KR100893394B1 - Imidazole derivatives having aryl piperidine substituents, method for the preparation thereof, and pharmaceutical compositions containing them - Google Patents

Imidazole derivatives having aryl piperidine substituents, method for the preparation thereof, and pharmaceutical compositions containing them Download PDF

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KR100893394B1
KR100893394B1 KR1020070046073A KR20070046073A KR100893394B1 KR 100893394 B1 KR100893394 B1 KR 100893394B1 KR 1020070046073 A KR1020070046073 A KR 1020070046073A KR 20070046073 A KR20070046073 A KR 20070046073A KR 100893394 B1 KR100893394 B1 KR 100893394B1
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piperidin
propyl
pyridine
formula
methyl
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KR20080100024A (en
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김낙정
유성은
이규양
서지희
이병호
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한국화학연구원
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Priority to PCT/KR2008/002653 priority patent/WO2008140239A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

본 발명은 하기 화학식 1의, 아릴 피페리딘기-함유 이미다졸 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 MCH(melanin concentrating hormone) 관련 질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to an aryl piperidine group-containing imidazole derivative of Formula 1, a method for preparing the same, and a composition for preventing or treating a disease related to melanin concentrating hormone (MCH) comprising the same as an active ingredient.

Figure 112007035093191-pat00001
Figure 112007035093191-pat00001

상기 식에서,Where

R1, R2, R3, A 및 n은 명세서에 정의한 바와 같다. R 1 , R 2 , R 3 , A and n are as defined in the specification.

Description

아릴 피페리딘기-함유 이미다졸 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 약학적 조성물{IMIDAZOLE DERIVATIVES HAVING ARYL PIPERIDINE SUBSTITUENTS, METHOD FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM}Aryl piperidine group-containing imidazole derivatives, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient.

본 발명은 아릴 피페리딘기-함유 이미다졸 유도체, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to an aryl piperidine group-containing imidazole derivative, a method for preparing the same, and a pharmaceutical composition comprising the same.

최근 10년간 생활양식과 영양상의 변화로 인해 비만인구가 급증하였으며, 이러한 현상은 어린이와 청소년층에서도 증가하는 추세이다. 비만과 과체중은 타입-2 당뇨병, 심장질환, 암, 고혈압을 유발하기 때문에 심각한 사회적 문제가 되고 있다. 따라서, 비만치료를 위한 연구가 활발히 진행되고 있으며, 그 중에서 MCH 수용체-1 길항제(melanin concentrating hormone receptor-1 antagonist)가 새로운 비만치료제로서 연구되고 있다.Over the last 10 years, obesity has surged due to lifestyle and nutritional changes, and this phenomenon is increasing in children and adolescents. Obesity and overweight are serious social problems because they cause type 2 diabetes, heart disease, cancer and high blood pressure. Therefore, studies for the treatment of obesity are actively progressed, among which MCH receptor-1 antagonist (melanin concentrating hormone receptor-1 antagonist) is being studied as a new obesity treatment.

MCH(melanin concentrating hormone)는 19개의 아미노산으로 구성된 환상 펩티드이며 포유동물의 섭식행동에 관여하는 것으로 알려져 있다. 동물모델을 대상으 로 한 연구 결과, MCH를 투여한 쥐에서는 음식물 섭취량이 증가하게 되고 MCH가 결실된 마우스에서는 섭식저하와 대사속도증가에 기인하는 체중감소 현상이 나타나는 것으로 보고되었다(D. Qu., et al., Nature, 380(6571), 243-7, 1996] 참조). 또한, 섭식행동에 대한 MCH의 효과는 MCH 수용체-1(melanin concentrating hormone receptor-1)에 기인하는 것으로 알려져 있고, MCH 수용체-1이 녹-아웃(knock-out)된 쥐에 MCH를 투여하면 섭식을 자극하거나 비만을 일으키지 않는 것으로 보고되었다.([A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006] 참조).Melanin concentrating hormone (MCH) is a cyclic peptide consisting of 19 amino acids and is known to be involved in mammalian feeding behavior. In animal studies, MCH-administered mice reported increased food intake, and MCH-deficient mice reported weight loss due to decreased feeding and increased metabolic rate (D. Qu., et al., Nature, 380 (6571) , 243-7, 1996). In addition, the effect of MCH on eating behavior is known to be due to melanin concentrating hormone receptor-1 (MCH receptor-1), and when MCH is administered to mice knocked out of MCH receptor-1, Has not been reported to stimulate or cause obesity (see 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).Meanwhile, MCH receptor-1 antagonist, one of the G-protein coupled receptors that mediates the effects of MCH, may 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 animals treated with MCH receptor-1 antagonists show significant weight loss and provide anxiety and antidepressant effects in addition to appetite loss. Have been reported (see B. Borowsky et al., Nature Medicine , 8 (8) , 825-30, 2002).

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).In addition, MCH receptor-1 antagonists have been shown to be effective in diabetic and metabolic disorders in addition to treating obesity, depression and anxiety (DS Ludwig et al., J. Clin . Invest . 107, 379-386, 2001). Reference).

MCH 수용체-1 길항제와 관련해서, 암젠(Amgen)과 글락소스미스클라인(GlaxoSmithKline, GW3430)에서 개발한 약물이 현재 임상 실험중인 것으로 알려져 있다(Dyck et al, Bioorg. Med. Chem, Lett. 2006, 16, 4237-4242).With regard to MCH receptor-1 antagonists, drugs developed by Amgen and GlaxoSmithKline (GW3430) are currently known to be in clinical trials (Dyck et al , Bioorg. Med. Chem, Lett. 2006, 16 , 4237-4242).

또한, 비만과 관련해서는, 제니컬(Xenical™), 리덕틸(Reductil™) 등의 비만 치료제가 시판되고 있으나 약효가 떨어지고 부작용을 나타내는 단점이 있다(Trisha Gura, Science 2003, 299, 849-852). In addition, in relation to obesity, Xenical ™ , Reductil ™ Although obesity treatments such as these are commercially available, they are less effective and have side effects (Trisha Gura, Science). 2003, 299 , 849-852).

Figure 112007035093191-pat00002
Figure 112007035093191-pat00002

이에, 본 발명자들은 MCH 수용체에 길항 효과를 나타내는 화합물을 개발하기 위해 노력하던 중, 특정 구조의 이미다졸 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 having an antagonistic effect on the MCH receptor, the imidazole derivative of a specific structure acts as an antagonist of the MCH receptor, it can be used as a preventive and therapeutic agent for MCH-related diseases such as obesity The present invention has been completed.

따라서, 본 발명의 목적은 아릴 피페리딘기-함유 이미다졸 유도체 및 이의 제조방법을 제공하는 것이다.It is therefore an object of the present invention to provide aryl piperidine group-containing imidazole derivatives and methods for their preparation.

또한, 본 발명의 다른 목적은 상기 아릴 피페리딘기-함유 이미다졸 유도체를 유효성분으로 함유하는 MCH 관련질환의 예방 및 치료용 조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a composition for the prevention and treatment of MCH-related diseases containing the aryl piperidine group-containing imidazole derivatives as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는, 아릴 피페리딘기-함유 이미다졸 유도체 및 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the above object, the present invention provides an aryl piperidine group-containing imidazole derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112007035093191-pat00003
Figure 112007035093191-pat00003

상기 식에서,Where

R1은 C1~C4의 직쇄 또는 측쇄 알킬이고,R 1 is C 1 -C 4 straight or branched alkyl,

R2는 서로 동일하거나 상이한 하나 이상의 기로서, H, 할로겐, C1~C3의 직쇄 또는 측쇄 알킬,

Figure 112007035093191-pat00004
, OR4, NO2, CN, 피리딜, CHO, -CONR5R6이고, 여기에서 X는 H, 할로겐, C1~C3의 직쇄 또는 측쇄 알킬, OR4 , NO2 이고, R4, R5 및 R6은 각각 독립적으로 H, C1~C3의 직쇄 또는 측쇄 알킬 또는 페닐이고,R 2 is one or more groups that are the same or different from each other, and are H, halogen, C 1 -C 3 straight or branched alkyl,
Figure 112007035093191-pat00004
, OR 4 , NO 2 , CN, pyridyl, CHO, -CONR 5 R 6 , wherein X is H, halogen, C 1 -C 3 straight or branched chain alkyl, OR 4 , NO 2 , R 4 , R 5 and R 6 are each independently H, C 1 to C 3 , straight or branched alkyl or phenyl,

R3은 C1~C3의 직쇄 또는 측쇄 알킬, 또는 비치환되거나 할로겐 또는 메틸로 치환된 페닐이고;R 3 is C 1 to C 3 straight or branched alkyl, or phenyl unsubstituted or substituted with halogen or methyl;

A는 CH 또는 N이고; 이때 전체 N의 개수는 1 또는 2개이고;A is CH or N; Wherein the total number of N is 1 or 2;

n은 2 내지 5의 정수이다.n is an integer of 2-5.

이하 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명의 화학식 1의 화합물 중 바람직한 화합물은Preferred compounds of the compound of formula 1 of the present invention

R1은 C1~C4의 직쇄 또는 측쇄 알킬이고,R 1 is C 1 -C 4 straight or branched alkyl,

R4는 H, 메틸 또는 페닐이고,R 4 is H, methyl or phenyl,

R5 및 R6은 각각 독립적으로 H 이고,R 5 and R 6 are each independently H,

R2는 서로 동일하거나 상이한 하나 이상의 기로서, H; 할로겐; C1~C3의 직쇄 또는 측쇄의 알킬;

Figure 112007035093191-pat00005
; OR4; NO2; CN; 피리딜; -CONR5R6 으로, 여기서 X는 H, 할로겐, 메틸, NO2 이고, R4, R5 및 R6 는 위에서 정의한 바와 같고;R 2 is one or more groups that are the same or different from one another and include H; halogen; C 1 -C 3 straight or branched alkyl;
Figure 112007035093191-pat00005
; OR 4 ; NO 2 ; CN; Pyridyl; -CONR 5 R 6 , wherein X is H, halogen, methyl, NO 2 , and R 4 , R 5 and R 6 are as defined above;

R3는 C1~C3의 직쇄 또는 측쇄의 알킬; 페닐; 할로겐이나 메틸로 치환된 페닐이고;R 3 is C 1 -C 3 straight or branched alkyl; Phenyl; Phenyl substituted with halogen or methyl;

A는 CH 또는 N이고; 이때 전체 N의 개수는 1개이고,A is CH or N; In this case, the total number of N is one,

n은 2 내지 5의 정수인 것이다. n is an integer of 2-5.

본 발명의 이미다졸 유도체 및 약학적으로 허용 가능한 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산,글루코산, 메탈설폰산, 아세트산, 글리콜산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있으며, 바람직하게는 메탄설폰산 또는 염산을 사용할 수 있다. As the imidazole derivatives and pharmaceutically acceptable salts of the present invention, acid addition salts formed with pharmaceutically acceptable free acids are useful. Organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, and metal sulfonic acid may be used as the organic acid. , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like can be used, and preferably methanesulfonic acid or hydrochloric acid can be used. .

본 발명에 의한 부가염은 통상의 방법, 즉, 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 당량 또는 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조하거나, 또는 용매나 과량의 산을 증발시킨 후 건조하거나 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention is conventionally used, that is, the compound of formula 1 is dissolved in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, and an equivalent or excess organic acid is added or an acid aqueous solution of an inorganic acid is added. It can be prepared by addition, followed by precipitation or crystallization, or by evaporation of the solvent or excess acid followed by suction filtration of the dried or precipitated salt.

본 발명은 상기 이미다졸 유도체 및 이의 약학적으로 허용 가능한 염뿐 아니라 이로부터 제조될 수 있는 가능한 용매화물, 수화물 및 입체이성질체를 모두 발명의 범주 내에 포함한다.The present invention includes all such imidazole derivatives and their pharmaceutically acceptable salts as well as possible solvates, hydrates and stereoisomers that may be prepared therefrom within the scope of the invention.

본 발명의 바람직한 이미다졸 유도체의 예는 다음과 같고, 이에 대한 각각의 구조식을 하기 표 1에 표시하였다:Examples of preferred imidazole derivatives of the present invention are as follows, and the respective structural formulas thereof are shown in Table 1 below:

1) 2-메틸-1-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-1H-벤지미다졸;1) 2-methyl-1- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -1 H -benzimidazole;

2) 2-메틸-1-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-5,6-다이메틸-1H-벤지미다졸;2) 2-methyl-1- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -5,6-dimethyl-1 H -benzimidazole;

3) 2-메틸-1-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-1H-벤지미다졸;3) 2-methyl-1- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -1 H -benzimidazole;

4) 2,5-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;4) 2,5-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5-b] pyridine;

5) 6-브로모-2,5-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;5) 6-bromo-2,5-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5- b] pyridine;

6) 6-브로모-2-에틸-5-메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;6) 6-bromo-2-ethyl-5-methyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5 -b] pyridine;

7) 6-브로모-2-부틸-5-메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;7) 6-bromo-2-butyl-5-methyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5 -b] pyridine;

8) 2-부틸-5,7-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;8) 2-butyl-5,7-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5-b ] Pyridine;

9) 2-부틸-5,7-다이메틸-6-페닐-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;9) 2-butyl-5,7-dimethyl-6-phenyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4 , 5-b] pyridine;

10) 2-부틸-5-메틸-6-피리딘-2-일-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1- 일]프로필}-3H-이미다조[4,5-b]피리딘;10) 2-butyl-5-methyl-6-pyridin-2-yl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [ 4,5-b] pyridine;

11) 6-브로모-2-부틸-5-메틸-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;11) 6-bromo-2-butyl-5-methyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3H-imidazo [4, 5-b] pyridine;

12) 2-부틸-5,7-다이메틸-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;12) 2-butyl-5,7-dimethyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5 -b] pyridine;

13) 2-부틸-5,7-다이메틸-6-페닐-3-{3-[4-(3-아이소부티릴아미노페닐) 피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;13) 2-butyl-5,7-dimethyl-6-phenyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5-b] pyridine;

14) 2-부틸-5-메틸-6-피리딘-2-일-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;14) 2-butyl-5-methyl-6-pyridin-2-yl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H -already Multizo [4,5-b] pyridine;

15) 2-부틸-5-포밀-6-페닐-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘; 및15) 2-butyl-5-formyl-6-phenyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3H-imidazo [4,5 -b] pyridine; And

16) 2-부틸-5-메틸-6-(4-나이트로페닐)-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘.16) 2-butyl-5-methyl-6- (4-nitrophenyl) -3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H Imidazo [4,5-b] pyridine.

Figure 112007035093191-pat00006
Figure 112007035093191-pat00006

또한, 본 발명은 상기 화학식 1의 이미다졸 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing the imidazole derivative of Formula 1.

본 발명에 따른 하기 화학식 1로 표시되는 이미다졸 유도체는 적절한 용매와 염기 존재 하에 하기 화학식 2의 이미다졸 유도체를 하기 화학식 3으로 표시되는 화합물과 반응시킴으로써 제조할 수 있다.The imidazole derivative represented by Formula 1 according to the present invention may be prepared by reacting an imidazole derivative of Formula 2 with a compound represented by Formula 3 in the presence of a suitable solvent and a base.

[화학식 1][Formula 1]

Figure 112007035093191-pat00007
Figure 112007035093191-pat00007

Figure 112007035093191-pat00008
Figure 112007035093191-pat00008

Figure 112007035093191-pat00009
Figure 112007035093191-pat00009

상기 식에서 R1, R2, R3, A 및 n 은 상기 화학식 1에서 정의한 바와 같고, L 은 이탈기로서, 메실레이트, 토실레이트 또는 할로겐이다. Wherein R 1 , R 2 , R 3 , A and n are as defined in Formula 1, and L is a leaving group, which is mesylate, tosylate or halogen.

또한, 상기 화학식 1로 표시되는 이미다졸 유도체는 하기 화학식 4로 표시되는 이미다졸 유도체를 적절한 용매와 염기 존재 하에 하기 화학식 5로 표시되는 화합물과 반응시킴으로써 제조할 수 있다.In addition, the imidazole derivative represented by Formula 1 may be prepared by reacting the imidazole derivative represented by Formula 4 with a compound represented by Formula 5 in the presence of a suitable solvent and a base.

Figure 112007035093191-pat00010
Figure 112007035093191-pat00010

Figure 112007035093191-pat00011
Figure 112007035093191-pat00011

상기 식에서 R1, R2, R3, A 및 n 은 상기 화학식 1에서 정의한 바와 같고, L은 이탈기로서, 메실레이트, 토실레이트 또는 할로겐이다.Wherein R 1 , R 2 , R 3 , A and n are as defined in Formula 1, and L is a leaving group, which is mesylate, tosylate or halogen.

이때, 사용하는 염기로는 피리딘, 트라이에틸아민, N,N-디이소프로필에틸아민, 1,8-디아자비시클로-[5.4.0]운데크-7-엔(DBU) 등의 유기염기 1종 이상 또는 NaOH, Na2CO3, K2CO3, Cs2CO3 등의 무기염기 1종 이상을 당량 또는 과량 사용할 수 있다.At this time, the base to be used includes organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), and the like. Equivalent or excessive amounts of one or more inorganic bases such as NaOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , or the like 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.

본 발명에 따른 방법에서 출발물질로 사용되는 상기 화학식 3의 화합물은 하기 반응식 1에 표시되는 바와 같이 상기 화학식 5의 화합물을

Figure 112007035093191-pat00012
와 알킬화반응을 시켜 화학식 5-1의 화합물을 얻은 후, MsCl 또는 TsCl과 반응시켜 제조하거나, 화학식 5의 화합물을 직접
Figure 112007035093191-pat00013
과 알킬화 반응을 시켜 제조할 수 있다. 여기서, X는 할로겐이고, L은 이탈기로서, 메실레이트, 토실레이트 또는 할로겐이다.The compound of Formula 3 used as a starting material in the method according to the invention is a compound of Formula 5 as shown in Scheme 1
Figure 112007035093191-pat00012
Alkylation with to obtain a compound of Formula 5-1, followed by reaction with MsCl or TsCl, or a compound of Formula 5 directly
Figure 112007035093191-pat00013
It can be prepared by an alkylation reaction with. Wherein X is halogen and L is a leaving group, which is mesylate, tosylate or halogen.

이때, 화학식 5의 아릴 피페리딘 화합물은 공지의 방법(국제특허공개 제WO03/004027호)으로 제조하여 사용할 수 있다.At this time, the aryl piperidine compound of formula (5) can be prepared and used by a known method (WO 03/004027).

Figure 112007035093191-pat00014
Figure 112007035093191-pat00014

상기 반응식에서, R3, n 은 상기 화학식 1에서 정의한 바와 같고, X 는 할로겐, L은 이탈기로서 메실레이트, 토실레이트 또는 할로겐이다.In the above scheme, R 3 , n are as defined in Formula 1, X is halogen, L is a mesylate, tosylate or halogen as leaving group.

상기 반응식 1의 단계 1에 따른 알킬화 반응에서는 화합물 5에 적절한 용매를 사용하여 염기 존재 하에 당량 또는 과량의

Figure 112007035093191-pat00015
과 반응시켜, 화학식 5-1의 화합물을 제조할 수 있다.In the alkylation reaction according to Step 1 of Scheme 1, an appropriate amount of an equivalent or excess in the presence of a base using a solvent appropriate for compound 5
Figure 112007035093191-pat00015
And the compound of Chemical Formula 5-1 can be prepared.

이때, 염기로는 피리딘, 트라이에틸아민, N,N-디이소프로필에틸아민, DBU 등의 유기염기를 사용하거나, NaOH, Na2CO3, K2CO3, Cs2CO3 등을 당량 또는 과량 사용할 수 있다.In this case, an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, DBU, or the like may be used as the base, or equivalents of NaOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , or the like may be used. Excessive use is possible.

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 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 0 ° C. to the boiling point of the solvent.

한편, 상기 반응식 1의 단계 2에 따른 아실화(acylation) 반응에서는, 화학식 5-1의 화합물을 적절한 용매를 사용하여 염기 존재 하에 당량 또는 과량의 MsCl 또는 TsCl과 반응시켜 화학식 3의 화합물을 제조할 수 있다. 이때, 사용하는 염기와 반응 용매는 반응식 1의 알킬화 반응에서와 같고, 반응 온도는 0℃에서 용매의 비등점까지이다.On the other hand, in the acylation reaction according to step 2 of Scheme 1, the compound of Formula 5-1 is reacted with an equivalent or excess of MsCl or TsCl in the presence of a base using a suitable solvent to prepare a compound of Formula 3 Can be. At this time, the base and reaction solvent used are the same as in the alkylation reaction of Scheme 1, and the reaction temperature is from 0 ° C. to the boiling point of the solvent.

또한, 본 발명에 따른 방법에서 출발물질로 사용되는 상기 화학식 4의 화합물은, 하기 반응식 2에 표시되는 바와 같이 이미다졸 화합물과

Figure 112007035093191-pat00016
을 알킬화 반응시켜 제조할 수 있다. 이때, 이미다졸 화합물은 상업적으로 시판되는 것을 사용하거나, 공지의 방법(국제특허공개 제WO07/43943호, 대한민국특허 제303944호, 논문[Oguchi et al., J. Med. Chem, 43(16),3052, 2000])으로 제조하여 사용할 수 있다.In addition, the compound of Formula 4 used as a starting material in the method according to the present invention, as shown in Scheme 2 and the imidazole compound
Figure 112007035093191-pat00016
Can be prepared by alkylation reaction. At this time, the imidazole compound is commercially available, or known methods (International Patent Publication No. WO07 / 43943, Korean Patent No. 303944, Oguchi et al., J. Med. Chem , 43 (16) , 3052, 2000 ]).

Figure 112007035093191-pat00017
Figure 112007035093191-pat00017

상기 반응식에서, R1, R2, A 및 n 은 상기 화학식 1에서 정의한 바와 같고, X는 할로겐, L은 이탈기로서 메실레이트, 토실레이트 또는 할로겐이다.In the above scheme, R 1 , R 2 , A and n are as defined in Formula 1, X is halogen, L is mesylate, tosylate or halogen as leaving group.

상기 반응식 2의 알킬화 반응에서는 이미다졸 화합물에 적절한 용매를 사용하여 염기 존재 하에 당량 또는 과량의

Figure 112007035093191-pat00018
과 반응시켜, 화학식 4의 화합물을 제조할 수 있다. 이때, 사용하는 염기와 반응 용매는 반응식 1의 알킬화 반응에서와 같고, 반응 온도는 상온에서 용매의 비등점까지이다.In the alkylation reaction of Scheme 2, an equivalent or excess of an equivalent or excess in the presence of a base using a suitable solvent for the imidazole compound
Figure 112007035093191-pat00018
And the compound of formula 4 can be prepared. At this time, the base and the reaction solvent used are the same as in the alkylation reaction of Scheme 1, and the reaction temperature is from the room temperature to the boiling point of the solvent.

상기 화학식 1에서 R3가 여러 종류로 변환된 유도체는 하기 반응식 3에서 나타낸 것과 같이, 화학식 1에서 R3가 메틸로 치환된 화합물을 산 또는 염기 존재 하에서 반응시켜 디아세틸화 된 아닐린 화합물을 만든 다음, 이를 여러 종류의 아실 클로라이드 또는 카르복실산 화합물과 반응시켜 아마이드 형성반응을 통해 제조할 수 있다. The derivative in which R 3 is converted into various kinds in Chemical Formula 1 is reacted with a compound in which R 3 is substituted with methyl in Chemical Formula 1 in the presence of an acid or a base to form a diacetylated aniline compound, as shown in Scheme 3 below. It can be prepared through the amide formation reaction by reacting it with various kinds of acyl chloride or carboxylic acid compound.

Figure 112007035093191-pat00019
Figure 112007035093191-pat00019

상기 반응식에서 R1, R2, A 및 n 은 상기 화학식 1에서 정의한 바와 같고, R3'은 화학식 1의 R3의 정의에서 메틸이 제외된 기이다.In the scheme, R 1 , R 2 , A and n are as defined in Formula 1, R 3 ' is a group excluding methyl from the definition of R 3 of Formula 1.

상기 반응식 3에서 화학식 1-1의 아세트아닐리드(acetanilide) 화합물에 적 절한 용매를 사용하여 산 또는 염기 존재 하에서 디아세틸화 반응을 수행하여 아닐린 화합물을 제조할 수 있다. 이때, 산으로는 당량 이상의 염산, 황산 등의 무기산 수용액, 또는 트리플루오로아세트산, 메탄설폰산 등의 유기산을 쓸 수 있고, 염기로는 NaOH, KOH 수용액, NaOMe 또는 NaOEt을 사용할 수 있다. 반응 용매는 쓰지 않거나 물, 메탄올 등의 알코올류; 테트라히드로퓨란; 다이옥산; 또는 아세토나이트릴을 사용할 수 있다. 반응 온도는 상온에서 용매의 비등점까지이다. In Scheme 3, aniline compounds may be prepared by performing a deacetylation reaction in the presence of an acid or a base using a solvent appropriate to the acetanilide compound of Formula 1-1. At this time, an acid may be an aqueous solution of inorganic acids such as hydrochloric acid or sulfuric acid or more, or an organic acid such as trifluoroacetic acid or methanesulfonic acid. The base may be NaOH, KOH aqueous solution, NaOMe or NaOEt. Alcohols such as water and methanol without using the reaction solvent; Tetrahydrofuran; Dioxane; Or acetonitrile can be used. The reaction temperature is from room temperature to the boiling point of the solvent.

상기 아닐린 화합물을 이용한 아마이드 형성반응에서는 상기 아닐린 화합물을 적절한 용매와 염기를 사용하여 아실 클로라이드 유도체와 반응시키거나, 또는 카르복실산 유도체와 적절한 축합제 존재에서 반응시켜 제조할 수 있다. 이때, 염기로는 피리딘, 트라이에틸아민 또는 N,N-디이소프로필에틸아민을 사용할 수 있다. 축합제로는 1,3-디시클로헥실카르보디미드(DCC), 1,3-디이소프로필카르보디미드(DIC), 1-(3-디메틸아미노프로필)-3-에틸카르보디미드(EDC), 1,1-카르보닐디이미다졸(CDI)을 단독으로 사용하거나, 1-하이드록시벤조트리아졸(HOBT); 4-디메틸아미노피리딘(DMAP); 또는 피리딘, 트리에틸아민, N,N-디이소프로필 에틸아민, 1,8-디아자비시클로-[5.4.0]운데크-7-엔(DBU) 등의 유기염기를 첨가하여 화학식 1-2의 아마이드 화합물을 제조할 수 있고, 이때, 반응 용매는 다이클로로메탄이나 클로로폼, 테트라하이드로퓨란, N,N-디메틸포름아미드(DMF), 아세토니트릴, 디메틸설폭사이드(DMSO) 등을 사용할 수 있으며, 반응 온도는 상온으로 하는 것이 바람직하다.In the amide formation reaction using the aniline compound, the aniline compound may be prepared by reacting the aniline compound with an acyl chloride derivative using an appropriate solvent and a base, or by reacting the carboxylic acid derivative with an appropriate condensing agent. In this case, pyridine, triethylamine or N, N-diisopropylethylamine may be used as the base. Examples of condensing agents include 1,3-dicyclohexylcarbodimide (DCC), 1,3-diisopropylcarbodimid (DIC), and 1- (3-dimethylaminopropyl) -3-ethylcarbodimide (EDC). , 1,1-carbonyldiimidazole (CDI) alone or 1-hydroxybenzotriazole (HOBT); 4-dimethylaminopyridine (DMAP); Or by adding organic base such as pyridine, triethylamine, N, N-diisopropyl ethylamine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU) Amide compound may be prepared, wherein the reaction solvent may be used dichloromethane or chloroform, tetrahydrofuran, N, N- dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO) and the like. It is preferable to make reaction temperature into normal temperature.

또한, 본 발명은 아릴 피페리딘기-함유 이미다졸 유도체 또는 약학적으로 허용되는 그의 염을 유효성분으로 함유하는, MCH 관련 질환의 예방 또는 치료용 조성 물을 제공한다.The present invention also provides a composition for the prevention or treatment of MCH-related diseases, containing an aryl piperidine group-containing imidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

MCH와 관련된 것으로 밝혀진 질환의 예로는 비만, 우울증, 불안증, 당뇨병, 대사장애 및 정신분열증 등이 있다.Examples of diseases found to be associated with MCH include obesity, depression, anxiety, diabetes, metabolic disorders and schizophrenia.

본 발명에 의한 조성물은 임상 투여시에 경구 또는 비경구로 투여가 가능하고 일반적인 의약품 제제의 형태로 사용할 수 있으며, 제제화 할 경우에는 일반적으로 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용할 수 있다. The composition according to the present invention can be administered orally or parenterally during clinical administration, and can be used in the form of general pharmaceutical preparations, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. Diluents or excipients may be used.

경구투여를 위한 고형제제는 본 발명에 의한 하나 이상의 이미다졸 유도체에 적어도 하나의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 혼합하여 제조할 수 있다. 또한, 단순한 부형제 외에 마그네슘 스테아레이트, 탈크 등의 윤활제들도 사용할 수 있다. 경구 투여를 위한 액상 제제에는 현탁제, 내용액제, 유제 또는 시럽제 등이 포함되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 사용할 수 있다.Solid preparations for oral administration may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin with at least one imidazole derivative according to the present invention. have. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like can also be used. Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. can be used in addition to commonly used simple diluents such as water and liquid paraffin. have.

비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제가 포함된다. 상기 비수성용제 또는 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등을 사용할 수 있으며, 상기 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등을 사용할 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent or the suspension solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used, and the bases of the suppositories may include Utopepsol, macrogol, Tween 61, Cacao butter, laurin butter, glycerol, gelatin and the like can be used.

또한, 본 발명의 이미다졸 유도체 및 이의 약학적으로 허용가능한 염, 및 이 를 포함하는 약학적 조성물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여 형태, 건강 상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로는 0.1~1000 ㎎/일, 바람직하게는 1~500 ㎎/일이며, 일정시간 간격으로 1일 1회 내지 수회에 분할 투여할 수도 있다.In addition, the dosage to the human body of the imidazole derivatives of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same, depends on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Based on an adult patient weighing 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, divided once to several times a day at regular intervals. It may also be administered.

이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예들은 본 발명을 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.

본 발명에서는 적외선 분광법, 핵자기 공명 스펙트럼, 질량 분광법, 액체 크로마토그래피법, X-선 구조결정법, 선광도 측정법 또는 대표적인 화합물의 원소분석 계산치와 실측치의 비교에 의해 화합물들의 분자구조를 확인하였다. In the present invention, the molecular structure of the compounds was confirmed by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement or elemental analysis of representative compounds and comparison of actual values.

화학식 5-1의 화합물의 제조 (제조예 1, 2)Preparation of Compound of Formula 5-1 (Preparation Examples 1, 2)

Figure 112007035093191-pat00020
Figure 112007035093191-pat00020

<제조예 1> 3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로판-1-올(화학식 5-1의 화합물: n=2, Y=Me)의 제조Preparation Example 1 Preparation of 3- [4- (3-acetylaminophenyl) piperidin-1-yl] propan-1-ol (Compound 5-1: n = 2, Y = Me)

4-(3-아세틸아미노페닐)피페리딘 하이드로클로라이드 5.3 g(20.8 mmol)을 N,N-디메틸포름아미드 50 ㎖에 용해한 후, 여기에 3-브로모-1-프로판올 3.8 g(27.0 mmol)과 K2CO3 8.6 g(62 mmol)을 가하고 60℃에서 5시간 동안 가열하였다. 반응액을 물 150 ㎖에 희석시키고 에틸아세테이트로 추출(100 ㎖× 5)한 후, 유기층을 무수황산나트륨으로 건조, 여과한 다음 용매를 감압하에 증발, 농축하여 얻어진 잔류물을 실리카겔 걸럼크로마토그래피(10% 메탄올/CH2Cl2)로 정제하여 4.8 g(수율 85%)의 표제 화합물을 얻었다.5.3 g (20.8 mmol) of 4- (3-acetylaminophenyl) piperidine hydrochloride was dissolved in 50 ml of N, N-dimethylformamide, followed by 3.8 g (27.0 mmol) of 3-bromo-1-propanol. And K 2 CO 3 8.6 g (62 mmol) was added and heated at 60 ℃ for 5 hours. The reaction solution was diluted with 150 mL of water, extracted with ethyl acetate (100 mL × 5), the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated and concentrated under reduced pressure to obtain a silica gel column chromatography (10). Purification with% methanol / CH 2 Cl 2 ) afforded 4.8 g (yield 85%) of the title compound.

1H-NMR(300MHz, CDCl3)δ 1.76-1.86(m, 6H), 2.13(m, 2H), 2.17(s, 3H), 2.55(m, 1H), 2.71(t, 2H), 3.25(brd, 2H), 3.84(t, 2H), 6.95(d, 1H), 7.19-7.31(m, 3H), 7.43(s, 1H, NH) ; MS(m/e, M+): 276 1 H-NMR (300 MHz, CDCl 3 ) δ 1.76-1.86 (m, 6H), 2.13 (m, 2H), 2.17 (s, 3H), 2.55 (m, 1H), 2.71 (t, 2H), 3.25 ( brd, 2H), 3.84 (t, 2H), 6.95 (d, 1H), 7.19-7.31 (m, 3H), 7.43 (s, 1H, NH); MS (m / e, M + ): 276

<제조예 2> 3-[4-(3-이소부티릴아미노페닐)피페리딘-1-일]프로판-1-올(화학식 5-1의 화합물: n=2, Y=i-Pr)의 제조Preparation Example 2 3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propan-1-ol (compound of Formula 5-1: n = 2, Y = i-Pr) Manufacture

3-[4-(3-이소부티릴아미노페닐) 피페리딘 하이드로클로라이드 3.5 g(12.4 mmol)를 제조예 1과 동일한 방법으로 처리하여 3.05 g(수율 81%)의 표제 화합물을 얻었다.3.5 g (12.4 mmol) of 3- [4- (3-isobutyrylaminophenyl) piperidine hydrochloride were treated in the same manner as in Production Example 1 to obtain 3.05 g (yield 81%) of the title compound.

1H-NMR(300MHz, CDCl3)δ 1.25(d, 6H), 1.69-1.78(m, 4H), 1.83(brd, 2H), 2.05(t, 2H), 2.50(m, 1H), 2.55(m, 1H), 2.66(t, 2H), 3.17(brd, 2H), 3.83(t, 2H), 6.92(d, 1H), 7.23(dd, 1H), 7.35-7.38(m, 2H), 7.40(s, 1H, NH); MS(m/e, M+): 304 1 H-NMR (300 MHz, CDCl 3 ) δ 1.25 (d, 6H), 1.69-1.78 (m, 4H), 1.83 (brd, 2H), 2.05 (t, 2H), 2.50 (m, 1H), 2.55 ( m, 1H), 2.66 (t, 2H), 3.17 (brd, 2H), 3.83 (t, 2H), 6.92 (d, 1H), 7.23 (dd, 1H), 7.35-7.38 (m, 2H), 7.40 (s, 1H, NH); MS (m / e, M + ): 304

화학식 3의 화합물의 제조 (제조예 3, 4)Preparation of Compound of Formula 3 (Preparation Examples 3, 4)

Figure 112007035093191-pat00021
Figure 112007035093191-pat00021

<제조예 3> 3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필 메탄설포네이트(화학식 3의 화합물: n=2, Y=Me)의 제조Preparation Example 3 Preparation of 3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl methanesulfonate (Compound of Formula 3: n = 2, Y = Me)

제조예 1에서 얻은 화합물 4.5 g(16.3 mmol)을 디클로로메탄 70 ㎖에 녹이고 0℃로 냉각시키고 트리에틸아민 6.7 ㎖(48.0 mmol)을 가한 후 메탄설포닐 클로라이드 1.51 ㎖(19.5 mmol)를 10 ㎖의 CH2Cl2에 희석하여 천천히 가한 후 0℃에서 3시간동안 교반하였다. 반응액을 물 100 ㎖과 NaHCO3 포화용액 30 ㎖에 묽히고 CH2Cl2로 추출(100㎖× 2)한 후, 유기층을 무수황산나트륨으로 건조, 여과한 다음 용매를 감압하에 증발, 농축하여 5.2 g(수율 90%)의 표제 화합물을 얻었다. 수득된 화합물은 추가의 정제과정 없이 다음 반응에 사용되었다.4.5 g (16.3 mmol) of the compound obtained in Preparation Example 1 were dissolved in 70 mL of dichloromethane, cooled to 0 ° C., and 6.7 mL (48.0 mmol) of triethylamine was added, followed by 1.51 mL (19.5 mmol) of methanesulfonyl chloride. Diluted in CH 2 Cl 2 and slowly added thereto, and stirred for 3 hours at 0 ℃. The reaction solution was diluted with 100 mL of water and 30 mL of saturated NaHCO 3 solution and extracted with CH 2 Cl 2 (100 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated and concentrated under reduced pressure to give 5.2. g (yield 90%) of the title compound were obtained. The compound obtained was used in the next reaction without further purification.

1H-NMR(300MHz, CDCl3)δ 1.90-2.03(m, 4H), 2.21(s, 3H), 2.39(m, 1H), 2.43(m, 2H), 2.80(s, 3H), 2.82(m, 2H), 3.07(m, 2H), 3.58(m, 2H), 4.40(t, 2H), 6.93(d, 1H), 7.20(dd, 1H), 7.42(brs, 1H, NH), 7.58(d, 1H), 8.48(s, 1H, NH); MS(m/e, M+): 354 1 H-NMR (300 MHz, CDCl 3 ) δ 1.90-2.03 (m, 4H), 2.21 (s, 3H), 2.39 (m, 1H), 2.43 (m, 2H), 2.80 (s, 3H), 2.82 ( m, 2H), 3.07 (m, 2H), 3.58 (m, 2H), 4.40 (t, 2H), 6.93 (d, 1H), 7.20 (dd, 1H), 7.42 (brs, 1H, NH), 7.58 (d, 1 H), 8.48 (s, 1 H, NH); MS (m / e, M + ): 354

<제조예 4> 3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필 메탄설포네이트(화학식 3의 화합물: n=2, Y=i-Pr)의 제조Preparation Example 4 Preparation of 3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl methanesulfonate (Compound of Formula 3: n = 2, Y = i-Pr)

제조예 2에서 얻은 화합물 3.0 g(9.87 mmol)을 제조예 3과 동일한 방법으로 처리하여 3.5g(수율 93%)의 표제 화합물을 얻었다. 수득된 화합물은 추가의 정제과정 없이 다음 반응에 사용되었다.3.0 g (9.87 mmol) of the compound obtained in Preparation Example 2 were treated in the same manner as in Preparation Example 3, to obtain 3.5 g (yield 93%) of the title compound. The compound obtained was used in the next reaction without further purification.

1H-NMR(300MHz, CDCl3)δ 1.23(d, 6H), 1.77-1.94(m, 4H), 2.62(m, 2H), 2.65(m, 1H), 2.76(m, 1H), 2.79(s, 3H), 3.38(m, 2H), 3.83(brd, 2H), 4.32(t, 2H), 4.40(t, 2H), 6.74(d, 1H), 7.17(dd, 1H), 7.51(s, 1H), 7.86(d, 1H), 9.34(s, 1H, NH); MS(m/e, M+): 382 1 H-NMR (300 MHz, CDCl 3 ) δ 1.23 (d, 6H), 1.77-1.94 (m, 4H), 2.62 (m, 2H), 2.65 (m, 1H), 2.76 (m, 1H), 2.79 ( s, 3H), 3.38 (m, 2H), 3.83 (brd, 2H), 4.32 (t, 2H), 4.40 (t, 2H), 6.74 (d, 1H), 7.17 (dd, 1H), 7.51 (s , 1H), 7.86 (d, 1H), 9.34 (s, 1H, NH); MS (m / e, M + ): 382

이미다졸 유도체의 제조 (실시예 1-3)Preparation of Imidazole Derivatives (Examples 1-3)

Figure 112007035093191-pat00022
Figure 112007035093191-pat00022

<실시예 1> 2-메틸-1-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-1Example 1 2-Methyl-1- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -1 HH -벤지미다졸Benzimidazole

2-메틸-1H-벤지미다졸 100 mg(0.75 mmol)을 5 ㎖의 N,N-디메틸 포름아미드에 용해하고, 여기에 제조예 3에서 얻은 3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필 메탄설포네이트 265 mg(0.75 mmol)과 K2CO3 310 mg(2.25mmol)을 첨가한 다음 80℃에서 5시간 동안 교반하였다. 반응액을 50 ㎖의 물에 희석하고 에틸아세테트로 추출(50 ㎖× 2)하면서 물과 소금물로 세척하였다. 추출한 유기층을 무수 황산나트륨으로 건조, 여과한 후 용매를 감압하에 증발시켜 제거하고 잔류물을 실리카겔 컬럼크로마토그래피(5%-MeOH/CH2Cl2)로 정제하여 160 mg(수율 55%)의 표제 화합물을 얻었다.100 mg (0.75 mmol) of 2-methyl-1 H -benzimidazole was dissolved in 5 mL of N, N-dimethyl formamide, and 3- [4- (3-acetylaminophenyl) obtained in Preparation Example 3 265 mg (0.75 mmol) of piperidin-1-yl] propyl methanesulfonate and 310 mg (2.25 mmol) of K 2 CO 3 were added, followed by stirring at 80 ° C. for 5 hours. The reaction solution was diluted with 50 ml of water and washed with water and brine while being extracted with ethyl acetate (50 ml × 2). The extracted organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (5% -MeOH / CH 2 Cl 2 ) to 160 mg (yield 55%) of the title compound. Got.

1H NMR(300MHz, CDCl3)δ 1.71-1.85(m, 4H), 1.97-2.06(m, 4H), 2.17(s, 3H), 2.34(t, 2H), 2.48(m, 1H), 2.65(s, 3H), 2.95(brd, 2H), 4.22(t, 2H), 6.97(d, 1H, J=7.5 Hz), 7.20-7.38(m, 6H), 7.43(brs, 1H, NH), 7.67(m, 1H) ; MS(m/e, M+): 390, 375, 348, 257, 245, 231, 159 1 H NMR (300 MHz, CDCl 3 ) δ 1.71-1.85 (m, 4H), 1.97-2.06 (m, 4H), 2.17 (s, 3H), 2.34 (t, 2H), 2.48 (m, 1H), 2.65 (s, 3H), 2.95 (brd, 2H), 4.22 (t, 2H), 6.97 (d, 1H, J = 7.5 Hz), 7.20-7.38 (m, 6H), 7.43 (brs, 1H, NH), 7.67 (m, 1 H); MS (m / e, M + ): 390 , 375, 348, 257, 245, 231, 159

<실시예 2> 2-메틸-1-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-5,6-다이메틸-1Example 2 2-Methyl-1- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -5,6-dimethyl-1 HH -벤지미다졸Benzimidazole

2,5,6-트리메틸-1H-벤지미다졸 100 mg(0.62mmol)을 실시예 1과 동일한 방법으로 처리하여 145 mg(수율 56%)의 표제 화합물을 얻었다.100 mg (0.62 mmol) of 2,5,6-trimethyl-1 H -benzimidazole were treated in the same manner as in Example 1 to obtain 145 mg (yield 56%) of the title compound.

1H NMR(300MHz, CDCl3)δ 1.70-1.85(m, 4H), 1.96-2.04(m, 4H), 2.17(s, 3H), 2.33(t, 2H), 2.35(s, 3H), 2.37(s, 3H), 2.48(m, 1H), 2.60(s, 3H), 2.94(brd, 2H), 4.16(t, 2H), 6.91(d, 1H, J=7.5 Hz), 7.12(s, 1H), 7.21-7.37(m, 2H), 7.43(m, 2H), 7.62(brs, 1H, NH) ; MS(m/e, M+): 418, 403, 376, 257, 245, 231, 187, 174 1 H NMR (300MHz, CDCl 3 ) δ 1.70-1.85 (m, 4H), 1.96-2.04 (m, 4H), 2.17 (s, 3H), 2.33 (t, 2H), 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (m, 1H), 2.60 (s, 3H), 2.94 (brd, 2H), 4.16 (t, 2H), 6.91 (d, 1H, J = 7.5 Hz), 7.12 (s, 1H), 7.21-7.37 (m, 2H), 7.43 (m, 2H), 7.62 (brs, 1H, NH); MS (m / e, M + ): 418 , 403, 376, 257, 245, 231, 187, 174

<실시예 3> 2-메틸-1-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-1Example 3 2-Methyl-1- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -1 HH -벤지미다졸Benzimidazole

2-메틸-1H-벤지미다졸 100 mg(0.75 mmol)을 5 ㎖의 N,N-디메틸 포름아미드에 용해하고 3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필 메탄설포네이트 286 mg(0.75 mmol)과 K2CO3 310 mg(2.25 mmol)을 첨가한 다음 80℃에서 5시간 동안 교반하였다. 반응액을 50 ㎖의 물에 희석하고 에틸아세테트로 추출(50㎖× 2)하면서 물과 소금물로 세척하였다. 추출한 유기층을 무수 황산나트륨으로 건조, 여과한 후 용매를 감압하에 증발시켜 제거하고 남는 잔류물을 실리카겔 컬럼크로마토그래피(5%-MeOH/CH2Cl2)로 정제하여 159 mg(수율 51%)의 표제 화합물을 얻었다.100 mg (0.75 mmol) of 2-methyl-1 H -benzimidazole are dissolved in 5 ml of N, N-dimethyl formamide and 3- [4- (3-isobutyrylaminophenyl) piperidine-1- 286 mg (0.75 mmol) of il] propyl methanesulfonate and 310 mg (2.25 mmol) of K 2 CO 3 were added, followed by stirring at 80 ° C. for 5 hours. The reaction solution was diluted with 50 ml of water and washed with water and brine while being extracted with ethyl acetate (50 ml × 2). The extracted organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure. The remaining residue was purified by silica gel column chromatography (5% -MeOH / CH 2 Cl 2 ) to give 159 mg (51% yield) of the title. The compound was obtained.

1H NMR(300MHz, CDCl3)δ 1.25(d, 6H), 1.74-1.83(m, 4H), 1.97-2.05(m, 4H), 2.33(t, 2H), 2.46(m, 1H), 2.53(m, 1H), 2.65(s, 3H), 2.95(brd, 2H), 4.22(t, 2H), 6.97(d, 1H), 7.09(m, 1H), 7.20-7.38(m, 5H), 7.53(brs, 1H, NH), 7.70(m, 1H) ; MS(m/e, M+): 418 1 H NMR (300 MHz, CDCl 3 ) δ 1.25 (d, 6H), 1.74-1.83 (m, 4H), 1.97-2.05 (m, 4H), 2.33 (t, 2H), 2.46 (m, 1H), 2.53 (m, 1H), 2.65 (s, 3H), 2.95 (brd, 2H), 4.22 (t, 2H), 6.97 (d, 1H), 7.09 (m, 1H), 7.20-7.38 (m, 5H), 7.53 (brs, 1 H, NH), 7.70 (m, 1 H); MS (m / e, M + ): 418

이미다졸 유도체의 제조 (실시예 4-10)Preparation of Imidazole Derivatives (Example 4-10)

Figure 112007035093191-pat00023
Figure 112007035093191-pat00023

<실시예 4> 2,5-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3Example 4 2,5-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2,5-다이메틸-3H-이미다조[4,5-b]피리딘 100 mg(0.68 mmol)을 5 ㎖의 N,N-디메틸 포름아미드에 용해하고, 여기에 제조예 3에서 얻은 3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필 메탄설포네이트 240 mg(0.68 mmol)과 K2CO3 282 mg(2.04 mmol)을 첨가한 다음 80℃에서 5시간 동안 교반하였다. 반응액을 50 ㎖의 물에 희석하고 에틸아세테트로 추출(50 ㎖× 2)하면서 물과 소금물로 세척하였다. 추출한 유기층을 무수 황산나트륨으로 건조, 여과한 후 용매는 감압하에 증발시켜 제거하고 남는 잔류물을 실리카겔 컬럼크로마토그래피(5%-MeOH/CH2Cl2)로 정제하여 124 mg(수율 45%)의 표제 화합물을 얻었다.100 mg (0.68 mmol) of 2,5-dimethyl- 3H -imidazo [4,5-b] pyridine was dissolved in 5 ml of N, N-dimethyl formamide, and 3- 240 mg (0.68 mmol) of [4- (3-acetylaminophenyl) piperidin-1-yl] propyl methanesulfonate and 282 mg (2.04 mmol) of K 2 CO 3 were added and then stirred at 80 ° C. for 5 hours. It was. The reaction solution was diluted with 50 ml of water and washed with water and brine while being extracted with ethyl acetate (50 ml × 2). The extracted organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (5% -MeOH / CH 2 Cl 2 ) to give 124 mg (45% yield) of the title. The compound was obtained.

1H NMR(300MHz, CDCl3)δ 1.67-1.81(m, 4H), 1.96-2.05(m, 4H), 2.17(m, 3H), 2.38(t, 2H), 2.46(m, 1H), 2.62(s, 3H), 2.65(s, 3H), 2.96(br-d, 2H), 4.30(t, 2H), 6.52(m, 1H), 6.95(m, 1H), 6.98(d, 1H, J=8.1Hz), 7.21-7.38(m, 3H), 7.76(d, 1H, J=8.1Hz) ; MS(m/e, M+): 405 1 H NMR (300 MHz, CDCl 3 ) δ 1.67-1.81 (m, 4H), 1.96-2.05 (m, 4H), 2.17 (m, 3H), 2.38 (t, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 2.65 (s, 3H), 2.96 (br-d, 2H), 4.30 (t, 2H), 6.52 (m, 1H), 6.95 (m, 1H), 6.98 (d, 1H, J = 8.1 Hz), 7.21-7.38 (m, 3H), 7.76 (d, 1H, J = 8.1 Hz); MS (m / e, M + ): 405

<실시예 5> 6-브로모-2,5-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3Example 5 6-Bromo-2,5-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

6-브로모-2,5-다이메틸-3H-이미다조[4,5-b]피리딘 100 mg(0.44 mmol)을 실시예 4와 동일한 방법으로 처리하여 100 mg(수율 47%)의 표제 화합물을 얻었다.100 mg (0.44 mmol) of 6-bromo-2,5-dimethyl- 3H -imidazo [4,5-b] pyridine were treated in the same manner as in Example 4 to give 100 mg (yield 47%) of the title. The compound was obtained.

1H NMR(300MHz, CDCl3)δ 1.67-1.83(m, 4H), 1.96-2.06(m, 4H), 2.17(m, 3H), 2.36(t, 2H), 2.46(m, 1H), 2.65(s, 3H), 2.72(s, 3H), 2.94(br-d, 2H), 4.27(t, 2H), 6.95(d, 1H, J=6.8 Hz), 7.21-7.42(m, 4H), 8.02(s, 1H); MS(m/e, M+): 484, 469, 267, 245, 231 1 H NMR (300MHz, CDCl 3 ) δ 1.67-1.83 (m, 4H), 1.96-2.06 (m, 4H), 2.17 (m, 3H), 2.36 (t, 2H), 2.46 (m, 1H), 2.65 (s, 3H), 2.72 (s, 3H), 2.94 (br-d, 2H), 4.27 (t, 2H), 6.95 (d, 1H, J = 6.8 Hz), 7.21-7.42 (m, 4H), 8.02 (s, 1 H); MS (m / e, M + ): 484 , 469, 267, 245, 231

<실시예 6> 6-브로모-2-에틸-5-메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3Example 6 6-Bromo-2-ethyl-5-methyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

6-브로모-2-에틸-5-메틸-3H-이미다조[4,5-b]피리딘 100 mg(0.41 mmol)을 실시예 4와 동일한 방법으로 처리하여 94 mg(수율 46%)의 표제 화합물을 얻었다.100 mg (0.41 mmol) of 6-bromo-2-ethyl-5-methyl- 3H -imidazo [4,5-b] pyridine was treated in the same manner as in Example 4 to obtain 94 mg (yield 46%) of The title compound was obtained.

1H NMR(300MHz, CDCl3)δ 1.47(t, 3H), 1.68-1.83(m, 4H), 1.96-2.07(m, 4H), 2.16(m, 3H), 2.38(t, 2H), 2.46(m, 1H), 2.72(s, 3H), 2.94(br-d, 2H), 2.99(q, 2H), 4.27(t, 2H), 6.95(d, 1H, J=6.9 Hz), 7.21-7.43(m, 4H), 8.06(s, 1H); MS(m/e, M+): 499, 497, 468, 280, 245, 231 1 H NMR (300 MHz, CDCl 3 ) δ 1.47 (t, 3H), 1.68-1.83 (m, 4H), 1.96-2.07 (m, 4H), 2.16 (m, 3H), 2.38 (t, 2H), 2.46 (m, 1H), 2.72 (s, 3H), 2.94 (br-d, 2H), 2.99 (q, 2H), 4.27 (t, 2H), 6.95 (d, 1H, J = 6.9 Hz), 7.21- 7.43 (m, 4 H), 8.06 (s, 1 H); MS (m / e, M + ): 499, 497 , 468, 280, 245, 231

<실시예 7> 6-브로모-2-부틸-5-메틸-3-{3-[4-(3-아세틸아미노페닐)-피페리딘-1-일]프로필}-3Example 7 6-Bromo-2-butyl-5-methyl-3- {3- [4- (3-acetylaminophenyl) -piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

6-브로모-2-부틸-5-메틸-3H-이미다조[4,5-b]피리딘 100 mg(0.37 mmol)을 실시예 4와 동일한 방법으로 처리하여 87 mg(수율 45%)의 표제 화합물을 얻었다.100 mg (0.37 mmol) of 6-bromo-2-butyl-5-methyl- 3H -imidazo [4,5-b] pyridine were treated in the same manner as in Example 4 to give 87 mg (yield 45%) of The title compound was obtained.

1H NMR(300MHz, CDCl3)δ 0.98(m, 3H), 1.25(m, 3H), 1.84(m, 6H), 1.97(m, 3H), 2.16(s, 3H), 2.37(m, 2H), 2.96(m, 5H), 4.25(t, 2H), 6.96(d, 1H), 7.32(m, 2H), 7.62(s, 1H), 8.05(s, 1H): MS(m/e, M+): 526, 468, 447 1 H NMR (300 MHz, CDCl 3 ) δ 0.98 (m, 3H), 1.25 (m, 3H), 1.84 (m, 6H), 1.97 (m, 3H), 2.16 (s, 3H), 2.37 (m, 2H ), 2.96 (m, 5H), 4.25 (t, 2H), 6.96 (d, 1H), 7.32 (m, 2H), 7.62 (s, 1H), 8.05 (s, 1H): MS (m / e, M + ): 526 , 468, 447

<실시예 8> 2-부틸-5,7-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3Example 8 2-Butyl-5,7-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5,7-다이메틸-3H-이미다조[4,5-b]피리딘 100 mg(0.49 mmol)을 화합물 실시예 4와 동일한 방법으로 처리하여 106 mg(수율 47%)의 표제 화합물을 얻었다.100 mg (0.49 mmol) of 2-butyl-5,7-dimethyl- 3H -imidazo [4,5-b] pyridine were treated in the same manner as in Example 4 to give 106 mg (yield 47%) of title The compound was obtained.

1H NMR(300MHz, CDCl3)δ 0.98(m, 3H), 1.45(m, 2H), 1.82(m, 6H), 2.04(m, 4H), 2.12(s, 3H), 2.42(m, 3H), 2.59(s, 6H), 2.96(m, 4H), 4.31(t, 2H), 6.97(d, 1H), 7.23(m, 1H), 7.35(m, 2H), 7.55(s, 1H): MS(m/e, M+): 461, 432, 404 1 H NMR (300 MHz, CDCl 3 ) δ 0.98 (m, 3H), 1.45 (m, 2H), 1.82 (m, 6H), 2.04 (m, 4H), 2.12 (s, 3H), 2.42 (m, 3H ), 2.59 (s, 6H), 2.96 (m, 4H), 4.31 (t, 2H), 6.97 (d, 1H), 7.23 (m, 1H), 7.35 (m, 2H), 7.55 (s, 1H) : MS (m / e, M + ): 461 , 432, 404

<실시예 9> 2-부틸-5,7-다이메틸-6-페닐-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3Example 9 2-Butyl-5,7-dimethyl-6-phenyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5,7-다이메틸-6-페닐-3H-이미다조[4,5-b]피리딘 100 mg(0.35 mmol)을 실시예 4와 동일한 방법으로 처리하여 83 mg(수율 44%)의 표제 화합물을 얻었다.100 mg (0.35 mmol) of 2-butyl-5,7-dimethyl-6-phenyl-3 H -imidazo [4,5-b] pyridine were treated in the same manner as in Example 4 to 83 mg (yield 44%). ), The title compound was obtained.

1H NMR(300MHz, CDCl3)δ 0.97(m, 3H), 1.46(m, 2H), 1.86(m, 6H), 2.04(m, 4H), 2.11(s, 3H), 2.32(s, 6H), 2.48(m, 3H), 2.99(m, 6H), 4.35(t, 2H), 6.95(d, 1H), 7.15(m, 2H), 7.38(m, 5H), 7.44(s, 1H): MS(m/e, M+): 537, 508, 482 1 H NMR (300MHz, CDCl 3 ) δ 0.97 (m, 3H), 1.46 (m, 2H), 1.86 (m, 6H), 2.04 (m, 4H), 2.11 (s, 3H), 2.32 (s, 6H ), 2.48 (m, 3H), 2.99 (m, 6H), 4.35 (t, 2H), 6.95 (d, 1H), 7.15 (m, 2H), 7.38 (m, 5H), 7.44 (s, 1H) MS (m / e, M + ): 537 , 508, 482

<실시예 10> 2-부틸-5-메틸-6-피리딘-2-일-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3Example 10 2-Butyl-5-methyl-6-pyridin-2-yl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5-메틸-6-피리딘-2-일-3H-이미다조[4,5-b]피리딘 100 mg(0.37 mmol)을 실시예 4와 동일한 방법으로 처리하여 83 mg(수율 43%)의 표제 화합물을 얻었다.100 mg (0.37 mmol) of 2-butyl-5-methyl-6-pyridin-2-yl- 3H -imidazo [4,5-b] pyridine was treated in the same manner as in Example 4 to obtain 83 mg (yield 43) %) Of the title compound.

1H NMR(300MHz, CDCl3)δ 0.98(m, 3H), 1.46(m, 2H), 1.78(m, 4H), 1.95(m, 3H), 2.10(m, 5H), 2.44(m, 3H), 2.63(s, 2H), 3.03(m, 4H), 4.35(t, 2H), 6.96(d, 1H), 7.22(m, 4H), 7.75(m, 4H), 7.92(s, 1H): MS(m/e, M+): 524, 509, 495 1 H NMR (300 MHz, CDCl 3 ) δ 0.98 (m, 3H), 1.46 (m, 2H), 1.78 (m, 4H), 1.95 (m, 3H), 2.10 (m, 5H), 2.44 (m, 3H ), 2.63 (s, 2H), 3.03 (m, 4H), 4.35 (t, 2H), 6.96 (d, 1H), 7.22 (m, 4H), 7.75 (m, 4H), 7.92 (s, 1H) : MS (m / e, M + ): 524 , 509, 495

이미다졸 유도체의 제조Preparation of Imidazole Derivatives

Figure 112007035093191-pat00024
Figure 112007035093191-pat00024

<실시예 11> 6-브로모-2-부틸-5-메틸-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3Example 11 6-Bromo-2-butyl-5-methyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

6-브로모-2-부틸-5-메틸-3H-이미다조[4,5-b]피리딘 100 mg(0.37 mmol)을 5 ㎖의 N,N-디메틸 포름아미드에 용해하고, 여기에 제조예 4에서 얻은 3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필 메탄설포네이트 140 mg(0.37 mmol)과 K2CO3 155 mg(1.11 mmol)을 첨가한 다음 80℃에서 5시간 동안 교반하였다. 반응액을 50 ㎖의 물에 희석하고 에틸아세테트로 추출(50㎖× 2)하면서 물과 소금물로 세척하였다. 추출한 유기층을 무수 황산나트륨으로 건조, 여과한 후 용매는 감압하에 증발시켜 제거하고 잔류물을 실리카겔 컬럼크로마토그래피(5%-MeOH/CH2Cl2)로 정제하여 94 mg(수율 46%)의 표제 화합물을 얻었다.100 mg (0.37 mmol) of 6-bromo-2-butyl-5-methyl- 3H -imidazo [4,5-b] pyridine are dissolved in 5 ml of N, N-dimethyl formamide and prepared herein. 140 mg (0.37 mmol) of 3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl methanesulfonate obtained in Example 4 and 155 mg (1.11 mmol) of K 2 CO 3 were added. Then stirred at 80 ° C. for 5 hours. The reaction solution was diluted with 50 ml of water and washed with water and brine while being extracted with ethyl acetate (50 ml × 2). The extracted organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (5% -MeOH / CH 2 Cl 2 ) to give 94 mg (46% yield) of the title compound. Got.

1H NMR(300MHz, CDCl3)δ 0.97(t, 3H), 1.24(m, 9H), 1.50(m, 3H), 1.82(m, 10H), 2.50(m, 5H), 2.89(m, 4H), 3.01(m, 5H), 4.30(t, 2H), 6.97(d, 1H), 7.30(m, 2H), 7.53(d, 1H), 8.05(s, 1H) : MS(m/e, M+): 554 1 H NMR (300MHz, CDCl 3 ) δ 0.97 (t, 3H), 1.24 (m, 9H), 1.50 (m, 3H), 1.82 (m, 10H), 2.50 (m, 5H), 2.89 (m, 4H ), 3.01 (m, 5H), 4.30 (t, 2H), 6.97 (d, 1H), 7.30 (m, 2H), 7.53 (d, 1H), 8.05 (s, 1H): MS (m / e, M + ): 554

<실시예 12> 2-부틸-5,7-다이메틸-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3Example 12 2-Butyl-5,7-dimethyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5,7-다이메틸-3H-이미다졸[4,5-b]피리딘 100 mg(0.49 mmol)을 실시예 11과 동일한 방법으로 처리하여 108 mg(수율 45%)의 표제 화합물을 얻었다.100 mg (0.49 mmol) of 2-butyl-5,7-dimethyl-3 H -imidazole [4,5- b ] pyridine were treated in the same manner as in Example 11 to give 108 mg (yield 45%) of the title compound. Got.

1H NMR(300MHz, CDCl3 )δ 0.98(m, 3H), 1.23(m, 7H), 1.50(m, 2H), 1.84(m, 7H), 2.06(m, 5H), 2.57(m, 7H), 3.03(m, 4H), 4.31(t, 2H), 6.83(s, 1H), 6.96(d, 1H), 7.25(m, 2H), 7.36(d, 1H), 7.46(s, 1H): MS(m/e, M+): 489, 460, 432 1 H NMR (300 MHz, CDCl 3 ) δ 0.98 (m, 3H), 1.23 (m, 7H), 1.50 (m, 2H), 1.84 (m, 7H), 2.06 (m, 5H), 2.57 (m, 7H ), 3.03 (m, 4H), 4.31 (t, 2H), 6.83 (s, 1H), 6.96 (d, 1H), 7.25 (m, 2H), 7.36 (d, 1H), 7.46 (s, 1H) : MS (m / e, M + ): 489 , 460, 432

<실시예 13> 2-부틸-5,7-다이메틸-6-페닐-3-{3-[4-(3-아이소부티릴아미노페닐)-피페리딘-1-일]프로필}-3Example 13 2-Butyl-5,7-dimethyl-6-phenyl-3- {3- [4- (3-isobutyrylaminophenyl) -piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5,7-다이메틸-6-페닐-3H-이미다조[4,5-b]피리딘 100 mg(0.35 mmol)을 실시예 11과 동일한 방법으로 처리하여 91 mg(수율 46%)의 표제 화합물을 얻었다.100 mg (0.35 mmol) of 2-butyl-5,7-dimethyl-6-phenyl-3 H -imidazo [4,5-b] pyridine was treated in the same manner as in Example 11 to give 91 mg (yield 46%). ), The title compound was obtained.

1H NMR(300MHz, CDCl3 )δ 0.97(t, 3H), 1.23(m, 7H), 1.54(m, 2H), 1.86(m, 6H), 2.04(m, 4H), 2.32(s, 6H), 2.43(m, 4H), 2.99(m, 3H), 4.35(t, 2H), 6.94(d, 1H), 7.20(m, 2H), 7.38(m, 6H): MS(m/e, M+): 565, 536, 508 1 H NMR (300MHz, CDCl 3 ) δ 0.97 (t, 3H), 1.23 (m, 7H), 1.54 (m, 2H), 1.86 (m, 6H), 2.04 (m, 4H), 2.32 (s, 6H ), 2.43 (m, 4H), 2.99 (m, 3H), 4.35 (t, 2H), 6.94 (d, 1H), 7.20 (m, 2H), 7.38 (m, 6H): MS (m / e, M + ): 565 , 536, 508

<실시예 14> 2-부틸-5-메틸-6-피리딘-2-일-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3Example 14 2-Butyl-5-methyl-6-pyridin-2-yl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5-메틸-6-피리딘-2-일-3H-이미다조[4,5-b]피리딘 100 mg(0.37 mmol)을 실시예 11과 동일한 방법으로 처리하여 84 mg(수율 41%)의 표제 화합물을 얻었다.100 mg (0.37 mmol) of 2-butyl-5-methyl-6-pyridin-2-yl- 3H -imidazo [4,5-b] pyridine were treated in the same manner as in Example 11 to 84 mg (yield 41). %) Of the title compound.

1H NMR(300MHz, CDCl3 )δ 0.97(m, 3H), 1.23(m, 6H), 1.52(m, 2H), 1.93(m, 8H), 2.45(m, 4H), 2.67(s, 3H), 2.96(m, 5H), 4.36(t, 2H), 6.96(d, 1H), 7.29(m, 2H), 7.38(m, 4H), 7.48(m, 1H), 7.91(s, 1H), 8.71(m 1H); MS(m/e, M+): 552, 523, 509 1 H NMR (300 MHz, CDCl 3 ) δ 0.97 (m, 3H), 1.23 (m, 6H), 1.52 (m, 2H), 1.93 (m, 8H), 2.45 (m, 4H), 2.67 (s, 3H ), 2.96 (m, 5H), 4.36 (t, 2H), 6.96 (d, 1H), 7.29 (m, 2H), 7.38 (m, 4H), 7.48 (m, 1H), 7.91 (s, 1H) , 8.71 (m 1 H); MS (m / e, M + ): 552 , 523, 509

<실시예 15> 2-부틸-5-포밀-6-페닐-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3Example 15 2-Butyl-5-formyl-6-phenyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-6-페닐-3H-이미다조[4,5-b]피리딘-5-카브알데하이드 100 mg(0.36 mmol)을 실시예 11과 동일한 방법으로 처리하여 95 mg(수율 47%)의 표제 화합물을 얻었다.100 mg (0.36 mmol) of 2-butyl-6-phenyl- 3H -imidazo [4,5-b] pyridine-5-carbaldehyde were treated in the same manner as in Example 11 to give 95 mg (yield 47%) of The title compound was obtained.

1H NMR(300MHz, CDCl3 )δ 1.02(t,3H), 1.23(d, 6H), 1.28(m, 2H), 1.52(m, 2H), 1.81-2.04(m, 8H), 2.16(m, 1H), 2.45(m, 2H), 2.52(m, 1H), 3.01(m, 2H), 3.04(t, 2H), 4.47(t, 2H), 6.94(d, 1H), 7.21-7.48(m, 8H), 7.95(s, 1H), 10.07(s, 1H) : MS(m/e, M+): 565 1 H NMR (300 MHz, CDCl 3 ) δ 1.02 (t, 3H), 1.23 (d, 6H), 1.28 (m, 2H), 1.52 (m, 2H), 1.81-2.04 (m, 8H), 2.16 (m , 1H), 2.45 (m, 2H), 2.52 (m, 1H), 3.01 (m, 2H), 3.04 (t, 2H), 4.47 (t, 2H), 6.94 (d, 1H), 7.21-7.48 ( m, 8H), 7.95 (s, 1H), 10.07 (s, 1H): MS (m / e, M + ): 565

<실시예 16> 2-부틸-5-메틸-6-(4-나이트로페닐)-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3Example 16 2-Butyl-5-methyl-6- (4-nitrophenyl) -3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 HH -이미다조[4,5-b]피리딘Imidazo [4,5-b] pyridine

2-부틸-5-메틸-6-(4-나이트로페닐)-3H-이미다조[4,5-b]피리딘-5-카브알데하이드 100 mg(0.32 mmol)을 실시예 11과 동일한 방법으로 처리하여 82 mg(수율 43%)의 표제 화합물을 얻었다.In the same way as in the imidazo [4,5-b] pyridine-5-carbaldehyde 100 mg (0.32 mmol) Example 11 - 2-butyl-5-methyl-6- (4-nitro-phenyl) -3 H Treatment gave 82 mg (43%) of the title compound.

1H NMR(300MHz, CDCl3 )δ 0.99(t, 3H), 1.23(d, 6H), 1.28(m, 2H), 1.50(m, 2H), 1.70-2.04(m, 8H), 2.12(m, 1H), 2.44(m, 1H), 2.49(t, 2H), 2.51(s, 3H), 2.97((t, 2H), 3.00(m, 2H), 4.36(t, 2H), 6.95(d, 1H), 7.16-7.27(m, 2H), 7.35(brs, 1H, NH), 7.50(d, 2H), 7.53(m, 1H), 7.75(s, 1H), 8.28(d, 2H) : MS(m/e, M+): 596 1 H NMR (300 MHz, CDCl 3 ) δ 0.99 (t, 3H), 1.23 (d, 6H), 1.28 (m, 2H), 1.50 (m, 2H), 1.70-2.04 (m, 8H), 2.12 (m , 1H), 2.44 (m, 1H), 2.49 (t, 2H), 2.51 (s, 3H), 2.97 ((t, 2H), 3.00 (m, 2H), 4.36 (t, 2H), 6.95 (d , 1H), 7.16-7.27 (m, 2H), 7.35 (brs, 1H, NH), 7.50 (d, 2H), 7.53 (m, 1H), 7.75 (s, 1H), 8.28 (d, 2H): MS (m / e, M + ): 596

본 발명의 화학식 1의 이미다졸 유도체 중 실시예에 기재된 화합물의 치환기들을 하기 표 2에 정리하여 나타내었다. Substituents of the compounds described in the examples of the imidazole derivative of Formula 1 of the present invention are shown in Table 2 below.

Figure 112007035093191-pat00025
Figure 112007035093191-pat00025

본 발명에 의한 아릴 피페리딘기-함유 이미다졸 유도체 대하여 하기와 같은 실험을 실시하고 여러 가지 약리효과에 대하여 평가하였다.The following experiments were performed on the aryl piperidine group-containing imidazole derivatives according to the present invention and evaluated for various pharmacological effects.

<실험예 1> 아릴 피페리딘기-함유 이미다졸 유도체의 MCH-1 결합 억제효과Experimental Example 1 Inhibitory Effect of Aryl Piperidine Group-Containing Imidazole Derivatives on MCH-1 Binding

완충용액은 세척용액(25 mM HEPES pH7.4, 5 mM MgCl2, 1 mM CaCl2)과 실험용액(세척용액에 BSA를 0.5 %가 되도록 첨가)의 두 종류를 준비하고, MCH R1(Melanin Concentration Hormone receptor-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 Eu-MCH와 1 mM MCH를 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 was prepared in two forms, a washing solution (25 mM HEPES pH7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and an experimental solution (adding 0.5% BSA to the washing solution), and MCH R1 (Melanin Concentration). Hormone receptor-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 Eu-MCH and 1 mM MCH 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 washing solution was used only to wash the plate at the end.

먼저 MCH R1(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 Eu-MCH 25 ㎕, 수용체 50 ㎕ 및 MCH 25 ㎕를 사용하였으며, 전체결합(total binding) 대조군으로는 10% DMSO 실험용액 25 ㎕, Eu-MCH 25 ㎕ 및 수용체 50 ㎕을 사용하였다. 실험군으로는 실시예에서 제조한 화합물 25 ㎕, Eu-MCH 25 ㎕ 및 수용체 50 ㎕를 사용하였다. 각 시험 화합물, Eu-MCH 및 MCH는 반응 시 전체부피의 25 %씩을 차지하게 되므로 첨가직전에는 4배의 농도로 준비하였다. 이후, 15초간 약하게 흔들어 주고 상온에서 90분간 반응시켰다. 반응이 끝나면, 부분적으로 수정하여 자체 제작한 세척기(microplate washer, EMBLA, Molecular Devices)에 압력을 걸어 플레이트를 세척하였다. 세척 용액으로 웰당 300 ㎕씩 3회 여과시켜 반응하지 않고 남아 있는 Eu-MCH를 제거하였다. 바닥의 물기를 닦아내고 웰당 150 ㎕가 되게 해리용액(DELFIA Enhancement solution, PerkinElmer, Turku, Finland)을 첨가하여 주었다. 상온에서 그대로 2~4시간 방치시킨 후 시차성 형광(Time-resolved fluorescence, TRF) 값을 다기능 형광측정기(multilabel counter, Victor2, PerkinElmer, Turku, Finland)를 이용하여 측정하였으며(방출파장: 615 nm, 여기파장: 340 nm), 하기 수학식에 따라 시차성 형광 억제율을 계산하고, 그 결과를 in vitro에서 MCH를 50% 저해한 시험물질의 농도인 IC50값으로 하기 표 3에 표시하였다. First, homogenize by diluting MCH R1 (200 assays / vial) in 1 ml of experimental solution, and then using an 8-channel pipette on a filter paper-attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). (multi 8-channel, Eppendorf, Hamburg, Germany) was used to dispense the reaction to 100 μl total volume per well. At this time, 25 μl of Eu-MCH, 50 μl of receptor and 25 μl of MCH were used as a non-specific binding control, and 25 μl of 10% DMSO experimental solution and Eu-MCH 25 were used as the total binding control. Μl and 50 μl of receptor were used. As the experimental group, 25 µl of the compound prepared in Example, 25 µl of Eu-MCH and 50 µl of receptor were used. Each test compound, Eu-MCH and MCH, accounted for 25% of the total volume during the reaction, and was prepared at a concentration of 4 times immediately before addition. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. After the reaction, the plate was washed by applying pressure to a partially prepared washer (microplate washer, EMBLA, Molecular Devices). 300 μl / well of the wash solution was filtered three times to remove Eu-MCH that remained 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). After standing at room temperature for 2 ~ 4 hours, the time-resolved fluorescence (TRF) value was measured using a multi-function fluorimeter (multilabel counter, Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615 nm, Excitation wavelength: 340 nm), the differential fluorescence inhibition rate was calculated according to the following equation, and the results are shown in Table 3 as the IC 50 value of the concentration of the test substance inhibited by 50% MCH in vitro .

시차성 형광 억제율=[(전체결합 평균값-시험물질의 시차성 형광값)/(전체결합 평균값-비특이적결합 평균값)]*100Differential Fluorescence Inhibition Ratio = [(Total Binding Average Value-Test Material's Differential Fluorescence Value) / (Total Binding Average Value-Nonspecific Binding Average Value)] * 100

Figure 112007035093191-pat00026
Figure 112007035093191-pat00026

상기 표 3에 표시한 바와 같이, 본 발명의 화합물들은 MCH 수용체에 대한 우수한 길항작용을 나타내었다. 이러한 결과로부터, 본 발명의 이미다졸 유도체가 MCH 수용체에 대한 길항제로서 유효하며, MCH 관련 질환에 대한 치료제로 응용될 수 있음을 확인하였다. As shown in Table 3 above, the compounds of the present invention showed excellent antagonism of the MCH receptor. From these results, it was confirmed that the imidazole derivative of the present invention is effective as an antagonist to the MCH receptor and can be applied as a therapeutic agent for MCH related diseases.

이상에서 살펴본 바와 같이, 본 발명의 아릴 피페리딘기-함유 이미다졸 유도체는 MCH(멜라닌농축호르몬) 수용체에 대한 길항제로서, 이를 유효성분으로 함유하는 조성물은 MCH와 관련된 질환의 예방 및 치료를 위해 유용하게 사용될 수 있다. As described above, the aryl piperidine group-containing imidazole derivative of the present invention is an antagonist to MCH (melanin enriched hormone) receptor, and the composition containing the same as an active ingredient is useful for the prevention and treatment of diseases related to MCH. Can be used.

Claims (10)

하기 화학식 1로 표시되는 이미다졸 유도체 또는 약학적으로 허용 가능한 그의 염:An imidazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112007035093191-pat00027
Figure 112007035093191-pat00027
 상기 식에서,Where R1은 C1~C4의 직쇄 또는 측쇄 알킬이고,R 1 is C 1 -C 4 straight or branched alkyl, R2는 서로 동일하거나 상이한 하나이상의 기로서, H, 할로겐, C1~C3의 직쇄 또는 측쇄 알킬,
Figure 112007035093191-pat00028
, OR4, NO2, CN, 피리딜, CHO, 또는 -CONR5R6이고, 여기에서 X는 H, 할로겐, C1~C3의 직쇄 또는 측쇄 알킬, OR4, 또는 NO2 이고, R4, R5 및 R6은 각각 독립적으로 H, C1~C3의 직쇄 또는 측쇄 알킬 또는 페닐이고,R 2 is one or more groups that are the same or different from each other, and are H, halogen, C 1 to C 3 straight or branched alkyl,
Figure 112007035093191-pat00028
, OR 4 , NO 2 , CN, pyridyl, CHO, or -CONR 5 R 6 , wherein X is H, halogen, C 1 -C 3 straight or branched chain alkyl, OR 4 , or NO 2 R 4 , R 5 and R 6 are each independently H, C 1 to C 3 , straight or branched alkyl or phenyl, R3은 C1~C3의 직쇄 또는 측쇄 알킬, 페닐 또는 할로겐 또는 메틸로 치환된 페닐이고;R 3 is C 1 to C 3 straight or branched alkyl, phenyl or phenyl substituted with halogen or methyl; A는 CH 또는 N이고; 이때 전체 N의 개수는 1 또는 2개이고;A is CH or N; Wherein the total number of N is 1 or 2; n은 2 내지 5의 정수이다.n is an integer of 2-5. 제 1항에 있어서,The method of claim 1, R1은 C1~C4의 직쇄 또는 측쇄 알킬이고,R 1 is C 1 -C 4 straight or branched alkyl, R4는 H, 메틸 또는 페닐이고,R 4 is H, methyl or phenyl, R5 및 R6은 각각 독립적으로 H 이고,R 5 and R 6 are each independently H, R2는 서로 동일하거나 상이한 하나이상의 기로서, H; 할로겐; C1~C3의 직쇄 또는 측쇄의 알킬;
Figure 112007035093191-pat00029
; OR4; NO2; CN; 피리딜; 또는 -CONR5R6 으로, 여기서 X는 H, 할로겐, 메틸, 또는 NO2 이고, R4, R5 및 R6 는 위에서 정의한 바와 같고;R 2 is one or more groups, the same or different from each other, and H; halogen; C 1 -C 3 straight or branched alkyl;
Figure 112007035093191-pat00029
; OR 4 ; NO 2 ; CN; Pyridyl; Or -CONR 5 R 6 , wherein X is H, halogen, methyl, or NO 2 R 4 , R 5 and R 6 Is as defined above; R3는 C1~C3의 직쇄 또는 측쇄의 알킬; 페닐; 또는 할로겐이나 메틸로 치환된 페닐이고;R 3 is C 1 -C 3 straight or branched alkyl; Phenyl; Or phenyl substituted with halogen or methyl; A는 CH 또는 N이고; 이때 전체 N의 개수는 1개이고,A is CH or N; In this case, the total number of N is one, n은 2 내지 5의 정수인 것을 특징으로 하는, 이미다졸 유도체 또는 약학적으로 허용 가능한 그의 염.n is an imidazole derivative, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 2 to 5. 제 1항에 있어서,The method of claim 1, 하기 화합물로 구성된 군으로부터 선택된 것임을 특징으로 하는, 이미다졸 유도체 또는 약학적으로 허용 가능한 그의 염:An imidazole derivative, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: 1) 2-메틸-1-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-1H-벤지미다졸;1) 2-methyl-1- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -1 H -benzimidazole; 2) 2-메틸-1-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-5,6-다이메틸-1H-벤지미다졸;2) 2-methyl-1- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -5,6-dimethyl-1 H -benzimidazole; 3) 2-메틸-1-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-1H-벤지미다졸;3) 2-methyl-1- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -1 H -benzimidazole; 4) 2,5-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;4) 2,5-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5-b] pyridine; 5) 6-브로모-2,5-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;5) 6-bromo-2,5-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5- b] pyridine; 6) 6-브로모-2-에틸-5-메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;6) 6-bromo-2-ethyl-5-methyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5 -b] pyridine; 7) 6-브로모-2-부틸-5-메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;7) 6-bromo-2-butyl-5-methyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5 -b] pyridine; 8) 2-부틸-5,7-다이메틸-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;8) 2-butyl-5,7-dimethyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5-b ] Pyridine; 9) 2-부틸-5,7-다이메틸-6-페닐-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;9) 2-butyl-5,7-dimethyl-6-phenyl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4 , 5-b] pyridine; 10) 2-부틸-5-메틸-6-피리딘-2-일-3-{3-[4-(3-아세틸아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;10) 2-butyl-5-methyl-6-pyridin-2-yl-3- {3- [4- (3-acetylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [ 4,5-b] pyridine; 11) 6-브로모-2-부틸-5-메틸-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;11) 6-bromo-2-butyl-5-methyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3H-imidazo [4, 5-b] pyridine; 12) 2-부틸-5,7-다이메틸-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;12) 2-butyl-5,7-dimethyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5 -b] pyridine; 13) 2-부틸-5,7-다이메틸-6-페닐-3-{3-[4-(3-아이소부티릴아미노페닐) 피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;13) 2-butyl-5,7-dimethyl-6-phenyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H -imidazo [4,5-b] pyridine; 14) 2-부틸-5-메틸-6-피리딘-2-일-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘;14) 2-butyl-5-methyl-6-pyridin-2-yl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H -already Multizo [4,5-b] pyridine; 15) 2-부틸-5-포밀-6-페닐-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘; 및15) 2-butyl-5-formyl-6-phenyl-3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3H-imidazo [4,5 -b] pyridine; And 16) 2-부틸-5-메틸-6-(4-나이트로페닐)-3-{3-[4-(3-아이소부티릴아미노페닐)피페리딘-1-일]프로필}-3H-이미다조[4,5-b]피리딘.16) 2-butyl-5-methyl-6- (4-nitrophenyl) -3- {3- [4- (3-isobutyrylaminophenyl) piperidin-1-yl] propyl} -3 H Imidazo [4,5-b] pyridine. 하기 화학식 2의 이미다졸 화합물을 용매와 염기 존재하에 하기 화학식 3의 화합물 과 반응시키는 것을 포함하는, 하기 화학식 1의 이미다졸 유도체의 제조방법:A method for preparing an imidazole derivative of Formula 1 comprising reacting an imidazole compound of Formula 2 with a compound of Formula 3 in the presence of a solvent and a base: [화학식 1][Formula 1]
Figure 112007035093191-pat00030
Figure 112007035093191-pat00030
 [화학식 2][Formula 2]
Figure 112007035093191-pat00031
Figure 112007035093191-pat00031
 [화학식 3][Formula 3]
Figure 112007035093191-pat00032
Figure 112007035093191-pat00032
 상기 식에서,Where R1, R2, R3, A, n은 제 1항에서 정의한 바와 같고, L은 할로겐, 메실레이트 또는 토실레이트이다.R 1 , R 2 , R 3 , A, n are as defined in claim 1 and L is halogen, mesylate or tosylate. 하기 화학식 4의 화합물을 용매와 염기 존재하에 하기 화학식 5의 아릴 피페리딘 화합물과 반응시키는 것을 포함하는, 하기 화학식 1의 이미다졸 유도체의 제조방법:A method for preparing an imidazole derivative of Formula 1, comprising reacting a compound of Formula 4 with an aryl piperidine compound of Formula 5 in the presence of a solvent and a base: [화학식 1][Formula 1]
Figure 112007035093191-pat00033
Figure 112007035093191-pat00033
 [화학식 4][Formula 4]
Figure 112007035093191-pat00034
Figure 112007035093191-pat00034
 [화학식 5][Formula 5]
Figure 112007035093191-pat00035
Figure 112007035093191-pat00035
 상기 식에서,Where R1, R2, R3, A, n은 제 1항에서 정의한 바와 같고, L은 할로겐, 메실레이트 또는 토실레이트이다.R 1 , R 2 , R 3 , A, n are as defined in claim 1 and L is halogen, mesylate or tosylate. 제 4항 또는 5항에 있어서, The method according to claim 4 or 5, 염기가 피리딘, 트라이에틸아민, N,N-디이소프로필에틸아민, 1,8-디아자비시클로-[5.4.0]운데크-7-엔(DBU) 및 이들의 혼합물 중에서 선택된 유기 염기, 또는 NaOH, Na2CO3, K2CO3, Cs2CO3 또는 이들의 혼합물 중에서 선택된 무기 염기인 것을 특징으로 하는, 이미다졸 유도체의 제조방법.An organic base selected from pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU) and mixtures thereof, or Method of producing an imidazole derivative, characterized in that the inorganic base selected from NaOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 or a mixture thereof. 제 4항 또는 5항에 있어서, The method according to claim 4 or 5, 용매가 에테르계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 또는 이들의 혼합물인 것을 특징으로 하는, 이미다졸 유도체의 제조방법. A solvent is an ether solvent, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile or a mixture thereof, characterized in that the method for producing an imidazole derivative. 삭제delete 제 1항의 이미다졸 유도체 또는 약학적으로 허용되는 그의 염을 유효성분으로 함유하는, 비만, 우울증, 불안증, 당뇨병 및 대사장애로 구성된 군으로부터 선택되는, 멜라닌 농축 호르몬(MCH) 관련 질환의 예방 또는 치료용 조성물.Prevention or treatment of melanin enrichment hormone (MCH) related disease, selected from the group consisting of obesity, depression, anxiety, diabetes mellitus and metabolic disorders, containing as an active ingredient the imidazole derivative of claim 1 or a pharmaceutically acceptable salt thereof. Composition. 삭제delete
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004287A1 (en) * 1994-07-29 1996-02-15 Laboratorios Del Dr. Esteve, S.A. Tetrahydropyridine-(or 4-hydroxypiperidine)alkylazoles having an affinity for sigma and/or 5ht1a receptors
KR20060125825A (en) * 2004-01-14 2006-12-06 하. 룬트벡 아크티에 셀스카브 4-aryl piperidines
KR20060128955A (en) * 2004-01-25 2006-12-14 사노피-아벤티스 도이칠란트 게엠베하 Substituted n-cyclohexyl imidazolinones having an mch-modulatory effect

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004287A1 (en) * 1994-07-29 1996-02-15 Laboratorios Del Dr. Esteve, S.A. Tetrahydropyridine-(or 4-hydroxypiperidine)alkylazoles having an affinity for sigma and/or 5ht1a receptors
KR20060125825A (en) * 2004-01-14 2006-12-06 하. 룬트벡 아크티에 셀스카브 4-aryl piperidines
KR20060128955A (en) * 2004-01-25 2006-12-14 사노피-아벤티스 도이칠란트 게엠베하 Substituted n-cyclohexyl imidazolinones having an mch-modulatory effect

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