KR20110130259A - Quinazolinone derivative compounds having the inhibition activity of protease-activated receptor-2 and manufacturing method thereof - Google Patents

Quinazolinone derivative compounds having the inhibition activity of protease-activated receptor-2 and manufacturing method thereof Download PDF

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KR20110130259A
KR20110130259A KR1020100049817A KR20100049817A KR20110130259A KR 20110130259 A KR20110130259 A KR 20110130259A KR 1020100049817 A KR1020100049817 A KR 1020100049817A KR 20100049817 A KR20100049817 A KR 20100049817A KR 20110130259 A KR20110130259 A KR 20110130259A
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곽형섭
김용주
김욱일
김태성
박병덕
박지연
박태교
우성호
이대연
이은경
이향숙
전정은
정세규
정은미
최형묵
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

PURPOSE: A novel quinazolinone derivative compound with PAR-2 inhibition is provided to suppress protease-activated receptor-2(PAR-2) and to relieve skin pigmentation, atopic dermatitis, and wound. CONSTITUTION: A quinazolinone derivative compound is denoted by chemical formula 1 or 2. A method for preparing the quinazolinone derivative compounds comprises: a step of reacting a compound of chemical formula 3 with a compound of chemical formula 4 to prepare a compound of chemical formula 5; a step of reacting the compound of chemical formula 5 with hydrazine monohydrate to prepare a compound of chemical formula 6; a step of reacting the compound of chemical formula 6 with a compound of chemical formula 7. A pharmaceutical composition for preventing or treating cardiovascular diseases, gastrointestinal diseases, asthma, pigmentation, atopic dermatitis, and wound contains the quinazolinone derivative compound as an active ingredient.

Description

ＰＡＲ-2 저해 효능을 갖는 퀴나졸리논 유도체 화합물 및 그 제조방법{Quinazolinone derivative compounds having the inhibition activity of Protease-activated receptor-2 and manufacturing method thereof}Quinazolinone derivative compounds having the inhibition activity of Protease-activated receptor-2 and manufacturing method

본 발명은 우수한 프로테아제-활성화 수용체-2 (Protease-activated receptor-2, PAR-2) 저해능을 보유하여 심혈관계 질환, 위장관계 질환, 천식, 간경변, 피부 내 색소 침착, 아토피 피부염 및 창상의 개선 효과를 나타내는 신규한 퀴나졸리논 유도체 화합물 및 그 제조방법에 관한 것으로, 이를 유효성분으로 함유하는 의학 조성물은 상기한 제반 증상의 치료 또는 예방 및 경감에 유용할 것으로 기대된다.The present invention has excellent protease-activated receptor-2 (PAR-2) inhibitory ability to improve cardiovascular disease, gastrointestinal disease, asthma, cirrhosis, pigmentation in the skin, atopic dermatitis and wounds The present invention relates to a novel quinazolinone derivative compound and a method for preparing the same, and a medical composition containing the same as an active ingredient is expected to be useful for treating or preventing and alleviating the above-mentioned symptoms.

프로테아제-활성화 수용체-2 (Protease-activated receptor-2, PAR-2)는 G 단백질 결합 수용체 (G-protein-coupled receptor, GPCR)에 속하는 수용체로서 트롬빈 (thrombin) 수용체 (PAR-1)와 연관되어 발견된 수용체이다.Protease-activated receptor-2 (PAR-2) is a receptor belonging to the G-protein-coupled receptor (GPCR) and is associated with the thrombin receptor (PAR-1). Receptors found.

상기 PAR-2 활성화 기전에 대한 연구 결과, 트립신 (trypsin)이나 비만세포에서 유래한 트립테이즈 (ryptase)와 같은 단백질 분해효소가 PAR-2 수용체의 세포 외 영역 말단에 존재하는 펩타이드 서열 중 특정 부위를 분해하면서 수용체 말단에 나타나는 펩타이드 서열(SLIGRL)이 PAR-2 수용체의 특정 부위에 결합하면서 활성화되는 특이적인 활성화 기전을 지닌 것으로 알려져 있다. As a result of studies on the PAR-2 activation mechanism, specific sites in the peptide sequence in which protease, such as trypsin or tryptase derived from mast cells, exist at the end of the extracellular region of the PAR-2 receptor It is known that the peptide sequence (SLIGRL) that appears at the end of the receptor while decomposing the compound has a specific activation mechanism that is activated by binding to a specific site of the PAR-2 receptor.

최근 PAR-2가 피부 장벽 기능의 유지와 회복에 중요한 역할을 하는 것이 보고되면서, PAR-2가 아토피 피부염에 미치는 영향에 대한 가능성이 강하게 제시되고 있다. PAR-2는 인체의 다양한 세포에서 발현되는 것으로 알려져 있으며, 특히 염증 반응과 신경세포의 활성화 반응을 유발하는 등의 효과가 있는 것으로 보고되고 있다. 이와 함께, 피부에서는 케라티노사이트 (keratinocyte)-멜라노사이트 (melanocyte) 간의 신호 전달 기전에 관여하면서 멜라노솜 (melanosome)의 이동을 촉진하는 효과가 있어 피부의 색소 침착과도 밀접한 관련이 있는 것으로 보고된 바 있다.Recently, as PAR-2 has been reported to play an important role in the maintenance and repair of skin barrier function, the possibility of the effect of PAR-2 on atopic dermatitis has been strongly suggested. PAR-2 is known to be expressed in various cells of the human body, and in particular, it is reported to have an effect such as causing an inflammatory response and an activation response of nerve cells. In addition, the skin is involved in the signaling mechanism between keratinocytes and melanocytes and has an effect of promoting the movement of melanosomes, which is reported to be closely related to pigmentation of skin. There is a bar.

또한 PAR-2의 활성화가 피부 장벽 기능과 매우 밀접한 관계가 있어, 피부의 장벽 기능이 손상되면, 각질층 내에서 단백질 분해효소의 활성이 급격히 증가되고, 이를 통하여 PAR-2가 활성화되는 것이 보고된 바 있으며 (J Invest Dermatol 126: 2074-2076, 2006), 아토피 피부염 유발 및 악화 효과가 있는 알레르겐의 일종인 집먼지 진드기 (dust mite)나 바퀴벌레 유래 물질도 PAR-2의 활성화 효과가 있는 것이 확인되었다. In addition, the activation of PAR-2 is closely related to the skin barrier function, and when the barrier function of the skin is impaired, the activity of protease in the stratum corneum is rapidly increased, thereby PAR-2 is activated. (J Invest Dermatol 126: 2074-2076, 2006), dust mite or cockroach-derived allergens, which have the effect of causing and exacerbating atopic dermatitis, have also been shown to be active in PAR-2.

본 연구자들의 선행 연구에 의하면, 피부 장벽이 손상된 피부에 알레르겐을 도포하는 경우, 이러한 PAR-2의 활성화에 의하여 피부 장벽 기능의 회복이 저해되며, PAR-2에 대한 저해제를 알레르겐과 동시에 도포하는 경우 이러한 피부 장벽 회복 기전이 정상화되는 것으로 나타난 바 있다 (J Invest Dermatol 128: 1930-1939, 2008). 이와 함께, 피부 장벽이 손상된 피부에 PAR-2 저해제를 도포하면, 피부 장벽의 회복이 촉진되는 것을 보고하였다. 아토피 피부염 환자의 피부에서 피부 장벽의 손상이 가장 일반적인 증상이라는 점에서 이러한 PAR-2 저해제의 피부 장벽 손상 회복 효과는 아토피 피부염의 증상 개선에 도움을 줄 수 있을 것으로 예상된다. According to previous studies by the researchers, when allergens are applied to the damaged skin barrier, the restoration of skin barrier function is inhibited by the activation of PAR-2, and when the inhibitor for PAR-2 is applied simultaneously with the allergen This mechanism of skin barrier repair has been shown to be normalized (J Invest Dermatol 128: 1930-1939, 2008). In addition, it has been reported that the application of a PAR-2 inhibitor to skin with damaged skin barrier promotes the recovery of the skin barrier. Since the damage of the skin barrier is the most common symptom in the skin of patients with atopic dermatitis, the effect of restoring the damage of the skin barrier of the PAR-2 inhibitor is expected to help improve the symptoms of atopic dermatitis.

또한 피부 내에서 PAR-2가 활성화되면 소양증이 발생하는 것이 보고된 바 있으며, 이러한 소양증의 결과로 피부를 긁는 행동이 유발되는 것으로 알려져 있다. PAR-2 저해제의 항소양증 효과에 대한 기존의 연구 결과 (일본특허 JP2004-170323)에 따르면, PAR-2 저해제를 피부에 도포하는 경우 가려움증이 유의하게 감소하는 것으로 보고된 바 있다. 이러한 소양증의 기전으로서는 피부 내에 존재하는 신경계 섬유 (neuro fiber)에 존재하는 PAR-2의 활성화에 의하여 신경 세포가 활성화되며, 이를 통하여 소양증의 신호가 뇌로 전달되는 것으로 알려져 있다. 소양증과 관련된 PAR-2의 기능은 PAR-2 활성화 물질을 피부에 도포하여 실험한 동물 모델에서 가려움증의 횟수가 급격히 증가하며, PAR-2의 활성을 억제하는 경우 이러한 현상이 억제되는 것이 확인된 바 있다 (J Neurosci 2003, 23, 6176-6180).In addition, it has been reported that pruritus occurs when PAR-2 is activated in the skin, and as a result of this pruritus, it is known that a scratching action is caused. According to previous studies on the antipruritic effect of PAR-2 inhibitors (Japanese Patent JP2004-170323), itching has been reported to be significantly reduced when the PAR-2 inhibitor is applied to the skin. As a mechanism of pruritus, nerve cells are activated by activation of PAR-2 present in neurofiber fibers present in the skin, and it is known that pruritus signals are transmitted to the brain. The function of PAR-2 related to pruritus is rapidly increased in the number of itching in animal models tested by applying PAR-2 activating substance to the skin, and it is confirmed that this phenomenon is suppressed when PAR-2 activity is inhibited. (J Neurosci 2003, 23, 6176-6180).

PAR-2에 대한 선택적인 저해 효능을 지닌 물질은 현재 전 세계적으로 2종이 개발된 것으로 파악되었으며, 이 중 학술지를 통하여 효능이 검증된 물질은 미국의 바이오벤쳐 회사인 Entremed사의 ENMD-1,068 (N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine)이 있다. 이와 함께 일본의 제약 회사인 住友製藥 (Sumitomo Pharmaceuticals)에서 특허 (JP2004-170323)로 보고한 예가 있다.Two kinds of substances with selective inhibitory effects on PAR-2 have been developed around the world, and among them, the ones whose efficacy has been verified through the journal are ENMD-1,068 (N 1 -3-methylbutyryl-N 4-6 -aminohexanoyl-piperazine). In addition, there is an example reported as a patent (JP2004-170323) by Japanese pharmaceutical company Sumitomo Pharmaceuticals.

Figure pat00001
Figure pat00001

PAR-2에 의한 피부 염증 악화 및 PAR-2 저해 활성을 지닌 물질의 항염 효과는 PAR-2를 활성화하는 단백 분해 효소인 트립신 (trypsin)이나 PAR-2에 대한 활성화물질인 활성 펩타이드 (activating peptide, AP)를 피부에 도포하면 피부의 염증이 증가되고, 단백 분해 효소의 활성 억제제를 동시에 도포하면 이러한 피부 염증 반응이 감소되는 것으로 확인된 바 있다 (FASEB J 2003, 17, 1871-1885).Decreased skin inflammation caused by PAR-2 and the anti-inflammatory effect of a substance having PAR-2 inhibitory activity is due to trypsin, a protease that activates PAR-2, or an activating peptide, Application of AP) to the skin has been shown to increase the inflammation of the skin, and simultaneous application of an inhibitor of protease activity reduces the skin inflammatory response (FASEB J 2003, 17, 1871-1885).

한편 국제특허공개번호 WO2008/067219호에서는 TGR5 조절제인 하기 화학식 (Ⅱ)로 표시되는 퀴나졸리논 유도체 화합물을 보고한 바 있다.Meanwhile, International Patent Publication No. WO2008 / 067219 has reported a quinazolinone derivative compound represented by the following formula (II) as a TGR5 modulator.

[화학식 Ⅱ][Formula II]

Figure pat00002
Figure pat00002

그러나 국제특허공개번호 WO2008/067219호에서는 상기 화학식 (Ⅱ)로 표시되는 퀴나졸리논 유도체 화합물이 PAR-2 저해 효능을 갖는다고 언급되어 있지는 않다.However, International Patent Publication No. WO2008 / 067219 does not mention that the quinazolinone derivative compound represented by the formula (II) has PAR-2 inhibitory effect.

따라서 본 발명자들은 PAR-2 저해 활성을 지닌 물질을 합성하고자 오랫동안 다양한 물질을 합성하고, 그 활성에 대해 실험한 결과 PAR-2 저해 효능이 뛰어난 신규한 퀴나졸리논 유도체 화합물을 합성하여 본 발명을 완성하였다.Therefore, the present inventors synthesized various substances for a long time to synthesize a substance having PAR-2 inhibitory activity, and tested the activity to synthesize a novel quinazolinone derivative compound having excellent PAR-2 inhibitory effect and completed the present invention. It was.

본 발명의 목적은 피부 유래의 각질 형성 세포와 피부 내에 존재하는 비만 세포에 있어서 PAR-2 저해 효능을 갖는 신규한 퀴나졸리논 유도체 화합물을 제공하는 것이다.An object of the present invention is to provide a novel quinazolinone derivative compound having PAR-2 inhibitory effect on keratinocytes derived from skin and mast cells present in the skin.

보다 구체적으로는 PAR-2 저해능을 보유하여 심혈관계 질환, 위장관계 질환, 천식, 간경변, 피부 내 색소 침착, 아토피 피부염 및 창상의 개선 효과를 나타내는 신규한 퀴나졸리논 유도체 화합물 및 그 제조방법을 제공하는데 목적이 있다.More specifically, the present invention provides a novel quinazolinone derivative compound having a PAR-2 inhibitory ability and improving a cardiovascular disease, a gastrointestinal disease, asthma, cirrhosis, pigmentation in the skin, atopic dermatitis, and a wound, and a method of preparing the same. The purpose is to.

본 발명의 다른 목적은 본 발명에 따른 퀴나졸리논 유도체 화합물을 유효성분으로 함유하여 상기한 제반 증상의 치료 또는 예방을 위한 의학 조성물을 제공하는데 있다.Another object of the present invention is to provide a medical composition for the treatment or prevention of the above-mentioned symptoms by containing a quinazolinone derivative compound according to the present invention as an active ingredient.

본 발명은 상기 목적을 달성하기 위하여 안출된 것으로, 우수한 프로테아제-활성화 수용체-2 (Protease-activated receptor-2, PAR-2) 저해능을 보유하여 심혈관계 질환, 위장관계 질환, 천식, 간경변, 피부 내 색소 침착, 아토피 피부염 및 창상의 개선 효과를 나타내는 신규한 퀴나졸리논 유도체 화합물 및 그 제조방법을 제공한다.
The present invention has been made to achieve the above object, has excellent protease-activated receptor-2 (PAR-2) inhibitory ability to cardiovascular diseases, gastrointestinal diseases, asthma, cirrhosis, skin Provided are a novel quinazolinone derivative compound which exhibits an effect of improving pigmentation, atopic dermatitis and wounds, and a preparation method thereof.

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

이때, 본 발명에서 사용되는 기술 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.
At this time, if there is no other definition in the technical terms used in the present invention, it has a meaning commonly understood by those skilled in the art to which the present invention belongs, and in the following description unnecessarily obscure the subject matter of the present invention. Description of known functions and configurations that may be omitted.

본 발명은 신규한 퀴나졸리논 유도체 화합물 및 그 제조방법에 관한 것으로, 하기 화학식 1로 표시되는 퀴나졸리논 유도체 화합물을 제공한다.The present invention relates to a novel quinazolinone derivative compound and a preparation method thereof, and provides a quinazolinone derivative compound represented by the following general formula (1).

[화학식 1][Formula 1]

Figure pat00003
Figure pat00003

[상기 화학식 1에서,[In Formula 1,

X는 탄소 또는 질소이고; R1 및 R2는 서로 독립적으로 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C1-C10)알콕시 또는 할로겐이며; 상기 R3는 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C3-C10)사이클로알킬, 치환 또는 비치환된 (C6-C10)아릴, 치환 또는 비치환된 (C6-C10)헤테로아릴, (C1-C10)알킬티오 또는 (C6-C10)아릴티오이고; 상기 R4는 수소, 치환 또는 비치환된 (C1-C10)알킬 또는 할로겐이며; 상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택되는 어느 하나 이상의 헤테로원자를 포함하고, 상기 R1 및 R2 중 어느 하나는 반드시 할로겐이며, 상기 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 말한다.] X is carbon or nitrogen; R 1 and R 2 are independently of each other substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C1-C10) alkoxy or halogen; R 3 is substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C3-C10) cycloalkyl, substituted or unsubstituted (C6-C10) aryl, substituted or unsubstituted (C6-C10) ) Heteroaryl, (C1-C10) alkylthio or (C6-C10) arylthio; R 4 is hydrogen, substituted or unsubstituted (C 1 -C 10) alkyl or halogen; The heteroaryl includes any one or more heteroatoms selected from the group consisting of N, O and S, wherein any one of R 1 and R 2 is necessarily halogen, and in the description of 'substituted or unsubstituted' Substitution 'refers to a case where the substituent is further substituted with an unsubstituted substituent.]

또한 본 발명의 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 뜻하며, 상기 R1 내지 R4의 (C1-C10)알킬, (C1-C10)알콕시, (C3-C10)사이클로알킬, (C6-C10)아릴 또는 (C6-C10)헤테로아릴에 더 치환되는 치환기는 서로 독립적으로 (C1-C10)알킬, (C1-C10)알콕시 및 할로겐으로 이루어진 군에서 선택되는 어느 하나 이상인 것을 특징으로 한다.In addition, in the description of "substituted or unsubstituted" of the present invention, "substituted" means a case that is further substituted with an unsubstituted substituent, the (C1-C10) alkyl, (C1-C10) alkoxy of R 1 to R 4 , Substituents further substituted with (C3-C10) cycloalkyl, (C6-C10) aryl or (C6-C10) heteroaryl independently of one another are groups consisting of (C1-C10) alkyl, (C1-C10) alkoxy and halogen It is characterized in that any one or more selected from.

구체적으로 본 발명에 따른 퀴나졸리논 유도체 화합물은 하기 화학식 2로 표시되는 것을 특징으로 한다.Specifically, the quinazolinone derivative compound according to the present invention is characterized by represented by the following formula (2).

[화학식 2][Formula 2]

Figure pat00004
Figure pat00004

[상기 화학식 2에서,[In the formula (2)

상기 X, R1 내지 R4는 상기 화학식 1에서의 정의와 동일하다.]
X, R 1 to R 4 are the same as defined in the formula (1).]

본 발명에 기재된 ‘알킬’, ‘알콕시’ 및 그 외 ‘알킬’부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함하고, ‘시클로알킬’은 단일 고리계 탄화수소를 포함한다. Substituents comprising the "alkyl", "alkoxy" and other "alkyl" moieties described herein include both straight or pulverized forms, and "cycloalkyl" includes single ring hydrocarbons.

본 발명에 기재된 ‘아릴’은 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 유기 라디칼로, 4 내지 7원, 바람직하게는 5 또는 6원을 포함하는 단일 또는 융합고리계를 포함하며, 하나 이상의 아릴이 화학결합을 통하여 결합되어 있는 구조도 포함한다. 상기 아릴의 구체적인 예로 페닐, 나프틸, 비페닐, 인데닐(indenyl) 등을 포함하지만, 이에 한정되지 않는다. 상기 나프틸은 1-나프틸 및 2-나프틸을 모두 포함한다. 본 발명에 기재된 ‘헤테로아릴’은 방향족 고리 골격 원자로서 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 포함하고, 나머지 방향족 고리 골격 원자가 탄소인 아릴 그룹을 의미하는 것으로, 5 내지 6원의 단환 헤테로아릴 또는 하나 이상의 벤젠환과 축합된 다환식 헤테로아릴이며, 부분적으로 포화될 수도 있다. 또한, 본 발명에서의 헤테로아릴은 하나 이상의 헤테로아릴이 화학결합을 통하여 결합되어 있는 구조도 포함한다. 상기 헤테로아릴기는 고리 내 헤테로원자가 산화되거나 사원화되어, 예를 들어 N-옥사이드 또는 4차 염을 형성하는 2가 아릴 그룹을 포함한다. 상기 헤테로아릴의 구체적인 예로 퓨릴, 티오펜일, 피롤릴, 이미다졸릴, 피라졸릴, 티아졸릴, 티아디아졸릴, 이소티아졸릴, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 트리아진일, 테트라진일, 트리아졸릴, 테트라졸릴, 퓨라잔일, 피리딜, 피라진일, 피리미딘일, 피리다진일 등의 단환 헤테로아릴, 벤조퓨란일, 벤조티오펜일, 이소벤조퓨란일, 벤조이미다졸릴, 벤조티아졸릴, 벤조이소티아졸릴, 벤조이속사졸릴, 벤조옥사졸릴, 이소인돌릴, 인돌릴, 인다졸릴, 벤조티아디아졸릴, 퀴놀릴, 이소퀴놀릴, 퀴나졸리닐 등의 다환식 헤테로아릴 및 이들의 상응하는 N-옥사이드(예를 들어, 피리딜 N-옥사이드, 퀴놀릴 N-옥사이드), 이들의 4차 염 등을 포함하지만, 이에 한정되지 않는다.'Aryl' described in the present invention is an organic radical derived from an aromatic hydrocarbon by one hydrogen removal, and includes a single or fused ring system containing 4 to 7 members, preferably 5 or 6 members, and at least one aryl It also includes structures bonded through this chemical bond. Specific examples of the aryl include, but are not limited to, phenyl, naphthyl, biphenyl, indenyl, and the like. The naphthyl includes both 1-naphthyl and 2-naphthyl. 'Heteroaryl' described in the present invention means an aryl group containing 1 to 4 heteroatoms selected from N, O, and S as an aromatic ring skeleton atom, and the remaining aromatic ring skeleton atoms are carbon. Monocyclic heteroaryl or polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present invention also includes a structure in which one or more heteroaryl is bonded through a chemical bond. Such heteroaryl groups include divalent aryl groups in which heteroatoms in the ring are oxidized or quaternized to form, for example, N-oxides or quaternary salts. Specific examples of the heteroaryl include furyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxdiazolyl, triazinyl, tetrazinyl, Monocyclic heteroaryl such as triazolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl , Polycyclic heteroaryl such as benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, quinazolinyl and the like and their corresponding N-oxides (eg, pyridyl N-oxides, quinolyl N-oxides), quaternary salts thereof, and the like, but are not limited thereto.

또한 상기 R1은 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, i-펜틸, 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, t-부톡시, n-펜톡시, i-펜톡시 또는 Cl이고; R2는 Cl 또는 Br인 것을 특징으로 한다.And R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, methoxy, ethoxy, n-propoxy, i- Propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, i-pentoxy or Cl; R 2 is characterized by being Cl or Br.

상기 화학식 2에서 R2가 Cl 또는 Br인 경우 본 발명에 따른 퀴나졸리논 유도체 화합물은 매우 우수한 PAR-2 저해 활성을 갖는다.In Formula 2, when R 2 is Cl or Br, the quinazolinone derivative compound according to the present invention has very good PAR-2 inhibitory activity.

본 발명에 따른 퀴나졸리논 유도체 화합물은 보다 구체적으로 하기의 화합물로서 예시될 수 있으나, 하기 화합물이 본 발명을 한정하는 것은 아니다.The quinazolinone derivative compound according to the present invention may be more specifically exemplified as the following compound, but the following compound is not intended to limit the present invention.

Figure pat00005
Figure pat00005

Figure pat00006
Figure pat00006

Figure pat00007

Figure pat00007

본 발명에 따른 퀴나졸리논 유도체 화합물은 하기 두 가지 제조방법으로 제조될 수 있으며, 먼저 제 1양태로는The quinazolinone derivative compound according to the present invention may be prepared by the following two preparation methods, and firstly,

a) 하기 화학식 3으로 표시되는 화합물과 하기 화학식 4로 표시되는 화합물을 반응시켜 하기 화학식 5로 표시되는 화합물을 제조하는 단계;a) preparing a compound represented by Chemical Formula 5 by reacting a compound represented by Chemical Formula 3 with a compound represented by Chemical Formula 4;

b) 화학식 5로 표시되는 화합물과 하이드라진 모노하이드레이트를 반응시켜 하기 화학식 6으로 표시되는 화합물을 제조하는 단계;b) preparing a compound represented by Chemical Formula 6 by reacting a compound represented by Chemical Formula 5 with hydrazine monohydrate;

c) 화학식 6으로 표시되는 화합물과 하기 화학식 7로 표시되는 화합물을 반응시켜 하기 화학식 1로 표시되는 퀴나졸리논 유도체 화합물을 제조하는 단계;c) reacting a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7 to prepare a quinazolinone derivative compound represented by Chemical Formula 1;

를 포함한다.It includes.

[화학식 1][Formula 1]

Figure pat00008
Figure pat00008

[화학식 3](3)

Figure pat00009
Figure pat00009

[화학식 4][Formula 4]

Figure pat00010
Figure pat00010

[화학식 5][Chemical Formula 5]

Figure pat00011
Figure pat00011

[화학식 6][Formula 6]

Figure pat00012
Figure pat00012

[화학식 7][Formula 7]

Figure pat00013
Figure pat00013

[상기 화학식 1 및 화학식 3 내지 화학식 7에서,[In Formula 1 and Formula 3 to Formula 7,

X는 탄소 또는 질소이고; R1 및 R2는 서로 독립적으로 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C1-C10)알콕시 또는 할로겐이며; 상기 R3는 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C3-C10)사이클로알킬, 치환 또는 비치환된 (C6-C10)아릴, 치환 또는 비치환된 (C6-C10)헤테로아릴, (C1-C10)알킬티오 또는 (C6-C10)아릴티오이고; 상기 R4는 수소, 치환 또는 비치환된 (C1-C10)알킬 또는 할로겐이며; 상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택되는 어느 하나 이상의 헤테로원자를 포함하고, 상기 R1 및 R2 중 어느 하나는 반드시 할로겐이며, 상기 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 말한다.] X is carbon or nitrogen; R 1 and R 2 are independently of each other substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C1-C10) alkoxy or halogen; R 3 is substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C3-C10) cycloalkyl, substituted or unsubstituted (C6-C10) aryl, substituted or unsubstituted (C6-C10) ) Heteroaryl, (C1-C10) alkylthio or (C6-C10) arylthio; R 4 is hydrogen, substituted or unsubstituted (C 1 -C 10) alkyl or halogen; The heteroaryl includes any one or more heteroatoms selected from the group consisting of N, O and S, wherein any one of R 1 and R 2 is necessarily halogen, and in the description of 'substituted or unsubstituted' Substitution 'refers to a case where the substituent is further substituted with an unsubstituted substituent.]

또한 제 2양태로는In a second aspect,

d) 하기 화학식 3으로 표시되는 화합물과 하기 화학식 4로 표시되는 화합물을 반응시켜 하기 화학식 5로 표시되는 화합물을 제조하는 단계;d) preparing a compound represented by the following Chemical Formula 5 by reacting the compound represented by the following Chemical Formula 3 with the compound represented by the following Chemical Formula 4;

e) 하기 화학식 5로 표시되는 화합물과 하기 화학식 8로 표시되는 화합물을 반응시켜 하기 화학식 1로 표시되는 퀴나졸리논 유도체 화합물을 제조하는 단계;e) preparing a quinazolinone derivative compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 8;

를 포함한다.It includes.

[화학식 1][Formula 1]

Figure pat00014
Figure pat00014

[화학식 3](3)

Figure pat00015
Figure pat00015

[화학식 4][Formula 4]

Figure pat00016
Figure pat00016

[화학식 5][Chemical Formula 5]

Figure pat00017
Figure pat00017

[화학식 8][Formula 8]

Figure pat00018
Figure pat00018

[상기 화학식 1, 화학식 3 내지 화학식 5 및 화학식 8에서,[In Formula 1, Formula 3 to Formula 5 and Formula 8,

X는 탄소 또는 질소이고; R1 및 R2는 서로 독립적으로 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C1-C10)알콕시 또는 할로겐이며; 상기 R3는 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C3-C10)사이클로알킬, 치환 또는 비치환된 (C6-C10)아릴, 치환 또는 비치환된 (C6-C10)헤테로아릴, (C1-C10)알킬티오 또는 (C6-C10)아릴티오이고; 상기 R4는 수소, 치환 또는 비치환된 (C1-C10)알킬 또는 할로겐이며; 상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택되는 어느 하나 이상의 헤테로원자를 포함하고, 상기 R1 및 R2 중 어느 하나는 반드시 할로겐이며, 상기 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 말한다.] X is carbon or nitrogen; R 1 and R 2 are independently of each other substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C1-C10) alkoxy or halogen; R 3 is substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C3-C10) cycloalkyl, substituted or unsubstituted (C6-C10) aryl, substituted or unsubstituted (C6-C10) ) Heteroaryl, (C1-C10) alkylthio or (C6-C10) arylthio; R 4 is hydrogen, substituted or unsubstituted (C 1 -C 10) alkyl or halogen; The heteroaryl includes any one or more heteroatoms selected from the group consisting of N, O and S, wherein any one of R 1 and R 2 is necessarily halogen, and in the description of 'substituted or unsubstituted' Substitution 'refers to a case where the substituent is further substituted with an unsubstituted substituent.]

보다 구체적으로 상기 제 1양태에 따른 퀴나졸리논 유도체 화합물은 하기 반응식 1에 나타난 바와 같이 제조 될 수 있으나, 이에 한정되는 것은 아니다.More specifically, the quinazolinone derivative compound according to the first aspect may be prepared as shown in Scheme 1, but is not limited thereto.

[반응식 1]Scheme 1

Figure pat00019
Figure pat00019

또한 제 2양태에 따른 퀴나졸리논 유도체 화합물은 하기 반응식 2에 나타난 바와 같이 제조 될 수 있으나, 이에 한정되는 것은 아니다.In addition, the quinazolinone derivative compound according to the second aspect may be prepared as shown in Scheme 2, but is not limited thereto.

[반응식 2]Scheme 2

Figure pat00020
Figure pat00020

또한 본 발명은 본 발명에 따른 퀴나졸리논 유도체 화합물을 유효성분으로 함유하여 심혈관계 질환, 위장관계 질환, 천식, 간경변, 피부 내 색소 침착, 아토피 피부염 및 창상 치료 또는 예방을 위한 것을 특징으로 하는 의학 조성물을 제공한다. In another aspect, the present invention comprises a quinazolinone derivative compound according to the present invention as an active ingredient for the treatment or prevention of cardiovascular diseases, gastrointestinal diseases, asthma, cirrhosis, intradermal pigmentation, atopic dermatitis and wounds To provide a composition.

본 발명에 따른 퀴나졸리논 유도체 화합물을 유효성분으로 함유하는 의학 조성물은 매우 우수한 PAR-2 저해 효능을 가지며, 이 밖에도 피부에 적용 가능한 화장료 조성물에도 유용하게 사용가능하다.The medical composition containing the quinazolinone derivative compound according to the present invention as an active ingredient has very good PAR-2 inhibitory effect, and can also be usefully used in cosmetic compositions applicable to the skin.

본 발명에 따른 퀴나졸리논 유도체 화합물은 우수한 프로테아제-활성화 수용체-2 (Protease-activated receptor-2, PAR-2) 저해능을 보유하여 심혈관계 질환, 위장관계 질환, 천식, 간경변, 피부 내 색소 침착, 아토피 피부염 및 창상의 개선 효과를 나타내며, 이를 유효성분으로 함유하는 의학 조성물은 상기한 제반 증상의 치료 또는 예방 및 경감에 유용한 효과가 있다.Quinazolinone derivative compounds according to the present invention possess excellent protease-activated receptor-2 (PAR-2) inhibitory ability, and thus, cardiovascular diseases, gastrointestinal diseases, asthma, cirrhosis, pigmentation in the skin, A medical composition having an atopic dermatitis and wound improvement effect, and containing it as an active ingredient has a useful effect in the treatment or prevention and alleviation of the above-mentioned symptoms.

도 1은 본 발명의 일 실시예에 따른 퀴나졸리논 유도체 화합물을 이용하여 PAR-2 저해 활성 효과를 평가하기 위해서 인-비트로(in-vitro) 실험을 수행한 칼슘 임모빌리제이션 분석 (Calcium Immobilization Assay) 결과 그래프를 나타낸 것이다.1 is a calcium immobilization assay for performing an in-vitro experiment to evaluate the effect of PAR-2 inhibitory activity using a quinazolinone derivative compound according to an embodiment of the present invention. ) Shows the result graph.

이하, 본 발명은 하기의 실시예에 의하여 보다 더 잘 이해될 수 있으며, 하기의 실시예는 본 발명의 예시 목적을 위한 것으로서 본 발명의 보호 범위를 제한하고자 하는 것은 아니다.Hereinafter, the present invention can be better understood by the following examples, which are intended to illustrate the present invention and are not intended to limit the protection scope of the present invention.

[실시예 1]Example 1

[단계 1] 2-(4-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one의 제조[Step 1] Preparation of 2- (4-fluorophenyl) -4H-benzo [d] [1,3] oxazin-4-one

Figure pat00021
Figure pat00021

안트라닐산 (anthranilic acid) 5.00 g (36.5 mmol)을 20 mL의 피리딘에 녹인 후 0 ℃에서 4-플루오로벤조일 클로라이드 (4-fluorobenzoyl chloride) 6.0 mL (50 mmol)를 천천히 가하였다. 온도를 올려 상온에서 반응 혼합물을 30분 간 교반한 후 100 ℃에서 2.5시간 동안 환류 교반하였다. 상온으로 식혀 감압 농축한 후 에틸아세테이트 80 mL에 희석시킨 후 20 mL의 1N HCl 수용액과 20 mL의 물로 추출하였다. 유기층을 무수 황산나트륨으로 탈수, 감압 농축한 후 20 mL의 무수아세트산 (acetic anhydride)을 가해 12시간 동안 환류 교반하였다. 반응 혼합물을 상온으로 식힌 후 용매를 감압 농축하여 제거한 후 얻어진 고체를 여과하여 메탄올로 씻어 표제화합물을 흰색의 고체로 7.39 g (30.6 mmol, 83%) 얻었다.5.00 g (36.5 mmol) of anthranilic acid was dissolved in 20 mL of pyridine, and 6.0 mL (50 mmol) of 4-fluorobenzoyl chloride was slowly added at 0 ° C. The reaction mixture was stirred for 30 minutes at room temperature and then stirred at reflux at 100 ° C. for 2.5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with 80 mL of ethyl acetate, and extracted with 20 mL of 1N HCl aqueous solution and 20 mL of water. The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and 20 mL of acetic anhydride was added thereto, followed by stirring under reflux for 12 hours. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and then the obtained solid was filtered and washed with methanol to obtain 7.39 g (30.6 mmol, 83%) of the title compound as a white solid.

1H NMR (600MHz, chloroform-d1)d = 8.33 (m, 2H), 8.25 (dd, J=7.8Hz,1.2Hz,1H),7.85(m,1H),7.68(d,J=7.8Hz,1H)7.53(td,J=0.9Hz,7.6Hz,1H),7.20(m,2H) 1 H NMR (600MHz, chloroform-d 1 ) d = 8.33 (m, 2H), 8.25 (dd, J = 7.8Hz, 1.2Hz, 1H), 7.85 (m, 1H), 7.68 (d, J = 7.8Hz , 1H) 7.53 (td, J = 0.9Hz, 7.6Hz, 1H), 7.20 (m, 2H)

[단계 2] 3-amino-2-(4-fluorophenyl)quinazolin-4(3H)-one의 제조[Step 2] Preparation of 3-amino-2- (4-fluorophenyl) quinazolin-4 (3H) -one

Figure pat00022
Figure pat00022

단계 1에서 얻은 화합물 1.00 g (4.15 mmol)을 에탄올 10 mL에 녹인 후 하이드라진 모노하이드레이트 (hydrazine monohydrate) 1.2 mL (23.2 mmol)를 가하여 1.5 시간 동안 환류 교반하였다. 상온으로 식힌 후 생성된 고체를 여과한 다음 물, 디에틸에테르, 메탄올로 순차적으로 씻어 중간체로서 3-플루오로-N-(2-하이드라진카보닐)-페닐)벤즈아미드 (3-fluoro-N-(2-(hydrazinecarbonyl)-phenyl)benzamide)를 흰색 고체로 0.81 g (2.94 mmol)을 얻었다. 얻어진 화합물을 DMF 3 mL에 녹여 마이크로웨이브를 조사하여 200 ℃에서 45분간 가열하였다. 반응혼합물을 상온으로 식힌 후 에틸아세테이트 70 mL에 희석시킨 후 물 50 mL로 세 차례 씻어주었다. 유기층을 무수 황산나트륨으로 탈수한 후 감압 농축하여 생성된 고체를 여과하고 디에틸에테르로 씻어 표제화합물을 흰색의 고체로 0.41 g (1.61 mmol, 39%) 얻었다.1.00 g (4.15 mmol) of the compound obtained in Step 1 was dissolved in 10 mL of ethanol, and 1.2 mL (23.2 mmol) of hydrazine monohydrate was added thereto, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, the resulting solid was filtered and washed sequentially with water, diethyl ether and methanol, and then 3-fluoro-N- (2-hydrazinecarbonyl) -phenyl) benzamide (3-fluoro-N- as an intermediate). 0.82- g (2.94 mmol) was obtained as a white solid of (2- (hydrazinecarbonyl) -phenyl) benzamide). The obtained compound was dissolved in 3 mL of DMF, irradiated with microwaves, and heated at 200 ° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with 70 mL of ethyl acetate, and washed three times with 50 mL of water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid was filtered and washed with diethyl ether to give 0.41 g (1.61 mmol, 39%) of the title compound as a white solid.

1H NMR (600MHz, chloroform-d1)d = 8.31 (d, J = 8.4 Hz, 1H), 7.86 (m, 2H), 7.79 (m, 2H), 7.53 (m, 2H), 7.20 (m, 2H), 5.01 (s, 2H) 1 H NMR (600 MHz, chloroform-d 1 ) d = 8.31 (d, J = 8.4 Hz, 1H), 7.86 (m, 2H), 7.79 (m, 2H), 7.53 (m, 2H), 7.20 (m, 2H), 5.01 (s, 2H)

[단계 3] 2-bromo-N-(2-(4-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-5-methoxy benzamide의 제조[Step 3] Preparation of 2-bromo-N- (2- (4-fluorophenyl) -4-oxoquinazolin-3 (4H) -yl) -5-methoxy benzamide

Figure pat00023
Figure pat00023

소듐하이드라이드(55%) 102 mg (2.33 mmol)을 무수 THF 1 mL로 세 차례 씻어준 후 건조하여 5 mL의 DMF에 현탁시켰다. 단계 2에서 얻은 화합물 120 mg (0.470 mmol)을 DMF 2 mL에 녹인 후 0 ℃에서 가하고 5분간 교반하였다. 2-브로모-5-메톡시벤조산 (2-bromo-5-methoxybenzoic acid) 570 mg (2.47 mmol)을 MC 1 mL에 녹인 후 SOCl2 1.7 mL (24.7 mmol)을 가하여 2 시간 동안 환류 교반한 후 감압 농축하여 상기의 반응혼합물에 천천히 가하고 상온에서 2시간 동안 교반하였다. 물 5 mL를 가하여 반응을 종결시킨 후 에틸아세테이트 30 mL를 가한 후 물 10 mL, 탄산나트륨 포화수용액 10 mL, 물 20 mL로 순차적으로 씻어주었다. 유기층을 무수 황산나트륨으로 탈수한 후 감압 농축한 뒤 얻어진 혼합물을 메탄올 15 mL에 녹인 후 1 N 수산화나트륨 수용액을 2.5 mL 가하여 1.5시간 동안 환류 교반하였다. 반응혼합물을 상온으로 식혀 감압 농축하고 에틸아세테이트 50 mL로 희석시켜 물 20 mL로 두 차례 씻어준 후 유기층을 건조, 감압 농축하여 관 크로마토그래프로 정제하여 표제화합물을 흰색 고체로 31.4 mg (0.0671 mmol, 14%) 얻었다.102 mg (2.33 mmol) of sodium hydride (55%) were washed three times with 1 mL of anhydrous THF, dried and suspended in 5 mL of DMF. 120 mg (0.470 mmol) of the compound obtained in Step 2 was dissolved in 2 mL of DMF, added at 0 ° C., and stirred for 5 minutes. 570 mg (2.47 mmol) of 2-bromo-5-methoxybenzoic acid was dissolved in 1 mL of MC, followed by SOCl 2 1.7 mL (24.7 mmol) was added thereto, the mixture was stirred under reflux for 2 hours, concentrated under reduced pressure, and slowly added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. 5 mL of water was added to terminate the reaction. 30 mL of ethyl acetate was added, followed by washing with 10 mL of water, 10 mL of saturated aqueous sodium carbonate solution, and 20 mL of water. The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting mixture was dissolved in 15 mL of methanol. Then, 2.5 mL of a 1 N aqueous sodium hydroxide solution was added thereto and stirred at reflux for 1.5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with 50 mL of ethyl acetate, washed twice with 20 mL of water, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 31.4 mg (0.0671 mmol, 14%).

1H NMR (600MHz, chloroform-d1)d = 8.85 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.77-7.85 (m, 4H), 7.51 (td, J = 1.2 Hz, 7.2 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.19 (t, J = 6.6 Hz, 2H), 6.86 (d, J = 3.0 Hz, 1H), 6.71 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 3.73 (s, 3H)
 1 H NMR (600 MHz, chloroform-d 1 ) d = 8.85 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.77-7.85 (m, 4H), 7.51 (td, J = 1.2 Hz, 7.2 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.19 (t, J = 6.6 Hz, 2H), 6.86 (d, J = 3.0 Hz, 1H), 6.71 (dd, J = 2.4 Hz , 8.4 Hz, 1H), 3.73 (s, 3H)

상기 실시예 1의 방법을 이용하여 하기 실시예 2 내지 7의 퀴나졸리논 유도체 화합물을 제조하였으며, 각각 제조된 퀴나졸리논 유도체 화합물들의 1H NMR을 나타내었다.The quinazolinone derivative compounds of Examples 2 to 7 were prepared using the method of Example 1, and 1 H NMR of the prepared quinazolinone derivative compounds was shown.

[실시예 2][Example 2]

Figure pat00024
Figure pat00024

1H NMR (600MHz, chloroform-d1)d = 9.20 (s, 1 H), 8.06 (d, J=7.8Hz,1H),7.78(m,4H),7.49(m,4H),7.14(d,J=9Hz,1H),6.63(d,J=3Hz,1H),6.59(dd,J=8.4Hz,3Hz,1H),3.67(s,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 9.20 (s, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.78 (m, 4H), 7.49 (m, 4H), 7.14 (d , J = 9Hz, 1H), 6.63 (d, J = 3Hz, 1H), 6.59 (dd, J = 8.4Hz, 3Hz, 1H), 3.67 (s, 3H)

[실시예 3]Example 3

Figure pat00025
Figure pat00025

1H NMR (400MHz, chloroform-d1)d = 8.76 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.72-7.81 (m, 4H), 7.47-7.51 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.99 (m, 2H), 6.88 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H) 1 H NMR (400 MHz, chloroform-d 1 ) d = 8.76 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.72-7.81 (m, 4H), 7.47-7.51 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.99 (m, 2H), 6.88 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H)

[실시예 4]Example 4

Figure pat00026
Figure pat00026

1H NMR (400MHz, chloroform-d1)d = 8.64 (s, 1H), 8.27 (m, 1H), 8.08 (dd, J = 1.2 Hz, 4.0 Hz, 1H), 7.79-7.82 (m, 2H), 7.47-7.56 (m, 3H), 7.44 (d, J = 2.8 Hz, 1H), 7.14 (m, 1H), 6.94 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 6.73 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 3.85 (s, 3H) 1 H NMR (400 MHz, chloroform-d 1 ) d = 8.64 (s, 1H), 8.27 (m, 1H), 8.08 (dd, J = 1.2 Hz, 4.0 Hz, 1H), 7.79-7.82 (m, 2H) , 7.47-7.56 (m, 3H), 7.44 (d, J = 2.8 Hz, 1H), 7.14 (m, 1H), 6.94 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 6.73 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 3.85 (s, 3H)

[실시예 5]Example 5

Figure pat00027
Figure pat00027

1H NMR (600MHz, chloroform-d1)d = 8.76 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.79-7.82 (m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 7.10 (d, J = 4.2 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H) 1 H NMR (600 MHz, chloroform-d 1 ) d = 8.76 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.79-7.82 (m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 7.10 (d, J = 4.2 Hz, 1H) , 6.91 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H)

[실시예 6]Example 6

Figure pat00028
Figure pat00028

1H NMR (600MHz, chloroform-d1)d = 8.75 (s, 1 H), 8.22 (d, J=7.8Hz,1H),7.83(m,2H),7.54(m,2H),7.48(m,2H),7.22(m,1H),6.91(d,J=3Hz,1H),6.74(dd,J=9Hz,3.6Hz,1H),3.74(s,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 8.75 (s, 1H), 8.22 (d, J = 7.8Hz, 1H), 7.83 (m, 2H), 7.54 (m, 2H), 7.48 (m , 2H), 7.22 (m, 1H), 6.91 (d, J = 3Hz, 1H), 6.74 (dd, J = 9Hz, 3.6Hz, 1H), 3.74 (s, 3H)

[실시예 7]Example 7

Figure pat00029
Figure pat00029

1H NMR (400MHz, chloroform-d1)d = 8.6 (br s, 1H), 8.2 (d, J=8Hz,1H),7.8-7.7(m,4H),7.5(t,J=6.8Hz,1H),7.4-7.3(m,2H),7.2-7.1(m,3H)
 1 H NMR (400 MHz, chloroform-d 1 ) d = 8.6 (br s, 1H), 8.2 (d, J = 8 Hz, 1H), 7.8-7.7 (m, 4H), 7.5 (t, J = 6.8 Hz, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 3H)

[실시예 8]Example 8

[단계 1] 2-methyl-4H-benzo[d][1,3]oxazin-4-one의 제조[Step 1] Preparation of 2-methyl-4H-benzo [d] [1,3] oxazin-4-one

Figure pat00030
Figure pat00030

안트라닐산 (anthranilic acid) 3.00 g (21.9 mmol)을 80 mL의 무수아세트산(acetic anhydride)에 녹인 후 13시간 동안 환류 교반하였다. 상온으로 식혀 감압 농축하고 관 크로마토그래프로 정제하여 표제화합물을 흰색 고체로 3.28 g (93%) 얻었다.3.00 g (21.9 mmol) of anthranilic acid was dissolved in 80 mL of acetic anhydride and stirred at reflux for 13 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain 3.28 g (93%) of the title compound as a white solid.

1H NMR (600MHz, chloroform-d1)d = 8.19 (d, J=7.8Hz,1H), 7.80(t,J=7.8Hz,1H), 7.54(d,J=7.8Hz,1H), 7.50(t,J=7.8Hz,1H),2.47(s,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 8.19 (d, J = 7.8Hz, 1H), 7.80 (t, J = 7.8Hz, 1H), 7.54 (d, J = 7.8Hz, 1H), 7.50 (t, J = 7.8Hz, 1H), 2.47 (s, 3H)

[단계 2] 2-bromo-5-methoxybenzohydrazide의 제조[Step 2] Preparation of 2-bromo-5-methoxybenzohydrazide

Figure pat00031
Figure pat00031

2-브로모-5-메톡시벤조산 (2-Bromo-5-methoxybenzoic acid) 3 g (19.8 mmol)을 메탄올 20 mL에 녹이고, 황산 0.3 mL를 넣고 마이크로웨이브를 조사하여 160 ℃에서 10분 가열하였다. 실온으로 식혀 감압 농축하고 에틸아세테이트:헥산=1:1 혼합용매 90 mL에 녹이고 탄산수소나트륨 포화수용액 10 mL로 두 차례, 물 5 mL로 씻어주었다. 유기층을 무수 황산마그네슘으로 탈수하고 감압 농축하여 얻은 메틸 2-브로모-5-메톡시벤조에이트 (methyl 2-bromo-5-methoxybenzoate) 1.168 g을 메탄올 15 mL에 녹이고, 하이드라진 모노하이드레이트 (hydrazine monohydrate) 2.33 mL (48 mmol)를 넣고 19시간 동안 환류 교반하였다. 실온으로 식혀 감압 농축하고 에틸아세테이트 150 mL에 희석시킨 후 물로 추출하였다. 유기층을 무수 황산마그네슘으로 탈수하고 감압 농축하여 표제화합물을 흰색 고체로 950 mg (60%) 얻었다.3 g (19.8 mmol) of 2-Bromo-5-methoxybenzoic acid was dissolved in 20 mL of methanol, 0.3 mL of sulfuric acid was added thereto, and microwave irradiation was performed for 10 minutes at 160 ° C. . The mixture was cooled to room temperature, concentrated under reduced pressure, dissolved in 90 mL of a mixture of ethyl acetate: hexane = 1: 1, and washed twice with 10 mL of saturated aqueous sodium hydrogen carbonate solution and 5 mL of water. The organic layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and 1.168 g of methyl 2-bromo-5-methoxybenzoate was dissolved in 15 mL of methanol, and hydrazine monohydrate. 2.33 mL (48 mmol) was added and stirred under reflux for 19 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, diluted with 150 mL of ethyl acetate, and extracted with water. The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to give 950 mg (60%) of the title compound as a white solid.

1H NMR (600MHz, chloroform-d1)d = 7.47 (d,J=9Hz,1H), 7.25(brs,1H), 7.07(d,J=3Hz,1H), 6.86(dd,J=12Hz,3Hz,1H), 4.13(brs,2H), 3.81(s,3H) 1 H NMR (600 MHz, chloroform-d 1 ) d = 7.47 (d, J = 9 Hz, 1 H), 7.25 (brs, 1 H), 7.07 (d, J = 3 Hz, 1 H), 6.86 (dd, J = 12 Hz, 3 Hz, 1 H), 4.13 (brs, 2 H), 3.81 (s, 3 H)

[단계 3] 2-bromo-5-methoxy-N-(2-methyl-4-oxoquinazolin-3(4H)-yl)benzamide의 제조[Step 3] Preparation of 2-bromo-5-methoxy-N- (2-methyl-4-oxoquinazolin-3 (4H) -yl) benzamide

Figure pat00032
Figure pat00032

단계 1에서 얻은 화합물 100 mg (0.621 mmol), 2-브로모-5-메톡시벤조하이드라지드 (2-bromo-5-methoxybenzohydrazide) 200 mg (0.816 mmol), DMAP 15 mg (0.124 mmol)을 THF 2 mL에 녹인 후 16시간 동안 환류 교반하였다. 상온으로 식혀 MC 40 mL를 가한 후 물 3 mL로 씻어주었다. 유기층을 무수 황산마그네슘으로 탈수하고 감압 농축한 뒤 관 크로마토그래프로 정제하여 표제화합물을 흰색 고체로 57 mg (24%) 얻었다.100 mg (0.621 mmol) of the compound obtained in step 1, 200 mg (0.816 mmol) of 2-bromo-5-methoxybenzohydrazide, and 15 mg (0.124 mmol) of DMAP were treated with THF. It was dissolved in 2 mL and stirred under reflux for 16 hours. After cooling to room temperature, MC 40 mL was added, and the mixture was washed with 3 mL of water. The organic layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography to obtain 57 mg (24%) of the title compound as a white solid.

1H NMR (600MHz, chloroform-d1)d = 9.33 (s, 1 H), 7.99 (d, J=7.8Hz,1H),7.77(t,J=7.8Hz,1H),7.66(d,J=8.4Hz,1H), 7.41(t,J=7.8Hz,1H), 7.28(d,J=9Hz,1H),7.10(d,J=3Hz,1H),6.63(dd,J=8.4Hz,3Hz,1H),3.69(s,3H), 2.47(s,3H)
 1 H NMR (600MHz, chloroform-d 1 ) d = 9.33 (s, 1H), 7.99 (d, J = 7.8Hz, 1H), 7.77 (t, J = 7.8Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.41 (t, J = 7.8Hz, 1H), 7.28 (d, J = 9Hz, 1H), 7.10 (d, J = 3Hz, 1H), 6.63 (dd, J = 8.4Hz, 3 Hz, 1 H), 3.69 (s, 3 H), 2.47 (s, 3 H)

상기 실시예 8의 방법을 이용하여 하기 실시예 9 내지 24의 퀴나졸리논 유도체 화합물을 제조하였으며, 각각 제조된 퀴나졸리논 유도체 화합물들의 1H NMR을 나타내었다.The quinazolinone derivative compounds of Examples 9 to 24 were prepared using the method of Example 8, and 1 H NMR of the prepared quinazolinone derivative compounds was shown.

[실시예 9]Example 9

Figure pat00033
Figure pat00033

1H NMR (600 MHz, CDCl3)d = 8.71(s,1H), 8.22(t,1H,J=5.6), 7.80-7.68(m,2H), 7.487.42(m,2H), 6.84(dd,1H,J=6.0,2.0), 3.84(s,3H), 2.93(quint,1H,J=4.4), 1.38(d,6H,J=4.8) 1 H NMR (600 MHz, CDCl 3 ) d = 8.71 (s, 1H), 8.22 (t, 1H, J = 5.6), 7.80-7.68 (m, 2H), 7.487.42 (m, 2H), 6.84 ( dd, 1H, J = 6.0,2.0), 3.84 (s, 3H), 2.93 (quint, 1H, J = 4.4), 1.38 (d, 6H, J = 4.8)

[실시예 10]Example 10

Figure pat00034
Figure pat00034

1H NMR (600 MHz, CDCl3)d = 8.60(s,1H), 8.22(d,1H,J=7.8), 7.80-7.68(m,2H), 7.507.44(m, 2H), 6.86 (dd, 1H, J = 8.7, 3.3), 3.82 (s, 3H), 3.03-2.91 (m, 2H), 1.91 - 1.84 (m, 2H), 1.45 1.38 (m, 4H), 0.93 (t, 3H, J = 7.2) 1 H NMR (600 MHz, CDCl 3 ) d = 8.60 (s, 1H), 8.22 (d, 1H, J = 7.8), 7.80-7.68 (m, 2H), 7.507.44 (m, 2H), 6.86 ( dd, 1H, J = 8.7, 3.3), 3.82 (s, 3H), 3.03-2.91 (m, 2H), 1.91-1.84 (m, 2H), 1.45 1.38 (m, 4H), 0.93 (t, 3H, J = 7.2)

[실시예 11]Example 11

Figure pat00035
Figure pat00035

1H NMR (400MHz, chloroform-d1)d = 8.45 (s, 1 H), 8.19 (d, J=8Hz,1H),7.73(t,J=7.2Hz,1H),7.60(d,J=8.4Hz,1H),7.51(d,J=9.2Hz,1H),7.41(t,J=7.2Hz,1H),7.35(d,J=3.2Hz,1H),6.90(dd,J=8.8Hz,2.8Hz,1H),2.48(m,1H),1.29(m,2H),1.09(m,2H) 1 H NMR (400 MHz, chloroform-d 1 ) d = 8.45 (s, 1 H), 8.19 (d, J = 8 Hz, 1 H), 7.73 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.51 (d, J = 9.2Hz, 1H), 7.41 (t, J = 7.2Hz, 1H), 7.35 (d, J = 3.2Hz, 1H), 6.90 (dd, J = 8.8Hz , 2.8 Hz, 1H), 2.48 (m, 1H), 1.29 (m, 2H), 1.09 (m, 2H)

[실시예 12]Example 12

Figure pat00036
Figure pat00036

1H NMR (600MHz, chloroform-d1)d = 9.11 (s, 1 H), 8.05 (d, J=8.4Hz,1H),7.77(t,J=7.8Hz,1H),7.67(d,J=8.4Hz,1H),7.42(t,J=7.8Hz,1H),7.32(d,J=8.4Hz,1H),7.16(d,J=3Hz,1H),6.68(dd,J=9Hz,3Hz,1H),4.45(m,1H),2.71(s,3H),1.30(s,3H),1.29(s,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 9.11 (s, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.77 (t, J = 7.8Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.42 (t, J = 7.8Hz, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.16 (d, J = 3Hz, 1H), 6.68 (dd, J = 9Hz, 3Hz, 1H), 4.45 (m, 1H), 2.71 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H)

[실시예 13]Example 13

Figure pat00037
Figure pat00037

1H NMR (600MHz, chloroform-d1)d = 8.97 (s, 1 H), 8.12 (d, J=8.4Hz,1H),7.80(m,4H),7.50(t,J=7.2Hz,1H),7.19(m,3H),6.77(d,J=3Hz,1H),6.64(dd,J=8.4Hz,2.4Hz,1H),4.40(m,1H),1.30(d,J=6Hz,3H),1.29(d,J=6Hz,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 8.97 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.80 (m, 4H), 7.50 (t, J = 7.2Hz, 1H ), 7.19 (m, 3H), 6.71 (d, J = 3 Hz, 1H), 6.64 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 4.40 (m, 1H), 1.30 (d, J = 6 Hz, 3H), 1.29 (d, J = 6Hz, 3H)

[실시예 14]Example 14

Figure pat00038
Figure pat00038

1H NMR (600MHz, chloroform-d1)d = 9.63 (s, 1 H), 7.82 (d, J=1.8Hz,1H),7.78(m,2H),7.73(m,2H),7.22(t,J=9Hz,2H),7.06(d,J=9Hz,1H),6.56(m,2H),3.67(s,3H) 1 H NMR (600 MHz, chloroform-d 1 ) d = 9.63 (s, 1 H), 7.82 (d, J = 1.8 Hz, 1H), 7.78 (m, 2H), 7.73 (m, 2H), 7.22 (t , J = 9Hz, 2H), 7.06 (d, J = 9Hz, 1H), 6.56 (m, 2H), 3.67 (s, 3H)

[실시예 15]Example 15

Figure pat00039
Figure pat00039

1H NMR (600MHz, chloroform-d1)d = 8.32 (m, 2 H), 8.16 (d, J=8.4Hz,1H),7.68(s,1H),7.48(d,J=8.4Hz,1H),7.20(t,J=8.4Hz,2H) 1 H NMR (600MHz, chloroform-d 1 ) d = 8.32 (m, 2H), 8.16 (d, J = 8.4Hz, 1H), 7.68 (s, 1H), 7.48 (d, J = 8.4Hz, 1H ), 7.20 (t, J = 8.4Hz, 2H)

[실시예 16]Example 16

Figure pat00040
Figure pat00040

1H NMR (600MHz, chloroform-d1)d = 11.69 (s, 1 H), 9.37 (d, J=2.4Hz,1H),8.39(d,J=8.4Hz,1H),8.16(d,J=2.4Hz,1H),7.86(t,J=7.8Hz,1H),7.79(d,J=8.4Hz,1H),7.60(t,J=7.82Hz,1H),7.00(d,J=9Hz,1H),6.73(d,J=3Hz,1H),6.45(dd,J=8.4Hz,3Hz,1H),3.35(s,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 11.69 (s, 1H), 9.37 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 8.4Hz, 1H), 8.16 (d, J = 2.4Hz, 1H), 7.86 (t, J = 7.8Hz, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.60 (t, J = 7.82Hz, 1H), 7.00 (d, J = 9Hz , 1H), 6.73 (d, J = 3Hz, 1H), 6.45 (dd, J = 8.4Hz, 3Hz, 1H), 3.35 (s, 3H)

[실시예 17]Example 17

Figure pat00041
Figure pat00041

1H NMR (600 MHz, DMSO)d = 8.08 (d, 1H, J = 8.4), 7.78 (t, 1H, J = 7.5), 7.57 (d, 1H, J = 8.4), 7.44 (t, 1H, J = 7.5), 5.79 (bs, 2H, NH 2 ),2.45(s,3H) 1 H NMR (600 MHz, DMSO) d = 8.08 (d, 1H, J = 8.4), 7.78 (t, 1H, J = 7.5), 7.57 (d, 1H, J = 8.4), 7.44 (t, 1H, J = 7.5), 5.79 (bs, 2H, NH 2 ), 2.45 (s, 3H)

[실시예 18]Example 18

Figure pat00042
Figure pat00042

1H NMR (600MHz, chloroform-d1)d = 9.1 ( br s, 1H), 8.0 (d, J=7.8Hz,1H),7.8-7.7(m,2H),7.6(d,J=8.4Hz2H),7.4(t,J=7.8Hz1H),7.3(d,J=8.4Hz2H),7.1(d,J=9Hz1H),6.7(d,J=3Hz1H),6.6(dd,J=6Hz,3Hz,1H),3.6(s,3H),2.4(s,3H) 1 H NMR (600MHz, chloroform-d 1 ) d = 9.1 (br s, 1H), 8.0 (d, J = 7.8Hz, 1H), 7.8-7.7 (m, 2H), 7.6 (d, J = 8.4Hz2H ), 7.4 (t, J = 7.8 Hz 1 H), 7.3 (d, J = 8.4 Hz 2 H), 7.1 (d, J = 9 Hz 1 H), 6.7 (d, J = 3 Hz 1 H), 6.6 (dd, J = 6 Hz, 3 Hz, 1H), 3.6 (s, 3H), 2.4 (s, 3H)

[실시예 19]Example 19

Figure pat00043
Figure pat00043

1H NMR (400MHz, chloroform-d1)d = 9.80 (s, 1 H), 8.75 (dd, J=4.4Hz,1.2Hz,1H),8.48(dd,J=8Hz,2Hz,1H),7.74(m,2H),7.39(m,2H),7.01(t,J=8.4Hz,2H),6.85(d,J=3.2Hz,1H),6.79(dd,J=8.8Hz,3.2Hz,1H),3.72(s,3H) 1 H NMR (400 MHz, chloroform-d 1 ) d = 9.80 (s, 1 H), 8.75 (dd, J = 4.4 Hz, 1.2 Hz, 1H), 8.48 (dd, J = 8Hz, 2Hz, 1H), 7.74 (m, 2H), 7.39 (m, 2H), 7.01 (t, J = 8.4Hz, 2H), 6.85 (d, J = 3.2Hz, 1H), 6.79 (dd, J = 8.8Hz, 3.2Hz, 1H ), 3.72 (s, 3H)

[실시예 20]Example 20

Figure pat00044
Figure pat00044

1H NMR (600 MHz, DMSO)d = 9.02 (s, 1H), 8.57 (d, 1H, J = 7.8), 7.68 (d, 1H, J = 9.0), 7.62 - 7.60 (m, 1H), 7.19 (d, 1H, J = 2.4), 7.12 (d, 1H, J = 3.0), 3.85 (s, 3H), 2.61 (s, 3H) 1 H NMR (600 MHz, DMSO) d = 9.02 (s, 1H), 8.57 (d, 1H, J = 7.8), 7.68 (d, 1H, J = 9.0), 7.62-7.60 (m, 1H), 7.19 (d, 1H, J = 2.4), 7.12 (d, 1H, J = 3.0), 3.85 (s, 3H), 2.61 (s, 3H)

[실시예 21]Example 21

Figure pat00045
Figure pat00045

1H NMR (600 MHz, CDCl3)d = 9.00 (d, 1H, J = 3.0), 8.78 (s, 1H), 8.53 (d, 1H, J = 6.6), 7.48 - 7.42 (m, 2H), 6.84 (dd, 1H, J = 8.7, 3.0), 3.82 (s, 3H), 3.55 (quint, 1H, J = 6.6), 1.47 (d, 3H, J = 7.2), 1.44 (d, 3H, J = 6.6) 1 H NMR (600 MHz, CDCl 3 ) d = 9.00 (d, 1H, J = 3.0), 8.78 (s, 1H), 8.53 (d, 1H, J = 6.6), 7.48-7.42 (m, 2H), 6.84 (dd, 1H, J = 8.7, 3.0), 3.82 (s, 3H), 3.55 (quint, 1H, J = 6.6), 1.47 (d, 3H, J = 7.2), 1.44 (d, 3H, J = 6.6)

[실시예 22][Example 22]

Figure pat00046
Figure pat00046

1H NMR (400 MHz, CDCl3)d = 8.96(dd,1H,J=4.8,2.0), 8.53(m,1H), 7.55(d,1H,J=8.8),7.40-7.36(m,2H),6.94(dd,1H,J=8.8,3.2),3.86(s,3H),2.572.52(m,1H),1.541.52(m,2H),1.231.20(m,2H) 1 H NMR (400 MHz, CDCl 3 ) d = 8.96 (dd, 1H, J = 4.8,2.0), 8.53 (m, 1H), 7.55 (d, 1H, J = 8.8), 7.40-7.36 (m, 2H ), 6.94 (dd, 1H, J = 8.8,3.2), 3.86 (s, 3H), 2.572.52 (m, 1H), 1.541.52 (m, 2H), 1.231.20 (m, 2H)

[실시예 23][Example 23]

Figure pat00047
Figure pat00047

1H NMR (400 MHz, CDCl3)d = 8.99 (s, 1H), 8.22 (t, 1H, J = 8.4)), 7.74 (m, 1H), 7.12 (m, 1H), 7.69 (m, 1H), 7.58 (m, 2H) 7.32 (m, 1H), 6.93 (m, 1H) 3.81 (s, 3H), 2.46 (m, 1H), 1.34 (m, 2H), 1.15 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) d = 8.99 (s, 1H), 8.22 (t, 1H, J = 8.4)), 7.74 (m, 1H), 7.12 (m, 1H), 7.69 (m, 1H ), 7.58 (m, 2H) 7.32 (m, 1H), 6.93 (m, 1H) 3.81 (s, 3H), 2.46 (m, 1H), 1.34 (m, 2H), 1.15 (m, 2H)

[실시예 24]Example 24

Figure pat00048
Figure pat00048

1H NMR (600 MHz, CDCl3)d = 8.95(d,1H,J=2.4),8.91(s,1H),8.548.52(m,1H),7.42-7.37(m,2H),7.00(dd,1H,J=9.0,3.0),3.85(s,3H),2.49(quint,1H,J=3.9),1.541.52(m,2H),1.231.19(m,2H)
 1 H NMR (600 MHz, CDCl 3 ) d = 8.95 (d, 1H, J = 2.4), 8.91 (s, 1H), 8.548.52 (m, 1H), 7.42-7.37 (m, 2H), 7.00 ( dd, 1H, J = 9.0,3.0), 3.85 (s, 3H), 2.49 (quint, 1H, J = 3.9), 1.541.52 (m, 2H), 1.231.19 (m, 2H)

상기 일 실시예에 따른 퀴나졸리논 유도체 화합물을 이용하여 PAR-2 저해 활성 효과를 평가하기 위해서 인-비트로(in-vitro) 실험을 수행 하였다.
In-vitro experiments were performed to evaluate the effect of PAR-2 inhibitory activity using the quinazolinone derivative compound according to the embodiment.

[시험예 1] 칼슘 임모빌리제이션 분석 (Calcium Immobilization Assay) Test Example 1 Calcium Immobilization Assay

합성된 물질의 PAR-2에 대한 저해 활성을 평가하기 위하여 세포 내 칼슘 이온의 농도 변화를 실시간으로 측정할 수 있는 분석 시스템을 구축하고 이를 이용하여 평가를 시행하였다. PAR-2는 GPCR (G-protein coupled receptor)의 일종으로서, PAR-2가 세포 내에서 활성화되면 포스포리파아제 (phospholipase) C-b (PLC-b)가 활성화되면서 PIP2 (phosphatidylinositol 4,5-bisphosphate)를 각각 IP3 (inositol triphosphate)와 DAG (diacyl glycerol)로 분해하게 된다. 이 때 생성되는 IP3가 세포 내의 칼슘 이온 저장소인 ER (endoplasmic reticulum)에서 칼슘 이온의 분비를 촉진하게 되어, 세포 내 칼슘 이온의 증가가 나타나게 된다. 기존의 연구 결과에 기초하여, PAR-2의 활성화에 의한 세포 내 칼슘 이온 농도 증가를 억제할 수 있는 물질을 검색할 수 있는 in-vitro screening assay system을 구축하였다. 하기 도 2에 나타낸 바와 같이 실험에 사용한 PAR-2 활성화제로서는 활성 펩타이드 (activating peptide, AP)를 이용하였으며, 세포 내 칼슘 이온 농도를 검출하기 위한 시약으로서는 Molecular Probe사의 Calcium-4 assay kit을 사용하였다. 실험에 이용한 세포주는 PAR-2가 과발현된 세포주인 HCT-15을 이용하였으며, 저해 후보 물질을 5분간 처리한 후, AP를 처리하고 Molecular Device사의 FlexStation II를 이용하여, 형광의 변화를 2분간 실시간으로 관찰하였다. In order to evaluate the inhibitory activity of the synthesized material against PAR-2, an analytical system capable of measuring the concentration change of intracellular calcium ions in real time was constructed and evaluated. PAR-2 is a type of G-protein coupled receptor (GPCR). When PAR-2 is activated in a cell, phospholipase Cb (PLC-b) is activated to release PIP2 (phosphatidylinositol 4,5-bisphosphate). They break down into IP3 (inositol triphosphate) and DAG (diacyl glycerol), respectively. IP3 produced at this time promotes the secretion of calcium ions in the endoplasmic reticulum (ER), which is a reservoir of calcium ions in cells, resulting in an increase in intracellular calcium ions. Based on the results of previous studies, we have established an in-vitro screening assay system that can search for substances that can suppress the increase of intracellular calcium ion concentration by PAR-2 activation. As shown in FIG. 2, an activating peptide (AP) was used as the PAR-2 activator used in the experiment, and a Calcium-4 assay kit manufactured by Molecular Probe was used as a reagent for detecting intracellular calcium ion concentration. . The cell line used in the experiment was HCT-15, a cell line overexpressed with PAR-2, and treated with inhibitor for 5 minutes, treated with AP, and then flexibly changed the fluorescence for 2 minutes using FlexStation II of Molecular Device. Observed by.

하기 도 1은 본 발명에 따른 각각의 퀴나졸리논 유도체 화합물에 대한 세포 내 칼슘 이온 증가 측정 결과를 나타낸 것으로, 처치한 화합물의 농도와 저해 정도 (POI: percentage of inhibition)의 상관 관계를 나타낸 것이다. Figure 1 shows the results of the measurement of intracellular calcium ion increase for each of the quinazolinone derivative compounds according to the present invention, showing the correlation between the concentration of the treated compound and the percentage of inhibition (POI).

각각의 화합물에 대하여 HCT-15 세포주에서 2.5 μM의 AP에 의한 세포 내 칼슘 이온 농도의 증가가 50% 저해되는 농도를 IC50로 결정하여 분석하였다.
For each compound, the concentration of 50% inhibition of the increase in intracellular calcium ion concentration by 2.5 μM AP in the HCT-15 cell line was determined by IC50 analysis.

상기 분석을 통하여 본 발명에 따른 퀴나졸리논 유도체 화합물의 PAR-2 저해 활성 평가에 대한 결과는 하기 표 1에 나타내었다.The results for the evaluation of PAR-2 inhibitory activity of the quinazolinone derivative compounds according to the present invention through the above analysis are shown in Table 1 below.

[표 1][Table 1]

Figure pat00049
Figure pat00049

Figure pat00050
Figure pat00050

상기 표 1에서 나타낸 바와 같이 미국의 바이오벤쳐 회사인 Entremed사의 ENMD-1,068 (N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine)에 비해 본 발명에 따른 퀴나졸리논 유도체 화합물의 PAR-2 저해 효능이 매우 우수한 것을 확인할 수 있었다.PAR-2 of the quinazolinone derivative compound according to the present invention as compared to ENMD-1,068 (N 1-3 -methylbutyryl-N 4-6 -aminohexanoyl-piperazine) of Entremed, a US bioventure company, as shown in Table 1 above. It was confirmed that the inhibitory effect is very excellent.

Claims (9)

하기 화학식 1로 표시되는 퀴나졸리논 유도체 화합물.
[화학식 1]
Figure pat00051

[상기 화학식 1에서,
X는 탄소 또는 질소이고; R1 및 R2는 서로 독립적으로 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C1-C10)알콕시 또는 할로겐이며; 상기 R3는 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C3-C10)사이클로알킬, 치환 또는 비치환된 (C6-C10)아릴, 치환 또는 비치환된 (C6-C10)헤테로아릴, (C1-C10)알킬티오 또는 (C6-C10)아릴티오이고; 상기 R4는 수소, 치환 또는 비치환된 (C1-C10)알킬 또는 할로겐이며; 상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택되는 어느 하나 이상의 헤테로원자를 포함하고, 상기 R1 및 R2 중 어느 하나는 반드시 할로겐이며, 상기 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 말한다.] Quinazolinone derivative compound represented by following formula (1).
[Formula 1]
Figure pat00051

[In the above formula (1)
X is carbon or nitrogen; R 1 and R 2 are independently of each other substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C1-C10) alkoxy or halogen; R 3 is substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C3-C10) cycloalkyl, substituted or unsubstituted (C6-C10) aryl, substituted or unsubstituted (C6-C10) ) Heteroaryl, (C1-C10) alkylthio or (C6-C10) arylthio; R 4 is hydrogen, substituted or unsubstituted (C 1 -C 10) alkyl or halogen; The heteroaryl includes any one or more heteroatoms selected from the group consisting of N, O and S, wherein any one of R 1 and R 2 is necessarily halogen, and in the description of 'substituted or unsubstituted' Substitution 'refers to a case where the substituent is further substituted with an unsubstituted substituent.] 제 1항에 있어서,
상기 R1 내지 R4의 (C1-C10)알킬, (C1-C10)알콕시, (C3-C10)사이클로알킬, (C6-C10)아릴 또는 (C6-C10)헤테로아릴에 더 치환되는 치환기는 서로 독립적으로 (C1-C10)알킬, (C1-C10)알콕시 및 할로겐으로 이루어진 군에서 선택되는 어느 하나 이상인 것을 특징으로 하는 퀴나졸리논 유도체 화합물.The method of claim 1,
Substituents further substituted with (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C10) cycloalkyl, (C6-C10) aryl or (C6-C10) heteroaryl of R 1 to R 4 A quinazolinone derivative compound, which is independently one or more selected from the group consisting of (C1-C10) alkyl, (C1-C10) alkoxy and halogen. 제 1항에 있어서,
하기 화학식 2로 표시되는 퀴나졸리논 유도체 화합물.
[화학식 2]
Figure pat00052

[상기 화학식 2에서,
상기 X, R1 내지 R4는 청구항 제1항에서의 정의와 동일하다.]The method of claim 1,
A quinazolinone derivative compound represented by the following formula (2).
(2)
Figure pat00052

[In Formula 2,
X, R 1 to R 4 are the same as defined in claim 1. 제 3항에 있어서,
상기 R1은 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, i-펜틸, 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, t-부톡시, n-펜톡시, i-펜톡시 또는 Cl이고; R2는 Cl 또는 Br인 것을 특징으로 하는 퀴나졸리논 유도체 화합물.The method of claim 3, wherein
R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, methoxy, ethoxy, n-propoxy, i-prop Foxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, i-pentoxy or Cl; R 2 is a quinazolinone derivative compound, characterized in that Cl or Br. 제 4항에 있어서,
하기 구조에서 선택되는 것을 특징으로 하는 퀴나졸리논 유도체 화합물.
Figure pat00053

Figure pat00054

Figure pat00055
The method of claim 4, wherein
A quinazolinone derivative compound characterized in that it is selected from the following structures.
Figure pat00053

Figure pat00054

Figure pat00055
 a) 하기 화학식 3으로 표시되는 화합물과 하기 화학식 4로 표시되는 화합물을 반응시켜 하기 화학식 5로 표시되는 화합물을 제조하는 단계;
b) 화학식 5로 표시되는 화합물과 하이드라진 모노하이드레이트를 반응시켜 하기 화학식 6으로 표시되는 화합물을 제조하는 단계;
c) 화학식 6으로 표시되는 화합물과 하기 화학식 7로 표시되는 화합물을 반응시켜 하기 화학식 1로 표시되는 퀴나졸리논 유도체 화합물을 제조하는 단계;
를 포함하는 퀴나졸리논 유도체 화합물의 제조방법.
[화학식 1]
Figure pat00056

[화학식 3]
Figure pat00057

[화학식 4]
Figure pat00058

[화학식 5]
Figure pat00059

[화학식 6]
Figure pat00060

[화학식 7]
Figure pat00061

[상기 화학식 1 및 화학식 3 내지 화학식 7에서,
X는 탄소 또는 질소이고; R1 및 R2는 서로 독립적으로 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C1-C10)알콕시 또는 할로겐이며; 상기 R3는 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C3-C10)사이클로알킬, 치환 또는 비치환된 (C6-C10)아릴, 치환 또는 비치환된 (C6-C10)헤테로아릴, (C1-C10)알킬티오 또는 (C6-C10)아릴티오이고; 상기 R4는 수소, 치환 또는 비치환된 (C1-C10)알킬 또는 할로겐이며; 상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택되는 어느 하나 이상의 헤테로원자를 포함하고, 상기 R1 및 R2 중 어느 하나는 반드시 할로겐이며, 상기 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 말한다.] a) preparing a compound represented by Chemical Formula 5 by reacting a compound represented by Chemical Formula 3 with a compound represented by Chemical Formula 4;
b) preparing a compound represented by Chemical Formula 6 by reacting a compound represented by Chemical Formula 5 with hydrazine monohydrate;
c) reacting a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7 to prepare a quinazolinone derivative compound represented by Chemical Formula 1;
Method for producing a quinazolinone derivative compound comprising a.
[Formula 1]
Figure pat00056

(3)
Figure pat00057

[Chemical Formula 4]
Figure pat00058

[Chemical Formula 5]
Figure pat00059

[Formula 6]
Figure pat00060

[Formula 7]
Figure pat00061

[In Formula 1 and Formula 3 to Formula 7,
X is carbon or nitrogen; R 1 and R 2 are independently of each other substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C1-C10) alkoxy or halogen; R 3 is substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C3-C10) cycloalkyl, substituted or unsubstituted (C6-C10) aryl, substituted or unsubstituted (C6-C10) ) Heteroaryl, (C1-C10) alkylthio or (C6-C10) arylthio; R 4 is hydrogen, substituted or unsubstituted (C 1 -C 10) alkyl or halogen; The heteroaryl includes any one or more heteroatoms selected from the group consisting of N, O and S, wherein any one of R 1 and R 2 is necessarily halogen, and in the description of 'substituted or unsubstituted' Substitution 'refers to a case where the substituent is further substituted with an unsubstituted substituent.] d) 하기 화학식 3으로 표시되는 화합물과 하기 화학식 4로 표시되는 화합물을 반응시켜 하기 화학식 5로 표시되는 화합물을 제조하는 단계;
e) 하기 화학식 5로 표시되는 화합물과 하기 화학식 8로 표시되는 화합물을 반응시켜 하기 화학식 1로 표시되는 퀴나졸리논 유도체 화합물을 제조하는 단계;
를 포함하는 퀴나졸리논 유도체 화합물의 제조방법.
[화학식 1]
Figure pat00062

[화학식 3]
Figure pat00063

[화학식 4]
Figure pat00064

[화학식 5]
Figure pat00065

[화학식 8]
Figure pat00066

[상기 화학식 1, 화학식 3 내지 화학식 5 및 화학식 8에서,
X는 탄소 또는 질소이고; R1 및 R2는 서로 독립적으로 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C1-C10)알콕시 또는 할로겐이며; 상기 R3는 치환 또는 비치환된 (C1-C10)알킬, 치환 또는 비치환된 (C3-C10)사이클로알킬, 치환 또는 비치환된 (C6-C10)아릴, 치환 또는 비치환된 (C6-C10)헤테로아릴, (C1-C10)알킬티오 또는 (C6-C10)아릴티오이고; 상기 R4는 수소, 치환 또는 비치환된 (C1-C10)알킬 또는 할로겐이며; 상기 헤테로아릴은 N, O 및 S로 이루어진 군에서 선택되는 어느 하나 이상의 헤테로원자를 포함하고, 상기 R1 및 R2 중 어느 하나는 반드시 할로겐이며, 상기 ‘치환 또는 비치환된’이라는 기재에서 ‘치환’은 비치환된 치환기에 더 치환되는 경우를 말한다.] d) preparing a compound represented by the following Chemical Formula 5 by reacting the compound represented by the following Chemical Formula 3 with the compound represented by the following Chemical Formula 4;
e) preparing a quinazolinone derivative compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 8;
Method for producing a quinazolinone derivative compound comprising a.
[Formula 1]
Figure pat00062

(3)
Figure pat00063

[Chemical Formula 4]
Figure pat00064

[Chemical Formula 5]
Figure pat00065

[Chemical Formula 8]
Figure pat00066

[In Formula 1, Formula 3 to Formula 5 and Formula 8,
X is carbon or nitrogen; R 1 and R 2 are independently of each other substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C1-C10) alkoxy or halogen; R 3 is substituted or unsubstituted (C1-C10) alkyl, substituted or unsubstituted (C3-C10) cycloalkyl, substituted or unsubstituted (C6-C10) aryl, substituted or unsubstituted (C6-C10) ) Heteroaryl, (C1-C10) alkylthio or (C6-C10) arylthio; R 4 is hydrogen, substituted or unsubstituted (C 1 -C 10) alkyl or halogen; The heteroaryl includes any one or more heteroatoms selected from the group consisting of N, O and S, wherein any one of R 1 and R 2 is necessarily halogen, and in the description of 'substituted or unsubstituted' Substitution 'refers to a case where the substituent is further substituted with an unsubstituted substituent.] 제 1항 내지 제 5항에서 선택되는 어느 한 항의 퀴나졸리논 유도체 화합물을 유효성분으로 함유하여 심혈관계 질환, 위장관계 질환, 천식, 간경변, 피부 내 색소 침착, 아토피 피부염 및 창상 치료 또는 예방을 위한 것을 특징으로 하는 의학 조성물.A quinazolinone derivative compound according to any one of claims 1 to 5 as an active ingredient for cardiovascular diseases, gastrointestinal diseases, asthma, cirrhosis, intradermal pigmentation, atopic dermatitis and wound treatment or prevention Medical composition, characterized in that. 제 1항 내지 제 5항에서 선택되는 어느 한 항의 퀴나졸리논 유도체 화합물을 유효성분으로 함유하여 PAR-2를 저해하는 것을 특징으로 하는 의학 조성물.A medical composition comprising the quinazolinone derivative compound of any one of claims 1 to 5 as an active ingredient to inhibit PAR-2.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201572A1 (en) 2019-04-05 2020-10-08 Université De Bretagne Occidentale Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201572A1 (en) 2019-04-05 2020-10-08 Université De Bretagne Occidentale Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning

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