KR102649592B1 - Novel macrocyclic compound, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer or autoimmune disease containing the same as an active ingredient - Google Patents
Novel macrocyclic compound, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer or autoimmune disease containing the same as an active ingredient Download PDFInfo
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- KR102649592B1 KR102649592B1 KR1020210108442A KR20210108442A KR102649592B1 KR 102649592 B1 KR102649592 B1 KR 102649592B1 KR 1020210108442 A KR1020210108442 A KR 1020210108442A KR 20210108442 A KR20210108442 A KR 20210108442A KR 102649592 B1 KR102649592 B1 KR 102649592B1
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- cancer
- formula
- compound
- diaza
- dipyridazina
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/18—Bridged systems
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
-
- 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
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Abstract
본 발명은 신규한 마크로사이클 화합물, 이의 제조방법, 이를 유효성분으로 포함하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물에 관한 것으로, 본 명세서에 기재된 화학식 1로 표시되는 화합물은 글루타미네이즈에 대한 우수한 억제 활성을 나타내면서, 암세포에 대한 세포 독성이 우수하여 암 또는 자가면역질환에 유용할 것으로 기대된다.The present invention relates to a novel macrocycle compound, a method for producing the same, and a pharmaceutical composition for preventing or treating cancer or autoimmune diseases containing the same as an active ingredient. The compound represented by Formula 1 described herein is glutaminase. It exhibits excellent inhibitory activity against and is expected to be useful for cancer or autoimmune diseases due to its excellent cytotoxicity against cancer cells.
Description
본 발명은 신규한 마크로사이클 화합물, 이의 제조방법, 이를 유효성분으로 포함하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel macrocycle compound, a method for producing the same, and a pharmaceutical composition for preventing or treating cancer or autoimmune diseases containing the same as an active ingredient.
최근 종양 특이적 대사 경로를 공략하여 암을 선택적으로 억제하고자 하는 대사 항암제가 급부상하고 있다. 암은 증식과 생존을 위해 선택적 대사 경로를 사용하기 때문에, 대사의 재조정은 암 표현형의 주요 특성이다. 따라서 특정 유전 변이를 가지고 있는 암세포들이 어떤 특이적 대사 회로를 재조정하여 증식하는지 많은 연구가 이루어지고 있다. Recently, metabolic anticancer drugs that aim to selectively suppress cancer by targeting tumor-specific metabolic pathways are rapidly emerging. Because cancer uses selective metabolic pathways for proliferation and survival, metabolic rebalancing is a key characteristic of the cancer phenotype. Therefore, much research is being conducted on how cancer cells with specific genetic mutations proliferate by reorganizing specific metabolic circuits.
글루코스(Glucose)와 글루타민(Glutamine)은 암 증식에 사용되는 주요 대사 연료이다. 대부분 암은 급속한 종양 성장을 유지하는데 필요한 단백질 동화 및 이화성 요구를 충족시키기 위해 글루코스 대사의 높은 수준을 활용한다. 이때 항암제 등에 의한 대사 스트레스를 받으면 이를 극복하기 위해 아미노산과 같은 대체 영양소를 이용한다. Glucose and glutamine are the main metabolic fuels used for cancer growth. Most cancers utilize high levels of glucose metabolism to meet the protein anabolic and catabolic demands necessary to sustain rapid tumor growth. At this time, when metabolic stress occurs due to anticancer drugs, etc., alternative nutrients such as amino acids are used to overcome this stress.
글루타민은 혈액에서 발견되는 가장 풍부한 아미노산이며, 거대 분자 생합성 (macromolecular synthesis)에 중요한 전구체인 뉴클레오타이드, 비필수 아미노산 및 지방산 등의 생합성에 필요한 탄소와 질소 원자의 주요 공급원이다. 또한 글루타민과 글루타민 유래 대사산물은 에너지 생산, 산화 환원의 항상성, 유전자 전사 및 암세포의 세포 내 신호전달에도 참여하는 것으로 알려져 있다. Glutamine is the most abundant amino acid found in blood and is a major source of carbon and nitrogen atoms required for the biosynthesis of nucleotides, non-essential amino acids, and fatty acids, which are important precursors for macromolecular synthesis. Additionally, glutamine and glutamine-derived metabolites are known to participate in energy production, redox homeostasis, gene transcription, and intracellular signaling in cancer cells.
이와 같이 암세포에 있어서 글루타민 대사의 변화는 에너지 대사 및 산화 환원 반응뿐만 아니라 암세포의 지속적인 증식과 관련된 여러 가지 신호 전달체계를 활성화하며, 세포 노화 과정과 세포 사멸을 억제하는 방향으로 작용하여 암의 진행과 악화에 영향을 끼칠 수 있다. 따라서 글루타민 대사를 표적으로 하는 것은 다수의 암 아형에서 매력적인 치료 옵션이다. In this way, changes in glutamine metabolism in cancer cells activate not only energy metabolism and redox reactions, but also various signaling systems related to the continuous proliferation of cancer cells, and act to inhibit the cellular aging process and cell death, thereby slowing the progression of cancer. It may contribute to worsening. Therefore, targeting glutamine metabolism is an attractive therapeutic option in multiple cancer subtypes.
특히 글루타민이 글루타메이트(Glutamate)로, 이어 알파-케토글루타레이트(Alpha-ketoglutarate, AKG)로 전환하는 일련의 과정인 글루타민 분해(glutaminolysis)의 재조정이 전이 및 항암제 내성과 밀접한 관련이 있다는 연구 보고와 함께, 글루타민 대사 관련 효소 중 글루타미네이즈 (glutaminase, GLS1)가 종양 대사의 중요한 표적으로 주목받고 있다(비특허문헌 1, Medina, et al, J. Nutr., September 1, 2001, Vol. 131, No. 9, 2539S-2542S). In particular, research reports that readjustment of glutaminolysis, a series of processes that convert glutamine to glutamate and then to alpha-ketoglutarate (AKG), is closely related to metastasis and anticancer drug resistance. Together, among enzymes related to glutamine metabolism, glutaminase (GLS1) is attracting attention as an important target of tumor metabolism (Non-patent Document 1, Medina, et al, J. Nutr ., September 1, 2001, Vol. 131, No. 9, 2539S-2542S).
특히, 폐 선암종 (lung adenocarcinomas)에서 세 번째로 가장 많이 돌연변이 된 유전자로 알려진 KEAP1은 KRAS 발암성 돌연변이와 빈번하게 동시 발생한다. KEAP1- 또는 NRF2- 돌연변이를 가진 암이 상향 조절된 글루타민 분해에 상당히 의존적이며, 이 특성이 글루타미네이즈의 약리학적 억제를 통해 치료적으로 이용될 수 있음이 보고되고 있다 (비특허문헌 2, R. Romero, et al, Nature Medicine, November 2017, Vol. 23, No. 11).In particular, KEAP1, known as the third most frequently mutated gene in lung adenocarcinomas, frequently co-occurs with KRAS oncogenic mutations. It has been reported that cancers with KEAP1- or NRF2- mutations are significantly dependent on upregulated glutaminolysis, and that this property can be exploited therapeutically through pharmacological inhibition of glutaminase (Non-patent Document 2, R Romero, et al, Nature Medicine, November 2017, Vol. 23, No. 11).
또한, 글루타미네이즈는 자가면역질환과도 관련되어 있다고 알려져 있다(비특허문헌 3, Michihito Kono, et al, Arthritis & Rheumatology, 2019 Nov;71(11):1869-1878).In addition, glutaminase is known to be related to autoimmune diseases (Non-patent Document 3, Michihito Kono, et al, Arthritis & Rheumatology, 2019 Nov;71(11):1869-1878).
대한민국 공개특허공보 제10-2015-0091389호에는 글루타미네이즈 저해제 화합물들이 개시되어 있고, 이중 CB-839 화합물이 항암제로서 개발되고 있다.Korean Patent Publication No. 10-2015-0091389 discloses glutaminase inhibitor compounds, and among them, CB-839 compound is being developed as an anticancer agent.
본 발명자들은 글루타미네이즈의 새로운 억제제를 개발하기 위하여, 신규한 마크로사이클 화합물을 합성하였고, 이들이 글루타미네이즈에 대한 저해 활성을 타내는 것을 확인하고 본 발명을 완성하였다.In order to develop a new inhibitor of glutaminase, the present inventors synthesized new macrocycle compounds, confirmed that they exhibit inhibitory activity against glutaminase, and completed the present invention.
본 발명의 일 목적은 글루타미네이즈를 저해하는 신규한 마크로사이클 화합물을 제공하는 데 있다.One object of the present invention is to provide a novel macrocycle compound that inhibits glutaminase.
본 발명의 다른 목적은 신규한 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer or autoimmune diseases.
상기 목적을 달성하기 위하여,In order to achieve the above purpose,
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
L은 C1-20의 직쇄 알킬렌이고, 여기서 알킬렌의 하나 이상의 탄소 원자는 산소 원자로 치환될 수 있다.L is a C 1-20 straight chain alkylene, where one or more carbon atoms of the alkylene may be replaced with an oxygen atom.
다른 측면에서, 본 발명은 하기 반응식 1에서 나타낸 바와 같이,In another aspect, the present invention is as shown in Scheme 1 below,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 아마이드화 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 1)를 포함하는 화학식 1로 표시되는 화합물의 제조방법을 제공한다.A method for producing a compound represented by Formula 1 is provided, which includes the step (step 1) of producing a compound represented by Formula 1 by subjecting a compound represented by Formula 2 to an amidation reaction with a compound represented by Formula 3.
[반응식 1][Scheme 1]
상기 반응식 1에서,In Scheme 1 above,
L은 상기 화학식 1에서 정의한 바와 같다.L is as defined in Formula 1 above.
다른 측면에서, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer or autoimmune disease containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
또 다른 측면에서, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In another aspect, the present invention provides a health functional food composition for preventing or improving cancer or autoimmune diseases containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. provides.
본 명세서에 기재된 화학식 1로 표시되는 화합물은 글루타미네이즈에 대한 우수한 억제 활성을 나타내면서, 암세포에 대한 세포 독성이 우수하여 암 또는 자가면역질환에 유용할 것으로 기대된다.The compound represented by Formula 1 described herein exhibits excellent inhibitory activity against glutaminase and has excellent cytotoxicity against cancer cells, so it is expected to be useful for cancer or autoimmune diseases.
도 1은 ALK-TKI 내성 세포에 본 발명에 따른 화합물을 처리한 후, 글루타민과 글루타메이트 레벨을 측정한 결과를 나타낸 것이다.Figure 1 shows the results of measuring glutamine and glutamate levels after treating ALK-TKI resistant cells with a compound according to the present invention.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
한편, 본 발명의 실시 형태는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한, 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다.Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, the embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field.
나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Furthermore, “including” a certain element throughout the specification means that other elements may be further included rather than excluding other elements, unless specifically stated to the contrary.
본 발명의 일 측면은,One aspect of the present invention is,
하기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.Provided is a compound represented by the following formula (1), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
본 발명의 일 실시형태에서,In one embodiment of the present invention,
상기 화학식 1에서,In Formula 1,
L은 C1-20의 알킬렌이고, 여기서 알킬렌의 하나 이상의 탄소 원자는 산소 원자로 치환될 수 있다.L is C 1-20 alkylene, where one or more carbon atoms of the alkylene may be replaced with an oxygen atom.
본 발명의 일 실시형태에서,In one embodiment of the present invention,
상기 화학식 1에서,In Formula 1,
L은 C1-20의 직쇄 알킬렌이고, 여기서 알킬렌의 하나 이상의 탄소 원자는 산소 원자로 치환될 수 있다.L is a C 1-20 straight chain alkylene, where one or more carbon atoms of the alkylene may be replaced with an oxygen atom.
본 발명의 일 실시형태에서,In one embodiment of the present invention,
상기 화학식 1에서,In Formula 1,
상기 L은 -O-C1-15 직쇄 알킬렌-O-이고, 여기서 알킬렌의 하나 이상의 탄소 원자는 산소 원자로 치환될 수 있되 산소 원자끼리는 결합하지 않는다.The L is -OC 1-15 straight chain alkylene-O-, where one or more carbon atoms of alkylene may be replaced with oxygen atoms, but the oxygen atoms do not bond to each other.
본 발명의 일 실시형태에서,In one embodiment of the present invention,
상기 화학식 1에서,In Formula 1,
상기 L은 -O-L1-이고, 상기 L1는 -[(CH2)p-O]m-이며, p는 1 내지 10의 정수, m은 1 내지 5의 정수이고, L1의 탄소 및 산소 개수의 합은 12 이내이다.The L is -OL 1 -, the L 1 is -[(CH 2 )pO]m-, p is an integer from 1 to 10, m is an integer from 1 to 5, and the number of carbon and oxygen of L 1 The sum is within 12.
본 발명의 일 실시형태에서,In one embodiment of the present invention,
상기 화학식 1에서,In Formula 1,
상기 L은 , , , , , , , , 또는 이다.The L is , , , , , , , , or am.
본 발명의 일 실시형태에서,In one embodiment of the present invention,
상기 화학식 1에서 하기 화합물 군으로부터 선택되는 어느 하나인 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.In Formula 1, any one compound selected from the following compound group, its solvate, its hydrate, or its pharmaceutically acceptable salt is provided.
<1> 6,9-디옥사-2,13-디아자-1,14(3,6)-디피리다지나-5,10(1,3)-디벤제나시클로옥타데카판-3,12-디온;<1> 6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3,12- Dion;
<2> 15,19-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로노나데카판-3,12-디온;<2> 15,19-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclononadecapane-3,12- Dion;
<3> 15,20-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로이코사판-3,12-디온;<3> 15,20-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloicosaphane-3,12-dione ;
<4> 15,21-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헤니코사판-3,12-디온;<4> 15,21-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosapan-3,12- Dion;
<5> 15,18,21-트리옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헤니코사판-3,12-디온;<5> 15,18,21-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosapan-3, 12-dione;
<6> 15,22-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로도코사판-3,12-디온;<6> 15,22-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclodocosaphane-3,12-dione ;
<7> 15,23-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온;<7> 15,23-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione ;
<8> 15,19,23-트리옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온;<8> 15,19,23-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosapan-3,12 -Dion;
<9> 15,18,21,24-테트라옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로테트라코사판-3,12-디온; 및<9> 15,18,21,24-tetraoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotetracosapan- 3,12-dione; and
<10> 15,18,21,24,27-펜타옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헵타코사판-3,12-디온.<10> 15,18,21,24,27-pentaoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloheptaco Sapan-3,12-dione.
용어 “알킬렌” 또는 "알킬"은, 달리 명시되지 않는 한, 직쇄 또는 분지쇄의 포화된 탄화수소 잔기를 포함한다. 예를 들어, "C1-6 알킬"은 1 내지 6개 탄소로 골격이 이루어진 알킬을 의미한다. 구체적으로 C1-6 알킬은 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, i-펜틸, t-펜틸, sec-펜틸, 네오펜틸, 헥실 등을 포함할 수 있다.The term “alkylene” or “alkyl,” unless otherwise specified, includes straight or branched chain saturated hydrocarbon moieties. For example, “C 1-6 alkyl” means alkyl with a skeleton of 1 to 6 carbons. Specifically, C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl. , hexyl, etc.
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, 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 as the salt. 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. It is obtained from 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. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-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, Includes glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.
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 conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular 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, 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 non-covalent intermolecular forces. 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 non-covalent intermolecular forces. The hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water. Such hydrates can be prepared by crystallizing the compounds represented by Formula 1 of the present invention and their pharmaceutically acceptable salts 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 invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.
본 발명의 다른 일 측면에서,In another aspect of the present invention,
하기 반응식 1에 나타낸 바와 같이,As shown in Scheme 1 below,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 아마이드화 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 1)를 포함하는 화학식 1로 표시되는 화합물의 제조방법을 제공한다.A method for producing a compound represented by Formula 1 is provided, which includes the step (step 1) of producing a compound represented by Formula 1 by subjecting a compound represented by Formula 2 to an amidation reaction with a compound represented by Formula 3.
[반응식 1][Scheme 1]
상기 반응식 1에서,In Scheme 1 above,
L은 상기 화학식 1에서 정의한 바와 같다.L is as defined in Formula 1 above.
이하, 상기 반응식 1의 제조방법을 상세히 설명한다.Hereinafter, the manufacturing method of Scheme 1 will be described in detail.
상기 반응식 1의 제조방법에서, 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 아마이드화 반응 시키는 단계로서, 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계이다. 이때 용매로는 유기용매, 예를 들면 DMF나 톨루엔 등이 사용될 수 있으며, 아마이드화 반응을 위해 통상적으로 사용되는 조건을 사용하여 수행할 수 있다.In the preparation method of Scheme 1, Step 1 is a step of amidation reaction between the compound represented by Formula 2 and the compound represented by Formula 3, and the compound represented by Formula 2 is reacted with the compound represented by Formula 3 to obtain Formula 1 This is the step of producing a compound represented by . At this time, an organic solvent such as DMF or toluene may be used as the solvent, and the amidation reaction may be performed using conditions commonly used for the amidation reaction.
상기 제조방법은 하나의 예시로서 제시된 본 발명의 일 실시예에 한정되는 것은 아니며, 통상의 유기화학적인 지식 하에 용매, 반응 물질, 온도 조건 등을 변형하여 수행 가능하다.The above manufacturing method is not limited to one embodiment of the present invention presented as an example, and can be performed by modifying the solvent, reaction material, temperature conditions, etc. under common organic chemistry knowledge.
본 발명의 다른 일 측면에서,In another aspect of the present invention,
상기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.Provided is a pharmaceutical composition for the prevention or treatment of cancer or autoimmune disease containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화합물은 글루타미네이즈를 억제하는 것을 특징으로 한다.The compound is characterized by inhibiting glutaminase.
상기 화합물은 암세포에 대해서 세포독성을 가지며, 암세포는 기존 항암제 내성 암세포일 수 있고, 일례로서 세리티닙(Ceritinib)에 내성을 갖는 암세포일 수 있다. The compound has cytotoxicity against cancer cells, and the cancer cells may be cancer cells resistant to existing anticancer drugs, and as an example, may be cancer cells resistant to Ceritinib.
상기 암은 방광암, 유방암, 결장암, 신장암, 간암, 폐암, 소세포폐암, 식도암, 담낭암, 난소암, 췌장암, 위암, 자궁 경부암, 갑상선암, 전립선암, 및 피부암 중 어느 하나인 것일 수 있다.The cancer may be any one of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.
상기 자가면역질환은 건선, 류마티스성 관절염, 혈관염, 염증성 장 질환, 피부염, 골관절염, 천식, 염증성 근육 질환, 알러지성 질환 (예를 들면, 알러지성 비염), 질염, 간질 방광염, 경피증, 골다공증, 습진, 동종이계 또는 이종발생성 이식 (장기, 골수, 줄기세포 및 다른 세포 및 조직) 이식 거부, 이식편대숙주질환, 홍반성 낭창, 염증성 질환, I형 당뇨병, 폐 섬유증, 피부근염, 쇼그렌 증후군, 갑상선염 (예를 들면, 하시모토 및 자가면역 갑상선염), 중증 근무력증, 자가면역 용혈성 빈혈, 다발성 경화증, 낭포성 섬유증, 만성적 재발성 간염, 원발성 담도성 간경변증, 알러지성 결막염 및 아토피 피부염 중 어느 하나인 것일 수 있다.The autoimmune diseases include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease (e.g., allergic rhinitis), vaginitis, interstitial cystitis, scleroderma, osteoporosis, and eczema. , allogeneic or xenogeneic transplantation (organs, bone marrow, stem cells and other cells and tissues), transplant rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis. (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis. .
본 발명에 있어서, 용어 “유효성분으로 함유하는”이란, 암 또는 자가면역질환의 예방, 개선, 또는 치료의 효과를 가져오는 용량 범위로 함유하는 것을 의미하고, 중증도 및 제형에 따라 용량 범위는 변할 수 있으며, 적용 횟수도 적용 대상의 연령, 체중 및 체질에 따라 변할 수 있다. 본 발명의 한 구체예에서, 본 발명의 약학적 조성물 내에서 화학식 1로 표시되는 화합물은 예를 들어, 0.001 mg/kg 이상, 바람직하게는 0.1 mg/kg 이상, 보다 바람직하게는 10 mg/kg 이상, 보다 더 바람직하게는 100 mg/kg 이상, 보다 더욱 더 바람직하게는 250 mg/kg 이상, 가장 바람직하게는 0.1 g/kg 이상 포함된다. 본 발명의 약학적 조성물 내에 포함되는 화학식 1로 표시되는 화합물의 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.In the present invention, the term “containing as an active ingredient” means containing in a dosage range that brings about the effect of preventing, improving, or treating cancer or autoimmune disease, and the dosage range may vary depending on the severity and formulation. The number of applications may also vary depending on the age, weight, and constitution of the subject. In one embodiment of the present invention, the compound represented by Formula 1 in the pharmaceutical composition of the present invention is used in an amount of, for example, 0.001 mg/kg or more, preferably 0.1 mg/kg or more, more preferably 10 mg/kg. or more, more preferably 100 mg/kg or more, even more preferably 250 mg/kg or more, and most preferably 0.1 g/kg or more. The upper quantitative limit of the compound represented by Formula 1 contained in the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.
본 발명에 따른 약학적 조성물은 유효량의 화학식 1로 표시되는 화합물을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다.The pharmaceutical composition according to the present invention may contain an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.
상기 약학적으로 허용되는 담체, 부형제 또는 희석제는 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 물질을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있으며, 이에 제한되는 것은 아니다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.The pharmaceutically acceptable carrier, excipient, or diluent refers to a substance that is physiologically acceptable and does not typically cause gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to humans. Examples of the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Examples include, but are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.
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 등이 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 dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.
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. A 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 can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you 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 with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form. It can be manufactured with The composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.
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.Dosage forms for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. These dosage forms contain a diluent (e.g. lactose) in addition to the active ingredient. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron agents such as starch, agar, alginic acid or its sodium salt, etc. The releasing or boiling mixture may contain absorbents, colorants, flavoring agents, and sweeteners.
본 발명에 있어서, 용어 “예방”이란, 본 발명의 약학적 조성물, 건강기능식품 조성물을 암 또는 자가면역질환의 투병중이지 않은 개체에게 투여, 섭취 또는 적용하여 암 또는 자가면역질환의 증세를 억제 또는 차단함으로써, 암 또는 자가면역질환의 증세가 사전에 발생되지 않도록 하는 것을 의미한다.In the present invention, the term “prevention” refers to suppressing symptoms of cancer or autoimmune disease by administering, ingesting, or applying the pharmaceutical composition or health functional food composition of the present invention to an individual who is not suffering from cancer or autoimmune disease. This means preventing symptoms of cancer or autoimmune disease from occurring in advance by blocking it.
본 발명에 있어서, 용어 “치료”란, 본 발명의 약학적 조성물을 암 또는 자가면역질환 투병중인 개체에게 투여한 결과로서 암 또는 자가면역질환의 증세의 완치는 물론 암 또는 자가면역질환의 증세의 부분적 완치, 호전 및 경감을 포함한다.In the present invention, the term “treatment” refers to the cure of symptoms of cancer or autoimmune disease as well as the treatment of symptoms of cancer or autoimmune disease as a result of administering the pharmaceutical composition of the present invention to an individual suffering from cancer or autoimmune disease. Includes partial cure, improvement, and relief.
본 발명의 약제학적 조성물은 약학적으로 유효한 양으로 투여한다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
본 발명에 있어서, 용어 “약학적으로 유효한 양”이란, 의학적 치료 또는 개선에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.In the present invention, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.
나아가, 상기 화학식 1로 표시되는 화합물은 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 수화물 등의 형태로 사용될 수 있다. Furthermore, the compound represented by Formula 1 can be used not only in the form of its pharmaceutically acceptable salt, but also in the form of solvates, hydrates, etc. that can be prepared therefrom.
또한, 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물은 개별 치료제로 투여하거나, 사용중인 다른 항암제와 병용투여하여 사용할 수 있다.In addition, the pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered as an individual treatment or used in combination with other anticancer drugs in use. there is.
또한, 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물은 항암제와 병용투여함으로써 항암 효과를 증진시킬 수 있다.In addition, a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can enhance the anticancer effect by coadministering it with an anticancer agent.
본 발명의 다른 일 측면에서,In another aspect of the present invention,
상기 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Provided is a health functional food composition for preventing or improving cancer or autoimmune disease, containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 있어서, 용어 “개선”이란, 본 발명의 약학적 조성물, 식품 조성물을 암 또는 자가면역질환 투병 개체에게 투여, 섭취 또는 적용하여 암 또는 자가면역질환의 증세의 경감 또는 완화를 포함하는 의미이다.In the present invention, the term “improvement” means reducing or alleviating the symptoms of cancer or autoimmune disease by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to an individual suffering from cancer or autoimmune disease. am.
본 발명의 약학적 조성물 및 건강기능식품 조성물에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the pharmaceutical composition and health functional food composition of the present invention apply equally unless they contradict each other.
본 발명은 다른 측면에서, 본 명세서에 기재된 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 필요한 대상에게 투여하는 단계를 포함하는 암 또는 자가면역질환의 예방 또는 치료 방법이 제공된다.In another aspect, the present invention provides the prevention or treatment of cancer or autoimmune disease, comprising administering to a subject in need a compound represented by Formula 1 described herein, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. Treatment methods are provided.
본 발명은 또 다른 측면에서, 암 또는 자가면역질환의 예방 또는 치료에 있어서의, 본 명세서에 기재된 화학식 1로 표시되는 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.In another aspect, the present invention provides the use of a compound represented by Formula 1 described herein, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer or autoimmune disease. .
상기 방법 또는 용도에 있어서, 전술한 약학적 조성물에 대한 상세한 설명이 적용될 수 있다.For the above method or use, the detailed description of the pharmaceutical composition described above may be applied.
이하, 본 발명을 실시예 및 실험예를 통해 상세히 설명한다.Hereinafter, the present invention will be described in detail through examples and experimental examples.
단, 후술하는 실시예 및 실험예는 본 발명을 일 측면에서 구체적으로 예시하는 것일 뿐, 본 발명이 이에 한정되는 것은 아니다.However, the examples and experimental examples described below only specifically illustrate the present invention from one aspect, and the present invention is not limited thereto.
<참조예> CB-839 (2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide)<Reference example> CB-839 (2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl) -1,3,4-thiadiazol-2-yl)acetamide)
글루타미네이즈의 억제제로 알려져 있는 CB-839를 레퍼런스로 사용하였으며, 셀렉캠코리아(SelleckChem Korea Co., Ltd)에서 구매하였다.CB-839, known as an inhibitor of glutaminase, was used as a reference and was purchased from SelleckChem Korea Co., Ltd.
<제조예 1> 2,2'-((에탄-1,2-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 1> 2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((ethane-1,2- Preparation of diylbis(oxy))bis(3,1-phenylene))diacetic acid)
<단계 1> 에탄-1,2-디일 비스(4-메틸벤젠술포네이트) (ethane-1,2-diyl bis(4-methylbenzenesulfonate))의 제조<Step 1> Preparation of ethane-1,2-diyl bis(4-methylbenzenesulfonate)
250mL의 둥근 바닥 플라스크에서 에틸렌 글리콜(1.00g, 16.1mmol) 및 NaOH(5.16g, 128.9mmol)를 0℃에서 DCM(30mL)에 용해시켰다. 혼합물에 DCM(20mL) 중 토실 클로라이드(12.3g, 64.4mmol)를 실온에서 첨가하였다. 혼합물을 실온에서 밤새 교반하였다. 조 물질(crude)을 DCM 및 물로 추출하고, 염수로 세척하고, MgSO4로 건조시키고, 여과하고, 농축시켰다. 잔류물을 추가 정제 없이 사용하였다.Ethylene glycol (1.00 g, 16.1 mmol) and NaOH (5.16 g, 128.9 mmol) were dissolved in DCM (30 mL) at 0°C in a 250 mL round bottom flask. Tosyl chloride (12.3 g, 64.4 mmol) in DCM (20 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature overnight. The crude was extracted with DCM and water, washed with brine, dried over MgSO 4 , filtered and concentrated. The residue was used without further purification.
1H NMR (300 MHz, Chloroform-d) δ 7.76 - 7.71 (m, 4 H), 7.37 - 7.31 (m, 4 H), 4.18 (s, 4H), 2.46 (s, 6 H); LCMS: 371.5 [M+H+]. 1H NMR (300 MHz, Chloroform- d ) δ 7.76 - 7.71 (m, 4 H), 7.37 - 7.31 (m, 4 H), 4.18 (s, 4H), 2.46 (s, 6 H); LCMS: 371.5 [M+H + ].
<단계 2> 디-<Step 2> D- terttert -부틸 2,2'-((에탄-1,2-디일비스(옥시))비스(3,1-페닐렌))디아세테이트 (di--Butyl 2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetate (di- terttert -butyl 2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetate)의 제조Preparation of -butyl 2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetate)
100mL의 둥근 바닥 플라스크에서, tert-부틸 2-(3-히드록시페닐)아세테이트(1.20g, 5.76mmol) 및 에탄-1,2-디일 비스(4-메틸벤젠술포네이트)(1.07g, 2.88mmol)를 용해시켰다. 실온에서 DMSO(20mL). 혼합물에 Cs2CO3(3.75g, 11.5mmol) 및 NaI(870mg, 5.76mmol)를 실온에서 첨가하였다. 혼합물을 90℃에서 밤새 교반하였다. 조 물질을 에틸 아세테이트 및 물로 추출하고, 염수로 세척하고, MgSO4로 건조시키고, 여과하고, 농축시켰다. 잔류물을 MPLC(0→20 EA/HX)를 사용하여 정제하여 무색 오일의 목적 생성물을 얻었다(820 mg, 수율: 64%).In a 100 mL round bottom flask, tert-butyl 2-(3-hydroxyphenyl)acetate (1.20 g, 5.76 mmol) and ethane-1,2-diyl bis(4-methylbenzenesulfonate) (1.07 g, 2.88 mmol). ) was dissolved. DMSO (20 mL) at room temperature. Cs 2 CO 3 (3.75 g, 11.5 mmol) and NaI (870 mg, 5.76 mmol) were added to the mixture at room temperature. The mixture was stirred at 90° C. overnight. The crude material was extracted with ethyl acetate and water, washed with brine, dried over MgSO 4 , filtered and concentrated. The residue was purified using MPLC (0→20 EA/HX) to obtain the desired product as a colorless oil (820 mg, yield: 64%).
1H NMR (400 MHz, Chloroform-d) δ 7.24 (t, J = 8.0 Hz, 2 H), 6.90 - 6.82 (m, 6 H), 4.31 (s, 4 H), 3.50 (s, 4 H), 1.44 (s, 18 H); LCMS: 443.8 [M+H+]. 1 H NMR (400 MHz, Chloroform- d ) δ 7.24 (t, J = 8.0 Hz, 2 H), 6.90 - 6.82 (m, 6 H), 4.31 (s, 4 H), 3.50 (s, 4 H) , 1.44 (s, 18 H); LCMS: 443.8 [M+H + ].
<단계 3> 2,2'-((에탄-1,2-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Step 3> 2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((ethane-1,2-diylbis Preparation of (oxy))bis(3,1-phenylene))dacetic acid)
100mL 둥근 바닥 플라스크에서, DCM(20mL)의 30% TFA에 디-tert-부틸 2,2'-((에탄-1,2-디일비스(옥시))비스(3,1-페닐렌))디아세테이트(820mg, 1.85mmol)를 용해시켰다. 혼합물을 실온에서 1시간 동안 교반하였다. 용매를 진공에서 증류 제거하였다. 잔류물을 DCM에 재용해하고 3회 증발시켰다. 제조예 1의 백색 고체는 추가 정제 없이 사용되었다.In a 100 mL round bottom flask, di-tert-butyl 2,2'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))dimethylsiloxane was dissolved in 30% TFA in DCM (20 mL). Acetate (820 mg, 1.85 mmol) was dissolved. The mixture was stirred at room temperature for 1 hour. The solvent was distilled off in vacuo. The residue was redissolved in DCM and evaporated three times. The white solid of Preparation Example 1 was used without further purification.
1H NMR (300 MHz, DMSO-d 6) δ 7.27 - 7.19 (m, 2 H), 6.91 - 6.79 (m, 6 H), 4.28 (s, 4 H), 3.54 (s, 4 H); LCMS: 331.5 [M+H+]. 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.27 - 7.19 (m, 2 H), 6.91 - 6.79 (m, 6 H), 4.28 (s, 4 H), 3.54 (s, 4 H); LCMS: 331.5 [M+H + ].
<제조예 2> 6,6'-(부탄-1,4-디일)비스(피리다진-3-아민) (6,6'-(butane-1,4-diyl)bis(pyridazin-3-amine))의 제조<Preparation Example 2> 6,6'-(butane-1,4-diyl)bis(pyridazin-3-amine) (6,6'-(butane-1,4-diyl)bis(pyridazin-3-amine) )) manufacturing
<단계 1> <Step 1> terttert -부틸(-Butyl( terttert -부톡시카르보닐)(6-클로로피리다진-3-일)카르바메이트 (-Butoxycarbonyl)(6-chloropyridazin-3-yl)carbamate ( terttert -butyl (-butyl ( terttert -butoxycarbonyl)(6-chloropyridazin-3-yl)carbamate)의 제조Manufacture of -butoxycarbonyl)(6-chloropyridazin-3-yl)carbamate)
DCM(80mL)에 6-클로로피리다진-3-아민(5.00g, 38.6mmol)가 용해된 용액에 트리메틸아민(26.8mL, 193mmol) 및 4-디메틸아미노피리딘(450mg, 3.86mmol)을 첨가하였다. 혼합물을 0℃에서 교반하여, DCM(50mL)에 디-tert-부틸 디카보네이트(25.3g, 111mmol)가 용해된 용액을 첨가하였다. 생성된 용액을 실온에서 밤새 교반하였다. 용매를 감압 하에 증발시켰다. 잔류물을 MPLC(0→10% EA/DCM)를 사용하여 정제하여 백색 고체의 원하는 생성물을 얻었다(7.98 g, 수율: 63%).Trimethylamine (26.8 mL, 193 mmol) and 4-dimethylaminopyridine (450 mg, 3.86 mmol) were added to a solution of 6-chloropyridazin-3-amine (5.00 g, 38.6 mmol) in DCM (80 mL). The mixture was stirred at 0°C, and a solution of di-tert-butyl dicarbonate (25.3 g, 111 mmol) dissolved in DCM (50 mL) was added. The resulting solution was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was purified using MPLC (0→10% EA/DCM) to give the desired product as a white solid (7.98 g, yield: 63%).
1H NMR (500 MHz, DMSO-d 6) δ 8.07 (d, J = 9.0 Hz, 1 H), 8.01 (d, J = 9.0 Hz, 1 H), 1.39 (s, 18 H); LCMS: 330.5 [M+H+]. 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.07 (d, J = 9.0 Hz, 1 H), 8.01 (d, J = 9.0 Hz, 1 H), 1.39 (s, 18 H); LCMS: 330.5 [M+H + ].
<단계 2> <Step 2> terttert -부틸 (-Butyl ( terttert -부톡시카르보닐)(6-((트리메틸실릴)에티닐)피리다진-3-일)카르바메이트 (-Butoxycarbonyl)(6-((trimethylsilyl)ethynyl)pyridazin-3-yl)carbamate ( terttert -butyl (-butyl ( terttert -butoxycarbonyl)(6-((trimethylsilyl)ethynyl)pyridazin-3-yl)carbamate)의 제조Preparation of -butoxycarbonyl)(6-((trimethylsilyl)ethynyl)pyridazin-3-yl)carbamate)
테트라히드로푸란(30mL)에 tert-부틸(tert-부톡시카르보닐)(6-클로로피리다진-3-일)카르바메이트(3.00g, 9.10mmol) 및 트리에틸아민(30mL)가 용해된 용액을 Ar 기체로 15분 동안 탈기시켰다(degassed). 에티닐트리메틸실란 (2.50mL, 18.2mmol), CuI(175mg, 0.91mmol) 및 PdCl2(PPh3)2(640mg, 0.91mmol)를 실온에서 첨가하였다. 생성된 혼합물을 50℃에서 밤새 가열하였다. 혼합물을 셀라이트(celite)를 통해 여과하고, 에틸 아세테이트로 세척하였다. 잔류물을 농축하였다. 조 물질을 MPLC(0→30% EA/HX)를 사용하여 정제하여 진한 녹색 고체의 원하는 생성물을 얻었다(2.83 g, 수율: 79%).A solution of tert-butyl (tert-butoxycarbonyl) (6-chloropyridazin-3-yl) carbamate (3.00 g, 9.10 mmol) and triethylamine (30 mL) in tetrahydrofuran (30 mL). was degassed with Ar gas for 15 minutes. Ethynyltrimethylsilane (2.50 mL, 18.2 mmol), CuI (175 mg, 0.91 mmol), and PdCl 2 (PPh 3 ) 2 (640 mg, 0.91 mmol) were added at room temperature. The resulting mixture was heated at 50°C overnight. The mixture was filtered through celite and washed with ethyl acetate. The residue was concentrated. The crude material was purified using MPLC (0→30% EA/HX) to give the desired product as a dark green solid (2.83 g, yield: 79%).
1H NMR (300 MHz, Chloroform-d) δ 7.58 (d, J = 8.9 Hz, 1 H), 7.50 (d, J = 8.9 Hz, 1 H), 1.46 (s, 18 H), 0.30 (s, 9 H). 1H NMR (300 MHz, Chloroform- d ) δ 7.58 (d, J = 8.9 Hz, 1 H), 7.50 (d, J = 8.9 Hz, 1 H), 1.46 (s, 18 H), 0.30 (s, 9H).
<단계 3> <Step 3> terttert -부틸(6-에티닐피리다진-3-일)카바메이트 (-Butyl(6-ethynylpyridazin-3-yl)carbamate ( terttert -butyl (6-ethynylpyridazin-3-yl)carbamate)의 제조-Manufacture of butyl (6-ethynylpyridazin-3-yl)carbamate)
메탄올(150mL)에 tert-부틸(tert-부톡시카르보닐)(6-((트리메틸실릴)에티닐)피리다진-3-일)카르바메이트(2.83g, 7.23mmol) 및 K2CO3(4.00g, 28.9mmol)가 용해된 혼합물을 실온에서 30분간 교반하였다. 혼합물을 감압 하에 농축시켰다. 잔류물을 DCM 및 H2O의 혼합물에 재용해시키고, 1N HCl 용액으로 pH 7로 중화시켰다. 유기물을 분리하고, 염수로 세척하고, MgSO4로 건조시키고, 여과하고, 농축시켰다. 조 물질을 추가 정제 없이 다음 단계에서 사용하였다.tert-butyl (tert-butoxycarbonyl) (6-((trimethylsilyl) ethynyl) pyridazin-3-yl) carbamate (2.83 g, 7.23 mmol) and K 2 CO 3 ( The mixture in which 4.00 g, 28.9 mmol) was dissolved was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was redissolved in a mixture of DCM and H 2 O and neutralized to pH 7 with 1N HCl solution. The organics were separated, washed with brine, dried over MgSO 4 , filtered and concentrated. The crude material was used in the next step without further purification.
1H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J = 9.3 Hz, 1 H), 7.90 (s, 1 H), 7.55 (dd, J = 9.3, 0.6 Hz, 1 H), 3.33 (s, 1 H), 1.54 (s, 9 H). 1H NMR (500 MHz, Chloroform- d ) δ 8.21 (d, J = 9.3 Hz, 1H), 7.90 (s, 1H), 7.55 (dd, J = 9.3, 0.6 Hz, 1H), 3.33 ( s, 1 H), 1.54 (s, 9 H).
<단계 4> 디-<Step 4> D- terttert -부틸 (부타-1,3-디인-1,4-디일비스(피리다진-6,3-디일))디카르바메이트 (di--Butyl (buta-1,3-diyne-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate (di- terttert -butyl (buta-1,3-diyne-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate)의 제조-Manufacture of butyl (buta-1,3-diyne-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate)
실온에서 피리딘(50mL) 중 tert-부틸(6-에티닐피리다진-3-일)카바메이트(1.34g, 6.11mmol)의 용액에 CuCl(450mg, 3.36mmol)을 첨가하였다. 모든 tert-부틸 (6-에티닐피리다진-3-일)카르바메이트가 소모됨에 따라 생성된 혼합물을 공기 스트림 하에 1시간 동안 교반하였다. 반응 혼합물을 포화 NH4Cl 수용액으로 희석하였다. 침전물을 흡인 여과에 의해 수집하고, H2O로 세척하고, 건조시켜 회색 고체의 생성물을 얻었다.CuCl (450 mg, 3.36 mmol) was added to a solution of tert-butyl(6-ethynylpyridazin-3-yl)carbamate (1.34 g, 6.11 mmol) in pyridine (50 mL) at room temperature. The resulting mixture was stirred under a stream of air for 1 hour as all tert-butyl (6-ethynylpyridazin-3-yl)carbamate was consumed. The reaction mixture was diluted with saturated aqueous NH 4 Cl solution. The precipitate was collected by suction filtration, washed with H 2 O and dried to give the product as a gray solid.
1H NMR (500 MHz, DMSO-d 6) δ 10.90 (s, 2 H), 8.13 (d, J = 9.3 Hz, 2 H), 7.97 (d, J = 9.4 Hz, 2 H), 1.49 (s, 18 H). 1H NMR (500 MHz, DMSO- d6 ) δ 10.90 (s, 2H) , 8.13 (d, J = 9.3 Hz, 2H), 7.97 (d, J = 9.4 Hz, 2H), 1.49 (s) , 18 H).
<단계 5> 디-<Step 5> D- terttert -부틸(부탄-1,4-디일비스(피리다진-6,3-디일))디카르바메이트 (di--Butyl(butane-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate (di- terttert -butyl (butane-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate)의 제조-Manufacture of butyl (butane-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate)
디-tert-부틸(부타-1,3-디인-1,4-디일비스(피리다진-6,3-디일))디카르바메이트(1.12g, 2.57mmol)를 THF/DMF(110mL/ 220mL)) 혼합물에 용해시켰다. Pd(OH)2(2.35g, 16.7mmol)를 천천히 첨가하였다. H2는 여러 번 추가 및 방출되었다. 혼합물을 실온에서 밤새 교반하였다. 혼합물을 셀라이트를 통해 여과하고 THF로 세척하였다. 여액을 감압 하에 증발시켰다. 조 물질을 MPLC(0→30% EA/HX에 이어 0→10% MeOH/DCM)를 사용하여 정제하여 밝은 갈색 고체의 원하는 생성물을 얻었다(750 mg, 수율: 56%).Di-tert-butyl(buta-1,3-diyne-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate (1.12 g, 2.57 mmol) was dissolved in THF/DMF (110 mL/220 mL). ) was dissolved in the mixture. Pd(OH) 2 (2.35 g, 16.7 mmol) was added slowly. H 2 was added and released several times. The mixture was stirred at room temperature overnight. The mixture was filtered through Celite and washed with THF. The filtrate was evaporated under reduced pressure. The crude material was purified using MPLC (0→30% EA/HX followed by 0→10% MeOH/DCM) to give the desired product as a light brown solid (750 mg, yield: 56%).
1H NMR (300 MHz, DMSO-d 6) δ 10.27 (s, 2 H), 7.95 (d, J = 9.2 Hz, 2 H), 7.50 (d, J = 9.2 Hz, 2 H), 2.92 - 2.79 (m, 4 H), 1.76 - 1.63 (m, 4 H), 1.47 (s, 18 H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 10.27 (s, 2 H), 7.95 (d, J = 9.2 Hz, 2 H), 7.50 (d, J = 9.2 Hz, 2 H), 2.92 - 2.79 (m, 4 H), 1.76 - 1.63 (m, 4 H), 1.47 (s, 18 H).
<단계 6> 6,6'-(부탄-1,4-디일)비스(피리다진-3-아민) (6,6'-(butane-1,4-diyl)bis(pyridazin-3-amine))의 제조<Step 6> 6,6'-(butane-1,4-diyl)bis(pyridazin-3-amine) (6,6'-(butane-1,4-diyl)bis(pyridazin-3-amine) )Manufacture of
디-tert-부틸(부탄-1,4-디일비스(피리다진-6,3-디일))디카르바메이트(750 mg, 1.69 mmol)를 트리플루오로아세트산(3 mL)에 용해시켰다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 조 물질(crude)을 농축하고 DCM에 3회 재용해시켰다. 제조예 2의 화합물을 추가 정제 없이 사용하였다.Di-tert-butyl(butane-1,4-diylbis(pyridazine-6,3-diyl))dicarbamate (750 mg, 1.69 mmol) was dissolved in trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The crude was concentrated and redissolved three times in DCM. The compound of Preparation Example 2 was used without further purification.
1H NMR (400 MHz, DMSO-d 6) δ 8.53 (s, 4 H), 7.79 (d, J = 9.5 Hz, 2 H), 7.44 (d, J = 9.4 Hz, 2 H), 2.77 - 2.71 (m, 4 H), 1.71 - 1.60 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.53 (s, 4 H), 7.79 (d, J = 9.5 Hz, 2 H), 7.44 (d, J = 9.4 Hz, 2 H), 2.77 - 2.71 (m, 4 H), 1.71 - 1.60 (m, 4 H).
<제조예 3> 2,2'-((프로판-1,3-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((propane-1,3-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 3> 2,2'-((propane-1,3-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((propane-1,3- Preparation of diylbis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 3의 화합물을 얻었다.By manufacturing in the same manner as Preparation Example 1, the compound of Preparation Example 3 as a white solid was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 7.21 (t, J = 7.7 Hz, 2 H), 6.88 - 6.78 (m, 6 H), 4.11 (t, J = 6.3 Hz, 4 H), 3.52 (s, 4 H), 2.16 (p, J = 6.2 Hz, 2 H); LCMS: 345.6 [M+H+]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.21 (t, J = 7.7 Hz, 2 H), 6.88 - 6.78 (m, 6 H), 4.11 (t, J = 6.3 Hz, 4 H), 3.52 (s, 4 H), 2.16 (p, J = 6.2 Hz, 2 H); LCMS: 345.6 [M+H + ].
<제조예 4> 2,2'-((부탄-1,4-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((butane-1,4-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 4> 2,2'-((butane-1,4-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((butane-1,4- Preparation of diylbis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 4의 화합물을 얻었다(수율: 95%).By preparing in the same manner as Preparation Example 1, the compound of Preparation Example 4 was obtained as a white solid (yield: 95%).
1H NMR (300 MHz, DMSO-d 6) δ 7.21 (td, J = 7.4, 1.5 Hz, 2 H), 6.86 - 6.77 (m, 6 H), 4.06 - 3.96 (m, 4 H), 3.52 (s, 4 H), 1.92 - 1.80 (m, 4 H); LCMS: 359.6 [M+H+]. 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.21 (td, J = 7.4, 1.5 Hz, 2 H), 6.86 - 6.77 (m, 6 H), 4.06 - 3.96 (m, 4 H), 3.52 ( s, 4 H), 1.92 - 1.80 (m, 4 H); LCMS: 359.6 [M+H + ].
<제조예 5> 2,2'-((펜탄-1,5-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((pentane-1,5-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 5> 2,2'-((pentane-1,5-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((pentane-1,5- Preparation of diylbis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 5의 화합물을 얻었다.By manufacturing in the same manner as Preparation Example 1, the compound of Preparation Example 5 as a white solid was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 7.20 (td, J = 7.4, 1.3 Hz, 2 H), 6.86 - 6.76 (m, 6 H), 3.96 (t, J = 6.4 Hz, 4 H), 3.52 (s, 4 H), 1.77 (p, J = 6.8 Hz, 4 H), 1.61 - 1.50 (m, 2 H); LCMS: 373.6 [M+H+]. 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.20 (td, J = 7.4, 1.3 Hz, 2 H), 6.86 - 6.76 (m, 6 H), 3.96 (t, J = 6.4 Hz, 4 H) , 3.52 (s, 4 H), 1.77 (p, J = 6.8 Hz, 4 H), 1.61 - 1.50 (m, 2 H); LCMS: 373.6 [M+H + ].
<제조예 6><Production Example 6> 2,2'-(((옥시비스(에탄-2,1-디일))비스(옥시))비스(3,1-페닐렌))디아세트산2,2'-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid)의 제조Preparation of (2,2'-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 연한 황갈색 고체의 제조예 6의 화합물을 얻었다.By preparing in the same manner as Preparation Example 1, the compound of Preparation Example 6 as a light yellow-brown solid was obtained.
1H NMR (500 MHz, DMSO-d 6) δ 12.32 (s, 2 H), 7.20 (t, J = 7.9 Hz, 2 H), 6.88 - 6.77 (m, 6 H), 4.13 - 4.05 (m, 4 H), 3.84 - 3.75 (m, 4 H), 3.52 (s, 4 H); LCMS: 375.8 [M+H+]. 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.32 (s, 2 H), 7.20 (t, J = 7.9 Hz, 2 H), 6.88 - 6.77 (m, 6 H), 4.13 - 4.05 (m, 4 H), 3.84 - 3.75 (m, 4 H), 3.52 (s, 4 H); LCMS: 375.8 [M+H + ].
<제조예 7> 2,2'-((헥산-1,6-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((hexane-1,6-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 7> 2,2'-((hexane-1,6-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((hexane-1,6- Preparation of diylbis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 7의 화합물을 얻었다.By manufacturing in the same manner as Preparation Example 1, the compound of Preparation Example 7 as a white solid was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 7.20 (td, J = 7.8, 7.4, 1.3 Hz, 2 H), 6.85 - 6.76 (m, 6 H), 3.94 (t, J = 6.4 Hz, 4 H), 3.52 (s, 4 H), 1.80 - 1.65 (m, 4 H), 1.54 - 1.42 (m, 4 H); 387.7 [M+H+]. 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.20 (td, J = 7.8, 7.4, 1.3 Hz, 2 H), 6.85 - 6.76 (m, 6 H), 3.94 (t, J = 6.4 Hz, 4 H), 3.52 (s, 4 H), 1.80 - 1.65 (m, 4 H), 1.54 - 1.42 (m, 4 H); 387.7 [M+H + ].
<제조예 8> 2,2'-((헵탄-1,7-디일비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((heptane-1,7-diylbis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 8> 2,2'-((heptane-1,7-diylbis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-((heptane-1,7- Preparation of diylbis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 8의 화합물을 얻었다.By preparing in the same manner as Preparation Example 1, the compound of Preparation Example 8 as a white solid was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 12.30 (s, 2 H), 7.19 (td, J = 7.4, 1.4 Hz, 2 H), 6.85 - 6.76 (m, 6 H), 3.93 (t, J = 6.4 Hz, 4 H), 3.51 (s, 4 H), 1.78 - 1.64 (m, 4 H), 1.50 - 1.34 (m, 6 H); LCMS: 401.6 [M+H+]. 1H NMR (300 MHz, DMSO- d6 ) δ 12.30 (s, 2H), 7.19 (td, J = 7.4 , 1.4 Hz, 2H), 6.85 - 6.76 (m, 6H), 3.93 (t, J = 6.4 Hz, 4 H), 3.51 (s, 4 H), 1.78 - 1.64 (m, 4 H), 1.50 - 1.34 (m, 6 H); LCMS: 401.6 [M+H + ].
<제조예 9> 2,2'-(((옥시비스(프로판-3,1-디일))비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-(((oxybis(propane-3,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 9> 2,2'-(((oxybis(propane-3,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid (2,2'-(( Preparation of (oxybis(propane-3,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid)
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 9의 화합물을 얻었다.By preparing in the same manner as Preparation Example 1, the compound of Preparation Example 9 as a white solid was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 7.19 (t, J = 8.1 Hz, 1 H), 6.84 - 6.75 (m, 3 H), 3.99 (t, J = 6.3 Hz, 2 H), 3.58 - 3.48 (m, 4 H), 1.94 (p, J = 6.3 Hz, 2 H); LCMS: 403.7 [M+H+]. 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.19 (t, J = 8.1 Hz, 1 H), 6.84 - 6.75 (m, 3 H), 3.99 (t, J = 6.3 Hz, 2 H), 3.58 - 3.48 (m, 4 H), 1.94 (p, J = 6.3 Hz, 2 H); LCMS: 403.7 [M+H + ].
<제조예 10> 2,2'-((((에탄-1,2-디일비스(옥시))비스(에탄-2,1-디일))비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 10> 2,2'-((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene ))Diacetic acid (2,2'-((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene)) Manufacture of diacetic acid
제조예 1과 같은 방법으로 제조하여, 흰색 고체의 제조예 10의 화합물을 얻었다.By manufacturing in the same manner as Preparation Example 1, the compound of Preparation Example 10 as a white solid was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 7.20 (td, J = 8.4, 7.4 Hz, 2 H), 6.85 - 6.78 (m, 6 H), 4.07 - 4.03 (m, 4 H), 3.76 - 3.71 (m, 4 H), 3.61 (s, 4 H), 3.52 (s, 4 H); LCMS: 419.6 [M+H+]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.20 (td, J = 8.4, 7.4 Hz, 2 H), 6.85 - 6.78 (m, 6 H), 4.07 - 4.03 (m, 4 H), 3.76 - 3.71 (m, 4 H), 3.61 (s, 4 H), 3.52 (s, 4 H); LCMS: 419.6 [M+H + ].
<제조예 11> 2,2'-(((((옥시비스(에탄-2,1-디일))비스(옥시))비스(에탄-2,1-디일))비스(옥시))비스(3,1-페닐렌))디아세트산 (2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))diacetic acid)의 제조<Preparation Example 11> 2,2'-((((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis( 3,1-phenylene)) diacetic acid (2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis( Preparation of oxy))bis(3,1-phenylene))dacetic acid)
제조예 1과 같은 방법으로 제조하여, 제조예 11의 화합물을 얻었다.By manufacturing in the same manner as Preparation Example 1, the compound of Preparation Example 11 was obtained.
1H NMR (400 MHz, Chloroform-d) δ 7.24 (t, J = 7.9 Hz, 2 H), 6.99 - 6.82 (m, 6 H), 4.15 (t, J = 4.8 Hz, 4 H), 3.86 (t, J = 4.8 Hz, 4 H), 3.77 - 3.67 (m, 8 H), 3.62 (s, 4 H). 1 H NMR (400 MHz, Chloroform-d) δ 7.24 (t, J = 7.9 Hz, 2 H), 6.99 - 6.82 (m, 6 H), 4.15 (t, J = 4.8 Hz, 4 H), 3.86 ( t, J = 4.8 Hz, 4 H), 3.77 - 3.67 (m, 8 H), 3.62 (s, 4 H).
<제조예 12> 5-(4-(6-아미노피리다진-3-일)부틸)-1,3,4-티아디아졸-2-아민 (5-(4-(6-aminopyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-amine)의 제조<Preparation Example 12> 5-(4-(6-aminopyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-amine (5-(4-(6-aminopyridazin-3- Preparation of yl)butyl)-1,3,4-thiadiazol-2-amine)
tert-부틸(6-(4-시아노부틸)피리다진-3-일)카르바메이트 (620 mg, 2.24 mmol)를 개방형 상부 환류 응축기가 장착된 둥근 바닥 플라스크에 채웠다. 플라스크에 히드라진카르보티오아미드 (225 mg, 2.47 mmol) 및 트리플루오로아세트산(5 mL)을 첨가하였다. 반응 슬러리를 65℃에서 3시간 동안 가열하였다. 조 물질을 농축하고 DCM에 3회 재용해시켰다. 디옥산 중 4 N HCl 1mL를 혼합물에 한 방울씩 첨가하였다. 감압 하에 용매를 제거하고, 에테르를 첨가하여 제거하였다. 잔류물을 MPLC(알루미나 염기성 컬럼 포함)(0→30% MeOH/DCM)를 사용하여 정제하여 회백색 고체의 제조예 12의 화합물을 얻었다(235 mg, 수율: 42%).tert-Butyl(6-(4-cyanobutyl)pyridazin-3-yl)carbamate (620 mg, 2.24 mmol) was charged to a round bottom flask equipped with an open top reflux condenser. Hydrazinecarbothioamide (225 mg, 2.47 mmol) and trifluoroacetic acid (5 mL) were added to the flask. The reaction slurry was heated at 65°C for 3 hours. The crude material was concentrated and redissolved three times in DCM. 1 mL of 4 N HCl in dioxane was added dropwise to the mixture. The solvent was removed under reduced pressure, and ether was added and removed. The residue was purified using MPLC (including an alumina basic column) (0→30% MeOH/DCM) to obtain the compound of Preparation Example 12 as an off-white solid (235 mg, yield: 42%).
1H NMR (500 MHz, DMSO-d 6) δ 7.13 (d, J = 9.0 Hz, 1H), 7.00 (s, 2H), 6.69 (d, J = 9.0 Hz, 1H), 6.11 (s, 2H), 2.81 (t, J = 6.7 Hz, 2H), 2.68 (t, J = 7.0 Hz, 2H), 1.68 - 1.57 (m, 4H). 1H NMR (500 MHz, DMSO- d6 ) δ 7.13 (d, J = 9.0 Hz, 1H), 7.00 (s, 2H), 6.69 (d, J = 9.0 Hz, 1H), 6.11 (s, 2H) , 2.81 (t, J = 6.7 Hz, 2H), 2.68 (t, J = 7.0 Hz, 2H), 1.68 - 1.57 (m, 4H).
<제조예 13> 5,5'-(부탄-1,4-디일)비스(1,3,4-티아디아졸-2-아민) (5,5'-(butane-1,4-diyl)bis(1,3,4-thiadiazol-2-amine))의 제조<Preparation Example 13> 5,5'-(butane-1,4-diyl)bis(1,3,4-thiadiazol-2-amine) (5,5'-(butane-1,4-diyl) Preparation of bis(1,3,4-thiadiazol-2-amine))
아디프산 (adipic acid)(5.00g, 31.1mmol) 및 티오세미카바지드 (thiosemicarbazide)(5.69g, 62.4mmol)가 용해된 포스포릴 클로라이드(45mL)의 혼합물을 90℃에서 밤새 가열하였다. 반응물을 실온으로 냉각시키고 얼음과 물의 혼합물에 부었다. 염기성(pH 14)이 될 때까지 수산화나트륨 펠릿을 혼합물에 첨가하였다. 백색 침전물을 흡인 여과로 수집하고 물로 헹구고 건조하여 흰색 고체의 제조예 13의 화합물을 얻었다(수율: 88%).A mixture of phosphoryl chloride (45 mL) in which adipic acid (5.00 g, 31.1 mmol) and thiosemicarbazide (5.69 g, 62.4 mmol) were dissolved was heated at 90°C overnight. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water, and dried to obtain the compound of Preparation Example 13 as a white solid (yield: 88%).
1H NMR (300 MHz, DMSO-d 6) δ 6.98 (s, 4 H), 2.89 - 2.69 (m, 4 H), 1.74 - 1.53 (m, 4 H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 6.98 (s, 4 H), 2.89 - 2.69 (m, 4 H), 1.74 - 1.53 (m, 4 H).
<실시예 1> 6,9-디옥사-2,13-디아자-1,14(3,6)-디피리다지나-5,10(1,3)-디벤제나시클로옥타데카판-3,12-디온 (6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3,12-dione)의 제조<Example 1> 6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3, Preparation of 12-dione (6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3,12-dione)
제조예 1의 화합물(0.11 mmol), 옥살릴 클로라이드 (30 μL, 0.33 mmol) 및 DMF 한 방울의 무수 톨루엔 (1.0 mL) 용액을 상온의 아르곤 기체 하에서 1시간 동안 저어주었다. 용매를 감압 하에 증발시켰다. 아실 클로라이드 조 물질(crude)을 추가 정제 없이 다음 변환에 사용하였다. 제조예 2의 화합물(0.10 mmol) 및 트리에틸아민 (30uL, 0.20mmol)이 녹아있는 차가운 DMF (2 mL) 용액에, 아르곤 기체 하에서 DMF (3 mL)에 녹인 아실 클로라이드를 한 방울씩 첨가하였다. 교반을 추가 20분 동안 계속한 후, 얼음 배스(ice bath)를 제거하고 혼합물을 실온에서 밤새 격렬하게 교반하였다. 반응 종료 후 물을 첨가하여 추출하였다. 석출된 고체를 여과하고 건조하여 실시예 1의 화합물을 얻었다(수율: 20%). A solution of the compound of Preparation Example 1 (0.11 mmol), oxalyl chloride (30 μL, 0.33 mmol), and a drop of DMF in anhydrous toluene (1.0 mL) was stirred for 1 hour under argon gas at room temperature. The solvent was evaporated under reduced pressure. The acyl chloride crude was used for the next transformation without further purification. To a cold DMF (2 mL) solution containing the compound of Preparation Example 2 (0.10 mmol) and triethylamine (30 uL, 0.20 mmol), acyl chloride dissolved in DMF (3 mL) was added dropwise under argon gas. Stirring was continued for an additional 20 minutes, then the ice bath was removed and the mixture was stirred vigorously at room temperature overnight. After completion of the reaction, water was added and extracted. The precipitated solid was filtered and dried to obtain the compound of Example 1 (yield: 20%).
1H NMR (400 MHz, DMSO-d 6) δ 11.45 - 11.21 (m, 2 H), 8.21 - 8.12 (m, 1 H), 7.57 - 7.49 (m, 1 H), 7.27 - 7.04 (m, 3 H), 7.03 - 6.63 (m, 7 H), 4.35 - 4.16 (m, 4 H), 3.73 (s, 4 H), 2.98 - 2.73 (m, 4 H), 1.85 - 1.49 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.45 - 11.21 (m, 2 H), 8.21 - 8.12 (m, 1 H), 7.57 - 7.49 (m, 1 H), 7.27 - 7.04 (m, 3) H), 7.03 - 6.63 (m, 7 H), 4.35 - 4.16 (m, 4 H), 3.73 (s, 4 H), 2.98 - 2.73 (m, 4 H), 1.85 - 1.49 (m, 4 H) .
<실시예 2> 15,19-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로노나데카판-3,12-디온 (15,19-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclononadecaphane-3,12-dione)의 제조<Example 2> 15,19-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclononadecapane-3, Preparation of 12-dione (15,19-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclononadecaphane-3,12-dione)
반응물은 제조예 3의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 실시예 2의 화합물을 얻었다(수율: 6%).The reactants were the compound of Preparation Example 3 and the compound of Preparation Example 2, and the compound of Example 2 was obtained by preparing in the same manner as Example 1 (yield: 6%).
1H NMR (400 MHz, DMSO-d 6) δ 11.51 - 11.18 (m, 2 H), 8.19 - 8.13 (m, 1 H), 7.57 - 7.47 (m, 1 H), 7.25 - 7.01 (m, 3 H), 7.02 - 6.61 (m, 7 H), 4.16 - 4.01 (m, 4 H), 3.71 (s, 4 H), 2.92 - 2.79 (m, 4 H), 2.21 - 2.06 (m, 2 H), 1.79 - 1.51 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.51 - 11.18 (m, 2 H), 8.19 - 8.13 (m, 1 H), 7.57 - 7.47 (m, 1 H), 7.25 - 7.01 (m, 3) H), 7.02 - 6.61 (m, 7 H), 4.16 - 4.01 (m, 4 H), 3.71 (s, 4 H), 2.92 - 2.79 (m, 4 H), 2.21 - 2.06 (m, 2 H) , 1.79 - 1.51 (m, 4 H).
<실시예 3> 15,20-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로이코사판-3,12-디온 (15,20-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloicosaphane-3,12-dione)의 제조<Example 3> 15,20-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloicosaphane-3,12 -Preparation of dione (15,20-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloicosaphane-3,12-dione)
반응물은 제조예 4의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 실시예 3의 화합물을 얻었다(수율: 18%).The reactants were the compound of Preparation Example 4 and the compound of Preparation Example 2, and the compound of Example 3 was obtained by preparing in the same manner as Example 1 (yield: 18%).
1H NMR (400 MHz, DMSO-d 6) δ 11.60 (s, 1 H), 11.41 - 11.20 (m, 1 H), 8.20 - 8.12 (m, 1 H), 7.56 - 7.49 (m, 1 H), 7.25 - 7.01 (m, 3 H), 6.99 - 6.59 (m, 7 H), 4.05 - 3.92 (m, 4 H), 3.73 (s, 4 H), 2.99 - 2.77 (m, 4 H), 1.89 - 1.78 (m, 4 H), 1.74 - 1.50 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.60 (s, 1 H), 11.41 - 11.20 (m, 1 H), 8.20 - 8.12 (m, 1 H), 7.56 - 7.49 (m, 1 H) , 7.25 - 7.01 (m, 3 H), 6.99 - 6.59 (m, 7 H), 4.05 - 3.92 (m, 4 H), 3.73 (s, 4 H), 2.99 - 2.77 (m, 4 H), 1.89 - 1.78 (m, 4 H), 1.74 - 1.50 (m, 4 H).
<실시예 4> 15,21-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헤니코사판-3,12-디온 (15,21-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosaphane-3,12-dione)의 제조<Example 4> 15,21-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosapan-3, Preparation of 12-dione (15,21-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosaphane-3,12-dione)
반응물은 제조예 5의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 실시예 4의 화합물을 얻었다(수율: 31%).The reactants were the compound of Preparation Example 5 and the compound of Preparation Example 2, and the compound of Example 4 was obtained by preparing in the same manner as Example 1 (yield: 31%).
1H NMR (400 MHz, DMSO-d 6) δ 11.39 - 11.17 (m, 2 H), 8.21 - 8.12 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 7.03 (m, 3 H), 6.96 - 6.59 (m, 7 H), 3.99 - 3.86 (m, 4 H), 3.71 (s, 4 H), 2.96 - 2.75 (m, 4 H), 1.81 - 1.48 (m, 10 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.39 - 11.17 (m, 2 H), 8.21 - 8.12 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 7.03 (m, 3) H), 6.96 - 6.59 (m, 7 H), 3.99 - 3.86 (m, 4 H), 3.71 (s, 4 H), 2.96 - 2.75 (m, 4 H), 1.81 - 1.48 (m, 10 H) .
<실시예 5> 15,18,21-트리옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헤니코사판-3,12-디온 (15,18,21-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosaphane-3,12-dione)의 제조<Example 5> 15,18,21-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosapan- Preparation of 3,12-dione (15,18,21-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosaphane-3,12-dione)
반응물은 제조예 6의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 실시예 5의 화합물을 얻었다(수율: 2.4%).The reactants were the compound of Preparation Example 6 and the compound of Preparation Example 2, and the compound of Example 5 was obtained by preparing in the same manner as Example 1 (yield: 2.4%).
1H NMR (400 MHz, DMSO-d 6) δ 11.45 - 11.12 (m, 2 H), 8.21 - 8.10 (m, 1 H), 7.57 - 7.45 (m, 1 H), 7.26 - 7.04 (m, 3 H), 6.99 - 6.61 (m, 7 H), 4.15 - 3.97 (m, 4 H), 3.87 - 3.58 (m, 8 H), 2.93 - 2.75 (m, 4 H), 1.83 - 1.52 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.45 - 11.12 (m, 2 H), 8.21 - 8.10 (m, 1 H), 7.57 - 7.45 (m, 1 H), 7.26 - 7.04 (m, 3) H), 6.99 - 6.61 (m, 7 H), 4.15 - 3.97 (m, 4 H), 3.87 - 3.58 (m, 8 H), 2.93 - 2.75 (m, 4 H), 1.83 - 1.52 (m, 4) H).
<실시예 6> 15,22-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로도코사판-3,12-디온 (15,22-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclodocosaphane-3,12-dione)의 제조<Example 6> 15,22-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclodocosaphane-3,12 -Preparation of dione (15,22-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclodocosaphane-3,12-dione)
반응물은 제조예 7의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 실시예 6의 화합물을 얻었다(수율: 7%).The reactants were the compound of Preparation Example 7 and the compound of Preparation Example 2, and the compound of Example 6 was obtained by preparing in the same manner as Example 1 (yield: 7%).
1H NMR (400 MHz, DMSO-d 6) δ 11.40 - 11.17 (m, 2 H), 8.22 - 8.10 (m, 1 H), 7.57 - 7.46 (m, 1 H), 7.24 - 7.03 (m, 3 H), 7.01 - 6.58 (m, 7 H), 4.00 - 3.84 (m, 4 H), 3.71 (s, 4 H), 3.04 - 2.72 (m, 4 H), 1.80 - 1.53 (m, 8 H), 1.50 - 1.38 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.40 - 11.17 (m, 2 H), 8.22 - 8.10 (m, 1 H), 7.57 - 7.46 (m, 1 H), 7.24 - 7.03 (m, 3) H), 7.01 - 6.58 (m, 7 H), 4.00 - 3.84 (m, 4 H), 3.71 (s, 4 H), 3.04 - 2.72 (m, 4 H), 1.80 - 1.53 (m, 8 H) , 1.50 - 1.38 (m, 4 H).
<실시예 7> 15,23-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온 (15,23-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)의 제조<Example 7> 15,23-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosapan-3,12 -Preparation of dione (15,23-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)
반응물은 제조예 8의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 실시예 7의 화합물을 얻었다(수율: 78%).The reactants were the compound of Preparation Example 8 and the compound of Preparation Example 2, and the compound of Example 7 was obtained by preparing in the same manner as Example 1 (yield: 78%).
1H NMR (400 MHz, DMSO-d 6) δ 11.35 - 11.16 (m, 1 H), 8.20 - 8.12 (m, 1 H), 7.55 - 7.46 (m, 1 H), 7.24 - 7.03 (m, 3 H), 6.97 - 6.61 (m, 7 H), 3.97 - 3.85 (m, 4 H), 3.70 (s, 4 H), 2.95 - 2.74 (m, 4 H), 1.81 - 1.52 (m, 8 H), 1.47 - 1.33 (m, 6 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.35 - 11.16 (m, 1 H), 8.20 - 8.12 (m, 1 H), 7.55 - 7.46 (m, 1 H), 7.24 - 7.03 (m, 3) H), 6.97 - 6.61 (m, 7 H), 3.97 - 3.85 (m, 4 H), 3.70 (s, 4 H), 2.95 - 2.74 (m, 4 H), 1.81 - 1.52 (m, 8 H) , 1.47 - 1.33 (m, 6 H).
<실시예 8> 15,19,23-트리옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온 (15,19,23-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)의 제조<Example 8> 15,19,23-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosapan-3 , Preparation of 12-dione (15,19,23-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)
반응물은 제조예 9의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 갈색 고체의 실시예 8의 화합물을 얻었다(수율: 24%).The reactants were the compound of Preparation Example 9 and the compound of Preparation Example 2, and were prepared in the same manner as Example 1 to obtain the compound of Example 8 as a brown solid (yield: 24%).
1H NMR (400 MHz, DMSO-d 6) δ 11.58 - 11.16 (m, 2 H), 8.20 - 8.10 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 6.99 (m, 3 H), 6.95 - 6.57 (m, 7 H), 4.01 - 3.90 (m, 4 H), 3.70 (s, 4 H), 3.54 - 3.49 (m, 4 H), 2.94 - 2.79 (m, 4 H), 1.99 - 1.86 (m, 4 H), 1.77 - 1.52 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.58 - 11.16 (m, 2 H), 8.20 - 8.10 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 6.99 (m, 3) H), 6.95 - 6.57 (m, 7 H), 4.01 - 3.90 (m, 4 H), 3.70 (s, 4 H), 3.54 - 3.49 (m, 4 H), 2.94 - 2.79 (m, 4 H) , 1.99 - 1.86 (m, 4 H), 1.77 - 1.52 (m, 4 H).
<실시예 9> 15,18,21,24-테트라옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로테트라코사판-3,12-디온 (15,18,21,24-tetraoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotetracosaphane-3,12-dione)의 제조<Example 9> 15,18,21,24-tetraoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotetraco Sapan-3,12-dione (15,18,21,24-tetraoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotetracosaphane-3,12- manufacture of dione)
반응물은 제조예 10의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 갈색 고체의 실시예 9의 화합물을 얻었다(수율: 27%).The reactants were the compound of Preparation Example 10 and the compound of Preparation Example 2, and were prepared in the same manner as Example 1 to obtain the compound of Example 9 as a brown solid (yield: 27%).
1H NMR (300 MHz, DMSO-d 6) 11.58 - 11.16 (m, 2 H), 8.20 - 8.10 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 6.99 (m, 3 H), 6.95 - 6.57 (m, 7 H), 4.06 (s, 4 H), 3.74 (s, 6 H), 3.61 (s, 6 H), 3.05 - 2.64 (m, 4 H), 1.34 - 1.19 (m, 2 H), 1.13 (m, 2 H). 1 H NMR (300 MHz, DMSO- d 6 ) 11.58 - 11.16 (m, 2 H), 8.20 - 8.10 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 6.99 (m, 3 H) ), 6.95 - 6.57 (m, 7 H), 4.06 (s, 4 H), 3.74 (s, 6 H), 3.61 (s, 6 H), 3.05 - 2.64 (m, 4 H), 1.34 - 1.19 ( m, 2 H), 1.13 (m, 2 H).
<실시예 10> 15,18,21,24,27-펜타옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헵타코사판-3,12-디온 (15,18,21,24,27-pentaoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloheptacosaphane-3,12-dione)의 제조<Example 10> 15,18,21,24,27-pentaoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclo Heptacosaphane-3,12-dione (15,18,21,24,27-pentaoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloheptacosaphane- Manufacture of 3,12-dione)
반응물은 제조예 11의 화합물과 제조예 2의 화합물이며, 실시예 1과 같은 방법으로 제조하여 갈색 고체의 실시예 10의 화합물을 얻었다(수율: 36%).The reactants were the compound of Preparation Example 11 and the compound of Preparation Example 2, and were prepared in the same manner as Example 1 to obtain the compound of Example 10 as a brown solid (yield: 36%).
1H NMR (400 MHz, DMSO-d 6) δ 811.58 - 11.16 (m, 2 H), 8.20 - 8.10 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 6.99 (m, 3 H), 6.95 - 6.57 (m, 7 H),, 4.12 - 3.93 (m, 4 H), 3.72 (s, 4 H), 3.56 (, J = 9.7, 9.1 Hz,6 H), 3.38 (s, 6 H), 3.03 - 2.74 (m, 4 H), 1.87 - 1.53 (m, 2 H), 1.37 - 1.19 (m, 2 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 811.58 - 11.16 (m, 2 H), 8.20 - 8.10 (m, 1 H), 7.56 - 7.46 (m, 1 H), 7.23 - 6.99 (m, 3) H), 6.95 - 6.57 (m, 7 H),, 4.12 - 3.93 (m, 4 H), 3.72 (s, 4 H), 3.56 (, J = 9.7, 9.1 Hz,6 H), 3.38 (s, 6 H), 3.03 - 2.74 (m, 4 H), 1.87 - 1.53 (m, 2 H), 1.37 - 1.19 (m, 2 H).
<비교예 1> 6,9-디옥사-2,13-디아자-1(2,5)-티아디아졸라-14(3,6)-피리다지나-5,10(1,3)-디벤제나시클로옥타데카판-3,12-디온 (6,9-dioxa-2,13-diaza-1(2,5)-thiadiazola-14(3,6)-pyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3,12-dione)의 제조<Comparative Example 1> 6,9-dioxa-2,13-diaza-1(2,5)-thiadiazola-14(3,6)-pyridazina-5,10(1,3)- Dibenzenacyclooctadecapane-3,12-dione (6,9-dioxa-2,13-diaza-1(2,5)-thiadiazola-14(3,6)-pyridazina-5,10(1,3 )-dibenzenacyclooctadecaphane-3,12-dione) Preparation
반응물은 제조예 1의 화합물과 제조예 12의 화합물이며, 실시예 1과 같은 방법으로 제조하여 비교예 1의 화합물을 얻었다(수율: 13%).The reactants were the compound of Preparation Example 1 and the compound of Preparation Example 12, and the compound of Comparative Example 1 was obtained by preparing in the same manner as Example 1 (yield: 13%).
1H NMR (300 MHz, DMSO-d6) δ 11.33 - 11.14 (m, 1 H), 8.23 - 8.11 (m, 1H), 7.58 - 7.46 (m, 1 H), 7.27 - 7.08 (m, 2 H), 7.00 - 6.66 (m, 6 H), 4.39 - 4.15 (m, 4 H), 3.72 (s, 4 H), 3.02 - 2.91 (m, 2 H), 2.90 - 2.79 (m, 2 H), 1.83 - 1.55 (m, 4 H). 1 H NMR (300 MHz, DMSO-d6) δ 11.33 - 11.14 (m, 1 H), 8.23 - 8.11 (m, 1H), 7.58 - 7.46 (m, 1 H), 7.27 - 7.08 (m, 2 H) , 7.00 - 6.66 (m, 6 H), 4.39 - 4.15 (m, 4 H), 3.72 (s, 4 H), 3.02 - 2.91 (m, 2 H), 2.90 - 2.79 (m, 2 H), 1.83 - 1.55 (m, 4 H).
<비교예 2> 15,19,23-트리옥사-4,11-디아자-5,10(2,5)-디티아디아졸라-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온 (15,19,23-trioxa-4,11-diaza-5,10(2,5)-dithiadiazola-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)의 제조<Comparative Example 2> 15,19,23-trioxa-4,11-diaza-5,10(2,5)-dithiadiazola-1,14(1,3)-dibenzenacyclotricosaphane- Preparation of 3,12-dione (15,19,23-trioxa-4,11-diaza-5,10(2,5)-dithiadiazola-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)
반응물은 제조예 9의 화합물과 제조예 13의 화합물이며, 실시예 1과 같은 방법으로 제조하여 노란색 고체의 비교예 2의 화합물을 얻었다(수율: 25%).The reactants were the compound of Preparation Example 9 and the compound of Preparation Example 13, and were prepared in the same manner as Example 1 to obtain the compound of Comparative Example 2 as a yellow solid (yield: 25%).
1H NMR (400 MHz, DMSO-d 6) δ 7.21 - 7.05 (m, 2 H), 6.91 - 6.63 (m, 6 H), 4.01 - 3.91 (m, 4 H), 3.71 (s, 4 H), 3.53 - 3.49 (m, 4 H), 3.00 - 2.91 (m, 4 H), 1.95 - 1.87 (m, 4 H), 1.76 - 1.66 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.21 - 7.05 (m, 2 H), 6.91 - 6.63 (m, 6 H), 4.01 - 3.91 (m, 4 H), 3.71 (s, 4 H) , 3.53 - 3.49 (m, 4 H), 3.00 - 2.91 (m, 4 H), 1.95 - 1.87 (m, 4 H), 1.76 - 1.66 (m, 4 H).
<비교예 3> 15,19,23-트리옥사-4,11-디아자-5(2,5)-티아디아졸라-10(3,6)-피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온 (15,19,23-trioxa-4,11-diaza-5(2,5)-thiadiazola-10(3,6)-pyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione)의 제조<Comparative Example 3> 15,19,23-trioxa-4,11-diaza-5(2,5)-thiadiazola-10(3,6)-pyridazina-1,14(1,3) )-Dibenzenacyclotricosaphane-3,12-dione (15,19,23-trioxa-4,11-diaza-5(2,5)-thiadiazola-10(3,6)-pyridazina-1,14( Preparation of 1,3)-dibenzenacyclotricosaphane-3,12-dione)
반응물은 제조예 9의 화합물과 제조예 12의 화합물이며, 실시예 1과 같은 방법으로 제조하여 비교예 3의 화합물을 얻었다(수율: 15%).The reactants were the compound of Preparation Example 9 and the compound of Preparation Example 12, and the compound of Comparative Example 3 was obtained by preparing in the same manner as Example 1 (yield: 15%).
1H NMR (400 MHz, DMSO-d 6) δ 11.30 - 11.18 (m, 1 H), 8.21 - 8.12 (m, 1 H), 7.56 - 7.45 (m, 1 H), 7.22 - 7.10 (m, 2 H), 6.94 - 6.68 (m, 6 H), 4.01 - 3.93 (m, 4 H), 3.72 (s, 4 H), 3.56 - 3.49 (m, 4 H), 3.01 - 2.92 (m, 2 H), 2.92 - 2.79 (m, 2 H), 1.97 - 1.87 (m, 4 H), 1.74 - 1.58 (m, 4 H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.30 - 11.18 (m, 1 H), 8.21 - 8.12 (m, 1 H), 7.56 - 7.45 (m, 1 H), 7.22 - 7.10 (m, 2) H), 6.94 - 6.68 (m, 6 H), 4.01 - 3.93 (m, 4 H), 3.72 (s, 4 H), 3.56 - 3.49 (m, 4 H), 3.01 - 2.92 (m, 2 H) , 2.92 - 2.79 (m, 2 H), 1.97 - 1.87 (m, 4 H), 1.74 - 1.58 (m, 4 H).
본 발명에 따른 제조예, 실시예 및 비교예 화합물을 정리하여 각각 하기 표 1 및 표 2에 나타내었다.Preparation examples, examples, and comparative examples compounds according to the present invention are summarized and shown in Tables 1 and 2, respectively.
<실험예 1> 세포 외에서의 글루타미네이즈 억제 활성 분석<Experimental Example 1> Analysis of extracellular glutaminase inhibitory activity
세포 외에서의 글루타미네이즈 억제 활성을 확인하기 위하여, 실시예 화합물을 처리하였을 때 글루타미네이즈에 대한 억제 활성 IC50를 측정하였다. 실험 방법은 다음과 같다.In order to confirm the extracellular glutaminase inhibitory activity, the inhibitory activity IC 50 against glutaminase was measured when the example compounds were treated. The experimental method is as follows.
글루타미네이즈 활성을 측정하기 위하여 BPS Bioscience사에서 제공하는 GLS1 inhibitor screening assay kit (카탈로그 번호 #79596)를 사용하였다. 먼저 GLS1(신장형 글루타미네이즈) 10 ng 을 포함하고 있는 8 μL 용액을 384 플레이트 (black, low volume, round bottom) 각각의 well에 분주하였다. 효소 용액에 최종 농도보다 5배 진하게 준비된 화합물 용액을 2 μL 추가하고 상온에서 두 시간 동안 반응시켰다. 반응이 끝난 뒤, L-글루타민, NAD+, 커플링 시약(coupling reagent)를 GLS1 완충용액을 사용하여 혼합하고, 이 혼합물 10 ul 를 각각의 well에 분주하였다. 그 후 추가로 30분동안 상온에서 반응시킨 후 형광값을 측정하여 효소 활성을 확인하였다. 글루타미네이즈 억제 활성 IC50 값은 6가지의 서로 다른 화합물 농도에서 글루타미네이즈의 활성을 각각 측정하고, 그 결과를 GraphPad Prism 으로 분석하여 결정하였다. 그 결과는 하기 표 3와 같다.To measure glutaminase activity, the GLS1 screening inhibitor assay kit (catalog number #79596) provided by BPS Bioscience was used. First, 8 μL of a solution containing 10 ng of GLS1 (kidney-type glutaminase) was dispensed into each well of a 384 plate (black, low volume, round bottom). 2 μL of a compound solution prepared 5 times stronger than the final concentration was added to the enzyme solution and reacted at room temperature for two hours. After the reaction was completed, L-glutamine, NAD+, and coupling reagent were mixed using GLS1 buffer solution, and 10 ul of this mixture was dispensed into each well. Afterwards, the reaction was performed at room temperature for an additional 30 minutes, and the enzyme activity was confirmed by measuring the fluorescence value. The glutaminase inhibitory activity IC 50 value was determined by measuring the glutaminase activity at six different compound concentrations and analyzing the results with GraphPad Prism. The results are shown in Table 3 below.
표 3를 보면, 실시예 1 내지 10의 평균 글루타미네이즈 억제 활성 IC50은 0.7 μM이며, 특히 실시예 1, 2 및 8의 경우 0.3 μM 정도로 낮은 값을 나타낸다. Looking at Table 3, the average glutaminase inhibitory activity IC 50 of Examples 1 to 10 is 0.7 μM, and in particular, Examples 1, 2, and 8 show a value as low as 0.3 μM.
한편, 본원의 실시예 화합물은 피리다지닐렌이 대칭적으로 결합된 구조적 특성을 가지고 있다. 이와 달리 비교예 화합물들은 티아디아졸릴렌이 1 또는 2 결합된 화합물인데, 비교예 1과 실시예 1을 비교해보면, 실시예 1의 IC50가 낮은 것을 통해서 피리다지닐렌이 대칭적으로 결합된 실시예 화합물은 글루타미나제 억제 활성이 우수한 것을 알 수 있다. Meanwhile, the example compounds of the present application have structural characteristics in which pyridazinylene is symmetrically bonded. On the other hand, the comparative example compounds are compounds in which 1 or 2 thiadiazolylene is bonded. When comparing Comparative Example 1 and Example 1, the low IC 50 of Example 1 shows that pyridazinylene is symmetrically bonded. It can be seen that the example compounds have excellent glutaminase inhibitory activity.
또한, 비교예 2 및 3과 실시예 8의 비교를 통해서도 피리다지닐렌이 대칭적으로 결합된 실시예 화합물의 글루타미나제 억제 활성이 우수한 것을 확인할 수 있다.In addition, through comparison between Comparative Examples 2 and 3 and Example 8, it can be confirmed that the example compound to which pyridazinylene is symmetrically bound has excellent glutaminase inhibitory activity.
따라서, 실시예 1 내지 10과 같이 양 쪽에 피리다지닐렌이 결합된 경우, 한 쪽에만 피리다지닐렌이 결합되어 있거나 양 쪽에 티아디아졸릴렌이 결합된 경우에 비하여 글루타미네이즈 억제 활성이 뛰어난 것으로 평가된다.Therefore, when pyridazinylene is bonded to both sides as in Examples 1 to 10, the glutaminase inhibitory activity is superior to that when pyridazinylene is bonded to only one side or thiadiazolylene is bonded to both sides. It is evaluated as
<실험예 2> 세포독성 실험<Experimental Example 2> Cytotoxicity experiment
본 발명에 따른 화합물의 항암 효과를 확인하기 위하여, ALK-TKI 내성 세포인 LR (Ceritinib (LDK378) resistant) pool 세포주에서 CB-839를 레퍼런스로 하여 농도에 따른 세포 생존성을 통해서 IC50를 측정하였다. In order to confirm the anticancer effect of the compound according to the present invention, IC 50 was measured through cell viability according to concentration in LR (Ceritinib (LDK378) resistant) pool cell line, which is ALK-TKI resistant cells, using CB-839 as a reference. .
ALK 저해제인 Ceritinib에 민감성을 보이는 ALK 양성 비소세포폐암인 H3122 세포주에, Ceritinib의 농도를 0.01μM에서 1μM까지 지속적으로 증가시켰다. 살아남은 H3122 세포주를 1μM Ceritinib이 첨가된 배지에서 계속 배양하여, 획득 내성 비소세포폐암 세포주를 구축하였다(이하 H3122-LR pool이라 명명함). In the H3122 cell line, an ALK-positive non-small cell lung cancer that is sensitive to the ALK inhibitor Ceritinib, the concentration of Ceritinib was continuously increased from 0.01 μM to 1 μM. The surviving H3122 cell line was continued to be cultured in medium supplemented with 1 μM Ceritinib to construct an acquired-resistant non-small cell lung cancer cell line (hereinafter referred to as H3122-LR pool).
시퀀싱 결과, 이 내성 세포주는 글루타미네이즈 억제제의 반응 예측 바이오 마커인 NRF2 증폭을 나타내었다. 이에 화합물의 항암 효과를 테스트하기 위해 적합한 모델로 선정하게 되었다. 실험 방법은 다음과 같다.As a result of sequencing, this resistant cell line showed amplification of NRF2, a biomarker predicting response to glutaminase inhibitors. Accordingly, it was selected as a suitable model to test the anticancer effect of the compound. The experimental method is as follows.
세포를 96 Well White/Clear Bottom Plate에 seeding 후, 다음날 화합물과 CB-839 레퍼런스를 각각 연속 희석(serial dilution)하여 세포에 처리하였다. 처리 후 72시간 째에 살아있는 세포에 존재하는 ATP를 측정하여 세포 생존성을 확인하는 CellTiter-Glo 시약을 첨가하여 GloMax® luminometer로 발광을 측정하였다. 약물 처리하지 않은 control 대비 처리한 약물 농도별 세포생존율 (% of control)을 계산 후 50% 세포 생존을 나타내는 약물 농도 (IC50: Half maximal inhibitory concentration)를 산출하였다. 그 결과는 하기 표 4와 같다.After seeding the cells in a 96 Well White/Clear Bottom Plate, the next day, the compound and the CB-839 reference were serially diluted and treated. At 72 hours after treatment, CellTiter-Glo reagent, which confirms cell viability by measuring ATP present in living cells, was added and luminescence was measured with a GloMax® luminometer. After calculating the cell survival rate (% of control) by drug concentration compared to the untreated control, the drug concentration representing 50% cell survival (IC 50 : Half maximal inhibitory concentration) was calculated. The results are shown in Table 4 below.
표 4를 보면, 실시예 화합물의 H3122-LR 세포독성 IC50는 모두 1 μM 이하이며, 특히 실시예 8의 경우 0.1 μM 이하로 항암 효과가 뛰어남을 알 수 있다.Looking at Table 4, the H3122-LR cytotoxic IC 50 of the example compounds are all 1 μM or less, and in particular, Example 8 is 0.1 μM or less, showing excellent anticancer effect.
<실험예 3> 세포 내에서의 글루타미네이즈 억제 활성 분석<Experimental Example 3> Analysis of glutaminase inhibition activity in cells
세포 내에서의 글루타미네이즈 억제 활성을 확인하기 위하여, 실시예 화합물을 세포에 처리한 후 글루타민과 글루타미네이트의 레벨을 비교하였다. 실험 방법은 다음과 같다.In order to confirm the glutaminase inhibitory activity within cells, the levels of glutamine and glutamate were compared after treating the cells with the example compounds. The experimental method is as follows.
세포를 96 Well White/Clear Bottom Plate에 seeding 후 다음날 화합물과 CB-839 레퍼런스를 각각 0.3 μM 처리하였다. 24시간 배양 후 Glutamine/Glutamate-Glo™ Assay kit를 이용하여 세포내 글루타민/글루타메이트 레벨을 측정하였다. 이때 배양 배지는 glucose, glutamine, 그리고 pyruvate가 없는 serum-free 배지에 5 mM glucose, 2 mM glutamine, dialyzed FBS 10%를 첨가하여 사용하였다.The cells were seeded in a 96 Well White/Clear Bottom Plate and treated with 0.3 μM of each compound and CB-839 reference the next day. After 24 hours of incubation, intracellular glutamine/glutamate levels were measured using the Glutamine/Glutamate-Glo™ Assay kit. At this time, the culture medium was a serum-free medium without glucose, glutamine, and pyruvate, with 5mM glucose, 2mM glutamine, and 10% dialyzed FBS added.
도 1을 보면, 실시예 화합물 0.3 μM을 처리한 경우 글루타민 농도는 높은 반면, 글루타메이트의 농도가 낮은 것을 확인할 수 있다. 글루타미네이즈에 의해 글루타민이 글루타메이트로 전환되므로, 글루타민의 농도가 글루타메이트의 농도에 비해 현저하게 높은 것을 통해, 본 발명에 따른 화합물은 세포 내로 흡수되어 세포 내에서도 글루타미네이즈 억제 활성이 뛰어남을 알 수 있다.Looking at Figure 1, it can be seen that when treated with 0.3 μM of the example compound, the glutamine concentration was high, while the glutamate concentration was low. Since glutamine is converted to glutamate by glutaminase, the concentration of glutamine is significantly higher than the concentration of glutamate, showing that the compound according to the present invention is absorbed into cells and has excellent glutaminase inhibitory activity even within cells. .
Claims (12)
[화학식 1]
상기 화학식 1에서,
L은 C1-20의 직쇄 알킬렌이고, 여기서 알킬렌의 하나 이상의 탄소 원자는 산소 원자로 치환될 수 있다.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,
L is a C 1-20 straight chain alkylene, where one or more carbon atoms of the alkylene may be replaced with an oxygen atom.
상기 L은 -O-C1-15 직쇄 알킬렌-O-이고, 여기서 알킬렌의 하나 이상의 탄소 원자는 산소 원자로 치환될 수 있되 산소 원자끼리는 결합하지 않는,
화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.According to paragraph 1,
The L is -OC 1-15 straight chain alkylene-O-, where one or more carbon atoms of the alkylene may be replaced with an oxygen atom, but the oxygen atoms do not bond to each other.
A compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
상기 L은 -O-L1-이고, 상기 L1는 -[(CH2)p-O]m-이며, p는 1 내지 10의 정수, m은 1 내지 5의 정수이고, L1의 탄소 및 산소 개수의 합은 12 이내인,
화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.According to paragraph 1,
The L is -OL 1 -, the L 1 is -[(CH 2 )pO]m-, p is an integer from 1 to 10, m is an integer from 1 to 5, and the number of carbon and oxygen of L 1 The sum is within 12,
A compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
상기 L은 , , , , , , , , 또는 인,
화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.According to paragraph 1,
The L is , , , , , , , , or person,
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 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:
<1> 6,9-디옥사-2,13-디아자-1,14(3,6)-디피리다지나-5,10(1,3)-디벤제나시클로옥타데카판-3,12-디온;
<2> 15,19-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로노나데카판-3,12-디온;
<3> 15,20-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로이코사판-3,12-디온;
<4> 15,21-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헤니코사판-3,12-디온;
<5> 15,18,21-트리옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헤니코사판-3,12-디온;
<6> 15,22-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로도코사판-3,12-디온;
<7> 15,23-디옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온;
<8> 15,19,23-트리옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로트리코사판-3,12-디온;
<9> 15,18,21,24-테트라옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로테트라코사판-3,12-디온; 및
<10> 15,18,21,24,27-펜타옥사-4,11-디아자-5,10(3,6)-디피리다지나-1,14(1,3)-디벤제나시클로헵타코사판-3,12-디온.According to paragraph 1,
The compound represented by Formula 1 is any one selected from the following compound group, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1> 6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3,12- Dion;
<2> 15,19-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclononadecapane-3,12- Dion;
<3>15,20-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloicosaphane-3,12-dione;
<4> 15,21-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosapan-3,12- Dion;
<5> 15,18,21-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclohenicosapan-3, 12-dione;
<6>15,22-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclodocosaphane-3,12-dione;
<7>15,23-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosaphane-3,12-dione;
<8> 15,19,23-trioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotricosapan-3,12 -Dion;
<9> 15,18,21,24-tetraoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacyclotetracosapan- 3,12-dione; and
<10> 15,18,21,24,27-pentaoxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloheptaco Sapan-3,12-dione.
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 아마이드화 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 1)를 포함하는 화학식 1로 표시되는 화합물의 제조방법:
[반응식 1]
상기 반응식 1에서,
L은 제1항의 화학식 1에서 정의한 바와 같다.As shown in Scheme 1 below,
Method for producing a compound represented by Formula 1, comprising the step (step 1) of producing a compound represented by Formula 1 by subjecting a compound represented by Formula 2 to an amidation reaction with a compound represented by Formula 3:
[Scheme 1]
In Scheme 1 above,
L is as defined in Formula 1 of Clause 1.
암의 예방 또는 치료용 약학적 조성물.Containing the compound represented by Formula 1 of claim 1, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient,
Pharmaceutical composition for preventing or treating cancer.
상기 화합물은 글루타미네이즈를 억제하는 것을 특징으로 하는,
약학적 조성물.In clause 7,
The compound is characterized by inhibiting glutaminase,
Pharmaceutical composition.
상기 암은 방광암, 유방암, 결장암, 신장암, 간암, 폐암, 소세포폐암, 식도암, 담낭암, 난소암, 췌장암, 위암, 자궁 경부암, 갑상선암, 전립선암, 또는 피부암인 것을 특징으로 하는 약학적 조성물.In clause 7,
A pharmaceutical composition, wherein the cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, or skin cancer.
자가면역질환의 예방 또는 치료용 약학적 조성물:
상기 자가면역질환은 건선, 류마티스성 관절염, 혈관염, 염증성 장 질환, 피부염, 골관절염, 천식, 염증성 근육 질환, 알러지성 질환, 질염, 간질 방광염, 경피증, 골다공증, 습진, 동종이계 또는 이종발생성 이식 거부, 이식편대숙주질환(GVHD), 홍반성 낭창, 염증성 질환, I형 당뇨병, 폐 섬유증, 피부근염, 쇼그렌 증후군, 갑상선염, 중증 근무력증, 자가면역 용혈성 빈혈, 다발성 경화증, 낭포성 섬유증, 만성적 재발성 간염, 원발성 담도성 간경변증, 알러지성 결막염 또는 아토피 피부염이다.Containing the compound represented by Formula 1 of claim 1, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient,
Pharmaceutical composition for preventing or treating autoimmune diseases:
The autoimmune diseases include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplant rejection. , graft-versus-host disease (GVHD), lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis. , primary biliary cirrhosis, allergic conjunctivitis, or atopic dermatitis.
상기 화합물은 글루타미네이즈를 억제하는 것을 특징으로 하는, 약학적 조성물.According to clause 10,
A pharmaceutical composition, characterized in that the compound inhibits glutaminase.
상기 자가면역질환은 건선, 류마티스성 관절염, 혈관염, 염증성 장 질환, 피부염, 골관절염, 천식, 염증성 근육 질환, 알러지성 질환, 질염, 간질 방광염, 경피증, 골다공증, 습진, 동종이계 또는 이종발생성 이식 거부, 이식편대숙주질환(GVHD), 홍반성 낭창, 염증성 질환, I형 당뇨병, 폐 섬유증, 피부근염, 쇼그렌 증후군, 갑상선염, 중증 근무력증, 자가면역 용혈성 빈혈, 다발성 경화증, 낭포성 섬유증, 만성적 재발성 간염, 원발성 담도성 간경변증, 알러지성 결막염 또는 아토피 피부염이다.A health functional food composition for preventing or improving cancer or autoimmune disease containing the compound represented by Formula 1 of paragraph 1, its solvate, hydrate or pharmaceutically acceptable salt thereof as an active ingredient:
The autoimmune diseases include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplant rejection. , graft-versus-host disease (GVHD), lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis. , primary biliary cirrhosis, allergic conjunctivitis, or atopic dermatitis.
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| WO2013078123A1 (en) | 2011-11-21 | 2013-05-30 | Calithera Biosciences Inc. | Heterocyclic inhibitors of glutaminase |
| US20150065486A1 (en) | 2013-08-29 | 2015-03-05 | Edward Skolnik | Methods for treating polycystic kidney disease |
| CN111440199A (en) | 2020-03-11 | 2020-07-24 | 中国药科大学 | Macrocyclic glutaminase G L S1 inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013078123A1 (en) | 2011-11-21 | 2013-05-30 | Calithera Biosciences Inc. | Heterocyclic inhibitors of glutaminase |
| US20150065486A1 (en) | 2013-08-29 | 2015-03-05 | Edward Skolnik | Methods for treating polycystic kidney disease |
| CN111440199A (en) | 2020-03-11 | 2020-07-24 | 中国药科大学 | Macrocyclic glutaminase G L S1 inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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| XU, X. 등, Journal of medicinal chemistry, 2021.04.01, 64권, 페이지 4588-4611 |
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