KR101977970B1 - Novel benzamide derivatives compounds, manufacturing method thereof, and phamaceutical composition for preventing and treating cancer containing the same - Google Patents

Novel benzamide derivatives compounds, manufacturing method thereof, and phamaceutical composition for preventing and treating cancer containing the same Download PDF

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KR101977970B1
KR101977970B1 KR1020170098785A KR20170098785A KR101977970B1 KR 101977970 B1 KR101977970 B1 KR 101977970B1 KR 1020170098785 A KR1020170098785 A KR 1020170098785A KR 20170098785 A KR20170098785 A KR 20170098785A KR 101977970 B1 KR101977970 B1 KR 101977970B1
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최현경
안지연
유화니
송지영
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중원대학교 산학협력단
한국원자력의학원
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring

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Abstract

본 발명은 PARP의 발현을 저해 또는 억제하는 신규한 히드록시벤즈아미드 유도체, 이의 제조방법 및 이를 유효성분으로 하는 암 예방 및 치료용 약학 조성물을 제공한다.The present invention provides a novel hydroxybenzamide derivative which inhibits or inhibits the expression of PARP, a process for producing the same, and a pharmaceutical composition for preventing and treating cancer comprising the same as an active ingredient.

Description

신규한 벤즈아미드계 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암 예방 또는 치료용 약학 조성물{Novel benzamide derivatives compounds, manufacturing method thereof, and phamaceutical composition for preventing and treating cancer containing the same}TECHNICAL FIELD [0001] The present invention relates to a novel benzamide derivative, a method for preparing the same, and a pharmaceutical composition for prevention or treatment of cancer containing the same as an active ingredient.

본 발명은 폴리(ADP-리보스) 폴리머라제(PARP) 억제 기능을 갖는 신규한 벤즈아미드계 유도체, 이의 제조방법 및 이를 유효성분으로 하는 암 예방 및 치료용 약학 조성물에 관한 것이다.The present invention relates to a novel benzamide derivative having a poly (ADP-ribose) polymerase (PARP) inhibitory function, a process for producing the same, and a pharmaceutical composition for preventing and treating cancer comprising the same.

폴리(ADP-리보스) 폴리머라제(PARP) 패밀리는 18개의 구성요소로 이루어져 있다. 이들 효소들은 세포핵에 위치하고 DNA 손상의 회복에 관여한다. DNA 단일 가닥 절단(SSBs:single-strand breaks)을 받는 BRCA1/2-결실 세포(defective cell)를 표적(target)하기 위해 PARP 억제제가 사용되어 왔다.The poly (ADP-ribose) polymerase (PARP) family consists of 18 components. These enzymes are located in the nucleus and are involved in the recovery of DNA damage. PARP inhibitors have been used to target BRCA1 / 2-defective cells subjected to single-strand breaks (SSBs).

BRCA1 또는 BRCA2 유전자는 손상된 이중 가닥 DNA의 상동 재조합-매개 회복의 원인이 된다. 그러나 BRCA1/2 유전자가 결실된 세포에 PARP를 사용하면 PAPR 억제제의 존재하에서 이들 DNA 단일 가닥 절단(SSBs)이 증가하고, 이러한 단일 가닥 절단(SSBs)은 복제 동안 회복할 수 없는 독성 이중 가닥 절단(DSBs:double-strand breaks)으로 전환되어 결국에는 손상된 상동-매개 회복계(impaired homologous-mediated repair system)에 의한 게놈 불안정성으로 인해 세포사를 유발한다.The BRCA1 or BRCA2 gene causes homologous recombination-mediated recovery of damaged double-stranded DNA. However, the use of PARP in cells lacking the BRCA1 / 2 gene resulted in an increase in these single strand breaks (SSBs) in the presence of PAPR inhibitors, and these single strand breaks (SSBs) are toxic double strand breaks DSBs: double-strand breaks) and eventually lead to cell death due to genomic instability caused by an impaired homologous-mediated repair system.

PARP-1 및 PARP-2 모두의 DNA-결합 도메인은 DNA 손상 부위에의 회복 효소의 이동을 촉진하는 두 개의 징크 핑커 모티프(zinc finger motif)를 함유한다. PARP-1 및 PARP-2는 니코틴아미드 아데닌 디뉴클레오티드(NAD+)로부터 핵수용체 단백질로의 ADP-리보스 단위체들의 이동에 촉매로 작용하여 ADP-리보스 중합체의 형성을 유발한다. 이는 염기 절제 회복(BER:base-excision repair)-매개 단일 가닥 절단 회복을 통해 DNA-손상 화학요법제 및 방사선에 의한 DNA 손상을 회복하는 핵심과정이다. 따라서, PARP-1(주요한 PARP 아형)의 돌연변이는 암 치료 이후에 종종 발생하는 내성에 기여한다. The DNA-binding domain of both PARP-1 and PARP-2 contains two zinc finger motifs that promote the transfer of the cleavage enzyme to the DNA damage site. PARP-1 and PARP-2 catalyze the migration of ADP-ribose units from the nicotinamide adenine dinucleotide (NAD +) to the nuclear receptor protein, leading to the formation of ADP-ribose polymers. This is a key process to restore DNA damage chemotherapy and radiation-induced DNA damage through base-excision repair (BER) -mediated single strand break repair. Thus, a mutation in PARP-1 (a major PARP subtype) contributes to the resistance that often arises after cancer treatment.

종양(oncology)에 대한 치료적 적용 외에도 광범위한 DNA 손상을 초래하는 PARP-1의 과활성화는 뇌졸중, 심근허혈, 관절염, 대장염 및 알레르기성 뇌척수염을 비롯한 몇몇의 다른 질병들과 관련이 있었다.In addition to therapeutic application to oncology, hyperactivation of PARP-1, which results in extensive DNA damage, has been associated with several other diseases including stroke, myocardial ischemia, arthritis, colitis, and allergic encephalomyelitis.

종래기술에서 DNA-메틸화제(DNA-methylation agents), 토포아이소머라제 독소(topoisomerase toxin) 또는 이온화 방사선제(ionizing radiation agent)와 같은 항암 약물의 치료 효능을 증가시키기 위하여 PARP1 억제제가 사용되는 다수의 전임상 연구가 있었다. In the prior art, a number of methods have been used to increase the therapeutic efficacy of anticancer drugs such as DNA-methylation agents, topoisomerase toxin, or ionizing radiation agents, in which PARP1 inhibitors are used There was preclinical research.

그 목적을 위해 다수의 PARP 억제제들이 이미 개발되어 오고 있으며 현재 몇몇의 PARP 억제제들이 임상시험에서 연구되고 있다. Numerous PARP inhibitors have been developed for that purpose and several PARP inhibitors are currently being studied in clinical trials.

최근에 벨리파립(ABT-888)은 진행성 비소세포 폐암(NSCLC)에 대한 카보플라틴 또는 파클리탁셀과 병용시 부작용으로 인해 최종 임상 단계 Ⅲ에서 효능을 나타내지 못했다. In recent years, valley lipid (ABT-888) failed to show efficacy in the final clinical phase III due to side effects when used in combination with carboplatin or paclitaxel for advanced non-small cell lung cancer (NSCLC).

루카파립(AG014699)은 BRCA-매개 난소암의 3차 선택 치료제(third-line treatment)로서 승인되었다. 올라파립(Olaparib)은 Ⅲ 단계의 임상시험에서, BRCA1 또는 BRCA2의 돌연변이에 의해 유발된 HER2-음성 전이성 유방암에 대하여 효과적인 것으로 확인되었다.Luca Furip (AG014699) was approved as a third-line treatment of BRCA-mediated ovarian cancer. Olaparib has been shown to be effective against HER2-negative metastatic breast tumors induced by BRCA1 or BRCA2 mutations in Phase III clinical trials.

따라서, 다수의 PARP 억제제들이 가능한 새로운 항암제로서 광범위하게 연구되어 왔고, 이들 중 많은 것들이 현재 임상시험 중에 있다. Thus, a large number of PARP inhibitors have been extensively studied as possible new anti-cancer agents, many of which are currently in clinical trials.

대한민국 공개특허공보 제10-2008-0007576호Korean Patent Publication No. 10-2008-0007576 대한민국 등록특허공보 제10-0820039호Korean Patent Publication No. 10-0820039 국제공개특허공보 WO02/22577호International Patent Publication No. WO 02/22577

본 발명은 폴리(ADP-리보스) 폴리머라제(PARP) 억제 기능을 갖는 신규한 벤즈아미드계 유도체, 이의 제조방법 및 이를 유효성분으로 하는 암 예방 및 치료용 약학 조성물을 제공하는데 그 목적이 있다.The present invention provides a novel benzamide derivative having a poly (ADP-ribose) polymerase (PARP) inhibitory function, a process for preparing the same, and a pharmaceutical composition for preventing and treating cancer comprising the same as an active ingredient.

본 발명은 PARP 발현을 저해 또는 억제하는 하기 화학식 1로 표시되는 벤즈아미드계 유도체 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a benzamide derivative or a pharmaceutically acceptable salt thereof represented by the following formula (I) for inhibiting or inhibiting the expression of PARP.

[화학식 1][Chemical Formula 1]

Figure 112017075260585-pat00001
Figure 112017075260585-pat00001

R1은

Figure 112017075260585-pat00002
이고, R2는
Figure 112017075260585-pat00003
,
Figure 112017075260585-pat00004
,
Figure 112017075260585-pat00005
,
Figure 112017075260585-pat00006
,
Figure 112017075260585-pat00007
,
Figure 112017075260585-pat00008
,
Figure 112017075260585-pat00009
,
Figure 112017075260585-pat00010
,
Figure 112017075260585-pat00011
,
Figure 112017075260585-pat00012
,
Figure 112017075260585-pat00013
,
Figure 112017075260585-pat00014
,
Figure 112017075260585-pat00015
,
Figure 112017075260585-pat00016
,
Figure 112017075260585-pat00017
,
Figure 112017075260585-pat00018
,
Figure 112017075260585-pat00019
,
Figure 112017075260585-pat00020
,
Figure 112017075260585-pat00021
,
Figure 112017075260585-pat00022
중 하나이거나,R1 is
Figure 112017075260585-pat00002
And R2 is
Figure 112017075260585-pat00003
,
Figure 112017075260585-pat00004
,
Figure 112017075260585-pat00005
,
Figure 112017075260585-pat00006
,
Figure 112017075260585-pat00007
,
Figure 112017075260585-pat00008
,
Figure 112017075260585-pat00009
,
Figure 112017075260585-pat00010
,
Figure 112017075260585-pat00011
,
Figure 112017075260585-pat00012
,
Figure 112017075260585-pat00013
,
Figure 112017075260585-pat00014
,
Figure 112017075260585-pat00015
,
Figure 112017075260585-pat00016
,
Figure 112017075260585-pat00017
,
Figure 112017075260585-pat00018
,
Figure 112017075260585-pat00019
,
Figure 112017075260585-pat00020
,
Figure 112017075260585-pat00021
,
Figure 112017075260585-pat00022
Lt; / RTI >

또는, R1은

Figure 112017075260585-pat00023
이고, R2는
Figure 112017075260585-pat00024
,
Figure 112017075260585-pat00025
,
Figure 112017075260585-pat00026
,
Figure 112017075260585-pat00027
,
Figure 112017075260585-pat00028
,
Figure 112017075260585-pat00029
,
Figure 112017075260585-pat00030
,
Figure 112017075260585-pat00031
중 하나이거나,Or R1 is
Figure 112017075260585-pat00023
And R2 is
Figure 112017075260585-pat00024
,
Figure 112017075260585-pat00025
,
Figure 112017075260585-pat00026
,
Figure 112017075260585-pat00027
,
Figure 112017075260585-pat00028
,
Figure 112017075260585-pat00029
,
Figure 112017075260585-pat00030
,
Figure 112017075260585-pat00031
Lt; / RTI >

또는, R1은

Figure 112017075260585-pat00032
이고, R2는
Figure 112017075260585-pat00033
,
Figure 112017075260585-pat00034
중 하나이다.Or R1 is
Figure 112017075260585-pat00032
And R2 is
Figure 112017075260585-pat00033
,
Figure 112017075260585-pat00034
Lt; / RTI >

또한, 본 발명은 상기한 벤즈아미드계 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 PARP 억제제를 제공한다.The present invention also provides a PARP inhibitor comprising the above-mentioned benzamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기한 PARP 억제제를 함유하는 방사선 치료 및 예방용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for treating and preventing radiation containing the above PARP inhibitor.

또한, 본 발명은 상기한 벤즈아미드계 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방 및 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing and treating cancer comprising the above-mentioned benzamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

그리고, 본 발명은 출발물질로서 하기 반응식 1의 하기 화학식 2로 표시되는 화합물로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계; 상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 및 상기 화학식 4로 표시되는 화합물로부터 하기 화학식 1로 표시되는 벤즈아미드계 유도체를 제조하는 단계; 를 포함하는 신규한 벤즈아미드계 유도체 또는 이의 약학적으로 허용 가능한 염의 제조방법을 제공한다.The present invention also provides a process for preparing a compound represented by the following general formula (3) from a compound represented by the following general formula (2) Preparing a compound represented by the following formula (4) from the compound represented by the formula (3); And a benzamide derivative represented by the following formula (1) from the compound represented by the formula (4); Or a pharmaceutically acceptable salt thereof. The present invention also provides a novel benzamide derivative or a pharmaceutically acceptable salt thereof.

[반응식 1][Reaction Scheme 1]

Figure 112017075260585-pat00035
Figure 112017075260585-pat00035

이때, R1은

Figure 112019002828453-pat00036
이고; R2는
Figure 112019002828453-pat00037
,
Figure 112019002828453-pat00038
,
Figure 112019002828453-pat00039
,
Figure 112019002828453-pat00040
,
Figure 112019002828453-pat00041
,
Figure 112019002828453-pat00042
,
Figure 112019002828453-pat00043
,
Figure 112019002828453-pat00044
,
Figure 112019002828453-pat00045
,
Figure 112019002828453-pat00046
,
Figure 112019002828453-pat00047
,
Figure 112019002828453-pat00048
,
Figure 112019002828453-pat00049
,
Figure 112019002828453-pat00050
,
Figure 112019002828453-pat00051
,
Figure 112019002828453-pat00052
,
Figure 112019002828453-pat00053
,
Figure 112019002828453-pat00054
,
Figure 112019002828453-pat00055
,
Figure 112019002828453-pat00056
중 하나이고; R은 R2와 동일하다.At this time,
Figure 112019002828453-pat00036
ego; R2 is
Figure 112019002828453-pat00037
,
Figure 112019002828453-pat00038
,
Figure 112019002828453-pat00039
,
Figure 112019002828453-pat00040
,
Figure 112019002828453-pat00041
,
Figure 112019002828453-pat00042
,
Figure 112019002828453-pat00043
,
Figure 112019002828453-pat00044
,
Figure 112019002828453-pat00045
,
Figure 112019002828453-pat00046
,
Figure 112019002828453-pat00047
,
Figure 112019002828453-pat00048
,
Figure 112019002828453-pat00049
,
Figure 112019002828453-pat00050
,
Figure 112019002828453-pat00051
,
Figure 112019002828453-pat00052
,
Figure 112019002828453-pat00053
,
Figure 112019002828453-pat00054
,
Figure 112019002828453-pat00055
,
Figure 112019002828453-pat00056
/ RTI > R is the same as R2.

나아가, 본 발명은 출발물질로서 하기 반응식 2의 하기 화학식 2로 표시되는 화합물로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계; 상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 상기 화학식 4로 표시되는 화합물로부터 하기 화학식 5로 표시되는 화합물을 제조하는 단계; 및 상기 화학식 5로 표시되는 화합물로부터 하기 화학식 1로 표시되는 벤즈아미드계 유도체를 제조하는 단계; 를 포함하는 벤즈아미드계 유도체 또는 이의 약학적으로 허용 가능한 염의 제조방법을 제공한다.Further, the present invention relates to a process for preparing a compound represented by the following general formula (3) from a compound represented by the following general formula (2) Preparing a compound represented by the following formula (4) from the compound represented by the formula (3); Preparing a compound represented by the following formula (5) from the compound represented by the formula (4); And preparing a benzamide derivative represented by the following formula (1) from the compound represented by the formula (5); Or a pharmaceutically acceptable salt thereof. The present invention also provides a method for producing a benzamide derivative or a pharmaceutically acceptable salt thereof.

[반응식 2][Reaction Scheme 2]

Figure 112017075260585-pat00057
Figure 112017075260585-pat00057

이때, R1은

Figure 112019002828453-pat00058
이고; R2는
Figure 112019002828453-pat00059
,
Figure 112019002828453-pat00060
,
Figure 112019002828453-pat00061
,
Figure 112019002828453-pat00062
,
Figure 112019002828453-pat00063
,
Figure 112019002828453-pat00064
,
Figure 112019002828453-pat00065
,
Figure 112019002828453-pat00066
중 하나이고; R은 R2와 동일하거나;At this time,
Figure 112019002828453-pat00058
ego; R2 is
Figure 112019002828453-pat00059
,
Figure 112019002828453-pat00060
,
Figure 112019002828453-pat00061
,
Figure 112019002828453-pat00062
,
Figure 112019002828453-pat00063
,
Figure 112019002828453-pat00064
,
Figure 112019002828453-pat00065
,
Figure 112019002828453-pat00066
/ RTI > R is the same as R2;

또는, R1은

Figure 112019002828453-pat00067
이고; R2는
Figure 112019002828453-pat00068
,
Figure 112019002828453-pat00069
중 하나이고; R은 R2와 동일하다.Or R1 is
Figure 112019002828453-pat00067
ego; R2 is
Figure 112019002828453-pat00068
,
Figure 112019002828453-pat00069
/ RTI > R is the same as R2.

본 발명에 따른 신규한 히드록시벤즈아미드 유도체는 폴리(ADP-리보스)폴리머라제(PARPs)의 억제에 효과가 있다.The novel hydroxybenzamide derivatives according to the present invention are effective in inhibiting poly (ADP-ribose) polymerases (PARPs).

본 발명에 따른 신규한 히드록시벤즈아미드 유도체 또는 이의 약학적으로 허용 가능한 염은 암세포의 전이이동을 억제하여 효과적으로 암을 예방, 치료할 수 있는 약학적 조성물을 제공할 수 있다.The novel hydroxybenzamide derivative or a pharmaceutically acceptable salt thereof according to the present invention can provide a pharmaceutical composition capable of effectively preventing and treating cancer by inhibiting metastasis of cancer cells.

본 발명에 따른 신규한 히드록시벤즈아미드 유도체는 방사선과 병행 처리시 암 세포의 사멸을 상승시키는 효과를 나타낸다.The novel hydroxybenzamide derivative according to the present invention has an effect of increasing cancer cell death upon concurrent treatment with radiation.

도 1은 본 발명에 따른 신규한 벤즈아미드계 유도체의 화합물 9c 및 28d가 인간 난소암 세포주인 SNU-251 및 인간 유방암 세포주인 MDA-MB-231에서 세포 자연사를 유도하는 실험예를 나타낸 막대그래프이고,
도 2는 본 발명에 따른 신규한 벤즈아미드 유도체의 화합물 28d와 방사선을 인간 난소암 세포주 SNU-251에 병용 처리시 아폽토시스 세포사멸이 상승함을 확인하는 실험예의 결과를 나타낸 막대그래프이며,
도 3a 및 도 3b는 본 발명에 따른 벤즈아미드 유도체의 38개 합성 화합물 중 PARP-1 억제제를 확인하기 위해 각각의 화합물의 PARP-1 효소 억제 활성을 10μM의 농도에서 측정한 결과를 기재한 도표이다. 1 is a bar graph showing experimental examples in which compounds 9c and 28d of the novel benzamide derivatives according to the present invention induce cellular apoptosis in human ovarian cancer cell line SNU-251 and human breast cancer cell line MDA-MB-231 ,
FIG. 2 is a bar graph showing the results of an experiment to confirm that apoptosis cell death is elevated when Compound 28d of the novel benzamide derivative according to the present invention and radiation are used in combination with human ovarian cancer cell line SNU-251,
FIGS. 3A and 3B are graphs showing the results of measuring the PARP-1 enzyme inhibitory activity of each compound at a concentration of 10 μM to identify PARP-1 inhibitor among the 38 synthetic compounds of the benzamide derivatives according to the present invention .

이하에서 본 발명을 구체적으로 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 PARP 발현을 저해 또는 억제하는 하기 화학식 1로 표시되는 신규한 벤즈아미드계 유도체, 이의 약학적으로 허용 가능한 염, 그리고 이를 유효성분으로 함유하는 암 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a novel benzamide derivative represented by the following general formula (1) for inhibiting or inhibiting the expression of PARP, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

[화학식 1][Chemical Formula 1]

Figure 112017075260585-pat00070
Figure 112017075260585-pat00070

화학식 1의 R1은

Figure 112017075260585-pat00071
이고, R2는
Figure 112017075260585-pat00072
,
Figure 112017075260585-pat00073
,
Figure 112017075260585-pat00074
,
Figure 112017075260585-pat00075
,
Figure 112017075260585-pat00076
,
Figure 112017075260585-pat00077
,
Figure 112017075260585-pat00078
,
Figure 112017075260585-pat00079
,
Figure 112017075260585-pat00080
,
Figure 112017075260585-pat00081
,
Figure 112017075260585-pat00082
,
Figure 112017075260585-pat00083
,
Figure 112017075260585-pat00084
,
Figure 112017075260585-pat00085
,
Figure 112017075260585-pat00086
,
Figure 112017075260585-pat00087
,
Figure 112017075260585-pat00088
,
Figure 112017075260585-pat00089
,
Figure 112017075260585-pat00090
,
Figure 112017075260585-pat00091
중 하나이거나,R < 1 >
Figure 112017075260585-pat00071
And R2 is
Figure 112017075260585-pat00072
,
Figure 112017075260585-pat00073
,
Figure 112017075260585-pat00074
,
Figure 112017075260585-pat00075
,
Figure 112017075260585-pat00076
,
Figure 112017075260585-pat00077
,
Figure 112017075260585-pat00078
,
Figure 112017075260585-pat00079
,
Figure 112017075260585-pat00080
,
Figure 112017075260585-pat00081
,
Figure 112017075260585-pat00082
,
Figure 112017075260585-pat00083
,
Figure 112017075260585-pat00084
,
Figure 112017075260585-pat00085
,
Figure 112017075260585-pat00086
,
Figure 112017075260585-pat00087
,
Figure 112017075260585-pat00088
,
Figure 112017075260585-pat00089
,
Figure 112017075260585-pat00090
,
Figure 112017075260585-pat00091
Lt; / RTI >

또는, R1은

Figure 112017075260585-pat00092
이고, R2는
Figure 112017075260585-pat00093
,
Figure 112017075260585-pat00094
,
Figure 112017075260585-pat00095
,
Figure 112017075260585-pat00096
,
Figure 112017075260585-pat00097
,
Figure 112017075260585-pat00098
,
Figure 112017075260585-pat00099
,
Figure 112017075260585-pat00100
중 하나이거나,Or R1 is
Figure 112017075260585-pat00092
And R2 is
Figure 112017075260585-pat00093
,
Figure 112017075260585-pat00094
,
Figure 112017075260585-pat00095
,
Figure 112017075260585-pat00096
,
Figure 112017075260585-pat00097
,
Figure 112017075260585-pat00098
,
Figure 112017075260585-pat00099
,
Figure 112017075260585-pat00100
Lt; / RTI >

또는, R1은

Figure 112017075260585-pat00101
이고, R2는
Figure 112017075260585-pat00102
,
Figure 112017075260585-pat00103
중 하나이다.Or R1 is
Figure 112017075260585-pat00101
And R2 is
Figure 112017075260585-pat00102
,
Figure 112017075260585-pat00103
Lt; / RTI >

이때, 바람직하게는 R1은

Figure 112017075260585-pat00104
, R2는
Figure 112017075260585-pat00105
이거나, 또는 R1은
Figure 112017075260585-pat00106
, R2는
Figure 112017075260585-pat00107
이다.Preferably, R < 1 >
Figure 112017075260585-pat00104
, R2 is
Figure 112017075260585-pat00105
Or R1 is
Figure 112017075260585-pat00106
, R2 is
Figure 112017075260585-pat00107
to be.

이러한 R1과 R2의 구체적인 구조(structure)는 후술하는 도 3a 및 도 3b에 신규한 벤즈아미드 유도체들에 따라 상세하게 도시되어 있다.The specific structures of these R1 and R2 are shown in detail in accordance with the novel benzamide derivatives in FIGS. 3A and 3B described later.

그리고, 본 발명에 따른 상기 벤즈아미드계 유도체는 바이페닐 벤즈아미드(biphenyl benzamide), 시클로알킬 벤즈아미드(cycloalkyl benzamide) 또는 히드록시벤즈아미드(hydroxybenzamide) 유도체 중 어느 하나를 포함한다.The benzamide derivative according to the present invention may include any one of biphenyl benzamide, cycloalkyl benzamide, and hydroxybenzamide derivatives.

또한, 본 발명은 상기한 벤즈아미드계 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 PARP 억제제 및 암 예방 및 치료용 약학 조성물을 제공한다. In addition, the present invention provides a PARP inhibitor and a pharmaceutical composition for preventing and treating cancer, which comprises the above-mentioned benzamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

그리고, 본 발명은 상기학 PARP 억제제를 함유하는 방사선 치료 및 예방용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for treating and preventing radiation containing the PARP inhibitor.

이를 위하여 본 발명자들은 PARP-1 억제제로서 종래에 보고된 벤족사졸(benzoxazole) 및 벤즈아미드(bezamide)의 일부(moiety)에 근거하여 복수의 새로운 벤즈아미드 유도체를 합성했다. 구체적으로 38개의 새로운 바이페닐(biphenyl) 또는 시클로알킬 벤즈아미드(cycloalkyl bezamide) 및 히드록시벤즈아미드(hydroxybenzamide) 유도체들을 합성했다. 나아가, 이들 유도체의 항암제로서의 가능성을 평가하기 위해 시험관 내에서 PARP-1 억제 분석법을 통해 이들 유도체들의 활성을 시험하였다.To this end, the present inventors have synthesized a plurality of novel benzamide derivatives based on the previously reported benzoxazole and bezamide moieties as PARP-1 inhibitors. Specifically, 38 new biphenyl or cycloalkyl bezamide and hydroxybenzamide derivatives were synthesized. Furthermore, the activity of these derivatives was tested in vitro by means of PARP-1 inhibition assay to evaluate the potential of these derivatives as anticancer agents.

이 시험에서 히드록사메이트기(hydroxamate group)를 함유한 화합물(28d)는 유의한 억제능력(3.2μM의 IC50 값)을 나타냈고, 나중에 DMSO 처리 세포주와 비교하여 SNU-251 및 MDA-MB-231 세포주의 각각 2.8배 및 4.2배의 감소를 나타냈다.In this test, the compound (28d) containing a hydroxamate group showed significant inhibitory ability (IC 50 value of 3.2 μM), and SNU-251 and MDA-MB- 231 cell lines decreased 2.8 and 4.2 fold, respectively.

이러한 결과로부터, 본 발명자들은 기존의 PARP 억제제 중에서 핵심 약물특이분자단(pharmacophore)으로 알려진 벤즈아미드의 일부(moiety)가 아닌 새로운 히드록시벤즈아미드 유도체가 유의한 PARP-1 억제 활성을 가짐을 확인했다.From these results, the present inventors confirmed that a novel hydroxybenzamide derivative, which is not a part of benzamide known as a key drug-specific molecular pharmacophore (PARP inhibitor), has a significant PARP-1 inhibitory activity .

상기한 바와 같이 본 발명은 암 예방 및/또는 치료용 약학 조성물을 제공한다. 이러한 약학 조성물은 본 발명의 신규한 벤즈아미드 유도체, 이의 약학적으로 허용 가능한 염 또는 이의 약학적으로 허용 가능한 담체를 유효성분으로 포함할 수 있다.As described above, the present invention provides a pharmaceutical composition for preventing and / or treating cancer. Such a pharmaceutical composition may contain, as an active ingredient, a novel benzamide derivative of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable carrier thereof.

본 발명에서 사용하는 용어 "조성물"은 본 발명에서 사용된 바와 같이, 특정 성분들(및 지정된다면, 특정 양들)을 포함하는 산출물뿐만 아니라, 특정 양으로 특정 성분들의 조합으로부터 직접적 또는 간접적으로 얻어지는 어떠한 산출물을 포함하도록 의도된다. "약학적으로 허용 가능한"이란 담체 또는 부형제가 제제의 다른 성분들에 적합하고, 이들의 수용체에 유해하지 않다는 것을 의미한다.As used herein, the term " composition " as used herein is intended to encompass a range of products, including, but not limited to, those containing specific ingredients (and, if specified, specific amounts) It is intended to include artifacts. &Quot; Pharmaceutically acceptable " means that the carrier or excipient is compatible with the other ingredients of the formulation and is not deleterious to their receptor.

약학 조성물을 제조함에 있어서, 담체는 제조하고자 하는 제형에 따라 선택되고, 이를 활성성분인 벤즈아미드 유도체와 적절한 비율로 혼합함으로써 제형화할 수 있다.In preparing the pharmaceutical composition, the carrier may be selected according to the formulation to be prepared, and may be formulated by mixing the active ingredient with the benzamide derivative in an appropriate ratio.

본 발명의 약학 조성물은 치료적 처치를 위해 비경구적, 국소적, 경구적 또는 국부적으로 투여될 수 있다. 그 용액은 사용을 위해 포장될 수 있고 무균조건에서 여과되고 냉동 건조될 수 있으며, 상기 냉동 건조된 제조물은 투여 전에 멸균된 용액과 결합된다.The pharmaceutical compositions of the present invention may be administered parenterally, topically, orally or locally for therapeutic treatment. The solution may be packaged for use, filtered under aseptic conditions and lyophilized, and the lyophilized product is combined with the sterile solution prior to administration.

경구 조성물은 일반적으로 불활성 희석제 또는 식용 운반체를 포함한다. 그들은 젤라틴 캡슐에 봉해 넣어지거나 또는 정제에 압축되어 있다. 경구 치료적 투여의 목적을 위해, 상기 활성 화합물은 부형제와 함께 포함되어 정제, 트로키 또는 캡슐의 형태로 사용될 수 있다.Oral compositions generally include an inert diluent or an edible carrier. They are encapsulated in gelatin capsules or compressed into tablets. For purposes of oral therapeutic administration, the active compounds may be included in association with excipients and used in the form of tablets, troches, or capsules.

본 발명의 약학 조성물의 치료 유효량은 치료를 요하는 병에 대한 공지된 생체내(in vivo) 및 시험관내(in vitro) 모델 시스템에서 해당 화합물을 실험함으로써 경험적으로 결정될 수 있다. 상기 치료 유효량(therapeutically effective amount)이란, 치료를 요하는 병의 증상을 경감 또는 줄이거나 예방을 요하는 병의 임상학적 마커 또는 증상의 개시를 줄이거나 지연시키는데 유효한 활성 성분의 양을 의미한다.A therapeutically effective amount of a pharmaceutical composition of the present invention can be determined empirically by testing the compound in a known in vivo and in vitro model system for a disease requiring treatment. The therapeutically effective amount means the amount of active ingredient effective to reduce or delay the onset of a clinical marker or symptom of a disease that alleviates, reduces or prevents symptoms of the disease requiring treatment.

본 발명의 신규한 벤즈아미드계 유도체는 하기 반응식 1, 2 또는 3 중 어느 하나에 의거한 반응을 통해 상기 화학식 1로 표시되는 벤즈아미드계 유도체를 제조할 수 있다.The novel benzamide derivatives of the present invention can be prepared by the reaction according to any one of the following Reaction Schemes 1, 2, or 3 to produce the benzamide derivatives represented by Formula 1 below.

[반응식 1][Reaction Scheme 1]

Figure 112017075260585-pat00108
Figure 112017075260585-pat00108

이때, R1은

Figure 112019002828453-pat00109
이고; R2는
Figure 112019002828453-pat00110
,
Figure 112019002828453-pat00111
,
Figure 112019002828453-pat00112
,
Figure 112019002828453-pat00113
,
Figure 112019002828453-pat00114
,
Figure 112019002828453-pat00115
,
Figure 112019002828453-pat00116
,
Figure 112019002828453-pat00117
,
Figure 112019002828453-pat00118
,
Figure 112019002828453-pat00119
,
Figure 112019002828453-pat00120
,
Figure 112019002828453-pat00121
,
Figure 112019002828453-pat00122
,
Figure 112019002828453-pat00123
,
Figure 112019002828453-pat00124
,
Figure 112019002828453-pat00125
,
Figure 112019002828453-pat00126
,
Figure 112019002828453-pat00127
,
Figure 112019002828453-pat00128
,
Figure 112019002828453-pat00129
중 하나이고; R은 R2와 동일하다.At this time,
Figure 112019002828453-pat00109
ego; R2 is
Figure 112019002828453-pat00110
,
Figure 112019002828453-pat00111
,
Figure 112019002828453-pat00112
,
Figure 112019002828453-pat00113
,
Figure 112019002828453-pat00114
,
Figure 112019002828453-pat00115
,
Figure 112019002828453-pat00116
,
Figure 112019002828453-pat00117
,
Figure 112019002828453-pat00118
,
Figure 112019002828453-pat00119
,
Figure 112019002828453-pat00120
,
Figure 112019002828453-pat00121
,
Figure 112019002828453-pat00122
,
Figure 112019002828453-pat00123
,
Figure 112019002828453-pat00124
,
Figure 112019002828453-pat00125
,
Figure 112019002828453-pat00126
,
Figure 112019002828453-pat00127
,
Figure 112019002828453-pat00128
,
Figure 112019002828453-pat00129
/ RTI > R is the same as R2.

[반응식 2][Reaction Scheme 2]

Figure 112017075260585-pat00130
Figure 112017075260585-pat00130

이때, R1은

Figure 112019002828453-pat00131
이고; R2는
Figure 112019002828453-pat00132
,
Figure 112019002828453-pat00133
,
Figure 112019002828453-pat00134
,
Figure 112019002828453-pat00135
,
Figure 112019002828453-pat00136
,
Figure 112019002828453-pat00137
,
Figure 112019002828453-pat00138
,
Figure 112019002828453-pat00139
중 하나이고; R은 R2와 동일하다.At this time,
Figure 112019002828453-pat00131
ego; R2 is
Figure 112019002828453-pat00132
,
Figure 112019002828453-pat00133
,
Figure 112019002828453-pat00134
,
Figure 112019002828453-pat00135
,
Figure 112019002828453-pat00136
,
Figure 112019002828453-pat00137
,
Figure 112019002828453-pat00138
,
Figure 112019002828453-pat00139
/ RTI > R is the same as R2.

[반응식 3][Reaction Scheme 3]

Figure 112017075260585-pat00140
Figure 112017075260585-pat00140

이때, R1은

Figure 112019002828453-pat00141
이고; R2는
Figure 112019002828453-pat00142
,
Figure 112019002828453-pat00143
중 하나이고; R은 R2와 동일하다.At this time,
Figure 112019002828453-pat00141
ego; R2 is
Figure 112019002828453-pat00142
,
Figure 112019002828453-pat00143
/ RTI > R is the same as R2.

상기 반응식 1 내지 3을 구체적으로 설명하면, 상기 반응식 1에서는 출발물질로서 상기 화학식 2로 표시되는 화합물로부터 상기 화학식 3(1a-9a)으로 표시되는 화합물을 제조하는 단계; 상기 화학식 3으로 표시되는 화합물로부터 상기 화학식 4(1b-9b,10b-38b)로 표시되는 화합물을 제조하는 단계; 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 1(1c-9c,10c-27c)로 표시되는 벤즈아미드계 유도체를 제조하는 단계를 포함하는 반응공정을 수행하여 본 발명의 신규한 벤즈아미드계 유도체를 제조할 수 있다.In the above Reaction Scheme 1, the compound of Formula 3 (1a-9a) is prepared from the compound of Formula 2 as a starting material. Preparing a compound represented by the formula 4 (1b-9b, 10b-38b) from the compound represented by the formula 3; (1c-9c, 10c-27c) from the compound represented by the formula (4) to produce a novel benzamide derivative of the present invention by performing a reaction process comprising the step of preparing the benzamide derivative represented by the formula can do.

또한, 상기 반응식 2에서는 출발물질로서 상기 화학식 2로 표시되는 화합물로부터 상기 화학식 3(1a-9a)으로 표시되는 화합물을 제조하는 단계; 상기 화학식 3으로 표시되는 화합물로부터 상기 화학식 4(1b-9b,10b-38b)로 표시되는 화합물을 제조하는 단계; 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 5(28c-37c)로 표시되는 화합물을 제조하는 단계; 상기 화학식 5로 표시되는 화합물로부터 상기 화학식 1(28d-35d)로 표시되는 벤즈아미드계 유도체를 제조하는 단계를 포함하는 반응공정을 수행하여 본 발명의 신규한 벤즈아미드계 유도체를 제조할 수 있다.In the above Reaction Scheme 2, the compound represented by Formula 3 (1a-9a) is prepared from the compound represented by Formula 2 as a starting material; Preparing a compound represented by the formula 4 (1b-9b, 10b-38b) from the compound represented by the formula 3; Preparing a compound represented by the formula 5 (28c-37c) from the compound represented by the formula 4; A novel benzamide derivative of the present invention can be prepared by carrying out a reaction step comprising the step of preparing a benzamide derivative represented by the formula (1) (28d-35d) from the compound represented by the formula (5).

또한, 상기 반응식 3에서는 출발물질로서 상기 화학식 2로 표시되는 화합물로부터 상기 화학식 3(1a-9a)으로 표시되는 화합물을 제조하는 단계; 상기 화학식 3으로 표시되는 화합물로부터 상기 화학식 4(1b-9b,10b-38b)로 표시되는 화합물을 제조하는 단계; 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 5(28c-37c)로 표시되는 화합물을 제조하는 단계; 상기 화학식 5로 표시되는 화합물로부터 상기 화학식 1(36d-37d)로 표시되는 벤즈아미드계 유도체를 제조하는 단계를 포함하는 반응공정을 수행하여 본 발명의 신규한 벤즈아미드계 유도체를 제조할 수 있다.In the above Reaction Scheme 3, the compound represented by Formula 3 (1a-9a) is prepared from the compound represented by Formula 2 as a starting material. Preparing a compound represented by the formula 4 (1b-9b, 10b-38b) from the compound represented by the formula 3; Preparing a compound represented by the formula 5 (28c-37c) from the compound represented by the formula 4; The novel benzamide derivative of the present invention can be prepared by carrying out a reaction process comprising the step of preparing a benzamide derivative represented by the above formula (1) (36d-37d) from the compound represented by the above formula (5).

상기 반응식 2와 반응식 3에서는 모두 화학식 5로 표시되는 화합물로부터 화학식 1로 표시되는 벤즈아미드계 유도체를 제조하는 것을 기재되어 있으나, 반응식 2와 반응식 3에서 제조되는 화학식 1의 화합물은 서로 다르다. 즉, 반응식 2에서는 화학식 1(28d-35d)로 표시되는 벤즈아미드계 유도체를 제조하고, 반응식 3에서는 화학식 1(36d-37d)로 표시되는 벤즈아미드계 유도체를 제조한다. 이는 이들 반응식 2와 3에서 화학식 5에서 화학식 1의 화합물을 제조하는 방식이 다르기 때문이다.In the above reaction schemes 2 and 3, it is described that the benzamide derivative represented by the general formula (1) is produced from the compound represented by the general formula (5), but the compounds of the general formula (1) prepared in the reaction formula (2) and the reaction formula (3) are different. That is, in Scheme 2, a benzamide derivative represented by Chemical Formula 1 (28d-35d) is prepared, and in Scheme 3, a benzamide derivative represented by Chemical Formula 1 (36d-37d) is prepared. This is because the method of preparing the compound of Chemical Formula 1 in Chemical Formula 5 is different in these Reaction Formulas 2 and 3.

그리고, 반응식 1 내지 3에 개시된 화학식 1에서 R2에 연결된 벤젠의 구조식과 상기 복수의 R2 각각에 포함된 벤젠의 구조식은 동일한 것이다. 이는 반응식 1 내지 3을 설명함에 있어 R2가 벤젠에 연결된다는 것을 표시하기 위한 것이다. 하지만 정확하게는 하기 화학식 1과 도 3a 및 3b에 각각 표시된 R1과 R2의 구조식(structure)이 매핑되는 것이다.The structural formulas of benzene connected to R2 in the formula (1) shown in Reaction Schemes 1 to 3 and the structural formulas of benzene contained in each of the plurality of R2 are the same. This is to illustrate that R2 is connected to benzene in describing Schemes 1-3. However, to be precise, the structure of R1 and R2 shown in the following Chemical Formula 1 and 3A and 3B is mapped.

[화학식 1][Chemical Formula 1]

Figure 112017075260585-pat00144
Figure 112017075260585-pat00144

하기에서 반응식 1 내지 3에서 화합물 제조를 구체적인 예를 설명한다.Specific examples of the preparation of the compounds in Reaction Schemes 1 to 3 are described below.

먼저, 반응식 1의 경우 상기 화학식 2로 표시되는 화합물로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계(ⅰ)는, Pd(dppf)Cl2-CH2Cl2 및 2M K2CO3을 디옥산에 용해된 메틸 4-브로모벤조에이트의 용액에 첨가하여 교반한 혼합물을 H2O로 희석하고 에틸아세테이트로 추출하여 메틸-4-카르복시레이트를 합성할 수 있다.In step (i), Pd (dppf) Cl 2 -CH 2 Cl 2 and 2M K 2 CO 3 are reacted with dioxane To the solution of methyl 4-bromobenzoate dissolved in dichloromethane, the mixture is diluted with H 2 O and extracted with ethyl acetate to synthesize methyl-4-carboxylate.

또한, 상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계(ⅱ)는, H2O 및 THF가 용해된 메틸-4-카르복시레이트의 용액을 NaOH으로 처리하여 교반한 혼합물을 H2O 및 CH2Cl2로 희석하고 1 N HCl로 산성화하고 CH2Cl2로 추출하여 [1,1'-비페닐]-4-카르복시산을 합성할 수 있다.Further, the step (ii) for producing a compound represented by the following general formula (4) from the compound represented by the general formula (3) can be carried out by mixing a solution obtained by treating a solution of methyl 4-carboxylate in which H 2 O and THF are dissolved with NaOH Is diluted with H 2 O and CH 2 Cl 2 , acidified with 1 N HCl and extracted with CH 2 Cl 2 to give [1,1'-biphenyl] -4-carboxylic acid.

또한, 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 1로 표시되는 화합물을 제조하는 단계(ⅲ)는, EDC 및 HOBT을 CH2Cl2에 용해된 4-카르복시산(1b-41b)을 3-아미노벤즈아미드의 용액에 첨가하여 교반한 혼합물을 H2O로 희석하고 CH2Cl2로 추출하여 상기 화학식 1로 표시되는 벤즈아미드계 유도체를 제조할 수 있다.The step (iii) of producing the compound represented by the formula (1) from the compound represented by the formula (4) can be carried out by reacting the 4-carboxylic acid (1b-41b) dissolved in CH 2 Cl 2 with EDC and HOBT, Amide, the mixture is stirred with H 2 O and extracted with CH 2 Cl 2 to prepare the benzamide derivative represented by the above formula (1).

반응식 2의 경우, i,ⅱ 단계는 반응식 1과 동일하고, 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 5로 표시되는 화합물을 제조하는 단계(ⅳ)는, EDC 및 HOBT을 CH2Cl2에 용해된 4-카르복시산을 메틸 3-아미노벤즈아미드의 용액에 첨가하여 교반한 혼합물을 H2O로 희석하고 CH2Cl2로 추출하여 상기 화학식 5로 표시되는 화합물을 제조할 수 있다.In the case of Scheme 2, Steps i and ii are the same as in Scheme 1, and Step (iv) of preparing the compound represented by Formula 5 from the compound represented by Formula 4 dissolves EDC and HOBT in CH 2 Cl 2 Carboxylic acid is added to a solution of methyl 3-aminobenzamide, and the resulting mixture is diluted with H 2 O and extracted with CH 2 Cl 2 to give the compound represented by Formula 5.

그리고, 상기 화학식 5로 표시되는 화합물로부터 상기 화학식 1로 표시되는 화합물을 제조하는 단계(ⅴ)는, 메틸 3-벤즈아미도벤조에이트를 CH2Cl2 및 메탄올의 혼합용액에 용해하여 냉각하고 히드록실아민을 첨가한 후 NaOH를 첨가한 용액을 실온에서 교반하여 상기 화학식 1로 표시되는 벤즈아미드계 유도체를 제조할 수 있다.The step (v) for preparing the compound represented by the formula (1) from the compound represented by the formula (5) is carried out by dissolving the methyl 3-benzamidobenzoate in a mixed solution of CH 2 Cl 2 and methanol, The benzamide derivative represented by the above formula (1) can be prepared by stirring a solution containing a hydroxylamine and adding NaOH at room temperature.

반응식 3의 경우, i,ⅱ,ⅲ,ⅳ, 단계는 반응식 2와 동일하고, 상기 화학식 5로 표시되는 화합물로부터 상기 화학식 1로 표시되는 화합물을 제조하는 단계(ⅵ)는, H2O 및 THF가 용해된 메틸-4-카르복시레이트의 용액을 NaOH으로 처리하여 교반함으로써 상기 화학식 1로 표시되는 벤즈아미드계 유도체를 제조할 수 있다.In the case of Scheme 3, steps i, ii, iii and iv are the same as those in scheme 2, and step (vi) of preparing the compound represented by formula 1 from the compound represented by formula 5 is carried out using H 2 O and THF Can be prepared by treating a solution of dissolved methyl-4-carboxylate with NaOH and stirring the mixture.

[[ 실험예Experimental Example ]]

[실험준비][Preparation of experiment]

화학적 시약은 상업적으로 입수했고 추가의 정제 없이 사용했다. 이들 시약의 녹는점은 Kruess M5000 녹는점 측정장치로 측정했고 보정하지는 않았다. 또한, 양자 NMR 스펙트럼은 500MHz에서 Avance-500(Bruker)을 이용하여 기록했다.Chemical reagents were obtained commercially and used without further purification. The melting points of these reagents were measured with a Kruess M5000 melting point meter and were not calibrated. The quantum NMR spectrum was also recorded using an Avance-500 (Bruker) at 500 MHz.

화학적 이동은 표준으로서 Me4Si를 이용하여 ppm 단위로 보고된다. 고해상도 질량 분광분석(HRMS) 스펙트럼은 JMS-700(Jeol사, 일본) High Resolution Tandem Mass Spectrometer을 이용하여 고속원자폭격법(FAB)을 통해 얻었다. Chemical shifts are reported in ppm using Me 4 Si as standard. High-resolution mass spectrometry (HRMS) spectra were obtained by fast atom bombardment (FAB) using JMS-700 (Jeol, Japan) High Resolution Tandem Mass Spectrometer.

모든 반응의 생성물들은 실리카겔 60(Merck EM9385, 230-400 매시)를 이용한 플래시 칼럼 크로마토그래피에 의해 정제했고, 미리 코팅된 실리카겔 60 F254(매시)(E. Merck사, Mumbai, 인도)상에서 박층크로마토그래피(TLC)에 의해 확인했다.The products of all reactions were purified by flash column chromatography on silica gel 60 (Merck EM9385, 230-400 mesh) and purified by thin layer chromatography on precoated silica gel 60 F254 (Mash) (E. Merck, Mumbai, India) (TLC).

스팟(spot)은 PMA 또는 Hanessian 용액으로 염색하고 UV 광(254 nm)하에서 시각화했다.The spot was stained with PMA or Hanessian solution and visualized under UV light (254 nm).

상기 반응식 1 및 2에 따라 신규한 벤즈아미드 유도체를 제조하되, 상기 화학식 1에서 R1과 R2를 각각 달리하는 벤즈아미드계 유도체를 하기와 같이 각각 제조하였으며, 이들의 특징은 제조 실험예를 설명한다.A novel benzamide derivative is prepared according to the above Reaction Schemes 1 and 2, wherein benzamide derivatives different from R1 and R2 in the above Formula 1 are prepared as follows, respectively.

메틸methyl [1,1'-비페닐]-4-[1,1'-biphenyl] -4- 카르복시레이트Carboxylate (1a 내지 9a) 합성 과정(1a to 9a) synthesis process

Pd(dppf)Cl2-CH2Cl2(0.05 당량) 및 2M K2CO3(2.0 당량)를 디옥산에 용해된 메틸 4-브로모벤조에이트(1.0 당량)의 용액에 첨가하고, 80℃에서 4시간 동안 교반했다. 이어서, 그 혼합물을 H2O로 희석하고 에틸 아세테이트로 복수 회 추출했다. 이처럼 합쳐진 유기층들을 무수(anhydrous) MgSO4로 건조한 후 여과 및 진공 농축했다. 그 잔류물을 용리액으로 EtOAc/헥산을 이용하여 실리카겔 상에서 플래시 칼럼 그로마토그래피에 의해 정제하여 생성물을 확인했다.Pd (dppf) Cl 2 -CH 2 Cl 2 (0.05 eq.) And 2M K 2 CO 3 (2.0 eq.) Were added to a solution of methyl 4-bromobenzoate (1.0 eq.) Dissolved in dioxane, Lt; / RTI > for 4 hours. The mixture was then diluted with H 2 O and extracted multiple times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by flash column grommography on silica gel using EtOAc / hexanes as eluent to confirm the product.

카르복시산(1b 내지 9b, 10b 내지 41b, 36d 내지 37d) 합성 과정Synthesis of carboxylic acid (1b to 9b, 10b to 41b, 36d to 37d)

H2O 및 THF가 1:2의 비율로 용해된 1a-9a(1.0 당량)의 용액을 수산화나트륨(NaOH)(3.0 당량)으로 처리하고 실온에서 4시간 동안 교반했다. 그 혼합물을 H2O 및 CH2Cl2로 희석하고 1 N HCl로 산성화하고 CH2Cl2로 복수 회 추출했다. 합쳐진 유기층들을 물과 염수로 세척하고 MgSO4로 건조한 후 진공농축했다. 4-카르복시산(1b-9b,36d-37d)을 디에틸에테르 및 n-헥산으로부터 결정화했다. 다른 4-카르복시산(10b-41b)은 구입하여 사용했다.A solution of 1a-9a (1.0 eq.) In which H 2 O and THF were dissolved in a ratio of 1: 2 was treated with sodium hydroxide (NaOH) (3.0 eq.) And stirred at room temperature for 4 hours. The mixture was diluted with H 2 O and CH 2 Cl 2 , acidified with 1 N HCl and extracted multiple times with CH 2 Cl 2 . The combined organic layer was washed with water and brine and was concentrated in vacuo and dried by MgSO 4. 4-carboxylic acid (1b-9b, 36d-37d) was crystallized from diethyl ether and n-hexane. Other 4-carboxylic acid (10b-41b) was purchased and used.

커플링(1c 내지 27c, 28c 내지 37c) 합성 과정Coupling (1c to 27c, 28c to 37c) synthesis process

EDC(1.5 당량) 및 HOBT(1.5 당량)을 CH2Cl2에 용해된 4-카르복시산(1b-41b)(1.0 당량), 3-아미노벤즈아미드 또는 메틸 3-아미노벤조에이트(1.5 당량)의 용액에 첨가하고, 그 혼합물을 실온에서 밤새 교반했다. EDC (1.5 eq.) And HOBT (1.5 eq.) Were added to a solution of 4-carboxylic acid (1b-41b) (1.0 eq.) Dissolved in CH 2 Cl 2 , 3-aminobenzamide or methyl 3-aminobenzoate And the mixture was stirred at room temperature overnight.

그 반응 혼합물을 H2O로 희석하고 CH2Cl2로 복수 회 추출했다. 합쳐진 유기층들을 MgSO4로 건조 및 여과하고 진공 농축했다. 얻어지는 진류물을 실리카겔 칼럼 크로마토그래피에 의해 정제했다.The reaction mixture was diluted with H 2 O and extracted multiple times with CH 2 Cl 2 . Drying and filtration the combined organic layer with MgSO 4, and concentrated in vacuo. The obtained seaweed was purified by silica gel column chromatography.

히드록삼산 유도체(28d 내지 35d) 합성 과정Synthesis of hydroxamic acid derivatives (28d to 35d)

메틸 3-벤즈아미도벤조에이트(28c 내지 37c)(1.0 당량)를 CH2Cl2 및 메탄올(1:2)에 용해시켰다. 얻어지는 용액을 0℃로 냉각하고, 히드록실아민(물에서 50 중량%, 30 당량)을 첨가한 다음, 수산화나트륨(10 당량)을 첨가했다. Methyl 3-benzamidobenzoate (28c to 37c) (1.0 eq.) Was dissolved in CH 2 Cl 2 and methanol (1: 2). The resulting solution was cooled to 0 < 0 > C, hydroxylamine (50 wt% in water, 30 eq.) Was added followed by sodium hydroxide (10 eq).

그 용액을 실온으로 승온하고 12시간 동안 교반했다. 다음에 감압 하에 용매를 제거하고, 얻어진 고체를 물에 용해시켰다. 그 pH를 1N HCl 수용액을 이용하여 pH 7로 조절했다. 얻어지는 침전물을 여과하고 감압하에 건조하여 히드록삼산 유도체들을 고체상태로 얻었다.The solution was warmed to room temperature and stirred for 12 hours. Then, the solvent was removed under reduced pressure, and the obtained solid was dissolved in water. The pH was adjusted to pH 7 using a 1N HCl aqueous solution. The resulting precipitate was filtered and dried under reduced pressure to obtain the hydroxamic acid derivatives in a solid state.

이와 같은 반응공정으로 얻어진 본 발명의 신규한 벤즈아미드계 유도체들의 특징은 다음과 같다.The novel benzamide derivatives of the present invention obtained by such a reaction process are characterized as follows.

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-)-4- 시클로펜틸벤즈아미드Cyclopentylbenzamide (1c) (1c)

백색 고체, 녹는점 = 284-286℃, 1H NMR (500 MHz, DMSO-d 6) δ 10.44 (s, 1H) 8.23 (s, 1H) 7.74-7.98 (m, 3H) 7.61 (d, J = 7.40 Hz, 2H) 7.42 (t, J = 7.79 Hz, 2H) 7.36 (br s, 2H) 2.51-2.55 (m, 1H) 1.68-1.93 (m, 4H) 1.37 - 1.56 (m, 4H); MS (FAB) m/z 308 (MH+)White solid, melting point = 284-286 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 10.44 (s, 1H) 8.23 (s, 1H) 7.74-7.98 (m, 3H) 7.61 (d, J = 7.40 Hz, 2H) 7.42 (t, J = 7.79 Hz, 2H) 7.36 (brs, 2H) 2.51-2.55 (m, 1H) 1.68-1.93 (m, 4H) 1.37-1.56 (m, 4H); MS (FAB) m / z 308 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-)-4- 시클로펜테닐벤즈아미드Cyclopentenyl benzamide (2c) (2c)

황색 고체, 녹는점 = 265-267℃, 1H NMR (300 MHz, DMSO-d 6 ) δ 7.90-7.99 (m, 3H), 7.57-7.68 (s, 2H), 7.44-7.49 (m, 1H), 7.05 (d, J = 8.80 Hz, 2H), 5.96 (q, J = 7.75 Hz, 1H), 2.48-2.49 (m, 4H), 1.22 (m, 2H); MS (FAB) m/z 307 (MH+)Yellow solid, melting point = 265-267 ℃, 1 H NMR ( 300 MHz, DMSO- d 6) δ 7.90-7.99 (m, 3H), 7.57-7.68 (s, 2H), 7.44-7.49 (m, 1H) , 7.05 (d, J = 8.80 Hz, 2H), 5.96 (q, J = 7.75 Hz, 1H), 2.48-2.49 (m, 4H), 1.22 (m, 2H); MS (FAB) m / z 307 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-(티오펜-3-일)벤즈아미드 (3c)) -4- (thiophen-3-yl) benzamide (3c)

백색 고체, 녹는점 = 290-292℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.07 (d, J = 8.41 Hz, 2H), 7.67 (d, J = 8.41 Hz, 2H), 7.39-7.49 (m, 3H), 7.20-7.32 (m, 4H); MS (FAB) m/z 323 (MH+)White solid, melting point = 290-292 ℃, 1 H NMR ( 500 MHz, CHLOROFORM-d) δ 8.07 (d, J = 8.41 Hz, 2H), 7.67 (d, J = 8.41 Hz, 2H), 7.39-7.49 (m, 3 H), 7.20-7.32 (m, 4 H); MS (FAB) m / z 323 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-(푸란-3-일)벤즈아미드 (4c)) -4- (furan-3-yl) benzamide (4c)

황색 고체, 녹는점 = 277-279 C, 1H NMR (300 MHz, DMSO-d 6 ) δδ 9.53 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.11-7.23 (m, 4H), 6.93-7.01 (m, 3H), 6.77 (d, J = 7.89 Hz, 1H), 6.59 (s, 2H), 6.25 (d, J = 1.10 Hz, 1H); MS (FAB) m/z 307 (MH+)Yellow solid, melting point = 277-279 C, 1 H NMR ( 300 MHz, DMSO- d 6) δδ 9.53 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.11-7.23 (m , 4H), 6.93-7.01 (m, 3H), 6.77 (d, J = 7.89 Hz, IH), 6.59 (s, 2H), 6.25 (d, J = 1.10 Hz, IH); MS (FAB) m / z 307 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4'-)-4'- 플루오로비페닐Fluorobiphenyl -4--4- 카르복사미드Carboxamide (5c) (5c)

백색 고체, 녹는점= 283-284℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 10.26-10.43 (m, 1H), 8.35 (s, 1H), 8.29-8.42 (m, 1H), 8.25 (t, J = 1.77 Hz, 1H), 8.02 (d, J = 7.57 Hz, 1H), 7.93-8.04 (m, 1H), 7.92-7.99 (m, 2H), 7.75-7.85 (m, 1H), 7.75-7.83 (m, 2H), 7.57-7.64 (m, 1H), 7.59 (d, J = 7.64 Hz, 1H), 7.42 (t, J = 7.76 Hz, 1H), 7.38-7.46 (m, 1H), 7.32-7.33 (m, 1H), 7.08 (dd, J = 0.89, 1.77 Hz, 1H), 7.05-7.11 (m, 1H), 2.51-2.55 (m, 2H), 2.37-2.47 (m, 1H); MS (FAB) m/z 335 (MH+)White solid, melting point = 283-284 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 10.35 (s, 1H), 10.26-10.43 (m, 1H), 8.35 (s, 1H), 8.29-8.42 (m, 1H), 8.25 ( t, J = 1.77 Hz, 1H), 8.02 (d, J = 7.57 Hz, 1H), 7.93-8.04 (m, 1H), 7.92-7.99 (m, 2H), 7.75- 7.85 (m, 1H), 7.75-7.83 (m, 2H), 7.57-7.64 (m, 1H), 7.59 (d, J = 7.64 Hz, 1H), 7.42 (t, J = 7.76 Hz, 1H), 7.38 (M, 2H), 2.37 (m, 1H), 7.32-7.36 (m, 1H), 7.08 (dd, J = 0.89, 1.77 Hz, -2.47 (m, 1 H); MS (FAB) m / z 335 (MH < + & gt ; ) [

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4'-)-4'- 비닐비페닐Vinylbiphenyl -4--4- 카르복사미드Carboxamide (6c) (6c)

황색 고체, 녹는점 = 271-273℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 10.07-10.11 (m, 1H), 8.14-8.19 (m, 2H), 8.08-8.14 (m, 2H), 7.68-7.83 (m, 5H), 7.59-7.64 (m, 2H), 7.52 (dd, J = 5.75, 8.40 Hz, 3H), 6.78 (ddd, J = 2.65, 10.73, 17.58 Hz, 1H), 5.84 (dd, J = 3.98, 17.69 Hz, 1H), 5.29-5.36 (m, 1H); MS (FAB) m/z 343 (MH+)Yellow solid, melting point = 271-273 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 10.07-10.11 (m, 1H), 8.14-8.19 (m, 2H), 8.08-8.14 (m, 2H), 7.68-7.83 (m, 5H), 7.59-7.64 (m, 2H), 7.52 (dd, J = 5.75, 8.40 Hz, 3H), 6.78 (ddd, J = 2.65, 10.73, 17.58 Hz, 1H), 5.84 ( dd, J = 3.98,17.69 Hz, 1H), 5.29-5.36 (m, 1H); MS (FAB) m / z 343 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-(피리딘-4-일)벤즈아미드 (7c)) -4- (pyridin-4-yl) benzamide (7c)

백색 고체, 녹는점 = 271-273℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 10.07-10.11 (m, 1H), 8.14-8.19 (m, 2H), 8.08-8.14 (m, 2H), 7.68-7.83 (m, 5H), 7.59-7.64 (m, 2H), 7.52 (dd, J = 5.75, 8.40 Hz, 3H), 6.78 (ddd, J = 2.65, 10.73, 17.58 Hz, 1H), 5.84 (dd, J = 3.98, 17.69 Hz, 1H), 5.29-5.36 (m, 1H); MS (FAB) m/z 343 (MH+)White solid, melting point = 271-273 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 10.07-10.11 (m, 1H), 8.14-8.19 (m, 2H), 8.08-8.14 (m, 2H), 7.68-7.83 (m, 5H), 7.59-7.64 (m, 2H), 7.52 (dd, J = 5.75, 8.40 Hz, 3H), 6.78 (ddd, J = 2.65, 10.73, 17.58 Hz, 1H), 5.84 ( dd, J = 3.98,17.69 Hz, 1H), 5.29-5.36 (m, 1H); MS (FAB) m / z 343 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-(피리미딘-5-일)벤즈아미드 (8c)) -4- (pyrimidin-5-yl) benzamide (8c)

백색 고체, 녹는점 = 251-252℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 10.4 (s, 1H), 8.13 (d, J = 8.52 Hz, 1H), 8.01-8.09 (m, 2H), 7.52-7.77 (m, 4H), 7.36-7.52 (m, 2H), 6.73-6.90 (m, 3H), 3.46 (s, 3H); MS (FAB) m/z 347 (MH+).White solid, melting point = 251-252 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 10.4 (s, 1H), 8.13 (d, J = 8.52 Hz, 1H), 8.01-8.09 (m, 2H) , 7.52-7.77 (m, 4H), 7.36-7.52 (m, 2H), 6.73-6.90 (m, 3H), 3.46 (s, 3H); MS (FAB) m / z 347 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4'-(디메틸아미노)비페닐-4-) -4 '- (dimethylamino) biphenyl-4- 카르복사미드Carboxamide (9c) (9c)

황색 고체, 녹는점 = 253-254℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.18 (d, J = 8.52 Hz, 1H), 8.01-8.11 (m, 1H), 7.52-7.77 (m, 5H), 7.36-7.52 (m, 2H), 6.73-6.90 (m, 4H), 3.92 (s, 6H); MS (FAB) m/z 360 (MH+)Yellow solid, melting point = 253-254 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.18 (d, J = 8.52 Hz, 1H), 8.01-8.11 (m, 1H), 7.52-7.77 (m, 5H), 7.36-7.52 (m, 2H), 6.73-6.90 (m, 4H), 3.92 (s, 6H); MS (FAB) m / z 360 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-)-4- 시클로핵실벤즈아미드Cyclohexylbenzamide (11c) (11c)

백색 고체, 녹는점= 141-143℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.19-8.24 (m, 2H), 8.09-8.14 (m, 1H), 7.53-7.59 (m, 1H), 7.43-7.50 (m, 4H), 2.67 (brs, 1H), 1.86-1.99 (m, 4H), 1.77-1.86 (m, 1H), 1.40-1.55 (m, 4H), 1.25-1.36 (m, 1H); MS (FAB) m/z 323 (MH+)White solid, melting point = 141-143 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.19-8.24 (m, 2H), 8.09-8.14 (m, 1H), 7.53-7.59 (m, 1H), 4H), 1.65-1. 36 (m, 4H), 1.77-1.86 (m, 1H), 1.40-1.55 ); MS (FAB) m / z 323 (MH < + & gt ; ).

3-(2-(2-3- (2- (2- 플루오로비페닐Fluorobiphenyl -4-일)Yl) 프로판아미도Propanamido )벤즈아미드 (12c)) Benzamide (12c)

백색 고체, 녹는점 = 152-153℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 7.53 (brd, J = 7.83 Hz, 3H), 7.32-7.48 (m, 6H), 7.10-7.22 (m, 3H), 3.79 (q, J = 7.34 Hz, 1H), 1.56 (d, J = 7.34 Hz, 3H); MS (FAB) m/z 317 (MH+)White solid, melting point = 152-153 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 7.53 (brd, J = 7.83 Hz, 3H), 7.32-7.48 (m, 6H), 7.10-7.22 (m, 3H), 3.79 (q, J = 7.34 Hz, 1 H), 1.56 (d, J = 7.34 Hz, 3H); MS (FAB) m / z 317 (MH < + & gt ; ).

4'-3차-부틸-N-(3-4'-tert-Butyl-N- (3- 카르바모일페닐Carbamoylphenyl )비페닐-4-) Biphenyl-4- 카르복사미드Carboxamide (13c) (13c)

백색 고체, 녹는점 = 152-153℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 7.53 (brd, J = 7.83 Hz, 3H), 7.32-7.48 (m, 6H), 7.10-7.22 (m, 3H), 3.79 (q, J = 7.34 Hz, 1H), 1.56 (d, J = 7.34 Hz, 3H); MS (FAB) m/z 317 (MH+)White solid, melting point = 152-153 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 7.53 (brd, J = 7.83 Hz, 3H), 7.32-7.48 (m, 6H), 7.10-7.22 (m, 3H), 3.79 (q, J = 7.34 Hz, 1 H), 1.56 (d, J = 7.34 Hz, 3H); MS (FAB) m / z 317 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4'-)-4'- 히드록시비페닐Hydroxybiphenyl -4--4- 카르복사미드Carboxamide (14c) (14c)

백색 고체, 녹는점 = 157-158℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.29-8.36 (m, 2H), 8.09-8.15 (m, 1H), 7.74-7.81 (m, 2H), 7.54-7.64 (m, 3H), 7.43-7.53 (m, 2H), 6.94-7.03 (m, 2H), 5.05 (br s, 1H); MS (FAB) m/z 333 (MH+)White solid, melting point = 157-158 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.29-8.36 (m, 2H), 8.09-8.15 (m, 1H), 7.74-7.81 (m, 2H), 7.54-7.64 (m, 3H), 7.43-7.53 (m, 2H), 6.94-7.03 (m, 2H), 5.05 (br s, 1H); MS (FAB) m / z 333 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )) 터페닐Terphenyl -4--4- 카르복사미드Carboxamide (16c) (16c)

백색 고체, 녹는점 = 171-173℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.35-8.40 (m, 2H), 8.13 (d, J = 8.60 Hz, 1H), 7.86-7.91 (m, 2H), 7.74-7.81 (m, 4H), 7.65-7.69 (m, 2H), 7.55-7.60 (m, 1H), 7.46-7.53 (m, 4H), 7.38-7.43 (m, 1H); MS (FAB) m/z 392 (MH+)White solid, melting point = 171-173 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.35-8.40 (m, 2H), 8.13 (d, J = 8.60 Hz, 1H), 7.86-7.91 (m, 2H), 7.74-7.81 (m, 4H), 7.65-7.69 (m, 2H), 7.55-7.60 (m, 1H), 7.46-7.53 (m, 4H), 7.38-7.43 (m, 1H); MS (FAB) m / z 392 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-(4,4-디메틸피페리딘-1-일)벤즈아미드 (18c)) -4- (4,4-dimethylpiperidin-1-yl) benzamide (18c)

백색 고체, 녹는점 = 160-161℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.07-8.16 (m, 3H), 7.52 (s, 1H), 7.47-7.51 (m, 1H), 7.43 (s, 1H), 6.94 (d, J = 9.31 Hz, 2H), 3.44-3.51 (m, 4H), 1.55 (s, 4H), 1.05 (s, 6H); MS (FAB) m/z 352 (MH+)White solid, melting point = 160-161 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.07-8.16 (m, 3H), 7.52 (s, 1H), 7.47-7.51 (m, 1H), 7.43 ( s, 1H), 6.94 (d, J = 9.31 Hz, 2H), 3.44-3.51 (m, 4H), 1.55 (s, 4H), 1.05 (s, 6H); MS (FAB) m / z 352 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-(3,4-) -4- (3,4- 디히드로Dihydro -2H--2H- 벤조[b][1,4]디옥세핀Benzo [b] [1,4] dioxepine -7-일)벤즈아미드(20c)-7-yl) benzamide (20c)

백색 고체, 녹는점 = 144-145℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.28-8.36 (m, 2H), 8.11 (d, J = 8.60 Hz, 1H), 7.73-7.81 (m, 2H), 7.52-7.61 (m, 1H), 7.42-7.52 (m, 2H), 7.32 (d, J = 2.51 Hz, 1H), 7.24-7.29 (m, 2H), 7.10 (d, J = 8.24 Hz, 1H), 4.30 (t, J = 5.73 Hz, 4H), 2.21-2.31 (m, 2H); MS (FAB) m/z 389 (MH+)White solid, melting point = 144-145 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.28-8.36 (m, 2H), 8.11 (d, J = 8.60 Hz, 1H), 7.73-7.81 (m, 2H), 7.52-7.61 (m, 1H ), 7.42-7.52 (m, 2H), 7.32 (d, J = 2.51 Hz, 1H), 7.24-7.29 (m, 2H), 7.10 (d, J = 8.24 Hz , ≪ / RTI > 1H), 4.30 (t, J = 5.73 Hz, 4H), 2.21-2.31 (m, 2H); MS (FAB) m / z 389 (MH < + & gt ; ).

3-(2-(4-(3- (2- (4- ( 벤질옥시Benzyloxy )페닐)) Phenyl) 아세트아미도Acetamido )벤즈아미드 (23c)) Benzamide (23c)

황색 고체, 녹는점 = 187-188℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 7.80-7.89 (m, 1H), 7.67 (brd, J = 8.23 Hz, 1H), 7.49-7.58 (m, 1H), 7.17-7.48 (m, 9H), 7.00-7.08 (m, 2H), 6.95 (d, J = 8.60 Hz, 2H), 5.03-5.13 (m, 2H), 3.58-3.75 (m, 2H); MS (FAB) m/z 361 (MH+)Yellow solid, melting point = 187-188 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 7.80-7.89 (m, 1H), 7.67 (brd, J = 8.23 Hz, 1H), 7.49-7.58 (m, (M, 2H), 3.58-3.75 (m, 2H), 6.95 (d, J = 8.60 Hz, 2H), 7.17-7.48 ; MS (FAB) m / z 361 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-()-4-( 피롤리딘Pyrrolidine -1-일)벤즈아미드 (24c)Yl) benzamide (24c) < RTI ID = 0.0 >

황색 고체, 녹는점 = 182-183℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.07-8.14 (m, 3H), 7.50 (s, 2H), 7.40-7.45 (m, 1H), 6.62 (d, J = 8.80 Hz, 2H), 3.45 (s, 4H), 2.07-2.15 (m, 4H); MS (FAB) m/z 310 (MH+)Yellow solid, melting point = 182-183 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.07-8.14 (m, 3H), 7.50 (s, 2H), 7.40-7.45 (m, 1H), 6.62 ( d, J = 8.80 Hz, 2H), 3.45 (s, 4H), 2.07 - 2.15 (m, 4H); MS (FAB) m / z 310 (MH < + & gt ; ).

N1-(3-N1- (3- 카르바모일페닐Carbamoylphenyl )) 테레프탈아미드Terephthalamide (26c) (26c)

백색 고체, 녹는점 = 140-141℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 8.07-8.21 (m, 3H), 7.82-7.93 (m, 3H), 7.54-7.67 (m, 1H), 7.39-7.49 (m, 1H), 6.87 (s, 2H), 6.08 (brs, 1H), 5.67 (brs, 1H); MS (FAB) m/z 284 (MH+)White solid, melting point = 140-141 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 8.07-8.21 (m, 3H), 7.82-7.93 (m, 3H), 7.54-7.67 (m, 1H), 7.39-7.49 (m, 1 H), 6.87 (s, 2 H), 6.08 (brs, 1 H), 5.67 (brs, 1 H); MS (FAB) m / z 284 (MH < + & gt ; ).

N-(3-N- (3- 카르바모일페닐Carbamoylphenyl )-4-옥소-1,2,3,) -4-oxo-1,2,3, 3a,43a, 4 ,5-, 5- 헥사히드로피롤로[1,2-a]퀴녹살Hexahydropyrrolo [1,2-a] quinoxaline 린-7-카르복사미드 (27c)7-carboxamide (27c)

황색 고체, 녹는점 = 150-151℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 10.57-10.79 (m, 1H), 8.16 (d, J = 8.80 Hz, 1H), 7.79-7.91 (m, 2H), 7.49-7.72 (m, 3H), 6.77 (d, J = 8.31 Hz, 1H), 4.05-4.16 (m, 1H), 3.41-3.59 (m, 2H), 2.18-2.32 (m, 1H), 1.91-2.14 (m, 3H); MS (FAB) m/z 351 (MH+)Yellow solid, melting point = 150-151 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 10.57-10.79 (m, 1H), 8.16 (d, J = 8.80 Hz, 1H), 7.79-7.91 (m (M, 2H), 7.49-7.72 (m, 3H), 6.77 (d, J = 8.31 Hz, 1H), 4.05-4.16 ), 1.91-2.14 (m, 3H); MS (FAB) m / z 351 (MH < + & gt ; ).

N-(3-(N- (3- ( 히드록시카르바모일Hydroxycarbamoyl )페닐)) Phenyl) 터페닐Terphenyl -4--4- 카르복사미드Carboxamide (28d) (28d)

백색 고체, 녹는점 = 157-159℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 11.28 (brs, 1H), 10.24 (s, 1H) 9.08 (br s, 1H), 7.98 (brd, J = 7.82 Hz, 1H), 7.66-7.93 (m, 12H), 7.30-7.56 (m, 4H); MS (FAB) m/z 409 (MH+)White solid, melting point = 157-159 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 11.28 (brs, 1H), 10.24 (s, 1H) 9.08 (br s, 1H), 7.98 (brd, J = 7.82 Hz, 1H), 7.66-7.93 (m, 12H), 7.30-7.56 (m, 4H); MS (FAB) m / z 409 (MH < + & gt ; ).

N-(3-(N- (3- ( 히드록시카르바모일Hydroxycarbamoyl )페닐)비페닐-4-) Phenyl) biphenyl-4- 카르복사미드Carboxamide (29d) (29d)

백색 고체, 녹는점 = 148-150℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 11.21 (brs, 1H), 10.43 (s, 1H) 9.04 (br s, 1H), 8.21 (s, 1H), 8.09 (d, J = 7.54 Hz, 2H), 7.95 (d, J = 7.77 Hz, 1H), 7.70-7.87 (m, 2H), 7.38-7.54 (m, 7H); MS (FAB) m/z 333 (MH+)White solid, melting point = 148-150 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 11.21 (brs, 1H), 10.43 (s, 1H) 9.04 (br s, 1H), 8.21 (s, 1H ), 8.09 (d, J = 7.54 Hz, 2H), 7.95 (d, J = 7.77 Hz, 1H), 7.70-7.87 (m, 2H), 7.38-7.54 (m, 7H); MS (FAB) m / z 333 (MH < + & gt ; ).

4'-히드록시-N-(3-(4'-hydroxy-N- (3- ( 히드록시카르바모일Hydroxycarbamoyl )페닐)비페닐-4-) Phenyl) biphenyl-4- 카르복사미드Carboxamide (30d) (30d)

백색 고체, 녹는점 = 163-165℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 10.36 (brs, 1H), 8.20 (s, 1H), 8.04 (brd, J = 8.31 Hz, 2H), 7.94 (b d, J = 8.31 Hz, 1H), 7.72-7.83 (m, 3H), 7.57-7.67 (m, 3H), 7.54 (d, J = 8.31 Hz, 1H), 7.43-7.47 (m, 1H), 7.35-7.42 (m, 1H), 6.81-6.92 (m, 2H); MS (FAB) m/z 349 (MH+)White solid, melting point = 163-165 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 10.36 (brs, 1H), 8.20 (s, 1H), 8.04 (brd, J = 8.31 Hz, 2H), 7.94 (bd, J = 8.31 Hz , 1H), 7.72-7.83 (m, 3H), 7.57-7.67 (m, 3H), 7.54 (d, J = 8.31 Hz, 1H), 7.43-7.47 (m, 1H) , 7.35-7.42 (m, 1 H), 6.81-6.92 (m, 2H); MS (FAB) m / z 349 (MH < + & gt ; ).

3-(4-(3- (4- ( 벤질옥시Benzyloxy )) 벤즈아미도Benzamido )-N-) -N- 히드록시벤즈아미드Hydroxybenzamide (31d) (31d)

백색 고체, 녹는점 = 160-162℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 11.05 (br s, 1H), 8.89 (s, 1H), 7.69-7.76 (m, 2H), 7.29-7.50 (m, 9H), 7.01-7.10 (m, 2H), 5.16 (s, 2H); MS (FAB) m/z 363 (MH+)White solid, melting point = 160-162 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 11.05 (br s, 1H), 8.89 (s, 1H), 7.69-7.76 (m, 2H), 7.29- 7.50 (m, 9H), 7.01-7.10 (m, 2H), 5.16 (s, 2H); MS (FAB) m / z 363 (MH < + & gt ; ).

N-히드록시-3-(4-N-hydroxy-3- (4- 페녹시벤즈아미도Phenoxybenzamide )벤즈아미드 (32d)) Benzamide (32d)

백색 고체, 녹는점 = 155-157℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.86 (brs, 1H), 7.99-8.10 (m, 3H), 7.83 (dd, J = 1.12, 7.83 Hz, 1H), 7.40-7.49 (m, 3H), 7.21-7.33 (m, 2H), 7.06-7.16 (m, 4H); MS (FAB) m/z 349 (MH+)White solid, melting point = 155-157 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 10.22 (s, 1H), 8.86 (brs, 1H), 7.99-8.10 (m, 3H), 7.83 (dd , J = 1.12, 7.83 Hz, 1H), 7.40-7.49 (m, 3H), 7.21-7.33 (m, 2H), 7.06-7.16 (m, 4H); MS (FAB) m / z 349 (MH < + & gt ; ).

3-(3- ( 벤질옥시Benzyloxy )-N-(3-() -N- (3- ( 히드록시카르바모일Hydroxycarbamoyl )페닐)벤즈아미드 (33d)) Phenyl) benzamide (33d)

백색 고체, 녹는점 = 165-167℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 11.15 (br s, 1H), 10.24 (s, 1H), 8.99 (brs, 1H), 7.97 (s, 1H), 7.74 (br d, J = 7.34 Hz, 1H), 7.41-7.47 (m, 2H), 7.28-7.41 (m, 5H), 7.25 (d, J = 8.31 Hz, 2H), 6.96 (d, J = 8.31 Hz, 2H), 5.08 (s, 2H), 3.56 (s, 2H); MS (FAB) m/z 377 (MH+)White solid, melting point = 165-167 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 11.15 (br s, 1H), 10.24 (s, 1H), 8.99 (brs, 1H), 7.97 (s, 1H), 7.74 (br d, J = 7.34 Hz, 1H), 7.41-7.47 (m, 2H), 7.28-7.41 (m, 5H), 7.25 (d, J = 8.31 Hz, 2H), 6.96 (d, J = 8.31 Hz, 2H), 5.08 (s, 2H), 3.56 (s, 2H); MS (FAB) m / z 377 (MH < + & gt ; ).

2-2- 플루오로Fluoro -N-(3-(-N- (3- ( 히드록시카르바모일Hydroxycarbamoyl )페닐)비페닐-3-) Phenyl) biphenyl-3- 카르복사미드Carboxamide (34d) (34d)

백색 고체, 녹는점 = 158-160℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 12.85 (brs, 1H), 11.19 (brs, 1H), 10.31 (s, 1H), 8.19 (s, 1H), 7.83 (dd, J = 0.98, 8.31 Hz, 1H), 7.60 (d, J = 7.82 Hz, 1H), 7.50-7.55 (m, 2H), 7.43-7.50 (m, 3H), 7.35-7.42 (m, 2H), 7.32 (d, J = 9.78 Hz, 2H), 3.91 (q, J = 6.85 Hz, 1H), 1.47 (d, J = 6.85 Hz, 3H); MS (FAB) m/z 379 (MH+)White solid, melting point = 158-160 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 12.85 (brs, 1H), 11.19 (brs, 1H), 10.31 (s, 1H), 8.19 (s, 1H ), 7.83 (dd, J = 0.98,8.31 Hz, 1H), 7.60 (d, J = 7.82 Hz, 1H), 7.50-7.55 (m, 2H), 7.43-7.50 (m, 3H), 7.35-7.42 m, 2H), 7.32 (d, J = 9.78 Hz, 2H), 3.91 (q, J = 6.85 Hz, 1H), 1.47 (d, J = 6.85 Hz, 3H); MS (FAB) m / z 379 (MH < + & gt ; ).

N-히드록시-3-(4-(피페리딘-1-일)N-hydroxy-3- (4- (piperidin-1-yl) 벤즈아미도Benzamido )벤즈아미드 (35d)) Benzamide (35d)

백색 고체, 녹는점 = 150-151℃, 1H NMR (500 MHz, DMSO-d 6 ) δ 7.51-7.56 (m, 2H), 7.44-7.50 (m, 3H), 7.32-7.43 (m, 2H), 7.20-7.26 (m, 1H), 3.33 (brs, 4H), 1.69 (s, 6H); MS (FAB) m/z 340 (MH+)White solid, melting point = 150-151 ℃, 1 H NMR ( 500 MHz, DMSO- d 6) δ 7.51-7.56 (m, 2H), 7.44-7.50 (m, 3H), 7.32-7.43 (m, 2H) , 7.20-7.26 (m, IH), 3.33 (brs, 4H), 1.69 (s, 6H); MS (FAB) m / z 340 (MH < + & gt ; ).

N-히드록시-3-(4-(N-Hydroxy-3- (4- ( 피롤리딘Pyrrolidine -1-일)-1 day) 벤즈아미도Benzamido )벤즈아미드 (36d)) Benzamide (36d)

백색 고체, 녹는점 = 152-154℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 7.90-8.01 (m, 3H), 7.76-7.85 (m, 1H), 7.44-7.50 (m, 1H), 6.45-6.57 (m, 3H), 3.30-3.43 (m, 4H), 1.99-2.09 (m, 4H); MS (FAB) m/z 311 (MH+)White solid, melting point = 152-154 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 7.90-8.01 (m, 3H), 7.76-7.85 (m, 1H), 7.44-7.50 (m, 1H), 6.45-6.57 (m, 3H), 3.30-3.43 (m, 4H), 1.99-2.09 (m, 4H); MS (FAB) m / z 311 (MH < + & gt ; ).

N-히드록시-3-(4-N-hydroxy-3- (4- 모르폴리노벤즈아미도Morpholino benzamido )벤즈아미드 (37d)) Benzamide (37d)

백색 고체, 녹는점 = 154-156℃, 1H NMR (500 MHz, CHLOROFORM-d) δ 7.97-8.01 (m, 2H), 7.76-7.87 (m, 2H), 7.45-7.50 (m, 2H), 6.85-6.91 (m, 2H), 3.84-3.89 (m, 4H), 3.28-3.35 (m, 4H); MS (FAB) m/z 327 (MH+)White solid, melting point = 154-156 ℃, 1 H NMR ( 500 MHz, CHLOROFORM- d) δ 7.97-8.01 (m, 2H), 7.76-7.87 (m, 2H), 7.45-7.50 (m, 2H), 6.85-6.91 (m, 2H), 3.84-3.89 (m, 4H), 3.28-3.35 (m, 4H); MS (FAB) m / z 327 (MH < + & gt ; ).

[시험관 내 [In vitro PARPPARP -1 억제 분석]-1 inhibition assay]

합성된 화합물은 상업적으로 입수 가능한 PARP 화학발광 분석 키트(카탈로그 # 4676-096-K, Travigen, Inc.사, R&D systems, USA)를 이용하여 제조사의 지시에 따라 평가했다. 구체적으로 시험 화합물 또는 기준 화합물인 올라파립을 디메틸 설폭사이드(DMSO)에 용해한 다음, 필요한 농도까지 증류수로 계대 희석했다.The synthesized compounds were evaluated according to the manufacturer's instructions using a commercially available PARP chemiluminescence assay kit (Catalog # 4676-096-K, Travigen, Inc., R & D systems, USA). Specifically, the test compound or the reference compound olaparip was dissolved in dimethylsulfoxide (DMSO) and then serially diluted to the required concentration with distilled water.

각각의 웰(well)을 50Ml의 1×PARP 완충액과 함께 30분간 인큐베이션하여 히스톤을 재수화한 다음, Tris-Cl 완충액에서 상기 희석된 화합물, PAPR 효소(0.5 unit/well를 제공) 및 비오티닐화 NAD+, 활성화 DNA를 함유하는 25μL의 PARP 칵테일을 첨가함으로써 각각의 웰을 실온에서 60분간 리보실화 반응을 수행했다. Each well was incubated with 50 Ml of 1x PARP buffer for 30 minutes to rehydrate the histone and then the diluted compound, PAPR enzyme (providing 0.5 unit / well) and biotinylated Each well was subjected to a ribosylation reaction at room temperature for 60 minutes by adding 25 [mu] L of PARP cocktail containing NAD + , activated DNA.

이러한 웰들을 200μL의 인산염 완충액(PBS)에 용해된 0.1% Triton X-100으로 2회 세척한 다음, 200μL의 PBS로 2회 세척했다. These wells were washed twice with 0.1% Triton X-100 in 200 μL of phosphate buffer (PBS) and then twice with 200 μL of PBS.

다음에, 종이타월 상에 뒤집어서 두드림으로써 모든 액체를 제거했다. 그리고 계속해서 각각의 웰에 50μL의 희석된 Strep-Horseradish Peroxidase(HRP)를 첨가한 다음에, 그 웰들을 실온에서 60분간 인큐베이션하여 리보실화를 비색적으로(colorimetrically) 검출한 후, 위에서 언급한 바와 같이 PBS로 세척했다.Next, all the liquid was removed by tapping on a paper towel. Subsequently, 50 μL of diluted Strep-Horseradish Peroxidase (HRP) was added to each well, and the wells were incubated for 60 minutes at room temperature to detect ribosylation colorimetrically, Followed by washing with PBS.

이후에, 동일 체적으로 혼합된 PeroxyFlowTM A 및 B (HRP 기질) 100μL를 상기 웰들에 첨가했다. 각각의 웰에 50μL의 5% 인산을 첨가하여 리보실화 반응을 정지했다. 450 nm의 파장에서 흡광도를 측정했다(Thermo Labsystems, Multiskan EX, USA). Thereafter, 100 μL of the same volume of mixed PeroxyFlow ™ A and B (HRP substrate) was added to the wells. 50 [mu] L of 5% phosphoric acid was added to each well to terminate the ribosylation reaction. Absorbance was measured at a wavelength of 450 nm (Thermo Labsystems, Multiskan EX, USA).

모든 화합물들은 3회 반복하여 시험하고, 그 결과는 평균 ± 표준편차(SD)로 나타낸다.All compounds were tested in triplicate and the results are expressed as mean ± standard deviation (SD).

[세포 배양][Cell culture]

인간 난소암 세포주인 SNU-251 및 인간 유방암 세포주인 MDA-MB-231를 37℃ 및 습기 있는 5% CO2 분위기에서 Roswell Pakr Memorial Institue (RPMI) 1640 (Welgene사, 대한민국) 및 10% 우태혈청(FBS; Welgene Inc.사), 그리고 1% 페니실린-스트렙토마이신(10,000 U 및 10,000 g/ml; Gibco사, 미국)이 첨가된 Dulbecco's modified Eagle's 배지(DMEM; Welgene Inc사, 대한민국)에서 각각 유지했다.Human ovarian cancer cell line in Roswell Pakr Memorial Institue (RPMI) 1640 (Welgene Inc., Republic of Korea) and 10% fetal calf serum in SNU-251 and the human breast cancer cell line MDA-MB-231 for 37 ℃ and humid 5% CO 2 atmosphere ( FBS; Welgene Inc.), and Dulbecco's modified Eagle's medium (DMEM; Welgene Inc., Korea) supplemented with 1% penicillin-streptomycin (10,000 U and 10,000 g / ml; Gibco, USA).

[세포 생존율 분석][Analysis of cell survival rate]

MTT 비색 분석법을 이용하여 세포 생존율을 평가했다. SNU-251 세포 및 MDA-MB231 세포(2×105 세포/mL)를 24-웰플레이트에 분주하고, 다양한 농도(0 내지 20μM)의 AU14022로 48시간 동안 처리했다. 인큐베이션한 후, MTT(0.5 mg/웰)를 첨가하고, 3시간 동안 추가로 인큐베이션했다. 상등액을 제거한 후, 얻어진 펠릿을 DMSO에 용해했다. 얻어지는 포름아존(formazon)의 흡광도를 540 nm에서 플레이트 리더(Thermo Labsystems 사)를 이용하여 측정했다.MTT colorimetric assay was used to evaluate cell viability. SNU-251 cells and MDA-MB231 cells (2 × 10 5 cells / mL) were dispensed into 24-well plates and treated with AU14022 at various concentrations (0 to 20 μM) for 48 hours. After incubation, MTT (0.5 mg / well) was added and further incubated for 3 hours. After removing the supernatant, the obtained pellet was dissolved in DMSO. The absorbance of the obtained formazone was measured at 540 nm using a plate reader (Thermo Labsystems).

[[ 아넥신Annexin V/PI 염색] V / PI dyeing]

세포 자연사(apoptosis) 수준을 확인하기 위하여, FITC 아넥신-V 세포사 검출 키트(BD Pharmingen사, 미국)를 이용하여 세포를 아넥신 V-FITC 및 PI로 염색했다. 즉, 1×105개의 세포를 60-mm 플레이트 상에 도말하고, 화합물 9c, 28d 또는 올라파립으로 48시간 동안 처리한 후 PBS로 세척한 다음, 0.1 M HEPES/NaOH(pH 7.4), 1.4 M NaCl 및 25 mM CaCl2를 함유하는 결합 완충액에 용해된 5μL의 아넥신 V-APC 및 5μL의 PI로 암소 및 실온에서 15분간 염색했다. Cells were stained with Annexin V-FITC and PI using the FITC Annexin-V cell death detection kit (BD Pharmingen, USA) to confirm apoptosis levels. That is, 1 × 10 5 of the cells plated on 60-mm plates, and compounds washed with 9c, PBS after 28d or up treatment for 48 hours with parip Next, 0.1 M HEPES / NaOH (pH 7.4), 1.4 M 5 μL of annexin V-APC and 5 μL of PI, dissolved in binding buffer containing NaCl and 25 mM CaCl 2 , were stained for 15 minutes in a cow and room temperature.

다음에, 그 염색된 세포를 유세포 분석법(FACSort flow cytometer; Becton-Dickinson사, 미국)을 이용하여 검출했다. 초기(Annexin V-양성/PI-음성) 및 후기 (Annexin-V 양성/PI-양성) 자연사멸 세포 모두를 분석했다.Next, the stained cells were detected by flow cytometry (FACSort flow cytometer; Becton-Dickinson, USA). Both early (Annexin V-positive / PI-negative) and late (Annexin-V positive / PI-positive) natural killer cells were analyzed.

[결과][result]

도 1은 본 발명에 따른 신규한 벤즈아미드 유도체의 화합물 9c 및 28d가 인간 난소암 세포주인 SNU-251 및 인간 유방암 세포주인 MDA-MB-231에서 세포 자연사를 유도하는 실험예이다..1 is an experimental example in which compounds 9c and 28d of the novel benzamide derivatives according to the present invention induce apoptosis in human ovarian cancer cell line SNU-251 and human breast cancer cell line MDA-MB-231.

도 1의 실험 결과는 SNU-251 및 MDA-MB-231 세포를 10μM의 화합물 9c 또는 28d로 48시간 동안 처리한 후 APC-결합 아넥신-V/PI 염색을 이용하여 자연사멸 세포수를 측정한 결과이다. 이때, 세포 집단을 실험 섹션에서 기재된 바와 같이 4개의 그룹으로 분류했다. 막대그래프는 자연사멸 세포(아넥신-V-양성/PI-음성 세포 및 아넥신-V-음성/PI-양성 세포)의 평균 백분율을 나타낸다. 데이터는 3회의 독립적인 실험들의 평균 ± SD를 나타낸다.1, SNU-251 and MDA-MB-231 cells were treated with 10 μM of compound 9c or 28d for 48 hours, and the number of natural killer cells was measured using APC-conjugated annexin-V / PI staining Results. At this time, the cell populations were classified into four groups as described in the experimental section. The bar graph represents the average percentage of natural apoptotic cells (annexin-V-positive / PI-negative cells and annexin-V-negative / PI-positive cells). Data represent the mean ± SD of three independent experiments.

도 2는 본 발명에 따른 신규한 벤즈아미드 유도체의 화합물 28d와 방사선을 인간 난소암 세포주 SNU-251에 병용으로 처리시 아폽토시스 세포사멸이 상승함을 확인하는 실험예이다.FIG. 2 is an experimental example for confirming that apoptosis cell death is increased when Compound 28d of the novel benzamide derivative according to the present invention and radiation are used in combination with human ovarian cancer cell line SNU-251.

도 2의 실험결과에서 알 수 있듯이, 인간 난소암 세포주 SNU-251에 본 발명에 따른 벤즈아미드 유도체 화합물 28d와 방사선 병용 처리시 아폽토시스 세포사멸이 현저히 증가함을 알 수 있다.As can be seen from the results of the experiment shown in FIG. 2, apoptosis cell death was remarkably increased in the human ovarian cancer cell line SNU-251 when the benzamide derivative compound 28d according to the present invention was administered in combination with radiation.

위 38개의 합성된 화합물 중에서 가능한 새로운 PARP-1 억제제를 확인하기 위해 각각의 화합물의 PARP-1 효소 억제 활성을 10μM의 농도에서 측정했다. 이러한 측정결과는 도 3a 및 도 3b와 같다.To identify possible new PARP-1 inhibitors among the above 38 synthesized compounds, the PARP-1 enzyme inhibitory activity of each compound was measured at a concentration of 10 μM. These measurement results are shown in Figs. 3A and 3B.

FDA에 의해 승인된 PARP-1 억제제인 올라파립(AZD-2281) 1μM를 PARP-1 효소 억제 분석에서 기준 대조구로 이용했다. 본 발명에서는 두 개의 화합물 9c 및 28d를 선택했고, 그 화합물들은 각각 8.0μM 및 3.2μM의 50% PARP-1 억제 활성(IC50 값)을 갖는 것을 확인했다.1 μM of Orafafil (AZD-2281), a PARP-1 inhibitor approved by the FDA, was used as a reference control in the PARP-1 enzyme inhibition assay. In the present invention, two compounds 9c and 28d were selected and the compounds were confirmed to have 50% PARP-1 inhibitory activity (IC 50 value) of 8.0 μM and 3.2 μM, respectively.

디메틸아미노-비페닐 기를 갖는 9c의 활성은 아미노 기를 갖는 1c 내지 27c 중에서 비교적 양호했다. 카르바모일페닐-모르폴린 구조를 공통적으로 갖는 화합물 25c, 37d 및 38c의 활성은 아미노 기를 갖는 벤즈아미드(25c)의 경우 약간 증가했고, 그 에스테르 기는 R1 위치에 영향을 미치지 않은 것으로 확인되었다. The activity of 9c with a dimethylamino-biphenyl group was relatively good among 1c to 27c with an amino group. The activity of the compounds 25c, 37d and 38c having a carbamoyl phenyl-morpholine structure in common was slightly increased in the case of the benzamide (25c) having an amino group, and it was confirmed that the ester group did not affect the R 1 position.

이를 종합하면, 히드록사메이트 기를 함유하는 유도체들의 활성은 아미노기를 갖는 것들보다 높았고, R2 위치에 터페닐 기(terphenyl group)가 존재하는 경우, 히드록사메이트 기의 활성은 화합물 28d의 경우에 현저히 개선되었다.Taken together, the activity of derivatives containing hydroxamate groups was higher than those with amino groups, and when a terphenyl group was present at the R 2 position, the activity of the hydroxamate group was significantly increased in the case of compound 28d Improved.

PARP 억제제는 BRCA-1 돌연변이 암세포에서 합성 치사(synthetic lethality)를 유도할 수 있기 때문에 본 발명에서 인간 난소암 BRCA-1-결실 SNU-251 (5565G>A 에서 BRCA1 돌연변이) 세포 및 삼중-음성 인간 유방암 BRCA1 이형접합 MDA-MB-231 (BRCA1+/-) 세포에서 MTT 세포 생존율 분석법을 이용하여 화합물 9c 및 28d의 활성을 평가했다.Since the PARP inhibitor is able to induce synthetic lethality in BRCA-1 mutant cancer cells, the present invention can be applied to human ovarian cancer BRCA-1-deficient SNU-251 (BRCA1 mutant in 5565G> A) and triple- The activity of compounds 9c and 28d was assessed using MTT cell viability assays in BRCA1 heterozygous MDA-MB-231 (BRCA1 +/-) cells.

하기 표 1와 같이 화합물 9c의 세포 생존 억제 농도 IC50는 SNU-251 세포 및 MDA-MB-231 세포에서 각각 27.0μM 및 31.4μM인 반면, 화합물 28d의 경우는 이들 세포주에서 각각 3.1μM 및 3.1μM이었다. PARP-1 효소 억제 활성의 결과와 마찬가지로, 화합물 28d는 화합물 9c와 비교하여 세포 성장의 유의한 억제를 나타냈다.As shown in Table 1, the inhibitory concentration IC 50 of the compound 9c was 27.0 μM and 31.4 μM in SNU-251 cells and MDA-MB-231 cells, respectively, while in the case of compound 28d, 3.1 μM and 3.1 μM . Similar to the results of PARP-1 enzyme inhibition activity, compound 28d showed significant inhibition of cell growth compared to compound 9c.

NoNo PARP-1 효소 활성의 IC50(μM)The IC 50 (μM) of PARP-1 enzyme activity 암세포 성장에 대한 IC50(μM)IC 50 (< RTI ID = 0.0 > uM) < / RTI & SNU251SNU251 MDA-MB-231MDA-MB-231 9c9c 8.0 ± 0.28.0 ± 0.2 27.0 ± 2.127.0 ± 2.1 31.4 ± 1.131.4 ± 1.1 28d28d 3.6 ± 0.33.6 ± 0.3 3.1 ± 0.33.1 ± 0.3 8.1 ± 0.38.1 ± 0.3

계속해서, 본 발명에서 화합물 9c 및 28d가 SNU-251 및 MDA-MB-231 세포에서 세포 자연사(apoptotic cell death)를 통해 세포 생존율을 억제하는 지의 여부를 조사했다. 아넥신 V/PI 이중 염색 FACS 분석법을 이용하여 세포 자연사를 검출했다. 세포를 화합물 28d로 처리한 결과, SNU-251 및 MDA-MB-231 세포에서의 세포사가 DMSO-처리 세포주와 비교하여 각각 2.8 배 및 4.2 배 증가했다. 또한, 화합물 9c는 DMSO-처리 세포와 비교하여 SNU-251 세포에서 1.5배, MDA-MB-231 세포에서 1.4배 만큼 세포 자연사를 증가시켰다. Subsequently, the present inventors investigated whether the compounds 9c and 28d inhibited cell survival through apoptotic cell death in SNU-251 and MDA-MB-231 cells. Cellular apoptosis was detected using the Annexin V / PI double-stained FACS assay. Cells were treated with compound 28d, resulting in a 2.8-fold and a 4.2-fold increase in cell death in SNU-251 and MDA-MB-231 cells compared with DMSO-treated cell lines, respectively. Compound 9c also increased cellular apoptosis by 1.5-fold in SNU-251 cells and 1.4-fold in MDA-MB-231 cells compared to DMSO-treated cells.

여기서, 화합물 28d는 기준 화합물인 올라파립 처리 세포와 비교하여 세포 자연사를 현저히 유도했다. 이들 결과는 일련의 새로운 벤즈아미드 유도체들 중에서 히드록시벤즈아미드 28d가 PARP-1 효소 활성의 가장 강력한 억제 및 항암 활성을 나타냈다는 것을 나타낸다.Here, Compound 28d significantly induced cellular apoptosis in comparison with the reference compound Olafil-treated cells. These results indicate that among the series of novel benzamide derivatives, hydroxybenzamide 28d exhibited the strongest inhibitory and anticancer activity of PARP-1 enzyme activity.

이상에서 설명한 바와 같이, 본 발명에 따르면 본 발명자들은 구조 활성 상관관계의 연구를 통해 가능한 새로운 PARP-1 억제제들을 확인했다. 히드록사메이트 기를 함유하는 화합물 28d는 3.2μM의 IC50 값의 유의한 억제 능력을 나타냈고, 대조군인 DMSO-처리 세포주와 비교하여 SNU-251 및 MDA-MB-231 세포수에서 각각 2.8배 및 4.4배의 감소를 나타냈다. As described above, according to the present invention, the present inventors have identified new PARP-1 inhibitors that are possible through studies on the structural activity correlation. Compound 28d containing the hydroxamate group exhibited significant inhibition of IC 50 values of 3.2 μM and was 2.8-fold and 4.4-fold higher in the SNU-251 and MDA-MB-231 cell counts, respectively, as compared to the control DMSO- And a decrease in the number of times.

이러한 결과로부터, 본 발명에서는 새로운 히드록시벤즈아미드 유도체가 벤즈아미드 부분(기존의 PARP 억제제 중에서 핵심 약물특이 분자단)이 아니지만 유의한 PARP 억제 능력을 갖는다는 것을 확인했다. 또한, 이러한 실험결과는 임상적으로 매우 유익한 PARP 억제제의 개발로 이어질 수 있다.From these results, it was confirmed in the present invention that the new hydroxybenzamide derivative is not a benzamide moiety (a key drug-specific molecule group in the conventional PARP inhibitor), but has a significant PARP inhibiting ability. In addition, these experimental results may lead to the development of clinically very beneficial PARP inhibitors.

Claims (14)

PARP 발현을 저해 또는 억제하는 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염.
[화학식 1]
Figure 112019002828453-pat00145

이때, R1은
Figure 112019002828453-pat00146
이고; R2는
Figure 112019002828453-pat00147
,
Figure 112019002828453-pat00148
,
Figure 112019002828453-pat00149
,
Figure 112019002828453-pat00150
,
Figure 112019002828453-pat00151
,
Figure 112019002828453-pat00152
,
Figure 112019002828453-pat00153
,
Figure 112019002828453-pat00154
,
Figure 112019002828453-pat00155
,
Figure 112019002828453-pat00156
,
Figure 112019002828453-pat00157
,
Figure 112019002828453-pat00158
,
Figure 112019002828453-pat00159
,
Figure 112019002828453-pat00160
,
Figure 112019002828453-pat00161
,
Figure 112019002828453-pat00162
,
Figure 112019002828453-pat00163
,
Figure 112019002828453-pat00164
,
Figure 112019002828453-pat00165
,
Figure 112019002828453-pat00166
중 하나이거나;
또는, R1은
Figure 112019002828453-pat00167
이고; R2는
Figure 112019002828453-pat00168
,
Figure 112019002828453-pat00169
,
Figure 112019002828453-pat00170
,
Figure 112019002828453-pat00171
,
Figure 112019002828453-pat00172
,
Figure 112019002828453-pat00173
,
Figure 112019002828453-pat00174
,
Figure 112019002828453-pat00175
중 하나이거나;
또는, R1은
Figure 112019002828453-pat00176
이고, R2는
Figure 112019002828453-pat00177
,
Figure 112019002828453-pat00178
중 하나이다.CLAIMS 1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which inhibits or inhibits PARP expression.
[Chemical Formula 1]
Figure 112019002828453-pat00145

At this time,
Figure 112019002828453-pat00146
ego; R2 is
Figure 112019002828453-pat00147
,
Figure 112019002828453-pat00148
,
Figure 112019002828453-pat00149
,
Figure 112019002828453-pat00150
,
Figure 112019002828453-pat00151
,
Figure 112019002828453-pat00152
,
Figure 112019002828453-pat00153
,
Figure 112019002828453-pat00154
,
Figure 112019002828453-pat00155
,
Figure 112019002828453-pat00156
,
Figure 112019002828453-pat00157
,
Figure 112019002828453-pat00158
,
Figure 112019002828453-pat00159
,
Figure 112019002828453-pat00160
,
Figure 112019002828453-pat00161
,
Figure 112019002828453-pat00162
,
Figure 112019002828453-pat00163
,
Figure 112019002828453-pat00164
,
Figure 112019002828453-pat00165
,
Figure 112019002828453-pat00166
Lt; / RTI >
Or R1 is
Figure 112019002828453-pat00167
ego; R2 is
Figure 112019002828453-pat00168
,
Figure 112019002828453-pat00169
,
Figure 112019002828453-pat00170
,
Figure 112019002828453-pat00171
,
Figure 112019002828453-pat00172
,
Figure 112019002828453-pat00173
,
Figure 112019002828453-pat00174
,
Figure 112019002828453-pat00175
Lt; / RTI >
Or R1 is
Figure 112019002828453-pat00176
And R2 is
Figure 112019002828453-pat00177
,
Figure 112019002828453-pat00178
Lt; / RTI > 제1항에 있어서, 상기 화합물은 바이페닐 벤즈아미드(biphenyl benzamide), 시클로알킬 벤즈아미드(cycloalkyl benzamide) 또는 히드록시벤즈아미드(hydroxybenzamide) 유도체 중 어느 하나를 포함하는 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 1, wherein the compound is selected from the group consisting of a biphenyl benzamide, a cycloalkyl benzamide, and a hydroxybenzamide derivative. Acceptable salt. 제1항 또는 제2항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하고 PARP 억제 기능을 발현하는 암 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, which comprises a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient and expresses a PARP inhibitory function. 제3항의 PARP 억제 기능의 약학적 조성물을 유효성분으로 함유하고 방사선 병용 처리시 암세포 사멸효과를 상승시키는 암 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, which comprises the pharmaceutical composition of claim 3 as an active ingredient and which enhances the cancer cell killing effect upon treatment with radiation. 제1항 또는 제2항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound represented by the general formula (1) of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 출발물질로서 하기 반응식 1의 하기 화학식 2로 표시되는 화합물로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계;
상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 및
상기 화학식 4로 표시되는 화합물로부터 하기 화학식 1로 표시되는 화합물을 제조하는 단계; 를 포함하는 신규한 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.
[반응식 1]
Figure 112019002828453-pat00179

이때, R1은
Figure 112019002828453-pat00180
이고; R2는
Figure 112019002828453-pat00181
,
Figure 112019002828453-pat00182
,
Figure 112019002828453-pat00183
,
Figure 112019002828453-pat00184
,
Figure 112019002828453-pat00185
,
Figure 112019002828453-pat00186
,
Figure 112019002828453-pat00187
,
Figure 112019002828453-pat00188
,
Figure 112019002828453-pat00189
,
Figure 112019002828453-pat00190
,
Figure 112019002828453-pat00191
,
Figure 112019002828453-pat00192
,
Figure 112019002828453-pat00193
,
Figure 112019002828453-pat00194
,
Figure 112019002828453-pat00195
,
Figure 112019002828453-pat00196
,
Figure 112019002828453-pat00197
,
Figure 112019002828453-pat00198
,
Figure 112019002828453-pat00199
,
Figure 112019002828453-pat00200
중 하나이고; R은 R2와 동일하다.Preparing a compound represented by the following formula (3) from a compound represented by the following formula (2) as a starting material;
Preparing a compound represented by the following formula (4) from the compound represented by the formula (3); And
Preparing a compound represented by the formula (1) from the compound represented by the formula (4); Lt; RTI ID = 0.0 > 1 < / RTI > or a pharmaceutically acceptable salt thereof.
[Reaction Scheme 1]
Figure 112019002828453-pat00179

At this time,
Figure 112019002828453-pat00180
ego; R2 is
Figure 112019002828453-pat00181
,
Figure 112019002828453-pat00182
,
Figure 112019002828453-pat00183
,
Figure 112019002828453-pat00184
,
Figure 112019002828453-pat00185
,
Figure 112019002828453-pat00186
,
Figure 112019002828453-pat00187
,
Figure 112019002828453-pat00188
,
Figure 112019002828453-pat00189
,
Figure 112019002828453-pat00190
,
Figure 112019002828453-pat00191
,
Figure 112019002828453-pat00192
,
Figure 112019002828453-pat00193
,
Figure 112019002828453-pat00194
,
Figure 112019002828453-pat00195
,
Figure 112019002828453-pat00196
,
Figure 112019002828453-pat00197
,
Figure 112019002828453-pat00198
,
Figure 112019002828453-pat00199
,
Figure 112019002828453-pat00200
/ RTI > R is the same as R2. 출발물질로서 하기 반응식 2의 하기 화학식 2로 표시되는 화합물로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계;
상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계;
상기 화학식 4로 표시되는 화합물로부터 하기 화학식 5로 표시되는 화합물을 제조하는 단계; 및
상기 화학식 5로 표시되는 화합물로부터 하기 화학식 1로 표시되는 화합물을 제조하는 단계; 를 포함하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.
[반응식 2]
Figure 112019002828453-pat00201

이때, R1은
Figure 112019002828453-pat00202
이고; R2는
Figure 112019002828453-pat00203
,
Figure 112019002828453-pat00204
,
Figure 112019002828453-pat00205
,
Figure 112019002828453-pat00206
,
Figure 112019002828453-pat00207
,
Figure 112019002828453-pat00208
,
Figure 112019002828453-pat00209
,
Figure 112019002828453-pat00210
중 하나이고; R은 R2와 동일하다.Preparing a compound represented by the following formula (3) from a compound represented by the following formula (2) in the following Reaction Scheme 2 as a starting material;
Preparing a compound represented by the following formula (4) from the compound represented by the formula (3);
Preparing a compound represented by the following formula (5) from the compound represented by the formula (4); And
Preparing a compound represented by the formula (1) from the compound represented by the formula (5); ≪ / RTI > or a pharmaceutically acceptable salt thereof.
[Reaction Scheme 2]
Figure 112019002828453-pat00201

At this time,
Figure 112019002828453-pat00202
ego; R2 is
Figure 112019002828453-pat00203
,
Figure 112019002828453-pat00204
,
Figure 112019002828453-pat00205
,
Figure 112019002828453-pat00206
,
Figure 112019002828453-pat00207
,
Figure 112019002828453-pat00208
,
Figure 112019002828453-pat00209
,
Figure 112019002828453-pat00210
/ RTI > R is the same as R2. 출발물질로서 하기 반응식 3의 하기 화학식 2로 표시되는 화합물로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계;
상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계;
상기 화학식 4로 표시되는 화합물로부터 하기 화학식 5로 표시되는 화합물을 제조하는 단계; 및
상기 화학식 5로 표시되는 화합물로부터 하기 화학식 1로 표시되는 화합물을 제조하는 단계; 를 포함하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.
[반응식 3]
Figure 112019002828453-pat00211

이때, R1은
Figure 112019002828453-pat00212
이고; R2는
Figure 112019002828453-pat00213
,
Figure 112019002828453-pat00214
중 하나이고; R은 R2와 동일하다.Preparing a compound represented by the following formula (3) from a compound represented by the following formula (2) as a starting material;
Preparing a compound represented by the following formula (4) from the compound represented by the formula (3);
Preparing a compound represented by the following formula (5) from the compound represented by the formula (4); And
Preparing a compound represented by the formula (1) from the compound represented by the formula (5); ≪ / RTI > or a pharmaceutically acceptable salt thereof.
[Reaction Scheme 3]
Figure 112019002828453-pat00211

At this time,
Figure 112019002828453-pat00212
ego; R2 is
Figure 112019002828453-pat00213
,
Figure 112019002828453-pat00214
/ RTI > R is the same as R2. 제6항 내지 제8항 중 어느 한 항에 있어서, 상기 화학식 2로 표시되는 화합물로부터 상기 화학식 3으로 표시되는 화합물을 제조하는 단계는, Pd(dppf)Cl2-CH2Cl2 및 2M K2CO3을 디옥산에 용해된 메틸 4-브로모벤조에이트의 용액에 첨가하여 교반한 혼합물을 H2O로 희석하고 에틸 아세테이트로 추출하여 메틸-4-카르복시레이트를 합성하는 단계를 포함하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.9. The method of claim 6, wherein the step of preparing the compound represented by the formula (3) from the compound represented by the formula (2) comprises reacting Pd (dppf) Cl 2 -CH 2 Cl 2 and 2M K 2 Adding CO 3 to a solution of methyl 4-bromobenzoate dissolved in dioxane, diluting the stirred mixture with H 2 O and extracting with ethyl acetate to synthesize methyl-4-carboxylate. ≪ / RTI > or a pharmaceutically acceptable salt thereof. 제6항 내지 제8항 중 어느 한 항에 있어서, 상기 화학식 3으로 표시되는 화합물로부터 상기 화학식 4로 표시되는 화합물을 제조하는 단계는, H2O 및 THF가 용해된 메틸-4-카르복시레이트의 용액을 NaOH으로 처리하여 교반한 혼합물을 H2O 및 CH2Cl2로 희석하고 1 N HCl로 산성화하고 CH2Cl2로 추출하여 [1,1'-비페닐]-4-카르복시산을 합성하는 단계를 포함하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.Claim 6 according to any one of the preceding claims, for preparing a compound represented by the above formula (IV) from a compound represented by the formula (3) is, H 2 O and methyl-4-carboxylate is dissolved in the THF The solution was treated with NaOH and the stirred mixture was diluted with H 2 O and CH 2 Cl 2 , acidified with 1 N HCl and extracted with CH 2 Cl 2 to synthesize [1,1'-biphenyl] -4-carboxylic acid Lt; RTI ID = 0.0 > 1 < / RTI > or a pharmaceutically acceptable salt thereof. 제6항에 있어서, 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 1로 표시되는 화합물을 제조하는 단계는, EDC 및 HOBT을 CH2Cl2에 용해된 4-카르복시산(1b-41b)을 3-아미노벤즈아미드의 용액에 첨가하여 교반한 혼합물을 H2O로 희석하고 CH2Cl2로 추출하여 상기 화학식 1로 표시되는 화합물을 제조하는 것을 특징으로 하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.The method according to claim 6, wherein the step of preparing the compound represented by Formula 1 from the compound represented by Formula 4 comprises reacting EDC and HOBT with 4-carboxylic acid (1b-41b) dissolved in CH 2 Cl 2 , Benzamide and stirring the mixture is diluted with H 2 O and extracted with CH 2 Cl 2 to give the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof Gt; 제7항 또는 제8항에 있어서, 상기 화학식 4로 표시되는 화합물로부터 상기 화학식 5로 표시되는 화합물을 제조하는 단계는, EDC 및 HOBT을 CH2Cl2에 용해된 4-카르복시산을 메틸 3-아미노벤즈아미드의 용액에 첨가하여 교반한 혼합물을 H2O로 희석하고 CH2Cl2로 추출하여 상기 화학식 5로 표시되는 화합물을 제조하는 것을 특징으로 하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.9. The method of claim 7 or 8, wherein the step of preparing the compound represented by the formula (5) from the compound represented by the formula (4) comprises reacting EDC and HOBT with 4-carboxylic acid dissolved in CH 2 Cl 2 , Benzamide and stirring the mixture is diluted with H 2 O and extracted with CH 2 Cl 2 to obtain the compound represented by the formula 5, or a pharmaceutically acceptable salt thereof. Gt; 제12항에 있어서, 상기 화학식 5로 표시되는 화합물로부터 상기 화학식 1로 표시되는 화합물을 제조하는 단계는, 메틸 3-벤즈아미도벤조에이트를 CH2Cl2 및 메탄올의 혼합용액에 용해하여 냉각하고 히드록실아민을 첨가한 후 NaOH를 첨가한 용액을 실온에서 교반하여 상기 화학식 1로 표시되는 화합물을 제조하는 것을 특징으로 하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.[14] The method of claim 12, wherein the step of preparing the compound represented by Formula 1 from the compound represented by Chemical Formula 5 is performed by dissolving methyl 3-benzamidobenzoate in a mixed solution of CH 2 Cl 2 and methanol, Wherein the compound represented by the formula (1) is prepared by adding hydroxylamine and then adding NaOH to the mixture at room temperature to prepare a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. 제12항에 있어서, 상기 화학식 5로 표시되는 화합물로부터 상기 화학식 1로 표시되는 화합물을 제조하는 단계는, H2O 및 THF가 용해된 메틸-4-카르복시레이트의 용액을 NaOH으로 처리하여 교반하여 상기 화학식 1로 표시되는 화합물을 제조하는 것을 특징으로 하는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 제조방법.The method according to claim 12, wherein the step of preparing the compound represented by Formula 1 from the compound represented by Chemical Formula 5 comprises: treating a solution of methyl 4-carboxylate in which H 2 O and THF are dissolved with NaOH, A process for preparing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (1) is prepared.
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