KR20130030329A - N-(2-acetyl-4-morpholinophenyl amide derivatives for inducing differentiation of mesenchymal stem cells to endothelial cells - Google Patents
N-(2-acetyl-4-morpholinophenyl amide derivatives for inducing differentiation of mesenchymal stem cells to endothelial cells Download PDFInfo
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- KR20130030329A KR20130030329A KR1020120103005A KR20120103005A KR20130030329A KR 20130030329 A KR20130030329 A KR 20130030329A KR 1020120103005 A KR1020120103005 A KR 1020120103005A KR 20120103005 A KR20120103005 A KR 20120103005A KR 20130030329 A KR20130030329 A KR 20130030329A
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- South Korea
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- hydrogen
- acetyl
- morpholinophenyl
- substituted
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- 210000002901 mesenchymal stem cell Anatomy 0.000 title claims abstract description 66
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- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
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- 125000003277 amino group Chemical group 0.000 claims abstract description 27
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
Description
본 발명은 중간엽 줄기세포의 혈관내피세포로의 분화 유도를 위한 2-아세틸-4-몰포리노페닐기를 함유하는 아마이드 유도체 및 이의 의약적 용도에 관한 것이다.
The present invention relates to an amide derivative containing a 2-acetyl-4-morpholinophenyl group for inducing differentiation of mesenchymal stem cells into vascular endothelial cells and a pharmaceutical use thereof.
자가 혈관 내피전구세포(endothelial progenitor cells, EPCs)는 혈관신생 및 재내피세포화를 위해 유용할 수 있다. 많은 수의 골수-유래 세포는 내피-유사 세포로 분화될 잠재력을 갖고 있다. 최근 동물과 인간에서의 연구는 골수 유래의 전구세포인 EPCs가 혈관신생 및 재내피화를 촉진할 잠재력을 갖고 있다고 제안하였으나, 혈액-유래의 EPCs를 이용할 때 이들 세포를 충분한 수로 얻기가 쉽지 않다. 또한, 성인 혈액으로부터 얻은 EPCs는 제대혈-유래의 EPCs에 비해 증식능이 제한적이다. 혈관 복구를 위한 대안으로서, 중간엽 줄기 세포(MSCs)에 대한 연구가 진행되고 있다. 다양한 혈관 내피전구세포 중에서, MSCs는 자가 또는 동종 세포 치료에 대해 제조하기 쉽고 유연성이 높은 장점을 갖는다. 또한, MSCs에서의 유전자 발현 패턴의 계열적 분석은 MSCs의 인비트로 분화 잠재력이 중배엽 계열로 제한되지 않고, MSCs가 인비트로 및 인비보에서 내피세포와 같은 다른 계열로도 전이분화할 수 있음을 밝혔다. 주입된 MSCs의 일부는 또한 새로운 혈관으로 도입되거나 측분비 메커니즘(paracrine mechanism)에 의한 측부 혈관 형성을 자극하는 것으로 나타났다. Autologous endothelial progenitor cells (EPCs) may be useful for angiogenesis and re-endothelial cellization. A large number of bone marrow-derived cells have the potential to differentiate into endothelial-like cells. Recent studies in animals and humans have suggested that EPCs, bone marrow-derived progenitor cells, have the potential to stimulate angiogenesis and re-endothelialization, but it is difficult to obtain sufficient numbers of these cells when using blood-derived EPCs. In addition, EPCs obtained from adult blood have limited proliferative capacity compared to cord blood-derived EPCs. As an alternative for vascular repair, research into mesenchymal stem cells (MSCs) is underway. Among various vascular endothelial progenitor cells, MSCs have the advantage of being easy to manufacture and highly flexible for the treatment of autologous or allogeneic cells. In addition, serial analysis of gene expression patterns in MSCs revealed that the in vitro differentiation potential of MSCs is not limited to mesodermal lineages, and that MSCs can be transdifferentiated into other lines such as endothelial cells in vitro and in vivo. . Some of the injected MSCs have also been shown to be introduced into new vessels or stimulate lateral vessel formation by paracrine mechanisms.
이에 본 발명자들은 골수 유래 중간엽 줄기세포를 활성화 시켜 특이적으로 내피세포로의 분화를 유도하는 저분자 화합물에 대해 연구하던 중, 신규한 몰포린/피페라진기를 가지는 화합물을 합성하였으며, 이 화합물이 MSCs의 내피세포로의 분화 유도로 재내피세포화 효과를 나타냄을 확인하고 본 발명을 완성하였다.
The inventors of the present invention, while studying a low molecular weight compound that specifically activates bone marrow-derived mesenchymal stem cells to induce differentiation into endothelial cells, synthesized a compound having a novel morpholine / piperazine group. Induction of differentiation into endothelial cells was confirmed to exhibit the effect of re-endothelialization and completed the present invention.
본 발명의 목적은 골수 유래 중간엽 줄기세포의 혈관질환에 대한 세포치료제로서의 활용을 위해 중간엽 줄기세포로부터 혈관내피세포로의 분화를 유도하는 신규한 저분자 화합물 및 이의 약학적 용도를 제공하는 것이다.
An object of the present invention is to provide a novel low molecular compound and its pharmaceutical use for inducing differentiation of mesenchymal stem cells into vascular endothelial cells for use as a cell therapy for vascular diseases of bone marrow-derived mesenchymal stem cells.
이식된 세포와 조직 간의 이종성을 줄인다면 이식된 세포의 생착율을 증가시킬 수 있을 것이다. 이러한 점에 착안하여 본 발명자들은 중간엽 줄기세포를 혈관내피세포로 유도할 수 있는 방법에 대해 지속적으로 연구하였다. 그 결과, 하기 화학식 1 또는 2의 몰포린/피페라진기를 함유하는 아마이드 유도체가 중간엽 줄기세포를 혈관내피세포로 분화 유도할 수 있음을 밝혔다. Reducing the heterogeneity between transplanted cells and tissues could increase the engraftment rate of transplanted cells. With this in mind, the present inventors continually studied how to induce mesenchymal stem cells into vascular endothelial cells. As a result, the amide derivative containing a morpholine / piperazine group of the following formula (1) or 2 can induce differentiation of mesenchymal stem cells into vascular endothelial cells.
하기 실시예에서는 화학식 1 또는 2의 화합물에 의해 엑스 비보(ex vivo) 상에서 변형된 랫트의 골수 유래의 중간엽 줄기세포가 혈관내피세포로 분화함을 보여준다.In the examples below, the bone marrow-derived mesenchymal stem cells of rats modified on ex vivo by the compound of
따라서, 본 발명은 일 관점에 있어서, 중간엽 줄기세포의 혈관내피세포로의 분화 유도를 위한 신규한 화학식 1의 화합물을 제공한다.Accordingly, in one aspect, the present invention provides a novel compound of
[화학식 1][Formula 1]
상기 식에서,Where
X는 탄소, 산소 또는 질소 원자이고, 여기서, X가 산소 원자일 때 R1은 존재하지 않으며,X is a carbon, oxygen or nitrogen atom, where R 1 is absent when X is an oxygen atom,
R1은 수소 또는 탄소수 1 내지 6의 알킬기이고, R 1 is hydrogen or an alkyl group having 1 to 6 carbon atoms,
R2는 수소, 니트로기, 아세틸기 또는 아미노기이고,R 2 is hydrogen, nitro group, acetyl group or amino group,
R3는 수소; 하이드록시기; 탄소수 1 내지 6의 알콕시기; 니트로기; 아세트아미드기; 또는 할로겐, 페닐 또는 피라졸일로 치환되거나 비치환된 벤즈아미드기이며,R 3 is hydrogen; Hydroxyl group; An alkoxy group having 1 to 6 carbon atoms; A nitro group; Acetamide group; Or a benzamide group substituted or unsubstituted with halogen, phenyl or pyrazolyl,
R4는 수소; 하이드록시기로 치환된 탄소수 1 내지 6의 알킬; 아세틸기; 할로겐; 니트로기; 아미노기; 할로겐으로 치환되거나 비치환된 아세트아미드기; 피코린아미드기; 티오펜카복스아미드기; 카르복실기; 또는 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 알콕시, 할로겐, 니트로, 페닐, 피라졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고, R 4 is hydrogen; Alkyl having 1 to 6 carbon atoms substituted with a hydroxy group; Acetyl group; halogen; A nitro group; An amino group; An acetamide group unsubstituted or substituted with halogen; Picolinamide groups; Thiophene carboxamide group; Carboxyl groups; Or a benzamide group unsubstituted or substituted with alkyl having 1 to 6 carbon atoms, alkoxy, halogen, nitro, phenyl, pyrazolyl or thiazolyl having 1 to 6 carbon atoms,
R5는 수소; 하이드록시기; 아미노기; 아세틸기; 피페리딘일로 치환된 탄소수 1 내지 6의 알킬; 할로겐 또는 피라졸일로 치환되거나 비치환된 니코틴아미드기; 또는 탄소수 1 내 6의 알킬, 피페라진일, 피페리딘일, 이미다졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고, R 5 is hydrogen; Hydroxyl group; An amino group; Acetyl group; Alkyl of 1 to 6 carbon atoms substituted with piperidinyl; Nicotinamide groups unsubstituted or substituted with halogen or pyrazolyl; Or a benzamide group unsubstituted or substituted with alkyl, piperazinyl, piperidinyl, imidazoyl or thiazolyl having 1 to 6 carbon atoms,
R6은 수소 또는 하이드록시기이며, R 6 is hydrogen or a hydroxyl group,
m은 0 내지 3의 정수를 나타내고,m represents an integer of 0 to 3,
여기서, X가 산소 원자인 경우, R2, R3, R5 및 R6이 수소이고 R4가 아세틸기인 화합물, R2, R3, R4 및 R6이 수소이고 R5가 하이드록시기 또는 아미드기인 화합물, R2, R3 및 R6이 수소이고 R4가 니트로기이고, R5가 하이드록시기인 화합물, R2, R3 및 R6이 수소이고 R4가 아미드기이고, R5가 아세틸기인 화합물 및 R2, R4, R5 및 R6이 수소이고 R3이 아세트아미드기인 화합물을 제외하고,Wherein when X is an oxygen atom, R 2 , R 3 , R 5 and R 6 are hydrogen and R 4 is an acetyl group, R 2 , R 3 , R 4 And R 6 is hydrogen and R 5 is a hydroxy group or an amide group, R 2 , R 3 And a compound in which R 6 is hydrogen and R 4 is a nitro group, R 5 is a hydroxy group, R 2 , R 3 and R 6 are hydrogen, R 4 is an amide group, and R 5 is an acetyl group and R 2 , R Except for compounds where 4 , R 5 and R 6 are hydrogen and R 3 is an acetamide group,
X가 질소 원자인 경우, R2, R3, R4 및 R6이 수소이고 R5가 하이드록시기인 화합물 및 R3, R5 및 R6이 수소이고 R2가 니트로기이고, R4가 아세틸기인 화합물은 제외한다.When X is a nitrogen atom, R 2 , R 3 , R 4 and R 6 are hydrogen and R 5 is a hydroxy group and R 3 , R 5 and R 6 are hydrogen and R 2 is nitro group, R 4 is The compound which is an acetyl group is excluded.
본 발명의 화합물의 치환체 정의에 사용된 용어는 하기와 같다.The terms used in the substituent definitions of the compounds of the present invention are as follows.
"할로겐"은 -F, -Cl, -Br 또는 -I이다."Halogen" is -F, -Cl, -Br or -I.
여기에서, "알킬"은 일반적으로 명시된 수의 탄소원자 (예컨대, 1 내지 12개의 탄소원자)를 갖는 직쇄 및 분지형 포화 탄화수소 기를 의미한다. 알킬기의 예는 제한없이 메틸, 에틸, n-프로필, i-프로필, n-부틸, s-부틸, i-부틸, t-부틸, 펜트-1-일, 펜트-2-일, 펜트-3-일, 3-메틸부트-1-일, 3-메틸부트-2-일, 2-메틸부트-2-일, 2,2,2-트리메틸에트-1-일, n-헥실, n-헵틸 및 n-옥틸 등을 포함한다.As used herein, "alkyl" generally refers to straight and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, 1 to 12 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t- butyl, pent- Methylbut-2-yl, 2,2,2-trimethylet-1-yl, n-hexyl, n-heptyl and n-octyl, and the like.
"알콕시"는 다른 기재가 없는 한, 상기 탄소수 1 내지 6, 예를 들어 탄소수 1 내지 4의 알킬기가 산소원자와 결합한 것을 나타낸다. C1 -4 알콕시기의 예는 메톡시, 에톡시, 프로폭시, 및 부톡시가 포함되나, 이들에 제한되지 않는다. "Alkoxy" means an alkyl group having 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, bonded to an oxygen atom unless otherwise specified. Examples of C 1 -4 alkoxy groups, including, methoxy, ethoxy, propoxy, and butoxy, and is not limited to these.
"아릴"은 다른 기재가 없는 한, 5 내지 12-환원의 방향족 고리화합물을 가리킨다. 아릴기의 예로는 페닐, 비페닐, 나프틸 및 안트라세닐을 포함하나, 이들에 제한되지 않는다. 아릴이 하나 이상의 헤테로원자를 포함하는 경우 "헤테로아릴"이라고도 언급한다. 일환 아릴기의 예는 제한없이 페닐, 피롤릴, 퓨란일, 티오펜에일, 티아졸릴, 이소티아졸릴, 이미다졸릴, 트리아졸릴, 테트라졸릴, 피라졸릴, 옥사졸릴, 이소옥사졸릴, 피리딘일, 피라진일, 피리다진일, 피리미딘일 등을 포함한다. 아릴기는 또한 상기 정의된 융합된 5- 및 6-원 고리를 포함한 이환 기, 삼환 기 등을 포함한다. 다환 아릴기의 예는 제한없이 나프틸, 바이펜일, 안트라센일, 피렌일, 카바졸릴, 벤족사졸릴, 벤조다이옥사졸릴, 벤조티아졸릴, 벤조이미다졸릴, 벤조티오펜에일, 퀸올린일, 이소퀸올린일, 인돌릴, 벤조퓨란일, 푸린일, 인돌리진일 등을 포함한다. 상기 아릴기는 부착이 원자가 요구조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기 또는 기재에 부착될 수 있다. 마찬가지로, 아릴기는 치환이 원자가 요구조건을 위반하지 않는다면 하나 이상의 비-수소 치환기를 포함할 수 있다."Aryl" refers to 5 to 12-reduced aromatic cyclic compounds unless otherwise stated. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and anthracenyl. When aryl contains one or more heteroatoms, it is also referred to as "heteroaryl". Examples of monocyclic aryl groups include, but are not limited to, phenyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl , Pyrazinyl, pyridazinyl, pyrimidinyl and the like. Aryl groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6-membered rings as defined above. Examples of polycyclic aryl groups include without limitation naphthyl, bifenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiopheneyl, quinolinyl , Isoquinolinyl, indolyl, benzofuranyl, furinyl, indolizinyl and the like. The aryl group can be attached to the parent group or substrate at any ring atom as long as the attachment does not violate valence requirements. Likewise, an aryl group may include one or more non-hydrogen substituents if the substitution does not violate valence requirements.
여기에서, "치환된" 기는 하나 이상의 수소 원자가 하나 이상의 비-수소원자기로 대체된 것이나, 단 원자가(valence) 요구조건이 만족되어야 하고 화학적으로 안정한 화합물이 치환으로부터 발생되어야 한다. 본 명세서 내에서, 명시적으로 "비치환된"이라고 기재되지 않은 한, 모든 치환기는 치환 또는 비치환될 수 있는 것으로 해석되어야 한다. 예를 들어, R1 내지 R6의 치환기는 각각 상기 정의된 치환기 중 하나 이상으로 다시 치환될 수 있다. Herein, a "substituted" group is where one or more hydrogen atoms have been replaced by one or more non-hydrogen atom groups, provided that the valence requirements are met and chemically stable compounds must be generated from the substitution. Within this specification, all substituents are to be interpreted as being optionally substituted, unless expressly stated to be "unsubstituted." For example, the substituents of R 1 to R 6 may each be substituted with one or more of the substituents defined above.
한 구체예에서, 화학식 1의 화합물은 X는 산소 또는 질소 원자이고,In one embodiment,
R1은 탄소수 1 내지 6의 알킬기이고, R 1 is an alkyl group having 1 to 6 carbon atoms,
R2는 수소 또는 아세틸기이며,R 2 is hydrogen or an acetyl group,
R3는 수소이고,R < 3 > is hydrogen,
R4는 아세틸기, 니트로기, 아미노기, 아세트아미드기, 페닐로 치환된 벤즈아미드기 또는 탄소수 1 내지 6의 알콕시로 치환된 벤즈아미드기이며,R 4 is an acetyl group, a nitro group, an amino group, an acetamide group, a benzamide group substituted with phenyl or a benzamide group substituted with alkoxy having 1 to 6 carbon atoms,
R5는 아미노기, 하이드록시기, 아세틸기, 티아졸일로 치환된 벤즈아미드기이고,R 5 is a benzamide group substituted with an amino group, a hydroxyl group, an acetyl group, thiazolyl,
R6은 수소이며, R 6 is hydrogen,
m은 1 내지 3의 정수를 나타내는 화합물일 수 있다.m may be a compound representing an integer of 1 to 3.
다른 구체예에서, 화학식 1의 화합물은 하기 화학식 1-1 내지 1-36으로 표시되는 화합물일 수 있다:In another embodiment, the compound of Formula 1 may be a compound represented by Formula 1-1 to 1-36:
[화학식 1-1][Formula 1-1]
[화학식 1-2] [Formula 1-2]
[화학식 1-3] [Formula 1-3]
[화학식 1-4] [Formula 1-4]
[화학식 1-5] [Formula 1-5]
[화학식 1-6] [Chemical Formula 1-6]
[화학식 1-7][Chemical Formula 1-7]
[화학식 1-8] [Chemical Formula 1-8]
[화학식 1-9][Chemical Formula 1-9]
[화학식 1-10] [Formula 1-10]
[화학식 1-11][Formula 1-11]
[화학식 1-12][Formula 1-12]
[화학식 1-13][Formula 1-13]
[화학식 1-14][Formula 1-14]
[화학식 1-15][Chemical Formula 1-15]
[화학식 1-16][Formula 1-16]
[화학식 1-17][Formula 1-17]
[화학식 1-18][Formula 1-18]
[화학식 1-19][Chemical Formula 1-19]
[화학식 1-20][Chemical Formula 1-20]
[화학식 1-21][Formula 1-21]
[화학식 1-22][Formula 1-22]
[화학식 1-23][Formula 1-23]
[화학식 1-24][Formula 1-24]
[화학식 1-25][Chemical Formula 1-25]
[화학식 1-26][Chemical Formula 1-26]
[화학식 1-27][Chemical Formula 1-27]
[화학식 1-28][Chemical Formula 1-28]
[화학식 1-29][Chemical Formula 1-29]
[화학식 1-30][Chemical Formula 1-30]
[화학식 1-31][Chemical Formula 1-31]
[화학식 1-32](1-32)
[화학식 1-33][Formula 1-33]
[화학식 1-34][Formula 1-34]
[화학식 1-35] [Formula 1-35]
[화학식 1-36][Formula 1-36]
바람직하게는, 화학식 1의 화합물은 상기 화학식 1-1 내지 1-5으로 표시되는 화합물일 수 있다.
Preferably, the compound of
본 발명은 또한 다른 관점에 있어서, 화학식 2의 화합물을 포함하는 중간엽 줄기세포의 혈관내피세포로의 분화 유도용 조성물 및 화학식 2의 화합물을 중간엽 줄기세포에 처리하는 것을 포함하는 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법을 제공한다:In another aspect, the present invention, the composition for inducing differentiation of mesenchymal stem cells into vascular endothelial cells comprising a compound of formula (2) and mesenchymal stem cells comprising treating the compound of formula (2) to mesenchymal stem cells To induce differentiation into vascular endothelial cells:
[화학식 2][Formula 2]
상기 식에서,Where
X는 탄소, 산소 또는 질소 원자이고, 여기서, X가 산소 원자일 때 R1은 존재하지 않으며,X is a carbon, oxygen or nitrogen atom, where R 1 is absent when X is an oxygen atom,
R1은 수소 또는 탄소수 1 내지 6의 알킬기이고, R 1 is hydrogen or an alkyl group having 1 to 6 carbon atoms,
R2는 수소, 니트로기, 아세틸기 또는 아미노기이고,R 2 is hydrogen, nitro group, acetyl group or amino group,
R3는 수소; 하이드록시기; 탄소수 1 내지 6의 알콕시기; 니트로기; 아세트아미드기; 또는 할로겐, 페닐 또는 피라졸일로 치환되거나 비치환된 벤즈아미드기이며,R 3 is hydrogen; Hydroxyl group; An alkoxy group having 1 to 6 carbon atoms; A nitro group; Acetamide group; Or a benzamide group substituted or unsubstituted with halogen, phenyl or pyrazolyl,
R4는 수소; 하이드록시기로 치환된 탄소수 1 내지 6의 알킬; 아세틸기; 할로겐; 니트로기; 아미노기; 할로겐으로 치환되거나 비치환된 아세트아미드기; 피코린아미드기; 티오펜카복스아미드기; 카르복실기; 또는 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 알콕시, 할로겐, 니트로, 페닐, 피라졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고, R 4 is hydrogen; Alkyl having 1 to 6 carbon atoms substituted with a hydroxy group; Acetyl group; halogen; A nitro group; An amino group; An acetamide group unsubstituted or substituted with halogen; Picolinamide groups; Thiophene carboxamide group; Carboxyl groups; Or a benzamide group unsubstituted or substituted with alkyl having 1 to 6 carbon atoms, alkoxy, halogen, nitro, phenyl, pyrazolyl or thiazolyl having 1 to 6 carbon atoms,
R5는 수소; 하이드록시기; 아미노기; 아세틸기; 피페리딘일로 치환된 탄소수 1 내지 6의 알킬; 할로겐 또는 피라졸일로 치환되거나 비치환된 니코틴아미드기; 또는 탄소수 1 내 6의 알킬, 피페라진일, 피페리딘일, 이미다졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고, R 5 is hydrogen; Hydroxyl group; An amino group; Acetyl group; Alkyl of 1 to 6 carbon atoms substituted with piperidinyl; Nicotinamide groups unsubstituted or substituted with halogen or pyrazolyl; Or a benzamide group unsubstituted or substituted with alkyl, piperazinyl, piperidinyl, imidazoyl or thiazolyl having 1 to 6 carbon atoms,
R6은 수소 또는 하이드록시기이며, R 6 is hydrogen or a hydroxyl group,
m은 0 내지 3의 정수를 나타낸다.m represents the integer of 0-3.
한 구체예에서, 화학식 2의 화합물은 X는 산소 또는 질소 원자이고,In one embodiment, the compound of formula 2 is X is oxygen or nitrogen atom,
R1은 탄소수 1 내지 6의 알킬기이고, R 1 is an alkyl group having 1 to 6 carbon atoms,
R2는 수소 또는 아세틸기이며,R 2 is hydrogen or an acetyl group,
R3는 수소이고,R < 3 > is hydrogen,
R4는 아세틸기, 니트로기, 아미노기, 아세트아미드기, 페닐로 치환된 벤즈아미드기 또는 탄소수 1 내지 6의 알콕시로 치환된 벤즈아미드기이며,R 4 is an acetyl group, a nitro group, an amino group, an acetamide group, a benzamide group substituted with phenyl or a benzamide group substituted with alkoxy having 1 to 6 carbon atoms,
R5는 아미노기, 하이드록시기, 아세틸기, 티아졸일로 치환된 벤즈아미드기이고,R 5 is a benzamide group substituted with an amino group, a hydroxyl group, an acetyl group, thiazolyl,
R6은 수소이며, R 6 is hydrogen,
m은 1 내지 3의 정수를 나타내는 화합물일 수 있다.m may be a compound representing an integer of 1 to 3.
또 다른 구체예에서, 화학식 2의 화합물은 In another embodiment, Compound of Formula 2 is
1-(4-몰포리노페닐)에탄온(1-(4-morpholinophenyl)ethanone), 3-몰포리노아닐린(3-morpholinoaniline), 5-몰포리노-2-니트로페놀(5-morpholino-2-nitrophenol), 1-(2-아미노-5-몰포리노페닐)에탄온(1-(2-amino-5-morpholinophenyl)ethanone), N-(2-아세틸-4-몰포리노페닐)아세트아미드(N-(2-acetyl-4-morpholinophenyl)acetamide), N-(2-아세틸-4-몰포리노페닐)비페닐-4-카복스아미드(N-(2-acetyl-4-morpholinophenyl)biphenyl-4-carboxamide), N-(2-아세틸-4-몰포리노페닐)-4-메톡시벤즈아미드(N-(2-acetyl-4-morpholinophenyl)-4-methoxybenzamide), 1-(5-아미노-2-(4-메틸피페라진-1-일)페닐)에탄온(1-(5-amino-2-(4-methylpiperazin-1-yl)phenyl)ethanone) 또는 N-(3-몰포리노페닐)-4-(티아졸-4-일)벤즈아미드(N-(3-morpholinophenyl)-4-(thiazol-4-yl)benzamide)일 수 있다.1- (4-morpholinophenyl) ethanone (1- (4-morpholinophenyl) ethanone), 3-morpholinoaniline, 5-morpholino-2-nitrophenol ), 1- (2-amino-5-morpholinophenyl) ethanone (1- (2-amino-5-morpholinophenyl) ethanone), N- (2-acetyl-4-morpholinophenyl) acetamide (N- (2-acetyl-4-morpholinophenyl) acetamide), N- (2-acetyl-4-morpholinophenyl) biphenyl-4-carboxamide (N- (2-acetyl-4-morpholinophenyl) biphenyl-4-carboxamide ), N- (2-acetyl-4-morpholinophenyl) -4-methoxybenzamide, N- (2-acetyl-4-morpholinophenyl) -4-methoxybenzamide, 1- (5-amino-2- ( 4-methylpiperazin-1-yl) phenyl) ethanone (1- (5-amino-2- (4-methylpiperazin-1-yl) phenyl) ethanone) or N- (3-morpholinophenyl) -4- (Thiazol-4-yl) benzamide (N- (3-morpholinophenyl) -4- (thiazol-4-yl) benzamide).
상기 화학식 2의 화합물의 약제학적으로 허용 가능한 염은 유기산 또는 무기산을 이용하여 형성된 산 부가염일 수 있으며, 상기 유기산은, 예를 들면 포름산, 아세트산, 프로피온산, 락트산, 부티르산, 이소부티르산, 트리플루오로아세트산, 말산, 말레산, 말론산, 푸마르산, 숙신산, 숙신산 모노아미드, 글루탐산, 타르타르산, 옥살산, 시트르산, 글리콜산, 글루쿠론산, 아스코르브산, 벤조산, 프탈산, 살리실산, 안트라닐산, 디클로로아세트산, 아미노옥시 아세트산, 벤젠술폰산, p-톨루엔술폰산 및 메탄술폰산계 염을 포함하며 무기산은 예를 들면 염산, 브롬산, 황산, 인산, 질산, 탄산 및 붕산계 염을 포함한다. 바람직하게는 염산염 또는 아세트산염 형태일 수 있으며, 보다 바람직하게는 염산염 형태일 수 있다.The pharmaceutically acceptable salt of the compound of Formula 2 may be an acid addition salt formed using an organic acid or an inorganic acid, and the organic acid may be, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid or trifluoroacetic acid. , Malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid And benzenesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid salts and inorganic acids include, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid salts. Preferably in the hydrochloride or acetate form, more preferably in the hydrochloride form.
상기 언급된 산 부가염은 a) 상기 화학식 2의 화합물 및 산을 직접 혼합하거나, b) 이들 중 한 가지를 용매 또는 함수 용매 중에 용해시키고 혼합시키거나, 또는 c) 화학식 2의 화합물을 용매 또는 수하 용매 중의 산에 위치시키고 이들을 혼합하는 일반적인 염 제조방법으로 제조된다.The above-mentioned acid addition salts can be a) directly mixed with a compound of formula (2) and an acid, or b) dissolving and mixing one of them in a solvent or a hydrous solvent, or c) solvent or under water with a compound of formula (2). It is prepared by a general salt preparation method which is placed in an acid in a solvent and mixed with them.
위와는 별도로 추가적으로 염이 가능한 형태는 가바염, 가바펜틴염, 프레가발린염, 니코틴산염, 아디페이트염, 헤미말론산염, 시스테인염, 아세틸시스테인염, 메티오닌염, 아르기닌염, 라이신염, 오르니틴염, 아스파르트산염 등이 있다. In addition to the above, additionally saltable forms include, but are not limited to, the salts of gabapentin, pregabalin, nicotinate, adipate, hemimarate, cysteine, acetylcysteine, methionine, arginine, Aspartate and the like.
또한, 본 발명에 있어서 혈관내피세포로의 분화 유도를 위해 사용되는 중간엽 줄기세포의 종류 또한 특별히 제한되지 않는다. 본 발명에서 사용되는 중배엽 줄기세포는 그것이 어디로부터 유래한 것인지 관계없이 이용될 수 있다. 중간엽 줄기세포는 공지의 중간엽 줄기세포 공급원, 예를 들어 골수, 조직, 배아, 제대혈, 혈액 또는 체액으로부터 얻을 수 있다. 골수, 조직 등의 채취 대상인 동물은 포유동물일 수 있다. 상기 동물이 인간일 경우 골수, 조직 등은 본 발명의 조성물의 처리에 의해 혈관내피세포로의 분화가 유도된 중배엽 줄기세포를 세포치료제로서 투여하게 될 환자 자신의 것이나 타인 유래의 것일 수 있다. 이러한 공지의 중간엽 줄기세포 공급원으로부터 중간엽 줄기세포를 수득하는 방법에 대해서는 당업계에 잘 알려져 있다.In addition, the type of mesenchymal stem cells used for inducing differentiation into vascular endothelial cells in the present invention is also not particularly limited. Mesodermal stem cells used in the present invention can be used regardless of where they are derived from. Mesenchymal stem cells can be obtained from known mesenchymal stem cell sources, for example bone marrow, tissue, embryo, umbilical cord blood, blood or body fluids. Animals to be harvested, such as bone marrow and tissue may be mammals. When the animal is a human, bone marrow, tissue, or the like may be from a patient's own or other person to be administered as a cell therapy the mesoderm stem cells induced differentiation into vascular endothelial cells by treatment of the composition of the present invention. Methods for obtaining mesenchymal stem cells from such known mesenchymal stem cell sources are well known in the art.
한편, 중간엽 줄기세포에 대해 화학식 2의 화합물을 처리하는 방법은 특별히 제한되지 않는다. 일정 시간 동안 화학식 2의 화합물과 중간엽 줄기세포를 접촉시켜 중간엽 줄기세포가 혈관내피세포로 분화 유도될 수 있기만 하면 된다. On the other hand, the method of treating the compound of Formula 2 for mesenchymal stem cells is not particularly limited. The mesenchymal stem cells may be differentiated into vascular endothelial cells by contacting the compound of Formula 2 with the mesenchymal stem cells for a certain time.
한 구체예에서, 화학식 2의 화합물의 처리는 중간엽 줄기세포를 화학식 2의 화합물을 포함하는 배지에서 배양함으로써 수행할 수 있다. In one embodiment, the treatment of the compound of Formula 2 may be carried out by culturing the mesenchymal stem cells in a medium comprising the compound of Formula 2.
중간엽 줄기세포에 처리되는 화학식 2의 화합물의 농도는 구체적인 화학식 2의 화합물의 종류나 중간엽 줄기세포에 처리되는 기간, 또는 혈관내피세포로의 분화 요구 정도 등에 따라 달라질 수 있을 것이다. 한 구체예에서, 화학식 2의 화합물의 농도는 0.01 내지 100 μM의 범위에서 사용될 수 있다. The concentration of the compound of formula (2) to be treated in the mesenchymal stem cells may vary depending on the type of compound of formula (2), the duration of treatment to the mesenchymal stem cells, or the degree of differentiation into vascular endothelial cells. In one embodiment, the concentration of the compound of Formula 2 can be used in the range of 0.01 to 100 [mu] M.
중간엽 줄기세포의 분화 유도에 일반적으로 요구되는 시간을 고려할 때, 화학식 2의 화합물을 포함하는 배지에서의 배양은 5일 내지 15일 동안 수행될 수 있으나, 이에 제한되는 것은 아니다. 중간엽 줄기세포에 대한 화학식 2의 화합물의 처리의 기간은 처리되는 화학식 2의 화합물의 종류 또는 농도에 따라 달라질 수 있을 것이다.Considering the time generally required for inducing differentiation of mesenchymal stem cells, the culture in a medium containing the compound of Formula 2 may be performed for 5 to 15 days, but is not limited thereto. The duration of treatment of the compound of formula 2 with mesenchymal stem cells may vary depending on the type or concentration of the compound of formula 2 being treated.
본 발명에 있어서 "혈관내피세포"는 중간엽 줄기세포로부터 분화 유도된 혈관내피세포 또는 혈관내피세포로의 분화 과정에 있는 세포를 모두 포함한다. 본 명세서에 있어서, "혈관내피세포", "혈관내피-유사 세포" 및 "내피-유사 세포"는 상호교환적으로 사용된다. 본 발명에 있어서, 화학식 2의 화합물의 처리에 의해 중간엽 줄기세포로부터 분화 유도된 혈관내피세포는 혈관내피세포와 관련된 특이적 마커의 발현을 나타낸다. 본 발명의 방법에 따라 수득한 혈관내피세포는 이러한 특이적 마커의 발현이 중간엽 줄기세포에 비해 증가되어 있는 것일 수 있다. 상기 특이적 마커는 이에 제한되는 것은 아니나, CD31일 수 있다. In the present invention, "vascular endothelial cells" include all the cells that undergo differentiation into vascular endothelial cells or vascular endothelial cells derived from differentiation from mesenchymal stem cells. In this specification, "vascular endothelial cells", "vascular endothelial-like cells" and "endothelial-like cells" are used interchangeably. In the present invention, vascular endothelial cells induced differentiation from mesenchymal stem cells by treatment of the compound of formula (2) show expression of specific markers related to vascular endothelial cells. Vascular endothelial cells obtained according to the method of the present invention may be that the expression of these specific markers is increased compared to mesenchymal stem cells. The specific marker may be CD31, but is not limited thereto.
본 발명은 또한 화학식 2의 화합물을 포함하는 중간엽 줄기세포의 혈관내피세포로의 분화 유도용 조성물을 제공한다. 화학식 2의 화합물 및 화학식 2의 화합물의 구체예는 앞서 설명한 바와 같다. 상기 조성물은 중배엽 줄기세포의 배양시 일반적으로 사용되는 배지를 포함할 수 있다. 이에 제한되는 것은 아니나, 이러한 배지로는 예컨대, MEM-alpha (Minimum Essential Medium alpha), MSCGM(Mesenchymal Stem Cell Growth Medium), DMEM (Dulbecco's Modified Eagle's Medium) 등이 포함될 수 있다. 다르게는, 화학식 2의 화합물을 포함하는 중간엽 줄기세포의 혈관내피세포로의 분화 유도용 조성물은 중간엽 줄기세포와는 별도로 체내에 도입될 수도 있을 것이다. 즉, 중간엽 줄기세포의 투여 전이나 후, 또는 중간엽 줄기세포의 투여와 동시에 화학식 2의 화합물을 포함하는 조성물이 별도로 투여될 수도 있다. 이 경우 상기 조성물은 화학식 2의 화합물의 투여에 적합한 공지의 약제학적 담체를 포함할 수 있다. The present invention also provides a composition for inducing differentiation of mesenchymal stem cells into vascular endothelial cells comprising the compound of formula (2). Specific examples of the compound of Formula 2 and the compound of Formula 2 are as described above. The composition may include a medium generally used in the culture of mesoderm stem cells. Although not limited thereto, such a medium may include, for example, Minimum Essential Medium alpha (MEM-alpha), Mesenchymal Stem Cell Growth Medium (MSCGM), Dulbecco's Modified Eagle's Medium (DMEM), and the like. Alternatively, the composition for inducing differentiation of mesenchymal stem cells into vascular endothelial cells comprising the compound of Formula 2 may be introduced into the body separately from the mesenchymal stem cells. That is, a composition comprising the compound of formula 2 may be administered separately before or after the mesenchymal stem cells or simultaneously with the mesenchymal stem cells. In this case the composition may comprise a known pharmaceutical carrier suitable for administration of the compound of formula (2).
또한 본 발명은 상기 방법에 의해 중간엽 줄기세포로부터 분화 유도된 혈관내피세포를 포함하는 혈관질환 치료용 의약 조성물을 제공한다. 이러한 혈관질환 치료용 의약 조성물은 이제 제한되는 것은 아니나, 풍선확장술 등에 의한 혈관내피세포 손상 등의 치료를 위해 유용하게 사용될 수 있다. 상기 의약 조성물은 줄기세포의 이식을 위해 당업계에서 사용되고 있는 공지의 담체를 추가로 포함할 수 있다. 또한, 상기 혈관내피세포의 유효량은 1×104 내지 1×108 세포/㎏일 수 있다. 그러나, 이들의 용량은 환자의 체중, 연령, 성별, 병변의 정도에 따라 적의 증감될 수 있다. 본 발명에 따른 제제는 비경구 또는 국소투여에 의해 인체에 적용될 수 있다. 이러한 목적을 위해, 유효성분을 통상의 방법에 따라 약제학적으로 허용가능한 담체에 현탁시키거나 용해시키는데, 이때 수용성 담체를 사용하는 것이 바람직하다.The present invention also provides a pharmaceutical composition for treating vascular diseases comprising vascular endothelial cells induced differentiation from mesenchymal stem cells by the above method. The pharmaceutical composition for treating such vascular diseases is not limited, but may be usefully used for the treatment of vascular endothelial cell damage by balloon dilatation or the like. The pharmaceutical composition may further include a known carrier used in the art for transplantation of stem cells. In addition, the effective amount of the vascular endothelial cells may be 1 × 10 4 to 1 × 10 8 cells / kg. However, their dose may be increased or decreased depending on the weight, age, sex, and extent of the lesion of the patient. The preparations according to the invention can be applied to the human body by parenteral or topical administration. For this purpose, the active ingredient is suspended or dissolved in a pharmaceutically acceptable carrier according to conventional methods, wherein a water soluble carrier is preferably used.
본 발명은 또한 상기 화학식 2의 화합물 및 이의 제조방법을 제공한다. 화학식 2의 화합물의 정의는 상기 기술한 바와 같으며, 예시적인 제조방법은 하기 실시예에 기술되어 있다.
The present invention also provides a compound of Formula 2 and a method for preparing the same. The definition of the compound of formula 2 is as described above, and exemplary methods of preparation are described in the Examples below.
본 발명의 아마이드 유도체로 처리된 중간엽 줄기세포는 혈관내피세포로 특이적으로 분화 유도되므로 이를 이용하면 풍선확장술 등에 의한 혈관내피세포 손상과 같은 혈관질환을 효과적으로 치료할 수 있게 된다.
Since the mesenchymal stem cells treated with the amide derivatives of the present invention are specifically induced to differentiate into vascular endothelial cells, it is possible to effectively treat vascular diseases such as vascular endothelial cell damage caused by balloon dilation.
도 1은 본 발명의 화합물에 의해 중간엽 줄기세포에서 내피세포로 분화된 세포에서 capillary-like tube 형성 여부를 확인한 결과이다.
도 2는 본 발명의 화합물에 의해 중간엽 줄기세포에서 내피세포로 분화된 세포에서 cell-migration를 확인한 결과이다.
도 3 내지 6은 동물실험계에서 본 발명의 화합물에 의한 재내피세포화 실험 결과를 나타낸 것으로, 창상의 단면적 변화(도 3), 조직병리학적 관찰 결과(도 4 및 5) 및 창상 부위에서의 관련 인자 변화(도 6)이다.1 is a result confirming the formation of capillary-like tube in cells differentiated into endothelial cells from mesenchymal stem cells by the compound of the present invention.
Figure 2 is a result of confirming the cell-migration in cells differentiated into endothelial cells from mesenchymal stem cells by the compound of the present invention.
Figures 3 to 6 show the results of re-endothelialization experiments with the compounds of the present invention in the animal test system, the cross-sectional area of the wound (Fig. 3), histopathological observations (Figs. 4 and 5) and related in the wound site Factor change (FIG. 6).
본 발명의 이점 및 특징, 그리고 그것들을 달성하는 방법은 상세하게 후술되어 있는 실시예들을 참조하면 명확해질 것이다. 그러나 본 발명은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 것이며, 단지 본 실시예들은 본 발명의 개시가 완전하도록 하고, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다.
Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the technical field to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.
[[ 실시예Example ] ]
실시예Example 1 : N-(2-아세틸-4- 1: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )) 아세트아미드Acetamide (N-(2-(N- (2- acetylacetyl -4-morpholinophenyl)acetamide)( -4-morpholinophenyl) acetamide) ( CYDCYD 02-02)의 제조 02-02)
[화학식 1-1][Formula 1-1]
아세틸 클로라이드 화합물(0.01ml, 0.136mmol)의 무수 디클로로메탄 0.1M 용액에 1-(2-아미노-5-몰포리노페닐)에탄온(30mg, 0.136mmol), 4-(디메틸아미노)피리딘(1.66mg, 0.014mmol), 트리에틸아민(0.028ml, 0.204mmol)을 교반상태에서 주입한 후 실온에서 4시간 교반하였다. 생성 혼합물을 에틸아세테이트로 희석하고 물로 세척하여 준 뒤, 유기층을 무수 황산마그네슘으로 건조하고 에틸아세테이트로 여과한 다음 감압농축하였다. 얻어진 일차 화합물을 실리카켈 컬럼크로마토그래피 방법(용출제: 헥산:에틸아세테이트=7:3)으로 정제하여 목적화합물을 51.4%의 수율 (18mg)로 얻었다. 1- (2-amino-5-morpholinophenyl) ethanone (30 mg, 0.136 mmol), 4- (dimethylamino) pyridine (1.66 mg) in 0.1 M anhydrous dichloromethane 0.1 M solution of acetyl chloride compound (0.01 ml, 0.136 mmol) , 0.014 mmol) and triethylamine (0.028 ml, 0.204 mmol) were injected under stirring, followed by stirring at room temperature for 4 hours. The resulting mixture was diluted with ethyl acetate and washed with water, and then the organic layer was dried over anhydrous magnesium sulfate, filtered with ethyl acetate and concentrated under reduced pressure. The obtained primary compound was purified by silica gel column chromatography method (eluent: hexane: ethyl acetate = 7: 3) to obtain the target compound in 51.4% yield (18 mg).
1H NMR (400MHz, DMSO-d 6) δ 8.22 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.21 (dd, J A = 7.6 Hz, J B = 3.2 Hz, 1H), 3.86-3.83 (m, 4H), 3.18-3.15 (m, 4H), 2.64 (s, 3H), 2.15 (s, 3H). * NH peak was not observed.
1 H NMR (400 MHz, DMSO- d 6 ) δ 8.22 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.21 (dd, J A = 7.6 Hz, J B = 3.2 Hz, 1H), 3.86-3.83 (m, 4H), 3.18-3.15 (m, 4H), 2.64 (s, 3H), 2.15 (s, 3H). N H peak was not observed.
실시예Example 2 내지 44 2 to 44
상기 실시예 1에 기재된 제조방법과 유사한 제조방법으로, 실시예 2~44의 화합물을 제조하였다. 제조된 화합물들의 화학구조 및 물성치는 다음과 같다.
In a similar manner to the preparation method described in Example 1, the compounds of Examples 2 to 44 were prepared. Chemical structures and physical properties of the prepared compounds are as follows.
실시예Example 2: 1-(4- 2: 1- (4- 몰포리노페닐Morpholinophenyl )) 에탄온Ethanone (1-(4-(1- (4- morpholinophenylmorpholinophenyl )) ethanoneethanone )() ( CYDCYD -01-01)-01-01)
[화학식 1-a][Chemical Formula 1-a]
실시예Example 3: 3- 3: 3- 몰포리노페놀Morpholinophenol (3-(3- morpholinophenolmorpholinophenol )() ( CYDCYD -01-02)-01-02)
[화학식 1-b][Chemical Formula 1-b]
실시예Example 4: 3- 4: 3- 몰포리노아닐린Morpholinoaniline (3-(3- morpholinoanilinemorpholinoaniline )( ) ( CYDCYD -01-03)-01-03)
[화학식 1-c][Chemical Formula 1-c]
실시예Example 5: 5- 5: 5- 몰포리노Morpholino -2-니트로페놀(5-2-nitrophenol (5- morpholinomorpholino -2--2- nitrophenolnitrophenol )() ( CYDCYD -01-04)-01-04)
[화학식 1-d][Formula 1-d]
실시예Example 6: 3-(피페라진-1-일)페놀(3-( 6: 3- (piperazin-1-yl) phenol (3- ( piperazinpiperazin -1--One- ylyl )) phenolphenol )() ( CYDCYD -01-05)-01-05)
[화학식 1-e][Formula 1-e]
실시예Example 7: 1-(2-아미노-5- 7: 1- (2-amino-5- 몰포리노페닐Morpholinophenyl )) 에탄온Ethanone (1-(2-(1- (2- aminoamino -5--5- morpholinophenylmorpholinophenyl )) ethanoneethanone )) (( CYDCYD -02-01)-02-01)
[화학식 1-f][Formula 1-f]
실시예Example 8: N-(2-아세틸-4- 8: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-2,2,2-트리플루오로아세트마이드(N-(2-) -2,2,2-trifluoroacetamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-2,2,2-) -2,2,2- trifluoroacetamidetrifluoroacetamide )() ( CYDCYD -02-03)-02-03)
[화학식 1-6][Chemical Formula 1-6]
1H NMR (400 MHz, CD3OD) δ 8.39 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.28 (dd, JA = 9.2 Hz, JB = 2.8 Hz, 1H), 3.87-3.84 (m, 4H), 3.23-3.21 (m, 4H), 2.70 (3H, s). * NH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 8.39 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.28 (dd, JA = 9.2 Hz, JB = 2.8 Hz, 1H), 3.87-3.84 (m, 4H), 3.23-3.21 (m, 4H), 2.70 (3H, s). NH peak was not observed.
실시예Example 9: N-(2-아세틸-4- 9: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-니트로벤즈아미드(N-(2-) -4-nitrobenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-)-4- nitrobenzamidenitrobenzamide )() ( CYDCYD -02-04)-02-04)
[화학식 1-7] [Chemical Formula 1-7]
1H NMR (400 MHz, CD3OD) δ 8.63-8.61 (m, 1H), 8.43-8.41 (m, 2H), 8.23-8.20 (m, 2H), 7.60 (s, 1H), 7.33-7.31 (m, 1H), 3.87 (brs, 4H), 3.22 (brs, 4H), 2.73 (s, 3H). * NH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 8.63-8.61 (m, 1H), 8.43-8.41 (m, 2H), 8.23-8.20 (m, 2H), 7.60 (s, 1H), 7.33-7.31 (m, 1H ), 3.87 (brs, 4H), 3.22 (brs, 4H), 2.73 (s, 3H). NH peak was not observed.
실시예Example 10: N-(2-아세틸-4- 10: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )비페닐-4-카복스아미드(N-(2-Biphenyl-4-carboxamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )) biphenylbiphenyl -4--4- carboxamidecarboxamide )() ( CYDCYD -02-05)-02-05)
[화학식 1-2][Formula 1-2]
1H NMR (400 MHz, CDCl3) δ 8.94-8.92 (m, 1H), 8.14-8.12 (m, 2H), 7.75-7.73 (m, 2H), 7.67-7.64 (m, 2H), 7.52-7.39 (m, 5H), 3.93-3.90 (m, 4H), 3.20-3.17 (m, 4H), 2.73 (s, 3H). * NH peak was not observed
1 H NMR (400 MHz, CDCl 3) δ 8.94-8.92 (m, 1H), 8.14-8.12 (m, 2H), 7.75-7.73 (m, 2H), 7.67-7.64 (m, 2H), 7.52-7.39 (m , 5H), 3.93-3.90 (m, 4H), 3.20-3.17 (m, 4H), 2.73 (s, 3H). NH peak was not observed
실시예Example 11: N-(2-아세틸-4- 11: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )) 벤즈아미드Benzamide (N-(2-(N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )) benzamidebenzamide )() ( CYDCYD -02-06)-02-06)
[화학식 1-8][Chemical Formula 1-8]
1H NMR (400 MHz, CD3OD) δ 8.66-8.64 (m, 1H), 8.01-7.98 (m, 2H), 7.63-7.53 (m, 4H), 7.33-7.30 (m, 1H), 3.88-3.86 (m, 4H), 3.22-3.19 (m, 4H), 2.73 (s, 3H). * NH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 8.66-8.64 (m, 1H), 8.01-7.98 (m, 2H), 7.63-7.53 (m, 4H), 7.33-7.30 (m, 1H), 3.88-3.86 (m , 4H), 3.22-3.19 (m, 4H), 2.73 (s, 3H). NH peak was not observed.
실시예Example 12: N-(2-아세틸-4- 12: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-메틸벤즈아미드(N-(2-) -4-methylbenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-)-4- methylbenzamidemethylbenzamide )() ( CYDCYD -02-07)-02-07)
[화학식 1-9][Chemical Formula 1-9]
1H NMR (400 MHz, CD3OD) δ 8.65-8.63 (m, 1H), 7.89-7.88 (m, 2H), 7.58-7.57 (m, 1H), 7.38-7.36 (m, 2H), 7.32-7.29 (m, 1H), 3.88-3.85 (m, 4H), 3.21-3.19 (m, 4H), 2.72 (s, 3H), 2.44 (s, 3H). * NH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 8.65-8.63 (m, 1H), 7.89-7.88 (m, 2H), 7.58-7.57 (m, 1H), 7.38-7.36 (m, 2H), 7.32-7.29 (m , 1H), 3.88-3.85 (m, 4H), 3.21-3.19 (m, 4H), 2.72 (s, 3H), 2.44 (s, 3H). NH peak was not observed.
실시예Example 13: N-(2-아세틸-4- 13: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-메톡시벤즈아미드(N-(2-) -4-methoxybenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-)-4- methoxybenzamidemethoxybenzamide )() ( CYDCYD -02-08)-02-08)
[화학식 1-3][Formula 1-3]
1H NMR (400 MHz, CDCl3) δ 12.3 (s, 1H), 8.90-8.88 (m, 1H), 8.04-8.01 (m, 2H), 7.42-7.41 (m, 1H), 7.23-7.22 (m, 1H), 7.03-6.99 (m, 2H), 3.92-3.89 (m, 4H), 3.88 (s, 3H), 3.18-3.16 (m, 4H), 2.71 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 12.3 (s, 1H), 8.90-8.88 (m, 1H), 8.04-8.01 (m, 2H), 7.42-7.41 (m, 1H), 7.23-7.22 (m, 1H ), 7.03-6.99 (m, 2H), 3.92-3.89 (m, 4H), 3.88 (s, 3H), 3.18-3.16 (m, 4H), 2.71 (s, 3H).
실시예Example 14: N-(2-아세틸-4- 14: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-브로모벤즈아미드(N-(2-) -4-bromobenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-)-4- bromobenzamidebromobenzamide )() ( CYDCYD -02-09)-02-09)
[화학식 1-10][Formula 1-10]
1H NMR (400 MHz, CD3OD) δ 8.61-8.59 (m, 1H), 7.92-7.89 (m, 2H), 7.74-7.72 (m, 2H), 7.58-7.57 (m, 1H), 7.32-7.29 (m, 1H), 3.88-3.85 (m, 4H), 3.22-3.19 (m, 4H), 2.72 (s, 3H). * NH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 8.61-8.59 (m, 1H), 7.92-7.89 (m, 2H), 7.74-7.72 (m, 2H), 7.58-7.57 (m, 1H), 7.32-7.29 (m , 1H), 3.88-3.85 (m, 4H), 3.22-3.19 (m, 4H), 2.72 (s, 3H). NH peak was not observed.
실시예Example 15: N-(2-아세틸-4- 15: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-피코린아미드(N-(2-)-Picolinamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )) picolinamidepicolinamide )() ( CYDCYD -02-10)-02-10)
[화학식 1-11][Formula 1-11]
1H NMR (400 MHz, CD3OD) δ 8.76-8.74 (m, 2H), 8.20-8.18 (m, 1H), 8.02-7.98 (m, 1H), 7.61-7.57 (m, 2H), 7.32-7.29 (m, 1H), 3.88-3.85 (m, 4H), 3.22-3.19 (m, 4H), 2.72 (s, 3H). * NH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 8.76-8.74 (m, 2H), 8.20-8.18 (m, 1H), 8.02-7.98 (m, 1H), 7.61-7.57 (m, 2H), 7.32-7.29 (m , 1H), 3.88-3.85 (m, 4H), 3.22-3.19 (m, 4H), 2.72 (s, 3H). NH peak was not observed.
실시예Example 16: N-(2-아세틸-4- 16: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )티오펜-2-카복스아미드(N-(2-) Thiophene-2-carboxamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )) thiophenethiophene -2--2- carboxamidecarboxamide )() ( CYDCYD -02-11)-02-11)
[화학식 1-12][Formula 1-12]
1H NMR (400 MHz, CDCl3) δ 12.4 (s, 1H), 8.81-8.79 (m, 1H), 7.80-7.79 (m, 1H), 7.56-7.55 (m, 1H), 7.42-7.41 (m, 1H), 7.24-7.21 (m, 1H), 7.16-7.14 (m, 1H), 3.92-3.89 (m, 4H), 3.18-3.16 (m, 4H), 2.71 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 12.4 (s, 1H), 8.81-8.79 (m, 1H), 7.80-7.79 (m, 1H), 7.56-7.55 (m, 1H), 7.42-7.41 (m, 1H ), 7.24-7.21 (m, 1H), 7.16-7.14 (m, 1H), 3.92-3.89 (m, 4H), 3.18-3.16 (m, 4H), 2.71 (s, 3H).
실시예Example 17: N-(2-아세틸-4- 17: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-3-메톡시벤즈아미드(N-(2-) -3-methoxybenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-3-) -3- methoxybenzamidemethoxybenzamide )() ( CYDCYD -02-12)-02-12)
[화학식 1-13][Formula 1-13]
1H NMR (400 MHz, CDCl3) δ 12.4 (s, 1H), 8.90-8.88 (m, 1H), 7.62-7.61 (m, 2H), 7.43-7.40 (m, 2H), 7.24-7.21 (m, 1H), 7.14-6.99 (m, 1H), 3.92-3.90 (m, 7H), 3.19-3.17 (m, 4H), 2.71 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 12.4 (s, 1H), 8.90-8.88 (m, 1H), 7.62-7.61 (m, 2H), 7.43-7.40 (m, 2H), 7.24-7.21 (m, 1H ), 7.14-6.99 (m, 1H), 3.92-3.90 (m, 7H), 3.19-3.17 (m, 4H), 2.71 (s, 3H).
실시예Example 18: N-(2-아세틸-4- 18: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-2-메톡시벤즈아미드(N-(2-) -2-methoxybenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-2-)-2- methoxybenzamidemethoxybenzamide )() ( CYDCYD -02-13)-02-13)
[화학식 1-14][Formula 1-14]
1H NMR (400 MHz, CDCl3) δ 12.3 (s, 1H), 8.82-8.79 (m, 1H), 8.20-8.18 (m, 1H), 7.50-7.35 (m, 1H), 7.34-7.32 (m, 1H), 7.19-7.17 (m, 1H), 7.10-6.97 (m, 2H), 4.14 (s, 3H), 3.92-3.89 (m, 4H), 3.18-3.16 (m, 4H), 2.65 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 12.3 (s, 1H), 8.82-8.79 (m, 1H), 8.20-8.18 (m, 1H), 7.50-7.35 (m, 1H), 7.34-7.32 (m, 1H ), 7.19-7.17 (m, 1H), 7.10-6.97 (m, 2H), 4.14 (s, 3H), 3.92-3.89 (m, 4H), 3.18-3.16 (m, 4H), 2.65 (s, 3H ).
실시예Example 19: N-(2-아세틸-4- 19: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-3-니트로벤즈아미드(N-(2-) -3-nitrobenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-3-) -3- nitrobenzamidenitrobenzamide )() ( CYDCYD -02-14)-02-14)
[화학식 1-15][Chemical Formula 1-15]
1H NMR (400 MHz, CDCl3) δ 12.7 (s, 1H), 8.94-8.93 (m, 1H), 8.87-8.85 (m, 1H), 8.42-8.35 (m, 2H), 7.75-7.71 (m, 1H), 7.46-7.45 (m, 1H), 7.25-7.24 (m, 1H), 3.93-3.91 (m, 4H), 3.21-3.18 (m, 4H), 2.74 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 12.7 (s, 1H), 8.94-8.93 (m, 1H), 8.87-8.85 (m, 1H), 8.42-8.35 (m, 2H), 7.75-7.71 (m, 1H ), 7.46-7.45 (m, 1H), 7.25-7.24 (m, 1H), 3.93-3.91 (m, 4H), 3.21-3.18 (m, 4H), 2.74 (s, 3H).
실시예Example 20: N-(2-아세틸-4- 20: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-(1H-) -4- (1H- 피라졸Pyrazole -1-일)-1 day) 벤즈아미드Benzamide (N-(2-(N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-(1H-) -4- (1H- pyrazolpyrazol -1--One- ylyl )) benzamidebenzamide )() ( CYDCYD -02-15)-02-15)
[화학식 1-16][Formula 1-16]
1H NMR (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 2.68 (3H, s), 8.37 (d, J = 8.8 Hz, 1H), 8.06 (s, 4H), 7.83 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.31 (dd, JA = 9.6 Hz, JB = 3.2 Hz, 1H), 6.63-6.62 (m, 1H), 3.79-3.77 (m, 4H), 3.20-3.17 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 2.68 (3H, s), 8.37 (d, J = 8.8 Hz, 1H), 8.06 (s, 4H), 7.83 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.31 (dd, JA = 9.6 Hz, JB = 3.2 Hz, 1H), 6.63-6.62 (m, 1 H), 3.79-3.77 (m, 4H), 3.20-3.17 (m, 4H).
실시예Example 21: N-(2-아세틸-4- 21: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-아이도벤즈아미드(N-(2-) -4-idobenzamide (N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-)-4- iodobenzamideiodobenzamide )() ( CYDCYD -02-16)-02-16)
[화학식 1-17][Formula 1-17]
1H NMR (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 7.99-7.96 (m, 2H), 7.72-7.69 (m, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.30 (dd, JA = 9.2 Hz, JB = 3.2 Hz, 1H), 3.78-3.76 (m, 4H), 3.19-3.16 (m, 4H), 2.67 (s, 3H).
1 H NMR (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 7.99-7.96 (m, 2H), 7.72-7.69 (m, 2H), 7.48 ( d, J = 3.2 Hz, 1H), 7.30 (dd, JA = 9.2 Hz, JB = 3.2 Hz, 1H), 3.78-3.76 (m, 4H), 3.19-3.16 (m, 4H), 2.67 (s, 3H ).
실시예Example 22: N-(2-아세틸-4- 22: N- (2-acetyl-4- 몰포리노페닐Morpholinophenyl )-4-(티아졸-4-일)) -4- (thiazol-4-yl) 벤즈아미드Benzamide (N-(2-(N- (2- acetylacetyl -4--4- morpholinophenylmorpholinophenyl )-4-()-4-( thiazolthiazol -4--4- ylyl )) benzamidebenzamide )() ( CYDCYD -02-17)-02-17)
[화학식 1-18][Formula 1-18]
1H NMR (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.42-8.39 (m, 2H), 8.21-8.19 (m, 2H), 8.04-8.02 (m, 2H), 7.50 (d, J = 2.8 Hz, 1H), 7.32(dd, JA = 9.2 Hz, JB = 3.2 Hz, 1H), 3.79-3.77 (m, 4H), 3.20-3.17 (m, 4H), 2.69 (s, 3H).
1 H NMR (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.42-8.39 (m, 2H), 8.21-8.19 (m, 2H), 8.04- 8.02 (m, 2H), 7.50 (d, J = 2.8 Hz, 1H), 7.32 (dd, JA = 9.2 Hz, JB = 3.2 Hz, 1H), 3.79-3.77 (m, 4H), 3.20-3.17 (m , 4H), 2.69 (s, 3H).
실시예Example 23: N-(4- 23: N- (4- 몰포리노Morpholino -2-(1-(피페리딘-1-일)에틸)-2- (1- (piperidin-1-yl) ethyl) 페닐Phenyl )-4-(티아졸-4-일)) -4- (thiazol-4-yl) 벤즈아미드Benzamide (N-(4-(N- (4- morpholinomorpholino -2-(1-(-2- (1- ( piperidinpiperidine -1--One- ylyl )) ethylethyl )) phenylphenyl )-4-()-4-( thiazolthiazol -4--4- ylyl )) benzamidebenzamide )() ( CYDCYD -02-18)-02-18)
[화학식 1-19][Chemical Formula 1-19]
1H NMR (400 MHz, CDCl3) δ 12.5 (s, 1H), 8.93-8.91 (m, 2H), 8.15-8.07 (m, 4H), 7.68 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.25-7.23 (m, 1H), 3.93-3.90 (m, 4H), 3.19-3.17 (m, 4H), 2.73 (s, 3H), 1.33-1.25 (m, 5H), 0.89-0.83 (m, 6H).
1 H NMR (400 MHz, CDCl 3) δ 12.5 (s, 1H), 8.93-8.91 (m, 2H), 8.15-8.07 (m, 4H), 7.68 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.25-7.23 (m, 1H), 3.93-3.90 (m, 4H), 3.19-3.17 (m, 4H), 2.73 (s, 3H), 1.33-1.25 (m, 5H) , 0.89-0.83 (m, 6 H).
실시예Example 24: 1-(2- 24: 1- (2- 하이드록시Hydroxy -4-(4--4- (4- 메틸피페라진Methylpiperazine -1-일)-1 day) 페닐Phenyl )-에탄온(1-(2-) -Ethanone (1- (2- hydroxyhydroxy -4-(4--4- (4- methylpiperazinmethylpiperazin -1--One- ylyl )) phenylphenyl )) ethanoneethanone )() ( CYDCYD -03-01)-03-01)
[화학식 1-20][Chemical Formula 1-20]
1H NMR (400 MHz, CD3OD) δ 7.69-7.67 (m, 1H), 6.53-6.49 (m, 1H), 6.29-6.28 (m, 1H), 3.42-3.39 (m, 4H), 2.57-2.54 (m, 4H), 2.49 (s, 3H), 2.34 (s, 3H). * OH peak was not observed.
1 H NMR (400 MHz, CD3OD) δ 7.69-7.67 (m, 1H), 6.53-6.49 (m, 1H), 6.29-6.28 (m, 1H), 3.42-3.39 (m, 4H), 2.57-2.54 (m , 4H), 2.49 (s, 3H), 2.34 (s, 3H). * OH peak was not observed.
실시예Example 25: (4- 25: (4- 플루오로Fluoro -2--2- 하이드록시페닐Hydroxyphenyl )(4-)(4- 메틸피페라진Methylpiperazine -1-일)-1 day) 메탄온Methanone ((4-((4- fluorofluoro -2--2- hydroxyphenylhydroxyphenyl )(4-)(4- methylpiperazinmethylpiperazin -1--One- ylyl )) methanonemethanone )() ( CYDCYD -03-02)-03-02)
[화학식 1-21][Formula 1-21]
1H NMR (400 MHz, CD3OD) δ 10.2 (s, 1H), 7.25-7.23 (m, 1H), 6.73-6.70 (m, 1H), 6.60-6.55 (m, 1H), 3.76 (brs, 4H), 2.48 (brs, 4H), 2.35 (s, 3H); 19F NMR (400 MHz, CD3OD) δ105.5.
1 H NMR (400 MHz, CD3OD) δ 10.2 (s, 1H), 7.25-7.23 (m, 1H), 6.73-6.70 (m, 1H), 6.60-6.55 (m, 1H), 3.76 (brs, 4H), 2.48 (brs, 4 H), 2.35 (s, 3 H); 19 F NMR (400 MHz, CD3 OD) δ 105.5.
실시예Example 26: 1-(2- 26: 1- (2- 하이드록시Hydroxy -4-(피페리딘-1-일)-4- (piperidin-1-yl) 페닐Phenyl )) 에탄온Ethanone (1-(2-(1- (2- hydroxyhydroxy -4-(-4-( piperidinpiperidine -1--One- ylyl )) phenylphenyl )) ethanoneethanone )() ( CYDCYD -03-03)-03-03)
[화학식 1-22][Formula 1-22]
1H NMR (400 MHz, CDCl3) δ 12.8 (s, 1H), 7.55-7.52 (m, 1H), 6.41-6.39 (m, 1H), 6.28 (brs, 1H), 3.39 (brs, 4H), 2.50 (s, 3H), 1.67 (s, 6H).
1 H NMR (400 MHz, CDCl 3) δ 12.8 (s, 1H), 7.55-7.52 (m, 1H), 6.41-6.39 (m, 1H), 6.28 (brs, 1H), 3.39 (brs, 4H), 2.50 ( s, 3 H), 1.67 (s, 6 H).
실시예Example 27: 1-(2- 27: 1- (2- 메톡시Methoxy -4--4- 몰포리노페닐Morpholinophenyl )) 에탄온Ethanone (1-(2-(1- (2- methoxymethoxy -4--4- morpholinophenylmorpholinophenyl )) ethanoneethanone )() ( CYDCYD -03-04)-03-04)
[화학식 1-23][Formula 1-23]
1H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 1H), 6.51-6.49 (m, 1H), 6.37 (brs, 1H), 3.91 (s, 3H), 3.88-3.86 (m, 4H), 3.31-3.29 (m, 4H), 2.56 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 7.83-7.81 (m, 1H), 6.51-6.49 (m, 1H), 6.37 (brs, 1H), 3.91 (s, 3H), 3.88-3.86 (m, 4H), 3.31-3.29 (m, 4 H), 2.56 (s, 3 H).
실시예Example 28: 1-(4-(4- 28: 1- (4- (4- 메틸피페라진Methylpiperazine -1-일)-3--1-yl) -3- 니트로페닐Nitrophenyl )) 에탄온Ethanone (1-(4-(4-(1- (4- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-3-) -3- nitrophenylnitrophenyl )) ethanoneethanone )() ( CYDCYD -05-01)-05-01)
[화학식 1-g][Formula 1-g]
1H NMR (400 MHz, CDCl3) δ 8.37-8.36 (m, 1H), 8.04-8.02 (m, 1H), 7.11-7.09 (m, 1H), 3.25-3.23 (m, 4H), 2.60-2.57 (m, 7H), 2.37 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 8.37-8.36 (m, 1H), 8.04-8.02 (m, 1H), 7.11-7.09 (m, 1H), 3.25-3.23 (m, 4H), 2.60-2.57 (m , 7H), 2.37 (s, 3H).
실시예Example 29: 1-92-(4- 29: 1-92- (4- 메틸피페라진Methylpiperazine -1-일)-5--1-yl) -5- 니트로페닐Nitrophenyl )) 에탄온Ethanone (1-(2-(4-(1- (2- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-5-) -5- nitrophenylnitrophenyl )) ethanoneethanone )() ( CYDCYD -05-02)-05-02)
[화학식 1-24][Formula 1-24]
1H NMR (400 MHz, CDCl3) δ 8.33-8.32 (m, 1H), 8.25-8.22 (m, 1H), 7.06-7.04 (m, 1H), 3.24-3.22 (m, 4H), 2.64 (s, 3H), 2.59 (brs, 4H), 2.38 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 8.33-8.32 (m, 1H), 8.25-8.22 (m, 1H), 7.06-7.04 (m, 1H), 3.24-3.22 (m, 4H), 2.64 (s, 3H ), 2.59 (brs, 4H), 2.38 (s, 3H).
실시예Example 30: 1-(4-(4- 30: 1- (4- (4- 메틸피페라진Methylpiperazine -1-일)-2-Yl) -2- 니트로페닐Nitrophenyl )에탄올(1-(4-(4-) Ethanol (1- (4- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-2-)-2- nitrophenylnitrophenyl )) ethanolethanol )() ( CYDCYD -05-03)-05-03)
[화학식 1-25][Chemical Formula 1-25]
1H NMR (400 MHz, CDCl3) δ 7.66-7.63 (m, 1H), 7.35-7.34 (m, 1H), 7.16-7.14 (m, 1H), 5.28 (q, J = 6.4 Hz, 1H), 3.28-3.25 (m, 4H), 2.59-2.56 (m, 4H), 2.36 (s, 3H), 1.55 (s, 3H).* OH peak was not observed.
1 H NMR (400 MHz, CDCl 3) δ 7.66-7.63 (m, 1H), 7.35-7.34 (m, 1H), 7.16-7.14 (m, 1H), 5.28 (q, J = 6.4 Hz, 1H), 3.28- 3.25 (m, 4H), 2.59-2.56 (m, 4H), 2.36 (s, 3H), 1.55 (s, 3H). * OH peak was not observed.
실시예Example 31: 1-(3-아미노-4-(4- 31: 1- (3-amino-4- (4- 메틸피페라진Methylpiperazine -1-일)-1 day) 페닐Phenyl )) 에탄온Ethanone (1-(3-(1- (3- aminoamino -4-(4--4- (4- methylpiperazinmethylpiperazin -1--One- ylyl )) phenylphenyl )) ethanoneethanone )() ( CYDCYD -05-04)-05-04)
[화학식 1-26][Chemical Formula 1-26]
1H NMR (400 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.02-6.99 (m, 1H), 3.96 (brs, 2H), 3.02 (brs, 4H), 2.58 (brs, 2H), 2.54 (s, 3H), 2.38 (s, 3H). * NH2 peak was not observed.
1 H NMR (400 MHz, CDCl 3) δ 7.39-7.34 (m, 2H), 7.02-6.99 (m, 1H), 3.96 (brs, 2H), 3.02 (brs, 4H), 2.58 (brs, 2H), 2.54 ( s, 3 H), 2.38 (s, 3 H). NH2 peak was not observed.
실시예Example 32: 1-(5-아미노-2-(4- 32: 1- (5-amino-2- (4- 메틸피페라진Methylpiperazine -1-일)-1 day) 페닐Phenyl )) 에탄온Ethanone (1-(5-(1- (5- aminoamino -2-(4--2- (4- methylpiperazinmethylpiperazin -1--One- ylyl )) phenylphenyl )) ethanoneethanone )() ( CYDCYD -05-05)-05-05)
[화학식 1-4][Formula 1-4]
1H NMR (400 MHz, CDCl3) δ 7.00-6.98 (m, 1H), 6.77-6.74 (m, 2H), 3.59 (m, 2H), 2.94 (brs, 4H), 2.66 (s, 3H), 2.57 (brs, 2H), 2.37 (s, 3H).* NH2 peak was not observed.
1 H NMR (400 MHz, CDCl 3) δ 7.00-6.98 (m, 1H), 6.77-6.74 (m, 2H), 3.59 (m, 2H), 2.94 (brs, 4H), 2.66 (s, 3H), 2.57 ( brs, 2H), 2.37 (s, 3H). * NH2 peak was not observed.
실시예Example 33: N-(3- 33: N- (3- 몰포리노페닐Morpholinophenyl )) 아세트아미드Acetamide (N-(3-(N- (3- morpholinophenylmorpholinophenyl )) acetamideacetamide )() ( CYDCYD -07-01)-07-01)
[화학식 1-h][Formula 1-h]
1H-NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.22-7.21 (m, 1H), 7.14-7.10 (m, 1H), 7.02-6.99 (m, 1H), 6.64-6.62 (m, 1H), 3.74-3.72 (m, 4H), 3.05-3.03 (m, 4H), 2.01 (s, 3H, s).
1H-NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.22-7.21 (m, 1H), 7.14-7.10 (m, 1H), 7.02-6.99 (m, 1H), 6.64-6.62 ( m, 1H), 3.74-3.72 (m, 4H), 3.05-3.03 (m, 4H), 2.01 (s, 3H, s).
실시예Example 34: N-(3- 34: N- (3- 몰포리노페닐Morpholinophenyl )비페닐-4-카복스아미드(N-(3-Biphenyl-4-carboxamide (N- (3- morpholinophenylmorpholinophenyl )) biphenylbiphenyl -4--4- carboxamidecarboxamide )() ( CYDCYD -07-02)-07-02)
[화학식 1-27][Chemical Formula 1-27]
1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.06-8.04 (m, 2H), 7.85-7.83 (m, 2H), 7.78- 7.76 (m, 2H), 7.54-7.49 (m, 2H), 7.46-7.41 (m, 2H), 7.32-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.74-6.71 (m, 1H), 3.77-3.75 (m, 4H), 3.12-3.09 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.06-8.04 (m, 2H), 7.85-7.83 (m, 2H), 7.78-7.76 (m, 2H), 7.54-7.49 (m , 2H), 7.46-7.41 (m, 2H), 7.32-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.74-6.71 (m, 1H), 3.77-3.75 (m, 4H), 3.12 -3.09 (m, 4 H).
실시예Example 35: 4- 35: 4- 플로오로Floro -N-(3--N- (3- 몰포리노페닐Morpholinophenyl )) 벤즈아미드Benzamide (4-(4- fluorofluoro -N-(3--N- (3- morpholinophenylmorpholinophenyl )) benzamidebenzamide )() ( CYDCYD -07-03)-07-03)
[화학식 1-28][Chemical Formula 1-28]
1H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.05-7.99 (m, 2H), 7.41-7.34 (m, 3H), 7.27-7.25 (m, 1H), 7.21-7.17 (m, 1H), 6.73-6.71 (m, 1H), 3.76-3.74 (m, 4H), 3.10-3.08 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.05-7.99 (m, 2H), 7.41-7.34 (m, 3H), 7.27-7.25 (m, 1H), 7.21-7.17 (m , 1H), 6.73-6.71 (m, 1H), 3.76-3.74 (m, 4H), 3.10-3.08 (m, 4H).
실시예Example 36: 4- 36: 4- 브로모Bromo -N-(3--N- (3- 몰포리노페닐Morpholinophenyl )) 벤즈아미드Benzamide (4-(4- bromobromo -N-(3--N- (3- morpholinophenylmorpholinophenyl )) benzamidebenzamide )() ( CYDCYD -07-04)-07-04)
[화학식 1-29][Chemical Formula 1-29]
1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.91-7.88 (m, 2H), 7.77-7.73 (m, 2H), 7.40-7.37 (m, 1H), 7.27-7.25 (m, 1H), 7.21-7.17 (m, 1H), 6.74-6.71 (m, 1H), 3.76-3.74 (m, 4H), 3.10-3.08 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.91-7.88 (m, 2H), 7.77-7.73 (m, 2H), 7.40-7.37 (m, 1H), 7.27-7.25 (m , 1H), 7.21-7.17 (m, 1H), 6.74-6.71 (m, 1H), 3.76-3.74 (m, 4H), 3.10-3.08 (m, 4H).
실시예Example 37: 4-(4- 37: 4- (4- 메틸피페라진Methylpiperazine -1-일)-N-(3--1-yl) -N- (3- 몰포리노페닐Morpholinophenyl )) 벤즈아미드Benzamide (4-(4-(4- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-N-(3-) -N- (3- morpholinophenylmorpholinophenyl )) benzamidebenzamide )() ( CYDCYD -07-05)-07-05)
[화학식 1-30][Chemical Formula 1-30]
1H NMR (400 MHz, CDCl3) δ 7.79-7.77 (m, 2H), 7.68 (brs, 1H), 7.57-7.56 (m, 1H), 7.24-7.22 (m, 1H), 6.96-6.92 (m, 2H), 6.90 (dd, JA = 7.6 Hz, JB = 1.6 Hz, 1H), 6.68 (dd, JA = 8.4 Hz, JB = 2.4 Hz, 1H), 3.87-3.85 (s, 4H), 3.39-3.36 (s, 4H), 3.22-3.19 (s, 4H), 2.62 (s, 3H).
1 H NMR (400 MHz, CDCl 3) δ 7.79-7.77 (m, 2H), 7.68 (brs, 1H), 7.57-7.56 (m, 1H), 7.24-7.22 (m, 1H), 6.96-6.92 (m, 2H ), 6.90 (dd, JA = 7.6 Hz, JB = 1.6 Hz, 1H), 6.68 (dd, JA = 8.4 Hz, JB = 2.4 Hz, 1H), 3.87-3.85 (s, 4H), 3.39-3.36 (s , 4H), 3.22-3.19 (s, 4H), 2.62 (s, 3H).
실시예Example 38: N-(3- 38: N- (3- 몰포리노페닐Morpholinophenyl )-4-(피페리딘-1-일)) -4- (piperidin-1-yl) 벤즈아미드Benzamide (N-(3-(N- (3- morpholinophenylmorpholinophenyl )-4-()-4-( piperidinpiperidine -1--One- ylyl )) benzamidebenzamide )() ( CYDCYD -07-06)-07-06)
[화학식 1-31][Chemical Formula 1-31]
1H NMR (400 MHz, CDCl3) δ 7.78-7.74 (m, 2H), 7.67 (brs, 1H), 7.58-7.57 (m, 1H), 7.25-7.21 (m, 1H), 6.94-6.88 (m, 3H), 6.67 (dd, JA = 8.0 Hz, JB = 2.4 Hz, 1H), 3.87-3.85 (m, 4H), 3.34-3.31 (m, 4H), 3.22-3.19 (m, 4H), 1.73-1.62 (m, 6H).
1 H NMR (400 MHz, CDCl 3) δ 7.78-7.74 (m, 2H), 7.67 (brs, 1H), 7.58-7.57 (m, 1H), 7.25-7.21 (m, 1H), 6.94-6.88 (m, 3H ), 6.67 (dd, JA = 8.0 Hz, JB = 2.4 Hz, 1H), 3.87-3.85 (m, 4H), 3.34-3.31 (m, 4H), 3.22-3.19 (m, 4H), 1.73-1.62 ( m, 6H).
실시예Example 39: 6- 39: 6- 브로모Bromo -N-(3--N- (3- 몰포리노페닐Morpholinophenyl )) 니코틴아미드Nicotinamide (6-(6- bromobromo -N-(3--N- (3- morpholinophenylmorpholinophenyl )) nicotinamidenicotinamide )() ( CYDCYD -07-07)-07-07)
[화학식 1-32](1-32)
1H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.24-8.21 (m, 1H), 7.86-7.84 (m, 1H), 7.38-7.37 (m, 1H), 7.25-7.19 (m, 2H), 6.76-6.73 (m, 1H), 3.76-3.74 (m, 4H), 3.11-3.08 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.24-8.21 (m, 1H), 7.86-7.84 (m, 1H), 7.38- 7.37 (m, 1 H), 7.25-7.19 (m, 2 H), 6.76-6.73 (m, 1 H), 3.76-3.74 (m, 4H), 3.11-3.08 (m, 4H).
실시예Example 40: N-(3- 40: N- (3- 몰포리노페닐Morpholinophenyl )-4-(1H-) -4- (1H- 피라졸Pyrazole -1-일)-1 day) 벤즈아미드Benzamide (N-(3-(N- (3- morpholinophenylmorpholinophenyl )-4-(1H-) -4- (1H- pyrazolpyrazol -1--One- ylyl )) benzamidebenzamide )() ( CYDCYD -07-08)-07-08)
[화학식 1-33][Formula 1-33]
1H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.11-8.08 (m, 2H), 8.02-7.99 (m, 2H), 7.82 (d, J = 1.6 Hz, 1H), 7.43-7.42 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.73-6.71 (m, 1H), 6.62-6.61 (m, 1H), 3.77-3.75 (m, 4H), 3.11-3.09 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.11-8.08 (m, 2H), 8.02-7.99 (m, 2H), 7.82 ( d, J = 1.6 Hz, 1H), 7.43-7.42 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.73-6.71 (m, 1H), 6.62-6.61 ( m, 1H), 3.77-3.75 (m, 4H), 3.11-3.09 (m, 4H).
실시예Example 41: 4-(1H- 41: 4- (1H- 이미다졸Imidazole -1-일)-N-(3--1-yl) -N- (3- 몰포리노페닐Morpholinophenyl )) 벤즈아미드Benzamide (4-(1H-(4- (1H- imidazolimidazol -1--One- ylyl )-N-(3-) -N- (3- morpholinophenylmorpholinophenyl )) benzamidebenzamide )() ( CYDCYD -07-09)-07-09)
[화학식 1-34][Formula 1-34]
1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.43 (s, 1H), 8.12-8.08 (m, 2H), 7.91-7.85 (m, 3H), 7.44-7.43 (m, 1H), 7.30-7.28 (m, 1H), 7.23-7.16 (m, 2H), 6.74-6.72 (m, 1H), 3.77-3.75 (m, 4H), 3.11-3.09 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.43 (s, 1H), 8.12-8.08 (m, 2H), 7.91-7.85 (m, 3H), 7.44-7.43 (m, 1H ), 7.30-7.28 (m, 1H), 7.23-7.16 (m, 2H), 6.74-6.72 (m, 1H), 3.77-3.75 (m, 4H), 3.11-3.09 (m, 4H).
실시예Example 42: N-(3- 42: N- (3- 몰포리노페닐Morpholinophenyl )-4-(티아졸-4-일)) -4- (thiazol-4-yl) 벤즈아미드Benzamide (N-(3-(N- (3- morpholinophenylmorpholinophenyl )-4-()-4-( thiazolthiazol -4--4- ylyl )) benzamidebenzamide )() ( CYDCYD -07-10)-07-10)
[화학식 1-5][Formula 1-5]
1H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.72-8.71 (m, 1H), 8.51-8.49 (m, 1H), 8.07-8.05 (m, 1H), 7.92-7.91 (m, 1H), 7.42-7.41 (m, 1H), 7.28-7.20 (m, 2H), 6.76-6.74 (m, 1H), 6.65-6.64 (m, 1H), 3.77-3.75 (m, 4H), 3.12-3.09 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.72-8.71 (m, 1H), 8.51-8.49 (m, 1H), 8.07- 8.05 (m, 1H), 7.92-7.91 (m, 1H), 7.42-7.41 (m, 1H), 7.28-7.20 (m, 2H), 6.76-6.74 (m, 1H), 6.65-6.64 (m, 1H ), 3.77-3.75 (m, 4H), 3.12-3.09 (m, 4H).
실시예Example 43: N-(3- 43: N- (3- 몰포리노페닐Morpholinophenyl )-6-(1H-) -6- (1H- 피라졸Pyrazole -1-일)-1 day) 니코틴아미드Nicotinamide (N-(3-(N- (3- morpholinophenylmorpholinophenyl )-6-(1H-) -6- (1H- pyrazolpyrazol -1--One- ylyl )) nicotinamidenicotinamide )() ( CYDCYD -07-11)-07-11)
[화학식 1-35][Formula 1-35]
1H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.72-8.71 (m, 1H), 8.51-8.49 (m, 1H), 8.07-8.05 (m, 1H), 7.92-7.91 (m, 1H), 7.42-7.41 (m, 1H), 7.28-7.20 (m, 2H), 6.76-6.74 (m, 1H), 6.65-6.64 (m, 1H), 3.77-3.75 (m, 4H), 3.09 (m, 4H).
1 H NMR (400 MHz, DMSO-d6) δ 10.3 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.72-8.71 (m, 1H), 8.51-8.49 (m, 1H), 8.07- 8.05 (m, 1H), 7.92-7.91 (m, 1H), 7.42-7.41 (m, 1H), 7.28-7.20 (m, 2H), 6.76-6.74 (m, 1H), 6.65-6.64 (m, 1H ), 3.77-3.75 (m, 4H), 3.09 (m, 4H).
실시예Example 44: 44: 메틸methyl 4-(4- 4- (4- 메틸피페라진Methylpiperazine -1-일)-2-니트로벤조에이트(-1-yl) -2-nitrobenzoate ( MethylMethyl 4-(4- 4- (4- methylpiperazinmethylpiperazin -1--One- ylyl )-2-)-2- nitrobenzoatenitrobenzoate )() ( CYDCYD -08-01)-08-01)
[화학식 1-36][Formula 1-36]
1H NMR (400 MHz, DMSO-d6) δ 7.75-7.77 (m, 1H), 7.04-7.03 (m, 1H), 6.97-6.94 (m, 1H), 3.85 (s, 3H), 3.41-3.38 (m, 4H), 2.58 (m, 4H), 2.38 (s, 3H).
1 H NMR (400 MHz, DMSO-d6) δ 7.75-7.77 (m, 1H), 7.04-7.03 (m, 1H), 6.97-6.94 (m, 1H), 3.85 (s, 3H), 3.41-3.38 (m , 4H), 2.58 (m, 4H), 2.38 (s, 3H).
실험예Experimental Example 1: One: 실시예Example 화합물에 의한 By compound 중간엽Intermediate lobe 줄기세포의 내피 세포로의 분화 확인 Confirmation of Differentiation of Stem Cells into Endothelial Cells
골수 유래 Bone marrow 중간엽Intermediate lobe 줄기세포의 분리 및 배양 Stem Cell Isolation and Culture
10%의 소태아 혈청 (fetal bovine serum), 1%의 penicillin과 streptomycin 용액이 첨가된 Dulbecco's modified Eagle's medium(DMEM)로 구성된 배지 10ml로 4주령의 수컷 Sprague-Dawley rat(약 100g)의 대퇴골과 경골에서 골수 유래 중간엽 줄기 세포를 추출하여 수집하였다. 1.073g/ml의 percoll의 상층에 분리된 골수를 넣고 원심분리하여 경계면에서 얻은 단핵세포를 두 번 세척 후 10% FBS-DMEM에 섞어 flask에 1×106cells/100cm2로 분주한다. 배양은 37℃로 유지되고 95% air, 5% CO2가 있는 Forma Scientific 배양기에서 이루어졌다. 48-72 시간 후 비흡착성 세포들은 제거되고 흡착성 세포들은 PBS로 두 번 세척하였다. 새 배지를 첨가하고 약 10일 동안 3-4일 간격으로 배지를 갈아주면서 배양하였고, 간엽줄기세포만 얻기 위하여 isolex magnetic cell 분리 시스템을 사용하였다. 요약하면 선택된 세포는 anti-CD34 monoclonal antibody를 가진 혼합된 배양액에 배양하여 부착하지 않은 항체는 제거하고, anti-CD34 antibody인 anti-Mouse IgG로 코팅된 Dynabeads M-450을 세포 부유물에 혼합한 후 magnetic 부분은 챔버에 연결시키고 CD34+ cell-bead는 세포 혼합물의 부분으로부터 자기를 띄어 분리할 수 있게 한다. 세포는 37℃에서 5분 동안 0.25% 트립신과 1mM EDTA로 걷어드리는데 이것은 100cm의 플레이트에서 반복하고 10일 동안 다시 배양한다.
Femur and tibia of a 4 week old male Sprague-Dawley rat (approx. 100 g) consisting of 10 ml of medium consisting of 10% fetal bovine serum, Dulbecco's modified Eagle's medium (DMEM) with 1% penicillin and streptomycin solution. Bone marrow-derived mesenchymal stem cells were extracted and collected. The bone marrow isolated from the upper layer of 1.073g / ml percoll was added and centrifuged to wash mononuclear cells at the interface, and then washed twice with 10% FBS-DMEM and aliquoted into flasks at 1 × 10 6 cells / 100 cm 2 . Cultures were maintained in a Forma Scientific incubator maintained at 37 ° C and 95% air, 5% CO 2 . After 48-72 hours non-adsorbed cells were removed and the adsorbed cells were washed twice with PBS. Fresh medium was added and cultured while changing medium at intervals of 3-4 days for about 10 days, and an isolex magnetic cell separation system was used to obtain only mesenchymal stem cells. In summary, selected cells were cultured in a mixed medium containing anti-CD34 monoclonal antibody to remove non-attached antibodies, mixed with Dynabeads M-450 coated with anti-Mouse IgG anti-CD34 antibody to cell suspension, and The part connects to the chamber and the CD34 + cell-bead lifts off magnetically from the part of the cell mixture. Cells are kicked with 0.25% trypsin and 1 mM EDTA at 37 ° C. for 5 minutes, which is repeated on a 100 cm plate and incubated for 10 days.
화합물 처리에 의한 By compound treatment 중간엽Intermediate lobe 줄기세포의 엑스 비보 변형 Ex vivo transformation of stem cells
2계대에서, 중간엽 줄기세포를 60 mm 플레이트에 2×105 cells/ml로 위와 동일한 배지를 이용하여 분주하고, 실시예 1 내지 44의 화합물을 최종농도 1μM 또는 10μM로 처리하고 매 3일에 한번씩 상기 화합물을 신선한 배지로 교체하여 16일간 배양하였다.
In two passages, mesenchymal stem cells were dispensed at 60 × plates at 2 × 10 5 cells / ml using the same medium as above, and the compounds of Examples 1-44 were treated at a final concentration of 1 μM or 10 μM and every 3 days. Once, the compound was incubated for 16 days by replacing with fresh medium.
RTRT -- PCRPCR
다양한 유전자의 발현 수준은 역전사 중합효소 연쇄 반응(RT-PCR)에 의해 분석하였다. 전체 RNA를 UltraspectTM-II RNA system(Biotecx Laboratories, Inc., USA) 및 easy-BLUETM(Intron Biotechnology, Seoul, South Korea)에 의해 제조하였다. 분리된 전체 RNA로부터 Avian Myeloblastosis virus (AMV) 역전사효소(Powver cDNA Synthesis Kit, Intron Biotechnology)에 의해 단일가닥 cDNA를 합성하였다. 1㎕의 전체 RNA, 1×역전사 완충액 (10mM Tris-HCl, pH 9.0, 50mM KCl, 0.1% Triton X-100), 1mM 데옥시뉴클레오사이드 트리포스페이트(dNTPs), 0.5유닛의 RNase 저해제, 0.5㎍의 oligo(dT)15, 및 15유닛의 AMV 역전사효소를 함유하는 20㎕의 역전사 반응 혼합물을 42℃에서 15분간 인큐베이션하고, 99℃에서 5분 동안 가열한 다음, 0 내지 5℃에서 5분 동안 인큐베이션하였다. PCR은 Tap 폴리머라아제(i-MaxTM DNA polymerase, Intron Biotechnology)로 표준 절차를 이용하여 수행하였다. 94℃에서 30초 동안 변성, 58℃ 내지 65℃에서 30초 동안 어닐링, 그리고 72℃에서 30초 동안 연장하는 것으로 하여 사이클 수는 25 내지 45 사이클로 변동되었다. 사용된 프라이머는 다음과 같다.Expression levels of various genes were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR). Total RNA was prepared by Ultraspect ™ -II RNA system (Biotecx Laboratories, Inc., USA) and easy-BLUE ™ (Intron Biotechnology, Seoul, South Korea). Single-stranded cDNA was synthesized from the isolated whole RNA by Avian Myeloblastosis virus (AMV) reverse transcriptase (Powver cDNA Synthesis Kit, Intron Biotechnology). 1 μl total RNA, 1 × reverse transcript buffer (10 mM Tris-HCl, pH 9.0, 50 mM KCl, 0.1% Triton X-100), 1 mM deoxynucleoside triphosphate (dNTPs), 0.5 unit of RNase inhibitor, 0.5 μg 20 μl of reverse transcription reaction mixture containing oligo (dT) 15 , and 15 units of AMV reverse transcriptase was incubated at 42 ° C. for 15 minutes, heated at 99 ° C. for 5 minutes, and then at 0-5 ° C. for 5 minutes. Incubated. PCR is Tap polymerase (i-Max TM DNA polymerase (Intron Biotechnology) was performed using standard procedures. The number of cycles varied from 25 to 45 cycles by denaturing at 94 ° C. for 30 seconds, annealing at 58 ° C. to 65 ° C. for 30 seconds, and extending at 72 ° C. for 30 seconds. The primers used were as follows.
CD31: 5’-caacagacatggcaacaagg-3’, 5’-ttctggatggtgaagttggc-3’ (280bp); vWF: 5’-cattggtcaggatggagtcc-3’, 5’-agcactggtctgcattctgg-3’ (188bp)CD31: 5'-caacagacatggcaacaagg-3 ', 5'-ttctggatggtgaagttggc-3' (280bp); vWF: 5’-cattggtcaggatggagtcc-3 ’, 5’-agcactggtctgcattctgg-3’ (188bp)
GAPDH 프라이머(5'-ctcccaacgtgtctgttgtg-3', 5'-tgagcttgacaaagtggtcg-3' (450bp) 및 5'-accacagtccatgccatca-3'', 5'-tccaccaccctgttgctgta-3'(450bp))를 내부 표준(internal standard)으로 사용하였다. GAPDH primers (5'-ctcccaacgtgtctgttgtg-3 ', 5'-tgagcttgacaaagtggtcg-3' (450bp) and 5'-accacagtccatgccatca-3 '', 5'-tccaccaccctgttgctgta-3 '(450bp)) as internal standards Used.
증폭 산물들의 신호 강도는 각각의 GAPDH 신호 강도에 대한 그들의 상대적인 강도로 정상화되었다(normalized).The signal strengths of the amplification products were normalized to their relative strengths for each GAPDH signal strength.
CD31과 vWF는 내피세포 특이적 마커로 골수유래 중간엽 줄기세포가 내피 세포로 분화하면 발현이 높아진다. 따라서 CD31과 vWF의 발현변화를 RT-PCR로 확인하여, 대조군과 비교하였다.CD31 and vWF are endothelial cell-specific markers, which increase expression when bone marrow-derived mesenchymal stem cells differentiate into endothelial cells. Therefore, the expression changes of CD31 and vWF were confirmed by RT-PCR and compared with the control group.
상기 실시예에서 제조된 대표적 화합물들의 내피 세포로의 분화 유도 정도를 하기 표 1 및 표 2에 나타내었다.The degree of differentiation induction into endothelial cells of the representative compounds prepared in the above Examples is shown in Tables 1 and 2 below.
상기 표 1과 표 2에 나타난 바와 같이, 본 발명에 따른 화합물은 골수 유래 중간엽 줄기세포의 내피세포로 분화를 유도함을 알 수 있다.
As shown in Table 1 and Table 2, it can be seen that the compound according to the present invention induces differentiation into endothelial cells of bone marrow-derived mesenchymal stem cells.
CapillaryCapillary -- likelike tubetube formationformation
내피세포는 특이적으로 capillary-like tube를 형성하는 성향을 가지고 있다. in vitro angiogenesis kit(MILLIPORE?)를 사용하여 화합물에 의해 중간엽 줄기세포에서 내피세포로 분화된 세포가 capillary-like tube를 형성하는지 확인하였다. 결과는 도 1에 나타내었다.Endothelial cells have a specific tendency to form capillary-like tubes. In vitro angiogenesis kit (MILLIPORE ? ) was used to determine whether cells differentiated from mesenchymal stem cells into endothelial cells by the compound form capillary-like tubes. The results are shown in FIG.
도 1에 나타난 바와 같이, 용매 대조군과 비교하여 본 발명의 화합물 시료 (실시예 6) 1μM 투여군에서 43.47%의 capillary-like tube 형성이 관찰되었다.
As shown in FIG. 1, 43.47% of capillary-like tube formation was observed in the 1 μM administration group of the compound sample of the present invention (Example 6) compared to the solvent control group.
CellCell -- migrationmigration assayassay
Cell-migration 역시 capillary-like tube formation과 같이 내피세포에서 특이적으로 나타난다. Trans-well system을 사용하여 화합물에 의해 중간엽 줄기세포에서 내피세포로 분화된 세포에서 cell-migration이 증가되는지 확인하였다. 결과는 도 2에 나타내었다.Cell-migration also occurs specifically in endothelial cells, such as capillary-like tube formation. Trans-well system was used to determine if cell-migration was increased in cells differentiated from mesenchymal stem cells to endothelial cells by compounds. The results are shown in Fig.
도 2에 나타난 바와 같이, 용매 대조군과 비교하여 본 발명의 화합물 시료 (실시예 6) 1μM 투여군에서 1.6배의 cell-migration이 증가되었다.
As shown in FIG. 2, 1.6-fold cell-migration was increased in the 1 μM administration group of the compound sample of the present invention (Example 6) compared to the solvent control group.
실험예Experimental Example 2: 2: 동물실험계의Animal testing system 재내피세포화Re-endothelial Cellization 실험 Experiment
건강한 마우스 20마리를 무작위로 4개의 군으로 분류한 뒤, 정상대조군(control, PBS injection, n=5)은 창상유발 후 관찰하고, 상기 실시예 6의 화합물을 1mg/kg 농도(n=5)와 0.2mg/kg (n=5)의 농도로 PBS에 녹여 제조한 화합물을 미정맥으로 투여하여 창상의 상피화(wound epithelialization), 세포내용 (cellular content), 육아조직형성(granulation tissue formation)등의 항목을 확인하여 창상치유의 정도를 비교하였다.After randomly classifying 20 healthy mice into 4 groups, the normal control group (control, PBS injection, n = 5) was observed after wound induction, and the compound of Example 6 was administered at a concentration of 1 mg / kg (n = 5). And a compound prepared by dissolving in PBS at a concentration of 0.2 mg / kg (n = 5) into the microvenous vein, such as wound epithelialization, cellular content, granulation tissue formation, etc. The items were checked and the degree of wound healing was compared.
창상은 창상 유발 지역에 소독을 실시한 다음, 지름 6 mm punch로 등에 근막층까지 일정한 깊이의 원형창상(wound)을 만든 후 각각 5일째 창상의 단면적을 확인하였으며(wound closure), sacrifice하여 조직병리학적 관찰을 실시하였다. 미세 혈관(CD31), granulation tissue formation 확인(H&E staining), 창상 지역에서의 관련 인자 확인(CD68, PDGF-β, SDF-1α, CXCR4)을 통하여 활성을 평가하였다. The wound was disinfected in the wound causing area, a circular wound of a certain depth was made to the fascia layer with a diameter of 6 mm punch, and then the cross-sectional area of the wound was checked on the fifth day (wound closure) and sacrificed for histopathology. Observation was performed. Activity was assessed through microcirculation (CD31), granulation tissue formation (H & E staining), and related factors in the wound area (CD68, PDGF-β, SDF-1α, CXCR4).
창상의 단면적 변화는 도 3에 나타내었고, 조직병리학적 관찰은 도 4 및 도 5에 나타내었으며, 창상 부위에서의 관련 인자는 도 6에 나타내었다.The cross-sectional area of the wound is shown in FIG. 3, histopathological observations are shown in FIGS. 4 and 5, and relevant factors at the wound site are shown in FIG. 6.
도 3에 나타난 바와 같이, 본 발명에 따른 화합물 (실시예 6)을 미정맥 투여한 마우스는 용매 대조군과 비교하여 원형창상이 더 빨리 회복되는 것을 확인할 수 있었다. 특히 실시예 6 화합물 0.2mg/kg를 넣어준 군이 실시예 6 화합물 1mg/kg 군보다 효과가 좋음을 확인할 수 있었다 (P<0.05).As shown in FIG. 3, the mice inoculated with the intravenous administration of the compound according to the present invention (Example 6) were able to confirm that the circular wound recovered more rapidly than the solvent control group. In particular, the group given the 0.2mg / kg compound of Example 6 was confirmed to be more effective than the 1mg / kg group of Example 6 compound (P <0.05).
도 4 및 도 5에 나타난 바와 같이, 실험 최종일(5일째)에 마우스를 희생시켜 창상 부위를 절제한 후 조직병리학적 관찰로 microvessel density를 CD31 염색을 통해서 확인하고, histological analysis를 통해서 육아조직형성(granulation tissue formation)을 확인하였다. 본 발명에 따른 화합물 (실시예 6)을 미정맥 투여한 마우스는 용매 대조군과 비교하여 microvessle density가 조금 더 형성되었고, 육아조직이 창상부위로 이동하고 증식하여 창상 부위의 세포를 재형성하는 것을 관찰할 수 있었다. 특히 실시예 6 화합물의 0.2mg/kg 군이 다른 군보다 창상치유에 있어서 뛰어난 효과를 보임을 알 수 있었다.As shown in Figure 4 and 5, the wound was sacrificed at the end of the experiment (day 5), the wound was excised, and histopathological observation confirmed the microvessel density through CD31 staining, and granulation tissue formation through histological analysis ( granulation tissue formation). Mice with microvenous administration of the compound according to the present invention (Example 6) had slightly more microvessle density compared to the solvent control group, and observed that granulation tissue moved to the wound site and proliferated to remodel the cells at the wound site. Could. In particular, it can be seen that the 0.2 mg / kg group of the compound of Example 6 showed superior effects in wound healing than the other groups.
도 6에 나타난 바와 같이, 창상치유에 있어서 뛰어난 효과를 보인 실시예 6 화합물을 0.2mg/kg 농도로 마우스에 미정맥 투여 후, 7일 째에 창상치유 증진효과에 대한 재내피세포화의 메커니즘을 확인하였다. 창상부위의 생검을 통한 조직병리학적 관찰로 wound healing에 관여하는 인자의 mRNA 발현변화를 확인하였다. 용매 대조군과 비교하여 화합물을 투여한 군에서 wound healing에 관여하는 CD68, PDGF-β, SDF-1α, CXCR4의 mRNA발현이 높아지는 것을 확인할 수 있었다. 특히 CD68의 경우는 monocyte/macrophage에 특이적인 인자이며, SDF-1α는 CXCR4와 결합하여 inflammation과 cell migration을 조절하는 것으로 알려져 있다. 또한 PDGF-β의 경우 전구세포 homing과 macrophage 활성화 그리고 섬유아세포 증식에 많은 영향을 미치는 인자로 알려져 있다. 따라서 이들의 증가는 실시예 6 화합물의 처리에 의한 neutrophil, mast cell, macrophage lymphocyte의 증가에 따른 신생 혈관 형성 및 섬유아세포 이동/증식, 그리고 이에 따른 재내피세포화와 관련이 있음을 보여준다.
As shown in Figure 6, Example 6 compound showing an excellent effect on wound healing, after administration of the microvenous vein to the mouse at a concentration of 0.2mg / kg, the mechanism of re-endothelial cell on the wound healing enhancement effect on day 7 Confirmed. Histopathological observations through biopsy of the wound confirmed the mRNA expression changes of the factors involved in wound healing. In comparison with the solvent control group, the mRNA expression of CD68, PDGF-β, SDF-1α, and CXCR4 involved in wound healing was increased in the compound-administered group. In particular, CD68 is a specific factor for monocyte / macrophage, and SDF-1α is known to regulate inflammation and cell migration by binding to CXCR4. PDGF-β is also known to affect progenitor cell homing, macrophage activation and fibroblast proliferation. Therefore, their increase is related to the formation of neovascularization and fibroblast migration / proliferation following the increase of neutrophil, mast cell and macrophage lymphocyte by treatment of Example 6 compound and thus re-endothelial cellization.
Claims (15)
[화학식 1]
상기 식에서,
X는 탄소, 산소 또는 질소 원자이고, 여기서, X가 산소 원자일 때 R1은 존재하지 않으며,
R1은 수소 또는 탄소수 1 내지 6의 알킬기이고,
R2는 수소, 니트로기, 아세틸기 또는 아미노기이고,
R3는 수소; 하이드록시기; 탄소수 1 내지 6의 알콕시기; 니트로기; 아세트아미드기; 또는 할로겐, 페닐 또는 피라졸일로 치환되거나 비치환된 벤즈아미드기이며,
R4는 수소; 하이드록시기로 치환된 탄소수 1 내지 6의 알킬; 아세틸기; 할로겐; 니트로기; 아미노기; 할로겐으로 치환되거나 비치환된 아세트아미드기; 피코린아미드기; 티오펜카복스아미드기; 카르복실기; 또는 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 알콕시, 할로겐, 니트로, 페닐, 피라졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고,
R5는 수소; 하이드록시기; 아미노기; 아세틸기; 피페리딘일로 치환된 탄소수 1 내지 6의 알킬; 할로겐 또는 피라졸일로 치환되거나 비치환된 니코틴아미드기; 또는 탄소수 1 내 6의 알킬, 피페라진일, 피페리딘일, 이미다졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고,
R6은 수소 또는 하이드록시기이며,
m은 0 내지 3의 정수를 나타내고,
여기서, X가 산소 원자인 경우, R2, R3, R5 및 R6이 수소이고 R4가 아세틸기인 화합물, R2, R3, R4 및 R6이 수소이고 R5가 하이드록시기 또는 아미드기인 화합물, R2, R3 및 R6이 수소이고 R4가 니트로기이고, R5가 하이드록시기인 화합물, R2, R3 및 R6이 수소이고 R4가 아미드기이고, R5가 아세틸기인 화합물 및 R2, R4, R5 및 R6이 수소이고 R3이 아세트아미드기인 화합물을 제외하고,
X가 질소 원자인 경우, R2, R3, R4 및 R6이 수소이고 R5가 하이드록시기인 화합물 및 R3, R5 및 R6이 수소이고 R2가 니트로기이고, R4가 아세틸기인 화합물은 제외한다.
A compound represented by the following formula (1):
[Formula 1]
In this formula,
X is a carbon, oxygen or nitrogen atom, where R 1 is absent when X is an oxygen atom,
R 1 is hydrogen or an alkyl group having 1 to 6 carbon atoms,
R 2 is hydrogen, nitro group, acetyl group or amino group,
R 3 is hydrogen; Hydroxyl group; An alkoxy group having 1 to 6 carbon atoms; A nitro group; Acetamide group; Or a benzamide group substituted or unsubstituted with halogen, phenyl or pyrazolyl,
R 4 is hydrogen; Alkyl having 1 to 6 carbon atoms substituted with a hydroxy group; Acetyl group; halogen; A nitro group; An amino group; An acetamide group unsubstituted or substituted with halogen; Picolinamide groups; Thiophene carboxamide group; Carboxyl groups; Or a benzamide group unsubstituted or substituted with alkyl having 1 to 6 carbon atoms, alkoxy, halogen, nitro, phenyl, pyrazolyl or thiazolyl having 1 to 6 carbon atoms,
R 5 is hydrogen; Hydroxyl group; An amino group; Acetyl group; Alkyl of 1 to 6 carbon atoms substituted with piperidinyl; Nicotinamide groups unsubstituted or substituted with halogen or pyrazolyl; Or a benzamide group unsubstituted or substituted with alkyl, piperazinyl, piperidinyl, imidazoyl or thiazolyl having 1 to 6 carbon atoms,
R 6 is hydrogen or a hydroxyl group,
m represents an integer of 0 to 3,
Wherein when X is an oxygen atom, R 2 , R 3 , R 5 and R 6 are hydrogen and R 4 is an acetyl group, R 2 , R 3 , R 4 And R 6 is hydrogen and R 5 is a hydroxy group or an amide group, R 2 , R 3 And a compound in which R 6 is hydrogen and R 4 is a nitro group, R 5 is a hydroxy group, R 2 , R 3 and R 6 are hydrogen, R 4 is an amide group, and R 5 is an acetyl group and R 2 , R Except for compounds where 4 , R 5 and R 6 are hydrogen and R 3 is an acetamide group,
When X is a nitrogen atom, R 2 , R 3 , R 4 and R 6 are hydrogen and R 5 is a hydroxy group and R 3 , R 5 and R 6 are hydrogen and R 2 is nitro group, R 4 is The compound which is an acetyl group is excluded.
X는 산소 또는 질소 원자이고,
R1은 탄소수 1 내지 6의 알킬기이고,
R2는 수소 또는 아세틸기이며,
R3는 수소이고,
R4는 아세틸기, 니트로기, 아미노기, 아세트아미드기, 페닐로 치환된 벤즈아미드기 또는 탄소수 1 내지 6의 알콕시로 치환된 벤즈아미드기이며,
R5는 아미노기, 하이드록시기, 아세틸기, 티아졸일로 치환된 벤즈아미드기이고,
R6은 수소이며,
m은 1 내지 3의 정수를 나타내는 화합물.
The method of claim 1,
X is oxygen or nitrogen atom,
R 1 is an alkyl group having 1 to 6 carbon atoms,
R 2 is hydrogen or an acetyl group,
R < 3 > is hydrogen,
R 4 is an acetyl group, a nitro group, an amino group, an acetamide group, a benzamide group substituted with phenyl or a benzamide group substituted with alkoxy having 1 to 6 carbon atoms,
R 5 is a benzamide group substituted with an amino group, a hydroxyl group, an acetyl group, thiazolyl,
R 6 is hydrogen,
m represents an integer of 1 to 3;
화학식 1의 화합물은 하기 화학식 1-1 내지 1-5로 표시되는 것인 화합물:
[화학식 1-1]
[화학식 1-2]
[화학식 1-3]
[화학식 1-4]
[화학식 1-5]
The method of claim 1,
Compound of Formula 1 is represented by the following formula 1-1 to 1-5:
[Formula 1-1]
[Formula 1-2]
[Formula 1-3]
[Formula 1-4]
[Formula 1-5]
[화학식 2]
상기 식에서,
X는 탄소, 산소 또는 질소 원자이고, 여기서, X가 산소 원자일 때 R1은 존재하지 않으며,
R1은 수소 또는 탄소수 1 내지 6의 알킬기이고,
R2는 수소, 니트로기, 아세틸기 또는 아미노기이고,
R3는 수소; 하이드록시기; 탄소수 1 내지 6의 알콕시기; 니트로기; 아세트아미드기; 또는 할로겐, 페닐 또는 피라졸일로 치환되거나 비치환된 벤즈아미드기이며,
R4는 수소; 하이드록시기로 치환된 탄소수 1 내지 6의 알킬; 아세틸기; 할로겐; 니트로기; 아미노기; 할로겐으로 치환되거나 비치환된 아세트아미드기; 피코린아미드기; 티오펜카복스아미드기; 카르복실기; 또는 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 알콕시, 할로겐, 니트로, 페닐, 피라졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고,
R5는 수소; 하이드록시기; 아미노기; 아세틸기; 피페리딘일로 치환된 탄소수 1 내지 6의 알킬; 할로겐 또는 피라졸일로 치환되거나 비치환된 니코틴아미드기; 또는 탄소수 1 내 6의 알킬, 피페라진일, 피페리딘일, 이미다졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고,
R6은 수소 또는 하이드록시기이며,
m은 0 내지 3의 정수를 나타낸다.
A composition for inducing differentiation of mesenchymal stem cells into vascular endothelial cells comprising a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof:
(2)
In this formula,
X is a carbon, oxygen or nitrogen atom, where R 1 is absent when X is an oxygen atom,
R 1 is hydrogen or an alkyl group having 1 to 6 carbon atoms,
R 2 is hydrogen, nitro group, acetyl group or amino group,
R 3 is hydrogen; Hydroxyl group; An alkoxy group having 1 to 6 carbon atoms; A nitro group; Acetamide group; Or a benzamide group substituted or unsubstituted with halogen, phenyl or pyrazolyl,
R 4 is hydrogen; Alkyl having 1 to 6 carbon atoms substituted with a hydroxy group; Acetyl group; halogen; A nitro group; An amino group; An acetamide group unsubstituted or substituted with halogen; Picolinamide groups; Thiophene carboxamide group; Carboxyl groups; Or a benzamide group unsubstituted or substituted with alkyl having 1 to 6 carbon atoms, alkoxy, halogen, nitro, phenyl, pyrazolyl or thiazolyl having 1 to 6 carbon atoms,
R 5 is hydrogen; Hydroxyl group; An amino group; Acetyl group; Alkyl of 1 to 6 carbon atoms substituted with piperidinyl; Nicotinamide groups unsubstituted or substituted with halogen or pyrazolyl; Or a benzamide group unsubstituted or substituted with alkyl, piperazinyl, piperidinyl, imidazoyl or thiazolyl having 1 to 6 carbon atoms,
R 6 is hydrogen or a hydroxyl group,
m represents the integer of 0-3.
X는 산소 또는 질소 원자이고,
R1은 수소 또는 탄소수 1 내지 6의 알킬기이고,
R1은 탄소수 1 내지 6의 알킬기이고,
R2는 수소 또는 아세틸기이며,
R3는 수소이고,
R4는 아세틸기, 니트로기, 아미노기, 아세트아미드기, 페닐로 치환된 벤즈아미드기 또는 탄소수 1 내지 6의 알콕시로 치환된 벤즈아미드기이며,
R5는 아미노기, 하이드록시기, 아세틸기, 티아졸일로 치환된 벤즈아미드기이고,
R6은 수소이며,
m은 1 내지 3의 정수를 나타내는 화합물인 중간엽 줄기세포의 혈관내피세포로의 분화 유도용 조성물.
The compound of claim 4, wherein the compound of formula 2 is
X is oxygen or nitrogen atom,
R 1 is hydrogen or an alkyl group having 1 to 6 carbon atoms,
R 1 is an alkyl group having 1 to 6 carbon atoms,
R 2 is hydrogen or an acetyl group,
R < 3 > is hydrogen,
R 4 is an acetyl group, a nitro group, an amino group, an acetamide group, a benzamide group substituted with phenyl or a benzamide group substituted with alkoxy having 1 to 6 carbon atoms,
R 5 is a benzamide group substituted with an amino group, a hydroxyl group, an acetyl group, thiazolyl,
R 6 is hydrogen,
m is a compound for inducing differentiation of mesenchymal stem cells into vascular endothelial cells, which is a compound having an integer of 1 to 3.
1-(4-몰포리노페닐)에탄온(1-(4-morpholinophenyl)ethanone), 3-몰포리노아닐린(3-morpholinoaniline), 5-몰포리노-2-니트로페놀(5-morpholino-2-nitrophenol), 1-(2-아미노-5-몰포리노페닐)에탄온(1-(2-amino-5-morpholinophenyl)ethanone), N-(2-아세틸-4-몰포리노페닐)아세트아미드(N-(2-acetyl-4-morpholinophenyl)acetamide), N-(2-아세틸-4-몰포리노페닐)비페닐-4-카복스아미드(N-(2-acetyl-4-morpholinophenyl)biphenyl-4-carboxamide), N-(2-아세틸-4-몰포리노페닐)-4-메톡시벤즈아미드(N-(2-acetyl-4-morpholinophenyl)-4-methoxybenzamide), 1-(5-아미노-2-(4-메틸피페라진-1-일)페닐)에탄온(1-(5-amino-2-(4-methylpiperazin-1-yl)phenyl)ethanone) 또는 N-(3-몰포리노페닐)-4-(티아졸-4-일)벤즈아미드(N-(3-morpholinophenyl)-4-(thiazol-4-yl)benzamide)인 중간엽 줄기세포의 내피세포로의 분화 유도용 조성물.
The compound of claim 4, wherein the compound of formula 2 is
1- (4-morpholinophenyl) ethanone (1- (4-morpholinophenyl) ethanone), 3-morpholinoaniline, 5-morpholino-2-nitrophenol ), 1- (2-amino-5-morpholinophenyl) ethanone (1- (2-amino-5-morpholinophenyl) ethanone), N- (2-acetyl-4-morpholinophenyl) acetamide (N- (2-acetyl-4-morpholinophenyl) acetamide), N- (2-acetyl-4-morpholinophenyl) biphenyl-4-carboxamide (N- (2-acetyl-4-morpholinophenyl) biphenyl-4-carboxamide ), N- (2-acetyl-4-morpholinophenyl) -4-methoxybenzamide, N- (2-acetyl-4-morpholinophenyl) -4-methoxybenzamide, 1- (5-amino-2- ( 4-methylpiperazin-1-yl) phenyl) ethanone (1- (5-amino-2- (4-methylpiperazin-1-yl) phenyl) ethanone) or N- (3-morpholinophenyl) -4- A composition for inducing differentiation of mesenchymal stem cells which are (thiazol-4-yl) benzamide (N- (3-morpholinophenyl) -4- (thiazol-4-yl) benzamide) into endothelial cells.
[화학식 2]
상기 식에서,
X는 탄소, 산소 또는 질소 원자이고, 여기서, X가 산소 원자일 때 R1은 존재하지 않으며,
R1은 수소 또는 탄소수 1 내지 6의 알킬기이고,
R2는 수소, 니트로기, 아세틸기 또는 아미노기이고,
R3는 수소; 하이드록시기; 탄소수 1 내지 6의 알콕시기; 니트로기; 아세트아미드기; 또는 할로겐, 페닐 또는 피라졸일로 치환되거나 비치환된 벤즈아미드기이며,
R4는 수소; 하이드록시기로 치환된 탄소수 1 내지 6의 알킬; 아세틸기; 할로겐; 니트로기; 아미노기; 할로겐으로 치환되거나 비치환된 아세트아미드기; 피코린아미드기; 티오펜카복스아미드기; 카르복실기; 또는 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 알콕시, 할로겐, 니트로, 페닐, 피라졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고,
R5는 수소; 하이드록시기; 아미노기; 아세틸기; 피페리딘일로 치환된 탄소수 1 내지 6의 알킬; 할로겐 또는 피라졸일로 치환되거나 비치환된 니코틴아미드기; 또는 탄소수 1 내 6의 알킬, 피페라진일, 피페리딘일, 이미다졸일 또는 티아졸일로 치환되거나 비치환된 벤즈아미드기이고,
R6은 수소 또는 하이드록시기이며,
m은 0 내지 3의 정수를 나타낸다.
Method for inducing differentiation of mesenchymal stem cells into vascular endothelial cells comprising a compound represented by the following Formula 2 or a pharmaceutically acceptable salt thereof:
(2)
In this formula,
X is a carbon, oxygen or nitrogen atom, where R 1 is absent when X is an oxygen atom,
R 1 is hydrogen or an alkyl group having 1 to 6 carbon atoms,
R 2 is hydrogen, nitro group, acetyl group or amino group,
R 3 is hydrogen; Hydroxyl group; An alkoxy group having 1 to 6 carbon atoms; A nitro group; Acetamide group; Or a benzamide group substituted or unsubstituted with halogen, phenyl or pyrazolyl,
R 4 is hydrogen; Alkyl having 1 to 6 carbon atoms substituted with a hydroxy group; Acetyl group; halogen; A nitro group; An amino group; An acetamide group unsubstituted or substituted with halogen; Picolinamide groups; Thiophene carboxamide group; Carboxyl groups; Or a benzamide group unsubstituted or substituted with alkyl having 1 to 6 carbon atoms, alkoxy, halogen, nitro, phenyl, pyrazolyl or thiazolyl having 1 to 6 carbon atoms,
R 5 is hydrogen; Hydroxyl group; An amino group; Acetyl group; Alkyl of 1 to 6 carbon atoms substituted with piperidinyl; Nicotinamide groups unsubstituted or substituted with halogen or pyrazolyl; Or a benzamide group unsubstituted or substituted with alkyl, piperazinyl, piperidinyl, imidazoyl or thiazolyl having 1 to 6 carbon atoms,
R 6 is hydrogen or a hydroxyl group,
m represents the integer of 0-3.
X는 산소 또는 질소 원자이고,
R1은 탄소수 1 내지 6의 알킬기이고,
R2는 수소 또는 아세틸기이며,
R3는 수소이고,
R4는 아세틸기, 니트로기, 아미노기, 아세트아미드기, 페닐로 치환된 벤즈아미드기 또는 탄소수 1 내지 6의 알콕시로 치환된 벤즈아미드기이며,
R5는 아미노기, 하이드록시기, 아세틸기, 티아졸일로 치환된 벤즈아미드기이고,
R6은 수소이며,
m은 1 내지 3의 정수를 나타내는 화합물인 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법.
The compound of claim 7 wherein
X is oxygen or nitrogen atom,
R 1 is an alkyl group having 1 to 6 carbon atoms,
R 2 is hydrogen or an acetyl group,
R < 3 > is hydrogen,
R 4 is an acetyl group, a nitro group, an amino group, an acetamide group, a benzamide group substituted with phenyl or a benzamide group substituted with alkoxy having 1 to 6 carbon atoms,
R 5 is a benzamide group substituted with an amino group, a hydroxyl group, an acetyl group, thiazolyl,
R 6 is hydrogen,
m is a compound representing an integer of 1 to 3 mesenchymal stem cells differentiation induction into vascular endothelial cells.
1-(4-몰포리노페닐)에탄온(1-(4-morpholinophenyl)ethanone), 3-몰포리노아닐린(3-morpholinoaniline), 5-몰포리노-2-니트로페놀(5-morpholino-2-nitrophenol), 1-(2-아미노-5-몰포리노페닐)에탄온(1-(2-amino-5-morpholinophenyl)ethanone), N-(2-아세틸-4-몰포리노페닐)아세트아미드(N-(2-acetyl-4-morpholinophenyl)acetamide), N-(2-아세틸-4-몰포리노페닐)비페닐-4-카복스아미드(N-(2-acetyl-4-morpholinophenyl)biphenyl-4-carboxamide), N-(2-아세틸-4-몰포리노페닐)-4-메톡시벤즈아미드(N-(2-acetyl-4-morpholinophenyl)-4-methoxybenzamide), 1-(5-아미노-2-(4-메틸피페라진-1-일)페닐)에탄온(1-(5-amino-2-(4-methylpiperazin-1-yl)phenyl)ethanone) 또는 N-(3-몰포리노페닐)-4-(티아졸-4-일)벤즈아미드(N-(3-morpholinophenyl)-4-(thiazol-4-yl)benzamide)인 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법.
The compound of claim 7 wherein
1- (4-morpholinophenyl) ethanone (1- (4-morpholinophenyl) ethanone), 3-morpholinoaniline, 5-morpholino-2-nitrophenol ), 1- (2-amino-5-morpholinophenyl) ethanone (1- (2-amino-5-morpholinophenyl) ethanone), N- (2-acetyl-4-morpholinophenyl) acetamide (N- (2-acetyl-4-morpholinophenyl) acetamide), N- (2-acetyl-4-morpholinophenyl) biphenyl-4-carboxamide (N- (2-acetyl-4-morpholinophenyl) biphenyl-4-carboxamide ), N- (2-acetyl-4-morpholinophenyl) -4-methoxybenzamide, N- (2-acetyl-4-morpholinophenyl) -4-methoxybenzamide, 1- (5-amino-2- ( 4-methylpiperazin-1-yl) phenyl) ethanone (1- (5-amino-2- (4-methylpiperazin-1-yl) phenyl) ethanone) or N- (3-morpholinophenyl) -4- A method of inducing differentiation of mesenchymal stem cells ((thiazol-4-yl) benzamide (N- (3-morpholinophenyl) -4- (thiazol-4-yl) benzamide) into vascular endothelial cells.
상기 중간엽 줄기세포는 골수, 조직, 배아, 제대혈, 혈액 또는 체액으로부터 얻은 것인 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법.
The method of claim 7, wherein
The mesenchymal stem cells are derived from bone marrow, tissue, embryo, umbilical cord blood, blood or body fluid differentiation of mesenchymal stem cells into vascular endothelial cells.
화학식 2의 화합물의 처리는 중간엽 줄기세포를 화학식 1의 화합물을 포함하는 배지에서 배양함으로써 수행되는 것인 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법.
The method of claim 7, wherein
The method of inducing differentiation of mesenchymal stem cells into vascular endothelial cells, which is performed by culturing the mesenchymal stem cells in a medium containing the compound of formula (1).
배양은 5일 내지 15일 동안 수행되는 것인 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법.
The method of claim 11,
The method of inducing differentiation of mesenchymal stem cells into vascular endothelial cells, which is performed for 5 to 15 days.
혈관내피세포는 CD31의 발현이 줄기세포에 비해 증가되어 있는 것인 중간엽 줄기세포의 혈관내피세포로의 분화 유도 방법.
The method of claim 7, wherein
Vascular endothelial cell is a method of inducing differentiation of mesenchymal stem cells into vascular endothelial cells in which the expression of CD31 is increased compared to that of stem cells.
A pharmaceutical composition for treating vascular diseases comprising vascular endothelial cells differentiated from mesenchymal stem cells by the method according to any one of claims 7 to 13.
상기 혈관질환은 혈관내피세포 손상인 혈관질환 치료용 의약 조성물.
15. The method of claim 14,
The vascular disease is a vascular endothelial cell damage pharmaceutical composition for vascular disease treatment.
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