KR102224677B1 - Thiazolopiperazine derivatives and composition for preventing or treating autoimmune diseases comprising the same - Google Patents

Thiazolopiperazine derivatives and composition for preventing or treating autoimmune diseases comprising the same Download PDF

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KR102224677B1
KR102224677B1 KR1020190103810A KR20190103810A KR102224677B1 KR 102224677 B1 KR102224677 B1 KR 102224677B1 KR 1020190103810 A KR1020190103810 A KR 1020190103810A KR 20190103810 A KR20190103810 A KR 20190103810A KR 102224677 B1 KR102224677 B1 KR 102224677B1
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tetrahydrothiazolo
pyridin
acetyl
propanoic acid
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신동윤
최지웅
지준구
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가천대학교 산학협력단
경북대학교 산학협력단
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Abstract

본 발명은 티아졸로 피페라진 유도체 및 이를 유효성분으로 함유하는 자가면역질환 예방 또는 치료용 약학조성물 및 건강기능식품 조성물을 제공한다. 본 발명에 따른 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 LPA1(Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 가질 수 있어, LPA1 관련 질환 예방 또는 치료용 약학조성물 및 건강기능식품 조성물로 유용하게 사용될 수 있다. 또한, 상기 약학조성물 및 건강기능식품 조성물로 자가면역질환 뿐만 아니라, 발생기전이 유사한 타 면역관련질환도 효과적으로 예방 또는 치료할 수 있다.The present invention provides thiazolo piperazine derivatives and pharmaceutical compositions and health functional food compositions for preventing or treating autoimmune diseases containing the same as an active ingredient. The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can have an inhibitory effect on LPA1 (Lysophosphatidic acid 1) receptor activation, and thus is useful as a pharmaceutical composition for preventing or treating LPA1-related diseases and a health functional food composition. Can be used. In addition, the pharmaceutical composition and the health functional food composition can effectively prevent or treat not only autoimmune diseases, but also other immune-related diseases having similar mechanisms of development.

Description

티아졸로 피페라진 유도체 및 이를 유효성분으로 함유하는 자가면역질환 예방 또는 치료용 조성물{THIAZOLOPIPERAZINE DERIVATIVES AND COMPOSITION FOR PREVENTING OR TREATING AUTOIMMUNE DISEASES COMPRISING THE SAME}Thiazolo piperazine derivatives and compositions for preventing or treating autoimmune diseases containing them as active ingredients {THIAZOLOPIPERAZINE DERIVATIVES AND COMPOSITION FOR PREVENTING OR TREATING AUTOIMMUNE DISEASES COMPRISING THE SAME}

본 발명은 티아졸로 피페라진 유도체 및 이를 유효성분으로 함유하는 자가면역질환 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a thiazolo piperazine derivative and a composition for preventing or treating autoimmune diseases containing the same as an active ingredient.

자가면역질환은 생체 자체의 물질을 항원으로 오인하여 비정상적인 면역 반응을 유발시키는 질환으로, 건선, 쇼그렌 증후군, 염증성 장질환, 류마티스성 관절염, 다발성경화증, 시신경척수염, 길렝바레 증후군, 그레이브스병, 베체트병 등이 있다. Autoimmune diseases are diseases that cause abnormal immune responses by mistaken substances in the body as antigens, psoriasis, Sjogren syndrome, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, optic nerve myelitis, Guillain-Barre syndrome, Graves' disease, Behcet's disease. Etc.

자가면역질환의 주 원인은 림프구가 조직으로 이동하여 자가면역체계에 이상이 촉발되는 것으로 여겨지고 있으나, 각 질환에 대한 명확한 발병기전은 아직 알려져 있지 않다. The main cause of autoimmune diseases is believed to trigger abnormalities in the autoimmune system due to the transfer of lymphocytes to tissues, but the pathogenesis of each disease is not yet known.

최근, 효율적 면역억제에 초점을 두고, 세포수준(림프구 및 질환 병변 조직에서 면역반응을 담당하는 세포종들의 활성화 억제) 및 분자수준에서의 면역억제를 핵심으로 자가면역질환 치료제 개발 연구가 진행되고 있다. Recently, with a focus on effective immunosuppression, research on the development of autoimmune disease treatments is underway, focusing on immunosuppression at the cellular level (suppression of activation of cell tumors responsible for immune responses in lymphocytes and diseased tissues) and molecular level.

리소포스파티딘산(Lysophosphatidic acid; LPA)과 스핑고신 1-인산(sphingosine 1-phosphate; S1P)으로 대변되는 리소인지질은 오랫동안 세포막 성분의 인지질 대사체로 여겨져 왔으나, 현재는 G 단백질 연결 수용체(G protein-coupled receptor; GPCR)로 분류되는 리소인지질 수용체 활성화를 통해 다양한 생체 기능을 조절하는 중요한 세포외 신호물질로 보고되었다.Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), represented by lysophospholipids, have long been considered as phospholipid metabolites of cell membrane components. coupled receptor (GPCR) is reported as an important extracellular signaling substance that regulates various biological functions through activation of lysophospholipid receptors.

그 중, LPA1은 리소인지질 수용체 중 최초로 규명된 수용체로(1996년 규명) 신경계 발달을 조절하는 핵심인자이며, 최근 연구들을 통해 다양한 질환에서의 중요성이 규명되고 있으며, LPA1의 T 세포 기능 조절을 통한 면역반응 조절이 주목받고 있다. 여러 연구 자료를 통해 밝혀진 LPA1의 신호 전달 매커니즘, 생체 내 조직과의 유기적 시스템 등이 쇼그렌증후군, 뇌졸중, 건선, 염증성 장질환, 당뇨병성 신증 및 섬유증, 전신경화증과 같은 자가면역질환 뿐만 아니라, 신경 정신계 장애, 신경성 통증, 불임, 심혈관 질환, 및 암을 포함하는 다양한 질환의 치료를 위한 중요 데이터가 되고 있다.(참고 문헌 Park et al, “Inhibition of lysophosphatidic acid receptor ameliorates Sjogren's syndrome in NOD mice” Oncotarget. 2017, 8(16), 27240-27251, Yung et al, “LPA receptor signaling: pharmacology, physiology, and pathophysiology“ J Lipid Res. 2014, 55, 1192-1214, Choi et al. "LPA receptors: subtypes and biological actions” Annu Rev Pharmacol Toxicol. 2010;50:157-86. Debendra Pattanaik et al, "A Role for Lysophosphatidic Acid and Sphingosine 1-Phosphate in the Pathogenesis of Systemic Sclerosis" Discov Med 10(51):161-167, August 2010.)Among them, LPA1 is the first receptor identified among lysophospholipid receptors (identified in 1996) and is a key factor regulating the development of the nervous system, and its importance in various diseases has been identified through recent studies. Immune response regulation is attracting attention. The signal transduction mechanism of LPA1 and the organic system with tissues in vivo revealed through various research data are not only autoimmune diseases such as Sjogren's syndrome, stroke, psoriasis, inflammatory bowel disease, diabetic nephropathy and fibrosis, and systemic sclerosis, but also the neuropsychiatric system. It is becoming important data for the treatment of a variety of diseases including disability, neurological pain, infertility, cardiovascular disease, and cancer. (Ref. Park et al, “Inhibition of lysophosphatidic acid receptor ameliorates Sjogren's syndrome in NOD mice” Oncotarget. 2017 , 8(16), 27240-27251, Yung et al, “LPA receptor signaling: pharmacology, physiology, and pathophysiology“ J Lipid Res. 2014, 55, 1192-1214, Choi et al. “LPA receptors: subtypes and biological actions “Annu Rev Pharmacol Toxicol. 2010;50:157-86. Debendra Pattanaik et al, “A Role for Lysophosphatidic Acid and Sphingosine 1-Phosphate in the Pathogenesis of Systemic Sclerosis” Discov Med 10(51):161-167, August 2010 .)

현재 스테로이드와 사이클로스포린(Cyclosporine), 라파마이신(Rapamycin), 메토트렉세이트(Methotrexate), 사이클로포스파미드(Cyclophosphamide), IV 면역글로불린(IV Immunoglobulin), 아자티오프린(Axathioprine), 인플릭시맙(Infliximab) 등의 다양한 면역억제제의 복합요법으로 치료하고 있지만, 대부분 지속적인 염증과 잦은 재발이 발생하고 있고 치료에 따른 전신적인 부작용도 많이 발생하고 있다.Currently, steroids, Cyclosporine, Rapamycin, Methotrexate, Cyclophosphamide, IV Immunoglobulin, Axathioprine, Infliximab, etc. Although it is treated with a combination therapy of various immunosuppressive drugs, most of them have persistent inflammation and frequent recurrence, and there are many systemic side effects following the treatment.

특히, 희귀성 자가면역질환은 환자 수가 적은 반면, 적용하는 치료제의 비용이 매우 고가여서 환자들의 경제적인 부담이 매우 크고, 장기간의 치료를 필요로 하기에 비용적 부담이 더 커지고 있다. 국내에서 희귀성 자가면역질환의 환자 수가 증가하고 있는 추세이지만, 뚜렷한 치료제가 없고 완치율이 낮아 여전히 경제적·사회적 문제가 되고 있다.In particular, rare autoimmune diseases have a small number of patients, but the cost of the therapeutic agent to be applied is very high, so the economic burden of the patients is very large, and the cost burden is increasing because a long-term treatment is required. Although the number of patients with rare autoimmune diseases is increasing in Korea, there are no clear treatments and the cure rate is low, which is still an economic and social problem.

한국등록특허 제10-1020431호(2011.02.28 등록)Korean Patent Registration No. 10-1020431 (registered on February 28, 2011)

상기와 같은 문제점을 해결하기 위하여, 본 발명은 티아졸로 피페라진 유도체를 제공한다.In order to solve the above problems, the present invention provides a thiazole piperazine derivative.

본 발명은 상기 티아졸로 피페라진 유도체를 유효성분으로 함유하는 자가면역질환 예방 또는 치료용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating autoimmune diseases containing the thiazole piperazine derivative as an active ingredient.

본 발명은 상기 티아졸로 피페라진 유도체를 유효성분으로 함유하는 자가면역질환 개선 또는 예방용 건강기능식품 조성물을 제공한다.The present invention provides a health functional food composition for improving or preventing autoimmune diseases containing the thiazolo piperazine derivative as an active ingredient.

본 발명에 따른 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은,The compound represented by the following formula 1 according to the present invention or a pharmaceutically acceptable salt thereof,

[화학식 1][Formula 1]

Figure 112019086940203-pat00001
Figure 112019086940203-pat00001

상기 식에서, R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로겐, 니트로, 또는 하기 화학식 2의 치환기에서 선택되고,In the above formula, R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro, or a substituent of the following formula (2),

[화학식 2][Formula 2]

Figure 112019086940203-pat00002
Figure 112019086940203-pat00002

이 때, R3 및 R4는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 트리플로로메틸, 페녹시, 할로겐 또는 니트로에서 선택되거나, R3와 R4가 연결되어 5환의 헤테로고리를 형성할 수 있다.At this time, R 3 and R 4 may be the same or different, respectively, and selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen or nitro, or R 3 and R 4 may be connected to form a 5-cyclic heterocycle.

본 발명에 따른 LPA1 관련 질환 예방 또는 치료용 약학조성물은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하며, LPA1 (Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 가질 수 있다.The pharmaceutical composition for preventing or treating LPA1-related diseases according to the present invention contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient, and may have an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation.

본 발명에 따른 LPA1 관련 질환 개선 또는 예방용 건강기능식품 조성물은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하며, LPA1 (Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 가질 수 있다. The health functional food composition for improving or preventing LPA1-related diseases according to the present invention contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient, and may have an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation.

본 발명에 따른 티아졸로 피페라진 유도체는 LPA1 수용체 활성화 저해 효과를 가지므로, 뇌졸중, 건선, 쇼그렌증후군, 염증성 장질환, 당뇨병성 신증 및 섬유증 등의 LPA1 관련 질환 예방 또는 치료용 약학조성물 및 건강기능식품 조성물로 유용하게 사용될 수 있다.Since thiazolo piperazine derivatives according to the present invention have an inhibitory effect on LPA1 receptor activation, pharmaceutical compositions and health functional foods for the prevention or treatment of LPA1-related diseases such as stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy and fibrosis It can be usefully used as a composition.

본 발명에 따른 LPA1 관련 질환 예방 또는 치료용 약학조성물 및 건강기능식품 조성물을 통해 자가면역질환을 효과적으로 예방 및 치료할 수 있다. 또한, 상기 자가면역질환 뿐만 아니라, 발생기전이 유사한 타 면역관련질환 치료에도 다양하게 적용될 수 있다.Autoimmune diseases can be effectively prevented and treated through the pharmaceutical composition and health functional food composition for preventing or treating LPA1-related diseases according to the present invention. In addition, it can be applied in various ways to the treatment of not only the autoimmune diseases, but also other immune-related diseases having a similar mechanism of development.

도 1은 본 발명의 일 실험예에 따른 칼슘 분석 결과를 나타낸 그래프이다.1 is a graph showing a calcium analysis result according to an experimental example of the present invention.

이하, 본 발명을 상세하게 설명하기로 한다.Hereinafter, the present invention will be described in detail.

본 발명은 쇼그렌 증후군(sjogren’s disease), 건선(psoriasis), 다발성경화증 등의 자가면역질환 및 당뇨병성 신증(diabetic nephropathy), 뇌졸중(cerebral ischemia) 등의 비정상적인 면역반응 질환의 동물 모델(in vivo 질환 모델)을 활용한 선행 연구를 통해 LPA1이 자가면역질환 치료를 위한 신규 표적 분자로서 유용함을 검증하고, LPA1 길항작용이 있는 화합물을 발견함으로써 본 발명을 완성하였다. The present invention is an animal model of autoimmune diseases such as sjogren's disease, psoriasis, multiple sclerosis, and abnormal immune response diseases such as diabetic nephropathy and cerebral ischemia (in vivo disease model). ) Through prior studies using LPA1 as a novel target molecule for the treatment of autoimmune diseases, and by discovering a compound with LPA1 antagonism, the present invention was completed.

본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112019086940203-pat00003
Figure 112019086940203-pat00003

상기 식에서, R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로겐, 니트로, 또는 하기 화학식 2의 치환기에서 선택된 어느 하나일 수 있다.In the above formula, R 1 and R 2 may each be the same or different, and may be any one selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro, or a substituent represented by the following formula (2).

[화학식 2][Formula 2]

Figure 112019086940203-pat00004
Figure 112019086940203-pat00004

이 때, R3 및 R4는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 트리플로로메틸, 페녹시, 할로겐 또는 니트로에서 선택된 어느 하나이거나, 또는 R3와 R4가 연결되어 5환의 헤테로고리를 형성할 수 있다.At this time, R 3 and R 4 may each be the same or different, and hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen, or any one selected from nitro, or R 3 and R 4 may be connected to each other to form a 5-ring heterocycle.

상기 화합물은 R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C2)알콕시, 할로겐, 또는 니트로에서 선택된 어느 하나일 수 있다.In the compound, R 1 and R 2 may be the same or different, respectively, and may be any one selected from hydrogen, (C1 ~ C2) alkoxy, halogen, or nitro.

보다 상세하게는, 상기 화합물은 3-(5-(2-페닐아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(2-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3,4-디클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3-플로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-브로모페닐)아세틸-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-메톡시페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3-메톡시페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산으로 이루어진 군에서 선택된 어느 하나일 수 있다.More specifically, the compound is 3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3- (5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2 -(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-chloro) Phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3,4-dichlorophenyl)acetyl )-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-fluorophenyl)acetyl)-4, 5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-bromophenyl)acetyl-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothia Zolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5, It may be any one selected from the group consisting of 4-c]pyridin-2-yl)propanoic acid.

또한, 상기 화합물은 하기 화학식 3으로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염일 수 있다.In addition, the compound may be a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof.

[화학식 3][Formula 3]

Figure 112019086940203-pat00005
Figure 112019086940203-pat00005

상기 화학식 3에서, R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 트리플로로메틸, 페녹시, 할로겐 또는 니트로에서 선택된 어느 하나이거나, R1과 R2가 연결되어 5환의 헤테로고리를 형성할 수 있다.In Formula 3, R 1 and R 2 may each be the same or different, and hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen, or any one selected from nitro, or , R 1 and R 2 may be connected to form a 5-ring heterocycle.

상기 화학식 3으로 표시되는 화합물은 R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C2)알콕시, 트리플로로메틸, 페녹시, 플로로, 또는 클로로에서 선택된 어느 하나이거나, R1과 R2가 연결되어 1,3-다이옥솔 고리를 형성할 수 있다.In the compound represented by Formula 3, R 1 and R 2 may each be the same or different, and hydrogen, (C1 ~ C4) alkyl, (C1 ~ C2) alkoxy, trifluoromethyl, phenoxy, fluoro, or chloro Any one selected from, or R 1 and R 2 may be linked to form a 1,3-dioxole ring.

보다 상세하게는, 상기 화합물은 3-(5-(2-(4'-메톡시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3'-메톡시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-페녹시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3'-플로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-플로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-(터트-부틸)-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-(트리플로로메틸)-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-메틸-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-(벤조[d][1,3]다이옥솔-5-일)페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-클로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산으로 이루어진 군에서 선택된 어느 하나일 수 있다.More specifically, the compound is 3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)- 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-phenoxy-[1,1'-bi Phenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-) Fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3- (5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine -2-yl)propanoic acid, 3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]- 4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-methyl-[ 1,1'-Biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-( 2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- Yl)propanoic acid, 3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5 It may be any one selected from the group consisting of ,4-c]pyridin-2-yl)propanoic acid.

본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염 중 어느 하나를 유효성분으로 함유하고, LPA1(Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 갖는 것을 특징으로 하는 LPA1 관련 질환 예방 또는 치료용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating LPA1-related diseases, characterized in that it contains the compound or any one of its pharmaceutically acceptable salts as an active ingredient and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation. do.

상기 LPA1 관련 질환은 뇌졸중, 건선, 쇼그렌증후군, 염증성 장질환, 당뇨병성 신증 및 섬유증으로 이루어진 군에서 선택된 어느 하나일 수 있고, 이에 제한되는 것은 아니다.The LPA1-related disease may be any one selected from the group consisting of stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy, and fibrosis, but is not limited thereto.

본 발명에 따른 약학조성물은 상기 제형에 따라 약학적으로 허용가능한 적절한 담체, 부형제 또는 희석제를 더 포함하여 제조할 수 있다. 상기 "약학적으로 허용가능한"이란, 상기 약학조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다.The pharmaceutical composition according to the present invention can be prepared further comprising a suitable pharmaceutically acceptable carrier, excipient, or diluent according to the above formulation. The "pharmaceutically acceptable" means exhibiting properties that are not toxic to cells or humans exposed to the pharmaceutical composition.

본 발명에서 사용가능한 담체, 부형제 또는 희석제로는, 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등을 들 수 있다.Carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

본 발명에 따른 약학조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical compositions according to the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. have.

본 발명에 따른 약학조성물을 상기 형태로 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calciumcarbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제할 수 있다.When the pharmaceutical composition according to the present invention is formulated in the above form, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid preparations include at least one excipient, such as starch, calcium carbonate, and sucrose. ) Or lactose (lactose), gelatin, etc. can be mixed to prepare.

또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. .

비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

본 발명에 따른 약학조성물에 있어서, 상기 약학조성물은 약학적으로 유효한 양으로 투여될 수 있다. 상기 "약학적으로 유효한 양"이란, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 건강상태, 궤양의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.In the pharmaceutical composition according to the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount. The "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the patient's health condition, It can be determined by the type, severity, activity of the drug, sensitivity to the drug, the method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field. .

본 발명에 따른 약학조성물의 유효성분인 화합물의 사용량은 환자의 나이, 성별, 체중, 질환에 따라 달라질 수 있으나, 0.001 내지 100mg/kg으로, 바람직하게는 0.01 내지 10mg/kg을 일일 1회 내지 수회 투여할 수 있다. 또한, 본 발명에 따른 화합물의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다.　따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The amount of the compound, which is the active ingredient of the pharmaceutical composition according to the present invention, may vary depending on the patient's age, sex, weight, and disease, but is 0.001 to 100 mg/kg, preferably 0.01 to 10 mg/kg, once to several times a day. Can be administered. In addition, the dosage of the compound according to the present invention may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any way.

상기 약학조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 기관지내 흡입, 자궁내 경막 또는 뇌혈관내(intracere-broventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, and humans by various routes. All modes of administration can be expected, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine dura mater or by intracere-broventricular injection.

본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하고, LPA1(Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 갖는 것을 특징으로 하는 LPA1 관련 질환 개선 또는 예방용 건강기능식품 조성물을 제공한다.The present invention provides a health functional food composition for improving or preventing LPA1-related diseases, characterized in that it contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation. .

상기 LPA1 관련 질환은 뇌졸중, 건선, 쇼그렌증후군, 염증성 장질환, 당뇨병성 신증 및 섬유증으로 이루어진 군에서 선택된 어느 하나일 수 있고, 이에 제한되는 것은 아니다.The LPA1-related disease may be any one selected from the group consisting of stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy, and fibrosis, but is not limited thereto.

본 발명에 따른 건강기능식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있고, 상기 건강기능식품은 유효성분인 본 발명에 따른 화합물 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적, 예를 들어, 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health functional food according to the present invention may be provided in the form of powder, granule, tablet, capsule, syrup or beverage, and the health functional food is used with other foods or food additives in addition to the compound according to the present invention, which is an active ingredient, It can be suitably used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use thereof, for example, prevention, health or therapeutic treatment.

본 발명에 따른 건강기능식품에 함유된 상기 화합물의 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있다.The effective dose of the compound contained in the health functional food according to the present invention can be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the above It may be less than the range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the range.

본 발명에 따른 건강기능식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There is no particular limitation on the type of health functional food according to the present invention, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, Beverages, teas, drinks, alcoholic beverages, and vitamin complexes.

본 발명에 따른 상기 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 상기 염은 약학적으로 허용 가능한 염기성 염 또는 산성염 중 어느 하나의 형태로 사용할 수 있다. The compound according to the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be used in the form of either a pharmaceutically acceptable basic salt or an acidic salt.

염기성 염은 유기염기염, 무기염기염 중 어느 하나의 형태로 사용할 수 있으며, 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염, 아미늄(aminium)염, 암모늄염, 트리에칠아미늄염 및 피리디늄염으로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.The basic salt can be used in the form of either an organic base salt or an inorganic base salt, and sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethyl salt It may be selected from the group consisting of an aminium salt and a pyridinium salt, but is not limited thereto.

산성 염은 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다. 바람직하게는 무기산으로는 염산, 유기산으로는 메탄설폰산을 사용할 수 있다.Acidic salts are useful acid addition salts formed by free acids. Inorganic acids and organic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, glucolic acid, and methanesulfonic acid can be used as organic acids. , Benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid Etc. can be used. Preferably, hydrochloric acid is used as the inorganic acid and methanesulfonic acid is used as the organic acid.

또한, 본 발명에 따른 상기 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함할 수 있다.In addition, the compound according to the present invention may include all salts, hydrates, and solvates that can be prepared by conventional methods, as well as pharmaceutically acceptable salts.

본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 상기 화학식 1 내지 상기 화학식 3으로 표시되는 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기염기를 가하거나 무기염기의 염기 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 또는 이 혼합물에서 용매나 과량의 염기를 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound represented by Chemical Formula 1 to Chemical Formula 3 in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile. It can be prepared by precipitating or crystallizing after adding an excessive amount of organic base or an aqueous base solution of an inorganic base. Alternatively, the mixture may be prepared by evaporating a solvent or an excess base and drying to obtain an addition salt, or by suction filtration of the precipitated salt.

이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

<합성방법><Synthesis method>

TCI, Sigma Aldrich, Alfa Aesar에서 합성에 필요한 모든 시약을 순도 97% 이상으로 구입하였다. 합성을 수행하기 전, 아세톤으로 반응에 사용될 유리 기구를 충분히 세척한 후 60℃ 오븐에서 건조하였고 질소 기류하에서 합성을 진행하였다. 디클로로메탄(Dichloromethane), 테트라하이드로퓨란(Tetrahydrofuran), 메탄올(Methanol), 아세톤(Acetone), 톨루엔(toluene), 디에틸에테르(Diethyl ether), 에틸아세테이트(Ethyl acetate), 헥산(Hexane)은 대정화금에서 구입하였고, 무수 용매의 경우 Sigma Aldrich에서 구입하였다. TLC에서 UV 램프와 발색 시약인 AA, CAM, 과망간산칼륨(KMnO4), 닌하이드린(Ninhydrin)을 사용하여 반응의 진행을 확인하였다. H NMR, C NMR Spectra는 BRUKER Ascend 600 spectrometer와 Varian VnmrS-400을 사용하였고, 분석을 위해서 CDCl3와 DMSO-d6를 용매로 사용하여 측정하였다. 화학적 이동(Chemical shift)값은 ppm 단위로 나타내었고, 결합 상수(Coupling constants)(J)는 Hz 단위로 나타내었다.All reagents required for synthesis were purchased from TCI, Sigma Aldrich, and Alfa Aesar with a purity of 97% or higher. Before performing the synthesis, after sufficiently washing the glassware to be used for the reaction with acetone, it was dried in an oven at 60° C. and the synthesis was carried out under a stream of nitrogen. Dichloromethane, tetrahydrofuran, methanol, acetone, toluene, diethyl ether, ethyl acetate, and hexane are largely purified. It was purchased from gold, and in the case of anhydrous solvent, it was purchased from Sigma Aldrich. In TLC, the progress of the reaction was confirmed using a UV lamp and color developing reagents AA, CAM, potassium permanganate (KMnO 4 ), and ninhydrin. For H NMR and C NMR spectra, a BRUKER Ascend 600 spectrometer and Varian VnmrS-400 were used, and CDCl3 and DMSO-d6 were used as solvents for analysis. Chemical shift values are expressed in ppm, and coupling constants (J) are expressed in Hz.

<실시예 1> <Example 1>

모핵 디하이드로티아졸로피라딘(Dihydrothiazolopyridine)의 합성Synthesis of Dihydrothiazolopyridine

[반응식 1][Scheme 1]

Figure 112019086940203-pat00006
Figure 112019086940203-pat00006

상기 반응식 1은 본 발명에 따른 핵심 모핵인 디하이드로티아졸로피리딘을 합성하는 과정으로, 상기 반응식 1과 같은 방법으로, 메틸 4-아미노-4-옥소부타노에이트(methyl 4-amino-4-oxobutanoate)를 출발 물질로 하여 하기 방법에 따라 디하이드로티아졸로피리딘의 합성이 수행되었다.Scheme 1 is a process for synthesizing dihydrothiazolopyridine, which is a core parent nucleus according to the present invention, in the same manner as in Scheme 1, methyl 4-amino-4-oxobutanoate ) As a starting material, the synthesis of dihydrothiazolopyridine was carried out according to the following method.

<실시예 1-1> 메틸 4-아미노-4-티옥소부타노에이트[Methyl 4-amino-4-thioxobutanoate]<Example 1-1> Methyl 4-amino-4-thioxobutanoate

메틸-4-아미노-4-옥소부타노에이트(5g, 0.038mol)와 라웨슨 시약(lawesson's reagent, 6.15g, 0.015mol)을 테트라하이드로퓨란(Tetrahydrofuran, 200ml)에 첨가하고 상온에서 1시간 동안 교반하였다. 그 후 용매를 제거하고, 칼럼크로마토그래피를 통해 분리 정제하여 화합물 1(4.4g, 80%)을 얻었다. Methyl-4-amino-4-oxobutanoate (5g, 0.038mol) and Lawesson's reagent (6.15g, 0.015mol) were added to tetrahydrofuran (200ml) and stirred at room temperature for 1 hour. I did. After that, the solvent was removed and separated and purified through column chromatography to obtain compound 1 (4.4g, 80%).

화합물 1 : 1H NMR (600 MHz, Chloroform-d) δ 7.52 (d, J = 58.7 Hz, 2H), 3.71 (s, 3H), 2.93 - 2.90 (m, 2H), 2.88 (dd, J = 5.6, 1.2 Hz, 2H); 13C NMR (151 MHz, Chloroform-d) δ 208.8, 173.8, 52.1, 39.1, 32.7.Compound 1: 1 H NMR (600 MHz, Chloroform-d) δ 7.52 (d, J = 58.7 Hz, 2H), 3.71 (s, 3H), 2.93-2.90 (m, 2H), 2.88 (dd, J = 5.6 , 1.2 Hz, 2H); 13 C NMR (151 MHz, Chloroform-d) δ 208.8, 173.8, 52.1, 39.1, 32.7.

<실시예 1-2> 터트-부틸 2-(3-메톡시-3-옥소프로필)-6,7-디하이드로티아졸로[5,4-c]피리딘-5(4H)-카르복시레이트 [Tert-butyl 2-(3-methoxy-3-oxopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate] <Example 1-2> Tert-butyl 2-(3-methoxy-3-oxopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-carboxylate [Tert -butyl 2-(3-methoxy-3-oxopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate]

화합물 1(2.28g, 0.015mol)과 터트-부틸 3-브로모-4-옥소피페리딘-1-카르복시레이트(Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate, 4.3g, 0.015mol)을 이소프로판올(Isopropanol, 38ml)에 첨가하여 1시간 동안 환류시켰다. 실온에서 화합물을 식힌 후, 에틸 아세테이트(Ethyl acetate)를 통해 추출하고 마그네슘 설페이트(Magnesium Sulfate)를 통해 물을 제거하였다. 여과액을 감압 농축한 뒤, 칼럼 크로마토그래피를 통해 분리 정제하여 화합물 2(2.9g, 60%)를 얻었다.Compound 1 (2.28 g, 0.015 mol) and tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (4.3 g, 0.015 mol) ) Was added to isopropanol (38ml) and refluxed for 1 hour. After cooling the compound at room temperature, extraction was performed through ethyl acetate and water was removed through magnesium sulfate. The filtrate was concentrated under reduced pressure, and then separated and purified through column chromatography to obtain compound 2 (2.9g, 60%).

화합물 2 : 1H NMR (600 MHz, Chloroform-d) δ 4.58 (s, 2H), 3.75 - 3.71 (m, 2H), 3.71 (s, 3H), 3.27 (s, 2H), 2.82 (s, 4H), 1.48 (s, 9H).Compound 2: 1 H NMR (600 MHz, Chloroform-d) δ 4.58 (s, 2H), 3.75-3.71 (m, 2H), 3.71 (s, 3H), 3.27 (s, 2H), 2.82 (s, 4H ), 1.48 (s, 9H).

<실시예 1-3> 핵심 중간체 화합물 3의 합성<Example 1-3> Synthesis of Core Intermediate Compound 3

화합물 2(1.1g, 3.37mmol)를 디클로로메탄(Dichloromethane, 19ml)에 첨가한 후, 트리플루오르아세틱에시드(Trifluoroacetic acid; TFA, 6.3ml)를 0℃에서 천천히 적가하였다. 그 후 상온에서 1시간 동안 교반하였다. 혼합물을 감압 농축한 뒤, 칼럼 크로마토그래피를 통해 분리 정제하여 화합물 3(1g, 99%)을 얻었다. After compound 2 (1.1g, 3.37mmol) was added to dichloromethane (19ml), trifluoroacetic acid (TFA, 6.3ml) was slowly added dropwise at 0°C. Then, it was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and then separated and purified through column chromatography to obtain compound 3 (1g, 99%).

화합물 3 : 1H NMR (600 MHz, Chloroform-d) δ 4.47 (s, 2H), 3.71 (d, J = 2.7 Hz, 3H), 3.62 (t, J = 5.9 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 3.21 (d, J = 6.1 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H).Compound 3: 1 H NMR (600 MHz, Chloroform-d) δ 4.47 (s, 2H), 3.71 (d, J = 2.7 Hz, 3H), 3.62 (t, J = 5.9 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 3.21 (d, J = 6.1 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H).

<실시예 1-4> 아미드 커플링 반응(4a~4i)<Example 1-4> Amide coupling reaction (4a to 4i)

클로로포름(Chloroform, 2ml)에 아민(Amine, 146mg, 0.56mmol), 산 (113.6mg, 0.67mmol), 트리에틸아민(Triethylamine;TEA, 0.14ml, 1.11mmol)을 첨가하여 혼합물을 생성하였다. 생성된 혼합물에 4-다이메틸아미노피리딘(4-dimethylaminopyridine, 6.8mg, 0.055mmol), N,N'-다이싸이클로헥실카르보다이아마이드(N,N'-dicyclohexylcarbodiamide, 114.5mg, 0.55mmol)를 첨가하고 상온에서 12시간 교반하였다. 반응 종료 후, 디클로로메탄을 통해 생성물을 추출하였다. 추출한 생성물에 마그네슘 설페이트를 첨가하여 물을 제거한 뒤, 여과액을 감압 농축하고 분리 없이 다음 반응을 진행하였다.A mixture was prepared by adding amine (Amine, 146mg, 0.56mmol), acid (113.6mg, 0.67mmol), and triethylamine (Triethylamine; TEA, 0.14ml, 1.11mmol) to chloroform (2ml). To the resulting mixture, 4-dimethylaminopyridine (6.8mg, 0.055mmol), N,N'-dicyclohexylcarbodiamide (N,N'-dicyclohexylcarbodiamide, 114.5mg, 0.55mmol) was added and It was stirred at room temperature for 12 hours. After completion of the reaction, the product was extracted through dichloromethane. After removing water by adding magnesium sulfate to the extracted product, the filtrate was concentrated under reduced pressure and the next reaction was carried out without separation.

<실시예 1-5> 가수분해(5a~5i)<Example 1-5> Hydrolysis (5a-5i)

테트라히드로푸란(0.4ml)에 에스터(Ester, 116mg, 0.3mmol)를 첨가하여 혼합물을 생성하였다. 그 후 물(0.8ml)에 녹아있는 수산화나트륨(24mg, 0.6mmol)을 첨가하고 상온에서 12시간 동안 교반하였다. 반응 종료 후, 1노르말 염산을 첨가하여 중화시키고 디클로로메탄을 통해 생성물을 추출하였다. 추출한 생성물에 마그네슘 설페이트를 첨가하여 물을 제거한 뒤, 여과액을 감압 농축하고 칼럼 크로마토그래피를 통해 분리 정제하여 화합물 5a~5i(100mg, 91%)를 얻었다.A mixture was produced by adding ester (Ester, 116 mg, 0.3 mmol) to tetrahydrofuran (0.4 ml). Then, sodium hydroxide (24mg, 0.6mmol) dissolved in water (0.8ml) was added and stirred at room temperature for 12 hours. After completion of the reaction, 1-normal hydrochloric acid was added to neutralize it, and the product was extracted through dichloromethane. After removing water by adding magnesium sulfate to the extracted product, the filtrate was concentrated under reduced pressure and separated and purified through column chromatography to obtain compounds 5a-5i (100mg, 91%).

[화합물 5a~5i][Compound 5a~5i]

Figure 112019086940203-pat00007
Figure 112019086940203-pat00007

1) 화합물 5a : 3-(5-(2-페닐아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]1) Compound 5a: 3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5- (2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, DMSO-d6) δ 7.31 (t, J = 7.5 Hz, 1H), 7.26 (dd, J = 6.7, 2.1 Hz, 2H), 7.22 (t, J = 7.2 Hz, 2H), 4.75 (s, 0.5H), 4.67 (s, 1.5H), 3.83 (s, 1.5H), 3.80 (s, 0.5H), 3.79 - 3.76 (m, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.69 (s, 0.5H), 2.67 (t, J = 7.1 Hz, 2H), 2.62 - 2.59 (m, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.7, 170.3, 167.5, 147.4, 134.5, 129.4, 128.9, 128.7, 128.6, 127.3, 127.1, 41.3, 41.0, 40.4, 33.4, 27.9, 27.1. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.31 (t, J = 7.5 Hz, 1H), 7.26 (dd, J = 6.7, 2.1 Hz, 2H), 7.22 (t, J = 7.2 Hz, 2H) , 4.75 (s, 0.5H), 4.67 (s, 1.5H), 3.83 (s, 1.5H), 3.80 (s, 0.5H), 3.79-3.76 (m, 2H), 3.11 (t, J = 7.2 Hz , 2H), 2.69 (s, 0.5H), 2.67 (t, J = 7.1 Hz, 2H), 2.62-2.59 (m, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.7, 170.3, 167.5, 147.4, 134.5, 129.4, 128.9, 128.7, 128.6, 127.3, 127.1, 41.3, 41.0, 40.4, 33.4, 27.9, 27.1.

2) 화합물 5b : 3-(5-(2-(2-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]2) Compound 5b: 3-(5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [ 3-(5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, DMSO-d6) δ 7.42 (ddd, J = 6.6, 5.7, 3.6 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.32 - 7.29 (m, 1H), 7.26 (s, 1H), 4.82 (s, 0.5H), 4.67 (d, J = 1.9 Hz, 1.5H), 3.94 (s, 1.5H), 3.87 (s, 0.5H), 3.84 (s, 1.5H), 3.79 (s, 0.5H), 3.12 (d, J = 8.2 Hz, 2H), 2.80 (s, 1.5H), 2.71 - 2.69 (m, 0.5H), 2.67 (d, J = 6.8 Hz, 2H); 13C NMR (151 MHz, DMSO) δ 173.6, 168.6, 167.4, 148.2, 134.2, 129.5, 129.4, 129.2, 128.9, 127.6, 127.5, 39.2, 38.4, 37.9, 33.4, 28.4, 27.6. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.42 (ddd, J = 6.6, 5.7, 3.6 Hz, 1H), 7.40-7.36 (m, 1H), 7.32-7.29 (m, 1H), 7.26 (s , 1H), 4.82 (s, 0.5H), 4.67 (d, J = 1.9 Hz, 1.5H), 3.94 (s, 1.5H), 3.87 (s, 0.5H), 3.84 (s, 1.5H), 3.79 (s, 0.5H), 3.12 (d, J = 8.2 Hz, 2H), 2.80 (s, 1.5H), 2.71-2.69 (m, 0.5H), 2.67 (d, J = 6.8 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 173.6, 168.6, 167.4, 148.2, 134.2, 129.5, 129.4, 129.2, 128.9, 127.6, 127.5, 39.2, 38.4, 37.9, 33.4, 28.4, 27.6.

3) 화합물 5c : 3-(5-(2-(3-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]3) Compound 5c: 3-(5-(2-(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [ 3-(5-(2-(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, DMSO-d6) δ 7.34 (dd, J = 4.9, 2.7 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.30 - 7.26 (m, 1H), 7.23 - 7.16 (m, 1H), 4.77 (s, 0.5H), 4.67 (d, J = 1.9 Hz, 1.5H), 3.87 (s, 1.5H), 3.81 (s, 0.5H), 3.83 - 3.77 (m, 2H), 3.12 (q, J = 7.0 Hz, 2H), 2.74 - 2.69 (m, 2H), 2.69 - 2.65 (m, 2H); 13C NMR (151 MHz, DMSO) δ 173.6, 169.4, 167.4, 148.1, 138.8, 133.2, 130.5, 129.7, 128.5, 126.9, 125.1, 55.4, 43.4, 39.3, 33.4, 28.4, 27.6, 26.7. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.34 (dd, J = 4.9, 2.7 Hz, 1H), 7.33-7.30 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.16 (m , 1H), 4.77 (s, 0.5H), 4.67 (d, J = 1.9 Hz, 1.5H), 3.87 (s, 1.5H), 3.81 (s, 0.5H), 3.83-3.77 (m, 2H), 3.12 (q, J = 7.0 Hz, 2H), 2.74-2.69 (m, 2H), 2.69-2.65 (m, 2H); 13 C NMR (151 MHz, DMSO) δ 173.6, 169.4, 167.4, 148.1, 138.8, 133.2, 130.5, 129.7, 128.5, 126.9, 125.1, 55.4, 43.4, 39.3, 33.4, 28.4, 27.6, 26.7.

4) 화합물 5d : 3-(5-(2-(4-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]4) Compound 5d: 3-(5-(2-(4-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [ 3-(5-(2-(4-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.31 - 7.24 (m, 2H), 7.21 - 7.12 (m, 2H), 4.76 (d, J = 2.0 Hz, 1.5H), 4.57 (s, 0.5H), 3.92 (s, 0.5H), 3.79 (s, 1.5H), 3.73 (s, 1.5H), 3.25 (t, J = 7.2 Hz, 0.5H), 2.85 (t, J = 1.7 Hz, 0.5H), 2.80 (t, J = 7.2 Hz, 2H), 2.71 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 174.9, 169.8, 167.8, 147.3, 133.0, 130.1, 130.1, 129.0, 129.0, 128.9, 125.1, 43.7, 40.5, 40.3, 33.5, 28.1, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.31-7.24 (m, 2H), 7.21-7.12 (m, 2H), 4.76 (d, J = 2.0 Hz, 1.5H), 4.57 (s, 0.5H) , 3.92 (s, 0.5H), 3.79 (s, 1.5H), 3.73 (s, 1.5H), 3.25 (t, J = 7.2 Hz, 0.5H), 2.85 (t, J = 1.7 Hz, 0.5H) , 2.80 (t, J = 7.2 Hz, 2H), 2.71 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 174.9, 169.8, 167.8, 147.3, 133.0, 130.1, 130.1, 129.0, 129.0, 128.9, 125.1, 43.7, 40.5, 40.3, 33.5, 28.1, 27.2.

5) 화합물 5e : 3-(5-(2-(3,4-디클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]5) Compound 5e: 3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propane Acid [3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.43 - 7.35 (m, 2H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 4.78 (t, J = 1.8 Hz, 1.5H), 4.60 (d, J = 1.9 Hz, 0.5H), 3.94 (s, 0.5H), 3.78 (s, 1.5H), 3.77 - 3.73 (m, 1.5H), 3.60 (s, 0.5H), 3.27 (t, J = 7.2 Hz, 2H), 2.89 - 2.86 (m, 0.5H), 2.84 (t, J = 7.2 Hz, 2H), 2.80 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.8, 169.2, 167.8, 147.2, 134.6, 132.8, 131.4, 130.9, 130.7, 128.3, 125.1, 43.7, 40.6, 39.8, 33.4, 27.9, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.43-7.35 (m, 2H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 4.78 (t, J = 1.8 Hz, 1.5H), 4.60 ( d, J = 1.9 Hz, 0.5H), 3.94 (s, 0.5H), 3.78 (s, 1.5H), 3.77-3.73 (m, 1.5H), 3.60 (s, 0.5H), 3.27 (t, J = 7.2 Hz, 2H), 2.89-2.86 (m, 0.5H), 2.84 (t, J = 7.2 Hz, 2H), 2.80 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.8, 169.2, 167.8, 147.2, 134.6, 132.8, 131.4, 130.9, 130.7, 128.3, 125.1, 43.7, 40.6, 39.8, 33.4, 27.9, 27.2.

6) 화합물 5f : 3-(5-(2-(3-플로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]6) Compound 5f: 3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.30 (d, J = 6.0 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.99 (td, J = 6.7, 6.1, 2.0 Hz, 1H), 6.96 - 6.92 (m, 1H), 4.79 (d, J = 1.8 Hz, 1.5H), 4.59 (s, 0.5H), 3.94 (s, 0.5H), 3.83 (s, 1.5H), 3.79 (s, 0.5H), 3.75 (s, 1.5H), 3.26 (s, 2H), 2.89 - 2.86 (m, 0.5H), 2.85 (d, J = 6.8 Hz, 2H), 2.72 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 169.6, 167.7, 163.8, 162.2, 147.2, 136.9, 130.4, 125.2, 124.4, 115.7, 114.1, 43.7, 40.8, 40.5, 33.4, 27.9, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.30 (d, J = 6.0 Hz, 1H), 7.06-7.02 (m, 1H), 6.99 (td, J = 6.7, 6.1, 2.0 Hz, 1H), 6.96 -6.92 (m, 1H), 4.79 (d, J = 1.8 Hz, 1.5H), 4.59 (s, 0.5H), 3.94 (s, 0.5H), 3.83 (s, 1.5H), 3.79 (s, 0.5 H), 3.75 (s, 1.5H), 3.26 (s, 2H), 2.89-2.86 (m, 0.5H), 2.85 (d, J = 6.8 Hz, 2H), 2.72 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 169.6, 167.7, 163.8, 162.2, 147.2, 136.9, 130.4, 125.2, 124.4, 115.7, 114.1, 43.7, 40.8, 40.5, 33.4, 27.9, 27.2.

7) 화합물 5g : 3-(5-(2-(4-브로모페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4-bromophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]7) Compound 5g: 3-(5-(2-(4-bromophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4-bromophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, DMSO-d6) δ 7.48 (dd, J = 19.9, 8.2 Hz, 2H), 7.20 (dd, J = 26.0, 8.1 Hz, 2H), 4.75 (s, 0.5H), 4.66 (s, 1.5H), 3.83 (s, 1.5H), 3.81 - 3.78 (m, 2H), 3.77 (s, 0.5H), 3.12 (q, J = 7.4 Hz, 2H), 2.71 - 2.68 (m, 2H), 2.67 (d, J = 7.2 Hz, 2H); 13C NMR (151 MHz, DMSO) δ 173.6, 169.5, 167.4, 148.1, 135.8, 132.0, 131.6, 131.6, 125.1, 124.8, 120.1, 43.4, 39.2, 33.4, 28.4, 27.6, 26.7. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.48 (dd, J = 19.9, 8.2 Hz, 2H), 7.20 (dd, J = 26.0, 8.1 Hz, 2H), 4.75 (s, 0.5H), 4.66 (s, 1.5H), 3.83 (s, 1.5H), 3.81-3.78 (m, 2H), 3.77 (s, 0.5H), 3.12 (q, J = 7.4 Hz, 2H), 2.71-2.68 (m, 2H), 2.67 (d, J = 7.2 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 173.6, 169.5, 167.4, 148.1, 135.8, 132.0, 131.6, 131.6, 125.1, 124.8, 120.1, 43.4, 39.2, 33.4, 28.4, 27.6, 26.7.

8) 화합물 5h : 3-(5-(2-(4-메톡시페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]8) Compound 5h: 3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.14 (dd, J = 33.8, 8.5 Hz, 2H), 6.83 (dd, J = 20.8, 8.6 Hz, 2H), 4.77 (t, J = 1.8 Hz, 1.5H), 4.57 (d, J = 1.9 Hz, 0.5H), 3.92 (s, 0.5H), 3.78 (s, 3H), 3.77 (s, 1.5H), 3.73 (s, 2H), 3.25 (s, 2H), 2.85 (d, J = 5.8 Hz, 1H), 2.81 (s, 2H), 2.66 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.4, 170.8, 167.8, 158.6, 147.4, 129.6, 129.6, 126.4, 125.2, 114.3, 114.3, 55.3, 43.7, 40.4, 40.4, 33.5, 28.0, 27.1. 1 H NMR (600 MHz, Chloroform-d) δ 7.14 (dd, J = 33.8, 8.5 Hz, 2H), 6.83 (dd, J = 20.8, 8.6 Hz, 2H), 4.77 (t, J = 1.8 Hz, 1.5 H), 4.57 (d, J = 1.9 Hz, 0.5H), 3.92 (s, 0.5H), 3.78 (s, 3H), 3.77 (s, 1.5H), 3.73 (s, 2H), 3.25 (s, 2H), 2.85 (d, J = 5.8 Hz, 1H), 2.81 (s, 2H), 2.66 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.4, 170.8, 167.8, 158.6, 147.4, 129.6, 129.6, 126.4, 125.2, 114.3, 114.3, 55.3, 43.7, 40.4, 40.4, 33.5, 28.0, 27.1.

9) 화합물 5i : 3-(5-(2-(3-메톡시페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]9) Compound 5i: 3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.26 - 7.17 (m, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.80 - 6.73 (m, 1H), 4.78 (d, J = 2.0 Hz, 1.5H), 4.56 (s, 0.5H), 3.93 (s, 0.5H), 3.81 (s, 1.5H), 3.78 (s, 3H), 3.74 (s, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.87 (s, 0.5H), 2.82 (s, 2H), 2.67 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.2, 170.2, 167.6, 156.0, 147.4, 136.0, 129.9, 125.2, 120.9, 114.3, 112.5, 55.3, 43.8, 41.3, 40.4, 33.5, 28.0, 27.1. 1 H NMR (600 MHz, Chloroform-d) δ 7.26-7.17 (m, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.80-6.73 (m , 1H), 4.78 (d, J = 2.0 Hz, 1.5H), 4.56 (s, 0.5H), 3.93 (s, 0.5H), 3.81 (s, 1.5H), 3.78 (s, 3H), 3.74 ( s, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.87 (s, 0.5H), 2.82 (s, 2H), 2.67 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.2, 170.2, 167.6, 156.0, 147.4, 136.0, 129.9, 125.2, 120.9, 114.3, 112.5, 55.3, 43.8, 41.3, 40.4, 33.5, 28.0, 27.1.

<실시예 2> 바이페닐아세트산 유도체 합성<Example 2> Synthesis of biphenylacetic acid derivative

<실시예 2-1> 바이페닐아세트산 합성(6a~6j)<Example 2-1> Biphenylacetic acid synthesis (6a to 6j)

바이페닐아세트산(Biphenylacetic acid) 유도체를 합성하기 위해서 하기 반응식 2와 같은 방법으로, 바이페닐아세트산을 먼저 합성하였다. In order to synthesize a biphenylacetic acid derivative, biphenylacetic acid was first synthesized in the same manner as in Scheme 2 below.

[반응식 2][Scheme 2]

Figure 112019086940203-pat00008
Figure 112019086940203-pat00008

메탄올(2.5ml)에 4-브로모페닐아세트산(4-Bromophenylacetic acid, 500mg, 2.325mmol)과 4-메틸페닐보론산(4-Methylphenylboronic acid, 340mg, 4.65mmol), 세슘 카보네이트(Cesium Carbonate, 1.5g, 4.6mmol)를 첨가하여 혼합물을 생성하였다. 그 후 팔라듐 촉매(2.5mg)를 첨가하고 하루 동안 환류시켰다. 반응종료 후, 혼합물의 온도를 상온에 근접하게 만들고 1 노르말 염산을 이용해 중화시키고 생성물을 디클로로메탄을 통해 추출하였다. 추출한 생성물에 마그네슘 설페이트를 첨가하여 물을 제거한 뒤, 여과액을 감압 농축하고 칼럼 크로마토그래피를 통해 분리 정제하여 화합물 6a~6j(470mg, 95%)를 얻었다.In methanol (2.5 ml), 4-Bromophenylacetic acid (4-Bromophenylacetic acid, 500 mg, 2.325 mmol), 4-methylphenylboronic acid (340 mg, 4.65 mmol), cesium carbonate (1.5 g, 4.6 mmol) was added to give a mixture. Thereafter, a palladium catalyst (2.5 mg) was added and refluxed for one day. After completion of the reaction, the temperature of the mixture was brought close to room temperature, neutralized with 1 normal hydrochloric acid, and the product was extracted through dichloromethane. After removing water by adding magnesium sulfate to the extracted product, the filtrate was concentrated under reduced pressure and separated and purified through column chromatography to obtain compounds 6a-6j (470mg, 95%).

[화합물 6a~6j][Compound 6a~6j]

Figure 112019086940203-pat00009
Figure 112019086940203-pat00009

1) 화합물 6a : 2-(4'-메톡시-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid]1) Compound 6a: 2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-methoxy-[1,1'-biphenyl]-4-yl) )acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.52 (m, 4H), 7.32 (m, 2H), 6.98 (m, 2H), 3.82 (s, 3H), 3.62 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.52 (m, 4H), 7.32 (m, 2H), 6.98 (m, 2H), 3.82 (s, 3H), 3.62 (s, 2H).

2) 화합물 6b : 2-(3'-메톡시-[1,1'-바이페닐]-4-일)아세트산 [2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid]2) Compound 6b: 2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid [2-(3'-methoxy-[1,1'-biphenyl]-4-yl) )acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.54 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 17.4, 8.2 Hz, 3H), 7.16 (d, J = 7.0 Hz, 1H), 7.12 (m, 1H), 6.88 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.82 (s, 3H), 3.63 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.54 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 17.4, 8.2 Hz, 3H), 7.16 (d, J = 7.0 Hz, 1H), 7.12 (m, 1H), 6.88 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.82 (s, 3H), 3.63 (s, 2H).

3) 화합물 6c : 2-(4'-페녹시-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetic acid]3) Compound 6c: 2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-phenoxy-[1,1'-biphenyl]-4-yl) )acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.60 (m, 2H), 7.55 (m, 2H), 7.36 (m, 4H), 7.12 (m, 1H), 7.03 (m, 4H), 3.64 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.60 (m, 2H), 7.55 (m, 2H), 7.36 (m, 4H), 7.12 (m, 1H), 7.03 (m, 4H), 3.64 (s , 2H).

4) 화합물 6d : 2-(3'-플로로-[1,1'-바이페닐]-4-일)아세트산 [2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid]4) Compound 6d: 2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid [2-(3'-fluoro-[1,1'-biphenyl]-4-yl) )acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.57 (m, 2H), 7.42 (m, 2H), 7.35 (m, 4H), 3.65 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.57 (m, 2H), 7.42 (m, 2H), 7.35 (m, 4H), 3.65 (s, 2H).

5) 화합물 6e : 2-(4'-플로로-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid]5) Compound 6e: 2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-fluoro-[1,1'-biphenyl]-4-yl) )acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.61 (m, 2H), 7.54 (m, 2H), 7.36 (m, 2H), 7.15 (m, 2H), 3.64 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.61 (m, 2H), 7.54 (m, 2H), 7.36 (m, 2H), 7.15 (m, 2H), 3.64 (s, 2H).

6) 화합물 6f : 2-(4'-(터트-부틸)-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetic acid]6) Compound 6f: 2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-(tert-butyl)-[1,1') -biphenyl]-4-yl)acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.54 (m, 4H), 7.45 (d, J = 8.6 Hz, 2H), 7.33 (m, 2H), 3.63 (s, 2H), 1.34 (s, 9H). 1 H NMR (600 MHz, Methanol-d4) δ 7.54 (m, 4H), 7.45 (d, J = 8.6 Hz, 2H), 7.33 (m, 2H), 3.63 (s, 2H), 1.34 (s, 9H) ).

7) 화합물 6g : 2-(4'-(트리플로로메틸)-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetic acid]7) Compound 6g: 2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-(trifluoromethyl)-[1,1'-) biphenyl]-4-yl)acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.80 (m, 2H), 7.72 (m, 2H), 7.64 (m, 2H), 7.41 (m, 2H), 3.67 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.80 (m, 2H), 7.72 (m, 2H), 7.64 (m, 2H), 7.41 (m, 2H), 3.67 (s, 2H).

8) 화합물 6h : 2-(4'-(메틸)-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-methyl-[1,1'-biphenyl]-4-yl)acetic acid]8) Compound 6h: 2-(4'-(methyl)-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-methyl-[1,1'-biphenyl]-4- yl)acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.54 (m, 2H), 7.48 (m, 2H), 7.33 (m, 2H), 7.23 (m, 2H), 3.63 (s, 2H), 2.36 (s, 3H). 1 H NMR (600 MHz, Methanol-d4) δ 7.54 (m, 2H), 7.48 (m, 2H), 7.33 (m, 2H), 7.23 (m, 2H), 3.63 (s, 2H), 2.36 (s , 3H).

9) 화합물 6i : 2-(4-(벤조[d][1,3]다이옥솔-5-일)페닐)아세트산 [2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetic acid]9) Compound 6i: 2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetic acid [2-(4-(benzo[d][1,3]dioxol-5- yl)phenyl)acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.49 (m, 2H), 7.32 (m, 2H), 7.08 (m, 2H), 6.87 (m, 1H), 5.97 (s, 2H), 3.62 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.49 (m, 2H), 7.32 (m, 2H), 7.08 (m, 2H), 6.87 (m, 1H), 5.97 (s, 2H), 3.62 (s , 2H).

10) 화합물 6j : 2-(4'-클로로-[1,1'-바이페닐]-4-일)아세트산 [2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetic acid]10) Compound 6j: 2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-chloro-[1,1'-biphenyl]-4-yl) acetic acid]

1H NMR (600 MHz, Methanol-d4) δ 7.57 (dd, J = 18.5, 8.4 Hz, 4H), 7.42 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 3.64 (s, 2H). 1 H NMR (600 MHz, Methanol-d4) δ 7.57 (dd, J = 18.5, 8.4 Hz, 4H), 7.42 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 3.64 (s, 2H).

<실시예 2-2> 바이페닐아세트산 유도체 합성<Example 2-2> Synthesis of biphenylacetic acid derivative

[반응식 3][Scheme 3]

Figure 112019086940203-pat00010
Figure 112019086940203-pat00010

상기 반응식 3과 같은 방법으로, 상기 실시예 1에서 합성된 핵심 중간체 화합물 3과 상기 합성된 화합물 6a~6j를 상기 실시예 1-4의 아미드 커플링 반응을 이용하여 화합물 7a~7j를 합성하였고, 상기 실시예 1-5의 가수분해를 이용하여 화합물 8a~8j를 합성하였다.In the same manner as in Scheme 3, the core intermediate compound 3 synthesized in Example 1 and the synthesized compounds 6a to 6j were synthesized using the amide coupling reaction of Example 1-4, and compounds 7a to 7j were synthesized, Compounds 8a to 8j were synthesized using the hydrolysis of Example 1-5.

[화합물 8a~8j][Compound 8a~8j]

Figure 112019086940203-pat00011
Figure 112019086940203-pat00011

1) 화합물 8a : 3-(5-(2-(4'-메톡시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]1) Compound 8a: 3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 8.2 Hz, 2H), 7.36 - 7.31 (m, 2H), 7.28 (s, 1H), 7.18 - 7.13 (m, 1H), 7.10 (dd, J = 2.6, 1.7 Hz, 1H), 6.89 (dd, J = 8.2, 1.0 Hz, 1H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.86 (d, J = 2.6 Hz, 3H), 3.84 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.88 (s, 0.5H), 2.82 (d, J = 7.0 Hz, 2H), 2.72 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.2, 170.2, 167.6, 159.9, 147.4, 142.1, 139.9, 133.7, 129.8, 129.0, 129.0, 127.6, 127.6, 125.3, 119.6, 112.8, 55.3, 43.8, 40.8, 40.4, 33.4, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 8.2 Hz, 2H), 7.36-7.31 (m, 2H), 7.28 (s, 1H), 7.18-7.13 (m, 1H), 7.10 (dd, J = 2.6, 1.7 Hz, 1H), 6.89 (dd, J = 8.2, 1.0 Hz, 1H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 ( s, 0.5H), 3.87 (s, 1.5H), 3.86 (d, J = 2.6 Hz, 3H), 3.84 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 7.1 Hz , 2H), 2.88 (s, 0.5H), 2.82 (d, J = 7.0 Hz, 2H), 2.72 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.2, 170.2, 167.6, 159.9, 147.4, 142.1, 139.9, 133.7, 129.8, 129.0, 129.0, 127.6, 127.6, 125.3, 119.6, 112.8, 55.3, 43.8, 40.8, 40.4 , 33.4, 28.0, 27.2.

2) 화합물 8b : 3-(5-(2-(3'-메톡시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]2) Compound 8b: 3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.53 - 7.49 (m, 3H), 7.49 - 7.44 (m, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.04 - 6.94 (m, 2H), 4.79 (s, 1.5H), 4.60 (s, 0.5H), 3.94 (s, 0.5H), 3.86 (s, 1.5H), 3.84 (d, J = 2.8 Hz, 3H), 3.82 (s, 0.5H), 3.77 (t, J = 5.8 Hz, 1.5H), 3.24 (d, J = 7.2 Hz, 2H), 2.87 (s, 0.5H), 2.81 (t, J = 7.1 Hz, 2H), 2.71 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.2, 170.3, 167.7, 159.2, 147.4, 139.6, 133.1, 132.9, 129.0, 129.0, 128.0, 128.0, 127.3, 127.1, 127.1, 125.2, 114.2, 55.4, 43.8, 40.8, 40.4, 33.5, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.53-7.49 (m, 3H), 7.49-7.44 (m, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.04 -6.94 (m, 2H), 4.79 (s, 1.5H), 4.60 (s, 0.5H), 3.94 (s, 0.5H), 3.86 (s, 1.5H), 3.84 (d, J = 2.8 Hz, 3H ), 3.82 (s, 0.5H), 3.77 (t, J = 5.8 Hz, 1.5H), 3.24 (d, J = 7.2 Hz, 2H), 2.87 (s, 0.5H), 2.81 (t, J = 7.1 Hz, 2H), 2.71 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.2, 170.3, 167.7, 159.2, 147.4, 139.6, 133.1, 132.9, 129.0, 129.0, 128.0, 128.0, 127.3, 127.1, 127.1, 125.2, 114.2, 55.4, 43.8, 40.8 , 40.4, 33.5, 28.0, 27.2.

3) 화합물 8c : 3-(5-(2-(4'-페녹시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]3) Compound 8c: 3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.53 (dd, J = 6.5, 4.5 Hz, 2H), 7.52 - 7.49 (m, 1H), 7.39 - 7.31 (m, 3H), 7.27 (s, 3H), 7.13 (s, 1H), 7.09 - 7.04 (m, 3H), 4.81 (s, 1.5H), 4.62 (s, 0.5H), 3.96 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.79 (s, 1.5H), 3.26 (s, 2H), 2.93 (d, J = 43.9 Hz, 2H), 2.84 (s, 1H), 2.72 (s, 1H); 1 H NMR (600 MHz, Chloroform-d) δ 7.53 (dd, J = 6.5, 4.5 Hz, 2H), 7.52-7.49 (m, 1H), 7.39-7.31 (m, 3H), 7.27 (s, 3H) , 7.13 (s, 1H), 7.09-7.04 (m, 3H), 4.81 (s, 1.5H), 4.62 (s, 0.5H), 3.96 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.79 (s, 1.5H), 3.26 (s, 2H), 2.93 (d, J = 43.9 Hz, 2H), 2.84 (s, 1H), 2.72 (s, 1H);

4) 화합물 8d : 3-(5-(2-(3'-플로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]4) Compound 8d: 3-(5-(2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.56 - 7.49 (m, 2H), 7.41 - 7.37 (m, 1H), 7.36 - 7.33 (m, 2H), 7.32 - 7.25 (m, 2H), 7.05 - 7.00 (m, 1H), 4.80 (t, J = 1.8 Hz, 1.5H), 4.61 (d, J = 1.8 Hz, 0.5H), 3.96 (s, 0.5H), 3.88 (s, 1.5H), 3.84 (s, 0.5H), 3.78 (t, J = 5.8 Hz, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.90 - 2.86 (m, 0.5H), 2.83 (s, 2H), 2.73 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 170.1, 167.7, 164.0, 162.4, 147.3, 138.7, 134.2, 130.3, 130.2, 129.2, 129.2, 127.5, 127.5, 125.2, 122.7, 122.7, 114.1, 43.8, 40.8, 40.5, 33.5, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.56-7.49 (m, 2H), 7.41-7.37 (m, 1H), 7.36-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.05- 7.00 (m, 1H), 4.80 (t, J = 1.8 Hz, 1.5H), 4.61 (d, J = 1.8 Hz, 0.5H), 3.96 (s, 0.5H), 3.88 (s, 1.5H), 3.84 (s, 0.5H), 3.78 (t, J = 5.8 Hz, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.90-2.86 (m, 0.5H), 2.83 (s, 2H), 2.73 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 170.1, 167.7, 164.0, 162.4, 147.3, 138.7, 134.2, 130.3, 130.2, 129.2, 129.2, 127.5, 127.5, 125.2, 122.7, 122.7, 114.1, 43.8, 40.8, 40.5 , 33.5, 28.0, 27.2.

5) 화합물 8e : 3-(5-(2-(4'-플로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]5) Compound 8e: 3-(5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.54 - 7.51 (m, 2H), 7.50 (s, 1.5H), 7.47 (d, J = 7.9 Hz, 0.5H), 7.33 (d, J = 8.1 Hz, 1.5H), 7.28 (s, 0.5H), 7.14 - 7.08 (m, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.62 (s, 0.5H), 3.96 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 6.9 Hz, 2H), 2.90 - 2.87 (m, 0.5H), 2.82 (d, J = 6.9 Hz, 2H), 2.72 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.1, 170.1, 167.6, 163.3, 147.4, 139.1, 136.7, 133.6, 129.2, 129.1, 128.6, 128.6, 128.5, 127.5, 127.4, 115.7, 115.6, 43.8, 40.8, 40.4, 33.5, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.54-7.51 (m, 2H), 7.50 (s, 1.5H), 7.47 (d, J = 7.9 Hz, 0.5H), 7.33 (d, J = 8.1 Hz , 1.5H), 7.28 (s, 0.5H), 7.14-7.08 (m, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.62 (s, 0.5H), 3.96 (s, 0.5H) , 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 6.9 Hz, 2H), 2.90-2.87 (m, 0.5H), 2.82 (d , J = 6.9 Hz, 2H), 2.72 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.1, 170.1, 167.6, 163.3, 147.4, 139.1, 136.7, 133.6, 129.2, 129.1, 128.6, 128.6, 128.5, 127.5, 127.4, 115.7, 115.6, 43.8, 40.8, 40.4 , 33.5, 28.0, 27.2.

6) 화합물 8f : 3-(5-(2-(4'-(터트-부틸)-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]6) Compound 8f: 3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl )-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.56 (d, J = 8.2 Hz, 2H), 7.51 (s, 2H), 7.48 - 7.44 (m, 2H), 7.32 (d, J = 8.1 Hz, 1.5H), 7.27 (s, 0.5H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s,0.51H), 3.78 (s, 1.5H), 3.26 (s, 2H), 2.88 (s, 0.5H), 2.82 (d, J = 7.0 Hz, 2H), 2.72 (s, 1.5H), 1.36 (s, 9H); 13C NMR (151 MHz, CDCl3) δ 175.4, 170.3, 167.7, 150.4, 147.4, 139.9, 137.7, 133.2, 129.0, 129.0, 129.0, 127.4, 127.4, 126.7, 126.6, 125.8, 125.2, 43.8, 40.8, 40.5, 34.6, 33.5, 31.4, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.56 (d, J = 8.2 Hz, 2H), 7.51 (s, 2H), 7.48-7.44 (m, 2H), 7.32 (d, J = 8.1 Hz, 1.5 H), 7.27 (s, 0.5H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.83 ( s,0.51H), 3.78 (s, 1.5H), 3.26 (s, 2H), 2.88 (s, 0.5H), 2.82 (d, J = 7.0 Hz, 2H), 2.72 (s, 1.5H), 1.36 (s, 9H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.4, 170.3, 167.7, 150.4, 147.4, 139.9, 137.7, 133.2, 129.0, 129.0, 129.0, 127.4, 127.4, 126.7, 126.6, 125.8, 125.2, 43.8, 40.8, 40.5 , 34.6, 33.5, 31.4, 28.0, 27.2.

7) 화합물 8g : 3-(5-(2-(4'-(트리플로로메틸)-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]7) Compound 8g: 3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl) -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.70 - 7.64 (m, 4H), 7.55 (dd, J = 21.9, 8.1 Hz, 2H), 7.35 (dd, J = 33.4, 8.0 Hz, 2H), 4.81 (d, J = 1.8 Hz, 1.5H), 4.63 (s, 0.5H), 3.96 (s, 0.5H), 3.89 (s, 1.5H), 3.85 (s, 0.5H), 3.79 (t, J = 5.8 Hz, 1.5H), 3.26 (t, J = 7.1 Hz, 2H), 2.88 (s, 0.5H), 2.83 (t, J = 7.0 Hz, 2H), 2.75 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.3, 170.0, 167.6, 147.3, 144.1, 138.5, 134.6, 129.4, 129.3, 127.7, 127.6, 127.3, 127.3, 125.8, 125.7, 125.7, 125.2, 125.2, 43.8, 40.7, 40.5, 33.5, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.70-7.64 (m, 4H), 7.55 (dd, J = 21.9, 8.1 Hz, 2H), 7.35 (dd, J = 33.4, 8.0 Hz, 2H), 4.81 (d, J = 1.8 Hz, 1.5H), 4.63 (s, 0.5H), 3.96 (s, 0.5H), 3.89 (s, 1.5H), 3.85 (s, 0.5H), 3.79 (t, J = 5.8 Hz, 1.5H), 3.26 (t, J = 7.1 Hz, 2H), 2.88 (s, 0.5H), 2.83 (t, J = 7.0 Hz, 2H), 2.75 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.3, 170.0, 167.6, 147.3, 144.1, 138.5, 134.6, 129.4, 129.3, 127.7, 127.6, 127.3, 127.3, 125.8, 125.7, 125.7, 125.2, 125.2, 43.8, 40.7 , 40.5, 33.5, 28.0, 27.2.

8) 화합물 8h : 3-(5-(2-(4'-메틸-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-methyl-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]8) Compound 8h: 3-(5-(2-(4'-methyl-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5 ,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-methyl-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.54 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 1.5H), 7.26 (s, 0.5H), 7.23 (d, J = 8.0 Hz, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.60 (s, 0.5H), 3.95 (s, 0.5H), 3.86 (s, 1.5H), 3.83 (s, 0.5H), 3.77 (t, J = 5.7 Hz, 1.5H), 3.24 (dt, J = 15.3, 7.1 Hz, 2H), 2.87 (s, 0.5H), 2.84 - 2.78 (m, 2H), 2.74 - 2.69 (m, 1.5H), 2.39 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 175.2, 170.2, 170.1, 167.6, 147.4, 139.9, 137.7, 137.1, 133.2, 129.5, 129.0, 129.0, 127.4, 127.3, 126.9, 126.8, 125.2, 43.8, 40.8, 40.4, 33.5, 28.0, 27.2, 21.1. 1 H NMR (600 MHz, Chloroform-d) δ 7.54 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 1.5H), 7.26 (s, 0.5H), 7.23 (d, J = 8.0 Hz, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.60 (s, 0.5H), 3.95 (s, 0.5H), 3.86 ( s, 1.5H), 3.83 (s, 0.5H), 3.77 (t, J = 5.7 Hz, 1.5H), 3.24 (dt, J = 15.3, 7.1 Hz, 2H), 2.87 (s, 0.5H), 2.84 -2.78 (m, 2H), 2.74-2.69 (m, 1.5H), 2.39 (s, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.2, 170.2, 170.1, 167.6, 147.4, 139.9, 137.7, 137.1, 133.2, 129.5, 129.0, 129.0, 127.4, 127.3, 126.9, 126.8, 125.2, 43.8, 40.8, 40.4 , 33.5, 28.0, 27.2, 21.1.

9) 화합물 8i : 3-(5-(2-(4-(벤조[d][1,3]다이옥솔-5-일)페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]9) Compound 8i: 3-(5-(2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4, 5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.42 (m, 2H), 7.32 - 7.24 (m, 2H), 7.05 - 7.00 (m, 2H), 6.88 - 6.85 (m, 1H), 5.99 (s, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.60 (s, 0.5H), 3.95 (s, 0.5H), 3.86 (s, 1.5H), 3.82 (s, 0.5H), 3.77 (t, J = 5.8 Hz, 1.5H), 3.25 (d, J = 6.9 Hz, 2H), 2.87 (s, 0.5H), 2.82 (t, J = 7.3 Hz, 2H), 2.72 (td, J = 5.6, 2.7 Hz, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.2, 170.2, 167.6, 148.1, 147.4, 147.1, 139.7, 135.0, 133.2, 129.0, 129.0, 127.3, 127.2, 125.2, 120.5, 108.6, 107.5, 101.2, 43.8, 40.8, 40.4, 33.5, 28.0, 27.2. 1 H NMR (600 MHz, Chloroform-d) δ 7.49-7.42 (m, 2H), 7.32-7.24 (m, 2H), 7.05-7.00 (m, 2H), 6.88-6.85 (m, 1H), 5.99 ( s, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.60 (s, 0.5H), 3.95 (s, 0.5H), 3.86 (s, 1.5H), 3.82 (s, 0.5H), 3.77 (t, J = 5.8 Hz, 1.5H), 3.25 (d, J = 6.9 Hz, 2H), 2.87 (s, 0.5H), 2.82 (t, J = 7.3 Hz, 2H), 2.72 (td, J = 5.6, 2.7 Hz, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.2, 170.2, 167.6, 148.1, 147.4, 147.1, 139.7, 135.0, 133.2, 129.0, 129.0, 127.3, 127.2, 125.2, 120.5, 108.6, 107.5, 101.2, 43.8, 40.8 , 40.4, 33.5, 28.0, 27.2.

10) 화합물 8j : 3-(5-(2-(4'-클로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산 [3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]10) Compound 8j: 3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5 ,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

1H NMR (600 MHz, Chloroform-d) δ 7.53 ? 7.49 (m, 2H), 7.48 (d, J = 9.5 Hz, 2H), 7.41 - 7.37 (m, 2H), 7.34 (d, J = 8.1 Hz, 1.5H), 7.28 (d, J = 8.1 Hz, 0.5H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.87 (s, 0.5H), 2.81 (d, J = 7.3 Hz, 2H), 2.73 (s, 1.5H); 13C NMR (151 MHz, CDCl3) δ 175.4, 170.1, 167.7, 147.3, 139.0, 138.8, 134.0, 133.5, 129.2, 129.2, 129.0, 128.3, 128.2, 127.4, 127.4, 125.2, 43.8, 40.7, 40.5, 1 H NMR (600 MHz, Chloroform-d) δ 7.53? 7.49 (m, 2H), 7.48 (d, J = 9.5 Hz, 2H), 7.41-7.37 (m, 2H), 7.34 (d, J = 8.1 Hz, 1.5H), 7.28 (d, J = 8.1 Hz, 0.5H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.87 (s, 0.5H), 2.81 (d, J = 7.3 Hz, 2H), 2.73 (s, 1.5H); 13 C NMR (151 MHz, CDCl 3 ) δ 175.4, 170.1, 167.7, 147.3, 139.0, 138.8, 134.0, 133.5, 129.2, 129.2, 129.0, 128.3, 128.2, 127.4, 127.4, 125.2, 43.8, 40.7, 40.5,

<실험예 1> 칼슘 분석(Calcium assay)<Experimental Example 1> Calcium assay

LPA1 과발현 세포주(RH7777-human EDG1 cell)를 96웰 블랙 플레이트(96well black plate, clear bottom)에 1×105/well로 시딩(seeding)하고 하루 동안 배양하였다. 그 후, 0.1% 지방산 없는 BSA(fatty acid-free BSA)가 들어있는 무혈청(serum-free) 배양액으로 교체하여 하루 추가 배양하였다. The LPA1 overexpressing cell line (RH7777-human EDG1 cell) was seeded at 1×10 5 /well in a 96 well black plate (clear bottom) and cultured for one day. Then, it was replaced with a serum-free culture solution containing 0.1% fatty acid-free BSA (fatty acid-free BSA) and cultured for an additional day.

다음, 약물(화합물 5a~5i, 6a~6j 또는 AM152(LPA1 길항제), 1μM)로 30분간 전처치한 뒤, 칼슘(calcium) 측정용 형광 염료(dye)인 Fluo-3AM(5μM)을 처치하여 60분 동안 배양하였고, 10μM LPA를 세포에 처치한 뒤 1분 후에 형광 세기를 측정(absorption: 506 nm) 하였다. (Fluorescence intensity: 3층 victor 사용) Next, pretreatment with drugs (compounds 5a-5i, 6a-6j or AM152 (LPA1 antagonist), 1 μM) for 30 minutes, followed by treatment with Fluo-3AM (5 μM), a fluorescent dye for calcium measurement. After incubation for 60 minutes, the cells were treated with 10 μM LPA, and fluorescence intensity was measured (absorption: 506 nm) 1 minute later. (Fluorescence intensity: 3rd floor victor used)

도 1은 본 발명의 일 실험예에 따른 칼슘 분석 결과를 나타낸 그래프이다. 상기 그래프의 ‘Ca2+ response’는 비히클(vehicle) 대비 증가 정도(fold increase)를 나타낸다.1 is a graph showing a calcium analysis result according to an experimental example of the present invention. The'Ca 2+ response' in the graph represents a fold increase compared to a vehicle.

도 1을 참조하면, 화합물 6c는 AM152(1μM)와 거의 유사한 효능을 나타내었고, 그 외 다른 화합물들은 AM152(1μM) 효능 대비 약 50%의 효능을 나타내는 것으로 확인되었다.Referring to FIG. 1, it was confirmed that compound 6c exhibited almost similar efficacy to AM152 (1 μM), and other compounds showed about 50% efficacy compared to AM152 (1 μM) efficacy.

<실험예 2> 독성 평가<Experimental Example 2> Toxicity evaluation

웅성 Balb/c 마우스에 화합물 5a, 화합물 5g, 및 화합물 5h를 0.5% 메틸셀룰로즈 용액에 각각 현탁하여 0.5g/kg, 1g/kg 및 2g/kg의 용량으로 1회 단회 경구투여하고 7일간 마우스의 생존율 및 체중을 조사하였다.To male Balb/c mice, compound 5a, compound 5g, and compound 5h were each suspended in 0.5% methylcellulose solution and orally administered once at a dose of 0.5g/kg, 1g/kg and 2g/kg. Survival rate and body weight were investigated.

이러한 투여 후 동물의 폐사여부, 임상증상, 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적 검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강장기의 이상여부를 관찰하였다.After these administrations, mortality, clinical symptoms, and weight change were observed, hematologic and hematologic tests were performed, and abnormalities of the abdominal and thoracic organs were observed visually by autopsy.

그 결과, 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학검사, 부검소견 등에서도 독성변화는 관찰되지 않았다.As a result, there were no significant clinical symptoms or deceased animals in all animals, and no toxic changes were observed in weight change, blood test, blood biochemical test, and autopsy findings.

이상의 결과, 본 발명의 화합물들은 마우스에서 2g/㎏까지 독성변화를 나타내지 않으며, 따라서, 경구 투여 중간 치사량(LD50)은 2g/kg 이상인 안전한 물질로 판단되었다.As a result of the above, the compounds of the present invention did not show a toxic change up to 2g/kg in mice, and therefore, the intermediate lethal dose (LD50) of oral administration was determined to be a safe substance with 2g/kg or more.

하기에 본 발명에 따른 화합물 5h를 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, an example of the preparation of the composition containing the compound 5h according to the present invention will be described, but the present invention is not intended to limit it, but is intended to be described in detail.

<처방예 1> 약학조성물의 처방예<Prescription Example 1> Formulation example of pharmaceutical composition

<처방예 1-1> 산제의 제조<Prescription Example 1-1> Preparation of powder

화합물 5h 20 mg, 유당 100 mg 및 탈크 10 mg을 혼합하고 기밀포에 충진하여 산제를 제조하였다.Compound 5h 20 mg, lactose 100 mg, and talc 10 mg were mixed and filled in an airtight bag to prepare a powder.

<처방예 1-2> 정제의 제조<Prescription Example 1-2> Preparation of tablets

화합물 5h 20 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing 20 mg of compound 5h, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, tablets were prepared by tableting according to a conventional tablet preparation method.

<처방예 1-3> 캅셀제의 제조<Prescription Example 1-3> Preparation of capsules

화합물 5h 10 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2mg을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing 10 mg of compound 5h, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method, and then filled into a gelatin capsule to prepare a capsule.

<처방예 1-4> 주사제의 제조<Prescription Example 1-4> Preparation of injection

화합물 5h 10 mg, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1앰플당(2㎖) 상기의 성분 함량으로 제조하였다.After mixing 10 mg of compound 5h, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster, it was prepared with the above component content per ampoule (2 ml) according to a conventional preparation method for injection.

<처방예 1-5> 연고제의 제조<Prescription Example 1-5> Preparation of ointment

화합물 5h 10mg, PEG-4000 250mg, PEG-400 650mg, 백색바셀린 10mg, 파라옥시안식향산메칠 1.44mg, 파라옥시안식향산프로필 0.18mg 및 잔량의 정제수를 혼합한 후 통상의 연고제의 제조방법에 따라서 연고제를 제조하였다.Compound 5h 10mg, PEG-4000 250mg, PEG-400 650mg, white petrolatum 10mg, paraoxybenzoate methyl 1.44mg, paraoxybenzoate 0.18mg and the remaining amount of purified water are mixed to prepare an ointment according to a conventional ointment preparation method. I did.

<처방예 2> 건강기능식품<Prescription Example 2> Health functional food

<처방예 2-1> 건강식품의 제조<Prescription Example 2-1> Preparation of health food

화합물 5h 1 ㎎, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B 1 0.13 ㎎, 비타민 B 2 0.15 ㎎, 비타민 B 6 0.5 ㎎, 비타민 B 12 0.2 ㎍, 비타민 C 10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎) 및 무기질 혼합물 적량(황산제1철 1.75 ㎎, 산화아연 0.82 ㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90 ㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강식품을 제조하였다.Compound 5h 1 mg, vitamin mixture appropriate amount (vitamin A acetate 70 μg, vitamin E 1.0 mg, vitamin B 1 0.13 mg, vitamin B 2 0.15 mg, vitamin B 6 0.5 mg, vitamin B 12 0.2 μg, vitamin C 10 mg, biotin 10 μg, nicotinic acid amide 1.7 mg, folic acid 50 μg, calcium pantothenate 0.5 mg) and an appropriate amount of inorganic mixture (ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium monophosphate 15 mg, dibasic calcium phosphate) 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, magnesium chloride 24.8 mg) were mixed, and then granules were prepared and health food was prepared according to a conventional method.

<처방예 2-2> 건강음료의 제조<Prescription Example 2-2> Preparation of health drink

화합물 5h 1 ㎎, 구연산 1000 ㎎, 올리고당 100 g, 매실농축액 2 g, 타우린 1 g 및 정제수를 가하여 전체 900 ㎖가 되도록 하며, 통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관하였다.Add 1 mg of compound 5h, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine and purified water to make a total of 900 ml. After mixing the above ingredients according to the general health drink manufacturing method, about 1 After stirring and heating at 85° C. for an hour, the resulting solution was filtered and obtained in a sterilized 2 L container, sealed and sterilized, and then stored in a refrigerator.

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다.As described above, a specific part of the present invention has been described in detail, and for those of ordinary skill in the art, it is obvious that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. Do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
Figure 112019086940203-pat00012

상기 식에서, R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로겐, 니트로, 또는 하기 화학식 2의 치환기에서 선택되고,
[화학식 2]
Figure 112019086940203-pat00013

이 때, R3 및 R4는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 트리플로로메틸, 페녹시, 할로겐 또는 니트로에서 선택되거나, R3와 R4가 연결되어 5환의 헤테로고리를 형성함.A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure 112019086940203-pat00012

In the above formula, R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro, or a substituent of the following formula (2),
[Formula 2]
Figure 112019086940203-pat00013

At this time, R 3 and R 4 may be the same or different, respectively, and selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen or nitro, or R 3 and R 4 is connected to form a 5-ring heterocycle. 청구항 1에 있어서,
상기 화합물은 R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C2)알콕시, 할로겐, 또는 니트로에서 선택되는 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용가능한 염. The method according to claim 1,
In the compound, R 1 and R 2 may be the same or different, respectively, and hydrogen, (C1 ~ C2) alkoxy, halogen, or nitro, a compound or a pharmaceutically acceptable salt thereof. 청구항 2에 있어서,
상기 화합물은 3-(5-(2-페닐아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(2-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3,4-디클로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3-플로로페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-브로모페닐)아세틸-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-메톡시페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3-메톡시페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산으로 이루어진 군에서 선택된 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용가능한 염.The method according to claim 2,
The compound is 3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2 -(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-chloro) Phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-chlorophenyl)acetyl)- 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5 ,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-bromophenyl)acetyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of -2-yl) propanoic acid. 청구항 1에 있어서,
상기 화합물은 하기 화학식 3으로 표시되는 화합물인 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용가능한 염:
[화학식 3]
Figure 112019086940203-pat00014

상기 식에서, R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 트리플로로메틸, 페녹시, 할로겐 또는 니트로에서 선택되거나, R1과 R2가 연결되어 5환의 헤테로고리를 형성함.The method according to claim 1,
The compound is characterized in that the compound represented by the following formula (3), a compound or a pharmaceutically acceptable salt thereof:
[Formula 3]
Figure 112019086940203-pat00014

In the above formula, R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen or nitro, or R 1 and R 2 is connected to form a 5-ring heterocycle. 청구항 4에 있어서,
상기 화합물은 R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C2)알콕시, 트리플로로메틸, 페녹시, 플로로, 또는 클로로에서 선택되거나, R1과 R2가 연결되어 1,3-다이옥솔 고리를 형성하는 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용가능한 염.The method of claim 4,
In the compound, R 1 and R 2 may be the same or different, respectively, and selected from hydrogen, (C1∼C4)alkyl, (C1∼C2)alkoxy, trifluoromethyl, phenoxy, fluoro, or chloro, or R A compound or a pharmaceutically acceptable salt thereof, characterized in that 1 and R 2 are linked to form a 1,3-dioxole ring. 청구항 4에 있어서,
상기 화합물은 3-(5-(2-(4'-메톡시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3'-메톡시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-페녹시-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(3'-플로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-플로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-(터트-부틸)-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-(트리플로로메틸)-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-메틸-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4-(벤조[d][1,3]다이옥솔-5-일)페닐)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산, 3-(5-(2-(4'-클로로-[1,1'-바이페닐]-4-일)아세틸)-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)프로판산으로 이루어진 군에서 선택된 것을 특징으로 하는, 화합물 또는 이의 약학적으로 허용가능한 염.The method of claim 4,
The compound is 3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5, 4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4- Yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-fluoro-[1) ,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2) -(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl) Propanoic acid, 3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl )-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-methyl-[1,1'-) Biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4- (Benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c] A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of pyridin-2-yl) propanoic acid. 청구항 1 내지 청구항 6 중 어느 한 항의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하며, LPA1(Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 갖는 것을 특징으로 하는, LPA1 관련 질환 예방 또는 치료용 약학조성물로서,
상기 LPA1 관련 질환은 뇌졸중, 건선, 쇼그렌증후군, 염증성 장질환, 당뇨병성 신증 및 섬유증으로 이루어진 군에서 선택된 것을 특징으로 하는, LPA1 관련 질환 예방 또는 치료용 약학조성물.A pharmaceutical for preventing or treating LPA1-related diseases, characterized in that it contains the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation. As a composition,
The LPA1-related diseases are stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy and fibrosis, characterized in that selected from the group consisting of, LPA1-related disease prevention or treatment pharmaceutical composition. 삭제delete 청구항 1 내지 청구항 6 중 어느 한 항의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하며, LPA1(Lysophosphatidic acid 1) 수용체 활성화 저해 효과를 갖는 것을 특징으로 하는, LPA1 관련 질환 개선 또는 예방용 건강기능식품 조성물로서,
상기 LPA1 관련 질환은 뇌졸중, 건선, 쇼그렌증후군, 염증성 장질환, 당뇨병성 신증 및 섬유증으로 이루어진 군에서 선택된 것을 특징으로 하는, LPA1 관련 질환 개선 또는 예방용 건강기능식품 조성물.It contains the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation, LPA1-related disease improvement or prevention health As a nutraceutical composition,
The LPA1-related diseases are stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy and fibrosis, characterized in that selected from the group consisting of, LPA1-related disease improvement or prevention health functional food composition. 삭제delete
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JP2013544890A (en) 2010-12-07 2013-12-19 アミラ ファーマシューティカルス，インコーポレーテッド Polycyclic LPA1 antagonists and uses thereof

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