KR101422725B1 - Novel phthalazinone 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

Novel phthalazinone 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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KR101422725B1
KR101422725B1 KR1020110106962A KR20110106962A KR101422725B1 KR 101422725 B1 KR101422725 B1 KR 101422725B1 KR 1020110106962 A KR1020110106962 A KR 1020110106962A KR 20110106962 A KR20110106962 A KR 20110106962A KR 101422725 B1 KR101422725 B1 KR 101422725B1
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piperidin
phenyl
acetylamino
phthalazinone
propyl
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KR20130042847A (en
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이규양
임채조
서지희
김수희
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한국화학연구원
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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines

Abstract

본 발명은 신규한 프탈라지논 유도체 및 그의 MCH 수용체-1 관련 질환에 대한 치료학적 용도에 관한 것이다. 본 발명에 의한 신규한 프탈라지논 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 relates to novel phthalazinone derivatives and their therapeutic uses for MCH receptor-1 related diseases. The novel phthalazinone derivative according to the present invention acts as an antagonist to MCH (melanocyte hormone) receptor, thereby preventing MCH-related diseases such as obesity, diabetes, metabolic disorder, anxiety and depression induced by binding MCH to MCH receptor Or treatments.

Description

신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 ＭＣＨ 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물{Novel phthalazinone 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}TECHNICAL FIELD The present invention relates to a novel phthalazinone derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating MCH receptor-1-related diseases containing the same as an active ingredient. method therof and pharmaceutical composition for prevention or treatment of MCH receptor-

본 발명은 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 MCH 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention relates to a novel phthalazinone derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating MCH receptor-1-related diseases containing the same as an active ingredient.

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 112011081771684-pat00001
Figure 112011081771684-pat00002
Figure 112011081771684-pat00001
Figure 112011081771684-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. MCH (melanin concentrating hormone) is a cyclic peptide composed of 19 amino acids and is identical to 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). In addition, MCH receptor-1 antagonists have been shown to be effective in diabetes and metabolic disorders as well as in the treatment of obesity, depression and anxiety (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 프탈라지논 유도체가 MCH 수용체의 길항제로 작용함으로써, 비만과 같은 MCH 관련 질환의 예방 및 치료제로 사용될 수 있다는 것을 밝히고 본 발명을 완성하였다.
Accordingly, the present inventors have made efforts to develop a compound exhibiting an antagonistic effect on the MCH receptor, so that a phthalazinone derivative having a specific structure acts as an antagonist of the MCH receptor and thus can be used as a preventive and therapeutic agent for MCH-related diseases such as obesity And completed the present invention.

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 신규한 프탈지논 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.It is an object of the present invention to provide a novel phthalimone derivative or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 상기 신규한 프탈라지논 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a process for preparing the novel phthalazinone derivatives.

본 발명의 또 다른 목적은 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 길항제를 제공하는 것이다.Another object of the present invention is to provide an MCH receptor-1 antagonist comprising a novel phthalazinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 다른 목적은 상기 신규한 프탈라지논 유도체 또는 이의 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating an MCH-related disease containing the novel phthalazinone derivative or a salt thereof as an active ingredient.

본 발명의 또 다른 목적은 상기 신규한 프탈라지논 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 an MCH-related disease containing the novel phthalazinone derivative or a salt thereof as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 신규한 프탈지논 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다:In order to accomplish the above object, the present invention provides a novel phthalazinone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[화학식 1][Chemical Formula 1]

Figure 112011081771684-pat00003
Figure 112011081771684-pat00003

(상기 화학식 1의 A, R1 및 R2는 본 명세서에서 정의한 바와 같다).(A, R < 1 > and R < 2 > in the above formula (1) are as defined herein).

또한, 본 발명은 상기 화학식 1로 표시되는 신규한 프탈라지논 유도체의 제조방법을 제공한다.The present invention also provides a process for preparing a novel phthalazinone derivative represented by the general formula (1).

나아가, 본 발명은 상기 화학식 1로 표시되는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 길항제를 제공한다.Further, the present invention provides an MCH receptor-1 antagonist comprising the novel phthalazinone derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화학식 1로 표시되는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating an MCH-related disease containing the novel phthalazinone derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

나아가, 본 발명은 상기 화학식 1로 표시되는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 MCH 관련 질환의 예방 또는 예방용 건강식품 조성물을 제공한다.
Further, the present invention provides a health food composition for preventing or preventing MCH-related diseases, which comprises the novel phthalazinone derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 의한 신규한 프탈라지논 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 novel phthalazinone derivative according to the present invention acts as an antagonist to MCH (melanocyte hormone) receptor, thereby preventing MCH-related diseases such as obesity, diabetes, metabolic disorder, anxiety and depression induced by binding MCH to MCH receptor Or treatments.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 하기 화학식 1로 표시되는 신규한 프탈지논 유도체 및 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides novel phthalazone derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

Figure 112011081771684-pat00004
Figure 112011081771684-pat00004

상기 화학식 1에서, In Formula 1,

A는 탄소(C), 질소(N), 산소(O), 황(S) 및 설폰(SO2)으로 이루어진 군으로부터 선택되는 1종이고;A is one species selected from the group consisting of carbon (C), nitrogen (N), oxygen (O), sulfur (S) and sulfone (SO 2 );

R1 및 R2는 각각 독립적으로 수소; C1-C4 직쇄 또는 측쇄 알킬; 비치환이거나 할로겐, 또는 C1-C4 직쇄 또는 측쇄 알킬로 치환된 아릴; 비치환이거나 C1-C4 직쇄 또는 측쇄 알킬로 치환된 시클로알킬 또는 헤테로시클로알킬; 비치환이거나 할로겐, 또는 C1-C4 직쇄 또는 측쇄 알킬로 치환된 헤테로아릴 C1-C4 직쇄 알킬이고, 이때, 상기 헤테로아릴은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하고; R 1 and R 2 are each independently hydrogen; C 1 -C 4 straight or branched chain alkyl; Aryl unsubstituted or substituted with halogen or C 1 -C 4 straight chain or branched chain alkyl; Cycloalkyl or heterocycloalkyl which is unsubstituted or substituted by C 1 -C 4 straight chain or branched alkyl; Unsubstituted or halogen, or a heteroaryl C 1 -C 4 straight chain alkyl optionally substituted with C 1 -C 4 straight or branched chain alkyl, wherein the heteroaryl group is N, O, and 1 heteroaryl or more selected from the group consisting of S Atoms;

이때, 상기 A가 O, S 또는 SO2인 경우, R2는 부재이고; 및When A is O, S or SO 2 , R 2 is a member; And

R1 및 R2는 함께 비치환 또는 할로겐, 옥소(=O), 카르복실, C1-C4 직쇄 또는 측쇄 알킬, C1-C4 직쇄 또는 측쇄 알킬옥시카보닐, 아미노 및 t-부틸옥시카보닐아미노로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 C5-C7의 헤테로시클로알킬을 형성할 수 있고, 이때, 상기 헤테로시클로알킬은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함한다.
R 1 and R 2 taken together represent an unsubstituted or substituted radical selected from the group consisting of halogen, oxo (═O), carboxyl, C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkyloxycarbonyl, amino and t- carbonyl amino with at least one member selected from the group may form a heterocycloalkyl group of the substituted C 5 -C 7 consisting of, at this time, one kind of the heterocycloalkyl is selected from the group consisting of N, O and S Or more hetero atoms.

바람직하게는, 상기 화학식 1에서,Preferably, in the above formula (1)

A는 탄소(C), 질소(N), 산소(O), 황(S) 및 설폰(SO2)으로 이루어진 군으로부터 선택되는 1종이고;A is one species selected from the group consisting of carbon (C), nitrogen (N), oxygen (O), sulfur (S) and sulfone (SO 2 );

R1 및 R2는 각각 독립적으로 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸,

Figure 112011081771684-pat00005
,
Figure 112011081771684-pat00006
,
Figure 112011081771684-pat00007
,
Figure 112011081771684-pat00008
,
Figure 112011081771684-pat00009
,
Figure 112011081771684-pat00010
,
Figure 112011081771684-pat00011
,
Figure 112011081771684-pat00012
,
Figure 112011081771684-pat00013
및
Figure 112011081771684-pat00014
로 이루어지는 군으로부터 선택되는 1종이고, 이때, 상기 A가 O, S 또는 SO2인 경우, R2는 부재이고; 및R 1 and R 2 are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Figure 112011081771684-pat00005
,
Figure 112011081771684-pat00006
,
Figure 112011081771684-pat00007
,
Figure 112011081771684-pat00008
,
Figure 112011081771684-pat00009
,
Figure 112011081771684-pat00010
,
Figure 112011081771684-pat00011
,
Figure 112011081771684-pat00012
,
Figure 112011081771684-pat00013
And
Figure 112011081771684-pat00014
And when A is O, S or SO 2 , R 2 is a member; And

R1 및 R2는 함께 비치환 또는 클로로, 플루오로, 브로모, 옥소, 카르복시, 메톡시카보닐, 에톡시카보닐, 프로폭시카보닐, 부톡시카보닐, t-부톡시카보닐, 아미노, t-부톡시카보닐아미노로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 피롤리딘, 몰폴린, 싸이오몰포린, 피페리딘 또는 피페라진을 형성한다.
R 1 and R 2 together are an unsubstituted or substituted radical selected from the group consisting of chloro, fluoro, bromo, oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, amino pyrrolidine, morpholine, thiomorpholine, piperidine or piperazine substituted with at least one member selected from the group consisting of t-butoxycarbonylamino, and t-butoxycarbonylamino.

또한, 상기 화학식 1로 표시되는 신규한 프탈라지논 유도체를 보다 구체적으로 예시하면 다음과 같다.Further, the novel phthalazinone derivatives represented by the above formula (1) are more specifically exemplified as follows.

(1) 4-벤질-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(1) 4-Benzyl-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(2) 4-(4-클로로벤질)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(2) 4- (4-Chlorobenzyl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(3) 4-[2-(피리딘-4-일)에틸]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - 1 (2H) -quinolin-2-one hydrochloride (3) Synthesis of 4- [2- (pyridin- - phthalazinone;

(4) 4-[2-(피리딘-2-일)에틸]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - 1 (2H) -quinolinone. (4) Synthesis of 4- [2- (pyridin- - phthalazinone;

(5) 4-[2-(피리딘-3-일)에틸]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - 1 (2H) -quinolinone (5) 4- [2- (pyridin- - phthalazinone;

(6) 4-(4-클로로페녹시)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(6) 4- (4-Chlorophenoxy) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(7) 4-[[1-(t-부톡시카보닐)피페리딘-4-일]옥시]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(7) Synthesis of 4 - [[1- (t-butoxycarbonyl) piperidin-4-yl] oxy] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -Yl] propyl] -1 (2H) -phthalazinone;

(8) 4-[피페리딘-4-일옥시]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(8) 4- [Piperidin-4-yloxy] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- 1 -yl] Thalasinone;

(9) 4-[(4-클로로페닐)싸이오]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(9) Synthesis of 4 - [(4-chlorophenyl) thio] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Thalasinone;

(10) 4-페닐설포닐-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(10) 4-Phenylsulfonyl-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(11) 4-[(4-메틸페닐)설포닐]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(11) 4- [(4-methylphenyl) sulfonyl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Zinon;

(12) 4-[(4-클로로페닐)설포닐]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(12) 4 - [(4-chlorophenyl) sulfonyl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Thalasinone;

(13) 4-[(4-클로로페닐)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(13) 4-r4- (4-chlorophenyl) amino] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Zinon;

(14) 4-[(피리딘-4-일)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(14) 4 - [(pyridin-4-yl) amino] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Thalasinone;

(15) 4-[(피리딘-2-일메틸)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - (1 H) - [2- (3-fluorophenyl) piperidin- Phthalazinone;

(16) 4-사이클로헥실아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(16) 4-Cyclohexylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(17) 4-[메틸(페닐)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(17) 4- [methyl (phenyl) amino] -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(18) 4-다이에틸아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(18) 4-Diethylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(19) 4-다이프로필아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(19) 4-dipropylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(20) 4-다이아이소부틸아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(20) 4-Diisobutylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;

(21) 4-(피롤리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(21) 4- (pyrrolidin-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Zinon;

(22) 4-(몰포린-4-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(22) Synthesis of 4- (morpholin-4-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- ;

(23) 4-(싸이오몰포린-4-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(23) 4- (thiomorpholin-4-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- 1- yl] Zinon;

(24) 4-(피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(24) 4- (Piperidin-l-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- 1- yl] Zinon;

(25) 4-(4-메틸피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(25) 4- (4-methylpiperidin- 1 -yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone;

(26) 4-(3-메틸피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - 1 (2H) -pyridin-2-yl] - (2- - phthalazinone;

(27) 4-(4-옥소피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - 1 (2H) -quinolin-2-one (27) 4- (4-oxopiperidin- - phthalazinone;

(28) 4-(4-클로로피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;Yl] propyl] - 1 (2H) -pyridin-2-ylmethyll-2- - phthalazinone;

(29) 4-[4-(t-부톡시카보닐)피페라진-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(29) Synthesis of 4- [4- (t-butoxycarbonyl) piperazin-1-yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- ] -1 (2H) -phthalazinone;

(30) 4-(피페라진-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(30) A mixture of 4- (piperazin-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- ;

(31) 4-(4-메틸피페라진-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(31) 4- (4-methylpiperazin-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Phthalazinone;

(32) 4-[4-(메톡시카보닐)피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(32) 4- [4- (methoxycarbonyl) piperidin-1-yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -1 (2H) -phthalazinone;

(33) 4-[4-카르복시피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(33) 4- [4-carboxypiperidin- 1 -yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone;

(34) 4-[3-(에톡시카보닐)피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(34) 4- [3- (ethoxycarbonyl) piperidin-1-yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -1 (2H) -phthalazinone;

(35) 4-[3-카르복시피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;(35) 4- [3-carboxypiperidin- 1 -yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone;

(36) 4-[[4-(t-부톡시카보닐)아미노]피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논; 및(36) 4 - [[4- (t-butoxycarbonyl) amino] piperidin- 1 -yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -Yl] propyl] -1 (2H) -phthalazinone; And

(37) 4-(4-아미노피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논.
(37) 4- (4-aminopiperidin-l-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - Phthalazineon.

본 발명에 따른 상기 화학식 1로 표시되는 신규한 프탈라지논 유도체의 바람직한 구조를 하기 표 1에 나타내었다.The preferred structures of the novel phthalazinone derivatives represented by Formula 1 according to the present invention are shown in Table 1 below.

실시예Example 구조식constitutional formula 실시예Example 구조식constitutional formula 1One

Figure 112011081771684-pat00015
Figure 112011081771684-pat00015
22
Figure 112011081771684-pat00016
Figure 112011081771684-pat00016
 33
Figure 112011081771684-pat00017
Figure 112011081771684-pat00017
 44
Figure 112011081771684-pat00018
Figure 112011081771684-pat00018
 55
Figure 112011081771684-pat00019
Figure 112011081771684-pat00019
 66
Figure 112011081771684-pat00020
Figure 112011081771684-pat00020
 77
Figure 112011081771684-pat00021
Figure 112011081771684-pat00021
 88
Figure 112011081771684-pat00022
Figure 112011081771684-pat00022
 99
Figure 112011081771684-pat00023
Figure 112011081771684-pat00023
 1010
Figure 112011081771684-pat00024
Figure 112011081771684-pat00024
 1111
Figure 112011081771684-pat00025
Figure 112011081771684-pat00025
 1212
Figure 112011081771684-pat00026
Figure 112011081771684-pat00026
 1313
Figure 112011081771684-pat00027
Figure 112011081771684-pat00027
 1414
Figure 112011081771684-pat00028
Figure 112011081771684-pat00028
 1515
Figure 112011081771684-pat00029
Figure 112011081771684-pat00029
 1616
Figure 112011081771684-pat00030
Figure 112011081771684-pat00030
 1717
Figure 112011081771684-pat00031
Figure 112011081771684-pat00031
 1818
Figure 112011081771684-pat00032
Figure 112011081771684-pat00032
 1919
Figure 112011081771684-pat00033
Figure 112011081771684-pat00033
 2020
Figure 112011081771684-pat00034
Figure 112011081771684-pat00034
 2121
Figure 112011081771684-pat00035
Figure 112011081771684-pat00035
 2222
Figure 112011081771684-pat00036
Figure 112011081771684-pat00036
 2323
Figure 112011081771684-pat00037
Figure 112011081771684-pat00037
 2424
Figure 112011081771684-pat00038
Figure 112011081771684-pat00038
 2525
Figure 112011081771684-pat00039
Figure 112011081771684-pat00039
 2626
Figure 112011081771684-pat00040
Figure 112011081771684-pat00040
 2727
Figure 112011081771684-pat00041
Figure 112011081771684-pat00041
 2828
Figure 112011081771684-pat00042
Figure 112011081771684-pat00042
 2929
Figure 112011081771684-pat00043
Figure 112011081771684-pat00043
 3030
Figure 112011081771684-pat00044
Figure 112011081771684-pat00044
 3131
Figure 112011081771684-pat00045
Figure 112011081771684-pat00045
 3232
Figure 112011081771684-pat00046
Figure 112011081771684-pat00046
 3333
Figure 112011081771684-pat00047
Figure 112011081771684-pat00047
 3434
Figure 112011081771684-pat00048
Figure 112011081771684-pat00048
 3535
Figure 112011081771684-pat00049
Figure 112011081771684-pat00049
 3636
Figure 112011081771684-pat00050
Figure 112011081771684-pat00050
 3737
Figure 112011081771684-pat00051
Figure 112011081771684-pat00051

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 derivatives of formula (I) of the present invention can be used in the form of pharmaceutically acceptable salts, and as salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. Acid addition salts include those derived from 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, hydroxyalkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. 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. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an 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 신규한 프탈라지논 유도체 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물 등을 모두 포함한다.
The present invention also includes novel phthalazinone derivatives represented by the above formula (1) and pharmaceutically acceptable salts thereof, as well as possible solvates, hydrates and the like which can be prepared therefrom.

나아가, 본 발명은 상기 화학식 1로 표시되는 프탈라지논 유도체의 제조방법을 제공한다.Further, the present invention provides a process for preparing the phthalazinone derivative represented by the above formula (1).

본 발명에 따른 화학식 1의 유도체의 제조방법은 하기 반응식 1에 나타난 바와 같이, 화학식 2로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 3으로 표시되는 피페리딘 화합물과 알킬화 반응을 시켜 화학식 1로 표시되는 화합물을 얻는 단계를 포함한다:The method for preparing a derivative of formula (1) according to the present invention is characterized in that the compound represented by formula (2) is subjected to an alkylation reaction with a piperidine compound represented by formula (3) under an organic solvent and base, Lt; RTI ID = 0.0 > of:

[반응식 1][Reaction Scheme 1]

Figure 112011081771684-pat00052
Figure 112011081771684-pat00052

(상기 반응식 1에서 A, R1 및 R2는 상기 화학식 1에서 정의한 바와 같고, L은 이탈기로써, 메실레이트, 토실레이트 또는 할로겐이다).
(Wherein A, R 1 and R 2 are as defined in Formula 1 and L is a leaving group, mesylate, tosylate or halogen).

구체적으로, 상기 화학식 2로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 3으로 표시되는 피페리딘 화합물과 알킬화 반응시켜 화학식 1로 표시되는 화합물을 얻을 수 있다.Specifically, the compound represented by the formula (2) may be alkylated with the piperidine compound represented by the formula (3) under an organic solvent and a base to obtain a compound represented by the formula (1).

이때, 사용가능한 용매는 테트라하이드로퓨란; 다이옥산; 에틸에테르, 1,2-다이메톡시에탄 등을 포함하는 에테르용매; 메탄올, 에탄올, 프로판올 및 부탄올을 포함하는 저급 알코올; 디메틸포름아미드(DMF); 디메틸설폭사이드(DMSO); 아세토나이트릴; 물(H2O) 등을 단독 또는 혼합하여 사용할 수 있다.At this time, usable solvents include tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile; Water (H2O), etc. may be used alone or in combination.

또한, 상기 염기는 피리딘, 트리에틸아민, N,N-다이이소프로필에틸아민(DIPEA), 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU) 등의 유기염기; 또는 소듐하이드록사이드, 소듐카보네이트, 포타슘카보네이트, 세슘카보네이트, 소듐하이드라이드 등의 무기염기를 당량 또는 과량으로 사용할 수 있다.The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and the like may be used in an equivalent amount or in an excess amount.

상기 반응을 수행한 후, 유기용매로 추출, 건조, 여과 및 감압 증류하는 과정을 수행하고 추가적으로 컬럼크로마토그래피를 수행하여 상기 화학식 1로 표시되는 화합물을 얻을 수 있다.
After carrying out the above reaction, extraction with an organic solvent, drying, filtration and distillation under reduced pressure are carried out, and further column chromatography is carried out to obtain a compound represented by the above formula (1).

제법 1Recipe 1

본 발명의 반응식 1에 있어서, 상기 화학식 2의 화합물은 하기 반응식 2에 나타난 바와 같이, 유기용매 및 염기 하에서 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 알킬화 반응을 수행함으로써 얻을 수 있다:In Scheme 1 of the present invention, the compound of Formula 2 can be obtained by subjecting the compound represented by Formula 4 and the compound represented by Formula 5 to an alkylation reaction under an organic solvent and base, as shown in Reaction Scheme 2 below.

[반응식 2][Reaction Scheme 2]

Figure 112011081771684-pat00053
Figure 112011081771684-pat00053

(상기 반응식 2에서 A, R1 및 R2는 상기 화학식 1에서 정의한 바와 같고, L은 이탈기로써, 메실레이트, 토실레이트 또는 할로겐이며; Y는 할로겐이다).
Wherein A, R 1 and R 2 are as defined in the above formula (1), L is a leaving group, mesylate, tosylate or halogen, and Y is halogen.

이때, 사용가능한 용매는 테트라하이드로퓨란; 다이옥산; 에틸에테르, 1,2-다이메톡시에탄 등을 포함하는 에테르용매; 디메틸포름아미드(DMF); 디메틸설폭사이드(DMSO); 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다.At this time, usable solvents include tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile and the like can be used alone or in combination.

또한, 상기 염기는 피리딘, 트리에틸아민, N,N-다이이소프로필에틸아민(DIPEA), 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU) 등의 유기염기; 또는 소듐하이드록사이드, 소듐카보네이트, 포타슘카보네이트, 세슘카보네이트, 소듐하이드라이드 등의 무기염기를 당량 또는 과량으로 사용할 수 있다.The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and the like may be used in an equivalent amount or in an excess amount.

구체적으로, 상기 화학식 4로 표시되는 화합물을 디메틸포름아미드(DMF)에 녹인 후, 소듐하이드라이드(NaH)를 첨가하고, 화학식 5로 표시되는 화합물을 첨가한 후, 상온에서 2 내지 4시간 동안 알킬화반응을 수행한다. Specifically, the compound represented by Chemical Formula 4 is dissolved in dimethylformamide (DMF), sodium hydride (NaH) is added, the compound represented by Chemical Formula 5 is added, and alkylation at room temperature for 2 to 4 hours The reaction is carried out.

상기 반응을 수행한 후, 유기용매로 추출, 건조, 여과 및 감압 증류하는 과정을 수행하고 추가적으로 컬럼크로마토그래피를 수행하여 상기 화학식 2로 표시되는 화합물을 얻을 수 있다.
After carrying out the above reaction, extraction with an organic solvent, drying, filtration and distillation under reduced pressure are carried out, and further column chromatography is carried out to obtain a compound represented by the above formula (2).

제법 2Recipe 2

본 발명의 상기 반응식 2에 있어서, 상기 화학식 4로 표시되는 화합물은 하기와 같은 방법으로 제조될 수 있으나, 이에 한정하지 않는다.In the Reaction Scheme 2 of the present invention, the compound represented by Formula 4 may be prepared by the following method, but is not limited thereto.

본 발명에 따른 반응식 2에 포함되는 화학식 4에서 A가 N, O, S 또는 SO2인 경우, 4-a로 표시되는 유도체의 제조방법은 하기 반응식 3에 나타난 바와 같이, 화학식 6으로 표시되는 화합물과 화학식 7로 표시되는 화합물을 반응시켜 화학식 8로 표시되는 화합물을 얻는 단계(단계 1);In the case where A is N, O, S or SO 2 in Chemical Formula 4 included in Reaction Formula 2 according to the present invention, the process for producing a derivative represented by 4-a can be carried out by reacting a compound represented by Chemical Formula 6 With a compound represented by the formula (7) to obtain a compound represented by the formula (8) (step 1);

화학식 8로 표시되는 화합물을 가수분해반응을 수행하여 화학식 4-a로 표시되는 화합물을 얻는 단계(단계 2)를 포함하는 방법에 의해 제조될 수 있다:(Step 2) of performing the hydrolysis reaction of the compound represented by the formula (8) to obtain the compound represented by the formula (4-a): < EMI ID =

[반응식 3][Reaction Scheme 3]

Figure 112011081771684-pat00054
Figure 112011081771684-pat00054

(상기 반응식 3에서 A는 N, O, S 또는 SO2이고, R1 및 R2은 상기 화학식 1에서 정의한 바와 같다).(Wherein A is N, O, S or SO 2 and R 1 And R < 2 > are the same as defined in Formula 1).

본 발명에 따른 제법에 있어서,In the process according to the present invention,

상기 단계 1은 화학식 6으로 표시되는 화합물과 화학식 7로 표시되는 화합물을 염기 및 유기용매 하에서 반응시켜 화학식 8로 표시되는 화합물을 얻는 단계이다.Step 1 is a step of reacting a compound represented by formula (6) with a compound represented by formula (7) in a base and an organic solvent to obtain a compound represented by formula (8).

이때 사용가능한 유기용매는 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. Examples of the organic solvent include an ether solvent such as tetrahydrofuran, dioxane, dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide, acetonitrile, etc., Can be used.

또한, 상기 염기는 피리딘, 트라이에틸아민, N,N-디이소프로필에틸아민, 1,8-디아자비시클로-[5.4.0]운데크-7-엔(DBU) 등의 유기염기 또는 NaH, NaOH, Na2CO3, K2CO3, Cs2CO3 등의 무기염기를 당량 또는 과량 사용할 수 있다.The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU) NaOH, Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 can be used in an equivalent amount or in an excess amount.

구체적으로, 화학식 7로 표시되는 화합물을 테트라하이드로퓨란 용매에 녹인 후, 화학식 6으로 표시되는 화합물 첨가하고, 0 ℃ 내지 용매의 비등점의 온도에서 반응시켜 화학식 8로 표시되는 화합물을 얻을 수 있다.Specifically, the compound represented by the formula (7) is dissolved in a tetrahydrofuran solvent, and the compound represented by the formula (6) is added and reacted at 0 ° C to the boiling point of the solvent to obtain the compound represented by the formula (8).

또한, 상기 단계 2는 상기 단계 1에서 얻은 화학식 8로 표시되는 화합물을 유기용매에 녹인 후, 염기 또는 산을 첨가하여 가수분해 반응시켜 화학식 4-a로 표시되는 화합물을 얻는 단계이다.Step 2 is a step of dissolving the compound of Formula 8 obtained in Step 1 in an organic solvent and then adding a base or an acid to obtain a compound represented by Formula 4-a.

이때, 사용가능한 유기용매는 메탄올, 에탄올, 프로판올, 부탄올 같은 알코올계 용매, 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴, 물 등을 단독 또는 혼합하여 사용할 수 있다. Examples of the organic solvent include alcohol solvents such as methanol, ethanol, propanol and butanol, ether solvents such as tetrahydrofuran, dioxane, dimethoxyethane and 1,2-dimethoxyethane, dimethylformamide (DMF) , Dimethylsulfoxide, acetonitrile, water, etc. may be used alone or in combination.

또한, 염기로 NaOH, Na2CO3, K2CO3, Cs2CO3 등의 무기염기를 사용하거나, 산으로 아세트산, 염산, 황산, 메탄설폰산의 산으로부터 선택하여 사용할 수 있는데 무기염기를 사용하는 것이 바람직하다. It is also possible to use an inorganic base such as NaOH, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 as a base, or an acid such as acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid. Is preferably used.

상기 염기 또는 산은 당량 또는 과량 사용할 수 있다.The base or acid may be used in an equivalent amount or in an excess amount.

구체적으로, 상기 단계 1에서 얻은 화학식 8로 표시되는 화합물을 에탄올에 녹인후, 염기를 1 내지 10 당량을 첨가한 후, 1 내지 5시간 동안 가열환류시켜 화학식 4-a로 표시되는 화합물을 얻을 수 있다.
Specifically, the compound represented by the formula (8) obtained in the above step 1 was dissolved in ethanol, 1 to 10 equivalents of a base was added, and the mixture was heated under reflux for 1 to 5 hours to obtain a compound represented by the formula (4-a) have.

나아가, 본 발명은 화학식 1로 표시되는 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 길항제를 제공한다.Further, the present invention provides an MCH receptor-1 antagonist comprising the phthalazinone derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 따른 프탈라지논 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).
The phthalazinone derivative according to the present invention has an excellent antagonistic effect on MCH receptor-1 as a result of measuring MCH receptor-1 binding inhibition, and thus can be effectively used as an MCH receptor-1 antagonist 1).

또한, 본 발명은 화학식 1로 표시되는 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating MCH receptor-1-related diseases, which comprises the phthalazinone derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

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 프탈라지논 유도체는 MCH 수용체-1 결합 억제 활성을 측정한 결과, 본 발명에 따른 실시예 1, 2, 6, 10, 12, 13, 16, 23, 24의 화합물이 IC50 값이 50 nM 이하 농도에서 MCH 수용체-1에 대하여 길항작용을 하는 것으로 확인되었으며, 특히, 본 발명의 실시예 23의 화합물은 IC50 값이 5 nM로 매우 우수한 MCH 수용체-1에 대한 길항작용을 하는 효과를 나타내는 것을 알 수 있다(실험예 1 참조).
Thus, the phthalazinone derivative represented by Formula 1 according to the present invention was tested for inhibition of MCH receptor-1 binding, and as a result, it was confirmed that Examples 1, 2, 6, 10, 12, 13, 16, 23 , 24 of the compounds of the present invention were found to antagonize MCH receptor-1 at an IC 50 value of 50 nM or less. In particular, the compound of Example 23 of the present invention has an IC 50 value of 5 nM, -1 < / RTI > (see Experimental Example 1).

따라서, 본 발명에 따른 화학식 1로 표시되는 프탈라지논 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.
Accordingly, the phthalazinone derivative represented by the formula (1) according to the present invention acts as an antagonist to MCH receptor-1, thereby inhibiting MCH receptor-1 binding to MCH receptor-1 such as obesity, diabetes, metabolic disorder, anxiety and depression Can be usefully used for preventing or treating receptor-1 related diseases.

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 medicine, the pharmaceutical composition containing the derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient may be administered orally or parenterally May be formulated and administered, but the present invention 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.Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , 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). The 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. The pharmaceutical composition containing the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be performed by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 프탈라지논 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. In this case, in order to formulate the composition for parenteral administration, the phthalazinone derivative of Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then administered in an ampule or vial unit Can be manufactured. The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the 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 may be varied depending on the age, body weight, sex, dosage form, health condition and disease severity of the patient, and preferably 0.01 to 200 mg / Kg / day, depending on the judgment of the physician or pharmacist, may be administered by oral or parenteral route by dividing the time interval by several times a day, preferably once or three times a day.

나아가, 상기 화학식 1로 표시되는 프탈라지논 유도체 및 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 MCH 수용체-1 관련 질환의 예방 또는 개선용 건강식품 조성물을 제공한다.Further, there is provided a health food composition for preventing or ameliorating an MCH receptor-1-related disease comprising the phthalazinone derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient.

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 프탈라지논 유도체를 식품, 음료 등의 건강보조 식품에 첨가할 수 있다.The composition according to the present invention acts as an antagonist to MCH receptor-1, so that the phthalazinone derivative can be administered to the health of foods, beverages and the like for the purpose of preventing or ameliorating MCH receptor-1 related diseases caused by binding of MCH to MCH receptor May be added to the supplement.

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 프탈라지논 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 phthalazinone derivatives of the present invention can be added directly to food or used together with other food or food ingredients, and can 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 polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the composition of the present invention.

상기 외에 본 발명의 프탈라지논 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 프탈라지논 유도체는 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition to the above, the phthalazinone derivatives of the present invention can be used as flavorants such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and aggravating agents (cheese, chocolate etc.), pectic acid and its salts, Alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the phthalazinone derivatives of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 프탈라지논 유도체를 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
These components may be used independently or in combination. Although the proportion of such an additive is not so important, the phthalazinone derivative of the present invention is generally selected 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 with reference to 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> 4-벤질-2-(3- 1 > 4-Benzyl-2- (3- 클로로프로필Chloropropyl )-2H-) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00055
Figure 112011081771684-pat00055

4-벤질-2H-프탈라진-1-온(160 mg, 0.68 mmol)을 DMF(5 ml)에 녹인 후, 소듐 하이드라이드(33 mg, 0.82 mmol)를 첨가한후 30분 교반한뒤, 3-요오드-1-클로로 프로판(0.11 ml, 1.02 mmol)을 첨가한후 2시간 30분 추가교반하였다. 반응이 완결된후 에틸 아세테이트(10 ml)로 두 번 추출하고, 포화염화나트륨 용액(10 ml)로 세척하였다. 무수황산마그네슘(MgSO4)으로 건조시킨후 감압 농축시키고 여액을 실리카겔 컬럼 크로마토그라피(헥산:에틸아세테이트=3:1)로 정제하여 노란색 오일(200 mg, 0.64 mmol, 94%)의 목적화합물을 얻었다. (160 mg, 0.68 mmol) was dissolved in DMF (5 ml), and sodium hydride (33 mg, 0.82 mmol) was added thereto. The mixture was stirred for 30 minutes, 3-iodo-1-chloropropane (0.11 ml, 1.02 mmol) was added, followed by further stirring for 2 hours and 30 minutes. After the reaction was completed, the reaction mixture was extracted twice with ethyl acetate (10 ml) and washed with saturated sodium chloride solution (10 ml). Concentrated after drying with anhydrous magnesium sulfate (MgSO 4), reduced pressure and the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound a yellow oil (200 mg, 0.64 mmol, 94 %) .

Rf=0.39(EA:Hx=1:3)Rf = 0.39 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.43-7.46(m, 1H), 7.68-7.73(m, 3H), 7.22-7.30(m, 5H), 4.42(t, J=6.8 Hz, 2H), 4.30(s, 2H), 3.65(t, J=6.8 Hz, 2H), 2.33-2.42(m, 2H).
 1 H-NMR (300 MHz, CDCl 3) δ 8.43-7.46 (m, 1H), 7.68-7.73 (m, 3H), 7.22-7.30 (m, 5H), 4.42 (t, J = 6.8 Hz, 2H) , 4.30 (s, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.33 - 2.42 (m, 2H).

<< 제조예Manufacturing example 2> 4-(4- 2 > 4- (4- 클로로벤질Chlorobenzyl )-2-(3-) -2- (3- 클로로프로필Chloropropyl )-2H-) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00056
Figure 112011081771684-pat00056

4-(4-클로로벤질)-2H-프탈라진-1-온(220 mg, 0.81 mmol)을 제조예 1과 동일한 방법으로 처리하여 노란색 오일(280 mg, 0.81 mmol, 99%)의 표제화합물을 얻었다. (220 mg, 0.81 mmol) was treated in the same manner as in Production Example 1 to give a yellow oil (280 mg, 0.81 mmol, 99%) of the title compound &Lt; / RTI &gt;

Rf=0.37(EA:Hx=1:3)Rf = 0.37 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.44-8.47(m, 1H), 7.67-7.74(m, 3H), 7.20-7.29(m, 4H), 4.41(t, J=6.8 Hz, 2H), 4.27(s, 2H), 3.64(t, J=6.8 Hz, 2H), 2.32-2.41(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.44-8.47 (m, 1H), 7.67-7.74 (m, 3H), 7.20-7.29 (m, 4H), 4.41 (t, J = 6.8 Hz, 2H) , 4.27 (s, 2H), 3.64 (t, J = 6.8Hz, 2H), 2.32-2.41

<< 제조예Manufacturing example 3> 2-(3- 3 > 2- (3- 클로로프로필Chloropropyl )-4-[(2-피리딘-4-일)에틸]-2H-) -4 - [(2-pyridin-4-yl) ethyl] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00057
Figure 112011081771684-pat00057

4-[(2-피리딘-4-일)에틸]-2H-프탈라진-1-온(150 mg, 0.60 mmol)을 제조예 1과 동일한 방법으로 처리하여(141 mg, 0.43 mmol, 72%)의 표제 화합물을 얻었다. (141 mg, 0.43 mmol, 72%) was treated in the same manner as in PREPARATION 1 to give (141 mg, 0.43 mmol, 0.60 mmol) of 4 - [(2- pyridin- ) Of the title compound.

Rf=0.60(10% MeOH in MC)Rf = 0.60 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.52(d, J=5.7 Hz, 2H), 8.48(d, J=7.6 Hz, 1H), 7.75-7.85(m, 3H), 7.20(d, J=5.7 Hz, 2H), 4.35(t, J=6.8 Hz, 2H), 3.58(t, J=6.8 Hz, 2H), 3.28-3.33(m, 2H), 3.14-3.19(m, 2H), 2.22-2.31(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.52 (d, J = 5.7 Hz, 2H), 8.48 (d, J = 7.6 Hz, 1H), 7.75-7.85 (m, 3H), 7.20 (d, J 2H), 3.14-3.19 (m, 2H), 2.22 (m, 2H), 4.35 (t, J = 6.8 Hz, 2H) -2.31 (m, 2 H)

<제조예 4> 2-(3-클로로프로필)-4-[(2-피리딘-2-일)에틸]-2H-프탈라진-1-온의 제조PREPARATION EXAMPLE 4 Preparation of 2- (3-chloropropyl) -4 - [(2-pyridin-2-yl) ethyl] -2H-phthalazin-

Figure 112011081771684-pat00058
Figure 112011081771684-pat00058

4-[(2-피리딘-2-일)에틸]-2H-프탈라진-1-온(160 mg, 0.64 mmol)을 제조예 1과 동일한 방법으로 처리하여(178 mg, 0.54 mmol, 85%)의 표제 화합물을 얻었다. (178 mg, 0.54 mmol, 85%) was obtained by treating 4 - [(2-pyridin-2-yl) ethyl] ) Of the title compound.

Rf=0.41(10% MeOH in MC)*2Rf = 0.41 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.54-8.56(m, 1H), 8.44-8.47(m, 1H), 7.89-7.91(m, 1H), 7.72-7.83(m, 2H), 7.59-7.63(m, 1H), 7.23(d, J=7.9 Hz, 1H), 7.12-7.16(m, 1H), 4.34(t, J=6.7 Hz, 2H), 3.56(t, J=6.7 Hz, 2H), 3.56(t, J=6.7 Hz, 2H), 3.43-3.48(m, 2H), 3.28-3.33(m, 2H), 2.21-2.30(m, 2H)
1 H-NMR (300 MHz, CDCl 3 )? 8.54-8.56 (m, IH), 8.44-8.47 (m, IH), 7.89-7.91 (m, IH), 7.72-7.83 J = 6.7 Hz, 2H), 7.63 (m, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.12-7.16 ), 3.56 (t, J = 6.7 Hz, 2H), 3.43-3.48 (m, 2H), 3.28-3.33 (m, 2H), 2.21-2.30

<< 제조예Manufacturing example 5> 2-(3- 5 > 2- (3- 클로로프로필Chloropropyl )-4-[(2-피리딘-3-일)에틸]-2H-) -4 - [(2-pyridin-3-yl) ethyl] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00059
Figure 112011081771684-pat00059

4-[(2-피리딘-3-일)에틸]-2H-프탈라진-1-온(100 mg, 0.40 mmol)을 제조예 1과 동일한 방법으로 처리하여(92 mg, 0.28 mmol, 71%)의 표제 화합물을 얻었다. (100 mg, 0.40 mmol) was treated in the same manner as in Production Example 1 to give 92 mg (0.28 mmol, 71%) of 4 - [(2-pyridin- ) Of the title compound.

Rf=0.36(3% MeOH in MC)Rf = 0.36 (3% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.53(s, 1H), 8.46-8.48(m, 2H), 7.74-7.82(m, 3H), 7.64-7.70(m, 1H), 7.52-7.58(m, 1H), 7.43-7.49(m, 1H), 7.21-7.26(m, 1H), 4.35(t, J=6.8 Hz, 2H), 3.57(t, J=6.8 Hz, 2H), 3.27-3.32(m, 2H), 3.16-3.20(m, 2H), 2.22-2.31(m, 2H)
1 H-NMR (300 MHz, CDCl 3 )? 8.53 (s, 1H), 8.46-8.48 (m, 2H), 7.74-7.82 (m, 3H), 7.64-7.70 J = 6.8 Hz, 2H), 3.27-3.32 (m, 1H), 7.43-7.49 (m, (m, 2 H), 3.16 - 3.20 (m, 2 H), 2.22 - 2.31 (m,

<< 제조예Manufacturing example 6> 2-(3- 6> 2- (3- 클로로프로필Chloropropyl )-4-(4-) -4- (4- 클로로페녹시Chlorophenoxy )-2H-) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00060
Figure 112011081771684-pat00060

4-(4-클로로페녹시)-2H-프탈라진-1-온(198 mg, 0.73 mmol)을 제조예 1과 동일한 방법으로 처리하여(92 mg, 0.28 mmol, 71%)의 표제 화합물을 얻었다. (198 mg, 0.73 mmol) was treated in the same manner as in Production Example 1 to give the title compound (92 mg, 0.28 mmol, 71%) as a colorless solid. .

Rf=0.26(EA:Hx=1:3)Rf = 0.26 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.43-8.47(m, 1H), 8.08-8.12(m, 1H), 7.82-7.91(m, 2H), 7.36-7 1 H-NMR (300 MHz, CDCl 3 )? 8.43-8.47 (m, IH), 8.08-8.12 (m, IH), 7.82-7.91

42(m, 2H), 7.15-7.21(m, 2H), 4.18(t, J=6.5 Hz, 2H), 3.52(t, J=6.5 Hz, 2H), 2.14-2.23(m, 2H)
2H), 2.14-2.23 (m, 2H), 4.18 (t, J = 6.5 Hz, 2H)

<< 제조예Manufacturing example 7> 2-(3- 7 > 2- (3- 클로로프로필Chloropropyl )-4-[[1-(t-) -4 - [[1- (t- 부톡시카보닐Butoxycarbonyl )피페리딘-4-일]) &Lt; / RTI &gt; piperidin-4-yl] 옥시Oxy ]-2H-] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00061
Figure 112011081771684-pat00061

4-[[1-(t-부톡시카보닐)피페리딘-4-일]옥시]-2H-프탈라진-1-온(240 mg, 0.70 mmol)을 제조예 1과 동일한 방법으로 처리하여(290 mg, 0.69 mmol, 99%)의 표제 화합물을 얻었다. Yl] oxy] -2H-phthalazin-1-one (240 mg, 0.70 mmol) was treated in the same manner as in Production Example 1 to give a pale yellow solid (290 mg, 0.69 mmol, 99%) of the title compound.

Rf=0.38(EA:Hx=1:3)Rf = 0.38 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.39-8.42(m, 1H), 7.97-8.00(m, 1H), 7.78-7.81(m, 2H), 5.14-5.18(m, 1H), 4.28(t, J=6.4 Hz, 2H), 3.72-3.80(m, 2H), 3.63(t, J=6.4 Hz, 2H), 3.37-3.46(m, 2H), 2.26-2.35(m, 2H), 2.02-2.08(m, 2H), 1.83-1.90(m, 2H), 1.49(s, 9H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.39-8.42 (m, IH), 7.97-8.00 (m, IH), 7.78-7.81 (m, 2H), 5.14-5.18 2H, J = 6.4 Hz, 2H), 3.72-3.80 (m, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.37-3.46 -2.08 (m, 2H), 1.83-1.90 (m, 2H), 1.49 (s, 9H)

<< 제조예Manufacturing example 8> 2-(3- 8> 2- (3- 클로로프로필Chloropropyl )-4-[(4-) -4 - [(4- 클로로페닐Chlorophenyl )싸이오]-2H-) Thio] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00062
Figure 112011081771684-pat00062

4-[(4-클로로페닐)싸이오]-2H-프탈라진-1-온(99 mg, 0.34 mmol)을 제조예 1과 동일한 방법으로 처리하여(120 mg, 0.33 mmol, 96%)의 표제 화합물을 얻었다. (99 mg, 0.34 mmol) was treated in the same manner as in PREPARATION 1 to give (120 mg, 0.33 mmol, 96%) of 4 - [(4- chlorophenyl) thio] -2H-phthalazin- The title compound was obtained.

Rf=0.46(EA:Hx=1:3)*1.5Rf = 0.46 (EA: Hx = 1: 3) * 1.5

1H-NMR(300 MHz, CDCl3) δ 8.43-8.47(m, 1H), 7.9-8.02(m, 1H), 7.77-7.85(m, 2H), 7.41-7.44(m, 2H), 7.32-7.36(m, 2H), 4.29(t, J=6.6 Hz, 2H), 3.49(t, J=6.6 Hz, 2H), 2.17-2.26(m, 2H)
1 H-NMR (300 MHz, CDCl 3) δ 8.43-8.47 (m, 1H), 7.9-8.02 (m, 1H), 7.77-7.85 (m, 2H), 7.41-7.44 (m, 2H), 7.32- J = 6.6 Hz, 2H), 2.17-2.26 (m, 2H), 7.39 (d, J =

<< 제조예Manufacturing example 9> 2-(3- 9> 2- (3- 클로로프로필Chloropropyl )-4-)-4- 페닐설포닐Phenylsulfonyl -2H--2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00063
Figure 112011081771684-pat00063

4-페닐설포닐-2H-프탈라진-1-온(352 mg, 1.23 mmol)을 제조예 1과 동일한 방법으로 처리하여(432 mg, 1.19 mmol, 97%)의 표제 화합물을 얻었다. (352 mg, 1.23 mmol) was treated in the same manner as in Production Example 1 to give the title compound (432 mg, 1.19 mmol, 97%).

Rf=0.25(EA:Hx=1:3)*1.5Rf = 0.25 (EA: Hx = 1: 3) * 1.5

1H-NMR(300 MHz, CDCl3) δ 8.74(d, J=7.9 Hz, 1H), 8.46(d, J=7.9 Hz, 1H), 8.05-8.07(m, 2H), 7.83-7.96(m, 2H), 7.70-7.75(m, 1H), 7.59-7.64(m, 2H), 4.22(t, J=6.2 Hz, 2H), 3.37(t, J=6.2 Hz, 2H), 2.05-2.13(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.74 (d, J = 7.9 Hz, 1H), 8.46 (d, J = 7.9 Hz, 1H), 8.05-8.07 (m, 2H), 7.83-7.96 (m , 2H), 7.70-7.75 (m, 1H), 7.59-7.64 (m, 2H), 4.22 (t, J = 6.2 Hz, 2H), 3.37 m, 2H)

<< 제조예Manufacturing example 10> 2-(3- 10> 2- (3- 클로로프로필Chloropropyl )-4-[(4-) -4 - [(4- 메틸페닐Methylphenyl )) 설포닐Sulfonyl ]-2H-] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00064
Figure 112011081771684-pat00064

4-[(4-메틸페닐)설포닐]-2H-프탈라진-1-온(274 mg, 0.91 mmol)을 제조예 1과 동일한 방법으로 처리하여(315 mg, 0.84 mmol, 92%)의 표제 화합물을 얻었다. (274 mg, 0.91 mmol) was treated in the same manner as in Production Example 1 to give (315 mg, 0.84 mmol, 92%) of 4 - [(4- methylphenyl) sulfonyl] -2H- phthalazin- Compound.

Rf=0.24(EA:Hx=1:3)Rf = 0.24 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.72-8.75(m, 1H), 8.44-8.46(m, 1H), 7.93(d, J=7.8 Hz, 2H), 7.82-7.90 m, 2H), 7.41(d, J=7.8 Hz, 2H), 4.24(t, J=6.6 Hz, 2H), 3.38(t, J=6.6 Hz, 2H), 2.48(s, 3H), 2.07-2.15(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.72-8.75 (m, 1H), 8.44-8.46 (m, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.82-7.90 m, 2H), 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.48 (s, 3H), 2.07-2.15 )

<< 제조예Manufacturing example 11> 2-(3- 11 > 2- (3- 클로로프로필Chloropropyl )-4-[(4-) -4 - [(4- 클로로페닐Chlorophenyl )) 설포닐Sulfonyl ]-2H-] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00065
Figure 112011081771684-pat00065

4-[(4-클로로페닐)설포닐]-2H-프탈라진-1-온(444 mg, 1.38 mmol)을 제조예 1과 동일한 방법으로 처리하여(407 mg, 1.02 mmol, 74%)의 표제 화합물을 얻었다. (444 mg, 1.38 mmol) was treated in the same manner as in Production Example 1 to give the title compound (407 mg, 1.02 mmol, 74%) as a pale yellow solid. The title compound was obtained.

Rf=0.29(EA:Hx=1:3)Rf = 0.29 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.70-8.72(m, 1H), 8.45-8.48(m, 1H), 7.84-8.01(m, 4H), 7.57-7.62(m, 2H), 4.23(t, J=6.5 Hz, 2H), 3.40(t, J=6.5 Hz, 2H), 2.07-2.16(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.70-8.72 (m, 1H), 8.45-8.48 (m, 1H), 7.84-8.01 (m, 4H), 7.57-7.62 (m, 2H), 4.23 ( (t, J = 6.5 Hz, 2H), 3.40 (t, J = 6.5 Hz, 2H), 2.07-2.16

<< 제조예Manufacturing example 12> 2-(3- 12> 2- (3- 클로로프로필Chloropropyl )-4-[(4-) -4 - [(4- 클로로페닐Chlorophenyl )아미노]-2H-) Amino] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00066
Figure 112011081771684-pat00066

4-[(4-클로로페닐)아미노]-2H-프탈라진-1-온(207 mg, 0.76 mmol)을 제조예 1과 동일한 방법으로 처리하여(189 mg, 0.54 mmol, 71%)의 표제 화합물을 얻었다. (207 mg, 0.76 mmol) was treated in the same manner as in PREPARATION 1 to obtain (189 mg, 0.54 mmol, 71%) of 4 - [(4- chlorophenyl) amino] -2H-phthalazin- Compound.

Rf=0.41(EA:Hx=1:1)Rf = 0.41 (EA: Hx = 1: 1)

1H-NMR(300 MHz, DMSO-d6) δ 8.84(s, 1H), 8.28-8.34(m, 1H), 7.85-7.98(m, 2H), 7.68(d, J=9.0 Hz, 2H), 7.30(d, J=9.0 Hz, 2H), 4.15(t, J=6.6 Hz, 2H), 3.69(t, J=6.6 Hz, 2H), 2.15-2.21(m, 2H)
1 H-NMR (300 MHz, DMSO-d 6) δ 8.84 (s, 1H), 8.28-8.34 (m, 1H), 7.85-7.98 (m, 2H), 7.68 (d, J = 9.0 Hz, 2H) 2H, J = 6.6 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H), 4.15

<< 제조예Manufacturing example 13> 2-(3- 13 > 2- (3- 클로로프로필Chloropropyl )-4-[(피리딘-4-일)아미노]-2H-) -4 - [(pyridin-4-yl) amino] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00067
Figure 112011081771684-pat00067

4-[(피리딘-4-일)아미노]-2H-프탈라진-1-온(120 mg, 0.50 mmol)을 제조예 1과 동일한 방법으로 처리하여(92 mg, 0.29 mmol, 58%)의 표제 화합물을 얻었다. (120 mg, 0.50 mmol) was treated in the same manner as in Production Example 1 to give (92 mg, 0.29 mmol, 58%) of 4 - [(pyridin-4-yl) amino] -2H-phthalazin- The title compound was obtained.

Rf=0.46(10% MeOH in MC)*2Rf = 0.46 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.53-8.56(m, 1H), 8.46(d, J=5.8 Hz, 2H), 7.77-7.88(m, 3H), 7.32-7.34(m, 2H), 6.73(s, 1H), 4.40(t, J=6.7 Hz, 2H), 3.67(t, J=6.7 Hz, 2H), 2.36-2.42(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.53-8.56 (m, 1H), 8.46 (d, J = 5.8 Hz, 2H), 7.77-7.88 (m, 3H), 7.32-7.34 (m, 2H) 2H), 3.67 (t, J = 6.7 Hz, 2H), 2.36-2.42 (m, 2H)

<< 제조예Manufacturing example 14> 2-(3- 14> 2- (3- 클로로프로필Chloropropyl )-4-[(피리딘-2-) -4 - [(pyridin-2- 일메틸Yl methyl )아미노]-2H-) Amino] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00068
Figure 112011081771684-pat00068

4-[(피리딘-2-일메틸)아미노]-2H-프탈라진-1-온(65 mg, 0.26 mmol)을 제조예 1과 동일한 방법으로 처리하여(72 mg, 0.022 mmol, 85%)의 표제 화합물을 얻었다. (72 mg, 0.022 mmol, 85%) was treated in the same manner as in PREPARATION 1 to give (72 mg, 0.26 mmol) of 4 - [(pyridin- 2- ylmethyl) amino] -2H-phthalazin- Of the title compound.

Rf=0.44(5% MeOH in MC)*1.5Rf = 0.44 (5% MeOH in MC) * 1.5

1H-NMR(300 MHz, CDCl3) δ 8.60(d, J=4.5 Hz, 1H), 8.43-8.46(m, 1H), 7.67-7.84(m, 4H), 7.39(d, J=7.6 Hz, 1H), 7.21-7.25(m, 1H), 6.21-6.23(m, 1H), 4.66(d, J=4.5 Hz, 2H), 4.26(t, J=6.8 Hz, 2H), 3.58(t, J=6.8 Hz, 2H), 2.23-2.32(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.60 (d, J = 4.5 Hz, 1H), 8.43-8.46 (m, 1H), 7.67-7.84 (m, 4H), 7.39 (d, J = 7.6 Hz 2H), 4.28 (t, J = 6.8 Hz, 2H), 3.58 (t, J = 6.8 Hz, 2H), 2.23-2.32 (m, 2H)

<< 제조예Manufacturing example 15> 2-(3- 15> 2- (3- 클로로프로필Chloropropyl )-4-)-4- 사이클로헥실아미노Cyclohexylamino -2H--2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00069
Figure 112011081771684-pat00069

4-사이클로헥실아미노-2H-프탈라진-1-온(220 mg, 0.90 mmol)을 제조예 1과 동일한 방법으로 처리하여(251 mg, 0.79 mmol, 87%)의 표제 화합물을 얻었다. (220 mg, 0.90 mmol) was treated in the same manner as in Preparation Example 1 to give the title compound (251 mg, 0.79 mmol, 87%).

Rf=0.47(EA:Hx=1:1)Rf = 0.47 (EA: Hx = 1: 1)

1H-NMR(300 MHz, CDCl3) δ 8.45-8.48(m, 1H), 7.71-7.76(m, 2H), 7.58-7.60(m, 1H), 4.27(t, J=6.4 Hz, 3H), 3.76-3.80(m, 1H), 3.66(t, J=6.4 Hz, 2H), 2.28-2.36(m, 2H), 2.13-2.17(m, 2H), 1.77-1.82(m, 2H), 1.65-1.73(m, 2H), 1.39-1.48(m, 2H), 1.20-1.32(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.45-8.48 (m, 1H), 7.71-7.76 (m, 2H), 7.58-7.60 (m, 1H), 4.27 (t, J = 6.4 Hz, 3H) , 3.76-3.80 (m, 1H), 3.66 (t, J = 6.4 Hz, 2H), 2.28-2.36 (m, 2H), 2.13-2.17 (m, 2H), 1.77-1.82 -1.73 (m, 2H), 1.39-1.48 (m, 2H), 1.20-1.32 (m, 2H)

<< 제조예Manufacturing example 16> 2-(3- 16 > 2- (3- 클로로프로필Chloropropyl )-4-[메틸() -4- [methyl ( 페닐Phenyl )아미노]-2H-) Amino] -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00070
Figure 112011081771684-pat00070

4-[메틸(페닐)아미노]-2H-프탈라진-1-온(334mg, 1.32mmol)을 제조예 1과 동일한 방법으로 처리하여 약간 녹색오일(300mg, 0.91mmol, 46%)의 표제화합물을 얻었다. (334 mg, 1.32 mmol) was treated in the same manner as in Production Example 1 to give a slight green oil (300 mg, 0.91 mmol, 46%) of the title compound &Lt; / RTI &gt;

Rf=0.31(EA:Hx=1:2)Rf = 0.31 (EA: Hx = 1: 2)

1H-NMR(300 MHz, CDCl3) δ 2.32-2.41(m, 2H), 3.41(s, 3H), 3.65(t, 2H), 4.38(t, 2H), 6.88(d, J =8.4 Hz, 2H), 6.90-6.99(m, 1H), 7.22-7.27(m, 2H), 7.43(d, J =7.6 Hz, 1H), 7.50-7.55(m, 1H), 7.63-7.68(m, 1H), 8.44(d, J =7.9 Hz, 1H)
 1 H-NMR (300 MHz, CDCl 3) δ 2.32-2.41 (m, 2H), 3.41 (s, 3H), 3.65 (t, 2H), 4.38 (t, 2H), 6.88 (d, J = 8.4 Hz 2H), 6.90-6.99 (m, 1H), 7.22-7.27 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.50-7.55 ), 8.44 (d, J = 7.9 Hz, 1 H)

<< 제조예Manufacturing example 17> 2-(3- 17> 2- (3- 클로로프로필Chloropropyl )-4-)-4- 다이에틸아미노Diethylamino -2H--2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00071
Figure 112011081771684-pat00071

4-다이에틸아미노-2H-프탈라진-1-온(105 mg, 0.48 mmol)을 제조예 1과 동일한 방법으로 처리하여(113 mg, 0.39 mmol, 80%)의 표제 화합물을 얻었다. Diethylamino-2H-phthalazin-1-one (105 mg, 0.48 mmol) was treated in the same manner as in Preparation Example 1 to give the title compound (113 mg, 0.39 mmol, 80%).

Rf=0.36(EA:Hx=1:3)Rf = 0.36 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.41-8.44(m, 1H), 7.91-7.93(m, 1H), 7.71-7.79(m, 2H), 4.32(t, J=6.8 Hz, 2H), 3.63(t, J=6.8 Hz, 2H), 3.21-.3028(m, 4H), 2.28-2.37(m, 4H), 1.15(t, J=7.1 Hz, 6H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.41-8.44 (m, 1H), 7.91-7.93 (m, 1H), 7.71-7.79 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H) , 3.63 (t, J = 6.8 Hz, 2H), 3.21.3028 (m, 4H), 2.28-2.37

<< 제조예Manufacturing example 18> 2-(3- 18 > 2- (3- 클로로프로필Chloropropyl )-4-)-4- 다이프로필아미노Dipropylamino -2H--2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00072
Figure 112011081771684-pat00072

4-다이프로필아미노-2H-프탈라진-1-온(190 mg, 0.77 mmol)을 제조예 1과 동일한 방법으로 처리하여(232 mg, 0.072 mmol, 93%)의 표제 화합물을 얻었다. (190 mg, 0.77 mmol) was treated in the same manner as in Production Example 1 to give the title compound (232 mg, 0.072 mmol, 93%).

Rf=0.64(EA:Hx=1:3)*2Rf = 0.64 (EA: Hx = 1: 3) * 2

1H-NMR(300 MHz, CDCl3) δ 8.38(d, J=7.4 Hz, 1H), 7.90(d, J=7.4 Hz, 1H), 7.64-7.74(m, 2H), 4.26(t, J=6.5 Hz, 2H), 3.55-3.60(m, 2H), 3.10(t, J=7.4 Hz, 4H), 2.22-2.31(m, 2H), 1.49-1.61(m, 4H), 0.84(td, J=7.4, 1.7 Hz, 6H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.38 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.64-7.74 (m, 2H), 4.26 (t, J 2H), 3.50-3.60 (m, 2H), 3.10 (t, J = 7.4 Hz, 4H), 2.22-2.31 (m, 2H), 1.49-1.61 (m, 4H), 0.84 J = 7.4, 1.7 Hz, 6H)

<< 제조예Manufacturing example 19> 2-(3- 19> 2- (3- 클로로프로필Chloropropyl )-4-)-4- 다이아이소부틸아미노Diisobutylamino -2H--2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00073
Figure 112011081771684-pat00073

4-다이아이소부틸아미노-2H-프탈라진-1-온(90 mg, 0.33 mmol)을 제조예 1과 동일한 방법으로 처리하여(100 mg, 0.29 mmol, 87%)의 표제 화합물을 얻었다. Diisobutylamino-2H-phthalazin-1-one (90 mg, 0.33 mmol) was treated in the same manner as in Production Example 1 to give the title compound (100 mg, 0.29 mmol, 87%).

Rf=0.74(EA:Hx=1:3)Rf = 0.74 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.44(m, 1H), 8.01-8.04(m, 1H), 7.69-7.79(m, 2H), 4.30(t, J=6.6 Hz, 2H), 3.61(t, J=6.6 Hz, 2H), 3.01(d, J=7.2 Hz, 4H), 2.26-2.35(m, 2H), 1.92-2.01(m, 2H), 0.91(d, J=6.8 Hz, 12H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.44 (m, 1H), 8.01-8.04 (m, 1H), 7.69-7.79 (m, 2H), 4.30 (t, J = 6.6 Hz, 2H) 2H), 0.91 (d, J = 6.8 Hz, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.01 (d, J = 7.2 Hz, 4H), 2.26-2.35 Hz, 12H)

<< 제조예Manufacturing example 20> 2-(3- 20> 2- (3- 클로로프로필Chloropropyl )-4-()-4-( 피롤리딘Pyrrolidine -1-일)-2H--1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00074
Figure 112011081771684-pat00074

4-(피롤리딘-1-일)-2H-프탈라진-1-온(160 mg, 0.74 mmol)을 제조예 1과 동일한 방법으로 처리하여 노란색 오일의(170 mg, 0.58 mmol, 79%)표제 화합물을 얻었다. (170 mg, 0.58 mmol, 79%) of 4- (pyrrolidin- 1 -yl) -2H-phthalazin-1-one (160 mg, 0.74 mmol) ), &Lt; / RTI &gt;

Rf=0.47(EA:Hx=1:3)Rf = 0.47 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.44-8.47(m, 1H), 7.98-8.01(m, 1H), 7.69-7.77(m, 2H), 4.28(t, J=6.5 Hz, 2H), 3.64(t, J=6.5 Hz, 2H), 3.51-3.55(m, 4H), 2.28-2.37(m, 2H), 1.96-2.37(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.44-8.47 (m, 1H), 7.98-8.01 (m, 1H), 7.69-7.77 (m, 2H), 4.28 (t, J = 6.5 Hz, 2H) , 3.64 (t, J = 6.5 Hz, 2H), 3.51-3.55 (m, 4H), 2.28-2.37 (m, 2H), 1.96-2.37

<< 제조예Manufacturing example 21> 2-(3- 21> 2- (3- 클로로프로필Chloropropyl )-4-()-4-( 몰포린Morpholine -4-일)-2H-Yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00075
Figure 112011081771684-pat00075

4-(몰포린-4-일)-2H-프탈라진-1-온(130 mg, 0.56 mmol)을 제조예 1과 동일한 방법으로 처리하여(157 mg, 0.51 mmol, 91%)의 표제 화합물을 얻었다. (130 mg, 0.56 mmol) was treated in the same manner as in Production Example 1 to give 157 mg (0.51 mmol, 91%) of the title compound &Lt; / RTI &gt;

Rf=0.29(EA:Hx=1:3)Rf = 0.29 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.43-8.46(m, 1H), 7.87-7.91(m, 1H), 7.72-7.82(m, 2H), 4.32(t, J=6.6 Hz, 2H), 3.94(t, J=4.6 Hz, 2H), 3.63(t, J=6.6 Hz, 2H), 3.21(t, J=4.6 Hz, 2H), 2.28-2.37(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.43-8.46 (m, 1H), 7.87-7.91 (m, 1H), 7.72-7.82 (m, 2H), 4.32 (t, J = 6.6 Hz, 2H) , 3.94 (t, J = 4.6 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H)

<< 제조예Manufacturing example 22> 2-(3- 22> 2- (3- 클로로프로필Chloropropyl )-4-()-4-( 싸이오몰포린Thiomorpholine -4-일)-2H-Yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00076
Figure 112011081771684-pat00076

4-(싸이오몰포린-4-일)-2H-프탈라진-1-온 (250 mg, 1.01 mmol)을 제조예 1과 동일한 방법으로 처리하여(309 mg, 0.95 mmol, 95%)의 표제 화합물을 얻었다. (250 mg, 1.01 mmol) was treated in the same manner as in Production Example 1 to give (309 mg, 0.95 mmol, 95%) of 4- (thiomorpholin-4-yl) -2H-phthalazin- Compound.

Rf=0.25(EA:Hx=1:3)Rf = 0.25 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.45(m, 1H), 7.72-7.84(m, 3H), 4.32(t, J=6.7 Hz, 2H), 3.63(t, J=6.7 Hz, 2H), 3.45-3.48(m, 4H), 2.87-2.90(m, 4H), 2.28-2.37(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.45 (m, 1H), 7.72-7.84 (m, 3H), 4.32 (t, J = 6.7 Hz, 2H), 3.63 (t, J = 6.7 Hz , 2H), 3.45-3.48 (m, 4H), 2.87-2.90 (m, 4H), 2.28-2.37

<< 제조예Manufacturing example 23> 2-(3- 23> 2- (3- 클로로프로필Chloropropyl )-4-(피페리딘-1-일)-2H-) -4- (piperidin-1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00077
Figure 112011081771684-pat00077

4-(피페리딘-1-일)-2H-프탈라진-1-온(130 mg, 0.56 mmol)을 제조예 1과 동일한 방법으로 처리하여 노란색 오일의(210 mg, 0.56 mmol, 99%)표제 화합물을 얻었다. (210 mg, 0.56 mmol, 99%) was obtained in the same manner as in PREPARATION 1 by treating 4- (piperidin-1-yl) -2H- phthalazin- ), &Lt; / RTI &gt;

Rf=0.60(EA:Hx=1:3)Rf = 0.60 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.41-8.44(m, 1H), 7.86-7.89(m, 1H), 7.69-7.79(m, 2H), 4.30(t, J=6.5 Hz, 2H), 3.63(t, J=6.5 Hz, 2H), 3.11-3.15(m, 4H), 2.27-2.36(m, 2H), 1.73-1.83(m, 4H), 1.64-1.70(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.41-8.44 (m, 1H), 7.86-7.89 (m, 1H), 7.69-7.79 (m, 2H), 4.30 (t, J = 6.5 Hz, 2H) 2H), 3.63 (t, J = 6.5 Hz, 2H), 3.11-3.15 (m, 4H), 2.27-2.36

<< 제조예Manufacturing example 24> 2-(3- 24 > 2- (3- 클로로프로필Chloropropyl )-4-(4-) -4- (4- 메틸피페리딘Methylpiperidine -1-일)-2H--1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00078
Figure 112011081771684-pat00078

4-(4-메틸피페리딘-1-일)-2H-프탈라진-1-온(324 mg, 1.33 mmol)을 제조예 1과 동일한 방법으로 처리하여(405 mg, 1.26 mmol, 95%)의 표제 화합물을 얻었다. (324 mg, 1.33 mmol) was treated in the same manner as in Production Example 1 to give (405 mg, 1.26 mmol, 95%) of 4- (4-methylpiperidin- ) Of the title compound.

Rf=0.39(EA:Hx=1:3)Rf = 0.39 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.40-8.43(m, 1H), 7.85-7.87(m, 1H), 7.69-7.79(m, 2H), 4.30(t, J=6.8 Hz, 2H), 3.63(t, J=6.8 Hz, 2H), 3.49(d, J=12.7 Hz, 2H), 2.79(t, J=12.2 Hz, 2H), 2.27-2.36(m, 2H), 1.76-1.81(m, 2H), 1.41-1.63(m, 3H), 1.04(d, J=6.2 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.40-8.43 (m, 1H), 7.85-7.87 (m, 1H), 7.69-7.79 (m, 2H), 4.30 (t, J = 6.8 Hz, 2H) , 3.63 (t, J = 6.8 Hz, 2H), 3.49 (d, J = 12.7 Hz, 2H), 2.79 (t, J = 12.2 Hz, 2H), 2.27-2.36 m, 2H), 1.41-1.63 (m, 3H), 1.04 (d, J = 6.2 Hz,

<< 제조예Manufacturing example 25> 2-(3- 25> 2- (3- 클로로프로필Chloropropyl )-4-(3-) -4- (3- 메틸피페리딘Methylpiperidine -1-일)-2H--1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00079
Figure 112011081771684-pat00079

4-(3-메틸피페리딘-1-일)-2H-프탈라진-1-온(246 mg, 1.01 mmol)을 제조예 1과 동일한 방법으로 처리하여(317 mg, 0.99 mmol, 98%)의 표제 화합물을 얻었다. (246 mg, 1.01 mmol) was treated in the same manner as in Production Example 1 to give 317 mg (0.99 mmol, 98%) of 4- (3-methylpiperidin- ) Of the title compound.

Rf=0.40(EA:Hx=1:3)Rf = 0.40 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.41-8.44(m, 1H), 7.86-7.89(m, 1H), 7.69-7.80(m, 2H), 4.31(t, J=6.8 Hz, 2H), 3.64(t, J=6.8 Hz, 2H), 3.43(t, J=10.9 Hz, 2H), 2.71-2.80(m, 1H), 2.42-2.50(m, 1H), 2.30-2.37(m, 2H), 1.81-1.91(m, 4H), 1.09-1.19(m, 1H), 0.98(d, J=6.4 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.41-8.44 (m, 1H), 7.86-7.89 (m, 1H), 7.69-7.80 (m, 2H), 4.31 (t, J = 6.8 Hz, 2H) , 3.64 (t, J = 6.8 Hz, 2H), 3.43 (t, J = 10.9 Hz, 2H), 2.71-2.80 (m, ), 1.81-1.91 (m, 4H), 1.09-1.19 (m, IH), 0.98 (d, J = 6.4 Hz,

<< 제조예Manufacturing example 26> 2-(3- 26> 2- (3- 클로로프로필Chloropropyl )-4-(4-) -4- (4- 옥소피페리딘Oxopiperidine -1-일)-2H--1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00080
Figure 112011081771684-pat00080

4-(4-옥소피페리딘-1-일)-2H-프탈라진-1-온(76 mg, 0.31 mmol)을 제조예 1과 동일한 방법으로 처리하여(85 mg, 0.27 mmol, 85%)의 표제 화합물을 얻었다. (76 mg, 0.31 mmol) was treated in the same manner as in PREPARATION 1 to give 85 mg (0.27 mmol, 85%) of 4- (4-oxopiperidin- ) Of the title compound.

Rf=0.16(EA:Hx=1:3)*2Rf = 0.16 (EA: Hx = 1: 3) * 2

1H-NMR(300 MHz, CDCl3) δ 8.46-8.48(m, 1H), 7.91-7.93(m, 1H), 7.76-7.86(m, 2H), 4.33(t, J=6.5 Hz, 2H), 3.62(t, J=6.5 Hz, 2H), 3.56(t, J=6.0 Hz, 4H), 2.70(t, J=6.0 Hz, 4H), 2.28-2.37(m, 2H)
1 H-NMR (300 MHz, CDCl 3) δ 8.46-8.48 (m, 1H), 7.91-7.93 (m, 1H), 7.76-7.86 (m, 2H), 4.33 (t, J = 6.5 Hz, 2H) 2H), 3.56 (t, J = 6.0Hz, 4H), 2.70 (t, J = 6.0Hz, 4H), 2.28-2.37

<< 제조예Manufacturing example 27> 2-(3- 27> 2- (3- 클로로프로필Chloropropyl )-4-(4-) -4- (4- 클로로피페리딘Chloropiperidine -1-일)-2H--1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00081
Figure 112011081771684-pat00081

4-(4-클로로피페리딘-1-일)-2H-프탈라진-1-온(120 mg, 0.46 mmol)을 제조예 1과 동일한 방법으로 처리하여(153 mg, 0.45 mmol, 99%)의 표제 화합물을 얻었다. (120 mg, 0.46 mmol) was treated in the same manner as in PREPARATION 1 to give 153 mg (0.45 mmol, 99%) of 4- (4-chloropiperidin- ) Of the title compound.

Rf=0.41(EA:Hx=1:3)Rf = 0.41 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.44(m, 1H), 7.71-7.85(m, 3H), 4.31(t, J=6.8 Hz, 2H), 4.24-4.27(m, 1H), 3.62(t, J=6.8 Hz, 2H), 3.45-3.52(m, 2H), 3.02-3.10(m, 2H), 2.27-2.36(m, 4H), 2.06-2.17(m, 2H)
1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.44 (m, 1H), 7.71-7.85 (m, 3H), 4.31 (t, J = 6.8 Hz, 2H), 4.24-4.27 (m, 1H) 2H), 3.02-3.10 (m, 2H), 2.27-2.36 (m, 4H), 2.06-2.17 (m, 2H), 3.62 (t, J = 6.8 Hz, 2H)

<< 제조예Manufacturing example 28> 2-(3- 28> 2- (3- 클로로프로필Chloropropyl )-4-[4-(t-) -4- [4- (t- 부톡시카보닐Butoxycarbonyl )피페라진-1-일]-2H-프탈라진-1-온의 제조) Piperazin-1-yl] -2H-phthalazin-1-one

Figure 112011081771684-pat00082
Figure 112011081771684-pat00082

4-[4-(t-부톡시카보닐)피페라진-1-일]-2H-프탈라진-1-온(260 mg, 0.79 mmol)을 제조예 1과 동일한 방법으로 처리하여(273 mg, 0.67 mmol, 85%)의 표제 화합물을 얻었다. L-yl] -2H-phthalazin-1-one (260 mg, 0.79 mmol) was treated in the same manner as in Production Example 1 to give 273 mg , 0.67 mmol, 85%) of the title compound.

Rf=0.18(EA:Hx=1:3)Rf = 0.18 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.45(m, 1H), 7.72-7.84(m, 3H), 4.32(t, J=6.7 Hz, 2H), 3.63(t, J=6.7 Hz, 2H), 3.45-3.48(m, 4H), 2.87-2.90(m, 4H), 2.28-2.37(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.45 (m, 1H), 7.72-7.84 (m, 3H), 4.32 (t, J = 6.7 Hz, 2H), 3.63 (t, J = 6.7 Hz , 2H), 3.45-3.48 (m, 4H), 2.87-2.90 (m, 4H), 2.28-2.37

<< 제조예Manufacturing example 29> 2-(3- 29> 2- (3- 클로로프로필Chloropropyl )-4-(4-) -4- (4- 메틸피페라진Methylpiperazine -1-일)-2H--1-yl) -2H- 프탈라진Phthalazine -1-온의 제조-1-one

Figure 112011081771684-pat00083
Figure 112011081771684-pat00083

4-(4-메틸피페라진-1-일)-2H-프탈라진-1-온 (330 mg, 1.35 mmol)을 제조예 1과 동일한 방법으로 처리하여(322 mg, 1.00 mmol, 74%)의 표제 화합물을 얻었다. (330 mg, 1.35 mmol) was treated in the same manner as in Preparation Example 1 to give (322 mg, 1.00 mmol, 74%) of 4- (4-methylpiperazin-1-yl) Of the title compound.

Rf=0.65(10% MeOH in MC)Rf = 0.65 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.45(m, 1H), 7.86-7.89(m, 1H), 7.73-7.80(m, 2H), 4.32(t, J=6.5 Hz, 2H), 3.63(t, J=6.5 Hz, 2H), 3.24(m, 4H), 2.66(m, 4H), 2.41(s, 3H), 2.27-2.36(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.45 (m, 1H), 7.86-7.89 (m, 1H), 7.73-7.80 (m, 2H), 4.32 (t, J = 6.5 Hz, 2H) 2H), 3.24 (m, 4H), 2.66 (m, 4H), 2.41 (s, 3H), 2.27-2.36

<< 제조예Manufacturing example 30> 2-(3- 30> 2- (3- 클로로프로필Chloropropyl )-4-[4-() -4- [4- ( 메톡시카보닐Methoxycarbonyl )피페리딘-1-일]-2H-) &Lt; / RTI &gt; piperidin-1-yl] -2H- 프탈라진Phthalazine -1-온의 제조 -1-one

Figure 112011081771684-pat00084
Figure 112011081771684-pat00084

4-[4-(메톡시카보닐)피페리딘-1-일]-2H-프탈라진-1-온(340 mg, 1.18 mmol)을 제조예 1과 동일한 방법으로 처리하여(386 mg, 1.06 mmol, 90%)의 표제 화합물을 얻었다. (340 mg, 1.18 mmol) was treated in the same manner as in Production Example 1 to give 386 mg of the title compound as a colorless solid. 1H-NMR (DMSO-d6) 1.06 mmol, 90%) of the title compound.

Rf=0.2(EA:Hx=1:3)Rf = 0.2 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.41-8.44(m, 1H), 7.70-7.86(m, 3H), 4.30(t, J=6.6 Hz, 2H), 3.74(s, 3H), 3.62(t, J=6.8 Hz, 2H), 2.50-3.55(m, 2H), 2.87(td, J=13.0, 3.0 Hz, 2H), 2.51-2.58(m, 1H), 2.27-2.36(m, 2H), 1.98-2.10(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.41-8.44 (m, 1H), 7.70-7.86 (m, 3H), 4.30 (t, J = 6.6 Hz, 2H), 3.74 (s, 3H), 3.62 2H), 2.50-3.55 (m, 2H), 2.87 (td, J = 13.0, 3.0 Hz, 2H), 2.51-2.58 ), 1.98-2. 10 (m, 4H)

<< 제조예Manufacturing example 31> 2-(3- 31> 2- (3- 클로로프로필Chloropropyl )-4-[3-() -4- [3- ( 에톡시카보닐Ethoxycarbonyl )피페리딘-1-일]-2H-) &Lt; / RTI &gt; piperidin-1-yl] -2H- 프탈라진Phthalazine -1-온의 제조 -1-one

Figure 112011081771684-pat00085
Figure 112011081771684-pat00085

4-[3-(에톡시카보닐)피페리딘-1-일]-2H-프탈라진-1-온 (420 mg, 1.39 mmol)을 제조예 1과 동일한 방법으로 처리하여(484 mg, 1.28 mmol, 92%)의 표제 화합물을 얻었다. (420 mg, 1.39 mmol) was treated in the same manner as in Production Example 1 to give 484 mg of the title compound as a white amorphous solid. 1H-NMR (DMSO-d6) 1.28 mmol, 92%) of the title compound.

Rf=0.36(EA:Hx=1:3)*2Rf = 0.36 (EA: Hx = 1: 3) * 2

1H-NMR(300 MHz, CDCl3) δ 8.42-8.45(m, 1H), 7.89-7.92(m, 1H), 7.71-7.82(m, 2H), 4.32(t, J=6.8 Hz, 2H), 4.16-4.23(m, 2H), 3.64(t, J=6.8 Hz, 2H), 3.56-3.59(m, 1H), 3.36-3.40(m, 1H), 3.11-3.19(m, 1H), 2.83-2.95(m, 2H), 2.28-2.37(m, 2H), 2.06-2.14(m, 1H), 1.68-1.93(m, 3H), 1.28(t, J=7.2 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.45 (m, 1H), 7.89-7.92 (m, 1H), 7.71-7.82 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H) , 4.16-4.23 (m, 2H), 3.64 (t, J = 6.8 Hz, 2H), 3.56-3.59 (m, 2H), 2.28-2.37 (m, 2H), 2.06-2.14 (m, 1H), 1.68-1.93 (m, 3H), 1.28

<< 제조예Manufacturing example 32> 2-(3- 32> 2- (3- 클로로프로필Chloropropyl )-4-[[4-(t-) -4 - [[4- (t- 부톡시카보닐Butoxycarbonyl )아미노]피페리딘-1-일]-2H-) Amino] piperidin-1-yl] -2H- 프탈라진Phthalazine -1-온의 제조 -1-one

Figure 112011081771684-pat00086
Figure 112011081771684-pat00086

4-[[4-(t-부톡시카보닐)아미노]피페리딘-1-일]-2H-프탈라진-1-온(180 mg, 0.52 mmol)을 제조예 1과 동일한 방법으로 처리하여(215 mg, 0.51 mmol, 98%)의 표제 화합물을 얻었다. 4 - [[4- (t- butoxycarbonyl) amino] piperidin-1-yl] -2H- phthalazine-1-one (180 mg, 0.52 mmol) treated in the same manner as in Production Example 1 (215 mg, 0.51 mmol, 98%) of the title compound.

Rf=0.18(EA:Hx=1:3)Rf = 0.18 (EA: Hx = 1: 3)

1H-NMR(300 MHz, CDCl3) δ 8.44-8.47(m, 1H), 7.87-7.90(m, 1H), 7.76-7.83(m, 2H), 4.32(t, J=6.7 Hz, 2H), 3.66-3.67(m, 4H), 3.63(t, J=6.7 Hz, 2H), 3.15-3.18(m, 4H), 2.30-2.35(m, 2H), 1.51(s, 9H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.44-8.47 (m, 1H), 7.87-7.90 (m, 1H), 7.76-7.83 (m, 2H), 4.32 (t, J = 6.7 Hz, 2H) 2H), 3.11-3.18 (m, 4H), 2.30-2.35 (m, 2H), 1.51 (s, 9H)

<< 실시예Example 1> 4-벤질-2-[3-[4-[3-( 1 > 4-Benzyl-2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-프] Piperidin-1-yl] propyl] - 1 (2H) 탈라Tala 지논의 제조Manufacture of zinon

Figure 112011081771684-pat00087
Figure 112011081771684-pat00087

4-벤질-2-(3-클로로프로필)-2H-프탈라진-1-온(54 mg, 0.17 mmol)을 DMF(1 ml)에 녹인 후, N-(3-피페리딘-4-일페닐)아세트아마이드(52 mg 0.20 mmol), Na2CO3(54 mg, 0.51 mmol), 그리고 촉매량의 소듐 요오드화물을 첨가하고 100도에서 2시간 동안 교반하였다. 반응이 완결된 후, 에틸 아세테이트(10 ml)로 두 번 추출하고, 포화염화나트륨 용액(5 ml)로 세척하였다. 무수황산마그네슘(MgSO4)으로 건조시킨 후 감압 농축시키고 여액을 실리카겔 컬럼 크로마토그라피(메탄올:다이클로로메탄=1:10)로 정제하여 목적 화합물(20 mg, 0.04 mmol, 23%)을 얻었다. (54 mg, 0.17 mmol) was dissolved in DMF (1 ml), N- (3-piperidin-4-yl) (52 mg, 0.20 mmol), Na 2 CO 3 (54 mg, 0.51 mmol) and a catalytic amount of sodium iodide were added and stirred at 100 ° C. for 2 hours. After the reaction was complete, it was extracted twice with ethyl acetate (10 ml) and washed with saturated sodium chloride solution (5 ml). The organic layer was dried over anhydrous magnesium sulfate (MgSO 4 ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (methanol: dichloromethane = 1: 10) to obtain the desired compound (20 mg, 0.04 mmol, 23%).

Rf=0.40(10% MeOH in MC)Rf = 0.40 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.43-8.46(m, 1H), 7.69-7.76(m, 3H), 7.52(s, 1H), 7.44(d, J=8.3 Hz, 1H), 7.20-7.32(m, 7H), 6.93(d, J=7.6 Hz, 1H), 4.34(t, J=6.8 Hz, 2H), 4.31(s, 2H), 3.18(d, J=11.5 Hz, 2H), 2.66(t, J=6.8 Hz, 2H), 2.47-2.54(m, 1H), 2.18(s, 3H), 2.13-2.27(m, 4H), 1.80-1.96(m, 4H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.43-8.46 (m, IH), 7.69-7.76 (m, 3H), 7.52 (s, IH), 7.44 (d, J = 8.3 Hz, 2H), 4.31 (s, 2H), 3.18 (d, J = 11.5 Hz, 2H), 7.93 (d, J = 7.6 Hz, 2H), 2.47-2.54 (m, 1H), 2.18 (s, 3H), 2.13-2.27 (m, 4H), 1.80-1.96 (m, 4H)

<< 실시예Example 2> 4-(4- 2 > 4- (4- 클로로벤질Chlorobenzyl )-2-[3-[4-[3-() -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00088
Figure 112011081771684-pat00088

4-(4-클로로벤질)-2-(3-클로로프로필)-2H-프탈라진-1-온(54 mg, 0.16 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(32 mg, 0.06 mmol, 39%)의 표제 화합물을 얻었다. The reaction was carried out by following a procedure similar to that of Example 1, except using 4- (4-chlorobenzyl) -2- (3-chloropropyl) -2H-phthalazin-1-one (54 mg, 0.16 mmol) (32 mg, 0.06 mmol, 39%) of the title compound.

Rf=0.42(10% MeOH in MC)Rf = 0.42 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.44-8.47(m, 1H), 7.67-7.74(m, 3H), 7.42(d, J=8.0 Hz, 1H), 7.31-7.35(m, 2H), 7.20-7.29(m, 5H), 6.94(d, J=7.5 Hz, 1H), 4.33(t, J=6.7 Hz, 2H), 4.27(s, 2H), 3.18(d, J=10.7 Hz, 2H), 2.64(t, J=6.7 Hz, 2H), 2.50-2.54(m, 1H), 2.18(s, 3H), 2.11-2.26(m, 4H), 1.80-1.94(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.44-8.47 (m, 1H), 7.67-7.74 (m, 3H), 7.42 (d, J = 8.0 Hz, 1H), 7.31-7.35 (m, 2H) , 7.20-7.29 (m, 5H), 6.94 (d, J = 7.5 Hz, 1 H), 4.33 (t, J = 6.7 Hz, 2H), 4.27 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.50-2.54 (m, IH), 2.18 (s, 3H), 2.11-2.26 (m, 4H), 1.80-1.94

<< 실시예Example 3> 4-[2-(피리딘-4-일)에틸]-2-[3-[4-[3-( 3> 4- [2- (Pyridin-4-yl) ethyl] -2- [3- [4- [3- 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00089
Figure 112011081771684-pat00089

2-(3-클로로프로필)-4-[2-(피리딘-4-일)에틸]-2H-프탈라진-1-온(58 mg, 0.18 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(14 mg, 0.027 mmol, 15%)의 표제 화합물을 얻었다. The title compound was prepared following the procedure described in Example 1 (5), except that 2- (3-chloropropyl) -4- [2- (pyridin- 4- yl) ethyl] -2H- phthalazin- (14 mg, 0.027 mmol, 15%) of the title compound.

Rf=0.39(10% MeOH in MC)*2Rf = 0.39 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.47-8.53(m, 3H), 7.77-7.82(m, 3H), 7.38-7.40(m, 2H), 7.31(s, 1H), 7.20-7.23(m, 3H), 6.92(d, J=8.0 Hz, 1H), 4.27(t, J=6.9 Hz, 2H), 3.32-3.27(m, 2H), 3.14-3.18(m, 2H), 3.08(d, J=10.3 Hz, 2H), 2.54(t, J=6.9 Hz, 2H), 2.45-2.50(m, 1H), 2.17(s, 3H), 2.02-2.15(m, 4H), 1.75-1.82(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.47-8.53 (m, 3H), 7.77-7.82 (m, 3H), 7.38-7.40 (m, 2H), 7.31 (s, 1H), 7.20-7.23 ( 2H), 3.14-3.18 (m, 2H), 3.08 (d, J = 6.9 Hz, 2H) 2H), 2.54 (t, J = 6.9 Hz, 2H), 2.45-2.50 (m, 1H), 2.17 (s, 3H), 2.02-2.15 (m, 4H), 1.75-1.82 m, 4H)

<< 실시예Example 4> 4-[2-(피리딘-2-일)에틸]-2-[3-[4-[3-( 4> 4- [2- (Pyridin-2-yl) ethyl] -2- [3- [4- [3- 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00090
Figure 112011081771684-pat00090

2-(3-클로로프로필)-4-[2-(피리딘-2-일)에틸]-2H-프탈라진-1-온(91 mg, 0.28 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(15 mg, 0.039 mmol, 10%)의 표제 화합물을 얻었다. The procedure of Example 1 was repeated except for using 2- (3-chloropropyl) -4- [2- (pyridin-2-yl) ethyl] -2H- phthalazin- (15 mg, 0.039 mmol, 10%) of the title compound.

Rf=0.33(10% MeOH in MC)*2Rf = 0.33 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.56-8.57(m, 1H), 8.45-8.48(m, 1H), 7.89-7.91(m, 1H), 7.72-7.82(m, 2H), 7.58-7.64(m, 1H), 7.42(d, J=8.0 Hz, 2H), 7.30(s, 1H), 7.18-7.25(m, 2H), 7.12-7.16(m, 1H), 6.92(d, J=7.1 Hz, 1H), 4.27(t, J=6.9 Hz, 2H), 3.42-3.47(m, 2H), 3.28-3.33(m, 2H), 3.11(d, J=12.0 Hz, 2H), 2.56(t, J=6.9 Hz, 2H), 2.42-2.52(m, 1H), 2.17(s, 3H), 2.02-2.15(m, 4H), 1.81-1.87(m, 4H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.56-8.57 (m, IH), 8.45-8.48 (m, IH), 7.89-7.91 J = 8.0 Hz, 2H), 7.30 (s, 1H), 7.18-7.25 (m, 2H), 7.12-7.16 (M, 2H), 3.11 (d, J = 12.0 Hz, 2H), 2.56 (m, 2H) 2H), 2.42-2.52 (m, 1H), 2.17 (s, 3H), 2.02-2.15 (m, 4H), 1.81-1.87

<< 실시예Example 5> 4-[2-(피리딘-3-일)에틸]-2-[3-[4-[3-( 5> 4- [2- (Pyridin-3-yl) ethyl] -2- [3- [4- [3- 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00091
Figure 112011081771684-pat00091

2-(3-클로로프로필)-4-[2-(피리딘-3-일)에틸]-2H-프탈라진-1-온(92 mg, 0.28 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(29 mg, 0.057 mmol, 20%)의 표제 화합물을 얻었다. The title compound was prepared following the procedure described in Example 1 (1) except that 2- (3-chloropropyl) -4- [2- (pyridin-3- yl) ethyl] -2H- phthalazin- (29 mg, 0.057 mmol, 20%) of the title compound.

Rf=0.42(10% MeOH in MC)Rf = 0.42 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.56(d, J=2.1 Hz, 1H), 8.46-8.50(m, 2H), 7.74-7.81(m, 3H), 7.55-7.59(m, 1H), 7.38-7.41(m, 2H), 7.30(s, 1H), 7.20-7.25(m, 2H), 6.92(d, J=7.6 Hz, 1H), 4.27(t, J=7.2 Hz, 2H), 3.26-3.31(m, 2H), 3.14-3.19(m, 2H), 3.07(d, J=11.3 Hz, 2H), 2.52(t, J=7.2 Hz, 2H), 2.42-2.47(m, 1H), 2.17(s, 3H), 2.02-2.11(m, 4H), 1.73-1.85(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.56 (d, J = 2.1 Hz, 1H), 8.46-8.50 (m, 2H), 7.74-7.81 (m, 3H), 7.55-7.59 (m, 1H) , 7.28 (t, J = 7.2 Hz, 2H), 7.38-7.41 (m, 2H), 7.30 J = 7.2 Hz, 2H), 2.42-2.47 (m, IH), 3.26-3.31 (m, 2H), 3.14-3.19 , 2.17 (s, 3H), 2.02-2.11 (m, 4H), 1.73-1.85 (m, 4H)

<< 실시예Example 6> 4-(4- 6 > 4- (4- 클로로페녹시Chlorophenoxy )-2-[3-[4-[3-() -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00092
Figure 112011081771684-pat00092

4-(4-클로로페녹시)-2-(3-클로로프로필)-2H-프탈라진-1-온(66 mg, 0.19 mmol)을 을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(75 mg, 0.14 mmol, 75%)의 표제 화합물을 얻었다. (66 mg, 0.19 mmol) was used in place of 4- (4-chlorophenoxy) -2- (3-chloropropyl) -2H-phthalazin- (75 mg, 0.14 mmol, 75%) of the title compound.

Rf=0.43(10% MeOH in MC)Rf = 0.43 (10% MeOH in MC)

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

δ 8.44-8.47(m, 1H), 8.10-8.13(m, 1H), 7.85-7.88(m, 2H), 7.37-7.43(m, 3H), 7.30(s, 1H), 7.17-7.23(m, 3H), 6.92(d, J=7.4 Hz, 1H), 4.11(t, J=6.8 Hz, 2H), 3.05(d, J=10.4 Hz, 2H), 2.43-2.51(m, 3H), 2.18(s, 3H), 1.96-2.11(m, 4H), 1.79-1.80(m, 4H)
1H), 7.17-7.23 (m, 2H), 7.37-7.43 (m, 3H) (M, 3H), 6.92 (d, J = 7.4 Hz, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.05 s, 3H), 1.96-2.11 (m, 4H), 1.79-1.80 (m, 4H)

<< 실시예Example 7> 4-[[1-(t- 7 > 4 - [[1- (t- 부톡시카보닐Butoxycarbonyl )피페리딘-4-일]) &Lt; / RTI &gt; piperidin-4-yl] 옥시Oxy ]-2-[3-[4-[3-(] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00093
Figure 112011081771684-pat00093

4-[[1-(t-부톡시카보닐)피페리딘-4-일]옥시-2-(3-클로로프로필)-2H-프탈라진-1-온(83 mg, 0.20 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(65 mg, 0.108 mmol, 55%)의 표제 화합물을 얻었다. 2- (3-chloropropyl) -2H-phthalazin-1-one (83 mg, 0.20 mmol) was added to a solution of 4 - [[1- (t-butoxycarbonyl) piperidin- (65 mg, 0.108 mmol, 55%) of the title compound were obtained by the reaction similar to Example 1,

Rf=0.26(10% MeOH in MC)Rf = 0.26 (10% MeOH in MC)

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

δ 8.39-8.41(m, 1H), 7.97-7.99(m, 1H), 7.78-7.80(m, 2H), 7.40-7.42(m, 2H), 7.32(s, 1H), 7.23(d, J=7.6 Hz, 1H), 6.93(d, J=6.0 Hz, 1H), 5.17-5.21(m, 1H), 4.20(t, J=6.5 Hz, 2H), 3.71-3.78(m, 2H), 3.39-3.45(m, 2H), 3.14-3.17(m, 2H), 2.57-2.63(m, 2H), 2.47-2.56(m, 1H), 2.18(s, 3H), 1.98-2.13(m, 6H), 1.85-1.89(m, 6H), 1.48(s, 9H)
2H), 7.32 (s, 1H), 7.23 (d, J = 8.39-8.41 (m, 1H), 7.97-7.99 2H), 3.71-3.78 (m, 2H), 3.39 (d, J = 6.0 Hz, 1H) 2H), 3.14-3.17 (m, 2H), 2.57-2.63 (m, 2H), 2.47-2.56 (m, 1.85-1.89 (m, 6H), 1.48 (s, 9H)

<< 실시예Example 8> 4-[피페리딘-4- 8> 4- [Piperidin-4- 일옥시Sake ]-2-[3-[4-[3-(] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00094
Figure 112011081771684-pat00094

상기 실시예 7에서 얻은 화합물(49 mg, 0.081 mmol)을 1,4-다이옥산(3 ml) 용매에 녹인 뒤, 1N 염산(2 ml)을 첨가한 뒤 상온에서 반응시켰다. 반응이 완결된 뒤, 용매를 완전히 제거하여(43 mg, 0.08 mmol, 99%)의 표제 화합물을 얻었다. The compound (49 mg, 0.081 mmol) obtained in Example 7 was dissolved in a solvent of 1,4-dioxane (3 ml), followed by the addition of 1N hydrochloric acid (2 ml), followed by reaction at room temperature. After the reaction was complete, the solvent was removed completely (43 mg, 0.08 mmol, 99%) of the title compound.

1H-NMR(300 MHz, MeOH-d4) δ 8.34-8.36(m, 1H), 8.14-8.15(m, 1H), 7.91-7.94(m, 2H), 7.56-7.57(m, 1H), 7.33-7.35(m, 1H), 7.23-7.27(m, 1H), 7.01-7.02(m, 1H), 5.39-5.42(m, 1H), 4.28-4.29(m, 2H), 3.62-3.74(m, 3H), 3.35-3.56(m, 4H), 3.07-3.23(m, 3H), 2.86-2.91(m, 1H), 2.00-2.36(m, 10H), 2.11(s, 3H)
 1 H-NMR (300 MHz, MeOH-d 4) δ 8.34-8.36 (m, 1H), 8.14-8.15 (m, 1H), 7.91-7.94 (m, 2H), 7.56-7.57 (m, 1H), 1H), 7.23-7.27 (m, 1H), 7.01-7.02 (m, 1H), 5.39-5.42 (m, 1H), 4.28-4.29 (m, 2H), 3.62-3.74 3H), 2.00-2.36 (m, 10H), 2.11 (s, 3H), 3.35-3.56 (m, 4H), 3.07-3.23

<< 실시예Example 9> 4-[(4- 9> 4 - [(4- 클로로페닐Chlorophenyl )싸이오]-2-[3-[4-[3-() Thio] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00095
Figure 112011081771684-pat00095

4-[(4-클로로페닐)싸이오]-2-(3-클로로프로필)-2H-프탈라진-1-온(60 mg, 0.16 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(37 mg, 0.068 mmol, 42%)의 표제 화합물을 얻었다. Similar to example 1, but using 4 - [(4-chlorophenyl) thio] -2- (3-chloropropyl) -2H- phthalazin- 1-one (60 mg, 0.16 mmol) (37 mg, 0.068 mmol, 42%) of the title compound.

Rf=0.31(10% MeOH in MC)Rf = 0.31 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.44-8.47(m, 1H), 8.00-8.02(m, 1H), 7.79-7.82(m, 2H), 7.23-7.44(m, 8H), 6.92(d, J=7.5 Hz, 1H), 4.23(t, J=6.8 Hz, 2H), 3.02(d, J=11.1 Hz, 2H), 2.43-2.48(m, 3H), 2.18(s, 3H), 1.96-2.07(m, 4H), 1.73-1.78(m, 4H)
1 H-NMR (300 MHz, CDCl 3) δ 8.44-8.47 (m, 1H), 8.00-8.02 (m, 1H), 7.79-7.82 (m, 2H), 7.23-7.44 (m, 8H), 6.92 ( (d, J = 7.5 Hz, 1H), 4.23 (t, J = 6.8 Hz, 2H), 3.02 (d, J = 11.1 Hz, 2H), 2.43-2.48 1.96-2.07 (m, 4H), 1.73-1.78 (m, 4H)

<< 실시예Example 10> 4- 10> 4- 페닐설포닐Phenylsulfonyl -2-[3-[4-[3-(-2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00096
Figure 112011081771684-pat00096

4-페닐설포닐-2-(3-클로로프로필)-2H-프탈라진-1-온(60 mg, 0.17 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(65 mg, 0.12 mmol, 72%)의 표제 화합물을 얻었다. (60 mg, 0.17 mmol) was used in place of 4-phenylsulfonyl-2- (3-chloropropyl) -2H-phthalazin- , 0.12 mmol, 72%) of the title compound.

Rf=0.39(10% MeOH in MC)Rf = 0.39 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.73(d, J=8.3 Hz, 1H), 8.47(d, J=7.6 Hz, 1H), 8.07(d, J=7.6 Hz, 2H), 7.81-7.94(m, 2H), 7.68-7.70(m, 1H), 7.58-7.63(m, 2H), 7.31-7.34(m, 3H), 7.22(d, J=7.6 Hz, 1H), 6.85(d, J=6.8 Hz, 1H), 4.16(d, J=6.8 Hz, 2H), 2.89(d, J=10.6 Hz, 2H), 2.41-2.46(m, 1H), 2.37(t, J=6.8 Hz, 2H), 2.18(s, 3H), 1.81-1.98(m, 4H), 1.55-1.74(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.73 (d, J = 8.3 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.81- 7.94 (m, 2H), 7.68-7.70 (m, 1H), 7.58-7.63 (m, 2H), 7.31-7.34 J = 6.8 Hz, 1H), 4.16 (d, J = 6.8 Hz, 2H), 2.89 (d, J = 10.6 Hz, 2H), 2.41-2.46 2H), 2.18 (s, 3H), 1.81-1.98 (m, 4H), 1.55-1.74 (m, 4H)

<< 실시예Example 11> 4-[(4- 11 > 4 - [(4- 메틸페닐Methylphenyl )) 설포닐Sulfonyl ]-2-[3-[4-[3-(] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00097
Figure 112011081771684-pat00097

4-[(4-메틸페닐)설포닐]-2-(3-클로로프로필)-2H-프탈라진-1-온(78 mg, 0.21 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(95 mg, 0.17 mmol, 82%)의 표제 화합물을 얻었다. The title compound was prepared by a similar method to Example 1, except that 4 - [(4-methylphenyl) sulfonyl] -2- (3- chloropropyl) -2H- phthalazin- 1 -one (78 mg, 0.21 mmol) (95 mg, 0.17 mmol, 82%) of the title compound.

Rf=0.34(10% MeOH in MC)Rf = 0.34 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.73(d, J=8.0 Hz, 1H), 8.46(d, J=8.0 Hz, 1H), 7.94(d, J=8.3 Hz, 2H), 7.80-7.88(m, 2H), 7.38(d, J=8.3 Hz, 2H), 7.30-7.33(m, 2H), 7.21(d, J=8.3 Hz, 1H), 6.84(d, J=7.7 Hz, 1H), 4.17(t, J=6.7 Hz, 2H), 2.87(d, J=10.9 Hz, 2H), 2.45(s, 3H), 2.38-2.41(m, 1H), 2.33(t, J=6.7 Hz, 2H), 2.18(s, 3H), 1.83-1.94(m, 4H), 1.70-7.74(m, 2H), 1.50-1.54(m, 2H)
1 H-NMR (300 MHz, CDCl 3) δ 8.73 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.80- 7.88 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.30-7.33 2H), 2.45 (s, 3H), 2.38-2.41 (m, 1H), 2.33 (t, J = 6.7 Hz, 2H) 2H), 2.10 (s, 3H), 1.83-1.94 (m, 4H), 1.70-7.74

<< 실시예Example 12> 4-[(4- 12 > 4 - [(4- 클로로페닐Chlorophenyl )) 설포닐Sulfonyl ]-2-[3-[4-[3-(] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00098
Figure 112011081771684-pat00098

4-[(4-클로로페닐)설포닐]-2-(3-클로로프로필)-2H-프탈라진-1-온(66 mg, 0.17 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(48 mg, 0.083 mmol, 50%)의 표제 화합물을 얻었다. Similar to example 1, but using 4 - [(4-chlorophenyl) sulfonyl] -2- (3-chloropropyl) -2H- phthalazin-1-one (66 mg, 0.17 mmol) (48 mg, 0.083 mmol, 50%) of the title compound.

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

1H-NMR(300 MHz, CDCl3) δ 8.69-8.72(m, 1H), 8.46-8.49(m, 1H), 7.97-8.02(m, 2H), 7.82-7.95(m, 2H), 7.56-8.02(m, 2H), 7.82-7.95(m, 2H), 7.56-7.60(m, 2H), 7.33-7.35(m, 1H), 7.29(s, 1H), 7.19-7.24(m, 2H), 6.85(d, J=7.7 Hz, 1H), 4.15(d, J=7.3 Hz, 2H), 2.85(d, J=11.6 Hz, 2H), 2.37-2.46(m, 1H), 2.32(t, J=7.3 Hz, 2H), 2.18(s, 3H), 1.72-1.94(m, 6H), 1.50-1.54(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.69-8.72 (m, 1H), 8.46-8.49 (m, 1H), 7.97-8.02 (m, 2H), 7.82-7.95 (m, 2H), 7.56- 2H), 8.02 (m, 2H), 7.82-7.95 (m, 2H), 7.56-7.60 (m, 2H), 7.33-7.35 J = 7.7 Hz, 1H), 4.15 (d, J = 7.3 Hz, 2H), 2.85 (d, J = 11.6 Hz, 2H), 2.37-2.46 = 7.3 Hz, 2H), 2.18 (s, 3H), 1.72-1.94 (m, 6H), 1.50-1.54

<< 실시예Example 13> 4-[(4- 13 > 4 - [(4- 클로로페닐Chlorophenyl )아미노]-2-[3-[4-[3-() Amino] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00099
Figure 112011081771684-pat00099

4-[(4-클로로페닐)아미노]-2-(3-클로로프로필)-2H-프탈라진-1-온(55 mg, 0.16 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(24 mg, 0.045 mmol, 29%)의 표제 화합물을 얻었다. The title compound was prepared by a similar method to Example 1, but using 4- [(4-chlorophenyl) amino] -2- (3-chloropropyl) -2H- phthalazin-1-one (55 mg, 0.16 mmol) (24 mg, 0.045 mmol, 29%) of the title compound.

Rf=0.29(10% MeOH in MC)Rf = 0.29 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.50-8.53(m, 1H), 7.78-7.85(m, 3H), 7.44-7.47(m, 3H), 7.26-7.36(m, 4H), 7.21(d, J=7.7 Hz, 1H), 6.90(d, J=7.3 Hz, 1H), 6.78(s, 1H), 4.26(t, J=6.9 Hz, 2H), 3.01(d, J=11.3 Hz, 2H), 2.52(t, J=6.9 Hz, 2H), 2.38-2.41(m, 1H), 2.20(s, 3H), 1.96-2.14(m, 4H), 1.61-1.74(m, 4H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.50-8.53 (m, 1H), 7.78-7.85 (m, 3H), 7.44-7.47 (m, 3H), 7.26-7.36 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H), 6.78 2H), 2.52 (t, J = 6.9 Hz, 2H), 2.38-2. 41 (m, 1H), 2.20 (s, 3H), 1.96-2.14 (m, 4H), 1.61-1.74

<< 실시예Example 14> 4-[(피리딘-4-일)아미노]-2-[3-[4-[3-( 14> 4 - [(Pyridin-4-yl) amino] -2- [3- [4- [3- 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00100
Figure 112011081771684-pat00100

4-[(피리딘-4-일)아미노]-2-(3-클로로프로필)-2H-프탈라진-1-온(57 mg, 0.18 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(29 mg, 0.058 mmol, 32%)의 표제 화합물을 얻었다. (57 mg, 0.18 mmol) was used in place of 4 - [(pyridin-4- yl) amino] -2- (3- chloropropyl) -2H-phthalazin- (29 mg, 0.058 mmol, 32%) of the title compound.

Rf=0.21(10% MeOH in MC)*2Rf = 0.21 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.52-8.55(m, 1H), 8.43-8.46(m, 2H), 7.80-7.87(m, 3H), 7.63(s, 1H), 7.42-7.44(m, 2H), 7.29-7.33(m, 2H), 7.20(d, J=7.5 Hz, 1H), 7.13-7.14(m, 1H), 6.87(d, J=7.4 Hz, 1H), 4.34(t, J=6.7 Hz, 2H), 2.95(d, J=10.6 Hz, 2H), 2.49(t, J=6.7 Hz, 2H), 2.34-2.38(m, 1H), 2.24(s, 3H), 2.05-2.12(m, 3H), 1.89-1.93(m, 2H), 1.65-1.69(m, 2H), 1.44-1.53(m, 2H)
1 H-NMR (300 MHz, CDCl 3 )? 8.52-8.55 (m, 1H), 8.43-8.46 (m, 2H), 7.80-7.87 (m, 3H), 7.63 (m, 2H), 7.29-7.33 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 7.13-7.14 2H), 2.24 (s, 3H), 2.05 (d, J = 6.7 Hz, 2H) 2H), 1.65-1.69 (m, 2H), 1.44-1. 53 (m, 2H)

<< 실시예Example 15> 4-[(피리딘-2- 15> 4 - [(Pyridin-2- 일메틸Yl methyl )아미노]-2-[3-[4-[3-() Amino] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00101
Figure 112011081771684-pat00101

4-[(피리딘-2-일메틸)-아미노]-2-(3-클로로프로필)-2H-프탈라진-1-온(72 mg, 0.22 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(23 mg, 0.045 mmol, 21%)의 표제 화합물을 얻었다. 2-ylmethyl) - amino] -2- (3-chloropropyl) -2H-phthalazin-1-one (72 mg, 0.22 mmol) To give the title compound (23 mg, 0.045 mmol, 21%).

Rf=0.18(10% MeOH in MC)*1.5Rf = 0.18 (10% MeOH in MC) * 1.5

1H-NMR(300 MHz, CDCl3) δ 8.61(d, J=4.1 Hz, 1H), 8.49(d, J=7.3 Hz, 1H), 7.67-7.82(m, 4H), 7.38(d, J=7.8 Hz, 2H), 7.28-7.31(m, 2H), 7.23(d, J=6.9 Hz, 2H), 6.94(d, J=7.6 Hz, 1H), 6.07-6.10(m, 1H), 4.67(d, J=4.6 Hz, 2H), 4.20(t, J=7.1 Hz, 2H), 3.05(d, J=11.0 Hz, 2H), 2.46-2.53(m, 3H), 2.17(s, 3H), 1.98-2.10(m, 4H), 1.71-1.86(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.61 (d, J = 4.1 Hz, 1H), 8.49 (d, J = 7.3 Hz, 1H), 7.67-7.82 (m, 4H), 7.38 (d, J = 7.8 Hz, 2H), 7.28-7.31 (m, 2H), 7.23 (d, J = 6.9 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H) (d, J = 4.6 Hz, 2H), 4.20 (t, J = 7.1 Hz, 2H), 3.05 (d, J = 11.0 Hz, 2H), 2.46-2.53 , 1.98-2.10 (m, 4H), 1.71-1.86 (m, 4H)

<< 실시예Example 16> 4- 16> 4- 사이클로헥실아미노Cyclohexylamino -2-[3-[4-[3-(-2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00102
Figure 112011081771684-pat00102

4-사이클로헥실아미노-2-(3-클로로프로필)-2H-프탈라진-1-온(56 mg, 0.18 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(21 mg, 0.042 mmol, 24%)의 표제 화합물을 얻었다. Reaction was performed in a similar manner to Example 1, but using 4-cyclohexylamino-2- (3-chloropropyl) -2H-phthalazin-1-one (56 mg, 0.18 mmol) , 0.042 mmol, 24%) of the title compound.

Rf=0.23(10% MeOH in MC)Rf = 0.23 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.45-8.47(m, 1H), 7.72-7.77(m, 2H), 7.60-7.62(m, 2H), 7.48(d, J=7.8 Hz, 1H), 7.30(s, 1H), 7.23(d, J=7.8 Hz, 1H), 6.94(d, J=7.5 Hz, 1H), 4.32(d, J=6.2 Hz, 1H), 4.21(t, J=6.5 Hz, 2H), 3.77-3.81(m, 1H), 3.26(d, J=10.6 Hz, 2H), 2.73(t, J=6.5 Hz, 2H), 2.48-2.58(m, 1H), 2.22-2.36(m, 4H), 2.19(s, 3H), 1.95-2.14(m, 4H), 1.66-1.89(m, 4H), 1.20-1.51(m, 6H)
1 H-NMR (300 MHz, CDCl 3) δ 8.45-8.47 (m, 1H), 7.72-7.77 (m, 2H), 7.60-7.62 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H) , 7.30 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H) 2H), 2.48-2.58 (m, 1H), 2.22-2.52 (m, 2H), 3.77-3.81 (M, 4H), 2.19 (s, 3H), 1.95-2.14 (m, 4H), 1.66-1.89

<< 실시예Example 17> 4-[메틸( 17> 4- [methyl ( 페닐Phenyl )아미노]-2-[3-[4-[3-() Amino] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00103
Figure 112011081771684-pat00103

4-[메틸(페닐)아미노]-2-(3-클로로프로필)-2H-프탈라진-1-온(67 mg, 0.20 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(42 mg, 0.082 mmol, 40%)의 표제 화합물을 얻었다. The title compound was prepared according to a similar manner to that described in Example 1, except that 4- [methyl (phenyl) amino] -2- (3-chloropropyl) -2H- phthalazin-1-one (67 mg, 0.20 mmol) (42 mg, 0.082 mmol, 40%) of the title compound.

Rf=0.36(10% MeOH in MC)*2Rf = 0.36 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.44(d, J=7.6 Hz, 1H), 7.64-7.69(m, 1H), 7.52-7.57(m, 1H), 7.39-7.46(m, 3H), 7.31(s, 1H), 7.20-7.25(m, 3H), 6.87-7.00(m, 4H), 4.30(t, J=7.0 Hz, 2H), 3.42(s, 3H), 3.12(t, J=11.0 Hz, 2H), 2.59(t, J=7.0 Hz, 2H), 2.46-2.52(m, 1H), 2.18(s, 3H), 2.00-2.15(m, 4H), 1.81-1.87(m, 4H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.44 (d, J = 7.6 Hz, 1 H), 7.64-7.69 (m, 1 H), 7.52-7.57 (S, 3H), 7.31 (s, 1H), 7.20-7.25 (m, 3H), 6.87-7.00 (m, 4H), 4.30 2H), 2.46-2.52 (m, 1H), 2.18 (s, 3H), 2.00-2. 15 (m, 4H), 1.81-1.87 4H)

<< 실시예Example 18> 4- 18> 4- 다이에틸아미노Diethylamino -2-[3-[4-[3-(-2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00104
Figure 112011081771684-pat00104

4-다이에틸아미노-2-(3-클로로프로필)-2H-프탈라진-1-온(56 mg, 0.19 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(50 mg, 0.11 mmol, 55%)의 표제 화합물을 얻었다. Reaction was carried out in a similar manner to example 1, but using 4-diethylamino-2- (3-chloropropyl) -2H-phthalazin-1-one (56 mg, 0.19 mmol) , 0.11 mmol, 55%) of the title compound.

Rf=0.56(10% MeOH in MC)Rf = 0.56 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.44(m, 1H), 7.91-7.94(m, 1H), 7.69-7.79(m, 2H), 7.31-7.49(m, 3H), 7.23(d, J=7.9 Hz, 1H), 6.94(d, J=7.9 Hz, 1H), 4.23(t, J=7.1 Hz, 2H), 3.21-3.28(m, 4H), 3.10(d, J=11.3 Hz, 2H), 2.55(t, J=7.1 Hz, 2H), 2.39-2.50(m, 1H), 2.18(s, 3H), 2.03-2.14(m, 4H), 1.80-1.82(m, 4H), 1.15(t, J=6.8 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.44 (m, 1H), 7.91-7.94 (m, 1H), 7.69-7.79 (m, 2H), 7.31-7.49 (m, 3H), 7.23 ( J = 7.9 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 4.23 (t, J = 7.1 Hz, 2H), 3.21-3.28 (m, 4H), 3.10 1H), 2.18 (s, 3H), 2.03-2.14 (m, 4H), 1.80-1.82 (m, 4H) , 1.15 (t, J = 6.8 Hz, 3H)

<< 실시예Example 19> 4- 19> 4- 다이프로필아미노Dipropylamino -2-[3-[4-[3-(-2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00105
Figure 112011081771684-pat00105

4-다이프로필아미노-2-(3-클로로프로필)-2H-프탈라진-1-온(55 mg, 0.17 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(41 mg, 0.081 mmol, 47%)의 표제 화합물을 얻었다. The reaction was carried out in a similar manner to Example 1, except using 4-dipropylamino-2- (3-chloropropyl) -2H-phthalazin-1-one (55 mg, 0.17 mmol) , 0.081 mmol, 47%) of the title compound.

Rf=0.48(10% MeOH in MC)*2Rf = 0.48 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.41-8.44(m, 1H), 7.93-7.96(m, 1H), 7.69-7.79(m, 2H), 7.39-7.53(m, 2H), 7.31(s, 1H), 7.22(d, J=7.9 Hz, 1H), 6.94(d, J=7.6 Hz, 1H), 4.22(t, J=7.0 Hz, 2H), 3.07-3.16(m, 6H), 2.53(t, J=7.0 Hz, 2H), 2.39-2.46(m, 1H), 2.17(s, 3H), 2.05-2.14(m, 4H), 1.79-1.82(m, 4H), 1.53-1.63(m, 4H), 0.89(t, J=7.4 Hz, 6H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.41-8.44 (m, 1H), 7.93-7.96 (m, 1H), 7.69-7.79 (m, 2H), 7.39-7.53 (m, 2H), 7.31 ( J = 7.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.94 2H), 2.39-2.46 (m, 1H), 2.17 (s, 3H), 2.05-2.14 (m, 4H), 1.79-1.82 (m, 4H), 1.53-1.63 m, 4H), 0.89 (t, J = 7.4 Hz, 6H)

<< 실시예Example 20> 4- 20> 4- 다이아이소부틸아미노Diisobutylamino -2-[3-[4-[3-(-2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00106
Figure 112011081771684-pat00106

4-다이아이소부틸아미노-2-(3-클로로프로필)-2H-프탈라진-1-온(100 mg, 0.29 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(99 mg, 0.19 mmol, 65%)의 표제 화합물을 얻었다. (100 mg, 0.29 mmol) was used instead of 4-diisobutylamino-2- (3-chloropropyl) -2H-phthalazin- mg, 0.19 mmol, 65%) of the title compound.

Rf=0.35(10% MeOH in MC)Rf = 0.35 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.44(m, 1H), 8.02(d, J=7.2 Hz, 1H), 7.71-7.76(m, 2H), 7.37-7.40(m, 2H), 7.32(s, 1H), 7.23(d, J=8.0 Hz, 1H), 6.94(d, J=7.2 Hz, 1H), 4.21(t, J=6.8 Hz, 2H), 3.07(d, J=11.4 Hz, 2H), 3.01(d, J=7.2 Hz, 4H), 2.51(t, J=6.8 Hz, 2H), 2.41-2.46(m, 1H), 2.17(s, 3H), 1.93-2.13(m, 6H), 1.75-1.81(m, 4H), 0.91(d, J=6.8 Hz, 12H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.44 (m, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.71-7.76 (m, 2H), 7.37-7.40 (m, 2H) , 7.32 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H) 2H), 2.41-2.46 (m, 1H), 2.17 (s, 3H), 1.93-2.13 (d, J = 7.2 Hz, 2H) m, 6H), 1.75-1.81 (m, 4H), 0.91 (d, J = 6.8 Hz, 12H)

<< 실시예Example 21> 4-( 21 > 4- ( 피롤리딘Pyrrolidine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00107
Figure 112011081771684-pat00107

4-(피롤리딘-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(50 mg, 0.17 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여 노란색 고체의(31 mg, 0.07 mmol, 38%)표제 화합물을 얻었다.The title compound was prepared using a similar method to Example 1, but using 4- (pyrrolidin-1-yl) -2- (3-chloropropyl) -2H- phthalazin- To give the title compound (31 mg, 0.07 mmol, 38%) as a yellow solid.

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

1H-NMR(300 MHz, CDCl3) δ 8.43-8.46(m, 1H), 8.00-8.03(m, 1H), 7.70-7.79(m, 2H), 7.54-7.57(m, 1H), 7.47(d, J=7.8 Hz, 1H), 7.31(s, 1H), 7.23(d, J=7.8 Hz, 1H), 6.94(d, J=7.4 Hz, 1H), 4.21(t, J=6.6 Hz, 2H), 3.52-3.56(m, 4H), 3.26(d, J=10.5 Hz, 2H), 2.73(t, J=6.6 Hz, 2H), 2.49-2.54(m, 1H), 2.20-2.29(m, 4H), 2.18(s, 3H), 1.94-2.03(m, 6H), 1.82-1.86(m, 2H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.43-8.46 (m, 1H), 8.00-8.03 (m, 1H), 7.70-7.79 (m, 2H), 7.54-7.57 (m, 1H), 7.47 ( J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.94 2H), 3.52-3.56 (m, 4H), 3.26 (d, J = 10.5 Hz, 2H), 2.73 (t, J = 6.6 Hz, 2H), 2.49-2.54 , 4H), 2.18 (s, 3H), 1.94-2.03 (m, 6H), 1.82-1.86 (m, 2H)

<< 실시예Example 22> 4-( 22 > 4- ( 몰포린Morpholine -4-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조  Produce

Figure 112011081771684-pat00108
Figure 112011081771684-pat00108

4-(몰포린-4-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(58 mg, 0.19 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여 횐색 고체의(56 mg, 0.11 mmol, 61%)표제 화합물을 얻었다.The title compound was prepared in analogy to example 1, except using 4- (morpholin-4-yl) -2- (3-chloropropyl) -2H- phthalazin- 1-one (58 mg, 0.19 mmol) To give the title compound (56 mg, 0.11 mmol, 61%) as a pale solid.

Rf=0.28(10% MeOH in MC)Rf = 0.28 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.43-8.46(m, 1H), 7.88-7.91(m, 1H), 7.66-7.82(m, 3H), 7.44(d, J=8.1 Hz, 1H), 7.32(s, 1H), 7.22(d, J=8.0 Hz, 1H), 6.92(d, J=7.6 Hz, 1H), 4.24(t, J=6.8 Hz, 2H), 3.93(t, J=4.4 Hz, 2H), 3.21(d, J=4.4 Hz, 2H), 3.15-3.20(m, 2H), 2.63(t, J=6.8 Hz, 2H), 2.46-2.53(m, 1H), 2.18(s, 3H), 2.15-2.22(m, 4H), 1.79-1.86(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.43-8.46 (m, 1H), 7.88-7.91 (m, 1H), 7.66-7.82 (m, 3H), 7.44 (d, J = 8.1 Hz, 1H) , 7.32 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H) 2H), 2.46-2.53 (m, 1H), 2.18 (m, 2H), 3.21 (d, J = 4.4 Hz, 2H) s, 3H), 2.15-2.22 (m, 4H), 1.79-1.86 (m, 4H)

<< 실시예Example 23> 4-( 23 > 4- ( 싸이오몰포린Thiomorpholine -4-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00109
Figure 112011081771684-pat00109

4-(싸이오몰포린-4-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(57 mg, 0.18 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(22 mg, 0.044 mmol, 25%)의 표제 화합물을 얻었다. The title compound was prepared by a similar method to Example 1, but using 4- (thiomorpholin-4-yl) -2- (3-chloropropyl) -2H- phthalazin- (22 mg, 0.044 mmol, 25%) of the title compound.

Rf=0.44(10% MeOH in MC)Rf = 0.44 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.45(m, 1H), 7.71-7.84(m, 3H), 7.31-7.41(m, 3H), 7.23(d, J=7.9 Hz, 1H), 6.93(d, J=7.9 Hz, 1H), 4.23(t, J=7.0 Hz, 2H), 3.45-3.48(m, 4H), 3.14(d, J=11.3 Hz, 2H), 2.86-2.90(m, 4H), 2.57-2.61(m, 2H), 2.46-2.53(m, 1H), 2.17(s, 3H), 2.13-2.15(m, 4H), 1.83-1.90(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.45 (m, 1H), 7.71-7.84 (m, 3H), 7.31-7.41 (m, 3H), 7.23 (d, J = 7.9 Hz, 1H) , 6.93 (d, J = 7.9 Hz, 1H), 4.23 (t, J = 7.0 Hz, 2H), 3.45-3.48 (m, 4H), 3.14 (d, J = 11.3 Hz, 2H), 2.86-2.90 2H), 2.46-2.53 (m, 4H), 2.13-2.15 (m, 4H), 1.83-1.90 (m, 4H)

<< 실시예Example 24> 4-(피페리딘-1-일)-2-[3-[4-[3-( 24> 4- (Piperidin-1-yl) -2- [3- [4- [3- 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00110
Figure 112011081771684-pat00110

4-(피페리딘-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(54 mg, 0.18 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여 노란색 고체의(39 mg, 0.08 mmol, 45%)표제 화합물을 얻었다.The title compound was prepared using a similar procedure to Example 1, but using 4- (piperidin-l-yl) -2- (3-chloropropyl) -2H- phthalazin- To give the title compound (39 mg, 0.08 mmol, 45%) as a yellow solid.

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

1H-NMR(300 MHz, CDCl3) δ 8.40-8.43(m, 1H), 7.86-7.89(m, 1H), 7.69-7.82(m, 3H), 7.46(d, J=8.7 Hz, 1H), 7.32(s, 1H), 7.21(d, J=7.9 Hz, 1H), 6.92(d, J=7.9 Hz, 1H), 4.23(t, J=6.8 Hz, 2H), 3.20(t, J=11.3 Hz, 2H), 3.12-3.15(m, 4H), 2.67(t, J=6.8 Hz, 2H), 2.39-2.54(m, 1H), 2.20-2.27(m, 2H), 2.18(s, 3H), 1.87-2.00(m, 2H), 1.75-1.83(m, 6H), 1.61-1.71(m, 2H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.40-8.43 (m, IH), 7.86-7.89 (m, IH), 7.69-7.82 , 7.32 (s, 1H), 7.21 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H) (M, 2H), 2.18 (s, 3H), 2.32-2.27 (m, 2H), 3.12-3.15 ), 1.87-2.00 (m, 2H), 1.75-1.83 (m, 6H), 1.61-1.71 (m, 2H)

<< 실시예Example 25> 4-(4- 25> 4- (4- 메틸피페리딘Methylpiperidine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00111
Figure 112011081771684-pat00111

4-(4-메틸피페리딘-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(60 mg, 0.19 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(53 mg, 0.11 mmol, 57%)의 표제 화합물을 얻었다. The procedure of Example 1 was repeated except for using 4- (4-methylpiperidin-l-yl) -2- (3-chloropropyl) -2H- phthalazin- To give the title compound (53 mg, 0.11 mmol, 57%).

Rf=0.22(10% MeOH in MC)Rf = 0.22 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.41-8.43(m, 1H), 7.85-7.88(m, 1H), 7.68-7.78(m, 2H), 7.30-7.40(m, 3H), 7.22(d, J=7.9 Hz, 1H), 6.93(d, J=7.9 Hz, 1H), 4.21(t, J=7.1 Hz, 2H), 3.50(d, J=12.6 Hz, 2H), 3.07(d, J=11.1 Hz, 2H), 2.79(t, J=12.0 Hz, 2H), 2.51(t, J=7.1 Hz, 2H), 2.40-2.46(m, 1H), 2.17(s, 3H), 1.96-2.11(m, 4H), 1.72-1.80(m, 4H), 1.54-1.64(m, 1H), 1.41-1.53(m, 2H), 1.04(d, J=6.2 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3 )? 8.41-8.43 (m, IH), 7.85-7.88 (m, IH), 7.68-7.78 (m, 2H), 7.30-7.40 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.21 2H), 2.79 (t, J = 12.0 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H), 2.40-2.46 (m, 2H), 1.04 (d, J = 6.2 Hz, 3H), 2.11 (m, 4H), 1.72-1.80 (m, 4H), 1.54-1.64

<< 실시예Example 26> 4-(3- 26> 4- (3- 메틸피페리딘Methylpiperidine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00112
Figure 112011081771684-pat00112

4-(3-메틸-피페리딘-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(62 mg, 0.19 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(53 mg, 0.11 mmol, 55%)의 표제 화합물을 얻었다. The title compound was prepared in the same manner as in Example 1, except for using 4- (3-methyl-piperidin-l-yl) -2- (3- chloropropyl) -2H- phthalazin- 1 to give the title compound (53 mg, 0.11 mmol, 55%).

Rf=0.28(10% MeOH in MC)Rf = 0.28 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.41-8.43(m, 1H), 7.87(d, J=7.6 Hz, 1H), 7.69-7.79(m, 2H), 7.47(s, 1H), 7.40(d, J=7.6 Hz, 1H), 7.30(s, 1H), 7.22(d, J=7.6 Hz, 1H), 6.93(d, J=7.6 Hz, 1H), 4.22(t, J=7.1 Hz, 2H), 3.43(t, J=12.5 Hz, 2H), 3.08(d, J=11.3 Hz, 2H), 2.69-2.76(m, 1H), 2.42-2.55(m, 4H), 2.18(S, 3H), 2.05-2.15(m, 4H), 1.74-1.96(m, 8H), 1.10-1.15(m, 1H), 0.97(d, J=6.2 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.41-8.43 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.69-7.79 (m, 2H), 7.47 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.93 2H), 2.43-2.56 (m, 4H), 2.18 (s, 2H), 3.43 (t, J = 12.5 Hz, 2H) 3H), 2.05-2.15 (m, 4H), 1.74-1.96 (m, 8H), 1.10-1.15

<< 실시예Example 27> 4-(4- 27> 4- (4- 옥소피페리딘Oxopiperidine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00113
Figure 112011081771684-pat00113

4-(4-옥소피페리딘-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(53 mg, 0.17 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(35 mg, 0.07 mmol, 42%)의 표제 화합물을 얻었다. The procedure of Example 1 was repeated except for using 4- (4-oxopiperidin-l-yl) -2- (3-chloropropyl) -2H- phthalazin- (35 mg, 0.07 mmol, 42%) of the title compound.

Rf=0.36(10% MeOH in MC)*2Rf = 0.36 (10% MeOH in MC) * 2

1H-NMR(300 MHz, CDCl3) δ 8.46-8.48(m, 1H), 7.91-7.93(m, 1H), 7.75-7.84(m, 2H), 7.36-7.41(m, 2H), 7.32(s, 1H), 7.22(d, J=7.7 Hz, 1H), 6.92(d, J=7.5 Hz, 1H), 4.23(t, J=7.2 Hz, 2H), 3.56(t, J=6.0 Hz, 4H), 3.08(d, J=11.5 Hz, 2H), 2.69(t, J=6.0 Hz, 4H), 2.52(t, J=7.2 Hz, 2H), 2.43-2.48(m, 1H), 2.17(s, 3H), 2.00-2.13(m, 4H), 1.71-1.82(m, 4H)
1 H-NMR (300 MHz, CDCl 3) δ 8.46-8.48 (m, 1H), 7.91-7.93 (m, 1H), 7.75-7.84 (m, 2H), 7.36-7.41 (m, 2H), 7.32 ( J = 7.6 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H) 2H), 2.69 (t, J = 6.0 Hz, 4H), 3.08 (d, J = s, 3H), 2.00-2.13 (m, 4H), 1.71-1.82 (m, 4H)

<< 실시예Example 28> 4-(4- 28 > 4- (4- 클로로피페리딘Chloropiperidine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00114
Figure 112011081771684-pat00114

4-(4-클로로피페리딘-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(74 mg, 0.22 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(43 mg, 0.082 mmol, 38%)의 표제 화합물을 얻었다. The procedure of Example 1 was followed except that 4- (4-chloropiperidin-l-yl) -2- (3-chloropropyl) -2H- phthalazin- (43 mg, 0.082 mmol, 38%) of the title compound.

Rf=0.30(10% MeOH in MC)Rf = 0.30 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.45(m, 1H), 7.71-7.85(m, 3H), 7.37-7.39(m, 2H), 7.31(s, 1H), 7.22(d, J=7.7 Hz, 1H), 6.93(d, J=7.7 Hz, 1H), 4.27-4.29(m, 1H), 4.22(t, J=7.0 Hz, 2H), 3.45-3.51(m, 2H), 3.02-3.10(m, 4H), 2.54(t, J=7.0 Hz, 2H), 2.41-2.49(m, 1H), 2.26-2.34(m, 2H), 2.17(s, 3H), 2.03-2.16(m, 6H), 1.79-1.81(m, 4H)
1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.45 (m, 1H), 7.71-7.85 (m, 3H), 7.37-7.39 (m, 2H), 7.31 (s, 1H), 7.22 (d, J = 7.7 Hz, 1 H), 6.93 (d, J = 7.7 Hz, 1 H), 4.27-4.29 (m, 2H), 2.41-2.49 (m, 1H), 2.26-2.34 (m, 2H), 2.17 (s, 3H), 2.03-2.16 (m, m, 6H), 1.79-1.81 (m, 4H)

<< 실시예Example 29> 4-[4-(t- 29> 4- [4- (t- 부톡시카보닐Butoxycarbonyl )피페라진-1-일]-2-[3-[4-[3-() Piperazin-1-yl] -2- [3- [4- [3- ( 아세틸아미Acetylamino 노)furnace) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00115
Figure 112011081771684-pat00115

4-[4-(t-부톡시카보닐)피페라진-1-일]-2-(3-클로로프로필)-2H-프탈라진-1-온(75 mg, 0.19 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(30 mg, 0.051 mmol, 28%)의 표제 화합물을 얻었다. 2- (3-chloropropyl) -2H-phthalazin-1-one (75 mg, 0.19 mmol) was used in place of 4- [4- (t-butoxycarbonyl) piperazin- (30 mg, 0.051 mmol, 28%) of the title compound were obtained by a similar method to that of Example 1.

Rf=0.22(10% MeOH in MC)Rf = 0.22 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.43-8.46(m, 1H), 7.85-7.90(m, 1H), 7.73-7.82(m, 2H), 7.42-7.45(m, 1H), 7.31(s, 2H), 7.22-7.26(m, 1H), 6.94(d, J=7.3 Hz, 1H), 4.23(t, J=6.5 Hz, 2H), 3.62-3.70(m, 4H), 3.11-3.22(m, 6H), 2.58-2.67(m, 2H), 2.49-2.55(m, 1H), 2.19(s, 3H), 2.12-2.25(m, 4H), 1.79-1.97(m, 4H), 1.51(s, 9H)
1 H-NMR (300 MHz, CDCl 3) δ 8.43-8.46 (m, 1H), 7.85-7.90 (m, 1H), 7.73-7.82 (m, 2H), 7.42-7.45 (m, 1H), 7.31 ( (m, 2H), 7.22-7.26 (m, 1H), 6.94 (d, J = 7.3 Hz, 1H) (m, 4H), 1.79-1.97 (m, 4H), 1.51 (m, 2H), 2.58-2.67 (s, 9 H)

<< 실시예Example 30> 4-(피페라진-1-일)-2-[3-[4-[3-( 30> 4- (Piperazin-1-yl) -2- [3- [4- [3- 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00116
Figure 112011081771684-pat00116

상기 실시예 29에서 얻은 화합물(30 mg, 0.051 mmol)을 실시예 8과 동일한 방법으로 처리하여(26 mg, 0.05 mmol, 98%)의 표제 화합물을 얻었다. The compound (30 mg, 0.051 mmol) obtained in Example 29 was treated in the same manner as in Example 8 to give the title compound (26 mg, 0.05 mmol, 98%).

1H-NMR(300 MHz, MeOH-d4) δ 8.41-8.43(m, 1H), 8.05-8.08(m, 1H), 7.90-7.98(m, 2H), 7.66(s, 1H), 7.25-7.28(m, 2H), 7.00-7.02(m, 1H), 4.28-4.35(m, 2H), 3.64-3.74(m, 2H), 3.46-3.59(m, 10H), 3.06-3.23(m, 2H), 2.84-2.93(m, 1H), 2.32-2.40(m, 2H), 2.12(s, 3H), 1.99-2.06(m, 4H)
1 H-NMR (300 MHz, MeOH-d 4 )? 8.41-8.43 (m, 1 H), 8.05-8.08 (m, 1 H), 7.90-7.98 2H), 3.64-3.54 (m, 10H), 3.06-3.23 (m, 2H), 7.28 (m, 2H), 7.00-7.02 ), 2.84-2.93 (m, 1 H), 2.32-2.40 (m, 2H), 2.12 (s, 3H), 1.99-2.06

<< 실시예Example 31> 4-(4- 31> 4- (4- 메틸피페라진Methylpiperazine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00117
Figure 112011081771684-pat00117

4-(4-메틸피페라진-1-일)-2-(3-클로로프로필)-2H-프탈라진-1-온(58 mg, 0.18 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(26 mg, 0.05 mmol, 29%)의 표제 화합물을 얻었다. The procedure of Example 1 was repeated except that 4- (4-methylpiperazin-1-yl) -2- (3-chloropropyl) -2H- phthalazin- Reaction in a similar manner (26 mg, 0.05 mmol, 29%) of the title compound was obtained.

Rf=0.58(10% MeOH in MC)Rf = 0.58 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.43-8.45(m, 1H), 7.86-7.89(m, 1H), 7.70-7.79(m, 2H), 7.48-7.56(m, 1H), 7.39(d, J=7.6 Hz, 1H), 7.30(s, 1H), 7.22(d, J=7.6 Hz, 1H), 6.91(d, J=7.4 Hz, 1H), 4.22(t, J=7.0 Hz, 2H), 3.29(m, 4H), 3.03(d, J=10.8 Hz, 2H), 2.66(m, 4H), 2.48(t, J=7.0 Hz, 2H), 2.43-2.44(m, 1H), 2.40(s, 3H), 2.18(s, 3H), 1.96-2.11(m, 4H), 1.67-1.79(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.43-8.45 (m, 1H), 7.86-7.89 (m, 1H), 7.70-7.79 (m, 2H), 7.48-7.56 (m, 1H), 7.39 ( J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H) 2H), 3.29 (m, 4H), 3.03 (d, J = 10.8 Hz, 2H), 2.66 (m, 4H) 3H), 2.18 (s, 3H), 1.96-2.11 (m, 4H), 1.67-1.79 (m, 4H)

<< 실시예Example 32> 4-[4-( 32> 4- [4- ( 메톡시카보닐Methoxycarbonyl )피페리딘-1-일]-2-[3-[4-[3-() Piperidin-1-yl] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )페닐]피페리딘-1-일]프로필]-1(2H)-) Phenyl] piperidin-1-yl] propyl] -1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00118
Figure 112011081771684-pat00118

4-[4-(메톡시카보닐)피페리딘-1-일]-2-(3-클로로프로필)-2H-프탈라진-1-온(111 mg, 0.30 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(70 mg, 0.13 mmol, 42%)의 표제 화합물을 얻었다. Except that 111 mg (0.30 mmol) of 4- [4- (methoxycarbonyl) piperidin-1-yl] -2- (3- chloropropyl) -2H- phthalazin- (70 mg, 0.13 mmol, 42%) of the title compound were obtained by reaction in a similar manner to Example 1.

Rf=0.32(10% MeOH in MC)Rf = 0.32 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.44(m, 1H), 7.84-7.86(m, 1H), 7.72-7.80(m, 2H), 7.47(s, 1H), 7.40(d, J=7.9 Hz, 1H), 7.31(s, 1H), 7.22(d, J=7.9 Hz, 1H), 6.93(d, J=7.2 Hz, 1H), 4.21(t, J=6.9 Hz, 2H), 3.74(s, 3H), 3.53(d, J=13.0 Hz, 2H), 3.09(d, J=11.1 Hz, 2H), 2.87(td, J=10.7, 3.0 Hz, 2H), 2.47-2.56(m, 4H), 2.18(s, 3H), 1.98-2.10(m, 8H), 1.78-1.81(m, 4H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.44 (m, 1H), 7.84-7.86 (m, 1H), 7.72-7.80 (m, 2H), 7.47 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H) , 3.74 (s, 3H), 3.53 (d, J = 13.0 Hz, 2H), 3.09 (d, J = 11.1 Hz, 2H), 2.87 (td, J = 10.7, 3.0 Hz, 2H), 2.47-2.56 (m, 4H), 2.18 (s, 3H), 1.98-2.10 (m, 8H), 1.78-1.81

<< 실시예Example 33> 4-[4- 33> 4- [4- 카르복시피페리딘Carboxypiperidine -1-일]-2-[3-[4-[3-(-1-yl] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00119
Figure 112011081771684-pat00119

상기 실시예 32에서 얻은 화합물(64 mg, 0.12 mmol)을 메탄올(3 ml)용매에 녹인뒤, 2N 소듐 하이드록사이드 용액(0.18 mmol, 0.088 ml)을 첨가한뒤 50도에서 10시간 가열하였다. 반응이 완결된뒤, 용매를 완전히 제거한뒤, 1N HCl(3 ml)로 산성화 시키고 에틸 아세테이트(10 ml)로 두 번 추출하고, 포화염화나트륨 용액(10 ml)로 세척하였다. 무수황산마그네슘(MgSO4)으로 건조시킨후 감압 농축시켜(14 mg, 0.04 mmol, 17%)의 표제 화합물을 얻었다. The compound (64 mg, 0.12 mmol) obtained in Example 32 was dissolved in methanol (3 ml), 2N sodium hydroxide solution (0.18 mmol, 0.088 ml) was added, and the mixture was heated at 50 ° C for 10 hours. After the reaction was complete, the solvent was removed completely, then acidified with 1N HCl (3 ml), extracted twice with ethyl acetate (10 ml), and washed with saturated sodium chloride solution (10 ml). The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure to obtain the title compound (14 mg, 0.04 mmol, 17%).

1H-NMR(300 MHz, MeOH-d4) δ 8.28(d, J=8.0 Hz, 1H), 7.74-8.00(m, 4H), 7.52(s, 1H), 7.14-7.23(m, 2H), 6.92(d, J=6.6 Hz, 1H), 4.21(t, J=6.3 Hz, 2H), 3.58-3.63(m, 2H), 3.48-3.52(m, 2H), 3.14-3.17(m, 2H), 3.03(t, J=12.3 Hz, 2H), 2.87(t, J=10.8 Hz, 2H), 2.74-2.82(m, 1H), 2.42-2.51(m, 1H), 2.24-2.28(m, 2H), 2.03(s, 3H), 1.84-2.01(m, 8H)
 1 H-NMR (300 MHz, MeOH-d 4) δ 8.28 (d, J = 8.0 Hz, 1H), 7.74-8.00 (m, 4H), 7.52 (s, 1H), 7.14-7.23 (m, 2H) , 6.92 (d, J = 6.6 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.58-3.63 (m, 2H), 3.48-3.52 (m, 2H), 3.14-3.17 2H), 2.74-2.82 (m, 1H), 2.42-2.51 (m, 1H), 2.24-2.28 (m, 1H), 3.03 (t, J = 2H), 2.03 (s, 3H), 1.84-2.01 (m, 8H)

<< 실시예Example 34> 4-[3-( 34> 4- [3- ( 에톡시카보닐Ethoxycarbonyl )피페리딘-1-일]-2-[3-[4-[3-() Piperidin-1-yl] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )페닐]피페리딘-1-일]프로필]-1(2H)-) Phenyl] piperidin-1-yl] propyl] -1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00120
Figure 112011081771684-pat00120

4-[3-(에톡시카보닐)피페리딘-1-일]-2-(3-클로로프로필)-2H-프탈라진-1-온(127 mg, 0.336 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(69 mg, 0.12 mmol, 37%)의 표제 화합물을 얻었다. Except using 127 mg (0.336 mmol) of 4- [3- (ethoxycarbonyl) piperidin-1-yl] -2- (3- chloropropyl) -2H- phthalazin- (69 mg, 0.12 mmol, 37%) was obtained as a white solid.

Rf=0.5(10% MeOH in MC)Rf = 0.5 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.42-8.44(m, 1H), 7.89-7.91(m, 1H), 7.70-7.80(m, 2H), 7.39-7.42(m, 2H), 7.29(s, 1H), 7.23(d, J=7.9 Hz, 1H), 6.93(d, J=7.2 Hz, 1H), 4.22(t, J=7.0 Hz, 2H), 4.13-4.20(m, 2H), 3.55-3.66(m, 1H), 3.35-3.39(m, 1H), 3.14-3.18(m, 1H), 3.06-3.11(m, 2H), 2.79-2.93(m, 2H), 2.53(t, J=7.0 Hz, 2H), 2.43-2.48(m, 1H), 2.18(s, 3H), 2.02-2.15(m, 4H), 1.73-1.92(m, 4H), 1.27(t, J=7.2 Hz, 3H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.42-8.44 (m, 1H), 7.89-7.91 (m, 1H), 7.70-7.80 (m, 2H), 7.39-7.42 (m, 2H), 7.29 ( J = 7.0 Hz, 2H), 4.13-4.20 (m, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.53 (m, 2H), 2.53 (m, 2H), 2.53 (m, 1H), 3.35-3.39 = 7.0 Hz, 2H), 2.43-2.48 (m, 1H), 2.18 (s, 3H), 2.02-2.15 (m, 4H), 1.73-1.92 3H)

<< 실시예Example 35> 4-[3- 35> 4- [3- 카르복시피페리딘Carboxypiperidine -1-일]-2-[3-[4-[3-(-1-yl] -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00121
Figure 112011081771684-pat00121

상기 실시예 34에서 얻은 화합물(59 mg, 0.11 mmol)을 실시예 33과 동일한 방법으로 처리하여(29 mg, 0.055 mmol, 52%)의 표제 화합물을 얻었다. The compound (59 mg, 0.11 mmol) obtained in Example 34 was treated in the same manner as in Example 33 to give the title compound (29 mg, 0.055 mmol, 52%).

1H-NMR(300 MHz, MeOH-d4) δ 8.38(d, J=7.0 Hz, 1H), 8.07(d, J=8.1 Hz, 1H), 7.86-7.96(m, 3H), 7.63(s, 1H), 7.27-7.29(m, 2H), 7.01(d, J=7.0 Hz, 1H), 4.28-4.30(m, 2H), 3.59-3.71(m, 3H), 3.44-3.48(m, 1H), 3.09-3.25(m, 4H), 2.83-2.95(m, 3H), 2.34-2.38(m, 2H), 2.12(s, 3H), 1.77-2.07(m, 9H)
1 H-NMR (300 MHz, MeOH-d 4) δ 8.38 (d, J = 7.0 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.86-7.96 (m, 3H), 7.63 (s 1H), 7.27-7.29 (m, 2H), 7.01 (d, J = 7.0 Hz, 1H), 4.28-4.30 (m, 2H), 3.59-3.71 (m, 3H), 3.44-3.48 ), 3.09-3.25 (m, 4H), 2.83-2.95 (m, 3H), 2.34-2.38

<< 실시예Example 36> 4-[[4-(t- 36 > 4 - [[4- (t- 부톡시카보닐Butoxycarbonyl )아미노]피페리딘-1-일]-2-[3-[4-[3-() Amino] piperidin-1-yl] -2- [3- [4- [3- ( 아Ah 세틸아미노)Cetylamino) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00122
Figure 112011081771684-pat00122

4-[[4-(t-부톡시카보닐)아미노]피페리딘-1-일]-2-(3-클로로프로필)-2H-프탈라진-1-온(81 mg, 0.19 mmol)을 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 반응하여(45 mg, 0.075 mmol, 39%)의 표제 화합물을 얻었다. 2- (3-chloropropyl) -2H-phthalazin-1-one (81 mg, 0.19 mmol) was added to a solution of 4 - [[4- (t-butoxycarbonyl) amino] piperidin- (45 mg, 0.075 mmol, 39%) of the title compound were obtained.

Rf=0.22(10% MeOH in MC)Rf = 0.22 (10% MeOH in MC)

1H-NMR(300 MHz, CDCl3) δ 8.43(d, J=7.2 Hz, 1H), 7.71-7.84(m, 3H), 7.39-7.44(m, 2H), 7.29(s, 1H), 7.21-7.23(m, 1H), 6.94(d, J=7.6 Hz, 1H), 4.65-4.67(m, 0.5H), 4.22(t, J=6.5 Hz, 2H), 3.65-3.73(m, 0.5H), 3.49(d, J=12.6 Hz, 2H), 3.15(d, J=11.0 Hz, 2H), 2.95(t, J=6.5 Hz, 2H), 2.55-2.62(m, 2H), 2.47-2.54(m, 1H), 2.18(s, 3H), 2.01-2.17(m, 6H), 1.78-1.97(m, 4H), 1.62-1.72(m, 2H), 1.47(s, 9H)
 1 H-NMR (300 MHz, CDCl 3) δ 8.43 (d, J = 7.2 Hz, 1H), 7.71-7.84 (m, 3H), 7.39-7.44 (m, 2H), 7.29 (s, 1H), 7.21 J = 6.5 Hz, 2H), 3.65-3.73 (m, 0.5H), 7.22 (m, 2H), 2.45 (t, J = 6.5 Hz, 2H), 2.55-2.62 (m, 2H), 2.47-2.54 (m, 2H), 1.47 (s, 9H), 2.18 (s, 3H), 2.01-2.17 (m, 6H), 1.78-1.97

<< 실시예Example 37> 4-(4- 37> 4- (4- 아미노피페리딘Aminopiperidine -1-일)-2-[3-[4-[3-(Yl) -2- [3- [4- [3- ( 아세틸아미노Acetylamino )) 페닐Phenyl ]피페리딘-1-일]프로필]-1(2H)-] Piperidin-1-yl] propyl] - 1 (2H) - 프탈라지논의Phthalazinone 제조 Produce

Figure 112011081771684-pat00123
Figure 112011081771684-pat00123

상기 실시예 36에서 얻은 화합물(34 mg, 0.056 mmol)를 실시예 8과 동일한 방법으로 처리하여(29 mg, 0.054 mmol, 96%)의 표제 화합물을 얻었다. The compound (34 mg, 0.056 mmol) obtained in Example 36 was treated in the same manner as in Example 8 to give the title compound (29 mg, 0.054 mmol, 96%).

1H-NMR(300 MHz, MeOH-d4) δ 8.39-8.41(m, 1H), 7.88-8.02(m, 3H), 7.66(s, 1H), 7.25-7.28(m, 2H), 7.00-7.04(m, 1H), 4.30(t, J=6.1 Hz, 2H), 3.68-3.76(m, 3H), 3.66(m, 2H), 3.59(m, 2H), 3.07-3.22(m, 2H), 2.94-3.03(m, 2H), 2.85-2.90(m, 1H), 2.32-2.40(m, 2H), 2.12(s, 3H), 1.90-2.10(m, 8H)
1 H-NMR (300 MHz, MeOH-d 4) δ 8.39-8.41 (m, 1H), 7.88-8.02 (m, 3H), 7.66 (s, 1H), 7.25-7.28 (m, 2H), 7.00- 2H), 3.07-3.22 (m, 2H), 3.50 (m, 2H), 3.50 (m, , 2.94-3.03 (m, 2H), 2.85-2.90 (m, 1H), 2.32-2.40 (m, 2H)

<< 실험예Experimental Example 1>  1> 프탈라지논Phthalazineon 유도체의  Derivative MCHMCH 수용체-1 결합 억제활성 측정 Measurement of receptor-1 binding inhibition activity

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, 발명에 따른 프탈라지논 유도체의 MCH 수용체-1 결합 억제 활성을 확인하기 위하여 하기와 같은 실험을 수행하였다.
The following experiments were conducted to confirm the activity of the phthalazinone derivatives according to the present invention to inhibit MCH receptor-1 binding.

먼저, 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. First, two kinds of buffer solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (0.5% BSA in washing solution) were prepared and MCH receptor-1 (Europium-labeled MCH, Eu-MCH) labeled with 1 μM Europium, PerkinElmer, Turku, Finland) and 1 mM melanin-enriched hormone (melanin-enriched hormone receptor subtype-1; Euroscreen, Gosselies, Belgium) (MCH, # 070-47, Phoenix, Belmont CA, USA) 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 37의 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 37 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. After that, it was shaken 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. Bottom water was wiped off and the solution was added with DELFIA Enhancement solution (PerkinElmer, Turku, Finland) to 150 μl per well. 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 112011081771684-pat00124
Figure 112011081771684-pat00124

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 4040 실시예 2Example 2 3030 실시예 3Example 3 19801980 실시예 4Example 4 11001100 실시예 5Example 5 > 1000> 1000 실시예 6Example 6 3030 실시예 7Example 7 920920 실시예 8Example 8 > 1000> 1000 실시예 9Example 9 6060 실시예 10Example 10 3030 실시예 11Example 11 8080 실시예 12Example 12 5050 실시예 13Example 13 1010 실시예 14Example 14 > 1000> 1000 실시예 15Example 15 350350 실시예 16Example 16 3030 실시예 17Example 17 760760 실시예 18Example 18 190190 실시예 19Example 19 250250 실시예 20Example 20 490490 실시예 21Example 21 9090 실시예 22Example 22 110110 실시예 23Example 23 55 실시예 24Example 24 3030 실시예 25Example 25 620620 실시예 26Example 26 260260 실시예 27Example 27 6060 실시예 28Example 28 190190 실시예 29Example 29 320320 실시예 30Example 30 > 1000> 1000 실시예 31Example 31 > 1000> 1000 실시예 32Example 32 390390 실시예 33Example 33 > 1000> 1000 실시예 34Example 34 > 150> 150 실시예 35Example 35 > 1000> 1000 실시예 36Example 36 960960 실시예 37Example 37 > 1000> 1000

상기 표 2에 나타낸 바와 같이, 본 발명에 따른 프탈라지논 유도체 중 실시예 1, 2, 6, 10, 12, 13, 16, 23, 24의 화합물이 IC50 값이 50 nM 이하 농도에서 MCH 수용체-1에 대하여 길항작용을 하는 것으로 확인되었으며, 특히, 본 발명의 실시예 23의 화합물은 IC50 값이 5 nM로 매우 우수한 MCH 수용체-1에 대하여 길항작용을 하는 것으로 확인되었다.Compounds of Examples 1, 2, 6, 10, 12, 13, 16, 23, and 24 among the phthalazinone derivatives according to the present invention had an IC 50 value of 50 nM or less, -1, and in particular, the compound of Example 23 of the present invention was found to antagonize MCH receptor-1 with an IC 50 value of 5 nM, which is very excellent.

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 프탈라지논 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 phthalazinone derivatives represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. Hereinafter, some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient are exemplified, and the present invention is not limited thereto.

<< 제제예Formulation example 1>  1> 산제의Sanje 제조 Produce

화학식 1의 프탈라지논 유도체 2 g2 g of the phthalazinone derivative of the formula (1)

유당 1 gLactose 1 g

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 프탈라지논 유도체 100 ㎎100 mg of the phthalazinone derivative of the 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 프탈라지논 유도체 100 ㎎100 mg of the phthalazinone derivative of the 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 프탈라지논 유도체 100 ㎎100 mg of the phthalazinone derivative of the formula (1)

만니톨 180 ㎎180 mg mannitol

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

증류수 2974 ㎎2974 mg of distilled water

통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.
According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

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

화학식 1의 프탈라지논 유도체 1000 ㎎1000 mg of the phthalazinone derivative of the formula (1)

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 프탈라지논 유도체 1000 ㎎1000 mg of the phthalazinone derivative of the formula (1)

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 relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, demand country, use purpose, and the like.

<< 제제예Formulation example 7> 기타 건강식품의 제조 7> Manufacture of other health food

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

꿀 522 ㎎Honey 522 mg

치옥토산아미드 5 ㎎5 mg &lt; RTI ID = 0.0 &gt;

니코틴산아미드 10 ㎎Nicotinic acid amide 10 mg

염산리보플라빈나트륨 3 ㎎3 mg of sodium riboflavin hydrochloride

염산피리독신 2 ㎎Pyridoxine hydrochloride 2 mg

이노시톨 30 ㎎Inositol 30 mg

오르트산 50 ㎎Orthoic acid 50 mg

화학식 1의 프탈라지논 유도체 0.48~1.28 ㎎0.48 to 1.28 mg of the phthalazinone derivative of the formula (1)

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 프탈라지논 유도체 0.24~0.64 %Phthalazinone derivative of formula (1) 0.24 to 0.64%

후르츠향 1 %Fruit flavor 1%

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 프탈라지논 유도체 0.24~0.64 %Phthalazinone derivative of formula (1) 0.24 to 0.64%

오렌지향 0.1 %
Orange fragrance 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 프탈라지논 유도체를 0.5 내지 5 중량부를 밀가루 100 중량부에 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.
0.5 to 5 parts by weight of a phthalazinone derivative represented by the formula (1) was added to 100 parts by weight of wheat flour, and bread, cake, cookies, crackers and noodles were prepared by using this mixture to prepare health improving foods.

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

화학식 1의 프탈라지논 유도체를 5 내지 10 중량부를 우유 100 중량부에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.
5-10 parts by weight of the phthalazinone derivative of the formula (1) was added to 100 parts by weight of milk, and various dairy 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 프탈라지논 유도체를 다음과 같은 비율로 배합하여 제조하였다.
Brown rice, barley, glutinous rice, and yulmu were alphalized by a known method and dried, and the powder was made into a powder having a particle size of 60 mesh by a pulverizer. Black beans, black sesame seeds, and perilla seeds were steamed and dried by a known method, and then powdered with a particle size of 60 meshes by a grinder. The grains and seeds prepared above and the phthalazinone derivatives of formula (I) of the present invention were prepared in the following proportions.

현미 30 % Brown rice 30%

율무 15 %Yulmu 15%

보리 20 %Barley 20%

들깨 7 % Perilla 7%

검정콩 7 % Black soybeans 7%

검은깨 7 %Black sesame 7%

화학식 1의 프탈라지논 유도체 3 %Phthalazinone derivatives of formula (1) 3%

영지 0.5 %Manure 0.5%

지황 0.5 %0.5%

Claims (9)

하기 화학식 1로 표시되는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
Figure 112013114300221-pat00125

(상기 화학식 1에서,
A는 탄소(C), 질소(N), 산소(O), 황(S) 및 설폰(SO2)으로 이루어진 군으로부터 선택되는 1종이고;
R1 및 R2는 독립적으로 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸,
Figure 112013114300221-pat00137
,
Figure 112013114300221-pat00138
,
Figure 112013114300221-pat00139
,
Figure 112013114300221-pat00140
,
Figure 112013114300221-pat00141
,
Figure 112013114300221-pat00142
,
Figure 112013114300221-pat00143
,
Figure 112013114300221-pat00144
,
Figure 112013114300221-pat00145
및
Figure 112013114300221-pat00146
로 이루어지는 군으로부터 선택되는 1종이고,
이때, 상기 A가 O, S 또는 SO2인 경우, R2는 부재이고;
상기 A가 N인 경우, R1 및 R2는 함께 비치환 또는 클로로, 플루오로, 브로모, 옥소, 카르복시, 메톡시카보닐, 에톡시카보닐, 프로폭시카보닐, 부톡시카보닐, t-부톡시카보닐, 아미노 및 t-부톡시카보닐아미노로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 치환되는 피롤리딘, 몰폴린, 싸이오몰포린, 피페리딘 또는 피페라진을 형성할 수 있다).
1. A novel phthalazinone derivative represented by the following formula (1): or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure 112013114300221-pat00125

(In the formula 1,
A is one species selected from the group consisting of carbon (C), nitrogen (N), oxygen (O), sulfur (S) and sulfone (SO 2 );
R 1 and R 2 are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Figure 112013114300221-pat00137
,
Figure 112013114300221-pat00138
,
Figure 112013114300221-pat00139
,
Figure 112013114300221-pat00140
,
Figure 112013114300221-pat00141
,
Figure 112013114300221-pat00142
,
Figure 112013114300221-pat00143
,
Figure 112013114300221-pat00144
,
Figure 112013114300221-pat00145
And
Figure 112013114300221-pat00146
And one species selected from the group consisting of
When A is O, S or SO 2 , R 2 is a member;
When A is N, then R 1 and R 2 together are an unsubstituted or substituted group selected from chloro, fluoro, bromo, oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t Pyrrolidine, morpholine, thiomorpholine, piperidine or piperazine substituted with at least one substituent selected from the group consisting of -O-, -butoxycarbonyl, amino and t-butoxycarbonylamino ).
삭제delete 제1항에 있어서, 상기 화학식 1의 유도체는:
(1) 4-벤질-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(2) 4-(4-클로로벤질)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(3) 4-[2-(피리딘-4-일)에틸]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(4) 4-[2-(피리딘-2-일)에틸]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(5) 4-[2-(피리딘-3-일)에틸]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(6) 4-(4-클로로페녹시)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(7) 4-[[1-(t-부톡시카보닐)피페리딘-4-일]옥시]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(8) 4-[피페리딘-4-일옥시]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(9) 4-[(4-클로로페닐)싸이오]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(10) 4-페닐설포닐-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(11) 4-[(4-메틸페닐)설포닐]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(12) 4-[(4-클로로페닐)설포닐]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(13) 4-[(4-클로로페닐)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(14) 4-[(피리딘-4-일)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(15) 4-[(피리딘-2-일메틸)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(16) 4-사이클로헥실아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(17) 4-[메틸(페닐)아미노]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(18) 4-다이에틸아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(19) 4-다이프로필아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(20) 4-다이아이소부틸아미노-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(21) 4-(피롤리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(22) 4-(몰포린-4-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(23) 4-(싸이오몰포린-4-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(24) 4-(피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(25) 4-(4-메틸피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(26) 4-(3-메틸피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(27) 4-(4-옥소피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(28) 4-(4-클로로피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(29) 4-[4-(t-부톡시카보닐)피페라진-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(30) 4-(피페라진-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(31) 4-(4-메틸피페라진-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(32) 4-[4-(메톡시카보닐)피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(33) 4-[4-카르복시피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(34) 4-[3-(에톡시카보닐)피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(35) 4-[3-카르복시피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논;
(36) 4-[[4-(t-부톡시카보닐)아미노]피페리딘-1-일]-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논; 및
(37) 4-(4-아미노피페리딘-1-일)-2-[3-[4-[3-(아세틸아미노)페닐]피페리딘-1-일]프로필]-1(2H)-프탈라지논으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1, wherein the derivative of formula (1)
(1) 4-Benzyl-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(2) 4- (4-Chlorobenzyl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
Yl] propyl] - 1 (2H) -quinolin-2-one hydrochloride (3) Synthesis of 4- [2- (pyridin- - phthalazinone;
Yl] propyl] - 1 (2H) -quinolinone. (4) Synthesis of 4- [2- (pyridin- - phthalazinone;
Yl] propyl] - 1 (2H) -quinolinone (5) 4- [2- (pyridin- - phthalazinone;
(6) 4- (4-Chlorophenoxy) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(7) Synthesis of 4 - [[1- (t-butoxycarbonyl) piperidin-4-yl] oxy] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -Yl] propyl] -1 (2H) -phthalazinone;
(8) 4- [Piperidin-4-yloxy] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- 1 -yl] Thalasinone;
(9) Synthesis of 4 - [(4-chlorophenyl) thio] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Thalasinone;
(10) 4-Phenylsulfonyl-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(11) 4- [(4-methylphenyl) sulfonyl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Zinon;
(12) 4 - [(4-chlorophenyl) sulfonyl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Thalasinone;
(13) 4-r4- (4-chlorophenyl) amino] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Zinon;
(14) 4 - [(pyridin-4-yl) amino] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Thalasinone;
Yl] propyl] - (1 H) - [2- (3-fluorophenyl) piperidin- Phthalazinone;
(16) 4-Cyclohexylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(17) 4- [methyl (phenyl) amino] -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(18) 4-Diethylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(19) 4-dipropylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(20) 4-Diisobutylamino-2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazine;
(21) 4- (pyrrolidin-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Zinon;
(22) Synthesis of 4- (morpholin-4-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- ;
(23) 4- (thiomorpholin-4-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- 1- yl] Zinon;
(24) 4- (Piperidin-l-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- 1- yl] Zinon;
(25) 4- (4-methylpiperidin- 1 -yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone;
Yl] propyl] - 1 (2H) -pyridin-2-yl] - (2- - phthalazinone;
Yl] propyl] - 1 (2H) -quinolin-2-one (27) 4- (4-oxopiperidin- - phthalazinone;
Yl] propyl] - 1 (2H) -pyridin-2-ylmethyll-2- - phthalazinone;
(29) Synthesis of 4- [4- (t-butoxycarbonyl) piperazin-1-yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- ] -1 (2H) -phthalazinone;
(30) A mixture of 4- (piperazin-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- ;
(31) 4- (4-methylpiperazin-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- Phthalazinone;
(32) 4- [4- (methoxycarbonyl) piperidin-1-yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -1 (2H) -phthalazinone;
(33) 4- [4-carboxypiperidin- 1 -yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone;
(34) 4- [3- (ethoxycarbonyl) piperidin-1-yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -1 (2H) -phthalazinone;
(35) 4- [3-carboxypiperidin- 1 -yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone;
(36) 4 - [[4- (t-butoxycarbonyl) amino] piperidin- 1 -yl] -2- [3- [4- [3- (acetylamino) phenyl] piperidin- -Yl] propyl] -1 (2H) -phthalazinone; And
(37) 4- (4-aminopiperidin-l-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin- - phthalazinone, or a pharmacologically acceptable salt thereof. 10. The phthalazinone derivative according to claim 1, wherein R &lt; 1 &gt;
하기 반응식 1에 나타난 바와 같이,
화학식 2로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 3으로 표시되는 피페리딘 화합물과 알킬화 반응을 시켜 화학식 1로 표시되는 화합물을 얻는 단계를 포함하는 것을 특징으로 하는 제1항의 신규한 프탈라지논 유도체의 제조방법:
[반응식 1]
Figure 112011081771684-pat00136

(상기 반응식 1에서 A, R1 및 R2는 제1항의 화학식 1에서 정의한 바와 같고, L은 이탈기로써, 메실레이트, 토실레이트 또는 할로겐이다).
As shown in Scheme 1 below,
The novel phthalazinone compound of claim 1, which comprises a step of subjecting a compound represented by the formula (2) to an alkylation reaction with a piperidine compound represented by the formula (3) under an organic solvent and a base to obtain a compound represented by the formula Preparation of derivatives:
[Reaction Scheme 1]
Figure 112011081771684-pat00136

(Wherein A, R 1 and R 2 are as defined in formula (1) of claim 1, and L is a leaving group, mesylate, tosylate or halogen.
제1항에 있어서,
상기 화학식 1로 표시되는 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염은 MCH(Melanin Concentrating Hormone) 수용체-1 길항제인 것을 특징으로 하는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
The phthalazinone derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof is a MCH (Melanin Concentrating Hormone) receptor-1 antagonist, or a pharmacologically acceptable salt thereof.
제1항 또는 제3항의 화학식 1로 표시되는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 비만, 당뇨병, 대사장애, 불안증 및 우울증으로 이루어지는 군으로부터 선택되는 어느 하나의 MCH(Melanin Concentrating Hormone) 관련 질환의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition comprising a novel phthalazinone derivative represented by the general formula (1) or (3), or a pharmaceutically acceptable salt thereof, as an active ingredient, selected from the group consisting of obesity, diabetes, metabolic disorders, anxiety and depression For the prevention or treatment of melanin concentrating hormone (MCH) related diseases.
삭제delete 제1항 또는 제3항의 화학식 1로 표시되는 신규한 프탈라지논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 비만, 당뇨병, 대사장애, 불안증 및 우울증으로 이루어지는 군으로부터 선택되는 어느 하나의 MCH(Melanin Concentrating Hormone) 관련 질환의 예방 또는 개선용 건강식품 조성물.A pharmaceutical composition comprising a novel phthalazinone derivative represented by the general formula (1) or (3), or a pharmaceutically acceptable salt thereof, as an active ingredient, selected from the group consisting of obesity, diabetes, metabolic disorders, anxiety and depression For preventing or ameliorating melanin concentrating hormone (MCH) -related diseases. 삭제delete
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