KR102218861B1 - Novel phenoxy aromatic amide derivatives as protein kinase inhibitors - Google Patents
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Abstract
본 발명은 단백질 키나아제 저해활성을 갖는 신규한 페녹시 아로마틱 아마이드 유도체 화합물, 이의 약학적으로 허용 가능한 염, 그리고 이 화합물을 유효성분으로 함유하는 암 질환의 예방 및 치료용 약학적 조성물에 관한 것이다. 본 발명의 신규 화합물은 암질환 중 특히, DAPK1 단백질 키나아제에 대하여 우수한 억제 효과를 나타내므로, 이들 단백질 키나아제에 의해 유발되는 비정상적인 세포성장 질환의 예방 및 치료제로서 유용하다.The present invention relates to a novel phenoxy aromatic amide derivative compound having protein kinase inhibitory activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing and treating cancer diseases containing the compound as an active ingredient. The novel compounds of the present invention exhibit excellent inhibitory effects on DAPK1 protein kinase, especially among cancer diseases, and are therefore useful as a prevention and treatment of abnormal cell growth diseases caused by these protein kinases.
Description
본 발명은 단백질 키나아제 저해활성을 갖거나 항암활성을 갖는 신규의 페녹시 아로마틱 아마이드 유도체와, 상기한 신규 화합물을 유효성분으로 함유하는 암 질환의 예방, 개선 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel phenoxy aromatic amide derivative having protein kinase inhibitory activity or anti-cancer activity, and a pharmaceutical composition for preventing, improving or treating cancer diseases containing the above-described novel compound as an active ingredient.
DAPK1 (Ca2+/칼모듈린 의존적 세린/트레오닌 인산화효소)은 세포사와 신호와 연관된 자가포식작용에 필수적인 매개물질이다. DAPK1은 DAPK 단백질 군에서 가장 큰 구성원으로서 Ca2+/CaM 자가조절영역, 사멸 영역, 그리고 인산화 활성이 특정한 세포사멸 형태의 원인이 되는 세린이 풍부한 C 말단을 포함하는 1430개의 잔기들로 구성된다.DAPK1 (Ca 2+ /calmodulin-dependent serine/threonine kinase) is an essential mediator for autophagy related to cell death and signaling. DAPK1 is the largest member of the DAPK protein family and is composed of 1430 residues containing a Ca 2+ /CaM autoregulatory region, a death region, and a serine-rich C-terminus whose phosphorylation activity is responsible for certain apoptosis forms.
DAPK1은 사멸 수용체 활성화, 사이토카인, 세포간질 분리, 세라마이드, 국소 빈혈, 글루탐산 독성과 같은 다양한 자극에 반응하여 세포사의 신호전달 경로를 조정한다. 다양한 연구에서 이미 논의된 바와 같이, 자극에 반응하는 인산화 효소로서의 DAPK1은 소포체 자극 신호를 카스파제 활성 (타입I 세포사멸적 카스파제 의존적 세포사 조절을 통해)과 자가포식 (타입II 자가 소화 작용의 카스파제 비 의존적 세포사 조절을 통해)의 두 가지 방향으로 보내는 중요한 구성 요소이다. 세포사 경로를 저해하기 위한 새로운 효과적인 방법 중에서, 몇몇의 융합 단백질이 보고되었다. 그러나 펩타이드 기반의 전략은 경구 투여 후 급속 분해 외에 펩타이드 화물에 영향을 미치면서 효과적인 치료 농도의 불확실성뿐만 아니라 세포 선택성, 불안정성의 부족으로 인해 개발에 한계점을 가지고 있다. DAPK1 modulates the signaling pathways of cell death in response to a variety of stimuli such as death receptor activation, cytokines, interstitial separation, ceramides, ischemia, and glutamic acid toxicity. As already discussed in various studies, DAPK1 as a phosphorylating enzyme in response to stimulus signals caspase activity (through type I apoptosis caspase-dependent cell death regulation) and autophagy (type II self-digesting caspase). It is an important component of sending in two directions (via non-dependent cell death regulation). Among the new effective methods for inhibiting the cell death pathway, several fusion proteins have been reported. However, the peptide-based strategy has limitations in its development due to lack of cell selectivity and instability, as well as uncertainty of effective therapeutic concentration, affecting peptide cargo in addition to rapid degradation after oral administration.
따라서 저분자 저해제의 합리적인 약물 설계가 이러한 결점을 극복 할 수 있는 유일한 방법이 될 수 있다. DAPK1은 그 기능을 이해하기 위해 많은 연구가 진행되었으나, 아미노피리다진, 이미다조[1,2-b]피리다진, 피리딘-3-일메틸렌-1,3-옥사졸-5-온, 피라졸로[3,4-d]피리미디논과 1H-피롤[2,3-b]피리딘과 같은 소수의 화학적 골격만이 DAPK1 저해 효능을 가진 것으로 알려져 있다.Therefore, rational drug design of small molecule inhibitors may be the only way to overcome these drawbacks. DAPK1 has been studied a lot to understand its function, but aminopyridazine, imidazo[1,2-b]pyridazine, pyridin-3-ylmethylene-1,3-oxazol-5-one, pyrazolo Only a few chemical skeletons, such as [3,4-d]pyrimidinone and 1H-pyrrole[2,3-b]pyridine, are known to have DAPK1 inhibitory effects.
본 발명은 신규 구조의 페녹시 아로마틱 아마이드 유도체 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하고자 한다.The present invention is to provide a novel structure of a phenoxy aromatic amide derivative compound or a pharmaceutically acceptable salt thereof.
또한, 본 발명의 일측면은 상기한 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 암의 예방, 개선 또는 치료용 약학적 조성물을 제공하고자 한다. In addition, an aspect of the present invention is to provide a pharmaceutical composition for the prevention, improvement or treatment of cancer, containing the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명의 일측면은 상기한 신규 화합물의 제조방법을 제공하고자 한다.In addition, an aspect of the present invention is to provide a method for preparing the novel compound.
또한, 본 발명의 일측면은 상기한 제조방법을 수행하는 과정에서 합성된 신규의 중간체 화합물을 제공하고자 한다.In addition, an aspect of the present invention is to provide a novel intermediate compound synthesized in the process of performing the above preparation method.
상기한 과제 해결을 위하여, 본 발명의 일측면은 하기 화학식 1로 표시되는 페녹시 아로마틱 아마이드 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 광학 이성질체로부터 선택된 화합물을 제공한다.In order to solve the above problems, an aspect of the present invention provides a compound selected from a phenoxy aromatic amide compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and an optical isomer thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 수소원자; 비치환 또는 치환된 C1-6의 직쇄 또는 측쇄의 알킬, 비치환 또는 치환된 C1-6의 직쇄 또는 측쇄의 알콕시, 히드록시기, 할로젠, 아미노, 나이트로 또는 시아노기이고, R 1 is a hydrogen atom; Unsubstituted or substituted C1-6 straight or branched alkyl, unsubstituted or substituted C1-6 straight or branched alkoxy, hydroxy group, halogen, amino, nitro or cyano group,
R2는 비치환 또는 치환된 C3-10의 사이클로알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1개 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 C3-10의 헤테로사이클로알킬, 비치환 또는 치환된 C6-10의 아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1개 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5 내지 10각환의 헤테로아릴이다.R 2 is unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted C3-10 heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O and S, unsubstituted or A substituted C6-10 aryl, or an unsubstituted or substituted 5 to 10 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S.
본 발명의 일측면에서, 상기 R1은 할로젠이며, 상기 R2는 피리다진; 피라진; 이미다졸; 피라졸; 퓨란; 피리미딘; 옥사졸; 피롤; 피리딘; 옥사디아졸; 트리아진; 시아디아졸; 이소사졸; 테트라졸; 트리아졸;또는 사이아졸;인, 페녹시 아로마틱 아마이드 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 광학 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R 1 is halogen, and R 2 is pyridazine; Pyrazine; Imidazole; Pyrazole; Furan; Pyrimidine; Oxazole; Pyrrole; Pyridine; Oxadiazole; Triazine; Cyanadiazole; Isozazole; Tetrazole; Triazole; or cyazole; phosphorus, phenoxy aromatic amide compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and optical isomers thereof.
본 발명의 일측면에서, 상기 R1은 4-F, 3-F 또는 3-Cl이고, 상기 R2는 2-피리딘, 3-피리딘, 4-피리딘, 3-피리다진, 4-피리다진 또는 2-피라진인, 페녹시 아로마틱 아마이드 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 광학 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R 1 is 4-F, 3-F or 3-Cl, and R 2 is 2-pyridine, 3-pyridine, 4-pyridine, 3-pyridazine, 4-pyridazine or 2-pyrazine, a phenoxy aromatic amide compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and an optical isomer thereof.
본 발명의 다른 측면은 상기의 화합물이 유효성분으로 포함된 DAPK1 단백질 키나아제에 의해 유발되는 질환의 예방, 개선 또는 치료용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing, improving or treating diseases caused by DAPK1 protein kinase containing the above compound as an active ingredient.
본 발명의 다른 측면에서, 상기 DAPK1 단백질 키나아제에 의해 유발되는 질환은 DAPK1 단백질 키나아제에 의해 유발되는 암질환, 허혈, 또는 알츠하이머인, 약학 조성물을 제공한다.In another aspect of the present invention, there is provided a pharmaceutical composition, wherein the disease caused by the DAPK1 protein kinase is a cancer disease, ischemia, or Alzheimer's caused by the DAPK1 protein kinase.
본 발명의 다른 측면에서, 상기 암질환은 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 혈액암, 림프종, 및 섬유선종으로 이루어진 군으로부터 선택되는 질환일 수 있다.In another aspect of the present invention, the cancer disease is endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, It may be a disease selected from the group consisting of parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, hematologic cancer, lymphoma, and fibroadenoma.
본 발명의 또 다른 측면은 하기 단계를 포함하는, 화학식 1의 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 입체 이성질체로부터 선택된 화합물의 제조방법을 제공한다: Another aspect of the present invention provides a method for preparing a compound selected from a compound of Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof, comprising the following steps:
(a) 2-클로로-1-플루오로-4-나이트로벤젠과 R1 작용기가 치환된 페놀 유도체를 반응 시켜 하기 화학식 2 화합물을 제조하는 단계;(a) reacting 2-chloro-1-fluoro-4-nitrobenzene with a phenol derivative substituted with an R1 functional group to prepare a compound of Formula 2;
(b) 화학식 2 화합물을 환원시켜 화학식 3 화합물을 제조하는 단계; 및(b) reducing the compound of formula 2 to prepare the compound of formula 3; And
(c) 화학식 3 화합물을 R2 작용기가 치환된 벤조산 유도체와 반응 시켜 화학식 1 화합물을 제조하는 단계;(c) preparing a compound of Formula 1 by reacting the compound of Formula 3 with a benzoic acid derivative substituted with an R2 functional group;
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
상기 화학식 1, 화학식 2 및 화학식 3에서,In Formula 1, Formula 2 and Formula 3,
R1은 수소원자; 비치환 또는 치환된 C1-6의 직쇄 또는 측쇄의 알킬, 비치환 또는 치환된 C1-6의 직쇄 또는 측쇄의 알콕시, 히드록시기, 할로젠, 아미노, 나이트로 또는 시아노기이고, R 1 is a hydrogen atom; Unsubstituted or substituted C1-6 straight or branched alkyl, unsubstituted or substituted C1-6 straight or branched alkoxy, hydroxy group, halogen, amino, nitro or cyano group,
R2는 비치환 또는 치환된 C3-10의 사이클로알킬, N, O 및 S로 이루어진 군으로부터 선택되는 1개 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 C3-10의 헤테로사이클로알킬, 비치환 또는 치환된 C6-10의 아릴, 또는 N, O 및 S로 이루어진 군으로부터 선택되는 1개 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5 내지 10각환의 헤테로아릴이다.R 2 is unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted C3-10 heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O and S, unsubstituted or A substituted C6-10 aryl, or an unsubstituted or substituted 5 to 10 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S.
본 발명의 화합물은 DAPK1을 저해하는 효과가 있으므로 악성 종양 등의 예방 또는 치료에 유용하게 사용될 수 있다. Since the compound of the present invention has an effect of inhibiting DAPK1, it can be usefully used in the prevention or treatment of malignant tumors.
따라서 본 발명에 따른 화합물은 비정상적인 세포 성장 및 대사로 인해 유발되는 질환으로서 예를 들면 당뇨, 비만 등의 대사성질환 및 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 백혈병, 다발성골수종, 골수이형성증후군과 같은 혈액암, 호치킨병과 비호치킨림프종과 같은 림프종, 또는 섬유선종 등으로부터 선택된 각종 종양 질환의 예방 및 치료제로 사용될 수 있다.Therefore, the compounds according to the present invention are diseases caused by abnormal cell growth and metabolism, for example, metabolic diseases such as diabetes and obesity, and endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer. , Bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, Hochicken's disease and non-hochicken It can be used as a preventive and therapeutic agent for various tumor diseases selected from lymphoma such as lymphoma or fibroadenoma.
도 1 내지 도 3은 본원발명 실험예의 결과 그래프이다.1 to 3 are graphs of results of experimental examples of the present invention.
달리 명시되지 않는 한, 본 명세서에서 사용된 성분, 반응 조건, 성분의 함량을 표현하는 모든 숫자, 값 및/또는 표현은, 이러한 숫자들이 본질적으로 다른 것들 중에서 이러한 값을 얻는 데 발생하는 측정의 다양한 불확실성이 반영된 근사치들이므로, 모든 경우 "약"이라는 용어에 의해 수식되는 것으로 이해되어야 한다. 또한, 본 기재에서 수치범위가 개시되는 경우, 이러한 범위는 연속적이며, 달리 지적되지 않는 한 이러한 범 위의 최소값으로부터 최대값이 포함된 상기 최대값까지의 모든 값을 포함한다. 더 나아가, 이러한 범위가 정수를 지칭하는 경우, 달리 지적되지 않는 한 최소값으로부터 최대값이 포함된 상기 최대값까지를 포함하는 모든 정수가 포함된다.Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and content of ingredients used herein are the variety of measurements that occur in obtaining such values, among other things, in which these numbers are essentially different. Since they are approximations that reflect uncertainty, they should be understood as being modified in all cases by the term "about". In addition, when numerical ranges are disclosed herein, these ranges are continuous and, unless otherwise indicated, include all values from the minimum value of this range to the maximum value including the maximum value. Furthermore, when this range refers to an integer, all integers from the minimum value to the maximum value including the maximum value are included, unless otherwise indicated.
본 명세서에 있어서, 범위가 변수에 대해 기재되는 경우, 상기 변수는 상기 범위의 기재된 종료점들을 포함하는 기재된 범위 내의 모든 값들을 포함하는 것으로 이해될 것이다. 예를 들면, "5 내지 10"의 범위는 5, 6, 7, 8, 9, 및 10의 값들뿐만 아니라 6 내지 10, 7 내지 10, 6 내지 9, 7 내지 9 등의 임의의 하위 범위를 포함하고, 5.5, 6.5, 7.5, 5.5 내지 8.5 및 6.5 내지 9 등과 같은 기재된 범위의 범주에 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다. 또한 예를 들면, "10% 내지 30%"의 범위는 10%, 11%, 12%, 13% 등의 값들과 30%까지를 포함하는 모든 정수들뿐만 아니라 10% 내지 15%, 12% 내지 18%, 20% 내지 30% 등의 임의의 하위 범위를 포함하고, 10.5%, 15.5%, 25.5% 등과 같이 기재된 범위의 범주 내의 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다.In the present specification, when a range is described for a variable, it will be understood that the variable includes all values within the stated range, including the stated endpoints of the range. For example, a range of "5 to 10" includes values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. Inclusive, and it will be understood to include any values between integers that are reasonable in the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also, for example, the range of "10% to 30%" is 10% to 15%, 12% to 10%, 11%, 12%, 13%, etc., as well as all integers including up to 30%. It will be understood to include any subranges such as 18%, 20% to 30%, and the like, and include any values between reasonable integers within the scope of the stated range, such as 10.5%, 15.5%, 25.5%, and the like.
이하, 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에 따른 상기 화학식 1로 표시되는 페녹시 아로마틱 아마이드 유도체 화합물의 약학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있다. 약학적으로 허용된 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용된 염 제조에 사용될 수 있는 유리산은 무기산과 유기산으로 나눌 수 있다. 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 유기염기부가염 제조에 사용될 수 있는 유기염기는 트리스(히드록시메틸)메틸아민, 디시클로헥실아민 등이다. 아미노산부가염기 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다. A pharmaceutically acceptable salt of the phenoxy aromatic amide derivative compound represented by Formula 1 according to the present invention can be prepared by a conventional method in the art. Pharmaceutically acceptable salts have low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and bromic acid may be used. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like can be used. Organic bases that can be used in the preparation of organic base addition salts are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used to prepare an amino acid addition base are natural amino acids such as alanine and glycine.
본 발명에 따른 상기 화학식 1로 표시되는 페녹시 아로마틱 아마이드 유도체 화합물은 상기한 약학적으로 허용된 염과 더불어 모든 수화물 그리고 용매화물도 포함한다. 수화물 및 용매화물은 상기 화학식 1로 표시되는 벤자미드 화합물을 메탄올, 에탄올, 아세톤, 1,4-디옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화되거나 또는 재결정화될 수 있다. 그러한 경우, 용매화물(특히 수화물)이 형성될 수 있다. 따라서, 본 발명의 화합물로서 동결건조와 같은 방법으로 제조 가능한 다양한 양의 물 함유 화합물 이외에 수화물을 비롯한 화학 양론적 용매화물도 포함한다.The phenoxy aromatic amide derivative compound represented by Formula 1 according to the present invention includes all hydrates and solvates in addition to the pharmaceutically acceptable salts described above. Hydrates and solvates are crystallized after dissolving the benzamide compound represented by Formula 1 in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, and adding a free acid or a free base, or It can be recrystallized. In such cases, solvates (especially hydrates) may be formed. Accordingly, as the compound of the present invention, in addition to the compound containing various amounts of water that can be prepared by a method such as lyophilization, stoichiometric solvates including hydrates are also included.
본 발명에 따른 화합물을 정의하기 위해 사용된 치환기에 대해 보다 상세히 설명하면 다음과 같다.The substituents used to define the compounds according to the present invention will be described in more detail as follows.
본 발명에서의 ‘할로겐 원자’라 함은 클로로, 플루오로, 브로모, 요오도를 의미한다. In the present invention, the term "halogen atom" means chloro, fluoro, bromo, and iodo.
본 발명에서의 ‘알킬기’라 함은 메틸, 에틸, n-프로필, i-프로필, 시클로프로필, n-부틸, i-부틸, t-부틸, 시클로부틸, 시클로프로필메틸, n-펜틸, i-펜틸, 네오펜틸, t-펜틸, 시클로펜틸, 시클로부틸메틸, n-헥실, i-헥실, 시클로헥실, 시클로펜틸메틸, 헵틸, 시클로헥실메틸, 옥틸 등을 포함하는 1개에서 8개까지의 탄소원자를 가지는 선형, 가지형 또는 고리형의 지방족 포화 탄화수소기를 의미한다. The term'alkyl group' in the present invention refers to methyl, ethyl, n -propyl, i -propyl, cyclopropyl, n -butyl, i -butyl, t -butyl, cyclobutyl, cyclopropylmethyl, n -pentyl, i- 1 to 8 carbon sources including pentyl, neopentyl, t -pentyl, cyclopentyl, cyclobutylmethyl, n -hexyl, i -hexyl, cyclohexyl, cyclopentylmethyl, heptyl, cyclohexylmethyl, octyl, etc. It means a linear, branched or cyclic aliphatic saturated hydrocarbon group having a ruler.
본 발명에서의‘할로알킬기’라 함은 트리플루오르메틸기와 같이 한개 이상의 할로겐 원자에 의해 수소원자가 치환된 알킬기를 의미한다. The term "haloalkyl group" in the present invention refers to an alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as a trifluoromethyl group.
본 발명에서의 ‘알콕시기’라 함은 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, t-부톡시를 포함하는, C1-C8의 알킬기에서 선택된 치환체에 의해 수소원자가 치환된 하이드록시기를 의미한다. In the present invention, the term'alkoxy group' refers to C 1 -C 8 , including methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, t-butoxy It means a hydroxy group in which a hydrogen atom is substituted by a substituent selected from an alkyl group of.
본 발명에서의 ‘아릴기’라 함은 페닐, 나프틸, 안트라니릴, 페난트리닐 등을 포함하여, 6개에서 15개까지의 탄소원자를 가지는 단일고리, 두고리, 또는 세고리의 방향족 탄화수소기를 의미한다. In the present invention, the term'aryl group' refers to a single ring, double ring, or three ring aromatic hydrocarbon group having 6 to 15 carbon atoms, including phenyl, naphthyl, anthraniryl, phenanthrinyl, etc. do.
본 발명에서의 ‘헤테로아릴기’라 함은 피롤릴, 퓨라닐, 티오페닐, 피라졸릴, 이미다졸릴, 옥사졸릴, 이소옥사졸릴, 티아졸릴, 이소티아졸릴, 트리아졸릴, 옥사디아졸릴, 티아디아졸릴, 테트라졸릴, 피리디닐, 피라지닐, 피리다지닐, 피리미디닐, 인돌릴, 이소인돌릴, 벤조퓨라닐, 벤조퓨라자닐, 디벤조퓨라닐, 이소벤조퓨라닐, 인다졸릴, 벤즈이미다졸릴, 벤즈옥사졸릴, 벤즈이소옥사졸릴, 벤조티아졸릴, 디벤조티오페닐, 나프티리딜, 벤즈이소티아졸릴, 퀴놀리닐, 이소퀴놀리닐, 퀴녹살리닐, 프탈라지닐, 치놀리닐, 퀴나졸리닐 등을 포함하여, N, O 및 S 중에서 선택된 헤테로원자가 1개 이상 포함된 단일고리, 두고리, 또는 세고리 방향족 헤테로탄화수소기를 의미한다. The term'heteroaryl group' in the present invention refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thia Diazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, isobenzofuranyl, indazolyl, benz Imidazolyl, benzoxazolyl, benzisooxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, chinolinyl Including, quinazolinyl, and the like, N, O, and S refers to a monocyclic, double, or tricyclic aromatic heterohydrocarbon group containing one or more heteroatoms selected from.
본 발명에서의 ‘ 헤테로시클로알킬기’라 함은 몰포리닐, 피페리디닐, 피페라지닐, N-보호된 피페라지닐 등을 포함하여, N 및 O 중에서 선택된 헤테로원자가 1개 이상 포함된 5각형 또는 6각형의 지방족 헤테로탄화수소 고리기를 의미한다. 피페라지닐의 N-보호기로는 통상적으로 알킬기가 포함될 수 있다.The term'heterocycloalkyl group' in the present invention refers to a pentagonal containing at least one heteroatom selected from N and O, including morpholinyl, piperidinyl, piperazinyl, and N-protected piperazinyl. Or it means a hexagonal aliphatic heterohydrocarbon ring group. The N -protecting group of piperazinyl may generally include an alkyl group.
본 발명에 따른 상기 화학식 1로 표시되는 화합물을 구체적으로 예시하면 다음과 같다.A specific example of the compound represented by Chemical Formula 1 according to the present invention is as follows.
(화합물 번호 1) N-(3-클로로-4-(4-플루오로페녹시)페닐)피콜린아마이드; (Compound No. 1) N- (3-chloro-4-(4-fluorophenoxy)phenyl)picolinamide;
(화합물 번호 2) N-(3-클로로-4-(4-플루오로페녹시)페닐)피리다진-3-카복사마이드;(Compound No. 2) N- (3-chloro-4-(4-fluorophenoxy)phenyl)pyridazine-3-carboxamide;
(화합물 번호 3) N-(3-클로로-4-(4-플루오로페녹시)페닐)피라진-2-카복사마이드;(Compound No. 3) N- (3-chloro-4-(4-fluorophenoxy)phenyl)pyrazine-2-carboxamide;
(화합물 번호 4) N-(3-클로로-4-(4-플루오로페녹시)페닐)니코틴아마이드;(Compound No. 4) N- (3-chloro-4-(4-fluorophenoxy)phenyl)nicotinamide;
(화합물 번호 5) N-(3-클로로-4-(4-플루오로페녹시)페닐)아이소니코틴아마이드;(Compound No. 5) N- (3-chloro-4-(4-fluorophenoxy)phenyl)isonicotinamide;
(화합물 번호 6) N-(3-클로로-4-(4-플루오로페녹시)페닐)피리다진-4-카복사마이드;(Compound No. 6) N- (3-chloro-4-(4-fluorophenoxy)phenyl)pyridazine-4-carboxamide;
(화합물 번호 7) N-(3-클로로-4-(3-플루오로페녹시)페닐)피콜린아마이드;(Compound No. 7) N- (3-chloro-4-(3-fluorophenoxy)phenyl)picolinamide;
(화합물 번호 8) N-(3-클로로-4-(3-플루오로페녹시)페닐)피리다진-3-카복사마이드;(Compound No. 8) N- (3-chloro-4-(3-fluorophenoxy)phenyl)pyridazine-3-carboxamide;
(화합물 번호 9) N-(3-클로로-4-(3-플루오로페녹시)페닐)피라진-2-카복사마이드;(Compound No. 9) N- (3-chloro-4-(3-fluorophenoxy)phenyl)pyrazine-2-carboxamide;
(화합물 번호 10) N-(3-클로로-4-(3-플루오로페녹시)페닐)니코틴아마이드;(Compound No. 10) N- (3-chloro-4-(3-fluorophenoxy)phenyl)nicotinamide;
(화합물 번호 11) N-(3-클로로-4-(3-플루오로페녹시)페닐)아이소니코틴아마이드;(Compound No. 11) N- (3-chloro-4-(3-fluorophenoxy)phenyl)isonicotinamide;
(화합물 번호 12) N-(3-클로로-4-(3-플루오로페녹시)페닐)피리다진-4-카복사마이드;(Compound No. 12) N- (3-chloro-4-(3-fluorophenoxy)phenyl)pyridazine-4-carboxamide;
(화합물 번호 13) N-(3-클로로-4-(3-클로로페녹시)페닐)피콜린아마이드;(Compound No. 13) N- (3-chloro-4-(3-chlorophenoxy)phenyl)picolinamide;
(화합물 번호 14) N-(3-클로로-4-(3-클로로페녹시)페닐)피리다진-3-카복사마이드;(Compound No. 14) N- (3-chloro-4-(3-chlorophenoxy)phenyl)pyridazine-3-carboxamide;
(화합물 번호 15) N-(3-클로로-4-(3-클로로페녹시)페닐)피라진-2-카복사마이드;(Compound No. 15) N- (3-chloro-4-(3-chlorophenoxy)phenyl)pyrazine-2-carboxamide;
(화합물 번호 16) N-(3-클로로-4-(3-클로로페녹시)페닐)니코틴아마이드;(Compound No. 16) N- (3-chloro-4-(3-chlorophenoxy)phenyl)nicotinamide;
(화합물 번호 17) N-(3-클로로-4-(3-클로로페녹시)페닐)아이소니코틴아마이드; 및(Compound No. 17) N- (3-chloro-4-(3-chlorophenoxy)phenyl)isonicotinamide; And
(화합물 번호 18) N-(3-클로로-4-(3-클로로페녹시)페닐)피리다진-4-카복사마이드.(Compound No. 18) N- (3-chloro-4-(3-chlorophenoxy)phenyl)pyridazine-4-carboxamide.
한편, 본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 그 특징으로 한다. On the other hand, the present invention is characterized by a method of preparing the compound represented by Chemical Formula 1.
본 발명은 본 발명에 따른 상기 화학식 Ⅰ로 표시되는 페녹시 아로마틱 아마이드 화합물의 제조방법을 제공한다.The present invention provides a method for preparing a phenoxy aromatic amide compound represented by Formula I according to the present invention.
(단계 a) 하기 화학식 1로 표시되는 화합물과 페놀 유도체를 반응시켜 하기 화학식 2a-c로 표시되는 화합물을 제조하는 단계;(Step a) preparing a compound represented by the following Formula 2a-c by reacting a compound represented by the following Formula 1 with a phenol derivative;
(단계 b) 하기 화학식 2a-c로 표시되는 화합물을 환원시켜 하기 화학식 3a-c로 표시되는 화합물을 제조하는 단계; 및(Step b) preparing a compound represented by the following Formula 3a-c by reducing the compound represented by the following Formula 2a-c; And
(단계 c) 하기 화학식 3a-c로 표시되는 화합물을 벤조산 유도체와 반응시켜 하기 화학식 4a-r로 표시되는 화합물을 제조하는 단계; 를 포함한다.(Step c) preparing a compound represented by the following Formula 4a-r by reacting a compound represented by the following Formula 3a-c with a benzoic acid derivative; Includes.
[반응식 1][Scheme 1]
(상기 반응식 1에서 R1 및 R2는 상기 화학식 1에서 정의한 바와 같다.) (R 1 and R 2 in Reaction Scheme 1 are as defined in Formula 1.)
상기 반응식 1에 나타낸 본 발명의 제조방법을 각 단계별로 보다 구체적으로 설명하면 하기와 같다.The manufacturing method of the present invention shown in Scheme 1 will be described in more detail for each step as follows.
단계aStep a
본 발명에 따른 상기 단계 a는 출발물질인 화학식 1을 염기와 용매하에서 페놀 유도체와 반응시켜 화학식 2a-c의 화합물을 제조하는 단계이다.The step a according to the present invention is a step of preparing a compound of formula 2a-c by reacting the starting material, formula 1, with a phenol derivative in a base and a solvent.
상기 출발물질인 화학식 1은 시판되는 것을 사용 할 수 있다.Formula 1, which is the starting material, may be commercially available.
구체적으로는 탄산칼륨 염기 존재 하에 아세토나이트릴 용매에서 85도에서 가열시켜 상기 화학식 2a-c의 화합물을 수득하였다.Specifically, the compound of Formula 2a-c was obtained by heating at 85° C. in an acetonitrile solvent in the presence of a potassium carbonate base.
단계 bStep b
본 발명에 따른 상기 단계 b는 출발물질인 2a-c의 화합물을 용매와 촉매 존재 하에서 화학식 3a-c을 제조하는 단계이다.The step b according to the present invention is a step of preparing the compound of 2a-c as a starting material in the presence of a solvent and a catalyst to prepare Formula 3a-c.
구체적으로는 상기 화학식 2a-c의 화합물을 메탄올에 용해시켜 백금 촉매 존재 하에 수소조건에서 상온에서 6시간 교반시켜 화학식 3a-c의 화합물을 수득하였다. Specifically, the compound of Formula 2a-c was dissolved in methanol and stirred for 6 hours at room temperature under hydrogen conditions in the presence of a platinum catalyst to obtain a compound of Formula 3a-c.
단계 cStep c
본 발명에 따른 상기 단계 c는 출발물질인 3a-c의 화합물을 염기, HATU 그리고 용매하에서 벤조산 유도체와 반응시켜 화학식 4a-r을 제조하는 단계이다. Step c according to the present invention is a step of reacting the compound of 3a-c as a starting material with a benzoic acid derivative in a base, HATU, and a solvent to prepare Formula 4a-r.
구체적으로는 상기 화학식 3a-c의 화합물을 테트라하이드로퓨란에 넣고 HATU와 N,N-다이아이소프로필에틸아민 염기 존재 하에 벤조산 유도체를 첨가하여 밤새 가열 환류 시켜 화학식 4a-r의 화합물을 수득하였다.Specifically, the compound of Formula 3a-c was added to tetrahydrofuran, and a benzoic acid derivative was added in the presence of HATU and N , N -diisopropylethylamine base, followed by heating to reflux overnight to obtain a compound of Formula 4a-r.
상기 단계 a, b 및 c의 반응은 유기화학 분야에서 통상적으로 널리 알려져 있으며, 반응 용매, 반응 온도, 반응 시간 등의 반응 조건은 반응 물질, 생성 물질 등을 고려하여 적절히 선택할 수 있다.The reactions of steps a, b, and c are generally well known in the field of organic chemistry, and reaction conditions such as a reaction solvent, reaction temperature, and reaction time may be appropriately selected in consideration of a reaction substance and a product.
상기 반응식 1의 제조방법을 통하여 제조된 화합물은 일반적인 분리 정제과정 예를 들면 유기 용매로 희석 및 세척한 후 유기층을 감압 농축할 수 있으며, 필요시 관 크로마토그래피로 정제할 수 있다.The compound prepared through the preparation method of Reaction Scheme 1 may be diluted and washed with an organic solvent, for example, in a general separation and purification process, and then the organic layer may be concentrated under reduced pressure, and may be purified by column chromatography if necessary.
나아가 본 발명은 상기 화학식 Ⅰ로 표시되는 페녹시 아로마틱 아마이드 유도체를 유효성분으로 함유하는 암 예방 및 치료용 약학적 조성물을 제공한다. Furthermore, the present invention provides a pharmaceutical composition for preventing and treating cancer containing a phenoxy aromatic amide derivative represented by Formula I as an active ingredient.
한편, 본 발명은 상기 화학식 1로 표시되는 페녹시 아로마틱 아마이드 유도체 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 이의 수화물 또는 이의 광학 이성질체가 유효성분으로 포함된 약학 조성물을 제공한다. Meanwhile, the present invention provides a pharmaceutical composition comprising the phenoxy aromatic amide derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, or an optical isomer thereof as an active ingredient.
본 발명의 화합물은 단백질 키나아제의 활성을 저해하는 능력이 우수하므로 비정상적인 세포 대사로 유발되는 질환의 예방 및 치료를 위한 약제조성물의 유효성분으로 사용될 수 있다. 따라서 본 발명에 따른 화합물은 비정상적인 세포 대사 질환으로서 예를 들면 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 백혈병, 다발성골수종, 골수이형성증후군과 같은 혈액암, 호치킨병과 비호치킨림프종과 같은 림프종, 또는 섬유선종 등으로부터 선택된 각종 종양 질환의 예방 및 치료제로 사용될 수 있다.Since the compound of the present invention has excellent ability to inhibit the activity of protein kinase, it can be used as an active ingredient in a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal cellular metabolism. Therefore, the compounds according to the present invention are abnormal cell metabolic diseases such as endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, Various tumor diseases selected from esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hochicken disease and non-Hochicken lymphoma, or fibroadenoma It can be used as a preventive and therapeutic agent.
따라서, 본 발명은 상기 화학식 1로 표시되는 페녹시 아로마틱 아마이드 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 이의 수화물을 유효성분으로 포함하는 약제조성물과, 비정상적인 세포 대사로 유발되는 질환의 예방 및 치료제를 특징으로 한다. Accordingly, the present invention provides a pharmaceutical composition comprising a phenoxy aromatic amide compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient, and prevention of diseases caused by abnormal cellular metabolism. And a therapeutic agent.
본 발명의 약제조성물은 상기 화학식 1로 표시되는 페녹시 아로마틱 아마이드 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 및 이의 수화물로부터 선택된 1종 이상을 유효성분으로 함유하고, 여기에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화할 수 있다. The pharmaceutical composition of the present invention contains, as an active ingredient, at least one selected from a phenoxy aromatic amide compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof, as an active ingredient. Formulated into preparations for oral administration or parenteral administration such as tablets, capsules, troches, solutions, suspensions, etc. that are common in the pharmaceutical field by adding a pharmaceutically acceptable carrier, adjuvant, and excipient can do.
본 발명의 약제 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소디움 알진산염, 메틸셀룰로오스, 소디움 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. Excipients that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, tonicity agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, alginic acid, sodium Alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.
또한, 본 발명에 따른 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70kg인 성인환자를 기준으로 할 때 일반적으로 0.01 ∼ 1,000 mg/일이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the dosage of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally 0.01 based on an adult patient weighing 70 kg. ~ 1,000 mg/day, and may be administered in divided doses from once a day to several times a day at regular intervals according to the judgment of a doctor or pharmacist.
이상에서 설명한 바와 같은 본 발명은 하기 실시예, 제제예, 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 하기의 실시예, 제제예, 및 실험예는 본 발명을 예시하는 것일 뿐 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.The present invention as described above will be described in more detail based on the following examples, formulation examples, and experimental examples, and the following examples, formulation examples, and experimental examples are merely illustrative of the present invention and the scope of the present invention Is not limited by these.
[실시예] 화합물의 합성[Example] Synthesis of compound
실시예 1. Example 1. NN -(3-클로로-4-(4-플루오로페녹시)페닐)피콜린아마이드의 제조 Preparation of -(3-chloro-4-(4-fluorophenoxy)phenyl)picolinamide
단계 a: 2-클로로-1-(4-플루오로페녹시)-4-나이트로벤젠의 제조 (2a)Step a: Preparation of 2-chloro-1-(4-fluorophenoxy)-4-nitrobenzene ( 2a )
시판되는 2-클로로-1-플루오로-4-나이트로벤젠 (1 mmol, 175.5 mg)을 아세토나이트릴 (12 mL)에 용해시킨 후 탄산칼륨 (1.25 mmol, 172.8 mg)과 4-플루오로페놀(1 mmol, 112.1 mg)을 넣는다. 혼합물을 6시간 동안 85도에서 반응시킨다. 반응이 종결되면 혼합물을 에틸아세테이트와 물로 추출한 후 유기층을 무수 황산 나트륨으로 건조시키고 감압 하에 용매를 증발시켜 77%의 수율로 목적 화합물을 얻었다. After dissolving commercially available 2-chloro-1-fluoro-4-nitrobenzene (1 mmol, 175.5 mg) in acetonitrile (12 mL), potassium carbonate (1.25 mmol, 172.8 mg) and 4-fluorophenol (1 mmol, 112.1 mg) is added. The mixture was reacted at 85 degrees for 6 hours. When the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the target compound in a yield of 77%.
1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 8.9 Hz, 1H), 7.00-7.09 (m, 4H), 7.98 (d, J = 8.9 Hz, 1H), 8.31 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 6.76 (d, J = 8.9 Hz, 1H), 7.00-7.09 (m, 4H), 7.98 (d, J = 8.9 Hz, 1H), 8.31 (s, 1H) .
단계 b: 3-클로로-4-(4-플루오로페녹시)아닐린의 제조 (3a)Step b: Preparation of 3-chloro-4-(4-fluorophenoxy)aniline ( 3a )
화합물 2a(0.1 mmol, 26.8 mg)를 메탄올 (15 mL)에 용해시킨 용액에 백금 촉매와 수소기체 조건하에 상온에서 6시간 동안 교반시킨다. 반응이 종결된 후, 셀라이트를 이용하여 용액을 여과하고 여과한 여액을 감압 하에 증발시킨 다음 혼합물을 관 크로마토그래피를 통해 정제하여 65%의 수율로 목적 화합물을 얻었다.Compound 2a (0.1 mmol, 26.8 mg) was dissolved in methanol (15 mL) and stirred for 6 hours at room temperature under conditions of a platinum catalyst and hydrogen gas. After the reaction was completed, the solution was filtered using Celite, the filtered filtrate was evaporated under reduced pressure, and the mixture was purified through column chromatography to obtain the title compound in a yield of 65%.
1H NMR (400 MHz, DMSO-d 6 ) δ 5.34 (s, 2H), 6.55 (d, J = 8.8 Hz, 1H), 6.72 (s, 1H), 6.80-6.84 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 7.13 (t, J = 8.2 Hz, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.34 (s, 2H), 6.55 (d, J = 8.8 Hz, 1H), 6.72 (s, 1H), 6.80-6.84 (m, 2H), 6.90 ( d, J = 8.6 Hz, 1H), 7.13 (t, J = 8.2 Hz, 2H).
단계 c: N-(3-클로로-4-(4-플루오로페녹시)페닐)피콜린아마이드의 제조 (4a)Step c: Preparation of N- (3-chloro-4-(4-fluorophenoxy)phenyl)picolinamide ( 4a )
화합물 3a (0.1 mmol, 23.8 mg)를 테트라하이드로퓨란 (12 mL)에 용해시킨 후 N,N-다이아이소프로필에틸아민 (0.27 mmol, 0.05 mL) 염기와 HATU (0.11 mmol, 41.8 mg) 존재 하에 피콜린산(0.1 mmol, 12.3 mg)을 넣고 밤새 가열 환류 시킨다. 반응이 종결되면 혼합액을 에틸아세테이트, 물 그리고 소금물로 추출한다. 유기층을 무수 황산 나트륨으로 건조시킨 후 감압 하에 용매를 증발시키고 관 크로마토그래피를 이용하여 정제하여 82%의 수율로 목적 화합물을 얻었다. After dissolving compound 3a (0.1 mmol, 23.8 mg) in tetrahydrofuran (12 mL), blood in the presence of N , N -diisopropylethylamine (0.27 mmol, 0.05 mL) base and HATU (0.11 mmol, 41.8 mg) Add cholic acid (0.1 mmol, 12.3 mg) and heat to reflux overnight. When the reaction is complete, the mixture is extracted with ethyl acetate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and purified using column chromatography to obtain the title compound in a yield of 82%.
1H NMR (400 MHz, CDCl3) δ 6.91-6.95 (m, 2H), 7.01 (dd, J = 8.8 Hz, 17.2 Hz, 3H), 7.49-7.52 (m, 1H), 7.60 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.61 (d, J = 4.6 Hz, 1H), 10.04 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 6.91-6.95 (m, 2H), 7.01 (dd, J = 8.8 Hz, 17.2 Hz, 3H), 7.49-7.52 (m, 1H), 7.60 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.61 (d, J = 4.6 Hz, 1H), 10.04 (s, 1H).
이하에는 상기 실시예 1과 같은 방법으로 페녹시 아로마틱 아마이드 화합물인 실시예 2 내지 18을 합성하였으며 그 구조 및 1H NMR 데이터를 하기 표 1에 나타내었다.Hereinafter, Examples 2 to 18, which are phenoxy aromatic amide compounds, were synthesized in the same manner as in Example 1, and the structures and 1 H NMR data are shown in Table 1 below.
한 편, 본 발명에 따른 상기 화학식 Ⅰ로 표시되는 신규 화합물에 대해서는 하기 실험예에 나타낸 바와 같은 방법으로 활성을 확인하였다.On the other hand, with respect to the novel compound represented by Formula I according to the present invention, the activity was confirmed by the method as shown in the following Experimental Examples.
실험예Experimental example
실험예 1. Experimental Example 1. In vitroIn vitro kinases assay kinases assay
새로 준비된 Reaction buffer에 기질을 준비한다. 준비된 기질 용액에 필요한 보조인자와 인산화효소를 넣고 부드럽게 섞는다. Acoustic technology에 의해 100% DMSO에 녹인 화합물을 인산화 효소 혼합물에 넣고 상온에서 20분 동안 배양시킨다. 실험 시작을 위해 실험 혼합물에 33P-ATP를 넣은 후 상온에서 2시간 동안 배양시킨 다음 필터 바인딩 방법에 의해 방사능을 측정한다. 인산화 효소 활성 데이터는 DMSO 대비 시험 샘플에서 남아있는 인산화 효소 활성의 비율로서 나타내어지며 IC50값과 곡선은 Prism(Graphpad Software)을 사용하여 얻는다.Prepare a substrate in a newly prepared reaction buffer. Add the necessary cofactors and kinase to the prepared substrate solution, and mix gently. The compound dissolved in 100% DMSO by Acoustic technology was added to the phosphorylase mixture and incubated for 20 minutes at room temperature. To start the experiment, 33 P-ATP was added to the experimental mixture, and then incubated at room temperature for 2 hours, and the radioactivity was measured by the filter binding method. Phosphorylase activity data are expressed as the ratio of phosphorylase activity remaining in the test sample to DMSO, and IC 50 values and curves are obtained using Prism (Graphpad Software).
실험결과는 도 1 내지 도 3과 표 2와 같았다.Experimental results were shown in FIGS. 1 to 3 and Table 2.
도 1에 대표 화합물 4b(실시예 2)의 45개의 인산화 효소에 대한 저해효능(%)을 나타내었다. Figure 1 shows the inhibitory effect (%) of the representative compound 4b (Example 2) against 45 phosphorylation enzymes.
도 2에 화합물 4a-r(실시예 1-18)의 DAPK1에 대한 저해 효능(%)을 나타내었다.Figure 2 shows the inhibitory efficacy (%) of compounds 4a-r (Examples 1-18) against DAPK1.
도 3에 화합물 4b와 4q(실시예2, 실시예 17)의 DAPK2와 DAPK3에 대한 저해 효능(%)을 나타내었다.Figure 3 shows the inhibitory efficacy (%) of compounds 4b and 4q (Example 2, Example 17) against DAPK2 and DAPK3.
또한, 표 2에 DAPK1을 화합물 4a, 4d, 4e 그리고 4q(실시예 1, 4, 5, 17)의 IC50값을 나타내었다. In addition, DAPK1 in Table 2 shows the IC 50 values of compounds 4a, 4d, 4e and 4q (Examples 1, 4, 5, and 17).
Claims (8)
(화합물 번호 2) N-(3-클로로-4-(4-플루오로페녹시)페닐)피리다진-3-카복사마이드;
(화합물 번호 3) N-(3-클로로-4-(4-플루오로페녹시)페닐)피라진-2-카복사마이드;
(화합물 번호 9) N-(3-클로로-4-(3-플루오로페녹시)페닐)피라진-2-카복사마이드;
(화합물 번호 12) N-(3-클로로-4-(3-플루오로페녹시)페닐)피리다진-4-카복사마이드; 및
(화합물 번호 15) N-(3-클로로-4-(3-클로로페녹시)페닐)피라진-2-카복사마이드.
A compound selected from a phenoxy aromatic amide compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and an optical isomer thereof, characterized by any one selected from the following compounds:
(Compound No. 2) N- (3-chloro-4-(4-fluorophenoxy)phenyl)pyridazine-3-carboxamide;
(Compound No. 3) N- (3-chloro-4-(4-fluorophenoxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 9) N- (3-chloro-4-(3-fluorophenoxy)phenyl)pyrazine-2-carboxamide;
(Compound No. 12) N- (3-chloro-4-(3-fluorophenoxy)phenyl)pyridazine-4-carboxamide; And
(Compound No. 15) N- (3-chloro-4-(3-chlorophenoxy)phenyl)pyrazine-2-carboxamide.
Prevention of cancer disease caused by DAPK1 protein kinase containing a compound selected from the phenoxy aromatic amide compound according to claim 4, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and an optical isomer thereof as an active ingredient, Pharmaceutical composition for improvement or treatment.
상기 암질환은 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 혈액암, 림프종, 및 섬유선종으로 이루어진 군으로부터 선택되는 질환인, 약학 조성물.
The method of claim 5,
The cancer diseases include endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma. , Prostate cancer, urethral cancer, blood cancer, lymphoma, and a disease selected from the group consisting of fibroadenoma, a pharmaceutical composition.
(a) 2-클로로-1-플루오로-4-나이트로벤젠과 R1 작용기가 치환된 페놀 유도체를 반응 시켜 하기 화학식 2 화합물을 제조하는 단계;
(b) 화학식 2 화합물을 환원시켜 화학식 3 화합물을 제조하는 단계; 및
(c) 화학식 3 화합물을 R2 작용기가 치환된 벤조산 유도체와 반응 시켜 화학식 1 화합물을 제조하는 단계;
[화학식 1]
[화학식 2]
[화학식 3]
상기 화학식 1, 화학식 2 및 화학식 3에서,
R1은 할로젠이고,
R2는 C6의 헤테로아릴기에서 탄소가 1개 또는 2개의 N으로 치환된 헤테로아릴기이다.
A method for preparing a compound selected from the compound according to claim 4, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof, comprising the following steps:
(a) reacting 2-chloro-1-fluoro-4-nitrobenzene with a phenol derivative substituted with an R1 functional group to prepare a compound of Formula 2;
(b) reducing the compound of formula 2 to prepare the compound of formula 3; And
(c) preparing a compound of Formula 1 by reacting the compound of Formula 3 with a benzoic acid derivative substituted with an R2 functional group;
[Formula 1]
[Formula 2]
[Formula 3]
In Formula 1, Formula 2 and Formula 3,
R 1 is halogen,
R 2 is a heteroaryl group in which 1 or 2 carbon atoms are substituted in the C6 heteroaryl group.
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| RO82772B1 (en) * | 1982-01-19 | 1984-10-30 | Institutul De Cercetari Chimico-Farmaceutice | Isonicotinanilide derivatives and process for the preparation thereof |
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| CN105687172A (en) * | 2016-03-04 | 2016-06-22 | 中国科学院上海药物研究所 | Application of rafoxanide and closantel in preparing anti-tumor drugs |
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| GB1255161A (en) * | 1967-10-19 | 1971-12-01 | Ciba Geigy A G Formerly Ciba L | Cyclopropanecarboxylic acid anilides as pesticides |
| RO78113A2 (en) * | 1979-12-18 | 1982-02-01 | Institutul De Cercetari Chimico-Farmaceutice,Ro | NICOTINANILIDE DERIVATIVES AND PROCESS FOR PREPARING THE SAME |
| RO82772B1 (en) * | 1982-01-19 | 1984-10-30 | Institutul De Cercetari Chimico-Farmaceutice | Isonicotinanilide derivatives and process for the preparation thereof |
| WO2009010454A2 (en) * | 2007-07-13 | 2009-01-22 | Addex Pharma S.A. | Amido derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors |
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