KR101272320B1 - Naphtho[1,2-b]furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for prevention or treatment of MCH receptor-1 related diseases containing the same as an active ingredient - Google Patents

Naphtho[1,2-b]furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for prevention or treatment of MCH receptor-1 related diseases containing the same as an active ingredient Download PDF

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KR101272320B1
KR101272320B1 KR1020110106961A KR20110106961A KR101272320B1 KR 101272320 B1 KR101272320 B1 KR 101272320B1 KR 1020110106961 A KR1020110106961 A KR 1020110106961A KR 20110106961 A KR20110106961 A KR 20110106961A KR 101272320 B1 KR101272320 B1 KR 101272320B1
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furan
naphtho
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piperidin
acetamidophenyl
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이규양
임채조
김낙정
김지영
이가은
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Abstract

본 발명은 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 ＭＣＨ 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명에 의한 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 MCH(멜라닌 농축 호르몬) 수용체에 대한 길항제로 작용함으로써 MCH가 MCH 수용체에 결합함으로써 유발되는 비만, 당뇨병, 대사장애, 불안증 및 우울증과 같은 MCH 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.The present invention is for the prevention or treatment of naphtho [1,2-b] furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, methods for preparing the same, and MHC receptor-1 related diseases containing the same as an active ingredient. It relates to a pharmaceutical composition. Naphtho [1,2-b] furan-2-carboxamide derivatives according to the present invention act as an antagonist to MCH (melanin enrichment hormone) receptors, resulting in obesity, diabetes and metabolic disorders caused by MCH binding to MCH receptors. It can be usefully used to prevent or treat MCH related diseases such as anxiety and depression.

Description

나프토［1,2-ｂ］퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 ＭＣＨ 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물{Naphtho[1,2-b]furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for prevention or treatment of MCH receptor-1 related diseases containing the same as an active ingredient}Naphtho [1,2-X] furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions for the prevention or treatment of MHC receptor-1 related diseases containing the same as active ingredients {Naphtho [1,2-b] furan-2-carboxamide derivatives or pharmaceutically acceptable salts particular, preparation method therof and pharmaceutical composition for prevention or treatment of MCH receptor-1 related diseases containing the same as an active ingredient}

본 발명은 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 ＭＣＨ 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention is for the prevention or treatment of naphtho [1,2-b] furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, methods for preparing the same, and MHC receptor-1 related diseases containing the same as an active ingredient. It relates to a pharmaceutical composition.

최근 현대화에 따른 유전적, 환경적, 정신적 요인 등에 의해 인체 내 에너지밸런스 변화와 더불어 생활습관 변화와 산업화 등으로 인해 비만인구가 급속하게 증가하는 추세이다. 이러한 비만과 과체중은 심장질환, 뇌졸중, 타입-2형 당뇨병, 호흡기 질환, 특정 암 같은 합병증의 위험이 크므로 인해 심각한 사회적 문제로 대두 되고 있다. Due to genetic, environmental, and psychological factors such as recent energy changes in the human body, changes in lifestyle and industrialization, the obesity population is rapidly increasing. These obesity and overweight are becoming serious social problems due to the high risk of complications such as heart disease, stroke, type 2 diabetes, respiratory disease, and certain cancers.

비만과 관련해서 췌장 및 소화기계에서 분비되는 리파아제를 억제하는 제니컬(Xenical™)과 세로토닌 재흡수를 억제하는 리덕틸(Reductil™) 등의 비만 치료제가 현재 시판되고 있으나 항 비만 효과가 낮고 부작용이 높은 단점으로 사용이 제한되는 문제점이 있다(Trisha Gura, Science 2003, 299, 849-852).In relation to obesity, Xenical ™, which inhibits lipase secretion from the pancreas and digestive system, and Reductil ™, which inhibits serotonin reuptake, are currently on the market, but they are now on the market with low anti-obesity effects and high side effects (Trisha Gura, Science 2003, 299, 849-852).

Figure 112011081771538-pat00001
Figure 112011081771538-pat00002
Figure 112011081771538-pat00001
Figure 112011081771538-pat00002

비만은 복잡한 여러 신경계와 에너지 대사작용을 통해 발병이 되며, 다양한 호르몬 및 펩티드들이 이를 조절하는데 관여되고 있다. 최근 비만 치료제의 개발은 이러한 체중조절에 관련된 새로운 펩티드를 규명하고 이들 작용기전을 이용하여 새로운 비만치료제를 개발하는데 초점을 두고 있다. 식욕조절에 관련된 주요 신경펩타이드 타겟들 중, MCH 수용체-1 길항제(melanin concentrating hormone receptor-1 antagonist)가 식욕 및 에너지 조절 기능에 중요한 역할을 한다고 알려지면서, 비만 치료의 유망한 타겟으로 연구가 진행중에 있다. Obesity is caused by complex nervous systems and energy metabolism, and various hormones and peptides are involved in controlling it. Recent development of obesity drugs has focused on identifying new peptides related to weight control and developing new obesity drugs using these mechanisms. Among the major neuropeptide targets involved in appetite regulation, studies have been conducted on a promising target for obesity therapy, as the melanin concentrating hormone receptor-1 antagonist is known to play an important role in appetite and energy regulation functions .

MCH(melanin concentrating hormone)는 19개의 아미노산으로 구성된 환상 펩티드이며 모든 포유 동물에 동일하다. 주로 뇌의 외측 시상하부와 불확핵(zona incerta)에서 주로 발현되며, MCH 뉴런은 뇌의 다른 지역에도 널리 분포되어 있는데 주로 음식섭취와 에너지 밸런스를 조절한다고 알려져 있다. MCH는 고아(orphan) G-단백질 연결 수용체의 SLC-1(somatostatin-like receptor, GPR 24)로 알려져있는 수용체에 결합하고 활성화 시킨다고 알려져 있다. 이 MCH는 두 가지 종류로 알려져 있다. 하나는 7TM GPCR(seven transmembrane G-protein-coupled receptor)의 하나인 MCH R-1으로서, 설치류와 사람에 동시에 존재한다. 다른 하나는 MCH-R2로서 사람에게만 존재한다. 이는 설치류에는 발견되지 않아 음석섭취와 에너지 밸런스에 관한 MCH-R2의 역할은 연구하는 동물 모델이 없어 연구에 어려움이 있다. Melanin concentrating hormone (MCH) is a cyclic peptide consisting of 19 amino acids and is identical in all mammals. It is mainly expressed in the lateral hypothalamus and zona incerta of the brain. MCH neurons are widely distributed in other parts of the brain and are known to regulate food intake and energy balance. MCH is known to bind and activate receptors known as SLC-1 (somatostatin-like receptor, GPR 24), an orphan G-protein coupled receptor. This MCH is known as two types. One is MCH R-1, one of the seven transmembrane G-protein-coupled receptors (GPCRs), present in both rodents and humans. The other one exists only in humans as MCH-R2. This is not found in rodents, and there is no animal model to study the role of MCH-R2 in fish intake and energy balance, making research difficult.

동물모델을 대상으로 MCH의 기능을 연구한 결과, 금식 시킨 쥐에서 MCH mRNA가 표준형 쥐 및 렙틴 결핍인 ob/ob 쥐 보다는 3배 더 증가했다. 그리고 MCH를 쥐(rat)의 뇌심실을 통해(icv) 직접 주입하면 과식증 및 중간 정도의 비만을 야기 한다(D. Qu., et al., Nature, 380(6571), 243-7, 1996] 참조). MCH 유전자를 과발현하는 형질전환(transgenic) 쥐는 비만 및 과식증 유발과 인슐린 내성이며 유발된 비만을 다이어트 시키기 쉽다. MCH-R1유전자를 생성하지 않는 형질전환된 쥐는 안정시 대사율이 비교적 증가하기 때문에 말랐고 저탐식증을 나타낸다. MCH-R1 유전자가 녹아웃(knockout)된 쥐는 고지방 식이-유발된 비만에 내성이 있으며, 야생의 상응하는 마우스보다 가볍다([A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006] 참조).Studies of the function of MCH in animal models have shown that MCH mRNA was increased three-fold in fasted rats compared to ob / ob mice, which are standard and leptin deficient. Direct injection of MCH through the brain ventricle of the rat (icv) results in hyperphagia and moderate obesity (D. Qu., Et al., Nature, 380 (6571), 243-7, 1996) Reference). Transgenic mice overexpressing the MCH gene are prone to obesity and hyperglycemia and insulin resistance and are likely to diabetise induced obesity. Transgenic mice that do not produce the MCH-R1 gene are prone to dryness and hypoglamia because of a relatively increased metabolic rate at rest. Mice that are knocked out of the MCH-R1 gene are resistant to high fat diet-induced obesity and are lighter than the wild equivalent mouse (AL Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006).

한편, MCH 효과를 매개하는 GPCR(G-protein coupled receptor) 중의 하나인 MCH 수용체-1 길항제가 음식물 섭취를 조절할 뿐만 아니라 우울증 또는 불안증을 치료하는데 유용할 것이라는 연구결과([B. Borowsky et al., Nature Medicine, 8(8), 825-30, 2002] 참조), 및 MCH 수용체-1 길항제를 처리한 동물이 상당량의 체중감소를 나타내며 식욕감퇴 효과 이외에도 불안제거 효과와 항우울 효과를 제공한다는 연구 결과도 보고되었다(문헌 [B. Borowsky et al., Nature Medicine, 8(8), 825-30, 2002] 참조). 또한, MCH 수용체-1 길항제는 비만, 우울증, 불안증 치료 이외에도 당뇨병, 대사장애에도 효과가 있음이 밝혀졌다(문헌 [D. S. Ludwig et al., J. Clin. Invest. 107, 379-386, 2001] 참조).On the other hand, studies that MCH receptor-1 antagonists, one of the G-protein coupled receptors (GPCRs) mediating the MCH effect, would be useful for treating depression or anxiety as well as controlling food intake (B. Borowsky et al. Nature Medicine, 8 (8), 825-30, 2002), and studies in which animals treated with MCH receptor-1 antagonists show significant weight loss and provide anxiolytic and antidepressant effects in addition to anorexia (See B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002). MCH receptor-1 antagonists have also been shown to be effective in diabetic and metabolic disorders in addition to treating obesity, depression and anxiety (see DS Ludwig et al., J. Clin. Invest. 107, 379-386, 2001). ).

MCH 수용체-1 길항제와 관련해서, 다국적 제약회사가 경구 투여, CNS 침투, 그리고 in vivo 체중감소 효과를 보여주는 다양한 골격을 가진 치료후보 물질 개발을 하고 있는 중에 있으나, 여러 가지 PK 프로파일 문제, hERG 결합 문제들로 인해 본격적인 임상연구는 이루어 지지 않고 있는 실정이다. Regarding MCH receptor-1 antagonists, multinational pharmaceutical companies are developing therapeutic candidates with diverse skeletons that demonstrate oral administration, CNS penetration, and in vivo weight loss effects, but there are several PK profile problems, hERG binding problems The clinical studies have not been conducted in earnest.

이에, 본 발명자들은 MCH 수용체에 길항 효과를 나타내는 화합물을 개발하기 위해 노력하던 중, 특정 구조의 나프토[1,2-b]퓨란-2-카르복사미드 유도체가 MCH 수용체의 길항제로 작용함으로써, 비만과 같은 MCH 관련 질환의 예방 및 치료제로 사용될 수 있다는 것을 밝히고 본 발명을 완성하였다.
Therefore, the present inventors are trying to develop a compound that exhibits an antagonistic effect on the MCH receptor, and the naphtho [1,2-b] furan-2-carboxamide derivative having a specific structure acts as an antagonist of the MCH receptor, The present invention has been accomplished by revealing that it can be used as a prophylactic and therapeutic agent for MCH related diseases such as obesity.

1. Trisha Gura, Science 2003, 299, 849-8521. Trisha Gura, Science 2003, 299, 849-852 2. D. Qu., et al., Nature, 380(6571), 243-7, 19962. D. Qu., Et al., Nature, 380 (6571), 243-7, 1996 3. A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 20063. A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006 4. B. Borowsky et al., Nature Medicine, 8(8), 825-30, 20024. B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002 5. D. S. Ludwig et al., J. Clin. Invest. 107, 379-386, 20015. D. S. Ludwig et al., J. Clin. Invest. 107, 379-386, 2001

본 발명의 목적은 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.It is an object of the present invention to provide naphtho [1,2-b] furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof.

본 발명의 다른 목적은 상기 나프토[1,2-b]퓨란-2-카르복사미드 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the naphtho [1,2-b] furan-2-carboxamide derivative.

본 발명의 또 다른 목적은 상기 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 길항제를 제공하는 것이다.Still another object of the present invention is to provide an MCH receptor-1 antagonist containing the naphtho [1,2-b] furan-2-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 다른 목적은 상기 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of MCH-related diseases containing the naphtho [1,2-b] furan-2-carboxamide derivative or a salt thereof as an active ingredient.

본 발명의 또 다른 목적은 상기 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 예방용 건강식품 조성물을 제공하는 것이다.
Still another object of the present invention is to provide a health food composition for preventing or preventing MCH-related diseases containing the naphtho [1,2-b] furan-2-carboxamide derivative or a salt thereof as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다:In order to achieve the above object, the present invention provides a naphtho [1,2-b] furan-2-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure 112011081771538-pat00003
Figure 112011081771538-pat00003

(상기 화학식 1의 n 및 R1은 본 명세서에서 정의한 바와 같다).(N and R 1 of Formula 1 are as defined herein).

또한, 본 발명은 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체의 제조방법을 제공한다.The present invention also provides a method for producing a naphtho [1,2-b] furan-2-carboxamide derivative represented by Chemical Formula 1.

나아가, 본 발명은 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 길항제를 제공한다.Furthermore, the present invention provides an MCH receptor-1 antagonist containing a naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. .

또한, 본 발명은 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention is for the prevention or treatment of MCH-related diseases containing naphtho [1,2-b] furan-2-carboxamide derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient It provides a pharmaceutical composition.

나아가, 본 발명은 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 예방용 건강식품 조성물을 제공한다.
Furthermore, the present invention is for preventing or preventing MCH-related diseases containing naphtho [1,2-b] furan-2-carboxamide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Provide a health food composition.

본 발명에 의한 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 MCH(멜라닌 농축 호르몬) 수용체에 대한 길항제로 작용함으로써 MCH가 MCH 수용체에 결합함으로써 유발되는 비만, 당뇨병, 대사장애, 불안증 및 우울증과 같은 MCH 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.
Naphtho [1,2-b] furan-2-carboxamide derivatives according to the present invention act as an antagonist to MCH (melanin enrichment hormone) receptors, resulting in obesity, diabetes and metabolic disorders caused by MCH binding to MCH receptors. It can be usefully used to prevent or treat MCH related diseases such as anxiety and depression.

본 발명은 하기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 below or a pharmaceutically acceptable salt thereof.

Figure 112011081771538-pat00004
Figure 112011081771538-pat00004

상기 화학식 1에서,In Formula 1,

n은 2 내지 10의 정수이고; 및n is an integer from 2 to 10; And

R1은 수소; 할로겐; C1-C4 직쇄 또는 측쇄 알킬; 비치환 또는 할로겐, 시아노, 니트로, 할로겐으로 치환된 C1-C4 직쇄 또는 측쇄 알킬, C1-C4 직쇄 또는 측쇄 알킬 및 C1-C4 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 C5-C6 아릴; 또는 비치환되거나, 할로겐, 시아노, 니트로, C1-C4 직쇄 또는 측쇄 알킬, C1-C4 직쇄 또는 측쇄 알킬 및 C1-C4 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 C5-C12 단일 또는 이중고리의 헤테로아릴이고, 이때, 상기 헤테로아릴은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함한다.
R 1 is hydrogen; halogen; C 1 -C 4 straight or branched chain alkyl; 1 selected from the group consisting of unsubstituted or halogen, cyano, nitro, halogen substituted C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkyl and C 1 -C 4 straight or branched alkoxy C 5 -C 6 aryl substituted with one or more species; Or unsubstituted or at least one selected from the group consisting of halogen, cyano, nitro, C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkyl and C 1 -C 4 straight or branched alkoxy Substituted with C 5 -C 12 single or double ring heteroaryl, wherein the heteroaryl includes one or more hetero atoms selected from the group consisting of N, O and S.

바람직하게는, 상기 화학식 1에서,Preferably, in Chemical Formula 1,

상기 n은 2 내지 6의 정수이고; 및N is an integer from 2 to 6; And

R1은 수소; 클로로; 플루오로; 브로모; 메틸; 에틸; 프로필; 이소프로필; 부틸; 이소부틸; 비치환되거나, 클로로, 플루오로, 브로모, 시아노, 니트로, 트리플루오로메틸, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 메톡시, 에톡시, 프로폭시 및 부톡시로 이루어진 군으로부터 선택되는 1종 이상을 치환된 페닐; 또는 비치환되거나, 클로로, 플루오로, 브로모, 시아노, 니트로, 트리플루오로메틸, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 메톡시, 에톡시, 프로폭시 및 부톡시로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 피리딘, 싸이오펜, 퓨란 또는 인돌이다.
R 1 is hydrogen; Chloro; Fluoro; Bromo; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; Unsubstituted or consisting of chloro, fluoro, bromo, cyano, nitro, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy At least one member selected from substituted phenyl; Or unsubstituted or consisting of chloro, fluoro, bromo, cyano, nitro, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy Pyridine, thiophene, furan or indole substituted with one or more selected from the group.

더욱 바람직하게는, 상기 화학식 1에서,More preferably, in Formula 1,

상기 n은 2 내지 6의 정수이고; 및N is an integer from 2 to 6; And

R1은 수소, 클로로, 플루오로, 브로모, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸,

Figure 112011081771538-pat00005
,
Figure 112011081771538-pat00006
,
Figure 112011081771538-pat00007
,
Figure 112011081771538-pat00008
,
Figure 112011081771538-pat00009
,
Figure 112011081771538-pat00010
,
Figure 112011081771538-pat00011
,
Figure 112011081771538-pat00012
,
Figure 112011081771538-pat00013
,
Figure 112011081771538-pat00014
,
Figure 112011081771538-pat00015
,
Figure 112011081771538-pat00016
,
Figure 112011081771538-pat00017
,
Figure 112011081771538-pat00018
,
Figure 112011081771538-pat00019
,
Figure 112011081771538-pat00020
,
Figure 112011081771538-pat00021
,
Figure 112011081771538-pat00022
및
Figure 112011081771538-pat00023
로 이루어지는 군으로부터 선택되는 1종이다.
R 1 is hydrogen, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Figure 112011081771538-pat00005
,
Figure 112011081771538-pat00006
,
Figure 112011081771538-pat00007
,
Figure 112011081771538-pat00008
,
Figure 112011081771538-pat00009
,
Figure 112011081771538-pat00010
,
Figure 112011081771538-pat00011
,
Figure 112011081771538-pat00012
,
Figure 112011081771538-pat00013
,
Figure 112011081771538-pat00014
,
Figure 112011081771538-pat00015
,
Figure 112011081771538-pat00016
,
Figure 112011081771538-pat00017
,
Figure 112011081771538-pat00018
,
Figure 112011081771538-pat00019
,
Figure 112011081771538-pat00020
,
Figure 112011081771538-pat00021
,
Figure 112011081771538-pat00022
And
Figure 112011081771538-pat00023
It is 1 type chosen from the group which consists of these.

또한, 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체를 보다 구체적으로 예시하면 다음과 같다.In addition, the naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 may be exemplified in more detail as follows.

(1) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(1) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;

(2) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(2) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;

(3) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]부틸]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(3) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] butyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;

(4) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]펜틸]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(4) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] pentyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;

(5) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(4-시아노페닐)나프토[1,2-b]퓨란-2-카르복사미드;(5) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (4-cyanophenyl) naphtho [1,2-b] furan- 2-carboxamide;

(6) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-시아노페닐)나프토[1,2-b]퓨란-2-카르복사미드;(6) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-cyanophenyl) naphtho [1,2-b] furan- 2-carboxamide;

(7) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(피리딘-4-일)나프토[1,2-b]퓨란-2-카르복사미드;(7) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (pyridin-4-yl) naphtho [1,2-b] furan- 2-carboxamide;

(8) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(피리딘-4-일)나프토[1,2-b]퓨란-2-카르복사미드;(8) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (pyridin-4-yl) naphtho [1,2-b] furan- 2-carboxamide;

(9) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(2-클로로피리딘-4-일)나프토[1,2-b]퓨란-2-카르복사미드;(9) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (2-chloropyridin-4-yl) naphtho [1,2-b ] Furan-2-carboxamide;

(10) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(6-플푸오로피리딘-3-일)나프토[1,2-b]퓨란-2-카르복사미드;(10) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (6-flufuopyridin-3-yl) naphtho [1,2- b] furan-2-carboxamide;

(11) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(6-메톡시피리딘-3-일)나프토[1,2-b]퓨란-2-카르복사미드;(11) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (6-methoxypyridin-3-yl) naphtho [1,2- b] furan-2-carboxamide;

(12) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]나프토[1,2-b]퓨란-2-카르복사미드;(12) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] naphtho [1,2-b] furan-2-carboxamide;

(13) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-브로모나프토[1,2-b]퓨란-2-카르복사미드;(13) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5-bromonaphtho [1,2-b] furan-2-carboxamide;

(14) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-메틸나프토[1,2-b]퓨란-2-카르복사미드;(14) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5-methylnaphtho [1,2-b] furan-2-carboxamide;

(15) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-페닐나프토[1,2-b]퓨란-2-카르복사미드;(15) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5-phenylnaphtho [1,2-b] furan-2-carboxamide;

(16) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-플루오로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(16) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-fluorophenyl) naphtho [1,2-b] furan- 2-carboxamide;

(17) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(17) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;

(18) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-메틸페닐)나프토[1,2-b]퓨란-2-카르복사미드;(18) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-methylphenyl) naphtho [1,2-b] furan-2- Carboxamides;

(19) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3-시아노페닐)나프토[1,2-b]퓨란-2-카르복사미드;(19) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3-cyanophenyl) naphtho [1,2-b] furan- 2-carboxamide;

(20) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3,5-다이클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(20) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3,5-dichlorophenyl) naphtho [1,2-b] Furan-2-carboxamide;

(21) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3-클로로-4-플루오로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(21) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3-chloro-4-fluorophenyl) naphtho [1,2- b] furan-2-carboxamide;

(22) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3,4-다이플루오로페닐)나프토[1,2-b]퓨란-2-카르복사미드;(22) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3,4-difluorophenyl) naphtho [1,2-b ] Furan-2-carboxamide;

(23) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(피리딘-2-일)나프토[1,2-b]퓨란-2-카르복사미드;(23) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (pyridin-2-yl) naphtho [1,2-b] furan- 2-carboxamide;

(24) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(피리딘-3-일)나프토[1,2-b]퓨란-2-카르복사미드;(24) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (pyridin-3-yl) naphtho [1,2-b] furan- 2-carboxamide;

(25) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(싸이오펜-3-일)나프토[1,2-b]퓨란-2-카르복사미드;(25) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (thiophen-3-yl) naphtho [1,2-b] furan -2-carboxamide;

(26) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(퓨란-3-일)나프토[1,2-b]퓨란-2-카르복사미드; 및(26) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (furan-3-yl) naphtho [1,2-b] furan- 2-carboxamide; And

(27) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(1-메틸-1H-인돌-5-일)나프토[1,2-b]퓨란-2-카르복사미드.
(27) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (1-methyl-1H-indol-5-yl) naphtho [1, 2-b] furan-2-carboxamide.

본 발명에 따른 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체의 바람직한 구조를 하기 표 1에 나타내었다.The preferred structure of the naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 according to the present invention is shown in Table 1 below.

실시예Example 구조rescue 실시예Example 구조rescue 1One

Figure 112011081771538-pat00024
Figure 112011081771538-pat00024
22
Figure 112011081771538-pat00025
Figure 112011081771538-pat00025
 33
Figure 112011081771538-pat00026
Figure 112011081771538-pat00026
 44
Figure 112011081771538-pat00027
Figure 112011081771538-pat00027
 55
Figure 112011081771538-pat00028
Figure 112011081771538-pat00028
 66
Figure 112011081771538-pat00029
Figure 112011081771538-pat00029
 77
Figure 112011081771538-pat00030
Figure 112011081771538-pat00030
 88
Figure 112011081771538-pat00031
Figure 112011081771538-pat00031
 99
Figure 112011081771538-pat00032
Figure 112011081771538-pat00032
 1010
Figure 112011081771538-pat00033
Figure 112011081771538-pat00033
 1111
Figure 112011081771538-pat00034
Figure 112011081771538-pat00034
 1212
Figure 112011081771538-pat00035
Figure 112011081771538-pat00035
 1313
Figure 112011081771538-pat00036
Figure 112011081771538-pat00036
 1414
Figure 112011081771538-pat00037
Figure 112011081771538-pat00037
 1515
Figure 112011081771538-pat00038
Figure 112011081771538-pat00038
 1616
Figure 112011081771538-pat00039
Figure 112011081771538-pat00039
 1717
Figure 112011081771538-pat00040
Figure 112011081771538-pat00040
 1818
Figure 112011081771538-pat00041
Figure 112011081771538-pat00041
 1919
Figure 112011081771538-pat00042
Figure 112011081771538-pat00042
 2020
Figure 112011081771538-pat00043
Figure 112011081771538-pat00043
 2121
Figure 112011081771538-pat00044
Figure 112011081771538-pat00044
 2222
Figure 112011081771538-pat00045
Figure 112011081771538-pat00045
 2323
Figure 112011081771538-pat00046
Figure 112011081771538-pat00046
 2424 2525
Figure 112011081771538-pat00048
Figure 112011081771538-pat00048
 2626
Figure 112011081771538-pat00049
Figure 112011081771538-pat00049
 2727
Figure 112011081771538-pat00050
Figure 112011081771538-pat00050
 2828

본 발명의 화학식 1의 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. From non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 유도체를 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜셔 제조할 수 있다. The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or after the solvent and excess acid are distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속 염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

또한, 본 발명은 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물 등을 모두 포함한다.
In addition, the present invention is a naphtho [1,2-b] furan-2-carboxamide derivative represented by the formula (1) and pharmaceutically acceptable salts thereof, as well as possible solvates, hydrates that can be prepared therefrom It includes all of them.

나아가, 본 발명은 나프토[1,2-b]퓨란-2-카르복사미드 유도체의 제조방법을 제공한다.Furthermore, the present invention provides a method for preparing a naphtho [1,2-b] furan-2-carboxamide derivative.

본 발명에 따른 화학식 1의 유도체의 제조방법은 하기 반응식 1에 나타난 바와 같이, 화학식 2로 표시되는 나프토[1,2-b]퓨란-2-카르복실산 유도체와 화학식 3으로 표시되는 아민 화합물을 축합제 및 염기존재 하에 용매 하에서 반응시키는 축합반응 단계를 포함한다:Method for preparing a derivative of formula 1 according to the present invention, as shown in Scheme 1, the naphtho [1,2-b] furan-2-carboxylic acid derivative represented by the formula (2) and the amine compound represented by the formula (3) Condensation reaction step of reacting in a solvent in the presence of a condensing agent and a base:

[반응식 1][Reaction Scheme 1]

Figure 112011081771538-pat00051
Figure 112011081771538-pat00051

(상기 식에서 R1 및 n은 상기 화학식 1에서 정의한 바와 같다.)(Wherein R 1 and n are as defined in Formula 1).

본 발명에 따른 화학식 1로 표시되는 화합물을 제조하기 위한 화학식 2로 표시되는 나프토[1,2-b]퓨란-2-카르복실산과 화학식 3으로 표시되는 아민 화합물의 축합반응은 통상적인 두 가지의 방법을 통해 제조할 수 있다.
Condensation reaction of naphtho [1,2-b] furan-2-carboxylic acid represented by Formula 2 with an amine compound represented by Formula 3 to prepare a compound represented by Formula 1 according to the present invention is conventional It can be prepared through the method.

제법 1-APreparation method 1-A

첫번째 방법은 염기 존재 하에 축합제를 사용하는 방법으로서, 이때, 사용 가능한 사용가능한 축합제로는 카보다이이미드 계열의 시약으로 다이사이클로헥실카보다이이미드(DCC), 다이아이소프로필카보다이이미드(DIC), 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드(EDC)등이 있고, N,N-카보닐다이이미다졸(N,N-carbonyldiimidazole), 다이페닐포스포닐아자이드(diphenylphosphonylazide, DPPA) 등을 사용할 수 있다.The first method is the use of a condensing agent in the presence of a base, wherein available condensing agents that can be used include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and the like, and N, N-carbonyldiimidazole and diphenylphosphonylazide (DPPA). ) Can be used.

반응을 촉진하고 수율을 높이기 위해 N,N-다이메틸아미노피리딘(DMAP), 피리딘, 트라이에틸아민, N,N-다이이소프로필에틸아민, DBU 등의 유기염기 또는 소듐바이카보네이트, 수산화나트륨, 수산화칼륨 등의 무기염기를 사용할 수 있다.Organic bases such as N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N, N-diisopropylethylamine, DBU, or sodium bicarbonate, sodium hydroxide, hydroxide to promote the reaction and increase the yield Inorganic bases, such as potassium, can be used.

반응 용매는 테트라하이드로퓨란, 다이옥산, 디클로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 벤젠, 톨루엔, 자일렌과 같은 아로마틱 하이드로카본용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.
Reaction solvents include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, dimethylformamide (DMF), dimethyl sulfoxide, Acetonitrile and the like can be used alone or in combination. The reaction temperature is from 0 ° C. to the boiling point of the solvent.

제법 1-BPreparation method 1-B

또한, 두번째 방법은 화학식 2의 나프토[1,2-b]퓨란-2-카르복실산 화합물을 공지의 방법에 아실할라이드, 카르복실산 무수물 또는 활성 에스터(active ester)(예, p-나이트로페닐 에스터, N-하이드록시석신이미드 에스터, 페타플루오로페닐 에스터 등)로 변환 시킨 후 염기 존재 하에 아민 화합물 3과 반응하여 화학식 1로 표시되는 화합물을 제조할 수 있다. In addition, the second method uses the naphtho [1,2-b] furan-2-carboxylic acid compound of formula (2) to acyl halides, carboxylic anhydrides or active esters (e.g. p-knight Rophenyl ester, N-hydroxysuccinimide ester, petafluorophenyl ester, etc.) and then react with amine compound 3 in the presence of a base to prepare a compound represented by Formula 1.

이때, 사용가능한 염기로는 트라이에틸아민, 이소프로필에틸아민과 같은 삼차아민 유기염기와 탄산나트륨, 탄산칼륨, 수산화칼륨, 수산화나트륨, 탄산세슘, 수산화바륨등과 같은 무기염기가 있으며, 당량 또는 과량 사용할 수 있다. At this time, usable bases include tertiary amine organic bases such as triethylamine and isopropylethylamine and inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, etc. Can be.

또한, 사용 가능한 반응용매는 다이옥산, 테트라하이드로퓨란, 1,2-다이메톡시에탄과 같은 에테르계 용매와 1,2-다이클로로메탄, 혹은 1,2-다이클로로에탄 같은 할로겐 포함 용매 그리고 벤젠, 톨루엔 같은 아로마틱 하이드로카본용매를 단독 혹은 혼합용매로 사용할 수 있고 용매 없이도 반응시킬 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.
In addition, usable reaction solvents include ether solvents such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, halogen-containing solvents such as 1,2-dichloromethane or 1,2-dichloroethane, benzene, Aromatic hydrocarbon solvents such as toluene can be used alone or as a mixed solvent and can be reacted without a solvent. The reaction temperature is from 0 ° C. to the boiling point of the solvent.

본 발명의 상기 반응식 1에 있어서, 상기 화학식 2로 표시되는 화합물은 하기와 같은 방법으로 제조될 수 있으나, 이에 한정하지 않는다.In Scheme 1, the compound represented by Formula 2 may be prepared by the following method, but is not limited thereto.

[반응식 2][Reaction Scheme 2]

Figure 112011081771538-pat00052
Figure 112011081771538-pat00052

(상기 반응식 2에서 X는 수소, 직쇄 혹은 측쇄 C1-C4 알킬, 또는 할로겐이고, Y는 F, Cl, Br, 또는 NO2이고, R2는 메틸, 에틸 또는 프로필이고, R1은 상기 화학식 1에서 정의한 바와 같다.)
Wherein X is hydrogen, straight or branched C 1 -C 4 alkyl, or halogen, Y is F, Cl, Br, or NO 2 , R 2 is methyl, ethyl or propyl, and R 1 is As defined in Formula 1.)

이하, 상기 반응식 2를 더욱 구체적으로 설명한다.Hereinafter, Scheme 2 will be described in more detail.

먼저, 본 발명에 따른 상기 단계 1은 화학식 8로 표시되는 화합물을 제조하는 단계이다. 화학식 8로 표시되는 화합물은 하기 두가지 방법으로 제조될 수 있다.
First, Step 1 according to the present invention is a step of preparing a compound represented by Formula 8. The compound represented by Formula 8 may be prepared by the following two methods.

제법 2-APreparation 2-A

먼저, 상기 화학식 8로 표시되는 화합물의 제조방법은 화학식 4로 표시되는 1위치에 이탈기를 갖는 2-나프트알데히드 유도체와 화학식 5로 표시되는 2-하이드록시아세테이트 화합물을 염기 존재 하에서 치환반응 및 분자내 고리화반응을 통해 화학식 8로 표시되는 화합물을 제조할 수 있다.
First, the preparation method of the compound represented by the formula (8) is a substitution reaction and a molecule of a 2-naphthaldehyde derivative having a leaving group at the position represented by the formula (4) and the 2-hydroxyacetate compound represented by the formula (5) in the presence of a base Through the cyclization reaction can be prepared a compound represented by the formula (8).

제법 2-BPreparation 2-B

또한, 상기 화학식 8로 표시되는 화합물의 다른 제조방법은 화학식 6으로 표시되는 1-하이드록시-2-나프트알데히드 화합물과 화학식 7로 표시되는 메틸 브로모아세테이트 화합물을 염기 존재 하에서 알킬화반응 및 분자내 고리화반응을 통해 화학식 8로 표시되는 화합물을 제조할 수 있다.
In addition, another method for preparing a compound represented by Formula 8 is an alkylation reaction and intramolecular reaction of 1-hydroxy-2-naphthaldehyde compound represented by Formula 6 and methyl bromoacetate compound represented by Formula 7 in the presence of a base. Through the cyclization reaction, a compound represented by Chemical Formula 8 may be prepared.

상기 반응에서 사용가능한 염기로는 피리딘, 트라이에틸아민, N,N-디이소프로필에틸아민, DBU 등의 유기염기를 사용하거나, NaOH, Na2CO3, K2CO3, Cs2CO3 등의 무기염기를 당량 또는 과량 사용할 수 있다.As a base usable in the reaction, an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, DBU, or the like is used, or NaOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3, or the like. The inorganic base of can be used equivalent or in excess.

반응 용매는 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.The reaction solvent may be used alone or in combination with an ether solvent such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and the like. have. The reaction temperature is from 0 ° C. to the boiling point of the solvent.

또한, 상기 단계 2는 상기 단계 1에서 얻은 화학식 8로 표시되는 화합물을 보론산 화합물과 촉매 및 염기존재 하에 스즈키(Suzuki)형 커플링 반응을 통해 화학식 9로 표시되는 화합물을 제조하는 단계이다.In addition, step 2 is a step of preparing the compound represented by the formula (9) through a Suzuki-type coupling reaction of the compound represented by the formula (8) obtained in the step 1 in the presence of a boronic acid compound, a catalyst and a base.

상기 반응에서 보론산 화합물은 상업적으로 시판되는 화합물들을 사용하거나, 대응되는 할라이드 화합물로부터 공지의 방법으로 제조하여 사용한다. The boronic acid compound in the reaction is used commercially available compounds, or prepared by using a known method from the corresponding halide compound.

상기 반응에서 촉매로는 팔라듐, 니켈, 플래티늄 유도체를 사용할 수 있고 팔라듐 촉매를 사용하는 것이 바람직하다. 팔라듐 촉매로는 Pd(PPh3)4, Pd-C, PdCl2(PPh3)2, Pd2(dba)3, PdCl2(dppf), [PdCl(allyl)]2, Pd(OAc)2 또는 PdCl2 등을 사용할 수 있다. In the reaction, palladium, nickel, platinum derivatives may be used as the catalyst, and a palladium catalyst is preferably used. Palladium catalysts include Pd (PPh 3 ) 4 , Pd-C, PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , PdCl 2 (dppf), [PdCl (allyl)] 2 , Pd (OAc) 2 or PdCl 2 and the like can be used.

또한, 반응을 촉진하고 수율을 높이기 위하여 PPh3, P-(O-tolyl)3, PBu3 등의 포스핀 화합물을 부가물로 사용하거나, 염화리튬, 브롬화리튬, 요오드화 리튬 등의 염을 부가물로 사용할 수 있다. In order to promote the reaction and increase the yield, phosphine compounds such as PPh 3 , P- (O-tolyl) 3 , PBu 3, etc. are used as adducts, or salts such as lithium chloride, lithium bromide, and lithium iodide are adducts. Can be used as

반응 용매는 테트라하이드로퓨란, 다이옥산, 1,2-다이메톡시에탄과 같은 에테르계 용매, 벤젠, 톨루엔, 자일렌과 같은 아로마틱 하이드로카본 용매, 메탄올, 에탄올과 같은 알코올계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴, 물 등을 단독 또는 혼합하여 사용할 수 있고 반응 온도는 0 ℃에서 용매의 비등점까지이다.The reaction solvent is an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, an aromatic hydrocarbon solvent such as benzene, toluene, xylene, an alcohol solvent such as methanol or ethanol, dimethylformamide (DMF ), Dimethyl sulfoxide, acetonitrile, water and the like can be used alone or in combination. The reaction temperature is from 0 deg. C to the boiling point of the solvent.

또한, 상기 반응은 염기 존재 하에 반응시키는데 사용가능한 염기로는 탄산나트륨, 탄산칼륨, 수산화칼륨, 수산화나트륨, 탄산세슘, 수산화바륨등과 같은 무기염기를 사용할 수 있는데, 당량 또는 과량 사용할 수 있다.
In addition, the reaction may be used as the base that can be used to react in the presence of a base, such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, etc., can be used equivalent or excess.

다음으로, 상기 단계 3은 상기 단계 2에서 얻은 화학식 9로 표시되는 화합물을 염기 또는 산으로 가수분해하여 화학식 2로 표시되는 카르복실산 화합물을 제조하는 단계이다.Next, step 3 is a step of preparing a carboxylic acid compound represented by the formula (2) by hydrolyzing the compound represented by the formula (9) obtained in step 2 with a base or an acid.

상기 반응에서 사용가능한 염기로는 탄산나트륨, 탄산칼륨, 수산화칼륨, 수산화나트륨, 탄산세슘, 수산화바륨등과 같은 무기염기가 있으며, 산으로는 염산, 황산, 메탄설폰산 등이 있다. Bases used in the reaction include inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, and the like, and acids include hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like.

반응 용매는 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 벤젠, 톨루엔, 자일렌과 같은 아로마틱 하이드로카본용매, 메탄올, 에탄올과 같은 알코올계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.
Reaction solvents include ether solvents such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohol solvents such as methanol and ethanol, Dimethyl formamide (DMF), dimethyl sulfoxide, acetonitrile and the like can be used alone or in combination. The reaction temperature is from 0 ° C. to the boiling point of the solvent.

상기 반응식 1에서 사용되는 화학식 3의 아민 화합물은 하기 반응식 3에 나타낸 바와 같이 제조될 수 있으나, 이에 한정하지 않는다.The amine compound of Formula 3 used in Scheme 1 may be prepared as shown in Scheme 3, but is not limited thereto.

[반응식 3]Scheme 3

Figure 112011081771538-pat00053
Figure 112011081771538-pat00053

(상기 반응식 3에서, n은 2 내지 6의 정수이고, m은 1 내지 5의 정수이다.)
(In Reaction Scheme 3, n is an integer of 2 to 6, m is an integer of 1 to 5.)

이하, 상기 반응식 3을 더욱 구체적으로 설명한다.Hereinafter, Scheme 3 will be described in more detail.

반응식 3에서 화학식 10으로 표시되는 N-[3-(피페리딘-4-일)페닐]아세트아미드 화합물은 공지의 방법(PCT/US02/21063, WO 03/004027)을 통해 제조하여 사용할 수 있다.
The N- [3- (piperidin-4-yl) phenyl] acetamide compound represented by Formula 10 in Scheme 3 can be prepared and used by known methods (PCT / US02 / 21063, WO 03/004027). .

본 발명에 따른 화학식 3으로 표시되는 화합물은 반응식 3에서와 같이 두 가지 방법으로 제조할 수 있다.
The compound represented by Formula 3 according to the present invention may be prepared by two methods as in Scheme 3.

제법 3-APreparation 3-A

화학식 10으로 표시되는 화합물과 (n-브로모알킬)아이소인돌린-1,3-다이온을 염기 존재 하에 알킬화반응으로 화학식 11로 표시되는 화합물을 제조하고(단계 1-A), 이어서 하이드라진을 사용하여 화학식 3으로 표시되는 아민 화합물을 제조할 수 있다(단계 2-A).
A compound represented by the formula (11) was prepared by alkylation of a compound represented by the formula (10) with (n-bromoalkyl) isoindolin-1,3-dione in the presence of a base (step 1-A), followed by hydrazine. Can be used to prepare the amine compound represented by the formula (3) (Step 2-A).

제법 3-BPreparation 3-B

상기 화학식 3으로 표시되는 아민 화합물의 다른 방법으로는 화학식 10으로 표시되는 화합물과 m-브로모알킬니트릴 화합물을 염기 존재 하에 알킬화반응하여 화학식 12로 표시되는 화합물을 얻고(단계 1-B), 이어서 환원반응으로 니트릴기를 환원하여 아민 화합물 3을 제조할 수 있다(단계 2-B).
As another method of the amine compound represented by Chemical Formula 3, the compound represented by Chemical Formula 12 and the m-bromoalkylnitrile compound are alkylated in the presence of a base to obtain a compound represented by Chemical Formula 12 (Step 1-B). An amine compound 3 may be prepared by reducing the nitrile group by a reduction reaction (step 2-B).

상기 반응식 3에서 알킬화 반응에 사용가능한 염기로는 트라이에틸아민, 이소프로필에틸아민과 같은 삼차아민 유기염기와 탄산나트륨, 탄산칼륨, 수산화칼륨, 수산화나트륨, 탄산세슘, 수산화바륨등과 같은 무기염기가 있으며, 당량 또는 과량 사용할 수 있다. Bases available for alkylation in Scheme 3 include tertiary amine organic bases such as triethylamine and isopropylethylamine and inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, and the like. , Equivalents or excess may be used.

반응 용매는 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매; 디메틸포름아미드(DMF); 디메틸설폭사이드; 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 상온에서 용매의 비등점까지이다.The reaction solvent is an ether solvent such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane; Dimethylformamide (DMF); Dimethyl sulfoxide; Acetonitrile and the like can be used alone or in combination. The reaction temperature is from room temperature to the boiling point of the solvent.

상기 반응식 3에서 하이드라진을 사용하는 반응에서 하이드라진은 당량 혹은 과량 사용할 수 있고, 이때 사용가능한 반응 용매는 메탄올, 프로판올, 부탄올 같은 알콜류 용매; 벤젠, 톨루엔 같은 용매; 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매; 디메틸포름아미드(DMF); 디메틸설폭사이드; 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 상온에서 용매의 비등점까지이다.In the reaction using hydrazine in Scheme 3, hydrazine may be used in an equivalent or excessive amount, and the reaction solvent may be an alcohol solvent such as methanol, propanol, butanol; Solvents such as benzene and toluene; Ether solvents such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane; Dimethylformamide (DMF); Dimethyl sulfoxide; Acetonitrile and the like can be used alone or in combination. The reaction temperature is from room temperature to the boiling point of the solvent.

상기 반응식 3에서 환원반응은 금속촉매와 암모니아 또는 하이드라진 존재 하에 수소가스를 사용한다. 금속촉매는 니켈, 팔라듐, 플래티늄 등의 금속 촉매를 사용할 수 있다. 반응 용매는 메탄올, 프로판올, 부탄올 같은 알콜류 용매; 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 상온에서 용매의 비등점까지이다.
Reduction reaction in Scheme 3 uses hydrogen gas in the presence of a metal catalyst and ammonia or hydrazine. As the metal catalyst, a metal catalyst such as nickel, palladium or platinum may be used. Reaction solvents include alcohol solvents such as methanol, propanol and butanol; Ether solvents, such as tetrahydrofuran, dioxane, ditlo methane, and 1, 2- dimethoxyethane, etc. can be used individually or in mixture. The reaction temperature is from room temperature to the boiling point of the solvent.

나아가, 본 발명은 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 길항제를 제공한다.Furthermore, the present invention provides an MCH receptor-1 antagonist containing a naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 따른 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 MCH 수용체-1 결합 억제 활성을 측정한 결과, MCH 수용체-1에 대한 길항작용을 하는 효과가 매우 우수하므로 MCH 수용체-1 길항제로 유용하게 사용될 수 있다(실험예 1 참조).
Naphtho [1,2-b] furan-2-carboxamide derivatives according to the present invention have a very good effect of antagonizing MCH receptor-1 as a result of measuring MCH receptor-1 binding inhibitory activity. It can be usefully used as a receptor-1 antagonist (see Experimental Example 1).

또한, 본 발명은 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a method for preventing MCH receptor-1 related diseases containing naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient or Provided is a therapeutic pharmaceutical composition.

상기 MCH 수용체-1 관련 질환으로는 비만, 당뇨병, 대사장애, 불안증 및 우울증을 포함할 수 있다.
The MCH receptor-1 related diseases may include obesity, diabetes, metabolic disorders, anxiety, and depression.

MCH 효과를 매개하는 GPCR(G-protein coupled receptor) 중의 하나인 MCH 수용체-1 길항제는 우울증 또는 불안증을 치료효과([B. Borowsky et al., Nature Medicine, 8(8), 825-30, 2002] 참조), 체중감소를 나타내며 식욕감퇴 효과(문헌 [B. Borowsky et al., Nature Medicine, 8(8), 825-30, 2002] 참조)뿐만 아니라, 당뇨병, 대사장애에도 효과가 있는 것으로 밝혀졌다(문헌 [D. S. Ludwig et al., J. Clin. Invest. 107, 379-386, 2001] 참조).MCH receptor-1 antagonists, one of the G-protein coupled receptors (GPCRs) mediating the MCH effect, have been shown to be effective in the treatment of depression or anxiety (B. Borowsky et al., Nature Medicine, 8 (8) (See B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002), as well as an effect on diabetes and metabolic disorders (See DS Ludwig et al., J. Clin. Invest. 107, 379-386, 2001).

이에, 본 발명에 따른 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 MCH 수용체-1 결합 억제 활성을 측정한 결과, 본 발명에 따른 실시예 1, 3, 5, 6, 7, 8, 9, 10, 및 11의 화합물이 IC50 값이 10 nM 이하 농도에서 MCH 수용체-1에 대하여 길항작용을 하는 것으로 확인되었으며, 특히, 본 발명의 실시예 1 및 실시예 3의 화합물은 IC50 값이 각각 3 nM 및 7 nM로 매우 우수한 MCH 수용체-1에 대하여 길항작용을 하는 효과를 나타내는 것을 알 수 있다(실험예 1 참조).Therefore, the naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 according to the present invention measured MCH receptor-1 binding inhibitory activity, Example 1, It has been found that the compounds of 3, 5, 6, 7, 8, 9, 10, and 11 antagonize MCH receptor-1 at concentrations up to 10 nM with IC 50 values, in particular, Example 1 of the present invention. And it can be seen that the compound of Example 3 exhibits an antagonistic effect on MCH receptor-1, which is very good at IC 50 values of 3 nM and 7 nM, respectively (see Experimental Example 1).

따라서, 본 발명에 따른 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 MCH 수용체-1에 대한 길항제로 작용함으로써 MCH가 MCH 수용체-1에 결합함으로써 유발되는 비만, 당뇨병, 대사장애, 불안증 및 우울증과 같은 MCH 수용체-1 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.
Therefore, the naphtho [1,2-b] furan-2-carboxamide derivative represented by Formula 1 according to the present invention acts as an antagonist to MCH receptor-1 and is induced by MCH binding to MCH receptor-1. It can be usefully used to prevent or treat MCH receptor-1 related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression.

본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1로 표시되는 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a pharmaceutical, the pharmaceutical composition containing the derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

상기 화학식 1로 표시되는 유도체를 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. Pharmaceutical compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다. At this time, the naphtho [1,2-b] furan-2-carboxamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to be formulated into a formulation for parenteral administration. It may be prepared in solution or in suspension and prepared in ampoules or vial unit dosage forms. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

상기 화학식 1의 유도체를 유효성분으로 함유하는 약학적 조성물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 바람직하게는 0.01 내지 200 ㎎/㎏/일의 양으로 의사 또는 약사의 판단에 따라 일정시간 간격을 1일 수회, 바람직하게는 1일 1회 내지 3회로 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다.
The dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg. / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.

나아가, 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 및 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 관련 질환의 예방 또는 개선용 건강식품 조성물을 제공한다.Furthermore, for the prevention or improvement of MCH receptor-1 related diseases containing naphtho [1,2-b] furan-2-carboxamide derivative represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient. Provide a health food composition.

상기 MCH 수용체-1 관련 질환으로는 비만, 당뇨병, 대사장애, 불안증 및 우울증을 포함할 수 있다.
The MCH receptor-1 related diseases may include obesity, diabetes, metabolic disorders, anxiety, and depression.

본 발명에 따른 조성물은 MCH 수용체-1에 대한 길항제로 작용하므로써 MCH가 MCH 수용체에 결합함으로써 유발되는 MCH 수용체-1 관련 질환의 예방 또는 개선을 목적으로 상기 나프토[1,2-b]퓨란-2-카르복사미드 유도체를 식품, 음료 등의 건강보조 식품에 첨가할 수 있다.
The composition according to the present invention acts as an antagonist to MCH receptor-1, thereby preventing or ameliorating MCH receptor-1 related diseases caused by MCH binding to the MCH receptor. The naphtho [1,2-b] furan- 2-carboxamide derivatives can be added to dietary supplements such as foods and beverages.

상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.

본 발명의 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The naphtho [1,2-b] furan-2-carboxamide derivatives of the present invention may be added as is to foods or used with other foods or food ingredients, and may be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health functional beverage composition of the present invention is not particularly limited to the other ingredients other than the above-mentioned compounds as essential ingredients in the indicated ratios and may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally from about 1 to 20 g, preferably from about 5 to 12 g per 100 compositions of the present invention.

상기 외에 본 발명의 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition to the above, naphtho [1,2-b] furan-2-carboxamide derivatives of the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, such as flavoring agents, coloring agents and neutralizing agents. (Cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. . In addition, the naphtho [1,2-b] furan-2-carboxamide derivative of the present invention may contain fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.

이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 나프토[1,2-b]퓨란-2-카르복사미드 유도체를 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
These components may be used independently or in combination. The proportion of such additives is not so critical but it is generally chosen that the naphtho [1,2-b] furan-2-carboxamide derivative of the present invention is in the range of 0.1 to about 20 parts by weight per 100 parts by weight.

이하 본 발명을 제조예, 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples.

단, 하기의 제조예 및 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 제조예 및 실시예에 의해 한정되는 것은 아니다.
However, the following Production Examples and Examples are illustrative of the present invention, and the content of the present invention is not limited by the following Production Examples and Examples.

<< 제조예Manufacturing example 1>  1> 메틸methyl 5- 5- 브로모나프토[1,2-b]퓨란Bromonaphtho [1,2-b] furan -2--2- 카르복실레이트의Carboxylate 제조  Produce

Figure 112011081771538-pat00054
Figure 112011081771538-pat00054

4-브로모-1-플루오로-2-나트트알데히드(2.0 g, 7.90 mmol)와 메틸 2-하이드록시아세테이트(854 mg, 9.48 mmo), 탄산칼륨을 30 ml의 N,N-디메틸포름아마이드에 용해시킨 후 60 ℃에서 15 시간 교반 시켰다. 용매를 감압 농축한 후 50 ml의 물을 가한 후 50 ml의 에틸 아세테이트로 추출하였다. 2 차례 물층을 50 m의 에틸 아세테이트로 추출하였다. 유기층을 무수 MgSO4로 건조 시킨 후 감압 여과하여 농축하였다. 잔류물을 실리카겔 컬럼크로마토그래피(노말 헥산과 디클로로메탄, 20/1, v/v)로 정제하여 목적화합물을 노란고체화합물로 얻었다.(713 mg, 2.34 mmol, 30%)4-bromo-1-fluoro-2-nathaldehyde (2.0 g, 7.90 mmol), methyl 2-hydroxyacetate (854 mg, 9.48 mmo) and potassium carbonate in 30 ml of N, N -dimethylformamide It was dissolved in and stirred at 60 ℃ for 15 hours. The solvent was concentrated under reduced pressure, 50 ml of water was added, and then extracted with 50 ml of ethyl acetate. The water layer was extracted twice with 50 m of ethyl acetate. The organic layer was dried over anhydrous MgSO 4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane and dichloromethane, 20/1, v / v) to give the title compound as a yellow solid (713 mg, 2.34 mmol, 30%).

Rf =0.29(노말 헥산과 에틸 아세테이트, 20/1, v/v)R f = 0.29 (normal hexane and ethyl acetate, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.67(m, 1H), 8.34(m, 1H), 8.01(s, 1H), 7.69(m, 2H), 7.59(d, J=0.39 Hz, 1H), 4.01(s, 3H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.67 (m, 1H), 8.34 (m, 1H), 8.01 (s, 1H), 7.69 (m, 2H), 7.59 (d, J = 0.39 Hz, 1H) , 4.01 (s, 3H).

<< 제조예Manufacturing example 2>  2> 메틸methyl 나프토[1,2-b]퓨란Naphtho [l, 2-b] furan -2--2- 카르복실레이트의Carboxylate 제조  Produce

Figure 112011081771538-pat00055
Figure 112011081771538-pat00055

1-하이드록시-2-나프트알데하이드(100 mg, 0.58 mmol)와 메틸 2-브로모아세테이트(98 ul, 0.64 mmol), 탄산칼륨(161 mg, 1.16 mmol)을 3 ml의 아세트니트릴 용매에 용해시킨 후 마이크로웨이브를 사용하여 150℃에서 1시간 30분간한다. 30ml의 물을 가한 후 30 ml의 에틸아세테이트로 추출한다. 소금물로 유기층을 세척하고 유기층을 무수 MgSO4로 건조 시킨 후 감압 여과하여 농축하였다. 잔류물을 실리카겔 컬럼크로마토그래피(노말 헥산과 에틸 아세테이트, 10/1, v/v)로 정제하여 목적화합물을 노란 고체 화합물로 얻었다.(100 mg, 0.44 mmol, 76%)Dissolve 1-hydroxy-2-naphthaldehyde (100 mg, 0.58 mmol), methyl 2-bromoacetate (98 ul, 0.64 mmol) and potassium carbonate (161 mg, 1.16 mmol) in 3 ml of acetonitrile solvent After doing so, use a microwave at 150 ° C. for 1 hour 30 minutes. 30 ml of water is added, followed by extraction with 30 ml of ethyl acetate. The organic layer was washed with brine, the organic layer was dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane and ethyl acetate, 10/1, v / v) to give the title compound as a yellow solid (100 mg, 0.44 mmol, 76%).

Rf=0.54(노말 헥산과 에틸 아세테이트, 10/1, v/v)Rf = 0.54 (normal hexane and ethyl acetate, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.45(d, J=8.1 Hz, 1H), 7.93(d, J=8.1 Hz, 1H), 7.75-7.50(m, 5H), 4.0(s, 3H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75-7.50 (m, 5H), 4.0 (s, 3H) .

<< 제조예Manufacturing example 3>  3> 메틸methyl 5-(4- 5- (4- 클로로페닐Chlorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복실레이트의Carboxylate 제조  Produce

Figure 112011081771538-pat00056
Figure 112011081771538-pat00056

메틸 5-브로모나프토[1,2-b]퓨란-2-카르복실레이트(210 mg, 0.68 mmol)과 팔라듐 테트라키스트라이페닐 포스핀(Pd(PPh3)4, 73 mg, 0.06 mmol), 4-클로로페닐보론산(104 mg, 0.82 mmol)을 에틸렌 글리콜 다이메틸 에테르(6 ml)에 용해시킨 후, 2N 탄산나트륨(Na2CO3, 0.68 ml, 1.36 mmol) 첨가하여 7시간 동안 교반하면서 가열, 환류하였다. 반응액을 셀라이트에 거른 후 감압농축한 뒤, 반응여액을 실리카겔 칼럼 크로마토그라피(헥산:에틸 아세테이트=10:1)로 정제하여 연한 노란색 고체 형태의 목적 화합물(199 mg, 0.59 mmol, 86%)을 얻었다.Methyl 5-bromonaphtho [1,2-b] furan-2-carboxylate (210 mg, 0.68 mmol) and palladium tetrakistriphenyl phosphine (Pd (PPh 3 ) 4 , 73 mg, 0.06 mmol), 4-chlorophenylboronic acid (104 mg, 0.82 mmol) was dissolved in ethylene glycol dimethyl ether (6 ml), followed by addition of 2N sodium carbonate (Na 2 CO 3 , 0.68 ml, 1.36 mmol) and stirring with stirring for 7 hours. It was refluxed. The reaction solution was filtered through Celite, concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a pale yellow solid (199 mg, 0.59 mmol, 86%). Got.

Rf=0.59(EA:Hx=1:10)*1.5Rf = 0.59 (EA: Hx = 1: 10) * 1.5

1H-NMR(300MHz, CDCl3) δ 8.55(d, J=8.3 Hz, 1H), 7.85(d, J=8.3 Hz, 1H), 7.63-7.69(m, 2H), 7.57(s, 1H), 7.41-7.55(m, 5H), 4.00(s, 3H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 8.55 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.63-7.69 (m, 2H), 7.57 (s, 1H) , 7.41-7.55 (m, 5H), 4.00 (s, 3H).

<< 제조예Manufacturing example 4> 5-(4- 4> 5- (4- 클로로페닐Chlorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복실산의Carboxylic acid 제조 Produce

Figure 112011081771538-pat00057
Figure 112011081771538-pat00057

상기 제조예 3에서 얻은 화합물(92 mg, 0.27 mmol)을 메탄올(5 ml)에 용해 시킨후, 5M 수산화나트륨 용액(0.11 ml, 0.54 mmol)을 첨가한 뒤 60도에서 12시간 반 동안 가열하였다. 반응이 완결된 후, 용매를 감압 농축한뒤, 1N HCl용액(10 ml)으로 산성화 시킨후, 에틸 아세테이트(10 ml)로 두 번 추출하고 포화염화클로라이드 용액(1 ml)으로 세척한다. 황산마그네슘(MgSO4)으로 건조시킨후 여과하여, 여액을 감압하에서 농축시켜, 연한 노란색 고체의 목적 화합물(84 mg, 0.26 mmol, 95%)을 얻었다.The compound (92 mg, 0.27 mmol) obtained in Preparation Example 3 was dissolved in methanol (5 ml), and 5M sodium hydroxide solution (0.11 ml, 0.54 mmol) was added thereto, followed by heating at 60 degrees for 12 hours and a half. After completion of the reaction, the solvent was concentrated under reduced pressure, acidified with 1N HCl solution (10 ml), extracted twice with ethyl acetate (10 ml) and washed with saturated chloride solution (1 ml). After drying over magnesium sulfate (MgSO 4 ) and filtration, the filtrate was concentrated under reduced pressure to give the target compound (84 mg, 0.26 mmol, 95%) as a pale yellow solid.

1H-NMR(300MHz, DMSO-d6) δ 8.39(d, J=7.6 Hz, 1H), 7.73-7.82(m, 4H), 7.58-7.65(m, 3H), 7.50-7.54(m, 2H)
 1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.39 (d, J = 7.6 Hz, 1H), 7.73-7.82 (m, 4H), 7.58-7.65 (m, 3H), 7.50-7.54 (m, 2H )

<제조예 5> N-[3-[1-[2-(1,3-다이옥소아이소인돌린-2-일)에틸]피페리딘-4-일]Preparation Example 5 N- [3- [1- [2- (1,3-dioxoisoindolin-2-yl) ethyl] piperidin-4-yl] 페닐Phenyl ]] 아세트아마이드의Acetamide 제조 Produce

Figure 112011081771538-pat00058
Figure 112011081771538-pat00058

N-[3-(피페리딘-4-일)페닐]아세트아미드(600 mg, 2.36 mmol)와 N-(2-브로모에틸)프탈이미드(720 mg, 2.83 mmol), 탄산칼륨(979 mg, 7.08 mmol)을 10 ml의 N,N-디메틸포름아마이드 용액에 용해시킨후 70도에서 18 시간 교반 시켰다. 용매 제거 후 30 ml의 디클로로메탄과 30 ml의 소금물로 추출하였다. 유층을 무수 MgSO4로 건조 시킨 후 감압 여과하여 농축하였다. 잔여물을 실리카겔 컬럼크로마토그래피(디클로로메탄과 메탄올, 50/1, v/v)로 정제하여 옅은 노란색 목적화합물을 얻었다.(924 mg, 2.36 mmol, 100%)N- [3- (piperidin-4-yl) phenyl] acetamide (600 mg, 2.36 mmol) and N- (2-bromoethyl) phthalimide (720 mg, 2.83 mmol), potassium carbonate (979 mg, 7.08 mmol) was dissolved in 10 ml of N, N -dimethylformamide solution and stirred at 70 ° C. for 18 hours. After solvent removal, the mixture was extracted with 30 ml of dichloromethane and 30 ml of brine. The oil layer was dried over anhydrous MgSO 4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 50/1, v / v) to give a pale yellow target compound (924 mg, 2.36 mmol, 100%).

Rf=0.29(디클로로메탄과 메탄올, 20/1, v/v)R f = 0.29 (dichloromethane and methanol, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 7.84(m, 2H), 7.71(m, 2H), 7.58(br, s, 1H), 7.41-7.30(m, 2H), 7.21(t, J=7.8 Hz, 1H), 6.93(d, J=7.6 Hz, 1H), 3.85(t, J=6.8 Hz, 2H), 3.08(m ,2H), 2.66(t, J =6.8 Hz, 2H), 2.44(m, 1H), 2.15(s, 3H), 2.10(m, 2H), 1.80-1.58(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.84 (m, 2H), 7.71 (m, 2H), 7.58 (br, s, 1H), 7.41-7.30 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.85 (t, J = 6.8 Hz, 2H), 3.08 (m, 2H), 2.66 (t, J = 6.8 Hz, 2H), 2.44 ( m, 1H), 2.15 (s, 3H), 2.10 (m, 2H), 1.80-1.58 (m, 4H).

<제조예 6> N-[3-[1-[2-(1,3-다이옥소아이소인돌린-2-일)프로필]피페리딘-4-일]Preparation Example 6 N- [3- [1- [2- (1,3-dioxoisoindolin-2-yl) propyl] piperidin-4-yl] 페닐Phenyl ]] 아세트아마이드의Acetamide 제조 Produce

Figure 112011081771538-pat00059
Figure 112011081771538-pat00059

N-[3-(피페리딘-4-일)페닐]아세트아미드(2.6 g, 10.21 mmol)와 N-(3-브로모프로필)프탈이미드(3.6 g, 13.27 mmol)를 상기 제조예 5와 동일한 방법으로 반응하여 옅은 노란색 표제 화합물을(4.13 g, 10.21 mmol, 99%) 얻었다. N- [3- (piperidin-4-yl) phenyl] acetamide (2.6 g, 10.21 mmol) and N- (3-bromopropyl) phthalimide (3.6 g, 13.27 mmol) were prepared in Preparation Example 5 The reaction was carried out in the same manner as to obtain the pale yellow title compound (4.13 g, 10.21 mmol, 99%).

Rf=0.32(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.32 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 7.86(m, 2H), 7.72(m, 2H), 7.34(d, J=7.6 Hz, 1H), 7.23(m, 3H), 6.83(d, J=7.6 Hz, 1H), 3.79(t, J=6.9 Hz, 2H), 3.00(d, J=11.22 Hz, 2H), 2.46(t, J=6.9 Hz, 2H), 2.40(m, 1H), 2.17(s, 3H), 1.95(m, 4H), 1.74(d, J=11.22 Hz, 2H), 1.56(m, 2H).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.86 (m, 2H), 7.72 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.23 (m, 3H), 6.83 (d, J = 7.6 Hz, 1H), 3.79 (t, J = 6.9 Hz, 2H), 3.00 (d, J = 11.22 Hz, 2H), 2.46 (t, J = 6.9 Hz, 2H), 2.40 (m, 1H), 2.17 (s, 3H), 1.95 (m, 4H), 1.74 (d, J = 11.22 Hz, 2H), 1.56 (m, 2H).

<< 제조예Manufacturing example 7> N-[3-[1-(2- 7> N- [3- [1- (2- 아미노에틸Aminoethyl )피페리딘-4-일]) Piperidin-4-yl] 페닐Phenyl ]] 아세트아마이드의Acetamide 제조 Produce

Figure 112011081771538-pat00060
Figure 112011081771538-pat00060

상기 제조예 5에서 얻은 화합물(924 mg, 2.36 mmol)을 10 ml 에탄올에 용해시킨 후 히드라진수화물(80%)(310 ul, 7.08 mmol)을 가한후 상온에서 18 시간 교반하였다. 감압하에서 용매를 제거 하여 노란색 오일 화합물을 얻었다.( 270 mg, 1.03 mmol, 44%)The compound (924 mg, 2.36 mmol) obtained in Preparation Example 5 was dissolved in 10 ml ethanol, followed by addition of hydrazine hydrate (80%) (310 ul, 7.08 mmol), followed by stirring at room temperature for 18 hours. The solvent was removed under reduced pressure to give a yellow oil compound (270 mg, 1.03 mmol, 44%).

1H NMR(300 MHz, CDCl3) δ 8.70(br, s ,1H), 7.38(m, 2H), 7.20(t, J=8.1 Hz, 1H), 6.92(d, J=7.6 Hz, 1H), 2.95(m, 2H), 2.82(t, J=6.1 Hz, 2H), 2.44(t, J=6.1 Hz, 2H), 2.40(m, 1H), 2.15(s, 3H), 2.01(m, 2H), 1.80-1.61(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.70 (br, s, 1H), 7.38 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H) , 2.95 (m, 2H), 2.82 (t, J = 6.1 Hz, 2H), 2.44 (t, J = 6.1 Hz, 2H), 2.40 (m, 1H), 2.15 (s, 3H), 2.01 (m, 2H), 1.80-1.61 (m, 4H).

<< 제조예Manufacturing example 8> N-[3-[1-(2-아미노프로필)피페리딘-4-일] 8> N- [3- [1- (2-aminopropyl) piperidin-4-yl] 페닐Phenyl ]] 아세트아마이드의Acetamide 제조 Produce

Figure 112011081771538-pat00061
Figure 112011081771538-pat00061

상기 제조예 6에서 얻은 화합물(1.5 g, 3.70 mmol)을 제조예 7과 동일한 방법으로 처리하여 갈색 표제 화합물을(1.02 g, 3.70 mmol, 100 %) 얻었다. Compound (1.5 g, 3.70 mmol) obtained in Preparation Example 6 was treated in the same manner as Preparation Example 7, to obtain a brown title compound (1.02 g, 3.70 mmol, 100%).

1H NMR(300 MHz, CDCl3) δ 9.23(br, s, 1H), 8.20(m, 1H), 7.64(m, 1H), 7.14(t, J=6.2 Hz, 1H), 6.77(d, J=6.2 Hz, 1H), 5.91(br, s, 2H), 3.08(t, J=5.8 Hz, 2H), 2.92(d, J=11.28 Hz, 2H), 2.47(t, J=5.8 Hz, 2H), 2.29(s, 3H), 2.22(m, 1H), 1.81(m, 4H), 1.43(m, 2H), 1.28(m, 2H).
1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (br, s, 1H), 8.20 (m, 1H), 7.64 (m, 1H), 7.14 (t, J = 6.2 Hz, 1H), 6.77 (d, J = 6.2 Hz, 1H), 5.91 (br, s, 2H), 3.08 (t, J = 5.8 Hz, 2H), 2.92 (d, J = 11.28 Hz, 2H), 2.47 (t, J = 5.8 Hz, 2H), 2.29 (s, 3H), 2.22 (m, 1H), 1.81 (m, 4H), 1.43 (m, 2H), 1.28 (m, 2H).

<< 실시예Example 1> N-[2-[4-(3- 1> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(4-) Piperidin-1-yl] propyl] -5- (4- 클로Claw 로페닐)Rophenyl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00062
Figure 112011081771538-pat00062

5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(40 mg, 0.12 mmol)을 다이클로로에탄(1 ml)에 용해 시킨후, 싸이오닐클로라이드(1 ml)를 첨가한뒤 80도에서 3시간동안 가열하였다. 반응이 완결되면, 용매를 감압 농축한 후, 여액을 다이클로로메탄(3 ml)에 용해시킨후, N-[3-[1-(3-아미노프로필)피페리딘-4-일]페닐]아세트아마이드(41 mg, 0.15 mmol)와 트리에틸아민(35 ul, 0.25 mmol)을 순차적으로 첨가한 뒤, 12시간동안 상온에서 교반시켰다. 반응이 완결된 후, 물(10 ml)을 가하고 다이클로로메탄(10 ml)으로 두 번 추출한다. 황산마그네슘(MgSO4)으로 건조시킨 후 여과하여, 여액을 감압하에서 농축시키고 실리카겔 컬럼 크로마토그라피(메탄올:다이클로로메탄=1:10)로 정제하여 고체의 목적 화합물(15 mg, 0.03 mmol, 21%)을 얻었다.5- (4-chlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (40 mg, 0.12 mmol) was dissolved in dichloroethane (1 ml), followed by thionyl chloride (1 ml). ) Was heated at 80 degrees for 3 hours. When the reaction was completed, the solvent was concentrated under reduced pressure, the filtrate was dissolved in dichloromethane (3 ml), and then N- [3- [1- (3-aminopropyl) piperidin-4-yl] phenyl] Acetamide (41 mg, 0.15 mmol) and triethylamine (35 ul, 0.25 mmol) were added sequentially, followed by stirring at room temperature for 12 hours. After completion of the reaction, water (10 ml) is added and extracted twice with dichloromethane (10 ml). After drying over magnesium sulfate (MgSO 4 ) and filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane = 1: 10) to give the title compound as a solid (15 mg, 0.03 mmol, 21%). )

Rf= 0.47(10% MeOH in MC)Rf = 0.47 (10% MeOH in MC)

1H-NMR(300MHz, CDCl3) δ 8.40-8.42(m, 1H), 7.84-7.91(m, 1H), 7.60(d, J=6.8 Hz, 2H), 7.40-7.50(m, 4H), 7.36-7.43(m, 3H), 7.09-7.26(m, 3H), 6.88(d, J=7.6 Hz, 1H), 3.65-3.71(m, 2H), 3.25(d, J=11.0 Hz, 2H), 2.69(t, J=6.4 Hz, 2H), 2.51-2.59(m, 1H), 2.11(s, 3H), 1.88-2.04(m, 8H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 8.40-8.42 (m, 1H), 7.84-7.91 (m, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.40-7.50 (m, 4H), 7.36-7.43 (m, 3H), 7.09-7.26 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 3.65-3.71 (m, 2H), 3.25 (d, J = 11.0 Hz, 2H) , 2.69 (t, J = 6.4 Hz, 2H), 2.51-2.59 (m, 1H), 2.11 (s, 3H), 1.88-2.04 (m, 8H)

<< 실시예Example 2> N-[2-[4-(3- 2> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]에틸]-5-(4-) Piperidin-1-yl] ethyl] -5- (4- 클로로Chloro 페닐)Phenyl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00063
Figure 112011081771538-pat00063

5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(100 mg, 0.31 mmol)을 5 ml의 디클로로에탄에 용해시킨 후 500 ul의 SOCl2를 첨가하여 3 시간 환류교반 하였다. 용매를 완전히 제거한 후 10 ml의 디클로로메탄에 용해시킨 후 트리에틸아민(86 ul, 0.62 mmol)과 N-[3-[1-(2-아미노에틸)피페리딘-4-일]페닐]아세트아마이드(97 mg, 0.37 mmol)을 첨가하여 상온에서 15 시간 교반 시켰다. 30 ml의 디클로로메탄과 30 ml의 물로 추출하였다. 물층을 한 차례 더 추출하였다. 유층을 무수 MgSO4로 건조 시킨 후 감압 여과하여 농축하였다. 잔여물을 실리카겔 컬럼크로마토그래피(디클로로메탄과 메탄올, 10/1, v/v)로 정제하여 목적화합물을 하얀 고체 화합물로 얻었다.(138 mg, 0.24 mmol, 79%)5- (4-chlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (100 mg, 0.31 mmol) was dissolved in 5 ml of dichloroethane and 500 ul of SOCl 2 was added to give 3 Time reflux was stirred. The solvent was completely removed and dissolved in 10 ml of dichloromethane, followed by triethylamine (86 ul, 0.62 mmol) and N- [3- [1- (2-aminoethyl) piperidin-4-yl] phenyl] acet Amide (97 mg, 0.37 mmol) was added and stirred at room temperature for 15 hours. Extracted with 30 ml of dichloromethane and 30 ml of water. The water layer was extracted once more. The oil layer was dried over anhydrous MgSO 4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 10/1, v / v) to give the title compound as a white solid compound (138 mg, 0.24 mmol, 79%).

Rf=0.14(디클로로메탄과 메탄올, 20/1, v/v)Rf = 0.14 (dichloromethane and methanol, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.43(d, J =8.0 Hz, 1H), 7.87(d, J=8.5 Hz, 1H), 7.70-7.58(m, 4H), 7.54-45(m, 3H), 7.44-7.36(m, 4H), 7.33-7.25(m, 2H), 7.04(d, J=7.2 Hz, 1H), 3.65(m, 2H), 3.12(d, J =11.4 Hz, 2H), 2.72(t, J=6.0 Hz, 2H), 2.58(m, 1H), 2.23(m, 2H), 2.16(s, 3H), 1.98-1.78(m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.70-7.58 (m, 4H), 7.54-45 (m, 3H), 7.44-7.36 (m, 4H), 7.33-7.25 (m, 2H), 7.04 (d, J = 7.2 Hz, 1H), 3.65 (m, 2H), 3.12 (d, J = 11.4 Hz, 2H ), 2.72 (t, J = 6.0 Hz, 2H), 2.58 (m, 1H), 2.23 (m, 2H), 2.16 (s, 3H), 1.98-1.78 (m, 4H).

<< 실시예Example 3> N-[2-[4-(3- 3> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]부틸]-5-(4-) Piperidin-1-yl] butyl] -5- (4- 클로로페닐Chlorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00064
Figure 112011081771538-pat00064

5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(100 mg, 0.31 mmol)을 5 ml의 디클로로에탄에 용해시킨 후 500 ul의 SOCl2를 첨가하여 3 시간 환류교반 하였다. 용매를 완전히 제거한 후 10 ml의 디클로로메탄에 용해시킨 후 트리에틸아민(86 ul, 0.62 mmol)과 N-[3-[1-(4-아미노부틸)피페리딘-4-일]페닐]아세트아마이드(108 mg, 0.37 mmol)을 첨가하여 상온에서 15 시간 교반 시켰다. 30 ml의 디클로로메탄과 30 ml의 물로 추출하였다. 물층을 한 차례 더 추출하였다. 유층을 무수 MgSO4로 건조 시킨 후 감압 여과하여 농축하였다. 잔여물을 실리카겔 컬럼크로마토그래피(디클로로메탄과 메탄올, 10/1, v/v)로 정제하여 목적화합물을 노란 고체 화합물로 얻었다.(136 mg, 0.23 mmol, 79%)5- (4-chlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (100 mg, 0.31 mmol) was dissolved in 5 ml of dichloroethane and 500 ul of SOCl 2 was added to give 3 Time reflux was stirred. The solvent was completely removed and dissolved in 10 ml of dichloromethane, followed by triethylamine (86 ul, 0.62 mmol) and N- [3- [1- (4-aminobutyl) piperidin-4-yl] phenyl] acet Amide (108 mg, 0.37 mmol) was added and stirred at room temperature for 15 hours. Extracted with 30 ml of dichloromethane and 30 ml of water. The water layer was extracted once more. The oil layer was dried over anhydrous MgSO 4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 10/1, v / v) to give the title compound as a yellow solid (136 mg, 0.23 mmol, 79%).

Rf=0.12(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.12 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.57(d, J =8.0 Hz, 1H), 8.31(s, 1H), 7.82(m, 2H), 7.66(s, 1H), 7.64-7.56(m, 2H), 7.53(s, 1H), 7.49-7.41(m, 3H), 7.41-7.33(m, 2H), 7.31(br, s, 1H0, 7.02(t, J=7.9 Hz, 1H), 6.89(d, J=7.9 Hz, 1H), 3.61(q, J=4.7, 10.9 Hz, 2H), 3.55(m, 2H), 3.02(m, 2H), 2.75-2.56(m, 3H), 2.31(m, 2H), 2.22(3H), 2.02(m ,2H), 1.95-1.76(m, 4H).
1 H NMR (300 MHz, CDCl 3 ) δ 8.57 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 7.82 (m, 2H), 7.66 (s, 1H), 7.64-7.56 (m, 2H), 7.53 (s, 1H), 7.49-7.41 (m, 3H), 7.41-7.33 (m, 2H), 7.31 (br, s, 1H0, 7.02 (t, J = 7.9 Hz, 1H), 6.89 ( d, J = 7.9 Hz, 1H), 3.61 (q, J = 4.7, 10.9 Hz, 2H), 3.55 (m, 2H), 3.02 (m, 2H), 2.75-2.56 (m, 3H), 2.31 (m , 2H), 2.22 (3H), 2.02 (m, 2H), 1.95-1.76 (m, 4H).

<< 실시예Example 4> N-[2-[4-(3- 4> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]) Piperidin-1-yl] 펜틸Pentyl ]-5-(4-] -5- (4- 클로로페닐Chlorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00065
Figure 112011081771538-pat00065

5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(80 mg, 0.25 mmol)을 5 ml의 디클로로에탄에 용해시킨 후 500 ul의 SOCl2를 첨가하여 3 시간 환류교반 하였다. 용매를 완전히 제거한 후 10 ml의 디클로로메탄에 용해시킨 후 트리에틸아민(70 ul, 0.50 mmol)과 N-[3-[1-(5-아미노펜틸)피페리딘-4-일]페닐]아세트아마이드(114 mg, 0.38 mmol)을 첨가하여 상온에서 15 시간 교반 시켰다. 30 ml의 디클로로메탄과 30 ml의 물로 추출하였다. 물층을 한 차례 더 추출하였다. 유층을 무수 MgSO4로 건조 시킨 후 감압 여과하여 농축하였다. 잔여물을 실리카겔 컬럼크로마토그래피(디클로로메탄과 메탄올, 10/1, v/v)로 정제하여 목적화합물을 노란 고체 화합물로 얻었다.(38 mg, 0.06 mmol, 25%)5- (4-chlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (80 mg, 0.25 mmol) was dissolved in 5 ml of dichloroethane and then 500 ul of SOCl 2 was added to Time reflux was stirred. The solvent was completely removed and dissolved in 10 ml of dichloromethane, followed by triethylamine (70 ul, 0.50 mmol) and N- [3- [1- (5-aminopentyl) piperidin-4-yl] phenyl] acet Amide (114 mg, 0.38 mmol) was added and stirred at room temperature for 15 hours. Extracted with 30 ml of dichloromethane and 30 ml of water. The water layer was extracted once more. The oil layer was dried over anhydrous MgSO 4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 10/1, v / v) to give the title compound as a yellow solid (38 mg, 0.06 mmol, 25%).

Rf=0.06(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.06 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.43(d, J =8.2 Hz, 1H), 7.86(d, J=8.3 Hz, 1H), 7.67-7.53(m, 3H), 7.51-7.36(m, 3H), 7.51-7.36(m, 8H), 7.22(t, J=7.8 Hz, 1H), 6.94(m, 2H), 3.56(m, 2H), 3.15(d, J=11.5 Hz, 2H), 2.92(q, J=7.2, 14.4 Hz, 2H), 2.51(m, 3H), 2.18(s, 3H), 2.22-2.12(m, 3H), 1.91-1.61(m, 6H), 1.50(m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.67-7.53 (m, 3H), 7.51-7.36 (m, 3H), 7.51-7.36 (m, 8H), 7.22 (t, J = 7.8 Hz, 1H), 6.94 (m, 2H), 3.56 (m, 2H), 3.15 (d, J = 11.5 Hz, 2H), 2.92 (q, J = 7.2, 14.4 Hz, 2H), 2.51 (m, 3H), 2.18 (s, 3H), 2.22-2.12 (m, 3H), 1.91-1.61 (m, 6H), 1.50 (m, 2H).

<< 실시예Example 5> N-[2-[4-(3- 5> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]에틸]-5-(4-) Piperidin-1-yl] ethyl] -5- (4- 시아노페닐Cyanophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00066
Figure 112011081771538-pat00066

5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(100 mg, 0.32 mmol)을 상기 실시예 2와 동일한 방법으로 처리하여 옅은 노란색 표제 화합물을(90 mg, 0.16 mmol, 50%) 얻었다. 5- (4-chlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (100 mg, 0.32 mmol) was treated in the same manner as in Example 2 to obtain the pale yellow title compound (90 mg). , 0.16 mmol, 50%).

Rf=0.07(디클로메탄과 메탄올, 10/1, v/v) Rf = 0.07 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.46(d, J=8.0 Hz, 1H), 7.81(m, 3H), 7.70-7.49(m, 6H), 7.47(br, s, 1H), 7.34(m, 1H), 7.26(m, 3H), 7.04(d, J=6.9 Hz, 1H), 3.67(m, 2H), 3.14(d, J=11.6 Hz, 2H), 2.74(t, J=5.2 Hz, 2H), 2.60(m, 1H), 2.25(m, 2H), 2.16(s, 3H), 1.97(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.46 (d, J = 8.0 Hz, 1H), 7.81 (m, 3H), 7.70-7.49 (m, 6H), 7.47 (br, s, 1H), 7.34 ( m, 1H), 7.26 (m, 3H), 7.04 (d, J = 6.9 Hz, 1H), 3.67 (m, 2H), 3.14 (d, J = 11.6 Hz, 2H), 2.74 (t, J = 5.2 Hz, 2H), 2.60 (m, 1H), 2.25 (m, 2H), 2.16 (s, 3H), 1.97 (m, 4H).

<< 실시예Example 6> N-[2-[4-(3- 6> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(4-) Piperidin-1-yl] propyl] -5- (4- 시아노페닐Cyanophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00067
Figure 112011081771538-pat00067

5-(4-시아노페닐)나프토[1,2-b]퓨란-2-카르복실산(130 mg, 0.41 mmol)을 상기 실시예 1와 동일한 방법으로 처리하여 옅은 노란색 표제 화합물을(134 mg, 0.23 mmol, 57%) 얻었다. 5- (4-cyanophenyl) naphtho [1,2-b] furan-2-carboxylic acid (130 mg, 0.41 mmol) was treated in the same manner as in Example 1 to obtain a pale yellow title compound (134 mg, 0.23 mmol, 57%).

Rf=0.14(디클로메탄과 메탄올, 10/1, v/v)Rf = 0.14 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.46(m, 1H), 8.00(m, 1H), 7.85-7.78(m, 3H), 7.65-7.56(m, 4H), 7.51(m, 2H), 7.33(m, 2H), 7.18(br, s, 1H), 7.10(t, J=7.5 Hz, 1H), 6.87(d, J=7.3 Hz, 1H), 3.70(m, 2H), 3.27(d, J=11.0 Hz, 2H), 2.71(m, 2H), 2.57(m, 1H), 2.23(m, 2H), 2.13(s, 3H), 2.04-1.88(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.46 (m, 1H), 8.00 (m, 1H), 7.85-7.78 (m, 3H), 7.65-7.56 (m, 4H), 7.51 (m, 2H), 7.33 (m, 2H), 7.18 (br, s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 3.70 (m, 2H), 3.27 (d , J = 11.0 Hz, 2H), 2.71 (m, 2H), 2.57 (m, 1H), 2.23 (m, 2H), 2.13 (s, 3H), 2.04-1.88 (m, 6H).

<< 실시예Example 7> N-[2-[4-(3- 7> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]에틸]-5-(피리딘-4-일)) Piperidin-1-yl] ethyl] -5- (pyridin-4-yl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00068
Figure 112011081771538-pat00068

5-(피리딘-4-일)나프토[1,2-b]퓨란-2-카르복실산(75 mg, 0.26 mmol)을 상기 실시예 2와 동일한 방법으로 처리하여 옅은 노란색 표제 화합물을(55 mg, 0.10 mmol, 77%) 얻었다. 5- (pyridin-4-yl) naphtho [1,2-b] furan-2-carboxylic acid (75 mg, 0.26 mmol) was treated in the same manner as in Example 2 to obtain a pale yellow title compound (55 mg, 0.10 mmol, 77%).

Rf=0.30(디클로메탄과 메탄올, 10/1, v/v)Rf = 0.30 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.76(d, J=4.4 Hz, 2H), 8.45(d, J=8.0 Hz, 1H), 7.89(d, J=8.4 Hz, 1H), 7.65(m, 3H), 7.55(m, 2H), 7.46(m, 3H), 7.39-7.19(m, 3H), 7.05(d, J=6.5 Hz, 1H), 3.67(m, 2H), 3.15(d, J=11.6 Hz, 2H), 2.74(t, J=5.2 Hz, 2H), 2.60(m, 1H), 2.25(m, 2H), 2.16(s, 3H), 1.93(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.76 (d, J = 4.4 Hz, 2H), 8.45 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.65 (m , 3H), 7.55 (m, 2H), 7.46 (m, 3H), 7.39-7.19 (m, 3H), 7.05 (d, J = 6.5 Hz, 1H), 3.67 (m, 2H), 3.15 (d, J = 11.6 Hz, 2H), 2.74 (t, J = 5.2 Hz, 2H), 2.60 (m, 1H), 2.25 (m, 2H), 2.16 (s, 3H), 1.93 (m, 4H).

<< 실시예Example 8> N-[2-[4-(3- 8> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(피리딘-4-일)) Piperidin-1-yl] propyl] -5- (pyridin-4-yl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00069
Figure 112011081771538-pat00069

5-(피리딘-4-일)나프토[1,2-b]퓨란-2-카르복실산(120 mg, 0.41 mmol)을 상기 실시예 1와 동일한 방법으로 처리하여 살구색 표제 화합물을(100 mg, 0.18 mmol, 45%) 얻었다.5- (pyridin-4-yl) naphtho [1,2-b] furan-2-carboxylic acid (120 mg, 0.41 mmol) was treated in the same manner as in Example 1 to obtain an apricot title compound (100 mg , 0.18 mmol, 45%) was obtained.

Rf=0.22(디클로로메탄과 메탄올, 5/1, v/v)Rf = 0.22 (dichloromethane and methanol, 5/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.44(m, 1H), 8.03(m, 1H), 7.91(m, 1H), 7.61(d, J=2.3 Hz, 2H), 7.56-7.39(m, 7H), 7.23(s, br, 1H), 7.12(t, J=7.8 Hz, 1H), 6.87(d, J=7.7 Hz, 1H), 3.68(m, 2H), 3.26(d, J=11.7 Hz, 2H), 7.23(m, 2H), 2.56(m, 1H), 2.23(m, 2H), 2.12(s, 3H), 2.07-1.84(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.44 (m, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.61 (d, J = 2.3 Hz, 2H), 7.56-7.39 (m, 7H), 7.23 (s, br, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.68 (m, 2H), 3.26 (d, J = 11.7 Hz, 2H), 7.23 (m, 2H), 2.56 (m, 1H), 2.23 (m, 2H), 2.12 (s, 3H), 2.07-1.84 (m, 6H).

<< 실시예Example 9> N-[2-[4-(3- 9> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]에틸]-5-(2-) Piperidin-1-yl] ethyl] -5- (2- 클로로Chloro 피리딘-4-일)Pyridin-4-yl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00070
Figure 112011081771538-pat00070

5-(2-클로로피리딘-4-일)나프토[1,2-b]퓨란-2-카르복실산(123 mg, 0.35 mmol)을 상기 실시예 2과 동일한 방법으로 처리하여 상아색 표제 화합물을(106 mg, 0.19 mmol, 53%) 얻었다.5- (2-chloropyridin-4-yl) naphtho [1,2-b] furan-2-carboxylic acid (123 mg, 0.35 mmol) was treated in the same manner as in Example 2 to obtain an ivory title compound. (106 mg, 0.19 mmol, 53%) was obtained.

Rf=0.25(디클로메탄과 메탄올, 10/1, v/v) Rf = 0.25 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.53(d, J=5.3 Hz, 1H), 8.46(d, J=7.8 Hz, 1H), 7.86(d, J=8.8 Hz, 1H), 7.66(m, 2H), 7.63(m, 2H), 7.52(s, 1H), 7.48(s, 1H), 7.40(d, J=5.3 Hz, 1H), 7.31(m, 1H), 7.28(m, 2H), 7.12(s, 1H), 7.04(m, 1H), 3.67(m, 2H), 3.14(d, J=11 Hz, 2H), 2.74(t, J=7.3 Hz, 2H), 2.59(m, 1H), 2.25(m, 2H), 2.16(s, 3H), 1.93(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.53 (d, J = 5.3 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.66 (m) , 2H), 7.63 (m, 2H), 7.52 (s, 1H), 7.48 (s, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.31 (m, 1H), 7.28 (m, 2H) , 7.12 (s, 1H), 7.04 (m, 1H), 3.67 (m, 2H), 3.14 (d, J = 11 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.59 (m, 1H), 2.25 (m, 2H), 2.16 (s, 3H), 1.93 (m, 4H).

<< 실시예Example 10> N-[2-[4-(3- 10> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]에틸]-5-(6-) Piperidin-1-yl] ethyl] -5- (6- 플푸오로피리딘Flufuropyridine -3-일)-3 days) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00071
Figure 112011081771538-pat00071

5-(6-플푸오로피리딘-3-일)나프토[1,2-b]퓨란-2-카르복실산(78 mg, 0.25 mmol)을 상기 실시예 2와 동일한 방법으로 처리하여 노란색 표제 화합물을(51 mg, 0.1 mmol, 37%) 얻었다.5- (6-Fluoropyridin-3-yl) naphtho [1,2-b] furan-2-carboxylic acid (78 mg, 0.25 mmol) was treated in the same manner as in Example 2 above to give the yellow title compound. (51 mg, 0.1 mmol, 37%) was obtained.

Rf=0.05(디클로메탄과 메탄올, 20/1, v/v) Rf = 0.05 (dichloromethane and methanol, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.47(d, J=7.9 Hz, 1H), 8.35(d, J=2.3 Hz, 1H), 7.92(m, 1H), 7.78(d, J=8.4 Hz, 1H), 7.68(d, J=7.9 Hz, 1H), 7.63(m, 3H), 7.55(m, 2H), 7.45(s, 1H), 7.36(d, J=8.1 Hz, 1H), 7.27(m, 2H), 7.10(dd, J=2.6, 8.4 Hz, 1H), 7.04(d, J=7.5 Hz, 1H), 3.68(q, J=5.9, 10.9 Hz, 2H), 3.16(d, J=11.5 Hz, 2H), 2.75(t, J=5.9 Hz, 2H), 2.60(m, 1H), 2.27(m, 2H), 2.16(s, 3H), 1.92(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.47 (d, J = 7.9 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.92 (m, 1H), 7.78 (d, J = 8.4 Hz , 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.63 (m, 3H), 7.55 (m, 2H), 7.45 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.27 (m, 2H), 7.10 (dd, J = 2.6, 8.4 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 3.68 (q, J = 5.9, 10.9 Hz, 2H), 3.16 (d, J = 11.5 Hz, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.60 (m, 1H), 2.27 (m, 2H), 2.16 (s, 3H), 1.92 (m, 4H).

<< 실시예Example 11> N-[2-[4-(3- 11> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]에틸]-5-(6-) Piperidin-1-yl] ethyl] -5- (6- 메톡시피리딘Methoxypyridine -3-일)-3 days) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00072
Figure 112011081771538-pat00072

5-(6-메톡시피리딘-3-일)나프토[1,2-b]퓨란-2-카르복실산(80 mg, 0.25 mmol)을 상기 실시예 2와 동일한 방법으로 처리하여 옅은 노란색 표제화합물을(56 mg, 0.10 mmol, 40%) 얻었다.5- (6-methoxypyridin-3-yl) naphtho [1,2-b] furan-2-carboxylic acid (80 mg, 0.25 mmol) was treated in the same manner as in Example 2 to obtain a pale yellow title. Compound (56 mg, 0.10 mmol, 40%) was obtained.

Rf=0.05(디클로메탄과 메탄올, 10/1, v/v) Rf = 0.05 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.43(d, J=8.2 Hz, 1H), 8.27(d, J=1.9 Hz, 1H), 7.85(d, J=8.3 Hz, 1H), 7.68(m, 2H), 7.64-7.56(m, 3H), 7.51(d, J=7.7 Hz, 1H), 7.42(s, 1H), 7.38(d, J=8.2 Hz, 1H), 7.27(m, 2H), 7.03(d, J=7.1 Hz, 1H), 6.89(d, J=8.3 Hz, 1H), 4.04(s, 3H), 3.70(m, 2H), 3.23(d, J=11.3 Hz, 2H), 2.82(m, 2H), 2.61(m, 1H), 2.32(m, 2H), 2.15(s, 3H), 1.94(m, 4H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.68 (m , 2H), 7.64-7.56 (m, 3H), 7.51 (d, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.27 (m, 2H) , 7.03 (d, J = 7.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.04 (s, 3H), 3.70 (m, 2H), 3.23 (d, J = 11.3 Hz, 2H) , 2.82 (m, 2H), 2.61 (m, 1H), 2.32 (m, 2H), 2.15 (s, 3H), 1.94 (m, 4H).

<< 실시예Example 12> N-[2-[4-(3- 12> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]) Piperidin-1-yl] propyl] 나프토Naft [[ 1,2-b]퓨란1,2-b] furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00073
Figure 112011081771538-pat00073

나프토[1,2-b]퓨란-2-카르복실산(140 mg, 0.66 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 옅은 노란색 표제 화합물을(133 mg, 0.28 mmol, 43%) 얻었다.Naphtho [1,2-b] furan-2-carboxylic acid (140 mg, 0.66 mmol) was treated in the same manner as in Example 1 to obtain a pale yellow title compound (133 mg, 0.28 mmol, 43%). .

Rf=0.16(디클로로메탄과 메탄올, 20/1, v/v)Rf = 0.16 (dichloromethane and methanol, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.32(d, J=7.7 Hz,1H), 7.93(d, J =8.2 Hz, 1H), 7.99(m, 1H), 7.68(m, 2H), 7.60(s, 1H), 7.51(m, 1H), 7.43(m, 3H), 7.16(s, 1H), 7.12(t, J =7.9 Hz, 1H), 6.86(d, J =7.6 Hz, 1H), 3.64(m, 2H), 3.22(d, J =11.5 Hz, 2H), 2.68(t, J =6.4 Hz, 2H), 2.50(m, 1H), 2.20(m, 2H), 2.12(s, 3H), 1.98-1.86(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.99 (m, 1H), 7.68 (m, 2H), 7.60 (s, 1H), 7.51 (m, 1H), 7.43 (m, 3H), 7.16 (s, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H) , 3.64 (m, 2H), 3.22 (d, J = 11.5 Hz, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.50 (m, 1H), 2.20 (m, 2H), 2.12 (s, 3H), 1.98-1.86 (m, 6H).

<< 실시예Example 13> N-[2-[4-(3- 13> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-) Piperidin-1-yl] propyl] -5- 브로모나프토[1,2-b]퓨란Bromonaphtho [1,2-b] furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00074
Figure 112011081771538-pat00074

5-브로모나프토[1,2-b]퓨란-2-카르복실산(40 mg, 0.14 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 고체화합물을(58 mg, 0.11 mmol, 77%)얻었다.5-Bromonaphtho [1,2-b] furan-2-carboxylic acid (40 mg, 0.14 mmol) was treated in the same manner as in Example 1 to obtain a solid compound (58 mg, 0.11 mmol, 77%). Got it.

Rf= 0.46(10% MeOH in MC)Rf = 0.46 (10% MeOH in MC)

1H-NMR(300MHz, CDCl3) 1 H-NMR (300 MHz, CDCl 3 )

δ= 8.43(d, J=8.1 Hz, 1H), 8.32(d, J=8.1 Hz, 1H), 8.26-8.28(m, 1H), 8.00(s, 1H), 7.52-7.66(m, 4H), 7.46(d, J=9.0 Hz, 1H), 7.25(m, 1H), 7.15(d, J=7.8 Hz, 1H), 6.87(d, J=7.5 Hz, 1H), 3.65-3.72(m, 2H), 3.38(t, J=11.7 Hz, 2H), 2.86(t, J=6.6 Hz, 2H), 2.53-2.59(m, 1H), 2.39(t, J=11.7 Hz, 2H), 2.17(s, 3H), 2.06-2.12(m, 4H), 1.89-1.93(m, 2H)
delta = 8.43 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.26-8.28 (m, 1H), 8.00 (s, 1H), 7.52-7.66 (m, 4H) , 7.46 (d, J = 9.0 Hz, 1H), 7.25 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 3.65-3.72 (m, 2H), 3.38 (t, J = 11.7 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H), 2.53-2.59 (m, 1H), 2.39 (t, J = 11.7 Hz, 2H), 2.17 ( s, 3H), 2.06-2.12 (m, 4H), 1.89-1.93 (m, 2H)

<< 실시예Example 14> N-[2-[4-(3- 14> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-) Piperidin-1-yl] propyl] -5- 메틸나프토[1,2-b]퓨란Methylnaphtho [1,2-b] furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00075
Figure 112011081771538-pat00075

5-메틸나프토[1,2-b]퓨란-2-카르복실산(117 mg, 0.52 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 하얀색 표제 화합물을(69 mg, 0.14 mmol, 27%) 얻었다.5-Methylnaphtho [1,2-b] furan-2-carboxylic acid (117 mg, 0.52 mmol) was treated in the same manner as in Example 1 to yield the white title compound (69 mg, 0.14 mmol, 27%. )

Rf=0.23(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.23 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.37(d, J=7.6 Hz, 1H), 8.05(d, J=8.4 Hz, 1H), 7.98(m, 1H), 7.62-7.40(m, 5H), 7.19(s, 1H), 7.62-7.40(m, 5H), 7.19(s, 1H), 7.14(t, J=7.9 Hz, 1H), 6.88(d, J=7.7 Hz, 1H), 3.66(m, 2H), 3.30(d, J =10.6 Hz, 2H), 2.78-2.67(m, 2H), 2.72(s, 3H), 2.55(m, 1H), 2.25(m, 1H), 2.12(s, 3H), 2.07-1.84(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.37 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.98 (m, 1H), 7.62-7.40 (m, 5H) , 7.19 (s, 1H), 7.62-7.40 (m, 5H), 7.19 (s, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 3.66 ( m, 2H), 3.30 (d, J = 10.6 Hz, 2H), 2.78-2.67 (m, 2H), 2.72 (s, 3H), 2.55 (m, 1H), 2.25 (m, 1H), 2.12 (s , 3H), 2.07-1.84 (m, 6H).

<< 실시예Example 15> N-[2-[4-(3- 15> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-) Piperidin-1-yl] propyl] -5- 페닐나프토[1,2-b]퓨란Phenylnaphtho [1,2-b] furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00076
Figure 112011081771538-pat00076

5-페닐나프토[1,2-b]퓨란-2-카르복실산(120 mg, 0.42 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 옅은 노란색 표제 화합물을(98 mg, 0.18 mmol, 43%) 얻었다.5-phenylnaphtho [1,2-b] furan-2-carboxylic acid (120 mg, 0.42 mmol) was treated in the same manner as in Example 1 to obtain the pale yellow title compound (98 mg, 0.18 mmol, 43 %) Obtained.

Rf=0.22(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.22 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.44(m, 1H), 8.03(m, 1H), 7.91(m, 1H), 7.61(d, J=2.3 Hz, 2H), 7.56-7.39(m, 7H), 7.23(s, br, 1H), 7.12(t, J=7.8 Hz, 1H), 6.87(d, J=7.7 Hz, 1H), 3.68(m, 2H), 3.26(d, J=11.7 Hz, 2H), 7.23(m, 2H), 2.56(m, 1H), 2.23(m, 2H), 2.12(s, 3H), 2.07-1.84(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.44 (m, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.61 (d, J = 2.3 Hz, 2H), 7.56-7.39 (m, 7H), 7.23 (s, br, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.68 (m, 2H), 3.26 (d, J = 11.7 Hz, 2H), 7.23 (m, 2H), 2.56 (m, 1H), 2.23 (m, 2H), 2.12 (s, 3H), 2.07-1.84 (m, 6H).

<< 실시예Example 16> N-[2-[4-(3- 16> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(4-) Piperidin-1-yl] propyl] -5- (4- 플루오로페닐Fluorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00077
Figure 112011081771538-pat00077

5-(4-플루오로페닐)나프토[1,2-b]퓨란-2-카르복실산(95 mg, 0.31 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(96 mg, 0.17 mmol, 55%) 얻었다.5- (4-fluorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (95 mg, 0.31 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound (96 mg , 0.17 mmol, 55%) was obtained.

Rf=0.16(디클로로메탄과 메탄올, 20/1, v/v)Rf = 0.16 (dichloromethane and methanol, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.44(m, 1H), 8.04(m, 1H), 7.83(m, 1H), 7.66(m, 2H), 7.57(s, 1H), 7.52-7.40(m, 5H), 7.27(m, 1H), 7.19(t, J =8.7 Hz, 2H), 7.11(t, J =7.8 Hz, 1H), 6.86(d, J =7.6 Hz, 1H), 3.68(m, 2H), 3.27(d, J =11.7 Hz, 2H), 3.24(t, J =6.3 Hz, 2H), 2.53(m,1H), 2.25(m, 2H), 2.13(s, 3H), 2.10-1.89(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.44 (m, 1H), 8.04 (m, 1H), 7.83 (m, 1H), 7.66 (m, 2H), 7.57 (s, 1H), 7.52-7.40 ( m, 5H), 7.27 (m, 1H), 7.19 (t, J = 8.7 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 3.68 ( m, 2H), 3.27 (d, J = 11.7 Hz, 2H), 3.24 (t, J = 6.3 Hz, 2H), 2.53 (m, 1H), 2.25 (m, 2H), 2.13 (s, 3H), 2.10-1.89 (m, 6 H).

<< 실시예Example 17> N-[2-[4-(3- 17> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(3-) Piperidin-1-yl] propyl] -5- (3- 클로로페닐Chlorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00078
Figure 112011081771538-pat00078

5-(3-클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(123 mg, 0.38 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(72 mg, 0.12 mmol, 27%) 얻었다.5- (3-chlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (123 mg, 0.38 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound (72 mg, 0.12 mmol, 27%).

Rf=0.17(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.17 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.45(m, 1H), 8.06(m, 1H), 7.84(m, 1H), 7.61(s, 1H), 7.58(s, 1H), 7.53-7.26(m, 9H), 7.11(t, J=7.3 Hz, 1H), 6.87(d, J=7.7 Hz, 1H), 3.68(m, 2H), 3.27(d, J=10.9 Hz, 2H), 2.74(t, J=5.8 Hz, 2H), 2.55(m, 1H), 2.25(m, 2H), 2.13(s, 3H), 2.05-1.84(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (m, 1H), 8.06 (m, 1H), 7.84 (m, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.53-7.26 ( m, 9H), 7.11 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.68 (m, 2H), 3.27 (d, J = 10.9 Hz, 2H), 2.74 ( t, J = 5.8 Hz, 2H), 2.55 (m, 1H), 2.25 (m, 2H), 2.13 (s, 3H), 2.05-1.84 (m, 6H).

<< 실시예Example 18> N-[2-[4-(3- 18> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(4-) Piperidin-1-yl] propyl] -5- (4- 메틸페닐Methylphenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00079
Figure 112011081771538-pat00079

5-(4-메틸페닐)나프토[1,2-b]퓨란-2-카르복실산(120 mg, 0.40 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(88 mg, 0.16 mmol, 39%) 얻었다.5- (4-methylphenyl) naphtho [1,2-b] furan-2-carboxylic acid (120 mg, 0.40 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound (88 mg, 0.16 mmol, 39%).

Rf=0.15(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.15 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.43(m, 1H), 8.08(s, 1H), 7.91(m, 1H), 7.61(s, 2H), 7.57(s, 1H), 7.51-7.41(m, 3H), 7.36(d, J=8.0 Hz, 2H), 7.30(d, J=8.0 Hz, 2H), 7.21(s, 1H), 7.11(t, J=7.8 Hz, 1H), 6.85(d, J=7.6 Hz, 1H,), 3.66(m, 2H), 3.22(d, J=11.7 Hz, 2H), 2.71(t, J=6.1 Hz, 2H), 2.56-2.48(m, 1H), 2.46(s, 3H), 2.20(m, 2H), 2.12(s, 3H), 2.04-1.83(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (m, 1H), 8.08 (s, 1H), 7.91 (m, 1H), 7.61 (s, 2H), 7.57 (s, 1H), 7.51-7.41 ( m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.85 ( d, J = 7.6 Hz, 1H,), 3.66 (m, 2H), 3.22 (d, J = 11.7 Hz, 2H), 2.71 (t, J = 6.1 Hz, 2H), 2.56-2.48 (m, 1H) , 2.46 (s, 3H), 2.20 (m, 2H), 2.12 (s, 3H), 2.04-1.83 (m, 6H).

<< 실시예Example 19> N-[2-[4-(3- 19> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(3-) Piperidin-1-yl] propyl] -5- (3- 시아노페닐Cyanophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00080
Figure 112011081771538-pat00080

5-(3-시아노페닐)나프토[1,2-b]퓨란-2-카르복실산(113 mg, 0.36 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 하얀색 표제 화합물을(109 mg, 0.19 mmol, 53%) 얻었다. 5- (3-cyanophenyl) naphtho [1,2-b] furan-2-carboxylic acid (113 mg, 0.36 mmol) was treated in the same manner as in Example 1 to obtain the white title compound (109 mg). , 0.19 mmol, 53%) was obtained.

Rf=0.33(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.33 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.51(d, J=7.4 Hz, 1H), 8.21(m, 1H), 7.80-7.36(m, 12H), 7.14(t, J=8.3 Hz, 1H), 6.90(d, J=7.6 Hz, 1H), 3.72(m, 2H), 3.43(m, 2H), 2.90(m, 2H), 2.64(m, 1H), 2.45(m, 2H), 2.14(s, 3H), 2.23-1.93(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.51 (d, J = 7.4 Hz, 1H), 8.21 (m, 1H), 7.80-7.36 (m, 12H), 7.14 (t, J = 8.3 Hz, 1H) , 6.90 (d, J = 7.6 Hz, 1H), 3.72 (m, 2H), 3.43 (m, 2H), 2.90 (m, 2H), 2.64 (m, 1H), 2.45 (m, 2H), 2.14 ( s, 3H), 2.23-1.93 (m, 6H).

<< 실시예Example 20> N-[2-[4-(3- 20> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(3,5-) Piperidin-1-yl] propyl] -5- (3,5- 다이클로로페닐Dichlorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00081
Figure 112011081771538-pat00081

5-(3,5-다이클로로페닐)나프토[1,2-b]퓨란-2-카르복실산(130 mg, 0.36 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(89 mg, 0.21 mmol, 40%) 얻었다.5- (3,5-Dichlorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (130 mg, 0.36 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound ( 89 mg, 0.21 mmol, 40%).

Rf=0.16(디클로로메탄과 메탄올, 20/1, v/v)Rf = 0.16 (dichloromethane and methanol, 20/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.42(m, 1H), 8.03(s, 1H), 7.82(m, 1H), 7.64-7.45(m, 6H), 7.42-7.30(m, 4H), 7.11(t, J =8.4 Hz, 1H), 6.86(d, J =7.7 Hz, 1H), 3.67(m, 2H), 3.24(d, J =11.0 Hz, 2H), 2.71(m, 2H), 2.55(m, 2H), 2.21(m, 2H), 2.13(s, 3H), 2.07-1.85(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.42 (m, 1H), 8.03 (s, 1H), 7.82 (m, 1H), 7.64-7.45 (m, 6H), 7.42-7.30 (m, 4H), 7.11 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 3.67 (m, 2H), 3.24 (d, J = 11.0 Hz, 2H), 2.71 (m, 2H), 2.55 (m, 2H), 2.21 (m, 2H), 2.13 (s, 3H), 2.07-1.85 (m, 6H).

<< 실시예Example 21> N-[2-[4-(3- 21> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(3-) Piperidin-1-yl] propyl] -5- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00082
Figure 112011081771538-pat00082

5-(3-클로로-4-플루오로페닐)나프토[1,2-b]퓨란-2-카르복실산(130 mg, 0.38 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 하얀색 표제 화합물을(109 mg, 0.18 mmol, 26%) 얻었다.5- (3-Chloro-4-fluorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (130 mg, 0.38 mmol) was treated in the same manner as in Example 1, to give a white title compound. (109 mg, 0.18 mmol, 26%) was obtained.

Rf=0.33(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.33 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.46(m, 1H), 8.20(s, 1H), 7.78(m, 1H), 7.65(s, 1H), 7.56(s, 1H), 7.54-7.34(m, 7H), 7.34-7.21(m, 1H), 7.16(t, J=7.9 Hz, 2H), 6.91(d, J =7.6 Hz, 1H), 3.71(m, 2H), 3.46(m, 2H), 2.94(m, 2H), 2.64(m, 1H), 2.44(m, 2H), 2.23-1.89(m, 11H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.46 (m, 1H), 8.20 (s, 1H), 7.78 (m, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.54-7.34 ( m, 7H), 7.34-7.21 (m, 1H), 7.16 (t, J = 7.9 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 3.71 (m, 2H), 3.46 (m, 2H ), 2.94 (m, 2H), 2.64 (m, 1H), 2.44 (m, 2H), 2.23-1.89 (m, 11H).

<< 실시예Example 22> N-[2-[4-(3- 22> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(3,4-) Piperidin-1-yl] propyl] -5- (3,4- 다이플루오로페닐Difluorophenyl )) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00083
Figure 112011081771538-pat00083

5-(3,4-다이플루오로페닐)나프토[1,2-b]퓨란-2-카르복실산(104 mg, 0.32 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 하얀색 표제화합물을(68 mg, 0.12 mmol, 34%) 얻었다.5- (3,4-difluorophenyl) naphtho [1,2-b] furan-2-carboxylic acid (104 mg, 0.32 mmol) was treated in the same manner as in Example 1 to obtain a white title compound. (68 mg, 0.12 mmol, 34%) was obtained.

Rf=0.21(디클로로메탄과 메탄올, 10/1, v/v)Rf = 0.21 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.32(d, J=7.7 Hz, 1H), 7.93(d, J =8.2 Hz, 1H), 7.99(m, 1H), 7.68(m, 2H), 7.60(s, 1H), 7.51(m, 1H), 7.43(m, 3H), 7.16(s, 1H), 7.12(t, J =7.9 Hz, 1H), 6.86(d, J =7.6 Hz, 1H), 3.64(m, 2H), 3.22(d, J =11.5 Hz, 2H), 2.68(t, J =6.4 Hz, 2H), 2.50(m, 1H), 2.20(m, 2H), 2.12(s, 3H), 1.98-1.86(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.99 (m, 1H), 7.68 (m, 2H), 7.60 (s, 1H), 7.51 (m, 1H), 7.43 (m, 3H), 7.16 (s, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H) , 3.64 (m, 2H), 3.22 (d, J = 11.5 Hz, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.50 (m, 1H), 2.20 (m, 2H), 2.12 (s, 3H), 1.98-1.86 (m, 6H).

<< 실시예Example 23> N-[2-[4-(3- 23> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(피리딘-2-일)) Piperidin-1-yl] propyl] -5- (pyridin-2-yl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조  Produce

Figure 112011081771538-pat00084
Figure 112011081771538-pat00084

5-(피리딘-2-일)나프토[1,2-b]퓨란-2-카르복실산(78 mg, 0.28 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(78 mg, 0.14 mmol, 77%) 얻었다.5- (pyridin-2-yl) naphtho [1,2-b] furan-2-carboxylic acid (78 mg, 0.28 mmol) was treated in the same manner as in Example 1 to give the yellow title compound (78 mg , 0.14 mmol, 77%).

Rf=0.11(디클로메탄과 메탄올, 10/1, v/v)Rf = 0.11 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.78(d, J=4.0 Hz, 1H), 8.60(d, J=8.1 Hz, 1H), 8.50(m, 1H), 8.07(d, J=8.1 Hz, 2H), 7.85(m, 1H), 7.77(s, 1H), 7.67(s, 1H), 7.62-7.56(m, 2H), 7.50(m, 2H), 7.36(m, 1H), 7.22(s, 1H), 7.15(t, J=8.0 Hz, 1H), 6.85(d, J=7.7 Hz, 1H), 3.70(m, 2H), 3.47(m, 2H), 3.03(m, 2H), 2.49(m, 3H), 2.21(m, 4H), 2.17(s, 3H), 1.80(m, 2H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.78 (d, J = 4.0 Hz, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.50 (m, 1H), 8.07 (d, J = 8.1 Hz , 2H), 7.85 (m, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.62-7.56 (m, 2H), 7.50 (m, 2H), 7.36 (m, 1H), 7.22 ( s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 3.70 (m, 2H), 3.47 (m, 2H), 3.03 (m, 2H), 2.49 (m, 3H), 2.21 (m, 4H), 2.17 (s, 3H), 1.80 (m, 2H).

<< 실시예Example 24> N-[2-[4-(3- 24> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(피리딘-3-일)) Piperidin-1-yl] propyl] -5- (pyridin-3-yl) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00085
Figure 112011081771538-pat00085

5-(피리딘-3-일)나프토[1,2-b]퓨란-2-카르복실산(110 mg, 0.38 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(153 mg, 0.28 mmol, 74%) 얻었다. 5- (pyridin-3-yl) naphtho [1,2-b] furan-2-carboxylic acid (110 mg, 0.38 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound (153 mg). , 0.28 mmol, 74%) was obtained.

Rf=0.22(디클로메탄과 메탄올, 5/1, v/v)Rf = 0.22 (dichloromethane and methanol, 5/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.75(m, 1H), 8.71(d, J=3.6 Hz, 1H), 8.46(m, 1H), 8.03(br, s, 1H), 7.85-7.78(m, 2H), 7.63(d, J=2.6 Hz, 2H), 7.53-7.42(m, 3H), 7.36-7.29(m, 2H), 7.18(m, 1H), 7.11(t, J=7.8 Hz, 1H), 6.89(d, J=7.7 Hz, 1H), 3.70(m, 2H), 3.29(d, J=11.2 Hz, 2H), 2.73(m, 2H), 2.59(m, 1H), 2.24(m, 2H), 2.12(s, 3H), 2.05-1.88(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.75 (m, 1H), 8.71 (d, J = 3.6 Hz, 1H), 8.46 (m, 1H), 8.03 (br, s, 1H), 7.85-7.78 ( m, 2H), 7.63 (d, J = 2.6 Hz, 2H), 7.53-7.42 (m, 3H), 7.36-7.29 (m, 2H), 7.18 (m, 1H), 7.11 (t, J = 7.8 Hz , 1H), 6.89 (d, J = 7.7 Hz, 1H), 3.70 (m, 2H), 3.29 (d, J = 11.2 Hz, 2H), 2.73 (m, 2H), 2.59 (m, 1H), 2.24 (m, 2H), 2.12 (s, 3H), 2.05-1.88 (m, 6H).

<< 실시예Example 25> N-[2-[4-(3- 25> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-() Piperidin-1-yl] propyl] -5- ( 싸이오펜Thiophene -3-일)-3 days) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00086
Figure 112011081771538-pat00086

5-(싸이오펜-3-일)나프토[1,2-b]퓨란-2-카르복실산(106 mg, 0.38 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(128 mg, 0.23 mmol, 63%) 얻었다.5- (thiophen-3-yl) naphtho [1,2-b] furan-2-carboxylic acid (106 mg, 0.38 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound (128 mg, 0.23 mmol, 63%).

Rf=0.24(디클로메탄과 메탄올, 5/1, v/v)Rf = 0.24 (dichloromethane and methanol, 5/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.35(d, J=7.9 Hz, 1H), 8.03(d, J=8.3 Hz, 1H), 7.96(m, 1H), 7.66(m, 1H), 7.65(s, 1H), 7.57(s, 1H), 7.50-7.35(m, 5H), 7.26(m, 2H), 7.09(t, J=7.9 Hz, 1H), 6.84(d, J=7.3 Hz, 1H), 3.62(d, J=4.8 Hz, 2H), 3.12(d, J=10.4 Hz, 2H), 2.58(m, 2H), 2.48(m, 1H), 2.11(s, 3H), 2.06(m, 2H), 1.93-1.72(m, 4H).
1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.96 (m, 1H), 7.66 (m, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.50-7.35 (m, 5H), 7.26 (m, 2H), 7.09 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 3.62 (d, J = 4.8 Hz, 2H), 3.12 (d, J = 10.4 Hz, 2H), 2.58 (m, 2H), 2.48 (m, 1H), 2.11 (s, 3H), 2.06 ( m, 2H), 1.93-1.72 (m, 4H).

<< 실시예Example 26> N-[2-[4-(3- 26> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-() Piperidin-1-yl] propyl] -5- ( 퓨란Furan -3-일)-3 days) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00087
Figure 112011081771538-pat00087

5-(퓨란-3-일)나프토[1,2-b]퓨란-2-카르복실산(106 mg, 0.38 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(128 mg, 0.24 mmol, 63%) 얻었다. 5- (furan-3-yl) naphtho [1,2-b] furan-2-carboxylic acid (106 mg, 0.38 mmol) was treated in the same manner as in Example 1 to obtain the yellow title compound (128 mg , 0.24 mmol, 63%).

Rf=0.20(디클로메탄과 메탄올, 10/1, v/v)Rf = 0.20 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.42(d, J=8.0 Hz, 1H), 8.15(d, J=7.2 Hz, 1H), 8.08(m, 1H), 7.70-7.56(m, 5H), 7.54-7.40(m, 4H), 7.12(t, J=7.8 Hz, 1H), 6.85(d, J=7.4 Hz, 1H), 6.68(d, J=7.4 Hz, 1H), 3.66(m, 2H), 3.27(d, J=10.4 Hz, 2H), 2.74(m, 2H), 2.54(m, 1H), 2.25(m, 2H), 2.14(s, 3H), 2.08-1.82(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.42 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H), 8.08 (m, 1H), 7.70-7.56 (m, 5H) , 7.54-7.40 (m, 4H), 7.12 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 3.66 (m, 2H), 3.27 (d, J = 10.4 Hz, 2H), 2.74 (m, 2H), 2.54 (m, 1H), 2.25 (m, 2H), 2.14 (s, 3H), 2.08-1.82 (m, 6H ).

<< 실시예Example 27> N-[2-[4-(3- 27> N- [2- [4- (3- 아세트아미도페닐Acetamidophenyl )피페리딘-1-일]프로필]-5-(1-) Piperidin-1-yl] propyl] -5- (1- 메틸methyl -1H-인돌-5-일)-1H-indole-5-day) 나프토Naft [1,2-b][1,2-b] 퓨란Furan -2--2- 카르복사미드의Carboxamide 제조 Produce

Figure 112011081771538-pat00088
Figure 112011081771538-pat00088

5-(1-메틸-1H-인돌-5-일)나프토[1,2-b]퓨란-2-카르복실산(85 mg, 0.25 mmol)을 상기 실시예 1과 동일한 방법으로 처리하여 노란색 표제 화합물을(45 mg, 0.08 mmol, 31%) 얻었다. 5- (1-methyl-1H-indol-5-yl) naphtho [1,2-b] furan-2-carboxylic acid (85 mg, 0.25 mmol) was treated in the same manner as in Example 1, and yellow. The title compound (45 mg, 0.08 mmol, 31%) was obtained.

Rf=0.27(디클로메탄과 메탄올, 10/1, v/v)Rf = 0.27 (dichloromethane and methanol, 10/1, v / v)

1H NMR(300 MHz, CDCl3) δ 8.48(m, 1H), 8.07(m, 1H), 7.90(d, J=8.3 Hz, 1H), 7.67-7.59(m, 3H), 7.53-7.35(m, 5H), 7.22(m, 2H), 7.13( m, 2H), 6.89(d, J=7.3 Hz, 1H), 3.84(s, 3H), 3.69(m, 2H), 3.23(m, 2H), 2.78(m, 2H), 2.58(m, 1H), 2.28(m, 2H), 2.11(s, 3H), 2.07-1.83(m, 6H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.48 (m, 1H), 8.07 (m, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.67-7.59 (m, 3H), 7.53-7.35 ( m, 5H), 7.22 (m, 2H), 7.13 (m, 2H), 6.89 (d, J = 7.3 Hz, 1H), 3.84 (s, 3H), 3.69 (m, 2H), 3.23 (m, 2H ), 2.78 (m, 2H), 2.58 (m, 1H), 2.28 (m, 2H), 2.11 (s, 3H), 2.07-1.83 (m, 6H).

<< 실험예Experimental Example 1>  1> 나프토[1,2-b]퓨란Naphtho [l, 2-b] furan -2--2- 카르복사미드Carboxamide 유도체의  Derivative MCHMCH 수용체-1 결합 억제활성 측정 Measurement of receptor-1 binding inhibition activity

발명에 따른 나프토[1,2-b]퓨란-2-카르복사미드 유도체의 MCH 수용체-1 결합 억제 활성을 확인하기 위하여 하기와 같은 실험을 수행하였다.In order to confirm the MCH receptor-1 binding inhibitory activity of the naphtho [1,2-b] furan-2-carboxamide derivative according to the present invention, the following experiment was performed.

완충용액은 세척용액(25 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2)과 실험용액(세척용액에 BSA를 0.5%가 되도록 첨가)의 두 종류를 준비하고, MCH 수용체-1(멜라닌 농축 호르몬 수용체 서브타입-1; Euroscreen, Gosselies, Belgium)과 1 μM 유로피움으로 표지된 멜라닌 농축호르몬(Europium-labeled MCH, Eu-MCH), PerkinElmer, Turku, Finland) 및 1 mM 멜라닌 농축호르몬(MCH, #070-47, Phoenix, Belmont CA, USA)을 4 ℃에서 준비하였다. 1 μM의 유로피움으로 표지된 멜라닌 농축호르몬(Eu-MCH)과 1 mM 멜라닌 농축호르몬을 각각 8 nM(최종 반응농도: 2 nM)과 2 μM(최종 반응농도: 0.5 μM)이 되도록 희석하였다. 모든 희석과 준비과정에서 사용되는 완충용액은 실험용액이며, 세척용액은 마지막에 플레이트를 씻어 줄 때만 사용하였다. The buffer solution is prepared by two kinds of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH receptor-1 (melanin). Enriched Hormone Receptor Subtype-1; Euroscreen, Gosselies, Belgium) and 1 μM Europium labeled melanin enriched hormone (Europium-labeled MCH, Eu-MCH), PerkinElmer, Turku, Finland) and 1 mM melanin enriched hormone (MCH) , # 070-47, Phoenix, Belmont CA, USA) was prepared at 4 ° C. 1 μM of europium-labeled melanin-enriched hormone (Eu-MCH) and 1 mM of melanin-enriched hormone were diluted to 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. The buffer solution used in all dilutions and preparations was the experimental solution, and the wash solution was used only to wash the plate at the end.

MCH 수용체-1(200 assays/vial)을 1 ㎖의 실험용액에 희석하여 균질화시킨 후, 여과지가 부착된 미소판(Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA)에 8채널 파이펫(multi 8-channel, Eppendorf, Hamburg, Germany)을 이용하여 각 웰당 전체부피가 100 ㎕가 되게 반응물을 분주하였다. 이때, 비특이적결합(non specific binding) 대조군으로는 유로피움으로 표지 된 멜라닌 농축호르몬(Eu-MCH) 25 ㎕, 수용체 50 ㎕ 및 멜라닌 농축호르몬 25 ㎕를 사용하였으며, 전체결합(total binding) 대조군으로는 10% DMSO 실험용액 25 ㎕, 유로피움으로 표지된 멜라닌 농축호르몬(Eu-MCH) 25 ㎕ 및 수용체 50 ㎕을 사용하였다. 실험군으로는 본 발명에 따른 실시예 1 내지 27의 화합물 25 ㎕, 유로피움으로 표지된 멜라닌 농축호르몬(Eu-MCH) 25 ㎕ 및 수용체 50 ㎕를 사용하였다. 각 시험 화합물, 유로피움으로 표지된 멜라닌 농축호르몬(Eu-MCH) 및 멜라닌 농축호르몬은 반응 시 전체부피의 25%씩을 차지하게 되므로 첨가 직전에는 4배의 농도로 준비하였다. 이후, 15초간 약하게 흔들어 주고 상온에서 90분간 반응시켰다. 반응이 끝나면, 부분적으로 수정하여 자체 제작 화세척기(microplate washer, EMBLA, Molecular Devices)에 압력을 걸어 플레이트를 세척하였다. 세척 용액으로 웰당 300 ㎕씩 3회 여과시켜 반응하지 않고 남아 있는 유로피움으로 표지된 멜라닌 농축호르몬(Eu-MCH)을 제거하였다. 바닥의 물기를 닦아내고 웰당 150 ㎕가 되게 해리용액(DELFIA Enhancement solution, PerkinElmer, Turku, Finland)을 첨가하여 주었다. 상온에서 그대로 2 내지 4시간 동안 방치한 후 시차성 형광(Time-resolved fluorescence, TRF) 값을 다기능 형광측정기(multilabel counter, Victor2, PerkinElmer, Turku, Finland)를 이용하여 측정하였으며(방출파장:615 ㎚, 여기파장:340 ㎚), 하기 수학식 1에 의해 시차성 형광 억제율을 계산하였다.
MCH receptor-1 (200 assays / vial) was diluted in 1 ml of the test solution and homogenized. Microchannels (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA) The reactants were dispensed into a total volume of 100 μl per well using a multi-channel (Eppendorf, Hamburg, Germany). As a non-specific binding control, 25 μl of a melanin-enriched hormone (Eu-MCH) labeled with europium, 50 μl of a receptor and 25 μl of melanin-enriched hormone were used. As a total binding control, 25 μl of a 10% DMSO test solution, 25 μl of melanin-enriched hormone (Eu-MCH) labeled with europium and 50 μl of a receptor were used. As the experimental group, 25 μl of the compounds of Examples 1 to 27 according to the present invention, 25 μl of melanin enriched hormone (Eu-MCH) labeled with europium and 50 μl of the receptor were used. Each test compound, europium-labeled melanin-enriched hormone (Eu-MCH) and melanin-enriched hormone, accounted for 25% of the total volume during the reaction. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. At the end of the reaction, the plate was partially cleaned and pressure was applied to the microplate washer (EMBLA, Molecular Devices). 300 [mu] l per well of the washing solution was filtered three times to remove the residual europium-labeled melanin-enriched hormone (Eu-MCH) without reaction. Wipe off the water on the bottom and 150 μl per well was added to the dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland). Time-resolved fluorescence (TRF) values were measured using a multilabel counter (Victor2, PerkinElmer, Turku, Finland) after emptying at room temperature for 2 to 4 hours (emission wavelength: 615 nm , Excitation wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated by the following equation (1).

Figure 112011081771538-pat00089
Figure 112011081771538-pat00089

시차성 형광 억제율을 측정한 후, 50% 이상 억제된 시험물질에 한하여 IC50 값을 계산하였으며, 그 결과를 하기 표 2에 나타내었다.
After measuring the differential fluorescence inhibition rate, IC 50 values were calculated for test substances inhibited by 50% or more, and the results are shown in Table 2 below.

화합물compound IC50(nM)IC 50 (nM) 실시예 1Example 1 55 실시예 2Example 2 7070 실시예 3Example 3 77 실시예 4Example 4 450450 실시예 5Example 5 <10<10 실시예 6Example 6 1010 실시예 7Example 7 <10<10 실시예 8Example 8 1010 실시예 9Example 9 <10<10 실시예 10Example 10 1010 실시예 11Example 11 1010 실시예 12Example 12 377377 실시예 13Example 13 370370 실시예 14Example 14 690690 실시예 15Example 15 150150 실시예 16Example 16 370370 실시예 17Example 17 160160 실시예 18Example 18 211211 실시예 19Example 19 7070 실시예 20Example 20 11001100 실시예 21Example 21 200200 실시예 22Example 22 120120 실시예 23Example 23 570570 실시예 24Example 24 6060 실시예 25Example 25 270270 실시예 26Example 26 130130 실시예 27Example 27 390390

상기 표 2에 나타낸 바와 같이, 본 발명에 따른 나프토[1,2-b]퓨란-2-카르복사미드 유도체 중 실시예 1, 3, 5, 6, 7, 8, 9, 10, 및 11의 화합물이 IC50 값이 10 nM 이하 농도에서 MCH 수용체-1에 대하여 길항작용을 하는 것으로 확인되었으며, 특히, 본 발명의 실시예 1 및 실시예 3의 화합물이 IC50 값이 각각 3 nM 및 7 nM로 매우 우수한 MCH 수용체-1에 대하여 길항작용을 하는 것으로 확인되었다.As shown in Table 2, Examples 1, 3, 5, 6, 7, 8, 9, 10, and 11 of naphtho [1,2-b] furan-2-carboxamide derivatives according to the present invention. of the compound has been found to antagonize the action on MCH receptor-1 in the IC 50 value below 10 nM concentration, in particular, each of the examples 1 and 3 the compound IC 50 value of 3 nM of the present invention and 7 nM has been shown to antagonize very good MCH receptor-1.

따라서, 본 발명에 따른 유도체는 MCH 수용체-1에 대한 길항제로 작용함으로써 MCH가 MCH 수용체에 결합함으로써 유발되는 비만, 당뇨병, 대사장애, 불안증 및 우울증과 같은 MCH 수용체-1 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.
Accordingly, the derivatives according to the present invention are useful for preventing or treating MCH receptor-1 related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression caused by binding of MCH to MCH receptor by acting as an antagonist for MCH receptor- It can be useful.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
Meanwhile, the naphtho [1,2-b] furan-2-carboxamide derivative represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

<< 제제예Formulation example 1>  1> 산제의Sanje 제조 Produce

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 2 g2 g of naphtho [1,2-b] furan-2-carboxamide derivative of formula 1

유당 1 g1 g lactose

상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.
The above components were mixed and packed in airtight bags to prepare powders.

<< 제제예Formulation example 2> 정제의 제조 2> Preparation of tablets

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 100 ㎎100 mg of naphtho [1,2-b] furan-2-carboxamide derivative of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<< 제제예Formulation example 3> 캡슐제의 제조 3> Preparation of capsules

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 100 ㎎100 mg of naphtho [1,2-b] furan-2-carboxamide derivative of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<< 제제예Formulation example 4> 주사제의 제조 4> Preparation of injection

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 100 ㎎100 mg of naphtho [1,2-b] furan-2-carboxamide derivative of formula 1

만니톨 180 ㎎Mannitol 180 mg

Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 2H 2 O 26 mg

증류수 2974 ㎎Distilled water 2974 mg

통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.
According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.

<< 제제예Formulation example 5> 건강식품의 제조 5> Manufacture of health food

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 1000 ㎎Naphtho [1,2-b] furan-2-carboxamide derivative of formula 1 1000 mg

비타민 혼합물 적량Vitamin mixture quantity

비타민 A 아세테이트 70 ㎍70 [mu] g of vitamin A acetate

비타민 E 1.0 ㎎Vitamin E 1.0 mg

비타민 0.13 ㎎0.13 mg of vitamin

비타민 B2 0.15 ㎎0.15 mg of vitamin B 2

비타민 B6 0.5 ㎎0.5 mg of vitamin B 6

비타민 B12 0.2 ㎍Vitamin B 12 0.2 g

비타민 C 10 ㎎10 mg vitamin C

비오틴 10 ㎍Biotin 10 μg

니코틴산아미드 1.7 ㎎Nicotinic acid amide 1.7 mg

엽산 50 ㎎50 mg of folic acid

판토텐산 칼슘 0.5 ㎎Calcium pantothenate 0.5 mg

무기질 혼합물 적량Mineral mixture quantity

황산제1철 1.75 ㎎1.75 mg of ferrous sulfate

산화아연 0.82 ㎎0.82 mg of zinc oxide

탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg

제1인산칼륨 15 ㎎15 mg of potassium phosphate monobasic

제2인산칼슘 55 ㎎Secondary calcium phosphate 55 mg

구연산칼륨 90 ㎎Potassium citrate 90 mg

탄산칼슘 100 ㎎100 mg of calcium carbonate

염화마그네슘 24.8 ㎎
24.8 mg of magnesium chloride

상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.
Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

<< 제제예Formulation example 6> 건강 음료의 제조 6> Manufacture of health drinks

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 1000 ㎎Naphtho [1,2-b] furan-2-carboxamide derivative of formula 1 1000 mg

구연산 1000 ㎎Citric acid 1000 mg

올리고당 100 g100 g of oligosaccharide

매실농축액 2 gPlum concentrate 2 g

타우린 1 gTaurine 1 g

정제수를 가하여 전체 900 ㎖
Purified water was added to a total of 900 ml

통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2l 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 음료 조성물 제조에 사용하였다.The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 for about 1 hour. The resulting solution was filtered and sterilized in a sterilized 2 liter container, And used for manufacturing.

상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호 도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.
Although the composition ratio is a composition that is relatively suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

<< 제제예Formulation example 7> 기타 건강식품의 제조 7> Manufacture of Other Health Foods

7-1. 음료의 제조7-1. Manufacturing of beverages

꿀 522 ㎎522 mg of honey

치옥토산아미드 5 ㎎Chioctosanamide 5 mg

니코틴산아미드 10 ㎎Nicotinamide 10 mg

염산리보플라빈나트륨 3 ㎎Riboflavin Sodium Hydrochloride 3 mg

염산피리독신 2 ㎎Pyridoxine hydrochloride 2 mg

이노시톨 30 ㎎Inositol 30 mg

오르트산 50 ㎎Orthoic acid 50 mg

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 0.48~1.28 ㎎Naphtho [1,2-b] furan-2-carboxamide derivative of Formula 1 0.48-1.28 mg

물 200 ㎖
200 ml of water

상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 음료를 제조하였다.
A beverage was prepared using the above-mentioned composition and content by a conventional method.

7-2. 7-2. 츄잉껌의Of chewing gum 제조 Produce

껌베이스 20 %Gum base 20%

설탕 76.36~76.76 %Sugar 76.36-76.76%

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 0.24~0.64 %Naphtho [1,2-b] furan-2-carboxamide derivative of Formula 1 0.24 ~ 0.64%

후르츠향 1 %1% fruit flavor

물 2 %
Water 2%

상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 츄잉껌을 제조하였다.
Chewing gum was prepared using the above-mentioned composition and content by a conventional method.

7-3. 캔디의 제조7-3. Manufacture of candy

설탕 50~60 %Sugar 50 to 60%

물엿 39.26~49.66 %Syrup 39.26 ~ 49.66%

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 0.24~0.64 %Naphtho [1,2-b] furan-2-carboxamide derivative of Formula 1 0.24 ~ 0.64%

오렌지향 0.1 %
Orange flavor 0.1%

상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 캔디를 제조하였다.
The composition and the content of the candy were prepared using a conventional method.

7-4. 밀가루 식품의 제조7-4. Manufacture of flour food products

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체를 0.5 내지 5 중량부를 밀가루 100 중량부에 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.
Add 0.5 to 5 parts by weight of naphtho [1,2-b] furan-2-carboxamide derivative of formula 1 to 100 parts by weight of flour, and use this mixture to prepare bread, cake, cookies, crackers and noodles. To produce a health promoting food.

7-5. 유제품(7-5. dairy product( dairydairy productsproducts )의 제조Manufacturing

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체를 5 내지 10 중량부를 우유 100 중량부에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.
5 to 10 parts by weight of naphtho [1,2-b] furan-2-carboxamide derivative of formula 1 was added to 100 parts by weight of milk, and various milk products such as butter and ice cream were prepared using the milk.

7-6. 7-6. 선식의Solar 제조 Produce

현미, 보리, 찹쌀, 율무를 공지의 방법으로 알파화 시켜서 건조한 것을 배전한 후 분쇄기로 입도 60 메시의 분말로 제조하였다. 검은콩, 검정깨, 들깨도 공지의 방법으로 쪄서 건조한 것을 배전한 후 분쇄기로 입도 60 메시의 분말로 제조하였다. 상기에서 제조한 곡물류 및 종실류와 본 발명의 화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체를 다음과 같은 비율로 배합하여 제조하였다.
Brown rice, barley, glutinous rice, and yulmu were alphanated by a known method to distribute the dried ones, and then prepared into a powder having a particle size of 60 mesh. Black soybeans, black sesame seeds, and perilla were also steamed and dried in a known manner to prepare a powder having a particle size of 60 mesh using a grinder. The grains and seeds prepared above and the naphtho [1,2-b] furan-2-carboxamide derivatives of the general formula (1) of the present invention were prepared by combining the following ratios.

현미 30 % Brown Rice 30%

율무 15 %15% rate

보리 20 %Barley 20%

들깨 7 % Perilla 7%

검정콩 7 % Black Bean 7%

검은깨 7 %Black sesame 7%

화학식 1의 나프토[1,2-b]퓨란-2-카르복사미드 유도체 3 %Naphtho [1,2-b] furan-2-carboxamide derivative of formula 1 3%

영지 0.5 %Manure 0.5%

지황 0.5 %0.5%

Claims (10)

하기 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
Figure 112013003553565-pat00090

(상기 화학식 1에서,
n은 2 내지 10의 정수이고; 및
R1은 수소; 할로겐; C1-C4 직쇄 또는 측쇄 알킬; 비치환 또는 할로겐, 시아노, 니트로, 할로겐으로 치환된 C1-C4 직쇄 또는 측쇄 알킬, C1-C4 직쇄 또는 측쇄 알킬 및 C1-C4 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 C5-C6 아릴; 또는 비치환되거나, 할로겐, 시아노, 니트로, C1-C4 직쇄 또는 측쇄 알킬, C1-C4 직쇄 또는 측쇄 알킬 및 C1-C4 직쇄 또는 측쇄 알콕시로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 C5-C12 단일 또는 이중고리의 헤테로아릴이고, 이때, 상기 헤테로아릴은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 피리딘, 싸이오펜, 퓨란 또는 인돌이다).
Naphtho [1,2-b] furan-2-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure 112013003553565-pat00090

(In Formula 1,
n is an integer from 2 to 10; And
R 1 is hydrogen; halogen; C 1 -C 4 straight or branched chain alkyl; 1 selected from the group consisting of unsubstituted or halogen, cyano, nitro, halogen substituted C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkyl and C 1 -C 4 straight or branched alkoxy C 5 -C 6 aryl substituted with one or more species; Or unsubstituted or at least one selected from the group consisting of halogen, cyano, nitro, C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkyl and C 1 -C 4 straight or branched alkoxy C 5 -C 12 single or bicyclic heteroaryl substituted with a heteropyrid, wherein said heteroaryl is pyridine, thiophene, furan or indole comprising at least one hetero atom selected from the group consisting of N, O and S to be).
제1항에 있어서,
상기 n은 2 내지 6의 정수이고; 및
R1은 수소; 클로로; 플루오로; 브로모; 메틸; 에틸; 프로필; 이소프로필; 부틸; 이소부틸; 비치환되거나, 클로로, 플루오로, 브로모, 시아노, 니트로, 트리플루오로메틸, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 메톡시, 에톡시, 프로폭시 및 부톡시로 이루어진 군으로부터 선택되는 1종 이상을 치환된 페닐; 또는 비치환되거나, 클로로, 플루오로, 브로모, 시아노, 니트로, 트리플루오로메틸, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 메톡시, 에톡시, 프로폭시 및 부톡시로 이루어진 군으로부터 선택되는 1종 이상으로 치환된 피리딘, 싸이오펜, 퓨란 또는 인돌인 것을 특징으로 하는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염.
The method of claim 1,
N is an integer from 2 to 6; And
R 1 is hydrogen; Chloro; Fluoro; Bromo; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; Unsubstituted or consisting of chloro, fluoro, bromo, cyano, nitro, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy At least one member selected from substituted phenyl; Or unsubstituted or consisting of chloro, fluoro, bromo, cyano, nitro, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy A naphtho [1,2-b] furan-2-carboxamide derivative or a pharmaceutically acceptable salt thereof, characterized in that it is pyridine, thiophene, furan or indole substituted with at least one member selected from the group.
제1항에 있어서,
상기 n은 2 내지 6의 정수이고; 및
R1은 수소, 클로로, 플루오로, 브로모, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸,
Figure 112011081771538-pat00091
,
Figure 112011081771538-pat00092
,
Figure 112011081771538-pat00093
,
Figure 112011081771538-pat00094
,
Figure 112011081771538-pat00095
,
Figure 112011081771538-pat00096
,
Figure 112011081771538-pat00097
,
Figure 112011081771538-pat00098
,
Figure 112011081771538-pat00099
,
Figure 112011081771538-pat00100
,
Figure 112011081771538-pat00101
,
Figure 112011081771538-pat00102
,
Figure 112011081771538-pat00103
,
Figure 112011081771538-pat00104
,
Figure 112011081771538-pat00105
,
Figure 112011081771538-pat00106
,
Figure 112011081771538-pat00107
,
Figure 112011081771538-pat00108
및
Figure 112011081771538-pat00109
로 이루어지는 군으로부터 선택되는 1종인 것을 특징으로 하는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염.
The method of claim 1,
N is an integer from 2 to 6; And
R 1 is hydrogen, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Figure 112011081771538-pat00091
,
Figure 112011081771538-pat00092
,
Figure 112011081771538-pat00093
,
Figure 112011081771538-pat00094
,
Figure 112011081771538-pat00095
,
Figure 112011081771538-pat00096
,
Figure 112011081771538-pat00097
,
Figure 112011081771538-pat00098
,
Figure 112011081771538-pat00099
,
Figure 112011081771538-pat00100
,
Figure 112011081771538-pat00101
,
Figure 112011081771538-pat00102
,
Figure 112011081771538-pat00103
,
Figure 112011081771538-pat00104
,
Figure 112011081771538-pat00105
,
Figure 112011081771538-pat00106
,
Figure 112011081771538-pat00107
,
Figure 112011081771538-pat00108
And
Figure 112011081771538-pat00109
Naphtho [1,2-b] furan-2-carboxamide derivatives or pharmaceutically acceptable salts thereof, characterized in that one species is selected from the group consisting of:
제1항에 있어서, 상기 화학식 1의 유도체는,
(1) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(2) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(3) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]부틸]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(4) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]펜틸]-5-(4-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(5) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(4-시아노페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(6) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-시아노페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(7) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(피리딘-4-일)나프토[1,2-b]퓨란-2-카르복사미드;
(8) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(피리딘-4-일)나프토[1,2-b]퓨란-2-카르복사미드;
(9) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(2-클로로피리딘-4-일)나프토[1,2-b]퓨란-2-카르복사미드;
(10) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(6-플푸오로피리딘-3-일)나프토[1,2-b]퓨란-2-카르복사미드;
(11) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]에틸]-5-(6-메톡시피리딘-3-일)나프토[1,2-b]퓨란-2-카르복사미드;
(12) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]나프토[1,2-b]퓨란-2-카르복사미드;
(13) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-브로모나프토[1,2-b]퓨란-2-카르복사미드;
(14) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-메틸나프토[1,2-b]퓨란-2-카르복사미드;
(15) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-페닐나프토[1,2-b]퓨란-2-카르복사미드;
(16) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-플루오로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(17) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3-클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(18) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(4-메틸페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(19) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3-시아노페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(20) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3,5-다이클로로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(21) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3-클로로-4-플루오로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(22) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(3,4-다이플루오로페닐)나프토[1,2-b]퓨란-2-카르복사미드;
(23) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(피리딘-2-일)나프토[1,2-b]퓨란-2-카르복사미드;
(24) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(피리딘-3-일)나프토[1,2-b]퓨란-2-카르복사미드;
(25) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(싸이오펜-3-일)나프토[1,2-b]퓨란-2-카르복사미드;
(26) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(퓨란-3-일)나프토[1,2-b]퓨란-2-카르복사미드; 및
(27) N-[2-[4-(3-아세트아미도페닐)피페리딘-1-일]프로필]-5-(1-메틸-1H-인돌-5-일)나프토[1,2-b]퓨란-2-카르복사미드로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 또는 이의 약학적으로 허용가능한 염.
The method of claim 1, wherein the derivative of Formula 1,
(1) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;
(2) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;
(3) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] butyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;
(4) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] pentyl] -5- (4-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;
(5) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (4-cyanophenyl) naphtho [1,2-b] furan- 2-carboxamide;
(6) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-cyanophenyl) naphtho [1,2-b] furan- 2-carboxamide;
(7) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (pyridin-4-yl) naphtho [1,2-b] furan- 2-carboxamide;
(8) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (pyridin-4-yl) naphtho [1,2-b] furan- 2-carboxamide;
(9) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (2-chloropyridin-4-yl) naphtho [1,2-b ] Furan-2-carboxamide;
(10) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (6-flufuopyridin-3-yl) naphtho [1,2- b] furan-2-carboxamide;
(11) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] ethyl] -5- (6-methoxypyridin-3-yl) naphtho [1,2- b] furan-2-carboxamide;
(12) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] naphtho [1,2-b] furan-2-carboxamide;
(13) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5-bromonaphtho [1,2-b] furan-2-carboxamide;
(14) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5-methylnaphtho [1,2-b] furan-2-carboxamide;
(15) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5-phenylnaphtho [1,2-b] furan-2-carboxamide;
(16) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-fluorophenyl) naphtho [1,2-b] furan- 2-carboxamide;
(17) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3-chlorophenyl) naphtho [1,2-b] furan-2 Carboxamide;
(18) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (4-methylphenyl) naphtho [1,2-b] furan-2- Carboxamides;
(19) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3-cyanophenyl) naphtho [1,2-b] furan- 2-carboxamide;
(20) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3,5-dichlorophenyl) naphtho [1,2-b] Furan-2-carboxamide;
(21) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3-chloro-4-fluorophenyl) naphtho [1,2- b] furan-2-carboxamide;
(22) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (3,4-difluorophenyl) naphtho [1,2-b ] Furan-2-carboxamide;
(23) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (pyridin-2-yl) naphtho [1,2-b] furan- 2-carboxamide;
(24) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (pyridin-3-yl) naphtho [1,2-b] furan- 2-carboxamide;
(25) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (thiophen-3-yl) naphtho [1,2-b] furan -2-carboxamide;
(26) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (furan-3-yl) naphtho [1,2-b] furan- 2-carboxamide; And
(27) N- [2- [4- (3-acetamidophenyl) piperidin-1-yl] propyl] -5- (1-methyl-1H-indol-5-yl) naphtho [1, 2-b] furan-2-carboxamide, naphtho [1,2-b] furan-2-carboxamide derivative, or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of.
하기 반응식 1에 나타난 바와 같이,
화학식 2로 표시되는 나프토[1,2-b]퓨란-2-카르복실산 유도체와 화학식 3으로 표시되는 아민 화합물을 축합제 및 염기존재 하에 용매 하에서 반응시키는 축합반응 단계를 포함하는 제1항의 나프토[1,2-b]퓨란-2-카르복사미드 유도체의 제조방법.
[반응식 1]
Figure 112013003553565-pat00110

(상기 반응식 1에서 R1 및 n은 제1항의 화학식 1에서 정의한 바와 같고,
상기 축합제는 다이사이클로헥실카보다이이미드(DCC), 다이아이소프로필카보다이이미드(DIC) 및 1-에틸-3-(3-다이메틸아미노프로 필)카보다이이미드(EDC) 중에서 선택되는 어느 1종이 카보다이이미드 계열의 시약, N,N-카보닐다이이미다졸(N,N-carbonyldiimidazole), 또는 다이페닐포스포닐아자이드(diphenylphosphonylazide, DPPA)이고,
상기 염기는 N,N-다이메틸아미노피리딘(DMAP), 피리딘, 트라이에틸아민, N,N-다이이소프로필에틸아민 및 DBU로 이루어지는 군으로부터 선택되는 어는 1종의 유기염기 또는 소듐바이카보네이트, 수산화나트륨 및 수산화칼륨으로 이루어지는 군으로부터 선택되는 어느 1종의 무기염기이다.)
As shown in Scheme 1 below,
The method of claim 1 comprising a condensation reaction step of reacting a naphtho [1,2-b] furan-2-carboxylic acid derivative represented by Formula 2 with an amine compound represented by Formula 3 in a solvent in the presence of a condensing agent and a base. Method for preparing naphtho [1,2-b] furan-2-carboxamide derivative.
[Reaction Scheme 1]
Figure 112013003553565-pat00110

(In Formula 1, R 1 and n are as defined in Formula 1 of claim 1,
The condensing agent is any one selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). Species are carbodiimide-based reagents, N, N-carbonyldiimidazole, or diphenylphosphonylazide (DPPA),
The base is at least one organic base or sodium bicarbonate selected from the group consisting of N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N, N-diisopropylethylamine and DBU. It is any one inorganic base selected from the group consisting of sodium and potassium hydroxide.)
삭제delete 제1항 내지 제4항 중 어느 한 항의 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 및 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 비만, 당뇨병, 대사장애, 불안증 및 우울증으로 이루어지는 군으로부터 선택되는 어느 하나의 MCH관련 질환의 예방 또는 치료용 약학적 조성물.
Obesity, diabetes mellitus containing naphtho [1,2-b] furan-2-carboxamide derivative represented by the formula (1) of any one of claims 1 to 4 as an active ingredient and a pharmaceutically acceptable salt thereof Pharmaceutical composition for the prevention or treatment of any one MCH-related disease selected from the group consisting of, metabolic disorders, anxiety and depression.
삭제delete 제1항 내지 제4항 중 어느 한 항의 화학식 1로 표시되는 나프토[1,2-b]퓨란-2-카르복사미드 유도체 및 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 비만, 당뇨병, 대사장애, 불안증 및 우울증으로 이루어지는 군으로부터 선택되는 어느 하나의 MCH관련 질환의 예방 또는 개선용 건강식품 조성물.Obesity, diabetes mellitus containing naphtho [1,2-b] furan-2-carboxamide derivative represented by the formula (1) of any one of claims 1 to 4 as an active ingredient and a pharmaceutically acceptable salt thereof Health food composition for the prevention or improvement of any one MCH-related diseases selected from the group consisting of, metabolic disorders, anxiety and depression. 삭제delete
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