KR102010947B1 - Pharmaceutical compositions for preventing or treating atopy comprising the compound having BLT-inhibitory activity as an active ingredient - Google Patents
Pharmaceutical compositions for preventing or treating atopy comprising the compound having BLT-inhibitory activity as an active ingredient Download PDFInfo
- Publication number
- KR102010947B1 KR102010947B1 KR1020180007262A KR20180007262A KR102010947B1 KR 102010947 B1 KR102010947 B1 KR 102010947B1 KR 1020180007262 A KR1020180007262 A KR 1020180007262A KR 20180007262 A KR20180007262 A KR 20180007262A KR 102010947 B1 KR102010947 B1 KR 102010947B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- prop
- fluorophenyl
- phenyl
- biphenyl
- Prior art date
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Abstract
본 발명은 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 아토피(atopic dermatitis)의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명자들은 BTL2 억제 활성을 나타내는 화합물의 우수한 주화성 억제 효과 및 아토피 치료 효과 등을 실험적으로 확인하였는바, 본 발명의 화합물은 아토피를 치료하기 위한 약학적 조성물로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a pharmaceutical composition for the prevention or treatment of atopic dermatitis, comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity. The present inventors have experimentally confirmed the excellent chemotaxis inhibitory effect and atopic treatment effect of the compound showing the BTL2 inhibitory activity, it is expected that the compound of the present invention can be usefully used as a pharmaceutical composition for treating atopy.
Description
본 발명은 아토피 예방 또는 치료용 약학적 조성물에 관한 것으로서, 보다 구체적으로는 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 화합물을 유효성분으로 포함하는 아토피 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating atopic dermatitis, and more particularly to a pharmaceutical composition for preventing or treating atopic dermatitis comprising a compound exhibiting inhibitory activity of Leukotriene B4 receptor 2 (BLT2) as an active ingredient.
아토피(atopy)는 알레르기 항원에 대한 접촉 없이 신체가 극도로 민감해지는 알레르기 반응으로서, 알레르기 질환인 아나필락시스(anaphylaxis)와는 다른 알레르기 경향을 구분하기 위해 사용하기 시작하였으며, 아토피라는 말은 고대그리스어에서 유래한 단어로 '이상한, 비정상적인'을 뜻한다. 아토피 반응은 국소적인 알레르기 항원에 과민 반응을 나타내는 것으로 아직까지도 아토피 질환의 발병 원인과 기전을 정확히 밝히지 못하고 있다. 그러나 보편적으로 감염, 정신적인 스트레스, 계절과 기후변화, 자극 및 알레르기에 의해 악화될 수 있으며, 주로 유전적, 면역학적 요인이 관여하는 것으로 생각되며 환경적 및 정신적 요인이 악화 요인으로 작용한다고 추정되고 있다. 병태의 형성에는 피부 방어 기능의 저하로 인해 침입하기 쉬워진 항원에 대한 알레르기 반응이 관여하는 것으로 보이며 대표적인 항원으로는 집먼지진드기나 곰팡이 등의 환경 인자가 관여한다.Atopy is an allergic reaction in which the body becomes extremely sensitive without contact with allergens, and has started to use it to distinguish allergic tendencies from anaphylaxis, an allergic disease.The term atopy comes from ancient Greek The word 'weird' or 'unusual'. Atopic reactions are hypersensitivity to local allergens, and the cause and mechanism of atopic disease have not been elucidated. However, it is commonly aggravated by infection, mental stress, seasonal and climate change, irritation and allergies, presumably involving genetic and immunological factors, and environmental and mental factors are presumed to be exacerbations. have. The formation of the condition appears to be involved in allergic reactions to antigens that are prone to invasion due to deterioration of skin defenses, and environmental factors such as house dust mites and molds.
그 중, 아토피 피부염(atopic dermatitis)은 가려움증이 심한 습진 병변이 피부에 생겨 오래 지속되는 만성 피부염이다. 아토피 피부염은 대부분 소아기에 첫 증상이 나타나며 유아기(2개월 내지 2세), 소아기(2세 내지 10세), 사춘기 및 성인기 등 시기별로 임상 양상에 차이가 있다. 유아기의 아토피 피부염 증상은 피부가 거칠어지고 건조해지며 팔다리의 바깥쪽으로 피부염이 생기는데, 뺨이나 이마, 머리 부위에 흔히 나타나며 손으로 긁고 나면 진물이나 딱지가 앉게 된다. 소아기의 아토피 피부염 증상은 얼굴보다는 팔과 다리와 목 등의 접히는 부위에 주로 나타나고 피부가 건조해진다. 사춘기 및 성인기의 아토피 피부염은 팔다리나 목과 같이 접히는 부위에 나타나며 얼굴이나 손과 같은 부위의 피부가 두껍게 변하는 증상이 나타난다.Among them, atopic dermatitis is a long-lasting chronic dermatitis with an itchy eczema lesion on the skin. Atopic dermatitis is the first symptom in childhood, and there are differences in clinical manifestations between infants (2 months to 2 years), childhood (2 to 10 years), puberty and adulthood. The symptoms of atopic dermatitis in infancy are rough, dry skin, and dermatitis on the outside of the limbs, which are common on the cheeks, forehead, and head, and when they are scratched by hand, a scab or scab sits. Symptoms of atopic dermatitis in childhood usually appear on the folding areas of the arms, legs and neck rather than on the face, and the skin becomes dry. Atopic dermatitis in puberty and adulthood appears on the folding areas such as the limbs and neck, and thickening of the skin on areas such as the face and hands.
따라서, 아토피의 치료는 우선 아토피 질환을 유발하거나 악화시키는 항원이나 자극 물질, 또는 스트레스와 같은 사회환경적인 요인을 피하도록 하고, 건조로 인한 피부염을 막기 위해 피부의 보습을 유지시키는 치료를 한다. 경우에 따라 국소 또는 전신 스테로이드제, 국소 또는 전신 면역조절(억제제), 항히스타민제 등의 약물 치료를 하며 광선 치료도 한다.Therefore, the treatment of atopic dermatitis is first to avoid social environmental factors such as antigens, irritants, or stress that cause or worsen atopic diseases, and to maintain the moisturizing of the skin to prevent dermatitis due to drying. In some cases, local or systemic steroids, local or systemic immunomodulation (inhibitors), and antihistamines are treated with phototherapy.
이에, 아토피를 치료하고자 하는 시도가 다양하게 진행되고 있으나 (한국공개특허 10-2008-0112270), 아토피성 피부염의 치료에는 현재 스테로이드제와 항히스타민제 등의 약물이 많이 사용되고 있으며, 중증에는 면역억제제가 사용되고 있다. 그러나 이러한 약물은 대부분 그 효과가 일시적이고, 골다공증, 무혈성괴사, 동맥경화, 녹내장, 발암 가능성 등의 부작용이 심하여 많은 문제점을 가지고 있다. 따라서, 아토피의 완화 및 치료를 위하여, 치료 효과가 좋고 부작용이 적으며 지속적인 치료 효과를 나타내는 새로운 치료제의 개발이 절실히 필요하다.Thus, various attempts have been made to treat atopy (Korea Patent Publication No. 10-2008-0112270), but a lot of drugs such as steroids and antihistamines are currently used for the treatment of atopic dermatitis. It is used. However, most of these drugs have temporary problems, and many side effects such as osteoporosis, avascular necrosis, arteriosclerosis, glaucoma, and possible carcinogenesis have many problems. Therefore, in order to alleviate and treat atopic dermatitis, there is an urgent need for the development of new therapeutic agents with good therapeutic effects, fewer side effects, and continuous therapeutic effects.
한편, 류코트리엔 (Leukotriene B4; LTB4)은 급성 및 만성염증을 매개하는 5-리폭시제나제 경로에 의해 아라키돈산(AA)으로부터 합성되는 염증성 리피드 매개체 군이다. LTB4는 BLT1과 BLT2 의 두 가지 형태의 수용체들에 결합함으로써 생물학적 영향을 주는 것으로 알려져 있다. BLT2(Leukotriene B4 receptor 2)는 GPCR(G protein-coupled receptor) 군 중 하나로 LTB4에 대해 낮은 친화력을 갖는 수용체이며, 5-리폭시제나제 의존성 경로를 통해 유도된 아라키돈산(AA)의 리피드 매개체이다.On the other hand, leukotriene B4 (LTB 4 ) is a group of inflammatory lipid mediators synthesized from arachidonic acid (AA) by the 5-lipoxygenase pathway that mediates acute and chronic inflammation. LTB 4 is known to have a biological effect by binding to two types of receptors, BLT1 and BLT2. Leukotriene B4 receptor 2 (BLT2) is a group of G protein-coupled receptors (GPCRs) that has low affinity for LTB 4 and is a lipid mediator of arachidonic acid (AA) induced through a 5-lipoxygenase dependent pathway. to be.
이에, 본 발명자들은 상기와 같은 종래의 문제점을 해결하기 위하여, 보다 효과적인 아토피 치료 물질을 개발하기 위한 연구를 계속하던 중, BLT2 억제 활성을 나타내는 화합물을 제조하였으며, 상기 화합물을 포함하는 아토피 치료제를 최초로 고안하였다.Accordingly, the present inventors, while continuing to research to develop a more effective atopic therapeutic agent in order to solve the above-mentioned conventional problems, and produced a compound showing a BLT2 inhibitory activity, the first atopic therapeutic agent containing the compound Devised.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 BLT2 억제 활성을 나타내는 화합물의 아토피 치료 효과를 확인하고 이에 기초하여 본 발명을 완성하게 되었다.The present invention has been made to solve the above problems, the present inventors have confirmed the atopic therapeutic effect of the compound exhibiting BLT2 inhibitory activity and based on this, the present invention has been completed.
이에, 본 발명의 목적은 BLT2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 아토피 (atopy) 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating atopy, comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits BLT2 inhibitory activity.
또한, 본 발명의 목적은 BLT2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 아토피 예방 또는 개선용 화장료 조성물을 제공하는 것이다.It is also an object of the present invention to provide a cosmetic composition for preventing or improving atopy, comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof that exhibits BLT2 inhibitory activity.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 BLT2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 아토피 (atopy) 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object of the present invention, the present invention comprises a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits BLT2 inhibitory activity, as an active ingredient, an atopy (atopy) preventive or therapeutic pharmaceutical composition To provide.
본 발명의 일 구현예로서, 상기 화합물은 tert-부틸 4-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-페닐-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-에틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(2-하이드록시에틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로프로필메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-사이클로헥실피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로헥실메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소부틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(4-(프로프-2-이닐)피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-시아노피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(3-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; tert-부틸 4-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(몰폴린-4-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(피페리딘-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N,N-다이에틸-4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤즈아마이드; N-페닐-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸-4-(3-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-하이드록시페닐)프로프-2-이닐)-N-페닐펜탄아마이드; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)페녹시)아세트산; tert-부틸 4-(5-(3-((N-페닐펜탄아미도)프로프-1-인-1-일)피콜리노일)피페라진-1-카복실레이트; N-페닐-N-(3-(6-(피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)펜탄아마이드; N-(3-(6-(4-아이소프로필피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)-N-페닐펜탄아마이드; N,N-다이에틸-4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N,N-다이에틸-4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(3-(4-(N,N-다이에틸설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(N-아이소프로필설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤조에이트; 4-(3-(N-페닐펜탄아미도)프로-1-핀-1-일)벤조익산; N-에틸-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(2-(다이메틸아미노)에틸)-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; 에틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세테이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세틱산; 메틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로파노에이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로피오닉산; 2-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; 2-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산; 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산; (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산; 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산; N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트; N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산; N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the compound is tert -butyl 4- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N -phenyl- N- (3- (4- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-ethylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (2-hydroxyethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclopropylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclohexylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isobutylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N -phenyl- N- (3- (4- (4- (prop-2-ynyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-cyanopiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; tert -butyl 4- (4- (3- ( N- (3-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (3-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (3-fluorophenyl) - N - (3- (4- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; tert -butyl 4- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4-fluorophenyl) - N - (3- (4- (4-isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N -phenyl- N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N , N -diethyl-4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzamide; N -phenyl- N- (3- (3- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (3- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl-4- (3- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (3- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4- fluorophenyl) - N - (3- (3- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N -phenylpentanamide; 2- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) phenoxy) acetic acid; tert -butyl 4- (5- (3-(( N -phenylpentaneamido) prop-1-yn-1-yl) picolinoyl) piperazin-1-carboxylate; N -phenyl- N- ( 3- (6- (piperazin-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentaneamide; N- (3- (6- (4-isopropylpiperazin- 1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) -N -phenylpentanamide; N, N -diethyl-4- (3- ( N- (3-fluorophenyl ) Pentaneamido) prop-1-yn-1-yl) benzamide; N, N -diethyl-4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1- In-1-yl) benzamide; N- (3- (4- ( N, N -diethylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4 -( N -isopropylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl 4- (3- ( N -phenylpentaneamido) prop-1-yn-1- Yl) benzoate; 4- (3- ( N -phenylpentaneamido) prop-1-pin-1-yl) benzoic acid; N -ethyl-4- (3- ( N -phenylpentaneamido) prop -1-yn-1-yl) benzamide; N -(2- (dimethylamino) ethyl) -4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamide; ethyl 2- (4- (3- ( N -Phenylpentaneamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) Benzamido) acetic acid; methyl 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3 -( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- ( N- (3-fluorophenyl) pentaneamido) Prop-1-ynyl) phenoxy) acetic acid 2- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) phenoxy) acetic acid; N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide; 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid; 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid; ( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid; 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide; Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide; 2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide; N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide .
본 발명의 다른 구현예로서, 상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시킬 수 있다. In another embodiment of the present invention, the composition may inhibit Leukotriene B4 receptor 2 (BLT2) activity.
상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 아토피의 치료방법을 제공한다.It provides a method for treating atopy comprising administering the pharmaceutical composition to a subject.
본 발명은 상기 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물의 아토피의 치료용도를 제공한다.The present invention provides a therapeutic use of atopy of a composition comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 아토피의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명자들은 BTL2 억제 활성을 나타내는 화합물의 우수한 주화성 억제 효과 및 아토피 치료 효과 등을 실험적으로 확인하였는바, 본 발명의 화합물은 아토피를 치료하기 위한 약학적 조성물로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a pharmaceutical composition for preventing or treating atopy, comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity. The present inventors have experimentally confirmed the excellent chemotaxis inhibitory effect and atopic treatment effect of the compound showing the BTL2 inhibitory activity, it is expected that the compound of the present invention can be usefully used as a pharmaceutical composition for treating atopy.
도 1a 내지 도 1e 및 도 2a 내지 도 2d는 BLT2가 발현된 세포 (CHO-BLT2)에서, 본 발명의 화합물 처리에 의한 성장 억제 효과를 확인한 결과이다.
도 3a 및 도 3b는 BLT2가 발현된 세포 (CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과 및 IC50 (50% 억제 농도)를 확인한 결과이다.
도 4a 및 도 4b는 BLT2가 발현된 세포 (CHO-BLT2 cells) 또는 BLT1이 발현된 세포 (CHO-BLT1)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과를 확인한 결과이다.
도 5a 내지 도 5d는 BLT2가 발현된 세포 (CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과 및 IC50 (50% 억제 농도)를 확인한 결과이다.
도 6a 내지 도 6c는 BLT2가 발현된 세포 (CHO-BLT2 cells) 또는 BLT1이 발현된 세포 (CHO-BLT1)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과를 확인한 결과이다.
도 7a 내지 도 7c는 BLT2가 발현된 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 LTB4와 BLT2 결합 저해 효과를 확인한 결과이다.
도 8a는 아토피 동물모델에서의 외형 변화를 확인한 결과이다.
도 8b는 아토피 동물모델에서의 가려움증 변화를 확인한 결과이다.
도 8c는 아토피 동물모델에서의 조직검사를 확인한 결과이다.
도 9는 DNCB 유도 아토피 동물 모델에서 외형 변화를 확인한 결과이다.
도 10은 DNCB 유도 아토피 동물 모델에서 경피수분손실량 및 피부수분함유량을 측정한 결과이다.
도 11은 DNCB 유도 아토피 동물 모델의 등 조직을 H&E 염색하여 확인한 결과이다.
도 12는 DNCB 유도 아토피 동물 모델의 조직을 톨루이딘 블루 염색하여 확인한 결과이다.
도 13은 DNCB 유도 아토피 동물 모델의 혈액을 채취하여 확인한 결과이다.
도 14는 RBL-2H3 세포에서 탈과립화를 측정한 결과이다.1A to 1E and 2A to 2D are results of confirming the growth inhibitory effect of the compound treatment of the present invention in cells expressing BLT2 (CHO-BLT2).
3A and 3B show the results of confirming chemotaxis inhibitory effect and IC 50 (50% inhibitory concentration) of cells by the compound treatment of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
4A and 4B show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
5A to 5D show results of confirming chemotaxis inhibitory effect and IC 50 (50% inhibitory concentration) of cells by treatment with a compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
6A to 6C show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
7A to 7C show the results of confirming the effect of inhibiting the binding of LTB4 and BLT2 by the compound treatment of the present invention in BLT2-expressing cells (CHO-BLT2 cells).
Figure 8a is the result of confirming the appearance change in the atopy animal model.
8b is a result of confirming the itch change in an atopic animal model.
Figure 8c is the result of confirming the biopsy in the atopic animal model.
9 is a result of confirming the appearance change in the DNCB-induced atopy animal model.
Figure 10 is the result of measuring the transdermal moisture loss and skin moisture content in the DNCB-induced atopic animal model.
Figure 11 shows the results confirmed by H & E staining the back tissue of the DNCB-induced atopy animal model.
12 shows the results obtained by toluidine blue staining of tissues of a DNCB-induced atopy animal model.
FIG. 13 shows the results obtained by collecting blood from a DNCB-induced atopy animal model.
14 shows the results of measuring degranulation in RBL-2H3 cells.
본 발명자들은, 실시예에서 제조한 화합물을 처리한 경우, BLT2 발현 세포의 성장을 현저히 억제시킬 수 있다는 점에 기반하여 상기 화합물의 BLT2 의존적인 주화성 저해, 및 아토피 치료 효과 등을 구체적으로 확인하고, 이에 기초하여 본 발명을 완성하였다.The present inventors specifically confirmed the BLT2-dependent chemotaxis inhibition, atopic treatment effect, and the like of the compound based on the fact that when the compound prepared in Example can significantly inhibit the growth of BLT2 expressing cells, Based on this, the present invention has been completed.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 아토피 (atopy) 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating atopy, comprising as an active ingredient a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Chemical Formula 1,
R1은 C1~C10의 알킬이고,R 1 is C 1 -C 10 is alkyl,
R2는 , , , , 또는 이며, R 2 is , , , , or ,
Ra는 , , , , , , , , , , , , , , , , , , , , , , , 또는 하이드록시이고,R a is , , , , , , , , , , , , , , , , , , , , , , , Or hydroxy,
Rb는 , , , 또는 이고,R b is , , , or ego,
RC는 , , 또는 이고,R C is , , or ego,
Rd는 수소 또는 이고,R d is hydrogen or ego,
Re는 또는 이고,R e is or ego,
R3는 수소 또는 플루오르이다.R 3 is hydrogen or fluorine.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예는 하기와 같다:Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
tert-부틸 4-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-페닐-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-에틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(2-하이드록시에틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로프로필메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-사이클로헥실피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로헥실메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소부틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(4-(프로프-2-이닐)피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-시아노피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(3-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; tert-부틸 4-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(몰폴린-4-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(피페리딘-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N,N-다이에틸-4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤즈아마이드; N-페닐-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸-4-(3-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-하이드록시페닐)프로프-2-이닐)-N-페닐펜탄아마이드; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)페녹시)아세트산; tert-부틸 4-(5-(3-((N-페닐펜탄아미도)프로프-1-인-1-일)피콜리노일)피페라진-1-카복실레이트; N-페닐-N-(3-(6-(피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)펜탄아마이드; N-(3-(6-(4-아이소프로필피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)-N-페닐펜탄아마이드; N,N-다이에틸-4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N,N-다이에틸-4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(3-(4-(N,N-다이에틸설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(N-아이소프로필설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤조에이트; 4-(3-(N-페닐펜탄아미도)프로-1-핀-1-일)벤조익산; N-에틸-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(2-(다이메틸아미노)에틸)-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; 에틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세테이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세틱산; 메틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로파노에이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로피오닉산; 2-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; 및 2-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산. tert -butyl 4- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzoyl) piperazin-1-carboxylate; N -phenyl- N- (3- (4- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-ethylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (2-hydroxyethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclopropylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclohexylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isobutylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N -phenyl- N- (3- (4- (4- (prop-2-ynyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-cyanopiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; tert -butyl 4- (4- (3- ( N- (3-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (3-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (3-fluorophenyl) - N - (3- (4- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; tert -butyl 4- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4-fluorophenyl) - N - (3- (4- (4-isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N -phenyl- N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N , N -diethyl-4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzamide; N -phenyl- N- (3- (3- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (3- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl-4- (3- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (3- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4- fluorophenyl) - N - (3- (3- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N -phenylpentanamide; 2- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) phenoxy) acetic acid; tert -butyl 4- (5- (3-(( N -phenylpentaneamido) prop-1-yn-1-yl) picolinoyl) piperazin-1-carboxylate; N -phenyl- N- ( 3- (6- (piperazin-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentaneamide; N- (3- (6- (4-isopropylpiperazin- 1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) -N -phenylpentanamide; N, N -diethyl-4- (3- ( N- (3-fluorophenyl ) Pentaneamido) prop-1-yn-1-yl) benzamide; N, N -diethyl-4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1- In-1-yl) benzamide; N- (3- (4- ( N, N -diethylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4 -( N -isopropylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl 4- (3- ( N -phenylpentaneamido) prop-1-yn-1- Yl) benzoate; 4- (3- ( N -phenylpentaneamido) prop-1-pin-1-yl) benzoic acid; N -ethyl-4- (3- ( N -phenylpentaneamido) prop -1-yn-1-yl) benzamide; N -(2- (dimethylamino) ethyl) -4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamide; ethyl 2- (4- (3- ( N -Phenylpentaneamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) Benzamido) acetic acid; methyl 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3 -( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- ( N- (3-fluorophenyl) pentaneamido) Prop-1-ynyl) phenoxy) acetic acid and 2- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) phenoxy) acetic acid.
또한, 본 발명은 하기 화학식 2로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 아토피 (atopy) 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating atopy, comprising as an active ingredient a compound represented by Formula 2, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 2][Formula 2]
상기 화학식 2에서,In
R1은 C1~C10의 알킬, , 또는 이고,R 1 is C 1 -C 10 alkyl, , or ego,
R2는 수소, , 또는 이고,R 2 is hydrogen, , or ego,
R3는 수소, , 또는 이고,R 3 is hydrogen, , or ego,
R4는 수소, , 또는 이고,R 4 is hydrogen, , or ego,
여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실, , , , , 또는 이고,Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl, , , , , or ego,
R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
이 때, R1이 C1~C10의 알킬이고, Ra가 수소 또는 C1~C10의 알킬인 경우; 및 R2, R3, 및 R4가 모두 동시에 수소인 경우;는 제외한다.Wherein R 1 is C 1 -C 10 alkyl and R a is hydrogen or C 1 -C 10 alkyl; And when R 2 , R 3 , and R 4 are all hydrogen at the same time.
본 발명에 따른 상기 화학식 2로 표시되는 화합물의 바람직한 예는 하기와 같다:Preferred examples of the compound represented by
N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산; 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산; (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산; 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산; N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트; N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산; N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드. N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide; 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid; 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid; ( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid; 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide; Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide; 2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide; N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide.
본 발명에서 사용되는 "약학적으로 허용되는" 이라는 용어는 과도한 독성, 자극, 알러지 반응 또는 기타 문제점 또는 합병증 없이 이득/위험 비가 합리적이어서 대상체 (예: 인간)의 조직과 접촉하여 사용하기에 적합하며 건전한 의학적 판단의 범주 이내인 화합물 또는 조성물을 의미한다.As used herein, the term "pharmaceutically acceptable" is suitable for use in contact with the tissues of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications. A compound or composition is within the scope of sound medical judgment.
본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful for acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1 또는 화학식 2로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by the formula (1) or (2) in an excess of aqueous acid solution, and the salt is water-miscible organic solvent such as methanol, ethanol, acetone Or by precipitation with acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
본 발명의 일실시예에서는 BLT2 억제 활성을 나타내는 화합물을 제조하여 (실시예 1 참조), 상기 화합물 처리에 의한 BLT2 발현 세포의 성장 억제를 확인하였다 (실험예 2 참조). 또한, BLT2 발현 세포의 주화성을 억제시킬 수 있음을 확인하였으며 (실험예 3 참조), 본 발명의 화합물을 이용하여 LTB4와 BLT2 결합 저해효과를 확인하고 (실험예 4 참조), 아토피가 유도된 마우스에서 외형 변화, 가려움증 변화 및 조직 검사를 수행하여 아토피 효과를 구체적으로 확인하였는바 (실험예 5 참조) 아토피의 약학적 조성물로 매우 유용하게 사용될 수 있음을 확인하였다. 아울러, 본 발명의 다른 실시예에서는 DNCB 유도한 아토피 동물 모델을 제조하여 BLT2 억제 활성을 나타내는 화합물 LMT-1013의 효능을 확인하였다(실험예 6 참조).In one embodiment of the present invention, a compound showing BLT2 inhibitory activity was prepared (see Example 1), and the growth inhibition of BLT2 expressing cells by the compound treatment was confirmed (see Experimental Example 2). In addition, it was confirmed that the chemotaxis of BLT2 expressing cells can be inhibited (see Experimental Example 3), and the inhibitory effect of LTB4 and BLT2 binding was confirmed using the compound of the present invention (see Experimental Example 4), and atopy was induced. Changes in appearance, itching, and histology were performed in mice to specifically confirm the atopy effect (see Experimental Example 5). As a result, it was confirmed that it can be very useful as a pharmaceutical composition of atopy. In addition, in another embodiment of the present invention, the DNCB-induced atopy animal model was prepared to confirm the efficacy of the compound LMT-1013 exhibiting BLT2 inhibitory activity (see Experimental Example 6).
따라서, 본 발명의 화합물은 아토피의 예방 및 치료용 약학적 조성물의 유효성분으로써 유용하게 이용할 수 있다Therefore, the compound of the present invention can be usefully used as an active ingredient of the pharmaceutical composition for the prevention and treatment of atopy.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 아토피를 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits or delays onset of atopy by administration of a pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 아토피에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" means any action that improves or advantageously alters the symptoms of atopy by administration of the pharmaceutical composition according to the present invention.
본 발명에서, 아토피 (atopic dermatitis)는 대부분 유아기나 소아 때 발생하여 호전과 악화를 반복하는 비교적 흔한 만성 염증성 피부질환으로, 심한 소양증(가려움증)과 피부건조증, 피부 병변이 주요 증상이다. 아토피의 개인 또는 가족력, 심한 가려움증 및 습진의 3가지 특징으로 진단할 수 있으며 감염, 정신적인 스트레스, 계절과 기후변화, 자극 및 알레르기에 의해 악화될 수 있다. 유아기에는 습윤형인 경우 목, 이마, 손목, 팔, 다리 등에 심한 진물이 흐르고, 가피(딱지) 등의 병변을 관찰할 수 있으며, 때로는 곪기도 하며, 지루형인 경우 발진은 홍피증이나 피부가 비듬같이 벗겨지는 박탈현상을 보이며, 건조형인 경우 피부가 겹치는 팔 내측, 다리내측 등 굽히는 부위에 습진성 병변을 보인다. 소아기로 접어들면 팔다리의 겹치는 부위와, 손목, 안검, 안면, 목 주위 등에 각질이 일어나고 피부가 두꺼워지는 태선화 병변이 나타나며, 사춘기 및 성인기에는 어느 부위에 국한되어 홍반, 인설, 태선화 반이 겹치는 부위와, 목, 이마, 눈 주위 및 손, 손목 등에 흔히 나타나며 특히 굴절부에 심한 병변을 보이고, 때로는 피부에 갈색 색소침착과 함께 가죽같이 두꺼워진 피부 병변을 보이기도 한다. 아토피의 한 종류로서 상기 증상이 이에 속할 수 있으나, 이로써 제한되는 것은 아니다.In the present invention, atopic dermatitis is a relatively common chronic inflammatory skin disease that occurs mostly in infancy or childhood and repeats improvement and deterioration. Severe pruritus (itch), dry skin, and skin lesions are the main symptoms. It can be diagnosed with three characteristics: personal or family history of atopic dermatitis, severe itching and eczema, and can be exacerbated by infection, mental stress, seasonal and climate change, irritation and allergies. In infancy, severe bleeding occurs in the neck, forehead, wrists, arms, and legs if wet, and lesions such as crusts can be observed, sometimes swelling. Loss is seen, and in the case of dry type, eczema lesions appear on the bent areas such as the inner arms and inner legs where the skin overlaps. Entering childhood, the skin overlaps the limbs of the limbs, the skin, the eyelids, the face, and the neck around the skin, and the thickening of the skin appears. It is common in the neck, forehead, around the eyes, hands and wrists, and especially in the refraction area, sometimes with brown pigmentation on the skin and thickened skin lesions. As a kind of atopy, the symptoms may belong to, but are not limited to.
또한, 본 발명의 아토피는 BLT2 (Leukotriene B4 receptor 2)의 과발현에 기인한 질병일 수 있다. 보다 구체적으로, 류코트리엔(Leukotriene)은 아라키돈산이 리폭시제나아제(LOX; Lipoxygenase)와 결합하여 생성되며, 이는 아토피를 일으키는 원인이 되며, 따라서, BLT2 (Leukotriene B4 receptor 2)의 과발현은 아토피를 일으킬 수 있다.In addition, the atopy of the present invention may be a disease due to overexpression of Leukotriene B4 receptor 2 (BLT2). More specifically, leukotriene is produced by the combination of arachidonic acid with lipoxygenase (LOX), which causes atopy, so overexpression of BLT2 (Leukotriene B4 receptor 2) can cause atopy. have.
본 명세서에서 예시한 상기 질환 외에도, 당업계에 알려져 있는 BLT2-연관된 아토피는 모두 본 발명의 화학식 1 또는 화학식 2의 구조를 갖는 화합물로 예방 또는 치료할 수 있는 아토피에 포함되는 것으로 본다.In addition to the diseases exemplified herein, all of the BLT2-associated atopies known in the art are considered to be included in an atopy that can be prevented or treated with a compound having the structure of
본 발명에서, BLT2 Leukotriene B4 receptor 2)는 GPCR(G protein-coupled receptor) 군 중 하나로 LTB4 (Leukotriene B4; LTB4)에 대해 낮은 친화력을 갖는 수용체로서, 본 발명의 조성물은 BLT2에 의한 세포 성장을 억제함으로써, 아토피를 예방 또는 치료할 수 있다. 보다 구체적으로 BLT2 활성으로 유도된 ROS의 생성을 저해하여 LTB4-유도된 주화성을 저해할 수 있다.In the present invention, BLT2 Leukotriene B4 receptor 2) is one of the group of G protein-coupled receptors (GPCR), which has a low affinity for LTB 4 ( Leukotriene B4; LTB 4 ), and the composition of the present invention is a cell growth by BLT2. By inhibiting the atopic dermatitis can be prevented or treated. More specifically, the inhibition of the production of ROS induced by BLT2 activity may inhibit LTB 4 -induced chemotaxis.
본 발명에서 사용되는 용어, "저해"는 유전자의 전사, mRNA 프로세싱, 번역, 전좌 및 성숙 중 임의의 단계를 저해하거나, 단백질과 단백질간의 결합, 단백질의 활성화 또는 이를 통한 신호전달의 저해를 의미한다. As used herein, the term "inhibition" means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .
본 발명의 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
또한, 본 발명의 약학적 조성물은 피부외용 제형을 가질 수 있다. 피부외용 제형은 특별히 한정되지 않으며 바람직하게는 파우더, 젤, 연고, 크림, 액체 또는 에어로졸 제형이다.In addition, the pharmaceutical composition of the present invention may have an external dermal formulation. The external dermal formulation is not particularly limited and is preferably a powder, gel, ointment, cream, liquid or aerosol formulation.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field. The pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01 내지 100mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
또한, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 아토피의 치료방법을 제공한다. 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.The present invention also provides a method for treating atopy comprising administering the pharmaceutical composition to a subject. As used herein, "individual" means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
또한, 본 발명의 화학식 1 또는 화학식 2의 화합물은 아토피 개선용 화장료 조성물의 유효성분으로 사용될 수 있다.In addition, the compound of
본 발명의 화장품 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 유연 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 클렌징 크림, 클렌징 포옴, 클렌징 워터, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.Cosmetic compositions of the present invention may be prepared in any formulation conventionally prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 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 following examples.
[[ 실시예Example ]]
실시예Example 1. One. BLT2BLT2 저해 활성을 갖는 화합물의 합성 Synthesis of Compounds with Inhibitory Activity
본 발명에 따른 약학적 조성물의 유효성분으로 사용되는 비-한정적인 화합물의 예는 하기의 화합물, 이의 이성질체 및 이의 약학적으로 허용 가능한 염을 포함한다. 공지된 방법의 반응물 및/또는 출발물질을 적절히 변경하여, 본 발명에 따른 하기 화합물들을 합성하였으며 수율 및 1H NMR 측정 결과는 하기에 기재하였다.Examples of non-limiting compounds to be used as active ingredients of the pharmaceutical composition according to the present invention include the following compounds, isomers thereof and pharmaceutically acceptable salts thereof. By appropriately modifying the reactants and / or starting materials of known methods, the following compounds according to the invention were synthesized and the yield and 1 H NMR measurement results are described below.
1-1. 1-1. terttert -부틸 4-(4-(3-(-Butyl 4- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(4-(3-(-butyl 4- (4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-ynyl)benzoyl)piperazine-1-carboxylate) () prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -693)-693)
73% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H, s), 3.62-3.32 (8H, br), 2.02-1.97 (2H, t), 1.52-1.48 (2H, m), 1.40 (9H, s), 1.19-1.12 (2H, m), 0.76-0.72 (3H, t).73% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H, s), 3.62-3.32 (8H, br), 2.02-1.97 (2H, t), 1.52-1.48 ( 2H, m), 1.40 (9H, s), 1.19-1.12 (2H, m), 0.76-0.72 (3H, t).
1-2. 1-2. NN -페닐--Phenyl- NN -(3-(4-(피페라진-1--(3- (4- (piperazin-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (LMT-694)-(3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) (LMT-694)
60% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.73-3.39 (4H, br), 2.97-2.86 (4H, br), 2.09-2.06 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).60% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.73-3.39 (4H, br), 2.97-2.86 (4H, br), 2.09-2.06 ( 2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).
1-3. 1-3. NN -(3-(4-(4--(3- (4- (4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- methylpiperazinemethylpiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -692)-692)
20% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.21 (9H, m), 4.65 (2H, s), 3.71-3.34 (4H, br), 2.41-2.25 (4H, br), 2.25 (3H, s), 2.02-1.99 (2H, t), 1.54-1.46 (2H, m), 1.18-1.12 (2H, m), 0.76-0.71 (3H, t).20% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.21 (9H, m), 4.65 (2H, s), 3.71-3.34 (4H, br), 2.41-2.25 (4H, br), 2.25 (3H, s), 2.02-1.99 (2H, t), 1.54-1.46 (2H, m), 1.18-1.12 (2H, m), 0.76-0.71 (3H, t).
1-4. 1-4. NN -(3-(4-(4--(3- (4- (4- 에틸피페라진Ethyl piperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- EthylpiperazineEthylpiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -695)-695)
68% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H,s), 3.73-3.35 (4H,br), 2.44-2.31 (6H,m), 2.03-1.99 (2H,t), 1.54-1.46 (2H,m), 1.20-1.13 (2H,m), 1.05-1.01 (3H,t), 0.78-0.73 (3H,t).68% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H, s), 3.73-3.35 (4H, br), 2.44-2.31 (6H, m), 2.03-1.99 ( 2H, t), 1.54-1.46 (2H, m), 1.20-1.13 (2H, m), 1.05-1.01 (3H, t), 0.78-0.73 (3H, t).
1-5. 1-5. NN -(3-(4-(4--(3- (4- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- isopropylpiperazineisopropylpiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -696)-696)
57% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.47-7.30 (9H, m), 4.73 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 (1H, m), 2.59-2.44 (4H, br), 2.09-2.06 (2H, t), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 1.06-1.04 (6H, d), 0.83-0.80 (3H, t).57% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.47-7.30 (9H, m), 4.73 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 (1H, m), 2.59-2.44 ( 4H, br), 2.09-2.06 (2H, t), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 1.06-1.04 (6H, d), 0.83-0.80 (3H, t).
1-6. 1-6. NN -(3-(4-(4-(2-하이드록시에틸)피페라진-1--(3- (4- (4- (2-hydroxyethyl) piperazin-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(4-(4-(2-hydroxyethyl)-(3- (4- (4- (2-hydroxyethyl) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -827)-827)
84% 수율; 1H-NMR (CDCl3, 500MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.79 (2H, br), 3.66-3.64 (2H, t), 3.43 (2H, br), 2.60-2.46 (7H, br), 2.10-2.07 (2H, t), 1.59-1.56 (2H, m), 1.25-1.22 (2H, m), 0.83-0.80 (3H, t).84% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.79 (2H, br), 3.66-3.64 (2H, t), 3.43 (2H, br), 2.60-2.46 (7H, br), 2.10-2.07 (2H, t), 1.59-1.56 (2H, m), 1.25-1.22 (2H, m), 0.83-0.80 (3H, t).
1-7. 1-7. NN -(3-(4-(4-(-(3- (4- (4- ( 사이클로프로필메틸Cyclopropylmethyl )피페라진-1-Piperazine-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(4-(4-(-(3- (4- (4- ( cyclopropylmethylcyclopropylmethyl )) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -828)-828)
28% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.45 (4H, br), 2.63-2.49 (4H, br), 2.32-2.31 (2H, d), 2.09-2.06 (2H, t), 1.60-1.56 (2H, m), 1.25-1.20 (3H, m), 0.83-0.80 (3H, t), 0.55-0.53 (2H, m), 0.12-0.11 (2H, m).28% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.45 (4H, br), 2.63-2.49 (4H, br), 2.32-2.31 ( 2H, d), 2.09-2.06 (2H, t), 1.60-1.56 (2H, m), 1.25-1.20 (3H, m), 0.83-0.80 (3H, t), 0.55-0.53 (2H, m), 0.12-0.11 (2H, m).
1-8. N -(3-(4-(4- 사이클로헥실피페라진 -1- 카보닐 )페닐) 프로프 -2- 이닐 )- N - 페닐펜탄아마이드 ( N -(3-(4-(4- cyclohexylpiperazine -1-carbonyl)phenyl)prop-2-ynyl)- N -phenylpentanamide) ( LMT -830) 1-8. N - (3- (4- (4- cyclohexyl silpi Blow-1-carbonyl) phenyl) prop-2-ynyl) - N - phenyl pentane amide (N - (3- (4- ( 4- cyclohexylpiperazine -1-carbonyl) phenyl) prop-2-ynyl) -N- phenylpentanamide) ( LMT -830 )
33% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.31 (9H, m), 4.73 (2H, s), 3.77-3.39 (4H, br), 2.63-2.49 (4H, br), 2.31-2.28 (1H, m), 2.09-2.06 (2H, m), 1.91-1.79 (4H, m), 1.65-1.54 (3H, m), 1.28-1.16 (6H, m), 1.13-1.08 (1H, m), 0.83-0.80 (3H, t).33% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.31 (9H, m), 4.73 (2H, s), 3.77-3.39 (4H, br), 2.63-2.49 (4H, br), 2.31-2.28 ( 1H, m), 2.09-2.06 (2H, m), 1.91-1.79 (4H, m), 1.65-1.54 (3H, m), 1.28-1.16 (6H, m), 1.13-1.08 (1H, m), 0.83-0.80 (3H, t).
1-9. 1-9. NN -(3-(4-(4-(-(3- (4- (4- ( 사이클로헥실메틸Cyclohexylmethyl )피페라진-1-Piperazine-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(4-(4-(-(3- (4- (4- ( cyclohexylmethylcyclohexylmethyl )) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -831)-831)
56% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.76-3.38 (4H, br), 2.45-2.31 (4H, br), 2.15-2.13 (2H, m), 2.09-2.06 (2H, m), 1.77-1.66 (5H, m), 1.59-1.56 (2H, m), 1.47-1.45 (1H, m), 1.25-1.17 (5H, m), 0.90-0.80 (5H, t).56% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.76-3.38 (4H, br), 2.45-2.31 (4H, br), 2.15-2.13 ( 2H, m), 2.09-2.06 (2H, m), 1.77-1.66 (5H, m), 1.59-1.56 (2H, m), 1.47-1.45 (1H, m), 1.25-1.17 (5H, m), 0.90-0.80 (5H, t).
1-10. 1-10. NN -(3-(4-(4--(3- (4- (4- 아이소부틸피페라진Isobutyl Piperazine -1--One- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- isobutylpiperazineisobutylpiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -832)-832)
60% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.47-7.28 (9H, m), 4.73 (2H, s), 3.76-3.39 (4H, br), 2.46-2.32 (4H, br), 2.11-2.07 (4H, m), 1.79-1.76 (1H, m), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 0.91-0.89 (6H, d), 0.83-0.80 (3H, t).60% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.47-7.28 (9H, m), 4.73 (2H, s), 3.76-3.39 (4H, br), 2.46-2.32 (4H, br), 2.11-2.07 ( 4H, m), 1.79-1.76 (1H, m), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 0.91-0.89 (6H, d), 0.83-0.80 (3H, t).
1-11. 1-11. NN -페닐--Phenyl- NN -(3-(4-(4-(-(3- (4- (4- ( 프로프Prof -2--2- 이닐Inil )피페라진-1-Piperazine-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2-이닐)펜탄아마이드 (-2-ynyl) pentaneamide ( NN -phenyl--phenyl- NN -(3-(4-(4-(prop-2--(3- (4- (4- (prop-2- ynylynyl )) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -833)-833)
51% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.44 (4H, br), 3.36 (2H, s), 2.65-2.51 (4H, br), 2.30 (1H, s), 2.10-2.07 (2H, m), 1.60-1.54 (2H, m), 1.26-1.19 (2H, m), 0.83-0.80 (3H, t).51% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.44 (4H, br), 3.36 (2H, s), 2.65-2.51 (4H, br), 2.30 (1H, s), 2.10-2.07 (2H, m), 1.60-1.54 (2H, m), 1.26-1.19 (2H, m), 0.83-0.80 (3H, t).
1-12. 1-12. NN -(3-(4-(4--(3- (4- (4- 시아노피페라진Cyanopiperazine -1--One- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- cyanopiperazinecyanopiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -829)-829)
21% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.81-3.26 (8H, br), 2.09-2.06 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).21% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.81-3.26 (8H, br), 2.09-2.06 (2H, t), 1.60-1.54 ( 2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).
1-13. 1-13. terttert -- 부틸 4-(4-(3-(Butyl 4- (4- (3- ( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(4-(3-(-butyl 4- (4- (3- ( NN -(3-fluorophenyl)pentanamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate) (-(3-fluorophenyl) pentanamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -884)-884)
73% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.44-7.32 (5H, m), 7.12-7.06 (3H, m), 4.72 (2H, s), 3.73-3.38 (8H, br), 2.10-2.07 (2H, t), 1.59-1.57 (2H, m), 1.47 (9H, s), 1.23-1.20 (2H, m), 0.83-0.80 (3H, t).73% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.32 (5H, m), 7.12-7.06 (3H, m), 4.72 (2H, s), 3.73-3.38 (8H, br), 2.10-2.07 ( 2H, t), 1.59-1.57 (2H, m), 1.47 (9H, s), 1.23-1.20 (2H, m), 0.83-0.80 (3H, t).
1-14. 1-14. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(피페라진-1--(3- (4- (piperazin-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -(3-(4-(-(3- (4- ( piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -885)-885)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.45-7.32 (5H, m), 7.15-7.07 (3H, m), 4.72 (2H, s), 3.75-3.37 (4H, br), 2.94-2.80 (4H, br), 2.10-2.07 (2H, t), 1.89 (1H, br), 1.60-1.57 (2H, m), 1.25-1.24 (2H, m), 0.84-0.82 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.45-7.32 (5H, m), 7.15-7.07 (3H, m), 4.72 (2H, s), 3.75-3.37 (4H, br), 2.94-2.80 ( 4H, br), 2.10-2.07 (2H, t), 1.89 (1H, br), 1.60-1.57 (2H, m), 1.25-1.24 (2H, m), 0.84-0.82 (3H, t).
1-15. 1-15. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(4--(3- (4- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)프로프-2-이닐)펜탄아마이드 () Phenyl) prop-2-ynyl) pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-(3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -886)-886)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.44-7.32 (5H, m), 7.15-7.06 (3H, m), 4.72 (2H, s), 3.78-3.41 (4H, br), 2.75-2.72 (1H, m), 2.59-2.45 (4H, br), 2.11-2.09 (2H, t), 1.60-1.57 (2H, m), 1.25-1.22 (2H, m), 1.06-1.05 (6H, d), 0.85-0.82 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.32 (5H, m), 7.15-7.06 (3H, m), 4.72 (2H, s), 3.78-3.41 (4H, br), 2.75-2.72 ( 1H, m), 2.59-2.45 (4H, br), 2.11-2.09 (2H, t), 1.60-1.57 (2H, m), 1.25-1.22 (2H, m), 1.06-1.05 (6H, d), 0.85-0.82 (3H, t).
1-16. 1-16. terttert -부틸 4-(4-(3-(-Butyl 4- (4- (3- ( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트(Piperazine-1-carboxylate ( terttert -butyl 4-(4-(3-(-butyl 4- (4- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate) (-(4-fluorophenyl) pentanamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -839)-839)
73% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.71 (2H, s), 3.73-3.38 (8H, br), 2.07-2.04 (2H, t), 1.60-1.54 (2H, m), 1.47 (9H, s), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).73% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.71 (2H, s), 3.73-3.38 (8H, br), 2.07-2.04 ( 2H, t), 1.60-1.54 (2H, m), 1.47 (9H, s), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).
1-17. 1-17. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(피페라진-1--(3- (4- (piperazin-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )펜탄아마이드 (Pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(4-(-(3- (4- ( piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -840)-840)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.38-7.30 (6H, m), 7.17-7.15 (2H, m), 4.71 (2H, s), 3.77-3.40 (4H, br), 2.96-2.79 (5H, br), 2.06-2.03 (2H, t), 1.57-1.54 (2H, m), 1.25-1.22 (2H, m), 0.84-0.82 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.38-7.30 (6H, m), 7.17-7.15 (2H, m), 4.71 (2H, s), 3.77-3.40 (4H, br), 2.96-2.79 ( 5H, br), 2.06-2.03 (2H, t), 1.57-1.54 (2H, m), 1.25-1.22 (2H, m), 0.84-0.82 (3H, t).
1-18. 1-18. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(4--(3- (4- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)프로프-2-이닐)펜탄아마이드 () Phenyl) prop-2-ynyl) pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-(3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -841)-841)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.37-7.28 (6H, m), 7.17-7.13 (2H, m), 4.71 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 (1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.04 (6H, d), 0.84-0.81 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.37-7.28 (6H, m), 7.17-7.13 (2H, m), 4.71 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 ( 1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.04 (6H, d), 0.84-0.81 (3H, t).
1-19. 1-19. NN -(3-(4-(-(3- (4- ( 몰폴린Morpholine -4--4- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(morpholine-4-carbonyl)phenyl)prop-2-ynyl)--(3- (4- (morpholine-4-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (LMT-682)-phenylpentanamide) (LMT-682)
수율 90%; 1H-NMR (CDCl3, 400 MHz) δ 7.48-7.28 (m, 9H), 4.73 (s, 2H), 3.74-3.66 (br, 6 H), 3.43 (br, 2H), 2.08 (m, 2H), 1.57 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H).Yield 90%; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.48-7.28 (m, 9H), 4.73 (s, 2H), 3.74-3.66 (br, 6H), 3.43 (br, 2H), 2.08 (m, 2H ), 1.57 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H).
1-20. 1-20. NN -페닐--Phenyl- NN -(3-(4-(피페리딘-1--(3- (4- (piperidine-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(4-(piperidine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (LMT-683)-(3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) (LMT-683)
15% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.13 (9H, m), 4.65 (2H, s, CH2), 3.62-3.24 (4H, br), 2.02-1.99 (2H,t), 1.60 (4H, br), 1.52-1.46 (2H, m), 1.44 (2H, br), 1.20-1.08 (2H, m), 0.78-0.73 (3H, t).15% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.13 (9H, m), 4.65 (2H, s, CH 2 ), 3.62-3.24 (4H, br), 2.02-1.99 (2H, t), 1.60 (4H, br), 1.52-1.46 (2H, m), 1.44 (2H, br), 1.20-1.08 (2H, m), 0.78-0.73 (3H, t).
1-21. 1-21. NN ,, NN -- 다이에틸Diethyl -4-(3-(-4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1--One- 이닐Inil )) 벤즈아마이드Benzamide ( ( NN ,, NN -diethyl-4-(3-(-diethyl-4- (3- ( NN -phenylpentanamido)prop-1-ynyl)benzamide) (-phenylpentanamido) prop-1-ynyl) benzamide) ( LMTLMT -883)-883)
39% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.53-3.23 (4H, br), 2.10-2.07 (2H, t), 1.59-1.57 (2H, m), 1.23-1.10 (8H, m), 0.83-0.80 (3H, t).39% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.53-3.23 (4H, br), 2.10-2.07 (2H, t), 1.59-1.57 ( 2H, m), 1.23-1.10 (8H, m), 0.83-0.80 (3H, t).
1-22. 1-22. NN -페닐--Phenyl- NN -(3-(3-(피페라진-1--(3- (3- (piperazin-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(3-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (LMT-837)-(3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) (LMT-837)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.45-7.26 (9H, m), 4.69 (2H, s), 3.75-3.36 (4H, br), 2.94-2.80 (4H, br), 2.59 (1H, br), 2.07-2.04 (2H, t), 1.56-1.53 (2H, m), 1.22-1.18 (2H, m), 0.80-0.77 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.45-7.26 (9H, m), 4.69 (2H, s), 3.75-3.36 (4H, br), 2.94-2.80 (4H, br), 2.59 (1H, br), 2.07-2.04 (2H, t), 1.56-1.53 (2H, m), 1.22-1.18 (2H, m), 0.80-0.77 (3H, t).
1-23. 1-23. NN -(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)--(3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl)- NN -페닐펜탄아마이드(-Phenylpentaneamide ( NN -(3-(3-(4-methylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)--(3- (3- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -838)-838)
46% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.46-7.29 (9H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.48-2.32 (7H, br), 2.08-2.05 (2H, t), 1.57-1.54 (2H, m), 1.23-1.19 (2H, m), 0.81-0.78 (3H, t).46% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.46-7.29 (9H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.48-2.32 (7H, br), 2.08-2.05 ( 2H, t), 1.57-1.54 (2H, m), 1.23-1.19 (2H, m), 0.81-0.78 (3H, t).
1-24. 1-24. NN -(3-(3-(4--(3- (3- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(3-(4--(3- (3- (4- isopropylpiperazineisopropylpiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -842)-842)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.47-7.29 (9H, m), 4.71 (2H, s), 3.79-3.40 (4H, br), 2.78-2.75 (1H, m), 2.60-2.46 (4H, br), 2.09-2.06 (2H, t), 1.58-1.55 (2H, m), 1.24-1.20 (2H, m), 1.07-1.05 (6H, d), 0.82-0.79 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.47-7.29 (9H, m), 4.71 (2H, s), 3.79-3.40 (4H, br), 2.78-2.75 (1H, m), 2.60-2.46 ( 4H, br), 2.09-2.06 (2H, t), 1.58-1.55 (2H, m), 1.24-1.20 (2H, m), 1.07-1.05 (6H, d), 0.82-0.79 (3H, t).
1-25. 1-25. terttert -부틸-4-(3-(3-(-Butyl-4- (3- (3- ( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(3-(3-(-butyl 4- (3- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate) (-(4-fluorophenyl) pentanamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -887)-887)
85% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.33-7.20 (6H, m), 7.09-7.06 (2H, m), 4.62 (2H, s), 3.66-3.31 (8H, br), 2.00-1.97 (2H, t), 1.52-1.49 (2H, m), 1.47 (9H, s), 1.18-1.13 (2H, m), 0.76-0.73 (3H, t).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.33-7.20 (6H, m), 7.09-7.06 (2H, m), 4.62 (2H, s), 3.66-3.31 (8H, br), 2.00-1.97 ( 2H, t), 1.52-1.49 (2H, m), 1.47 (9H, s), 1.18-1.13 (2H, m), 0.76-0.73 (3H, t).
1-26. 1-26. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(3-(피페라진-1--(3- (3- (piperazin-1- 카보닐Carbonyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )펜탄아마이드 (Pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(3-(-(3- (3- ( piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -888)-888)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.70 (2H, s), 3.77-3.39 (4H, br), 2.98-2.85 (4H, br), 2.08-2.05 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.70 (2H, s), 3.77-3.39 (4H, br), 2.98-2.85 ( 4H, br), 2.08-2.05 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).
1-27. 1-27. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(3-(4--(3- (3- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)프로프-2-이닐)펜탄아마이드 () Phenyl) prop-2-ynyl) pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(3-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-(3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -889)-889)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.37-7.29 (6H, m), 7.16-7.13 (2H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.75-2.73 (1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.05 (6H, d), 0.84-0.81 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.37-7.29 (6H, m), 7.16-7.13 (2H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.75-2.73 ( 1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.05 (6H, d), 0.84-0.81 (3H, t).
1-28. 1-28. NN -(3-(4--(3- (4- 하이드록시페닐Hydroxyphenyl )) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-hydroxyphenyl)prop-2-ynyl)--(3- (4-hydroxyphenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -890)-890)
75% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.15 (1H, br), 7.47-6.83 (9H, m), 4.66 (2H, s), 2.13-2.10 (2H, t), 1.60-1.54 (2H, m), 1.22-1.17 (2H, m), 0.80-0.77 (3H, t).75% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.15 (1H, br), 7.47-6.83 (9H, m), 4.66 (2H, s), 2.13-2.10 (2H, t), 1.60-1.54 (2H, m), 1.22-1.17 (2H, m), 0.80-0.77 (3H, t).
1-29. 2-(4-(3-(1-29. 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1--One- 이닐Inil )) 페녹시Phenoxy )아세트산 (2-(4-(3-(Acetic acid (2- (4- (3- ( NN -phenylpentanamido)prop-1-ynyl)phenoxy)acetic acid) (-phenylpentanamido) prop-1-ynyl) phenoxy) acetic acid) ( LMTLMT -891)-891)
50% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.47-6.78 (9H, m), 4.68 (2H, s), 4.58 (2H, s), 2.11-2.08 (2H, t), 1.58-1.53 (2H, m), 1.23-1.18 (2H, m), 0.81-0.78 (3H, t).50% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.47-6.78 (9H, m), 4.68 (2H, s), 4.58 (2H, s), 2.11-2.08 (2H, t), 1.58-1.53 (2H, m), 1.23-1.18 (2H, m), 0.81-0.78 (3H, t).
1-30. 1-30. terttert -부틸 4-(5-(3-((-Butyl 4- (5- (3-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 피콜리노일Picolinoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(5-(3-(-butyl 4- (5- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1-yl)picolinoyl)piperazine-1-carboxylate) (-1-yl) picolinoyl) piperazine-1-carboxylate) ( LMTLMT -834)-834)
35% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.64 (dd, 1H),7.54 (dd, 1H), 7.36 (dd, 3H), 7.18 (m, 2H), 4.68 (s, 2H), 3.69 (br, 2H), 3.53-3.38 (br, 6H), 2.01 (m, 2H), 1.52 (m, 2H), 1.39 (s, 9H), 1.18 (m, 2H), 0.73 (t, 3H).35% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.43 (s, 1H), 7.64 (dd, 1H), 7.54 (dd, 1H), 7.36 (dd, 3H), 7.18 (m, 2H), 4.68 (s , 2H), 3.69 (br, 2H), 3.53-3.38 (br, 6H), 2.01 (m, 2H), 1.52 (m, 2H), 1.39 (s, 9H), 1.18 (m, 2H), 0.73 ( t, 3H).
1-31. 1-31. NN -페닐--Phenyl- NN -(3-(6-(피페라진-1--(3- (6- (piperazin-1- 카보닐Carbonyl )피리딘-3-일)Pyridin-3-yl) 프로프Prof -2-인-1-일)-2-yn-1-yl) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(6-(-(3- (6- ( piperazinepiperazine -1-carbonyl)-1-carbonyl) pyridinpyridin -3--3- ylyl )prop-2-prop-2- ynyn -1-yl)pentanamide) (-1-yl) pentanamide) ( LMTLMT -835)-835)
64% 수율; 1H-NMR (CDCl3, 400MHz) δ 8.43 (s, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 7.36 (dd, 3H), 7.21 (m, 2H), 4.67 (s, 2H), 3.70 (br, 2H), 3.48 (br, 2H), 2.90 (br, 2H), 2.81 (br, 2H), 2.01 (m, 2H), 1.49 (m, 2H), 1.17 (m, 2H), 0.73 (t, 3H).64% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.43 (s, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 7.36 (dd, 3H), 7.21 (m, 2H), 4.67 (s, 2H), 3.70 (br, 2H), 3.48 (br, 2H), 2.90 (br, 2H), 2.81 (br, 2H), 2.01 (m, 2H), 1.49 (m, 2H), 1.17 (m, 2H ), 0.73 (t, 3 H).
1-32. 1-32. NN -(3-(6-(4--(3- (6- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )피리딘-3-일)Pyridin-3-yl) 프로프Prof -2-인-1-일)--2-yn-1-yl)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(6-(4--(3- (6- (4- isopropylpiperazineisopropylpiperazine -1-carbonyl)-1-carbonyl) pyridinpyridin -3-yl)prop-2-yn-1-yl)--3-yl) prop-2-yn-1-yl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -836)-836)
51% 수율; 1H-NMR (CDCl3, 400MHz) δ 8.44 (s, 1H), 7.65 (dd, 1H), 7.51 (dd, 1H), 7.39 (dd, 3H), 7.22 (m, 2H), 4.68 (s, 2H), 3.74 (br, 2H), 3.52 (br, 2H), 2.67 (m, 1H), 2.55 (br, 2H), 2.41 (br, 2H), 2.02 (m, 2H), 1.50 (m, 2H), 1.15 (m, 2H), 0.98 (d, 6H), 0.74 (t,3H).51% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.44 (s, 1H), 7.65 (dd, 1H), 7.51 (dd, 1H), 7.39 (dd, 3H), 7.22 (m, 2H), 4.68 (s, 2H), 3.74 (br, 2H), 3.52 (br, 2H), 2.67 (m, 1H), 2.55 (br, 2H), 2.41 (br, 2H), 2.02 (m, 2H), 1.50 (m, 2H ), 1.15 (m, 2H), 0.98 (d, 6H), 0.74 (t, 3H).
1-33. 1-33. N,NN, N -- 다이에틸Diethyl -4-(3-(-4- (3- ( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1-인-1-일)벤즈아마이드 (-1-yn-1-yl) benzamide ( N,NN, N -diethyl-4-(3-(-diethyl-4- (3- ( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )prop-1-prop-1- ynyn -1-yl)benzamide) (-1-yl) benzamide) ( LMTLMT -926)-926)
70% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.43 (1H, t, J = 7.5 Hz and 15.0 Hz, aromatic), 7.33 (4H, m, aromatic), 7.09 (3H, m, aromatic), 4.71 (2H, s, CH2), 3.53 (2H, s, CH2), 3.23 (2H, s, CH2), 2.10 (2H, m, CH2), 1.59 (2H, m, CH2), 1.24 (2H, m, CH2), 1.10 (6H, m, (CH3)2), 0.83 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).70% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.43 (1H, t, J = 7.5 Hz and 15.0 Hz, aromatic), 7.33 (4H, m, aromatic), 7.09 (3H, m, aromatic), 4.71 (2H , s, CH 2 ), 3.53 (2H, s, CH 2 ), 3.23 (2H, s, CH 2 ), 2.10 (2H, m, CH 2 ), 1.59 (2H, m, CH 2 ), 1.24 (2H , m, CH 2 ), 1.10 (6H, m, (CH 3 ) 2 ), 0.83 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-34. 1-34. N,NN, N -다이에틸-4-(3-(-Diethyl-4- (3- ( NN -(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드(-(4-fluorophenyl) pentaneamido) prop-1-yn-1-yl) benzamide ( N,NN, N -diethyl-4-(3-(-diethyl-4- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-yn-1-yl)benzamide) (-(4-fluorophenyl) pentanamido) prop-1-yn-1-yl) benzamide) ( LMTLMT -927)-927)
70% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.31 (2H, d, J = 3.5 Hz, aromatic), 7.29 (4H, d, J = 3.0 Hz, aromatic), 7.15 (2H, t, J = 8.5 Hz and 17.0 Hz, aromatic), 4.71 (2H, s, CH2), 3.53 (2H, s, CH2), 3.23 (2H, s, CH2), 2.06 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.57 (2H, m, CH2), 1.22 (2H, m, CH2), 1.10 (6H, s, (CH3)2), 0.82 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).70% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.31 (2H, d, J = 3.5 Hz, aromatic), 7.29 (4H, d, J = 3.0 Hz, aromatic), 7.15 (2H, t, J = 8.5 Hz and 17.0 Hz, aromatic), 4.71 (2H, s, CH 2 ), 3.53 (2H, s, CH 2 ), 3.23 (2H, s, CH 2 ), 2.06 (2H, t, J = 7.5 Hz and 15.0 Hz , CH 2 ), 1.57 (2H, m, CH 2 ), 1.22 (2H, m, CH 2 ), 1.10 (6H, s, (CH 3 ) 2 ), 0.82 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-35. 1-35. NN -(3-(4-(-(3- (4- ( N,NN, N -- 다이에틸설파모일Diethylsulfamoyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(-(3- (4- ( N,NN, N -- diethylsulfamoyldiethylsulfamoyl )phenyl)prop-2-) phenyl) prop-2- ynylynyl )-)- NN -- phenylpentanamidephenylpentanamide ) (LMT-946)(LMT-946)
70% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz), 7.51 (4H, m), 7.43 (3H, m), 4.73 (2H, s), 3.21 (4H, s), 2.11 (2H, t), 1.52 (2H, m), 1.21 (2H, m), 0.10 (6H, t), 0.80 (3H, t).70% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz), 7.51 (4H, m), 7.43 (3H, m), 4.73 (2H, s), 3.21 (4H, s ), 2.11 (2H, t), 1.52 (2H, m), 1.21 (2H, m), 0.10 (6H, t), 0.80 (3H, t).
1-36. 1-36. NN -(3-(4-(-(3- (4- ( NN -- 아이소프로필설파모일Isopropyl sulfamoyl )페닐)Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(-(3- (4- ( NN -- isopropylsulfamoylisopropylsulfamoyl )phenyl)prop-2-) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -947)-947)
49.5 % 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.78 (2H, d, J = 8.5 Hz), 7.51-7.37 (7H, m), 4.72 (2H, s), 3.33 (1H, m), 2.10 (2H, t), 1.51 (2H, m), 1.19 (2H, m), 0.99 (6H, d, J = 6.5 Hz), 0.78 (3H, t)49.5% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.78 (2H, d, J = 8.5 Hz), 7.51-7.37 (7H, m), 4.72 (2H, s), 3.33 (1H, m), 2.10 (2H , t), 1.51 (2H, m), 1.19 (2H, m), 0.99 (6H, d, J = 6.5 Hz), 0.78 (3H, t)
1-37. 1-37. terttert -부틸 4--Butyl 4- (3-((3- ( NN -페닐펜탄아미도)프로프Phenylpentane amido) prop -1-인-1-일)-1-yn-1-yl) 벤조에이트Benzoate (( terttert -butyl 4-(3-(-butyl 4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1--One- ylyl )benzoate) () benzoate) ( LMTLMT -1012)-1012)
78.3% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.88 (2H, d, J = 8.0 Hz, aromatic), 7.45 (2H, m, aromatic), 7.39 (1H, d, J = 7.0 Hz, aromatic), 7.35 (2H, d, J = 8.0 Hz, aromatic), 7.30 (2H, d, J = 5.0 Hz, aromatic), 4.72 (2H, s, CH2), 2.07 (2H, t, J = 7.5 Hz and 15 Hz, CH2), 1.56 (2H, m, CH2), 1.51 (9H, s, (CH3)3), 1.22 (2H, m, CH2), 0.80 (3H, t, 7.5 Hz and 15 Hz7.5 Hz and 15 Hz, CH3).78.3% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.88 (2H, d, J = 8.0 Hz, aromatic), 7.45 (2H, m, aromatic), 7.39 (1H, d, J = 7.0 Hz, aromatic), 7.35 (2H, d, J = 8.0 Hz, aromatic), 7.30 (2H, d, J = 5.0 Hz, aromatic), 4.72 (2H, s, CH 2 ), 2.07 (2H, t, J = 7.5 Hz and 15 Hz , CH 2 ), 1.56 (2H, m, CH 2 ), 1.51 (9H, s, (CH 3 ) 3 ), 1.22 (2H, m, CH 2 ), 0.80 (3H, t, 7.5 Hz and 15 Hz 7. 5 Hz and 15 Hz, CH 3 ).
1-38. 4-1-38. 4- (3-((3- ( NN -페닐펜탄아미도)프로-1-핀-1-일)벤조익산-Phenylpentaneamido) prop-1-pin-1-yl) benzoic acid (4-(3-((4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzoic acid) (-phenylpentanamido) prop-1-yn-1-yl) benzoic acid) ( LMTLMT -1013)-1013)
95% 수율; 1H-NMR (MeOD, 500 MHz): δ 7.95 (2H, d, J = 8.5 Hz, aromatic), 7.51 (2H, m, aromatic), 7.45 (1H, m, aromatic), 7.44 (2H, d, J = 8.5 Hz, aromatic), 7.39 (2H, d, J = 8.0 Hz, aromatic), 4.73 (2H, s, CH2), 2.11 (2H, t, CH3), 1.21 (2H, m, CH2), 0.83 (3H, t, CH3).95% yield; 1 H-NMR (MeOD, 500 MHz): δ 7.95 (2H, d, J = 8.5 Hz, aromatic), 7.51 (2H, m, aromatic), 7.45 (1H, m, aromatic), 7.44 (2H, d, J = 8.5 Hz, aromatic), 7.39 (2H, d, J = 8.0 Hz, aromatic), 4.73 (2H, s, CH 2 ), 2.11 (2H, t, CH 3 ), 1.21 (2H, m, CH 2 ), 0.83 (3H, t, CH 3 ).
1-39. 1-39. NN -에틸-4-(3-(-Ethyl-4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아마이드Benzamide ( ( NN -ethyl-4-(3-(-ethyl-4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzamide) (-phenylpentanamido) prop-1-yn-1-yl) benzamide) ( LMTLMT -1017)-1017)
66% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.69 (2H, d, J = 8.5 Hz, aromatic), 7.39 (7H, m, aromatic), 4.72 (2H, s, CH2), 3.49 (2H, t, J = 6.0 Hz and 13.0 Hz, CH2), 2.08 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.57 (2H, m, CH2), 1.23 (2H, m, CH2), 0.81 (3H, t, J = 7.5 Hz and 14.5 Hz, CH3).66% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.69 (2H, d, J = 8.5 Hz, aromatic), 7.39 (7H, m, aromatic), 4.72 (2H, s, CH 2 ), 3.49 (2H, t , J = 6.0 Hz and 13.0 Hz, CH 2 ), 2.08 (2H, t, J = 7.5 Hz and 15.0 Hz, CH 2 ), 1.57 (2H, m, CH 2 ), 1.23 (2H, m, CH 2 ) , 0.81 (3H, t, J = 7.5 Hz and 14.5 Hz, CH 3 ).
1-40. 1-40. NN -(2-(-(2-( 다이메틸아미노Dimethylamino )에틸)-4-(3-() Ethyl) -4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)벤즈아마이드 (-1-yn-1-yl) benzamide ( NN -(2-(-(2-( dimethylaminodimethylamino )ethyl)-4-(3-() ethyl) -4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-yn-1-yl)benzamide) () prop-1-yn-1-yl) benzamide) ( LMTLMT -1016)-1016)
74% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.38 (7H, m, aromatic), 4.70 (2H, s, CH2), 3.48 (2H, m, CH2), 2.50 (2H, t, J = 6.0 Hz and 11.5 Hz, CH2), 2.24 (6H, s, (CH3)2), 2.05 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.54 (2H, m, CH2), 1.20 (2H, m, CH2), 0.78 (3H, t, J = 7.0 Hz and 14.0 Hz, CH3).74% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.38 (7H, m, aromatic), 4.70 (2H, s, CH 2 ), 3.48 (2H, m , CH 2 ), 2.50 (2H, t, J = 6.0 Hz and 11.5 Hz, CH 2 ), 2.24 (6H, s, (CH 3 ) 2 ), 2.05 (2H, t, J = 7.5 Hz and 15.0 Hz, CH 2 ), 1.54 (2H, m, CH 2 ), 1.20 (2H, m, CH 2 ), 0.78 (3H, t, J = 7.0 Hz and 14.0 Hz, CH 3 ).
1-41. 에틸 2-(4-(3-(1-41. Ethyl 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )아세테이트(ethyl 2-(4-(3-(Acetate (ethyl 2- (4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1--One- ylyl )) benzamidobenzamido )acetate) (LMT-1014)) acetate) (LMT-1014)
54% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz, aromatic), 7.37 (7H, m, aromatic), 4.22 (4H, m, (CH2)2), 2.07 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.56 (2H, m, CH2), 1.30 (5H, m, CH3, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.5 Hz and 14.5 Hz, CH3).54% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz, aromatic), 7.37 (7H, m, aromatic), 4.22 (4H, m, (CH 2 ) 2 ), 2.07 ( 2H, t, J = 7.5 Hz and 15.0 Hz, CH 2 ), 1.56 (2H, m, CH 2 ), 1.30 (5H, m, CH 3 , CH 2 ), 1.22 (2H, m, CH 2 ), 0.80 (3H, t, J = 7.5 Hz and 14.5 Hz, CH 3 ).
1-42. 2-(4-(3-(1-42. 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )) 아세틱산Acetic acid (2-(4-(3-( (2- (4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzamido)acetic acid) (-phenylpentanamido) prop-1-yn-1-yl) benzamido) acetic acid) ( LMTLMT -1015)-1015)
53% 수율; 1H-NMR (CDCl3 , 500 MHz) δ 7.71 (2H, d, J = 8.5 Hz, aromatic), 7.40 (7H, m, aromatic), 4.71 (2H, s, CH2), 4.23 (2H, d, J = 5.0 Hz, CH2), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.56 (2H, m, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.0 Hz and 14.5 Hz, CH3).53% yield; 1 H-NMR (
1-43. 1-43. 메틸methyl 2-(4-(3-( 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )) 프로파노에이트Propanoate (methyl 2-(4-(3-( (methyl 2- (4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1-yl)benzamido)propanoate) (-1-yl) benzamido) propanoate) ( LMTLMT -1018)-1018)
42% 수율; 1H-NMR (CDCl3 , 500 MHz) δ 7.72 (2H, d, J = 8.5 Hz, aromatic), 7.37 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz CH), 4.71 (2H, s, CH2), 3.76 (3H, s, CH3), 2.06 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.53 (2H, m, CH2), 1.50 (3H, d, J = 7.5 Hz, CH3), 1.20 (2H, m, CH2), 0.79 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).42% yield; 1 H-NMR (
1-44. 2-1-44. 2- (4-(3-((4- (3- ( NN -페닐펜탄아미도)프로프Phenylpentane amido) prop -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )) 프로피오닉산Propionic acid (2-(4-(3-((2- (4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzamido)propanoic acid) (LMT-1019)-phenylpentanamido) prop-1-yn-1-yl) benzamido) propanoic acid) (LMT-1019)
55% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.40 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz, CH), 4.72 (2H, s, CH2), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.57 (5H, m, CH3, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).55% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.40 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz, CH ), 4.72 (2H, s, CH 2 ), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH 2 ), 1.57 (5H, m, CH 3 , CH 2 ), 1.22 (2H, m, CH 2 ), 0.80 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-45. 2-(4-(3-(1-45. 2- (4- (3- ( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 페녹시Phenoxy )아세트산(2-(4-(3-(Acetic acid (2- (4- (3- ( NN -(3-fluorophenyl)pentanamido)prop-1-ynyl)phenoxy)acetic acid) (LMT-1009)-(3-fluorophenyl) pentanamido) prop-1-ynyl) phenoxy) acetic acid) (LMT-1009)
16% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.52 (1H, d, J = 7.0 Hz), 7.24 (5H, m), 6.88 (2H, d, J = 8.5 Hz), 4.68 (2H, s), 4.66 (2H, s), 2.14 (2H, t), 1.55 (2H, m), 1.24 (2H, m), 0.83 (3H, t).16% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.52 (1H, d, J = 7.0 Hz), 7.24 (5H, m), 6.88 (2H, d, J = 8.5 Hz), 4.68 (2H, s), 4.66 (2H, s), 2.14 (2H, t), 1.55 (2H, m), 1.24 (2H, m), 0.83 (3H, t).
1-46. 2-(4-(3-(1-46. 2- (4- (3- ( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 페녹시Phenoxy )아세트산(2-(4-(3-(Acetic acid (2- (4- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-ynyl)phenoxy)acetic acid) (LMT-1010)-(4-fluorophenyl) pentanamido) prop-1-ynyl) phenoxy) acetic acid) (LMT-1010)
27 % 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.41 (2H, m), 7.26 (4H, m), 6.88 (2H, d, J = 7.0 Hz), 4.66 (2H, s), 4.60 (2H, s), 2.10 (2H, t), 1.52 (2H, m), 1.23 (2H, m), 0.82 (3H, t).27% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.41 (2H, m), 7.26 (4H, m), 6.88 (2H, d, J = 7.0 Hz), 4.66 (2H, s), 4.60 (2H, s ), 2.10 (2H, t), 1.52 (2H, m), 1.23 (2H, m), 0.82 (3H, t).
1-47. 1-47. NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((3'-(4--((3 '-(4- methylphenylsulfonamidomethylphenylsulfonamido )biphenyl-4-) biphenyl-4- ylyl )methyl)-) methyl)- NN -phenylpentanamide) (AC-1079)-phenylpentanamide) (AC-1079)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d, J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d , J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).
1-48. 1-48. NN -(4'-((-(4'-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3-일)-4-(-3- days) -4- ( 트리플루오로메틸Trifluoromethyl )벤즈아마이드 (Benzamide ( NN -(4'-((-(4'-(( NN -- phenylpentanamidophenylpentanamido )methyl)biphenyl-3-) methyl) biphenyl-3- ylyl )-4-(trifluoromethyl)benzamide) (AC-1310)) -4- (trifluoromethyl) benzamide) (AC-1310)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.45 (1H, s), 8.03 (2H, d, J = 8.0 Hz), 7.89 (1H, s), 7.73 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.49 (2H, d, J = 8.0 Hz), 7.44-7.38 (2H, m), 7.36-7.31 (3H, m), 7.238 (2H, d, J = 8.4 Hz), 7.00-6.98 (2H, m), 4.89 (2H, s), 2.06 (2H, t), 1.58-1.54 (2H, m), 1.23-1.169 (2H, m), 0.78 (3H, t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.45 (1H, s), 8.03 (2H, d, J = 8.0 Hz), 7.89 (1H, s), 7.73 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.49 (2H, d, J = 8.0 Hz), 7.44-7.38 (2H, m), 7.36-7.31 (3H, m), 7.238 (2H, d, J = 8.4 Hz), 7.00-6.98 (2H, m), 4.89 (2H, s), 2.06 (2H, t), 1.58-1.54 (2H, m), 1.23-1.169 (2H, m), 0.78 (3H, t ).
1-49. 1-49. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)pentanamide) (AC-1080)-((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide) (AC-1080)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d, J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d , J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).
1-50. 1-50. NN -(4'-((-(4'-(( NN -3--3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3-일)-4-(-3- days) -4- ( 트리플루오로메틸Trifluoromethyl )벤즈아마이드 (Benzamide ( NN -(4'-((-(4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-3-yl)-4-(trifluoromethyl)benzamide) (AC-1311)-(3-fluorophenyl) pentanamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide) (AC-1311)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.20 (1H, br, s), 8.03 (2H, d, J = 8.4 Hz), 7.89 (1H, m), 7.76 (2H. d. J = 8.0 Hz), 7.65 (1H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.46-738 (2H, m), 7.34-7.28 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.06-7.02 (1H, m), 6.81-6.74 (2H, m), 4.90 (2H, s), 2.08 (2H. t), 1.64-1.55 (2H, m), 1.33-1.19 (2H, m), 0.84 (3H,t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.20 (1H, br, s), 8.03 (2H, d, J = 8.4 Hz), 7.89 (1H, m), 7.76 (2H.d. J = 8.0 Hz ), 7.65 (1H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.46-738 (2H, m), 7.34-7.28 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.06-7.02 (1H, m), 6.81-6.74 (2H, m), 4.90 (2H, s), 2.08 (2H.t), 1.64-1.55 (2H, m), 1.33-1.19 (2H, m), 0.84 (3H, t).
1-51. 1-(3-1-51. 1- (3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)유레아 (1-(3-) Phenyl) urea (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea) (AC-1317)-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1317)
23.4% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (1H, s), 7.53-7.48 (5H, m), 7.45-7.35 (2H, m), 7.32-7.29 (3H, m), 7.14-7.09 (1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.96 (3H, d, J = 8.8 Hz), 6.32 (1H, s, br), 4.96 (2H, s), 3.85 (3H, s).23.4% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (1H, s), 7.53-7.48 (5H, m), 7.45-7.35 (2H, m), 7.32-7.29 (3H, m), 7.14-7.09 ( 1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.96 (3H, d, J = 8.8 Hz), 6.32 (1H, s, br), 4.96 (2H, s), 3.85 (3H, s ).
1-52. 1-52. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-1-(4-) -1- (4- 메톡시페닐설폰일Methoxyphenylsulfonyl )메탄아마이드 (Methaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)-1-(4-methoxyphenylsulfonyl)methanamide) (AC-1312)-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methanamide) (AC-1312)
61% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.62-7.59 (2H, m), 7.48-7.45 (2H, m), 7.43 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J = 0.8 Hz), 7.21-7.15 (1H, m), 6.99-6.89 (5H, m), 6.85-6.83 (1H, m), 6.79-6.76 (1H, m), 4.72 (2H, s), 3.91 (3H, s), 3.83 (3H, s).61% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.62-7.59 (2H, m), 7.48-7.45 (2H, m), 7.43 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J = 0.8 Hz), 7.21-7.15 (1H, m), 6.99-6.89 (5H, m), 6.85-6.83 (1H, m), 6.79-6.76 (1H, m), 4.72 (2H, s), 3.91 (3H , s), 3.83 (3H, s).
1-53. 1-(3-1-53. 1- (3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)유레아 (1-(3-) Phenyl) urea (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- hydroxybiphenylhydroxybiphenyl -4-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea) (AC-1318)-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1318)
55% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.60 (1H, s), 7.53 (1H, d, J = 7.4 Hz), 7.48-7.45 (4H, m), 7.43-7.35 (2H, m), 7.31 (3H, d, J = 8.0 Hz), 7.14-7.09 (1H, m), 7.02 (1H, d, J = 8.0 Hz), 6.98-6.95 (1H, m), 6.91-6.88 (2H, m), 6.33 (1H, s), 4.96 (2H, s), 4.85 (1H, s).55% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (1H, s), 7.53 (1H, d, J = 7.4 Hz), 7.48-7.45 (4H, m), 7.43-7.35 (2H, m), 7.31 (3H, d, J = 8.0 Hz), 7.14-7.09 (1H, m), 7.02 (1H, d, J = 8.0 Hz), 6.98-6.95 (1H, m), 6.91-6.88 (2H, m), 6.33 (1 H, s), 4.96 (2 H, s), 4.85 (1 H, s).
1-54. 2-(4'-((1-(3-1-54. 2- (4 '-((1- (3- 플루오로페닐Fluorophenyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)Phenyl) 유레이도Eureido )메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((1-(3-) Methyl) biphenyl-4-yloxy) acetic acid (2- (4 '-((1- (3- fluorophenylfluorophenyl )-3-(3-(trifluoromethyl)phenyl)ureido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1320)) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1320)
96% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (1H, s), 7.52-7.47 (5H, m), 7.45-7.35 (2H, m), 7.32-7.26 (3H, m), 7.09-7.15 (1H, m), 7.02-7.00 (1H, d, J = 8.4 Hz), 6.98-6.96 (3H, d, J = 8.4 Hz), 6.32 (1H, s), 4.96 (2H, s), 4.66 (2H, s), 4.31-4.26 (2H, q), 1.26 (3H, t).96% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (1H, s), 7.52-7.47 (5H, m), 7.45-7.35 (2H, m), 7.32-7.26 (3H, m), 7.09-7.15 ( 1H, m), 7.02-7.00 (1H, d, J = 8.4 Hz), 6.98-6.96 (3H, d, J = 8.4 Hz), 6.32 (1H, s), 4.96 (2H, s), 4.66 (2H , s), 4.31-4.26 (2H, q), 1.26 (3H, t).
1-55. 4-(4'-((1-55. 4- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )부탄산 (4-(4'-((Butanoic acid (4- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )) butanoicbutanoic acid) (AC-1322) acid) (AC-1322)
100% 수율; 1H-NMR (DMSO-d6, 400 MHz) δ 12.2 (1H, br, s), 7.58-7.53 (4H, m), 7.43-7.41 (1H, m), 7.23 (2H, d, J = 8.0 Hz), 7.20-7.17 (2H, m), 7.05 (1H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 4.91 (2H, s), 4.02 (2H, t), 2.51 (2H, t), 2.40 (2H, t), 1.98-1.94 (2H, m), 1.52-1.48(2H, m), 1.24-1.18 (2H, m), 0.79 (3H, t).100% yield; 1 H-NMR (DMSO-d 6 , 400 MHz) δ 12.2 (1H, br, s), 7.58-7.53 (4H, m), 7.43-7.41 (1H, m), 7.23 (2H, d, J = 8.0 Hz), 7.20-7.17 (2H, m), 7.05 (1H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 4.91 (2H, s), 4.02 (2H, t), 2.51 (2H, t), 2.40 (2H, t), 1.98-1.94 (2H, m), 1.52-1.48 (2H, m), 1.24-1.18 (2H, m), 0.79 (3H, t).
1-56. 2-(4'-((1-56. 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )-2-)-2- 메틸프로판산Methylpropanoic acid (2-(4'-(( (2- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )-2-methylpropanoic acid) (AC-1321)) -2-methylpropanoic acid) (AC-1321)
100% 수율; 1H-NMR (DMSO-d6, 400 MHz) δ 7.54-7.51 (4H, m), 7.40-7.39 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.02 (1H, d, J = 7.6 Hz), 6.87 (2H, d, J = 9.2 Hz), 4.88 (2H, s), 2.49 (2H, t), 1.52 (6H, s), 1.49-1.45 (2H, m), 1.22-1.15 (2H, m), 0.77 (3H, t).100% yield; 1 H-NMR (DMSO-d 6 , 400 MHz) δ 7.54-7.51 (4H, m), 7.40-7.39 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.02 (1H, d, J = 7.6 Hz), 6.87 (2H, d, J = 9.2 Hz), 4.88 (2H, s), 2.49 (2H, t), 1.52 (6H, s) , 1.49-1.45 (2H, m), 1.22-1.15 (2H, m), 0.77 (3H, t).
1-57. (1-57. ( EE )-3-(4'-(() -3- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아크릴산 ((Acrylic Acid (( EE )-3-(4'-(() -3- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-yloxy)acrylic acid) (AC-1323)) methyl) biphenyl-4-yloxy) acrylic acid) (AC-1323)
29% 수율; 1H-NMR (DMSO-d6, 400 MHz) δ 12.1 (1H, s, br), 7.80 (1H, d, J = 12.0 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.58 (2H, d, J = 8.0 Hz), 7.41-7.26 (1H, m), 7.24-7.19 (4H, m), 7.18-7.16 (2H, m), 7.04 (1H, d, J = 8.0 Hz), 5.52 (1H, d, J = 11.2 Hz), 4.90 (2H, s), 2.49 (2H, t), 1.50-1.44 (2H, m), 1.21-1.14 (2H, m), 0.77 (3H,t).29% yield; 1 H-NMR (DMSO-d 6 , 400 MHz) δ 12.1 (1H, s, br), 7.80 (1H, d, J = 12.0 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.58 (2H , d, J = 8.0 Hz), 7.41-7.26 (1H, m), 7.24-7.19 (4H, m), 7.18-7.16 (2H, m), 7.04 (1H, d, J = 8.0 Hz), 5.52 ( 1H, d, J = 11.2 Hz), 4.90 (2H, s), 2.49 (2H, t), 1.50-1.44 (2H, m), 1.21-1.14 (2H, m), 0.77 (3H, t).
1-58. 3-(4'-((1-58. 3- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )프로판산 (3-(4'-((Propanoic acid (3- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )) propanoicpropanoic acid) (AC-1324) acid) (AC-1324)
45% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.57-7.51 (4H, m), 7.43-7.38 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.03 (2H, d, J = 8.0 Hz), 6.98 (2H, d, J = 8.4 Hz), 4.88 (2H, s), 4.18 (2H, t), 2.68 (2H, t), 2.12 (2H, t), 1.51-1.44 (2H, m), 1.24-1.15 (2H, m), 0.77 (3H,t).45% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.57-7.51 (4H, m), 7.43-7.38 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.03 (2H, d, J = 8.0 Hz), 6.98 (2H, d, J = 8.4 Hz), 4.88 (2H, s), 4.18 (2H, t), 2.68 (2H, t), 2.12 (2H, t), 1.51-1.44 (2H, m), 1.24-1.15 (2H, m), 0.77 (3H, t).
1-59. 1-59. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(2-(4--((4 '-(2- (4- 메틸피페라진Methylpiperazine -1-일)-2--1-yl) -2- 옥소에톡시Oxoethoxy )바이페닐-4-일)메틸)펜탄아마이드 () Biphenyl-4-yl) methyl) pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)biphenyl-4-yl)methyl)pentanamide) (AC-1309)-((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentanamide) (AC-1309)
65% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.51 (2H, m), 7.458 (2H, d, J = 8.0 Hz), 7.33-7.27 (1H, m), 7.24 (2H, d, J = 8.4 Hz), 7.05-6.99 (3H, m), 6.88-6.75 (2H, m), 4.89 (2H, s), 4.68 (2H, s), 3.67-3.60 (4H, m), 2.43-2.38 (4H, m), 2.30 (3H, s), 2.10 (2H, t), 1.64-1.57 (2H, m), 1.30-1.22 (2H, m), 0.83 (3H, t).65% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.51 (2H, m), 7.458 (2H, d, J = 8.0 Hz), 7.33-7.27 (1H, m), 7.24 (2H, d, J = 8.4 Hz), 7.05-6.99 (3H, m), 6.88-6.75 (2H, m), 4.89 (2H, s), 4.68 (2H, s), 3.67-3.60 (4H, m), 2.43-2.38 (4H , m), 2.30 (3H, s), 2.10 (2H, t), 1.64-1.57 (2H, m), 1.30-1.22 (2H, m), 0.83 (3H, t).
1-60. 1-60. 프로프Prof -2-인일 2-(4'-((2-person 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4-일옥시)아세테이트 (Prop-2-4-yloxy) acetate (Prop-2- ynylynyl 2-(4'-(( 2- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate) (AC-1390)-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) (AC-1390)
61.3% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.33-7.28 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.05-7.01 (1H, m), 6.97 (2H, d, J = 8.4 Hz), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.83 (2H, d, J = 1.6 Hz), 4.72 (2H, s), 2.53 (1H, s), 2.09 (2H, t), 1.64-1.58 (2H, m), 1.27-1.20 (2H, m), 0.831 (3H, t).61.3% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.33-7.28 (1H, m), 7.21 (2H, d , J = 8.0 Hz), 7.05-7.01 (1H, m), 6.97 (2H, d, J = 8.4 Hz), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.83 (2H, d, J = 1.6 Hz), 4.72 (2H, s), 2.53 (1H, s), 2.09 (2H, t), 1.64-1.58 (2H, m), 1.27-1.20 (2H, m), 0.831 (3H, t ).
1-61. 1-61. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(-((4'-( 프로프Prof -2--2- 이닐옥시Iniloxy )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(prop-2--((4 '-(prop-2- ynyloxyynyloxy )biphenyl-4-yl)methyl)pentanamide) (AC-1389)) biphenyl-4-yl) methyl) pentanamide) (AC-1389)
58.2% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.54-7.50 (2H, m), 7.46 (2H, d, J = 8.4 Hz), 7.33-7.28 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.06-7.03 (3H, m), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.73 (2H, d, J = 2.0 Hz), 2.54 (1H. t), 2.09 (2H, t), 1.64-1.57 (2H, m), 1.29-1.20 (2H, m), 0.83 (3H, m).58.2% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54-7.50 (2H, m), 7.46 (2H, d, J = 8.4 Hz), 7.33-7.28 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.06-7.03 (3H, m), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.73 (2H, d, J = 2.0 Hz), 2.54 (1H.t), 2.09 ( 2H, t), 1.64-1.57 (2H, m), 1.29-1.20 (2H, m), 0.83 (3H, m).
1-62. 1-62. NN -((2'-(1H--((2 '-(1H- 테트라졸Tetrazole -5-일)-5 days) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)--((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-952)-phenylpentanamide) (AC-952)
92% 수율; 1H-NMR (MeOD, 500 MHz) δ 8.16 (1H, d, J = 6.0 Hz), 7.60-7.52 (2H, m), 7.43-7.39 (3H, m), 7.34 (1H, t), 7.25 (2H, t), 7.15 (2H, d, J = 6.4 Hz), 7.03 (2H, d, J = 6.0 Hz), 4.90 (2H, s), 2.09 (2H, t), 1.57-1.50 (2H, m), 1.22-1.18 (2H, m), 0.79 (3H, t).92% yield; 1 H-NMR (MeOD, 500 MHz) δ 8.16 (1H, d, J = 6.0 Hz), 7.60-7.52 (2H, m), 7.43-7.39 (3H, m), 7.34 (1H, t), 7.25 ( 2H, t), 7.15 (2H, d, J = 6.4 Hz), 7.03 (2H, d, J = 6.0 Hz), 4.90 (2H, s), 2.09 (2H, t), 1.57-1.50 (2H, m ), 1.22-1.18 (2H, m), 0.79 (3H, t).
1-63. 2-(4'-((1-63. 2- (4 '-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -phenylpentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1073)-phenylpentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1073)
85% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.49 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.34-7.32 (3H, m), 7.22 (2H, d, J = 8.0 Hz), 7.01-6.95 (4H, m), 4.91 (2H, s), 4.97 (2H, s), 2.10 (2H, t), 1.65-1.55 (2H, m), 1.26-1.17 (2H, m), 0.80 (3H, t).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.49 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.34-7.32 (3H, m), 7.22 (2H, d , J = 8.0 Hz), 7.01-6.95 (4H, m), 4.91 (2H, s), 4.97 (2H, s), 2.10 (2H, t), 1.65-1.55 (2H, m), 1.26-1.17 ( 2H, m), 0.80 (3H, t).
1-64. 2-(4'-((1-64. 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1074)acetic acid) (AC-1074)
80% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.49-7.46 (4H, t), 7.39-7.37 (1H, m), 7.18-7.14 (4H, m), 7.01 (1H, d, J = 8.0 Hz), 6.88 (2H, d, J = 8.4 Hz), 4.86 (2H, s), 4.38 (2H, s), 2.09 (2H, m), 1.47-1.44 (2H, m), 1.19-1.13 (2H, m), 0.75 (3H, t).80% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.49-7.46 (4H, t), 7.39-7.37 (1H, m), 7.18-7.14 (4H, m), 7.01 (1H, d, J = 8.0 Hz) , 6.88 (2H, d, J = 8.4 Hz), 4.86 (2H, s), 4.38 (2H, s), 2.09 (2H, m), 1.47-1.44 (2H, m), 1.19-1.13 (2H, m ), 0.75 (3H, t).
1-65. 2-(4'-((1-65. 2- (4 '-(( NN -(3--(3- 클로로페닐Chlorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- chlorophenylchlorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1630)acetic acid) (AC-1630)
98% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.37 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 4.89 (s, 2H), 4.70 (s, 2H), 2.11 (t, 2H), 1.52-1.45 (m, 2H), 1.23-1.16 (m, 2H), 0.78 (d, J = 7.6 Hz, 3H).98% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.37 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H ), 4.89 (s, 2H), 4.70 (s, 2H), 2.11 (t, 2H), 1.52-1.45 (m, 2H), 1.23-1.16 (m, 2H), 0.78 (d, J = 7.6 Hz, 3H).
1-66. 2-(4'-((1-66. 2- (4 '-(( NN -(3--(3- 브로모페닐Bromophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- bromophenylbromophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1633)acetic acid) (AC-1633)
87% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 3H), 7.23-7.18 (m, 4H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.71 (s, 2H), 2.09 (t, 2H), 1.63-1.57 (m, 2H), 1.25-1.21 (m, 2H), 0.83 (t, J= 7.2 Hz, 3H).87% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 3H), 7.23-7.18 (m, 4H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.71 (s, 2H), 2.09 (t, 2H), 1.63-1.57 (m, 2H), 1.25 -1.21 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-67. 2-(4'-((1-67. 2- (4 '-(( NN -(3-(-(3- ( 트리플루오로메틸Trifluoromethyl )페닐)Phenyl) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1636)-(3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1636)
69% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.59 (d, J = 7.2 Hz, 1H), 7.52-7.43 (m, 5H), 7.28 (s, 1H), 7.21 (d, J = 7.6 Hz, 3H), 6.99 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H), 4.77 (s, 2H), 2.08 (t, 2H), 1.62-1.54 (m, 2H), 1.23-1.19 (m, 2H), 0.82 (t, J = 7.0 Hz, 3H).69% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.59 (d, J = 7.2 Hz, 1H), 7.52-7.43 (m, 5H), 7.28 (s, 1H), 7.21 (d, J = 7.6 Hz, 3H ), 6.99 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H), 4.77 (s, 2H), 2.08 (t, 2H), 1.62-1.54 (m, 2H), 1.23-1.19 (m, 2H), 0.82 (t, J = 7.0 Hz, 3H).
1-68. 2-(4'-((1-68. 2- (4 '-(( N-m-N-m- 톨릴펜탄아미도Tolylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( N-m-N-m- tolylpentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1639)tolylpentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1639)
62% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H), 7.42 (s, 2H), 7.23 (t, J = 7.4 Hz, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.00 (s, 2H), 4.767 (s, 2H), 2.35 (s, 3H), 2.10 (t, J = 7.6 Hz, 2H), 1.64-1.53 (m, 2H), 1.26-1.25 (m, 2H), 0.81 (t, J = 6.0 Hz, 3H).62% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H), 7.42 (s, 2H), 7.23 (t, J = 7.4 Hz, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.00 (s, 2H), 4.767 (s, 2H), 2.35 (s, 3H), 2.10 (t, J = 7.6 Hz, 2H), 1.64-1.53 (m, 2H), 1.26-1.25 (m, 2H), 0.81 (t, J = 6.0 Hz, 3H).
1-69. 1-69. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -(3--(3- 니트로페닐Nitrophenyl )) 펜탄아마이드Pentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)--((4'-hydroxybiphenyl-4-yl) methyl)- NN -(3-nitrophenyl)pentanamide) (AC-1641)-(3-nitrophenyl) pentanamide) (AC-1641)
30% 수율; 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 4H), 7.33 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.95 (s, 2H), 4.89 (s, 1H), 2.09 (t, 2H), 1.66-1.54 (m, 2H), 1.27-1.22 (m, 2H), 0.86 (t, J = 9.2 Hz, 3H).30% yield; 1 H NMR (CDCl 3 , 400 MHz) δ 8.18 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 8.0 Hz , 4H), 7.33 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.95 (s, 2H), 4.89 (s, 1H), 2.09 (t, 2H), 1.66-1.54 (m, 2H), 1.27-1.22 (m, 2H), 0.86 (t, J = 9.2 Hz, 3H).
1-70. 2-(4'-((1-70. 2- (4 '-(( NN -(3--(3- 니트로페닐Nitrophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- nitrophenylnitrophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1642)acetic acid) (AC-1642)
49% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.69-7.63 (m, 2H), 7.55 (t, J = 8.2 Hz, 4H), 7.25 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 4.70 (s, 2H), 2.15 (t, 2H), 1.53-1.46 (m, 2H), 1.24-1.17 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).49% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.15 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.69-7.63 (m, 2H), 7.55 (t, J = 8.2 Hz, 4H ), 7.25 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 4.70 (s, 2H), 2.15 (t, 2H), 1.53-1.46 (m, 2H), 1.24-1.17 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).
1-71. 2-(4'-((1-71. 2- (4 '-(( NN -(3--(3- 아이오도페닐Iodophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- iodophenyliodophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1645)acetic acid) (AC-1645)
94% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 8.8 Hz, 3H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 4.87 (s, 2H), 4.71 (s, 2H), 2.1 (t, 2H), 1.63-1.55 (m, 2H), 1.26-1.19 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).94% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 8.8 Hz, 3H), 7.21 ( d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 4.87 (s, 2H), 4.71 (s, 2H), 2.1 (t, 2H), 1.63-1.55 (m, 2H), 1.26-1.19 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-72. 2-((4'-((1-72. 2-((4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 아세트아미도Acetamido )) 메틸methyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl ]-4-일)옥시)아세트산 (2-((4'-((] -4-yl) oxy) acetic acid (2-((4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) acetamidoacetamido )methyl)-[1,1'-biphenyl]-4-yl)oxy)acetic acid) (AC-1648)) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid) (AC-1648)
67% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (q, J = 7.3 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 4.93 (s, 2H), 4.69 (s, 2H), 1.93 (s, 3H)67% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (q, J = 7.3 Hz, 1H), 7.24 ( d, J = 8.0 Hz, 2H), 7.11 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 4.93 (s, 2H), 4.69 (s, 2H), 1.93 (s, 3H)
1-73. 1-73. NN -((4'-(4--((4 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'-(4--((4 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)--1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1649)-phenylpentanamide) (AC-1649)
50% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (m, J = 4.8 Hz, 4H), 7.36 (d, J = 6.4 Hz, 3H), 7.29 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 4.92 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.55 (d, 4H), 2.09 (t, J = 7.6 Hz, 2H), 1.60 (m, 2H), 1.22 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H).50% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (m, J = 4.8 Hz, 4H), 7.36 (d, J = 6.4 Hz, 3H), 7.29 ( d, J = 8.4 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 4.92 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.55 (d, 4H), 2.09 (t, J = 7.6 Hz, 2H), 1.60 (m, 2H), 1.22 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H).
1-74. 1-74. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -((4'-(4--((4 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -((4'-(4--((4 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-1650)-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1650)
41% 수율; 1H-NMR (CDCl3 ,400 MHz) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (m, J = 6.0 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 (m, J = 6.7 Hz, 4H), 4.89 (s, 2H), 3.67 (d, 4H), 2.77 (m, 1H), 2.57 (d, 4H), 2.07 (t, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.07 (d, J = 6.0 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).41% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (m, J = 6.0 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 ( m, J = 6.7 Hz, 4H), 4.89 (s, 2H), 3.67 (d, 4H), 2.77 (m, 1H), 2.57 (d, 4H), 2.07 (t, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.07 (d, J = 6.0 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).
1-75. 1-75. NN -((3'-(4--((3 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( N-N- ((3'-(4-((3 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)--1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1651)-phenylpentanamide) (AC-1651)
70% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 6.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, 1H), 7.354 (m, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H,), 4.92 (s, 2H), 3.64 (d, 4H), 2.72 (m, 1H), 2.53 (d, 4H), 2.09 (t, J = 7.4 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H).70% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (d, J = 6.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, 1H), 7.354 (m, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H,), 4.92 (s, 2H), 3.64 (d, 4H), 2.72 (m, 1H), 2.53 (d, 4H), 2.09 ( t, J = 7.4 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H).
1-76. 1-76. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -((3'-(4--((3 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( N-N- (4-(4- fluorophenylfluorophenyl )-)- NN -((3'-(4--((3 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-1652)-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1652)
70% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (q, 2H), 7.47 (m, J = 6.0 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (m, 2H), 6.96 (m, 2H), 4.88 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.54 (d, 4H), 2.06 (t, J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).70% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (q, 2H), 7.47 (m, J = 6.0 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (m, 2H), 6.96 (m, 2H), 4.88 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.54 (d, 4H), 2.06 (t , J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).
1-77. 4'-((1-77. 4'-(( NN -(2--(2- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-1071)-(2-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-1071)
94 % 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.16 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 7.6 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.18-7.08 (3H, m), 7.00-6.96 (1H, t), 5.28 (1H, d, J = 14.4 Hz), 4.56 (1H, d, J = 14.4 Hz), 2.09 (2H, t), 1.63-1.59 (2H, m), 1.27-1.22 (2H, m), 0.83 (3H, t).94% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.16 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 7.6 Hz), 7.31 ( 2H, d, J = 8.4 Hz), 7.18-7.08 (3H, m), 7.00-6.96 (1H, t), 5.28 (1H, d, J = 14.4 Hz), 4.56 (1H, d, J = 14.4 Hz ), 2.09 (2H, t), 1.63-1.59 (2H, m), 1.27-1.22 (2H, m), 0.83 (3H, t).
1-78. 4'-((1-78. 4'-(( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-1072)-(4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-1072)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.17 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 7.6 Hz), 7.04-6.98 (4H, m), 4.91 (2H, s), 2.07 (2H, t), 1.62-1.58 (2H, m), 1.25-1.23 (2H, m), 0.83 (3H, t).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.17 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.30 ( 2H, d, J = 7.6 Hz), 7.04-6.98 (4H, m), 4.91 (2H, s), 2.07 (2H, t), 1.62-1.58 (2H, m), 1.25-1.23 (2H, m) , 0.83 (3H, t).
1-79. 4'-((1-79. 4'-(( NN -(2--(2- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1076)-(2-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1076)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.13 (1H, s), 7.90-7.86 (2H, m), 7.62-7.54 (3H, m), 7.26 (2H, d, J = 7.6 Hz), 7.06 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 4.83 (2H, s), 3.70 (3H, s), 2.05-2.01 (2H, m), 1.46-1.41 (2H, m), 0.75 (3H, t).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.13 (1H, s), 7.90-7.86 (2H, m), 7.62-7.54 (3H, m), 7.26 (2H, d, J = 7.6 Hz), 7.06 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 4.83 (2H, s), 3.70 (3H, s), 2.05-2.01 (2H, m), 1.46-1.41 ( 2H, m), 0.75 (3H, t).
1-80. 4'-((1-80. 4'-(( NN -(3--(3- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1077)-(3-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1077)
92% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.24 (1H, s), 7.89 (1H, d, J = 7.2 Hz), 7.84 (1H, d, J = 7.2 Hz), 7.59-7.52 (3H, m), 7.29 (2H, d, J = 7.6 Hz), 7.00-6.60 (4H, m), 4.89 (2H, s), 3.78 (3H. s), 2.13 (2H, t), 1.62-1.52 (2H, m), 1.19-1.16 (2H, m), 0.83 (3H, t).92% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.24 (1H, s), 7.89 (1H, d, J = 7.2 Hz), 7.84 (1H, d, J = 7.2 Hz), 7.59-7.52 (3H, m ), 7.29 (2H, d, J = 7.6 Hz), 7.00-6.60 (4H, m), 4.89 (2H, s), 3.78 (3H.s), 2.13 (2H, t), 1.62-1.52 (2H, m), 1.19-1.16 (2H, m), 0.83 (3H, t).
1-81. 4'-((1-81. 4'-(( NN -(4--(4- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(4-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1078)-(4-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1078)
92% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.32 (1H, s), 8.07 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.55-7.53 (3H, m), 7.30 (2H, d, J = 7.6 Hz) 6.92-6.83 (4H, m), 4.90 (2H, s), 3.81 (3H, s), 2.09 (2H, t), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 0.83 (3H, t).92% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.32 (1H, s), 8.07 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.55-7.53 (3H, m ), 7.30 (2H, d, J = 7.6 Hz) 6.92-6.83 (4H, m), 4.90 (2H, s), 3.81 (3H, s), 2.09 (2H, t), 1.59-1.56 (2H, m ), 1.25-1.20 (2H, m), 0.83 (3H, t).
1-82. 1-82. NN -((2'-(4--((2 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(4--((2 '-(4- methylpiperazinemethylpiperazine -1-carbonyl)biphenyl-4--1-carbonyl) biphenyl-4- ylyl )methyl)-) methyl)- NN -phenylpentanamide) (AC-888)-phenylpentanamide) (AC-888)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.6 (d, 4H), 2.36 (d, 4H), 2.19 (s, 3H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.6 (d, 4H), 2.36 (d, 4H), 2.19 (s, 3H), 2.07 (m, 2H), 1.48 ( m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).
1-83. 1-83. NN -((3'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)--((3 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl)- NN -페닐펜탄아마이드(-Phenylpentaneamide ( NN -((3'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)--((3 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-889)-phenylpentanamide) (AC-889)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.16 (d, 4H), 2.38 (d, 4H), 2.18 (s, 3H), 2.07 (m, 2H) 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.16 (d, 4H), 2.38 (d, 4H), 2.18 (s, 3H), 2.07 (m, 2H) 1.48 (m , 2H), 1.18 (m, 2H), 0.76 (t, 3H).
1-84. 4'-((1-84. 4'-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -2--2- 카복실산Carboxylic acid (4'-(((4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-2-carboxylic acid) (AC-891)-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid) (AC-891)
94% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 12.8 (s, br, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.25 (m, 2H), 7.20 (m, 3H), 7.05 (m, 1H), 4.93 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.20 (m, 2H), 0.78 (t, 3H).94% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 12.8 (s, br, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H) , 7.25 (m, 2H), 7.20 (m, 3H), 7.05 (m, 1H), 4.93 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.20 (m, 2H), 0.78 (t, 3 H).
1-85. 4'-((1-85. 4'-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-893)-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-893)
94% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 13.1 (s, br, 1H), 8.12 (d, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.56 (m, 2H), 7.20 (m, 2H), 7.20 (m, 2H,) 7.05 (m, 1H), 4.91 (s, 2H), 2.08 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).94% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 13.1 (s, br, 1H), 8.12 (d, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.56 (m, 2H) , 7.20 (m, 2H), 7.20 (m, 2H,) 7.05 (m, 1H), 4.91 (s, 2H), 2.08 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3 H).
1-86. 1-86. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(-((4'-( 몰폴린Morpholine -4--4- 카보닐Carbonyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( N-N- (3-(3- fluorophenylfluorophenyl )-)- NN -((4'-(-((4'-( morpholinemorpholine -4-carbonyl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide) (AC-950)-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) (AC-950)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.95 (m, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.36 m, 2H), 7.27 (m, 2H), 7.19 (d, 2H), 4.90 (s, 2H), 3.01 (d, 4H), 2.5 (s, 3H), 2.36 (d, 4H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.95 (m, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.36 m, 2H), 7.27 ( m, 2H), 7.19 (d, 2H), 4.90 (s, 2H), 3.01 (d, 4H), 2.5 (s, 3H), 2.36 (d, 4H), 2.07 (m, 2H), 1.48 (m , 2H), 1.18 (m, 2H), 0.76 (t, 3H).
1-87. 1-87. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(4--((4 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(4--((4 '-(4- methylpiperazinemethylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-951)-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-951)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.95 (1H, m), 7.70 (2H, d), 7.62 (2H, d), 7.44 (2H, d), 7.36 (2H, m), 7.27 (2H, m), 7.19 (2H, d), 4.90 (2H, s), 3.01 (4H, d), 2.5 (3H, s), 2.36 (4H, d), 2.07 (2H, m), 1.48 (2H, m), 1.18 (2H, m), 0.76 (3H, t).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.95 (1H, m), 7.70 (2H, d), 7.62 (2H, d), 7.44 (2H, d), 7.36 (2H, m), 7.27 (2H, m), 7.19 (2H, d), 4.90 (2H, s), 3.01 (4H, d), 2.5 (3H, s), 2.36 (4H, d), 2.07 (2H, m), 1.48 ( 2H, m), 1.18 (2H, m), 0.76 (3H, t).
1-88. 1-88. NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1067)-phenylpentanamide) (AC-1067)
100% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.34-7.30 (3H, m), 7.24 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 7.2 Hz), 6.96 (2H, d, J = 8.8 Hz), 4.90 (2H, s), 3.85 (3H, s), 2.08 (2H, t), 1.63-1.57 (2H, m), 1.26-1.20 (2H, m), 0.83 (3H, t).100% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.34-7.30 (3H, m), 7.24 (2H, d , J = 8.0 Hz), 7.01 (2H, d, J = 7.2 Hz), 6.96 (2H, d, J = 8.8 Hz), 4.90 (2H, s), 3.85 (3H, s), 2.08 (2H, t ), 1.63-1.57 (2H, m), 1.26-1.20 (2H, m), 0.83 (3H, t).
1-89. 1-89. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)--((4'-hydroxybiphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1069)-phenylpentanamide) (AC-1069)
80% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.44-7.37 (4H, m), 7.35-7.31 (3H, m), 7.26 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 6.8 Hz), 6.88 (2H, d, J = 8.4 Hz), 5.37 (1H, br, s), 4.91 (2H, s), 2.10 (2H, t), 1.63-1.57 (2H, m), 1.25-1.20 (2H, m), 0.83 (3H, t).80% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.37 (4H, m), 7.35-7.31 (3H, m), 7.26 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 6.8 Hz), 6.88 (2H, d, J = 8.4 Hz), 5.37 (1H, br, s), 4.91 (2H, s), 2.10 (2H, t), 1.63-1.57 (2H, m), 1.25- 1.20 (2H, m), 0.83 (3H, t).
1-90. 1-90. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1068)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1068)
100% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.45 (4H, m), 7.31-7.30 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.03-7.03 (1H, m), 6.97 (2H, d, J = 8.8 Hz), 6.82-6.80 (2H, m), 4.89 (2H, s), 3.85 (3H, s), 2.10 (2H, t), 1.62-1.57 (2H, m), 1.27-1.22 (2H, m), 0.83 (3H, t).100% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.45 (4H, m), 7.31-7.30 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.03-7.03 (1H, m) , 6.97 (2H, d, J = 8.8 Hz), 6.82-6.80 (2H, m), 4.89 (2H, s), 3.85 (3H, s), 2.10 (2H, t), 1.62-1.57 (2H, m ), 1.27-1.22 (2H, m), 0.83 (3H, t).
1-91. 1-91. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)methyl) pentanamidepentanamide ) (AC-1070)(AC-1070)
85% 수율; 1H-NMR (CDCl3 , 400 MHz) δ 7.44-7.42 (4H, m), 7.35-7.29 (1H, m), 7.22 (2H, d, J = 8.0 Hz), 7.06-7.02 (1H, m), 6.88 (2H, d, J = 8.0 Hz), 6.85-6.78 (2H, m), 5.60 (1H, br, s), 4.90 (2H, s), 2.12 (2H, t), 1.65-1.57 (2H, m), 1.30-1.20 (2H, m), 0.83 (3H, t).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.42 (4H, m), 7.35-7.29 (1H, m), 7.22 (2H, d, J = 8.0 Hz), 7.06-7.02 (1H, m) , 6.88 (2H, d, J = 8.0 Hz), 6.85-6.78 (2H, m), 5.60 (1H, br, s), 4.90 (2H, s), 2.12 (2H, t), 1.65-1.57 (2H , m), 1.30-1.20 (2H, m), 0.83 (3H, t).
1-92. 1-92. NN -(3--(3- 클로로페닐Chlorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-chlorophenyl)--(3-chlorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1628)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1628)
85% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.49 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H) 7.22 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.98-6.94 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 (t, J = 7.0 Hz, 2H), 1.65-1.56 (m, 2H), 1.29-1.20 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.49 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H) 7.22 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.98-6.94 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 ( t, J = 7.0 Hz, 2H), 1.65-1.56 (m, 2H), 1.29-1.20 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-93. 1-93. NN -(3--(3- 클로로페닐Chlorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-chlorophenyl)--(3-chlorophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1629)-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1629)
88% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.43 (d, J = 8.4 Hz, 4H), 7.32-7.25 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 6.91-6.85 (m, 3H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.57 (m, 2H), 1.27-1.22 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).88% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.43 (d, J = 8.4 Hz, 4H), 7.32-7.25 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H ), 6.91-6.85 (m, 3H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.57 (m, 2H), 1.27-1.22 ( m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-94. 1-94. NN -(3--(3- 브로모페닐Bromophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-bromophenyl)--(3-bromophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1631)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1631)
73% 수율; 1H-NMR (CDCl3, 400MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 3H), 7.23-7.18 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 (t, J = 7.2 Hz, 2H), 1.61 -1.55 (m, 2H), 1.27-1.21 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).73% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 3H), 7.23-7.18 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 (t, J = 7.2 Hz, 2H), 1.61 -1.55 (m, 2H), 1.27-1.21 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-95. 1-95. N-N- (3-(3- 브로모페닐Bromophenyl )-)- N-N- ((4'-((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-bromophenyl)--(3-bromophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1632)-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1632)
89% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.47-7.42 (m, 5H), 7.24-7.19 (m, 4H), 6.94 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.58 (m, 2H), 1.29-1.20 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).89% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.47-7.42 (m, 5H), 7.24-7.19 (m, 4H), 6.94 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz , 2H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.58 (m, 2H), 1.29-1.20 (m, 2H), 0.83 ( t, J = 7.2 Hz, 3H).
1-96. 1-96. NN -((4'-메톡시바이페닐-4-일)메틸)--((4'-methoxybiphenyl-4-yl) methyl)- NN -(3-(트리플루오로메틸)페닐)펜탄아마이드(-(3- (trifluoromethyl) phenyl) pentaneamide ( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- NN -(3-(trifluoromethyl)phenyl)pentanamide) (AC-1634)-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1634)
75% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 7.6 Hz, 1H), 7.5 (dd, J = 3.0, 11.8 Hz, 2H), 7.46 (d, J = 7.6 Hz, 3H), 7.28 (s, 1H), 7.21 (d , J = 8.0 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 6.97 (dd, J = 3.0, 11.8 Hz, 2H), 4.91 (s, 2H), 3.84 (s, 3H), 2.05 (s, 2H), 1.64-1.56 (m, 2H), 1.28-1.19 (m, 2H), 0.82 (t, J = 7.6 Hz, 3H).75% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.58 (d, J = 7.6 Hz, 1H), 7.5 (dd, J = 3.0, 11.8 Hz, 2H), 7.46 (d, J = 7.6 Hz, 3H), 7.28 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 6.97 (dd, J = 3.0, 11.8 Hz, 2H), 4.91 (s, 2H ), 3.84 (s, 3H), 2.05 (s, 2H), 1.64-1.56 (m, 2H), 1.28-1.19 (m, 2H), 0.82 (t, J = 7.6 Hz, 3H).
1-97. 1-97. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- N-N- (3-((3- ( 트리플루오로메틸Trifluoromethyl )페닐)펜탄아마이드 ((Phenyl) pentaneamide ( NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)-) methyl)- NN -(3-(trifluoromethyl)phenyl)pentanamide) (AC-1635)-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1635)
96% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 4H), 7.29 (s, 1H), 7.21 (q, 3H), 6.89 (d, J = 11.6 Hz, 2H), 5.14 (s, 1H), 4.91 (s, 2H), 2.06 (t, 2H), 1.64-1.58 (m, 2H), 1.28-1.2 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H).96% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 4H), 7.29 ( s, 1H), 7.21 (q, 3H), 6.89 (d, J = 11.6 Hz, 2H), 5.14 (s, 1H), 4.91 (s, 2H), 2.06 (t, 2H), 1.64-1.58 (m , 2H), 1.28-1.2 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H).
1-98. 1-98. N-N- ((4'-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- N-m-N-m- 톨릴펜탄아마이드Tolylpentaneamide ( ( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- N-mN-m -tolylpentanamide) (AC-1637)-tolylpentanamide) (AC-1637)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 10.0 Hz, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.84 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 3.848 (s, 3H), 2.31 (s, 3H), 2.08 (t, J = 7.4 Hz, 2H), 1.63-1.55 (m, 2H), 1.26-1.20 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 10.0 Hz, 3H), 7.11 ( d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.84 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 3.848 ( s, 3H), 2.31 (s, 3H), 2.08 (t, J = 7.4 Hz, 2H), 1.63-1.55 (m, 2H), 1.26-1.20 (m, 2H), 0.82 (t, J = 7.4 Hz , 3H).
1-99. 1-99. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- mm -- 톨릴펜탄아마이드Tolylpentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)-((4'-hydroxybiphenyl-4-yl) methyl) -N-m--N-m- tolylpentanamide) (AC-1638)tolylpentanamide) (AC-1638)
83% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.41-7.36 (m, 4H), 7.25-7.21 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H), 6.97 (s, br, 1H), 6.89 (s, 1H), 6.85 (d, J = 6.8 Hz, 3H), 4.89 (s, 2H), 2.33 (s, 3H), 2.14 (t, J = 7.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.28-1.18 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).83% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.41-7.36 (m, 4H), 7.25-7.21 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H), 6.97 (s, br, 1H) , 6.89 (s, 1H), 6.85 (d, J = 6.8 Hz, 3H), 4.89 (s, 2H), 2.33 (s, 3H), 2.14 (t, J = 7.6 Hz, 2H), 1.64-1.56 ( m, 2H), 1.28-1.18 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).
1-100. 1-100. NN -(3--(3- 아이오도페닐Iodophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-iodophenyl)--(3-iodophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1643)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1643)
80% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.64 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 3H), 4.87 (s, 2H), 3.84 (s, 3H), 2.07 (t, J = 7.0 Hz, 2H), 1.63-4.57 (m, 2H), 1.29-1.2(m, 2H), 0.83 (t, J = 7.4 Hz, 3H).80% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.64 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 ( s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 3H), 4.87 (s, 2H), 3.84 ( s, 3H), 2.07 (t, J = 7.0 Hz, 2H), 1.63-4.57 (m, 2H), 1.29-1.2 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H).
1-101. 1-101. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -(3--(3- 아이오도페닐Iodophenyl )) 펜탄아마이드Pentaneamide ( ( NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)-) methyl)- NN -(3--(3- iodophenyliodophenyl )) pentanamidepentanamide ) (AC-1644)(AC-1644)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 8.0 Hz, 1H), 7.46-7.43 (m, 5H), 7.21 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.08 (s, 1H), 4.871 (s, 2H), 2.07 (t, 2H), 1.63-1.59 (m, 2H), 1.29-1.21 (m, 2H), 0.86 (t, 3H).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 8.0 Hz, 1H), 7.46-7.43 (m, 5H), 7.21 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.08 (s, 1H), 4.871 (s, 2H), 2.07 (t, 2H ), 1.63-1.59 (m, 2H), 1.29-1.21 (m, 2H), 0.86 (t, 3H).
1-102. 1-102. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 아세트아마이드Acetamide ( ( NN -(3--(3- fluorophenylfluorophenyl )-)- N-N- ((4'-((4'- methoxybiphenylmethoxybiphenyl -4--4- ylyl )methyl)methyl) acetamideacetamide ) (AC-1646)(AC-1646)
81% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31 (q, J = 7.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 8.4, 20.0 Hz, 2H), 4.90 (s, 2H), 3.85 (s, 3H), 1.93 (s, 3H).81% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31 (q, J = 7.6 Hz, 1H), 7.25 ( d, J = 8.4 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 8.4, 20.0 Hz, 2H), 4.90 ( s, 2H), 3.85 (s, 3H), 1.93 (s, 3H).
1-103. 1-103. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 하이드록시Hydroxy -[1,1'--[1,1'- 바이페닐Biphenyl ]-4-일)] -4-day) 메틸methyl )아세트아마이드 (Acetamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- N-N- ((4'-((4'- hydroxyhydroxy -[1,1'-biphenyl]-4-yl)methyl)acetamide) (AC-1647)-(1,1'-biphenyl] -4-yl) methyl) acetamide) (AC-1647)
69% 수율; 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 8.8 Hz, 4H), 7.32 (q, J = 7.3 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 8.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.013 (s, 1H), 4.90 (s, 2H), 1.93 (s, 3H).69% yield; 1 H NMR (CDCl 3 , 400 MHz) δ 7.45 (d, J = 8.8 Hz, 4H), 7.32 (q, J = 7.3 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.04 (t , J = 8.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.013 (s, 1H ), 4.90 (s, 2H), 1.93 (s, 3H).
[[ 실험예Experimental Example ]]
실험예Experimental Example 1. One. BLT2가BLT2 is 발현된 세포 또는 Expressed cells or BLT2가BLT2 is 발현되지 않은 세포의 준비 Preparation of Unexpressed Cells
본 실험을 위하여, BLT2가 발현되지 않은 세포 및 BLT2가 발현된 세포 (CHO-BLT2 cells)를 하기와 같은 방법으로 준비하였다. For this experiment, cells without BLT2 expression and cells with BLT2 expression (CHO-BLT2 cells) were prepared in the following manner.
CHO 세포는 한국세포주은행 (KCLB, 10061)으로부터 얻었으며, 이를 10%의 FBS (fetal bovine serum; Life technologies, Inc.), 페니실린 (50 units/㎖) 및 antibiotic antimycotic solution (Life technologies, Inc.)이 포함된 RPMI 1640 medium (Invitrogen) 에서 37 ℃, 5% CO2 조건에서 배양하였다. 상기 세포를 3일간 각각 Trypsin-EDTA를 사용하여 나누어 (splitting) 성장 단계로 유지시켰으며, PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2m MKH2PO4)로 세척하고, 이 후 새로운 배지에 첨가하여 BLT2가 발현되지 않은 세포를 준비하였다. CHO cells were obtained from the Korea Cell Line Bank (KCLB, 10061), which contained 10% FBS (fetal bovine serum; Life technologies, Inc.), penicillin (50 units / ml), and antibiotic antimycotic solution (Life technologies, Inc.). It was incubated at 37 ℃, 5% CO 2 conditions in RPMI 1640 medium (Invitrogen) containing the. The cells were maintained in the growth phase by splitting with Trypsin-EDTA for 3 days, respectively, with PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2m MKH 2 PO 4 ) And then added to fresh medium to prepare cells without BLT2 expression.
또한, 안정된 CHO/BLT2 클론 (stable CHO/BLT2 clones)의 제조를 위해, CHO-K1 세포를 HA-tagged human BLT2를 코딩하는 pcDNA3-long form BLT2로 형질전환하고, 0.4 ㎎/㎖의 G418 (Invitrogen, Carlsbad, CA, USA)로 선별하였다. BLT2 발현을 스크리닝하기 위해, 상기 선별된 클론을 인간-특이적 BLT2 프라이머를 사용하는 RT-PCR로 분석하였고, 대표적인 클론을 BLT2가 발현된 세포(CHO-BLT2)로 실험에 사용하였다.In addition, for the preparation of stable CHO / BLT2 clones, CHO-K1 cells were transformed with pcDNA3-long form BLT2 encoding HA-tagged human BLT2, and 0.4 mg / ml of G418 (Invitrogen). , Carlsbad, CA, USA). To screen for BLT2 expression, the selected clones were analyzed by RT-PCR using human-specific BLT2 primers, and representative clones were used in the experiments with cells expressing BLT2 (CHO-BLT2).
실험예Experimental Example 2. 2. BLT2가BLT2 is 발현된 Manifested 세포에 대한 성장 억제효과Growth inhibitory effect on cells 확인 Confirm
상기 실시예에서 제조한 화합물의 처리에 따른 세포 생존율을 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨 브로마이드 (MTT) 방법으로 측정하였다.Cell viability according to the treatment of the compound prepared in the above Example was measured by the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) method.
보다 구체적으로, 상기 실험예 1에서 준비한 1 × 104 개의 BLT2가 발현되지 않은 세포 (CHO-pcDNA 3.1 cells) 및 BLT2가 발현된 세포 (CHO-BLT2 cells)를 96 ㎜ 배양 접시 (culture dish)에 분주하고 24시간 동안 세포를 배양시켰다. 이 후, 배양액을 제거하고 무혈청 RPMI 배지를 첨가하였으며. 2시간 후, 상기 실시예에서 준비한 화합물 10 μM, 대조군인 DMSO (화합물 용매) 10 μM, 양성 대조군인 LY255283 ((1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy] phenyl]-ethanone) (Cayman) 10 μM을 각각의 세포에 1시간 동안 전처리하였다. 이 후, LTB4 (300nM)를 처리한 후 24시간 동안 배양하였다. 20μL의 MTT 용액 (5 ㎎/㎖, Sigma-Aldrich)을 각 웰에 가하고 습한 CO2 인큐베이터에서 37 ℃, 4 시간 동안 배양한 후, 상층액을 제거하고, 200 ㎕의 DMSO를 각 웰에 가해 불용성 보라색 포마잔 결정을 용해시켰다. 550 ㎚에서의 흡광도를 마이크로플레이트 리더(Molecular Devices, Sunnyvale, CA)를 이용하여 측정하였으며, 모든 측정은 3회 반복 수행하였다.More specifically, 1 × 10 4 prepared in Experimental Example 1 Cells without BLT2 expression (CHO-pcDNA 3.1 cells) and cells with BLT2 expression (CHO-BLT2 cells) were dispensed into a 96 mm culture dish and cultured for 24 hours. Thereafter, the culture was removed and serum-free RPMI medium was added. After 2 hours, 10 μM of the compound prepared in the above example, 10 μM of DMSO (compound solvent) as a control, LY255283 ((1- [5-ethyl-2-hydroxy-4-[[6-methyl-6-) as a
그 결과, 도 1a 내지 도 1e에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 성장이 20%에서 35%까지 증가하였고, BLT2가 발현된 세포 (CHO-BLT2)에서, 양성 대조군인 LY255283을 전 처리한 경우, 대조군인 DMSO를 처리한 경우와 비교하여 약 90%의 세포 성장을 나타냈으며, 상기 실시예의 화합물 처리에 따른 세포 성장 억제 효과를 확인하였다. 구체적으로, 본 발명의 화합물 (LMT-692, LMT-694, LMT-696, LMT-1013)을 10μM 전 처리한 경우, 대조군인 DMSO와 비교하여 각각 88.0%, 16.7%, 56.6%, 96.3%의 세포 성장을 나타내었는바, 성장 억제 효과를 확인하였다. 이와 마찬가지로 LMT-837 (65%), LMT-841 (60%), LMT-842 (70%), LMT-883 (99%), LMT-886 (99%), LMT-1016 (99%), LMT-1018 (71.6%), LMT-1019 (99%)의 화합물에서도 성장 억제효과를 확인하였다.As a result, as shown in FIGS. 1A to 1E, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, when the compound of the present invention (LMT-692, LMT-694, LMT-696, LMT-1013) 10μM pretreatment, compared to the control group DMSO of 88.0%, 16.7%, 56.6%, 96.3% respectively Cell growth was shown, confirming the growth inhibitory effect. Similarly, LMT-837 (65%), LMT-841 (60%), LMT-842 (70%), LMT-883 (99%), LMT-886 (99%), LMT-1016 (99%), LMT-1018 (71.6%), LMT-1019 (99%) also confirmed the growth inhibitory effect.
또한, 도 2a 내지 도 2d에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 성장이 20%에서 35%까지 증가하였고, BLT2가 발현된 세포 (CHO-BLT2)에서, 양성 대조군인 LY255283을 전 처리한 경우, 대조군인 DMSO를 처리한 경우와 비교하여 약 90%의 세포 성장을 나타냈으며, 상기 실시예의 화합물 처리에 따른 세포 성장 억제 효과를 확인하였다. 구체적으로, 본 발명의 화합물 AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) 및 AC-1650 (82.2%)의 화합물에서 성장 억제효과를 확인하였다.In addition, as shown in Figures 2a to 2d, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, the growth inhibitory effect of the compounds of the present invention AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) and AC-1650 (82.2%) was confirmed.
상기 실험결과는, 본 발명의 화합물 (LMT-692, LMT-696, LMT-837, LMT-841, LMT-842, LMT-883, LMT-886, LMT-1013, LMT-1016, LMT-1018, LMT-1019, AC-1632, AC-1635, AC-1646 및 AC-1650)은 BLT2로 유도된 세포 증식을 매우 우수한 효율로 억제할 수 있으며, 상기 화합물은 BLT2 관련 만성 폐쇄성 폐질환의 치료제로 활용 가능한 약학적 성분 (BLT2-blocking pharmacological molecules)으로 이용될 수 있음을 의미한다.The experimental results, the compounds of the present invention (LMT-692, LMT-696, LMT-837, LMT-841, LMT-842, LMT-883, LMT-886, LMT-1013, LMT-1016, LMT-1018, LMT-1019, AC-1632, AC-1635, AC-1646 and AC-1650) can inhibit BLT2-induced cell proliferation with excellent efficiency, and the compound is used as a therapeutic agent for BLT2-related chronic obstructive pulmonary disease. It can be used as a possible pharmaceutical ingredient (BLT2-blocking pharmacological molecules).
실험예Experimental Example 3. 3. LTBLTB 44 로in 유도된 Induced BLT2BLT2 의존적인 주화성 저해효과 확인 Identify dependent chemotaxis inhibitory effect
주화성 (Chemotactic motility)은 6.5-㎜ 직경의 폴리카보네이트 필터 (8-μm 의 공극 크기, Corning Costar)를 구비한 Transwell 챔버를 이용하여 분석하였다. 구체적으로, 필터의 아래쪽 표면을 37 ℃에서 1시간 동안 무혈청 RPMI 1640 배지 중의 10 ㎍/㎖ 파이브로넥틴으로 코팅하였다. 다양한 양의 LTB4를 포함한 RPMI 1640 배지와 함께 건조, 코팅된 필터를 Transwell 챔버의 아래쪽 웰에 두고, 무혈청 RPMI 1640 배지에 BLT1 및 BLT2를 안정적으로 발현하는 CHO 세포를 최종적으로 2 × 104 cells/100 ㎕로 윗쪽 웰에 로딩하여 실험하였다.Chemotactic motility was analyzed using a Transwell chamber equipped with a 6.5-mm diameter polycarbonate filter (8-μm pore size, Corning Costar). Specifically, the bottom surface of the filter was coated with 10 μg / ml fibronectin in serum free RPMI 1640 medium at 37 ° C. for 1 hour. A dry, coated filter with RPMI 1640 medium containing varying amounts of LTB 4 is placed in the bottom well of the Transwell chamber and finally 2 × 10 4 cells of CHO cells stably expressing BLT1 and BLT2 in serum-free RPMI 1640 medium. Experiments were performed by loading the upper wells with / 100 μl.
저해제들의 효과를 평가할 때 세포들은 분주 전 30분 동안 각각의 저해제로 전처리하였다. 37 ℃, 5% CO2에서 3시간 동안 배양한 후, 필터들을 메탄올로 3분 동안 고정시키고, 헤마톡실린 및 에오신으로 10분 동안 염색하였다. 본 실험에서, 세포는 BLT2가 발현된 세포(CHO-BLT2 cells) 및 BLT1이 발현된 세포(CHO-BLT1)를 이용하였으며, 양성대조군으로 각각 LY255283 및 U75302를, 비교대조군으로 BLT2의 리간드인 LTB4 , (300 nM), BLT1의 리간드인 LTB4 (10nM), LPA (lysophosphatidic acid; 100nM)를 이용하였다. 주화성은 광학현미경 하에서 (배율, × 200), 필터의 아래쪽 측면 상의 세포를 계수함으로써 정량하였다. 각 분석에서 6개의 필드를 계수하였고, 각각의 샘플은 2회씩 분석하였으며, 상기 분석은 3회씩 반복 수행하였다.When evaluating the effects of the inhibitors, the cells were pretreated with each inhibitor for 30 minutes before dispensing. After 3 hours of incubation at 37 ° C., 5% CO 2 , the filters were fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes. In this experiment, the cells used BLT2-expressing cells (CHO-BLT2 cells) and BLT1-expressing cells (CHO-BLT1), LY255283 and U75302 as the positive control, respectively, and LTB 4 , the ligand of BLT2 as the control. , (300 nM), LTB 4 , the ligand of BLT1 (10nM) and LPA (lysophosphatidic acid; 100nM) were used. Chemotaxis was quantified by counting cells on the lower side of the filter under an optical microscope (magnification, x 200). Six fields were counted in each assay, each sample analyzed twice, and the assay was repeated three times.
그 결과, 도 3a, 도 3b 및 하기 표 1에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (LMT-692, LMT-696)의 농도가 증가함에 따라 (10-4, 10-3, 10-2, 10-1, 1, 10 및 102), 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, LMT-692 및 LMT-696의 화합물의 IC50 (50% 억제 농도)는 각각 7.566 μM 및 2.003 μM 이었다.As a result, as shown in Figures 3a, 3b and Table 1 below, in the BLT2 expressing cells (CHO-BLT2 cells), as the concentration of the compounds of the present invention (LMT-692, LMT-696) increases ( 10 -4 , 10 -3 , 10 -2 , 10 -1 , 1, 10 and 10 2 ), it was confirmed that chemotaxis of CHO-BLT2 cells under serum-free conditions, compounds of LMT-692 and LMT-696 IC 50 (50% inhibitory concentration) was 7.566 μM and 2.003 μM, respectively.
또한, 하기 표 2에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 LMT-1013의 농도가 증가함에 따라, 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, LMT-1013 화합물의 IC50 (50% 억제 농도)는 62.35 nM 이었다. 마찬가지로 BLT1을 발현하는 세포(CHO-BLT1 cells)에서, 본 발명의 화합물 LMT-1013의 농도가 증가함에 따라, 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, LMT-1013 화합물의 IC50 (50% 억제 농도)는 10 μM 이상이였다.In addition, as shown in Table 2 below, in the cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound LMT-1013 of the present invention increases, chemotaxis of CHO-BLT2 cells is suppressed under serum-free conditions. The IC 50 (50% inhibitory concentration) of the LMT-1013 compound was 62.35 nM. Likewise, in the cells expressing BLT1 (CHO-BLT1 cells), as the concentration of the compound LMT-1013 of the present invention was increased, it was confirmed that chemotaxis of CHO-BLT2 cells was suppressed under serum-free conditions. IC 50 (50% inhibitory concentration) was at least 10 μΜ.
또한, 도 4a 및 도 4b에 나타낸 바와 같이, BLT2가 발현된 세포 (CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.4배 증가 되었으며, 양성대조군으로 사용된 LY255283를 전처리 (10μM)한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 대비 90%의 주화성을 나타냄을 확인하였다. 이와 마찬가지로 BLT1이 발현된 세포 (CHO-BLT1)에서, 리간드인 LTB4 (10nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.2배 증가되었으며, 양성대조군으로 사용된 U75302를 전처리 (10μM)한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 90%의 주화성을 나타냄을 확인하였다. 다만, 본 발명의 화합물 (LMT-692, LMT-694, LMT-696)의 경우, BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4 처리 (DMSO+)에 비해 주화성이 각각 66%, 90%, 70.3% 억제됨을 확인한 반면, BLT1가 발현된 세포(CHO-BLT1)에서는 리간드인 LTB4 처리 (DMSO+)에 비해 주화성이 억제되지 않음을 확인하였다.In addition, as shown in FIGS. 4A and 4B, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) When (300nM) treated (DMSO +) and ethanol treated (DMSO-), cell chemotaxis was 2.4-fold increased, and LY255283 used as a positive control pretreated (10μM), the ligand LTB Compared to the case of 4 treated, it was confirmed that the coinability of 90%. Similarly, in the cells expressing BLT1 (CHO-BLT1), the ligand LTB 4 (10 nM) treated (DMSO +), ethanol treated compared to (DMSO-), the cell chemotaxis increased 2.2 times, the pretreatment (10 μM) of U75302 used as a positive control, the ligand LTB It was confirmed that 90% of chemotaxis was shown in comparison with the case where 4 was treated. However, in the case of the compound of the present invention (LMT-692, LMT-694, LMT-696), when the BLT2 expressed
또한, 도 5a 내지 도 5d 및 하기 표 3에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (AC-1074)의 농도가 증가함에 따라 (10-4, 10-3, 10-2, 10-1, 1, 10 및 102), 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, AC-1074의 화합물의 IC50 (50% 억제 농도)는 6.024 μM 이었다.In addition, as shown in FIGS. 5A to 5D and Table 3 below, in the cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound of the present invention (AC-1074) increases (10 −4 , 10) -3 , 10 -2 , 10 -1 , 1, 10 and 10 2 ), it was confirmed that chemotaxis of CHO-BLT2 cells under serum-free conditions, IC 50 (50% inhibitory concentration) of the compound of AC-1074 Was 6.024 μΜ.
또한, 도 6a에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.9배 증가되었고, 양성대조군으로 사용된 LY255283를 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 90% 의 주화성을 나타내었으며, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우 (DMSO+)와 비교하여 주화성이 53% 억제됨을 확인하였다.In addition, as shown in Figure 6a, LTB 4 which is a ligand of BLT2 in BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-), compared to 2.9-fold increase in cell chemotaxis, 10 μM pretreated LY255283 used as a positive control, the ligand LTB 4 To It showed 90% chemotaxis compared to the treatment, and when the compound of the present invention (AC-1074) was pretreated with 10 μM of cells expressing BLT2, the ligand was treated with LTB 4 (DMSO +). It was confirmed that 53% inhibition of chemotaxis.
또한, 도 6b에 나타낸 바와 같이, BLT1이 발현된 세포(CHO-BLT1 cells)에 BLT1의 리간드인 LTB4 (10nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.8배 증가되었고, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우 (DMSO+)와 비교하여 주화성의 변화가 없음을 확인하였다.In addition, as shown in FIG. 6B, LTB 4 which is a ligand of BLT1 in BLT1-expressing cells (CHO-BLT1 cells) When treated with (10 nM) (DMSO +), compared with (DMSO-) with ethanol, the cell chemotaxis was increased by 2.8-fold, and the compound (AC-1074) of the present invention was added to
또한, 도 6c에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 LPA (lysophosphatidic acid) (100nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 3.4배 증가되었고, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LPA를 처리한 경우 (DMSO+)와 비교하여 주화성의 변화가 없음을 확인하였다.In addition, as shown in FIG. 6C, when BLT2-expressing cells (CHO-BLT2 cells) were treated with LPA (lysophosphatidic acid) (100nM) (DMSO +) and ethanol-treated (DMSO-), Cell chemotaxis was increased 3.4-fold, and when the compound of the present invention (AC-1074) was pretreated with 10 μM of BLT2-expressing cells, there was no change in chemotaxis compared to the ligand-treated LPA (DMSO +). It was confirmed.
상기 결과로부터, BLT2가 안정하게 발현되고 있는 세포 (CHO-BLT2)에서, 주화성 활성은 LTB4 자극에 인해 증가되며, 본 발명의 화합물 (LMT-692, LMT-696, LMT-1013, 및 AC-1074)은 이러한 주화성을 현저히 저해시킬 수 있는바, LTB4에 의해 유도된 BLT2-의존적 주화성을 저해시키기 위한 약학적 성분으로 이용될 수 있음을 의미한다.From the above results, chemotactic activity was LTB 4 in cells stably expressing BLT2 (CHO-BLT2). Increased due to stimulation, the compounds of the present invention (LMT-692, LMT-696, LMT-1013, and AC-1074) can significantly inhibit this chemotaxis, as the BLT2-dependent strain induced by LTB 4 It can be used as a pharmaceutical component to inhibit Mars.
실험예 4. LTBExperimental Example 4. LTB 44 와 BLT2 결합 저해효과 확인And BLT2 binding inhibitory effect
LTB4와 BLT2 결합 (ligand binding affinity) 저해는 동위원소 트리튬(H3) 표기표 LTB4([3H]LTB4, ARC)(specific activity 160.0 Ci/mmol)를 사용하여 분석하였다. 실험방법은 CHO-BLT2 세포 2 × 106 개를 100 ㎜ 배양접시에 깔고 48 시간 동안 배양한 후 다음 과정을 진행한다. 수확한 세포를 균질기(homogenizer)로 1분씩 총 5회 사용하여 세포막의 단백질들을 분리한다. 그 후 4 ℃에서 45,000 RPM으로 40 분간 원심분리를 진행하여 세포막의 단백질만 수확하고 이를 40 ㎍/45 ㎕ 농도로 정량하였다. 동일하게 정량된 BLT2가 포함된 세포막 단백질에 각각 동일한 양의 [3H]LTB4 (5 nM)를 처리하고 농도별(10-9, 10-8, 10-7, 10-6 및 10-5 M)로 화합물을 처리하였을 때, 트리튬이 표기된 LTB4와 BLT2의 결합 억제정도를 Hidex 300sL 액체섬광계수기를 사용하여 측정하였다.LTB 4 and BLT2 binding (ligand binding affinity) inhibition was analyzed using the isotope tritium (H3) label LTB 4 ([3H] LTB 4, ARC) (specific activity 160.0 Ci / mmol). Experimental method is to put 2 × 10 6 CHO-BLT2 cells in a 100 mm culture dish and incubate for 48 hours before proceeding. The harvested cells are used five times for one minute in a homogenizer to separate the proteins of the cell membrane. Thereafter, centrifugation was performed for 40 minutes at 45,000 RPM at 4 ° C. to harvest only protein of the cell membrane and quantitate it at a concentration of 40 μg / 45 μl. Cell membrane proteins containing equally quantified BLT2 were treated with the same amount of [3H] LTB 4 (5 nM), respectively, and at different concentrations (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 M). ), The degree of inhibition of the binding of tritium-labeled LTB 4 and BLT2 was measured using a Hidex 300sL liquid scintillation counter.
그 결과, 도 7a 및 도 7b에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (LMT-696 및 LMT-1013)의 농도가 증가함에 따라 (10-9, 10-8, 10-7, 10-6 및 10-5) LTB4와 BLT2의 결합이 억제됨을 확인하였으며, LMT-696 및 LMT-1013의 화합물의 IC50 (50% 결합 억제 농도)는 각각 5.6 nM 및 30.74 nM이었다.As a result, as shown in FIGS. 7A and 7B, in the BHO expressing cells (CHO-BLT2 cells), as the concentration of the compounds of the present invention (LMT-696 and LMT-1013) increased (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 ) showed that the binding of LTB 4 to BLT2 was inhibited, and the IC 50 (50% binding inhibition concentration) of the compounds of LMT-696 and LMT-1013 was 5.6, respectively. nM and 30.74 nM.
또한, 도 7c에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (AC-1074)의 농도가 증가함에 따라 (10-9, 10-8, 10-7, 10-6 및 10-5) LTB4와 BLT2의 결합이 억제됨을 확인하였으며, AC-1074 화합물의 IC50 (50% 결합 억제 농도)는 140.35 nM 이었다.In addition, as shown in Figure 7c, in the BLT2 expressing cells (CHO-BLT2 cells), as the concentration of the compound (AC-1074) of the present invention increases (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 ) the binding of LTB 4 and BLT2 was inhibited, the IC 50 (50% binding inhibition concentration) of the AC-1074 compound was 140.35 nM.
실험예 5. BLT2 억제를 통한 아토피 치료 효과 확인Experimental Example 5. Confirmation of atopy treatment effect by inhibiting BLT2
5-1. 아토피 동물 모델의 제조5-1. Preparation of Atopy Animal Models
DBL(한국)에서 공급받은 암컷 6주령의 마우스(ICR mouse)에 제모를 수행한 다음날 아토피 피부염 유발 물질인 DNCB(dinitrochlorobenzene)를 도포하였다. 보다 구체적으로 아세톤(acetone) : 올리브오일의 비가 3:1로 구성된 용매에 DNCB를 1 %의 농도로 녹여서 제모된 부위에 도포하여 아토피 피부염을 유도하여, 아토피 마우스 모델을 만들었다.DNCB (dinitrochlorobenzene), a substance that induces atopic dermatitis, was applied the next day after depilation to female 6-week-old mice (ICR mice) supplied from DBL (Korea). More specifically, acetone (acetone): olive oil is dissolved in DNCB at a concentration of 1% in a solvent composed of 3: 1 and applied to the depilated area to induce atopic dermatitis, thereby creating an atopic mouse model.
5-2. 아토피 동물 모델에서의 외형 변화 확인5-2. Identifying Changes in Appearance in Atopic Animal Models
상기 실시예 5-1에 기재된 아토피 마우스에 DMSO 또는 BLT2 저해 물질로 알려진 LY255283을 10㎎/㎏의 용량으로 총 2회, 복강 내 주사(intraperitoneal injection)한 후, 1주 후 외형 변화를 관찰하였다.Atopy mice described in Example 5-1 were subjected to intraperitoneal injection of LY255283, known as DMSO or BLT2 inhibitor, at a dose of 10 mg / kg in total twice, followed by changes in appearance after 1 week.
그 결과, 도 8a에 나타낸 바와 같이, LY255283의 약제를 투여한 마우스에서 아토피 피부 질환의 치료 효과를 확인하였다.As a result, as shown in FIG. 8A, the therapeutic effect of atopic skin disease was confirmed in the mouse to which the LY255283 drug was administered.
5-3. 아토피 동물 모델에서의 가려움증(scratch) 변화 확인5-3. Confirmation of scratch changes in atopic animal models
상기 실시예 5-1에 기재된 아토피 마우스에 DMSO 또는 BLT2 저해 물질로 알려진 LY255283을 10㎎/㎏의 용량으로 총 2회, 복강 내 주사(intraperitoneal injection)한 후, 1주 후 가려움증(scratch) 변화를 관찰하였다.After a week of intraperitoneal injection of LY255283, known as DMSO or BLT2 inhibitor, to atopic dermatitis described in Example 5-1 at a dose of 10 mg / kg, a change in itching was observed 1 week later. Observed.
그 결과, 도 8b에 나타낸 바와 같이, LY255283의 약제를 투여한 마우스에서 가려움증이 개선되어, 아토피 피부 질환의 치료 효과를 확인하였다.As a result, as shown in FIG. 8B, the itch was improved in the mouse to which the LY255283 drug was administered, confirming the therapeutic effect of the atopic skin disease.
5-4. 아토피 동물 모델에서의 조직 검사 결과 확인5-4. Confirmation of biopsy results in atopic animal models
상기 실시예 5-1에 기재된 아토피 마우스에 DMSO 또는 BLT2 저해 물질로 알려진 LY255283을 10㎎/㎏의 용량으로 총 2회, 복강 내 주사(intraperitoneal injection)한 후, 1주 후 hematoxylin-eosin 염색을 통해 마우스 피부 조직 검사를 수행하였다.After a total of two intraperitoneal injections of LY255283, known as DMSO or BLT2 inhibitor, at a dose of 10 mg / kg in atopic mice described in Example 5-1, one week later, hematoxylin-eosin staining was performed. Mouse skin histology was performed.
그 결과, 도 8c에 나타낸 바와 같이, LY255283의 약제를 투여한 마우스에서 아토피 피부 질환의 치료 효과를 확인하였다.As a result, as shown in FIG. 8C, the therapeutic effect of atopic skin disease was confirmed in the mouse to which the LY255283 drug was administered.
실험예 6. 화합물 LMT-1013의 아토피 치료 효과 확인Experimental Example 6. Confirmation of atopy treatment effect of compound LMT-1013
6-1. DNCB 유도 아토피 동물 모델에서 LMT-1013의 효능 확인6-1. Efficacy of LMT-1013 in DNCB-induced Atopic Animal Models
6-1-1. DNCB 유도 아토피 동물 모델의 제조6-1-1. Preparation of DNCB-Induced Atopic Animal Models
LMT-1013 (분자량 335.4)은 한국파비스제약에서 파우더 형태로 제공받아 적절한 용매에 녹여서 사용하였고, DNCB(2,4-dinitrochlorobenzen)(#138630, Aldrich)는 99% acetone(100014, Merck)과 올리브 오일(압착 올리브유, CJ)을 3:1로 섞은 용액을 용매로 사용하였다. Vehicle은 Propylene glycol 과 에탄올을 7:3으로 혼합한 것을 사용하였다. 6주령 암컷 무모 마우스 (hairless mouse)(CrljOri:SKH1-hr, 오리엔트바이오)를 1주일간 순응시킨 후 4군으로 분리하여, 아무것도 처리하지 않은 무처리군, DNCB로 아토피피부염 유도 후 vehicle처리군, DNCB유도 후 LMT-1013 1%, 2% 처리군 총 4개의 군으로 나누어 실험에 사용하였다. LMT-1013 (molecular weight 335.4) was supplied in powder form by PARVIS Korea and dissolved in an appropriate solvent.DNCB (2,4-dinitrochlorobenzen) (# 138630, Aldrich) was 99% acetone (100014, Merck) and olive oil. (Pressed olive oil, CJ) in a mixture of 3: 1 was used as a solvent. Vehicle used a mixture of propylene glycol and ethanol 7: 3. Six-week-old female hairless mouse (CrljOri: SKH1-hr, Orient Bio) was acclimated for 1 week and separated into 4 groups, untreated group treated with nothing, vehicle treated group and DNCB after induction of atopic dermatitis with DNCB. After induction, LMT-1013 1%, 2% treatment group divided into four groups were used in the experiment.
상기와 같이 마우스 군을 분리한 후, 7일 동안 1% DNCB 용액을 mouse 등에 매일 200㎕ 씩 도포하였다. 일주일 후 2일 간격으로 총 7번 0.1% DNCB용액을 위와 같은 방법으로 도포하였다. 0.1% DNCB용액을 도포하며 14일 동안 Vehicle을 용매로 한 LMT-1013시료와 vehicle을 오전, 오후로 나누어 mouse 등에 200㎕씩 도포하였다. 사진은 처음 아토피피부염을 유도하기 전, 유도 7일 후, 14일 후 21일 후 측정하였다. 병변을 유도한지 21일째 mouse의 등을 사진을 촬영하고, 해부하여 등 조직 및 혈액, 비장을 채취하였다. After separating the mouse group as described above, 200 μl of 1% DNCB solution was applied daily to the mouse for 7 days. A total of 7% 0.1% DNCB solution was applied in the same manner as above, two days apart, one week later. After applying 0.1% DNCB solution, the vehicle was coated with LMT-1013 sample and vehicle for 14 days in the morning and afternoon. The photographs were measured before the first induction of atopic dermatitis, 7 days after induction, and 21 days after 14 days of induction. On 21 days after the lesion was induced, the back of the mouse was photographed and dissected to collect back tissue, blood, and spleen.
그 결과, 도 9에 나타낸 바와 같이, 1% DNCB로 병변을 유도하고 3일후부터 등 피부는 벗겨지고 각질이 일어나기 시작하였다. 병변 유도 7일 후 피부가 벗겨져 각질이 딱딱해지는 과각화증이 일어나는 것이 관찰되었으며, 시료 처리 후 시간 의존적으로 병변이 감소하는 것을 확인하였다. 병변 유도 후 14일부터 Vehicle군과 비교하여 LMT-1013 2% 처리군들은 각질이 많이 적어지고 피부 상태도 호전되었다. 병변 유도 21일에는 vehicle군은 부분적으로 약간의 각질이 확인되었지만, LMT-1013 처리군 중 LMT-1013 2%가 육안 상으로 개선효능을 보였다. As a result, as shown in Fig. 9, 3 days after the lesion was induced with 1% DNCB, the back skin was peeled off and keratin began to occur. Seven days after the induction of the lesions, the skin was peeled off and keratinosis was observed to occur. It was confirmed that the lesions decreased in time-dependent manner after sample treatment. From the 14th day after lesion induction, LMT-1013 2% treated group had less keratin and improved skin condition compared to vehicle group. On the 21st day of lesion induction, the vehicle group showed some keratin, but LMT-1013 2% of the LMT-1013 treated group showed visual improvement.
6-1-2. 경피수분손실량 및 피부수분함유량 측정6-1-2. Transdermal moisture loss and skin moisture content measurement
일반적으로 아토피 피부염은 피부장벽이 망가져 보습이 잘 되지 않고, 수분이 손실되는 특징을 가지므로, 수분 손실을 억제하는 것을 아토피 병변 개선 효과의 지표로 삼을 수 있기 때문에 mouse 등의 경표피 수분 손실량(TEWL) 및 피부수분함유량(hydration)을 측정하였다. 상기 실시예 6-1-1에 기재된 아토피 마우스의 경피수분손실량 (TEWL, Trans Epidermal Water Loss)은 AquaFlux (Biox, London, UK)를 이용해서 측정하였고, 피부수분함유량(hydration)는 Skin-O-Mat (COSMOMEP, Berlin, Germany)를 이용하여 측정하였다. In general, atopic dermatitis is not moisturized due to breakage of the skin barrier, and moisture is lost. Therefore, the amount of water loss to hard epidermis such as mouse can be used as an indicator of atopic lesion improvement. TEWL) and skin moisture content (hydration) were measured. Trans Epidermal Water Loss (TEWL) of the atopy mouse described in Example 6-1-1 was measured using AquaFlux (Biox, London, UK), and skin moisture content (hydration) was determined using Skin-O-. Measurement was made using Mat (COSMOMEP, Berlin, Germany).
그 결과, 도 10에 나타낸 바와 같이, DNCB로 아토피 병변 유도 7일 후 Vehicle의 TEWL수치는 100 g/m2/h 이상으로 증가하였고, LMT-1013 2% 처리군은 유도 14일 후 vehicle군에 대비 10% 감소하였으며, 유도 21일에 LMT-1013 2% 처리군은 75 g/m2/h 정도로 약간 감소되었다. 또한, DNCB로 유도한 마우스의 등 수분함유량(hydration)을 측정한 결과, 무처리군에 비하여 DNCB로 유도한 군들이 무처리군 대비 50%이하로 저하되었지만, 21일차에는 LMT-1013 2% 처리군이 vehicle 대비 유의한 수준으로 증가된 것을 확인하였다. 따라서 LMT-1013 2% 처리군은 무모 마우스에서 vehicle에 비해 피부장벽 기능을 강화시킨다는 것을 알 수 있다. As a result, as shown in Figure 10, 7 days after induction of atopic lesions with DNCB TEWL value of the vehicle increased to more than 100 g / m2 / h, LMT-1013 2% treatment group compared to
6-1-3. H&E 염색6-1-3. H & E Dyeing
상기 실시예 6-1-1에 기재된 아토피 마우스의 등 조직을 4% 포르말린(#F8775, Sigma)으로 고정한 후 H&E(Hematoxylin and eosin)으로 염색 하였다. 헤마톡실린은 세포의 핵과 같은 산성과 만나서 청색으로 염색하고, 에오신은 염기성과 만나서 다른 세포질 성분과 아교질(collagen)을 붉은 색으로 염색하였다. 표피(epidermis)의 두께는 마리당 2번씩 촬영한 조직 사진을 이용하여 image J program을 사용해 임의로 3군데 측정한 후 평균값을 구하였다. The back tissue of the atopy mouse described in Example 6-1-1 was fixed with 4% formalin (# F8775, Sigma) and stained with H & E (Hematoxylin and eosin). Hematoxylin meets acidity, such as the nucleus of cells, and is stained blue. Eosin meets basicity and stains other cytoplasmic components and collagen in red. The epidermis thickness was measured by using an image J program using three tissue photographs taken twice per horse, and then averaged.
그 결과, 도 11에 나타낸 바와 같이, 무처리군에 비해 DNCB를 처리하여 아토피 피부염을 유도한 군에서는 표피(Epidermis)의 두께가 증가하였으며, 표피층의 두께를 측정한 결과 DNCB 유도 후 vehicle 처리군의 표피 두께는 100 um 이상으로 증가하였고, LMT-1013 2% 처리군은 표피의 두께가 감소하였다. 또한 Vehicle 처리군은 표피의 최상위 층의 세포 수가 증가한 것으로 보아 과각화가 일어났음을 알 수 있으며, 진피 위층에 세포핵이 많이 관찰되어 이를 통해 면역세포가 진피(dermis)의 위층으로 이동하여 면역반응이 활발히 일어났음을 알 수 있다. 반면, LMT-1013 2% 처리군은 Vehicle군보다 면역세포가 덜 침투하는 것을 확인하였다.As a result, as shown in Figure 11, compared to the untreated group treated with DNCB to induce atopic dermatitis, the thickness of the epidermis (Epidermis) was increased, as a result of measuring the thickness of the epidermal layer of the vehicle treated group after induction of DNCB Epidermal thickness was increased above 100 μm, and the LMT-1013 2% treatment group had decreased epidermal thickness. In addition, the vehicle treatment group showed that hyperkeratosis occurred due to the increase in the number of cells in the uppermost layer of the epidermis, and many cell nuclei were observed in the upper layer of the dermis, through which the immune cells moved to the upper layer of the dermis and the immune response was active. You can see that it happened. On the other hand, LMT-1013 2% treatment group was confirmed that less immune cells penetrate than the vehicle group.
6-1-4. 톨루이딘 블루 염색6-1-4. Toluidine blue staining
상기 실시예 6-1-1에 기재된 아토피 마우스 조직의 Mast cell 염색을 위하여 1% NaCl pH2.3 용액에 70% 에탄올에 1% 로 만든 톨루이딘 블루 (toluidine blue)(#T3260, Sigma Aldrich) 용액을 섞어 0.1%로 만든 뒤, deparaffinization이 끝난 조직 슬라이드를 2-3분간 염색하였다. 염색이 끝난 슬라이드를 증류수에 3회 (5분/회) 세척한 뒤, dehydration과정을 95%, 100% 에탄올, xylene(280130101, Junsei)용액에 각 1회씩 (5분/회) 세척하여 완료하였다. 완성된 슬라이드는 커버 슬라이드로 덮어 굳힌 뒤, image J program을 이용하여 진피층에 존재하는 mast cell의 수를 조사한다. 임의로 선정한 3곳의 사진을 찍어 평균값을 구하여 mast cell의 수를 조사하였다. Toluidine blue (# T3260, Sigma Aldrich) solution made of 1% in 70% ethanol in 1% NaCl pH2.3 solution for Mast cell staining of atopic mouse tissue described in Example 6-1-1 After mixing to 0.1%, deparaffinized tissue slides were stained for 2-3 minutes. After washing the stained slides in distilled
그 결과, 도 12에 나타낸 바와 같이, 1240(w)x700±150(h)의 면적당 mast cell을 counting하였을 때, 무처리군은 45개였고 DNCB 유도 후 vehicle처리군은 100개였다. 한편 DNCB 유도 후 LMT-1013 처리군은 감소하였고, 이중 LMT-1013 2%가 vehicle군에 비해 절반수준으로 mast cell의 수를 감소시켰다. 상기로부터 LMT-1013 1% 처리군도 mast cell infiltration에 대해서는 감소시켜 주는 효능이 있음을 확인하였다.As a result, as shown in Figure 12, when counting mast cells per area of 1240 (w) x 700 ± 150 (h), there were 45 untreated groups and 100 vehicle treated groups after DNCB induction. On the other hand, LMT-1013 treatment group decreased after DNCB induction. Among them, 2% LMT-1013 reduced the number of mast cells by half compared to vehicle group. From the above it was confirmed that LMT-1013 1% treatment group also has an effect of reducing the mast cell infiltration.
6-1-5. 혈액 분석6-1-5. Blood analysis
상기 실시예 6-1-1에 기재된 아토피 마우스의 무처리군 및 Vehicle군, LMT-1013 처리군의 혈액을 채취하고 채취한 혈액을 8,000RPM에서 15분간 원심 분리하여 혈장을 분리하였다. 아토피피부염의 마커로 쓰이며 아토피 피부염에서 가장 중요한 요인 중 하나인 면역글로불린E(IgE)와 면역세포의 Th2 싸이토카인 중 하나인 인터류킨-4(IL-4)의 양을 ELISA실험법을 이용하여 혈장에서 측정하였다. IgE ELISA kit(Mouse IgE Ready-SER-Go!, eBioscience) 와 IL-4 ELISA kit(Mouse IL-4 ELISA Ready-SET-Go!,eBioscience)를 사용하였다.Blood was collected from the untreated group, vehicle group, and LMT-1013 treated group of the atopy mouse described in Example 6-1-1, and the collected blood was centrifuged at 8,000 RPM for 15 minutes to separate plasma. The amount of immunoglobulin E (IgE), one of the most important factors in atopic dermatitis, and interleukin-4 (IL-4), which is one of Th2 cytokines in immune cells, was measured in the plasma using ELISA. . IgE ELISA kit (Mouse IgE Ready-SER-Go !, eBioscience) and IL-4 ELISA kit (Mouse IL-4 ELISA Ready-SET-Go !, eBioscience) were used.
그 결과, 도 13에 나타낸 바와 같이, IgE 단백질 양은 vehicle군에서 증가 하였고 LMT-1013 처리군에서는 감소하였다. 또한, IL-4 단백질 양도 vehicle군에서는 증가하였으며 LMT-1013 처리군에서는 감소하였다. As a result, as shown in Figure 13, the amount of IgE protein was increased in the vehicle group and decreased in the LMT-1013 treatment group. The amount of IL-4 protein also increased in the vehicle group and decreased in the LMT-1013 treatment group.
6-2. 아토피 피부염 유효마커 확인6-2. Validation of Atopic Dermatitis Markers
6-2-1. RBL-2H3 세포에서 탈과립 측정6-2-1. Degranulation measurement in RBL-2H3 cells
Rat basophilic leukemia cell인 RBL-2H3 세포는 한국 세포주 은행(Korea Cell Line Bank; Seo, Korea)에서 분양받아 사용하였다. 상기 RBL-2H3 세포로부터 탈과립화 측정은 탈과립의 바이오마커 인 β-hexosaminidase 분비 저해 활성을 측정하였다. 0.5 μg/ml 농도의 dinitropheny-immunoglobulin E(DNP-IgE)를 함유한 DMEM 배지를 사용하여, 24-well plates에 RBL-2H3 세포를 2 × 105 cells/well의 밀도로 분주한 뒤, 37oC, 5% CO2 incubator에서 12시간 배양하였다. 각 세포들을 Siraganian buffer (119 mM NaCl, 5 mM KCl, 5.6 mM glucose, 0.4 mM MgCl2, 25 mM PIPES, 1 mM CaCl2, 0.1% BSA, pH 7.2)로 2회 세척 한 다음, 37oC, 5% CO2 incubator에서 동일 buffer로 10분간 배양한 후 추출물 및 분획을 농도별(10, 30, 100 μM)로 희석시켜 세포에 처리하여 37oC, 5% CO2 incubator에서 30분 동안 반응 시켰다. 이후 DNP-bovine serum albumin(DNP-BSA)을 최종 농도 100 ng/ml이 되도록 가하여 37oC, 5% CO2 incubator에서 2 시간 반응시키고, ice bath에서 10분간 배양한 후 반응을 종결시켰다. 상층액 40 μl를 96-well plate에 옮기고 substrate buffer (2 mM 4-p-nitrophenyl-N-acetyl-β-D-glucosaminide, 0.05 M Sodium citrate, pH 4.5) 40 μl를 가하고 37℃에서 1시간 동안 배양시킨 다음 각 well 당 stop solution(0.1 M Na2CO3/NaHCO3, pH 10.5) 200 μl를 첨가하여 반응을 종결시키고 405 nm에서 흡광도를 측정하였다.RBL-2H3 cells, which are rat basophilic leukemia cells, were distributed from Korea Cell Line Bank (Seo, Korea). Degranulation measurement from the RBL-2H3 cells measured β-hexosaminidase secretion inhibitory activity, a biomarker of degranulation. Using DMEM medium containing 0.5 μg / ml dinitropheny-immunoglobulin E (DNP-IgE), RBL-2H3 cells were dispensed in 24-well plates at a density of 2 x 105 cells / well, followed by 37oC, 5 Incubated for 12 hours in a% CO2 incubator. Each cell was washed twice with Siraganian buffer (119 mM NaCl, 5 mM KCl, 5.6 mM glucose, 0.4
그 결과, 도 14에 나타낸 바와 같이, 30 uM 농도에서 탈과립을 저해하는 것으로 나타났는바, 이는 알러지 반응으로 인한 가려움증을 개선시켜줄 수 있다는 것을 의미한다. As a result, as shown in Figure 14, it was shown to inhibit the degranulation at 30 uM concentration, which means that it can improve the itch caused by the allergic reaction.
상기로부터, DNCB를 이용하여 mouse 등에 아토피 피부염을 유도한 경우, 전반적인 아토피 피부염 증상을 개선시킬 수 있음을 의미한다. 등 표면은 육안으로 보았을 때 LMT-1013 2% 처리 시 개선됨이 관찰되었으며, 경표피수분손실량(TEWL), 피부수분함유량 (Hydration) 에서 모두 개선된 결과치를 보여주었다. 또한, 등조직을 분리하여 H&E 염색을 하였을 때, 아토피 피부염에서 나타나는 표피 증식 현상이 LMT-1013 2% 처리 시 많이 호전되는 것을 관찰할 수 있었으며, 진피에서는 Mast cell infiltration 역시 LMT-1013 처리 시 감소되는 것을 확인할 수 있었다. 아울러 혈액에서 아토피 피부염의 주요 요인인 IgE와 IL-4의 발현도 감소시켜 주었다. From the above, when atopic dermatitis is induced in mice and the like using DNCB, it means that the overall atopic dermatitis symptoms can be improved. The back surface was visually observed to be improved by 2% LMT-1013 treatment, and both the epidermal moisture loss (TEWL) and skin moisture content (Hydration) showed improved results. In addition, when H & E staining was performed on the back tissue, it was observed that the epidermal hyperplasia in atopic dermatitis was significantly improved by 2% LMT-1013 treatment, and in the dermis, Mast cell infiltration was also decreased. I could confirm that. In addition, it reduced the expression of IgE and IL-4, which are the major causes of atopic dermatitis in the blood.
따라서 LMT-1013은 DNCB 유도 아토피피부염 모델에서 아토피 피부염을 개선하는 효능을 보이며 저하된 피부장벽 기능을 회복시킬 수 있을 것으로 판단되며, LMT-1013은 mast cell의 탈과립을 저해하는 것으로 보아 아토피 피부염에 효능을 나타내는 것을 의미한다. Therefore, LMT-1013 is effective in improving atopic dermatitis in DNCB-induced atopic dermatitis model, and it is possible to restore reduced skin barrier function. It means to indicate.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.
Claims (5)
[화학식 1]
상기 화학식 1에서,
R1은 C1~C10의 알킬이고,
R2는 이며,
Ra는 하이드록시이고,
R3는 수소이다.
A pharmaceutical composition for preventing or treating atopy, comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 1]
In Chemical Formula 1,
R 1 is C 1 -C 10 is alkyl,
R 2 is ,
R a is hydroxy,
R 3 is hydrogen.
상기 화학식 1로 표시되는 화합물은 4-(3-(N-페닐펜탄아미도)프로-1-핀-1-일)벤조익산 (4-(3-(N-phenylpentanamido)prop-1-yn-1-yl)benzoic acid)인 것을 특징으로 하는, 아토피 예방 또는 치료용 약학적 조성물.
The method of claim 1,
Compound represented by Formula 1 is 4- (3- (N-phenylpentaneamido) prop-1-pin-1-yl) benzoic acid (4- (3- (N-phenylpentanamido) prop-1-yn- 1-yl) benzoic acid), characterized in that the atopy preventive or therapeutic pharmaceutical composition.
상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시키는 것을 특징으로 하는, 아토피 예방 또는 치료용 약학적 조성물.The method according to claim 1 or 2,
The composition is characterized in that to inhibit the Leukotriene B4 receptor 2 (BLT2) activity, atopy preventive or therapeutic pharmaceutical composition.
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