KR102174395B1 - Coumarin-3-carboxamide derivatives, preparation method therof, and pharmaceutical composition for use in preventing or treating Urotensin-Ⅱ receptor activity related diseases containing the same as an active ingredient - Google Patents
Coumarin-3-carboxamide derivatives, preparation method therof, and pharmaceutical composition for use in preventing or treating Urotensin-Ⅱ receptor activity related diseases containing the same as an active ingredient Download PDFInfo
- Publication number
- KR102174395B1 KR102174395B1 KR1020180139135A KR20180139135A KR102174395B1 KR 102174395 B1 KR102174395 B1 KR 102174395B1 KR 1020180139135 A KR1020180139135 A KR 1020180139135A KR 20180139135 A KR20180139135 A KR 20180139135A KR 102174395 B1 KR102174395 B1 KR 102174395B1
- Authority
- KR
- South Korea
- Prior art keywords
- piperidin
- coumarin
- bromo
- benzyl
- yloxy
- Prior art date
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- 201000010099 disease Diseases 0.000 title claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 28
- 230000000694 effects Effects 0.000 title claims abstract description 22
- 102000012327 Urotensin II receptors Human genes 0.000 title claims abstract description 19
- 108050002984 Urotensin II receptors Proteins 0.000 title claims abstract description 19
- 239000004480 active ingredient Substances 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 50
- XMQOBGDXGQSRID-UHFFFAOYSA-N 2-oxochromene-3-carboxamide Chemical class C1=CC=C2OC(=O)C(C(=O)N)=CC2=C1 XMQOBGDXGQSRID-UHFFFAOYSA-N 0.000 title 1
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- 150000001875 compounds Chemical class 0.000 claims description 151
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- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 7
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
쿠마린-3-카복시아마이드 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것으로, 상기 유도체는 유로텐신-Ⅱ 수용체에 대한 길항제로 작용함으로써 울혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 우울증, 정신병, 암 등과 같은 유로텐신-Ⅱ 수용체 활성 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.It relates to a coumarin-3-carboxyamide derivative, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to urotensin-II receptor activity comprising the same as an active ingredient, wherein the derivative is an antagonist against the urotensin-II receptor. Congestive heart failure, heart ischemia, myocardial infarction, cardiac hypertrophy, heart fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vascular inflammation, neurodegenerative disease, stroke, pain, depression, psychosis, cancer, etc. It can be usefully used to prevent or treat diseases related to the same urotensin-II receptor activity.
Description
쿠마린-3-카복시아마이드 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.It relates to a coumarin-3-carboxyamide derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating diseases related to urotensin-II receptor activity comprising the same as an active ingredient.
유로텐신-Ⅱ는 시스테인 결합된 사이클릭 펩타이드로서, 엔도테린-1보다 10배 이상 강한 현재까지 알려진 가장 강력한 혈관수축제 중 하나로 알려져 있다(비특허문헌 1). 유로텐신-Ⅱ는 사람에서의 11개의 아미노산으로부터 쥐에서의 14개의 아미노산으로 조성되어 있으며, 망둥이(goby fish)에서 처음 발견되었지만 현재는 모든 척추동물에서 확인되고 있다(비특허문헌 2).Eurotensin-II is a cysteine-linked cyclic peptide and is known to be one of the most powerful vasoconstrictors known to date, which is 10 times stronger than endoterin-1 (Non-Patent Document 1). Eurotensin-II is composed of 11 amino acids in humans and 14 amino acids in mice, and was first discovered in goby fish, but is now identified in all vertebrates (Non-Patent Document 2).
유로텐신-Ⅱ는 심근세포의 비대 및 평활근 세포의 증식을 유도하는 것으로 보고되어 심부전 및 동맥 경화증 등 만성 혈관질환에서의 관련성이 있음을 나타낸다(비특허문헌 3). 또한, 유로텐신-Ⅱ는 만성 심부전의 특징인 말초혈관 긴장도(peripheral vascular tone)를 증가시키는 것으로 보고되었다(비특허문헌 4). 신장 기능장애 환자의 혈장에서 유로텐신-Ⅱ가 높게 발현된다(비특허문헌 5). 유로텐신-Ⅱ는 당뇨병과도 관련되어 있다고 보고되었다(비특허문헌 6). 유로텐신-Ⅱ는 중추신경계 장애에도 관련되어 있음이 보고되었다(비특허문헌 7). 특정 종양 세포주에서 유로텐신-Ⅱ 수용체를 과발현시키는 것으로 나타났다(비특허문헌 8).Eurotensin-II has been reported to induce hypertrophy of cardiomyocytes and proliferation of smooth muscle cells, indicating a relevance in chronic vascular diseases such as heart failure and arteriosclerosis (Non-Patent Document 3). In addition, it has been reported that eurotensin-II increases peripheral vascular tone, a characteristic of chronic heart failure (Non-Patent Document 4). Eurotensin-II is highly expressed in the plasma of patients with renal dysfunction (Non-Patent Document 5). It has been reported that eurotensin-II is also associated with diabetes (Non-Patent Document 6). It has been reported that eurotensin-II is also related to central nervous system disorders (Non-Patent Document 7). It has been shown to overexpress the eurotensin-II receptor in certain tumor cell lines (Non-Patent Document 8).
유로텐신-Ⅱ의 생리학적 활성은 유로텐신-Ⅱ 수용체(UT)의 활성화를 통해 매개된다. 이전에 7개-도메인 막통과 수용체로서 G-단백질-커플링-수용체(GPCR)인 고아(orphan) 수용체 GPR14가 유로텐신-Ⅱ 수용체로 확인되었다(비특허문헌 9). 유로텐신-Ⅱ 수용체는 혈관, 심장, 간, 신장, 근육 및 폐 등 여러 조직에서 발현된다(비특허문헌 10). The physiological activity of eurotensin-II is mediated through activation of the eurotensin-II receptor (UT). Previously, an orphan receptor GPR14, a G-protein-coupling-receptor (GPCR) as a seven-domain transmembrane receptor, was identified as a eurotensin-II receptor (Non-Patent Document 9). The eurotensin-II receptor is expressed in various tissues such as blood vessels, heart, liver, kidney, muscle, and lung (Non-Patent Document 10).
유로텐신-Ⅱ 수용체 길항제는 울혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병 및 혈관염증 치료에 유용할 수 있다. 또한 U- 수용체 길항제는 중추신경계 장애, 예를 들어 신경퇴행성 질환, 뇌졸중, 통증, 우울증 및 정신병의 치료에 유용할 수 있으며, 특정 암의 치료에 유용할 수 있다.Eurotensin-II receptor antagonists may be useful in the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes and vascular inflammation. In addition, U-receptor antagonists may be useful in the treatment of central nervous system disorders such as neurodegenerative diseases, stroke, pain, depression and psychosis, and may be useful in the treatment of certain cancers.
유로텐신-Ⅱ수용체 길항제 개발 연구는 유란타이드(Urandtide)를 기반으로 한 펩티도미메틱(peptidomimetics) 연구에서 탈피, 다양한 화학적 골격을 가진 저분자 합성 화합물을 도출하기 위한 연구가 진행 중이다.The study on the development of urotensin-II receptor antagonists is in progress to derive low-molecular synthetic compounds with various chemical skeletons, breaking away from Urandtide-based peptidomimetic studies.
본 발명의 일 목적은, 쿠마린-3-카복시아마이드 유도체를 제공하는 것이다.One object of the present invention is to provide a coumarin-3-carboxyamide derivative.
본 발명의 다른 목적은, 쿠마린-3-카복시아마이드 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing a coumarin-3-carboxyamide derivative.
본 발명의 다른 목적은, 쿠마린-3-카복시아마이드 유도체를 유효성분으로 함유하는 유로텐신-Ⅱ 수용체 활성 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 diseases related to urotensin-II receptor activity, containing a coumarin-3-carboxyamide derivative as an active ingredient.
본 발명의 다른 목적은, 쿠마린-3-카복시아마이드 유도체를 유효성분으로 함유하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for the prevention or improvement of diseases related to urotensin-II receptor activity, containing a coumarin-3-carboxyamide derivative as an active ingredient.
상기 목적을 달성하기 위하여,To achieve the above object,
본 발명의 일 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염이 제공된다:According to an aspect of the present invention, there is provided a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
(상기 화학식 1에서,(In Formula 1,
R1은 수소, 할로겐, NO2, CN, 직쇄 또는 분지쇄의 C1-10알킬 또는 직쇄 또는 분지쇄의 C1-10알콕시이고;R 1 is hydrogen, halogen, NO 2 , CN, straight or branched C 1-10 alkyl or straight or branched C 1-10 alkoxy;
R2는 할로겐이고; 및R 2 is halogen; And
r은 1-4의 정수이다).r is an integer from 1-4).
본 발명의 다른 측면에 따라, 하기 반응식 1에 나타낸 바와 같이,According to another aspect of the present invention, as shown in Scheme 1 below,
화학식 3으로 표시되는 화합물과 화학식 4으로 표시되는 화합물을 반응시켜 화학식 2으로 표시되는 화합물을 제조하는 단계(단계 1); 및Preparing a compound represented by Formula 2 by reacting a compound represented by Formula 3 with a compound represented by Formula 4 (Step 1); And
화학식 2로 표시되는 화합물을 반응시켜 화학식 11로 표시되는 화합물을 제조하는 단계(단계 2)를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법이 제공된다:There is provided a method for preparing a compound represented by Formula 1, comprising the step of reacting a compound represented by Formula 2 to prepare a compound represented by Formula 11 (Step 2):
[반응식 1][Scheme 1]
(상기 반응식 1에서,(In the above Scheme 1,
R1, R2 및 r은 제1항의 화학식 1에서 정의한 바와 같고; 및R 1 , R 2 and r are as defined in Formula 1 of claim 1; And
PGa는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이다).PG a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc)).
본 발명에 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, the prevention of a disease related to urotensin-II receptor activity comprising the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient, or A therapeutic pharmaceutical composition is provided.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 개선용 건강기능식품 조성물이 제공된다.According to another aspect of the present invention, the prevention of a disease related to urotensin-II receptor activity comprising the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient, or A health functional food composition for improvement is provided.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료 방법이 제공된다.According to another aspect of the present invention, a subject in need of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof as an active ingredient There is provided a method for preventing or treating a disease related to eurotensin-II receptor activity comprising administering to a patient.
본 발명의 다른 측면에 따라, 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도가 제공된다.According to another aspect of the present invention, a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of a disease related to the eurotensin-II receptor activity The use of the containing pharmaceutical composition or dietary supplement composition is provided.
본 발명의 쿠마린-3-카복시아마이드 유도체는 유로텐신-Ⅱ 수용체에 대한 길항제로 작용함으로써 울혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 우울증, 정신병, 암 등과 같은 유로텐신-Ⅱ 수용체 활성 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.The coumarin-3-carboxyamide derivative of the present invention acts as an antagonist to the eurotensin-II receptor, thereby congesting heart failure, heart ischemia, myocardial infarction, heart hypertrophy, heart fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure. , Diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer, such as eurotensin-II receptor activity-related diseases can be usefully used to prevent or treat.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면은, 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.One aspect of the present invention provides a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 수소, 할로겐, NO2, CN, 직쇄 또는 분지쇄의 C1-10알킬 또는 직쇄 또는 분지쇄의 C1-10알콕시이고;R 1 is hydrogen, halogen, NO 2 , CN, straight or branched C 1-10 alkyl or straight or branched C 1-10 alkoxy;
R2는 할로겐이고; 및R 2 is halogen; And
r은 1-4의 정수이다.r is an integer from 1-4.
상기 R1은 수소, 할로겐, NO2, CN, 직쇄 또는 분지쇄의 C1-6알킬 또는 직쇄 또는 분지쇄의 C1-6알콕시일 수 있다.The R 1 may be hydrogen, halogen, NO 2 , CN, straight or branched C 1-6 alkyl or straight or branched C 1-6 alkoxy.
또한, 상기 R1은 수소, 할로겐, NO2, CN, C1-4알킬 또는 C1-4알콕시일 수 있다.In addition, R 1 may be hydrogen, halogen, NO 2 , CN, C 1-4 alkyl or C 1-4 alkoxy.
또한, 상기 R1은 수소, F, Cl, Br, NO2, CN, 메틸 또는 메톡시일 수 있다.In addition, R 1 may be hydrogen, F, Cl, Br, NO 2 , CN, methyl or methoxy.
상기 R2는 Br일 수 있고, 피페리딘 옥시의 ortho위치에 결합될 수 있다.R 2 may be Br, and may be bonded to the ortho position of piperidine oxy.
상기 r은 1-3의 정수 있수 있고, 1 또는 2일 수 있다.The r may be an integer of 1-3, and may be 1 or 2.
상기 화학식 1에서, 는 쿠마린의 벤젠에서 각 CH에 가 결합된 것을 의미하며, 구체적으로 벤젠의 C-R1 결합형태를 나타내고, 벤젠에 가 r개 결합될 수 있음을 의미한다. 벤젠에 결합된 각각의 은 동일 또는 상이할 수 있다.In Formula 1, To each CH in benzene of coumarin Means bonded, specifically represents the CR 1 bond form of benzene, and It means that r can be combined. Each bonded to benzene May be the same or different.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 예로는 하기의 화합물들을 들 수 있다: Examples of the compound represented by Formula 1 according to the present invention include the following compounds:
(1)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-쿠마린-3-카복시아마이드;(1) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide;
(2)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-나이트로-쿠마린-3-카복시아마이드;(2) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-nitro-coumarin-3-carboxyamide;
(3)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-메톡시-쿠마린-3-카복시아마이드;(3) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methoxy-coumarin-3-carboxyamide;
(4)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-쿠마린-3-카복시아마이드;(4) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-coumarin-3-carboxyamide;
(5)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-브로모-쿠마린-3-카복시아마이드;(5) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-bromo-coumarin-3-carboxyamide;
(6)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-메틸-쿠마린-3-카복시아마이드;(6) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methyl-coumarin-3-carboxyamide;
(7)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-플루오로-쿠마린-3-카복시아마이드;(7) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-fluoro-coumarin-3-carboxyamide;
(8)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-시아노-쿠마린-3-카복시아마이드;(8) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-cyano-coumarin-3-carboxyamide;
(9)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-메톡시-쿠마린-3-카복시아마이드;(9) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methoxy-coumarin-3-carboxyamide;
(10)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-메틸-쿠마린-3-카복시아마이드;(10) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methyl-coumarin-3-carboxyamide;
(11)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-플루오로-쿠마린-3-카복시아마이드;(11) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-coumarin-3-carboxyamide;
(12)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-클로로-쿠마린-3-카복시아마이드;(12) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-coumarin-3-carboxyamide;
(13)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-브로모-쿠마린-3-카복시아마이드;(13) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-bromo-coumarin-3-carboxyamide;
(14)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-시아노-쿠마린-3-카복시아마이드;(14) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-cyano-coumarin-3-carboxyamide;
(15)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-플루오로-쿠마린-3-카복시아마이드;(15) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-fluoro-coumarin-3-carboxyamide;
(16)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-메틸-쿠마린-3-카복시아마이드;(16) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;
(17)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-메틸-쿠마린-3-카복시아마이드;(17) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;
(18)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이메톡시-쿠마린-3-카복시아마이드;(18) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethoxy-coumarin-3-carboxy Amide;
(19)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이플루오로-쿠마린-3-카복시아마이드;(19) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-difluoro-coumarin-3-carboxy Amide;
(20)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이메틸-쿠마린-3-카복시아마이드;(20) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethyl-coumarin-3-carboxyamide ;
(21)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이클로로-쿠마린-3-카복시아마이드;(21) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dichloro-coumarin-3-carboxyamide ;
(22)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-7-메틸-쿠마린-3-카복시아마이드;(22) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-methyl-coumarin-3-carboxy Amide;
(23)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-7-플루오로-쿠마린-3-카복시아마이드;(23) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-fluoro-coumarin-3- Carboxyamide;
(24)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-클로로-6-플루오로-쿠마린-3-카복시아마이드;(24) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-6-fluoro-coumarin-3- Carboxyamide;
(25)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-플루오로-6-메틸-쿠마린-3-카복시아마이드.(25) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-6-methyl-coumarin-3- Carboxyamide.
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 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, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid May be prepared by filtration and drying, or may be prepared by distilling off a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.
또한, 염기를 사용하여 약학적으로 허용가능한 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, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Further, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, hydrates, etc. that may be prepared therefrom.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecμLar force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 본 발명의 상기 화학식 1로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1당량 이상, 바람직하게는, 1 당량 내지 5당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecule force. Or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. These hydrates may be prepared by crystallizing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof from water or a solvent containing water.
용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term "solvate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include volatile, non-toxic, and/or suitable solvents for administration to humans.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변이성질체(tautomer) 등의 구조 이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성체, 기하이성질체(트랜스, 시스) 등의 입체 이성질체, 광학 이성질체(enantiomer)가 모두 포함된다. 이들 모든 이성체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term “isomer” refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but structurally or sterically different. Such isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers. All these isomers and mixtures thereof are also included within the scope of the present invention.
본 발명의 다른 측면은, 하기 반응식 1에 나타낸 바와 같이,Another aspect of the present invention, as shown in Scheme 1 below,
화학식 3으로 표시되는 화합물과 화학식 4으로 표시되는 화합물을 반응시켜 화학식 2으로 표시되는 화합물을 제조하는 단계(단계 1); 및Preparing a compound represented by Formula 2 by reacting a compound represented by Formula 3 with a compound represented by Formula 4 (Step 1); And
화학식 2로 표시되는 화합물을 반응시켜 화학식 11로 표시되는 화합물을 제조하는 단계(단계 2)를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.It provides a method for preparing the compound represented by Formula 1, including the step of reacting the compound represented by Formula 2 to prepare the compound represented by Formula 11 (Step 2).
[반응식 1][Scheme 1]
(상기 반응식 1에서,(In the above Scheme 1,
R1, R2 및 r은 제1항의 화학식 1에서 정의한 바와 같고; 및R 1 , R 2 and r are as defined in Formula 1 of claim 1; And
PGa는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이다).PG a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc)).
이하, 본 발명에 따른 상기 반응식 1로 표시되는 제조방법에 대하여 상세히 설명한다.Hereinafter, the manufacturing method represented by Scheme 1 according to the present invention will be described in detail.
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 상기 반응식 1에 나타난 바와 같이, 화학식 3으로 표시되는 카르복실산 화합물 및 화학식 4로 표시되는 아민 화합물을 출발물질로 사용하여 축합 및 탈보호 반응을 통하여 제조할 수 있다.The compound represented by Formula 1 according to the present invention is obtained through condensation and deprotection reactions using a carboxylic acid compound represented by Formula 3 and an amine compound represented by Formula 4 as starting materials as shown in Scheme 1 above. Can be manufactured.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 1은 화학식 3으로 표시되는 화합물과 화학식 4로 표시되는 화합물을 반응시켜 화학식 2로 표시되는 화합물을 얻는 단계로서, 구체적으로, 화학식 3으로 표시되는 화합물과 화학식 4로 표시되는 화합물을 축합제 존재하에 축합반응시켜 화학식 1로 표시되는 화합물을 제조할 수 있으며, 보다 구체적으로, 화학식 3으로 표시되는 카르복실산 화합물과 화학식 4로 표시되는 아민 화합물을 축합제 및 염기 존재하에 축합반응시켜 아마이드 본드를 가지는 화학식 1로 표시되는 화합물을 제조할 수 있다.In the method for preparing a compound represented by Formula 1 according to the present invention, step 1 is a step of reacting a compound represented by Formula 3 with a compound represented by Formula 4 to obtain a compound represented by Formula 2, specifically , The compound represented by Formula 1 may be prepared by condensing the compound represented by Formula 3 and the compound represented by Formula 4 in the presence of a condensing agent, and more specifically, the carboxylic acid compound represented by Formula 3 and Formula 4 A condensation reaction of the amine compound represented by is carried out in the presence of a condensing agent and a base to prepare a compound represented by Formula 1 having an amide bond.
이때, 상기 축합반응은 통상적인 두가지 방법을 통하여 수행할 수 있으며, 구체적인 예로는 다음과 같다.At this time, the condensation reaction can be carried out through two conventional methods, and specific examples are as follows.
제법 1-AFormula 1-A
상기 반응식 1의 화학식 3으로 표시되는 화합물과 화학식 4로 표시되는 화합물을 염기 존재하에 축합제를 사용하는 방법을 통하여 제조할 수 있다.The compound represented by Formula 3 and the compound represented by Formula 4 in Scheme 1 can be prepared through a method of using a condensing agent in the presence of a base.
이때, 사용 가능한 사용가능한 축합제로는 유기포스포러스계열의 시약으로 비스 (2-옥소-3-옥사졸리디닐)포스피닉 클로라이드 (BOP-Cl), 벤조트리아졸-1-일옥시트리스(다이메틸아미노)포스포늄 헥사플루오로포스페이트 (BOP), 다이페닐포스포닐아자이드(diphenylphosphonylazide, DPPA) 등이 있고, 카보다이이미드 계열의 시약으로 다이사이클로헥실카보다이이미드(DCC), 다이아이소프로필카보다이이미드(DIC), 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드(EDC)등이 있고, N,N-카보닐다이이미다졸(N,N-carbonyldiimidazole), O-벤조트리아졸-N,N,N’,N’-테트라메틸-우로니늄-헥사플루오로포스페이트 (HBTU) 등을 사용할 수 있다.At this time, usable condensing agents are organic phosphorus-based reagents, bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), benzotriazol-1-yloxytris (dimethylamino ) Phosphonium hexafluorophosphate (BOP), diphenylphosphonylazide (DPPA), etc., and carbodiimide-based reagents include dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide ( DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), etc., and N,N-carbonyldiimidazole, O -benzotriazole- N ,N,N',N' -tetramethyl-uroninium-hexafluorophosphate (HBTU) and the like can be used.
또한, 상기 염기는 반응을 촉진하고 수율을 높이기 위하여 사용되며, 사용가능한 염기로는 N,N-다이메틸아미노피리딘(DMAP), 피리딘, 트라이에틸아민, N,N-다이이소프로필에틸아민, 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU) 등의 유기염기 또는 소듐바이카보네이트, 수산화나트륨, 수산화칼륨 등의 무기염기가 있으며, 이를 단독 또는 혼합하여, 당량 또는 과량으로 사용할 수 있다.In addition, the base is used to accelerate the reaction and increase the yield, and the available bases include N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1 There are organic bases such as ,8-diazabicyclo[5.4.0]-7-undecene (DBU) or inorganic bases such as sodium bicarbonate, sodium hydroxide, potassium hydroxide, etc., alone or in combination, in an equivalent amount or in excess Can be used.
나아가, 반응 용매는 테트라하이드로퓨란, 다이옥산, 디클로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 벤젠, 톨루엔, 자일렌과 같은 아로마틱 하이드로카본용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다. Further, the reaction solvent is tetrahydrofuran, dioxane, dichloromethane, ether solvents such as 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, dimethylformamide (DMF), dimethylsulfoxide. Side, acetonitrile, etc. can be used alone or in combination. The reaction temperature is from 0° C. to the boiling point of the solvent.
제법 1-BPreparation 1-B
또한, 상기 반응식 1의 화학식 3으로 표시되는 카르복실산 화합물을 공지의 방법에 의해 아실할라이드, 카르복실산 무수물 또는 활성 에스터(active ester)(예, p-나이트로페닐 에스터, N-하이드록시석신이미드 에스터, 페타플루오로페닐 에스터 등)로 변환시킨 후, 화학식 4로 표시되는 아민 화합물과 염기 존재하에 반응시켜 화학식 1로 표시되는 화합물을 얻을 수 있다.In addition, the carboxylic acid compound represented by Formula 3 in Scheme 1 is used as an acyl halide, a carboxylic anhydride, or an active ester (e.g., p-nitrophenyl ester, N-hydroxysuccin) by a known method. Imide ester, fetafluorophenyl ester, etc.), and then reacted with an amine compound represented by Formula 4 in the presence of a base to obtain a compound represented by Formula 1.
이때, 상기 염기로는 트라이에틸아민, 디이소프로필에틸아민과 같은 삼차아민 유기염기와 탄산나트륨, 탄산칼륨, 수산화칼륨, 수산화나트륨, 탄산세슘, 수산화바륨 등과 같은 무기염기가 있으며, 이를 단독 또는 혼합하여, 당량 또는 과량으로 사용할 수 있다. At this time, the base includes a tertiary amine organic base such as triethylamine and diisopropylethylamine, and an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, etc., alone or in combination. , Can be used in equivalent or excess.
또한, 상기 반응에서 사용 가능한 용매로는 다이옥산, 테트라하이드로퓨란, 1,2-다이메톡시에탄과 같은 에테르계 용매와 1,2-다이클로로메탄, 혹은 1,2-다이클로로에탄 같은 할로겐 포함 용매 그리고 벤젠, 톨루엔 같은 아로마틱 하이드로카본용매등이 있으며, 이를 단독 또는 혼합하여 사용할 수 있고, 용매 없이도 반응시킬 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.In addition, solvents that can be used in the reaction include ether solvents such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and halogen-containing solvents such as 1,2-dichloromethane or 1,2-dichloroethane. In addition, there are aromatic hydrocarbon solvents such as benzene and toluene, which can be used alone or in combination, and can be reacted without a solvent. The reaction temperature is from 0° C. to the boiling point of the solvent.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 얻은 화학식 2로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계로, 구체적으로, 상기 단계 2는 상기 단계 1에서 얻은 화학식 2로 표시되는 화합물을 반응시켜 아민 보호기를 탈보호 반응을 통해 제거하여 화학식 1로 표시되는 최종 화합물을 제조하는 단계이다.In the method for preparing the compound represented by Formula 1 according to the present invention, step 2 is a step of obtaining a compound represented by Formula 1 by reacting the compound represented by Formula 2 obtained in step 1, specifically, the Step 2 is a step of reacting the compound represented by Chemical Formula 2 obtained in Step 1 to remove the amine protecting group through a deprotection reaction to prepare a final compound represented by Chemical Formula 1.
이때, 상기 아민 보호기는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이며, t-부틸옥시카보닐(Boc)일 수 있다.At this time, the amine protecting group is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn) , p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc ), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc) is one type of amine protecting group selected from the group consisting of, and may be t-butyloxycarbonyl (Boc).
또한, 상기 탈보호 반응의 반응조건은 아민 보호기의 종류에 따라 상이하며, 통상적인 탈보호 반응 조건을 사용하여 수행할 수 있다.In addition, the reaction conditions of the deprotection reaction are different depending on the type of the amine protecting group, and may be carried out using conventional deprotection reaction conditions.
본 발명에서는 산 조건을 사용하였으며, 상기 산으로는 염산, 황산, 메탄설폰산, 트리플루오로아세트산 등을 사용할 수 있다.In the present invention, an acid condition was used, and hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and the like may be used as the acid.
또한, 상기 반응에서 사용 가능한 용매로는 테트라하이드로퓨란, 다이옥산, 디클로로메탄, 1,2-다이메톡시에탄 등의 에테르계 용매; 벤젠, 톨루엔, 자일렌 등의 아로마틱 하이드로카본용매; 메탄올, 에탄올 등의 알코올계 용매; 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴, 물 등이 있으며, 이를 단독 또는 혼합하여 사용할 수 있다.Further, examples of the solvent usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, and 1,2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene, and xylene; Alcohol solvents such as methanol and ethanol; There are dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and water, and these may be used alone or in combination.
나아가, 반응온도는 0℃에서 용매의 비등점 사이에서 수행할 수 있다.Furthermore, the reaction temperature can be carried out between the boiling point of the solvent at 0°C.
출발물질(화학식 3로 표시되는 화합물)의 제법 1Preparation of starting material (compound represented by formula 3) 1
상기 반응식 1의 출발 물질인 화학식 3의 화합물은 하기 반응식 2에 나타낸 바와 같이,As the starting material of Scheme 1, the compound of Formula 3 is shown in Scheme 2 below,
화학식 5로 표시되는 화합물과 화학식 6으로 표시되는 화합물을 반응시켜 화학식 3으로 표시되는 화합물을 얻는 단계(단계 1)를 포함하는 제조방법으로 제조할 수 있다.It can be prepared by a manufacturing method including the step (step 1) of obtaining a compound represented by Formula 3 by reacting a compound represented by Formula 5 with a compound represented by Formula 6.
[반응식 2][Scheme 2]
상기 반응식 2에서, In Scheme 2 above,
R1 및 r은 상기 화학식 1에서 정의한 바와 같다.R 1 and r are as defined in Chemical Formula 1.
이하, 상기 반응식 2의 제조방법을 상세히 설명한다.Hereinafter, the manufacturing method of Scheme 2 will be described in detail.
상기 반응식 2의 제조방법은, 화학식 5로 표시되는 화합물과 화학식 6으로 표시되는 화합물을 반응시켜 화학식 3으로 표시되는 화합물을 얻는 단계를 포함하며, 구체적으로, 화학식 5로 표시되는 2-하이드록시 벤즈알데히드화합물을 화합식 6으로 표시되는 화합물과 촉매 존재하에서 축합 반응을 통해 화학식 3로 표시되는 화합물을 얻는 단계를 포함한다.The preparation method of Scheme 2 includes the step of reacting a compound represented by Formula 5 with a compound represented by Formula 6 to obtain a compound represented by Formula 3, and specifically, 2-hydroxy benzaldehyde represented by Formula 5 And a step of obtaining a compound represented by Formula 3 through a condensation reaction of the compound represented by Formula 6 and a catalyst.
상기 반응에 사용가능한 촉매로는 피페리딘 아세테이트, 피페리딘, 암모늄 아세테이트, 프롤린, 트리에틸아민 등과 같은 염기가 있으며, 이외에도 티타늄 클로라이드 (TiCl4), 틴 클로라이드 (SnCl2) 등과 같은 루이스 산이 사용가능하다. Examples of catalysts that can be used in the reaction include bases such as piperidine acetate, piperidine, ammonium acetate, proline, and triethylamine, and in addition, Lewis acids such as titanium chloride (TiCl 4 ) and tin chloride (SnCl 2 ) are used. It is possible.
반응 용매는 메탄올, 에탄올, 아이소프로필 알코올과 같은 알코올계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. As the reaction solvent, alcohol-based solvents such as methanol, ethanol, and isopropyl alcohol, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and the like may be used alone or in combination.
출발물질(화학식 4로 표시되는 화합물)의 제법 2Preparation 2 of starting material (compound represented by formula 4)
상기 반응식 1의 출발 물질인 화학식 4 화합물은 하기 반응식 3에 나타낸 바와 같이,As shown in the following Scheme 3, the compound of Formula 4, which is the starting material of Scheme 1,
화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물을 반응시켜 화학식 9로 표시되는 화합물을 얻는 단계(단계 1); Reacting a compound represented by Formula 7 with a compound represented by Formula 8 to obtain a compound represented by Formula 9 (Step 1);
상기 단계 1에서 얻은 화학식 9로 표시되는 화합물과 화학식 10으로 표시되는 화합물을 반응시켜 화학식 11로 표시되는 화합물을 얻는 단계(단계 2); 및Reacting the compound represented by Formula 9 with the compound represented by Formula 10 to obtain a compound represented by Formula 11 (step 2); And
상기 단계 2에서 얻은 화학식 11로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 얻는 단계(단계 3)를 포함하는 제조방법으로 제조할 수 있다.It can be prepared by a manufacturing method including the step of reacting the compound represented by Formula 11 obtained in step 2 to obtain the compound represented by Formula 4 (step 3).
[반응식 3][Scheme 3]
상기 반응식 3에서,In Scheme 3 above,
R2는 상기 화학식 1에서 정의한 바와 같고;R 2 is as defined in Formula 1;
PGa는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이고; PG a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
PGb는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이되;PG b is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -One type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
상기 PGa 및 PGb는 서로 다른 조건에서 탈보호화되는 아민보호기 이다.The PG a and PG b are amine protecting groups that are deprotected under different conditions.
이하, 상기 반응식 3의 제조방법을 상세히 설명한다.Hereinafter, the manufacturing method of Scheme 3 will be described in detail.
상기 반응식 3의 제조방법에서, 단계 1은 화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물을 반응시켜 화학식 9로 표시되는 화합물을 얻는 단계로, 구체적으로, 화학식 8로 표시되는 알데히드 화합물의 OH와 화학식 9로 표시되는 피페리딘올 화합물의 OH가 축합제 및 포스핀 존재하에서 커플링 반응을 통해 화학식 8로 표시되는 화합물을 제조하는 단계이다.In the preparation method of Reaction Scheme 3, step 1 is a step of obtaining a compound represented by Formula 9 by reacting a compound represented by Formula 7 with a compound represented by Formula 8, specifically, OH of the aldehyde compound represented by Formula 8 And OH of the piperidinol compound represented by Formula 9 is a step of preparing a compound represented by Formula 8 through a coupling reaction in the presence of a condensing agent and phosphine.
상기 반응에서 사용가능한 축합제로는 다이 알킬 아조 계열의 시약으로, 대표적인 시약으로는 다이에틸 아조 다이카복실레이트 (DEAD)가 있으며, 다이아이소프로필 아조 다이카르복실레이트 등도 사용 할수 있다. 또한, 포스핀으로는 트라이페닐포스핀 (PPh3)이 대표적이며, 트라이메틸포스핀 (PMe3), 트라이에틸포스핀(PEt3)등도 사용이 가능하다.The condensing agent usable in the above reaction is a dialkyl azo-based reagent, and a representative reagent is diethyl azo dicarboxylate (DEAD), and diisopropyl azo dicarboxylate may also be used. In addition, triphenylphosphine (PPh 3 ) is a representative phosphine, and trimethylphosphine (PMe 3 ), triethylphosphine (PEt 3 ), and the like can be used.
반응 용매는 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.The reaction solvent may be used alone or in combination with an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, etc. have. The reaction temperature is from 0° C. to the boiling point of the solvent.
상기 반응식 3의 제조방법에서, 단계 2는 상기 단계 1에서 얻은 화학식 9로 표시되는 화합물과 화학식 10으로 표시되는 화합물을 반응시켜 화학식 11로 표시되는 화합물을 얻는 단계로, 구체적으로, 화학식 9로 표시되는 알데히드 화합물의 알데히드와 화학식 10으로 표시되는 피페리딘 화합물의 NH가 금속환원제 존재하에 환원성 아민화 반응하여 화학식 11로 표시되는 화합물을 얻는 단계이다.In the preparation method of Scheme 3, step 2 is a step of obtaining a compound represented by Formula 11 by reacting the compound represented by Formula 9 and the compound represented by Formula 10 obtained in Step 1, specifically, represented by Formula 9. This is a step to obtain a compound represented by Formula 11 by reductive amination reaction between the aldehyde of the aldehyde compound and NH of the piperidine compound represented by Formula 10 in the presence of a metal reducing agent.
상기 반응에서 사용가능한 금속환원제는 소듐 보로하이드라이드 (NaBH4), 소듐트라이아세톡시 보로하이드라이드 (NaBH(OAc)3), 소듐 시아노 보로하이드라이드(NaBH3CN)를 사용할 수 있다. The metal reducing agent that can be used in the reaction may be sodium borohydride (NaBH 4 ), sodium triacetoxy borohydride (NaBH(OAc) 3 ), sodium cyano borohydride (NaBH 3 CN).
반응 용매는 메탄올, 에탄올과 같은 알코올계 용매, 테트라하이드로퓨란, 다이옥산, 1,2-다이메톡시에탄과 같은 에테르계 용매 등을 단독 또는 혼합하여 사용할 수 있고 반응 온도는 0 ℃에서 용매의 비등점까지이다. The reaction solvent can be used alone or in combination with alcohol-based solvents such as methanol and ethanol, tetrahydrofuran, dioxane, and ether-based solvents such as 1,2-dimethoxyethane, and the reaction temperature is from 0 °C to the boiling point of the solvent. to be.
상기 반응식 3의 제조방법에서, 단계 3은 상기 단계 2에서 얻은 화학식 11로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 얻는 단계로, 구체적으로, 화학식 11로 표시되는 화합물의 아민보호기를 탈보호 반응을 통해 제거하여 화학식 4로 표시되는 화합물을 제조하는 단계이다.In the preparation method of Scheme 3, step 3 is a step of obtaining a compound represented by Formula 4 by reacting the compound represented by Formula 11 obtained in step 2, and specifically, removing the amine protecting group of the compound represented by Formula 11 This is a step of preparing a compound represented by Chemical Formula 4 by removing through a protection reaction.
이때, 상기 아민 보호기는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이며, t-부틸옥시카보닐(Boc)일 수 있다.At this time, the amine protecting group is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn) , p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc ), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc) is one type of amine protecting group selected from the group consisting of, and may be t-butyloxycarbonyl (Boc).
또한, 상기 탈보호 반응의 반응조건은 아민 보호기의 종류에 따라 상이하며, 통상적인 탈보호 반응 조건을 사용하여 수행할 수 있다.In addition, the reaction conditions of the deprotection reaction are different depending on the type of the amine protecting group, and may be carried out using conventional deprotection reaction conditions.
본 발명에서는 염기 조건을 사용하였으며, 상기 반응에서 사용가능한 염기로는 피페리딘이 대표적이며, 이외에 피롤리딘, 피리딘, 트라이에틸아민, N,N-디이소프로필에틸아민, DBU 등의 유기염기를 사용하거나, NaOH, Na2CO3, K2CO3, Cs2CO3 등의 무기염기를 당량 또는 과량 사용할 수 있다.In the present invention, basic conditions were used, and piperidine is a representative base that can be used in the reaction, and in addition to organic bases such as pyrrolidine, pyridine, triethylamine, N , N -diisopropylethylamine, DBU, etc. Or, NaOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 It is possible to use an equivalent or excessive amount of an inorganic base such as.
반응 용매는 테트라하이드로퓨란, 다이옥산, 디틀로로메탄, 1,2-다이메톡시에탄과 같은 에테르계 용매, 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴 등을 단독 또는 혼합하여 사용할 수 있다. 반응 온도는 0℃에서 용매의 비등점까지이다.The reaction solvent may be used alone or in combination with an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, etc. have. The reaction temperature is from 0° C. to the boiling point of the solvent.
본 발명에 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is the prevention or treatment of diseases related to the activity of the eurotensin-II receptor containing the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient. It provides a pharmaceutical composition for use.
상기 유로텐신-Ⅱ 수용체 활성 관련 질환은 혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 정신병 및 암으로 이루어지는 군으로부터 선택되는 1종 이상의 질환일 수 있다.The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , It may be one or more diseases selected from the group consisting of psychosis and cancer.
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 유로텐신-Ⅱ 수용체에 대하여 길항작용할 수 있다.The compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may antagonize the eurotensin-II receptor.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 유로텐신-Ⅱ 수용체 길항효과를 측정한 결과, As a result of measuring the eurotensin-II receptor antagonistic effect of the compound represented by Formula 1 according to the present invention,
본 발명의 모든 실시예 화합물이 낮은 농도에서 유로텐신-Ⅱ 수용체에 대해 길항작용을 하는 것으로 확인되었다. 특히, 본 발명에 따른 실시예 3-4, 6, 11-13, 16-17, 19, 21, 23-25 화합물은 IC50 값 30 nM 이하의 낮은 농도에서도 유로텐신-Ⅱ 수용체에 대하여 길항작용을 하는 바, 유로텐신-Ⅱ 수용체에 대한 길항효과가 우수하다(실험예 1 및 표 2 참조). It was confirmed that all of the compounds of the examples of the present invention had an antagonistic action against the eurotensin-II receptor at low concentrations. In particular, the compounds of Examples 3-4, 6, 11-13, 16-17, 19, 21, and 23-25 according to the present invention have an antagonistic effect on the urotensin-II receptor even at low concentrations of 30 nM or less with an IC 50 value. As a bar, the antagonistic effect against the eurotensin-II receptor is excellent (see Experimental Example 1 and Table 2).
따라서, 본 발명에 따른 화합물은 유로텐신-Ⅱ 수용체에 대한 길항제로 작용함으로써, 울혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 우울증, 정신병 및 암과 같은 유로텐신-Ⅱ 수용체 과활성에 의한 질환을 예방, 개선 또는 치료하는데 유용하게 사용할 수 있다.Therefore, the compound according to the present invention acts as an antagonist to the urotensin-II receptor, so that congestive heart failure, heart ischemia, myocardial infarction, cardiac hypertrophy, heart fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, kidney failure, diabetes , Vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, and can be usefully used to prevent, ameliorate or treat diseases caused by hyperactivity of the eurotensin-II receptor such as cancer.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, preservatives, etc. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 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 compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection It depends on how to do it.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulation. It can be formulated according to the method of painting or coating.
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 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches.These formulations include diluents (e.g., lactose) in addition to the active ingredients. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salt and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another aspect of the present invention is the prevention or improvement of diseases related to the activity of the eurotensin-II receptor containing the compound represented by Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient. It provides a health functional food composition for use.
상기 유로텐신-Ⅱ 수용체 활성 관련 질환은 혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 정신병 및 암으로 이루어지는 군으로부터 선택되는 1종 이상의 질환일 수 있다.The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , It may be one or more diseases selected from the group consisting of psychosis and cancer.
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 유로텐신-Ⅱ 수용체에 대하여 길항작용할 수 있다.The compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may antagonize the eurotensin-II receptor.
본 발명에 따른 화학식 1로 표시되는 화합물은, 유로텐신-Ⅱ 수용체 길항작용을 나타냄으로써, 유로텐신-Ⅱ 수용체 과활성에 의한 질환의 예방 또는 개선용 건강기능식품 조성물로 식품, 음료 등의 건강기능보조 식품에 첨가할 수 있다.The compound represented by Formula 1 according to the present invention is a health functional food composition for preventing or improving diseases caused by overactivity of eurotensin-II receptors by exhibiting antagonism of eurotensin-II receptors. Can be added to supplements.
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 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 compound represented by Formula 1 according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in the health food may be added in 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, 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 above the above range.
또한, 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 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages. have. Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
나아가, 상기 외에 본 발명에 따른 화학식 1로 표시되는 화합은 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 화학식 1로 표시되는 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. Further, in addition to the above, the compound represented by Chemical Formula 1 according to the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pects. Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages.
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention is to provide a pharmaceutical composition or a health functional food composition containing as an active ingredient the compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof. It provides a method for preventing or treating a disease related to urotensin-II receptor activity comprising the step of administering.
본 발명의 다른 측면은, 유로텐신-Ⅱ 수용체 활성 관련 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도를 제공한다.Another aspect of the present invention contains a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, in the prevention or treatment of a disease related to eurotensin-II receptor activity. It provides the use of a pharmaceutical composition or a health functional food composition.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.
<제조예 1> 6-나이트로-쿠마린-3-카복실산의 제조<Production Example 1> Preparation of 6-nitro-coumarin-3-carboxylic acid
2-하이드록시-5-나이트로벤즈알데하이드 232 mg (1.38 mmol)을 8 ml의 에탄올에 용해시킨 후 멜드럼즈 에시드 200 mg (1.38 mmol)과 피페리딘을 촉매량만큼 첨가하여 상온에서 3시간 동안 교반하였다. 반응 종결 후, 감압 농축한 뒤 2N 수산화나트륨을 이용하여 산성화시킨 후 30 ml 에틸 아세테이트를 이용하여 추출하고, 무기염 용액 50 ml를 첨가하여 세척한 후, 무수황산나트륨(Na2SO4)으로 건조시키고, 감압 농축하여 목적 화합물을 12%의 수율로 37 mg (0.16 mmol)을 얻었다.After dissolving 232 mg (1.38 mmol) of 2-hydroxy-5-nitrobenzaldehyde in 8 ml of ethanol, 200 mg (1.38 mmol) of Meldrums acid and piperidine were added in a catalytic amount at room temperature for 3 hours. Stirred. After completion of the reaction, concentrated under reduced pressure, acidified with 2N sodium hydroxide, extracted with 30 ml ethyl acetate, washed with 50 ml of an inorganic salt solution, and dried over anhydrous sodium sulfate (Na 2 SO 4 ). And concentrated under reduced pressure to give the target compound 37 mg (0.16 mmol) in a yield of 12%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.81 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.41 (dd, J = 8.7, 2.1 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.81 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.41 (dd, J = 8.7, 2.1 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H)
<제조예 2> 4-[4-[(4-아미노피페리딘-1-일)메틸]-2-브로모페녹시]피페리딘-1-tert-부틸 카르복실레이트의 제조<Preparation Example 2> Preparation of 4-[4-[(4-aminopiperidin-1-yl)methyl]-2-bromophenoxy]piperidine-1-tert-butyl carboxylate
단계 1: 4-(2-브로모-4-포밀페녹시)피페리딘-1-tert-부틸 카르복실레이트의 제조Step 1: Preparation of 4-(2-bromo-4-formylphenoxy)piperidine-1-tert-butyl carboxylate
3-브로모-4-하이드록시벤즈알데하이드 (30 g, 149.2 mmol)를 400 ml의 테트라하이드로퓨란에 용해시킨 후, 0℃에서 tert-부틸 4-하이드록시피페리딘-1-카복실레이트 (33 g, 164.2 mmol), 트리페닐포스핀 (51 g, 193.96 mmol)을 첨가하였다. 2.2M 다이에틸 아조다이카복실레이트 (88 ml, 193.96 mmol)을 0℃에서 15분에 걸쳐 천천히 가한 후 4시간 동안 교반하였다. 반응 종결 후 용매를 감압농축한 후, 500 ml의 에틸 아세테이트를 첨가하였다. 3N 소듐 하이드록사이드 수용액으로 (500 ml) 세척하였다. 유기층을 무수황산나트륨 (Na2SO4)로 건조시키고, 감압 농축한 후 여액을 실리카겔 컬럼 크로마토그래피 (노말헥산 : 에틸 아세테이트 = 3 : 1, v/v)로 정제하여 목적화합물을 34%의 수율로 (19.68 g, 51.21 mmol)을 얻었다.After dissolving 3-bromo-4-hydroxybenzaldehyde (30 g, 149.2 mmol) in 400 ml of tetrahydrofuran, tert -butyl 4-hydroxypiperidine-1-carboxylate (33 g, 164.2 mmol), triphenylphosphine (51 g, 193.96 mmol) were added. 2.2M diethyl azodicarboxylate (88 ml, 193.96 mmol) was slowly added at 0° C. over 15 minutes, followed by stirring for 4 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and 500 ml of ethyl acetate was added. Washed with 3N aqueous sodium hydroxide solution (500 ml). The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ), concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (normal hexane: ethyl acetate = 3: 1, v/v) to obtain the target compound in a yield of 34%. (19.68 g, 51.21 mmol) was obtained.
Rf= 0.37 (노말헥산 : 에틸 아세테이트 = 3 : 1, v/v)Rf = 0.37 (normal hexane: ethyl acetate = 3: 1, v/v)
1H NMR (500 MHz, CDCl3) δ 9.84 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.72-4.76 (m, 1H), 3.56-3.62 (m, 4H), 1.86-1.94 (m, 4H), 1.47 (s, 9H). 1 H NMR (500 MHz, CDCl 3 ) δ 9.84 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.72 -4.76 (m, 1H), 3.56-3.62 (m, 4H), 1.86-1.94 (m, 4H), 1.47 (s, 9H).
단계 2: 4-[4-[[4-[[[(9H-플루오렌-9-일)메톡시]카보닐]아미노]피페리딘-1-일]메틸]-2-브로모페녹시]피페리딘-1-Step 2: 4-[4-[[4-[[[(9H-fluoren-9-yl)methoxy]carbonyl]amino]piperidin-1-yl]methyl]-2-bromophenoxy ]Piperidine-1- terttert -부틸 카르복실레이트의 제조-Preparation of butyl carboxylate
상기 단계 1에서 제조한 4-(2-브로모-4-포밀페녹시)피페리딘-1-tert-부틸 카르복실레이트 (12.24 g, 31.85 mmol)를 250 ml의 다이클로로메탄에 용해시킨 후, (9H-플루오렌-9-일)메틸 피페리딘-4-일카바메이트 하이드로클로라이드 (12.57 g, 35.04 mmol)을 첨가하고 상온에서 1시간 교반한 후, 소듐 트리아세톡보로하이드라이드 (8.78 g, 41.41 mmol)을 가하고 상온에서 4시간 교반하였다. 300 ml의 물을 천천히 첨가한 후, 포화 소듐바이카보네이트로 중성화 (pH7)하고 500 ml의 에틸 아세테이트로 추출하였다. 유기층을 무수황산나트륨 (Na2SO4)로 건조시키고, 감압 농축한 후 여액을 실리카겔 컬럼 크로마토그래피 (3% 메탄올/다이클로로메탄, v/v)로 정제하여 목적화합물을 82%의 수율로 (17.91 g, 25.98 mmol)을 얻었다.After dissolving 4-(2-bromo-4-formylphenoxy)piperidine-1- tert -butyl carboxylate (12.24 g, 31.85 mmol) prepared in step 1 in 250 ml of dichloromethane. , (9H-fluoren-9-yl)methyl piperidin-4-ylcarbamate hydrochloride (12.57 g, 35.04 mmol) was added and stirred at room temperature for 1 hour, followed by sodium triacetoxyborohydride (8.78) g, 41.41 mmol) was added and stirred at room temperature for 4 hours. After slowly adding 300 ml of water, it was neutralized (pH7) with saturated sodium bicarbonate and extracted with 500 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ), concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (3% methanol/dichloromethane, v/v) to obtain the target compound in 82% yield (17.91). g, 25.98 mmol) was obtained.
Rf= 0.25 (5% 메탄올/다이클로로메탄, v/v)Rf = 0.25 (5% methanol/dichloromethane, v/v)
1H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.50 (s, 1H), 7.39 (dd, J = 7.4, 7.0 Hz, 2H), 7.30 (dd, J = 7.4, 7.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.64-4.73 (m, 1H), 4.36-4.44 (m, 2H), 4.17-4.23 (m, 1H), 3.58-4.64 (m, 2H), 3.49-3.54 (m, 2H), 3.43 (s, 2H), 2.78-2.90 (m, 2H), 2.07-2.18 (m, 2H), 1.82-1.90 (m, 6H), 1.47 (s, 9H), 1.41-1.46 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.50 (s, 1H), 7.39 (dd, J = 7.4, 7.0 Hz, 2H), 7.30 (dd, J = 7.4, 7.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.64-4.73 (m, 1H), 4.36-4.44 (m, 2H), 4.17-4.23 (m, 1H), 3.58-4.64 (m, 2H), 3.49-3.54 (m, 2H), 3.43 (s, 2H), 2.78-2.90 ( m, 2H), 2.07-2.18 (m, 2H), 1.82-1.90 (m, 6H), 1.47 (s, 9H), 1.41-1.46 (m, 2H).
단계 3: 4-[4-[(4-아미노피페리딘-1-일)메틸]-2-브로모페녹시]피페리딘-1-tert-부틸 카르복실레이트의 제조Step 3: Preparation of 4-[4-[(4-aminopiperidin-1-yl)methyl]-2-bromophenoxy]piperidine-1-tert-butyl carboxylate
상기 단계 2에서 제조한 화합물 (17.91 g, 25.98 mmol)을 250 ml의 메탄올/테트라하이드로퓨란(2/1, v/v)에 용해시킨 후, 2N 소듐 하이드록사이드 (38.97 ml, 77.94 mmol)을 첨가하고 상온에서 20분간 교반하였다. 200 ml의 물을 가하고 500 ml의 에틸 아세테이트로 추출하였다. 유기층을 무수황산나트륨 (Na2SO4)로 건조시키고, 감압 농축한 후 여액을 실리카겔 컬럼 크로마토그래피 (5% 메탄올/다이클로로메탄, v/v)로 정제하여 목적화합물을 82%의 수율로 (10.35 g, 21.42 mmol)을 얻었다.After dissolving the compound (17.91 g, 25.98 mmol) prepared in step 2 in 250 ml of methanol/tetrahydrofuran (2/1, v/v), 2N sodium hydroxide (38.97 ml, 77.94 mmol) was added. It was added and stirred at room temperature for 20 minutes. 200 ml of water was added and extracted with 500 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ), concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (5% methanol/dichloromethane, v/v) to obtain the target compound in 82% yield (10.35). g, 21.42 mmol) was obtained.
Rf= 0.25 (10% 메탄올/다이클로로메탄, v/v)Rf= 0.25 (10% methanol/dichloromethane, v/v)
1H NMR (500 MHz, CDCl3) δ 7.49 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.50-4.55 (m, 1H), 3.60-3.66 (m, 2H), 3.44-3.50 (m, 2H), 3.38 (s, 2H), 2.77-2.82 (m, 2H), 2.61-2.68 (m, 1H), 1.96-2.03 (m, 2H), 1.82-1.91 (m, 4H), 1.75-1.81 (m, 2H), 1.46 (s, 9H), 1.33-1.42 (m, 2H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.49 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.50-4.55 (m, 1H) , 3.60-3.66 (m, 2H), 3.44-3.50 (m, 2H), 3.38 (s, 2H), 2.77-2.82 (m, 2H), 2.61-2.68 (m, 1H), 1.96-2.03 (m, 2H), 1.82-1.91 (m, 4H), 1.75-1.81 (m, 2H), 1.46 (s, 9H), 1.33-1.42 (m, 2H).
<실시예 1> <Example 1> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide
단계 1: 4-(4-((4-(쿠마린-3-카보아미도)피페리딘-1-일)메틸)페녹시)피페리딘-1-tert-부틸 카복실에이트의 제조Step 1: Preparation of 4-(4-((4-(coumarin-3-carboamido)piperidin-1-yl)methyl)phenoxy)piperidine-1-tert-butyl carboxylate
쿠마린-3-카복실산 15 mg (0.08 mmol)과 4-(4-((4-아미노피페리딘-1-일)메틸)-2-브로모페녹시)피페리딘-1-tert-부틸 카복실에이트 40 mg (0.09 mmol) 5 ml의 N,N-디메틸포름아마이드로 용해시킨 후 BOPCl 30 mg (0.12 mmol), 트리에틸아민 33 ul (0.24 mmol)을 가하여 상온에서 16 시간 교반 시켰다. 반응 종결 후 20 ml의 에틸 아세테이트와 20 ml의 물로 추출하였다. 유기층을 소금물로 2차례 씻어주었다. 물층에 목적화합물이 녹아있음 유충을 무수황산마그네슘(MgSO4)으로 건조시키고 여액을 실리카겔 컬럼 크로마토그래피(디클로로메탄 : 메탄올, 30 : 1, v/v)로 정제하여 옅은노란포말의 목적화합물을 75%의 수율로 40 mg (0.06 mmol)을 얻었다.15 mg (0.08 mmol) of coumarin-3-carboxylic acid and 4-(4-((4-aminopiperidin-1-yl)methyl)-2-bromophenoxy)piperidine-1-tert-butyl carboxyl After dissolving 40 mg (0.09 mmol) of 8 in 5 ml of N,N-dimethylformamide, 30 mg (0.12 mmol) of BOPCl and 33 ul (0.24 mmol) of triethylamine were added, followed by stirring at room temperature for 16 hours. After completion of the reaction, extraction was performed with 20 ml of ethyl acetate and 20 ml of water. The organic layer was washed twice with brine. The target compound is dissolved in the water layer. Dry the larvae with anhydrous magnesium sulfate (MgSO 4 ), and the filtrate is purified by silica gel column chromatography (dichloromethane: methanol, 30: 1, v/v) to obtain the target compound in a pale yellow foam. To give 40 mg (0.06 mmol) in% yield.
Rf =0.24 (디클로로메탄 : 메탄올, 20 : 1, v/v)Rf =0.24 (dichloromethane: methanol, 20: 1, v/v)
1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 8.84 (d, J = 7.8 Hz, NH), 7.71 (d, J = 7.9 Hz, 1H), 7.68 (dd, J = 8.4, 7.3 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.9, 7.3 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.54-4.59 (m, 1H), 3.99-4.08 (m, 1H), 3.62-3.69 (m, 2H), 3.47-3.55 (m, 2H), 3.46 (s, 2H), 2.80-2.87 (m, 2H), 2.20-2.29 (m, 2H), 1.99-2.06 (m, 2H), 1.83-1.93 (m, 4H), 1.63-1.72 (m, 2H), 1.49 (s, 9H). 1 H NMR (500 MHz, CDCl 3 ) δ 8.92 (s, 1H), 8.84 (d, J = 7.8 Hz, NH), 7.71 (d, J = 7.9 Hz, 1H), 7.68 (dd, J = 8.4, 7.3 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.9, 7.3 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.54-4.59 (m, 1H), 3.99-4.08 (m, 1H), 3.62-3.69 (m, 2H), 3.47-3.55 (m, 2H), 3.46 (s, 2H), 2.80-2.87 (m, 2H), 2.20-2.29 (m, 2H), 1.99-2.06 (m, 2H), 1.83-1.93 (m, 4H), 1.63 -1.72 (m, 2H), 1.49 (s, 9H).
단계 2:Step 2: NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide
상기 단계 1에서 얻은 화합물 40 mg (0.06 mmol)을 5 ml의 다이옥산에 용해시킨 후 2 ml의 HCl(con.)을 가하여 2 시간 상온 교반 시켰다. 반응 종결후 용매를 감압농축하여 실리카겔 컬럼 크로마토그래피 정제과정 없이 흰고체의 목적화합물을 99%의 수율로 34 mg (0.06 mmol)을 얻었다.After dissolving 40 mg (0.06 mmol) of the compound obtained in step 1 in 5 ml of dioxane, 2 ml of HCl (con.) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure to obtain 34 mg (0.06 mmol) of the target compound as a white solid in a yield of 99% without silica gel column chromatography purification.
1H NMR (500 MHz, CD3OD) δ 8.70 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.47 (dd, J = 8.6, 2.0 Hz, 1H), 7.32 (dd, J = 8.0, 7.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.78-4.85 (m, 1H), 4.19 (s, 2H), 4.00-4.08 (m, 1H), 3.42-3.48 (m, 2H), 3.26-3.34 (m, 2H), 3.14-3.21 (m, 2H), 3.04-3.12 (m, 2H), 1.79-2.19 (m, 8H). 1 H NMR (500 MHz, CD 3 OD) δ 8.70 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.3 , 7.3 Hz, 1H), 7.47 (dd, J = 8.6, 2.0 Hz, 1H), 7.32 (dd, J = 8.0, 7.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (d , J = 8.6 Hz, 1H), 4.78-4.85 (m, 1H), 4.19 (s, 2H), 4.00-4.08 (m, 1H), 3.42-3.48 (m, 2H), 3.26-3.34 (m, 2H) ), 3.14-3.21 (m, 2H), 3.04-3.12 (m, 2H), 1.79-2.19 (m, 8H).
<실시예 2> <Example 2> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-나이트로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-nitro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 상기 제조예 1에서 얻은 6-나이트로-쿠마린-3-카복실산 18 mg (0.07 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 6%의 수율로 2 mg (0.004 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 18 mg (0.07 mmol) of 6-nitro-coumarin-3-carboxylic acid obtained in Preparation Example 1 was used. 2 mg (0.004 mmol) of the target compound was obtained in a yield of 6% in two steps.
1H NMR (500 MHz, CD3OD) δ 8.97 (s, 1H), 8.84 (d, J = 2.2 Hz ,1H), 8.58 (dd, J = 8.8, 2.2 Hz, 1H), 7.86 (d, J = 1.9 Hz ,1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.9 Hz ,1H), 7.30 (d, J = 8.8 Hz, 1H), 4.94-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.43-3.45 (m, 2H), 3.29-3.31 (m, 2H), 3.16-3.03 (m, 2H), 2.30-2.34 (m, 2H), 2.12-2.22 (m, 4H), 1.87-1.05 (m, 2H) 1 H NMR (500 MHz, CD 3 OD) δ 8.97 (s, 1H), 8.84 (d, J = 2.2 Hz ,1H), 8.58 (dd, J = 8.8, 2.2 Hz, 1H), 7.86 (d, J = 1.9 Hz ,1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.9 Hz ,1H), 7.30 (d, J = 8.8 Hz, 1H), 4.94-4.98 (m , 1H), 4.32 (s, 2H), 4.14-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.43-3.45 (m, 2H), 3.29-3.31 (m, 2H), 3.16-3.03 (m, 2H), 2.30-2.34 (m, 2H), 2.12-2.22 (m, 4H), 1.87-1.05 (m, 2H)
<실시예 3> <Example 3> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-메톡시-쿠마린-3-카복시아마이드의 제조-(1-(3-Bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methoxy-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-메톡시-쿠마린-3-카복실산 14 mg (0.06 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 39%의 수율로 12 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 14 mg (0.06 mmol) of 6-methoxy-coumarin-3-carboxylic acid was used to integrate the target compound in two steps. 12 mg (0.02 mmol) was obtained in a yield of 39%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.68 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 2.9 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.9 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.99-4.05 (m, 1H), 3.83 (s, 3H), 3.16-3.22 (m, 2H), 3.10-3.15 (m, 2H), 2.02-2.08 (m, 2H), 2.03-2.14 (m, 5H), 1.83-1.94 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.79 (s, 1H), 8.68 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H) , 7.56 (d, J = 2.9 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.9 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H) , 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.99-4.05 (m, 1H), 3.83 (s, 3H), 3.16-3.22 (m, 2H), 3.10-3.15 (m, 2H) , 2.02-2.08 (m, 2H), 2.03-2.14 (m, 5H), 1.83-1.94 (m, 5H)
<실시예 4> <Example 4> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-클로로-쿠마린-3-카복실산 21 mg (0.09 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 18%의 수율로 9 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 21 mg (0.09 mmol) of 6-chloro-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps 18 To give 9 mg (0.02 mmol) in% yield.
1H NMR (500 MHz, CD3OD) δ 8.97 (d, J = 7.1 Hz, 1H), 8.83 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.87 (s, 1H), 7.75 (dd, J = 8.6, 2.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.15-4.19 (m, 1H), 3.56-3.60 (m, 2H), 3.40-3.47 (m, 2H), 3.28-3.31 (m, 2H), 3.17-3.22 (m, 2H), 2.29-2.32 (m, 2H), 2.09-2.23 (m, 4H), 1.88-1.95 (m, 2H) 1 H NMR (500 MHz, CD 3 OD) δ 8.97 (d, J = 7.1 Hz, 1H), 8.83 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.87 (s, 1H), 7.75 (dd, J = 8.6, 2.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.15-4.19 (m, 1H), 3.56-3.60 (m, 2H), 3.40-3.47 (m, 2H), 3.28-3.31 (m, 2H) ), 3.17-3.22 (m, 2H), 2.29-2.32 (m, 2H), 2.09-2.23 (m, 4H), 1.88-1.95 (m, 2H)
<실시예 5> <Example 5> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-브로모-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-bromo-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-브로모-쿠마린-3-카복실산 20 mg (0.07 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 6%의 수율로 2 mg (0.004 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, the target compound was integrated in two steps by performing the same method as in Example 1, except that 20 mg (0.07 mmol) of 6-bromo-coumarin-3-carboxylic acid was used. 2 mg (0.004 mmol) was obtained in a yield of 6%.
1H NMR (500 MHz, CD3OD) δ 8.84 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 8.1 Hz ,1H), 7.80 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.78-4.84 (m, 1H), 7.30 (s, 2H), 4.14-4.19 (m, 1H), 3.51-3.66 (m, 4H), 3.43-3.49 (m, 2H), 3.14-3.24 (m, 2H), 2.31-2.33 (m, 2H), 2.12-2.23 (m, 2H), 1.91-2.00 (m, 2H), 1.77-1.89 (m, 2H) 1 H NMR (500 MHz, CD 3 OD) δ 8.84 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 8.1 Hz ,1H), 7.80 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.78-4.84 (m, 1H), 7.30 (s, 2H), 4.14-4.19 (m, 1H), 3.51-3.66 (m, 4H), 3.43-3.49 (m, 2H), 3.14-3.24 (m, 2H), 2.31-2.33 (m, 2H), 2.12-2.23 (m, 2H) , 1.91-2.00 (m, 2H), 1.77-1.89 (m, 2H)
<실시예 6> <Example 6> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-메틸-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methyl-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-메틸-쿠마린-3-카복실산 18 mg (0.08 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 41%의 수율로 17 mg (0.03 mmol)을 얻었다.In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 6-methyl-coumarin-3-carboxylic acid 18 mg (0.08 mmol) was used, the target compound was combined in two steps 41 To give 17 mg (0.03 mmol) in% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.74 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.61 (s, 1H), 7.62 (dd, J = 8.6, 1.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.97-4.04 (m, 1H), 3.18-3.24 (m, 2H), 3.08-3.14 (m, 2H), 3.02-3.06 (m, 2H), 2.39 (s, 3H), 2.05-2.15 (m, 5H), 1.89-1.96 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.74 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.61 (s, 1H) , 7.62 (dd, J = 8.6, 1.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H) , 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.97-4.04 (m, 1H), 3.18-3.24 (m, 2H), 3.08-3.14 (m, 2H), 3.02-3.06 (m, 2H) 2H), 2.39 (s, 3H), 2.05-2.15 (m, 5H), 1.89-1.96 (m, 5H)
<실시예 7> <Example 7> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-플루오로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-fluoro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-플루오로-쿠마린-3-카복실산 16 mg (0.12 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 4%의 수율로 2 mg (0.004 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 16 mg (0.12 mmol) of 6-fluoro-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps. 2 mg (0.004 mmol) was obtained in a 4% yield.
1H NMR (500 MHz, CD3OD) δ 8.86 (s, 1H), 7.86 (s, 1H), 7.66 (dd, J = 8.0, 2.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.55 (ddd, J = 9.2, 8.9, 2.8 Hz, 1H), 7.49 (dd, J = 9.2, 4.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.20 (m, 1H), 3.58-3.60 (m, 2H), 3.42-3.47 (m, 3H), 3.16-3.22 (m, 2H), 2.30-2.33 (m, 2H), 2.12-2.23 (m, 5H), 1.87-1.94 (m, 2H) 1 H NMR (500 MHz, CD 3 OD) δ 8.86 (s, 1H), 7.86 (s, 1H), 7.66 (dd, J = 8.0, 2.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H ), 7.55 (ddd, J = 9.2, 8.9, 2.8 Hz, 1H), 7.49 (dd, J = 9.2, 4.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.20 (m, 1H), 3.58-3.60 (m, 2H), 3.42-3.47 (m, 3H), 3.16-3.22 (m, 2H), 2.30-2.33 ( m, 2H), 2.12-2.23 (m, 5H), 1.87-1.94 (m, 2H)
<실시예 8> <Example 8> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-시아노-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-cyano-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-시아노-쿠마린-3-카복실산 25 mg (0.12 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 22%의 수율로 14 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, 6-cyano-coumarin-3-carboxylic acid 25 mg (0.12 mmol) was used, and the target compound was integrated in two steps by performing the same method as in Example 1 above. 14 mg (0.02 mmol) was obtained in a yield of 22%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 8.6, 1.6 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 8.3, 1.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.84-4.87 (m, 1H), 4.21 (s, 2H), 4.00-4.04 (m, 2H), 3.35-3.37 (m, 2H), 3.17-3.23 (m, 2H), 3.10-3.15 (m, 2H), 3.02-3.08 (m, 2H), 2.07-2.15 (m, 4H), 1.90-1.97 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.75 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 8.6, 1.6 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 8.3, 1.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.84-4.87 (m, 1H), 4.21 (s, 2H), 4.00-4.04 (m, 2H), 3.35-3.37 (m, 2H), 3.17-3.23 (m, 2H) , 3.10-3.15 (m, 2H), 3.02-3.08 (m, 2H), 2.07-2.15 (m, 4H), 1.90-1.97 (m, 4H)
<실시예 9> <Example 9> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-메톡시-쿠마린-3-카복시아마이드의 제조-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methoxy-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-메톡시-쿠마린-3-카복실산 14 mg (0.06 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 54%의 수율로 18 mg (0.03 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 14 mg (0.06 mmol) of 7-methoxy-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps. 18 mg (0.03 mmol) was obtained in a yield of 54%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.60 (dd, J = 8.6, 1.3 Hz ,1H), 7.32 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 8.6, 2.2 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.04 (m, 1H), 3.90 (s, 3H), 3.16-3.23 (m, 2H), 3.08-3.14 (m, 2H), 3.01-3.07 (m, 2H), 2.03-2.14 (m, 5H), 1.85-1.95 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.81 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.60 (dd, J = 8.6, 1.3 Hz ,1H), 7.32 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 8.6, 2.2 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.04 (m, 1H), 3.90 (s, 3H), 3.16-3.23 (m, 2H), 3.08 -3.14 (m, 2H), 3.01-3.07 (m, 2H), 2.03-2.14 (m, 5H), 1.85-1.95 (m, 5H)
<실시예 10> <Example 10> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-메틸-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methyl-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-메틸-쿠마린-3-카복실산 17 mg (0.08 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 63%의 수율로 33 mg (0.05 mmol)을 얻었다.In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 7-methyl-coumarin-3-carboxylic acid 17 mg (0.08 mmol) was used, the target compound was integrated in two steps 63 To give 33 mg (0.05 mmol) in% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 1.9 Hz ,1H), 7.87 (d, J = 7.9 Hz ,1H), 7.60 (dd, J = 7.9, 1.9 Hz ,1H), 7.36 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.84-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.05 (m, 1H), 3.18-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.20-3.08 (m, 2H), 2.46 (s, 3H), 2.04-2.15 (m, 5H), 1.84-1.95 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.79 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 1.9 Hz ,1H), 7.87 (d, J = 7.9 Hz ,1H), 7.60 (dd, J = 7.9, 1.9 Hz ,1H), 7.36 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H) , 4.84-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.05 (m, 1H), 3.18-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.20-3.08 (m, 2H), 2.46 (s, 3H), 2.04-2.15 (m, 5H), 1.84-1.95 (m, 5H)
<실시예 11> <Example 11> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-플루오로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-플루오로-쿠마린-3-카복실산 15 mg (0.07 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 35%의 수율로 14 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, in the same manner as in Example 1 except for using 7-fluoro-coumarin-3-carboxylic acid 15 mg (0.07 mmol), the target compound was integrated in two steps. 14 mg (0.02 mmol) was obtained in a 35% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.82 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.08 (dd, J = 8.9, 6.5 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.59 (dd, J = 8.6, 1.7 Hz, 1H), 7.54 (dd, J = 9.6, 2.4 Hz, 1H), 7.37 (ddd, J = 8.9, 8.6, 2.4 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.99-4.05 (m, 1H), 3.16-3.23 (m, 2H), 3.10-3.16 (m, 2H), 3.02-3.07 (m, 2H), 2.03-2.15 (m, 5H), 1.85-1.95 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.82 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.08 (dd, J = 8.9, 6.5 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.59 (dd, J = 8.6, 1.7 Hz, 1H), 7.54 (dd, J = 9.6, 2.4 Hz, 1H), 7.37 (ddd, J = 8.9, 8.6, 2.4 Hz, 1H ), 7.31 (d, J = 8.6 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.99-4.05 (m, 1H), 3.16-3.23 (m, 2H), 3.10- 3.16 (m, 2H), 3.02-3.07 (m, 2H), 2.03-2.15 (m, 5H), 1.85-1.95 (m, 5H)
<실시예 12> <Example 12> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-클로로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-클로로-쿠마린-3-카복실산 17 mg (0.07 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 44%의 수율로 19 mg (0.03 mmol)을 얻었다.In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 7-chloro-coumarin-3-carboxylic acid 17 mg (0.07 mmol) was used, the target compound was integrated in two steps 44 To give 19 mg (0.03 mmol) in% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 8.5 Hz ,1H), 7.90 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 1.6 Hz ,1H), 7.60 (dd, J = 8.5, 1.6 Hz ,1H), 7.53 (dd, J = 8.1, 1.6 Hz, 1H), 7.32 (d, J = 8.1 Hz ,1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.04 (m, 1H), 3.18-3.23 (m, 2H), 3.09-3.16 (m, 2H), 3.02-3.08 (m, 2H), 2.03-2.15 (m, 5H), 1.86-1.97 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.80 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 8.5 Hz ,1H), 7.90 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 1.6 Hz ,1H), 7.60 (dd, J = 8.5, 1.6 Hz ,1H), 7.53 (dd, J = 8.1, 1.6 Hz, 1H), 7.32 (d, J = 8.1 Hz ,1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.04 (m, 1H), 3.18-3.23 (m, 2H), 3.09-3.16 (m, 2H) , 3.02-3.08 (m, 2H), 2.03-2.15 (m, 5H), 1.86-1.97 (m, 5H)
<실시예 13> <Example 13> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-브로모-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-bromo-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-브로모-쿠마린-3-카복실산 21 mg (0.07 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 28%의 수율로 12 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, 7-bromo-coumarin-3-carboxylic acid 21 mg (0.07 mmol) was used in the same manner as in Example 1, and the target compound was integrated in two steps. 12 mg (0.02 mmol) was obtained in a yield of 28%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.59 (d, J = 7.2 Hz ,1H), 7.92 (d, J = 8.1 Hz ,1H), 7.89 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.1, 1.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.03 (m, 1H), 3.17-3.24 (m, 2H), 3.10-3.16 (m, 2H), 3.01-3.09 (m, 2H), 2.02-2.14 (m, 5H), 1.85-1.95 (m, 5H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.79 (s, 1H), 8.59 (d, J = 7.2 Hz ,1H), 7.92 (d, J = 8.1 Hz ,1H), 7.89 (s, 1H) , 7.87 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.1, 1.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H) , 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.03 (m, 1H), 3.17-3.24 (m, 2H), 3.10-3.16 (m, 2H), 3.01-3.09 (m, 3) 2H), 2.02-2.14 (m, 5H), 1.85-1.95 (m, 5H)
<실시예 14> <Example 14> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-시아노-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-cyano-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-시아노-쿠마린-3-카복실산 18 mg (0.08 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 19%의 수율로 10 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, it was carried out in the same manner as in Example 1, except that 18 mg (0.08 mmol) of 7-cyano-coumarin-3-carboxylic acid was used, and the target compound was integrated in two steps. 10 mg (0.02 mmol) was obtained with a yield of 19%.
1H NMR (500 MHz, CD3OD-d 4 ) δ 8.90 (d, J = 7.0 Hz, 1H), 8.87 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.16-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.43-3.37 (m, 2H), 3.30-3.32 (m, 2H), 3.17-3.22 (m, 2H), 2.28-2.32 (m, 2H), 2.19-2.24 (m, 2H), 2.12-2.16 (m, 2H), 1.93-1.98 (m, 2H) 1 H NMR (500 MHz, CD 3 OD- d 4 ) δ 8.90 (d, J = 7.0 Hz, 1H), 8.87 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 4.95-4.98 ( m, 1H), 4.32 (s, 2H), 4.16-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.43-3.37 (m, 2H), 3.30-3.32 (m, 2H), 3.17- 3.22 (m, 2H), 2.28-2.32 (m, 2H), 2.19-2.24 (m, 2H), 2.12-2.16 (m, 2H), 1.93-1.98 (m, 2H)
<실시예 15> <Example 15> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-플루오로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-fluoro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 8-플루오로-쿠마린-3-카복실산 18 mg (0.08 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 21%의 수율로 10 mg (0.02 mmol)을 얻었다.In the same manner as in Example 1, except for using 8-fluoro-coumarin-3-carboxylic acid 18 mg (0.08 mmol) instead of using coumarin-3-carboxylic acid, the target compound was integrated in two steps. 10 mg (0.02 mmol) was obtained with a yield of 21%.
1H NMR (500 MHz, CD3OD) δ 8.93 (d, J = 7.1 Hz, 1H), 8.88 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.58-7.62 (m, 2H), 7.41-7.45 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.95-4.98 (m, 1H), 4.33 (s, 2H), 4.16-4.22 (m, 1H), 3.58-3.60 (m, 2H), 3.42-3.48 (m, 2H), 3.29-3.32 (m, 2H), 3.15-3.23 (m, 2H), 2.30-2.33 (m, 2H), 2.20-2.25 (m, 2H), 2.10-2.17 (m, 2H), 1.90-1.98 (m, 2H) 1 H NMR (500 MHz, CD 3 OD) δ 8.93 (d, J = 7.1 Hz, 1H), 8.88 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.58-7.62 (m, 2H), 7.41-7.45 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.95-4.98 (m, 1H), 4.33 (s, 2H), 4.16-4.22 ( m, 1H), 3.58-3.60 (m, 2H), 3.42-3.48 (m, 2H), 3.29-3.32 (m, 2H), 3.15-3.23 (m, 2H), 2.30-2.33 (m, 2H), 2.20-2.25 (m, 2H), 2.10-2.17 (m, 2H), 1.90-1.98 (m, 2H)
<실시예 16> <Example 16> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-메틸-쿠마린-3-카복시아마이드의 제조-(1-(3-Bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 8-메틸-쿠마린-3-카복실산 12 mg (0.06 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 58%의 수율로 18 mg (0.03 mmol)을 얻었다.In the same manner as in Example 1, except that instead of using coumarin-3-carboxylic acid, 8-methyl-coumarin-3-carboxylic acid 12 mg (0.06 mmol) was used, the target compound was integrated in two steps 58 To give 18 mg (0.03 mmol) in% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.64 (d, J = 7.0 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.9 Hz, 1H), 7.35 (dd, J = 7.8, 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 4.83-4.86 (m, 1H), 4.21 (s, 2H), 3.99-4.05 (m, 1H), 3.35-3.37 (m, 2H), 3.18-3.22 (m, 2H), 3.09-3.16 (m, 2H), 3.03-3.08 (m, 2H), 2.40 (s, 3H), 2.08-2.15 (m, 4H), 1.89-1.96 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.78 (s, 1H), 8.64 (d, J = 7.0 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.9 Hz, 1H), 7.35 (dd, J = 7.8, 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 4.83-4.86 (m, 1H), 4.21 (s, 2H), 3.99-4.05 (m, 1H), 3.35-3.37 (m, 2H), 3.18-3.22 (m, 2H) , 3.09-3.16 (m, 2H), 3.03-3.08 (m, 2H), 2.40 (s, 3H), 2.08-2.15 (m, 4H), 1.89-1.96 (m, 4H)
<실시예 17> <Example 17> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-5-클로로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-5-chloro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 5-클로로-쿠마린-3-카복실산 26 mg (0.12 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 57%의 수율로 36 mg (0.06 mmol)을 얻었다.In the same manner as in Example 1, except for using 5-chloro-coumarin-3-carboxylic acid 26 mg (0.12 mmol) instead of using coumarin-3-carboxylic acid, the target compound was integrated in two steps 57 To give 36 mg (0.06 mmol) in% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.62 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 4.01-4.05 (m, 1H), 3.35-3.37 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.02-3.07 (m, 2H), 2.08-2.15 (m, 4H), 1.90-1.96 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.73 (s, 1H), 8.62 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 4.01-4.05 (m, 1H), 3.35-3.37 (m, 2H), 3.17-3.23 (m, 2H), 3.09 -3.15 (m, 2H), 3.02-3.07 (m, 2H), 2.08-2.15 (m, 4H), 1.90-1.96 (m, 4H)
<실시예 18> <Example 18> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이메톡시-쿠마린-3-카복시아마이드의 제조-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethoxy-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6,7-다이메톡시-쿠마린-3-카복실산 22 mg (0.09 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 71%의 수율로 30 mg (0.05 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, the target compound was prepared in the same manner as in Example 1, except that 22 mg (0.09 mmol) of 6,7-dimethoxy-coumarin-3-carboxylic acid was used. Two steps combined to give 30 mg (0.05 mmol) in 71% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 8.3, 1.9 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.05 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.35-3.38 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.08-2.14 (m, 4H), 1.86-1.94 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.80 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 8.3, 1.9 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.05 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.35-3.38 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.08-2.14 (m, 4H), 1.86-1.94 (m, 4H)
<실시예 19> <Example 19> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이플루오로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-difluoro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6,7-다이플루오로-쿠마린-3-카복실산 18 mg (0.08 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 35%의 수율로 17 mg (0.03 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, the target compound was prepared in the same manner as in Example 1, except that 18 mg (0.08 mmol) of 6,7-difluoro-coumarin-3-carboxylic acid was used. The two-step integration yielded 17 mg (0.03 mmol) in 35% yield.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.14 (dd, J = 10.1, 8.8 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 11.1, 6.8 Hz, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.97-4.04 (m, 1H), 3.33-3.36 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.14 (m, 2H), 3.01-3.08 (m, 2H), 2.07-2.14 (m, 4H), 1.88-1.96 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.76 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.14 (dd, J = 10.1, 8.8 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 11.1, 6.8 Hz, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83- 4.87 (m, 1H), 4.21 (s, 2H), 3.97-4.04 (m, 1H), 3.33-3.36 (m, 2H), 3.17-3.23 (m, 2H), 3.09-3.14 (m, 2H), 3.01-3.08 (m, 2H), 2.07-2.14 (m, 4H), 1.88-1.96 (m, 4H)
<실시예 20> <Example 20> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이메틸-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethyl-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6,7-다이메틸-쿠마린-3-카복실산 15 mg (0.07 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 24%의 수율로 9 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, 6,7-dimethyl-coumarin-3-carboxylic acid 15 mg (0.07 mmol) was used, and the target compound was prepared in the same manner as in Example 1 above. Step integration yielded 9 mg (0.02 mmol) in 24% yield.
1H NMR (500 MHz, CD3OD-d 4 ) δ 9.04 (d, J = 7.5 Hz, 1H), 8.79 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.59 (s, 1H), 7.58 (dd, J = 8.4, 1.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 4.95-4.98 (m, 1H), 4.33 (s, 2H), 4.15-4.19 (m, 1H), 3.57-3.60 (m, 2H), 3.42-3.47 (m, 2H), 3.29-3.32 (m, 2H), 3.17-3.22 (m, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 2.30-2.32 (m, 2H), 2.19-2.24 (m, 2H), 2.12-2.17 (m, 4H), 1.90-1.96 (m, 4H) 1 H NMR (500 MHz, CD 3 OD- d 4 ) δ 9.04 (d, J = 7.5 Hz, 1H), 8.79 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.59 (s, 1H), 7.58 (dd, J = 8.4, 1.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 4.95-4.98 (m, 1H), 4.33 (s, 2H ), 4.15-4.19 (m, 1H), 3.57-3.60 (m, 2H), 3.42-3.47 (m, 2H), 3.29-3.32 (m, 2H), 3.17-3.22 (m, 2H), 2.43 (s , 3H), 2.37 (s, 3H), 2.30-2.32 (m, 2H), 2.19-2.24 (m, 2H), 2.12-2.17 (m, 4H), 1.90-1.96 (m, 4H)
<실시예 21> <Example 21> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이클로로-쿠마린-3-카복시아마이드의 제조-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dichloro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6,7-다이클로로-쿠마린-3-카복실산 17 mg (0.06 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 39%의 수율로 16 mg (0.02 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, 6,7-dichloro-coumarin-3-carboxylic acid was used in the same manner as in Example 1, except that 17 mg (0.06 mmol) was used to prepare two target compounds. Step integration gave 16 mg (0.02 mmol) in a yield of 39%.
1H NMR (500 MHz, CD3OD-d 4 ) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.74 (s, 1H), 7.57 (dd, J = 8.2, 1.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.19 (m, 1H), 3.57-3.59 (m, 2H), 3.42-3.47 (m, 2H), 3.29-3.31 (m, 2H), 3.16-3.21 (m, 2H), 2.29-2.31 (m, 2H), 2.18-2.24 (m, 2H), 2.11-2.16 (m, 2H), 1.87-1.94 (m, 2H) 1 H NMR (500 MHz, CD 3 OD- d 4 ) δ 8.82 (s, 1H), 8.11 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.74 (s, 1H), 7.57 ( dd, J = 8.2, 1.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 4.95-4.98 (m, 1H), 4.32 (s, 2H), 4.14-4.19 (m, 1H), 3.57 -3.59 (m, 2H), 3.42-3.47 (m, 2H), 3.29-3.31 (m, 2H), 3.16-3.21 (m, 2H), 2.29-2.31 (m, 2H), 2.18-2.24 (m, 2H), 2.11-2.16 (m, 2H), 1.87-1.94 (m, 2H)
<실시예 22> <Example 22> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-7-메틸-쿠마린-3-카복시아마이드의 제조-(1-(3-Bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-methyl-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-클로로-7-메틸-쿠마린-3-카복실산 24 mg (0.10 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 38%의 수율로 21 mg (0.03 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, the target compound was prepared in the same manner as in Example 1, except that 24 mg (0.10 mmol) of 6-chloro-7-methyl-coumarin-3-carboxylic acid was used. Two steps combined to give 21 mg (0.03 mmol) in a yield of 38%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.74 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.63 (dd, J = 8.4, 1.3 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.04 (m, 1H), 3.34-3.36 (m, 2H), 3.17-3.22 (m, 2H), 3.10-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.46 (s, 3H), 2.06-2.16 (m, 4H), 1.89-1.97 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.74 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 1.3 Hz, 1H) , 7.63 (dd, J = 8.4, 1.3 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.22 (s, 2H), 3.98-4.04 (m, 1H), 3.34-3.36 (m, 2H), 3.17-3.22 (m, 2H), 3.10-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.46 (s, 3H) ), 2.06-2.16 (m, 4H), 1.89-1.97 (m, 4H)
<실시예 23> <Example 23> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-7-플루오로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-fluoro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 6-클로로-7-플루오로-쿠마린-3-카복실산 24 mg (0.10 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 42%의 수율로 25 mg (0.04 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, the target compound was carried out in the same manner as in Example 1, except that 24 mg (0.10 mmol) of 6-chloro-7-fluoro-coumarin-3-carboxylic acid was used. To give 25 mg (0.04 mmol) in a yield of 42% in two steps.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.61 (dd, J = 8.5, 1.7 Hz ,1H), 7.31 (d, J = 8.5 Hz ,1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.03 (m, 1H), 3.34-3.37 (m, 2H), 3.17-3.22 (m, 2H), 3.09-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.05-2.15 (m, 4H), 1.89-1.96 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.76 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.61 (dd, J = 8.5, 1.7 Hz ,1H), 7.31 (d, J = 8.5 Hz ,1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.03 (m, 1H), 3.34-3.37 (m, 2H), 3.17-3.22 (m, 2H), 3.09-3.15 (m, 2H), 3.01-3.07 ( m, 2H), 2.05-2.15 (m, 4H), 1.89-1.96 (m, 4H)
<실시예 24> <Example 24> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-클로로-6-플루오로-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-6-fluoro-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-클로로-6-플루오로-쿠마린-3-카복실산 29 mg (0.12 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 28%의 수율로 20 mg (0.03 mmol)을 얻었다.The target compound was carried out in the same manner as in Example 1, except that 29 mg (0.12 mmol) of 7-chloro-6-fluoro-coumarin-3-carboxylic acid was used instead of using coumarin-3-carboxylic acid. The two-step integration yielded 20 mg (0.03 mmol) in a yield of 28%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.74 (s, 1H), 8.60 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.05 (m, 1H), 3.34-3.37 (m, 2H), 3.17-3.22 (m, 2H), 3.10-3.15 (m, 2H), 3.01-3.07 (m, 2H), 2.06-2.15 (m, 4H), 1.88-1.96 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.74 (s, 1H), 8.60 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.98-4.05 (m, 1H), 3.34-3.37 (m, 2H), 3.17-3.22 (m, 2H), 3.10-3.15 (m, 2H), 3.01-3.07 ( m, 2H), 2.06-2.15 (m, 4H), 1.88-1.96 (m, 4H)
<실시예 25> <Example 25> NN -(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-플루오로-6-메틸-쿠마린-3-카복시아마이드의 제조Preparation of -(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-6-methyl-coumarin-3-carboxyamide
쿠마린-3-카복실산을 사용하는 대신에, 7-플루오로-6-메틸-쿠마린-3-카복실산 19 mg (0.08 mmol)을 사용하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 수행하여 목적화합물을 두 단계 통합 63%의 수율로 27 mg (0.05 mmol)을 얻었다.Instead of using coumarin-3-carboxylic acid, the target compound was carried out in the same manner as in Example 1, except that 19 mg (0.08 mmol) of 7-fluoro-6-methyl-coumarin-3-carboxylic acid was used. The two steps combined to give 27 mg (0.05 mmol) in a yield of 63%.
1H NMR (500 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.61 (dd, J = 8.4, 1.5 Hz, 1H), 7.50 (d, J = 10.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.99-4.03 (m, 1H), 3.36-3.37 (m, 2H), 3.18-3.22 (m, 2H), 3.11-3.14 (m, 2H), 3.01-3.07 (m, 2H), 2.30 (s, 3H), 2.06-2.15 (m, 4H), 1.88-1.96 (m, 4H) 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.75 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.61 (dd, J = 8.4, 1.5 Hz, 1H), 7.50 (d, J = 10.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.83-4.87 (m, 1H), 4.21 (s, 2H), 3.99-4.03 (m, 1H), 3.36-3.37 (m, 2H), 3.18-3.22 (m, 2H), 3.11-3.14 (m, 2H), 3.01-3.07 ( m, 2H), 2.30 (s, 3H), 2.06-2.15 (m, 4H), 1.88-1.96 (m, 4H)
하기 표 1에 실시예 1-25에서 제조한 화합물의 화학구조식을 정리하여 나타내었다.The chemical structural formulas of the compounds prepared in Examples 1-25 are summarized and shown in Table 1 below.
<실험예 1> 쿠마린-3-카복시아마이드 유도체의 유로텐신-Ⅱ 수용체 결합 억제활성 측정<Experimental Example 1> Measurement of urotensin-II receptor binding inhibitory activity of coumarin-3-carboxyamide derivatives
본 발명에 따른 쿠마린-3-카복시아마이드 유도체의 유로텐신-Ⅱ 수용체에 대한 결합 억제 활성을 확인하기 위하여, 자동여과법 기반 시차성형광분석법 (Filtration-based Time-resolved fluorescence assay)으로 하기와 같은 실험을 수행하였다.In order to confirm the binding inhibitory activity of the coumarin-3-carboxyamide derivatives according to the present invention to the eurotensin-II receptor, the following experiment was performed using a Filtration-based Time-resolved fluorescence assay based on an automatic filtration method. Performed.
완충용액은 세척용액 (25 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2)과 실험용액(세척용액에 BSA 0.5%가 되도록 첨가)의 두 종류를 준비하고, 1 uM 유로피움으로 표지된 유로텐신 농축호르몬(Europium-labeled Urotensin-Ⅱ, Eu-UⅡ), PerkinElmer, Turku, Finland) 및 1 mM 유로텐신 농축호르몬(유로텐신-Ⅱ, #070-47, Sigma-Aldrich, St.Louis, MO, USA)을 4℃에서 준비하였다. 1 uM의 Eu-UⅡ과 1 mM 유로텐신-Ⅱ를 각각 8 nM(최종 반응농도: 2 nM)과 4 μM(최종 반응농도: 1 μM)이 되도록 희석하였다. 모든 희석과 준비과정에서 사용되는 완충용액은 실험용액이며, 세척용액은 마지막에 플레이트를 씻어 줄 때만 사용하였다. 결합시험법을 위한 유로텐신-Ⅱ 수용체 세포막 준비는 100 cm2 flask에서 대량 배양된 유로텐신-Ⅱ 수용체가 과발현된 HEK293UT 세포주를 이용하였다. 세포가 90% 이상 자라면 배지를 제거하고 PBS buffer로 2회 세척한 후에 2 ml의 1 mM EDTA-PBS buffer를 첨가하여 37℃, 5분 동안 반응시켜 세포를 수확하였다. 수확된 세포는 PBS buffer로 다시 2회 세척한 후에 0.5% Protease Inhibitor cocktail이 첨가된 lysis buffer (10 mM Tris pH 7.4, 5 mM Na-EDTA)에 현탁 시킨 후 초음파 분쇄기로 분쇄하였다. 세포파편은 300g에서 5분 동안 원심 분리하여 제거하였고, 상층액은 47000g에서 20분 동안 초원심 분리하여 세포막 분획이 포함된 침전물을 얻었다. 세포막 분획 침전물을 storage buffer (50 mM Tris-HCl pH 7.4, 0.5 mM EDTA, 5 mM MgCl2, 10% sucrose)에 용해시킨 후, Bradford 방법에 의해 농도를 측정하였다.Two kinds of buffer solutions were prepared: washing solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (added to 0.5% BSA to the washing solution), and labeled with 1 uM europium. Eurotensin-concentrated hormone (Europium-labeled Urotensin-II, Eu-UII), PerkinElmer, Turku, Finland) and 1 mM urotensin-concentrated hormone (Eurotensin-II, #070-47, Sigma-Aldrich, St.Louis, MO) , USA) was prepared at 4°C. 1 uM of Eu-UII and 1 mM urotensin-II were diluted to 8 nM (final reaction concentration: 2 nM) and 4 μM (final reaction concentration: 1 μM), respectively. The buffer solution used in all dilution and preparation processes was the experimental solution, and the washing solution was used only when washing the plate at the end. Urotensin-II receptor cell membranes were prepared for the binding assay using HEK293 UT cell line overexpressing the eurotensin-II receptor cultured in a 100 cm 2 flask. When the cells grew more than 90%, the medium was removed, washed twice with PBS buffer, and then 2 ml of 1 mM EDTA-PBS buffer was added and reacted at 37° C. for 5 minutes to harvest the cells. The harvested cells were washed twice with PBS buffer and then suspended in lysis buffer (10 mM Tris pH 7.4, 5 mM Na-EDTA) to which 0.5% Protease Inhibitor cocktail was added, and then crushed with an ultrasonic grinder. Cell debris was removed by centrifugation at 300 g for 5 minutes, and the supernatant was ultracentrifuged at 47000 g for 20 minutes to obtain a precipitate containing the cell membrane fraction. The cell membrane fraction precipitate was dissolved in a storage buffer (50 mM Tris-HCl pH 7.4, 0.5 mM EDTA, 5 mM MgCl2, 10% sucrose), and the concentration was measured by the Bradford method.
유로텐신-Ⅱ 수용체 (30 mg/ml) 50 ul를 5 ml 실험용액에 희석하여 균질화 시킨 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 50 ml씩 유로텐신-Ⅱ 수용체를 분주하였다. 이때, 비특이적결합(non specific binding) 대조군으로는 Eu-UⅡ 25 ml 및 유로텐신-Ⅱ 25 ml를 분주하였으며, 전체결합 (total binding) 대조군으로는 10% DMSO 실험용액 25 ml 및 Eu-MCH 25 ml를 사용하였다. 실험 군으로는 본 발명에 따른 상기 화학식으로 표시되는 신규 화합물 25 ml 및 Eu-UⅡ 25 ml를 사용하였다. 각 시험 화합물, Eu-UⅡ 및 유로텐신-Ⅱ은 반응 시 전체부피의 25%씩을 차지하게 되므로 첨가 직전에는 4배의 농도로 준비하였다. 이후, 15초간 약하게 흔들어 주고 상온에서 90분간 반응시켰다.After diluting 50 ul of eurotensin-II receptor (30 mg/ml) in 5 ml experimental solution and homogenizing, 8 microplates with filter paper (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA) were placed 8 Using a channel pipette (multi 8-channel, Eppendorf, Hamburg, Germany), the eurotensin-II receptor was dispensed at 50 ml per well. At this time, 25 ml of Eu-UII and 25 ml of Eurotensin-II were dispensed as a non-specific binding control, and 25 ml of 10% DMSO experimental solution and 25 ml of Eu-MCH were dispensed as a total binding control. Was used. As an experimental group, 25 ml of a novel compound represented by the above formula according to the present invention and 25 ml of Eu-UII were used. Each test compound, Eu-UII and Eurotensin-II, occupied 25% of the total volume during the reaction, so they were prepared at a concentration of 4 times just before addition. Then, it was gently shaken for 15 seconds and reacted for 90 minutes at room temperature.
반응이 끝나면, 부분적으로 수정하여 자체 제작한 자동여과세척기(microplate filtration washer, EMBLA, Molecular Devices)에 압력을 걸어 플레이트를 여과 세척하였다. 세척 용액으로 웰당 300 ml씩 3회 여과시켜 반응하지 않고 남아 있는 Eu-UⅡ을 제거하였다. 바닥의 물기를 닦아내고 웰당 150 ml가 되게 해리용액(DELFIA Enhancement solution, PerkinElmer, Turku, Finland)을 첨가하여 주었다. 상온에서 15분 동안 약하게 흔들어 준 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.When the reaction was over, the plate was filtered and washed by applying pressure to a self-made automatic filtration washer (microplate filtration washer, EMBLA, Molecular Devices) that was partially modified. The washing solution was filtered three times at 300 ml per well to remove Eu-UII remaining without reaction. The water on the bottom was wiped off, and a dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) was added to make 150 ml per well. After gently shaking for 15 minutes at room temperature, the value of time-resolved fluorescence (TRF) was measured using a multilabel counter (Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615 nm, excitation Wavelength: 340 nm), and the parallax fluorescence inhibition rate was calculated by the following equation (1).
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 only for test substances inhibited by 50% or more, and the results are shown in Table 2 below.
상기 표 2에 나타낸 바와 같이, 본 발명의 모든 실시예 화합물이 낮은 농도에서 유로텐신-Ⅱ 수용체에 대해 길항작용을 하는 것으로 확인되었다. 특히, 본 발명에 따른 실시예 3-4, 6, 11-13, 16-17, 19, 21, 23-25 화합물은 IC50 값 30 nM 이하의 낮은 농도에서도 유로텐신-Ⅱ 수용체에 대하여 길항작용을 하는 바, 유로텐신-Ⅱ 수용체에 대한 길항효과가 우수한 것을 알 수 있다.As shown in Table 2, it was confirmed that all of the compounds of the examples of the present invention had an antagonistic action against the eurotensin-II receptor at a low concentration. In particular, the compounds of Examples 3-4, 6, 11-13, 16-17, 19, 21, and 23-25 according to the present invention have an antagonistic effect on the urotensin-II receptor even at low concentrations of 30 nM or less with an IC 50 value. As a bar, it can be seen that the antagonistic effect against the eurotensin-II receptor is excellent.
따라서, 본 발명에 따른 화합물은 유로텐신-Ⅱ 수용체에 대한 길항제로 작용함으로써 울혈성 심부전, 심장 허혈, 심근경색, 심장 비대증 및 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 우울증, 정신병, 암 등과 같은 유로텐신-Ⅱ 수용체 활성 관련 질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.Therefore, the compound according to the present invention acts as an antagonist to the urotensin-II receptor, thereby congesting heart failure, heart ischemia, myocardial infarction, cardiac hypertrophy and fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, kidney failure, diabetes, blood vessels. Inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer, such as eurotensin-II receptor activity-related diseases can be usefully used to prevent or treat.
<제제예 1> 산제의 제조<Formulation Example 1> Preparation of powder
화학식 1로 표시되는 유도체 2g2g of derivatives represented by Formula 1
유당 1g1g lactose
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in an airtight cloth to prepare a powder.
<제제예 2> 정제의 제조<Formulation Example 2> Preparation of tablets
화학식 1로 표시되는 유도체 100 ㎎100 mg of derivatives represented by Formula 1
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎100 mg lactose
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.
<제제예 3> 캡슐제의 제조<Formulation Example 3> Preparation of capsules
화학식 1로 표시되는 유도체 100 ㎎100 mg of derivatives represented by Formula 1
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎100 mg lactose
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 ingredients, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule.
<제제예 4> 주사제의 제조<Formulation Example 4> Preparation of injection
화학식 1로 표시되는 유도체 100 ㎎100 mg of derivatives represented by Formula 1
만니톨 180 ㎎Mannitol 180 mg
Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 ㆍ2H 2 O 26 mg
증류수 2974 ㎎Distilled water 2974 mg
통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to a conventional method for preparing injections, injections were prepared by containing the above ingredients in the indicated amount.
<제제예 5> 건강식품의 제조<Formulation Example 5> Preparation of health food
화학식 1로 표시되는 유도체 500ng500 ng of derivatives represented by formula 1
비타민 혼합물 적량Vitamin mixture right amount
비타민 A 아세테이트 70mg 70mg vitamin A acetate
비타민 E 1.0mg1.0mg vitamin E
비타민 0.13mg0.13mg vitamin
비타민 B2 0.15mg0.15mg vitamin B2
비타민 B6 0.5mg0.5mg vitamin B6
비타민 B12 0.2mg0.2mg vitamin B12
비타민 C 10mg10mg vitamin C
비오틴 10mg10mg biotin
니코틴산아미드 1.7mg1.7 mg of nicotinic acid amide
엽산 50mg50mg folic acid
판토텐산 칼슘 0.5mg0.5mg calcium pantothenate
무기질 혼합물 적량Suitable amount of inorganic mixture
황산제1철 1.75mg1.75 mg ferrous sulfate
산화아연 0.82mgZinc oxide 0.82mg
탄산마그네슘 25.3mg25.3mg magnesium carbonate
제1인산칼륨 15mg15 mg of potassium monophosphate
제2인산칼슘 55mgDicalcium phosphate 55mg
구연산칼륨 90mg90mg potassium citrate
탄산칼슘 100mg100mg calcium carbonate
염화마그네슘 24.8mgMagnesium chloride 24.8mg
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.The composition ratio of the vitamin and mineral mixture is relatively suitable for health food, but it may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. , To prepare granules, and can be used to prepare a health food composition according to a conventional method.
<제제예 6> 건강음료의 제조<Formulation Example 6> Preparation of health drink
화학식 1로 표시되는 유도체 500ng500 ng of derivatives represented by formula 1
구연산 1000mg1000mg citric acid
올리고당 100g100g oligosaccharide
매실농축액 2g2g plum concentrate
타우린 1g1 g taurine
정제수를 가하여 전체 900mlTotal 900ml with purified water
통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 음료 조성물 제조에 사용하였다.After mixing the above ingredients according to a normal health drink manufacturing method, stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then stored in a refrigerator. Used in preparation.
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.The composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.
Claims (10)
[화학식 1]
(상기 화학식 1에서,
R1은 수소, 할로겐, NO2, CN, 직쇄 또는 분지쇄의 C1-10알킬 또는 직쇄 또는 분지쇄의 C1-10알콕시이고;
R2는 할로겐이고; 및
r은 1-4의 정수이다).
A compound represented by the following formula (1), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In Formula 1,
R 1 is hydrogen, halogen, NO 2 , CN, straight or branched C 1-10 alkyl or straight or branched C 1-10 alkoxy;
R 2 is halogen; And
r is an integer from 1-4).
상기 R1은 수소, 할로겐, NO2, CN, 직쇄 또는 분지쇄의 C1-6알킬 또는 직쇄 또는 분지쇄의 C1-6알콕시인 것을 특징으로 하는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
The method of claim 1,
The R 1 is hydrogen, halogen, NO 2 , CN, a straight-chain or branched C 1-6 alkyl or a straight-chain or branched C 1-6 alkoxy compound, a solvate thereof, a hydrate thereof, or a pharmaceutical thereof An acceptable salt.
상기 R1은 수소, 할로겐, NO2, CN, C1-4알킬 또는 C1-4알콕시인 것을 특징으로 하는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
The method of claim 1,
The R 1 is hydrogen, halogen, NO 2 , CN, C 1-4 alkyl or C 1-4 alkoxy A compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
상기 R1은 수소, F, Cl, Br, NO2, CN, 메틸 또는 메톡시이고;
R2는 Br이고; 및
r은 1 또는 2인 것을 특징으로 하는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
The method of claim 1,
R 1 is hydrogen, F, Cl, Br, NO 2 , CN, methyl or methoxy;
R 2 is Br; And
r is 1 or 2, a compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:
(1)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-쿠마린-3-카복시아마이드;
(2)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-나이트로-쿠마린-3-카복시아마이드;
(3)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-메톡시-쿠마린-3-카복시아마이드;
(4)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-쿠마린-3-카복시아마이드;
(5)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-브로모-쿠마린-3-카복시아마이드;
(6)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-메틸-쿠마린-3-카복시아마이드;
(7)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-플루오로-쿠마린-3-카복시아마이드;
(8)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-시아노-쿠마린-3-카복시아마이드;
(9)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-메톡시-쿠마린-3-카복시아마이드;
(10)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-메틸-쿠마린-3-카복시아마이드;
(11)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-플루오로-쿠마린-3-카복시아마이드;
(12)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-클로로-쿠마린-3-카복시아마이드;
(13)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-브로모-쿠마린-3-카복시아마이드;
(14)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-시아노-쿠마린-3-카복시아마이드;
(15)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-플루오로-쿠마린-3-카복시아마이드;
(16)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-메틸-쿠마린-3-카복시아마이드;
(17)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-8-메틸-쿠마린-3-카복시아마이드;
(18)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이메톡시-쿠마린-3-카복시아마이드;
(19)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이플루오로-쿠마린-3-카복시아마이드;
(20)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이메틸-쿠마린-3-카복시아마이드;
(21)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6,7-다이클로로-쿠마린-3-카복시아마이드;
(22)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-7-메틸-쿠마린-3-카복시아마이드;
(23)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-6-클로로-7-플루오로-쿠마린-3-카복시아마이드;
(24)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-클로로-6-플루오로-쿠마린-3-카복시아마이드;및
(25)N-(1-(3-브로모-4-(피페리딘-4-일옥시)벤질)피페리딘-4-일)-7-플루오로-6-메틸-쿠마린-3-카복시아마이드.
The method of claim 1,
The compound represented by Formula 1 is a compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following compound group:
(1) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-coumarin-3-carboxyamide;
(2) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-nitro-coumarin-3-carboxyamide;
(3) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methoxy-coumarin-3-carboxyamide;
(4) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-coumarin-3-carboxyamide;
(5) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-bromo-coumarin-3-carboxyamide;
(6) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-methyl-coumarin-3-carboxyamide;
(7) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-fluoro-coumarin-3-carboxyamide;
(8) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-cyano-coumarin-3-carboxyamide;
(9) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methoxy-coumarin-3-carboxyamide;
(10) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-methyl-coumarin-3-carboxyamide;
(11) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-coumarin-3-carboxyamide;
(12) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-coumarin-3-carboxyamide;
(13) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-bromo-coumarin-3-carboxyamide;
(14) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-cyano-coumarin-3-carboxyamide;
(15) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-fluoro-coumarin-3-carboxyamide;
(16) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;
(17) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-8-methyl-coumarin-3-carboxyamide;
(18) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethoxy-coumarin-3-carboxy Amide;
(19) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-difluoro-coumarin-3-carboxy Amide;
(20) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dimethyl-coumarin-3-carboxyamide ;
(21) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6,7-dichloro-coumarin-3-carboxyamide ;
(22) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-methyl-coumarin-3-carboxy Amide;
(23) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-6-chloro-7-fluoro-coumarin-3- Carboxyamide;
(24) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-chloro-6-fluoro-coumarin-3- Carboxyamide; and
(25) N- (1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)-7-fluoro-6-methyl-coumarin-3- Carboxyamide.
화학식 3으로 표시되는 화합물과 화학식 4으로 표시되는 화합물을 반응시켜 화학식 2으로 표시되는 화합물을 제조하는 단계(단계 1); 및
화학식 2로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 2)를 포함하는 제1항의 화학식 1로 표시되는 화합물의 제조방법:
[반응식 1]
(상기 반응식 1에서,
R1, R2 및 r은 제1항의 화학식 1에서 정의한 바와 같고; 및
PGa는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이다).
As shown in Scheme 1 below,
Preparing a compound represented by Formula 2 by reacting a compound represented by Formula 3 with a compound represented by Formula 4 (Step 1); And
A method for preparing a compound represented by Formula 1 of claim 1 comprising the step of preparing a compound represented by Formula 1 (step 2) by reacting a compound represented by Formula 2:
[Scheme 1]
(In the above Scheme 1,
R 1 , R 2 and r are as defined in Formula 1 of claim 1; And
PG a is t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p- Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2 -Is one type of amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc)).
상기 유로텐신-Ⅱ 수용체 활성 관련 질환은 혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 정신병 및 암으로 이루어지는 군으로부터 선택되는 1종 이상의 질환인 것을 특징으로 하는 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for the prevention or treatment of diseases related to urotensin-II receptor activity containing a compound represented by Formula 1 of claim 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , A pharmaceutical composition for prevention or treatment, characterized in that at least one disease selected from the group consisting of psychosis and cancer.
상기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염은 유로텐신-Ⅱ 수용체에 대하여 길항작용을 하는 것을 특징으로 하는 예방 또는 치료용 약학적 조성물.
The method of claim 7,
The compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is a pharmaceutical composition for prophylaxis or treatment, characterized in that antagonistic action against the eurotensin-II receptor.
상기 유로텐신-Ⅱ 수용체 활성 관련 질환은 혈성 심부전, 심장 허혈, 심근경색, 심장 비대증, 심장 섬유증, 관상동맥 질환, 동맥경화증, 고혈압, 천식, 신부전, 당뇨병, 혈관염증, 신경퇴행성 질환, 뇌졸중, 통증, 정신병 및 암으로 이루어지는 군으로부터 선택되는 1종 이상의 질환인 것을 특징으로 하는 예방 또는 개선용 건강기능식품 조성물.It is a health functional food composition for the prevention or improvement of diseases related to urotensin-II receptor activity containing the compound represented by Formula 1 of claim 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
The diseases related to the activity of the eurotensin-II receptor include blood heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, high blood pressure, asthma, kidney failure, diabetes, vasculitis, neurodegenerative diseases, stroke, pain. , Health functional food composition for preventing or improving, characterized in that at least one disease selected from the group consisting of psychosis and cancer.
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EP0416581A1 (en) | 1989-09-05 | 1991-03-13 | G.D. Searle & Co. | Substituted N-benzylpiperidine amides |
KR101725451B1 (en) | 2016-05-25 | 2017-04-13 | 한국화학연구원 | N--4--1H--2- - N-piperidin-4-yl-1H-indole-2-carboxamide derivatives preparation method thereof and pharmaceutical composition for use in preventing or treating Urotensin- receptor activity related diseases containing the same as an active ingredient |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0416581A1 (en) | 1989-09-05 | 1991-03-13 | G.D. Searle & Co. | Substituted N-benzylpiperidine amides |
KR101725451B1 (en) | 2016-05-25 | 2017-04-13 | 한국화학연구원 | N--4--1H--2- - N-piperidin-4-yl-1H-indole-2-carboxamide derivatives preparation method thereof and pharmaceutical composition for use in preventing or treating Urotensin- receptor activity related diseases containing the same as an active ingredient |
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