium (containing 5 mg / ml insulin, 1 mM dexamethasone, and 0.5 mM IBMX) and changed into differentiation medium every other day for 8 days. . At this time, the experiment was performed by comparing the cells treated with IL-6 or Formula 1 alone and not treated with differentiation medium or mixed with IL-6 and Formula 1 in differentiation medium. After 8 days, the cells were washed with PBS, fixed with a solution containing 3.7% formaldehyde in PBS, and stained with Oil Red O dye for 1 hour. And 25% isopropanol was added to wash and observed under a microscope. As a result, as shown in Figure 5, the compound of formula 1 of the present invention showed the activity to restore the IL-6 effect that inhibits insulin-induced adipogenesis (adipogenesis).

Claims (7)

하기 화학식 1로 표시되는 인돌계 화합물 또는 이의 약학적으로 허용되는 염:
<화학식 1>
Figure 112011069568910-pat00025

상기에서 R1은 수소, 또는 치환 또는 비치환된 C1-10 알킬이고;
R2는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬이고;
R3는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이고;
R4는 수소, 또는 C1-10의 직쇄, 측쇄 또는 사이클로 알킬, 또는 치환 또는 비치환된 벤질이고;
X는 수소, 할로겐, 하이드록시, 메톡시, 치환 또는 비치환된 C1-10 알킬이고;
Y는 산소이고;
Z는 하이드록시, C1-10의 알콕시, -OCOCH3 또는 산소이고; 및
상기
Figure 112011069568910-pat00026
는 단일 또는 이중 결합이다.Indole compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
<Formula 1>
Figure 112011069568910-pat00025

R 1 is hydrogen or substituted or unsubstituted C 1-10 alkyl;
R 2 is hydrogen or C 1-10 straight, branched or cycloalkyl;
R 3 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl;
R 4 is hydrogen or C 1-10 straight, branched or cycloalkyl, or substituted or unsubstituted benzyl;
X is hydrogen, halogen, hydroxy, methoxy, substituted or unsubstituted C 1-10 alkyl;
Y is oxygen;
Z is hydroxy, C 1-10 alkoxy, —OCOCH 3 or oxygen; And
remind
Figure 112011069568910-pat00026
Is a single or double bond. 제1항에 있어서, 상기 R1은 하이드록시에틸 또는 터트-부틸디메틸실릴옥시에틸이고;
R2는 C1-5의 직쇄, 측쇄 또는 사이클로 알킬이고;
R3는 수소이고;
R4는 수소 또는 C1-5의 직쇄, 측쇄 또는 사이클로 알킬이고;
X는 수소, 할로겐, 하이드록시, 메톡시, 치환 또는 비치환된 C1-10 알킬이고;
Y는 산소이고;
Z는 하이드록시, C1-5의 알콕시, -OCOCH3 또는 산소이고; 및
상기
Figure 112011069568910-pat00027
는 단일 또는 이중 결합인 화합물, 또는 이의 약학적으로 허용가능한 염.The compound of claim 1, wherein R 1 is hydroxyethyl or tert-butyldimethylsilyloxyethyl;
R 2 is C 1-5 straight, branched or cycloalkyl;
R 3 is hydrogen;
R 4 is hydrogen or C 1-5 straight, branched or cycloalkyl;
X is hydrogen, halogen, hydroxy, methoxy, substituted or unsubstituted C 1-10 alkyl;
Y is oxygen;
Z is hydroxy, C 1-5 alkoxy, —OCOCH 3 or oxygen; And
remind
Figure 112011069568910-pat00027
Is a single or double bond, or a pharmaceutically acceptable salt thereof. 1) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온,
2) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트,
3) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트,
4) (2S,3S)-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트,
5) (2S,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-3-하이드록시-2-메틸-4-메틸렌노난-1-온,
6) (2S,3S)-3-하이드록시-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-1-온,
7) (2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-3-올,
8) (2R,3S)-1-(3-(2-(터트-부틸디메틸실릴옥시)에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-3-올,
9) (2R,3S)-1-(3-(2-하이드록시에틸)-1H-인돌-1-일)-2-메틸-4-메틸렌노난-3-올,
10) (2S,3S)-3-하이드록시-1-(3-(2-하이드록시에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-1-온,
11) (2S,3S)-1-(3-(2-하이드록시에틸)인돌린-1-일)-2-메틸-4-메틸렌-1-옥소노난-3-일 아세테이트 및
12) (2R,3S)-1-(3-(2-하이드록시에틸)인돌린-1-일)-2-메틸-4-메틸렌노난-3-올
으로 이루어진 군으로부터 선택되는 인돌계 화합물 또는 이의 약학적으로 허용가능한 염.1) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -3-hydroxy-2-methyl-4-methylenenonan-1- On,
2) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylene-1-oxononane-3- Work acetate,
3) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -2-methyl-4-methylene-1-oxononane- 3-yl acetate,
4) (2S, 3S) -1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2-methyl-4-methylene-1-oxononan-3-yl acetate,
5) (2S, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -3-hydroxy-2-methyl-4-methylenenonan- 1-On,
6) (2S, 3S) -3-hydroxy-1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-1-one,
7) (2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) indolin-1-yl) -2-methyl-4-methylenenonan-3-ol,
8) (2R, 3S) -1- (3- (2- (tert-butyldimethylsilyloxy) ethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-3-ol,
9) (2R, 3S) -1- (3- (2-hydroxyethyl) -1H-indol-1-yl) -2-methyl-4-methylenenonan-3-ol,
10) (2S, 3S) -3-hydroxy-1- (3- (2-hydroxyethyl) indolin-1-yl) -2-methyl-4-methylenenonan-1-one,
11) (2S, 3S) -1- (3- (2-hydroxyethyl) indolin-1-yl) -2-methyl-4-methylene-1-oxononan-3-yl acetate and
12) (2R, 3S) -1- (3- (2-hydroxyethyl) indolin-1-yl) -2-methyl-4-methylenenonan-3-ol
Indole compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 염증성 질환 또는 암의 예방 및 치료용 약학 조성물.A pharmaceutical composition for preventing and treating an inflammatory disease or cancer, comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 제4항에 있어서, 상기 염증성 질환 또는 암은 IL-6 또는 IL-11 에 의해 유발되는 것인 조성물.The composition of claim 4, wherein the inflammatory disease or cancer is caused by IL-6 or IL-11. 제4항에 있어서, 상기 염증성질환은 류마티스 관절염, 골다공증, 형질구 증가증, 초면역 글로불린 혈증, 빈혈, 신염, 악액질, 맥관증식신염, 다발성 경화증, 포도막염, 만성 갑상선염, 지연과민증, 접촉피부염 아토피성 피부염, 전신성 홍반증, 크론병, 췌장염, 건선, 연소성 특발성 위축증, 당뇨병 및 알쯔하이머로 구성되는 군으로부터 선택되는 질환인 조성물.The method of claim 4, wherein the inflammatory disease is rheumatoid arthritis, osteoporosis, plasmacytosis, hyperimmunoglobulinemia, anemia, nephritis, cachexia, vasculitis, multiple sclerosis, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis atopic dermatitis And systemic erythematosis, Crohn's disease, pancreatitis, psoriasis, juvenile idiopathic atrophy, diabetes and Alzheimer's disease. 제4항에 있어서, 상기 암은 췌장암, 유방암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 흑색종, 백혈병, 림프종, 간암, 위암, 결장암, 골암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종 및 중추신경계 종양로 구성되는 군으로부터 선택되는 암인 조성물.According to claim 4, wherein the cancer is pancreatic cancer, breast cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, melanoma, leukemia, lymphoma, liver cancer, gastric cancer, colon cancer, bone cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, Small bowel cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor A composition which is a cancer selected from the group consisting of.
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