KR20110132355A - Algicidal composition for inhibiting of harmful algae - Google Patents

Algicidal composition for inhibiting of harmful algae Download PDF

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KR20110132355A
KR20110132355A KR1020117020527A KR20117020527A KR20110132355A KR 20110132355 A KR20110132355 A KR 20110132355A KR 1020117020527 A KR1020117020527 A KR 1020117020527A KR 20117020527 A KR20117020527 A KR 20117020527A KR 20110132355 A KR20110132355 A KR 20110132355A
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algae
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KR101340245B1 (en
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조훈
진언선
한명수
김시욱
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조선대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4

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Abstract

PURPOSE: A composition for preventing harmful algae is provided to suppress growth and proliferation of cyanophyceae and bacillariophyceae. CONSTITUTION: A composition for preventing harmful algae contains a compound of chemical formula 1 or salt thereof as an active ingredient. In chemical formula 1, X and Y is independently O, S, C, or N. The harmful algae are cyanophyceae, bacillariophyceae, euglenoids, flagellates, or chrysophyceae. The final concentration of the compound or salt thereof is 0.001uM-10uM.

Description

유해조류 방제용 조성물{Algicidal composition for inhibiting of harmful algae}Algalidal composition for inhibiting of harmful algae

본 발명은 유해조류의 이상 증식을 방지하기 위한 신규한 유해조류 방제용 조성물에 관한 것이다.The present invention relates to a novel harmful algae control composition for preventing abnormal growth of harmful algae.

녹조현상이란 부영양화된 호수나 유속이 느린 하천에서 부유성의 조류, 즉, 식물플랑크톤이 대량 증식하여 수면에 집적함으로써 물색을 현저하게 녹색으로 변화시키는 현상을 가리키는 말이다. 이러한 녹조현상은 일반적으로 담수에서만 발생하는데 공장폐수와 생활하수, 비료, 농약, 가축과 사람의 분뇨 등등 각종 육상 오염물질들이 강 또는 호수로 유입되고 수역의 하부에 침작되어 박테리아에 의해 분해되며 분해된 유기물들이 플랑크톤의 먹이가 되는 질소와 인을 생성시켜 해수 및 담수에서 녹조가 발생하게 된다. 이러한 녹조는 수중의 용존산소를 감소시키며, 독성녹조 및 각종 녹조플랑크톤을 생성시켜 어류 및 수생생물을 폐사시키고, 또한 육지로부터 대량 유입된 유기물들이 침전된 수역 저부에는 침전된 중금속들이 수중으로 용출되어 담수를 오염시키고 어류를 중독시킬 수 있으며, 나아가서는 환경파괴 및 자연 미관의 손상 등 많은 문제점을 불러일으키게 된다.Green algae refers to a phenomenon in which floating algae, or phytoplankton, multiply and accumulate on the surface of water in eutrophic lakes or slow-flowing streams, thereby turning the color of the green color significantly green. These green algae generally occur only in fresh water. Plant wastewater, domestic sewage, fertilizers, pesticides, livestock and human manure, and other land pollutants enter rivers or lakes, are sedimented in the lower part of the body of water, decomposed by bacteria and decomposed. Organics produce nitrogen and phosphorus, which feed plankton, causing green algae in sea and fresh water. These green algae reduce dissolved oxygen in the water, produce toxic green algae and various green alga planktons, killing fish and aquatic organisms, and depositing heavy metals in the bottom of the water where organic matters from the land are deposited. It can pollute and poison fish, and cause many problems such as environmental damage and damage to natural beauty.

한편, 녹조를 일으키는 미생물로는 녹조류, 규조류, 남조류 및 식물성 편모충류 등이 있으며, 이 중에서 남조류가 주된 원인이 된다. 특히, 남조류는 다른 조류에 비해 부영양화된 수역에서 우점하여 녹조현상을 일으키는데 이는 남조류가 하기 표에 기재된 바와 같은 특성을 가지고 있기 때문이다.On the other hand, microorganisms causing green algae include green algae, diatoms, cyanobacteria and vegetable flagella, among which cyanobacteria are a major cause. In particular, cyanobacteria predominate in eutrophicated waters compared to other algae, causing green algae, because cyanobacteria have the characteristics shown in the following table.

[남조류의 특징][Characteristics of Cyanobacteria]

Figure pct00001
Figure pct00001

또한, 녹조현상으로 인한 큰 문제점 중의 하나가 조류가 생산하는 독소인데, 특히 유독 남조류가 생산하는 독소가 문제이다. 유독 남조류의 독소로 인한 피해사례는 1878년 Fransic에 의해 처음으로 보고된 바 있고, 최근에는 상수원으로 사용되는 호수나 하천에서의 유독성 남조류에 의한 녹조현상이 종종 발생하고 있어 인체에 대한 영향에 대해서는 논란이 일어나고 있는 실정이다.In addition, one of the major problems due to green algae is the toxins produced by algae, in particular the toxins produced by toxic cyanobacteria. Toxic algae toxin damage was first reported by Fransic in 1878, and recently, algae phenomena are caused by poisonous algae in lakes and rivers, which are used as water sources. This is happening.

또한, 유독 남조류에 대한 연구는 근래에 들어 HAB(Harmful Algal Bloom)의 일부분으로 활발하게 진행되고 있으나, 유독 남조류의 동정, 독소의 종류, 독소의 생합성 경로 및 생태학적인 의미 등 많은 부분이 아직도 밝혀지지 않고 있다. 현재까지 알려진 유독 남조류의 종류 및 생산 독소의 종류는 하기 표에 기재된 바와 같다.In addition, research on toxic cyanobacteria has been actively conducted as a part of a healthy algal bloom (HAB) in recent years, but many parts such as identification of toxic cyanobacteria, types of toxins, biosynthetic pathways of toxins, and ecological significance are still unknown. It is not. The types of toxic cyanobacteria known to date and the types of toxins produced are as listed in the table below.

[유독 남조류의 종류 및 생산 독소의 종류][Types of toxic cyanobacteria and types of toxins produced]

Figure pct00002
Figure pct00002

한편, 상기 기술된 유독 남조류가 생산하는 독소는 척추동물의 간에 유독한 작용을 하는 것으로 밝혀져 있고, 특히 Microcystin은 간출혈 및 간기능부전 등의 급성독성을 일으키는 것 외에도 okadaic acid 계열의 화합물과 같이 단백질 인산화(phosphatase)의 기능을 저해하는 것이 밝혀져 발암의 촉진제로서 작용할 가능성도 보고된 바 있다(Nishiwaki-Matsushima et al., 1992). 나아가 미국, 캐나다, 영국, 일본 등 많은 나라에서 독성 물질 생산 남조류의 수화에 의한 동물의 피해가 보고된 바 있다.On the other hand, the toxin produced by the toxic cyanobacteria described above has been shown to have a toxic effect on the liver of vertebrates, and in particular, microcystin is a protein such as the compound of the okadaic acid family in addition to causing acute toxicity such as hemorrhage and liver failure. It has been shown to inhibit the function of phosphatase and has been reported to act as an accelerator of carcinogenesis (Nishiwaki-Matsushima et al., 1992). Furthermore, many countries, including the United States, Canada, the United Kingdom, and Japan, have reported damage to animals caused by hydration of toxic-producing cyanobacteria.

적조현상은 육지로부터 유기오염 물질이나 질소 인 등이 바다로 다량 유입되어 플랑크톤의 비정상적인 증식으로 인해 바다의 색깔이 적색, 적갈색, 황갈색, 녹색, 황녹색 및 황색 등으로 변하는 현상을 말한다. 이러한 적조를 일으키는 원인생물은 주로 편모조류 및 규조류이며, 이 외에도 섬모충류, 남조류 및 적색세균 등이 적조를 유발시키는 것으로 알려져 있다.Red tide is a phenomenon in which the color of the sea turns red, reddish brown, tan, green, yellow green and yellow due to abnormal growth of plankton due to the influx of organic pollutants or nitrogen phosphorus from the land into the sea. The causes of such red tide are mainly flagella algae and diatoms, and in addition, ciliated insects, cyanobacteria and red bacteria are known to cause red tide.

또한 최근 들어 적조현상은 산업화의 발전에 따라 해양 오염물의 증가로 인해 전 세계적으로 증가 추세에 있는데, 우리나라의 경우에도 1961년 진해만 부근의 진동만에서 적조가 목격된 이래 1970년대에는 104건의 적조가 진해만 일대에서 발생했으며, 1995년 이후 매년 남해안과 남동해안에서 적조가 발생하고 있는 실정이다.In recent years, the trend of red tide has increased globally due to the increase of marine pollutants with the development of industrialization.In Korea, 104 red tide peaks in the 1970s have been observed since red tide was observed in the vibrating bay near Jinhae Bay in 1961. In 1995, red tide has occurred in the south and southeast coasts since 1995.

한편, 적조가 발생하게 되면 수중의 용존 산소가 결핍되어 바다는 순식간에 산소가 희박한 상태가 되어 물고기 및 어폐류가 대량 폐사하게 되고, 대량 번식된 플랑크톤은 물고기의 아가미에 붙어서 물고기를 질식시키기도 하며, 특히 편모조류인 코콜리디니움은 유해 독소를 발생시켜 물고기의 죽음을 초래하게 된다. 또한 현재 세계 20억 이상의 인구가 소비하는 동물성 단백질의 50％ 가량은 바다에서 공급되는데 적조현상에 따른 해양생태계의 파괴는 이러한 식량자원에도 심각한 영향을 미치게 되며, 나아가 수역 이용 가치를 저하시키고, 더 나아가 경제적인 가치를 초월하여 커다란 환경 문제를 야기하게 된다.On the other hand, when red tide occurs, the dissolved oxygen in the water is depleted, and the ocean is in a state in which oxygen is scarcely rapidly, resulting in the mass death of fish and fish and fish, and the mass propagation of plankton is also attached to the fish's gills, which also chokes the fish. In particular, flagella algae, Cocollidinium, generates harmful toxins, causing fish to die. In addition, about 50% of the animal protein consumed by more than 2 billion people in the world is supplied from the sea, and the destruction of marine ecosystems due to red tide can seriously affect these food resources, further degrading the value of water use, Beyond economic value, it causes a large environmental problem.

따라서 적조 원인생물에 의한 적조 현상을 제거 또는 완화시키기 위한 기술들이 개발되었는데, 지금까지 알려진 기술들로는 화학약품 살포법, 초음파 및 오존처리법, 해면회수 및 침강법, 황토살포법 등이 있다.Therefore, techniques for removing or mitigating red tide caused by red tide cause organisms have been developed. The techniques known to date include chemical spraying, ultrasonic and ozone treatment, sponge recovery and sedimentation, and yellow soil spraying.

그러나 화학약품 살포법은 황산구리(CuSO4), 이산화염소(ClO2), 시마진(Simazine) 등을 살포하는 방법으로서 과거부터 이용되어 왔는데, 그 중 비용이 가장 저렴하여 널리 이용되는 황산구리는 적조원인 생물 외에 다른 해양생물에까지 영향을 끼쳐 수중의 다른 생물에 대한 독성 및 부식의 측면에서 문제를 일으킬 수 있으며, 또한 일시적 효과만 나타내기 때문에 반복 사용해야 하고, 적조 발생시 수반되는 높은 알칼리성 환경 조건하에서는 황산구리가 불안정해지기 때문에 많은 양을 처리하여야 하므로 비경제적이라는 단점이 있다.However, chemical spraying has been used since the past as a method of spraying copper sulfate (CuSO 4 ), chlorine dioxide (ClO 2 ), simazine (Simazine), etc. Among them, copper sulfate, which is widely used because of its low cost, It affects other marine organisms besides living organisms, which may cause problems in terms of toxicity and corrosion to other organisms in the water, and because they show only temporary effects, they should be used repeatedly, and copper sulfate is unstable under the high alkaline environment conditions when red tide occurs. There is a disadvantage in that it is uneconomical because a large amount must be processed.

초음파 처리법은 초음파(160∼400kHz)로 적조원인생물의 세포를 파괴하는 방법이고, 오존처리법은 적조 발생 수역에 고압의 오존을 투입하여 적조로 인한 독성을 중화시키는 방법이나, 두 방법 모두 실용화단계에는 아직 이르지 못하고 있는 실정이다.Ultrasonic treatment is a method of destroying cells of red tide causative organisms by ultrasonic waves (160-400 kHz), and ozone treatment is a method to neutralize the toxic effects of red tide by putting high pressure ozone into the red tide generating area. It is not yet reached.

해면회수 및 침강법은 원심분리기, 응집본조, 혼합조 및 가압부상조로 구성된 가압부상분리장치를 이용하여 기포를 발생시켜 적조 생물을 흡착, 부상시키고 해표면에서 회수하는 방법이며, 황토살포법은 황토를 해수 중에 살포하여 적조생물을 흡착 침강시키고, 황토속의 알루미늄 이온이 적조원인 생물의 세포를 파괴시키는 성질을 이용한 방법이다. 그러나 해수 중에 황토를 살포하면 부유물질이 증가되어 어류 양식장과 저층에 정착생물이 살고 있는 어장에서는 어류 아가미 폐쇄로 호흡 장애 등 생물에 영향을 미칠 수 있는 문제점이 있다.Sponge recovery and sedimentation is a method of generating bubbles by using a pressure flotation device consisting of a centrifuge, agglomeration main tank, a mixing tank, and a pressure flotation tank to adsorb, float, and recover red tide organisms from the sea surface. Is adsorbed and precipitated red tide organisms in seawater, and aluminum ions in loess destroy the cells of living organisms. However, when the yellow soil is sprayed in seawater, suspended solids are increased, and there is a problem that fish gill closure may affect living organisms such as respiratory failure in fish farms and fish farms where settlement organisms live in the lower layers.

이에 본 발명자들은 녹조 및 적조를 유발시키는 유해조류의 생성 및 증식을 억제할 수 있는 새로운 조성물을 개발하던 중, 티아졸리딘디온 유도체 화합물들이 유해조류에 대하여 우수한 살조 효과가 있음을 확인함으로써 본 발명을 완성하였다.Therefore, the inventors of the present invention, while developing a new composition that can suppress the production and proliferation of harmful algae causing green algae and red algae, the present invention by confirming that the thiazolidinedione derivative compounds have an excellent algae effect against the harmful algae Completed.

따라서 본 발명의 목적은 신규한 유해조류 방제용 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel harmful algae control composition.

또한, 본 발명의 다른 목적은 상기 유해조류 방제용 조성물을 유해조류가 발생한 지역 또는 발생예상 지역에 처리하는 것을 포함하는 유해조류의 방제방법을 제공하는 것이다.In addition, another object of the present invention is to provide a method for controlling harmful algae comprising treating the harmful algae control composition to the area where the harmful algae is generated or expected to occur.

상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 신규한 유해조류 방제용 조성물을 제공한다.In order to achieve the object of the present invention as described above, the present invention provides a novel harmful algae control composition.

또한, 본 발명은 상기 유해조류 방제용 조성물을 유해조류가 발생한 지역 또는 발생예상 지역에 처리하는 것을 포함하는 유해조류의 방제방법을 제공한다.In addition, the present invention provides a method for controlling harmful algae comprising treating the harmful algae control composition to the area where the harmful algae is generated or expected to occur.

본 발명에 따른 신규한 유해조류 방제용 조성물은 해양, 하천 또는 강 등에서 녹조 및 적조와 같은 조류의 이상 증식을 유발하는 녹조류, 남조류, 규조류, 유글레노이드류, 편모조류 및 황녹색조류의 생장 및 증식을 억제하는 살조 효과가 우수하므로 녹조 및 적조 피해를 예방하고 수질오염을 방지하는데 매우 유용하게 사용될 수 있다.The novel harmful algae control composition according to the present invention is the growth and proliferation of green algae, southern algae, diatoms, euglenoids, flagella algae and yellow green algae that cause abnormal growth of algae such as green algae and red algae in the ocean, rivers or rivers Because of its excellent algae effect, it can be very useful to prevent green algae and red tide damage and to prevent water pollution.

발명의 실시를 위한 최선의 형태Best Mode for Carrying Out the Invention

본 발명은 하기 화학식 1로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는 신규한 유해조류 방제용 조성물을 제공함을 특징으로 한다.The present invention is characterized by providing a novel harmful algae control composition comprising a compound represented by the following formula (1) or a salt thereof as an active ingredient.

＜화학식 1＞<Formula 1>

Figure pct00003
Figure pct00003

상기 식에서, X 및 Y 는 각각 독립적으로 O, S, C 또는 N 이고, R1은 H, CH3, CH2CH3 또는 CH2CH2OH이고, R2는 치환 또는 비치환 (헤테로)사이클로알킬, (헤테로)사이클로알케닐 또는 (헤테로)아릴이며, 점선은 단일 결합 또는 이중 결합일 수 있다.Wherein X and Y are each independently O, S, C or N, R 1 is H, CH 3 , CH 2 CH 3 or CH 2 CH 2 OH, and R 2 is substituted or unsubstituted (hetero) cyclo Alkyl, (hetero) cycloalkenyl or (hetero) aryl, and the dotted line may be a single bond or a double bond.

또한, 상기 화학식 1로 표시되는 본 발명에 따른 화합물에 있어서, 상기 X가 S이고, Y가 O이며, R1이 H일 경우, 상기 R2는,In addition, in the compound according to the present invention represented by Formula 1, when X is S, Y is O, and R 1 is H, R 2 is

Figure pct00004
Figure pct00004

또는or

Figure pct00005
Figure pct00005

일 수 있고,Can be,

상기 R3, R4, R5 및 R6는 각각 독립적으로 수소, 니트로기, 아민, 메톡시, 에톡시, 알킬, 트리플루오로메틸, 카르복실, 할로겐 또는R 3 , R 4 , R 5 and R 6 are each independently hydrogen, nitro group, amine, methoxy, ethoxy, alkyl, trifluoromethyl, carboxyl, halogen or

Figure pct00006
Figure pct00006

이고,ego,

이때 상기At this time

Figure pct00007
Figure pct00007

는 벤젠고리의 3번(R4 위치) 또는 4번(R5 위치) 탄소 위치에서 결합하며,Are bonded at the 3 (R 4 position) or 4 (R 5 position) carbon position of the benzene ring,

상기 R7는 수소, 알킬, 치환 또는 비치환 (헤테로)사이클로알킬, (헤테로)사이클로알케닐 또는 (헤테로)아릴로 이루어진 군 중에서 선택되고, n은 0 내지 5의 정수일 수 있다.R 7 is selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted (hetero) cycloalkyl, (hetero) cycloalkenyl, or (hetero) aryl, and n may be an integer of 0 to 5.

또한, 상기 화학식 1의 화합물에서 점선이 단일 결합일 경우, 상기 X는 S이고, Y는 O이며, R2는 하기 표에 기재된 6개의 화학식들 중에서 선택된 어느 하나일 수 있다.In addition, when the dotted line in the compound of Formula 1 is a single bond, X is S, Y is O, R 2 may be any one selected from the six formulas listed in the table below.

Figure pct00008
Figure pct00008

바람직하게 상기 화학식 1로 표시되는 본 발명의 화합물의 구체예로는 본원의 실시예 1 내지 74에서 제조된 화합물들 일 수 있다.Preferably, specific examples of the compound of the present invention represented by Formula 1 may be a compound prepared in Examples 1 to 74 of the present application.

한편, 상기 화학식 1로 표시되는 화합물을 기술하기 위해 사용된 여러 가지 용어에 대한 정의를 설명하면 다음과 같으며, 하기 기술한 용어들에 대한 정의들은 개별적이거나 또는 큰 그룹의 일부분으로서 특정 경우에 한하여 다르게 한정하지 않는 한, 본원의 전체에 걸쳐 사용된 용어에 적용된다.On the other hand, the definition of the various terms used to describe the compound represented by the formula (1) is as follows, the definitions for the terms described below are individual or as part of a large group only in certain cases Unless defined otherwise, the terms apply to the terms used throughout this application.

상기에서 알킬이란 용어는 1 내지 20개의 탄소 원자, 바람직하게는 1 내지 7개의 탄소 원자를 갖는 비치환 또는 치환된 직쇄 또는 분지쇄 탄화수소기를 나타낸다. 대표적인 비치환된 알킬기는 메틸, 에틸, 프로필, 이소프로필, n-부틸, t-부틸, 이소부틸, 펜틸, 헥실, 이소헥실, 헵틸, 4,4-디메틸펜틸, 옥틸 등을 포함한다. 치환된 알킬기는 할로, 히드록시, 시클로알킬, 알카노일, 알콕시, 알킬옥시알콕시, 알카노일옥시, 아미노, 알킬아미노, 디알킬아미노, 아실아미노, 카르바모일, 티올, 알킬티오, 알킬티오노, 술포닐, 술폰아미도, 술파모일, 니트로, 시아노, 카르복시, 알콕시카르보닐, 아릴, 알케닐, 알키닐, 아랄콕시, 구아니디노, 인돌릴, 이미다졸릴, 푸릴, 티에닐, 티아졸릴, 피롤리딜, 피리딜, 피리미딜, 피페리딜 및 모르폴리닐로 이루어진 군중에서 선택된 하나 이상에 의해 치환된 알킬기를 포함하지만, 이에 한정되지는 않는다.The term alkyl herein denotes an unsubstituted or substituted straight or branched chain hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Representative unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups are halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, Sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkyloxy, guanidino, indolyl, imidazolyl, furyl, thienyl, thia Alkyl groups substituted by one or more selected from the group consisting of zolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl and morpholinyl, but are not limited to these.

할로겐이란 용어는 불소, 염소, 브롬 및 요오드를 나타낸다.The term halogen refers to fluorine, chlorine, bromine and iodine.

알케닐이란 용어는, 2개 이상의 탄소 원자를 갖고 이중 결합을 포함하는 임의의 상기 알킬기를 나타내며, 2 내지 4개의 탄소 원자를 갖는 것이 바람직하다.The term alkenyl refers to any of the above alkyl groups having two or more carbon atoms and comprising a double bond, preferably having two to four carbon atoms.

아릴이란 용어는 고리 부분에 6 내지 12개의 탄소 원자를 갖는 모노사이클릭 또는 비사이클릭 방향족 탄화수소기, 예를 들어 페닐, 나프틸, 테트라히드로나프틸, 비페닐 및 디페닐기를 나타내고, 이들 각각은 1 내지 4개의 치환기, 예를 들어 알킬, 할로, 히드록시, 알콕시, 아실, 알카노일옥시, 임의로 치환된 아미노, 티올, 알킬티오, 니트로, 시아노, 카르복시, 카르복시알킬, 알콕시카르보닐, 카르바모일, 알킬티오노, 술포닐, 술폰아미도, 헤테로시클릴 등으로 임의로 치환될 수 있다.The term aryl denotes monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, for example phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which 1 to 4 substituents such as alkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, carba Optionally substituted with moyl, alkylthioo, sulfonyl, sulfonamido, heterocyclyl and the like.

"사이클로알킬"이란 용어는, 3 내지 12개의 탄소 원자를 갖는 임의로 치환된 모노사이클릭, 비사이클릭 또는 트리사이클릭 탄화수소기를 나타내고, 이들 각각은 하나 이상의 치환기, 예를 들어 알킬, 할로, 옥소, 히드록시, 알콕시, 알카노일, 아실아미노, 카르바모일, 알킬아미노, 디알킬아미노, 티올, 알킬티오, 니트로, 시아노, 카르복시, 카르복시알킬, 알콕시카르보닐, 술포닐, 술폰아미도, 술파모일, 헤테로시클릴 등으로 치환될 수 있다.The term “cycloalkyl” denotes an optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon group having 3 to 12 carbon atoms, each of which is one or more substituents such as alkyl, halo, oxo, Hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl , Heterocyclyl, and the like.

헤테로사이클로"란 용어는 임의로 치환된 완전 포화 또는 불포화, 방향족 또는 비방향족 사이클릭기를 나타내는 고리계로서, 하나 이상의 탄소 원자를 포함하는 고리에 하나 이상의 헤테로 원자를 갖는다. 헤테로원자를 포함하는 헤테로사이클릭기의 각 고리는 질소 원자, 산소 원자 및 황 원자로부터 선택되는 1, 2 또는 3개의 헤테로원자를 가질 수 있고, 헤테로사이클릭기는 헤테로원자 또는 탄소 원자에 결합될 수 있다.Heterocyclo "is a ring system that represents an optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic group, having at least one hetero atom in a ring containing at least one carbon atom. Heterocyclic comprising heteroatoms Each ring of the group may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and the heterocyclic groups may be bonded to heteroatoms or carbon atoms.

또한, 상기 염은 본 발명의 화합물을 최종적으로 분리, 정제 및 합성하는 동안에 동일반응계에서 제조하거나 별도로 무기 염기 또는 유기 염기와 반응시켜 제조할 수 있다. 상기 염으로는 본 발명의 화합물이 산성기를 함유하고 있을 경우, 염기와 염을 형성할 수 있으며, 이러한 염으로는 예를 들면, 이에 한정되지는 않으나 리튬염, 나트륨염 또는 칼륨염과 같은 알칼리금속과의 염; 바륨 또는 칼슘과 같은 알칼리토금속과의 염; 마그네슘염과 같은 기타 금속과의 염; 디시클로헥실아민과의 염과 같은 유기 염기염; 리신 또는 아르기닌과 같은 염기성 아미노산과의 염을 포함할 수 있다. 또한, 본 발명의 화합물이 분자 내에 염기성 기를 함유하는 경우에는 산부가염을 형성할 수 있으며, 이러한 산부가염의 예로는, 이에 한정되지는 않으나, 무기산, 특히 할로겐화수소산(예컨대, 불소화수소산, 브롬화수소산, 요오드화수소산 또는 염소화수소산), 질산, 탄산, 황산 또는 인산과의 염; 메탄술폰산, 트리플루오로메탄술폰산 또는 에탄술폰산과 같은 저급알킬 술폰산과의 염; 벤젠술폰산 또는 p-톨루엔술폰산과의 염; 아세트산, 푸마르산, 타르타르산, 옥살산, 말레산, 말산, 숙신산 또는 시트르산과 같은 유기카르복실산과의 염; 및 글루탐산 또는 아스파르트산과 같은 아미노산과의 염을 포함할 수 있다.In addition, the salts may be prepared in situ or separately reacted with an inorganic base or an organic base during the final separation, purification and synthesis of the compounds of the present invention. The salt may form a salt with a base when the compound of the present invention contains an acidic group. Examples of the salt include, but are not limited to, alkali metals such as lithium salts, sodium salts or potassium salts. Salts of; Salts with alkaline earth metals such as barium or calcium; Salts with other metals such as magnesium salts; Organic base salts such as salts with dicyclohexylamine; Salts with basic amino acids such as lysine or arginine. In addition, when the compound of the present invention contains a basic group in the molecule, an acid addition salt may be formed. Examples of such acid addition salt include, but are not limited to, inorganic acids, especially hydrofluoric acid (eg, hydrofluoric acid, hydrobromic acid, Hydroiodic acid or hydrochloric acid), salts with nitric acid, carbonate, sulfuric acid or phosphoric acid; Salts with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; Salts with benzenesulfonic acid or p-toluenesulfonic acid; Salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; And salts with amino acids such as glutamic acid or aspartic acid.

또한, 상기 화학식 1로 표시되는 본 발명의 화합물은 상기 화합물의 수화물 또는 용매화물의 형태로 된 유도체를 포함할 수 있다(J. M. Keith, 2004, Trahedron Letters, 45(13), 2739-2742).In addition, the compound of the present invention represented by Formula 1 may include a derivative in the form of a hydrate or solvate of the compound (JM Keith, 2004, Trahedron Letters , 45 (13), 2739-2742).

본 발명에 따른 상기 화학식 1의 화합물은 천연으로부터 분리되거나 당 업계에 공지된 티아졸리딘디온계 화합물의 화학적 합성법으로 제조될 수 있으며, 통상적으로 티아졸리딘디온의 5 부분에 치환될 치환기 화합물들을 적절한 반응용매와 함께 반응시켜 중간체 생성물을 수득한 후, 상기 중간체 생성물을 다시 2,4-티아졸리딘디온과 함께 적절한 반응용매에서 반응시킴으로써 본 발명에 따른 화합물을 제조할 수 있다.The compound of formula 1 according to the present invention may be prepared by chemical synthesis of a thiazolidinedione-based compound that is isolated from nature or known in the art, and typically, substituent compounds to be substituted for 5 parts of thiazolidinedione are appropriate. After reacting with the reaction solvent to obtain an intermediate product, the compound according to the present invention can be prepared by reacting the intermediate product with 2,4-thiazolidinedione in an appropriate reaction solvent.

상기 제조과정에서 사용될 수 있는 반응용매로는 반응에 관여하지 않는 한 특별한 제한은 없으며, 예를 들면 디에틸 에테르, 테트라히드로푸란, 디옥산 등의 에테르류; 디클로로메탄, 클로로포름 등의 할로겐화 탄화수소류; 피리딘, 피페리딘, 트리에틸아민 등의 아민류, 아세톤; 메틸에틸케톤, 메틸이소부틸 등의 알킬케톤류; 메탄올, 에탄올, 프로판올 등의 알코올류; N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 아세토니트릴, 디메틸술폭시드, 헥사메틸인산트리아미드 등의 비프로톤성 극성용매를 들 수 있으며, 특히 통상적으로 유기합성에서 사용되는 비반응성 유기용매 중에서 딘-스탁 트랩에 의해 반응 중 생성되는 물을 분리할 수 있는 용매가 선호된다. 이러한 용매의 예로는, 벤젠, 톨루엔, 크실렌 등이 있으나 이에 한정되지는 않는다. 반응 생성물의 분리 및 정제는 유기합성에서 통상적으로 수행되는 농축, 추출 등의 과정을 통해 이루어지며, 필요에 따라 실리카겔 상에서 컬럼 크로마토그래피에 의한 정제 작업을 통해 분리 및 정제를 수행할 수 있다.The reaction solvent that can be used in the production process is not particularly limited as long as it is not involved in the reaction, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane; Halogenated hydrocarbons such as dichloromethane and chloroform; Amines such as pyridine, piperidine and triethylamine, acetone; Alkyl ketones such as methyl ethyl ketone and methyl isobutyl; Alcohols such as methanol, ethanol and propanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, hexamethyl phosphate triamide, and the like, and especially non-reactive used in organic synthesis. Among the organic solvents, a solvent capable of separating the water generated during the reaction by the Dean-Stark trap is preferred. Examples of such a solvent include, but are not limited to, benzene, toluene, xylene, and the like. Separation and purification of the reaction product is carried out through a process such as concentration, extraction, and the like, which is commonly performed in organic synthesis, and separation and purification may be performed through purification by column chromatography on silica gel, if necessary.

본 발명은 또한 본 발명에 따른 상기 화학식 1의 화합물 제조방법들에 대한 임의의 변형을 포함하고, 여기서 그의 임의의 단계에서 수득할 수 있는 중간체 생성물은 나머지 단계들의 출발물질로 사용될 수 있으며, 상기 출발물질은 반응 조건하에 반응계 내에서 형성되거나, 반응 성분들은 그의 염 또는 광학적으로 거울상체의 형태로 사용될 수 있다.The present invention also includes any modification to the methods for preparing the compound of formula 1 according to the present invention, wherein the intermediate product obtainable at any stage thereof can be used as starting material for the remaining stages, The material may be formed in the reaction system under reaction conditions, or the reaction components may be used in the form of its salts or optically enantiomers.

또한 본 발명에 따른 화합물을 제조하기 위해 사용된 치환기들의 종류, 중간체 생성물 및 제조방법의 선택에 따라 가능한 이성질체, 예컨대 실질적으로 순수한 기하학적(시스 또는 트랜스) 이성질체, 광학 이성질체(거울상체) 또는 라세미체의 형태일 수 있으며, 이러한 가능한 이성질체 모두 본 발명의 영역에 포함된다. 한편, 조류(algae)는 바닷물 또는 민물에서 서식하면서 생태계에 많은 영향을 주는데, 본 발명에서 유해조류(harmful algae)란 녹조 또는 적조현상을 야기시켜 수중환경 및 경제활동에 악영향을 미치는 조류를 말한다.Also possible isomers, such as substantially pure geometric (cis or trans) isomers, optical isomers (enantiomers) or racemates, depending on the type of substituents, intermediate products and preparation methods used to prepare the compounds according to the invention. And all such possible isomers are included in the scope of the present invention. On the other hand, algae (algae) inhabit the sea or fresh water and affect the ecosystem a lot, in the present invention harmful algae (harmful algae) refers to algae causing algae or red tide phenomenon adversely affect the aquatic environment and economic activity.

이에 본 발명자들은 상기 화학식 1로 표시되는 본 발명의 화합물들이 녹조 및 적조현상들을 방지할 수 있는 효과가 있는지 확인한 결과, 상기 화학식 1로 표시되는 화합물들이 유해조류를 살조하는 효과가 있음을 확인하였다(실험예 1 참조).Thus, the present inventors confirmed that the compounds of the present invention represented by the formula (1) has an effect that can prevent the green algae and red tide phenomena, it was confirmed that the compounds represented by the formula (1) has the effect of killing harmful algae ( See Experimental Example 1).

따라서 본 발명은 상기 화학식 1로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는 유해조류 방제용 조성물을 제공한다.Therefore, the present invention provides a composition for controlling harmful algae comprising the compound represented by Formula 1 or a salt thereof as an active ingredient.

본 발명의 유해조류 방제용 조성물은 공지의 방법에 따라 다양한 형태로 제조할 수 있으며, 상기 화학식 1로 표시되는 화합물을 물이나 유기용매와 혼합하여 사용할 수 있고, 효과의 안정성 및 약물의 표적 생물과의 부착 증진을 위해 비-이온성 또는 이온성 계면활성제를 함께 사용할 수 있다. 또한 적절한 담체 및 첨가제 등을 추가로 포함할 수 있다.The harmful algae control composition of the present invention can be prepared in various forms according to a known method, the compound represented by the formula (1) can be used in combination with water or an organic solvent, the stability of the effect and the target organism of the drug and Non-ionic or ionic surfactants can be used together to promote adhesion of the scavenger. In addition, it may further include a suitable carrier and additives.

또한, 본 발명의 유해조류 방제용 조성물에 의해 살조 효과를 나타낼 수 있는 유해조류로는 남조류, 규조류, 녹조류, 유글레노이드조류, 편모조류 또는 황녹색조류일 수 있으며, 상기 남조류로는 이에 제한되지는 않으나, 마이크로시스티스(Microcystis), 아나베나(Anabaena), 아파니존메논(Aphanizomenon) 및 오실라토리아(Oscillatoria) 속 조류가 포함될 수 있다. 상기 규조류로는 이에 제한되지는 않으나, 시네드라(Synedra), 아스테리오넬라(Asterionella), 시클로텔라(Cyclotella), 멜로시라(Melosira), 스켈레토네마(Skeletonema costatum), 카에토세로스(Chaetoceros), 탈라시오시라(Thalassiosira), 렙토실린드루스(Leptocylindrus), 니츠쉬이아(Nitzschia), 실린드로세카(Cylindrotheca), 유캄피아(Eucampia) 및 오돈텔라(Odontella)속 조류가 포함될 수 있다. 상기 녹조류로는 이에 제한되지는 않으나, 클로스테리움(Closterium), 페디아스트룸(Pediastrum) 및 세네데스무스(Scenedesmus)속 조류가 포함될 수 있고, 상기 유글레노이드(Euglenoids) 조류는 이에 제한되지는 않으나, 트라첼로모나스(Trachelomonas) 및 유글레나(Euglena)속 조류가 포함될 수 있다. 상기 편모조류는 이에 제한되지는 않으나, 페리디늄(Peridinium), 헤테로시그마(Heterosigma), 헤테로캡사 (Heterocapsa), 코클로디니움(Cochlodinium), 프로로센트룸(Prorocentrum), 세라티움(Ceratium), 녹틸루카(Noctiluca), 스크립시엘라(Scrippsiella), 디노피시스(dinophysis), 알렉산드리움(Alexandrium), 유트렙티엘라(Eutreptiella), 피스테리아(Pfiesteria), 카톤넬라(Chattonella), 에밀리아니아(Emiliania) 및 짐노디니움(Gymnodinium)속 조류가 포함될 수 있고, 상기 황녹색조류로는 이에 제한되지는 않으나, 유로글레나(Uroglena)속 조류가 포함될 수 있다.In addition, the harmful algae that can exhibit the algae effect by the composition for controlling harmful algae of the present invention may be southern algae, diatoms, green algae, euglenoid algae, flagella algae or yellow green algae, but the algae is not limited thereto. However, algae of the genus Microcystis , Anabaena , Aphanizomenon and Oscillatoria may be included. In the diatoms it includes, but are not limited to, cine drive (Synedra), asterisks Lionel La (Asterionella), cycloalkyl telra (Cyclotella), Mello Shirakawa (Melosira), skeletal retrograde nematic (Skeletonema costatum), Chitose in Karos (Chaetoceros ), Tala Please Syrah (Thalassiosira), published repto de Luz (Leptocylindrus), may be included Chemnitz sheet Ah (Nitzschia), published Seca draw (Cylindrotheca), yukam Pia (Eucampia) and Odontoglossum telra (Odontella) in birds. The algae may include, but is not limited to, Closterium , Pediastrum , and Scenedesmus genus algae, and the euglenoids algae are not limited thereto. but it may be included in the bird Tribe cello Monastir (Trachelomonas) and euglena (Euglena). The single mother birds include, but are not limited to, Perry pyridinium (Peridinium), heteroaryl Sigma (Heterosigma), heteroaryl kaepsa (Heterocapsa), kokeulrodinium (Cochlodinium), pro Centrum (Prorocentrum), ceramide tium (Ceratium), noktil Luca (Noctiluca ), script when Ella (Scrippsiella), Dino pisiseu (dinophysis), Alexandria Solarium (Alexandrium), yuteu repti Ella (Eutreptiella), pieces terrier (Pfiesteria), carton Nella (Chattonella), Emilia California (Emiliania) and load nodi nium ( Gymnodinium ) may include algae, and the yellow-green algae may include, but are not limited to, algae ( Uroglena ) algae.

나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 그의 염을 유해조류가 발생한 지역 또는 발생예상 지역에 처리하는 것을 포함하는 유해조류의 방제방법을 제공한다. 이때, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 그의 염을 방제지역에 처리할 경우, 처리 지역의 최종 농도를 기준으로 0.001uM 내지 10uM의 범위로 사용할 수 있으며, 바람직하게는 0.001uM 내지 5uM의 범위로 사용할 수 있다.Furthermore, the present invention provides a method for controlling harmful algae, comprising treating the compound represented by Formula 1 or a salt thereof in a region in which harmful algae occur or in an expected region. At this time, when the compound represented by the formula (1) of the present invention or a salt thereof is treated in the control zone, it can be used in the range of 0.001uM to 10uM based on the final concentration of the treatment zone, preferably 0.001uM to 5uM Can be used as a range.

이하, 본 발명을 실시예에 의해 상세히 설명하기로 한다. 그러나 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, these examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited to these examples.

발명의 실시를 위한 형태DETAILED DESCRIPTION OF THE INVENTION

유해조류를 살조하는 활성이 있는 본 발명의 유도체 화합물들을 하기에 기술된 바와 같이 제조하였다.Derivative compounds of the present invention having activity to kill harmful algae were prepared as described below.

＜실시예 1＞<Example 1>

본 발명에 따른 유도체 1의 제조Preparation of Derivative 1 according to the invention

하기 화학식으로 나타내는 유도체 1을 다음과 같은 방법으로 제조하였다.Derivative 1 represented by the following formula was prepared in the following manner.

＜유도체 1의 화학식＞<Chemical formula of derivative 1>

Figure pct00009
Figure pct00009

2-이소프로폭시에탄올(600mg, 5.76mmol), p-히드록시벤즈알데히드(0.78g, 6.34mM) 및 THF(20ml) 중의 트리페닐포스핀(1.6g, 6.1mmol)이 혼합된 용액에 디에틸 아조디카복실레이트(톨루엔 중의 40％)를 0℃에서 10분에 걸쳐 교반하면서 첨가하였다. 이후 상온에서 18시간 동안 2-이소프로폭시에탄올 및 p-히드록시벤즈알데히드의 초기반응물질이 사라질 때 까지 교반하였다. 상기 용액을 농축한 다음 실리카 겔을 통한 크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 5:1이 되는 조건에서 용출시켜 노란색 오일의 4-(2-이소프로폭시에톡시)벤즈알데히드(0.98g, 수율: 82％)를 수득하였다(제1 단계). 상기 수득물의 1H NMR (300MHz, CDCl3) 분석 결과는, δ 9.87(s, 1H), 7.82(d, J=9Hz, 2H), 6.97(d, J=9Hz, 2H), 4.19(t, J=9.9Hz, 2H), 3.81(t, J=10.2Hz, 2H), 3.63-3.75(m, J=24.3Hz, 1H), 1.20(d, J=0.36Hz, 6H)이었다. 이후, 상기 제1 단계에서 수득한 4-(2-이소프로폭시에톡시)벤즈알데히드(0.98g, 4.71mmol) 및 2,4-티아졸리딘디온(0.55g, 4.71mmol)을 20ml의 톨루엔 용액으로 용해시켰고, 여기에 피페리딘(0.23ml, 2.36mmol) 및 아세트산(0.13ml, 2.36mmol)을 순차적으로 첨가한 후, 혼합액을 Dean-Stark 워터 트랩의 환류하에서 밤새도록 가열하였다. 이후 상기 혼합액을 냉각시켰고 여과시켰다. 이후 침전물은 에테르 또는 헥산으로 세척한 후 건조시켜 노란색 고체의 5-[4-(2-이소프록시에톡시)벤질리덴]티아졸리딘-2,4-디온(5-(4-(2-Isopropoxyethoxy)benzylidene)thiazolidine-2,4-dione)(1.26g, 수율: 87.5％)을 수득하였다(제2 단계). 상기 수득물의 1H NMR (300MHz, CDCl3)은 δ 8.04(s, 1H), 7.805(s, 1H), 7.432(d, J=9Hz, 2H), 7.022(d, J=9Hz, 2H), 4.19(t, J=9.6Hz, 2H), 3.84(t, J=9.6Hz, 2H), 3.65-3.76(m, J=24.6Hz, 1H), 1.24(d, J=6Hz, 6H)이었다.Diethyl azo in a solution mixed with 2-isopropoxyethanol (600 mg, 5.76 mmol), p-hydroxybenzaldehyde (0.78 g, 6.34 mM) and triphenylphosphine (1.6 g, 6.1 mmol) in THF (20 ml) Dicarboxylate (40% in toluene) was added with stirring at 0 ° C. over 10 minutes. Thereafter, the mixture was stirred for 18 hours at room temperature until the initial reactants of 2-isopropoxyethanol and p-hydroxybenzaldehyde disappeared. The solution was concentrated and purified by chromatography on silica gel, eluting with hexanes to ethyl acetate at 5: 1 to give 4- (2-isopropoxyoxy) benzaldehyde (0.98 g) as a yellow oil. , Yield: 82%) was obtained (first step). The result of 1 H NMR (300 MHz, CDCl 3 ) analysis of the obtained product was δ 9.87 (s, 1 H), 7.82 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 4.19 (t, J = 9.9 Hz, 2H), 3.81 (t, J = 10.2 Hz, 2H), 3.63-3.75 (m, J = 24.3 Hz, 1H), 1.20 (d, J = 0.36 Hz, 6H). Thereafter, 4- (2-isopropoxyethoxy) benzaldehyde (0.98 g, 4.71 mmol) and 2,4-thiazolidinedione (0.55 g, 4.71 mmol) obtained in the first step were added to 20 ml of toluene solution. After dissolving, piperidine (0.23 ml, 2.36 mmol) and acetic acid (0.13 ml, 2.36 mmol) were added sequentially, followed by heating the mixture overnight under reflux of Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate is then washed with ether or hexane and dried to give 5- [4- (2-isoproxyethoxy) benzylidene] thiazolidine-2,4-dione as a yellow solid (5- (4- (2-Isopropoxyethoxy). ) benzylidene) thiazolidine-2,4-dione) (1.26 g, yield: 87.5%) was obtained (second step). 1 H NMR (300 MHz, CDCl 3 ) of the obtained product was obtained by δ 8.04 (s, 1H), 7.805 (s, 1H), 7.432 (d, J = 9 Hz, 2H), 7.022 (d, J = 9 Hz, 2H), 4.19 (t, J = 9.6 Hz, 2H), 3.84 (t, J = 9.6 Hz, 2H), 3.65-3.76 (m, J = 24.6 Hz, 1H), 1.24 (d, J = 6 Hz, 6H).

＜실시예 2＞<Example 2>

본 발명에 따른 유도체 2의 제조Preparation of Derivative 2 according to the invention

하기 화학식으로 나타내는 유도체 2를 다음과 같은 방법으로 제조하였다.Derivative 2 represented by the following formula was prepared by the following method.

＜유도체 2의 화학식＞<Chemical formula of derivative 2>

Figure pct00010
Figure pct00010

4-(2-히드록시에틸)모르폴린(1g, 7.62mmol)이 용해되어 있는 건조된 디메틸포름아미드(20ml)용액에 소듐 하이드라이드(201.2mg, 8.38mmol)를 상온의 질소 하에서 천천히 첨가하였다. 상기 혼합물을 상온에서 30분간 교반시켰고, 건조된 디메틸포름아미드(5ml) 중의 4-플루오로벤즈알데히드(1.1g, 8.86mmol)을 10분에 걸쳐 첨가하였다. 반응 혼합물을 상온에서 18시간 동안 초기 반응물질들이 사라질 때 까지 교반하였다. 이후 상기 혼합물에 얼음물을 20ml 첨가한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물로 여러번 세척한 다음 무수의 황산마그네슘을 이용하여 수분을 제거하고 여과한 다음 용매를 증발시켰다. 잔여 오일은 실리카겔이 충진된 컬럼크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 5:1이 되는 조건에서 용출시켜 중간체 화합물 4-(2-(모르폴리노에톡시)벤즈알데히드(1.42g, 79％)을 수득하였다. 이때 상기 수득물은 1H NMR (300MHz, CDCl3) δ 10.17(s, 1H), 7.85(d, J=8.7Hz, 2H), 7.00(d, J=8.7Hz, 2H), 4.19(t, J=11.4, 2H), 3.74(t, J=9.0Hz, 4H), 2.83(t, J=11.4, 2H), 2.59(t, J=9Hz, 4H)이었다. 이후 상기 방법으로 제조된 중간체 화합물인 4-(2-(모르폴리노에톡시)벤즈알데히드(1g, 4.3 mmol)와 2,4-티아졸리딘디온(504 mg, 4.3mmol)을 이용하여 상기 실시예 1의 유도체 제조과정 중 제2 단계의 과정을 통해 상기 화학식으로 표시되는 유도체 2인 5-(4-(2-모르폴리노에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Morpholinoethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체의 수율은 90％이며, 1H NMR (300MHz, DMSO-d6)은 δ 8.14(s, 1H), 7.705(s, 1H), 7.544(d, J=8.7Hz, 2H), 7.104(d, J=8.7Hz, 2H), 4.15(t, J=11.4Hz, 2H), 3.57(m, J=9.0Hz, 8H), 2.722(t, J=11.4Hz, 2H)이었다.Sodium hydride (201.2 mg, 8.38 mmol) was slowly added to a dry dimethylformamide (20 ml) solution in which 4- (2-hydroxyethyl) morpholine (1 g, 7.62 mmol) was dissolved, at room temperature under nitrogen. The mixture was stirred at room temperature for 30 minutes, and 4-fluorobenzaldehyde (1.1 g, 8.86 mmol) in dried dimethylformamide (5 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours until the initial reactants disappeared. Thereafter, 20 ml of ice water was added to the mixture, followed by extraction with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The remaining oil was purified by silica gel-filled column chromatography, eluting with hexane to ethyl acetate at 5: 1 to give the intermediate compound 4- (2- (morpholinoethoxy) benzaldehyde (1.42 g, 79 %), Wherein the yield was 1 H NMR (300 MHz, CDCl 3 ) δ 10.17 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H). ), 4.19 (t, J = 11.4, 2H), 3.74 (t, J = 9.0 Hz, 4H), 2.83 (t, J = 11.4, 2H), 2.59 (t, J = 9 Hz, 4H). Example 1 using the 4- (2- (morpholinoethoxy) benzaldehyde (1g, 4.3mmol) and 2,4-thiazolidinedione (504 mg, 4.3mmol) as an intermediate compound prepared by the method 5- (4- (2-morpholinoethoxy) benzylidene) thiazolidine-2,4-dione (5- (4) which is a derivative 2 represented by the above formula through a process of the second step of the derivative manufacturing process. -(2-Morpholinoethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.14 (s, 1H), 7.705 (s, 1H), 7.544 (d, J = 8.7Hz, 2H), 7.104 (d, J = 8.7 Hz, 2H), 4.15 (t, J = 11.4 Hz, 2H), 3.57 (m, J = 9.0 Hz, 8H), 2.722 (t, J = 11.4 Hz, 2H).

＜실시예 3＞<Example 3>

본 발명에 따른 유도체 3의 제조Preparation of Derivative 3 according to the invention

하기 화학식으로 나타내는 유도체 3을 다음과 같은 방법으로 제조하였다.Derivative 3 represented by the following formula was prepared in the following manner.

＜유도체 3의 화학식＞<Chemical formula of derivative 3>

Figure pct00011
Figure pct00011

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-티오펜에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-티오펜에톡시)벤즈알데히드 화합물을 먼저 수득하였으며, 이때 상기 화합물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.89(s, 1H), 7.85(d, J=10.2Hz, 2H), 7.20(dd, J=1.2, 1.2Hz, 1H), 7.03(d, J=10.2Hz, 2H), 6.92-6.98(m, J=16.2Hz, 2H), 4.30(t, J=12.5Hz, 2H), 3.37(t, J=12.5Hz, 2H)이었다. 이후 상기 수득한 화합물을 상기 실시예 1 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 3인 5-(4-(2-(티오펜-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.12(s, 1H), 7.73(s, 1H), 7.558(d, J=8.7Hz, 2H), 7.354(dd, J=1.2, 1.2Hz, 1H), 7.12(d, J=8.7Hz, 2H), 6.942-6.973(m, J=9.3Hz, 2H), 4.28(t, J=12.6Hz, 2H), 3.285(t, J=12.5Hz, 2H)이었다.In the process of preparing the derivative of Example 1, except that 2-thiophenethanol is added instead of 2-isopropoxyethanol in the first step to the intermediate 4- (2-thiophene) A oxy) benzaldehyde compound was first obtained, wherein the yield of the compound was 94%, and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.89 (s, 1H), 7.85 (d, J = 10.2 Hz, 2H), 7.20 (dd, J = 1.2, 1.2 Hz, 1H), 7.03 (d, J = 10.2 Hz, 2H), 6.92-6.98 (m, J = 16.2 Hz, 2H), 4.30 (t, J = 12.5 Hz, 2H) , 3.37 (t, J = 12.5 Hz, 2H). Thereafter, the obtained compound was obtained in the same manner as in Example 2, except that instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process, the derivative 3 of Formula 5 -(4- (2- (thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. Yield is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.12 (s, 1H), 7.73 (s, 1H), 7.558 (d, J = 8.7Hz, 2H), 7.354 (dd, J) = 1.2, 1.2 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.942-6.973 (m, J = 9.3 Hz, 2H), 4.28 (t, J = 12.6 Hz, 2H), 3.285 (t , J = 12.5 Hz, 2H).

＜실시예 4＞<Example 4>

본 발명에 따른 유도체 4의 제조Preparation of Derivative 4 according to the invention

하기 화학식으로 나타내는 유도체 4를 다음과 같은 방법으로 제조하였다.Derivative 4 represented by the following formula was prepared by the following method.

＜유도체 4의 화학식＞<Chemical formula of derivative 4>

Figure pct00012
Figure pct00012

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 3-티오펜에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-(티오펜-3-일)에톡시)벤즈알데히드 화합물을 수득하였으며, 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.89(s, 1H), 7.86(d, J=13.8Hz, 2H), 7.03(d, J=13.8Hz, 2H), 4.20(t, J=10.5Hz, 2H), 3.20(dd, J=10.2, 10.2Hz, 8H), 3.04(t, J=10.5Hz, 2H)이었다. 이후 상기 수득한 화합물을 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 4인 5-[4-(2-(티오펜-3-일)에톡시)벤질리덴]티아졸리딘-2,4-디온(5-(4-(2-(Thiophen-3-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.12(s, 1H), 7.69(s, 1H), 7.556(d, J=11.7Hz, 2H), 7.45(d, J=3Hz, 3Hz, 1H), 7.305(s, 1H), 7.11(d, J=11.7Hz, 2H), 4.28(t, J=13.8Hz, 2H), 3.07(t, J=13.8Hz, 2H)이었다.In the process of preparing the derivative of Example 1, except that 3-thiophenethanol was added instead of 2-isopropoxyethanol in the first step, the intermediate 4- (2- (thiophene) was used in the same manner. -3-yl) ethoxy) benzaldehyde compound was obtained, yield 94%, 1 H NMR (300MHz, CDCl 3 ) was δ 9.89 (s, 1H), 7.86 (d, J = 13.8 Hz, 2H), was 7.03 (d, J = 13.8Hz, 2H ), 4.20 (t, J = 10.5Hz, 2H), 3.20 (dd, J = 10.2, 10.2Hz, 8H), 3.04 (t, J = 10.5Hz, 2H) . Thereafter, the obtained compound was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. -[4- (2- (thiophen-3-yl) ethoxy) benzylidene] thiazolidine-2,4-dione (5- (4- (2- (Thiophen-3-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. Yield is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.12 (s, 1H), 7.69 (s, 1H), 7.556 (d, J = 11.7 Hz, 2H), 7.45 (d, J = 3 Hz, 3 Hz, 1H), 7.305 (s, 1H), 7.11 (d, J = 11.7 Hz, 2H), 4.28 (t, J = 13.8 Hz, 2H), 3.07 (t, J = 13.8 Hz, 2H) It was.

＜실시예 5＞<Example 5>

본 발명에 따른 유도체 5의 제조Preparation of Derivative 5 According to the Invention

하기 화학식으로 나타내는 유도체 5를 다음과 같은 방법으로 제조하였다.Derivative 5 represented by the following formula was prepared by the following method.

＜유도체 5의 화학식＞<Chemical formula of derivative 5>

Figure pct00013
Figure pct00013

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-티오모르폴린-1,1-디옥시드에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-티오모르폴린-1,1-디옥시드에톡시)벤즈알데히드 화합물을 수득하였으며, 수율은 95％이고, 1H NMR (300MHz, CDCl3)은 δ 9.90(s, 1H), 7.87(d, J=13.8Hz, 2H), 7.03(d, J=13.8Hz, 2H), 4.20(t, J=10.5Hz, 2H), 3.20(dd, J=10.2, 10.2Hz, 8H), 3.04(t, J=10.5Hz, 2H)이었다. 이후 상기 수득한 화합물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 5인 5-[4-(2-티오모르폴린-1,1-디옥시드에톡시)벤질리덴]티아졸리딘-2,4-디온(5-[4-(2-Thiomorpholine-1,1-dioxideethoxy)benzylidene]thiazolidine-2,4-dione)을 수득하였다. 이때 수율은 96％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.19(s, 1H), 7.73(s, 1H), 7.56(d, J=8.7Hz, 2H), 7.11(d, J=8.7 Hz, 2H), 4.169(t, J=10.8Hz, 2H), 3.086(dd, J=10.2, 10.2Hz, 8H), 2.945(t, J=10.8Hz, 2H)이었다.In the process of preparing the derivative of Example 1, except that 2-thiomorpholine-1,1-dioxide ethanol is added instead of 2-isopropoxyethanol in the first step, 4- (2-thiomorpholine-1,1-dioxideethoxy) benzaldehyde compound was obtained, yield was 95%, and 1 H NMR (300MHz, CDCl 3 ) was δ 9.90 (s, 1H), 7.87 ( d, J = 13.8Hz, 2H) , 7.03 (d, J = 13.8Hz, 2H), 4.20 (t, J = 10.5Hz, 2H), 3.20 (dd, J = 10.2, 10.2Hz, 8H), 3.04 ( t, J = 10.5 Hz, 2H). Thereafter, the obtained compound represented by the above formula 5 was subjected to the same method, except that the obtained compound was used instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. 5- [4- (2-thiomorpholine-1,1-dioxideethoxy) benzylidene] thiazolidine-2,4-dione (5- [4- (2-Thiomorpholine-1,1-dioxideethoxy) benzylidene] thiazolidine-2,4-dione). The yield is 96%, 1 H NMR (300MHz, DMSO-d6) is δ 8.19 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 8.7Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 4.169 (t, J = 10.8 Hz, 2H), 3.086 (dd, J = 10.2, 10.2 Hz, 8H), 2.945 (t, J = 10.8 Hz, 2H).

＜실시예 6＞<Example 6>

본 발명에 따른 유도체 6의 제조Preparation of Derivative 6 According to the Invention

하기 화학식으로 나타내는 유도체 6을 다음과 같은 방법으로 제조하였다.Derivative 6 represented by the following formula was prepared by the following method.

＜유도체 6의 화학식＞<Chemical formula of derivative 6>

Figure pct00014
Figure pct00014

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-피리딘에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-(피리딘-2-일)에톡시)벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 85％이고, 1H NMR (300MHz, DMSO-d6)은 δ 9.86(s, 1H), 8.572(d, J=4.5Hz, 1H), 7.834(d, J=8.7Hz, 2H), 7.64(d, J=1.8Hz, 1H), 7.199(m, J=13.2Hz, 1H), 7.278(m, J=4.8Hz, 1H), 7.025(d, J=8.7Hz, 2H), 4.489(t, J=13.5Hz, 2H), 3.32(t, J=13.5Hz, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 6인 5-(4-(2-(피리딘-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Pyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 유도체 6의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 10.36(s, 1H), 8.452(d, J=4.8Hz, 1H), 7.783(s, 1H), 7.719(t, J=17.4Hz, 1H), 7.488(d, J=8.4 Hz, 2H), 7.277(d, J=7.11, 1H), 7.232(m, J=12.6Hz, 1H), 4.169(t, J=14.7Hz, 2H), 3.048(t, J=14.7Hz, 2H)이었다.In the process of preparing the derivative of Example 1, using the same method, except that 2-pyridineethanol was added instead of 2-isopropoxyethanol in the first step, intermediate 4- (2- (pyridine-2- Il) ethoxy) benzaldehyde was obtained, wherein the yield of the product was 85%, 1 H NMR (300MHz, DMSO-d6) was δ 9.86 (s, 1H), 8.572 (d, J = 4.5Hz, 1H) , 7.834 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.199 (m, J = 13.2 Hz, 1H), 7.278 (m, J = 4.8 Hz, 1H), 7.025 (d, J = 8.7 Hz, 2H), 4.489 (t, J = 13.5 Hz, 2H), and 3.32 (t, J = 13.5 Hz, 2H). Subsequently, the derivative 6 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative preparation process of Example 1. Phosphorus 5- (4- (2- (pyridin-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Pyridin-2-yl) ethoxy) benzylidene ) thiazolidine-2,4-dione) was obtained. The yield of the derivative 6 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 10.36 (s, 1H), 8.452 (d, J = 4.8 Hz, 1H), 7.783 (s, 1H), 7.719 (t, J = 17.4 Hz, 1H), 7.488 (d, J = 8.4 Hz, 2H), 7.277 (d, J = 7.11, 1H), 7.232 (m, J = 12.6 Hz, 1H), 4.169 (t, J = 14.7 Hz, 2H) and 3.048 (t, J = 14.7 Hz, 2H).

＜실시예 7＞<Example 7>

본 발명에 따른 유도체 7의 제조Preparation of Derivative 7 According to the Invention

하기 화학식으로 나타내는 유도체 7을 다음과 같은 방법으로 제조하였다.Derivative 7 represented by the following formula was prepared in the following manner.

＜유도체 7의 화학식＞<Chemical formula of derivative 7>

Figure pct00015
Figure pct00015

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 N-사이클로헥실에탄올아민을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-사이클로헥실아미노)에톡시벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 79％이고, 1H NMR (300MHz, CDCl3)은 δ 9.81(s, 1H), 7.772 (d, J=8.7Hz, 2H), 6.953(d, J=8.7Hz, 2H), 4.108(t, J=10.5Hz, 2H) 3.013(t, J=10.5Hz, 2H), 2.072(s, 1H). 2.470(m, J=20.4Hz, 1H), 2.072(s, 1H), 1.838-1.148(m, 10H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체를 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 7인5-(4-(2-(사이클로헥실아미노)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Cyclohexylamino)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 유도체 7의 수율은 82％이고, 1H NMR (300MHz, DMSO-d6)은 δ 7.504(d, J=8.7 Hz, 2H), 7.310(s, 1H), 7.069(d, J=8.7Hz, 2H), 4.244 (t, J=9.9Hz, 2H), 3.299(t, J=9.9Hz, 2H), 3.017(s, 1H), 2.284(s, 1H), 2.071(s, 2H) 1.894(s, 2H), 1.61(d, J=11.7Hz), 1.304(m, 5H)이었다.Except for using N -cyclohexylethanolamine instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2, the intermediate was 4- (2-cyclohexylamino, using the same method. Ethoxybenzaldehyde was obtained, wherein the yield of the product was 79%, and 1 H NMR (300 MHz, CDCl 3 ) yields δ 9.81 (s, 1H), 7.772 (d, J = 8.7 Hz, 2H), 6.953 ( d, J = 8.7 Hz, 2H), 4.108 (t, J = 10.5 Hz, 2H) 3.013 (t, J = 10.5 Hz, 2H), 2.072 (s, 1H). 2.470 (m, J = 20.4 Hz, 1H), 2.072 (s, 1H), 1.838-1.148 (m, 10H). The derivative represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation process of the derivative of Example 1. 7-in 5- (4- (2- (cyclohexylamino) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Cyclohexylamino) ethoxy) benzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the derivative 7 is 82%, 1 H NMR (300MHz, DMSO-d6) is δ 7.504 (d, J = 8.7 Hz, 2H), 7.310 (s, 1H), 7.069 (d, J = 8.7 Hz, 2H), 4.244 (t, J = 9.9 Hz, 2H), 3.299 (t, J = 9.9 Hz, 2H), 3.017 (s, 1H), 2.284 (s, 1H), 2.071 (s, 2H) 1.894 (s , 2H), 1.61 (d, J = 11.7 Hz), and 1.304 (m, 5H).

＜실시예 8＞<Example 8>

본 발명에 따른 유도체 8의 제조Preparation of Derivative 8 According to the Invention

하기 화학식으로 나타내는 유도체 8을 다음과 같은 방법으로 제조하였다.Derivative 8 represented by the following formula was prepared by the following method.

＜유도체 8의 화학식＞<Chemical formula of derivative 8>

Figure pct00016
Figure pct00016

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 4-플루오로-m-아니스알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-사이클로헥실에톡시)-3-메톡시벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.774(s, 1H), 7.383(s, 1H), 7.365(d, J=11.7Hz, 1H), 6.912(d, J=11.7Hz, 1H), 4.096(t, J=9.9Hz, 2H), 3.846(s, 3H), 1.617-1.755(m, 8H), 1.388-1.46(m, 1H), 1.146-1.258(m, 2H), 0.87-0.978(m, 2H)이었다. 이후 상기 수득한 생성물을 상기 실시예 1의 유도체를 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 8인 5-(4-(2-사이클로헥실에톡시)-3-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-methoxybenzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 유도체 8의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.221(s, 1H), 7.728(s, 1H), 7.028(d, J=10.2 Hz, 2H), 6.924(d, J=10.2Hz, 2H), 6.895(s, 1H), 4.074(t, J=14.4 Hz, 2H), 3.846(s, 1H), 1.716(t, J=14.4Hz, 2H), 1.620(m, 1H), 1.434-1.515(m, 4H), 1.078-1.214(m, 4H), 0.867-0.976(m, 2H)이었다.Except for using cyclohexylethanol instead of 4- (2-hydroxyethyl) morpholine in the process of preparing the derivative of Example 2 and 4-fluoro-m-anisaldehyde instead of 4-fluorobenzaldehyde Using the same method, intermediate 4- (2-cyclohexylethoxy) -3-methoxybenzaldehyde was obtained with a yield of 85% and 1 H NMR (300 MHz, CDCl 3 ) yielding δ 9.774 (s , 1H), 7.383 (s, 1H), 7.365 (d, J = 11.7 Hz, 1H), 6.912 (d, J = 11.7 Hz, 1H), 4.096 (t, J = 9.9 Hz, 2H), 3.846 (s , 3H), 1.617-1.755 (m, 8H), 1.388-1.46 (m, 1H), 1.146-1.258 (m, 2H), 0.87-0.978 (m, 2H). Thereafter, the obtained product was subjected to the same method as in the second step of the preparation of the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used in the same manner as the derivative 8 Phosphorus 5- (4- (2-cyclohexylethoxy) -3-methoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-methoxybenzylidene) thiazolidine-2 , 4-dione) was obtained. The yield of the derivative 8 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 8.221 (s, 1H), 7.728 (s, 1H), 7.028 (d, J = 10.2 Hz, 2H), 6.924 ( d, J = 10.2Hz, 2H) , 6.895 (s, 1H), 4.074 (t, J = 14.4 Hz, 2H), 3.846 (s, 1H), 1.716 (t, J = 14.4Hz, 2H), 1.620 ( m, 1H), 1.434-1.515 (m, 4H), 1.078-1.214 (m, 4H), 0.867-0.976 (m, 2H).

＜실시예 9＞<Example 9>

본 발명에 따른 유도체 9의 제조Preparation of Derivative 9 According to the Invention

하기 화학식으로 나타내는 유도체 9를 다음과 같은 방법으로 제조하였다.Derivative 9 represented by the following formula was prepared by the following method.

＜유도체 9의 화학식＞<Chemical formula of derivative 9>

Figure pct00017
Figure pct00017

상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 4-히드록시-3-메틸벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 중간체 생성물의 수율은 89％이고, 1H NMR (300MHz, CDCl3)은 δ 9.845(s, 1H), 7.707(d, J=8.7Hz, 2H), 7.678(s, 1H), 6.89(d, J=8.7Hz, 2H), 4.111(t, J=13.2Hz, 2H), 2.259(s, 3H), 1.749(t, J=13.2Hz, 2H) 1.493-1.585(m, 5H), 1.217-1.325(m, 5H), 1.009-1.048(m, 1H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시) 벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 9인 5-(4-(2-사이클로헥실에톡시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-methylbenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 수득한 유도체 9의 수율은 92％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.20(s, 1H), 7.783(s, 1H), 7.087(d, J=8.7 Hz, 2H), 7.058(s, 1H), 6.788(d, J=8.7Hz, 2H), 4.023(t, J=14.7 Hz, 2H), 1.739(t, J=14.7Hz, 2H), 1.577(m, 1H), 1.213-1.284(m, 2H), 0.965-1.044(m, 4H), 0.826-0.880(m, 4H)이었다.Except for using cyclohexylethanol instead of 2-isopropoxyethanol and 4-hydroxy-3-methylbenzaldehyde instead of p-hydroxybenzaldehyde in the preparation of the derivative of Example 1 using the same method An intermediate product was obtained, wherein the yield of the intermediate product was 89%, and 1 H NMR (300 MHz, CDCl 3 ) yields δ 9.845 (s, 1H), 7.707 (d, J = 8.7 Hz, 2H), 7.678 (s , 1H), 6.89 (d, J = 8.7 Hz, 2H), 4.111 (t, J = 13.2 Hz, 2H), 2.259 (s, 3H), 1.749 (t, J = 13.2 Hz, 2H) 1.493-1.585 ( m, 5H), 1.217-1.325 (m, 5H), and 1.009-1.048 (m, 1H). Subsequently, the derivative 9 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2-cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the obtained derivative 9 is 92%, 1 H NMR (300MHz, DMSO-d6) is δ 8.20 (s, 1H), 7.783 (s, 1H), 7.087 (d, J = 8.7 Hz, 2H) , 7.058 (s, 1H), 6.788 (d, J = 8.7 Hz, 2H), 4.023 (t, J = 14.7 Hz, 2H), 1.739 (t, J = 14.7 Hz, 2H), 1.577 (m, 1H) , 1.213-1.284 (m, 2H), 0.965-1.044 (m, 4H) and 0.826-0.880 (m, 4H).

＜실시예 10＞<Example 10>

본 발명에 따른 유도체 10의 제조Preparation of Derivative 10 According to the Invention

하기 화학식으로 나타내는 유도체 10을 다음과 같은 방법으로 제조하였다.Derivative 10 represented by the following formula was prepared in the following manner.

＜유도체 10의 화학식＞<Chemical formula of derivative 10>

Figure pct00018
Figure pct00018

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 시링알데히드(syringaldehyde)를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 생성물의 수율은 90％이고, 1H NMR (300MHz, CDCl3)은 9.904(s, 1H), 7.273(s, 2H), 4.129(t, J=13.2Hz, 2H), 3.914(s, 6H), 1.646(t, J=13.2Hz, 2H), 1.424-1.781(m, 3H), 1.095-1.169(m, 4H), 0.882-0.989(m, 4H)이었다. 이후 상기 수득한 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 10인 5-(4-(2-사이클로헥실에톡시)-3,5-디메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3,5-dimethoxybenzylidene)thiazolidine-2,4-dione )을 수득하였다. 상기 수득한 유도체 10의 수율은 92％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.623(s, 1H), 7.781(s, 1H), 6.768(s, 2H), 4.10(t, J=13.5 Hz, 2H), 3.887(s, 6H), 2.176(s, 1H), 1.620(t, J=13.5Hz, 2H), 1.505-1.738(m, 2H), 1.096-1.325(m, 4H), 0.884-0.951(m, 4H)이었다.In the process of preparing the derivative of Example 1, the same method is used except that in the first step, cyclohexyl ethanol is used instead of 2-isopropoxyethanol and siringaldehyde is added instead of p-hydroxybenzaldehyde. To give an intermediate product, wherein the yield of the product is 90%, 1 H NMR (300 MHz, CDCl 3 ) is 9.904 (s, 1H), 7.273 (s, 2H), 4.129 (t, J = 13.2 Hz , 2H), 3.914 (s, 6H), 1.646 (t, J = 13.2 Hz, 2H), 1.424-1.781 (m, 3H), 1.095-1.169 (m, 4H), 0.882-0.989 (m, 4H) . Thereafter, the obtained product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that instead of 4- (2-isopropoxyethoxy) benzaldehyde, 5- (4- (2-cyclohexylethoxy) -3,5-dimethoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3,5-dimethoxybenzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 10 is 92%, 1 H NMR (300MHz, DMSO-d6) is δ 8.623 (s, 1H), 7.781 (s, 1H), 6.768 (s, 2H), 4.10 (t, J = 13.5 Hz, 2H), 3.887 (s, 6H), 2.176 (s, 1H), 1.620 (t, J = 13.5 Hz, 2H), 1.505-1.738 (m, 2H), 1.096-1.325 (m, 4H) , 0.884-0.951 (m, 4H).

＜실시예 11＞<Example 11>

본 발명에 따른 유도체 11의 제조Preparation of Derivative 11 According to the Invention

하기 화학식으로 나타내는 유도체 11을 다음과 같은 방법으로 제조하였다.Derivative 11 represented by the following formula was prepared in the following manner.

＜유도체 11의 화학식＞<Chemical formula of derivative 11>

Figure pct00019
Figure pct00019

상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 생성물의 수율은 82％이고, 1H NMR (300MHz, CDCl3)은 δ 9.858(s, 1H), 8.271(s, 1H), 7.679(d, J=8.7Hz, 2H), 7.145(d, J=8.7Hz, 2H), 4.118(t, J=13.2Hz, 2H), 4.063(d, J=6.9Hz, 1H), 3.579(t, J=13.8Hz, 4H), 0.762-1.977(m, 10H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 11인 5-(4-(3-사이클로헥실프로폭시)-3-니트로벤질리덴)티아졸리딘-2,4-디온(5-(4-(3-Cyclohexylpropoxy)-3-nitrobenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 수득한 유도체 11의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.043(s, 1H), 7.716(s, 1H), 7.399(d, J=11.1Hz, 1H), 7.262(s, 1H), 7.041(d, J=11.1Hz, 1H), 4.563(dd, J=12.6, 1H), 4.048-4.087(t, J=11.7Hz, 2H), 4.029-4.179(m, 1H), 1.631-1.889(m, 8H), 1.159-1.389(m, 2H), 1.236-1.284(t, J=14.4Hz, 2H), 0.840-0.961(m, 2H)이었다.Except for using cyclohexylethanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of p-hydroxybenzaldehyde in the preparation of the derivative of Example 1 using the same method An intermediate product was obtained, wherein the yield was 82%, and 1 H NMR (300 MHz, CDCl 3 ) yields δ 9.858 (s, 1H), 8.271 (s, 1H), 7.679 (d, J = 8.7 Hz, 2H), 7.145 (d, J = 8.7 Hz, 2H), 4.118 (t, J = 13.2 Hz, 2H), 4.063 (d, J = 6.9 Hz, 1H), 3.579 (t, J = 13.8 Hz, 4H) , 0.762-1.977 (m, 10H). Subsequently, the derivative 11 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (3-cyclohexylpropoxy) -3-nitrobenzylidene) thiazolidine-2,4-dione (5- (4- (3-Cyclohexylpropoxy) -3-nitrobenzylidene) thiazolidine-2 , 4-dione) was obtained. The yield of the obtained derivative 11 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.043 (s, 1H), 7.716 (s, 1H), 7.399 (d, J = 11.1 Hz, 1H) , 7.262 (s, 1H), 7.041 (d, J = 11.1 Hz, 1H), 4.563 (dd, J = 12.6, 1H), 4.048-4.087 (t, J = 11.7 Hz, 2H), 4.029-4.179 (m , 1H), 1.631-1.889 (m, 8H), 1.159-1.389 (m, 2H), 1.236-1.284 (t, J = 14.4 Hz, 2H) and 0.840-0.961 (m, 2H).

＜실시예 12＞<Example 12>

본 발명에 따른 유도체 12의 제조Preparation of Derivative 12 According to the Invention

하기 화학식으로 나타내는 유도체 12를 다음과 같은 방법으로 제조하였다.Derivative 12 represented by the following formula was prepared in the following manner.

＜유도체 12의 화학식＞<Chemical formula of derivative 12>

Figure pct00020
Figure pct00020

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 1-피페리딘에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-피페리딘-1-일)에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 83％이고, 1H NMR (300MHz, CDCl3)은 δ 9.880(s, 1H), 7.839(d, J=8.7Hz, 2H), 7.013(d, J=8.7Hz, 2H), 4.223(t, J=11.7Hz, 2H), 2.828(t, J=11.7Hz, 2H), 2.544(t, J=10.5Hz, 4H), 1.583-1.657(m, 4H), 1.418-1.494(m, 2H), 1.256-1.303(m, 1H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 12인 5-(4-(2-(피페리딘-1-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Piperidin-1-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 12의 수율은 82％이고, 1H NMR (300MHz, DMSO-d6)은 δ 7.522(s, 1H), 7.411(d, J=10.2Hz, 2H), 6.967(d, J=10.2Hz, 2H), 4.096(t, J=11.1Hz, 2H), 2.814(t, J=11.1Hz, 2H), 2.379(m, 4H), 1.410-1.513(m, 5H), 1.291-1.307(m, 2H)이었다.Except for using 1-piperidineethanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2 using the same method as the intermediate 4- (2-piperidine -1-yl) ethoxy) benzaldehyde, wherein the yield of the intermediate product is 83%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.880 (s, 1H), 7.839 (d, J = 8.7Hz , 2H), 7.013 (d, J = 8.7 Hz, 2H), 4.223 (t, J = 11.7 Hz, 2H), 2.828 (t, J = 11.7 Hz, 2H), 2.544 (t, J = 10.5 Hz, 4H ), 1.583-1.657 (m, 4H), 1.418-1.494 (m, 2H), 1.256-1.303 (m, 1H). Thereafter, the derivative 12 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2- (piperidin-1-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Piperidin-1-yl) ethoxy ) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the resulting derivatives 12 and 82%, 1 H NMR (300MHz, DMSO -d6) is δ 7.522 (s, 1H), 7.411 (d, J = 10.2Hz, 2H), 6.967 (d, J = 10.2 Hz, 2H), 4.096 (t , J = 11.1Hz, 2H), 2.814 (t, J = 11.1Hz, 2H), 2.379 (m, 4H), 1.410-1.513 (m, 5H), 1.291-1.307 (m , 2H).

＜실시예 13＞<Example 13>

본 발명에 따른 유도체 13의 제조Preparation of Derivative 13 According to the Invention

하기 화학식으로 나타내는 유도체 13을 다음과 같은 방법으로 제조하였다.Derivative 13 represented by the following formula was prepared in the following manner.

＜유도체 13의 화학식＞<Chemical formula of derivative 13>

Figure pct00021
Figure pct00021

상기 실시예 2의 유도체를 제조하는 과정 중, 제1 단계에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 4-플루오로-3-(트리플루오로메칠)벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-사이클로헥실에톡시)-3-(트리플루오로메칠)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89％이고, 1H NMR (300MHz, CDCl3)은 δ 9.915(s, 1H), 8.102(s, 1H), 8.044(d, J=10.5Hz, 2H), 7.125(d, J=8.7Hz, 2H), 4.208(t, J=12.6Hz, 2H), 1.639-1.788(m, 6H), 1.466-1.567(m, 1H), 1.177-1.338(m, 4H), 0.882-1.041(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 13인 5-(4-(2-사이클로헥실에톡시)-3-트리플루오로메틸)벤질리덴)티아졸리딘-2,4-디온 (5-(4-(2-Cyclohexylethoxy)-3-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 13의 수율은 92％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.270(s, 1H), 7.812(s, 1H), 7.461(d, J=8.7 Hz, 2H), 7.262(s, 1H), 6.934(d, J=8.7Hz, 2H), 4.080(t, J=13.5Hz, 2H), 1.576-1.738(m, 7H), 1.284-1.506(m, 1H), 1.035-1.245(m, 3H), 0.926-0.995(m, 2H)이었다.In the process of preparing the derivative of Example 2, cyclohexylethanol is used instead of 4- (2-hydroxyethyl) morpholine in the first step, and 4-fluoro-3- (trifluoro is used instead of 4-fluorobenzaldehyde. Intermediate 4- (2-cyclohexylethoxy) -3- (trifluoromethyl) benzaldehyde was obtained using the same method except adding locyl) benzaldehyde, where the yield of the intermediate product was 89%. 1 H NMR (300MHz, CDCl 3 ) is δ 9.915 (s, 1H), 8.102 (s, 1H), 8.044 (d, J = 10.5Hz, 2H), 7.125 (d, J = 8.7Hz, 2H) , 4.208 (t, J = 12.6 Hz, 2H), 1.639-1.788 (m, 6H), 1.466-1.567 (m, 1H), 1.177-1.338 (m, 4H), 0.882-1.041 (m, 2H). Subsequently, the derivative 13 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2-cyclohexylethoxy) -3-trifluoromethyl) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3- (trifluoromethyl ) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 13 is 92%, 1 H NMR (300MHz, DMSO-d6) is δ 8.270 (s, 1H), 7.812 (s, 1H), 7.461 (d, J = 8.7 Hz, 2H), 7.262 (s, 1H), 6.934 (d, J = 8.7Hz, 2H), 4.080 (t, J = 13.5Hz, 2H), 1.576-1.738 (m, 7H), 1.284-1.506 (m, 1H), 1.035 -1.245 (m, 3H) and 0.926-0.995 (m, 2H).

＜실시예 14＞<Example 14>

본 발명에 따른 유도체 14의 제조Preparation of Derivative 14 According to the Invention

하기 화학식으로 나타내는 유도체 14를 다음과 같은 방법으로 제조하였다.Derivative 14 represented by the following formula was prepared in the following manner.

＜유도체 14의 화학식＞<Chemical formula of derivative 14>

Figure pct00022
Figure pct00022

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-(2-하이드록시에틸)티오모르폴린-1,1-디옥사이드를 사용하고 p-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(2-티오모르폴린-1,1-디옥사이드에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 91％이고, 1H NMR (300MHz, CDCl3)은 δ 9.897(s, 1H), 7.70(s, 1H), 7.59(d, J=9.0Hz, 2H), 6.99(d, J=9.0Hz, 2H), 4.14(t, J=10.5Hz, 2H), 3.27(dd, J= 10.2,10.2, 8H), 3.04(t, J=10.5Hz, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 14인 5-[3-클로로-4-(2-티오모르폴린-1,1-디옥시드에톡시)벤질리덴]-티아졸리딘-2,4-디온(5-[3-Chloro-4-(2-thiomorpholine-1,1-dioxideethoxy)benzylidene]-thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 14의 수율은 94％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.564(s, 1H), 7.724(s, 1H), 7.706(s, 1H), 7.547(d, J=11.1Hz, 2H), 7.11(d, J=9.0Hz, 2H), 4.263(t, J=10.5Hz, 2H), 3.076(s, 1H), 2.990(t, J=10.5Hz, 2H)이었다.During the preparation of the derivative of Example 1, 4- (2-hydroxyethyl) thiomorpholine-1,1-dioxide instead of 2-isopropoxyethanol in the first step and p-hydroxybenzaldehyde instead Using the same method, except adding 3-chloro-4-hydroxybenzaldehyde, the intermediate product 3-chloro-4- (2-thiomorpholine-1,1-dioxideethoxy) benzaldehyde was obtained. In this case, the yield of the intermediate product is 91%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.897 (s, 1H), 7.70 (s, 1H), 7.59 (d, J = 9.0 Hz, 2H), 6.99 ( d, J = was 9.0Hz, 2H), 4.14 (t , J = 10.5Hz, 2H), 3.27 (dd, J = 10.2,10.2, 8H), 3.04 (t, J = 10.5Hz, 2H). Subsequently, the derivative 14 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- [3-chloro-4- (2-thiomorpholine-1,1-dioxideethoxy) benzylidene] -thiazolidine-2,4-dione (5- [3-Chloro-4- ( 2-thiomorpholine-1,1-dioxideethoxy) benzylidene] -thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 14 was 94%, 1 H NMR (300MHz, DMSO-d6) was δ 12.564 (s, 1H), 7.724 (s, 1H), 7.706 (s, 1H), 7.547 (d, J = 11.1 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 4.263 (t, J = 10.5 Hz, 2H), 3.076 (s, 1H), 2.990 (t, J = 10.5 Hz, 2H). .

＜실시예 15＞<Example 15>

본 발명에 따른 유도체 15의 제조Preparation of Derivative 15 According to the Invention

하기 화학식으로 나타내는 유도체 15를 다음과 같은 방법으로 제조하였다.Derivative 15 represented by the following formula was prepared in the following manner.

＜유도체 15의 화학식＞<Chemical formula of derivative 15>

Figure pct00023
Figure pct00023

상기 실시예 2의 유도체를 제조하는 과정 중, 제1 단계에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 2-클로로-4-플루오로벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 2-클로로-4-(2-사이클로헥실에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89％이고, 1H NMR (300MHz, CDCl3)은 δ 9.447(s, 1H), 7.867(d, J=8.4Hz, 2H), 7.369(s, 1H), 7.043(d, J=8.4Hz, 2H), 4.195(t, J=13.2Hz, 2H), 1.221-1.475(m, 6H), 1.183-1.434(m, 1H), 1.095-1.161(m, 4H), 0.847-0.945(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-2(-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-Chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 15를 수득하였다. 상기 수득한 유도체 15의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.654(s, 1H), 7.877(s, 1H), 7.517(d, J=9Hz, 1H), 7.110(s, 1H), 7.012(d, J=9Hz, 1H), 4.111(t, J=13.2Hz, 2H), 1.434-1.642(m, 4H), 1.263-1.434(m, 1H), 1.094-1.221(m, 4H), 0.847-0.989(m, 2H)이었다.In the process of preparing the derivative of Example 2, cyclohexylethanol is used instead of 4- (2-hydroxyethyl) morpholine in the first step, and 2-chloro-4-fluorobenzaldehyde is used instead of 4-fluorobenzaldehyde. Using the same method except adding, intermediate 2-chloro-4- (2-cyclohexylethoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 89%, 1 H NMR (300 MHz, CDCl 3 ) Is δ 9.447 (s, 1H), 7.867 (d, J = 8.4 Hz, 2H), 7.369 (s, 1H), 7.043 (d, J = 8.4 Hz, 2H), 4.195 (t, J = 13.2 Hz, 2H), 1.221-1.475 (m, 6H), 1.183-1.434 (m, 1H), 1.095-1.161 (m, 4H), 0.847-0.945 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. (2-chloro-4-2 (-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (2-Chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4- A derivative 15, dione) was obtained. The yield of the obtained derivative 15 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.654 (s, 1H), 7.877 (s, 1H), 7.517 (d, J = 9Hz, 1H), 7.110 (s, 1H), 7.012 (d, J = 9 Hz, 1H), 4.111 (t, J = 13.2 Hz, 2H), 1.434-1.642 (m, 4H), 1.263-1.434 (m, 1H), 1.094-1.221 (m, 4H) and 0.847-0.989 (m, 2H).

＜실시예 16＞<Example 16>

본 발명에 따른 유도체 16의 제조Preparation of Derivative 16 According to the Invention

하기 화학식으로 나타내는 유도체 16을 다음과 같은 방법으로 제조하였다.Derivative 16 represented by the following formula was prepared in the following manner.

＜유도체 16의 화학식＞<Chemical formula of derivative 16>

Figure pct00024
Figure pct00024

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-티오핀메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(티오핀-2-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89％이고, 1H NMR (300MHz, CDCl3)은 δ 9.893(s, 1H), 7.862(d, J=8.4Hz, 2H), 7.368(d, J=5.1Hz, 1H), 7.153(d, J=3.3Hz, 1H), 7.103(d, J=8.4Hz, 2H), 7.042(t, J=8.4Hz, 1H), 5.309(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(티오펜-2-일메톡시)티아졸리딘-2,4-디온(5-(4-(Thiophen-2-ylmethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 16을 수득하였다. 상기 수득한 유도체 16의 수율은 94％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.513(s, 1H), 7.745(s, 1H), 7.569(d, J=8.4Hz, 2H), 7.559(t, J=2.4Hz, 1H), 7.248(t, J=3.3Hz, 1H), 7.194(d, J=8.4Hz, 2H) 7.052(m, J=10.5Hz, 1H) 5.37(s, 2H)이었다.In the process of preparing the derivative of Example 1, the intermediate product 4- (thioffin-2) was prepared using the same method except that 2-thiopinmethanol was added instead of 2-isopropoxyethanol in the first step. -Ylmethoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 89%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.893 (s, 1H), 7.862 (d, J = 8.4 Hz, 2H), 7.368 (d, J = 5.1 Hz, 1H), 7.153 (d, J = 3.3 Hz, 1H), 7.103 (d, J = 8.4 Hz, 2H), 7.042 (t, J = 8.4 Hz, 1H), 5.309 ( s, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. A derivative 16 was obtained which was (4- (thiophen-2-ylmethoxy) thiazolidine-2,4-dione (5- (4- (Thiophen-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione) The yield of the obtained derivative 16 was 94%, 1 H NMR (300MHz, DMSO-d6) was δ 12.513 (s, 1H), 7.745 (s, 1H), 7.569 (d, J = 8.4Hz, 2H). , 7.559 (t, J = 2.4 Hz, 1H), 7.248 (t, J = 3.3 Hz, 1H), 7.194 (d, J = 8.4 Hz, 2H) 7.052 (m, J = 10.5 Hz, 1H) 5.37 (s , 2H).

＜실시예 17＞<Example 17>

본 발명에 따른 유도체 17의 제조Preparation of Derivative 17 According to the Invention

하기 화학식으로 나타내는 유도체 17을 다음과 같은 방법으로 제조하였다.Derivative 17 represented by the following formula was prepared in the following manner.

＜유도체 17의 화학식＞<Chemical formula of derivative 17>

Figure pct00025
Figure pct00025

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 3-티오핀메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(티오핀-3-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.926(s, 1H), 7.865(d, J=13.8Hz, 2H), 7.350-7.405(m, 2H), 7.164(dd, J=1.5, 1.2Hz, 1H), 5.160(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 17인 5-(4-(티오펜-3-일메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Thiophen-3-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 17의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.504(s, 1H), 8.590(s, 1H), 7.864(t, J=17.1Hz, 1H) 7.733(s, 1H), 7.573(d, J=8.7Hz,2H), 7.521(d, J=6Hz, 1H), 7.373(dd, J=5.7, 4.8, 1H), 7.197(d, J=8.7Hz, 2H), 5.252(s, 2H)이었다.In the process of preparing the derivative of Example 1, except that 3-thiopinmethanol was added instead of 2-isopropoxyethanol in the first step, the intermediate product 4- (thioffin-3) was used. -Ylmethoxy) benzaldehyde, where the yield of the intermediate product is 94%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.926 (s, 1H), 7.865 (d, J = 13.8 Hz, 2H), 7.350-7.405 (m, 2H), 7.164 (dd, J = 1.5, 1.2 Hz, 1H), 5.160 (s, 2H). Subsequently, the derivative represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (thiophen-3-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Thiophen-3-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Obtained. The yield of the obtained derivative 17 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.504 (s, 1H), 8.590 (s, 1H), 7.864 (t, J = 17.1 Hz, 1H) 7.733 (s, 1H), 7.573 (d, J = 8.7 Hz, 2H), 7.521 (d, J = 6 Hz, 1H), 7.373 (dd, J = 5.7, 4.8, 1H), 7.197 (d, J = 8.7 Hz , 2H), 5.252 (s, 2H).

＜실시예 18＞<Example 18>

본 발명에 따른 유도체 18의 제조Preparation of Derivative 18 According to the Invention

하기 화학식으로 나타내는 유도체 18을 다음과 같은 방법으로 제조하였다.Derivative 18 represented by the following formula was prepared in the following manner.

＜유도체 18의 화학식＞<Chemical formula of derivative 18>

Figure pct00026
Figure pct00026

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로펜틸에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로펜틸에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.878(s, 1H), 7.850(d, J=11.4Hz, 2H), 7.014(d, J=11.4Hz, 2H), 4.085(t, J=13.5Hz, 2H), 1.878-2.031(m, 1H), 1.698-1.870(m, 4H), 1.494-1.675(m, 4H), 1.109-1.228(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로펜틸에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclopentylethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 18을 수득하였다. 상기 수득한 유도체 18의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.502(s, 1H), 7.737(s, 1H), 7.550 (d, J=8.7Hz, 2H), 7.093(d, J=8.7Hz, 2H), 4.136(t, J=13.2Hz, 2H), 2.06(s, 2H), 1.807-1.976(m, 1H), 1.700-1.769(m, 4H), 1.455-1.611(m, 4H), 1.102-1.185(m, 2H)이었다.The intermediate product 4- (2-cyclopentylethoxy) was used in the same manner as in the preparation of the derivative of Example 2, except that cyclopentylethanol was used instead of 4- (2-hydroxyethyl) morpholine. Benzaldehyde was obtained, wherein the yield of the intermediate product was 85%, 1 H NMR (300 MHz, CDCl 3 ) yields δ 9.878 (s, 1H), 7.850 (d, J = 11.4 Hz, 2H), 7.014 (d, J = 11.4 Hz, 2H), 4.085 (t, J = 13.5 Hz, 2H), 1.878-2.031 (m, 1H), 1.698-1.870 (m, 4H), 1.494-1.675 (m, 4H), 1.109-1.228 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. A derivative 18 was obtained, which was (4- (2-cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione). . The yield of the obtained derivative 18 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.502 (s, 1H), 7.737 (s, 1H), 7.550 (d, J = 8.7 Hz, 2H), 7.093 (d, J = 8.7 Hz, 2H), 4.136 (t, J = 13.2 Hz, 2H), 2.06 (s, 2H), 1.807-1.976 (m, 1H), 1.700-1.769 (m, 4H), 1.455 -1.611 (m, 4H) and 1.102-1.185 (m, 2H).

＜실시예 19＞<Example 19>

본 발명에 따른 유도체 19의 제조Preparation of Derivative 19 According to the Invention

하기 화학식으로 나타내는 유도체 19를 다음과 같은 방법으로 제조하였다.Derivative 19 represented by the following formula was prepared in the following manner.

＜유도체 19의 화학식＞<Chemical formula of derivative 19>

Figure pct00027
Figure pct00027

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 푸르푸릴 알콜(furfuryl alcohol)을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(퓨란-2-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.895(s, 1H), 7.872(d, J=11.4Hz, 2H), 7.473(s, 1H), 7.118(d, J=11.4Hz, 2H), 6.483(dd, J=3.3, 5.4Hz, 2H), 5.093(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 19인 5-(4-(퓨란-2-일메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Furan-2-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 19의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.518(s, 1H), 7.747(s, 1H), 7.705(s, 1H), 7.572(d, J=8.4Hz, 1H), 7.200(d, J=8.4Hz, 2H), 6.630(dd, J=3, 1.8,1H), 5.142(s, 2H)이었다.In the process of preparing the derivative of Example 1, 4- (furan-, which is an intermediate product, was used in the same manner, except that furfuryl alcohol was added instead of 2-isopropoxyethanol in the first step. 2-ylmethoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.895 (s, 1H), 7.872 (d, J = 11.4 Hz, 2H). , 7.473 (s, 1H), 7.118 (d, J = 11.4 Hz, 2H), 6.483 (dd, J = 3.3, 5.4 Hz, 2H), and 5.093 (s, 2H). Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (furan-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Furan-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Obtained. The yield of the obtained derivative 19 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.518 (s, 1H), 7.747 (s, 1H), 7.705 (s, 1H), 7.572 (d, J = 8.4 Hz, 1H), 7.200 (d, J = 8.4 Hz, 2H), 6.630 (dd, J = 3, 1.8,1H), 5.142 (s, 2H).

＜실시예 20＞<Example 20>

본 발명에 따른 유도체 20의 제조Preparation of Derivative 20 According to the Invention

하기 화학식으로 나타내는 유도체 20을 다음과 같은 방법으로 제조하였다.Derivative 20 represented by the following formula was prepared in the following manner.

＜유도체 20의 화학식＞<Chemical formula of derivative 20>

Figure pct00028
Figure pct00028

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-피리딘메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(피리딘-2-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ9.932(s, 1H), 8.630(d, J=4.8Hz, 1H), 7.870(d, J=13.8Hz, 2H), 7.767(t, J=17.1Hz, 1H), 7.513(d, J=7.8Hz, 1H), 7.284 (t, J=12.6Hz, 1H), 7.129(d, J=13.8Hz, 2H), 5.295(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 20인 5-(4-(피리딘-2-일메톡시)벤질리덴)티아졸리딘-2,2-디온(5-(4-(Pyridin-2-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 20의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.525(s, 1H), 8.585(d, J=4.2Hz, 1H), 7.865(t, J=16.8Hz, 1H), 7.735(s, 1H), 7.575(d, J=9Hz, 2H), 7.527(d, J=7.8Hz, 1H), 7.372(dd, J=4.8, 4.8, 1H), 7.197(d, J=8.7Hz, 2H), 5.251(s, 2H)이었다.In preparing the derivative of Example 1, 4- (pyridin-2-ylme, which is an intermediate product, was used in the same manner, except that 2-pyridinemethanol was added instead of 2-isopropoxyethanol in the first step. Oxy) benzaldehyde, wherein the yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.932 (s, 1H), 8.630 (d, J = 4.8 Hz, 1H), 7.870 (d, J = 13.8 Hz, 2H), 7.767 (t, J = 17.1 Hz, 1H), 7.513 (d, J = 7.8 Hz, 1H), 7.284 (t, J = 12.6 Hz, 1H), 7.129 (d , J = 13.8 Hz, 2H), and 5.295 (s, 2H). Subsequently, the derivative 20 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (pyridin-2-ylmethoxy) benzylidene) thiazolidine-2,2-dione (5- (4- (Pyridin-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Obtained. The yield of the obtained derivative 20 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.525 (s, 1H), 8.585 (d, J = 4.2Hz, 1H), 7.865 (t, J = 16.8 Hz, 1H), 7.735 (s, 1H), 7.575 (d, J = 9 Hz, 2H), 7.527 (d, J = 7.8 Hz, 1H), 7.372 (dd, J = 4.8, 4.8, 1H), 7.197 ( d, J = 8.7 Hz, 2H) and 5.251 (s, 2H).

＜실시예 21＞<Example 21>

본 발명에 따른 유도체 21의 제조Preparation of Derivative 21 According to the Invention

하기 화학식으로 나타내는 유도체 21을 다음과 같은 방법으로 제조하였다.Derivative 21 represented by the following formula was prepared in the following manner.

＜유도체 21의 화학식＞<Chemical formula of derivative 21>

Figure pct00029
Figure pct00029

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-메틸벤질알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-메틸벤질옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.885(s, 1H), 7.891(d, J=11.7Hz, 2H), 7.335(d, J=7.5Hz, 2H), 7.261(d, J=7.5Hz,2H), 7.095(d, J=11.7Hz, 2H), 5.11(s, 2H), 2.371(s, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 21인 5-(4-(4-메틸벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-Methylbenzyloxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 21의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.514(s, 1H), 7.800(s, 1H), 7.560(d, J=8.7Hz, 2H), 7.346(d, J=7.8Hz, 2H), 7.206(d, J=8.1Hz, 2H), 7.165(d, J=9Hz, 2H), 5.125(s, 2H), 2.295(s, 3H)이었다.In preparing the derivative of Example 1, 4- (4-methylbenzyl, which is an intermediate product, was used in the same manner, except that 4-methylbenzyl alcohol was added instead of 2-isopropoxyethanol in the first step. Oxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.885 (s, 1H), 7.891 (d, J = 11.7 Hz, 2H), 7.335 ( d, J = 7.5 Hz, 2H), 7.261 (d, J = 7.5 Hz, 2H), 7.095 (d, J = 11.7 Hz, 2H), 5.11 (s, 2H), 2.371 (s, 3H). Subsequently, the derivative 21 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (4-methylbenzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4-Methylbenzyloxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 21 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.514 (s, 1H), 7.800 (s, 1H), 7.560 (d, J = 8.7 Hz, 2H), 7.346 (d, J = 7.8 Hz, 2H), 7.206 (d, J = 8.1 Hz, 2H), 7.165 (d, J = 9 Hz, 2H), 5.125 (s, 2H), 2.295 (s, 3H).

＜실시예 22＞<Example 22>

본 발명에 따른 유도체 22의 제조Preparation of Derivative 22 According to the Invention

하기 화학식으로 나타내는 유도체 22를 다음과 같은 방법으로 제조하였다.Derivative 22 represented by the following formula was prepared in the following manner.

＜유도체 22의 화학식＞<Chemical formula of derivative 22>

Figure pct00030
Figure pct00030

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-메톡시벤질알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-메톡시벤질옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.889(s, 1H), 7.854(d, J=8.7 Hz, 2H), 7.378(d, J=8.4Hz, 2H), 7.087(d, J=8.7Hz, 2H), 7.095(d, J=9Hz, 2H), 5.077(s, 2H), 3.826(s, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 22인 5-(4-(4-메톡시벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-Methoxybenzyloxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 22의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.523(s, 1H), 7.897(s, 1H), 7.470(d, J=8.7Hz, 2H), 7.249(d, J=8.7Hz, 2H), 7.307(d, J=8.4Hz, 2H), 7.165(d, J=8.4Hz, 2H), 5.055(s, 2H), 3,785(s, 3H)이었다.In the process of preparing the derivative of Example 1, except that 4-methoxybenzyl alcohol is added instead of 2-isopropoxyethanol in the first step, the intermediate product 4- (4-meth Oxybenzyloxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.889 (s, 1H), 7.854 (d, J = 8.7 Hz, 2H), 7.378 (d, J = 8.4 Hz, 2H), 7.087 (d, J = 8.7 Hz, 2H), 7.095 (d, J = 9 Hz, 2H), 5.077 (s, 2H), 3.826 (s, 3H). Subsequently, the derivative 22 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (4-methoxybenzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4-Methoxybenzyloxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 22 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.523 (s, 1H), 7.897 (s, 1H), 7.470 (d, J = 8.7Hz, 2H), 7.249 (d, J = 8.7Hz, 2H), 7.307 (d, J = 8.4Hz, 2H), 7.165 (d, J = 8.4Hz, 2H), 5.055 (s, 2H), 3,785 (s, 3H) .

＜실시예 23＞<Example 23>

본 발명에 따른 유도체 23의 제조Preparation of Derivative 23 According to the Invention

하기 화학식으로 나타내는 유도체 23을 다음과 같은 방법으로 제조하였다.Derivative 23 represented by the following formula was prepared in the following manner.

＜유도체 23의 화학식＞<Chemical formula of derivative 23>

Figure pct00031
Figure pct00031

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 피페로닐알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 5-(4-(벤조[d][1,3]디옥솔-5-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.887(s, 1H), 7.861(d, J=13.2 Hz, 2H), 7.084(d, J=13.2Hz, 2H), 6.923(dd, J=1.5, 1.5Hz, 2H), 6.771(s, 1H), 5.98(s, 2H), 5.042(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 23인 5-(4-(벤조[d][1,3]디옥솔-5-일메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Benzo[d][1,3]dioxol-5-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 23의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.498(s, 1H), 7.722(s, 1H), 7.558(d, J=9Hz, 2H), 7.157(d, J=8.7Hz, 2H), 7.014(s, 1H), 6.962(dd, J=8.1, 8.1Hz, 2H), 6.011(s, 2H), 5.059(s, 2H)이었다.In the process of preparing the derivative of Example 1, the intermediate product of 5- (4- (benzo [] was used in the same manner, except that piperonyl alcohol was added instead of 2-isopropoxyethanol in the first step. d ] [1,3] dioxol-5-ylmethoxy) benzaldehyde, where the yield of the intermediate product is 94%, and 1 H NMR (300 MHz, CDCl 3 ) is δ 9.887 (s, 1H), 7.861 (d, J = 13.2 Hz, 2H), 7.084 (d, J = 13.2Hz, 2H), 6.923 (dd, J = 1.5, 1.5Hz, 2H), 6.771 (s, 1H), 5.98 (s, 2H) And 5.042 (s, 2H) The same procedure was followed except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation process of Example 1. 5- (4- (benzo [ d ] [1,3] dioxol-5-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Benzo [d] [1,3] dioxol-5-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Was obtained. The yield of the obtained derivative 23 was 89%, and, 1 H NMR (300MHz, DMSO -d6) is δ 12.498 (s, 1H), 7.722 (s, 1H), 7.558 (d, J = 9Hz, 2H ), 7.157 (d, J = 8.7 Hz, 2H), 7.014 (s, 1H), 6.962 (dd, J = 8.1, 8.1 Hz, 2H), 6.011 (s, 2H), 5.059 (s, 2H).

＜실시예 24＞<Example 24>

본 발명에 따른 유도체 24의 제조Preparation of Derivative 24 According to the Invention

하기 화학식으로 나타내는 유도체 24를 다음과 같은 방법으로 제조하였다.Derivative 24 represented by the following formula was prepared in the following manner.

＜유도체 24의 화학식＞<Chemical formula of derivative 24>

Figure pct00032
Figure pct00032

상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로헥산올을 사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(사이클로헥실옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.834(s, 1H), 7.906(d, J=3.9Hz, 1H), 7.745(dd, J=1.8,2.1Hz, 1H), 7.046(d, J=8.4Hz, 1H), 4.443-4.521(m, 1H), 1.943-1.972(m, 2H), 1.825-1.889(m, 2H),1.684-1.803(m, 2H), 1.511-1.673(m, 1H),1.351-1.489(m, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(사이클로헥실옥시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(cyclohexyloxy)benzylidene)thiazolidine-2,4-dione)인 유도체 24를 수득하였다. 상기 수득한 유도체 24의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.587(s, 1H), 7.724(s, 1H), 7.699(d, J=2.1Hz, 1H), 7.516(dd, J=2.1,2.4Hz, 1H), 7.371(d, J=8.7Hz, 1H), 4.564-4.615(m, 1H), 2.029-2.496(m, 2H), 1.693-1.861(m, 2H), 1.509-1.537(m, 2H), 1.350-1.450(m, 4H)이었다.Except for using cyclohexanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in the preparation of the derivative of Example 1 using the same method An intermediate product, 3-chloro-4- (cyclohexyloxy) benzaldehyde, was obtained, wherein the yield of the intermediate product was 85%, and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.834 (s, 1H), 7.906. (d, J = 3.9 Hz, 1H), 7.745 (dd, J = 1.8,2.1 Hz, 1H), 7.046 (d, J = 8.4 Hz, 1H), 4.443-4.521 (m, 1H), 1.943-1.972 ( m, 2H), 1.825-1.889 (m, 2H), 1.684-1.803 (m, 2H), 1.511-1.673 (m, 1H), 1.351-1.489 (m, 3H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Derivatives of (3-chloro-4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione) 24 was obtained. The yield of the obtained derivative 24 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.587 (s, 1H), 7.724 (s, 1H), 7.699 (d, J = 2.1 Hz, 1H), 7.516 (dd, J = 2.1, 2.4 Hz, 1H), 7.371 (d, J = 8.7 Hz, 1H), 4.564-4.615 (m, 1H), 2.029-2.496 (m, 2H), 1.693-1.861 (m, 2H), 1.509-1.537 (m, 2H), 1.350-1.450 (m, 4H).

＜실시예 25＞<Example 25>

본 발명에 따른 유도체 25의 제조Preparation of Derivative 25 According to the Invention

하기 화학식으로 나타내는 유도체 25를 다음과 같은 방법으로 제조하였다.Derivative 25 represented by the following formula was prepared in the following manner.

＜유도체 25의 화학식＞<Chemical formula of derivative 25>

Figure pct00033
Figure pct00033

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실메탄올을사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.840(s, 1H), 7.900(d, J=2.1Hz, 1H), 7.759(dd, J=1.5, 2.4Hz, 1H), 7.018(d, J=8.4Hz, 1H), 3.914(d, J=5.7Hz, 2H), 1.889-2.046(m, 3H), 1.748-1.862(m, 3H), 1.240-1.424(m, 3H), 1.042-1.231(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(사이클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 25를 수득하였다. 상기 수득한 유도체 25의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.586(s, 1H), 7.721(s, 1H), 7.697(d, J=2.4Hz, 1H), 7.527(dd, J=2.1, 2.4Hz, 1H), 7.305(d, J=8.7Hz, 1H), 3.949(d, J=6Hz, 2H), 1.626-1.826(m, 6H), 1.034-1.269(m, 5H)이었다.In the process of preparing the derivative of Example 1, except for using cyclohexyl methanol instead of 2-isopropoxyethanol in the first step and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde Using the same method to obtain the intermediate product 3-chloro-4- (cyclohexylmethoxy) benzaldehyde, where the yield of the intermediate product is 85%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.840 ( s, 1H), 7.900 (d, J = 2.1 Hz, 1H), 7.759 (dd, J = 1.5, 2.4 Hz, 1H), 7.018 (d, J = 8.4 Hz, 1H), 3.914 (d, J = 5.7 Hz, 2H), 1.889-2.046 (m, 3H), 1.748-1.862 (m, 3H), 1.240-1.424 (m, 3H), 1.042-1.231 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Derivatives of (3-chloro-4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) 25 was obtained. The yield of the obtained derivative 25 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.586 (s, 1H), 7.721 (s, 1H), 7.697 (d, J = 2.4 Hz, 1H), 7.527 (dd, J = 2.1, 2.4 Hz, 1H), 7.305 (d, J = 8.7 Hz, 1H), 3.949 (d, J = 6 Hz, 2H), 1.626-1.826 (m, 6H), 1.034-1.269 ( m, 5H).

＜실시예 26＞<Example 26>

본 발명에 따른 유도체 26의 제조Preparation of Derivative 26 According to the Invention

하기 화학식으로 나타내는 유도체 26을 다음과 같은 방법으로 제조하였다.Derivative 26 represented by the following formula was prepared in the following manner.

＜유도체 26의 화학식＞<Chemical formula of derivative 26>

Figure pct00034
Figure pct00034

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하였고, 4-히드록시벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 10.532 (s, 1H), 7.582(dd, J=2.7, 2.7Hz, 1H), 7.205-7.339(m, 1H), 7.162(dd, J=1.5, 1.5Hz, 1H), 4.125(t, J=13.2Hz, 2H), 1.645-1.804(m, 6H), 1.389-1.593(m, 1H), 1.118-1.339(m, 4H), 0.854-1.055(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 26인 5-(2-클로로-3-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,-4-디온(5-(2-Chloro-3-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 26의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.582(s, 1H), 7.908(s, 1H), 7.462(t, J=15.9Hz, 1H), 7.283(d, J=8.4Hz, 1H), 7.150(d, J=7.8Hz, 1H), 4.140(t, J=12.9Hz, 2H), 1.642-1.758(m, 7H), 1.493(m, 1H), 1.161-1.228(m, 3H), 0.933-0.969(m, 2H)이었다.In the process of preparing the derivative of Example 1, cyclohexylethanol was used instead of 2-isopropoxyethanol in the first step, except that 2-chloro-3-hydroxybenzaldehyde was added instead of 4-hydroxybenzaldehyde. Using the same method to obtain an intermediate product, the yield of the intermediate product is 85%, 1 H NMR (300MHz, CDCl 3 ) is δ 10.532 (s, 1H), 7.582 (dd, J = 2.7, 2.7 Hz, 1H), 7.205-7.339 (m, 1H), 7.162 (dd, J = 1.5, 1.5 Hz, 1H), 4.125 (t, J = 13.2 Hz, 2H), 1.645-1.804 (m, 6H), 1.389-1.593 (m, 1H), 1.118-1.339 (m, 4H) and 0.854-1.055 (m, 2H). Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (2-chloro-3- (2-cyclohexylethoxy) benzylidene) thiazolidine-2, -4-dione (5- (2-Chloro-3- (2-cyclohexylethoxy) benzylidene) thiazolidine- 2,4-dione) was obtained. The yield of the obtained derivative 26 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.582 (s, 1H), 7.908 (s, 1H), 7.462 (t, J = 15.9 Hz, 1H), 7.283 (d, J = 8.4 Hz, 1H), 7.150 (d, J = 7.8 Hz, 1H), 4.140 (t, J = 12.9 Hz, 2H), 1.642-1.758 (m, 7H), 1.493 (m, 1H ), 1.161-1.228 (m, 3H), and 0.933-0.969 (m, 2H).

＜실시예 27＞<Example 27>

본 발명에 따른 유도체 27의 제조Preparation of Derivative 27 According to the Invention

하기 화학식으로 나타내는 유도체 27을 다음과 같은 방법으로 제조하였다.Derivative 27 represented by the following formula was prepared in the following manner.

＜유도체 27의 화학식＞<Chemical formula of derivative 27>

Figure pct00035
Figure pct00035

상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로펜틸메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로펜틸메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.878(s, 1H), 7.848 (d, J=11.4Hz, 2H), 7.018(d, J=11.4Hz, 2H), 3.928(d, J=7.2Hz, 2H), 2.340-2.439(m, 1H), 1.822-1.911(m, 2H), 1.581-1.808(m, 4H), 1.312-1.424(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 27인 5-(4-(사이클로펜틸메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Cyclopentylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 27의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.503(s, 1H), 7.732(s, 1H), 7.547(d, J=9Hz, 2H), 7.094(d, J=9Hz, 2H), 3.922(d, J=7.2Hz, 2H), 2.253-2.351(m, 1H), 1.750-1.770(m, 2H), 1.525-1.603(m, 4H), 1.283-1.344(m, 2H)이었다.The intermediate product 4- (cyclopentylmethoxy) benzaldehyde was obtained by the same method except that cyclopentylmethanol was used instead of 2-isopropoxyethanol in the preparation of the derivative of Example 1, wherein The yield of the intermediate product is 85%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.878 (s, 1H), 7.848 (d, J = 11.4 Hz, 2H), 7.018 (d, J = 11.4 Hz, 2H) , 3.928 (d, J = 7.2 Hz, 2H), 2.340-2.439 (m, 1H), 1.822-1.911 (m, 2H), 1.581-1.808 (m, 4H), 1.312-1.424 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 27 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.503 (s, 1H), 7.732 (s, 1H), 7.547 (d, J = 9Hz, 2H), 7.094 (d, J = 9 Hz, 2H), 3.922 (d, J = 7.2 Hz, 2H), 2.253-2.351 (m, 1H), 1.750-1.770 (m, 2H), 1.525-1.603 (m, 4H), 1.283 -1.344 (m, 2H).

＜실시예 28＞<Example 28>

본 발명에 따른 유도체 28의 제조Preparation of Derivative 28 According to the Invention

하기 화학식으로 나타내는 유도체 28을 다음과 같은 방법으로 제조하였다.Derivative 28 represented by the following formula was prepared in the following manner.

＜유도체 28의 화학식＞<Chemical formula of derivative 28>

Figure pct00036
Figure pct00036

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-(클로로메틸)벤질알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-클로로메틸벤질옥시)벤즈알데히드를 수득하였으며, 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.932(s, 1H), 7.87(d, J=14.4 Hz, 2H), 7.433(s, 4H), 7.096(d, J=13.8Hz, 2H), 5.157(s, 2H), 4.605(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체의 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(4-(클로로메틸)벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-(Chloromethyl)benzyloxy)benzylidene)thiazolidine-2,4-dione)인 유도체 28을 수득하였다. 상기 수득한 유도체 28의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.549(s, 1H), 7.748(s, 1H), 7.58(dd, J=3.3,3.0Hz, 4H), 7.454(s, 2H) 7.190(dd, J=3.9,3.9Hz, 2H), 5.219(s, 2H), 4.760(s, 2H)이었다.In the process of preparing the derivative of Example 1, 4- (4), which is an intermediate product, was used in the same manner, except that 4- (chloromethyl) benzyl alcohol was added instead of 2-isopropoxyethanol in the first step. -Chloromethylbenzyloxy) benzaldehyde was obtained, yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.932 (s, 1H), 7.87 (d, J = 14.4 Hz, 2H) , 7.433 (s, 4H), 7.096 (d, J = 13.8 Hz, 2H), 5.157 (s, 2H), and 4.605 (s, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in Formula 2, except that the intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation of the derivative of Example 1. -(4- (4- (chloromethyl) benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4- (Chloromethyl) benzyloxy) benzylidene) thiazolidine-2,4-dione) Phosphorus derivative 28 was obtained. The yield of the obtained derivative 28 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.549 (s, 1H), 7.748 (s, 1H), 7.58 (dd, J = 3.3, 3.0 Hz, 4H ), 7.454 (s, 2H), 7.190 (dd, J = 3.9,3.9 Hz, 2H), 5.219 (s, 2H), 4.760 (s, 2H).

＜실시예 29＞<Example 29>

본 발명에 따른 유도체 29의 제조Preparation of the derivative 29 according to the invention

하기 화학식으로 나타내는 유도체 29를 다음과 같은 방법으로 제조하였다.Derivative 29 represented by the following formula was prepared in the following manner.

＜유도체 29의 화학식＞<Chemical formula of derivative 29>

Figure pct00037
Figure pct00037

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-메틸사이클로헥실메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-메틸사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 상기 생성물의 1H NMR (300MHz, CDCl3)은 δ 9.371(s, 1H), 7.378(d, J=8.7Hz, 2H), 6.66(d, J=8.7Hz, 2H), 3.531(d, J=7.2Hz, 1H), 3.419(d, J=6.6Hz, 1H), 1.19-1.499(m, 3H), 0.943-1.047(m, 4H), 0.64-0.821(m, 2H), 0.375-0.596(m, 4H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 29인 5-(4-((메틸사이클로헥실)메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-((4-Methylcyclohexyl)methoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 29의 수율은 89％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.493(s, 1H), 7.693(s, 1H), 7.536(d, J=9.0Hz, 2H), 7.101(dd, J=6.9,6.9Hz, 2H), 3.963(d, J=6.9Hz, 1H), 3.851(d, J=6.6Hz, 1H), 1.662-1.976(m, 4H), 1.185-1.516(m, 4H), 0.975-1.161(m, 2H), 0.852-0.935(m, 3H)이었다.In preparing the derivative of Example 1, 4- (4-methyl as an intermediate product, using the same method, except that 4-methylcyclohexylmethanol was added instead of 2-isopropoxyethanol in the first step. Cyclohexylmethoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, and the 1 H NMR (300 MHz, CDCl 3 ) of the product was δ 9.371 (s, 1H), 7.378 (d, J = 8.7 Hz , 2H), 6.66 (d, J = 8.7 Hz, 2H), 3.531 (d, J = 7.2 Hz, 1H), 3.419 (d, J = 6.6 Hz, 1H), 1.19-1.499 (m, 3H), 0.943 -1.047 (m, 4H), 0.64-0.821 (m, 2H), and 0.375-0.596 (m, 4H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4-((methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione (5- (4-((4-Methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione ) Was obtained. The yield of the obtained derivative 29 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.493 (s, 1H), 7.693 (s, 1H), 7.536 (d, J = 9.0 Hz, 2H), 7.101 (dd, J = 6.9,6.9 Hz, 2H), 3.963 (d, J = 6.9 Hz, 1H), 3.851 (d, J = 6.6 Hz, 1H), 1.662-1.976 (m, 4H), 1.185-1.516 (m, 4H), 0.975-1.161 (m, 2H) and 0.852-0.935 (m, 3H).

＜실시예 30＞<Example 30>

본 발명에 따른 유도체 30의 제조Preparation of Derivative 30 According to the Invention

하기 화학식으로 나타내는 유도체 30을 다음과 같은 방법으로 제조하였다.Derivative 30 represented by the following formula was prepared in the following manner.

＜유도체 30의 화학식＞<Chemical formula of derivative 30>

Figure pct00038
Figure pct00038

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 2-(테트라히드로-2H-피란-2-일)메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-(테트라히드로-2H-피란-2-일)메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 90％이고, 상기 생성물의 1H NMR (300MHz, CDCl3)은 δ 9.881(s, 1H), 7.839(d, J=14.1Hz, 2H), 7.044(d, J=14.1Hz, 2H), 4.034-4.087(m, 2H), 3.943-3.990(m, 1H), 3.703-3.780(m, 1H), 3.481-3.566(m, 1H), 1.908-1.948(m, 1H), 1.451-1.692(m, 5H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 30인 5-(4-(2-(테트라히드로-2H-퓨란-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Tetrahydro-2H-pyran-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 30의 수율은 93％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.290(s, 1H), 7.726 (s, 1H), 7.545(d, J=9.0Hz, 2H), 3.978(d, J=5.1Hz, 2H), 3.850-3.892(m, 2H), 3.595-3.638(m, 1H), 1.974-2.119(m, 4H), 1.601-1.858(m, 2H), 1.279-1.470(m, 2H)이었다.Except for using 2- (tetrahydro-2 H -pyran-2-yl) methanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2 using the same method An intermediate product 4- (2- (tetrahydro-2 H -pyran-2-yl) methoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 90%, and the 1 H NMR (300 MHz, CDCl) of the product was obtained. 3 ) is δ 9.881 (s, 1H), 7.839 (d, J = 14.1 Hz, 2H), 7.044 (d, J = 14.1 Hz, 2H), 4.034-4.087 (m, 2H), 3.943-3.990 (m, 1H), 3.703-3.780 (m, 1H), 3.481-3.566 (m, 1H), 1.908-1.948 (m, 1H), 1.451-1.692 (m, 5H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (2- (tetrahydro- 2H -furan-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Tetrahydro-2 H -pyran-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 30 is 93%, 1 H NMR (300MHz, DMSO-d6) is δ 8.290 (s, 1H), 7.726 (s, 1H), 7.545 (d, J = 9.0 Hz, 2H), 3.978 (d, J = 5.1 Hz, 2H), 3.850-3.892 (m, 2H), 3.595-3.638 (m, 1H), 1.974-2.119 (m, 4H), 1.601-1.858 (m, 2H), 1.279- 1.470 (m, 2 H).

＜실시예 31＞<Example 31>

본 발명에 따른 유도체 31의 제조Preparation of the derivative 31 according to the invention

하기 화학식으로 나타내는 유도체 31을 다음과 같은 방법으로 제조하였다.Derivative 31 represented by the following formula was prepared in the following manner.

＜유도체 31의 화학식＞<Chemical formula of derivative 31>

Figure pct00039
Figure pct00039

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 79％이었다. 이후 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(사이클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 31을 수득하였다. 상기 수득한 유도체 31의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.345(s, 1H), 7.748(s, 1H), 7.390(d, J=11.7Hz, 2H), 6.895(d, J=11.7Hz, 2H), 3.752(d, J=6.0Hz, 2H), 1.629-1.819(m, 6H). 1.152-1.301(m, 3H), 0.926-1.072(m, 2H)이었다.The intermediate product 4- (cyclohexylmethoxy) benzaldehyde was prepared in the same manner, except that cyclohexylmethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 79%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. A derivative 31 was obtained, which is 4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione). The yield of the obtained derivative 31 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.345 (s, 1H), 7.748 (s, 1H), 7.390 (d, J = 11.7 Hz, 2H), 6.895 (d, J = 11.7 Hz, 2H), 3.752 (d, J = 6.0 Hz, 2H), 1.629-1.819 (m, 6H). 1.152-1.301 (m, 3H) and 0.926-1.072 (m, 2H).

＜실시예 32＞<Example 32>

본 발명에 따른 유도체 32의 제조Preparation of the derivative 32 according to the invention

하기 화학식으로 나타내는 유도체 32를 다음과 같은 방법으로 제조하였다.Derivative 32 represented by the following formula was prepared in the following manner.

＜유도체 32의 화학식＞<Chemical formula of derivative 32>

Figure pct00040
Figure pct00040

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 1-메틸사이클로헥실메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(1-메틸사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 80％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 32인 5-(4-((1-메틸사이클로헥실)메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-((1-Methylcyclohexyl)methoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 32의 수율은 91％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.487(s, 1H), 7.722(s, 1H), 7.545(d, J=8.7Hz, 2H), 7.108(d, J=8.7Hz, 2H), 3.754(s, 2H), 1.139-1.453(m, 7H), 1.310-1.337(m, 3H), 0.985(s, 3H)이었다.Except for using 1-methylcyclohexylmethanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2 using the same method as the intermediate product 4- (1-methylcyclo Hexylmethoxy) benzaldehyde was obtained wherein the yield of the intermediate product was 80%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Phosphorus 5- (4-((1-methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione (5- (4-((1-Methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4 -dione) was obtained. The yield of the obtained derivative 32 is 91%, 1 H NMR (300MHz, DMSO-d6) is δ 12.487 (s, 1H), 7.722 (s, 1H), 7.545 (d, J = 8.7 Hz, 2H), 7.108 (d, J = 8.7 Hz, 2H), 3.754 (s, 2H), 1.139-1.453 (m, 7H), 1.310-1.337 (m, 3H), 0.985 (s, 3H).

＜실시예 33＞<Example 33>

본 발명에 따른 유도체 33의 제조Preparation of the derivative 33 according to the invention

하기 화학식으로 나타내는 유도체 33을 다음과 같은 방법으로 제조하였다.Derivative 33 represented by the following formula was prepared in the following manner.

＜유도체 33의 화학식＞<Chemical formula of derivative 33>

Figure pct00041
Figure pct00041

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 벤질알콜을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(벤질옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 92％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Benzyloxy)benzylidene)thiazolidine-2,4-dione)인 유도체 33을 수득하였다. 상기 수득한 유도체 33의 수율은 78％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.498(s, 1H), 7.736(s, 1H), 7.566(d, J=8.7Hz, 2H), 7.306-7.468(m, 5H), 7.18(d, J=8.7Hz, 2H), 5.176(s, 2H)이었다.The intermediate product 4- (benzyloxy) benzaldehyde was obtained by the same method except that benzyl alcohol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. The yield of this intermediate product was 92%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. A derivative 33 was obtained which was (4- (benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Benzyloxy) benzylidene) thiazolidine-2,4-dione). The yield of the obtained derivative 33 is 78%, 1 H NMR (300MHz, DMSO-d6) is δ 12.498 (s, 1H), 7.736 (s, 1H), 7.566 (d, J = 8.7 Hz, 2H), 7.306-7.468 (m, 5H), 7.18 (d, J = 8.7 Hz, 2H), 5.176 (s, 2H).

＜실시예 34＞<Example 34>

본 발명에 따른 유도체 34의 제조Preparation of Derivative 34 According to the Invention

하기 화학식으로 나타내는 유도체 34를 다음과 같은 방법으로 제조하였다.Derivative 34 represented by the following formula was prepared in the following manner.

＜유도체 34의 화학식＞<Chemical formula of derivative 34>

Figure pct00042
Figure pct00042

4-(2-이소프로폭시에톡시)벤즈알데히드(0.98g, 4.71mmnol) 및 2,4-티아졸리딘디온(0.55g, 4.71mmol)을 20ml의 톨루엔 용액으로 용해시켰고, 여기에 피페리딘(0.23ml, 2.36mmol) 및 아세트산(0.13ml, 2.36mmol)을 순차적으로 첨가한 후, 혼합액을 Dean-Stark 워터 트랩의 환류하에서 밤새도록 가열하였다. 이후 상기 혼합액을 냉각시켰고 여과시켰다. 이후 침전물은 에테르 또는 헥산으로 세척한 후 건조시켜 상기 화학식으로 표시되는 유도체 34를 수득하였다. 상기 방법으로 합성한 유도체 34의 수율은 90％이었고, 1H NMR (300MHz, DMSO-d6)은 δ12.606(s,1H),8.312(s,1H), 8.086 (d,J=9.6Hz,2H), 7.738(d,J=8.4Hz, 2H),7.47(t,J=15Hz,2H),7.313-7,362(m,1H)이었다.4- (2-isopropoxyethoxy) benzaldehyde (0.98 g, 4.71 mmol) and 2,4-thiazolidinedione (0.55 g, 4.71 mmol) were dissolved in 20 ml of toluene solution, where piperidine ( 0.23 ml, 2.36 mmol) and acetic acid (0.13 ml, 2.36 mmol) were added sequentially, then the mixture was heated overnight under reflux of the Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate was then washed with ether or hexane and dried to afford derivative 34 represented by the above formula. The yield of derivative 34 synthesized by the above method was 90%, 1 H NMR (300MHz, DMSO-d6) was δ 12.606 (s, 1H), 8.312 (s, 1H), 8.086 (d, J = 9.6 Hz, 2H), 7.738 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 15 Hz, 2H), 7.13-7, 362 (m, 1H).

＜실시예 35＞<Example 35>

본 발명에 따른 유도체 35의 제조Preparation of Derivative 35 According to the Invention

하기 화학식으로 나타내는 유도체 35를 다음과 같은 방법으로 제조하였다.Derivative 35 represented by the following formula was prepared in the following manner.

＜유도체 35의 화학식＞<Chemical formula of derivative 35>

Figure pct00043
Figure pct00043

물 10ml에 CoCl2 6H2O(4.5mg, 0.016mmol) 및 디메틸글리옥심(dimethylglyoxime) (70.1mg, 0.6mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(384.6mg, 10mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15ml) 중의 5-(4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylet hoxy)benzylidene)thiazolidine-2,4-dione)(1g, 3.02mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식의 유도체(0.8g, 수율:79％)를 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ11.998(s,1H) 7.135(d,J=7.5Hz,2H), 6.861 (d, J=7.8 Hz, 2H), 4.870(q,J= 12.6Hz,1H), 3.966(t,J=12.9Hz,2H), 3.07(q,J=22.8Hz,1H), 1.916(d,J=1.5Hz,2H), 1.548-1.615(m, 7H), 1.433-1.548 (m,1H), 1.097-1.261 (m,3H), 0.869-0.977 (m, 2H)이었다.1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.5 mg, 0.016 mmol) and dimethylglyoxime (70.1 mg, 0.6 mmol) in 10 ml of water, followed by NaBH 4 ( 384.6 mg, 10 mmol) was added and the mixture was cooled to 0 ° C. The mixture was then added with 5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylet) in THF-DMF (2: 1, 15 ml). hoxy) benzylidene) thiazolidine-2,4-dione) (1 g, 3.02 mmol) was added over 20 minutes and stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was purified by chromatography over silica gel to obtain a white solid derivative (0.8 g, yield: 79%). 1 H NMR of the derivative (300 MHz, DMSO-d6) is δ 11.998 (s, 1H) 7.135 (d, J = 7.5 Hz, 2H), 6.861 (d, J = 7.8 Hz, 2H), 4.870 (q , J = 12.6 Hz, 1H), 3.966 (t, J = 12.9 Hz, 2H), 3.07 (q, J = 22.8 Hz, 1H), 1.916 (d, J = 1.5 Hz, 2H), 1.548-1.615 (m , 7H), 1.433-1.548 (m, 1H), 1.097-1.261 (m, 3H), 0.869-0.977 (m, 2H).

＜실시예 36＞<Example 36>

본 발명에 따른 유도체 36의 제조Preparation of the derivative 36 according to the invention

하기 화학식으로 나타내는 유도체 36을 다음과 같은 방법으로 제조하였다.Derivative 36 represented by the following formula was prepared in the following manner.

＜유도체 36의 화학식＞<Chemical formula of derivative 36>

Figure pct00044
Figure pct00044

소듐 하이드라이드(96.51 mg, 2.41 mmol, 60％의 분산된 오일)을 20ml의 DMF 중의 상기 실시예 32에서 제조된 유도체 32(800 mg, 2.41 mmol)의 용액에 첨가하여 질소하의 상온에서 교반시켰다. 이후 상기 혼합물을 1시간 동안 추가로 교반시켰다. 그런 뒤, 상기 혼합물에 요오드메탄 (410.49 mg, 2.89 mmol)을 한 방울씩 떨어뜨리고 상온에서 밤새도록 교반시켰다. 상기 반응 혼합물을 에틸아세테이트로 추출하였고 유기 추출물은 염수로 세척하였으며, 무수황산마그네슘으로 건조시켰다. 이후, 감압 하에서 여과 및 농축을 수행하였고, 컬럼크로마토그래피(헥산/에틸 아세테이트 3:1)를 이용하여 정제함으로써 노란색 오일의 상기 유도체 36을 수득하였다.Sodium hydride (96.51 mg, 2.41 mmol, 60% dispersed oil) was added to a solution of the derivative 32 (800 mg, 2.41 mmol) prepared in Example 32 above in 20 ml of DMF and stirred at room temperature under nitrogen. The mixture was then further stirred for 1 hour. Thereafter, iodine methane (410.49 mg, 2.89 mmol) was added dropwise to the mixture and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate and the organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Thereafter, filtration and concentration were performed under reduced pressure, and purification using column chromatography (hexane / ethyl acetate 3: 1) gave the derivative 36 of yellow oil.

＜실시예 37＞<Example 37>

본 발명에 따른 유도체 37의 제조Preparation of the derivative 37 according to the invention

하기 화학식으로 나타내는 유도체 37을 다음과 같은 방법으로 제조하였다.Derivative 37 represented by the following formula was prepared in the following manner.

＜유도체 37의 화학식＞<Chemical formula of derivative 37>

Figure pct00045
Figure pct00045

4-(2-사이클로헥실에톡시)벤즈알데히드 및 톨루엔(20ml) 중의 3-에틸-2-티옥소-4-옥사졸리디온(504 mg, 4.3 mmol)의 용액에 피페리딘(0.21 mL, 2.15 mmol) 및 아세트산(0.14 mL, 2.15 mmol)을 첨가하였고, 이후의 과정은 상기 실시예 1의 유도체 제조 과정과 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 37인 노란색 고체의 3-(4-(2-사이클로헥실에톡시)벤질리덴)-3-에틸옥사졸리딘-2,4-디온 1.2g을 수득하였다. 상기 수득한 유도체 37의 1H NMR (300 MHz, DMSO-d 6)은 δ7.806 (d, J = 11.7 Hz, 2H), 6.969 (d, J = 11.7 Hz, 2H), 6.714 (s, 1H), 4.076 (t, J = 13.5 Hz, 2H), 4.006 (q, J= 14.7 Hz, 2H), 1.714 (t, J = 13.5 Hz, 2H), 1.568-1.786 (m, 4H), 1.568-1.462 (m, 1H), 1.354 (t, J = 14.7 Hz, 3H), 1.106-1.269 (m, 4H), 0.910-1.033 (m, 2H)이었다.Piperidine (0.21 mL, 2.15 mmol) in a solution of 3-ethyl-2-thioxo-4-oxazolidione (504 mg, 4.3 mmol) in 4- (2-cyclohexylethoxy) benzaldehyde and toluene (20 ml) ) And acetic acid (0.14 mL, 2.15 mmol) were added, and the subsequent procedure was carried out in the same manner as in the preparation of the derivative of Example 1, where 3- (4- (2) of the yellow solid as the derivative 37 represented by the above formula 1.2 g of cyclohexylethoxy) benzylidene) -3-ethyloxazolidine-2,4-dione was obtained. 1 H NMR of the obtained derivative 37 (300 MHz, DMSO- d 6 ) was shown as δ 7.806 (d, J = 11.7 Hz, 2H), 6.969 (d, J = 11.7 Hz, 2H), 6.714 (s, 1H). ), 4.076 (t, J = 13.5 Hz, 2H), 4.006 (q, J = 14.7 Hz, 2H), 1.714 (t, J = 13.5 Hz, 2H), 1.568-1.786 (m, 4H), 1.568-1.462 (m, 1H), 1.354 (t, J = 14.7 Hz, 3H), 1.106-1.269 (m, 4H), 0.910-1.033 (m, 2H).

＜실시예 38＞<Example 38>

본 발명에 따른 유도체 38의 제조Preparation of the derivative 38 according to the invention

하기 화학식으로 나타내는 유도체 38을 다음과 같은 방법으로 제조하였다.Derivative 38 represented by the following formula was prepared in the following manner.

＜유도체 38의 화학식＞<Chemical formula of derivative 38>

Figure pct00046
Figure pct00046

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로헥실에틸옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 38인 5-(4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 38의 수율은 81％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.195(s, 1H), 7.675(s, 1H), 7.473(d, J=14.7Hz, 2H), 6.895(d, J=14.7Hz, 2H), 4.036(t, J=11.7Hz, 2H), 1.565-1.727(m, 5H), 1.437-1.469(m, 1H), 1.041-1.223(m, 3H), 0.807-1.034(m, 2H)이었다.The intermediate product 4- (cyclohexylethyloxy) benzaldehyde was prepared in the same manner except that cyclohexylethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 89%. Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 38 is 81%, 1 H NMR (300MHz, DMSO-d6) is δ 8.195 (s, 1H), 7.675 (s, 1H), 7.473 (d, J = 14.7 Hz, 2H), 6.895 (d, J = 14.7 Hz, 2H), 4.036 (t, J = 11.7 Hz, 2H), 1.565-1.727 (m, 5H), 1.437-1.469 (m, 1H), 1.041-1.223 (m, 3H) , 0.807-1.034 (m, 2H).

＜실시예 39＞<Example 39>

본 발명에 따른 유도체 39의 제조Preparation of the derivative 39 according to the invention

하기 화학식으로 나타내는 유도체 39를 다음과 같은 방법으로 제조하였다.Derivative 39 represented by the following formula was prepared in the following manner.

＜유도체 39의 화학식＞<Chemical formula of derivative 39>

Figure pct00047
Figure pct00047

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 3-사이클로헥실-1-프로판올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-사이클로헥실프로폭시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 88％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 39인 5-(4-(3-사이클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(3-Cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 39의 수율은 80％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.505(s, 1H), 7.730(s, 1H), 7.547(d, J=9.0Hz, 2H), 7.084(d, J=9.0Hz, 2H), 4.028(t, J=12.9Hz, 2H), 1.628-1.711(m, 7H), 1.143-1.300(m, 6H), 0.839-0.911(m, 2H)이었다.Except for using 3-cyclohexyl-1-propanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2, the intermediate product 4- (3- Cyclohexylpropoxy) benzaldehyde was obtained with a yield of 88% of the intermediate product. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Phosphorus 5- (4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (3-Cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 39 is 80%, 1 H NMR (300MHz, DMSO-d6) is δ 12.505 (s, 1H), 7.730 (s, 1H), 7.547 (d, J = 9.0 Hz, 2H), 7.084 (d, J = 9.0 Hz, 2H), 4.028 (t, J = 12.9 Hz, 2H), 1.628-1.711 (m, 7H), 1.143-1.300 (m, 6H), 0.839-0.911 (m, 2H) It was.

＜실시예 40＞<Example 40>

본 발명에 따른 유도체 40의 제조Preparation of Derivative 40 According to the Invention

하기 화학식으로 나타내는 유도체 40을 다음과 같은 방법으로 제조하였다.Derivative 40 represented by the following formula was prepared in the following manner.

＜유도체 40의 화학식＞<Chemical formula of derivative 40>

Figure pct00048
Figure pct00048

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 4-사이클로헥실-1-부탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-사이클로헥실부톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 92％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 40인 5-(4-(4-사이클로헥실부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-Cyclohexylbutoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 40의 수율은 87％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.453(s, 1H), 7.407(s, 1H), 7.357(d, J=8.7Hz, 2H), 6.933(d, J=8.7Hz, 2H), 4.003(t, J=12.3Hz, 2H), 1.625-1.692(m, 6H), 1.37-1.1.398(m, 3H), 1.133-1.215(m, 4H), 0.815-0.956(m, 4H)이었다.Except that 4-cyclohexyl-1-butanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2, the intermediate product 4- (4- Cyclohexylbutoxy) benzaldehyde was obtained wherein the yield of the intermediate product was 92%. Subsequently, the derivative 40 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative preparation process of Example 1. Phosphorus 5- (4- (4-cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4-Cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 40 is 87%, 1 H NMR (300MHz, DMSO-d6) is δ 12.453 (s, 1H), 7.407 (s, 1H), 7.357 (d, J = 8.7 Hz, 2H), 6.933 (d, J = 8.7 Hz, 2H), 4.003 (t, J = 12.3 Hz, 2H), 1.625-1.692 (m, 6H), 1.37-1.1.398 (m, 3H), 1.133-1.215 (m, 4H) and 0.815-0.956 (m, 4H).

＜실시예 41＞<Example 41>

본 발명에 따른 유도체 41의 제조Preparation of the derivative 41 according to the invention

하기 화학식으로 나타내는 유도체 41을 다음과 같은 방법으로 제조하였다.Derivative 41 represented by the following formula was prepared in the following manner.

＜유도체 41의 화학식＞<Chemical formula of derivative 41>

Figure pct00049
Figure pct00049

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 생성물의 수율은 89％이고, 1H NMR (300MHz, CDCl3)은 δ 9.859(s, 1H), 7.906(s, 1H), 7.759 (d, J=8.4Hz, 2H), 7.034(d, J=8.4Hz, 2H), 4.158(t, J=13.5Hz, 2H), 1.815(t, J=13.5Hz, 2H), 1.698-1.892(m, 2H), 1.483-1.659(m, 1H), 1.184-1.350(m, 4H), 0.896-1.152(m, 4H)이었다. 이후 상기 수득한 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 41인 5-(3-클로로-4-(2-사이클로펙실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 수득한 유도체 41의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.19(s, 1H), 7.738(s, 1H), 7.522(s, 1H), 7.386(d, J=10.5Hz, 1H), 7.012(d, J=10.5Hz, 1H)), 4.155(t, J=13.2Hz, 2H), 1.800(t, J=13.2Hz, 2H), 1.657-1.800(m, 4H), 1.500-1.606(m, 1H), 1.151-1.335(m, 4H), 0.854-1.052(m, 2H)이었다.In the process of preparing the derivative of Example 1, except for using cyclohexyl ethanol instead of 2-isopropoxyethanol in the first step and 3-chloro-4-hydroxybenzaldehyde instead of p-hydroxybenzaldehyde Using the same method to obtain the intermediate product, the yield of the product is 89%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.859 (s, 1H), 7.906 (s, 1H), 7.759 (d , J = 8.4 Hz, 2H), 7.034 (d, J = 8.4 Hz, 2H), 4.158 (t, J = 13.5 Hz, 2H), 1.815 (t, J = 13.5 Hz, 2H), 1.698-1.892 (m , 2H), 1.483-1.659 (m, 1H), 1.184-1.350 (m, 4H), 0.896-1.152 (m, 4H). Thereafter, the obtained product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that instead of 4- (2-isopropoxyethoxy) benzaldehyde, 5- (3-chloro-4- (2-cyclofexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the obtained derivative 41 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.19 (s, 1H), 7.738 (s, 1H), 7.522 (s, 1H), 7.386 (d, J = 10.5 Hz, 1H), 7.012 (d, J = 10.5 Hz, 1H)), 4.155 (t, J = 13.2 Hz, 2H), 1.800 (t, J = 13.2 Hz, 2H), 1.657-1.800 (m , 4H), 1.500-1.606 (m, 1H), 1.151-1.335 (m, 4H), 0.854-1.052 (m, 2H).

＜실시예 42＞<Example 42>

본 발명에 따른 유도체 42의 제조Preparation of Derivative 42 According to the Invention

하기 화학식으로 나타내는 유도체 42를 다음과 같은 방법으로 제조하였다.Derivative 42 represented by the following formula was prepared in the following manner.

＜유도체 42의 화학식＞<Chemical formula of derivative 42>

Figure pct00050
Figure pct00050

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-사이클로헥실에톡시)벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 83％이고, 1H NMR (300MHz, CDCl3)은 δ 9.879(s, 1H), 7.849(d, J=13.8Hz, 2H), 7.014(d, J=13.8Hz, 2H), 4.134(t, J=13.2Hz, 2H), 1.745(t, J=13.2Hz, 2H), 1.474-1.745(m, 6H), 1.047-1.247(m, 3H), 0.875-0.930(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용하고 2,4-치아졸리딘디온 대신 로다닌을 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 42 유도체인 5-(4-(2-사이클로헥실에톡시)벤질리덴-4-티옥소티아졸리딘-2-원(5-(4-(2-Cyclohexylethoxy)benzylidene)-4-thioxothiazolidin-2-one)을 수득하였다. 상기 수득한 유도체 42의 수율은 82％이고, 1H NMR (300MHz, DMSO-d6)은 δ 7.758(s, 1H), 7.499(d, J=14.7Hz, 2H), 6.970(d, J=14.7Hz, 2H), 4.036(t, J=11.7Hz, 2H), 3.575(s, 1H), 1.704(t, J=11.7Hz, 2H), 1.565-1.756(m, 5H), 1.434-1.528(m, 1H), 1.103-1.260(m, 3H), 0.907-1.029(m, 2H)이었다.Intermediate 4- (2-cyclohexylethoxy) benzaldehyde was prepared in the same manner, except that cyclohexylethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. was obtained, wherein a yield of the product was 83%, 1 H NMR (300MHz , CDCl 3) is δ 9.879 (s, 1H), 7.849 (d, J = 13.8Hz, 2H), 7.014 (d, J = 13.8 Hz, 2H), 4.134 (t , J = 13.2Hz, 2H), 1.745 (t, J = 13.2Hz, 2H), 1.474-1.745 (m, 6H), 1.047-1.247 (m, 3H), 0.875-0.930 (m, 2H). The obtained intermediate product was then used in place of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1 and using rhodanine instead of 2,4-thiazolidinedione. Then, the same procedure was followed to obtain 5- (4- (2-cyclohexylethoxy) benzylidene-4-thioxothiazolidine-2-one (5- (4- (2-Cyclohexylethoxy)). benzylidene) -4-thioxothiazolidin-2-one) The yield of the obtained derivative 42 is 82%, 1 H NMR (300MHz, DMSO-d6) is δ 7.758 (s, 1H), 7.499 (d, J = 14.7 Hz, 2H), 6.970 (d, J = 14.7 Hz, 2H), 4.036 (t, J = 11.7 Hz, 2H), 3.575 (s, 1H), 1.704 (t, J = 11.7 Hz, 2H) , 1.565-1.756 (m, 5H), 1.434-1.528 (m, 1H), 1.103-1.260 (m, 3H), and 0.907-1.029 (m, 2H).

＜실시예 43＞<Example 43>

본 발명에 따른 유도체 43의 제조Preparation of the derivative 43 according to the invention

하기 화학식으로 나타내는 유도체 43을 다음과 같은 방법으로 제조하였다.Derivative 43 represented by the following formula was prepared in the following manner.

＜유도체 43의 화학식＞<Chemical formula of derivative 43>

Figure pct00051
Figure pct00051

4-(2-사이클로헥실에톡시)벤즈알데히드 (1g, 4.3 mmol) 및 하이단토인(504mg, 4.3mmol)을 20ml의 톨루엔 용액으로 용해시켰고, 여기에 피페리딘(0.21ml, 2.15mmol) 및 아세트산(0.14ml, 2.15mmol)을 순차적으로 첨가한 후, 혼합액을 Dean-Stark 워터 트랩의 환류 하에서 밤새도록 가열하였다. 이후 상기 혼합액을 냉각시켰고 여과시켰다. 이후 침전물은 에테르 또는 헥산으로 세척한 후 건조시켜 상기 화학식으로 표시되는 유도체 43을 수득하였다. 상기 수득한 유도체의 수율은 82％이고, 1H NMR (300 MHz, DMSO-d6) δ11.213(s,1H),10.374(s,1H), 7.517(d,J=7.8 Hz,2H), 6.884(d,J=7.8Hz,2H), 6.315(s,1H), 3.935 (t, J = 12.6 Hz, 2H), 1.655 (t, J = 12.6Hz, 2H), 1.577-1.922 (m, 4H), 1.028-1.269 (m, 5H), 0.787-0.862 (s, 2H)이었다.4- (2-cyclohexylethoxy) benzaldehyde (1 g, 4.3 mmol) and hydantoin (504 mg, 4.3 mmol) were dissolved in 20 ml of toluene solution, which contained piperidine (0.21 ml, 2.15 mmol) and acetic acid (0.14 ml, 2.15 mmol) was added sequentially, then the mixture was heated overnight under reflux of the Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate was then washed with ether or hexane and dried to give derivative 43 represented by the above formula. The yield of the obtained derivative is 82%, 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.213 (s, 1H), 10.374 (s, 1H), 7.517 (d, J = 7.8 Hz, 2H) , 6.884 (d, J = 7.8 Hz, 2H), 6.315 (s, 1H), 3.935 (t, J = 12.6 Hz, 2H), 1.655 (t, J = 12.6 Hz, 2H), 1.577-1.922 (m, 4H), 1.028-1.269 (m, 5H), 0.787-0.862 (s, 2H).

＜실시예 44＞<Example 44>

본 발명에 따른 유도체 44의 제조Preparation of the derivative 44 according to the invention

하기 화학식으로 나타내는 유도체 44를 다음과 같은 방법으로 제조하였다.Derivative 44 represented by the following formula was prepared in the following manner.

＜유도체 44의 화학식＞<Chemical formula of derivative 44>

Figure pct00052
Figure pct00052

상기 실시예 43의 유도체 화합물의 제조과정에서 하이난토 대신 석신이미드(succinimide)를 사용한 것을 제외하고는 동일한 방법을 사용하여 상기 화학식으로 표시되는 유도체 44를 수득하였다. 이때 수득한 유도체 44의 수율은 82％이고, 1H NMR (300 MHz, DMSO-d6)은 δ8.306 (s, 1H), 7.296 (s, 1H), 7.055 (d, J = 11.7 Hz, 2H), 6.838 (d, J = 11.7Hz, 2H), 3.992 (t, J = 13.2 Hz, 2H), 3.854 (s, 2H), 1.627 (t, J = 13.2Hz, 2H), 1.523-1.772 (m, 6H), 1.430-1.513 (m, 1H), 1.134-1.271 (m, 2H), 0.904-1.012 (m, 2H)이었다.Except for using succinimide (succinimide) instead of nananto in the preparation of the derivative compound of Example 43 to obtain a derivative 44 represented by the above formula using the same method. The yield of the derivative 44 obtained at this time is 82%, 1 H NMR (300 MHz, DMSO-d 6 ) is δ 8.306 (s, 1H), 7.296 (s, 1H), 7.055 (d, J = 11.7 Hz, 2H), 6.838 (d, J = 11.7 Hz, 2H), 3.992 (t, J = 13.2 Hz, 2H), 3.854 (s, 2H), 1.627 (t, J = 13.2 Hz, 2H), 1.523-1.772 ( m, 6H), 1.430-1.513 (m, 1H), 1.134-1.271 (m, 2H), 0.904-1.012 (m, 2H).

＜실시예 45＞<Example 45>

본 발명에 따른 유도체 45의 제조Preparation of Derivative 45 According to the Invention

하기 화학식으로 나타내는 유도체 45를 다음과 같은 방법으로 제조하였다.Derivative 45 represented by the following formula was prepared in the following manner.

＜유도체 45의 화학식＞<Chemical formula of derivative 45>

Figure pct00053
Figure pct00053

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 3-브로모-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 3-브로모-4-(2-사이클로헥실에톡시)벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 89％이고, 1H NMR (300MHz, CDCl3)은 δ 9.831(s, 1H), 8.077(s, 1H), 7.808(d, J=8.4Hz, 2H), 6.995(d, J=8.4Hz, 2H), 4.223(t, J=14.4Hz, 2H), 1.650-1.811(m, 7H), 1.468-1.627(m, 1H), 1.142-1.296(m, 3H), 0.947-1.111(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 45인 5-(3-브로모-4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Bromo-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 45의 수율은 90％이고, 1H NMR은 (300MHz, DMSO-d6)은 δ 12.576(s, 1H), 7.841(s, 1H), 7.833(s, 1H), 7.570(d, J=10.8 Hz, 1H), 7.284(d, J=10.8Hz, 1H), 4.174(t, J=12.6Hz, 2H), 1.617-1.750(m, 7H), 1.460-1.529(m, 1H), 1.062-1.265(m, 3H), 0.896-0.966(m, 2H)이었다.In the process of preparing the derivative of Example 1, except that in the first step using cyclohexyl ethanol instead of 2-isopropoxyethanol and 3-bromo-4-hydroxybenzaldehyde instead of p-hydroxybenzaldehyde And using the same method to obtain the intermediate 3-bromo-4- (2-cyclohexylethoxy) benzaldehyde, wherein the yield of the product is 89%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.831 (s, 1H), 8.077 (s, 1H), 7.808 (d, J = 8.4 Hz, 2H), 6.995 (d, J = 8.4 Hz, 2H), 4.223 (t, J = 14.4 Hz, 2H), 1.650 -1.811 (m, 7H), 1.468-1.627 (m, 1H), 1.142-1.296 (m, 3H), and 0.947-1.111 (m, 2H). Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (3-bromo-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Bromo-4- (2-cyclohexylethoxy) benzylidene) thiazolidine- 2,4-dione) was obtained. The yield of the obtained derivative 45 is 90%, 1 H NMR is (300MHz, DMSO-d6) is δ 12.576 (s, 1H), 7.841 (s, 1H), 7.833 (s, 1H), 7.570 (d, J = 10.8 Hz, 1H), 7.284 (d, J = 10.8 Hz, 1H), 4.174 (t, J = 12.6 Hz, 2H), 1.617-1.750 (m, 7H), 1.460-1.529 (m, 1H), 1.062-1.265 (m, 3H) and 0.896-0.966 (m, 2H).

＜실시예 46＞<Example 46>

본 발명에 따른 유도체 46의 제조Preparation of Derivative 46 According to the Invention

하기 화학식으로 나타내는 유도체 46을 다음과 같은 방법으로 제조하였다.Derivative 46 represented by the following formula was prepared in the following manner.

＜유도체 46의 화학식＞<Chemical formula of derivative 46>

Figure pct00054
Figure pct00054

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 5-(2-히드록시에칠)-4-메틸티아졸을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 4-(2-(4-메틸티아졸-2-일)에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94％이고, 1H NMR (300MHz, CDCl3)은 δ 9.89(s, 1H), 8.612(s, 1H), 7.854(d, J=10.2Hz, 2H), 7.014(d, J=10.2Hz, 2H), 4.247(t, J=11.7Hz, 2H), 3.309(t, J=11.7Hz, 2H), 2.463(s, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체의 제조 과정 중, 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-(4-메틸티아졸-5-일)에톡시)벤질리덴-2,4-디온(5-(4-(2-(4-Methylthiazol-5-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 46을 수득하였다. 상기 수득한 유도체 46의 수율은 84％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.487(s, 1H), 8.824(s, 1H), 7.721(s, 1H), 7.556(d, J=8.7Hz, 2H), 7.102(d, J=8.7Hz, 1H), 4.238(t, J=12.3Hz, 2H), 3.250(t, J=12.3Hz, 2H), 2.284(s, 3H)이었다.In the process of preparing the derivative of Example 1, the same method was used except that 5- (2-hydroxyethyl) -4-methylthiazole was added instead of 2-isopropoxyethanol in the first step. To obtain 4- (2- (4-methylthiazol-2-yl) ethoxy) benzaldehyde, where the yield of the intermediate product was 94%, and 1 H NMR (300 MHz, CDCl 3 ) was δ. 9.89 (s, 1H), 8.612 (s, 1H), 7.854 (d, J = 10.2 Hz, 2H), 7.014 (d, J = 10.2 Hz, 2H), 4.247 (t, J = 11.7 Hz, 2H), 3.309 (t, J = 11.7 Hz, 2H) and 2.463 (s, 3H). Thereafter, the obtained intermediate product was subjected to the same method as in the preparation of the derivative of Example 1, except that instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step, 5- (4- (2- (4-methylthiazol-5-yl) ethoxy) benzylidene-2,4-dione (5- (4- (2- (4-Methylthiazol-5-yl) ethoxy) A derivative of benzylidene) thiazolidine-2,4-dione) was obtained 46. The yield of the obtained derivative 46 was 84%, and 1 H NMR (300 MHz, DMSO-d6) yields δ 12.487 (s, 1H), 8.824 ( s, 1H), 7.721 (s, 1H), 7.556 (d, J = 8.7 Hz, 2H), 7.102 (d, J = 8.7 Hz, 1H), 4.238 (t, J = 12.3 Hz, 2H), 3.250 ( t, J = 12.3 Hz, 2H) and 2.284 (s, 3H).

＜실시예 47＞<Example 47>

본 발명에 따른 유도체 47의 제조Preparation of Derivative 47 According to the Invention

하기 화학식으로 나타내는 유도체 47을 다음과 같은 방법으로 제조하였다.Derivative 47 represented by the following formula was prepared in the following manner.

＜유도체 47의 화학식＞<Chemical formula of derivative 47>

Figure pct00055
Figure pct00055

상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 3,4-디플로로벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실에톡시)-3-플로로벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.857(s, 1H), 7.583-7.633(m, J=15Hz, 2H), 7.087(t, J=15.9Hz, 1H), 4.178(t, J=13.5Hz, 2H), 1.697-1.798(m, 6H), 1.217-1.290(m, 5H), 0.969-1.007(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 유도체 47인 5-(4-(2-사이클로헥실에톡시)-3-플루오로벤질리덴-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-fluorobenzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 47의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.183(s, 1H), 7.610(s, 1H), 7.239(m, 3H), 4.158(t, J=13.2Hz, 2H), 1.605-1.143(m, 6H), 1.445-1.605(m, 1H), 1.096-1.265(m, 4H), 0.917-0.991(m, 2H)이었다.Except for using the cyclohexyl ethanol instead of 4- (2-hydroxyethyl) morpholine and 3,4-difluorobenzaldehyde instead of 4-fluorobenzaldehyde in the process of preparing the derivative of Example 2 The method was used to obtain the intermediate product 4- (2-cyclohexylethoxy) -3-fluorobenzaldehyde, where the yield of the intermediate product was 85% and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.857. (s, 1H), 7.583-7.633 (m, J = 15 Hz, 2H), 7.087 (t, J = 15.9 Hz, 1H), 4.178 (t, J = 13.5 Hz, 2H), 1.697-1.798 (m, 6H ), 1.217-1.290 (m, 5H), and 0.969-1.007 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as the derivative 47 except that instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1, 5- ( 4- (2-cyclohexylethoxy) -3-fluorobenzylidene-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-fluorobenzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 47 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.183 (s, 1H), 7.610 (s, 1H), 7.239 (m, 3H), 4.158 (t, J = 13.2 Hz, 2H), 1.605-1.143 (m, 6H), 1.445-1.605 (m, 1H), 1.096-1.265 (m, 4H), and 0.917-0.991 (m, 2H).

＜실시예 48＞<Example 48>

본 발명에 따른 유도체 48의 제조Preparation of Derivative 48 According to the Invention

하기 화학식으로 나타내는 유도체 48을 다음과 같은 방법으로 제조하였다.Derivative 48 represented by the following formula was prepared in the following manner.

＜유도체 48의 화학식＞<Chemical formula of derivative 48>

Figure pct00056
Figure pct00056

상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-(3-히드록시프로필)티오모르폴린-1,1-디옥사이드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-티오모르폴린-1,1-디옥사이드프로폭시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 91％이고, 1H NMR (300MHz, CDCl3)은 δ 9.891(s, 1H), 7.865(d, J=11.4Hz, 2H), 7.014(d, J=11.4Hz, 2H), 4.158(t, J=12Hz, 2H), 3.077s, 8H), 2.749(t, J=14.4, 2H), 1.953-2.047(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(3-티오모르폴린-1,1-디옥사이드프로폭시)벤질리덴]-티아졸리딘-2,4-디온(5-[4-(3-Thiomorpholine-1,1-dioxidepropoxy)benzylidene]-thiazolidine-2,4-dione)인 유도체 48을 수득하였다. 상기 수득한 유도체 48의 수율은 94％이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.19(s, 1H), 7.705(s, 1H), 7.540(d, J=8.1 Hz, 2H), 7.088(d, J=8.1Hz, 2H), 4.09(t, J=12Hz, 2H), 3.06(m, 4H), 2.89(m, 4H), 2.616(t, J=14.1Hz, 2H). 1.819-1.911(m, 2H)이었다.In the process of preparing the derivative of Example 1, except that 4- (3-hydroxypropyl) thiomorpholine-1,1-dioxide is added instead of 2-isopropoxyethanol in the first step To obtain the intermediate product 4- (3-thiomorpholine-1,1-dioxidepropoxy) benzaldehyde, the yield of the intermediate product is 91%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.891 (s, 1H), 7.865 (d, J = 11.4 Hz, 2H), 7.014 (d, J = 11.4 Hz, 2H), 4.158 (t, J = 12 Hz, 2H), 3.077 s, 8H), 2.749 ( t, J = 14.4, 2H) and 1.953-2.047 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. [4- (3-thiomorpholine-1,1-dioxidepropoxy) benzylidene] -thiazolidine-2,4-dione (5- [4- (3-Thiomorpholine-1,1-dioxidepropoxy) benzylidene] -48 was obtained as a derivative of -thiazolidine-2,4-dione). The yield of the obtained derivative 48 is 94%, 1 H NMR (300MHz, DMSO-d6) is δ 8.19 (s, 1H), 7.705 (s, 1H), 7.540 (d, J = 8.1 Hz, 2H), 7.088 (d, J = 8.1 Hz, 2H), 4.09 (t, J = 12 Hz, 2H), 3.06 (m, 4H), 2.89 (m, 4H), 2.616 (t, J = 14.1 Hz, 2H). 1.819-1.911 (m, 2H).

＜실시예 49＞<Example 49>

본 발명에 따른 유도체 49의 제조Preparation of Derivative 49 According to the Invention

하기 화학식으로 나타내는 유도체 49를 다음과 같은 방법으로 제조하였다.Derivative 49 represented by the following formula was prepared in the following manner.

＜유도체 49의 화학식＞<Chemical formula of derivative 49>

Figure pct00057
Figure pct00057

상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 3-사이클로헥실-1-프로판올을사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(3-사이클로헥실프로폭시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.843(s, 1H), 7.908(d, J=1.8Hz, 1H), 7.766(d, J=10.5Hz, 1H), 7.026(d, J=8.4Hz, 1H), 4.123(t, J=13.2Hz, 2H), 1.864-1.938(m, 2H), 1.69-1.842(m, 5H), 1.344-1.679(m, 2H), 1.078-1.306(m, 4H), 0.854-0.974(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 49인 5-(3-클로로-4-(3-사이클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(3-cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 49의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.587(s, 1H), 7.717(s, 1H), 7.695(d, J=2.1Hz, 1H), 7.531(dd, J=2.4, 2.1Hz, 1H), 7.302(d, J=8.4Hz, 1H), 4.125(t, J=12.6Hz, 2H), 1.625-1.772(m, 7H), 1.079-1.348(m, 6H), 0.837-0.911(m, 2H)이었다.Except for using 3-cyclohexyl-1-propanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in the process of preparing the derivative of Example 1 The same method was used to obtain the intermediate product 3-chloro-4- (3-cyclohexylpropoxy) benzaldehyde, wherein the yield of the intermediate product was 85% and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.843. (s, 1H), 7.908 ( d, J = 1.8Hz, 1H), 7.766 (d, J = 10.5Hz, 1H), 7.026 (d, J = 8.4Hz, 1H), 4.123 (t, J = 13.2Hz 2H), 1.864-1.938 (m, 2H), 1.69-1.842 (m, 5H), 1.344-1.679 (m, 2H), 1.078-1.306 (m, 4H), 0.854-0.974 (m, 2H). Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (3-chloro-4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2 , 4-dione) was obtained. The yield of the obtained derivative 49 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.587 (s, 1H), 7.717 (s, 1H), 7.695 (d, J = 2.1 Hz, 1H), 7.531 (dd, J = 2.4, 2.1 Hz, 1H), 7.302 (d, J = 8.4 Hz, 1H), 4.125 (t, J = 12.6 Hz, 2H), 1.625-1.772 (m, 7H), 1.079-1.348 (m, 6H) and 0.837-0.911 (m, 2H).

＜실시예 50＞<Example 50>

본 발명에 따른 유도체 50의 제조Preparation of Derivative 50 According to the Invention

하기 화학식으로 나타내는 유도체 50을 다음과 같은 방법으로 제조하였다.Derivative 50 represented by the following formula was prepared in the following manner.

＜유도체 50의 화학식＞<Chemical formula of derivative 50>

Figure pct00058
Figure pct00058

상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 4-사이클로헥실-1-부탄올을사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(4-사이클로헥실부톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85％이고, 1H NMR (300MHz, CDCl3)은 δ 9.842 (s, 1H), 7.905 (t, J=5.4Hz, 1H), 7.764(dd, J=1.8, 2.7Hz, 1H), 7.029(d, J=11.7Hz, 1H), 4.136(t, J=12.6, 2H), 1.830-1.903(m, 2H), 1.679-1.809(m, 6H), 1.461-1.675(m, 2H), 1.112-1.294(m, 7H), 0.859-0.93(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 50인 5-(3-클로로-4-(4-사이클로헥실부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(4-cyclohexylbutoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 50의 수율은 90％이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.582(s, 1H), 7.730(s, 1H), 7.695(d, J=2.1Hz, 1H), 7.532 (dd, J=2.1, 2.1Hz, 1H), 7.309(d, J=9Hz, 1H), 4.141(t, J=12.3Hz, 2H), 1.652-1.761(m, 7H), 1.227-1.615(m, 2H), 1.067-1.205(m, 6H), 0.818-0.889(m, 2H)이었다.Except for using 4-cyclohexyl-1-butanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in the preparation of the derivative of Example 1 Using the same method, the intermediate product 3-chloro-4- (4-cyclohexylbutoxy) benzaldehyde was obtained, where the yield of the intermediate product was 85%, and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.842. (s, 1H), 7.905 (t, J = 5.4 Hz, 1H), 7.764 (dd, J = 1.8, 2.7 Hz, 1H), 7.029 (d, J = 11.7 Hz, 1H), 4.136 (t, J = 12.6, 2H), 1.830-1.903 (m, 2H), 1.679-1.809 (m, 6H), 1.461-1.675 (m, 2H), 1.112-1.294 (m, 7H), 0.859-0.93 (m, 2H). . Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the preparation of Example 1, except that instead of 4- (2-isopropoxyethoxy) benzaldehyde, 5- (3-chloro-4- (4-cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (4-cyclohexylbutoxy) benzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the obtained derivative 50 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.582 (s, 1H), 7.730 (s, 1H), 7.695 (d, J = 2.1 Hz, 1H), 7.532 (dd, J = 2.1, 2.1 Hz, 1H), 7.309 (d, J = 9 Hz, 1H), 4.141 (t, J = 12.3 Hz, 2H), 1.652-1.761 (m, 7H), 1.227-1.615 ( m, 2H), 1.067-1.205 (m, 6H) and 0.818-0.889 (m, 2H).

＜실시예 51＞<Example 51>

본 발명에 따른 유도체 51의 제조Preparation of Derivative 51 According to the Invention

하기 화학식으로 나타내는 유도체 51을 다음과 같은 방법으로 제조하였다.Derivative 51 represented by the following formula was prepared in the following manner.

＜유도체 51의 화학식＞<Chemical formula of derivative 51>

Figure pct00059
Figure pct00059

물 10ml에 CoCl2 6H2O(4.4mg, 0.016mmol) 및 디메틸글리옥심(dimethylglyoxime) (73.1mg, 0.58mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(409.3mg, 10.6mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15ml) 중의5-(4-(2-사이클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온5-(4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione (1g,3.13mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 51의 유도체(0.8g, 수율:79％)를 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.816 (s, 1H), 7.145 (d, J = 8.7Hz, 2H), 6.854 (d, J = 8.7Hz, 2H), 4.528 (dd, J = 3.6, 3.6Hz, 1H), 3.740 (d, J = 6.6Hz, 2H), 3.486 (dd, J = 4.2, 4.2Hz, 1H), 3.138 (dd, J = 9.6, 9.6Hz, 1H), 1.604-1.882 (m, 6H), 1.212-1.426 (m, 3H), 0.884-1.131 (m, 2H)이었다.1.0 N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.4 mg, 0.016 mmol) and dimethylglyoxime (73.1 mg, 0.58 mmol) in 10 ml of water, followed by NaBH 4 ( 409.3 mg, 10.6 mmol) was added and the mixture was cooled to 0 ° C. The mixture was then mixed with 5- (4- (2-cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione5- (4- (cyclohexylmethoxy) benzylidene) in THF-DMF (2: 1, 15 ml). thiazolidine-2,4-dione (1 g, 3.13 mmol) was added over 20 minutes and stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residual oil was purified by chromatography over silica gel to obtain a derivative of the formula 51 (0.8 g, yield: 79%) as a white solid. 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is shown at δ 7.816 (s, 1H), 7.145 (d, J = 8.7 Hz, 2H), 6.854 (d, J = 8.7 Hz, 2H), 4.528 (dd, J = 3.6, 3.6 Hz, 1H), 3.740 (d, J = 6.6 Hz, 2H), 3.486 (dd, J = 4.2, 4.2 Hz, 1H), 3.138 (dd, J = 9.6, 9.6 Hz, 1H), 1.604-1.882 (m, 6H), 1.212-1.426 (m, 3H), 0.884-1.131 (m, 2H).

＜실시예 52＞<Example 52>

본 발명에 따른 유도체 52의 제조Preparation of Derivative 52 According to the Invention

하기 화학식으로 나타내는 유도체 52를 다음과 같은 방법으로 제조하였다.Derivative 52 represented by the following formula was prepared in the following manner.

＜유도체 52의 화학식＞<Chemical formula of derivative 52>

Figure pct00060
Figure pct00060

물 10ml에 CoCl2 6H2O (3.83mg, 0.014mmol) 및 디메틸글리옥심(dimethylglyoxime) (63.56mg, 0.54mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(355.43mg, 9.24mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(3-chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione (1g, 2.72mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 52의 유도체(0.8g, 수율:79％)를 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.900(s, 1H), 7.242(s, 1H), 7.078(d, J = 10.8 Hz, 2H), 6.913 (d, J = 10.8 Hz, 2H), 4.523 (dd, J = 3.9, 3.9 Hz, 1H), 4.068 (t, J = 13.5Hz, 2H), 3.447 (dd, J = 4.2, 4.2Hz, 1H), 3.134(dd, J = 9.3, 9.3 Hz, 1H), 1.689-1.793 (m, 7H), 1.504-1.572 (m, 1H), 1.144-1.329 (m, 3H), 0.926-1.037 (m, 2H)이었다.1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (3.83 mg, 0.014 mmol) and dimethylglyoxime (63.56 mg, 0.54 mmol) in 10 ml of water, followed by NaBH 4 ( 355.43 mg, 9.24 mmol) was added and the mixture was cooled to 0 ° C. To the mixture was then added 5- (3-chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (1 g, 2.72 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes. And stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was purified by chromatography over silica gel to obtain a derivative of formula 52 (0.8 g, yield: 79%) as a white solid. 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is δ7.900 (s, 1H), 7.242 (s, 1H), 7.078 (d, J = 10.8 Hz, 2H), 6.913 (d, J = 10.8 Hz, 2H), 4.523 (dd, J = 3.9, 3.9 Hz, 1H), 4.068 (t, J = 13.5 Hz, 2H), 3.447 (dd, J = 4.2, 4.2 Hz, 1H), 3.134 (dd, J = 9.3, 9.3 Hz, 1H), 1.689-1.793 (m, 7H), 1.504-1.572 (m, 1H), 1.144-1.329 (m, 3H), 0.926-1.037 (m, 2H).

＜실시예 53＞<Example 53>

본 발명에 따른 유도체 53의 제조Preparation of Derivative 53 According to the Invention

하기 화학식으로 나타내는 유도체 53을 다음과 같은 방법으로 제조하였다.Derivative 53 represented by the following formula was prepared in the following manner.

＜유도체 53의 화학식＞<Chemical formula of derivative 53>

Figure pct00061
Figure pct00061

시클로헥산메탄올(1g, 8.8mmol), 4-히드록시-3-메틸벤즈알데히드(1.20g, 8.8mmol) 및 THF(20ml) 중의 트리페닐포스핀(2.54g, 9.7mmol)이 혼합된 용액에 디에틸 아조디카복실레이트(톨루엔 중의 40％, 9.7mmol)를 0℃에서 10분에 걸쳐 교반하면서 첨가하였다. 이후 상온에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드의 초기반응물질이 사라질 때까지 교반하였다. 상기 용액을 감압농축한 다음, 실리카 겔을 통한 크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 10:1이 되는 조건에서 용출시켜 노란색 오일의 4-(2-시클로메톡시)-3-메틸벤즈알데히드(1.69g, 수율:83％)를 수득하였다(제1 단계). 이후, 상기 제1 단계에서 수득한 4-(2-시클로메톡시)-3-메틸벤즈알데히드(1g, 4.3mmol)와 2,4-티아졸리딘디온(504mg, 4.3mmol)을 20ml의 톨루엔 용액으로 용해시켰고, 여기에 피페리딘(0.21ml, 2.15mmol) 및 아세트산(0.12ml, 2.15mmol)을 순차적으로 첨가한 후, 혼합액을 Dean-Stark 워터 트랩의 환류하에서 밤새도록 가열하였다. 이후 상기 혼합액을 냉각시킨 다음 여과시켰다. 이후 침전물은 헥산으로 세척한 후 건조시켜 노란색 고체의 상기 화학식으로 표시되는 유도체인 5-(4-(2-시클로핵실메톡시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylmethoxy)-3-methylbenzylidene)thiazolidine-2,4-dione)(1.10 g, 77.5％ 수율)을 수득하였다(제2 단계). 상기 수득한 유도체 53의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7. 784(s,1H), 7.345(d, J = 8.4 Hz, 2H), 7.289 (s, 1H), 6.912(d, J = 8.4 Hz, 2H), 4.074 (d, J = 5.7 Hz, 2H), 2.302 (s, 3H), 1.706-1.894 (m, 6H), 1.257-1.380 (m, 3H), 1.070-1.225 (m, 2H)이었다.Diethyl to a solution mixed with cyclohexanemethanol (1 g, 8.8 mmol), 4-hydroxy-3-methylbenzaldehyde (1.20 g, 8.8 mmol) and triphenylphosphine (2.54 g, 9.7 mmol) in THF (20 ml) Azodicarboxylate (40% in toluene, 9.7 mmol) was added with stirring at 0 ° C. over 10 minutes. Thereafter, the reaction mixture was stirred until the initial reactant of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde disappeared at room temperature. The solution was concentrated under reduced pressure and then purified by chromatography on silica gel, eluting with hexane to ethyl acetate at 10: 1 to give 4- (2-cyclomethoxy) -3-methyl as yellow oil. Benzaldehyde (1.69 g, yield: 83%) was obtained (first step). Thereafter, 4- (2-cyclomethoxy) -3-methylbenzaldehyde (1 g, 4.3 mmol) and 2,4-thiazolidinedione (504 mg, 4.3 mmol) obtained in the first step were added to 20 ml of toluene solution. After dissolving, piperidine (0.21 ml, 2.15 mmol) and acetic acid (0.12 ml, 2.15 mmol) were added sequentially, and the mixture was heated overnight under reflux of the Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate is then washed with hexane and dried to give 5- (4- (2-cyclonucleomethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione which is a derivative represented by the above formula as a yellow solid. 5- (4- (2-cyclohexylmethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione) (1.10 g, 77.5% yield) was obtained (second step). The compound of Derivative 53 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7. 784 (s, 1H), 7.345 (d, J = 8.4 Hz, 2H), 7.289 (s, 1H), 6.912 (d, J = 8.4 Hz, 2H), 4.074 (d, J = 5.7 Hz, 2H), 2.302 (s, 3H), 1.706-1.894 (m, 6H), 1.257-1.380 (m, 3H), 1.070-1.225 (m, 2H).

＜실시예 54＞<Example 54>

본 발명에 따른 유도체 54의 제조Preparation of Derivative 54 According to the Invention

하기 화학식으로 나타내는 유도체 54를 다음과 같은 방법으로 제조하였다.Derivative 54 represented by the following formula was prepared in the following manner.

＜유도체 54의 화학식＞<Chemical formula of derivative 54>

Figure pct00062
Figure pct00062

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-시클로헥실-1-프로판올(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(0.95g, 7.0mmol)를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실프로폭시)-3-메틸벤즈알데히드 1.46g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 80％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로헥실프로폭시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylpropoxy)-3-methylbenzylidene)thiazolidine-2,4-dione) 1.23g을 수득하였고, 수득율은 89.1％ 였다. 상기 수득한 유도체 54의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.793(s,1H),7.349(d, J = 8.4 Hz, 2H), 7.312 (s, 1H), 6.898 (d, J = 8.4 Hz, 2H), 4.029 (t, J = 13.2 Hz, 2H), 1.650-2.041 (m, 8H), 1.089-1.397 (m, 4H), 0.860-0.968 (m, 3H)이었다.In preparing the derivative of Example 53, 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. The same procedure was used to obtain 1.46 g of the intermediate product 4- (2-cyclohexylpropoxy) -3-methylbenzaldehyde, except that oxybenzaldehyde (0.95 g, 7.0 mmol) was used, wherein the yield of the intermediate product was obtained. Was 80%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4 -dione) was obtained. The yield was 89.1%. The compound of Derivative 54 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ7.793 (s, 1H), 7.349 (d, J = 8.4 Hz, 2H), 7.312 (s, 1H), 6.898 ( d, J = 8.4 Hz, 2H), 4.029 (t, J = 13.2 Hz, 2H), 1.650-2.041 (m, 8H), 1.089-1.397 (m, 4H), 0.860-0.968 (m, 3H).

＜실시예 55＞<Example 55>

본 발명에 따른 유도체 55의 제조Preparation of Derivative 55 According to the Invention

하기 화학식으로 나타내는 유도체 55를 다음과 같은 방법으로 제조하였다.Derivative 55 represented by the following formula was prepared in the following manner.

＜유도체 55의 화학식＞<Chemical formula of derivative 55>

Figure pct00063
Figure pct00063

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-시클로헥실-1-부판올(1g, 6.4mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드를 0.87g, 6.4mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실부톡시)-3-메틸벤즈알데히드를 1.43g 수득하였으며, 이때 상기 중간체 생성물의 수율은 81％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로헥실부톡시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylbutoxy)-3-methylbenzylidene)thiazolidine-2,4-dione) 1.19g을 수득하였고, 수득율은 87.5％ 였다. 상기 수득한 유도체 55의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.787(s,1H),7.421(d, J = 8.7 Hz, 2H), 7.291 (s, 1H), 6.903(d, J = 8.7Hz, 2H), 4.045 (t, J = 12.9 Hz, 2H), 1.806-1.852 (m, 2H), 1.694-1.779 (m, 5H), 1.438-1.510 (m, 2H), 1.174-1.266 (m, 6H), 0.857-0.890 (m, 2H)이었다.In preparing the derivative of Example 53, 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) was used instead of cyclohexane methanol, and 0.87 g of 4-hydroxy-3-methylbenzaldehyde was used. Using the same method except that the amount was used, 1.43 g of the intermediate product 4- (2-cyclohexylbutoxy) -3-methylbenzaldehyde was obtained, wherein the yield of the intermediate product was 81%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4- (2-cyclohexylbutoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylbutoxy) -3-methylbenzylidene) thiazolidine-2,4 -dione) was obtained. The yield was 87.5%. Compound of the obtained derivative 55 was 1 H NMR (300 MHz, DMSO- d 6 ) δ7.787 (s, 1H), 7.421 (d, J = 8.7 Hz, 2H), 7.291 (s, 1H), 6.903 ( d, J = 8.7 Hz, 2H), 4.045 (t, J = 12.9 Hz, 2H), 1.806-1.852 (m, 2H), 1.694-1.779 (m, 5H), 1.438-1.510 (m, 2H), 1.174 -1.266 (m, 6H), 0.857-0.890 (m, 2H).

＜실시예 56＞<Example 56>

본 발명에 따른 유도체 56의 제조Preparation of the derivative 56 according to the invention

하기 화학식으로 나타내는 유도체 56을 다음과 같은 방법으로 제조하였다.Derivative 56 represented by the following formula was prepared in the following manner.

＜유도체 56의 화학식＞<Chemical formula of derivative 56>

Figure pct00064
Figure pct00064

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 2-페닐에탄올(1g, 8.2.mmol) 및 4-히드록시벤즈알데히드(1.0g, 8.2mmol)을 사용하고, 트리페닐포스피린을 2.37g, 9.02mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-페닐에톡시)벤즈알데히드를 1.5g 수득하였으며, 이때 상기 중간체 생성물의 수율은 79％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(2-페닐에톡시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[4-(2-phenylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione) 을 0.94g 수득하였고, 수율은 62.7％였다. 상기 수득한 유도체 56의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.806(s,1H),7.466(d, J = 8.7 Hz, 2H), 7.262-7.369 (m, 5H), 7.196 (d, J = 8.7Hz, 2H), 4.261 (t, J = 14.1 Hz, 2H), 3.153 (t, J = 14.1 Hz, 2H)이었다.In preparing the derivative of Example 53, 2-phenylethanol (1 g, 8.2. Mmol) and 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) were substituted for cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde. 1.5 g of the intermediate product 4- (2-phenylethoxy) benzaldehyde was obtained using the same method, except that triphenylphosphine was used in an amount of 2.37 g and 9.02 mmol. The yield was 79%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- [4- (2-phenylethoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [4- (2-phenylethoxy) benzylidene] -1,3-thiazolidine-2 , 4-dione) was obtained and the yield was 62.7%. Compound of the obtained derivative 56 was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.806 (s, 1 H), 7.466 (d, J = 8.7 Hz, 2H), 7.262-7.369 (m, 5H), 7.196 (d, J = 8.7 Hz, 2H), 4.261 (t, J = 14.1 Hz, 2H), 3.153 (t, J = 14.1 Hz, 2H).

＜실시예 57＞<Example 57>

본 발명에 따른 유도체 57의 제조Preparation of the derivative 57 according to the invention

하기 화학식으로 나타내는 유도체 57을 다음과 같은 방법으로 제조하였다.Derivative 57 represented by the following formula was prepared in the following manner.

＜유도체 57의 화학식＞<Chemical formula of derivative 57>

Figure pct00065
Figure pct00065

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 3-페닐-1-프로판올(1g, 7.3mmol) 및 4-히드록시벤즈알데히드(0.89g, 7.3mmol)을 사용하고, 트리페닐포스피린을 2.11g, 8.03mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-페닐프로폭시)벤즈알데히드를 1.52g 수득하였으며, 이때 상기 중간체 생성물의 수율은 86.4％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(2-페닐프로폭시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[4-(2-phenylpropoxy)benzylidene]-1,3-thiazolidine-2,4-dione)을 1.12g 수득하였으며, 수득율을 80.1％이었다. 상기 수득한 유도체 57의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.820(s,1H),7.465(d, J = 8.7 Hz, 2H), 7.201-7.329 (m, 5H), 6.993 (d, J = 8.7 Hz, 2H), 4.020 (t, J = 12.3 Hz, 2H), 2.851 (t, J = 15.0 Hz, 2H), 2.094-2.187 (m, 2H)이었다.In the preparation of the derivative of Example 53, 3-phenyl-1-propanol (1 g, 7.3 mmol) and 4-hydroxybenzaldehyde (0.89 g, 7.3 mmol) instead of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde ) And 1.52 g of the intermediate product 4- (3-phenylpropoxy) benzaldehyde was obtained using the same method except that triphenylphosphine was used in an amount of 2.11 g and 8.03 mmol, wherein the intermediate The yield of the product was 86.4%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- [4- (2-phenylpropoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [4- (2-phenylpropoxy) benzylidene] -1,3-thiazolidine-2 , 4-dione) was obtained, and the yield was 80.1%. The compound of Derivative 57 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.820 (s, 1H), 7.465 (d, J = 8.7 Hz, 2H), 7.201-7.329 (m, 5H), 6.993 (d, J = 8.7 Hz, 2H), 4.020 (t, J = 12.3 Hz, 2H), 2.851 (t, J = 15.0 Hz, 2H), 2.094-2.187 (m, 2H).

＜실시예 58＞<Example 58>

본 발명에 따른 유도체 58의 제조Preparation of the derivative 58 according to the invention

하기 화학식으로 나타내는 유도체 58을 다음과 같은 방법으로 제조하였다.Derivative 58 represented by the following formula was prepared in the following manner.

＜유도체 58의 화학식＞<Chemical formula of derivative 58>

Figure pct00066
Figure pct00066

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 4-페닐-1-부탄올(1g, 6.7mmol) 및 4-히드록시벤즈알데히드(0.82g, 6.7mmol)을 사용하고, 트리페닐포스피린을 1.93g, 7.37mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-페닐부톡시)벤즈알데히드를 1.42g 수득하였으며, 이때 상기 중간체 생성물의 수율은 84％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(2-페닐부톡시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[4-(2-phenylbutoxy)benzylidene]-1,3-thiazolidine-2,4-dione)을 1.15g 수득하였으며, 수득율을 85％이었다. 상기 수득한 유도체 58의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.816(s,1H),7.468(d, J = 8.7 Hz, 2H), 7.174-7.323(m, 5H), 6.903 (d, J = 8.7 Hz, 2H), 4.048 (t, J = 11.7 Hz, 2H), 2.724 (t, J = 13.8 Hz, 2H), 1.786-1.876 (m, 4H)이었다.4-phenyl-1-butanol (1 g, 6.7 mmol) and 4-hydroxybenzaldehyde (0.82 g, 6.7 mmol) instead of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde in the preparation of the derivative of Example 53 ) And 1.42 g of the intermediate product 4- (3-phenylbutoxy) benzaldehyde were obtained in the same manner except that triphenylphosphine was used in an amount of 1.93 g and 7.37 mmol, wherein the intermediate The yield of the product was 84%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- [4- (2-phenylbutoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [4- (2-phenylbutoxy) benzylidene] -1,3-thiazolidine-2 , 4-dione) was obtained, and the yield was 85%. Compound of the obtained derivative 58 is 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.816 (s, 1H), 7.468 (d, J = 8.7 Hz, 2H), 7.174-7.323 (m, 5H), 6.903 (d, J = 8.7 Hz, 2H), 4.048 (t, J = 11.7 Hz, 2H), 2.724 (t, J = 13.8 Hz, 2H), 1.786-1.876 (m, 4H).

＜실시예 59＞<Example 59>

본 발명에 따른 유도체 59의 제조Preparation of the derivative 59 according to the invention

하기 화학식으로 나타내는 유도체 59을 다음과 같은 방법으로 제조하였다.Derivative 59 represented by the following formula was prepared in the following manner.

＜유도체 59의 화학식＞<Chemical formula of derivative 59>

Figure pct00067
Figure pct00067

수소화나트륨(24.14mg, 1.0mmol, 60％ 분산 오일)을 DMF 20ml에 5-4-(2-시클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(200mg, 0.60mmol)이 존재하는 용액에 첨가한 다음, 상온의 온도에서 질소 조건하에 교반하였다. 이후 혼합물을 10분 동안 더 교반한 후, 상기 혼합액에 DMF 5ml에 녹아있는 2-요오드에탄올(123.81mg, 0.72 mmol)을 천천히 첨가하였고, 60℃에서 48시간 동안 교반하였다. 이후 상기 반응 혼합물을 에틸 아세테이트로 추출하고 물로 세척하였다. 유기층은 무수화 황 마그네슘을 사용하여 건조시키고 여과 및 증발시켰다. 이후 잔여물은 실리카 겔 크로마토그래피를 사용하여 정제하였으며, 이대 용출은 헥산 및 에틸 아세테이트가 10:1로 혼합된 용매를 사용하였으며, 그 결과 180mg의 상기 화학식으로 표시되는 유도체 59 화합물인 5-(4-(2-시클로헥실에톡시)벤질리덴]-3-(히드록시에틸)-1,3-티아졸리디온-2,4-디온(5-[4-(2-cyclohexylethoxy)benzylidene]-3-(hydroxyethyl)-1,3-thiazolidine-2,4-dione)(79％ 수득율)을 수득하였으며, 상기 유도체 59의 화합물은 1H NMR (300 MHz, CDCl3) δ7.878(s, 1H), 7.485 (d, J = 14.4 Hz, 2H), 7.007 (d, J = 14.4 Hz, 2H), 4.078 (t, J = 13.2 Hz, 2H), 4.001 (t, J = 10.2 Hz, 2H), 3.891 (t, J = 10.2 Hz, 2H), 2.049 (m, 1H), 1.670-1.782 (m, 7H), 1.471-1.529 (m, 1H), 1.178-1.284 (m, 3H), 0.956-1.034 (m, 2H)이었다.Sodium hydride (24.14 mg, 1.0 mmol, 60% dispersion oil) is present in 20 ml of DMF with 5-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (200 mg, 0.60 mmol) The solution was added to the resulting solution, followed by stirring at room temperature under nitrogen. After further stirring the mixture for 10 minutes, 2-iodineethanol (123.81 mg, 0.72 mmol) dissolved in 5 ml of DMF was slowly added to the mixture, and the mixture was stirred at 60 ° C. for 48 hours. The reaction mixture was then extracted with ethyl acetate and washed with water. The organic layer was dried using magnesium sulfate anhydride, filtered and evaporated. The residue was then purified using silica gel chromatography. This elution was carried out using a solvent in which hexane and ethyl acetate were mixed at 10: 1, resulting in 180 mg of the derivative 59 compound represented by the above formula (5- (4). -(2-cyclohexylethoxy) benzylidene] -3- (hydroxyethyl) -1,3-thiazolidione-2,4-dione (5- [4- (2-cyclohexylethoxy) benzylidene] -3- (hydroxyethyl) -1,3-thiazolidine-2,4-dione) (79% yield) was obtained, and the compound of the derivative 59 was 1 H NMR (300 MHz, CDCl 3 ) δ 7.878 (s, 1H), 7.485 (d, J = 14.4 Hz, 2H), 7.007 (d, J = 14.4 Hz, 2H), 4.078 (t, J = 13.2 Hz, 2H), 4.001 (t, J = 10.2 Hz, 2H), 3.891 ( t, J = 10.2 Hz, 2H), 2.049 (m, 1H), 1.670-1.782 (m, 7H), 1.471-1.529 (m, 1H), 1.178-1.284 (m, 3H), 0.956-1.034 (m, 2H).

＜실시예 60＞<Example 60>

본 발명에 따른 유도체 60의 제조Preparation of Derivative 60 According to the Invention

하기 화학식으로 나타내는 유도체 60을 다음과 같은 방법으로 제조하였다.Derivative 60 represented by the following formula was prepared in the following manner.

＜유도체 60의 화학식＞<Chemical formula of derivative 60>

Figure pct00068
Figure pct00068

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올을 1g, 7.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-에톡시-4-히드록시알데히드(1.30g, 7.8mmol)를 사용하였으며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-시클로헥실에톡시)-3-에톡시벤즈알데히드를 1.85g 수득하였으며, 이때 상기 중간체 생성물의 수율은 85.7％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-시클로헥실에톡시)-3-에톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-3-ethoxybenzylidene)thiazolidine-2,4-dion)(1.12 g, 83.0％ 수율)을 수득하였으며, 상기 유도체 60의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ12.582 (s, 1H), 7.786 (s, 1H), 7.116 (d, J = 10.8 Hz, 1H), 6.959 (d, J=10.8 Hz, 1H), 7.000 (s, 1H), 4.089 (m, 4H), 1.653-1.795 (m, 7H), 1.459-1.577 (m, 4H), 1.146-1.282 (m, 3H), 0.941-1.05 (m, 2H)이었다.In preparing the derivative of Example 53, 1 g, 7.8 mmol of cyclohexaneethanol was used instead of cyclohexane methanol, and 3-ethoxy-4-hydroxy aldehyde (1.30 g, instead of 4-hydroxy-3-methylbenzaldehyde) was used. 7.8 mmol), and the intermediate product 4- (2-cyclohexylethoxy) -3-ethoxybenzaldehyde was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.85 g were obtained, wherein the yield of the intermediate product was 85.7%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4- (2-cyclohexylethoxy) -3-ethoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -3-ethoxybenzylidene) thiazolidine-2, 4-dion) (1.12 g, 83.0% yield) was obtained, and the compound of Derivative 60 was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ12.582 (s, 1H), 7.786 (s, 1H), 7.116 (d, J = 10.8 Hz, 1H), 6.959 (d, J = 10.8 Hz, 1H), 7.000 (s, 1H), 4.089 (m, 4H), 1.653-1.795 (m, 7H), 1.459-1.577 (m, 4H), 1.146-1.282 (m, 3H), and 0.941-1.05 (m, 2H).

＜실시예 61＞<Example 61>

본 발명에 따른 유도체 61의 제조Preparation of Derivative 61 According to the Invention

하기 화학식으로 나타내는 유도체 61을 다음과 같은 방법으로 제조하였다.Derivative 61 represented by the following formula was prepared in the following manner.

＜유도체 61의 화학식＞<Chemical formula of derivative 61>

Figure pct00069
Figure pct00069

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올 1g, 7.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-메톡시-4-히드록시벤즈알데히드(1.19g, 7.8mmol)를 사용하였으며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-시클로헥실에톡시)-2-메톡시벤즈알데히드를 1.78g 수득하였으며, 이때 상기 중간체 생성물의 수율은 87.3％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-시클로헥실에톡시)-2-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-2-methoxybenzylidene)thiazolidine-2,4-dione) (1.15 g, 83.9％ 수득율)을 수득하였으며, 상기 유도체 61 화합물은 1H NMR (300 MHz, DMSO-d 6)δ12.446 (s, 1H), 7.915 (s, 1H), 7.907 (d, J = 8.4 Hz, 1H), 6.709 (d, J=8.4 Hz, 1H), 6.667 (s, 1H), 4.102 (t, J = 5.1 Hz, 2H), 3.878 (s, 3H), 1.587-1.750 (m, 7H), 1.451-1.586 (m, 1H), 1.104-1.271 (m, 3H), 0.884-0.994 (m, 2H)이었다.In preparing the derivative of Example 53, instead of cyclohexanemethanol, 1 g of cyclohexane ethanol and 7.8 mmol were used, and 2-methoxy-4-hydroxy benzaldehyde (1.19 g, 7.8 instead of 4-hydroxy-3-methylbenzaldehyde) was used. mmol), and the intermediate product 4- (2-cyclohexylethoxy) -2-methoxybenzaldehyde was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. g was obtained, wherein the yield of the intermediate product was 87.3%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4- (2-cyclohexylethoxy) -2-methoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -2-methoxybenzylidene) thiazolidine-2, 4-dione) (1.15 g, 83.9% yield) was obtained and the derivative 61 compound was subjected to 1 H NMR (300 MHz, DMSO- d 6 ) δ12.446 (s, 1H), 7.915 (s, 1H), 7.907 (d, J = 8.4 Hz, 1H), 6.709 (d, J = 8.4 Hz, 1H), 6.667 (s, 1H), 4.102 (t, J = 5.1 Hz, 2H), 3.878 (s, 3H), 1.587 -1.750 (m, 7H), 1.451-1.586 (m, 1H), 1.104-1.271 (m, 3H), 0.884-0.994 (m, 2H).

＜실시예 62＞<Example 62>

본 발명에 따른 유도체 62의 제조Preparation of Derivative 62 According to the Invention

하기 화학식으로 나타내는 유도체 62를 다음과 같은 방법으로 제조하였다.Derivative 62 represented by the following formula was prepared in the following manner.

＜유도체 62의 화학식＞<Chemical formula of derivative 62>

Figure pct00070
Figure pct00070

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-(시클로헥실옥시)에탄올 1g, 6.9mmol을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시벤즈알데히드(0.84g, 6.9mmol)를 사용하였으며, 트리페닐포스피린을 1.99g, 7.59mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-(시클로헥실옥시)에톡시)벤즈알데히드를 1.46g 수득하였으며, 이때 상기 중간체 생성물의 수율은 84.9％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-(시클로헥실옥시)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Cyclohexyloxy)ethoxy)benzylidene)thiazolidine-2,4-dione)(1.14 g, 82.0％ 수율)을 수득하였고, 상기 유도체 62 화합물은 1H NMR (300 MHz, DMSO-d 6)δ8.645 (s, 1H), 7.733 (s, 1H), 7.437 (d, J = 14.7 Hz, 2H), 7.020 (d, J = 14.7 Hz, 2H), 4.197 (t, J = 9.9 Hz, 2H), 3.302 (t, J = 9.9 Hz, 2H), 3.321-3.397 (m, 1H), 1.956-2.179 (m, 2H), 1.754-1.770 (m, 2H), 1.549-1.592 (m, 1H), 1.218-1.389 (m, 5H)이었다.In preparing the derivative of Example 53, 1 g and 6.9 mmol of 2- (cyclohexyloxy) ethanol instead of cyclohexanemethanol were used, and 4-hydroxybenzaldehyde (0.84 g instead of 4-hydroxy-3-methylbenzaldehyde) was used. , 6.9 mmol), and the intermediate product 4- (2- (cyclohexyloxy) ethoxy) benzaldehyde was prepared in the same manner except that triphenylphosphine was used in an amount of 1.99 g and 7.59 mmol. 1.46 g were obtained, wherein the yield of the intermediate product was 84.9%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4- (2- (cyclohexyloxy) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Cyclohexyloxy) ethoxy) benzylidene) thiazolidine-2,4 -dione) (1.14 g, 82.0% yield), and the derivative 62 compound was subjected to 1 H NMR (300 MHz, DMSO- d 6 ) δ8.645 (s, 1H), 7.733 (s, 1H), 7.437 ( d, J = 14.7 Hz, 2H), 7.020 (d, J = 14.7 Hz, 2H), 4.197 (t, J = 9.9 Hz, 2H), 3.302 (t, J = 9.9 Hz, 2H), 3.321-3.397 ( m, 1H), 1.956-2.179 (m, 2H), 1.754-1.770 (m, 2H), 1.549-1.592 (m, 1H), 1.218-1.389 (m, 5H).

＜실시예 63＞<Example 63>

본 발명에 따른 유도체 63의 제조Preparation of Derivative 63 According to the Invention

하기 화학식으로 나타내는 유도체 63을 다음과 같은 방법으로 제조하였다.Derivative 63 represented by the following formula was prepared in the following manner.

＜유도체 63의 화학식＞<Chemical formula of derivative 63>

Figure pct00071
Figure pct00071

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-히드록시메틸-1,4-벤조디옥산 1g, 6.0mmol을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시벤즈알데히드(0.73g, 6.0mmol)를 사용하였으며, 트리페닐포스피린을 1.73g, 6.6mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-((2,3-디히드로벤조[b][1,4]디옥신-2-일)메톡시)벤즈알데히드를 1.34g 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.7％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-((2,3-디히드로벤조[b][1,4]디옥신-2-일)메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methoxy)benzylidene)thiazolidine-2,4-dione)(1.12 g, 82.4％ 수율)을 수득하였으며, 상기 유도체 63의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ12.513 (s, 1H), 7.733 (s, 1H), 7.576 (d, J=8.7 Hz, 2H), 7.167 (d, J=8.7 Hz, 2H), 6.817-6.922 (m, 4H), 4.458-4.578 (m, 1H), 4.409-4.455 (m, 1H), 4.263-4.409 (m, 2H), 4.111-4.173 (m, 1H)이었다.In preparing the derivative of Example 53, 2-hydroxymethyl-1,4-benzodioxane 1g, 6.0mmol was used instead of cyclohexanemethanol, and 4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (0.73 g, 6.0 mmol) was used, and the intermediate product 4-((2,3-dihydrobenzo [was used in the same manner except that triphenylphosphine was used in an amount of 1.73 g and 6.6 mmol. b] 1.34 g of [1,4] dioxin-2-yl) methoxy) benzaldehyde were obtained, wherein the yield of the intermediate product was 82.7%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-2-yl) methoxy) benzylidene) thiazolidine-2,4-dione (5- (4- ((2,3-Dihydrobenzo [b] [1,4] dioxin-2-yl) methoxy) benzylidene) thiazolidine-2,4-dione) (1.12 g, 82.4% yield) was obtained, and the compound of the derivative 63 was obtained. Silver 1 H NMR (300 MHz, DMSO- d 6 ) δ12.513 (s, 1H), 7.733 (s, 1H), 7.576 (d, J = 8.7 Hz, 2H), 7.167 (d, J = 8.7 Hz, 2H), 6.817-6.922 (m, 4H), 4.458-4.578 (m, 1H), 4.409-4.455 (m, 1H), 4.263-4.409 (m, 2H), 4.111-4.173 (m, 1H).

＜실시예 64＞<Example 64>

본 발명의 따른 유도체 64의 제조Preparation of the derivative 64 according to the present invention

하기 화학식으로 나타내는 유도체 64를 다음과 같은 방법으로 제조하였다.Derivative 64 represented by the following formula was prepared in the following manner.

＜유도체 64의 화학식＞<Chemical formula of derivative 64>

Figure pct00072
Figure pct00072

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올을 1g, 8.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.38g, 8.8mmol)를 사용하며, 트리페닐포스피린을 2.54g, 9.68mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(시클로헥실메톡시)벤즈알데히드를 1.89g 수득하였으며, 이때 상기 중간체 생성물의 수율은 85.5％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(시클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)(1.06 g, 76.3％ 수율)을 수득하였으며, 상기 유도체 64 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.721(s,1H),7.514 (d, J = 9.3 Hz, 1H), 7.138-7.327(m, 1H), 7.142 (d, J=9.3Hz,1H),3.862(d,J=6.0Hz,2H), 1.7.3-1.933 (m, 6H), 1.088-1.579 (m, 5H)이었다.In preparing the derivative of Example 53, 1 g, 8.8 mmol of cyclohexanemethanol was used, and 2-chloro-3-hydroxybenzaldehyde (1.38 g, 8.8 mmol) was used instead of 4-hydroxy-3-methylbenzaldehyde. Using the same method, except that triphenylphosphine was used in an amount of 2.54 g and 9.68 mmol, 1.89 g of an intermediate product, 2-chloro-3- (cyclohexylmethoxy) benzaldehyde, was obtained. The yield of the product was 85.5%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (2-chloro-3- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) (1.06 g, 76.3% yield), the derivative 64 compound having 1 H NMR (300 MHz, DMSO- d 6 ) δ7.721 (s, 1H), 7.514 (d, J = 9.3 Hz, 1H), 7.138-7.327 (m, 1H), 7.142 (d, J = 9.3 Hz, 1H), 3.862 (d, J = 6.0 Hz, 2H), 1.7.3-1.933 (m, 6H), 1.088-1.579 (m, 5H).

＜실시예 65＞<Example 65>

본 발명에 따른 유도체 65의 제조Preparation of the derivative 65 according to the invention

하기 화학식으로 나타내는 유도체 65를 다음과 같은 방법으로 제조하였다.Derivative 65 represented by the following formula was prepared in the following manner.

＜유도체 65의 화학식＞<Chemical formula of derivative 65>

Figure pct00073
Figure pct00073

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-시클로헥실-1-프로판올(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(855mg, 7.0mmol)를 사용하며, 트리페닐포스피린을 2.02g, 7.7mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(시클로헥실프로폭시)벤즈알데히드를 1.65g 수득하였으며, 이때 상기 중간체 생성물의 수율은 83.8％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(시클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)(1.00 g, 74.1％ 수율)을 수득하였으며, 상기 유도체 65 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.943(s,1H),7.521 (d, J = 9.3 Hz, 1H), 7.261-7.333 (m, 1H), 7.152 (d, J=9.3Hz,1H),4.045(t,J=13.2Hz,2H), 1.829-1.925 (m, 2H), 1.578-1.731 (m, 5H), 1.091-1.426 (m, 6H), 0.859-0.883 (m, 2H)이었다.In the preparation of the derivative of Example 53, 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Roxybenzaldehyde (855 mg, 7.0 mmol) was used, and the intermediate product 2-chloro-3- (cyclohexylpropoxy) was obtained using the same method except that triphenylphosphine was used in an amount of 2.02 g, 7.7 mmol. 1.65 g of benzaldehyde was obtained, wherein the yield of the intermediate product was 83.8%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (2-chloro-3- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) (1.00 g, 74.1% yield) was obtained, wherein the derivative 65 compound was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ7.943 (s, 1H), 7.521 (d, J = 9.3 Hz, 1H), 7.261-7.333 (m, 1H), 7.152 (d, J = 9.3 Hz, 1H), 4.045 (t, J = 13.2 Hz, 2H), 1.829-1.925 (m, 2H), 1.578-1.731 (m, 5H) , 1.091-1.426 (m, 6H) and 0.859-0.883 (m, 2H).

＜실시예 66＞<Example 66>

본 발명에 따른 유도체 66의 제조Preparation of the derivative 66 according to the invention

하기 화학식으로 나타내는 유도체 66을 다음과 같은 방법으로 제조하였다.Derivative 66 represented by the following formula was prepared in the following manner.

＜유도체 66의 화학식＞<Chemical formula of derivative 66>

Figure pct00074
Figure pct00074

상온에서 시약 등급의 메탄올 10ml에 용해된 4-히드록시메틸-1-시클로헥신카르복실산(1g, 6.3mmol) 용액에 티오닐 클로라이드(1.50g, 12.6mmol)를 한방울씩 떨어뜨렸다. 상기 혼합 용액은 밤새도록 가열처리하여 환류시켰고, 반응 혼합액은 감압하에서 농축시켰으며, 이후 실리카 겔 크로마토그래피를 통해 0.78g 4-히드록시메틸-1-시클로헥산카르복실산염(71.6％의 수율)을 수득하였다. 또한, 실리카 겔 컬럼 크로마토그래피를 통해 헥산 및 에틸아세테이트가 10:1로 혼합된 용출 용매를 사용하여 4-((4-아세틸시클로헥실)메톳기)벤즈알데히드 0.86g을 수득하였다(76.8％ 수율). 이후 상기에서 수득한 2가지의 화합물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 메틸-4-((4-((2,4-디옥소티아졸리딘-5-일이덴)메틸)페녹시)시클로헥산카르복실레이트(methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)methyl)cyclohexanecarboxylate)(1.03 g, 74.1％ 수율)을 수득하였고, 상기 수득한 유도체 66의 화합물은 1H NMR (300 MHz, DMSO-d 6) δ 12.482 (s, 1H), 7.736 (s, 1H), 7.552 (d, J = 15.9 Hz, 4H), 7.580 (t, J = 9.0 Hz, 2H), 7.103 (d, J = 9.0 Hz, 2H), 3.904 (d, J = 6.6 Hz, 2H), 3.610 (s, 3H), 2.604-2.623 (m, 1H), 1.891-1.984 (m, 3H), 1.450-1.675 (m, 4H), 1.273-1.342 (m, 2H)이었다.Thionyl chloride (1.50 g, 12.6 mmol) was added dropwise to a solution of 4-hydroxymethyl-1-cyclohexincarboxylic acid (1 g, 6.3 mmol) dissolved in 10 ml of reagent grade methanol at room temperature. The mixed solution was heated to reflux overnight, the reaction mixture was concentrated under reduced pressure, and then 0.78 g 4-hydroxymethyl-1-cyclohexanecarboxylate (71.6% yield) was obtained by silica gel chromatography. Obtained. Silica gel column chromatography also gave 0.86 g of 4-((4-acetylcyclohexyl) methic group) benzaldehyde (76.8% yield) using an eluting solvent in which hexane and ethyl acetate were mixed at 10: 1. Thereafter, the two compounds obtained above were used in the same manner as in Example 2, except that 4- (2-cyclomethoxy) -3-methylbenzaldehyde was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde. Methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene) methyl) phenoxy) cyclohexanecarboxylate (methyl-4-((4-(( 2,4-dioxothiazolidine-5-ylidene) methyl) phenoxy) methyl) cyclohexanecarboxylate) (1.03 g, 74.1% yield) was obtained, and the compound of the obtained derivative 66 was 1 H NMR (300 MHz, DMSO- d 6 ). δ 12.482 (s, 1H), 7.736 (s, 1H), 7.552 (d, J = 15.9 Hz, 4H), 7.580 (t, J = 9.0 Hz, 2H), 7.103 (d, J = 9.0 Hz, 2H) , 3.904 (d, J = 6.6 Hz, 2H), 3.610 (s, 3H), 2.604-2.623 (m, 1H), 1.891-1.984 (m, 3H), 1.450-1.675 (m, 4H), 1.273-1.342 (m, 2H).

＜실시예 67＞<Example 67>

본 발명에 따른 유도체 67의 제조Preparation of the derivative 67 according to the invention

하기 화학식으로 나타내는 유도체 67을 다음과 같은 방법으로 제조하였다.Derivative 67 represented by the following formula was prepared in the following manner.

＜유도체 67의 화학식＞<Chemical formula of derivative 67>

Figure pct00075
Figure pct00075

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올을 1g, 7.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 이소바닐린(1.19g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-(2-시클로헥실에톡시)-4-메톡시벤즈알데히드 1.68g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.1％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-(2-시클로헥실에톡시)4-메톡시벤질리덴)티아졸리디온-2,4-디온(5-(3-(2-cyclohexylethoxy)-4-methoxybenzylidene)thiazolidine-2,4-dione)(1.24 g, 87.2％ 수율)을 수득하였으며, 상기 수득한 유도체 67의 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.436 (s, 1H), 8.165 (s, 1H), 7.941 (d, J = 9.5 Hz, 1H), 7.661 (s, 1H), 7.273 (d, J = 9.5 Hz, 1H), 4.233 (t, J = 13.5 Hz, 2H), 3.864 (s, 3H), 1.682-1.759 (m, 7H), 1.442-1.586 (m, 1H), 1.182-1.242 (m, 3H), 0.896-0.926 (m, 2H)이었다.In the preparation of the derivative of Example 53, 1 g, 7.8 mmol of cyclohexaneethanol was used instead of cyclohexane methanol, and isovaniline (1.19 g, 7.8 mmol) was used instead of 4-hydroxy-3-methylbenzaldehyde. The same procedure was followed to obtain 1.68 g of the intermediate product 3- (2-cyclohexylethoxy) -4-methoxybenzaldehyde, except that phenylphosphoryne was used in an amount of 2.25 g and 8.58 mmol, wherein the intermediate The yield of the product was 82.1%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (3- (2-cyclohexylethoxy) 4-methoxybenzylidene) thiazolidione-2,4-dione (5- (3- (2-cyclohexylethoxy) -4-methoxybenzylidene) thiazolidine-2,4 -dione) (1.24 g, 87.2% yield), the obtained compound of derivative 67 was 1 H NMR (300 MHz, DMSO- d 6 ) δ12.436 (s, 1H), 8.165 (s, 1H) , 7.941 (d, J = 9.5 Hz, 1H), 7.661 (s, 1H), 7.273 (d, J = 9.5 Hz, 1H), 4.233 (t, J = 13.5 Hz, 2H), 3.864 (s, 3H) , 1.682-1.759 (m, 7H), 1.442-1.586 (m, 1H), 1.182-1.242 (m, 3H), 0.896-0.926 (m, 2H).

＜실시예 68＞<Example 68>

본 발명에 따른 유도체 68의 제조Preparation of the derivative 68 according to the invention

하기 화학식으로 나타내는 유도체 68을 다음과 같은 방법으로 제조하였다.Derivative 68 represented by the following formula was prepared in the following manner.

＜유도체 68의 화학식＞<Chemical formula of derivative 68>

Figure pct00076
Figure pct00076

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 벤질알콜(1g, 9.2mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.44g, 9.2mmol)를 사용하며, 트리페닐포스피린을 2.65g, 10.12mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(벤질옥시)-3-클로로벤즈알데히드 1.76g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 77.2％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(벤질옥시)-3-클로로벤질리덴)티아졸리딘-2,4-디온(5-(4-(benzyloxy)-3-chlorobenzylidene)thiazolidine-2,4-dione) (1.21 g, 86.4％ 수율)을 수득하였고, 상기 수득한 68 유도체 화합물은 1H NMR (300 MHz, DMSO-d 6) δ8.024 (s, 1H), 7.936 (s, 1H), 7.747 (d, J = 10.2 Hz, 1H), 7.324-7.479 (m, 5H), 7.093 (d, J = 10.2 Hz, 1H), 5.259 (s, 2H)이었다.Benzyl alcohol (1 g, 9.2 mmol) was used instead of cyclohexane methanol in the preparation of the derivative of Example 53, and 3-chloro-4-hydroxy benzaldehyde (1.44 g, instead of 4-hydroxy-3-methylbenzaldehyde). 9.2 mmol) and 1.76 g of the intermediate product 4- (benzyloxy) -3-chlorobenzaldehyde were obtained using the same method except that triphenylphosphine was used in an amount of 2.65 g and 10.12 mmol, The yield of this intermediate product was 77.2%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (4- (benzyloxy) -3-chlorobenzylidene) thiazolidine-2,4-dione (5- (4- (benzyloxy) -3-chlorobenzylidene) thiazolidine-2,4-dione) (1.21 g , 86.4% yield), and the 68 derivative compound obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.024 (s, 1H), 7.936 (s, 1H), 7.747 (d, J = 10.2 Hz, 1H), 7.324-7.479 (m, 5H), 7.093 (d, J = 10.2 Hz, 1H), 5.259 (s, 2H).

＜실시예 69＞<Example 69>

본 발명에 따른 유도체 69의 제조Preparation of the derivative 69 according to the invention

하기 화학식으로 나타내는 유도체 69를 다음과 같은 방법으로 제조하였다.Derivative 69 represented by the following formula was prepared in the following manner.

＜유도체 69의 화학식＞<Chemical formula of derivative 69>

Figure pct00077
Figure pct00077

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-페닐에탄올(1g, 8.2mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.28g, 8.2mmol)를 사용하며, 트리페닐포스피린을 2.37g, 9.02mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-페닐에톡시벤즈알데히드 1.69g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.3％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-페닐에톡시벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-phenylethoxybenzylidene)thiazolidine-2,4-dione) (1.19 g, 86.2％ 수율)을 수득하였고, 수득한 상기 유도체 69 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.547 (s, 1H), 7.894 (s, 1H), 7.694 (s, 1H), 7.533 (d, J = 11.1 Hz, 1H), 7.311-7.348 (m, 5H), 7.248 (d, J = 11.1 Hz, 1H), 4.367 (t,J = 13.5 Hz, 2H), 3.109 (t, J = 13.5 Hz, 2H)이었다.In preparing the derivative of Example 53, 2-phenylethanol (1 g, 8.2 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxybenzaldehyde (1.28) instead of 4-hydroxy-3-methylbenzaldehyde. g, 8.2 mmol) and 1.69 g of the intermediate product 3-chloro-4-phenylethoxybenzaldehyde were obtained using the same method except that triphenylphosphine was used in an amount of 2.37 g and 9.02 mmol. In this case, the yield of the intermediate product was 79.3%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative manufacturing process of Example 53 5- (3-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (3-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione) (1.19 g, 86.2% Yield), and the obtained derivative 69 compound was obtained by 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.547 (s, 1H), 7.894 (s, 1H), 7.694 (s, 1H), 7.533 ( d, J = 11.1 Hz, 1H), 7.311-7.348 (m, 5H), 7.248 (d, J = 11.1 Hz, 1H), 4.367 (t, J = 13.5 Hz, 2H), 3.109 (t, J = 13.5 Hz, 2H).

＜실시예 70＞<Example 70>

본 발명에 따른 유도체 70의 제조Preparation of the derivative 70 according to the invention

하기 화학식으로 나타내는 유도체 70을 다음과 같은 방법으로 제조하였다.A derivative 70 represented by the following formula was prepared in the following manner.

＜유도체 70의 화학식＞<Chemical formula of derivative 70>

Figure pct00078
Figure pct00078

상기 실시예 53의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-페닐-1-프로판올(1g, 7.3mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.14g, 7.3mmol)를 사용하며, 트리페닐포스피린을 2.11g, 8.03mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(3-페닐프로폭시)벤즈알데히드 1.48g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 73.6％이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 53의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 70으로 표시되는 5-(3-클로로-4-(3-페닐프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-(3-phenylpropoxy)benzylidene)thiazolidine-2,4-dione)(1.13 g, 83.1％ 수율)을 수득하였다. 상기 수득한 유도체 70 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.538 (s, 1H), 7.714 (s, 1H), 7.706 (s, 1H), 7.533 (d, J = 10.8 Hz, 1H), 7.158 7.311 (m, 6H), 4.143 (t, J = 12.3 Hz, 2H), 2.802 (t, J = 12.8 Hz, 2H), 2.022-2.093 (m, 2H)이었다.In preparing the derivative of Example 53, 3-phenyl-1-propanol (1 g, 7.3 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (1.14 g, 7.3 mmol) was used, and the intermediate product 3-chloro-4- (3-phenylpropoxy was used in the same manner, except that triphenylphosphine was used in an amount of 2.11 g and 8.03 mmol. 1.48 g of benzaldehyde was obtained, with a yield of 73.6% of the intermediate product. Thereafter, the obtained intermediate product was represented by Chemical Formula 70 by performing the same method as in the second step of preparing a derivative of Example 53, except that 4- (2-cyclomethoxy) -3-methylbenzaldehyde was used instead. 5- (3-chloro-4- (3-phenylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (3-phenylpropoxy) benzylidene) thiazolidine-2, 4-dione) (1.13 g, 83.1% yield) was obtained. The obtained derivative 70 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.538 (s, 1H), 7.714 (s, 1H), 7.706 (s, 1H), 7.533 (d, J = 10.8 Hz , 1H), 7.158 7.311 (m, 6H), 4.143 (t, J = 12.3 Hz, 2H), 2.802 (t, J = 12.8 Hz, 2H), 2.022-2.093 (m, 2H).

＜실시예 71＞<Example 71>

본 발명에 따른 유도체 71의 제조Preparation of Derivative 71 According to the Invention

하기 화학식으로 나타내는 유도체 71을 다음과 같은 방법으로 제조하였다.Derivative 71 represented by the following formula was prepared in the following manner.

＜유도체 71의 화학식＞<Chemical formula of derivative 71>

Figure pct00079
Figure pct00079

물 10 ml에 CoCl2 6H2O (4.92mg, 0.017mmol) 및 디메틸글리옥심(dimethylglyoxime) (76.60mg, 0.66mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(420.3mg, 11.22mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF (2:1, 15 ml) 중의 5-(4-(시클로펜틸메톡시)벤질리덴)티아졸리딘 -2,4-디온(5-(4-(cyclopentylmethoxy)benzylidene)thiazolidine-2,4-dione)(1g,3.3mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 71로 표시되는 유도체 화합물인 5-(4-(시클로펜틸메톡시)벤질)티아졸리딘-2,4-디온(5-(4-(cyclopentylmethoxy)benzyl)thiazolidine-2,4-dione)(0.79g, 수율:78.6％)을 수득하였다. 또한, 상기 수득한 유도체 71의 화합물은 1H NMR (300 MHz, CDCl3)δ7.742(s,1H), 7.146(d,J=8.7Hz,2H), 6.874(d,J=8.7Hz,2H), 4.531(dd,J=4.2,4.2Hz,1H),3.819(d,J=6.9Hz,2H),3.469(dd,J=3.9,3.6Hz,1H),3.145(dd,J=9.3,9.6Hz,1H),2.302-2.402(m,1H), 1.799-1.867(m,2H),1.565-1.646(m,4H),1.319-1.384(m,2H)이었다.1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.92 mg, 0.017 mmol) and dimethylglyoxime (76.60 mg, 0.66 mmol) in 10 ml of water, followed by NaBH 4 (420.3 mg, 11.22 mmol) was added and the mixture was cooled to 0 ° C. The mixture was then added with 5- (4- (cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (cyclopentylmethoxy) benzylidene) in THF-DMF (2: 1, 15 ml). thiazolidine-2,4-dione) (1 g, 3.3 mmol) was added over 20 minutes and stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was purified by chromatography over silica gel to obtain a white solid, which is a derivative compound represented by the above formula (71) 5- (4- (cyclopentylmethoxy) benzyl) thiazolidine-2,4-dione (5- ( 4- (cyclopentylmethoxy) benzyl) thiazolidine-2,4-dione) (0.79 g, yield: 78.6%) was obtained. In addition, the compound of Derivative 71 obtained was 1 H NMR (300 MHz, CDCl 3 ) δ7.742 (s, 1H), 7.146 (d, J = 8.7 Hz, 2H), 6.874 (d, J = 8.7 Hz, 2H), 4.531 (dd, J = 4.2, 4.2 Hz, 1H), 3.819 (d, J = 6.9 Hz, 2H), 3.469 (dd, J = 3.9, 3.6 Hz, 1H), 3.145 (dd, J = 9.3) , 9.6 Hz, 1H), 2.302-2.402 (m, 1H), 1.799-1.867 (m, 2H), 1.565-1.646 (m, 4H), and 1.319-1.384 (m, 2H).

＜실시예 72＞<Example 72>

본 발명에 따른 유도체 72의 제조Preparation of the derivative 72 according to the invention

하기 화학식으로 나타내는 유도체 72를 다음과 같은 방법으로 제조하였다.Derivative 72 represented by the following formula was prepared in the following manner.

＜유도체 72의 화학식＞<Formula of derivative 72>

Figure pct00080
Figure pct00080

상기 실시예 71에서 CoCl2·6H2O을 4.77mg, 0.016mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 74.29mg, 0.64mmol 사용하였으며, NaBH4를 407.5mg, 10.88mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(벤질옥시) 벤질리덴) 티아졸리딘 -2,4-디온(5-(4-(benzyloxy)benzylidene)thiazolidine-2,4-dion)(1g,3.2mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 72의 5-(4-(벤질옥시)벤질)티아졸리딘-2,4-디온(5-(4-(benzyloxy)benzyl)thiazolidine-2,4-dione) 화합물(0.83g, 수율:82.5％)을 수득하였다. 또한, 상기 수득한 유도체 72의 화합물은 1H NMR (300 MHz, CDCl3)δ7.444(s,1H), 7.308-7.418(m,5H), 7.167(d,J=8.7Hz,2H), 6.947(d,J=8.7Hz,2H),5.052(s,2H),4.533(dd,J=3.9,3.9Hz,1H),3.487(dd,J=3.6,4.2Hz,1H),3.156(dd,J=9.0,9.6Hz,1H)이었다.In Example 71, 4.77 mg and 0.016 mmol of CoCl 2 .6H 2 O were used, 74.29 mg and 0.64 mmol of dimethylglyoxime were used, and 407.5 mg and 10.88 mmol of NaBH 4 were added to prepare a mixed solution. The mixture was then mixed with 5- (4- (benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (benzyloxy) benzylidene) thiazolidine- in THF-DMF (2: 1, 15 ml). 5- (4- (benzyloxy) benzyl) thiazolidine-2,4 of the formula (72) was carried out in the same manner except that 2,4-dion) (1 g, 3.2 mmol) was added over 20 minutes. -Dione (5- (4- (benzyloxy) benzyl) thiazolidine-2,4-dione) compound (0.83 g, yield: 82.5%) was obtained. In addition, the compound of the obtained derivative 72 is 1 H NMR (300 MHz, CDCl 3 ) δ 7.444 (s, 1H), 7.308-7.418 (m, 5H), 7.167 (d, J = 8.7 Hz, 2H), 6.947 (d, J = 8.7 Hz, 2H), 5.052 (s, 2H), 4.533 (dd, J = 3.9, 3.9 Hz, 1H), 3.487 (dd, J = 3.6, 4.2 Hz, 1H), 3.156 (dd , J = 9.0,9.6 Hz, 1 H).

＜실시예 73＞<Example 73>

본 발명에 따른 유도체 73의 제조Preparation of the derivative 73 according to the invention

하기 화학식으로 나타내는 유도체 73을 다음과 같은 방법으로 제조하였다.Derivative 73 represented by the following formula was prepared in the following manner.

＜유도체 73의 화학식＞<Chemical formula of derivative 73>

Figure pct00081
Figure pct00081

상기 실시예 71에서 CoCl2·6H2O을 4.17mg, 0.014mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 64.99mg, 0.56mmol 사용하였으며, NaBH4를 356.6mg, 9.52mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(3-클로로-4-(시클로헥실프로폭시) 벤질리덴) 티아졸리딘 -2,4-디온(5-(3-chloro-4-(cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)(1g,2.8mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 73으로 표시되는 5-(3-클로로-4-(시클로헥실프로폭시)벤질)티아졸리딘-2,4-디온(5-(3-chloro-4-(cyclohexylpropoxy)benzyl)thiazolidine-2,4-dione) 화합물(0.83g, 수율:82.5％)을 수득하였다. 또한, 상기 수득한 유도체 73의 화합물은 1H NMR (300 MHz, CDCl3)δ7.891(s,1H), 7.238(s,1H), 7.072(d,J=8.4Hz,1H), 6.858(d,J=8.4Hz,1H),4.521(dd,J=3.6,3.9Hz,1H),3.807(d,J=6.3Hz,2H),3.444(dd,J=3.6,4.2Hz,1H),3.129(dd,J=9.0,9.6Hz,1H),1.693-1.917(m,6H),1.057-1.376(m,5H)이었다.In Example 71, CoCl 2 .6H 2 O was used as 4.17 mg and 0.014 mmol, dimethylglyoxime was used as 64.99 mg and 0.56 mmol, and NaBH 4 was added to 356.6 mg and 9.52 mmol to prepare a mixed solution. The mixture was then mixed with 5- (3-chloro-4- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro) in THF-DMF (2: 1, 15 ml). 5- (3-chloro represented by Formula 73 above by the same method except that 4- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) (1 g, 2.8 mmol) was added over 20 minutes 4- (cyclohexylpropoxy) benzyl) thiazolidine-2,4-dione (5- (3-chloro-4- (cyclohexylpropoxy) benzyl) thiazolidine-2,4-dione) compound (0.83 g, yield: 82.5%) was obtained. In addition, the compound of the obtained derivative 73 was 1 H NMR (300 MHz, CDCl 3 ) δ 7.891 (s, 1H), 7.238 (s, 1H), 7.072 (d, J = 8.4 Hz, 1H), 6.858 ( d, J = 8.4 Hz, 1H), 4.521 (dd, J = 3.6, 3.9 Hz, 1H), 3.807 (d, J = 6.3 Hz, 2H), 3.444 (dd, J = 3.6, 4.2 Hz, 1H), 3.129 (dd, J = 9.0, 9.6 Hz, 1H), 1.693-1.917 (m, 6H), and 1.057-1.376 (m, 5H).

＜실시예 74＞<Example 74>

본 발명에 따른 유도체 74의 제조Preparation of the derivative 74 according to the invention

하기 화학식으로 나타내는 유도체 74를 다음과 같은 방법으로 제조하였다.Derivative 74 represented by the following formula was prepared in the following manner.

＜유도체 74의 화학식＞<Chemical formula of derivative 74>

Figure pct00082
Figure pct00082

THF 20ml에 상기 실시예 38에서 합성된 5-(4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)이 용해된 용액에 소듐 하이드라이드(21.24mg, 0.885mmol, 오일 중 60％ 분산된 형태)를 질소 분위기 하의 0℃의 조건에서 10분 동안 교반하면서 첨가하였다. 이후 상기 혼합물은 10분 동안 추가 교반한 다음, 요오드메탄(iodomethane)(205.54mg, 1.45mmol)이 용해된 THF 5ml을 혼합물에 천천히 첨가시켰다. 이후 다시 3시간 동안 추가 교반한 다음, 반응 혼합물에 에틸아세테이트를 첨거하여 추출을 수행하였고, 이후 물로 세척하였다. 유기층은 무수 황산마그네슘을 이용하여 건조시키고, 여과한 다음, 용매를 증발시켰다. 잔여 오일은 실리카겔이 충진된 컬럼크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 10:1이 되는 조건에서 용출시켜 142mg의 상기 화학식 74로 표시되는 화합물인 5-[4-(2-시클로헥실에톡시)벤질리덴]-3-메틸-1,3-티아졸리딘-2,4-디온(5-[4-(2-cyclohexylethoxy)benzylidene]-3-methyl-1,3-thiazolidine-2,4-dione)을 수득하였다(85％의 수율). 또한, 수득한 상기 74 유도체 화합물은 1H NMR (300 MHz, CDCl3)δ7.866 (s, 1H), 7.483 (d, J= 8.7 Hz, 2H), 6.992 (d, J=8.7 Hz, 2H), 4.075 (t, J=13.2 Hz, 2H), 3.244 (s, 3H), 1.668-1.782 (m, 4H), 1.446-1.539 (m, 1H), 1.105-1.255 (m, 4H), 0.832-1.047 (m, 4H)이었다.5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) benzylidene) thiazolidine- synthesized in Example 38 above in THF 20ml. To a solution of 2,4-dione) was added sodium hydride (21.24 mg, 0.885 mmol, 60% dispersed form in oil) with stirring for 10 minutes at 0 ° C. under a nitrogen atmosphere. The mixture was then further stirred for 10 minutes, then 5 ml of THF dissolved in iodomethane (205.54 mg, 1.45 mmol) was slowly added to the mixture. After further stirring for another 3 hours, extraction was performed by adding ethyl acetate to the reaction mixture, which was then washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was purified by silica gel-filled column chromatography, where 142 mg of 5- [4- (2-cyclohexyl), a compound represented by the formula (74), was eluted under a condition of 10: 1 of hexane to ethyl acetate. Ethoxy) benzylidene] -3-methyl-1,3-thiazolidine-2,4-dione (5- [4- (2-cyclohexylethoxy) benzylidene] -3-methyl-1,3-thiazolidine-2, 4-dione) was obtained (85% yield). In addition, the obtained 74 derivative compound is 1 H NMR (300 MHz, CDCl 3 ) δ 7.866 (s, 1H), 7.483 (d, J = 8.7 Hz, 2H), 6.992 (d, J = 8.7 Hz, 2H ), 4.075 (t, J = 13.2 Hz, 2H), 3.244 (s, 3H), 1.668-1.782 (m, 4H), 1.446-1.539 (m, 1H), 1.105-1.255 (m, 4H), 0.832- 1.047 (m, 4H).

＜실험예 1＞<Experimental example 1>

본 발명에 따른 화합물들의 유해조류 살조 활성 분석Analysis of Algal Algae Activity of the Compounds According to the Present Invention

본 발명자들은 상기 실시예 1 내지 74에서 합성된 유도체 화합물들이 유해조류에 대하여 살조 효과가 있는지를 조사하였다. 이를 위해 상기 실시예 1 내지 74의 유도체 화합물들을 유해조류인 C. marina, H. akashiwo 와 C. polykrikoides 및 M. aeruginosa 조류들에 대하여 생장 및 증식을 억제하는 활성이 있는지를 조사하였다. 상기 조사는 유해성 조류들에 대해 각 화합물들을 처리한 후, 상기 처리된 화합물에 의해 조류의 생장이 억제되는 IC50값을 측정함으로써 분석하였는데, 유해성 조류로는 헤테로시그마속 조류인 H. akashiwo(CCMP 452)을 Provasoli-Cuilard CCMP(center for the culture of marine phytoplankton)로부터 수득한 것을 사용하였고, Chattonella marina 조류를 한양대학교 M-S. Han 교수님으로부터 수득한 것을 사용하였으며, Cocholodium polykrikoides 조류를 영남대학교 M-S. Kim교수님으로부터 수득한 것을 사용하였다. Microcystis aeruginosa는 일본의 NIES Collection Microbial Culture Collection에서 분양 받아 사용하였다.The present inventors investigated whether the derivative compounds synthesized in Examples 1 to 74 have a killing effect on harmful algae. To this end, the derivative compounds of Examples 1 to 74 were investigated for their inhibitory activity against growth and proliferation against C. marina, H. akashiwo and C. polykrikoides and M. aeruginosa algae. The investigation was performed by treating each compound for harmful algae, and then measuring the IC 50 value at which algal growth is inhibited by the treated compound. Hazardous algae, H. akashiwo (CCMP) 452) was obtained from Provasoli-Cuilard CCMP (center for the culture of marine phytoplankton), and Chattonella marina algae was used in Hanyang University MS. Cocholodium polykrikoides algae were obtained from Professor Han. The one obtained from Professor Kim was used. Microcystis aeruginosa was used by the NIES Collection Microbial Culture Collection in Japan.

먼저, 상기 조류들은 배양 플라스크 상에서 20℃의 온도 및 빛이 있는 조건에서 배양하였으며, 배지로는 당업계에서 사용되고 있는 길야드의 f/2배지를 여과하여 사용하였다(Guillard RRL 및Keller MD. Culturing dinoflagellates. In: Spector (Ed.), Dinoflagellates. New York: Academic Press; 1984. p. 391442 참조). Mirocystis aeruginosa의 경우는 CB 배지를 사용하였다 (출처:NIES :mcc.nies.go.jp).First, the algae were incubated in a culture flask at a temperature of 20 ° C. and light, and used as a medium by filtration of f / 2 medium of gill yards used in the art (Guillard RRL and Keller MD. Culturing dinoflagellates). In: Spector (Ed.), Dinoflagellates.New York: Academic Press; 1984. p. 391442). In the case of Mirocystis aeruginosa , CB medium was used (Source: NIES: mcc.nies.go.jp).

상기 배지를 이용하여 배양된 각 유해성 조류들을 24웰 플레이트로 옮긴 다음, 조류들이 지수 성장기에 있을 때, 본 발명에 따른 74개의 화합물을 각각의 농도별로(0.05, 0.1, 1, 2, 5, 10, 20, 50, 100 uM의 농도) 각 조류에 처리한 다음, 3일간 배양하였다. 이때 대조군으로는 화합물을 처리하지 않은 군을 사용하였다. 배양 이후, 각 조류별 세포밀도를 Burker Tukr hemacytometer를 이용하여 측정하였으며, IC50값을 측정하였으며, 실험 결과는 하기 표 1에 나타내었다.Each harmful algae cultured using the medium was transferred to a 24-well plate, and when the algae were in the exponential growth phase, 74 compounds according to the present invention were added at respective concentrations (0.05, 0.1, 1, 2, 5, 10). , 20, 50, 100 uM concentration) was treated in each bird, and then incubated for 3 days. In this case, a group not treated with the compound was used as a control. After incubation, the cell density of each bird was measured using a Burker Tukr hemacytometer, and IC 50 values were measured. The experimental results are shown in Table 1 below.

＜표 1＞<Table 1>

본 발명에 따른 화합물들의 유해조류 살조 효과Harmful Algae Effect of the Compounds According to the Present Invention

Figure pct00083
Figure pct00083

그 결과, 상기 표 1에 나타낸 바와 같이, 본 발명에 따른 74개의 화합물들은 유해성 조류인 C. marina, H. akashiwo,C. polykrikoides 및 M. aeruginosa 조류들에 대해 살조효과가 있다는 사실을 알 수 있었으며, 이러한 결과를 통해 본 발명자들은 본 발명의 74개의 화합물들을 유해 조류를 살조하기 위한 살조제로서 유용하게 사용할 수 있음을 알 수 있었다.As a result, as shown in Table 1, 74 compounds according to the present invention are harmful algae C. marina, H. akashiwo, C. It was found that there is an algicidal effect on polykrikoides and M. aeruginosa algae, and these results show that the present inventors can use the 74 compounds of the present invention as a useful algae for killing harmful algae. there was.

따라서 결론적으로 본 발명자들은 본 발명의 화합물을 유효성분으로 포함하는 조성물이 녹조 및 적조현상을 유발시키는 유해조류에 대하여 우수한 살조 효과가 있음을 알 수 있었다.Therefore, in conclusion, the present inventors have found that the composition comprising the compound of the present invention as an active ingredient has an excellent algae effect against harmful algae causing green algae and red tide.

이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (13)

하기 화학식으로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는 유해조류 방제용 조성물:
Figure pct00084

상기 식에서, X 및 Y 는 각각 독립적으로 O, S, C 또는 N 이고, R1은 H, CH3, CH2CH3 또는 CH2CH2OH이고, R2는 치환 또는 비치환 (헤테로)사이클로알킬, (헤테로)사이클로알케닐 또는 (헤테로)아릴이며, 점선은 단일 결합 또는 이중 결합이다.Composition for controlling harmful algae comprising a compound represented by the following formula or a salt thereof as an active ingredient:
Figure pct00084

Wherein X and Y are each independently O, S, C or N, R 1 is H, CH 3 , CH 2 CH 3 or CH 2 CH 2 OH, and R 2 is substituted or unsubstituted (hetero) cyclo Alkyl, (hetero) cycloalkenyl or (hetero) aryl, and the dotted line is a single bond or a double bond. 제1항에 있어서, 상기 X가 S이고, Y가 O이며, R1이 H일 경우, 상기 R2는
Figure pct00085

또는
Figure pct00086

이고,
상기 R3, R4, R5 및 R6는 각각 독립적으로 수소, 니트로기, 아민, 메톡시, 에톡시, 알킬, 트리플루오로메틸, 카르복실, 할로겐 또는
Figure pct00087

이고,
이때 상기
Figure pct00088

는 벤젠고리의 3번(R4 위치) 또는 4번(R5 위치) 탄소 위치에서 결합하며,
상기 R7는 수소, 알킬, 치환 또는 비치환 (헤테로)사이클로알킬, (헤테로)사이클로알케닐 또는 (헤테로)아릴로 이루어진 군 중에서 선택되고, n은 0 내지 5의 정수인 것을 특징으로 하는 유해조류 방제용 조성물.The method of claim 1, wherein when the X is S, and Y is O, R 1 is H, wherein R 2 is
Figure pct00085

or
Figure pct00086

ego,
R 3 , R 4 , R 5 and R 6 are each independently hydrogen, nitro group, amine, methoxy, ethoxy, alkyl, trifluoromethyl, carboxyl, halogen or
Figure pct00087

ego,
At this time
Figure pct00088

Are bonded at the 3 (R 4 position) or 4 (R 5 position) carbon position of the benzene ring,
R 7 is selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted (hetero) cycloalkyl, (hetero) cycloalkenyl or (hetero) aryl, and n is a harmful algae control, characterized in that an integer of 0 to 5 Composition. 제1항에 있어서, 상기 화학식에서 점선이 단일 결합일 경우, 상기 X는 S이고, Y는 O이며, R2는 하기 표에 기재된 화학식들 중에서 선택된 어느 하나인 것을 특징으로 하는 유해조류 방제용 조성물.
Figure pct00089
According to claim 1, wherein when the dotted line in the formula is a single bond, X is S, Y is O, R 2 is a composition for controlling harmful algae, characterized in that any one selected from the formulas listed in the following table. .
Figure pct00089
 제1항에 있어서, 하기 표의 화학식으로 표시되는 화합물 1 내지 74로 이루어진 군 중에서 선택되는 화합물 또는 그의 염을 유효성분으로 포함하는 유해조류 방제용 조성물.
Figure pct00090

Figure pct00091

Figure pct00092
The harmful algae control composition according to claim 1, further comprising a compound selected from the group consisting of compounds 1 to 74 represented by the chemical formula of the following table or a salt thereof as an active ingredient.
Figure pct00090

Figure pct00091

Figure pct00092
 제1항에 있어서, 상기 유해조류는 남조류, 규조류, 녹조류, 유글레노이드조류, 편모조류 및 황녹색조류로 이루어진 군중에서 선택되는 것을 특징으로 하는 유해조류 방제용 조성물.The composition of claim 1, wherein the harmful algae are selected from the group consisting of southern algae, diatoms, green algae, euglenoid algae, flagella algae and yellow green algae. 제5항에 있어서, 상기 남조류는 마이크로시스티스(Microcystis), 아나베나(Anabaena), 아파니존메논(Aphanizomenon) 및 오실라토리아(Oscillatoria) 속 조류로 이루어진 군중에서 선택되는 것을 특징으로 하는 유해조류 방제용 조성물.According to claim 5, wherein the cyanobacteria ( Microcystis ), Anabaena ( Anabaena ), Aphanizomenon ( Aphanizomenon ) and Oscillatoria ( Oscillatoria ) Osteoporosis ( Oscillatoria ) Osteoporosis ( Oscillatoria ( Oscillatoria )) The control of harmful algae, characterized in that selected from the population Composition. 제5항에 있어서, 상기 규조류는 시네드라(Synedra), 아스테리오넬라(Asterionella), 시클로텔라(Cyclotella), 멜로시라(Melosira), 스켈레토네마 코스타튬(Skeletonema costatum), 카에토세로스(Chaetoceros), 탈라시오시라(Thalassiosira), 렙토실린드루스(Leptocylindrus), 니츠쉬이아(Nitzschia), 실린드로세카(Cylindrotheca), 유캄피아(Eucampia) 및 오돈텔라(Odontella)속 조류로 이루어진 군중에서 선택되는 것을 특징으로 하는 유해조류 방제용 조성물.The method of claim 5, wherein the diatoms cine drive (Synedra), asterisks Lionel La (Asterionella), cycloalkyl telra (Cyclotella), Mello Shirakawa (Melosira), skeletal retrograde nematic Costa lithium (Skeletonema costatum), the car Chitose Ross ( Chaetoceros , Thalassiosira , Leptocylindrus , Nitzschia , Cylindrotheca , Eucampia , and Odontella Harmful algae composition for the control. 제5항에 있어서, 상기 녹조류는 클로스테리움(Closterium), 페디아스트룸(Pediastrum) 및 세네데스무스(Scenedesmus)속 조류로 이루어진 군중에서 선택되는 것을 특징으로 하는 유해조류 방제용 조성물.The composition of claim 5, wherein the green algae is selected from the group consisting of Closterium , Pediastrum , and Scenedesmus genus algae. 제5항에 있어서, 상기 유글레노이드(Euglenoids) 조류는 트라첼로모나스(Trachelomonas) 또는 유글레나(Euglena)속 조류인 것을 특징으로 하는 유해조류 방제용 조성물.The method of claim 5, wherein the oil Glacier cannabinoid (Euglenoids) Algae trad cello Pseudomonas (Trachelomonas) or euglena (Euglena) in birds of the composition for controlling harmful algae as claimed. 제5항에 있어서, 상기 편모조류는 페리디늄(Peridinium), 헤테로시그마(Heterosigma), 헤테로캡사 (Heterocapsa), 코클로디니움(Cochlodinium), 프로로센트룸(Prorocentrum), 세라티움(Ceratium), 녹틸루카(Noctiluca), 스크립시엘라(Scrippsiella), 디노피시스(dinophysis), 알렉산드리움(Alexandrium), 유트렙티엘라(Eutreptiella), 피스테리아(Pfiesteria), 카톤넬라(Chattonella), 에밀리아니아(Emiliania) 및 짐노디니움(Gymnodinium)속 조류로 이루어진 군중에서 선택되는 것을 특징으로 하는 유해조류 방제용 조성물.The method of claim 5, wherein the single mother birds Perry pyridinium (Peridinium), heteroaryl Sigma (Heterosigma), heteroaryl kaepsa (Heterocapsa), kokeulrodinium (Cochlodinium), pro Centrum (Prorocentrum), ceramide tium (Ceratium), noktil Luca (Noctiluca ), script when Ella (Scrippsiella), Dino pisiseu (dinophysis), Alexandria Solarium (Alexandrium), yuteu repti Ella (Eutreptiella), pieces terrier (Pfiesteria), carton Nella (Chattonella), Emilia California (Emiliania) and load nodi nium ( Gymnodinium ) genus algae composition for controlling harmful algae, characterized in that selected from the group consisting of. 제5항에 있어서, 상기 황녹색조류는 유로글레나(Uroglena)속 조류인 것을 특징으로 하는 유해조류 방제용 조성물.According to claim 5, The yellow green algae is a composition for controlling harmful algae, characterized in that the genus Algae ( Uroglena ) algae. 제1항의 화합물 또는 그의 염을 유해조류가 발생한 지역 또는 발생예상 지역에 처리하는 것을 포함하는 유해조류의 방제방법.A method of controlling harmful algae comprising treating the compound of claim 1 or a salt thereof in a region where the harmful algae occurred or in an expected area of occurrence. 제12항에 있어서, 제1항의 화합물 또는 그의 염을 최종농도가 0.001uM 내지 10uM이 되도록 처리하는 것을 특징으로 하는 유해조류의 방제방법.The method of controlling harmful algae according to claim 12, wherein the compound or salt thereof is treated to a final concentration of 0.001 uM to 10 uM.
KR1020117020527A 2009-02-04 2010-02-04 Algicidal composition for inhibiting of harmful algae KR101340245B1 (en)

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KR101402997B1 (en) * 2012-08-28 2014-06-11 경성대학교 산학협력단 Compositions containing dendrimer for controlling harmful algal blooms
WO2017065401A1 (en) * 2015-10-14 2017-04-20 주식회사 큐얼스 Composition for destruction of microalgae or sphaerocarpus
KR20200064729A (en) 2018-11-29 2020-06-08 (주)동양화학 Preliminary Observation and Prevention Method and System of harmful algae on board vessel
KR20200064730A (en) 2018-11-29 2020-06-08 (주)동양화학 Concentration control Method and System on eco-prevention chemicals of harmful algae
US11044909B2 (en) 2015-10-14 2021-06-29 Curearth, Inc. Composition for destruction of microalgae or sphaerocarpus
KR20210085197A (en) 2019-12-30 2021-07-08 (주)동양화학 Measurement Method to assume survival rate of harmful algae
KR20210085198A (en) 2019-12-30 2021-07-08 (주)동양화학 Reference alignment system for Measuring diffrent harmful algae
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KR101402997B1 (en) * 2012-08-28 2014-06-11 경성대학교 산학협력단 Compositions containing dendrimer for controlling harmful algal blooms
WO2017065401A1 (en) * 2015-10-14 2017-04-20 주식회사 큐얼스 Composition for destruction of microalgae or sphaerocarpus
US11044909B2 (en) 2015-10-14 2021-06-29 Curearth, Inc. Composition for destruction of microalgae or sphaerocarpus
KR20200064729A (en) 2018-11-29 2020-06-08 (주)동양화학 Preliminary Observation and Prevention Method and System of harmful algae on board vessel
KR20200064730A (en) 2018-11-29 2020-06-08 (주)동양화학 Concentration control Method and System on eco-prevention chemicals of harmful algae
KR20210085197A (en) 2019-12-30 2021-07-08 (주)동양화학 Measurement Method to assume survival rate of harmful algae
KR20210085198A (en) 2019-12-30 2021-07-08 (주)동양화학 Reference alignment system for Measuring diffrent harmful algae
KR20220001531A (en) 2020-06-29 2022-01-06 동양하이테크산업주식회사 Measuring System of harmful algae using Multi Spectral Camera with replaceable Band-Pass Filter

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