KR102290603B1 - Novel lipoic acid-heterocycle thioacetal compounds and uses of the same - Google Patents
Novel lipoic acid-heterocycle thioacetal compounds and uses of the same Download PDFInfo
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- HBFPBMDSSGRYEJ-UHFFFAOYSA-N CSC(c1cccc(C(F)(F)F)c1)S Chemical compound CSC(c1cccc(C(F)(F)F)c1)S HBFPBMDSSGRYEJ-UHFFFAOYSA-N 0.000 description 1
- HBFPBMDSSGRYEJ-MRVPVSSYSA-N CS[C@H](c1cc(C(F)(F)F)ccc1)S Chemical compound CS[C@H](c1cc(C(F)(F)F)ccc1)S HBFPBMDSSGRYEJ-MRVPVSSYSA-N 0.000 description 1
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Abstract
본 발명은 불안정한 다이설파이드 구조를 가진 리포익산을 싸이오아세탈로 변환시킨 신규한 리포익산-헤테로사이클 싸이오아세탈 화합물 및 이의 용도에 관한 것으로, 본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물을 포함하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물 및 퇴행성 질환의 예방 또는 개선용 건강보조식품 조성물에 관한 것이다.The present invention relates to a novel lipoic acid-heterocycle thioacetal compound obtained by converting lipoic acid having an unstable disulfide structure into thioacetal and uses thereof, including the lipoic acid-heterocycle thioacetal compound of the present invention It relates to a pharmaceutical composition for the prevention or treatment of degenerative diseases, and to a health supplement composition for preventing or improving degenerative diseases.
Description
본 발명은 리포익산으로부터 유도되며, 다양한 치환체가 도입된 싸이오아세탈 화합물 및 이의 용도에 관한 것으로, 보다 상세하게는 리포익산의 환원, 알데히드 화합물과의 반응 및 아민 화합물과의 반응을 통해 합성된 리포익산-헤테로사이클 싸이오아세탈 화합물 및 이를 유효성분으로 포함하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물 및 퇴행성 질환의 예방 또는 개선용 건강보조식품 조성물에 관한 것이다.The present invention relates to thioacetal compounds derived from lipoic acid and introduced with various substituents and uses thereof, and more particularly, lipoic acid synthesized through reduction of lipoic acid, reaction with an aldehyde compound, and reaction with an amine compound. Iksan-heterocycle thioacetal compound and a pharmaceutical composition for preventing or treating degenerative diseases comprising the same as an active ingredient, and to a health supplement composition for preventing or improving degenerative diseases.
의학산업의 발달과 급속한 경제성장에 따른 삶의 질이 향상됨과 동시에 각종 질병과 노인 인구가 증가하고 있다. 인간의 평균 수명은 연장되었지만 이에 따른 경제적 부담금이 가중되고 있다. 그중 하나가 바로 노인성 치매병이다. 그 중 50% 이상이 알츠하이머병(Alzheimer type, AD) 치매이다. 알츠하이머병(AD)은 비가역적이고 점진적으로 진행되는 뇌혈관질환 중의 하나로, 기억력, 언어 능력, 방향 감각, 주의력과 같은 인지 능력의 점진적 상실과 디프레션을 동반하는 나이와 관련된 퇴행성뇌신경계 질환(neurodegenerative disease)이다. 알츠하이머병(AD)의 발명원인이 정확하게 무엇인지는 밝혀지지 않았으며, 이에 따른 치료제도 없는 실정이다. 하지만 간접적으로 치매환자들의 뇌에서 정상적인 사람보다 아세틸콜린(ACh)을 합성하는 콜린아세틸트랜스퍼라제(ChAT)가 20~30%로 감소된 것으로 알려졌으며, 또한 신경(Neuron) 전달체인 아세틸콜린(ACh) 농도가 16~30%정도 감소한 것으로 확인되었다. With the development of the medical industry and rapid economic growth, the quality of life has improved, and the number of the elderly and various diseases is increasing. Although the average human lifespan has been extended, the economic burden is increasing accordingly. One of them is senile dementia. More than 50% of them are Alzheimer's disease (AD) dementia. Alzheimer's disease (AD) is one of the irreversible and progressive cerebrovascular diseases. It is an age-related neurodegenerative disease accompanied by gradual loss and depression of cognitive abilities such as memory, speech, direction, and attention. am. The exact cause of the invention of Alzheimer's disease (AD) is not known, and there is no treatment for it. However, it is known that choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh) in the brain of dementia patients indirectly decreased by 20 to 30% compared to normal people, and also the neurotransmitter acetylcholine (ACh) It was confirmed that the concentration decreased by about 16-30%.
알츠하이머병(AD)를 근본적으로 치료하기 위해서는 AD 환자의 뇌에서 발견되는 주 병변들의 제거와 인지학습기능의 손상을 예방하거나 억제할 수 있는 물질을 개발하여야 한다. 인지기능을 개선을 위해 시냅스 간격에 콜린성신경계를 보충하기 위한 방법으로는 a)아세틸콜린의 합성을 증진시키는 방법, b)아세틸콜린의 유리를 증진시키는 방법, c)아세틸콜린의 분해를 억제하는 방법 및 d)아세틸콜린 수용체를 직접 자극해 주는 방법 등이 있다. In order to fundamentally treat Alzheimer's disease (AD), it is necessary to develop a substance that can prevent or suppress the removal of major lesions found in the brain of AD patients and the impairment of cognitive learning functions. Methods for replenishing the cholinergic nervous system in the synaptic interval to improve cognitive function include a) a method for enhancing the synthesis of acetylcholine, b) a method for enhancing the release of acetylcholine, c) a method for inhibiting the degradation of acetylcholine and d) direct stimulation of acetylcholine receptors.
그러나, 알츠하이머병(AD) 환자에게 전구체인 콜린농도를 증가시키기 위해 콜린을 직접 주입하는 방식은 별다른 효과를 얻지 못하였다.However, direct injection of choline to increase the concentration of choline, which is a precursor, to Alzheimer's disease (AD) patients did not have any particular effect.
그로 인해 간접적인 치료방법으로 신경(Neuron) 전달물질인 아세틸콜린을 가수분해하는 효소인 콜린에스터라제(ChE)를 억제하는 억제제를 이용하는 연구가 진행되어 오고 있다. 콜린에스터라제는 아세틸콜린에스터라제(AChE)와 부틸콜린에스터라제(BuChE)의 두 가지 형태를 갖는다.Therefore, as an indirect treatment method, research using an inhibitor that inhibits cholinesterase (ChE), an enzyme that hydrolyzes acetylcholine, a neurotransmitter, has been studied. Cholinesterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE).
AChE는 멤브레인-결합 효소(membrane-bound enzyme)로, 뇌, 근육 및 콜린성 뉴런에 존재한다. 포유류 뇌에 있어서, AChE의 대부분은 멤브레인-결합 G4 형태로 존재하며, 뉴런이 퇴화함에 따라 감소한다. 이는 콜린성 시냅스에서 AChE에 의해 신경전달물질인 아세틸콜린이 가수분해가 일어나게 된다. BChE는 신경교 (neuroglia)에서 발현되고, 장, 간, 신장, 심장, 폐 및 혈청에 존재한다. BChE는 에스테르기를 가진 화합물의 대사에 중요한 역할을 하는 것으로 알려져 있다. 이 효소는 AChE와 같이 아세틸콜린을 가수분해시킬 수 있으며, AD 환자의 경우 이 효소의 농도는 반응이 일어나도 감소되지 않아 AD를 더욱 악화시킬 수 있다.AChE is a membrane-bound enzyme and is present in the brain, muscle and cholinergic neurons. In the mammalian brain, the majority of AChE exists in the membrane-bound G4 form, and decreases as neurons degenerate. This causes hydrolysis of the neurotransmitter acetylcholine by AChE at the cholinergic synapse. BChE is expressed in neuroglia and is present in the intestine, liver, kidney, heart, lung and serum. BChE is known to play an important role in the metabolism of compounds with ester groups. This enzyme, like AChE, can hydrolyze acetylcholine, and in AD patients, the concentration of this enzyme does not decrease even after the reaction, which can make AD worse.
이전에는 아세틸콜린에스터라제 억제제에 관한 합성이나 개발이 주가 되어 왔지만 최근 연구에서는 AD 뇌에서 부틸콜린에스터라제가 증가된다고 알려져 있어 치료제 개발에 높은 관심을 모으고 있다. 현재 각국에서 사용되고 있는 알츠하이머병(AD) 치료제는 이러한 아세틸콜린 분해효소(AChE) 억제제가 대부분이며, 타크린(tacrine, 상품명: 코그넥스(cognex)), 그리고 도네페질(donepezil, 상품명: 아리셉트(aricept)) 또는 리바스티그민(Rivastigmine, 상품명: 엑셀론(exelon)), 보다 최근에는 갈란타민(Galanthamine, 상품명: 레미닐(reminyl))으로서 출시되었으며 알츠하이머 환자의 인지 기능이 어느 정도 개선되었다. 이들 화합물은 여전히 일부 바람직하지 못한 부작용들, 예를 들어 떨림증, 현기증, 구토증, 간독성 등을 나타낸다.In the past, synthesis or development of acetylcholinesterase inhibitors has been the main focus, but recent research is known to increase butylcholinesterase in AD brain, attracting high interest in the development of therapeutic agents. Most Alzheimer's disease (AD) drugs currently used in countries are acetylcholinease (AChE) inhibitors, tacrine (trade name: cognex), and donepezil (trade name: aricept). )) or Rivastigmine (trade name: exelon), more recently as galanthamine (trade name: reminyl), which improved cognitive function to some extent in Alzheimer's patients. These compounds still exhibit some undesirable side effects, such as tremor, dizziness, vomiting, hepatotoxicity, and the like.
이제까지 대부분의 연구는 선택적 아세틸콜린에스테라제(AChE) 저해제들에도 촛점을 맞추어져 있었다. 수 년간 간과되어 왔지만, 부티릴콜린에스테라제(BuChE)도 아세틸콜린(ACh)을 가수분해할 수 있고 알츠하이머 병 환우에게 활성이 아세틸콜린 분해효소보다 높게 유지되어, AD의 병태생리학 및 증상학에서 중요한 역할을 할 것이다. 그러나 오늘날까지 선택적 BuChE 저해 활성을 갖는 매우 적은 화합물들이 보고되어 왔으며, 예로서 에토프로파진 (10-(2-디에틸아미노프로필) 페노티아진 염산염), 단실아르기닌 N-(3-에틸-1,5-펜탄디일)아미드 (DAPA), 페네틸노르심세린 및 WO1999-002154 또는 EP 1251131호에 개시된 화합물들이 있다.Most studies so far have also focused on selective acetylcholinesterase (AChE) inhibitors. Although overlooked for many years, butyrylcholinesterase (BuChE) can also hydrolyze acetylcholine (ACh), and its activity remains higher than that of acetylcholinease in Alzheimer's disease patients, suggesting that it is important in the pathophysiology and symptomology of AD. will play an important role. However, to date, very few compounds with selective BuChE inhibitory activity have been reported, for example, etopropazine (10-(2-diethylaminopropyl) phenothiazine hydrochloride), dansylarginine N-(3-ethyl-1, 5-pentanediyl)amide (DAPA), phenethylnorsimserine and compounds disclosed in WO1999-002154 or EP 1251131.
한편, 리포익산은 강력하고 유효한 항산화제로, 하기 화학식으로 표시되는 알파-리포익산 (Alpha Lipoic Acid = ALA, 이하 '리포익산'으로 기재함)은 지질(Lipids)에 용해되기 때문에 리포익산(Lipoic Acid)으로 명명된다:On the other hand, lipoic acid is a strong and effective antioxidant, alpha-lipoic acid (Alpha Lipoic Acid = ALA, hereinafter referred to as 'lipoic acid') represented by the following formula is dissolved in lipids (Lipids), so lipoic acid (Lipoic Acid) ) is named:
리포익산은 인체가 독성화합물에 압도될 때 야기되는 산화적 스트레스(Oxidative Stress)와 연관된 대부분의 질환을 효율적으로 예방하고 치유할 수가 있다. 치유 가능한 질환으로서는 치매(파킨슨씨병, 알츠하이머병 등)와 같은 뇌신경질환, 당뇨병, 심혈관계 질환, 심장질환, 뇌졸중, 고지혈증, 백내장, 류마티즘, 암 등이다.Lipoic acid can effectively prevent and cure most diseases associated with oxidative stress caused when the human body is overwhelmed by toxic compounds. The curable diseases include cranial nerve diseases such as dementia (Parkinson's disease, Alzheimer's disease, etc.), diabetes, cardiovascular disease, heart disease, stroke, hyperlipidemia, cataract, rheumatism, cancer, and the like.
한편, 상기 치매와 관련하여, 알쯔하이머 치매뿐 아니라 혈관성 치매의 인지기능 저하도 콜린 결핍과 관련이 있다. 콜린 형성을 담당하는 전뇌 기저부(basal forebrain)는 관통세동맥 (penetrating arterioles)에 의해 혈액공급을 받는데 이 혈관들은 고혈압에 쉽게 영향을 받는다. 콜린은 전뇌 기저부(basal forebrain)에 있는 브로카대각대(diagonal band of Broca), 내측 중격핵(medial septal nuclei), 그리고 마이너트기저핵(nucleus basalis of Meynert)에서 생성되며 대뇌 백질을 경유하여 대뇌 피질로 전달된다. 혈관성 치매환자의 전두엽에서 흔히 관찰되는 열공성 뇌경색이나 백질변성에 의하여 대뇌 피질로 가는 콜린 경로가 차단되어 실행기능(executive function)과 주의집중력에 장애가 초래될 수 있다. 생화학적으로는 혈관성 치매환자의 대뇌 피질, 해마, 선조체, 그리고 뇌척수액에서 아세틸콜린 활동도가 저하되었다. 이런 해부학적 또는 생화학적 증거가 혈관성 인지장애 환자에게 콜린에스테라제 억제제 효용성을 제시하였다. 현재 알쯔하이머 치매의 동반여부에 관계없이 혈관성 인지 장애 환자에게 콜린에스테라제 억제제 치료가 이용되고 있다. 즉, 이러한 콜린에스테라제 억제제로 아세틸콜린의 대사를 감소시키고 뇌에서의 콜린성 뇌신경 연접부위에서의 아세틸콜린의 작용을 증대시킨다.On the other hand, with respect to the dementia, cognitive decline in vascular dementia as well as Alzheimer's dementia is also related to choline deficiency. The basal forebrain, responsible for choline formation, is supplied with blood by penetrating arterioles, which are susceptible to hypertension. Choline is produced in the diagonal band of Broca, the medial septal nuclei, and the nucleus basalis of Meynert in the basal forebrain and enters the cerebral cortex via the cerebral white matter. is transmitted The choline pathway to the cerebral cortex is blocked by lacunar cerebral infarction or white matter degeneration, which is commonly observed in the frontal lobe of patients with vascular dementia, which may cause impairment in executive function and attention. Biochemically, acetylcholine activity was decreased in the cerebral cortex, hippocampus, striatum, and cerebrospinal fluid of patients with vascular dementia. This anatomical or biochemical evidence suggests the efficacy of cholinesterase inhibitors in patients with vascular cognitive impairment. Currently, cholinesterase inhibitor therapy is being used for patients with vascular cognitive impairment, whether or not they have Alzheimer's dementia. That is, these cholinesterase inhibitors reduce the metabolism of acetylcholine and increase the action of acetylcholine in the cholinergic cranial nerve junction in the brain.
그러나, 종래에는 리포익산과 폴리페놀 또는 4-아미노벤질피페리딘 유도체의 컨쥬케이트 화합물에 대해 보고되어 있을 뿐, 리포익산으로부터 유도된 싸이오아세탈 화합물 및 이의 콜린에스터라제에 대한 저해제로서의 용도에 대해서는 아직 보고된 바 없다.However, conventionally, only a conjugate compound of lipoic acid and a polyphenol or 4-aminobenzylpiperidine derivative has been reported, and a thioacetal compound derived from lipoic acid and its use as an inhibitor for cholinesterase have been reported. has not been reported yet.
본 발명자들은 알츠하이머병 치료제를 개발하기 위해 연구를 수행한 결과, 불안정한 다이설파이드 구조를 가진 리포익산을 싸이오아세탈로 변환시킨 신규 리포익산-헤테로사이클 싸이오아세탈 화합물이 콜린에스터라아제 활성을 저해하는 효과가 있음을 발견하고 본 발명을 완성하였다.The present inventors conducted research to develop a therapeutic agent for Alzheimer's disease, and as a result, a novel lipoic acid-heterocyclic thioacetal compound converted from lipoic acid having an unstable disulfide structure into thioacetal inhibits cholinesterase activity. It was found to be effective and the present invention was completed.
따라서, 본 발명의 목적은 콜린에스터라제(ChEs) 저해 활성을 갖는 신규한 리포익산-헤테로사이클 싸이오아세탈 화합물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel lipoic acid-heterocycle thioacetal compound having cholinesterase (ChEs) inhibitory activity.
본 발명의 다른 목적은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물을 유효성분으로 함유하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative diseases containing the lipoic acid-heterocycle thioacetal compound as an active ingredient.
본 발명의 또 다른 목적은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물을 유효성분으로 함유하는 인지능력 개선 또는 퇴행성 질환의 개선용 건강보조식품을 제공하는 것이다.Another object of the present invention is to provide a dietary supplement for improving cognitive ability or improving degenerative diseases containing the lipoic acid-heterocycle thioacetal compound as an active ingredient.
본 발명의 또 다른 목적은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물을 유효성분으로 함유하는 콜린에스터라제의 저해 활성을 위한 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for the inhibitory activity of cholinesterase containing the lipoic acid-heterocycle thioacetal compound as an active ingredient.
본 발명의 일 측면은, 하기 화학식 1로 표시되는 리포익산-헤테로사이클 싸이오아세탈 화합물을 제공한다:One aspect of the present invention provides a lipoic acid-heterocycle thioacetal compound represented by the following formula (1):
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 C6-C20아릴, C3-C20헤테로아릴 또는 이고;R 1 is C6-C20 aryl, C3-C20 heteroaryl or ego;
R2는 C6-C20아릴 또는 C3-C20헤테로아릴이고,R 2 is C6-C20 aryl or C3-C20 heteroaryl;
상기 R1 및 R2의 아릴 또는 헤테로아릴은 C1-C7알킬, 할로겐, C1-C7알콕시, 할로C1-C7알킬, C6-C20아릴옥시, -NR'R'', 시아노 및 니트로로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Aryl or heteroaryl of R 1 and R 2 is C1-C7 alkyl, halogen, C1-C7 alkoxy, haloC1-C7 alkyl, C6-C20 aryloxy, -NR'R'', cyano and nitro may be further substituted with one or more selected from;
R' 및 R''는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C20아릴이고;R' and R'' are each independently hydrogen, C1-C7 alkyl or C6-C20 aryl;
R은 수소 또는 C1-C7알킬이고;R is hydrogen or C 1 -C 7 alkyl;
La는 C1-C10알킬렌이고;L a is C1-C10 alkylene;
m은 2 내지 7의 정수이다.m is an integer from 2 to 7.
본 발명의 다른 측면은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating degenerative diseases containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 측면은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 인지능력 개선 또는 퇴행성 질환의 개선용 건강보조식품을 제공한다.Another aspect of the present invention provides a dietary supplement for improving cognitive ability or improving degenerative diseases containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 측면은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 콜린에스터라제의 저해 활성을 위한 조성물을 제공한다.Another aspect of the present invention provides a composition for the inhibitory activity of cholinesterase containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물은 항산화 활성을 가진 리포익산의 환원, 알데히드 화합물과의 반응 및 아민 화합물과의 반응을 통해 합성된 신규한 구조의 화합물이다.The lipoic acid-heterocyclic thioacetal compound of the present invention is a compound of a novel structure synthesized through reduction of lipoic acid having antioxidant activity, reaction with an aldehyde compound, and reaction with an amine compound.
본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물은 인체에 무해하고, 아세틸콜린에스터라제(AChE; acetylcholinesterase) 및 부티릴콜린에스터라제(BuChE; butyrylcholinesterase)와 같은 콜린에스터라제의 활성을 저해하여 퇴행성 질환, 구체적으로 파킨슨 병, 알츠하이머병 등의 뇌신경 질환의 예방 및 치료에 사용할 수 있을 뿐만 아니라, 퇴행성 질환을 개선시키거나 학습능력 및 기억력을 개선시키는 건강보조식품으로도 활용 가능하다.The lipoic acid-heterocyclic thioacetal compound of the present invention is harmless to the human body and inhibits the activity of cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE; butyrylcholinesterase). Therefore, it can be used not only for the prevention and treatment of degenerative diseases, specifically, for the prevention and treatment of cranial nerve diseases such as Parkinson's disease and Alzheimer's disease, but also can be used as a health supplement to improve degenerative diseases or improve learning ability and memory.
특히, 본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물은 AChE 저해제에 의한 부작용이 적을 뿐만 아니라 알츠하이머병 환자의 뇌에서 활성이 높아 콜린에스터라제 형태 중 최근 많은 관심을 가지고 있는 BuChE만을 선택적으로 저해함과 동시에 아주 강력한 저해활성을 가지고 있으므로, 퇴행성 질환의 예방 및 치료용 약제학적 조성물 및 인지능력 개선 또는 퇴행성 질환의 개선용 건강보조식품의 유효성분으로 사용가능하다.In particular, the lipoic acid-heterocycle thioacetal compound of the present invention selectively inhibits only BuChE, which is of recent interest among cholinesterase forms, due to its high activity in the brain of Alzheimer's disease patients as well as few side effects caused by AChE inhibitors. Since it has a very strong inhibitory activity at the same time, it can be used as an active ingredient in a pharmaceutical composition for the prevention and treatment of degenerative diseases and as an active ingredient in a health supplement for improving cognitive ability or improving degenerative diseases.
이하, 본 발명에 대하여 보다 구체적으로 설명한다. 이 때 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.Hereinafter, the present invention will be described in more detail. If there is no other definition in the technical and scientific terms used at this time, it has the meaning commonly understood by those of ordinary skill in the art to which this invention belongs, and may unnecessarily obscure the subject matter of the present invention in the following description. Descriptions of possible known functions and configurations will be omitted.
다른 정의가 없다면 본 명세서에서 사용되는 모든 용어(기술 및 과학적 용어를 포함)는 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 공통적으로 이해될 수 있는 의미로 사용될 수 있을 것이다. 명세서 전체에서 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있는 것을 의미한다. 또한 단수형은 문구에서 특별히 언급하지 않는 한 복수형도 포함한다.Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used with meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. When a part "includes" a certain component throughout the specification, this means that other components may be further included, rather than excluding other components, unless otherwise stated. The singular also includes the plural, unless the phrase specifically states otherwise.
용어 "치환기(substituent)", "라디칼(radical)", "기(group)", "모이어티(moiety)", 및 "절편(fragment)"은 서로 바꾸어 사용할 수 있다.The terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.
용어, "CA-CB"는 "탄소수가 A 이상이고 B 이하"인 것을 의미하고, 용어 "A 내지 B"는 "A 이상이고 B 이하"인 것을 의미한다.The term "C A -C B " means "the number of carbon atoms is greater than or equal to A and less than or equal to B", and the term "A to B" means "more than A and less than or equal to B".
용어 "알킬"은 탄소 및 수소 원자만으로 구성된 1가의 직쇄 또는 분쇄 포화 탄화수소 라디칼을 의미하는 것으로, 1 내지 7개의 탄소원자, 바람직하게는 1 내지 4개의 탄소원자를 가질 수 있다. 이러한 알킬 라디칼의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 헥실 등을 포함하지만 이에 한정되지는 않는다.The term “alkyl” refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed solely of carbon and hydrogen atoms, and may have from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
용어 "아릴"은 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 유기 라디칼로, 각 고리에 적절하게는 4 내지 7개, 바람직하게는 5 또는 6개의 고리원자를 포함하는 단일 또는 융합고리계를 포함하며, 이때 융합되는 고리는 방향족이거나 비방향족일 수 있다. 또한, 다수개의 아릴이 단일결합으로 연결되어 있는 형태까지 아릴에 포함된다. 본 발명의 도 아릴에 포함된다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐, 플루오레닐, 등을 포함하지만, 이에 한정되지는 않는다.The term "aryl" is an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, including single or fused ring systems comprising suitably 4 to 7, preferably 5 or 6 ring atoms in each ring. In this case, the fused ring may be aromatic or non-aromatic. In addition, even a form in which a plurality of aryls are connected by a single bond is included in aryl. of the present invention Also included in aryl. Specific examples include phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.
용어 "헤테로아릴"은 방향족 고리 골격 원자로서 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 포함하고, 나머지 방향족 고리 골격 원자가 탄소인 아릴 그룹을 의미하는 것으로, 5 내지 6원 단환 헤테로아릴, 및 하나 이상의 벤젠환과 축합된 다환식 헤테로아릴이며, 부분적으로 포화될 수도 있다. 또한, 본 명세서에서의 헤테로아릴은 하나 이상의 헤테로아릴이 단일결합으로 연결된 형태도 포함한다. 상기 헤테로아릴기의 예는 피롤, 퀴놀린, 이소퀴놀린, 피리딘, 피리미딘, 옥사졸, 티아졸, 티아디아졸, 트리아졸, 이미다졸, 벤조이미다졸, 이소옥사졸, 벤조이소옥사졸, 티오펜, 벤조티오펜, 퓨란, 벤조퓨란 등을 포함하지만, 이에 한정되지는 않는다. The term "heteroaryl" refers to an aryl group containing 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeleton atoms, and the remaining aromatic ring skeleton atoms are carbon, and 5 to 6 membered monocyclic heteroaryl , and polycyclic heteroaryl condensed with one or more benzene rings, which may be partially saturated. In addition, heteroaryl in the present specification includes a form in which one or more heteroaryl is connected by a single bond. Examples of the heteroaryl group include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisoxazole, thiophene, benzothiophene, furan, benzofuran, and the like.
용어 "할로" 또는 "할로겐"은 할로겐족 원소를 나타내며, 예컨대, 플루오로, 클로로, 브로모 및 요오도를 포함한다.The term “halo” or “halogen” refers to a halogen element and includes, for example, fluoro, chloro, bromo and iodo.
용어 "알콕시"는 -O-알킬 라디칼로, 1 내지 7개의 탄소원자, 바람직하게는 1 내지 4개의 탄소원자를 가질 수 있다. 여기서 '알킬'은 상기 정의한 바와 같다. 구체적인 예로는 메톡시, 에톡시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시 등을 포함되지만 이에 한정되지는 않는다.The term “alkoxy” is an —O-alkyl radical, which may have 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Here, 'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.
용어 "할로알킬"은 적어도 하나의 할로겐으로 치환된 알킬 라디칼을 의미하는 것으로, 여기서 '알킬'은 상기 정의한 바와 같다. 이러한 할로알킬 라디칼의 예는 플루오로메틸, 트리플루오로메틸, 브로모메틸, 퍼플루오로에틸 등을 포함하지만 이에 한정되지는 않는다.The term "haloalkyl" refers to an alkyl radical substituted with at least one halogen, wherein 'alkyl' is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.
용어 "아릴옥시"는 -O-아릴 라디칼을 의미하는 것으로, 여기서 '아릴'은 상기 정의한 바와 같다. 이러한 아릴옥시 라디칼의 예는 페녹시, 나프톡시 등을 포함하지만 이에 한정되지는 않는다.The term "aryloxy" refers to the radical -O-aryl, where 'aryl' is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, and the like.
용어 "시아노"는 -CN을 의미하고, "니트로"는 -NO2를 의미한다.The term “cyano” means —CN and “nitro” means —NO 2 .
용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 본 발명의 화합물 자체가 가지는 이로운 효능을 저하시키지 않는 본 발명의 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.The term "pharmaceutically acceptable salt" refers to any concentration of a compound of the present invention that has an effective action that is relatively non-toxic and harmless to a patient, in which side effects attributable to the salt do not reduce the beneficial efficacy of the compound of the present invention itself. Any organic or inorganic addition salt is meant.
용어 "예방"이란 본 발명의 조성물의 투여로 퇴행성 질환의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미한다.The term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of degenerative diseases by administration of the composition of the present invention.
용어 "개선"이란 본 발명의 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" refers to any action that at least reduces the severity of a parameter, eg, a symptom, associated with the condition being treated by administration of the composition of the present invention.
용어 "치료"란 본 발명의 조성물의 투여로 퇴행성 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" refers to any action in which symptoms of degenerative diseases are improved or beneficially changed by administration of the composition of the present invention.
용어 "약제학적으로 허용가능한"은 상기 조성물에 노출되는 세포나 인간 등의 개체에게 독성이 없는 특성을 나타내는 것으로, 약학적 제제로 사용하기에 적합한 것을 의미하며, 일반적으로 이러한 사용을 위하여 안전한 것으로 간주되며, 이러한 사용을 위하여 국가의 관리 기관에 의하여 공식적으로 승인되거나 한국 약전 또는 미국 약전의 명단에 있는 것을 의미한다.The term "pharmaceutically acceptable" refers to a property that is non-toxic to cells or humans exposed to the composition, and is suitable for use as a pharmaceutical preparation, and is generally considered safe for such use. and is officially approved for such use by a national regulatory agency or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.
용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다.The term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's sex, age, weight, Health status, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate, treatment duration, factors including drugs used in combination or concomitantly, and other factors well known in the medical field It can be easily determined by a person skilled in the art depending on the factors.
용어 "식품"이란, 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강 기능 식품 및 건강식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.The term "food" means meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes , health functional food, health food, etc., and includes all food in the ordinary sense.
용어 "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The term "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body in accordance with Act No. 6727 of the Health Functional Food Act, and "functionality" refers to the structure and function of the human body. It refers to intake for the purpose of obtaining useful effects for health purposes, such as regulating nutrients or physiological effects.
본 발명에 따른 리포익산-헤테로사이클 싸이오아세탈 화합물은 불안정한 다이설파이드 구조를 가진 리포익산을 싸이오아세탈로 변환시킨 신규 구조의 화합물로서, 아세틸콜린에스터라제(AChE)와 부틸콜린에스터라제(BuChE)의 두 가지 형태를 갖는 콜린에스터라제(ChE; cholinesterase)에 대한 저해 활성을 가지고 있어 퇴행성 질환의 예방 또는 치료용 약제학적 조성물의 유효성분으로 유용하며, 또한, 퇴행성 질환을 개선시키거나 학습능력 및 기억력을 개선시키는 건강보조식품의 유효성분으로도 활용 가능하다.The lipoic acid-heterocycle thioacetal compound according to the present invention is a compound of a novel structure in which lipoic acid having an unstable disulfide structure is converted into thioacetal, and acetylcholinesterase (AChE) and butylcholinesterase ( BuChE) has inhibitory activity on cholinesterase (ChE; cholinesterase) having two forms, so it is useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of degenerative diseases, and also improves or learns degenerative diseases It can also be used as an active ingredient in health supplements that improve ability and memory.
본 발명의 일 측면은, 하기 화학식 1로 표시되는 리포익산-헤테로사이클 싸이오아세탈 화합물을 제공한다:One aspect of the present invention provides a lipoic acid-heterocycle thioacetal compound represented by the following formula (1):
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 C6-C20아릴, C3-C20헤테로아릴 또는 이고;R 1 is C6-C20 aryl, C3-C20 heteroaryl or ego;
R2는 C6-C20아릴 또는 C3-C20헤테로아릴이고,R 2 is C6-C20 aryl or C3-C20 heteroaryl;
상기 R1 및 R2의 아릴 또는 헤테로아릴은 C1-C7알킬, 할로겐, C1-C7알콕시, 할로C1-C7알킬, C6-C20아릴옥시, -NR'R'', 시아노 및 니트로로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Aryl or heteroaryl of R 1 and R 2 is C1-C7 alkyl, halogen, C1-C7 alkoxy, haloC1-C7 alkyl, C6-C20 aryloxy, -NR'R'', cyano and nitro may be further substituted with one or more selected from;
R' 및 R''는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C20아릴이고;R' and R'' are each independently hydrogen, C1-C7 alkyl or C6-C20 aryl;
R은 수소 또는 C1-C7알킬이고;R is hydrogen or C 1 -C 7 alkyl;
La는 C1-C10알킬렌이고;L a is C1-C10 alkylene;
m은 2 내지 7의 정수이다.m is an integer from 2 to 7.
일 실시예에 있어서, 상기 R은 수소 또는 C1-C4알킬일 수 있고, m은 4 내지 6의 정수일 수 있다. In an embodiment, R may be hydrogen or C 1 -C 4 alkyl, and m may be an integer of 4 to 6.
일 실시예에 있어서, 상기 리포익산-헤테로사이클 싸이오아세탈 화합물은 하기 화학식 2로 표시될 수 있다.In one embodiment, the lipoic acid-heterocycle thioacetal compound may be represented by the following formula (2).
[화학식 2][Formula 2]
상기 화학식 2에서, R1 및 La는 상기 화학식 1에서의 정의와 동일하다.In Formula 2, R 1 and L a are the same as defined in Formula 1 above.
구체적으로, 상기 R1은 C6-C12아릴 또는 이고; R2는 C6-C12아릴이고; 상기 R1 및 R2의 아릴은 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 및 니트로로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고; R' 및 R''는 각각 독립적으로 수소 또는 C1-C4알킬이고; La는 C1-C5알킬렌일 수 있다.Specifically, R 1 is C6-C12 aryl or ego; R 2 is C6-C12 aryl; The aryl of R 1 and R 2 may be further substituted with one or more selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' and nitro; R' and R'' are each independently hydrogen or C1-C4 alkyl; L a may be C1-C5 alkylene.
보다 구체적으로, 상기 R1은 , 또는 이고; Ra 및 Rb는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 또는 니트로이고; R' 및 R''는 각각 독립적으로 수소 또는 C1-C4알킬이고; x 및 y는 각각 독립적으로 0 내지 5의 정수이고; La는 C1-C3알킬렌일 수 있다. More specifically, the R 1 is , or ego; R a and R b are each independently C1-C4alkyl, halogen, C1-C4alkoxy, haloC1-C4alkyl, -NR'R'' or nitro; R' and R'' are each independently hydrogen or C1-C4 alkyl; x and y are each independently an integer from 0 to 5; L a may be C1-C3 alkylene.
보다 바람직하게, 상기 R1은 , , 또는 이고; Ra 및 Rb는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 또는 니트로이고; R' 및 R''는 각각 독립적으로 C1-C4알킬이고; La는 C2-C3알킬렌일 수 있다.More preferably, the R 1 is , , or ego; R a and R b are each independently C1-C4alkyl, halogen, C1-C4alkoxy, haloC1-C4alkyl, -NR'R'' or nitro; R' and R'' are each independently C1-C4 alkyl; L a may be C2-C3 alkylene.
구체적으로, Ra 및 Rb는 각각 독립적으로 메틸, 에틸, 프로필, 부틸, 클로로, 플루오로, 메톡시, 에톡시, 부톡시, 트리플루오로메틸, 퍼플루오로에틸, 디메틸아미노 또는 니트로이고; La는 에틸렌 또는 프로필렌일 수 있다.Specifically, R a and R b are each independently methyl, ethyl, propyl, butyl, chloro, fluoro, methoxy, ethoxy, butoxy, trifluoromethyl, perfluoroethyl, dimethylamino or nitro; L a may be an ethylene or propylene.
일 실시예에 따른 리포익산-헤테로사이클 싸이오아세탈 화합물은 아세틸콜린에스터라제(AChE)와 부틸콜린에스터라제(BuChE)의 두 가지 형태의 콜린에스터라제(ChE)에 대해 우수한 저해 활성을 가지며, 특히 콜린에스터라제(ChE) 형태 중 선택적으로 부티릴콜린에스터라제(BuChE)에 대해 보다 우수한 저해 활성을 가진다.Lipoic acid-heterocycle thioacetal compound according to an embodiment exhibits excellent inhibitory activity against two types of cholinesterase (ChE), acetylcholinesterase (AChE) and butylcholinesterase (BuChE). In particular, it has better inhibitory activity against butyrylcholinesterase (BuChE) selectively among cholinesterase (ChE) forms.
일 실시예에 있어서, 상기 리포익산-헤테로사이클 싸이오아세탈 화합물은 하기 구조로부터 선택될 수 있으나, 이에 한정되는 것은 아니다.In one embodiment, the lipoic acid-heterocycle thioacetal compound may be selected from the following structures, but is not limited thereto.
본 발명에 따른 상기 리포익산-헤테로사이클 싸이오아세탈 화합물들은, 이후 설명하는 바와 같이, 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있으며, 하기의 제조방법들은 일부 예시에 지나지 않으며, 그 이외의 방법들도 존재할 수 있음은 물론이다.The lipoic acid-heterocycle thioacetal compounds according to the present invention may be prepared by known methods and/or various methods based on techniques in the field of organic synthesis, as described below, and the following method These are only some examples, and it goes without saying that other methods may exist.
일 실시예에 따른 리포익산-헤테로사이클 싸이오아세탈 화합물은 이후 설명하는 바와 같이, 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있으며, 하기의 제조방법들은 일부 예시에 지나지 않으며, 그 이외의 방법들도 존재할 수 있음은 물론이다.Lipoic acid-heterocycle thioacetal compound according to an embodiment may be prepared by various methods based on known methods and/or techniques in the field of organic synthesis, as described below, and the following preparation methods are Of course, these are only some examples, and other methods may exist.
예를 들어, 상기 화학식 1의 리포익산-헤테로사이클 싸이오아세탈 화합물은 하기 반응식 1에 도시된 바와 같이, 리포익산(Lipoic acid; LA)을 환원시켜 디하이드로리포익산(Dihydrolipoic acid; DHLA)를 제조한 후 다양한 알데히드 화합물(a1)과 반응시켜 싸이오아세탈 중간체 화합물(M)을 제조하고, 이를 다양한 아민 화합물(a2)과 반응시켜 제조될 수 있다:For example, as shown in Scheme 1 below, the lipoic acid-heterocycle thioacetal compound of Formula 1 reduces lipoic acid (LA) to prepare dihydrolipoic acid (DHLA). It can be prepared by reacting with various aldehyde compounds (a1) after preparing a thioacetal intermediate compound (M), and reacting it with various amine compounds (a2):
[반응식 1][Scheme 1]
상기 반응식 1에서, R1, R, La 및 m은 상기 화학식 1에서의 정의와 동일하다.In Scheme 1, R 1 , R, L a and m are the same as defined in Formula 1 above.
경우에 따라 상기 반응 생성물을 통상적인 방법, 예를 들어, 재결정과 크로마토그래피를 이용하여 분리 정제할 수 있다.In some cases, the reaction product may be separated and purified using a conventional method, for example, recrystallization and chromatography.
일 실시예에 따른 상기 리포익산-헤테로사이클 싸이오아세탈 화합물은 생체내 흡수를 증진시키거나 용해도를 증가시키기 위하여 프로드럭, 수화물, 용매화물 및 약학적으로 허용가능한 염의 형태로 만들어 사용할 수 있으므로, 상기의 프로드럭, 수화물, 용매화물 및 약학적으로 허용가능한 염 역시 본 발명의 범위에 속한다. 염 및 용매화물의 경우에 추가적인 이온 및 용매 잔기는 또한 무독성이어야 한다. 본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물은 상이한 동질이상 형태로 존재할 수 있으며, 본 발명은 상기와 같은 모든 형태들을 포함하고자 한다.The lipoic acid-heterocycle thioacetal compound according to an embodiment can be used in the form of prodrugs, hydrates, solvates, and pharmaceutically acceptable salts to enhance absorption or increase solubility in vivo. Prodrugs, hydrates, solvates and pharmaceutically acceptable salts of In the case of salts and solvates the additional ions and solvent moieties should also be non-toxic. The lipoic acid-heterocycle thioacetal compound of the present invention may exist in different polymorphic forms, and the present invention is intended to include all of the above forms.
일 실시예에 따른 상기 리포익산-헤테로사이클 싸이오아세탈 화합물, 그의 프로드럭, 수화물, 용매화물 및 약학적으로 허용가능한 염은 우수한 콜린에스테라제 저해 작용을 나타낸다.The lipoic acid-heterocycle thioacetal compound, prodrugs, hydrates, solvates and pharmaceutically acceptable salts thereof according to an embodiment exhibits excellent cholinesterase inhibitory action.
본 발명의 다른 측면은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating degenerative diseases containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.
일 실시예에 있어서, 상기 퇴행성 질환은 구체적으로 파킨슨 병, 알츠하이머병과 같은 뇌신경질환을 포함한다.In one embodiment, the degenerative disease specifically includes a cranial nerve disease such as Parkinson's disease or Alzheimer's disease.
상기 약제학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면 염산, 브롬산, 황산, 황산수소나트륨, 인산, 질산, 탄산 등과 같은 무기산과의 염, 개미산, 초산, 프로피온산, 옥살산, 석신산, 벤조산, 시트르산, 말레인산, 말론산, 타르타르산, 글루콘산, 락트산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과의 염, 글리신, 알라닌, 바닐린, 이소루신, 세린, 시스테인, 시스틴, 아스파라진산, 글루타민, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산과의 염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산과의 염, 나트륨, 칼륨 등의 알칼리금속과의 반응에 의한 금속염, 또는 암모늄 이온과의 염 등을 포함한다.The pharmaceutically acceptable salt can be prepared by a conventional method in the art, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, etc., formic acid , acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) Salts with organic acids, salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and salts with sulfonic acids such as phonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, or salts with ammonium ions.
일 실시예에 따른 상기 약제학적 조성물은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 약제학적으로 허용 가능한 이들의 염에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구 투여용 제제 또는 비경구 투여용 제제로 제조하여, 상기 퇴행성 질환의 치료에 사용될 수 있다.The pharmaceutical composition according to an embodiment is the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the pharmaceutical field. In conventional formulations, for example, tablets, capsules, troches, solutions, suspensions, etc. for oral administration or parenteral administration preparations can be prepared and used for the treatment of the degenerative disease.
상기 약제학적 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소듐 알진산염, 메틸셀룰로오스, 소듐 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. 이러한 부형제의 비율 및 성질은 선택된 정제의 용해도 및 화학적 특성, 선택된 투여경로 및 표준 약제 실무에 의해 결정될 수 있다.Excipients that can be used in the pharmaceutical composition include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, arginic acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like. The proportions and properties of these excipients can be determined by the solubility and chemical properties of the selected tablet, the route of administration selected, and standard pharmaceutical practice.
일 실시예에 따른 상기 리포익산-헤테로사이클 싸이오아세탈 화합물의 인체에 대한 투여용량은 총 1일 용량 범위는 0.01 내지 1000 ㎎/㎏/일(day) 일 수 있으나, 이는 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.The dosage for the human body of the lipoic acid-heterocycle thioacetal compound according to an embodiment may be in a total daily dosage range of 0.01 to 1000 mg/kg/day (day), but this is the patient's age, weight, It may vary depending on gender, dosage form, health condition and disease degree, and may be administered in divided doses once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.
본 발명의 또 다른 측면은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 인지능력 개선 또는 알츠하이머병 또는 퇴행성 질환의 개선용 건강보조식품을 제공한다.Another aspect of the present invention provides a health supplement for improving cognitive ability or Alzheimer's disease or degenerative disease containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient. .
상기 건강기능식품 조성물은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강기능식품은 유효성분인 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health functional food composition may be provided in the form of powders, granules, tablets, capsules, syrups or beverages, and the health functional food is an active ingredient, in addition to the lipoic acid-heterocycle thioacetal compound, other food or food additives and They are used together and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.
상기 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof , organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like. In addition, it may contain the pulp for the production of natural fruit juice and fruit juice beverages and vegetable beverages. These components may be used independently or in combination.
또한 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, '식품첨가물'로서의 적합여부는 다른 규정이 없는 한 식품의약품안정청에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the health functional food may additionally contain food additives, and the suitability as a 'food additive' is determined according to the general rules and general test methods of the Food Additives Code approved by the Food and Drug Administration, unless otherwise specified. It is judged according to the standards and standards.
상기 '식품첨가물공전'에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합 제제류들을 들 수 있다.Items listed in the 'Food Additives Codex', for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as depigmentation, licorice extract, crystalline cellulose, and guar gum, sodium L-glutamate Mixed preparations such as preparations, noodles-added alkalis, preservatives, and tar color preparations may be mentioned.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages, vitamin complexes, and the like, and includes all health foods in the ordinary sense.
본 발명의 또 다른 측면은 상기 리포익산-헤테로사이클 싸이오아세탈 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 콜린에스터라제의 저해 활성을 위한 조성물을 제공한다.Another aspect of the present invention provides a composition for the inhibitory activity of cholinesterase containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.
이하, 실시예 및 실험예를 통해 본 발명을 상세히 설명한다. 다만, 이는 본 발명의 예시로 제시되는 것으로 어떠한 의미로도 이에 의해 본 발명의 권리범위가 한정되는 것은 아니며, 본 발명의 권리범위는 후술하는 청구범위에 따라 정의될 뿐이다.Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, this is presented as an example of the present invention, and the scope of the present invention is not limited by this in any sense, and the scope of the present invention is only defined according to the following claims.
[제조예 1] Dihydrolipoic acid (화합물 DHLA)의 제조[Preparation Example 1] Preparation of Dihydrolipoic acid (Compound DHLA)
Lipoic acid (LA, 4 g, 19.3 mmol)을 0.25N Sodium bicarbonate (NaHCO3, 130 mL)에 용해시킨 후 0℃에서 Sodium borohydride (NaBH4, 1.86 g, 49.1 mmol)을 첨가하였다. 3시간 후, 4N HCl로 가하여 물 층의 pH를 1로 맞추었다. Dichloromethane (DCM)으로 워컵(work-up)한 후, 무수 MgSO4로 처리 후 여과하고, 얻어진 여액을 Evaporator로 감압 농축하여 노란색의 oily 화합물 DHLA (4.02 g, 99.5 % yield)을 얻었다.Lipoic acid (LA, 4 g, 19.3 mmol) was dissolved in 0.25N sodium bicarbonate (NaHCO 3 , 130 mL), and then sodium borohydride (NaBH 4 , 1.86 g, 49.1 mmol) was added at 0°C. After 3 hours, the pH of the water layer was adjusted to 1 by addition of 4N HCl. After work-up with dichloromethane (DCM), treated with anhydrous MgSO 4 , filtered, and the resulting filtrate was concentrated under reduced pressure with an evaporator to obtain a yellow oily compound DHLA (4.02 g, 99.5 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.31 (d, J = 7.6 Hz, 1H), 1.35 (t, J = 8 Hz, 1H), 1.62 (m, 7H), 1.91 (m, 1H), 2.38 (t, J = 7.6 Hz, 2H), 2.71 (m, 2H), 2.92 (m, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.31 (d, J = 7.6 Hz, 1H), 1.35 (t, J = 8 Hz, 1H), 1.62 (m, 7H), 1.91 (m, 1H), 2.38 (t, J = 7.6 Hz, 2H), 2.71 (m, 2H), 2.92 (m, 1H)
[실시예 1] 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 1)의 제조[Example 1] 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 1 ) Produce
(1) 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-1)의 제조(1) Preparation of 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-1)
Ar purge를 하고 drying tube를 설치한 뒤, 4-(dimethylamino)benzaldehyde (화합물 a1-1, 0.36 g, 2.4 mmol)을 DCM으로 용해시켰다. 화합물 DHLA (0.6 g, 2.9 mmol)을 가하고, Para-toluene sulfonic acid (p-TsOH, 0.02 g, 0.1 mmol)을 가하였다. 50℃에서 8시간동안 환류시킨 후, Brine를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:Hex:Ether=3:7:0.2)로 분리하여 흰색 고체의 화합물 M-1 (280 mg, 34% yield)을 얻었다.After Ar purge and drying tube was installed, 4-(dimethylamino)benzaldehyde (compound a1-1, 0.36 g, 2.4 mmol) was dissolved in DCM. Compound DHLA (0.6 g, 2.9 mmol) was added, and Para-toluene sulfonic acid (p-TsOH, 0.02 g, 0.1 mmol) was added. After refluxing at 50° C. for 8 hours, the reaction was terminated using Brine and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex:Ether=3:7:0.2) to obtain compound M-1 (280 mg, 34% yield) as a white solid.
1H NMR (DMSO, 400 MHz) δ 1.46 (m, 8H), 2.19 (t, J = 7.2 Hz, 2H), 2.88 (s, 6H), 2.91 (m, 1H), 3.01 (m, 2H), 5.24 (S, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 11.98 (s, 1H) 1 H NMR (DMSO, 400 MHz) δ 1.46 (m, 8H), 2.19 (t, J = 7.2 Hz, 2H), 2.88 (s, 6H), 2.91 (m, 1H), 3.01 (m, 2H), 5.24 (S, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 11.98 (s, 1H)
(2) 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 1)의 제조(2) Preparation of 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 1)
Ar purge를 하고 화합물 M-1 (300 mg, 0.89 mmol)을 DCM으로 용해시켰다. Ice Bath 하에서 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 429 mg, 2.23 mmol)를 소분하여 가하고 20분 후, N-Hydroxysuccinimide (NHS, 206 mg, 1.79 mmol)를 가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:HEX=1:1)로 분리하여 2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoate 를 얻었으며, 이는 바로 다음 반응에 이용하였다. Ice Bath 하에서 2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoate (180 mg, 0.43 mmol)을 DCM으로 용해시켰다. 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.09 mL, 0.64 mmol)을 적가하였다. overnight 반응시킨 후, 감압농축해서 컬럼 크로마토그래피(DCM:MeOH=9.2:0.8)로 분리하여 oily 화합물 1 (10 mg, 5% yield)을 수득하였다.Ar purge was carried out and compound M-1 (300 mg, 0.89 mmol) was dissolved with DCM. In an ice bath, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 429 mg, 2.23 mmol) was added in portions, and 20 minutes later, N-Hydroxysuccinimide (NHS, 206 mg, 1.79 mmol) was added. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=1:1) to 2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4- yl)pentanoate was obtained, which was immediately used in the next reaction. 2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoate (180 mg, 0.43 mmol) was dissolved in DCM under an ice bath. 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.64 mmol) was added dropwise. After overnight reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.2:0.8) to obtain oily compound 1 (10 mg, 5% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.5〕; 1H NMR (DMSO, 400 MHz) δ 1.41 (m, 14H), 2.03 (t, J = 7.2 Hz, 2H), 2.32 (s, 6H), 2.88 (m, 8H), 3.00 (m, 1H), 3.13 (m, 2H), 5.23 (S, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H).TLC [DCM:MeOH=9:1 Rf =0.5]; 1 H NMR (DMSO, 400 MHz) δ 1.41 (m, 14H), 2.03 (t, J = 7.2 Hz, 2H), 2.32 (s, 6H), 2.88 (m, 8H), 3.00 (m, 1H), 3.13 (m, 2H), 5.23 (S, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H).
[실시예 2] (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 2)의 제조[Example 2] (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide ( Preparation of compound 2 )
(1) (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-2)의 제조(1) Preparation of (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoic acid (Compound M-2)
Ar purge를 하고 drying tube를 설치한 뒤, 4-(dimethylamino)cinnamaldehyde (화합물 a1-2, 0.42 g, 2.4 mmol)을 DCM으로 용해시켰다. 화합물 DHLA (0.6 g, 2.9 mmol)을 넣고, P-TsOH (0.02 g, 0.1 mmol)을 가하였다. 50℃에서 10시간동안 환류한 뒤, Brine를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:Hex=1:1)로 분리하여 흰색 고체의 화합물 M-2 (280 mg, 31% yield)를 얻었다.After ar purge and drying tube was installed, 4-(dimethylamino)cinnamaldehyde (compound a1-2, 0.42 g, 2.4 mmol) was dissolved in DCM. Compound DHLA (0.6 g, 2.9 mmol) was added, and P-TsOH (0.02 g, 0.1 mmol) was added thereto. After refluxing at 50° C. for 10 hours, the reaction was terminated using Brine and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex=1:1) to obtain compound M-2 (280 mg, 31% yield) as a white solid.
1H NMR (DMSO, 400 MHz) δ 1.44 (m, 8H), 2.20 (t, J = 7.2 Hz, 2H), 2.90 (m, 8H), 2.97 (m, 1H), 4.98 (d, J = 8.4 Hz, 1H), 5.98 (dd, J = 8.4 Hz, 15.6 Hz, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 11.96 (s, 1H) 1 H NMR (DMSO, 400 MHz) δ 1.44 (m, 8H), 2.20 (t, J = 7.2 Hz, 2H), 2.90 (m, 8H), 2.97 (m, 1H), 4.98 (d, J = 8.4) Hz, 1H), 5.98 (dd, J = 8.4 Hz, 15.6 Hz, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 11.96 (s, 1H)
(2) (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 2)의 제조(2) (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (compound 2 ) manufacturing
Ar purge를 하고 화합물 M-2 (100 mg, 0.27 mmol)을 DCM으로 용해시켰다. Ice Bath 하에서 EDC (130 mg, 0.68 mmol)를 소분하여 넣고 20분 후, NHS (63 mg, 0.55 mmol)를 가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:HEX=6.4)로 분리하여 (E)-2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoate 를 얻었으며, 이는 바로 다음 반응에 이용하였다. Ice Bath 하에서 (E)-2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoate (89.4 mg, 0.19 mmol)을 DCM으로 용해시켰다. 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.04 mL, 0.29 mmol)을 적가하였다. overnight 반응시킨 후, 감압농축해서 컬럼 크로마토그래피(DCM:MeOH=9.3:0.7)로 분리하여 oily 화합물 2 (28 mg, 30% yield)을 수득하였다.Ar purge was carried out and compound M-2 (100 mg, 0.27 mmol) was dissolved in DCM. EDC (130 mg, 0.68 mmol) was added in small portions under an ice bath, and after 20 minutes, NHS (63 mg, 0.55 mmol) was added. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=6.4) to (E)-2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)styryl)-1,3-dithian- 4-yl)pentanoate was obtained, which was immediately used in the next reaction. (E)-2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoate (89.4 mg, 0.19 mmol) was dissolved in DCM under an ice bath. was dissolved with 1-(2-aminoethyl)piperidine (compound a2-1, 0.04 mL, 0.29 mmol) was added dropwise. After overnight reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.3:0.7) to obtain oily compound 2 (28 mg, 30% yield).
TLC 〔EA:Hex=1:1 Rf = 0.04(바닥)〕; 1H NMR (DMSO, 400 MHz) δ 1.43 (m, 12H), 2.05 (m, 4H), 2.31 (m, 4H), 2.95 (m, 9H), 3.14 (m, 2H), 4.98 (d, J = 8.4 Hz, 1H), 5.98 (dd, J = 8.4 Hz, 15.6 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.68 (m, 1H); 13C NMR (DMSO, 100MHz) δ 24.2, 25.5, 25.6, 25.6, 25.7, 30.9, 32.8, 35.9, 36.4, 40.4, 44.5, 49.3, 54.4, 58.1, 58.2, 112.5, 112.6, 121.1, 123.9, 128.0, 133.3, 150.7, 172.3.TLC [EA:Hex=1:1 R f = 0.04 (bottom)]; 1 H NMR (DMSO, 400 MHz) δ 1.43 (m, 12H), 2.05 (m, 4H), 2.31 (m, 4H), 2.95 (m, 9H), 3.14 (m, 2H), 4.98 (d, J = 8.4 Hz, 1H), 5.98 (dd, J = 8.4 Hz, 15.6 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.68 (m, 1H); 13 C NMR (DMSO, 100 MHz) δ 24.2, 25.5, 25.6, 25.6, 25.7, 30.9, 32.8, 35.9, 36.4, 40.4, 44.5, 49.3, 54.4, 58.1, 58.2, 112.5, 112.6, 121.1, 123.9, 128.0, 133.3 , 150.7, 172.3.
[실시예 3] N-(2-(piperidin-1-yl)ethyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 3)의 제조[Example 3] Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 3 )
(1) 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-3)의 제조(1) Preparation of 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-3)
Ar purge를 하고 drying tube를 설치한 뒤, o-tolualdehyde (화합물 a1-3, 0.29 g, 2.4 mmol)을 DCM으로 용해시켰다. 화합물 DHLA (0.6 g, 2.9 mmol)을 넣고, P-TsOH (0.02 g, 0.14 mmol)을 가하였다. 45℃에서 12시간동안 환류한 뒤, Brine를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:Hex=7:3)로 분리하여 흰색 고체의 화합물 M-3 (610 mg, 81% yield)을 얻었다.After ar purge and drying tube was installed, o-tolualdehyde (compound a1-3, 0.29 g, 2.4 mmol) was dissolved in DCM. Compound DHLA (0.6 g, 2.9 mmol) was added, and P-TsOH (0.02 g, 0.14 mmol) was added thereto. After refluxing at 45° C. for 12 hours, the reaction was terminated using Brine and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex=7:3) to obtain compound M-3 (610 mg, 81% yield) as a white solid.
1H NMR (DMSO, 400 MHz) δ 1.46 (m, 8H), 2.20 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.95 (m, 1H), 3.14 (m, 2H), 5.49 (s, 1H), 7.21 (m, 3H), 7.44 (m, 1H), 11.99 (s, 1H) 1 H NMR (DMSO, 400 MHz) δ 1.46 (m, 8H), 2.20 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.95 (m, 1H), 3.14 (m, 2H), 5.49 (s, 1H), 7.21 (m, 3H), 7.44 (m, 1H), 11.99 (s, 1H)
(2) N-(2-(piperidin-1-yl)ethyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 3)의 제조(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 3)
Ar purge를 하고 화합물 M-3 (300 mg, 0.97 mmol)을 DCM으로 용해시켰다. Ice Bath 하에서 EDC (460 mg, 2.42 mmol)를 소분하여 넣고 20분 후, NHS (220 mg, 1.93 mmol)를 가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:HEX=7:3)로 분리하여 2,5-dioxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoate 를 얻었으며, 이는 바로 다음 반응에 이용하였다. Ice Bath 하에서 2,5-dioxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoate (133 mg, 0.32 mmol)을 DCM으로 용해시켰다. 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.07 mL, 0.48 mmol)을 적가하였다. overnight 반응시킨 후, 감압농축해서 컬럼 크로마토그래피(DCM:MeOH=9.2:0.8)로 분리하여 끈적한 고체 화합물 3 (99 mg, 72% yield)을 수득하였다.Ar purge was carried out and compound M-3 (300 mg, 0.97 mmol) was dissolved with DCM. EDC (460 mg, 2.42 mmol) was added in small portions under an ice bath, and after 20 minutes, NHS (220 mg, 1.93 mmol) was added. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=7:3) to obtain 2,5-dioxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl 5-(2-(o-tolyl)-1, 3-dithian-4-yl)pentanoate was obtained, which was immediately used in the next reaction. 2,5-dioxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoate (133 mg, 0.32 mmol) in an ice bath was dissolved with DCM. 1-(2-aminoethyl)piperidine (compound a2-1, 0.07 mL, 0.48 mmol) was added dropwise. After the overnight reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.2:0.8) to obtain a sticky solid compound 3 (99 mg, 72% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.58〕; 1H NMR (DMSO, 400 MHz) δ 1.44 (m, 14H), 2.04 (t, J = 7.2 Hz, 2H), 2.29 (m, 6H), 2.38 (s, 3H), 2.94 (m, 1H), 3.12 (m, 4H), 5.47 (s, 1H), 7.20 (m, 3H), 7.43 (m, 1H), 7.68 (s, 1H); 13C NMR (DMSO, 100 MHz) δ 19.14 (2C), 24.3, 25.6 (2C), 25.8, 31.8, 32.9, 35.6, 35.9, 36.5, 45.5, 48.5, 54.4 (2C), 58.2, 126.8, 127.9, 128.4, 130.8, 135.4, 137.7, 172.3.TLC [DCM:MeOH=9:1 Rf =0.58]; 1 H NMR (DMSO, 400 MHz) δ 1.44 (m, 14H), 2.04 (t, J = 7.2 Hz, 2H), 2.29 (m, 6H), 2.38 (s, 3H), 2.94 (m, 1H), 3.12 (m, 4H), 5.47 (s, 1H), 7.20 (m, 3H), 7.43 (m, 1H), 7.68 (s, 1H); 13 C NMR (DMSO, 100 MHz) δ 19.14 (2C), 24.3, 25.6 (2C), 25.8, 31.8, 32.9, 35.6, 35.9, 36.5, 45.5, 48.5, 54.4 (2C), 58.2, 126.8, 127.9, 128.4 , 130.8, 135.4, 137.7, 172.3.
[실시예 4] 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 4)의 제조[Example 4] 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl) Preparation of ethyl)pentanamide (Compound 4 )
(1) 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-4)의 제조(1) Preparation of 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoic acid (Compound M-4)
Ar purge를 하고 drying tube를 설치한 뒤, Piperonal (화합물 a1-4, 0.69 g, 4.61 mmol)을 DCM으로 용해시켰다. 화합물 DHLA (0.8 g, 3.84 mmol)을 넣고, P-TsOH (0.03 g, 0.19 mmol)을 가하였다. overnight 후, Brine를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:Hex=2:3)로 분리하여 흰색 고체의 화합물 M-4 (810 mg, 61% yield)을 얻었다.After Ar purge and drying tube was installed, Piperonal (Compound a1-4, 0.69 g, 4.61 mmol) was dissolved with DCM. Compound DHLA (0.8 g, 3.84 mmol) was added, and P-TsOH (0.03 g, 0.19 mmol) was added thereto. After overnight, the reaction was terminated using Brine and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex=2:3) to obtain compound M-4 (810 mg, 61% yield) as a white solid.
1H NMR (DMSO, 400 MHz) δ 1.45 (m, 8H), 2.19 (t, J = 7.2 Hz, 2H), 2.94 (m, 1H), 3.02 (m, 2H), 5.30 (s, 1H), 6.02 (s, 2H), 6.88 (m, 1H), 8.89 (m, 1H), 6.92 (m, 1H), 12.00 (s, 1H) 1 H NMR (DMSO, 400 MHz) δ 1.45 (m, 8H), 2.19 (t, J = 7.2 Hz, 2H), 2.94 (m, 1H), 3.02 (m, 2H), 5.30 (s, 1H), 6.02 (s, 2H), 6.88 (m, 1H), 8.89 (m, 1H), 6.92 (m, 1H), 12.00 (s, 1H)
(2) 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 4)의 제조(2) 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl) Preparation of pentanamide (compound 4)
Ar purge를 하고 화합물 M-4 (500 mg, 1.47 mmol)을 DCM으로 용해시켰다. Ice Bath 하에서 EDC (700 mg, 3.67 mmol)를 소분하여 넣고 20분 후, NHS (340 mg, 2.94 mmol)를 가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(EA:HEX=7:3)로 분리하여 2,5-dioxopyrrolidin-1-yl 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoate 를 얻었으며, 이는 바로 다음 반응에 이용하였다. Ice Bath 하에서 2,5-dioxopyrrolidin-1-yl 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoate (342 mg, 0.78 mmol)을 DCM으로 용해시켰다. 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.17 mL, 1.17 mmol)을 적가하였다. overnight 반응시킨 후, 감압농축해서 컬럼 크로마토그래피(DCM:MeOH=9.7:0.3)로 분리하여 끈적한 고체 화합물 4 (289 mg, 82% yield)을 수득하였다.Ar purge was carried out and compound M-4 (500 mg, 1.47 mmol) was dissolved with DCM. EDC (700 mg, 3.67 mmol) was added in small portions under an ice bath, and after 20 minutes, NHS (340 mg, 2.94 mmol) was added. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=7:3) to 2,5-dioxopyrrolidin-1-yl 5-(2-(benzo[d][1,3]dioxol-5-yl)- 1,3-dithian-4-yl)pentanoate was obtained, which was immediately used in the next reaction. 2,5-dioxopyrrolidin-1-yl 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoate (342 mg, 0.78 mmol) was dissolved with DCM. 1-(2-aminoethyl)piperidine (compound a2-1, 0.17 mL, 1.17 mmol) was added dropwise. After the overnight reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.7:0.3) to obtain a sticky solid compound 4 (289 mg, 82% yield).
TLC 〔DCM:MeOH=9.5:0.5 Rf = 0.43, 0.26〕; 1H NMR (DMSO, 400 MHz) δ 1.43 (m, 14H), 2.03 (t, J = 7.2 Hz, 2H), 2.29 (m, 6H), 2.93 (m, 1H), 3.01 (t, J = 12.0 Hz, 2H), 3.12 (q, J = 6.4 Hz, 2H), 5.30 (s, 1H), 6.02 (s, 2H), 6.89 (m, 3H), 7.69 (s, 1H); 13C NMR (DMSO, 100 MHz) δ 24.4, 25.5, 25.6, 25.9 (2C), 31.8, 32.7, 35.6, 35.8, 36.6, 45.6, 51.0, 54.5 (2C), 58.3, 101.6, 108.3, 108.8, 121.5, 133.5, 147.5, 147.7, 172.2.TLC [DCM:MeOH=9.5:0.5 R f =0.43, 0.26]; 1 H NMR (DMSO, 400 MHz) δ 1.43 (m, 14H), 2.03 (t, J = 7.2 Hz, 2H), 2.29 (m, 6H), 2.93 (m, 1H), 3.01 (t, J = 12.0) Hz, 2H), 3.12 (q, J = 6.4 Hz, 2H), 5.30 (s, 1H), 6.02 (s, 2H), 6.89 (m, 3H), 7.69 (s, 1H); 13 C NMR (DMSO, 100 MHz) δ 24.4, 25.5, 25.6, 25.9 (2C), 31.8, 32.7, 35.6, 35.8, 36.6, 45.6, 51.0, 54.5 (2C), 58.3, 101.6, 108.3, 108.8, 121.5, 133.5, 147.5, 147.7, 172.2.
[실시예 5] 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 5)의 제조[Example 5] Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 5 )
(1) 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-5)의 제조(1) Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-5)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 4-Chlorobenzaldehyde (화합물 a1-5, 0.4 g, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 Boron trifluoride diethyl etherate (BF3OEt2, 0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 무색 oily 화합물 M-5 (660 mg, 83.1 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 4-Chlorobenzaldehyde (compound a1-5, 0.4 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, boron trifluoride diethyl etherate (BF 3 OEt 2 , 0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain colorless oily compound M-5 (660 mg, 83.1 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 5.12 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 5.12 (s, 1H) , 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H)
(2) 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 5)의 제조(2) Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 5)
Ar purge를 하고 화합물 M-5 (200 mg, 0.60 mmol)을 DCM으로 용해시켰다. N,N-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.10 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 하얀색 고체 화합물 5 (70 mg, 26.2 % yield)을 수득하였다.Ar purge was carried out and compound M-5 (200 mg, 0.60 mmol) was dissolved in DCM. After 10 minutes of addition of N,N-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol), EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (Compound a2-1 , 0.10 mL, 0.70 mmol) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give compound 5 (70 mg, 26.2 % yield) as a white solid.
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.18 (t, J = 4.8 Hz, 3H), 2.41 (m, 6H), 2.99 (m, 3H), 3.33 (d, J = 3.6 Hz, 2H), 5.11 (s, 1H), 7.30 (d, J = 5.6 Hz, 2H), 7.39 (d, J = 5.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 24.1, 25.4, 25.7 (3C), 32.4, 32.5, 35.7, 35.8, 36.4, 46.0, 51.5, 54.2 (2C), 57.2, 128.9 (2C), 129.1 (2C), 134.1, 137.3, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.18 (t, J = 4.8 Hz, 3H), 2.41 (m, 6H), 2.99 (m, 3H) , 3.33 (d, J = 3.6 Hz, 2H), 5.11 (s, 1H), 7.30 (d, J = 5.6 Hz, 2H), 7.39 (d, J = 5.6 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.1, 25.4, 25.7 (3C), 32.4, 32.5, 35.7, 35.8, 36.4, 46.0, 51.5, 54.2 (2C), 57.2, 128.9 (2C), 129.1 (2C) , 134.1, 137.3, 172.7.
[실시예 6] 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 6)의 제조[Example 6] Preparation of 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 6 )
(1) 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-6)의 제조(1) Preparation of 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-6)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 2-Chlorobenzaldehyde (화합물 a1-6, 0.32 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 무색 oily 화합물 M-6 (740 mg, 93.1 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 2-Chlorobenzaldehyde (compound a1-6, 0.32 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain colorless oily compound M-6 (740 mg, 93.1 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.62 (s, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.62 (s, 1H) , 7.22 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H)
(2) 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 6)의 제조(2) Preparation of 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 6)
Ar purge를 하고 화합물 M-6 (200 mg, 0.60 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.10 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 무색 oily 화합물 6 (40 mg, 15.0% yield)을 수득하였다.Ar purge was carried out and compound M-6 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to obtain colorless oily compound 6 (40 mg, 15.0% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.63 (m, 9H), 2.19 (t, J = 4.8 Hz, 3H), 2.46 (m, 6H), 2.99 (m, 1H), 3.06 (m, 2H), 3.34 (d, J = 2.0 Hz, 2H), 5.62 (s, 1H), 7.22 (t, J = 5.2 Hz, 1H), 7.27 (t, J = 4.8 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 4.8, 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.1, 25.4, 25.6 (2C), 25.7, 32.5, 32.7, 35.7, 35.8, 36.4, 46.1, 48.3, 54.2 (2C), 57.2, 127.4, 129.4, 129.6 (2C), 132.4, 136.3, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.63 (m, 9H), 2.19 (t, J = 4.8 Hz, 3H), 2.46 (m, 6H), 2.99 (m, 1H) , 3.06 (m, 2H), 3.34 (d, J = 2.0 Hz, 2H), 5.62 (s, 1H), 7.22 (t, J = 5.2 Hz, 1H), 7.27 (t, J = 4.8 Hz, 1H) , 7.36 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 4.8, 5.2 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.1, 25.4, 25.6 (2C), 25.7, 32.5, 32.7, 35.7, 35.8, 36.4, 46.1, 48.3, 54.2 (2C), 57.2, 127.4, 129.4, 129.6 (2C) ), 132.4, 136.3, 172.7.
[실시예 7] N-(2-(piperidin-1-yl)ethyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 7)의 제조[Example 7] Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 7 )
(1) 5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-7)의 제조(1) Preparation of 5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-7)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, p-Tolualdehyde (화합물 a1-7, 0.34 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 흰색 고체의 화합물 M-7 (589 mg, 79.0 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then p-Tolualdehyde (compound a1-7, 0.34 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain compound M-7 (589 mg, 79.0 % yield) as a white solid.
1H NMR (CDCl3, 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.17 (m, 1H), 2.32 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 5.12 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.17 (m, 1H), 2.32 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H) , 2.99 (m, 3H), 5.12 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H)
(2) N-(2-(piperidin-1-yl)ethyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 7)의 제조(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 7)
Ar purge를 하고 화합물 M-7 (200 mg, 0.64 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (180 mg, 0.93 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.09 mL, 0.69 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 주황색 고체 화합물 7 (140 mg, 34.7 % yield)을 수득하였다.Ar purge was carried out and compound M-7 (200 mg, 0.64 mmol) was dissolved with DCM. DMAP (40 mg, 0.32 mmol) was added and after 10 minutes, EDC (180 mg, 0.93 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.69 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an orange solid compound 7 (140 mg, 34.7 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.58 (m, 9H), 2.17 (t, J = 4.8 Hz, 3H), 2.32 (s, 3H), 2.40 (m, 6H), 2.99 (m, 3H), 3.32 (q, J = 3.6, 4.0 Hz, 2H), 5.12 (s, 1H), 7.13 (d, J = 5.2 Hz, 2H), 7.34 (d, J = 5.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.2, 24.2, 25.5, 25.7, 25.8 (2C), 32.5, 32.7, 35.8, 35.9, 36.4, 46.0, 52.1, 54.2 (2C), 57.2, 127.5 (2C), 129.4 (2C), 135.8, 138.2, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.58 (m, 9H), 2.17 (t, J = 4.8 Hz, 3H), 2.32 (s, 3H), 2.40 (m, 6H) , 2.99 (m, 3H), 3.32 (q, J = 3.6, 4.0 Hz, 2H), 5.12 (s, 1H), 7.13 (d, J = 5.2 Hz, 2H), 7.34 (d, J = 5.6 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 21.2, 24.2, 25.5, 25.7, 25.8 (2C), 32.5, 32.7, 35.8, 35.9, 36.4, 46.0, 52.1, 54.2 (2C), 57.2, 127.5 (2C), 129.4 (2C), 135.8, 138.2, 172.7.
[실시예 8] 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 8)의 제조[Example 8] Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 8 )
(1) 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-8)의 제조(1) Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-8)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, o-anisaldehyde (화합물 a1-8, 0.35 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 노란색 oily 화합물 M-8 (784 mg, 100.0 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and o-anisaldehyde (compound a1-8, 0.35 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain yellow oily compound M-8 (784 mg, 100.0 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 3.86 (s, 3H), 5.69 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 3.86 (s, 3H) , 5.69 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H)
(2) 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 8)의 제조(2) Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 8)
Ar purge를 하고 화합물 M-8 (400 mg, 1.23 mmol)을 DCM으로 용해시켰다. DMAP (80 mg, 0.65 mmol)을 첨가하고 10분 후, EDC (350 mg, 1.82 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.2 mL, 1.48 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 8 (280 mg, 52.3 % yield)을 수득하였다.Ar purge was carried out and compound M-8 (400 mg, 1.23 mmol) was dissolved with DCM. DMAP (80 mg, 0.65 mmol) was added and after 10 minutes, EDC (350 mg, 1.82 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.2 mL, 1.48 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 8 (280 mg, 52.3 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.17 (t, J = 5.2 Hz, 3H), 2.32 (s, 3H), 2.40 (m, 4H), 2.44 (t, J = 3.6 Hz, 2H), 2.96 (m, 1H), 3.06 (m, 2H), 3.33 (q, J = 3.6, 4.0 Hz, 2H), 3.86, (s, 3H), 5.69 (s, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.95 (t, J = 5.2 Hz, 1H), 7.25 (t, J = 5.2 Hz, 1H), 7.57 (d, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.2, 25.5, 25.7 (2C), 25.8, 32.7, 32.9, 35.8, 35.9, 36.4, 44.3, 46.1, 54.2 (2C), 55.7, 57.2, 110.7, 121.0, 126.9, 129.1, 129.4, 155.4, 172.8.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.17 (t, J = 5.2 Hz, 3H), 2.32 (s, 3H), 2.40 (m, 4H) , 2.44 (t, J = 3.6 Hz, 2H), 2.96 (m, 1H), 3.06 (m, 2H), 3.33 (q, J = 3.6, 4.0 Hz, 2H), 3.86, (s, 3H), 5.69 (s, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.95 (t, J = 5.2 Hz, 1H), 7.25 (t, J = 5.2 Hz, 1H), 7.57 (d, J = 5.2 Hz) , 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.2, 25.5, 25.7 (2C), 25.8, 32.7, 32.9, 35.8, 35.9, 36.4, 44.3, 46.1, 54.2 (2C), 55.7, 57.2, 110.7, 121.0, 126.9 , 129.1, 129.4, 155.4, 172.8.
[실시예 9] N-(2-(piperidin-1-yl)ethyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 9)의 제조[Example 9] N-(2-(piperidin-1-yl)ethyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 9 ) Produce
(1) 5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-9)의 제조(1) Preparation of 5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-9)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 2-(Trifluoromethyl)benzaldehyde (화합물 a1-9, 0.33 mL, 2.52 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 무색 oily 화합물 M-9 (870 mg, 99.4 % yield)을 얻었다.Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 2-(Trifluoromethyl)benzaldehyde (compound a1-9, 0.33 mL, 2.52 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain colorless oily compound M-9 (870 mg, 99.4 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.60 (m, 7H), 2.19 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 3.03 (m, 3H), 5.43 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.60 (m, 7H), 2.19 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 3.03 (m, 3H), 5.43 (s, 1H) , 7.38 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H)
(2) N-(2-(piperidin-1-yl)ethyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 9)의 제조(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 9)
Ar purge를 하고 화합물 M-9 (200 mg, 0.54 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (150 mg, 0.78 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.09 mL, 0.62 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 연한 노란색 oily 화합물 9 (165 mg, 63.3 % yield)을 수득하였다.Ar purge was carried out and compound M-9 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (150 mg, 0.78 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.62 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a pale yellow oily compound 9 (165 mg, 63.3 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.17 (t, J = 5.2 Hz, 3H), 2.37 (m, 4H), 2.42 (t, J = 5.6 Hz, 2H), 3.02 (m, 3H), 3.32 (q, J = 4.0, 5.6 Hz, 2H), 5.43 (s, 1H), 6.12 (bs, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.2, 25.4, 25.7, 25.8 (2C), 32.6, 32.7, 35.8 (2C), 36.4, 46.3, 48.1, 54.2 (2C), 57.2, 125.8 (q, J = 5.5, 5.7 Hz), 128.2, 128.3, 130.7, 130.9, 132.4, 137.4, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.17 (t, J = 5.2 Hz, 3H), 2.37 (m, 4H), 2.42 (t, J = 5.6 Hz, 2H), 3.02 (m, 3H), 3.32 (q, J = 4.0, 5.6 Hz, 2H), 5.43 (s, 1H), 6.12 (bs, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.2, 25.4, 25.7, 25.8 (2C), 32.6, 32.7, 35.8 (2C), 36.4, 46.3, 48.1, 54.2 (2C), 57.2, 125.8 (q, J = 5.5, 5.7 Hz), 128.2, 128.3, 130.7, 130.9, 132.4, 137.4, 172.7.
[실시예 10] N-(2-(piperidin-1-yl)ethyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 10)의 제조[Example 10] N-(2-(piperidin-1-yl)ethyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 10 ) Produce
(1) 5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-10)의 제조(1) Preparation of 5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-10)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 3-(Trifluoromethyl)benzaldehyde (화합물 a1-10, 0.3 mL, 2.5 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.32 mL, 2.6 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 무색 oily 화합물 M-10 (795 mg, 90.8 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 3-(Trifluoromethyl)benzaldehyde (compound a1-10, 0.3 mL, 2.5 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.32 mL, 2.6 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain colorless oily compound M-10 (795 mg, 90.8 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.54 (m, 3H), 1.64 (m, 4H), 2.18 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.01 (m, 3H), 5.19 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.54 (m, 3H), 1.64 (m, 4H), 2.18 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.01 (m, 3H) , 5.19 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H)
(2) N-(2-(piperidin-1-yl)ethyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 10)의 제조(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 10)
Ar purge를 하고 화합물 M-10 (200 mg, 0.54 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (150 mg, 0.78 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.09 mL, 0.62 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 상아색 고체 화합물 10 (157 mg, 60.2 % yield)을 수득하였다.Ar purge was carried out and compound M-10 (200 mg, 0.54 mmol) was dissolved with DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (150 mg, 0.78 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.62 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an ivory solid compound 10 (157 mg, 60.2 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.19 (t, J = 7.2 Hz, 3H), 2.45 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 3.01 (m, 3H), 3.36 (q, J = 5.2, 6.0 Hz, 2H), 5.19 (s, 1H), 6.40 (bs, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.0, 25.4, 25.5 (2C), 25.7, 32.4, 32.5, 35.6, 35.8, 36.3, 46.0, 51.7, 54.2 (2C), 57.2, 124.7 (q, J = 3.7, 3.8 Hz), 125.2 (q, J = 3.6, 3.7 Hz), 129.2 (2C), 131.2 (2C), 139.8, 172.8.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.19 (t, J = 7.2 Hz, 3H), 2.45 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 3.01 (m, 3H), 3.36 (q, J = 5.2, 6.0 Hz, 2H), 5.19 (s, 1H), 6.40 (bs, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.0, 25.4, 25.5 (2C), 25.7, 32.4, 32.5, 35.6, 35.8, 36.3, 46.0, 51.7, 54.2 (2C), 57.2, 124.7 (q, J = 3.7 , 3.8 Hz), 125.2 (q, J = 3.6, 3.7 Hz), 129.2 (2C), 131.2 (2C), 139.8, 172.8.
[실시예 11] N-(2-(piperidin-1-yl)ethyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 11)의 제조[Example 11] N-(2-(piperidin-1-yl)ethyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 11 ) Produce
(1) 5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-11)의 제조(1) Preparation of 5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-11)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 4-(Trifluoromethyl)benzaldehyde (화합물 a1-11, 0.4 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 흰색 화합물 M-11 (500 mg, 57.1 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 4-(Trifluoromethyl)benzaldehyde (compound a1-11, 0.4 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain white compound M-11 (500 mg, 57.1 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.01 (m, 3H), 5.19 (s, 1H), 7.59 (s, 4H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.01 (m, 3H) , 5.19 (s, 1H), 7.59 (s, 4H)
(2) N-(2-(piperidin-1-yl)ethyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 11)의 제조(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 11)
Ar purge를 하고 화합물 M-11 (200 mg, 0.54 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (150 mg, 0.78 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.09 mL, 0.62 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 고체 화합물 11 (249 mg, 95.5 % yield)을 수득하였다.Ar purge was carried out and compound M-11 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (150 mg, 0.78 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.62 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow solid compound 11 (249 mg, 95.5 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.58 (m, 9H), 2.18 (t, J = 7.2 Hz, 3H), 2.40 (m, 4H), 2.43 (t, J = 5.6 Hz, 2H), 3.01 (m, 3H), 3.32 (q, J = 5.2, 5.6 Hz, 2H), 5.18 (s, 1H), 6.14 (bs, 1H), 7.58 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 24.2, 25.4, 25.7 (3C), 32.4, 32.5, 35.8 (2C), 36.4, 46.0, 51.8, 54.2, 57.2, 125.7 (q, J = 3.5, 3.8 Hz), 128.4 (3C), 128.7, 130.5 (d, J = 32.3 Hz), 142.7, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.58 (m, 9H), 2.18 (t, J = 7.2 Hz, 3H), 2.40 (m, 4H), 2.43 (t, J = 5.6 Hz, 2H), 3.01 (m, 3H), 3.32 (q, J = 5.2, 5.6 Hz, 2H), 5.18 (s, 1H), 6.14 (bs, 1H), 7.58 (m, 4H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.2, 25.4, 25.7 (3C), 32.4, 32.5, 35.8 (2C), 36.4, 46.0, 51.8, 54.2, 57.2, 125.7 (q, J = 3.5, 3.8 Hz) , 128.4 (3C), 128.7, 130.5 (d, J = 32.3 Hz), 142.7, 172.7.
[실시예 12] 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 12)의 제조[Example 12] Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 12 )
(1) 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-12)의 제조(1) Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-12)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, m-anisaldehyde (화합물 a1-12, 0.35 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 노란색 oily 화합물 M-12 (781 mg, 100.0 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and m-anisaldehyde (compound a1-12, 0.35 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain yellow oily compound M-12 (781 mg, 100.0 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.16 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 3.80 (s, 3H), 5.12 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.16 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 3.80 (s, 3H) , 5.12 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H)
(2) 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 12)의 제조(2) Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 12)
Ar purge를 하고 화합물 M-12 (400 mg, 1.23 mmol)을 DCM으로 용해시켰다. DMAP (80 mg, 0.65 mmol)을 첨가하고 10분 후, EDC (350 mg, 1.82 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.2 mL, 1.48 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 12 (308 mg, 57.5 % yield)을 수득하였다.Ar purge was carried out and compound M-12 (400 mg, 1.23 mmol) was dissolved with DCM. DMAP (80 mg, 0.65 mmol) was added and after 10 minutes, EDC (350 mg, 1.82 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.2 mL, 1.48 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 12 (308 mg, 57.5 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.64 (m, 9H), 2.18 (t, J = 7.6 Hz, 3H), 2.46 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 2.98 (m, 3H), 3.36 (q, J = 5.2, 6.0 Hz, 2H), 5.12 (s, 1H), 6.37 (bs, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 23.9, 25.3, 25.4 (2C), 25.7, 32.5, 32.7, 35.6, 35.9, 36.4, 46.1, 52.5, 54.2 (2C), 55.3, 57.3, 112.9, 114.5, 120.0, 129.7, 140.2, 159.8, 172.9.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.64 (m, 9H), 2.18 (t, J = 7.6 Hz, 3H), 2.46 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 2.98 (m, 3H), 3.36 (q, J = 5.2, 6.0 Hz, 2H), 5.12 (s, 1H), 6.37 (bs, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 23.9, 25.3, 25.4 (2C), 25.7, 32.5, 32.7, 35.6, 35.9, 36.4, 46.1, 52.5, 54.2 (2C), 55.3, 57.3, 112.9, 114.5, 120.0 , 129.7, 140.2, 159.8, 172.9.
[실시예 13] 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 13)의 제조[Example 13] Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 13 )
(1) 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-13)의 제조(1) Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-13)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, p-Anisaldehyde (화합물 a1-13, 0.25 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 흰색 고체 화합물 M-13 (510 mg, 43.0 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then p-Anisaldehyde (compound a1-13, 0.25 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white solid compound M-13 (510 mg, 43.0 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.15 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.97 (m, 3H), 3.79 (s, 3H), 5.12 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.15 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.97 (m, 3H), 3.79 (s, 3H) , 5.12 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H)
(2) 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 13)의 제조(2) Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 13)
Ar purge를 하고 화합물 M-13 (200 mg, 0.61 mmol)을 DCM으로 용해시켰다. DMAP (37 mg, 0.30 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.1 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 하얀색 고체 화합물 13 (140 mg, 52.3 % yield)을 수득하였다.Ar purge was carried out and compound M-13 (200 mg, 0.61 mmol) was dissolved with DCM. DMAP (37 mg, 0.30 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.1 mL, 0.70 mmol) ) was added dropwise. After the overnight reaction, the reaction was terminated using H 2 O, and the pH was adjusted to 2 with 1N HCl, followed by extraction with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give compound 13 (140 mg, 52.3 % yield) as a white solid.
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.45 (m, 4H), 1.60 (m, 9H), 2.17 (t, J = 7.2 Hz, 3H), 2.38 (m, 4H), 2.42 (t, J = 5.6 Hz, 2H), 2.97 (m, 3H), 3.36 (q, J = 5.2, 5.6 Hz, 2H), 3.79 (s, 3H), 5.11 (s, 1H), 6.11 (bs, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 24.2, 25.5, 25.7, 25.8 (2C), 32.5, 32.6, 35.8, 35.9, 36.4, 46.1, 51.6, 54.2 (2C), 55.3, 57.2, 114.1 (2C), 128.9 (2C), 131.0, 159.5, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.45 (m, 4H), 1.60 (m, 9H), 2.17 (t, J = 7.2 Hz, 3H), 2.38 (m, 4H), 2.42 (t, J = 5.6 Hz, 2H), 2.97 (m, 3H), 3.36 (q, J = 5.2, 5.6 Hz, 2H), 3.79 (s, 3H), 5.11 (s, 1H), 6.11 (bs, 1H), 6.85 ( d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.2, 25.5, 25.7, 25.8 (2C), 32.5, 32.6, 35.8, 35.9, 36.4, 46.1, 51.6, 54.2 (2C), 55.3, 57.2, 114.1 (2C), 128.9 (2C), 131.0, 159.5, 172.7.
[실시예 14] N-(2-(piperidin-1-yl)ethyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 14)의 제조[Example 14] Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 14 )
(1) 5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-14)의 제조(1) Preparation of 5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-14)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, m-Tolualdehyde (화합물 a1-14, 0.33 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 연두색 oily 화합물 M-14 (597 mg, 80.1 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and m-Tolualdehyde (compound a1-14, 0.33 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a light green oily compound M-14 (597 mg, 80.1 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.19 (m, 1H), 2.41 (s, 3H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H), 5.12 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 7.22 (t, J = 6.8 Hz, 2H), 7.28 (s, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.19 (m, 1H), 2.41 (s, 3H), 2.35 (t, J = 7.2 Hz, 2H) , 3.00 (m, 3H), 5.12 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 7.22 (t, J = 6.8 Hz, 2H), 7.28 (s, 1H)
(2) N-(2-(piperidin-1-yl)ethyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 14)의 제조(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 14)
Ar purge를 하고 화합물 M-14 (200 mg, 0.64 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (180 mg, 0.93 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.09 mL, 0.69 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 주황색 oily 화합물 14 (140 mg, 51.6 % yield)을 수득하였다.Ar purge was carried out and compound M-14 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and after 10 minutes, EDC (180 mg, 0.93 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.69 mmol) ) was added dropwise. After the overnight reaction, the reaction was terminated using H 2 O, and the pH was adjusted to 2 with 1N HCl, followed by extraction with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an orange oily compound 14 (140 mg, 51.6 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.60 (m, 9H), 2.17 (t, J = 7.6 Hz, 3H), 2.23, (s, 3H), 2.40 (m, 4H), 2.43 (t, J = 5.6 Hz, 2H), 2.98 (m, 3H), 3.36 (q, J = 5.2, 5.6 Hz, 2H), 5.11 (s, 1H), 6.14 (bs, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.3, 24.1, 25.4, 25.7 (3C), 32.4, 32.7, 35.8 (2C), 36.4, 46.0, 52.4, 54.2 (2C), 57.2, 124.7, 128.2, 128.6, 129.2, 138.4, 138.6, 172.2.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.60 (m, 9H), 2.17 (t, J = 7.6 Hz, 3H), 2.23, (s, 3H), 2.40 (m, 4H) ), 2.43 (t, J = 5.6 Hz, 2H), 2.98 (m, 3H), 3.36 (q, J = 5.2, 5.6 Hz, 2H), 5.11 (s, 1H), 6.14 (bs, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 21.3, 24.1, 25.4, 25.7 (3C), 32.4, 32.7, 35.8 (2C), 36.4, 46.0, 52.4, 54.2 (2C), 57.2, 124.7, 128.2, 128.6, 129.2, 138.4, 138.6, 172.2.
[실시예 15] 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 15)의 제조[Example 15] Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 15 )
(1) 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-15)의 제조(1) Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-15)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 3-Chlorobenzaldehyde (화합물 a1-15, 0.32 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 무색 oily 화합물 M-15 (745 mg, 93.8 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 3-Chlorobenzaldehyde (compound a1-15, 0.32 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain colorless oily compound M-15 (745 mg, 93.8 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H), 5.11 (s, 1H), 7.27 (m, 2H), 7.33 (m, 1H), 7.46 (s, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H), 5.11 (s, 1H) , 7.27 (m, 2H), 7.33 (m, 1H), 7.46 (s, 1H)
(2) 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 15)의 제조(2) Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 15)
Ar purge를 하고 화합물 M-15 (200 mg, 0.60 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.10 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 15 (160 mg, 77.6% yield)을 수득하였다.Ar purge was carried out and compound M-15 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) was added dropwise. After the overnight reaction, the reaction was terminated using H 2 O, and the pH was adjusted to 2 with 1N HCl, followed by extraction with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to obtain yellow oily compound 15 (160 mg, 77.6% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.66 (m, 9H), 2.18 (t, J = 7.6 Hz, 3H), 2.45 (m, 4H), 2.47 (t, J = 5.6 Hz, 2H), 3.00 (m, 3H), 3.35 (q, J = 5.2, 5.6 Hz, 2H), 5.01 (s, 1H), 6.31 (bs, 1H), 7.27 (m, 2H), 7.33 (m, 1H), 7.46 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.2, 25.4, 25.7 (3C), 32.4, 32.6, 35.8 (2C), 36.4, 46.0, 51.7, 54.2 (2C), 57.2, 125.9, 128.0, 128.6, 130.0, 134.5, 140.7, 172.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.66 (m, 9H), 2.18 (t, J = 7.6 Hz, 3H), 2.45 (m, 4H), 2.47 (t, J = 5.6 Hz, 2H), 3.00 (m, 3H), 3.35 (q, J = 5.2, 5.6 Hz, 2H), 5.01 (s, 1H), 6.31 (bs, 1H), 7.27 (m, 2H), 7.33 ( m, 1H), 7.46 (s, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 24.2, 25.4, 25.7 (3C), 32.4, 32.6, 35.8 (2C), 36.4, 46.0, 51.7, 54.2 (2C), 57.2, 125.9, 128.0, 128.6, 130.0, 134.5, 140.7, 172.7.
[실시예 16] 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 16)의 제조[Example 16] Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 16 )
(1) 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-16)의 제조(1) Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-16)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 2-Nitrobenzaldehyde (화합물 a1-16, 0.43 g, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 무색 oily 화합물 M-16 (800 mg, 97.6 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 2-Nitrobenzaldehyde (compound a1-16, 0.43 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain colorless oily compound M-16 (800 mg, 97.6 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.87 (s, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.87 (s, 1H) , 7.44 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H)
(2) 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 16)의 제조(2) Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 16)
Ar purge를 하고 화합물 M-16 (200 mg, 0.58 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.10 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 16 (100 mg, 37.8% yield)을 수득하였다.Ar purge was carried out and compound M-16 (200 mg, 0.58 mmol) was dissolved with DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 16 (100 mg, 37.8% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.56 (m, 9H), 1.83 (bs, 4H), 2.22 (t, J = 7.6 Hz, 3H), 2.78 (bs, 6H), 3.05 (m, 3H), 3.51 (q, J = 5.2 Hz, 2H), 5.86 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.9 23.9 (2C), 25.3 25.6, 32.5, 32.6, 34.7, 35.7, 36.1, 46.4, 36.7, 54.2 (2C), 57.5, 124.6, 129.0, 130.7, 133.2, 133.4, 147.6, 173.4.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.56 (m, 9H), 1.83 (bs, 4H), 2.22 (t, J = 7.6 Hz, 3H), 2.78 (bs, 6H), 3.05 (m, 3H) , 3.51 (q, J = 5.2 Hz, 2H), 5.86 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.9 23.9 (2C), 25.3 25.6, 32.5, 32.6, 34.7, 35.7, 36.1, 46.4, 36.7, 54.2 (2C), 57.5, 124.6, 129.0, 130.7, 133.2, 133.4 , 147.6, 173.4.
[실시예 17] 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 17)의 제조[Example 17] Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 17 )
(1) 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-17)의 제조(1) Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-17)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 3-Nitrobenzaldehyde (화합물 a1-17, 0.43 g, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 상아색 고체 화합물 M-17 (688 mg, 83.9 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 3-Nitrobenzaldehyde (compound a1-17, 0.43 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give an ivory solid compound M-17 (688 mg, 83.9 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.23 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.23 (s, 1H) , 7.52 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H)
(2) 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 17)의 제조(2) Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 17)
Ar purge를 하고 화합물 M-17 (200 mg, 0.58 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.10 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 17 (160 mg, 60.4% yield)을 수득하였다.Ar purge was carried out and compound M-17 (200 mg, 0.58 mmol) was dissolved with DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give yellow oily compound 17 (160 mg, 60.4% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.46 (m, 4H), 1.66 (m, 9H), 2.19 (t, J = 7.6 Hz, 3H), 2.44 (m, 4H), 2.47 (t, J = 5.6 Hz, 2H), 3.04 (m, 3H), 3.35 (q, J = 5.2, 5.6 Hz, 2H), 5.23 (s, 1H), 6.30 (bs, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 23.9, 25.3 (2C), 25.4, 25.6, 32.3 (2C), 35.5, 35.7, 36.3, 46.0, 51.3, 54.2 (2C), 57.2, 123.0, 123.4, 129.7, 133.9, 140.9, 148.3, 172.8.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.46 (m, 4H), 1.66 (m, 9H), 2.19 (t, J = 7.6 Hz, 3H), 2.44 (m, 4H), 2.47 (t, J = 5.6 Hz, 2H), 3.04 (m, 3H), 3.35 (q, J = 5.2, 5.6 Hz, 2H), 5.23 (s, 1H), 6.30 (bs, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 23.9, 25.3 (2C), 25.4, 25.6, 32.3 (2C), 35.5, 35.7, 36.3, 46.0, 51.3, 54.2 (2C), 57.2, 123.0, 123.4, 129.7, 133.9, 140.9, 148.3, 172.8.
[실시예 18] 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 18)의 제조[Example 18] Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 18 )
(1) 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (화합물 M-18)의 제조(1) Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-18)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, 4-Nitrobenzaldehyde (화합물 a1-18, 0.4 g, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM→DCM:MeOH=19:1)로 분리하여 흰색 고체 화합물 M-18 (745 mg, 90.9 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 4-Nitrobenzaldehyde (compound a1-18, 0.4 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white solid compound M-18 (745 mg, 90.9 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.22 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.22 (s, 1H) , 7.63 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H)
(2) 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 18)의 제조(2) Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 18)
Ar purge를 하고 화합물 M-18 (300 mg, 0.87 mmol)을 DCM으로 용해시켰다. DMAP (50 mg, 0.40 mmol)을 첨가하고 10분 후, EDC (250 mg, 1.30 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.15 mL, 1.01 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 고체 화합물 18 (293 mg, 73.8% yield)을 수득하였다.Ar purge was carried out and compound M-18 (300 mg, 0.87 mmol) was dissolved with DCM. DMAP (50 mg, 0.40 mmol) was added and after 10 minutes, EDC (250 mg, 1.30 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.15 mL, 1.01 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow solid compound 18 (293 mg, 73.8% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 9H), 1.90 (bs, 4H), 2.27 (t, J = 7.6 Hz, 3H), 2.85 (bs, 6H), 3.03 (m, 3H), 3.54 (bs, 2H), 5.23 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 22.7, 23.6 (2C), 25.2, 25.6, 32.3, 32.4, 34.4, 35.7, 36.1, 45.9, 51.5, 54.2 (2C), 57.6, 123.9 (2C), 128.9 (2C), 146.0, 147.6, 173.4.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 9H), 1.90 (bs, 4H), 2.27 (t, J = 7.6 Hz, 3H), 2.85 (bs, 6H), 3.03 (m, 3H) , 3.54 (bs, 2H), 5.23 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.7, 23.6 (2C), 25.2, 25.6, 32.3, 32.4, 34.4, 35.7, 36.1, 45.9, 51.5, 54.2 (2C), 57.6, 123.9 (2C), 128.9 ( 2C), 146.0, 147.6, 173.4.
[실시예 19] 5-(2-phenyl-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 19)의 제조[Example 19] Preparation of 5-(2-phenyl-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 19 )
(1) 5-(2-phenyl-1,3-dithian-4-yl)pentanoic acid (화합물 M-19)의 제조(1) Preparation of 5-(2-phenyl-1,3-dithian-4-yl)pentanoic acid (Compound M-19)
Ar purge를 하고 화합물 DHLA (0.5 g, 2.4 mmol)을 DCM으로 녹인 후, Benzaldehyde (화합물 a1-19, 0.3 mL, 2.8 mmol)를 적가하였다. 상온에서 1시간 후에 BF3OEt2 (0.35 mL, 2.8 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피(DCM→DCM:MeOH=19:1)로 분리하여 흰색 고체 화합물 M-19 (555 mg, 78.0 % yield)을 얻었다.Ar purge was carried out and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then Benzaldehyde (compound a1-19, 0.3 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF 3 OEt 2 (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was terminated using H 2 O and extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white solid compound M-19 (555 mg, 78.0 % yield).
1H NMR (CDCl3, 400 MHz) δ 1.53 (m, 3H), 1.67 (m, 4H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H), 5.15 (s, 1H), 7.31 (m, 3H), 7.45 (d, J = 8.4 Hz, 2H) 1 H NMR (CDCl 3 , 400 MHz) δ 1.53 (m, 3H), 1.67 (m, 4H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H) , 5.15 (s, 1H), 7.31 (m, 3H), 7.45 (d, J = 8.4 Hz, 2H)
(2) 5-(2-phenyl-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (화합물 19)의 제조(2) Preparation of 5-(2-phenyl-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 19)
Ar purge를 하고 화합물 M-19 (200 mg, 0.67 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (200 mg, 1.04 mmol)를 소분하여 넣고 20분 후, 1-(2-aminoethyl)piperidine (화합물 a2-1, 0.11 mL, 0.77 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 19 (100 mg, 36.4% yield)을 수득하였다.Ar purge was carried out and compound M-19 (200 mg, 0.67 mmol) was dissolved in DCM. After 10 minutes of addition of DMAP (40 mg, 0.32 mmol), EDC (200 mg, 1.04 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.11 mL, 0.77 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give yellow oily compound 19 (100 mg, 36.4% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.3〕; 1H NMR (CDCl3, 400 MHz) δ 1.57 (m, 9H), 1.68 (bs, 4H), 2.18 (m, 1H), 2.26 (t, J = 7.6 Hz, 2H), 2.87 (bs, 6H), 3.00 (m, 3H), 3.55 (q, J = 5.2, 5.6 Hz, 2H), 5.15 (s, 1H), 7.32 (m, 3H), 7.45 (d, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 22.5, 23.4 (2C), 25.3, 25.6, 32.4, 32.7, 34.3, 35.8, 36.1, 46.0, 52.3, 54.1 (2C), 57.5, 127.7 (2C), 128.4, 128.7 (2C), 138.9, 173.7.TLC [DCM:MeOH=9:1 Rf =0.3]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.57 (m, 9H), 1.68 (bs, 4H), 2.18 (m, 1H), 2.26 (t, J = 7.6 Hz, 2H), 2.87 (bs, 6H) , 3.00 (m, 3H), 3.55 (q, J = 5.2, 5.6 Hz, 2H), 5.15 (s, 1H), 7.32 (m, 3H), 7.45 (d, J = 6.8 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.5, 23.4 (2C), 25.3, 25.6, 32.4, 32.7, 34.3, 35.8, 36.1, 46.0, 52.3, 54.1 (2C), 57.5, 127.7 (2C), 128.4, 128.7 (2C), 138.9, 173.7.
[실시예 20] 5-(2-phenyl-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 20)의 제조[Example 20] Preparation of 5-(2-phenyl-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 20 )
Ar purge를 하고 화합물 M-19 (200 mg, 0.67 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (200 mg, 1.04 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.11 mL, 0.77 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 20 (222 mg, 78.2 % yield)을 수득하였다.Ar purge was carried out and compound M-19 (200 mg, 0.67 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and after 10 minutes, EDC (200 mg, 1.04 mmol) was added in portions and after 20 minutes, 1- (3-aminopropyl) piperidine (compound a2-2, 0.11 mL, 0.77 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 20 (222 mg, 78.2 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.95 (bs, 4H), 2.02 (q, J = 6.4, 6.8 Hz, 3H), 2.18 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.90 (m, 9H), 3.35 (q, J = 5.6, 6.4 Hz, 2H), 5.15 (s, 1H), 7.31 (m, 3H), 7.45 (d, J = 6.8 Hz, 2H), 7.54 (t, J = 5.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.4, 32.7, 35.8, 36.2, 36.3, 46.0, 52.3, 53.4 (2C), 54.8, 127.7 (2C), 128.4, 128.7 (2C), 138.9, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.95 (bs, 4H), 2.02 (q, J = 6.4, 6.8 Hz, 3H), 2.18 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.90 (m, 9H), 3.35 (q, J = 5.6, 6.4 Hz, 2H), 5.15 (s, 1H), 7.31 (m, 3H), 7.45 (d, J = 6.8) Hz, 2H), 7.54 (t, J = 5.6 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.4, 32.7, 35.8, 36.2, 36.3, 46.0, 52.3, 53.4 (2C), 54.8, 127.7 (2C), 128.4, 128.7 (2C), 138.9, 173.9.
[실시예 21] N-(3-(piperidin-1-yl)propyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 21)의 제조[Example 21] N-(3-(piperidin-1-yl)propyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 21 ) Produce
Ar purge를 하고 화합물 M-9 (200 mg, 0.54 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (150 mg, 0.78 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.10 mL, 0.63 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 무색 oily 화합물 21 (116 mg, 43.2% yield)을 수득하였다.Ar purge was carried out and compound M-9 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (150 mg, 0.78 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.10 mL, 0.63 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to obtain colorless oily compound 21 (116 mg, 43.2% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.97 (m, 7H), 2.21 (t, J = 7.6 Hz, 3H), 3.30 (m, 9H), 3.36 (q, J = 5.6, 6.4 Hz, 2H), 5.41 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 5.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.4, 23.2 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.8, 36.2, 36.6, 46.3, 48.0, 53.5 (2C), 55.1, 125.7 (q, J = 5.6 Hz), 127.1 (d, J = 30.0 Hz), 128.2, 130.7 (2C), 132.4, 137.4, 173.7.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.97 (m, 7H), 2.21 (t, J = 7.6 Hz, 3H), 3.30 (m, 9H), 3.36 (q, J = 5.6, 6.4 Hz, 2H), 5.41 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 5.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H) , 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.4, 23.2 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.8, 36.2, 36.6, 46.3, 48.0, 53.5 (2C), 55.1, 125.7 (q, J = 5.6 Hz), 127.1 (d, J = 30.0 Hz), 128.2, 130.7 (2C), 132.4, 137.4, 173.7.
[실시예 22] N-(3-(piperidin-1-yl)propyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 22)의 제조[Example 22] N-(3-(piperidin-1-yl)propyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 22 ) Produce
Ar purge를 하고 화합물 M-10 (200 mg, 0.54 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (150 mg, 0.78 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.10 mL, 0.63 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 22 (197 mg, 73.4 % yield)을 수득하였다.Ar purge was carried out and compound M-10 (200 mg, 0.54 mmol) was dissolved with DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (150 mg, 0.78 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.10 mL, 0.63 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to obtain yellow oily compound 22 (197 mg, 73.4 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.98 (m, 7H), 2.28 (t, J = 7.6 Hz, 3H), 3.02 (m, 9H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.21 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 5.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.4, 25.6, 32.4, 32.5, 35.7, 36.2, 36.4, 46.0, 51.7, 53.5 (2C), 54.9, 124.7 (q, J = 3.6, 3.9 Hz), 125.2 (q, J = 3.6, 3.9 Hz), 129.2 (2C), 131.2 (2C), 139.9, 173.8.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.98 (m, 7H), 2.28 (t, J = 7.6 Hz, 3H), 3.02 (m, 9H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.21 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 5.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H) , 7.65 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.4, 25.6, 32.4, 32.5, 35.7, 36.2, 36.4, 46.0, 51.7, 53.5 (2C), 54.9, 124.7 (q, J = 3.6, 3.9 Hz), 125.2 (q, J = 3.6, 3.9 Hz), 129.2 (2C), 131.2 (2C), 139.9, 173.8.
[실시예 23] N-(3-(piperidin-1-yl)propyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (화합물 23)의 제조[Example 23] N-(3-(piperidin-1-yl)propyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 23 ) Produce
Ar purge를 하고 화합물 M-11 (200 mg, 0.54 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (150 mg, 0.78 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.10 mL, 0.63 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 흰색 고체 화합물 23 (202 mg, 75.3 % yield)을 수득하였다.Ar purge was carried out and compound M-11 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (150 mg, 0.78 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.10 mL, 0.63 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give compound 23 (202 mg, 75.3 % yield) as a white solid.
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.59 (m, 8H), 1.97 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.01 (m, 9H), 3.32 (q, J = 5.6, 6.0 Hz, 2H), 5.20 (s, 1H), 7.47 (bs, 1H), 7.59 (s, 4H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.4, 25.7, 32.4, 32.5, 35.7, 36.2, 36.4, 46.0, 51.7, 53.5 (2C), 54.9, 125.7 (q, J = 3.7, 3.9 Hz), 128.2 (3C), 130.4 (d, J = 32.4 Hz), 142.8 (2C), 173.8.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.59 (m, 8H), 1.97 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.01 (m, 9H), 3.32 (q, J = 5.6, 6.0 Hz, 2H), 5.20 (s, 1H), 7.47 (bs, 1H), 7.59 (s, 4H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.4, 25.7, 32.4, 32.5, 35.7, 36.2, 36.4, 46.0, 51.7, 53.5 (2C), 54.9, 125.7 (q, J = 3.7, 3.9 Hz), 128.2 (3C), 130.4 (d, J = 32.4 Hz), 142.8 (2C), 173.8.
[실시예 24] N-(3-(piperidin-1-yl)propyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 24)의 제조[Example 24] Preparation of N-(3-(piperidin-1-yl)propyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 24 )
Ar purge를 하고 화합물 M-3 (200 mg, 0.64 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (180 mg, 0.93 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.12 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 24 (204 mg, 72.8 % yield)을 수득하였다.Ar purge was carried out and compound M-3 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and after 10 minutes, EDC (180 mg, 0.93 mmol) was added in portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 24 (204 mg, 72.8 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.97 (m, 4H), 2.21 (q, J = 6.0, 6.4 Hz, 3H), 2.18 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 3.00 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 5.29 (s, 1H), 7.18 (m, 3H), 7.47 (t, J = 5.2 Hz, 1H), 7.56 (t, J = 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.1, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.6, 32.8, 35.9, 36.2, 36.3, 46.2, 48.9, 53.4 (2C), 54.8, 126.5, 127.8, 128.1, 130.4, 135.1, 137.0, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.97 (m, 4H), 2.21 (q, J = 6.0, 6.4 Hz, 3H), 2.18 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 3.00 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 5.29 (s, 1H), 7.18 (m, 3H), 7.47 ( t, J = 5.2 Hz, 1H), 7.56 (t, J = 6.4 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 19.1, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.6, 32.8, 35.9, 36.2, 36.3, 46.2, 48.9, 53.4 (2C), 54.8, 126.5, 127.8 , 128.1, 130.4, 135.1, 137.0, 173.9.
[실시예 25] N-(3-(piperidin-1-yl)propyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 25)의 제조[Example 25] Preparation of N-(3-(piperidin-1-yl)propyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 25 )
Ar purge를 하고 화합물 M-14 (200 mg, 0.64 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (180 mg, 0.93 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.12 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 25 (216 mg, 77.1 % yield)을 수득하였다.Ar purge was carried out and compound M-14 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and after 10 minutes, EDC (180 mg, 0.93 mmol) was added in portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 25 (216 mg, 77.1 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.28 (t, J = 7.6 Hz, 3H), 2.33 (s, 3H), 2.97 (m, 9H), 3.38 (q, J = 5.6, 6.4 Hz, 2H), 5.11 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 7.23 (m, 2H), 7.27 (s, 1H), 7.50 (t, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.3, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.8, 35.9, 36.2, 36.3, 46.1, 52.3, 53.4 (2C), 54.8, 124.8, 128.3, 128.6, 129.2, 138.5, 138.8, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.28 (t, J = 7.6 Hz, 3H), 2.33 (s, 3H), 2.97 (m, 9H) , 3.38 (q, J = 5.6, 6.4 Hz, 2H), 5.11 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 7.23 (m, 2H), 7.27 (s, 1H), 7.50 ( t, J = 5.2 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 21.3, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.8, 35.9, 36.2, 36.3, 46.1, 52.3, 53.4 (2C), 54.8, 124.8, 128.3 , 128.6, 129.2, 138.5, 138.8, 173.9.
[실시예 26] N-(3-(piperidin-1-yl)propyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (화합물 26)의 제조[Example 26] Preparation of N-(3-(piperidin-1-yl)propyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 26 )
Ar purge를 하고 화합물 M-7 (200 mg, 0.64 mmol)을 DCM으로 용해시켰다. DMAP (40 mg, 0.32 mmol)을 첨가하고 10분 후, EDC (180 mg, 0.93 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.12 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 26 (213 mg, 76.0 % yield)을 수득하였다.Ar purge was carried out and compound M-7 (200 mg, 0.64 mmol) was dissolved with DCM. DMAP (40 mg, 0.32 mmol) was added and after 10 minutes, EDC (180 mg, 0.93 mmol) was added in portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 26 (213 mg, 76.0 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.59 (m, 8H), 2.01 (m, 7H), 2.18 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H), 2.97 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 5.12 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.2, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.9, 36.3 (2C), 46.1, 52.0, 53.4 (2C), 54.8, 127.6 (2C), 129.4 (2C), 136.0, 138.2, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.59 (m, 8H), 2.01 (m, 7H), 2.18 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H) , 2.97 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 5.12 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H) , 7.47 (t, J = 5.2 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 21.2, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.9, 36.3 (2C), 46.1, 52.0, 53.4 (2C), 54.8, 127.6 ( 2C), 129.4 (2C), 136.0, 138.2, 173.9.
[실시예 27] 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 27)의 제조[Example 27] Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 27 )
Ar purge를 하고 화합물 M-16 (265 mg, 0.77 mmol)을 DCM으로 용해시켰다. DMAP (47 mg, 0.38 mmol)을 첨가하고 10분 후, EDC (220 mg, 1.14 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.14 mL, 0.91 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 27 (123 mg, 34.0 % yield)을 수득하였다.Ar purge was carried out and compound M-16 (265 mg, 0.77 mmol) was dissolved with DCM. DMAP (47 mg, 0.38 mmol) was added and after 10 minutes, EDC (220 mg, 1.14 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.14 mL, 0.91 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 27 (123 mg, 34.0 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.85 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.5, 32.6, 35.7, 36.2 (2C), 46.4, 46.7, 53.4 (2C), 54.7, 124.6, 129.0, 130.7, 133.2, 133.5, 147.7, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.85 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H) ; 13 C NMR (CDCl 3 , 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.5, 32.6, 35.7, 36.2 (2C), 46.4, 46.7, 53.4 (2C), 54.7, 124.6, 129.0, 130.7, 133.2, 133.5, 147.7, 173.9.
[실시예 28] 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 28)의 제조[Example 28] Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 28 )
Ar purge를 하고 M-17 (200 mg, 0.58 mmol)을 DCM으로 용해시켰다. DMAP (35 mg, 0.28 mmol)을 첨가하고 10분 후, EDC (160 mg, 0.83 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.11 mL, 0.69 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 28 (157 mg, 57.5 % yield)을 수득하였다.Ar purge was carried out and M-17 (200 mg, 0.58 mmol) was dissolved in DCM. DMAP (35 mg, 0.28 mmol) was added and after 10 minutes, EDC (160 mg, 0.83 mmol) was added in portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.69 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 28 (157 mg, 57.5 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (m, 3H), 3.02 (m, 9H), 3.37 (m, 2H), 5.26 (s, 1H), 6.40 (bs, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.3, 25.6, 32.3 (2C), 35.7, 36.2, 36.4, 46.0, 51.2, 53.5 (2C), 54.9, 123.0, 123.3, 129.7, 134.0, 141.0, 148.3, 173.8; ESI-MS: m/z [M]+ 465.9 (calcd. 465.21)TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (m, 3H), 3.02 (m, 9H), 3.37 (m, 2H), 5.26 (s, 1H), 6.40 (bs, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.3, 25.6, 32.3 (2C), 35.7, 36.2, 36.4, 46.0, 51.2, 53.5 (2C), 54.9, 123.0, 123.3, 129.7, 134.0, 141.0, 148.3, 173.8; ESI-MS: m/z [M] + 465.9 (calcd. 465.21)
[실시예 29] 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 29)의 제조[Example 29] Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 29 )
Ar purge를 하고 M-18 (137 mg, 0.40 mmol)을 DCM으로 용해시켰다. DMAP (20 mg, 0.16 mmol)을 첨가하고 10분 후, EDC (110 mg, 0.57 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.076 mL, 0.47 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 주황색 oily 화합물 29 (131 mg, 70.1 % yield)을 수득하였다.Ar purge was carried out and M-18 (137 mg, 0.40 mmol) was dissolved in DCM. DMAP (20 mg, 0.16 mmol) was added and after 10 minutes, EDC (110 mg, 0.57 mmol) was added in portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.076 mL, 0.47 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an orange oily compound 29 (131 mg, 70.1 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.23 (t, J = 7.2 Hz, 3H), 3.02 (m, 9H), 3.37 (q, J = 5.2, 5.6 Hz, 2H), 5.24 (s, 1H), 7.51 (bs, 1H), 7.64 (t, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.3, 25.6, 32.3, 32.4, 35.7, 36.2, 36.4, 45.9, 51.4, 53.5 (2C), 54.9, 123.9 (2C), 128.9 (2C), 146.0, 147.6, 173.8; ESI-MS: m/z [M]+ 465.9 (calcd. 465.21)TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.23 (t, J = 7.2 Hz, 3H), 3.02 (m, 9H), 3.37 (q, J = 5.2, 5.6 Hz, 2H), 5.24 (s, 1H), 7.51 (bs, 1H), 7.64 (t, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.3, 25.6, 32.3, 32.4, 35.7, 36.2, 36.4, 45.9, 51.4, 53.5 (2C), 54.9, 123.9 (2C), 128.9 (2C), 146.0, 147.6, 173.8; ESI-MS: m/z [M] + 465.9 (calcd. 465.21)
[실시예 30] 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 30)의 제조[Example 30] Preparation of 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 30 )
Ar purge를 하고 화합물 M-6 (200 mg, 0.60 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.12 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 30 (214 mg, 77.7% yield)을 수득하였다.Ar purge was carried out and compound M-6 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 30 (214 mg, 77.7% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.37 (q, J = 5.6, 6.4 Hz, 2H), 5.61 (s, 1H), 7.25 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 5.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 22.9 (2C), 23.5, 25.4, 25.7, 32.5, 32.6, 35.8, 36.2, 36.3, 46.2, 48.3, 53.4 (2C), 54.8, 127.4, 129.4, 129.5, 129.7, 132.4, 136.3, 173.8.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.37 (q, J = 5.6, 6.4 Hz, 2H), 5.61 (s, 1H), 7.25 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 5.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 22.9 (2C), 23.5, 25.4, 25.7, 32.5, 32.6, 35.8, 36.2, 36.3, 46.2, 48.3, 53.4 (2C), 54.8, 127.4, 129.4, 129.5 , 129.7, 132.4, 136.3, 173.8.
[실시예 31] 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 31)의 제조[Example 31] Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 31 )
Ar purge를 하고 화합물 M-15 (200 mg, 0.60 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.12 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 31 (192 mg, 69.7% yield)을 수득하였다.Ar purge was carried out and compound M-15 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 31 (192 mg, 69.7% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.17 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 3.00 (m, 9H), 3.36 (q, J = 5.6, 6.0 Hz, 2H), 5.12 (s, 1H), 7.26 (m, 2H), 7.34 (m, 1H), 7.46 (s, 1H), 7.54 (t, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.4, 32.6, 35.8, 36.2 (2C), 46.0, 51.6, 53.4 (2C), 54.7, 126.0, 128.0, 128.5, 130.0, 134.4, 140.8, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.17 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 3.00 (m, 9H) , 3.36 (q, J = 5.6, 6.0 Hz, 2H), 5.12 (s, 1H), 7.26 (m, 2H), 7.34 (m, 1H), 7.46 (s, 1H), 7.54 (t, J = 5.2) Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.4, 32.6, 35.8, 36.2 (2C), 46.0, 51.6, 53.4 (2C), 54.7, 126.0, 128.0, 128.5, 130.0, 134.4, 140.8, 173.9.
[실시예 32] 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 32)의 제조[Example 32] Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 32 )
Ar purge를 하고 화합물 M-5 (200 mg, 0.60 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.12 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 흰색 고체 화합물 32 (137 mg, 49.8% yield)을 수득하였다.Ar purge was carried out and compound M-5 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a white solid compound 32 (137 mg, 49.8% yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 2.90 (t, J = 6.8 Hz, 2H), 3.02 (m, 3H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.12 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.4, 25.7, 32.4, 32.5, 35.8, 36.2, 36.3, 46.0, 51.5, 53.4 (2C), 54.8, 128.8 (2C), 129.1 (2C), 134.0, 137.4, 173.8TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 2.90 (t, J = 6.8 Hz, 2H), 3.02 (m, 3H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.12 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H) , 7.43 (t, J = 4.8 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.4, 25.7, 32.4, 32.5, 35.8, 36.2, 36.3, 46.0, 51.5, 53.4 (2C), 54.8, 128.8 (2C), 129.1 (2C), 134.0, 137.4, 173.8
[실시예 33] 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 33)의 제조[Example 33] Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 33 )
Ar purge를 하고 화합물 M-8 (200 mg, 0.61 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.11 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 33 (176 mg, 63.7 % yield)을 수득하였다.Ar purge was carried out and compound M-8 (200 mg, 0.61 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 33 (176 mg, 63.7 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.22 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.36 (q, J = 5.6, 6.4 Hz, 2H), 3.88 (s, 3H), 5.67 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.25 (td, J = 1.6, 8.4 Hz, 1H), 7.56 (dd, J = 1.6, 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.5, 25.8, 32.6, 32.9, 35.9, 36.3, 36.4, 44.3, 46.2, 53.5 (2C), 54.9, 55.7, 110.7, 121.0, 127.0, 129.1, 129.3, 155.4, 173.8.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.22 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.36 (q, J = 5.6, 6.4 Hz, 2H), 3.88 (s, 3H), 5.67 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.25 (td, J = 1.6, 8.4 Hz, 1H), 7.56 (dd, J = 1.6, 7.6 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.5, 25.8, 32.6, 32.9, 35.9, 36.3, 36.4, 44.3, 46.2, 53.5 (2C), 54.9, 55.7, 110.7, 121.0 , 127.0, 129.1, 129.3, 155.4, 173.8.
[실시예 34] 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 34)의 제조[Example 34] Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 34 )
Ar purge를 하고 화합물 M-12 (200 mg, 0.61 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.11 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 34 (200 mg, 72.4 % yield)을 수득하였다.Ar purge was carried out and compound M-12 (200 mg, 0.61 mmol) was dissolved with DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 34 (200 mg, 72.4 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.17 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 3.00 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 3.81 (s, 3H), 5.12 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.8, 36.2, 36.3, 46.1, 52.4, 53.4 (2C), 54.9, 55.3, 113.0, 114.4, 120.0, 129.7, 140.3, 159.8, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.17 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 3.00 (m, 9H) , 3.36 (q, J = 6.0 Hz, 2H), 3.81 (s, 3H), 5.12 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 5.2 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.8, 36.2, 36.3, 46.1, 52.4, 53.4 (2C), 54.9, 55.3, 113.0, 114.4 , 120.0, 129.7, 140.3, 159.8, 173.9.
[실시예 35] 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (화합물 35)의 제조[Example 35] Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 35 )
Ar purge를 하고 화합물 M-13 (200 mg, 0.61 mmol)을 DCM으로 용해시켰다. DMAP (30 mg, 0.24 mmol)을 첨가하고 10분 후, EDC (170 mg, 0.88 mmol)를 소분하여 넣고 20분 후, 1-(3-aminopropyl)piperidine (화합물 a2-2, 0.11 mL, 0.70 mmol)을 적가하였다. overnight 반응시킨 후, H2O를 이용해 반응을 종결하고 1N HCl로 pH=2로 맞춘 후, DCM으로 추출하였다. 추출한 유기층을 무수 MgSO4로 수분 제거 후 감압 여과하고, 얻어진 여액을 감압 농축하였다. 조 잔류물을 컬럼 크로마토그래피 (DCM:MeOH=19:1 → DCM:MeOH=9:1)로 분리하여 노란색 oily 화합물 35 (143 mg, 51.7 % yield)을 수득하였다.Ar purge was carried out and compound M-13 (200 mg, 0.61 mmol) was dissolved with DCM. DMAP (30 mg, 0.24 mmol) was added and after 10 minutes, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.70 mmol) ) was added dropwise. After overnight reaction, the reaction was terminated using H 2 O, pH=2 was adjusted with 1N HCl, and the mixture was extracted with DCM. The extracted organic layer was filtered under reduced pressure after water removal with anhydrous MgSO 4 , and the resulting filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 35 (143 mg, 51.7 % yield).
TLC 〔DCM:MeOH=9:1 Rf = 0.4〕; 1H NMR (CDCl3, 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.17 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 2.98 (m, 9H), 3.37 (q, J = 5.6, 6.4 Hz, 2H), 3.79 (s, 3H), 5.11 (s, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.5, 32.6, 35.8, 36.2 (2C), 46.1, 51.6, 53.4 (2C), 54.8, 55.3, 114.0 (2C), 128.9 (2C), 131.1, 159.5, 173.9.TLC [DCM:MeOH=9:1 Rf =0.4]; 1 H NMR (CDCl 3 , 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.17 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 2.98 (m, 9H) , 3.37 (q, J = 5.6, 6.4 Hz, 2H), 3.79 (s, 3H), 5.11 (s, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1H); 13 C NMR (CDCl 3 , 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.5, 32.6, 35.8, 36.2 (2C), 46.1, 51.6, 53.4 (2C), 54.8, 55.3, 114.0 ( 2C), 128.9 (2C), 131.1, 159.5, 173.9.
[실험예 1] 아세틸콜린에스테라제(AChE) 및 부티릴콜린에스테라제(BuChE) 저해 시험([Experimental Example 1] Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition test ( In vitroin vitro assay) assay)
상기 실시예에서 제조된 리포익산-헤테로사이클 싸이오아세탈 화합물에 대하여, AChE 및 BuChE 억제 활성을 문헌[Ellman, G.L.; Courtney, K.D.; Andres, B.; Featherstone, R.M. Biochem. Pharmacol. 1961, 7, 88-95]에 보고된 비색 측정 방법에 의해 30 ℃에서 평가하였다. For the lipoic acid-heterocycle thioacetal compound prepared in the above Examples, AChE and BuChE inhibitory activity was evaluated by Ellman, G.L.; Courtney, K.D.; Andres, B.; Featherstone, R. M. Biochem. Pharmacol. 1961, 7, 88-95] and evaluated at 30 °C.
AChE 억제 활성용 분석 용액은 0.1M 포스페이트 완충액(pH 8), 0.3mM 5,5'-디티오-비스(2-니트로벤조산)(DTNB, 엘만 시약), 0.02 단위의 AChE(Sigma Chemical Co., 소 적혈구로부터), 및 효소 반응의 기질로서 0.5 mM 아세틸티오콜린 요오다이드로 이루어졌다. 상기 시험 화합물을 상기 분석 용액에 가하고 30℃에서 5 분 동안 상기 효소와 예비 배양하였다. 상기 기간 후에, 상기 기질을 가하였다. 412 nm에서의 흡광도 변화를 미세플레이트 판독기 디지스캔(Digiscan) 340T를 사용하여 5 분간 기록하고, 반응 속도를 비교하고, 시험 화합물의 존재로 인한 억제%를 계산하였다. 상기 반응 속도는 최소한 3 회 측정치를 사용하여 계산하였으며, 시험 화합물의 존재로 인한 억제%는 상기 화합물이 없는 대조군에 대해 계산하였다. 50%의 AChE 억제를 생성시키는 화합물 농도(IC50)를 측정하였다. 그 결과를 하기 표 1에 나타내었다.The assay solution for AChE inhibitory activity was 0.1 M phosphate buffer (pH 8), 0.3 mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, Ellman's reagent), 0.02 units of AChE (Sigma Chemical Co., from bovine red blood cells), and 0.5 mM acetylthiocholine iodide as a substrate for the enzymatic reaction. The test compound was added to the assay solution and pre-incubated with the enzyme at 30° C. for 5 minutes. After this period, the substrate was added. The change in absorbance at 412 nm was recorded for 5 min using a microplate reader Digiscan 340T, the reaction rates were compared, and the percent inhibition due to the presence of the test compound was calculated. The reaction rate was calculated using at least three measurements and the % inhibition due to the presence of the test compound was calculated for the control without the compound. The compound concentration (IC 50 ) that resulted in AChE inhibition of 50% was determined. The results are shown in Table 1 below.
BuChE 억제 활성용 분석 용액은 인간 혈청으로부터의 부티릴콜린에스테라제 0.01 단위, 0.1M 나트륨 포스페이트 완충액(pH 8), 0.3mM 5,5'-디티오-비스(2-니트로벤조산)(DTNB, 엘만 시약), 및 효소 반응의 기질로서 0.5mM 부티릴티오콜린 요오다이드로 이루어졌다. 효소 활성을, 412 nm에서의 흡광도를 미세플레이트 판독기 디지스캔 340T를 사용하여 5 분간 측정함으로써 측정하였다. 시험 화합물을 30 ℃에서 10 분 동안 상기 효소와 예비 배양하였다. 상기 반응 속도는 최소한 3 회 측정치를 사용하여 계산하였다. IC50은 억제제가 없는 경우에 대해 효소 활성을 50% 감소시키는 각 화합물의 농도로서 정의된다. 그 결과를 하기 표 1 및 표 2에 나타내었다.The assay solution for BuChE inhibitory activity contains 0.01 units of butyrylcholinesterase from human serum, 0.1 M sodium phosphate buffer (pH 8), 0.3 mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, Ellman's reagent), and 0.5 mM butyrylthiocholine iodide as a substrate for the enzymatic reaction. Enzyme activity was determined by measuring the absorbance at 412 nm using a microplate reader DigiScan 340T for 5 minutes. Test compounds were pre-incubated with the enzyme at 30° C. for 10 minutes. The reaction rate was calculated using at least three measurements. IC 50 is defined as the concentration of each compound that reduces enzyme activity by 50% relative to the absence of inhibitor. The results are shown in Tables 1 and 2 below.
하기 표 1은 DMSO 내에서 분석된 결과이고, 표 2는 메탄올 내에서 분석된 결과이다.Table 1 below is the analysis result in DMSO, Table 2 is the analysis result in methanol.
상기 표 1 및 표 2에 나타낸 바와 같이, 상기 실시예에서 제조된 리포익산-헤테로사이클 싸이오아세탈 화합물들은 콜린에스터라제(ChEs) 저해 활성을 나타내었다.As shown in Tables 1 and 2, the lipoic acid-heterocycle thioacetal compounds prepared in the Examples exhibited cholinesterase (ChEs) inhibitory activity.
특히, 본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물들은 콜린에스터라제 중 보다 선택적으로 부티릴콜린에스터라제(BuChE)을 저해함과 동시에 대조군인 갈란타민 대비 현저하게 향상된 부티릴콜린에스터라제 저해 활성을 나타내었다. 이로 인해 아세틸콜린에스터라제(AChE) 저해제가 가질 수 있는 부작용의 문제점을 해결할 수 있고, 알츠하이머병 환자의 뇌에서 활성이 높은 부티릴콜린에스터라제(BuChE)를 타켓으로 할 수 있다.In particular, the lipoic acid-heterocycle thioacetal compounds of the present invention inhibit butyrylcholinesterase (BuChE) more selectively among cholinesterases, and at the same time, significantly improved butyrylcholinesterase compared to the control group, galantamine. showed the second inhibitory activity. Due to this, the problem of side effects that acetylcholinesterase (AChE) inhibitors may have can be solved, and butyrylcholinesterase (BuChE), which is highly active in the brain of Alzheimer's disease patients, can be targeted.
따라서, 본 발명의 리포익산-헤테로사이클 싸이오아세탈 화합물은 아세틸콜린에스터라제(AChE) 및 부티릴콜린에스터라제(BuChE) 둘 다에 대해 저해 활성을 가지고 있으므로, 파킨슨 병, 알츠하이머병 등의 뇌신경 질환과 같은 퇴행성 질환을 예방하거나 개선하거나 치료할 수 있는 약제학적 조성물 또는 건강보조식품 조성물의 유효성분으로 매우 유용하게 사용될 수 있다. Therefore, the lipoic acid-heterocycle thioacetal compound of the present invention has inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), so It can be very usefully used as an active ingredient in a pharmaceutical composition or health supplement composition that can prevent, improve, or treat degenerative diseases such as cranial nerve diseases.
상기 본 발명은 전술한 실시예에 의해 한정되는 것이 아니고, 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 여러 가지 치환, 변형 및 변경이 가능하다는 것이 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 명백할 것이다.The present invention is not limited by the above-described embodiments, and it is those skilled in the art that various substitutions, modifications and changes are possible without departing from the technical spirit of the present invention. will be clear to
Claims (9)
[화학식 2]
상기 화학식 2에서,
R1은 C6-C12아릴 또는 이고; R2는 C6-C12아릴이고; 상기 R1 및 R2의 아릴은 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 및 니트로로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고; R' 및 R''는 각각 독립적으로 수소 또는 C1-C4알킬이고; La는 C1-C5알킬렌이다.
Lipoic acid represented by the following formula (2)-heterocycle thioacetal compound.
[Formula 2]
In Formula 2,
R 1 is C6-C12 aryl or ego; R 2 is C6-C12 aryl; The aryl of R 1 and R 2 may be further substituted with one or more selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' and nitro; R' and R'' are each independently hydrogen or C1-C4 alkyl; L a is C1-C5 alkylene.
상기 R1은 , 또는 이고; Ra 및 Rb는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 또는 니트로이고; R' 및 R''는 각각 독립적으로 수소 또는 C1-C4알킬이고; x 및 y는 각각 독립적으로 0 내지 5의 정수이고; La는 C1-C3알킬렌인, 리포익산-헤테로사이클 싸이오아세탈 화합물.3. The method of claim 2,
wherein R 1 is , or ego; R a and R b are each independently C1-C4alkyl, halogen, C1-C4alkoxy, haloC1-C4alkyl, -NR'R'' or nitro; R' and R'' are each independently hydrogen or C1-C4 alkyl; x and y are each independently an integer from 0 to 5; L a is C1-C3 alkylene, lipoic acid-heterocycle thioacetal compound.
상기 리포익산-헤테로사이클 싸이오아세탈 화합물은 하기 구조로부터 선택되는 리포익산-헤테로사이클 싸이오아세탈 화합물.
3. The method of claim 2,
The lipoic acid-heterocycle thioacetal compound is selected from the following structures: a lipoic acid-heterocycle thioacetal compound.
Claims 2, 4, and 5, wherein the lipoic acid-heterocycle thioacetal compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof is used as an active ingredient to improve cognitive ability or Parkinson's disease; A health supplement for improving degenerative diseases selected from the group consisting of Alzheimer's disease.
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