KR101551187B1 - Indazole derivatives selectively inhibiting the activity of Janus kinase 1 - Google Patents
Indazole derivatives selectively inhibiting the activity of Janus kinase 1 Download PDFInfo
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- KR101551187B1 KR101551187B1 KR1020130112617A KR20130112617A KR101551187B1 KR 101551187 B1 KR101551187 B1 KR 101551187B1 KR 1020130112617 A KR1020130112617 A KR 1020130112617A KR 20130112617 A KR20130112617 A KR 20130112617A KR 101551187 B1 KR101551187 B1 KR 101551187B1
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- indazole
- yield
- bromo
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Abstract
본 발명은 야누스 키나아제 1 (Janus Kinase 1)의 활성을 선택적으로 저해하는 활성을 갖는 인다졸 유도체 및 그 화합물의 류마티스성 관절염 치료제로서의 용도에 관한 것이다.INDUSTRIAL APPLICABILITY The present invention relates to an indazole derivative having an activity of selectively inhibiting the activity of Janus Kinase 1 and its use as a therapeutic agent for rheumatoid arthritis.
Description
본 발명은 인다졸 유도체 및 그것의 야누스 키나아제 1의 활성을 선택적으로 저해하는 특성과 류마티스성 관절염 치료제로서의 용도이다.INDUSTRIAL APPLICABILITY The present invention relates to an indazole derivative and its selective inhibition of the activity of Janus kinase 1 and its use as a therapeutic agent for rheumatoid arthritis.
면역억제제란 생체의 면역반응을 억제하는 약제의 총칭으로서, 장기이식거부반응 및 자가면역질환의 치료와 예방을 위한 약제로 주로 이용된다.An immunosuppressant is a generic term for an agent that inhibits the immune response of a living body. It is mainly used as a drug for the treatment and prevention of organ transplant rejection and autoimmune diseases.
장기이식은 새로운 치료법의 개발이 없는 한, 말기 장기부전증 치료에 최상의 치료법으로써, 필요성과 수요의 규모면에서 전망이 밝은 분야이다. 이식된 조직/장기를 면역거부반응으로부터 보호하기 위해 면역억제제를 이용하며, 오늘날 25가지의 장기이식이 이루어지고 있다.Organ transplantation is the best treatment for end-stage organ failure, unless there is development of new therapies, which is a bright field of view in terms of the need and demand. Immunosuppressants are used to protect implanted tissues / organs from immune rejection, and there are now 25 organ transplants.
자가면역질환(autoimmune disease)는 개체의 면역체계가 내인성 단백질을 외부항원으로 인식하여 형성된 항체나 면역기능을 가진 T세포들이 항원에 반응해서 조직을 파괴해서 생기는 질환으로써 류마티스(관절염), 아토피피부염, 건선, 크론씨 병, 등이 포함된다. 명확한 발생경로나 기전에 대해 밝혀지지 않아 현재는 근본적인 치료제 없이 스테로이드 등의 면역억제제에 의존하여 일시적 증상 개선효과 만을 보고 있는 실정이며, 면역억제요법은 이러한 자가면역반응을 억제하는데 효과적인 것으로 밝혀져 있다.An autoimmune disease is an autoimmune disease that occurs when an immune system of an individual recognizes an endogenous protein as an external antigen, or an immune-functioning T cell is destroyed by the action of an antigen to destroy the tissue. The disease is caused by rheumatoid arthritis, Psoriasis, Crohn's disease, and the like. It has not been clarified about the clear pathogenesis and mechanism. Currently, it is reported that the effect of the immunosuppressive drug such as steroids is temporarily improved without the fundamental treatment, and immunosuppressive therapy has been proved to be effective in suppressing such autoimmune response.
면역억제제는 크게 화학적 면역억제제와 생물학적 면역억제제로 나뉜다.Immunosuppressants are largely divided into chemical immunosuppressants and biological immunosuppressants.
화학적 면역억제제는 장기이식거부반응과 자가면역질환 치료를 위해 가장 많이 처방되는 면역억제제로서, 노바티스의 사이클로스포린 A (CsA, 전체의 85%)와 작용기작이 거의 같은 Fujisawa의 FK506이 대표적이다. 그러나 화학적 면역억제제의 약물 작용점이 되는 신호전달 과정은 활성화된 면역세포에 특이적이지 않으며 따라서 비선택적인 신호전달 저해에 의해 다양하고 심각한 부작용이 나타난다는 문제점을 가지고 있다.Chemical immunosuppressants are the most commonly prescribed immunosuppressants for the treatment of organ transplant rejection and autoimmune diseases, and Fujisawa's FK506, which has almost the same mechanism of action as Cyclosporine A (85% of the total) of Novartis is representative. However, the signal transduction pathway, which is the point of drug action of the chemical immunosuppressant, is not specific to activated immune cells, and thus has various problems such as nonselective signal transduction inhibition, which causes various serious side effects.
이에 반해, 생물학적 면역억제제 중에는 류마티스성 관절염 (RA), 건선, 크론씨병 등의 자가면역질환 치료제로 이용되는 TNF-α 저해제(etanercept, infliximab, adalimumab)가 대표적이다. 또한 장기이식 환자의 면역체계에 대한 단일항체(monoclonal antibody)나 복합항체 (polyclonal antibody)로 대표되는 치료용 항체 제제에는 Daclizumab(Zenapax)와 Basiliximab(Simulect) 등이 있으며 이외에도 Siplizumab(MEDI-507)과 ABXCBL 등이 개발되고 있다. 항체제제는 환자 면역체계요소의 작용을 소멸시켜서 면역반응이 일어나는 것을 억제하기도 하는데, 임상적으로 가장 많이 사용하는 항체는 B세포와 T세포에 대한 항체이며 그 외에도 IL-2 수용체(CD25)와 CTLA-4, CD40과 CD40 리간드에 대한 항체 등이 사용된다. 그러나, 생물학적 면역억제제는 다음과 같은 많은 문제점을 가지고 있다: 1) TNF-α의 경우, 모든 RA 환자에 효과를 나타내지 않으며 불응도가 30%를 상회하며, 2) 활성화된 면역세포에 대한 선택성의 부재로 인한 부작용이 여전한 문제로 남아 있고, 3) 개발 및 치료시 아주 많은 비용이 드는데, 면역억제제의 경우 평생 동안 복용해야 하므로 환자에게 매우 큰 경제적 부담을 줄 수 있으며, 4) 주사제로 개발되기 때문에 환자순응도가 매우 낮고 주사부작용 및 감염위험이 있다.In contrast, biological immunosuppressants include TNF-α inhibitors (etanercept, infliximab, and adalimumab), which are used as therapeutic agents for autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's disease. Daclizumab (Zenapax) and Basiliximab (Simulect) are also available for treatment of monoclonal antibodies or polyclonal antibodies to organ systems in organ transplant recipients. ABXCBL and the like are being developed. In addition, antibodies to B cells and T cells are the most clinically used antibodies. In addition, IL-2 receptor (CD25) and CTLA -4, antibodies against CD40 and CD40 ligands, and the like. However, biological immunosuppressants have a number of problems, including: 1) TNF-α has no effect on all RA patients and has more than 30% non-compliance; 2) selective immunity to activated immune cells 3) It is very expensive for development and treatment. Immunosuppressive drugs should be taken over a lifetime, which can give a great economic burden to patients. 4) Because they are developed as injections Patient compliance is very low and there is a risk of injection side effects and infection.
한편 이식수술이 늘고 환자의 잔여 생존기간도 길어짐에 따라 최근에는 면역억제제의 부작용을 최소화하여 이식수술을 받은 환자들의 '삶의 질'을 높이려는 노력이 요구되고 있다. 이상적인 면역억제제란 항원에 특이적으로 반응하는 클론(clone)만을 선택적으로 억제하는 특이적인 면역억제이어야 하나, 아직은 임상적 이용이 가능한 단계가 아니며, 현재 사용되고 있는 약제는 활성화된 면역세포에 대한 특이성이 없는 면역억제제로서 숙주의 정상 면역반응까지 저해하여 신장과 간 등에 치명적인 부작용을 나타내고, 감염증, 악성 종양 등의 합병증을 일으킨다. 현재까지는 단일약품으로는 거부반응을 방지할 만한 충분한 효능을 얻을 수 없기 때문에, 여러 가지 방법의 병합치료가 필요한 실정이다. 따라서 증가하는 수요와 맞물려 장기이식환자가 평생 복용해야 하는 면역억제제의 수요도 큰 폭으로 증가하고 있으나 장기복용에 따르는 부작용과 비싼 가격 등으로 인하여 신규 면역억제제의 개발에 대한 요구가 커지고 있다.As the number of transplantation surgeries increases and the patient's survival is prolonged, recent efforts to minimize the side effects of immunosuppressants and improve the 'quality of life' of patients undergoing transplant surgery are required. The ideal immunosuppressive agent should be a specific immunosuppression that selectively inhibits only the clone that specifically reacts with the antigen, but it is not yet a stage that can be used clinically, and the currently used agent has a specificity for the activated immune cells As a non-immunosuppressive agent, it inhibits the host's normal immune response and causes lethal side effects in the kidneys and liver, and causes complications such as infectious diseases and malignant tumors. Until now, a single drug can not achieve sufficient efficacy to prevent rejection, so it is necessary to combine several methods. Therefore, the demand for immunosuppressive drugs that organ transplant patients have to use for a lifetime is also increasing, but the demand for the development of new immunosuppressants is increasing due to the side effects and the high price of long-term use.
면역세포는 cytokine에 의해 신호를 전달받으며 따라서 각 cytokine에 특이적인 receptor가 존재한다. 이 중, IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 등과 결합하는 cytokine receptor는 ‘common cytokine receptor γ-chain (γc)'라는 핵심적인 부분을 가지고 있어 γc family라고 불리는데, 이들은 림프구의 형성과 작용에 결정적인 역할을 하는 것으로 알려져 있으며 따라서 γc를 coding 하는 유전자에 mutation이 생기거나, γc로부터의 신호전달과정 다음 단계에 있는 cytoplasmic tyrosine kinase JAK3 (janus kinase 3)를 coding 하는 유전자에 mutation이 생기면 선천성면역결핍증상(SCID)가 발생하는 것으로 알려져 있다. 결과적으로 JAK3의 활성을 선택적으로 저해할 수 있는 물질을 이용한 면역억제제 개발 연구가 활발히 시도되어져 왔다.Immune cells are signaled by the cytokine, and therefore, there is a specific receptor for each cytokine. The cytokine receptors that bind to IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 have a central part called the common cytokine receptor γ-chain γc family, which are known to play a crucial role in the formation and function of lymphocytes. Therefore, mutations in the gene coding for γc may occur, or the cytoplasmic tyrosine kinase JAK3 (janus kinase 3) (SCID) is known to occur when a mutation in a gene coding for a mutation occurs. As a result, studies on the development of immunosuppressive agents using a substance capable of selectively inhibiting the activity of JAK3 have been actively attempted.
많은 제약회사들은 JAK3의 선택적 저해활성에 의해 류마티스성 관절염(Rheumatoid arthritis, RA)과 같은 면역질환 치료제를 개발할 수 있을 것으로 기대하고 경쟁적으로 JAK3 저해제 개발 연구를 진행하였으며, 그 결과 최근 Pfizer사의 Xelianz (Tofacitinib, CP-690,550)가 류마티스성 관절염 치료제로서 FDA에 의해 승인되기에 이르렀다.Many pharmaceutical companies have competitively developed JAK3 inhibitors in anticipation of the development of therapeutic agents for immune diseases such as rheumatoid arthritis (RA) by the selective inhibition activity of JAK3. As a result, recently, Pfizer's Xelianz (Tofacitinib , CP-690,550) has been approved by the FDA as a treatment for rheumatoid arthritis.
그러나 개발 초기에 JAK3 선택적 저해활성을 갖는 것으로 알려졌던 CP-690,550은 그 이후 JAK kinase family에 대한 전반적인 저해활성을 갖는 pan-JAK inhibitor 임이 밝혀졌으며(Science 2003, 302:875), 따라서 류마티스성 관절염 치료제로서의 효능에 어떠한 JAK 이소자임의 저해활성이 가장 중요한 요소인지에 대한 논란이 계속되어져 왔다.However, CP-690,550, which was known to have JAK3 selective inhibitory activity at the early stage of development, has since been found to be a pan-JAK inhibitor with overall inhibitory activity against the JAK kinase family ( Science 2003, 302: 875) Has been controversial as to whether the inhibitory activity of any JAK isozyme is the most important factor.
최근 일련의 연구결과들을 종합하면(Cell 1998, 93:373; Immunity 2000, 13:561; Cell 1998, 93:385; Lancet 2008, 371:987; Chem . Biol . 2011, 18:314) γc와 관련된 cytokine 수용체에 의한 신호전달 과정에 있어 핵심적인 역할을 수행하는 JAK kinase는 JAK1이며 JAK3는 단지 매우 보조적인 역할 밖에는 담당하지 않는 것을 확인할 수 있다.A recent series of studies ( Cell 1998, 93: 373; Immunity 2000, 13: 561; Cell 1998, 93: 385; Lancet 2008, 371: 987; Chem . Biol . 2011, 18: 314). The JAK kinase, which plays a key role in the signal transduction pathway by γc-related cytokine receptors, is JAK1 and JAK3 plays only a very minor role.
따라서 RA 치료제 분야에 있어 JAK 저해제 개발 연구는 JAK3가 아닌 JAK1에 집중하고 있으며, 최근 JAK1 선택적인 활성을 갖는 물질들이 속속 발표되어지고 있다(J. Med. Chem. 2012, 55:5901; J. Med. Chem. 2012, 55:6176).Therefore, JAK inhibitor development research in the field of RA therapy focuses on JAK1 rather than JAK3, and recently JAK1 selective activating substances have been reported (J. Med. Chem. 2012, 55: 5901; J. Med Chem., 2012, 55: 6176).
한편, JAK2는 erythropoiesis에 관계된 신호전달 과정에서 결정적인 역할을 하고 있으므로, JAK2의 활성이 저해되게 되면 빈혈, 혈소판 감소증, 백혈구 감소증 등과 같은 조혈작용에 문제가 생길 수 있다. 자가면역질환 환자의 8-70%, 그리고 장기이식환자의 8-71%에서 적혈구 생성 저하에 의한 염증성 빈혈(Anemia in Inflammation, AI)이 발견되는데 염증성 cytokine IL-1, TNF-α, TGF-β 등은 빈혈 상황에서 적혈구 생산을 감소시킬 수 있다. 따라서, 평생 동안 복용하게 되는 면역억제제 개발에 있어 환자의 염증성 빈혈 악화를 막기 위해서는 JAK2에 대한 선택성이 반드시 확보되어야 할 것이다.On the other hand, JAK2 plays a crucial role in the signal transduction process related to erythropoiesis. Thus, when JAK2 activity is inhibited, hematopoiesis such as anemia, thrombocytopenia, and leukopenia may occur. Inflammatory cytokines IL-1, TNF-α, and TGF-β are found in 8-70% of autoimmune disease patients and in 8-71% of organ transplant patients. Etc. can reduce red blood cell production in anemia situations. Therefore, in the development of immunosuppressants to be taken over a lifetime, selectivity to JAK2 must be ensured to prevent the patient's inflammatory anemia deterioration.
[선행 특허 문헌][Prior Patent Literature]
한국특허공개번호 제1020100032886호Korean Patent Publication No. 1020100032886
본 발명은 상기의 문제점을 해결하고, 상기의 필요성에 의하여 안출된 것으로서 본 발명의 목적은 인다졸 유도체를 이용하여 JAK1/JAK2 선택성이 제고된 신규 저해제를 개발함으로써 신규 류마티스성 관절염 치료제를 개발하는데 그 목적을 두고 있다. DISCLOSURE OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to develop a new therapeutic agent for rheumatoid arthritis by developing a novel inhibitor with enhanced JAK1 / JAK2 selectivity using an indazole derivative, It is aimed at.
상기의 목적을 달성하기 위하여 본 발명은 하기 [화학식 1]의 화합물 또는 그의 약학적으로 허용 가능한 염을 제공한다:In order to accomplish the above object, the present invention provides a compound of the following general formula (I) or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
상기 화학식에서 n은 1 혹은 2의 정수, R2는 수소 혹은 아미노기를 갖는 것을 특징으로 한다.In the above formula, n is an integer of 1 or 2, and R 2 is hydrogen or an amino group.
또한 본 발명은 본 발명의 상기 화합물을 유효성분으로 포함하는 야누스 키나아제 1 저해용 조성물을 제공한다.The present invention also provides a composition for inhibiting Janus kinase 1 comprising the compound of the present invention as an active ingredient.
또 본 발명은 상기 본 발명의 화합물을 유효성분으로 포함하는 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition comprising the compound of the present invention as an active ingredient.
또한 본 발명의 일 구현예에 있어서, 상기 조성물은 류마티스성 관절염 치료 또는 예방 효과를 가지는 것이 바람직하나 이에 한정되지 아니한다.In addition, in one embodiment of the present invention, the composition is preferably but not limited to have a therapeutic or preventive effect on rheumatoid arthritis.
또 본 발명은 상기 본 발명의 화합물을 유효성분으로 포함하는 류마티스성 관절염 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for improving rheumatoid arthritis comprising the compound of the present invention as an active ingredient.
또한 본 발명은 3-알키놀일-5-브로모-인다졸-7-카르복사마이드와 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로란-2-일)-1H-인다졸 유도체의 수주키(Suzuki) 커플링 반응 및 Boc-보호기 제거 반응을 포함하는 상기 본 발명의 화합물의 제조방법을 제공한다.The present invention also relates to a process for the preparation of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- A Suzuki coupling reaction and a Boc-protecting group elimination reaction of the compound of the present invention.
본 발명의 조성물은 국소적으로, 경구로, 또는 비경구로 투여될 수 있다. 예를 들면 조성물은 체외로, 두개골 내로, 질 내로, 항문 내로, 피하고, 피부 안으로, 심장 내로, 위 내로, 정맥 내로, 근육 내로, 복강내 주사에 의해, 경피적으로, 비강 안으로, 또는 흡입에 의하여 투여될 수 있다. 본원에서 사용되는 "두개골 내 투여"는 물질을 키테테르 또는 주사바늘을 통해 뇌로 직접, 이를테면 예컨대 인트라테칼로(intrathecal), 인트라시스터널로(intracisternal), 심실내로, 또는 설상골을 통하여(transsphenoidal) 전달되는 것을 의미한다.The compositions of the present invention may be administered topically, orally, or parenterally. For example, the composition can be administered extracorporeally, into the skull, into the vagina, into the rectum, into the skin, into the heart, into the heart, into the stomach, intravenously, intramuscularly, intraperitoneally, percutaneously, intranasally, ≪ / RTI > As used herein, "intracranial administration" refers to administration of a substance directly to the brain via a catheter or needle, such as through an intrathecal, intracisternal, intracisternal, or transsphenoidal ).
조성물의 비경구 투여는, 사용되는 경우 일반적으로 주사에 의하여 이루어지는 것을 특징으로 한다. 주사가능한 것은 종래 형태로, 액체 용액 또는 현탁액으로서, 주사 전에 액체의 현탁 용액에 적당한 고체 형태, 또는 에멀션으로서 제조될 수 있다. 보다 최근에 개선된 비경구 투여를 위한 접근법은 느린 방출 또는 지속적인 방출 시스템을 사용함으로써 일정한 용량이 유지되도록 사는 것을 포함한다 (미국 특허 3,610,795호 참조).The parenteral administration of the composition, when used, is generally characterized by injection. The injectable can be prepared in conventional form, as a liquid solution or suspension, in the form of a solid suitable for suspension in liquid before injection, or as an emulsion. More recently, the approach for improved parenteral administration involves living to maintain a constant dose by using a slow release or sustained release system (see U.S. Patent No. 3,610,795).
필요한 조성물의 정확한 양은 환자에 따라서 종, 연령, 체중 및 일반적인 환자의 상태, 치료되고 있는 알레르기성 장애의 심각성, 그것의 투여 방식 등에 따라 다를 것이다. 그러므로 모든 조성물에 대하여 정확한 양을 규명하는 것은 불가능하다. 그러나 적절한 양은 당업자에 의해 당업계에서 제공되는 교시에 따라 기본적인 실험만을 사용하여서도 결정될 수 있다.The exact amount of composition required will depend on the patient, age, weight and general condition of the patient, the severity of the allergic disorder being treated, the manner of administration, etc., depending on the patient. It is therefore impossible to determine the exact amount for all compositions. However, the appropriate amount can also be determined by those skilled in the art using only basic experimentation according to the teachings provided in the art.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만,당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물은 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. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 0.001 to 100 mg / kg per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
본 발명의 약학조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.
본 발명의 조성물의 약학적 투여 형태는 이들의 약학적 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다.The pharmaceutical dosage forms of the compositions of the present invention may also be used in the form of their pharmaceutically acceptable salts and may be used alone or in combination with other therapeutically active compounds as well as in a suitable set.
산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 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 추출액에 적어도 하나 이상의 부형제 예를 들면, 전분,칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제,유제, 시럽제 등이 해당되는데 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.And may be formulated in the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized injection solutions. Examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose , Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명은 류마티스성 관절염 개선 효과를 나타내는 본 발명의 화합물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강보조식품을 제공한다. 본 발명의 화합물을 첨가할 수 있는 식품으로는,예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The present invention provides a health supplement comprising a compound of the present invention and a pharmaceutically acceptable food-aid additive exhibiting the effect of improving rheumatoid arthritis. Examples of foods to which the compound of the present invention can be added include various foods, beverages, gums, tea, vitamin complexes, health supplements and the like, and they can be used in powder, granule, tablet, have.
또한, 류마티스성 관절염 개선의 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 화합물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.It can also be added to foods or beverages for the purpose of improving rheumatoid arthritis. At this time, the amount of the compound in the food or drink may be 0.01 to 15% by weight of the total food, and the health beverage composition may be added in a proportion of 0.02 to 5 g, preferably 0.3 to 1 g, have.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물100 당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health functional beverage composition of the present invention is not particularly limited to the other ingredients other than the above-mentioned compounds as essential ingredients in the indicated ratios and may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the composition of the present invention.
상기 외에 본 발명의 화합물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 화합물은 천연 과일 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition to the above, the compound of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compounds of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 화합물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the compound of the present invention.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에서는 JAK2 보다 JAK1에 대해 선택적인 저해능을 가는 저해제를 개발하고자 하였다. 이를 위하여 우선 JAK1의 기질결합자리가 다른 이소자임의 기질결합자리와 비교했을 때 어떠한 특이성을 갖는지에 대해 이해할 필요가 있었는데, 동일한 기질 혹은 저해제와 결합하고 있는 각 이소자임의 삼차원 구조를 비교함으로써 이 문제를 해결하고자 하였다. In the present invention, an inhibitor which is more selective than JAK2 against JAK1 was developed. For this purpose, it was first necessary to understand the specificity of the JAK1 substrate binding site compared to the substrate binding sites of other isozymes. By comparing the three-dimensional structure of each isozyme binding to the same substrate or inhibitor, .
따라서 PDB에서 C-2 methyl imidazopyrrolopyridines (CMP)와 결합된 JAK1 (PDB ID = 3EYH), JAK2 (PDB ID = 2B7A), JAK3 (PDB ID = 3LXL), 그리고 Tyk2 (PDB ID = 3LXP)의 삼차원 구조를 내려받은 후, 이 구조를 분자모델링 소프트웨어인 Maestro의 ‘protein structure alignment’도구를 활용하여 함께 포개어 보았다 [도 1]. 상대적으로 나머지 kinase들과 구조적 유사성이 적은 Tyk2의 구조를 제외한 JAK 1 ~ 3의 구조는 매우 잘 포개어진 것을 볼 수 있었으나, 이들의 구조는 소위 ‘glycine-loop’라고 불리는 부분에서 미세한, 그렇지만 매우 특징적인 차이를 보임을 관찰할 수 있었다. 즉, JAK1은 이 부분에서 Asp1003와 His885가 수소결합함으로써 결과적으로 JAK2 및 JAK3와 비교했을 때 상대적으로 작은 기질결합자리를 갖는다. 또한, JAK1의 His885에 해당하는 JAK2의 아미노산 잔기인 Phe860은 N-말단 lobe에 있는 Asp976과 멀리 떨어진 상태로 방향족 사슬을 배치하는 것을 볼 수 있는데, 그 결과 JAK2의 기질결합자리는 상대적으로 열린 구조를 갖는다 [도 1]. Therefore, the three-dimensional structure of JAK1 (PDB ID = 3EYH), JAK2 (PDB ID = 2B7A), JAK3 (PDB ID = 3LXL) and Tyk2 (PDB ID = 3LXP) combined with C-2 methyl imidazopyrrolopyridines (CMP) After downloading, this structure was superimposed together using the 'protein structure alignment' tool of the molecular modeling software Maestro [Fig. 1]. The structure of JAK 1 ~ 3, except for the structure of tyk2, which is relatively less structurally similar to the rest of the kinases, can be seen to be superimposed very well, but their structure is finely, but very characteristic, in the so-called glycine- And it was observed that there was a significant difference. That is, JAK1 has a relatively small substrate binding site as compared to JAK2 and JAK3, resulting in hydrogen bonding of Asp1003 and His885 at this site. In addition, Phe860, an amino acid residue of JAK2 corresponding to His885 of JAK1, can be seen to place an aromatic chain away from Asp976 in the N-terminal lobe. As a result, the substrate binding site of JAK2 has a relatively open structure (Fig. 1).
이러한 구조적 특징으로 인하여 JAK1은 기질결합자리 바로 아래에 짧은 직선 사슬형태의 작용기와 결합하기에 적당한 크기를 갖는 작은 cavity를 갖게 된다 [도 2]. 또한 이 cavity 아래 부분에는 수소결합을 형성하는 Asp1003과 His885가 위치하므로 cavity에 결합하는 직선형태의 작용기 말단에 극성 작용기를 도입함으로써 cavity와의 결합력을 극대화할 수 있을 것으로 기대하였다.Due to this structural feature, JAK1 has a small cavity with a size suitable for binding with a short straight-chain functional group directly below the substrate binding site (Fig. 2). Asp1003 and His885, which form hydrogen bonds, are located in the lower part of the cavity, it is expected to maximize the bonding force with the cavity by introducing the polar functional group at the end of the straight type functional group bonding to the cavity.
이러한 발견에 근거하여 본 발명에서는 JAK1의 cavity에 효과적으로 결합할 수 있는 짧은 직선 사슬형태의 작용기로서 propargyl alcohol 및 but-3-yn-1-ol을 도입한 신규 JAK1 선택적 저해제를 고안하였는데, 구체적으로는 [화학식 1]에서와 같이 indazole-7-carboxamide 모핵을 kinase hinge motif와 수소결합하는 scaffold로 한 상태에서 indazole 3번 위치에 propargyl alcohol 혹은 but-3-yn-1-ol을 도입하며, 또한 indazole의 5번 위치에는 기질결합자리와의 혐수성 결합을 유도함으로써 JAK 기질결합자리와의 결합력을 높이기 위하여 또 하나의 indazole 고리를 결합한 물질의 구조를 고안하였다.Based on these findings, the inventors of the present invention have devised a novel JAK1 selective inhibitor that incorporates propargyl alcohol and but-3-yn-1-ol as short chain linear functional groups capable of effectively binding to the cavity of JAK1, 3-yn-1-ol is introduced at the 3-position of indazole in the state of the scaffold which hydrogen bonds the indazole-7-carboxamide nucleotide with the kinase hinge motif as shown in Formula 1, In order to induce the hydrophobic bond with the substrate binding site at
[화학식 1][Chemical Formula 1]
따라서 본 발명에서는, [화학식 1]로 대표되는 indazole 유도체를 화학적으로 합성하여 [도 3] ~ [도 5], JAK1, JAK2, JAK3, 및 Tyk2 저해능을 검증함으로써 [도 6] 선택적인 JAK1 저해제로서의 새로운 용도를 발견하고 발명을 완결하였다. Thus, in the present invention, an indazole derivative represented by Chemical Formula 1 is chemically synthesized to verify the inhibition of JAK1, JAK2, JAK3, and Tyk2 [Fig. 3] to [Fig. 5] Discovered new uses and completed inventions.
Indazole 유도체의 합성은 공지된 합성법을 준용하였다 [도 3] ~ [도 5]. 상술하자면, 5-(4′-indazolyl)indazole-7-carboxamide 유도체 (1a ~ 1f)는 3-alkynolyl-5-bromo-indazole-7-carboxamides (2a ~ 2c)와 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole derivatives (3a ~ 3b)의 Suzuki coupling 반응 및 Boc-protecting group 제거 반응에 의해 35% ~ 68%의 수율로 합성되었다 [도 3].The synthesis of the indazole derivative was applied in accordance with a known synthesis method (Fig. 3 to Fig. 5). Gritty above, 5- (4'-indazolyl) indazole -7-carboxamide derivative (1a ~ 1f) is 3-alkynolyl-5-bromo- indazole-7-carboxamides (2a ~ 2c) and 4- (4,4,5 Suzuki coupling reaction and Boc-protecting group removal of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole derivatives ( 3a to 3b ) [Fig. 3].
이 때, 주중간체인 3-alkynolyl-5-bromo-indazole-7-carboxamides (2a ~ 2c)와 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole derivatives (3a ~ 3b)는 각각 methyl 2-amino-3-methylbenzoate 4 [도 4]와 2,4-dinitrotoluene 8 [도 5]를 출발물질로 하여 합성되었다. At this time, the main intermediates 3-alkynolyl-5-bromo-indazole-7-carboxamides ( 2a to 2c ) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- -1H-indazole derivatives ( 3a to 3b ) were synthesized starting from methyl 2-amino-3-methylbenzoate 4 [FIG. 4] and 2,4-dinitrotoluene 8 [FIG.
우선, 화합물 4를 NBS와 반응하여 아미노기의 파라위치에 선택적으로 브롬화 반응을 실시함으로써 화합물 5를 62% 수율로 얻었다 [도 4]. Indazole 고리의 합성은 공지된 바대로[WO 2009146406, 2009], 아세틸화에 이은 다이아조화 반응에 의해 이루어졌으며, 그 결과 6a (46% 수율)와 6b (35% 수율)의 혼합물을 얻었다. 화합물 6a의 아세틸기를 메탄올 용매하에서 6N HCl로 처리함으로써 정량적으로 화합물 6b로 전환할 수 있었다. 그리하여 얻어진 화합물 6b는 일련의 가수분해, 아미드화 반응, 그리고 Boc-protection에 의하여 95% 수율로 아미드 2a로 전환되었으며, 화합물 2a를 NIS로 처리하여 3-iodoindazole 7을 54% 수율로 얻을 수 있었다. 화합물 7과 propargyl alcohol 혹은 but-3-yn-1-ol 과의 Sonogashira coupling 반응에 의해 목적하는 화합물 indazolyl-3-alkynols 2b 및 2c를 각각 36% 및 30%의 수율로 획득할 수 있었다.[도 4]First,
한편, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 유도체(3a ~ 3b)는 위와 비슷한 합성방법을 활용하여 합성되었다[도 5]. 즉, 시장 구입한 2,4-dinitrotoluene (8)을 NBS와 반응하여 브롬화한 후, 철 파우더를 이용한 니트로기의 환원반응에 의해 3-bromo-4-methyl-5-nitroaniline과3-bromo-2-methyl-5-nitroaniline을 3:1의 비율로 혼합된 상태로 얻었다 (74% 수율). 환원반응에 의해 얻어진 아미노기를 Boc-protection한 후, 남아있는 니트로기를 다시 환원함으로써 목적하는 화합물 9a를 위치이성질체인 9b와 함께 얻고, 각각을 실리카겔 관크로마토그래피에 의해 분리하였다. 위에서와 같은 반응 조건하에서 화합물 9a를 고리화함으로써 indazole 화합물 11a와 11b를 합성할 수 있었으며 (81% 수율), 이 때 화합물 11a는 탈아세틸화 반응에 의해 정량적으로 11b로 전환되었다. 마지막으로, 목적하는 화합물 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-1H-indazole 유도체 3a는 화합물 11b를 bis(pinacoloato)diboron 및PdCl2(dppf)2를 KOAc 존재하에서 반응함으로써 36%의 수율로 얻을 수 있었다. 한편, 화합물 3b는 시장 구입한 3-bromo-2-methylaniline 10을 출발물질로, 위에 기술한 바와 같은 합성방법에 의하여 전체 수율 44%로 합성할 수 있었다.Meanwhile, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole derivatives ( 3a to 3b ) were synthesized using a synthesis method similar to the above ]. That is, the market to buy a 2,4-dinitrotoluene (8) of NBS and the reaction was then brominated, nitro 3-bromo-4-methyl- 5-nitroaniline by reduction of the iron powder and using 3-bromo-2 -methyl-5-nitroaniline in a 3: 1 ratio (74% yield). After the amino group obtained by the reduction reaction was Boc-protected and the remaining nitro group was reduced again, the desired compound 9a was obtained together with the positional isomer 9b and each was separated by silica gel column chromatography. By cyclization of the compound 9a under the reaction conditions, such as the above it was able to synthesize the indazole compounds 11a and 11b (81% yield), where
합성된 indazole 유도체의 JAK kinase 저해활성은 Z'-LYTE™ Kinase Assay Kit-Tyr 6 Peptide (JAK1 ~ JAK3) 및 Tyr 3 Peptide (Tyk2) (Invitrogen)를 이용하여 Kit와 함께 제공된 실험방법에 의하여 측정하였으며, 10 μM 농도의 indazole 유도체에 의한 각각의 JAK 이소자임의 %-inhibition 결과를 종합하면 [도 6]과 같다.The JAK kinase inhibitory activity of the synthesized indazole derivatives was measured using the Z'-LYTE ™ Kinase Assay Kit-
예상한 바와 같이, 합성된 indazole 유도체들은 JAK2에 대한 저해활성을 거의 보이지 않았으며, 특히 화합물 1d의 경우 JAK2에 대한 JAK1 선택성이 67배 이상에 이르기는 것을 볼 수 있었다. 또한, 3번 위치에 alkynol 치환기를 갖지 않는 유도체 1a와 1b의 경우에는 JAK1 저해활성이 그리 크지 않았지만 alkynol 치환기를 갖는 유도체 1c ~ 1f는 상당한 JAK1 저해활성을 보이는 것을 확인할 수 있었는데, 특히 propargyl alcohol이 치환된 1c와 1d 유도체에서 치환기 효과가 매우 크게 나타났다. 한편, indazole 유도체들은 일반적으로 JAK3에 대해 JAK1과 비슷한 저해능을 보였지만, 이 경우에도 역시 propargyl alcohol이 치환된 유도체 1c와 1d는 2배 이상의 JAK1 선택성을 보임을 알 수 있다.As expected, the synthesized indazole derivatives showed almost no inhibitory activity on JAK2, and in particular, JAK1 selectivity for JAK2 in
따라서 선택적인 Janus kinase 1 (JAK1) 저해활성을 보이는 물질을 활용한 류마티스성 관절염 치료제 개발 연구는 전세계적으로 매우 활발하게 진행되고 있는 연구 분야이고, 본 발명자들은 JAK1에 대하여 높은 선택성을 갖는 저해제를 발굴하고자 예의 노력한 결과, 인다졸 유도체 중 JAK2에 비교하여 월등히 높은 JAK1 저해능을 갖는 물질을 발굴하고 발명을 완성하였다.
Therefore, the development of a therapeutic agent for rheumatoid arthritis using a selective inhibitor of Janus kinase 1 (JAK1) has been actively conducted worldwide, and the present inventors have found that inhibitors having high selectivity against JAK1 As a result of effort, the inventors have discovered a substance having a JAK1 inhibitory ability which is much higher than that of JAK2 among the indazole derivatives and completed the invention.
이상 상세히 기술한 바와 같이, 본 발명에서는 propargyl alcohol과 같은 짧은 직선형 사슬 치환기를 도입한 indazole 유도체들이 JAK2의 키나아제 활성은 저해하지 않으나 JAK1에 대해서는 선택적인 활성 저해능을 가질 수 있음을 확인하였고, 이를 통하여 효과적인 류마티스성 관절염 치료제로 사용될 수 있다는 것을 확인할 수 있었다. As described in detail above, in the present invention, indazole derivatives having a short linear chain substituent such as propargyl alcohol did not inhibit the kinase activity of JAK2, but it was confirmed that JAK1 could have a selective activity inhibitory effect, It can be used as a therapeutic agent for rheumatoid arthritis.
도 1은 JAK1, JAK2, JAK3의 삼차원 구조를 겹친 그림으로써 glycine-loop에서 JAK1과 다른 JAK 이소자임간에 기질결합자리의 구조적 차이점을 보여준다.
도 2는 JAK1의 기질결합자리 아래 부분에 형성된 특징적인 cavity를 보여준다.
도 3은 화학식 1로 대표되는 화합물들의 합성과정을 설명한다.
도 4는 주중간체인 3-alkynolyl-5-bromo-indazole-7-carboxamides 2a ~ 2c의 합성과정을 설명한다.
도 5는 주중간체인 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole 유도체 3a ~ 3b의 합성과정을 설명한다.
도 6은 10 μM 농도의 indazole 유도체 1a ~ 1f에 의한 JAK 이소자임 활성 저해활성 표FIG. 1 is a diagram showing the three-dimensional structure of JAK1, JAK2, and JAK3 superimposed on each other, showing the structural differences between JAK1 and other JAK isoenzymes in the glycine-loop.
Figure 2 shows a characteristic cavity formed in the lower part of the substrate binding site of JAK1.
FIG. 3 illustrates the synthesis process of the compounds represented by formula (1).
FIG. 4 illustrates the synthesis of 3-alkynolyl-5-bromo-indazole-7-carboxamides 2a to 2c as main intermediates.
Figure 5 illustrates the synthesis of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole derivatives 3a - 3b as the main intermediate.
Figure 6 shows the inhibition activity of JAK isozyme activity by
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 아니하는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these examples are for illustrative purposes only and that the scope of the invention is not construed as being limited by these examples.
실시예Example 1. 5- 1. 5- 브로모Bromo -1--One- N,NN, N -디--D- BocBoc -4-메틸벤젠-3-아민 (-4-methylbenzene-3-amine ( 9a9a ) 의 합성) Synthesis of
2,4-디니트로톨루엔 (1 g, 5.5 mmol) 을 황산 (10 mL)에 녹인 뒤, NBS (1.17 g, 6.6 mmol)를 45분 동안 세번에 걸쳐서 가해준다. 가해주는 동안의 반응물의 온도는 80 oC를 유지해준다. 반응이 끝나면, 반응물에 얼음물과 디메틸클로라이드를 넣어준다. 유기층을 포화된 Na2S2O3수용액으로 씻어주고, 감압농축하여 하얀색 고체인 화합물 1-브로모-2-메틸-3,5-디니트로벤젠 (1.4 g, 98 % yield)를 얻었다; 1H NMR (400 MHz, Acetone_d 6 ) δ 8.72 (d, J = 2.3 Hz, 1H), 8.68 (d, J = 8.3 Hz, 1H), 2.66 (s, 3H); 1-브로모-2-메틸-3,5-디니트로벤젠 (1 g, 3.83 mmol) 에 에탄올 (10 mL)과 THF (2 mL) 을 녹인 혼합물에 철가루 (642 mg, 19.15 mmol) 를 0 oC에서 가해준다. 반응물을 80 oC에서 2시간 동안 교반한다. 반응물을 상온으로 식힌 후 디클로로메탄과 물을 넣고 셀라이트로 걸러주고, 디클로로메탄으로 셀라이트를 씻어준다. 갈라진 유기층에 다시 물을 넣어준 뒤에 K2CO3을 물층이 염기성이 될 때까지 가해준다. 그 후에 유기층이 갈라지면 황산마그네슘으로 물을 제거하고 감압농축한다. 실리카켈 관 크로마토그래피를 통하여 정제해서 분리할 수 없는 환원된 중간체 (655 mg, 74 % yield)를 노란 고체로 얻었다. 디클로로메탄 (12 mL)에 녹아져 있는 환원된 중간체 (655 mg, 2.83 mmol) 에 DMAP (1.04 g, 8.49mmol) 과 BOC2O(1.85g,8.49mmol)을 가해준다. 반응물은 상온에서 3시간동안 교반한다. 얻어진 혼합물은 감압농축하여 실리카젤 관 크로마토그래피로 정제하여 (헥산: 디클로로메탄 : 디에틸에테르=100:100:1)분리할 수 없는 아민기가 Boc으로 가리워진 중간 (989 mg, 81 % yield) 를 연한 노랑색 고체로 얻었다. 아민기가 Boc으로 가리워진 중간체 (989 mg, 2.29 mmol)를 메탄올 (10 mL)에 녹이고 Pd/C (50 mg) 을 가해준 뒤에 플라스크 내의 기체를 제거한다. 이 반응 플라스크에 풍선을 이용하여 수소기체가 가하고, 이러한 조건 하에 상온에서 4시간 동안 교반한다. 반응물은 셀라이트를 통하여 걸러낸 뒤 감압농축하고 실리카젤 관 크로마토그래피로 정제하여 (헥산 : 아세트산에틸 = 5 : 1) 노란 가루의 형태로 화합물 9a (368 mg, 40 % yield)을 얻었다;After dissolving 2,4-dinitrotoluene (1 g, 5.5 mmol) in sulfuric acid (10 mL), NBS (1.17 g, 6.6 mmol) was added over three portions over 45 minutes. The temperature of the reactants during the addition is maintained at 80 ° C. At the end of the reaction, add ice water and dimethyl chloride to the reaction. The organic layer was washed with a saturated aqueous Na 2 S 2 O 3 solution and concentrated under reduced pressure to obtain a white solid compound 1-bromo-2-methyl-3,5-dinitrobenzene (1.4 g, 98% yield); 1 H NMR (400 MHz, Acetone- d 6 )? 8.72 (d, J = 2.3 Hz, 1H), 8.68 (d, J = 8.3 Hz, 1H), 2.66 (s, 3H); Iron powder (642 mg, 19.15 mmol) was added to a mixture of 1-bromo-2-methyl-3,5-dinitrobenzene (1 g, 3.83 mmol) dissolved in ethanol (10 mL) and THF o Apply in C. The reaction is stirred at 80 ° C for 2 hours. The reaction mixture is cooled to room temperature, dichloromethane and water are added, the mixture is filtered through celite, and washed with dichloromethane. Water is added to the cracked organic layer and K 2 CO 3 is added until the water layer becomes basic. After that, when the organic layer is separated, water is removed with magnesium sulfate and concentrated under reduced pressure. Purification via silica gel column chromatography afforded a non-separable reduced intermediate (655 mg, 74% yield) as a yellow solid. To a solution of the reduced intermediate (12 mL) dissolved in dichloromethane (655 mg, 2.83 mmol) was added DMAP (1.04 g, 8.49 mmol) and BOC 2 O (1.85 g, 8.49 mmol). The reaction is stirred at ambient temperature for 3 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane: dichloromethane: diethyl ether = 100: 100: 1) to give intermediate (989 mg, 81% yield) Obtained as a pale yellow solid. Intermediates in which the amine group is Boc (989 mg, 2.29 mmol) was dissolved in methanol (10 mL), Pd / C (50 mg) was added, and the gas in the flask was removed. Hydrogen gas was added to the reaction flask using a balloon, and the mixture was stirred at room temperature for 4 hours under these conditions. The reaction was filtered through celite, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give compound 9a (368 mg, 40% yield) in the form of a yellow powder;
1H NMR (400 MHz, Acetone_ d 6 ) δ 6.70 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 4.93 (br s, 2H), 2.24 (s, 3H), 1.45 (s, 18H). 1 H NMR (400 MHz, Acetone _ d 6) δ 6.70 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 4.93 (br s, 2H), 2.24 (s, 3H ), 1.45 (s, 18H).
실시예 2. 4- 브로모 - N,N -디- Boc - 1H - 인다졸 -6-아민 11b 의 합성 Example 2: 4-bromo - N, N - di - Boc - 1H - indazol-6-amine sum of 11b St.
5-브로모-1-N,N-디-Boc-4-메틸벤젠-3-아민 9a (368 mg, 0.91 mmol)을 클로로포름 (3 mL)에 녹인 후 KOAc (94 mg, 0.96 mmol)를 가해준다. 반응물의 온도를 0 oC로 낮춘 뒤에 아세트산무수물 (0.17 mL, 1.82 mmol)를 가해준다. 반응물을 15분 동안 상온에서 교반시키다가 하얀 고체가 형성이 되면 18-crown-6 (48 mg, 0.18 mmol) 과 아질산이소펜틸 (0.27 mL, 2.00 mmol) 을 넣고 65 oC에서 18 시간동안 교반시킨다. 반응이 끝나면 반응물을 상온으로 식혀준 뒤에 포화 NaHCO3수용액과 염화나트륨 수용액으로 씻어준다. 황산마그네슘으로 유기층의 물을 제거하고 감압농축한 뒤 실리카겔 관 크로마토그래피로 정제하여 (헥산 : 아세트산에틸 = 6:1) 연한 황토색의 1-(4-브로모-6-(디Boc)-1H-인다졸-1-yl)에타논 11a (186 mg, 45% yield) 을 얻었다;5-bromo -1- N, N - di -Boc-4- methylbenzene-3-amine 9a (368 mg, 0.91 mmol) was dissolved in chloroform (3 mL) added to KOAc (94 mg, 0.96 mmol) give. After the temperature of the reaction was lowered to 0 ° C, acetic anhydride (0.17 mL, 1.82 mmol) was added. 18-crown-6 (48 mg, 0.18 mmol) and isopentyl nitrite (0.27 mL, 2.00 mmol) were added to the reaction mixture and stirred at 65 ° C for 18 hours . At the end of the reaction, the reaction mixture is cooled to room temperature, and then washed with a saturated aqueous solution of NaHCO 3 and an aqueous solution of sodium chloride. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give 1- (4-bromo-6- (di-Boc) Indazol-1-yl)
1H NMR (400 MHz, Acetone_d 6 ) δ 8.33 (d, J = 0.5 Hz, 1H), 8.23 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 2.77 (s, 3H), 1.41 (s, 18H); 13CNMR(100MHz,Acetone_d6)δ171.7, 152.1, 142.2, 140.1, 139.3, 128.7, 125.8, 114.8, 113.7, 83.6, 28.0, 23.0; 얻어진 (4-브로모-6-(디Boc)-1H-인다졸-1-yl)에타논 11a (186 mg, 0.41 mmol)을 메탄올 (5 mL)에 녹인 후, 6N 염산 (2 mL)을 가하여 상온에서 2시간 동안 교반한다. 메탄올을 감압농축을 통하여 제거하고 아세트산에틸에 녹여 물로 씻어준다. 유기 용매 층을 감압농축하여 4-브로모-N,N-디-Boc-1H-인다졸-6-아민11 b (150 mg, 89% 수율)를 얻었다. 1 H NMR (400 MHz, Acetone_ d 6) δ 8.33 (d, J = 0.5 Hz, 1H), 8.23 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 2.77 (s, 3H), 1.41 (s, 18H); 13 CNMR (100 MHz, Acetone_d 6 )? 171.7, 152.1, 142.2, 140.1, 139.3, 128.7, 125.8, 114.8, 113.7, 83.6, 28.0, 23.0; Obtained, 6N hydrochloric acid (2 mL) was dissolved in (4-bromo-6- (di-Boc) -1H- indazole -1-yl) -
실시예Example 3. 4- 3. 4- 브로모Bromo -1H--1H- 인다졸Indazole ( ( 12b12b )의 합성) Synthesis of
3-브로모-2-메틸아닐린 (300 mg, 1.61 mmol)을 클로로포름 (5 mL)에 녹인 용액에 아세트산칼륨(166 mg, 1.69 mmol)을 상온에서 넣는다. 아세트산무수물(0.3 mL, 3.22 mmol을 0 oC에서 천천히 가한 뒤, 상온에서 15분 동안 교반시킨다. 하얀 고체가 형성 되면 18-crown-6 (85 mg, 0.32mmol)과 isopentyl nitrite (0.48 mL, 3.54 mmol)를 넣고 65 oC에서 18시간 동안 환류 교반한다. 반응이 끝나면 상온으로 식힌 후, 반응물에 디클로로메탄을 가한 뒤 실리카겔 관크로마토그래피(핵산 : 아세트산에틸 = 5 : 1)로 정제하여 12a (189 mg, 49% yield)와 12b (127 mg, 40% yield) 을 얻었다. 화합물 12a (189 mg, 0.79 mmol)을 메탄올(4 mL)에 녹인 용액에 6 N 염산(2 mL)을 가하여 상온에서 2시간 동안 교반한다. 반응이 끝나면 메탄올을 감압농축을 통하여 제거하고 아세트산에틸에 녹여 물로 씻어준다. 유기 용매 층을 감압농축하여 4-브로모-1H-인다졸 (12b) (140 mg, 90% yield)를 얻었다.To a solution of 3-bromo-2-methylaniline (300 mg, 1.61 mmol) in chloroform (5 mL) was added potassium acetate (166 mg, 1.69 mmol) at room temperature. Acetic anhydride (0.3 mL, 3.22 mmol) was slowly added at 0 ° C and stirred at room temperature for 15 minutes. When a white solid formed, 18-crown-6 (85 mg, 0.32 mmol) and isopentyl nitrite (0.48 mL, 3.54 Insert the mmol) and stirred under reflux at 65 o C for 18 hours after the end of the reaction is cooled to room temperature, and after adding dichloromethane and the reaction mixture was purified by silica gel column chromatography (nucleic acid: ethyl acetate = 5: purification by 1) 12a (189 mg, to obtain a 49% yield) and 12b (127 mg, 40% yield ). compound 12a (189 mg, 0.79 mmol) to at room temperature was added methanol (6 N hydrochloric acid (2 mL) dissolved in a solution in 4 mL) 2 The organic solvent layer was concentrated under reduced pressure to give 4-bromo-1H-indazole ( 12b ) (140 mg, yield 90% yield) as a colorless oil. ).
실시예Example 4. 4. 메틸methyl -2-아미노-5-Amino-5- 브로모Bromo -3--3- 메킬벤조에이트Mech benzoate ( ( 55 )의 합성) Synthesis of
메틸-2-아미노-3-메틸벤조에이트 4 (1 g, 6.1 mmol)를 디메틸포름아미드 (10 mL)에 녹인 후, N-브로모석신이미드 (1.1 g, 6.1 mmol)을 첨가한다. 상온에서 6시간 동안 교반 후, 아세트산에틸 (10 mL)을 첨가하고 탄산나트륨 수용액으로 10 mL 씩 3번 씻어준다. 얻어진 유기층을 황산마그네슘 (MgSO4)을 첨가하여 남은 물을 제거한 뒤, 여과지를 사용하여 걸러낸다. 이 혼합물을 감압 농축 한 뒤, 얻어진 농축액을 실리카겔 관컬럼크로마토그래피 (헥산 : 아세트산에틸 = 100 : 1)로 정제하여 화합물 5를 (928 mg, 62 % 수율) 옅은 회색의 고체형태로 얻었다:Methyl-2-amino-3-methylbenzoate 4 (1 g, 6.1 mmol) was dissolved in dimethylformamide (10 mL) and N -bromosuccinimide (1.1 g, 6.1 mmol) was added. After stirring at room temperature for 6 hours, add ethyl acetate (10 mL) and wash 3 times with 10 mL each with aqueous sodium carbonate solution. The obtained organic layer was treated with magnesium sulfate (MgSO 4 ) to remove residual water, and then filtered using a filter paper. The mixture was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 1) to give Compound 5 (928 mg, 62% yield) as a pale gray solid:
1H NMR (400 MHz, CDCl3) δ (ppm) 7.88 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 2.15 (s, 3H). 1 H NMR (400 MHz, CDCl 3) δ (ppm) 7.88 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 5.82 (s, 2H), 3.86 (s, 3H ), 2.15 (s, 3H).
실시예Example 5. 5. 메틸methyl -5--5- 브로모Bromo -- 1H1H -- 인다졸Indazole -7--7- 카복실레이트Carboxylate ( ( 6b6b )의 합성) Synthesis of
메틸-2-아미노-5-브로모-3-메킬벤조에이트 (5) (500 mg, 2.2 mmol)를 클로로포름 (5 mL)에 녹인 용액에 아세트산칼륨 (221 mg, 2.3 mmol)을 상온에서 넣는다. 아세트산무수물(0.4 mL, 4.2 mmol을 0 oC에서 천천히 가한 뒤, 상온에서 15분 동안 교반시킨다. 하얀 고체가 형성 되면 18-crown-6 (116 mg, 0.4 mmol)과 isoamyl nitrite (0.6 mL, 4.8 mmol)를 넣고 65 oC에서 18시간 동안 환류 교반한다. 반응이 끝나면 상온으로 식힌 후, 반응물에 디클로로메탄을 가한 뒤 실리카겔 관크로마토그래피 (핵산:아세트산에틸 = 6:1)로 정제하여 6a (300 mg, 46% yield)와 6b (196 mg, 35% yield)을 얻었다. 화합물 6a (300 mg, 1.0 mmol)을 메탄올 (5 mL)에 녹인 용액에 6 N 염산 (2 mL)을 가하여 상온에서 2시간 동안 교반한다. 메탄올을 감압농축을 통하여 제거하고 아세트산에틸에 녹여 물로 씻어준다. 유기 용매 층을 감압농축하여 6b (250 mg, 98% 수율)를 얻었다:Potassium acetate (221 mg, 2.3 mmol) was added to a solution of methyl-2-amino-5-bromo-3-methylbenzoate ( 5 ) (500 mg, 2.2 mmol) in chloroform (5 mL) at room temperature. Crown-6 (116 mg, 0.4 mmol) and isoamyl nitrite (0.6 mL, 4.8 mmol) were added slowly at 0 ° C and stirred at room temperature for 15 min. Acetic anhydride (0.4 mL, Insert the mmol) and stirred under reflux at 65 o C for 18 hours after the end of the reaction is cooled to room temperature, and after adding dichloromethane and the reaction mixture was purified by silica gel column chromatography (nucleic acid: ethyl acetate = 6: purification by 1) 6a (300 mg, to obtain a 46% yield) and 6b (196 mg, 35% yield ).
1H NMR (400 MHz, CDCl3) δ (ppm) 12.85 (s, 1H), 8.16 (d, J = 1.5 Hz, 1H), 8.13 (t, J = 1.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 4.04 (s, 3 H). 1 H NMR (400 MHz, CDCl 3) δ (ppm) 12.85 (s, 1H), 8.16 (d, J = 1.5 Hz, 1H), 8.13 (t, J = 1.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1 H), 4.04 (s, 3 H).
실시예Example 6. 6. terttert -- 뷰틸Butyl (5- (5- 브로모Bromo -- 1H1H -- 인다졸Indazole -7--7- 카보닐Carbonyl )) 카바메이트Carbamate ( ( 2a2a )의 합성) Synthesis of
메틸-5-브로모-1H-인다졸-7-카복실레이트 (6b) (550 mg, 2.2 mmol)을 테트라히드로퓨란 (2 mL)과 물 (8 mL)에 녹인 후, 수산화리튬 (206 mg, 8.6 mmol)을 첨가하여 50 oC에서 환류 가열한다. 4시간 후, 2N HCl로 pH 2를 맞추어 생긴 하얀색 고체를 여과지를 사용하여 걸러주어 카복실산 형태의 물질을 얻었다. 이 물질을 디클로로메탄 (5 mL)에 녹인 후 0 oC에서 oxalyl chloride (0.2 mL, 2.2 mmol)을 첨가한 후 1시간 동안 교반한다. 이 반응물을 감압증류 한 후 메탄올에 녹아있는 포화된 암모니아 (5 mL)를 첨가하여 4시간 동안 교반한 후, 감압증류 하고 실리카겔 관크로마토그래피 (핵산 : 아세톤 = 2 :1 )로 정제하여 아마이드 형태의 엷은 갈색 고체의 중간체 5-브로모-1H-인다졸-7-카복사마이드 (450 mg, 85% 수율)를 얻었다:Methyl-5-bromo- 1H -indazole-7-carboxylate (6b) was dissolved (550 mg, 2.2 mmol) in tetrahydrofuran (2 mL) and water (8 mL), was added lithium hydroxide (206 mg, 8.6 mmol) is heated under reflux at 50 o C. After 4 h, the pH was adjusted to pH 2 with 2N HCl and the resulting white solid was filtered using a filter paper to give the carboxylic acid form of the material. After dissolving this material in dichloromethane (5 mL), add oxalyl chloride (0.2 mL, 2.2 mmol) at 0 ° C and stir for 1 hour. The reaction mixture was distilled under reduced pressure, and saturated ammonia (5 mL) dissolved in methanol was added. After stirring for 4 hours, the mixture was distilled under reduced pressure and purified by silica gel column chromatography (nucleic acid: acetone = 2: 1) Intermediate 5-bromo-lH-indazole-7-carboxamide (450 mg, 85% yield) was obtained as a pale brown solid:
1H NMR (400 MHz, MeOD) δ (ppm) 11.24 (s, 1H), 10.63 (s, 2H), 8.16 (d, J = 1.5 Hz, 1H), 8.12 (t, J = 1.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H). 5-브로모-1H-인다졸-7-카복사마이드 (450 mg, 1.9 mmol)을 디클로로메탄 (5 mL)에 녹인 후, Di-tert-뷰틸 디카보네이트 (415 mg, 1.9 mmol) 과 4-디메틸아미노피리딘 (232 mg, 1.9 mmol)을 첨가하여 상온에서 교반한다. 6시간 후, 반응물을 감압증류하고 실리카겔 관크로마토그래피 (핵산 : 아세트산에틸 = 2:1)로 정제하여 옅은 갈색 오일 형태의 t-뷰틸-(5-브로모-1H-인다졸-7-카보닐)카바메이트 (2a) (614 mg, 95 % 수율)를 얻었다: 1H NMR (400 MHz, CDCl3) δ (ppm) 8.18 (d, J = 1.5 Hz, 1H), 8.14 (t, J = 1.5 Hz, 1H), 8.10 (d, J = 1.5 Hz, 1H), 1.50 (s, 9H). 1 H NMR (400 MHz, MeOD ) δ (ppm) 11.24 (s, 1H), 10.63 (s, 2H), 8.16 (d, J = 1.5 Hz, 1H), 8.12 (t, J = 1.5 Hz, 1H) , 8.09 (d, J = 1.5 Hz, 1 H). (450 mg, 1.9 mmol) was dissolved in dichloromethane (5 mL), di- tert -butyl dicarbonate (415 mg, 1.9 mmol) and 4- Dimethylaminopyridine (232 mg, 1.9 mmol) was added, and the mixture was stirred at room temperature. After 6 hours, the reaction product was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (nucleic acid: ethyl acetate = 2: 1) to obtain t -butyl- (5-bromo- 1H -indazole-7-carbonyl ) carbamate (2a) (614 mg, was obtained 95% yield): 1 H NMR (400 MHz , CDCl 3) δ (ppm) 8.18 (d, J = 1.5 Hz, 1H), 8.14 (t, J = 1.5 Hz, 1 H), 8.10 (d, J = 1.5 Hz, 1 H), 1.50 (s, 9H).
실시예Example 7. 7. terttert -- 뷰틸Butyl -(5-- (5- 브로모Bromo -3--3- 아이오도Iodo -- 1H1H -- 인다졸Indazole -7--7- 카보닐Carbonyl ) ) 카바메이트Carbamate ( ( 77 )의 합성) Synthesis of
t-뷰틸-(5-브로모-1H-인다졸-7-카보닐)카바메이트 2a (614 mg, 1.8 mmol)을 디메틸포름아미드 (5 mL)에 녹인 후, N-아이오도석신이미드 (240 g, 1.8 mmol)을 첨가한다. 상온에서 6시간 동안 교반 후, 아세트산에틸 (10 mL)을 첨가하고 탄산나트륨 수용액으로 10 mL 씩 3번 씻어준다. 얻어진 유기층을 황산마그네슘 (MgSO4)을 첨가하여 남은 물을 제거한 뒤, 여과지를 사용하여 걸러낸다. 이 혼합물을 감압 농축 한 뒤, 얻어진 농축액을 실리카겔 관컬럼크로마토그래피 (헥산 : 아세트산에틸 = 2 : 1)로 정제하여 화합물 t-뷰틸(5-브로모-3-아이오도-1H-인다졸-7-카보닐)카바메이트 7 (453 mg, 54 % 수율)을 옅은 회색의 고체형태로 얻었다: t-butyl (5-bromo-1H-indazol-7-carbonyl) carbamate 2a was dissolved (614 mg, 1.8 mmol) in dimethylformamide (5 mL), N-child ohdoseok god-carboxamide (240 g, 1.8 mmol). After stirring at room temperature for 6 hours, add ethyl acetate (10 mL) and wash 3 times with 10 mL each with aqueous sodium carbonate solution. The obtained organic layer was treated with magnesium sulfate (MgSO 4 ) to remove residual water, and then filtered using a filter paper. The mixture was concentrated under reduced pressure, and the resulting concentrate was purified by column chromatography on a silica gel column (hexane: ethyl acetate = 2: 1) to obtain the compound t-butyl (5-bromo-3-iodo-1H-indazol- -Carbonyl) carbamate 7 (453 mg, 54% yield) as a pale gray solid:
1H NMR (400 MHz, CDCl3) δ (ppm) 12.86 (s, 1H), 10.58 (s, 1H), 8.44 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H), 1.50 (s, 9H). 1 H NMR (400 MHz, CDCl 3) δ (ppm) 12.86 (s, 1H), 10.58 (s, 1H), 8.44 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H ), 1.50 (s, 9H).
실시예Example 8. 8. terttert -- butylbutyl -(5-- (5- bromobromo -3-(3--3- (3- hydroxyprophydroxyprop -1--One- ynyn -1--One- ylyl )-1H-) -1H- indazoleindazole -7--7- carbonylcarbonyl )) carbamatecarbamate ( ( 2b2b ) 와 ) Wow terttert -- butylbutyl (5- (5- bromobromo -3-(4--3- (4- hydroxybuthydroxybut -1--One- ynyn -1--One- ylyl )-1H-) -1H- indazoleindazole -7--7- carbonylcarbonyl )) carbamatecarbamate ( ( 2c2c )의 합성) Synthesis of
t-뷰틸(5-브로모-3-아이오도-1H-인다졸-7-카보닐)카바메이트 7 (453 mg, 1.0 mmol)을 디클로로메탄에 녹인 후, 테트라키스(트리페닐포스핀)팔라듐 (231 mg, 0.2 mmol)을 넣은 후, copper(I) iodide (95 mg, 0.5 mmol)을 첨가한다. 여기에 프로파질 알코올 또는 3-뷰티닐 알코올 (1.0 mmol)과 트리에틸아민 (0.3 mL, 2 mmol)을 첨가한 후 24시간 동안 상온 교반한다. 디클로로메탄 (10 mL)을 첨가하고 염화나트륨 수용액으로 10 mL 씩 3번 씻어준다. 얻어진 유기층을 황산마그네슘 (MgSO4)을 첨가하여 남은 물을 제거한 뒤, 여과지를 사용하여 걸러낸다. 이 혼합물을 감압 농축 한 뒤, 얻어진 농축액을 실리카겔 관컬럼크로마토그래피 (헥산 : 아세톤 = 2 : 1)로 정제하여 화합물 2b와 2c를 얻었다: 7-carbonyl) carbamate 7 (453 mg, 1.0 mmol) was dissolved in dichloromethane, and then tetrakis (triphenylphosphine) palladium (231 mg, 0.2 mmol), copper (I) iodide (95 mg, 0.5 mmol) was added. Propional alcohol or 3-butynyl alcohol (1.0 mmol) and triethylamine (0.3 mL, 2 mmol) were added thereto, followed by stirring at room temperature for 24 hours. Add dichloromethane (10 mL) and wash three times with 10 mL each with aqueous sodium chloride solution. The obtained organic layer was treated with magnesium sulfate (MgSO 4 ) to remove residual water, and then filtered using a filter paper. The mixture was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (hexane: acetone = 2: 1) to obtain compounds 2b and 2c :
화합물 2b (141 mg, 36 % 수율) 1H NMR (400 MHz, CDCl3) δ (ppm) 12.85 (s, 1H), 10.58 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 3.62-3.64 (m, 2H), 2.28-2.30 (m, 2H), 1.50 (s, 9H); 화합물 2c (122 mg, 30 % 수율) 1H NMR (400 MHz, CDCl3) δ (ppm) 12.85 (s, 1H), 10.58 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 4.12-4.16 (m, 2H), 1.49 (s, 9H). Compound 2b (141 mg, 36% yield) 1 H NMR (400 MHz, CDCl 3) δ (ppm) 12.85 (s, 1H), 10.58 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 1.5Hz, 1H), 3.62-3.64 (m, 2H), 2.28-2.30 (m, 2H), 1.50 (s, 9H); Compound 2c (122 mg, 30% yield) 1 H NMR (400 MHz, CDCl 3) δ (ppm) 12.85 (s, 1H), 10.58 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 4.12-4.16 (m, 2H), 1.49 (s, 9H).
실시예Example
9. 9.
인다졸Indazole
유도체의 합성 ( Synthesis of
화합물 2 (1 mmol)을 톨루엔 (10 mL)에 녹인 후, 탄산칼륨 (207 mg, 1.5 mmol)을 첨가하고 화합물 3 (1 mmol)과 테트라키스(트리페닐포스핀)팔라듐 (231 mg, 0.2 mmol)을 첨가하여 90 oC에서 환류가열한다. 12시간 후, 반응물에 아세트산에틸 (10 mL)을 첨가하고 염화나트륨 수용액으로 10 mL 씩 3번 씻어준다. 얻어진 유기층을 황산마그네슘 (MgSO4)을 첨가하여 남은 물을 제거한 뒤, 여과지를 사용하여 걸러낸다. 이 혼합물을 감압 농축 한 뒤, 테트라하이드로퓨란 (10 mL)에 녹인 후 2N 염산 수용액 (5 mL)을 첨가하여 상온에서 4시간 동안 교반한다. 반응물에 2N 수산화나트륨 수용액으로 중화 시킨 후, 아세트산에틸로 10 mL 씩 3번 추출한다. 얻어진 유기층을 황산마그네슘 (MgSO4)을 첨가하여 남은 물을 제거한 뒤, 여과지를 사용하여 걸러낸다. 이 혼합물을 감압 농축 한 뒤 얻어진 농축액을 실리카겔 관컬럼크로마토그래피 (디클로로메탄 : 메탄올 = 20 : 1)로 정제하여 화합물 1을 얻었다: Compound 2 (1 mmol) was dissolved in toluene (10 mL), potassium carbonate (207 mg, 1.5 mmol) was added and compound 3 (1 mmol) and tetrakis (triphenylphosphine) palladium (231 mg, 0.2 mmol ) Is added and heated to reflux at 90 ° C. After 12 hours, add ethyl acetate (10 mL) to the reaction and wash 3 times with 10 mL each with aqueous sodium chloride solution. The obtained organic layer was treated with magnesium sulfate (MgSO 4 ) to remove residual water, and then filtered using a filter paper. The mixture was concentrated under reduced pressure, and then dissolved in tetrahydrofuran (10 mL), followed by addition of a 2N aqueous hydrochloric acid solution (5 mL), followed by stirring at room temperature for 4 hours. The reaction is neutralized with aqueous 2N sodium hydroxide solution and extracted three times with 10 mL each with ethyl acetate. The obtained organic layer was treated with magnesium sulfate (MgSO 4 ) to remove residual water, and then filtered using a filter paper. The mixture was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain Compound 1 :
화합물 1a (188 mg, 68 % 수율) 1H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.14 (d, J = 1.5 Hz, 1H), 8.12 (t, J = 1.5 Hz, 1H), 8.08 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 (brs, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H); LC/MS (ESI) m/z Found: 278.2 [M+H]+; Calcdfor C15H11N5O: 278.10; 화합물 1b (120 mg, 41 % 수율) 1H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.14 (d, J = 1.5 Hz, 1H), 8.12 (t, J = 1.5 Hz, 1H), 8.08 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.52 (brs, 2H), 7.85 (d, J = 1.5 Hz, 1H), 4.95 (brs, 2H); LC/MS (ESI) m/z Found: 293.3 [M+H]+; Calcdfor C15H12N6O: 293.11; 화합물 1c (130 mg, 39 % 수율) 1H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.52 (brs, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.8 Hz), 4.95 (brs, 2H), 4.12-4.16 (m, 2H); LC/MS (ESI) m/z Found: 332.2 [M+H]+; Calcdfor C18H13N5O2: 332.11; 화합물 1d (128 mg, 37 % 수율) 1H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.52 (brs, 2H), 4.95 (brs, 2H), 4.12-4.16 (m, 2H); LC/MS (ESI) m/z Found: 347.3 [M+H]+; Calcdfor C18H14N6O2: 347.12; 화합물 1e (121 mg, 38 % 수율) 1H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 8.04 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (brs, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.8 Hz), 4.95 (brs, 2H), 4.12-4.16 (m, 2H), 2.26-2.30 (m, 2H); LC/MS (ESI) m/z Found: 346.5 [M+H]+; Calcdfor C19H15N5O2: 346.12; 화합물 1f (132 mg, 37 % 수율) 1H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.52 (brs, 2H), 4.95 (brs, 2H), 4.12-4.16 (m, 2H), 2.26-2.29 (m, 2H); LC/MS (ESI) m/z Found: 362.4 [M+H]+; Calcdfor C19H16N6O2: 362.13.
Compound 1a (188 mg, 68% yield) 1 H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.14 (d, J = 1.5 Hz, 1H), 8.12 (t, J = 1.5 Hz , 1H), 8.08 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 (brs, 2H), 7.32 (d, J = 7.8 Hz , ≪ / RTI > 1H), 7.28 (t, J = 7.8 Hz, 1H); LC / MS (ESI) m / z Found: 278.2 [M + H] < + >; Calcdfor C 15 H 11 N 5 O : 278.10; Compound 1b (120 mg, 41% yield) 1 H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.14 (d, J = 1.5 Hz, 1H), 8.12 (t, J = 1.5 Hz , 1H), 8.08 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.52 (brs, 2H), 7.85 (d, J = 1.5 Hz , ≪ / RTI > 1H), 4.95 (brs, 2H); LC / MS (ESI) m / z Found: 293.3 [M + H] < + >; Calcdfor C 15 H 12 N 6 O: 293.11; Compound 1c (130 mg, 39% yield) 1 H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz , 1H), 8.04 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.52 (brs, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.8 Hz ), 4.95 (brs, 2H), 4.12-4. 16 (m, 2H); LC / MS (ESI) m / z Found: 332.2 [M + H] < + >; Calcdfor C 18 H 13 N 5 O 2 : 332.11; Compound 1d (128 mg, 37% yield) 1 H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz , 1H), 8.04 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.52 (brs, 2H), 4.95 (brs, 2H), 4.12 -4.16 < / RTI > (m, 2H); LC / MS (ESI) m / z Found: 347.3 [M + H] < + >; Calcdfor C 18 H 14 N 6 O 2 : 347.12; Compound 1e (121 mg, 38% yield) 1 H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz , 1H), 8.04 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (brs, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.8 Hz ), 4.95 (br s, 2H), 4.12-4.16 (m, 2H), 2.26-2.30 (m, 2H); LC / MS (ESI) m / z Found: 346.5 [M + H] < + >; Calcdfor C 19 H 15 N 5 O 2 : 346.12; Compound 1f (132 mg, 37% yield) 1 H NMR (400 MHz, MeOD) δ (ppm) 12.86 (brs, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 1.5 Hz , 1H), 8.04 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.52 (brs, 2H), 4.95 (brs, 2H), 4.12 -4.16 < / RTI > (m, 2H), 2.26-2.29 (m, 2H); LC / MS (ESI) m / z Found: 362.4 [M + H] < + >; Calcdfor C 19 H 16 N 6 O 2 : 362.13.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구 항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (7)
[화학식 1]
상기 화학식 1에서 n은 1 혹은 2의 정수, R2는 수소 혹은 아미노기를 가짐.Claims 1. A compound of the formula 1: < EMI ID =
[Chemical Formula 1]
In Formula 1, n is an integer of 1 or 2, and R 2 is hydrogen or an amino group.
5-bromo-indazole-7-carboxamide and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- - Suzuki coupling reaction of an indazole derivative and a Boc-protecting group elimination reaction.
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