KR102409345B1 - Nlrp3 inflammasome inhibitor and uses thereof - Google Patents

Nlrp3 inflammasome inhibitor and uses thereof Download PDF

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KR102409345B1
KR102409345B1 KR1020200122479A KR20200122479A KR102409345B1 KR 102409345 B1 KR102409345 B1 KR 102409345B1 KR 1020200122479 A KR1020200122479 A KR 1020200122479A KR 20200122479 A KR20200122479 A KR 20200122479A KR 102409345 B1 KR102409345 B1 KR 102409345B1
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formula
nlrp3 inflammasome
compound
salt
inflammatory disease
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KR1020200122479A
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KR20220039977A (en
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이주영
최누리
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가톨릭대학교 산학협력단
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Abstract

본 발명은 NLRP3 인플라마좀 억제제 및 이의 NLRP3 인플라마좀 매개 염증성 질환의 치료 용도에 관한 것으로, 보다 상세하게는 우수한 인플라마좀 억제 효과를 가진 화합물, 이의 약학적 또는 식품학적으로 허용가능한 염, 또는 이의 조합을 포함하는 NLRP3 인플라마좀 억제제, NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물, 건강기능식품 조성물 등을 제공한다.
상기 화합물, 이의 염, 또는 이의 조합은 NLRP3 인플라마좀 활성을 유의적으로 억제함으로써, NLRP3 인플라마좀의 활성화에 따른 여러 가지 질환을 효과적으로 예방, 개선 또는 치료할 수 있다.The present invention relates to a NLRP3 inflammasome inhibitor and its use for the treatment of NLRP3 inflammasome-mediated inflammatory diseases, and more particularly, to a compound having an excellent inflammasome inhibitory effect, a pharmaceutically or food acceptable salt thereof, or Provided are NLRP3 inflammasome inhibitors, pharmaceutical compositions for preventing or treating NLRP3 inflammasome-mediated inflammatory diseases, health functional food compositions, and the like, including combinations thereof.
The compound, its salt, or a combination thereof significantly inhibits NLRP3 inflammasome activity, thereby effectively preventing, ameliorating or treating various diseases caused by activation of NLRP3 inflammasome.

Description

NLRP3 인플라마좀 억제제 및 이의 용도{NLRP3 INFLAMMASOME INHIBITOR AND USES THEREOF}NLRP3 inflammasome inhibitors and uses thereof

본 발명은 NLRP3 인플라마좀 억제제 및 이의 NLRP3 인플라마좀 매개 염증성 질환의 치료 용도에 관한 것이다.The present invention relates to NLRP3 inflammasome inhibitors and their use for the treatment of NLRP3 inflammasome mediated inflammatory diseases.

인플라마좀(inflammasome)은 전염증성 사이토카인 인터루킨-1β(IL-1β) 및 IL-18의 생산에 관여하는 선천성 면역에 중요한 역할을 하는 거대 다단백질(multiprotein) 복합체이다. 이와 관련된 사이토카인은 감염, 염증 및 자가 면역 과정과 관련된 다양한 생물학적 효과를 유발한다. 이들은 비활성 전구체로서, pro-IL-1β 및 pro-IL-18로 생성되며, 카스파제-1(caspase-1)을 필요로 하는 공통 성숙 메커니즘을 공유한다. 카스파제-1 자체는 프로-카스파제-1(pro-caspase-1)의 효소전구체(zymogen)로써 합성되고, 자동 촉매화 과정을 거쳐 활성 카스파제-1을 형성하는 두 개의 서브 유닛을 생성한다. 카스파제-1의 활성은 이의 조립 후 인플라마좀 내에서 발생한다.Inflammasome is a large multiprotein complex that plays an important role in innate immunity involved in the production of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The cytokines involved induce a variety of biological effects related to infection, inflammatory and autoimmune processes. They are inactive precursors, produced from pro-IL-1β and pro-IL-18, and share a common maturation mechanism that requires caspase-1. Caspase-1 itself is synthesized as a zymogen of pro-caspase-1, and produces two subunits that form active caspase-1 through an autocatalytic process. . The activity of caspase-1 occurs within the inflammasome after its assembly.

가장 특징적인 인플라마좀은 크리오피린(cryopyrin)으로도 불리는 NLRP3 (NOD-like receptor pyrin domain-containning protein 3, 또는 NALP3) 인플라마좀으로, 감염 및 세포 손상에 대한 반응으로 IL-1β, IL-18의 분비와 파이롭토시스(pyroptosis)를 유도한다. The most characteristic inflammasome is the NLRP3 (NOD-like receptor pyrin domain-containing protein 3, or NALP3) inflammasome, also called cryopyrin, in response to infection and cell damage, including IL-1β, IL- 18 and induces pyroptosis.

그러나 NLRP3 인플라마좀의 기능은 인체에 해를 끼칠 수 있는데, 비정상적인 또는 만성적인 NLRP3 인플라마좀의 활성화는 제 2형 당뇨병, 통풍성 관절염, 심혈관 질환, 알츠하이머병 등의 병리 및 CAPS (cryopyrin-associated-periodic-syndrome)와 같은 드문 유전적 장애와 연관이 있기 때문이다. 최근에는 NLRP3 인플라마좀 활성화에 대한 이해와 새로운 치료제 개발을 위하여 관련 연구가 빠르게 진행되고 있다.However, the function of the NLRP3 inflammasome can harm the human body, and abnormal or chronic activation of the NLRP3 inflammasome is associated with pathologies such as type 2 diabetes, gouty arthritis, cardiovascular disease, Alzheimer's disease, and cryopyrin-associated- periodic-syndrome), as it is associated with rare genetic disorders. Recently, related research has been rapidly progressing to understand the activation of NLRP3 inflammasome and to develop new therapeutic agents.

대한민국 공개특허 제10-2016-0009667호 (2016.01.26. 공개)Republic of Korea Patent Publication No. 10-2016-0009667 (published on January 26, 2016)

본 발명의 목적은 우수한 인플라마좀 억제 효과를 가진 화합물을 포함하는 NLRP3 인플라마좀 억제제를 제공하는 데에 있다.It is an object of the present invention to provide an NLRP3 inflammasome inhibitor comprising a compound having an excellent inflammasome inhibitory effect.

본 발명의 다른 목적은 상기 화합물을 포함하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease comprising the compound.

본 발명의 또 다른 목적은 상기 화합물을 포함하는 NLRP3 인플라마좀 활성 억제용 시약 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a reagent composition for inhibiting NLRP3 inflammasome activity comprising the compound.

본 발명의 또 다른 목적은 상기 화합물을 처리하는 단계를 포함하는 NLRP3 인플라마좀 활성 억제 방법을 제공하는 데에 있다.Another object of the present invention is to provide a method for inhibiting NLRP3 inflammasome activity comprising the step of treating the compound.

상기의 목적을 달성하기 위해, 본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀(inflammasome) 억제제를 제공한다.In order to achieve the above object, the present invention provides an NLRP3 inflammasome inhibitor containing a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient. to provide.

본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.

본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 식품학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention provides a health functional food composition for preventing or improving NLRP3 inflammasome-mediated inflammatory disease containing a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient do.

본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 활성 억제용 시약 조성물을 제공한다.The present invention provides a reagent composition for inhibiting NLRP3 inflammasome activity comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.

또한, 본 발명은 사람을 제외한 동물에 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 처리하는 단계를 포함하는 NLRP3 인플라마좀 활성 억제 방법을 제공한다.In addition, the present invention provides a method for inhibiting NLRP3 inflammasome activity, comprising treating an animal other than a human with a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof do.

<화학식 1><Formula 1>

Figure 112020100818857-pat00001
Figure 112020100818857-pat00001

<화학식 2><Formula 2>

Figure 112020100818857-pat00002
Figure 112020100818857-pat00002

<화학식 3><Formula 3>

Figure 112020100818857-pat00003
Figure 112020100818857-pat00003

<화학식 4><Formula 4>

Figure 112020100818857-pat00004
Figure 112020100818857-pat00004

<화학식 5><Formula 5>

Figure 112020100818857-pat00005
Figure 112020100818857-pat00005

<화학식 6><Formula 6>

Figure 112020100818857-pat00006
Figure 112020100818857-pat00006

<화학식 7><Formula 7>

Figure 112020100818857-pat00007
Figure 112020100818857-pat00007

<화학식 8><Formula 8>

Figure 112020100818857-pat00008
Figure 112020100818857-pat00008

<화학식 9><Formula 9>

Figure 112020100818857-pat00009
Figure 112020100818857-pat00009

<화학식 10><Formula 10>

Figure 112020100818857-pat00010
Figure 112020100818857-pat00010

<화학식 11><Formula 11>

Figure 112020100818857-pat00011
Figure 112020100818857-pat00011

<화학식 12><Formula 12>

Figure 112020100818857-pat00012
Figure 112020100818857-pat00012

<화학식 13><Formula 13>

Figure 112020100818857-pat00013
Figure 112020100818857-pat00013

<화학식 14><Formula 14>

Figure 112020100818857-pat00014
Figure 112020100818857-pat00014

<화학식 15><Formula 15>

Figure 112020100818857-pat00015
Figure 112020100818857-pat00015

본 발명에 따른 화합물 또는 이의 약학적 또는 식품학적으로 허용가능한 염은 요산염(MSU) 결정, ATP 등에 의해 유도된 NLRP3 인플라마좀의 활성을 유의하게 억제하기에, 상기 화합물, 이의 염, 또는 이의 조합을 NLRP3 인플라마좀 억제제, NLRP3 인플라마좀 매개 염증성 질환 예방, 개선 또는 치료용 조성물 등으로 활용할 수 있고, 이를 이용하여 NLRP3 인플라마좀의 활성화에 따른 여러 가지 질환을 효과적으로 예방, 개선 또는 치료할 수 있다.The compound according to the present invention, or a pharmaceutically or pharmaceutically acceptable salt thereof, significantly inhibits the activity of NLRP3 inflammasome induced by urate (MSU) crystals, ATP, etc., The combination can be used as an NLRP3 inflammasome inhibitor, a composition for preventing, improving, or treating NLRP3 inflammasome-mediated inflammatory diseases, etc. have.

도 1 내지 도 15는 본 발명의 실험예에 사용된 화합물의 LC-MS 분석 내용이다.
도 16 및 도 17은 본 발명의 실험예 1에 따른 요산염(MSU) 결정에 의해 유도된 NLRP3 인플라마좀 활성의 억제 효과를 확인한 것이다.
도 18은 본 발명의 실험예 2에 따른 ATP(adenosine triphosphate)에 의해 유도된 NLRP3 인플라마좀 활성의 억제 효과를 확인한 것이다.1 to 15 are LC-MS analysis of compounds used in Experimental Examples of the present invention.
16 and 17 confirm the inhibitory effect of NLRP3 inflammasome activity induced by urate (MSU) crystals according to Experimental Example 1 of the present invention.
18 shows the inhibitory effect of NLRP3 inflammasome activity induced by ATP (adenosine triphosphate) according to Experimental Example 2 of the present invention.

이하, 본 발명을 상세하게 설명하기로 한다.Hereinafter, the present invention will be described in detail.

본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀(inflammasome) 억제제를 제공한다.The present invention provides an NLRP3 inflammasome inhibitor comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.

<화학식 1><Formula 1>

Figure 112020100818857-pat00016
Figure 112020100818857-pat00016

<화학식 2><Formula 2>

Figure 112020100818857-pat00017
Figure 112020100818857-pat00017

<화학식 3><Formula 3>

Figure 112020100818857-pat00018
Figure 112020100818857-pat00018

<화학식 4><Formula 4>

Figure 112020100818857-pat00019
Figure 112020100818857-pat00019

<화학식 5><Formula 5>

Figure 112020100818857-pat00020
Figure 112020100818857-pat00020

<화학식 6><Formula 6>

Figure 112020100818857-pat00021
Figure 112020100818857-pat00021

<화학식 7><Formula 7>

Figure 112020100818857-pat00022
Figure 112020100818857-pat00022

<화학식 8><Formula 8>

Figure 112020100818857-pat00023
Figure 112020100818857-pat00023

<화학식 9><Formula 9>

Figure 112020100818857-pat00024
Figure 112020100818857-pat00024

<화학식 10><Formula 10>

Figure 112020100818857-pat00025
Figure 112020100818857-pat00025

<화학식 11><Formula 11>

Figure 112020100818857-pat00026
Figure 112020100818857-pat00026

<화학식 12><Formula 12>

Figure 112020100818857-pat00027
Figure 112020100818857-pat00027

<화학식 13><Formula 13>

Figure 112020100818857-pat00028
Figure 112020100818857-pat00028

<화학식 14><Formula 14>

Figure 112020100818857-pat00029
Figure 112020100818857-pat00029

<화학식 15><Formula 15>

Figure 112020100818857-pat00030
Figure 112020100818857-pat00030

상기 화합물 또는 이의 염은 당업계에서 잘 알려진 방법으로 분리 또는 추출되거나 화학적 합성법에 의해 제조될 수 있으며, 시판중인 것을 선택하여 사용할 수 있으나, 그 방법 또는 물질은 특별히 한정되지 않는다.The compound or its salt may be separated or extracted by a method well known in the art, or may be prepared by chemical synthesis, and a commercially available one may be selected and used, but the method or material is not particularly limited.

바람직하게는, 상기 화합물은 2,3,3,3-테트라플루오로-N-[2-(3-플루오로페닐)에틸]-2-페닐프로판아미드 (2,3,3,3-tetrafluoro-N-[2-(3-fluorophenyl)ethyl]-2-phenylpropanamide, 화합물 1), 5-메틸-3-[4-(트리플루오로메틸)페닐]-1H-2,1,4-벤족사디아진 (5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-2,1,4-benzoxadiazine, 화합물 2), 4,5-디에틸 1-(5-클로로-2-메톡시페닐)-1H-1,2,3-트리아졸-4,5-디카르복시레이트 (4,5-diethyl 1-(5-chloro-2-methoxyphenyl)-1H-1,2,3-triazole-4,5-dicarboxylate, 화합물 3), 에틸 4-[5-(에톡시카르보닐)-2-메틸-1,3-티아졸-4-일]피페라딘-1-카르복시레이트 (ethyl 4-[5-(ethoxycarbonyl)-2-methyl-1,3-thiazol-4-yl]piperidine-1-carboxylate, 화합물 4), 에틸 5-(2,2-디메틸프로판아미도)-1-{2-[(2,2-디메틸프로파노일)옥시]에틸}-1H-피라졸-4-카르복시레이트 (ethyl 5-(2,2-dimethylpropanamido)-1-{2-[(2,2-dimethylpropanoyl)oxy]ethyl}-1H-pyrazole-4-carboxylate, 화합물 5), N-(2-벤조일-4-클로로페닐)-2-(6-메틸-3-옥소-3,4-디하이드로-2H-1,4-벤족사진-2-일)아세트아미드 (N-(2-benzoyl-4-chlorophenyl)-2-(6-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)acetamide, 화합물 6), 1-(8-메틸-4-옥소-1,4-디하이드로퀴놀린-3-일)-3-(프롭-2-엔-1-일)우레아 (1-(8-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-3-(prop-2-en-1-yl)urea, 화합물 7), N-(4-플루오로페닐)-3-메틸-N-({5-메틸-7-옥소-4H,7H-[1,2,4]트리아졸[1,5-a]피리미딘-2-일}메틸)부탄아미드 (N-(4-fluorophenyl)-3-methyl-N-({5-methyl-7-oxo-4H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methyl)butanamide, 화합물 8), 1-{[5-(3,4-디메틸-1,2-옥사졸-5-일)티오펜-2-일]술포닐}-4-메틸피페라진 (1-{[5-(3,4-dimethyl-1,2-oxazol-5-yl)thiophen-2-yl]sulfonyl}-4-methylpiperazine, 화합물 9), 5-[2-(4-하이드록시페닐)하이드라진-1-일리덴]-2,2-디메틸-1,3-디옥세인-4,6-디온 (5-[2-(4-hydroxyphenyl)hydrazin-1-ylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione, 화합물 10), 메틸 4-{1-메틸-4,6-디옥소-1H,3aH,4H,5H,5H,6H,6aH-피롤[3,4-c]피라졸-3-일}벤조에이트 (methyl 4-{1-methyl-4,6-dioxo-1H,3aH,4H,5H,5H,6H,6aH-pyrrolo[3,4-c]pyrazol-3-yl}benzoate, 화합물 11), 3-(2-{[5-(2-클로로페닐)-4H-1,2,4-트리아졸-4-일]설파닐}아세틸)-3,8,8-트리메틸-2,7-디옥사스피로[4.4]노네인-1,6-디온 (3-(2-{[5-(2-chlorophenyl)-4H-1,2,4-triazol-4-yl]sulfanyl}acetyl)-3,8,8-trimethyl-2,7-dioxaspiro[4.4]nonane-1,6-dione, 화합물 12), 4-[4-(3-에틸피페라진-1-카르보닐)-2-메틸부트-3-인-2-올 (4-[4-(3-ethylpiperazine-1-carbonyl)-2-methylbut-3-yn-2-ol, 화합물 13), 4-페닐-3-(피페리딘-3-일)-1-[(피리미딘-2-일)메틸]-4,5-디하이드로-1H-1,2,4-트리아졸-5-원 (4-phenyl-3-(piperidin-3-yl)-1-[(pyrimidin-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one, 화합물 14), 및 N-메틸-N-[(4-메틸-1,2,3-티아디아졸-5-일)메틸]-4,5,6,7-테트라하이드로-1,3-벤조티아졸-2-카르복사미드 (N-methyl-N-[(4-methyl-1,2,3-thiadiazol-5-yl)methyl]-4,5,6,7-tetrahydro-1,3-benzothiazole-2-carboxamide, 화합물 15)일 수 있으나, 이에 제한되는 것은 아니다.Preferably, the compound is 2,3,3,3-tetrafluoro-N-[2-(3-fluorophenyl)ethyl]-2-phenylpropanamide ( 2,3,3,3-tetrafluoro- N-[2-(3-fluorophenyl)ethyl]-2-phenylpropanamide , compound 1), 5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-2,1,4-benzoxadia Gin ( 5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-2,1,4-benzoxadiazine , compound 2), 4,5-diethyl 1- (5-chloro-2-methoxyphenyl) -1H-1,2,3-triazole-4,5-dicarboxylate ( 4,5-diethyl 1-(5-chloro-2-methoxyphenyl)-1H-1,2,3-triazole-4,5 -dicarboxylate , compound 3), ethyl 4-[5-(ethoxycarbonyl)-2-methyl-1,3-thiazol-4-yl]piperadine-1-carboxylate ( ethyl 4-[5- (ethoxycarbonyl)-2-methyl-1,3-thiazol-4-yl]piperidine-1-carboxylate , compound 4), ethyl 5-(2,2-dimethylpropanamido)-1-{2-[(2) ,2-dimethylpropanoyl)oxy]ethyl}-1H-pyrazole-4-carboxylate ( ethyl 5-(2,2-dimethylpropanamido)-1-{2-[(2,2-dimethylpropanoyl)oxy]ethyl }-1H-pyrazole-4-carboxylate , compound 5), N-(2-benzoyl-4-chlorophenyl)-2-(6-methyl-3-oxo-3,4-dihydro-2H-1,4 -Benzoxazin-2-yl)acetamide ( N-(2-benzoyl-4-chlorophenyl)-2-(6-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2- yl)acetamide , compound 6), 1-(8-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-3-(prop-2-en-1-yl)urea ( 1-( 8-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-3-(prop-2-en-1-yl)ur ea , compound 7), N-(4-fluorophenyl)-3-methyl-N-({5-methyl-7-oxo-4H,7H-[1,2,4]triazole[1,5- a]pyrimidin-2-yl}methyl)butanamide ( N-(4-fluorophenyl)-3-methyl-N-({5-methyl-7-oxo-4H,7H-[1,2,4]triazolo) [1,5-a]pyrimidin-2-yl}methyl)butanamide , compound 8), 1-{[5-(3,4-dimethyl-1,2-oxazol-5-yl)thiophene-2- yl]sulfonyl}-4-methylpiperazine ( 1-{[5-(3,4-dimethyl-1,2-oxazol-5-yl)thiophen-2-yl]sulfonyl}-4-methylpiperazine , compound 9 ), 5- [2- (4-hydroxyphenyl) hydrazin-1-ylidene] -2,2-dimethyl-1,3-dioxane-4,6-dione ( 5- [2- (4-hydroxyphenyl )hydrazin-1-ylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione , compound 10), methyl 4-{1-methyl-4,6-dioxo-1H,3aH,4H ,5H,5H,6H,6aH-pyrrole[3,4-c]pyrazol-3-yl}benzoate ( methyl 4-{1-methyl-4,6-dioxo-1H,3aH,4H,5H,5H ,6H,6aH-pyrrolo[3,4-c]pyrazol-3-yl}benzoate , compound 11), 3-(2-{[5-(2-chlorophenyl)-4H-1,2,4-tria zol-4-yl]sulfanyl}acetyl)-3,8,8-trimethyl-2,7-dioxaspiro[4.4]nonane-1,6-dione ( 3-(2-{[5-(2) -chlorophenyl)-4H-1,2,4-triazol-4-yl]sulfanyl}acetyl)-3,8,8-trimethyl-2,7-dioxaspiro[4.4]nonane-1,6-dione , compound 12) , 4-[4-(3-ethylpiperazine-1-carbonyl)-2-methylbut-3-yn-2-ol ( 4-[4-(3-ethylpiperazine-1-carbonyl)-2-methylbut -3-yn-2-ol , compound 13), 4-phenyl-3-(piperidin-3-yl)-1-[( Pyrimidin-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one ( 4-phenyl-3-(piperidin-3-yl)-1-[( pyrimidin-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one , compound 14), and N-methyl-N-[(4-methyl-1,2, 3-thiadiazol-5-yl)methyl]-4,5,6,7-tetrahydro-1,3-benzothiazole-2-carboxamide ( N-methyl-N-[(4-methyl- 1,2,3-thiadiazol-5-yl)methyl]-4,5,6,7-tetrahydro-1,3-benzothiazole-2-carboxamide , compound 15), but is not limited thereto.

상기 화합물은 이와 동일한 효능을 갖는 범위 내에서 약학적 또는 식품학적으로 허용가능한 염의 형태로 사용할 수 있다.The compound may be used in the form of a pharmaceutically or food-acceptable salt within the range having the same efficacy.

본 명세서에서, "약학적 또는 식품학적으로 허용가능한"이란, 상기 조성물에 노출되는 세포나 인간에게 독성이 없어, 인간에게 투여하기에 적합한 안전성 및 효능 프로파일을 갖는 염을 의미한다. As used herein, "pharmaceutically or food acceptable" means a salt having a safety and efficacy profile suitable for administration to humans without toxicity to cells or humans exposed to the composition.

상기 염은 약학적 또는 식품학적으로 허용가능한 염기성 염 또는 산성염 중 어느 하나의 형태로 사용할 수 있다. 염기성염은 유기 염기염, 무기 염기염 중 어느 하나의 형태로 사용할 수 있으며, 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염, 아미늄염, 암모늄염, 트리에칠아미늄염 및 피리디늄염으로 이루어진 군에서 선택될 수 있다.The salt may be used in the form of any one of pharmaceutically or food-acceptable basic salt or acid salt. The basic salt can be used in the form of any one of an organic basic salt and an inorganic basic salt, and includes a sodium salt, a potassium salt, a calcium salt, a lithium salt, a magnesium salt, a cesium salt, an aminium salt, an ammonium salt, a triethylaminium salt, and pyrithyl. It may be selected from the group consisting of dinium salts.

산성염은 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산, 이중 인산, 질산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 말산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산, 스테아르산 등을 사용할 수 있으나, 이에 제한되지 않고 당업계에서 통상적으로 사용되는 다양한 무기산 및 유기산을 이용하여 형성되는 염이 모두 포함될 수 있다.As the acid salt, an acid addition salt formed by a free acid is useful. As the free acid, an inorganic acid and an organic acid can be used. As the inorganic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, double phosphoric acid, nitric acid, etc. can be used. As the organic acid, citric acid, acetic acid, maleic acid, malic acid, and fumaric acid can be used. , gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, Glutamic acid, citric acid, aspartan acid, stearic acid, etc. may be used, but is not limited thereto, and salts formed using various inorganic and organic acids commonly used in the art may be included.

또한, 상기 화합물은 상기 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물, 용매화물, 유도체 등을 모두 포함할 수 있다. 부가염은 통상의 방법으로 제조할 수 있고, 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹여 과량의 유기염기를 가하거나 무기염기의 염기 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 또는 이 혼합물에서 용매나 과량의 염기를 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.In addition, the compound may include all salts, hydrates, solvates, derivatives, etc. that can be prepared by a conventional method as well as the salt. The addition salt can be prepared by a conventional method, and is dissolved in a water-miscible organic solvent, for example, acetone, methanol, ethanol, or acetonitrile, and an excess of an organic base is added or an aqueous base of an inorganic base is added, followed by precipitation or crystallization. It can be manufactured by Alternatively, an addition salt may be obtained by evaporating the solvent or excess base from the mixture and drying, or it may be prepared by suction filtration of the precipitated salt.

본 발명에 따른 NLRP3 인플라마좀 억제제에 있어서, 상기 화합물, 이의 염 또는 이의 조합은 NLRP3 인플라마좀의 활성을 억제할 수 있다. In the NLRP3 inflammasome inhibitor according to the present invention, the compound, a salt thereof, or a combination thereof can inhibit the activity of the NLRP3 inflammasome.

상기 NLRP3 인플라마좀의 활성 억제는 목적하는 세포 등의 인플라마좀 활성화의 저하를 야기하는 생체 내 변형을 의미하며, 본 발명의 목적상 상기 인플라마좀의 생성 억제 또는 인플라마좀으로 인한 사이토카인 생성 억제일 수 있으나, 이에 제한되는 것은 아니다.Inhibition of the activity of the NLRP3 inflammasome means an in vivo modification that causes a decrease in inflammasome activation of a target cell, etc., and for the purpose of the present invention, inhibition of inflammasome production or cytokine caused by inflammasome It may be production inhibition, but is not limited thereto.

보다 상세하게는, 상기 화합물, 이의 염 또는 이의 조합은 요산염(monosodium urate monohydrate; MSU) 결정, ATP(adenosine triphosphate) 및 니제리신(nigericin)으로 이루어진 군에서 선택되는 하나 이상에 의해 유도된 NLRP3 인플라마좀의 활성을 억제할 수 있다.More specifically, the compound, a salt thereof, or a combination thereof is NLRP3 induced by at least one selected from the group consisting of monosodium urate monohydrate (MSU) crystals, adenosine triphosphate (ATP) and nigericin. It can inhibit the activity of the inflammasome.

상기 인플라마좀은 이 외에도 병원체 성분, UV 조사 등의 외래성 인자를 비롯하여, 콜레스테롤 결정, 아밀로이드 β(amyloid β), 포화 지방산, 수산화알루미늄(aluminum hydroxide) 등에 의해 활성화될 수 있으나, 이에 제한되는 것은 아니다.In addition to this, the inflammasome may be activated by pathogen components, exogenous factors such as UV irradiation, cholesterol crystals, amyloid β, saturated fatty acids, aluminum hydroxide, etc., but is not limited thereto. .

또한, 상기 화합물, 이의 염 또는 이의 조합은 인터루킨-1β(IL-1β), IL-18 또는 카스파제-1(caspase-1)의 생성을 억제할 수 있다.In addition, the compound, a salt thereof, or a combination thereof may inhibit the production of interleukin-1β (IL-1β), IL-18 or caspase-1.

보다 상세하게는, 상기 화합물, 이의 염 또는 이의 조합은 MSU, ATP 및 니제리신으로 이루어진 군에서 선택되는 하나 이상에 의해 활성화된 IL-1β, IL-18 또는 caspase-1의 생성을 억제할 수 있다.More specifically, the compound, its salt, or a combination thereof may inhibit the production of IL-1β, IL-18 or caspase-1 activated by at least one selected from the group consisting of MSU, ATP and nigericin. have.

본 발명의 일 실험예에 따르면, MSU, 또는 ATP에 의해 NLRP3 인플라마좀이 활성화된 세포에 상기 화합물을 처리하였을 때 IL-1β 또는 caspase-1의 생성이 유의하게 억제되는 것을 확인할 수 있었다.According to an experimental example of the present invention, it was confirmed that the production of IL-1β or caspase-1 was significantly inhibited when the compound was treated in cells in which NLRP3 inflammasome was activated by MSU or ATP.

본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.

<화학식 1><Formula 1>

Figure 112020100818857-pat00031
Figure 112020100818857-pat00031

<화학식 2><Formula 2>

Figure 112020100818857-pat00032
Figure 112020100818857-pat00032

<화학식 3><Formula 3>

Figure 112020100818857-pat00033
Figure 112020100818857-pat00033

<화학식 4><Formula 4>

Figure 112020100818857-pat00034
Figure 112020100818857-pat00034

<화학식 5><Formula 5>

Figure 112020100818857-pat00035
Figure 112020100818857-pat00035

<화학식 6><Formula 6>

Figure 112020100818857-pat00036
Figure 112020100818857-pat00036

<화학식 7><Formula 7>

Figure 112020100818857-pat00037
Figure 112020100818857-pat00037

<화학식 8><Formula 8>

Figure 112020100818857-pat00038
Figure 112020100818857-pat00038

<화학식 9><Formula 9>

Figure 112020100818857-pat00039
Figure 112020100818857-pat00039

<화학식 10><Formula 10>

Figure 112020100818857-pat00040
Figure 112020100818857-pat00040

<화학식 11><Formula 11>

Figure 112020100818857-pat00041
Figure 112020100818857-pat00041

<화학식 12><Formula 12>

Figure 112020100818857-pat00042
Figure 112020100818857-pat00042

<화학식 13><Formula 13>

Figure 112020100818857-pat00043
Figure 112020100818857-pat00043

<화학식 14><Formula 14>

Figure 112020100818857-pat00044
Figure 112020100818857-pat00044

<화학식 15><Formula 15>

Figure 112020100818857-pat00045
Figure 112020100818857-pat00045

상기 화합물, 이의 염 또는 이의 조합은 NLRP3 인플라마좀 활성을 억제할 수 있다.The compound, a salt thereof, or a combination thereof may inhibit NLRP3 inflammasome activity.

보다 상세하게는, 상기 화합물, 이의 염 또는 이의 조합은 MSU, ATP 및 니제리신으로 이루어진 군에서 선택되는 하나 이상에 의해 유도된 NLRP3 인플라마좀의 활성을 억제할 수 있다.More specifically, the compound, a salt thereof, or a combination thereof may inhibit the activity of NLRP3 inflammasome induced by at least one selected from the group consisting of MSU, ATP and nigericin.

상기 화합물, 이의 염 또는 이의 조합은 NLRP3 인플라마좀 활성을 억제함으로써, NLRP3 인플라마좀 매개 염증성 질환을 예방 또는 치료할 수 있다.The compound, a salt thereof, or a combination thereof inhibits NLRP3 inflammasome activity, thereby preventing or treating inflammatory diseases mediated by NLRP3 inflammasome.

본 발명에 따른 약학 조성물에 있어서, 상기 NLRP3 인플라마좀 매개 염증성 질환은 인플라마좀이 비정상적으로 과도하게 활성화된 경우에 발생하게 되는 이상 질환으로, 통풍, 관절염, 통풍성 관절염, 죽상동맥경화증, 알츠하이머, 아토피 피부염, 비알코올성지방간, 제 2형 당뇨, 대사증후군, 대사 장애 및 NLRP3가 매개하는 자가염증질환에서 이루어진 군에서 선택될 수 있고, 상기 NLRP3가 매개하는 자가염증질환은 크리오피린 관련 주기적 증후군(Cryopyrin-associated periodic syndromes, CAPS), 가족성 한랭 자가염증 증후군(Familial cold autoinflammatory syndrome, FCAS), 머클-웰스 증후군(Muckle-Wells syndrome, MWS), 신생아 발현 다발성 염증 질환(Neonatal-onset multisystem inflammatory disease, NOMID), 가족성 지중해열(Familial Mediterranean fever, FMF), 괴저성 농피증과 여드름을 동반한 화농성 관절염 증후군(Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome), 및 주기성 발열을 동반한 고면역글로불린 혈증 D 증후군(Hyperimmunoglobulinemia D with periodic fever syndrome, HIDS)로 이루어진 군에서 선택될 수 있으나, 이에 제한되지 않고, 당업계에 널리 공지된 관련 질환을 모두 포함할 수 있다.In the pharmaceutical composition according to the present invention, the NLRP3 inflammasome-mediated inflammatory disease is an abnormal disease that occurs when the inflammasome is abnormally and excessively activated, including gout, arthritis, gouty arthritis, atherosclerosis, Alzheimer's, It may be selected from the group consisting of atopic dermatitis, nonalcoholic fatty liver, type 2 diabetes, metabolic syndrome, metabolic disorders and NLRP3-mediated auto-inflammatory disease, and the NLRP3-mediated auto-inflammatory disease is cryopyrin-related periodic syndrome (Cryopyrin). -associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID) ), familial Mediterranean fever (FMF), Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome, and hyperimmunoglobulinemia with periodic fever D Syndrome (Hyperimmunoglobulinemia D with periodic fever syndrome, HIDS) may be selected from the group consisting of, but is not limited thereto, and may include all related diseases well known in the art.

본 발명에 따른 약학 조성물에 있어서, 상기 약학 조성물은 약학 조성물 총 100 중량부에 대하여, 상기 화합물, 이의 염 또는 이의 조합이 0.01 내지 90 중량부로 함유될 수 있으나, 이에 제한되는 것은 아니다.In the pharmaceutical composition according to the present invention, the pharmaceutical composition may contain 0.01 to 90 parts by weight of the compound, a salt thereof, or a combination thereof, based on 100 parts by weight of the total pharmaceutical composition, but is not limited thereto.

본 발명에 따른 약학 조성물은 약학적 분야의 통상적인 방법에 따라 제조될 수 있다. 상기 약학 조성물은 제형에 따라 약학적으로 허용가능한 적절한 담체와 배합될 수 있고, 필요에 따라, 부형제, 희석제, 분산제, 유화제, 완충제, 안정제, 결합제, 붕해제, 용제 등을 더 포함하여 제조될 수 있다. 상기 적절한 담체 등은 본 발명에 따른 화합물 또는 이의 약학적으로 허용가능한 염의 활성 및 특성을 저해하지 않는 것으로, 투여 형태 및 제형에 따라 달리 선택될 수 있다.The pharmaceutical composition according to the present invention may be prepared according to a conventional method in the pharmaceutical field. The pharmaceutical composition may be combined with a suitable pharmaceutically acceptable carrier according to the formulation, and if necessary, excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. may be prepared further comprising have. The appropriate carrier and the like do not inhibit the activity and properties of the compound according to the present invention or a pharmaceutically acceptable salt thereof, and may be selected differently depending on the dosage form and formulation.

본 발명에 따른 약학 조성물은 어떠한 제형으로도 적용될 수 있고, 보다 상세하게는 통상의 방법에 따라 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 비경구형 제형으로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention can be applied in any dosage form, and more specifically, it can be used by formulating oral dosage forms, external preparations, suppositories, and parenteral dosage forms of sterile injection solutions according to conventional methods.

상기 경구형 제형 중 고형 제형은 정제, 환제, 산제, 과립제, 캡슐제 등의 형태로, 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스, 락토오스, 솔비톨, 만니톨, 셀룰로오스, 젤라틴 등을 섞어 조제할 수 있고, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 포함될 수 있다. 또한, 캡술제형의 경우 상기 언급한 물질 외에도 지방유와 같은 액체 담체를 더 포함할 수 있다.The solid dosage form among the oral dosage forms is in the form of tablets, pills, powders, granules, capsules, etc., and at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may be included. In addition, the capsule formulation may further include a liquid carrier such as fatty oil in addition to the above-mentioned substances.

상기 경구형 제형 중 액상 제형은 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Among the oral dosage forms, liquid formulations include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. have.

상기 비경구 제형은 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함될 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 이에 제한되지 않고, 당해 기술 분야에 알려진 적합한 제제를 모두 사용 가능하다.The parenteral formulation may include a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a freeze-dried formulation, and a suppository. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, Tween 61, cacao butter, laurin fat, glycerogelatin, and the like can be used. It is not limited thereto, and any suitable agent known in the art may be used.

또한, 본 발명에 따른 약학 조성물은 치료 효능의 증진을 위해 칼슘이나 비타민 등을 더 첨가할 수 있다. In addition, the pharmaceutical composition according to the present invention may further add calcium or vitamins to enhance therapeutic efficacy.

본 발명에 따른 약학 조성물에 있어서, 상기 약학 조성물은 약학적으로 유효한 양으로 투여될 수 있다. In the pharmaceutical composition according to the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount.

본 명세서에서, "약학적으로 유효한 양"이란, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미한다.As used herein, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects.

상기 약학 조성물의 유효 용량 수준은 사용 목적, 환자의 연령, 성별, 체중 및 건강 상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 달리 결정될 수 있다. 예를 들어, 일정하지는 않지만 일반적으로 0.001 내지 100mg/kg으로, 바람직하게는 0.01 내지 10mg/kg을 일일 1회 내지 수회 투여될 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The effective dose level of the pharmaceutical composition may be determined according to the purpose of use, the age, sex, weight and health status of the patient, the type of disease, the severity, the activity of the drug, the sensitivity to the drug, the administration method, the administration time, the administration route and the excretion rate, the treatment The duration, formulation, or concomitant use may be determined differently depending on factors including drugs and other factors well known in the medical field. For example, although not constant, generally 0.001 to 100 mg/kg, preferably 0.01 to 10 mg/kg, may be administered once to several times a day. The above dosage does not limit the scope of the present invention in any way.

본 발명에 따른 약학 조성물은 NLRP3 인플라마좀 매개 염증성 질환이 발생할 수 있는 임의의 동물에 투여할 수 있고, 상기 동물은 예를 들어, 인간 및 영장류뿐만 아니라 소, 돼지, 말, 개 등의 가축 등을 포함할 수 있다.The pharmaceutical composition according to the present invention can be administered to any animal that can develop NLRP3 inflammasome-mediated inflammatory disease, and the animal is, for example, not only humans and primates, but also cattle, pigs, horses, dogs, and the like. may include

본 발명에 따른 약학 조성물은 제제 형태에 따른 적당한 투여 경로로 투여될 수 있고, 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다. 투여 방법은 특히 한정할 필요 없이, 예를 들면, 경구, 직장 또는 정맥, 근육, 피부 도포, 호흡기내 흡입, 자궁내 경막 또는 뇌혈관내(intracere-broventricular) 주사 등의 통상적인 방법으로 투여될 수 있다.The pharmaceutical composition according to the present invention may be administered by an appropriate administration route according to the form of the formulation, and may be administered via various routes, either oral or parenteral, as long as it can reach the target tissue. The administration method is not particularly limited, and for example, oral, rectal or intravenous, muscle, skin application, respiratory inhalation, intrauterine dural or intracerebroventricular injection, etc. can be administered in a conventional manner. have.

본 발명에 따른 약학 조성물은 NLRP3 인플라마좀 매개 염증성 질환의 예방 또는 치료를 위하여 단독으로 사용될 수 있고, 수술 또는 다른 약물 치료 등과 병용하여 사용될 수 있다.The pharmaceutical composition according to the present invention may be used alone for the prevention or treatment of NLRP3 inflammasome-mediated inflammatory disease, or may be used in combination with surgery or other drug treatment.

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 식품학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention provides a health functional food composition for preventing or improving NLRP3 inflammasome-mediated inflammatory disease comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.

<화학식 1><Formula 1>

Figure 112020100818857-pat00046
Figure 112020100818857-pat00046

<화학식 2><Formula 2>

Figure 112020100818857-pat00047
Figure 112020100818857-pat00047

<화학식 3><Formula 3>

Figure 112020100818857-pat00048
Figure 112020100818857-pat00048

<화학식 4><Formula 4>

Figure 112020100818857-pat00049
Figure 112020100818857-pat00049

<화학식 5><Formula 5>

Figure 112020100818857-pat00050
Figure 112020100818857-pat00050

<화학식 6><Formula 6>

Figure 112020100818857-pat00051
Figure 112020100818857-pat00051

<화학식 7><Formula 7>

Figure 112020100818857-pat00052
Figure 112020100818857-pat00052

<화학식 8><Formula 8>

Figure 112020100818857-pat00053
Figure 112020100818857-pat00053

<화학식 9><Formula 9>

Figure 112020100818857-pat00054
Figure 112020100818857-pat00054

<화학식 10><Formula 10>

Figure 112020100818857-pat00055
Figure 112020100818857-pat00055

<화학식 11><Formula 11>

Figure 112020100818857-pat00056
Figure 112020100818857-pat00056

<화학식 12><Formula 12>

Figure 112020100818857-pat00057
Figure 112020100818857-pat00057

<화학식 13><Formula 13>

Figure 112020100818857-pat00058
Figure 112020100818857-pat00058

<화학식 14><Formula 14>

Figure 112020100818857-pat00059
Figure 112020100818857-pat00059

<화학식 15><Formula 15>

Figure 112020100818857-pat00060
Figure 112020100818857-pat00060

상기 화합물, 이의 염 또는 이의 조합은 NLRP3 인플라마좀 활성을 억제할 수 있다.The compound, a salt thereof, or a combination thereof may inhibit NLRP3 inflammasome activity.

보다 상세하게는, 상기 화합물, 이의 염 또는 이의 조합은 MSU, ATP 및 니제리신으로 이루어진 군에서 선택되는 하나 이상에 의해 유도된 NLRP3 인플라마좀의 활성을 억제할 수 있다.More specifically, the compound, a salt thereof, or a combination thereof may inhibit the activity of NLRP3 inflammasome induced by at least one selected from the group consisting of MSU, ATP and nigericin.

상기 화합물, 이의 염 또는 이의 조합은 NLRP3 인플라마좀 활성을 억제함으로써, NLRP3 인플라마좀 매개 염증성 질환을 예방 또는 개선할 수 있다.The compound, a salt thereof, or a combination thereof may prevent or ameliorate NLRP3 inflammasome-mediated inflammatory diseases by inhibiting NLRP3 inflammasome activity.

본 발명에 따른 건강기능식품 조성물에 있어서, 상기 NLRP3 인플라마좀 매개 염증성 질환은 인플라마좀이 비정상적으로 과도하게 활성화된 경우에 발생하게되는 이상 질환으로, 통풍, 관절염, 통풍성 관절염, 죽상동맥경화증, 알츠하이머, 아토피 피부염, 비알코올성지방간, 제 2형 당뇨, 대사증후군, 대사 장애 및 NLRP3가 매개하는 자가염증질환에서 이루어진 군에서 선택될 수 있고, 상기 NLRP3가 매개하는 자가염증질환은 크리오피린 관련 주기적 증후군(Cryopyrin-associated periodic syndromes, CAPS), 가족성 한랭 자가염증 증후군(Familial cold autoinflammatory syndrome, FCAS), 머클-웰스 증후군(Muckle-Wells syndrome, MWS), 신생아 발현 다발성 염증 질환(Neonatal-onset multisystem inflammatory disease, NOMID), 가족성 지중해열(Familial Mediterranean fever, FMF), 괴저성 농피증과 여드름을 동반한 화농성 관절염 증후군(Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome), 및 주기성 발열을 동반한 고면역글로불린 혈증 D 증후군(Hyperimmunoglobulinemia D with periodic fever syndrome, HIDS)로 이루어진 군에서 선택될 수 있으나, 이에 제한되지 않고, 당업계에 널리 공지된 관련 질환을 모두 포함할 수 있다.In the health functional food composition according to the present invention, the NLRP3 inflammasome-mediated inflammatory disease is an abnormal disease that occurs when the inflammasome is abnormally and excessively activated, including gout, arthritis, gouty arthritis, atherosclerosis, It may be selected from the group consisting of Alzheimer's disease, atopic dermatitis, nonalcoholic fatty liver, type 2 diabetes, metabolic syndrome, metabolic disorders and NLRP3-mediated auto-inflammatory diseases, and the NLRP3-mediated auto-inflammatory disease is cryopyrin-related periodic syndrome. (Cryopyrin-associated periodic syndromes, CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease , NOMID), familial Mediterranean fever (FMF), Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome, and hyperimmunoglobulin with periodic fever It may be selected from the group consisting of hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), but is not limited thereto, and may include all related diseases well known in the art.

본 발명에 따른 건강기능식품 조성물에 있어서, 상기 건강기능식품 조성물은 건강기능식품 조성물 총 100 중량부에 대하여, 상기 화합물, 이의 염 또는 이의 조합이 0.01 내지 90 중량부로 함유될 수 있으나, 이에 제한되는 것은 아니다.In the health functional food composition according to the present invention, the health functional food composition may contain 0.01 to 90 parts by weight of the compound, its salt, or a combination thereof, based on 100 parts by weight of the total health functional food composition, but is limited thereto it is not

본 발명에 따른 건강기능식품 조성물에 있어서, 상기 건강기능식품은 NLRP3 인플라마좀 매개 염증성 질환의 예방 또는 개선 목적으로, 분말, 과립, 정제, 캡슐, 시럽 또는 음료 등으로 제조될 수 있다. 상기 건강기능식품이 취할 수 있는 형태에는 제한이 없으며, 상기 약학 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가될 수 있다. In the health functional food composition according to the present invention, the health functional food may be prepared as powder, granule, tablet, capsule, syrup or beverage for the purpose of preventing or improving NLRP3 inflammasome-mediated inflammatory disease. There is no limitation in the form that the health functional food can take, and it can be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.

본 발명에 따른 건강기능식품 조성물에 있어서, 상기 건강기능식품은 통상적인 의미의 식품을 모두 포함할 수 있다. 예를 들어, 음료 및 각종 드링크, 과실 및 그의 가공식품(과일통조림, 잼 등), 어류, 육류 및 그 가공식품(햄, 베이컨 등), 빵류 및 면류, 쿠키 및 스낵류, 유제품(버터, 치즈 등) 등이 가능하며, 통상적인 의미에서의 기능성 식품을 모두 포함할 수 있다. 또한 동물을 위한 사료로 이용되는 식품도 포함할 수 있다.In the health functional food composition according to the present invention, the health functional food may include all foods in a conventional sense. For example, beverages and various drinks, fruits and their processed foods (canned fruit, jam, etc.), fish, meat and their processed foods (ham, bacon, etc.), breads and noodles, cookies and snacks, dairy products (butter, cheese, etc.) ), etc. are possible, and may include all functional foods in a conventional sense. It may also include food used as feed for animals.

본 발명에 따른 건강기능식품 조성물은 당업계에서 통상적으로 사용되는 식품학적으로 허용가능한 식품 첨가제(식품 첨가물) 및 적절한 기타 보조 성분을 더 포함하여 제조될 수 있다. 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정할 수 있다. 상기 '식품첨가물공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합 제제류 등을 들 수 있다. The health functional food composition according to the present invention may be prepared by further including pharmaceutically acceptable food additives (food additives) and other suitable auxiliary ingredients commonly used in the art. Whether or not it is suitable as a food additive can be judged according to the standards and standards for the relevant item in accordance with the general rules and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety, unless otherwise specified. The items listed in the 'Food Additives Codex' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations, such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar dye preparation, etc. are mentioned.

상기 기타 보조 성분은 예를 들어, 향미제, 천연 탄수화물, 감미제, 비타민, 전해질, 착색제, 펙트산, 알긴산, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산화제 등을 추가로 함유할 수 있다. 특히, 상기 천연 탄수화물로는 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로오스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜을 사용할 수 있으며, 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.The other auxiliary ingredients include, for example, flavoring agents, natural carbohydrates, sweeteners, vitamins, electrolytes, coloring agents, pectic acid, alginic acid, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents, etc. may further contain. In particular, as the natural carbohydrate, monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol can be used. , As the sweetener, natural sweeteners such as taumatine and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used.

본 발명에 따른 건강기능식품에 함유된 상기 화합물 또는 이의 염의 유효용량은 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 개선 등 그 사용 목적에 따라 적절하게 조절될 수 있다. The effective dose of the compound or its salt contained in the health functional food according to the present invention may be appropriately adjusted according to the purpose of use, such as prevention or improvement of NLRP3 inflamasome-mediated inflammatory disease.

상기 건강기능식품 조성물은 식품을 원료로 하여 일반 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, NLRP3 인플라마좀 매개 염증성 질환 예방 또는 개선을 위한 보조제로 섭취될 수 있다.The health functional food composition uses food as a raw material and has the advantage of not having side effects that may occur when taking general drugs for a long time, and has excellent portability, so it can be taken as an adjuvant for preventing or improving NLRP3 inflammasome-mediated inflammatory disease. have.

또한, 본 발명은 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 활성 억제용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for inhibiting NLRP3 inflammasome activity containing a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.

<화학식 1><Formula 1>

Figure 112020100818857-pat00061
Figure 112020100818857-pat00061

<화학식 2><Formula 2>

Figure 112020100818857-pat00062
Figure 112020100818857-pat00062

<화학식 3><Formula 3>

Figure 112020100818857-pat00063
Figure 112020100818857-pat00063

<화학식 4><Formula 4>

Figure 112020100818857-pat00064
Figure 112020100818857-pat00064

<화학식 5><Formula 5>

Figure 112020100818857-pat00065
Figure 112020100818857-pat00065

<화학식 6><Formula 6>

Figure 112020100818857-pat00066
Figure 112020100818857-pat00066

<화학식 7><Formula 7>

Figure 112020100818857-pat00067
Figure 112020100818857-pat00067

<화학식 8><Formula 8>

Figure 112020100818857-pat00068
Figure 112020100818857-pat00068

<화학식 9><Formula 9>

Figure 112020100818857-pat00069
Figure 112020100818857-pat00069

<화학식 10><Formula 10>

Figure 112020100818857-pat00070
Figure 112020100818857-pat00070

<화학식 11><Formula 11>

Figure 112020100818857-pat00071
Figure 112020100818857-pat00071

<화학식 12><Formula 12>

Figure 112020100818857-pat00072
Figure 112020100818857-pat00072

<화학식 13><Formula 13>

Figure 112020100818857-pat00073
Figure 112020100818857-pat00073

<화학식 14><Formula 14>

Figure 112020100818857-pat00074
Figure 112020100818857-pat00074

<화학식 15><Formula 15>

Figure 112020100818857-pat00075
Figure 112020100818857-pat00075

또한, 본 발명은 사람을 제외한 동물에 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 처리하는 단계를 포함하는 NLRP3 인플라마좀 활성 억제 방법을 제공한다.In addition, the present invention provides a method for inhibiting NLRP3 inflammasome activity, comprising treating an animal other than a human with a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof do.

<화학식 1><Formula 1>

Figure 112020100818857-pat00076
Figure 112020100818857-pat00076

<화학식 2><Formula 2>

Figure 112020100818857-pat00077
Figure 112020100818857-pat00077

<화학식 3><Formula 3>

Figure 112020100818857-pat00078
Figure 112020100818857-pat00078

<화학식 4><Formula 4>

Figure 112020100818857-pat00079
Figure 112020100818857-pat00079

<화학식 5><Formula 5>

Figure 112020100818857-pat00080
Figure 112020100818857-pat00080

<화학식 6><Formula 6>

Figure 112020100818857-pat00081
Figure 112020100818857-pat00081

<화학식 7><Formula 7>

Figure 112020100818857-pat00082
Figure 112020100818857-pat00082

<화학식 8><Formula 8>

Figure 112020100818857-pat00083
Figure 112020100818857-pat00083

<화학식 9><Formula 9>

Figure 112020100818857-pat00084
Figure 112020100818857-pat00084

<화학식 10><Formula 10>

Figure 112020100818857-pat00085
Figure 112020100818857-pat00085

<화학식 11><Formula 11>

Figure 112020100818857-pat00086
Figure 112020100818857-pat00086

<화학식 12><Formula 12>

Figure 112020100818857-pat00087
Figure 112020100818857-pat00087

<화학식 13><Formula 13>

Figure 112020100818857-pat00088
Figure 112020100818857-pat00088

<화학식 14><Formula 14>

Figure 112020100818857-pat00089
Figure 112020100818857-pat00089

<화학식 15><Formula 15>

Figure 112020100818857-pat00090
Figure 112020100818857-pat00090

이에 상응하는 특징들은 상술된 부분에서 대신할 수 있다.Corresponding features may be substituted for the above-mentioned parts.

이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<실시예 1> 화합물 분석<Example 1> Compound analysis

도 1 내지 도 15는 본 발명의 실험예에 사용된 화합물의 LC-MS 분석 내용이다.1 to 15 are LC-MS analysis of compounds used in Experimental Examples of the present invention.

상기 화합물은 한국화학연구원 한국화합물은행으로부터 입수한 것으로, 도 1의 peck 10에서 화합물 1에 해당하는 분자량(MW=344.1)을 확인하였다(순도 100%).The compound was obtained from the Korea Chemical Research Institute, Korea Compound Bank, and the molecular weight (MW=344.1) corresponding to compound 1 was confirmed in peck 10 of FIG. 1 (purity 100%).

도 2의 peck 8에서 화합물 2에 해당하는 분자량(MW=293.1)을 확인하였고(순도 97%), 도 3의 peck 7에서 화합물 3에 해당하는 분자량(MW=354.2)을 확인하였으며(순도 100%), 도 4의 peck 14에서 화합물 4에 해당하는 분자량(MW=327.1)을 확인하였다(순도 100%). 도 5의 peck 7에서 화합물 5에 해당하는 분자량(MW=368.3)을 확인하였고(순도 100%), 도 6의 peck 11에서 화합물 6에 해당하는 분자량(MW=435.1)을 확인하였으며(순도 95%), 도 7의 peak 7에서 화합물 7에 해당하는 분자량(MW=258.2)을 확인하였으며(순도 100%), 도 8의 peck 7에서 화합물 8에 해당하는 분자량(MW=358.2)을 확인하였고(순도 96%), 도 9의 peck 4에서 화합물 9에 해당하는 분자량(MW=342.1)을 확인하였으며(순도 97%), 도 10의 peck 4에서 화합물 10에 해당하는 분자량(MW=265.1)을 확인하였고(순도 97%), 도 11의 peck 3에서 화합물 11에 해당하는 분자량(MW=288.1)을 확인하였으며(순도 100%), 도 12의 peck 10에서 화합물 12에 해당하는 분자량(MW=450.2)을 확인하였고(순도 96%), 도 13의 peck 5에서 화합물 13에 해당하는 분자량(MW=301.2)을 확인하였으며(순도 100%), 도 14의 peck 3에서 화합물 14에 해당하는 분자량(MW=337.2)을 확인하였고(순도 82%), 도 15의 peck 10에서 화합물 15에 해당하는 분자량(MW=309.1)을 확인하였다(순도 100%).The molecular weight (MW=293.1) corresponding to compound 2 was confirmed in peck 8 of FIG. 2 (purity 97%), and the molecular weight corresponding to compound 3 in peck 7 of FIG. 3 (MW=354.2) was confirmed (purity 100%) ), the molecular weight (MW=327.1) corresponding to compound 4 was confirmed in peck 14 of FIG. 4 (purity 100%). The molecular weight (MW=368.3) corresponding to compound 5 was confirmed in peck 7 of FIG. 5 (purity 100%), and the molecular weight corresponding to compound 6 in peck 11 of FIG. 6 (MW=435.1) was confirmed (purity 95%) ), the molecular weight (MW=258.2) corresponding to compound 7 was confirmed in peak 7 of FIG. 7 (purity 100%), and the molecular weight corresponding to compound 8 in peck 7 of FIG. 8 (MW=358.2) was confirmed (purity) 96%), the molecular weight (MW=342.1) corresponding to compound 9 was confirmed in peck 4 of FIG. 9 (purity 97%), and the molecular weight corresponding to compound 10 in peck 4 of FIG. 10 (MW=265.1) was confirmed. (purity 97%), the molecular weight corresponding to compound 11 (MW=288.1) in peck 3 of FIG. 11 was confirmed (purity 100%), and the molecular weight corresponding to compound 12 in peck 10 of FIG. 12 (MW=450.2) It was confirmed (purity 96%), and the molecular weight (MW=301.2) corresponding to compound 13 was confirmed in peck 5 of FIG. 13 (purity 100%), and the molecular weight corresponding to compound 14 in peck 3 of FIG. 14 (MW=337.2) ) was confirmed (purity 82%), and the molecular weight (MW=309.1) corresponding to compound 15 in peck 10 of FIG. 15 was confirmed (purity 100%).

<실험예 1> 요산염(MSU) 결정에 의해 유도된 NLRP3 인플라마좀 활성 억제 확인<Experimental Example 1> Confirmation of inhibition of NLRP3 inflammasome activity induced by crystallization of urate (MSU)

1. 실험과정1. Experimental process

C57BL/6 마우스로부터 종래 알려진 방법[Journal of immunology (Baltimore, Md.:1950) 186, 499-507, 2011]에 따라 골수를 분리한 후 골수-유래 프라이머리 대식세포(Mouse Bone-marrow-derived macrophage)를 준비하였다. 상기 대식세포는 10%(v/v) 태아소혈청 (invitrogen, Carlsbad, CA), 10,000 units/ml의 페니실린 및 10,000 mg/ml의 스트렙토마이신 (Invitrogen)을 함유한 DMEM 배지에서 배양하였다.After separating the bone marrow from C57BL/6 mice according to a known method [ Journal of immunology (Baltimore, Md.:1950) 186, 499-507, 2011], bone marrow-derived primary macrophages (Mouse Bone-marrow-derived macrophage) ) was prepared. The macrophages were cultured in DMEM medium containing 10% (v/v) fetal bovine serum (invitrogen, Carlsbad, CA), penicillin at 10,000 units/ml, and streptomycin at 10,000 mg/ml (Invitrogen).

배양한 BMDM을 5×104 세포/ml의 밀도로 96-웰 플레이트 상에 분주하고 100 ng/ml의 LPS [Purified LPS from Escherichia coli, List Biological Laboratory Inc. (Cambell, CA) 구매, 내독성이 없는 물에서 용해시켜 사용함]를 4시간 동안 처리하였다. LPS의 상기 화합물에 대한 영향을 배제하기 위하여, PBS로 LPS를 세정한 후 상기 화합물을 첨가하였다. 세포에 상기 화합물 0.1μM, 0.5μM, 1μM을 1시간 동안 처리하고 배지에 인플라마좀 활성화제인 요산염(monosodium urate, MSU; Invivogen, 500 μg/ml) 결정체로 자극시켰다. 상기 세포의 상등액을 ELISA 키트 (R&D systems, Minneapolis, MN)를 이용하여, 인플라마좀 활성화의 지표로서 IL-1β의 농도를 확인하였다. 표준곡선의 농도는 11.72-3000 pg/ml이었다.The cultured BMDM was dispensed on a 96-well plate at a density of 5×10 4 cells/ml and 100 ng/ml of LPS [Purified LPS from Escherichia coli , List Biological Laboratory Inc. (Cambell, CA) purchased, used by dissolving in non-toxic water] was treated for 4 hours. In order to exclude the effect of LPS on the compound, the compound was added after washing the LPS with PBS. Cells were treated with the compounds 0.1 μM, 0.5 μM, and 1 μM for 1 hour, and stimulated with monosodium urate (MSU; Invivogen, 500 μg/ml) crystals, an inflammasome activator, in the medium. The supernatant of the cells was checked using an ELISA kit (R&D systems, Minneapolis, MN) to determine the concentration of IL-1β as an indicator of inflammasome activation. The concentration of the standard curve was 11.72-3000 pg/ml.

2. 실험결과2. Experimental results

마우스 골수 유래 대식세포(Mouse Bone-marrow-derived macrophage)에 요산염(MSU) 결정을 처리하여 NLRP3 인플라마좀을 유도한 후 상기 화합물들을 0.1μM, 0.5μM, 1μM 씩 처리한 결과, 도 16과 같이 농도 의존적으로 IL-1β의 생성이 억제되는 것으로 나타났다.After inducing NLRP3 inflammasome by treating mouse bone-marrow-derived macrophage with urate (MSU) crystals, 0.1 μM, 0.5 μM, and 1 μM of each of the compounds were treated. It was also shown that the production of IL-1β was inhibited in a concentration-dependent manner.

또한, MSU를 처리하여 NLRP3 인플라마좀을 유도한 후 상기 화합물을 1μM, 5μM, 10μM 씩 처리한 결과, 도 17과 같이 IL-1β의 생성이 유의하게 억제되는 것으로 나타났다.In addition, as a result of treatment with 1 μM, 5 μM, and 10 μM of the compound after inducing NLRP3 inflammasome by treatment with MSU, the production of IL-1β was significantly inhibited as shown in FIG. 17 .

<실험예 2> ATP에 의해 유도된 NLRP3 인플라마좀 활성 억제 확인<Experimental Example 2> Confirmation of inhibition of ATP-induced NLRP3 inflammasome activity

1. 실험방법1. Experimental method

인간 단핵구성 세포(Human monocytic cell)인 THP-1 세포는 10%(v/v)태아소혈청 (invitrogen, Carlsbad, CA), 10,000 units/ml의 페니실린 및 10,000 mg/ml의 스트렙토마이신 (Invitrogen)을 함유한 DMEM 배지에서 배양하였다. 배양한 THP-1 세포를 2×104 세포/ml의 밀도로 96-웰 플레이트 상에 분주하고 100 nM의 PMA [(Sigma-Aldrich) 구매, DMSO 용해시켜 사용함]를 3일 동안 처리하였다. PMA의 상기 화합물에 대한 영향을 배제하기 위하여, PBS로 세정한 후 상기 화합물을 첨가하였다. 세포에 상기 화합물 0.1μM, 0.5μM, 1μM을 1시간 동안 처리하고 배지에 인플라마좀 활성화제인 ATP (5 mM)로 자극시켰다. 상기 세포의 상등액을 ELISA 키트 (R&D systems, Minneapolis, MN)를 이용하여, 인플라마좀 활성화의 지표로서 IL-1β의 농도를 확인하였다. 표준곡선의 농도는 0.078-20000 pg/ml이었다.THP-1 cells, which are human monocytic cells, contain 10% (v/v) fetal bovine serum (invitrogen, Carlsbad, CA), penicillin at 10,000 units/ml and streptomycin at 10,000 mg/ml (Invitrogen). was cultured in DMEM medium containing Cultured THP-1 cells were seeded on a 96-well plate at a density of 2×10 4 cells/ml, and 100 nM of PMA [purchased from (Sigma-Aldrich), used by dissolving in DMSO] was treated for 3 days. In order to exclude the effect of PMA on the compound, the compound was added after washing with PBS. Cells were treated with the above compounds 0.1 μM, 0.5 μM, and 1 μM for 1 hour, and the medium was stimulated with ATP (5 mM), an inflammasome activator. The supernatant of the cells was checked using an ELISA kit (R&D systems, Minneapolis, MN) to determine the concentration of IL-1β as an indicator of inflammasome activation. The concentration of the standard curve was 0.078-20000 pg/ml.

2. 실험결과2. Experimental results

THP-1 세포에 ATP를 처리하여 NLRP3 인플라마좀을 유도한 후 상기 화합물을 0.1μM, 0.5μM, 1μM 씩 처리한 결과, 도 18와 같이 IL-1β의 생성이 유의하게 억제되는 것으로 나타났다.After inducing NLRP3 inflammasome by treating THP-1 cells with ATP, the compound was treated at 0.1 μM, 0.5 μM, and 1 μM, and as a result, the production of IL-1β was significantly inhibited as shown in FIG. 18 .

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다.As described above in detail a specific part of the content of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

삭제delete 삭제delete 삭제delete 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물로서,
상기 NLRP3 인플라마좀 매개 염증성 질환은, 크리오피린 관련 주기적 증후군(Cryopyrin-associated periodic syndromes, CAPS), 가족성 한랭 자가염증 증후군(Familial cold autoinflammatory syndrome, FCAS), 머클-웰스 증후군(Muckle-Wells syndrome, MWS), 신생아 발현 다발성 염증 질환(Neonatal-onset multisystem inflammatory disease, NOMID), 가족성 지중해열(Familial Mediterranean fever, FMF), 괴저성 농피증과 여드름을 동반한 화농성 관절염 증후군(Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome), 및 주기성 발열을 동반한 고면역글로불린 혈증 D 증후군(Hyperimmunoglobulinemia D with periodic fever syndrome, HIDS)으로 이루어진 군에서 선택되는 NLRP3 매개 자가염증질환;, 통풍, 관절염, 통풍성 관절염, 죽상동맥경화증, 알츠하이머, 아토피 피부염, 비알코올성지방간 및 제 2형 당뇨로 이루어진 군에서 선택되는 질환인 것을 특징으로 하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물.
<화학식 1>
Figure 112022036221934-pat00106

<화학식 2>
Figure 112022036221934-pat00107

<화학식 3>
Figure 112022036221934-pat00108

<화학식 4>
Figure 112022036221934-pat00109

<화학식 5>
Figure 112022036221934-pat00110

<화학식 6>
Figure 112022036221934-pat00111

<화학식 7>
Figure 112022036221934-pat00112

<화학식 8>
Figure 112022036221934-pat00113

<화학식 9>
Figure 112022036221934-pat00114

<화학식 10>
Figure 112022036221934-pat00115

<화학식 11>
Figure 112022036221934-pat00116

<화학식 12>
Figure 112022036221934-pat00117

<화학식 13>
Figure 112022036221934-pat00118

<화학식 14>
Figure 112022036221934-pat00119

<화학식 15>
Figure 112022036221934-pat00120
A pharmaceutical composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient,
The NLRP3 inflammasome-mediated inflammatory disease is Cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, MWS), Neonatal-onset multisystem inflammatory disease (NOMID), Familial Mediterranean fever (FMF), Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome), and NLRP3-mediated autoinflammatory disease selected from the group consisting of Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS); gout, arthritis, gouty arthritis, atherosclerosis A pharmaceutical composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease, characterized in that it is a disease selected from the group consisting of sclerosis, Alzheimer's disease, atopic dermatitis, nonalcoholic fatty liver and type 2 diabetes.
<Formula 1>
Figure 112022036221934-pat00106

<Formula 2>
Figure 112022036221934-pat00107

<Formula 3>
Figure 112022036221934-pat00108

<Formula 4>
Figure 112022036221934-pat00109

<Formula 5>
Figure 112022036221934-pat00110

<Formula 6>
Figure 112022036221934-pat00111

<Formula 7>
Figure 112022036221934-pat00112

<Formula 8>
Figure 112022036221934-pat00113

<Formula 9>
Figure 112022036221934-pat00114

<Formula 10>
Figure 112022036221934-pat00115

<Formula 11>
Figure 112022036221934-pat00116

<Formula 12>
Figure 112022036221934-pat00117

<Formula 13>
Figure 112022036221934-pat00118

<Formula 14>
Figure 112022036221934-pat00119

<Formula 15>
Figure 112022036221934-pat00120
 제 4 항에 있어서,
상기 화합물, 이의 염, 또는 이의 조합은,
NLRP3 인플라마좀 활성을 억제하는 것을 특징으로 하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물.5. The method of claim 4,
The compound, its salt, or a combination thereof,
A pharmaceutical composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease, characterized in that it inhibits NLRP3 inflammasome activity. 삭제delete 제 4 항에 있어서,
상기 화합물 또는 이의 염은, 인터루킨-1β(IL-1β) 또는 카스파제-1(caspase-1)의 생성을 억제하는 것을 특징으로 하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 치료용 약학 조성물.5. The method of claim 4,
The compound or a salt thereof is a pharmaceutical composition for preventing or treating NLRP3 inflammasome-mediated inflammatory disease, characterized in that it inhibits the production of interleukin-1β (IL-1β) or caspase-1. 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 식품학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 매개 염증성 질환 예방 또는 개선용 건강기능식품 조성물.
<화학식 1>
Figure 112020100818857-pat00121

<화학식 2>
Figure 112020100818857-pat00122

<화학식 3>
Figure 112020100818857-pat00123

<화학식 4>
Figure 112020100818857-pat00124

<화학식 5>
Figure 112020100818857-pat00125

<화학식 6>
Figure 112020100818857-pat00126

<화학식 7>
Figure 112020100818857-pat00127

<화학식 8>
Figure 112020100818857-pat00128

<화학식 9>
Figure 112020100818857-pat00129

<화학식 10>
Figure 112020100818857-pat00130

<화학식 11>
Figure 112020100818857-pat00131

<화학식 12>
Figure 112020100818857-pat00132

<화학식 13>
Figure 112020100818857-pat00133

<화학식 14>
Figure 112020100818857-pat00134

<화학식 15>
Figure 112020100818857-pat00135
A health functional food composition for preventing or improving NLRP3 inflammasome-mediated inflammatory disease comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.
<Formula 1>
Figure 112020100818857-pat00121

<Formula 2>
Figure 112020100818857-pat00122

<Formula 3>
Figure 112020100818857-pat00123

<Formula 4>
Figure 112020100818857-pat00124

<Formula 5>
Figure 112020100818857-pat00125

<Formula 6>
Figure 112020100818857-pat00126

<Formula 7>
Figure 112020100818857-pat00127

<Formula 8>
Figure 112020100818857-pat00128

<Formula 9>
Figure 112020100818857-pat00129

<Formula 10>
Figure 112020100818857-pat00130

<Formula 11>
Figure 112020100818857-pat00131

<Formula 12>
Figure 112020100818857-pat00132

<Formula 13>
Figure 112020100818857-pat00133

<Formula 14>
Figure 112020100818857-pat00134

<Formula 15>
Figure 112020100818857-pat00135
 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 유효성분으로 함유하는 NLRP3 인플라마좀 활성 억제용 시약 조성물.
<화학식 1>
Figure 112020100818857-pat00136

<화학식 2>
Figure 112020100818857-pat00137

<화학식 3>
Figure 112020100818857-pat00138

<화학식 4>
Figure 112020100818857-pat00139

<화학식 5>
Figure 112020100818857-pat00140

<화학식 6>
Figure 112020100818857-pat00141

<화학식 7>
Figure 112020100818857-pat00142

<화학식 8>
Figure 112020100818857-pat00143

<화학식 9>
Figure 112020100818857-pat00144

<화학식 10>
Figure 112020100818857-pat00145

<화학식 11>
Figure 112020100818857-pat00146

<화학식 12>
Figure 112020100818857-pat00147

<화학식 13>
Figure 112020100818857-pat00148

<화학식 14>
Figure 112020100818857-pat00149

<화학식 15>
Figure 112020100818857-pat00150
A reagent composition for inhibiting NLRP3 inflammasome activity comprising a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof as an active ingredient.
<Formula 1>
Figure 112020100818857-pat00136

<Formula 2>
Figure 112020100818857-pat00137

<Formula 3>
Figure 112020100818857-pat00138

<Formula 4>
Figure 112020100818857-pat00139

<Formula 5>
Figure 112020100818857-pat00140

<Formula 6>
Figure 112020100818857-pat00141

<Formula 7>
Figure 112020100818857-pat00142

<Formula 8>
Figure 112020100818857-pat00143

<Formula 9>
Figure 112020100818857-pat00144

<Formula 10>
Figure 112020100818857-pat00145

<Formula 11>
Figure 112020100818857-pat00146

<Formula 12>
Figure 112020100818857-pat00147

<Formula 13>
Figure 112020100818857-pat00148

<Formula 14>
Figure 112020100818857-pat00149

<Formula 15>
Figure 112020100818857-pat00150
 사람을 제외한 동물에 하기 화학식 1 내지 화학식 15 중 어느 하나로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이의 조합을 처리하는 단계를 포함하는 NLRP3 인플라마좀 활성 억제 방법.
<화학식 1>
Figure 112020100818857-pat00151

<화학식 2>
Figure 112020100818857-pat00152

<화학식 3>
Figure 112020100818857-pat00153

<화학식 4>
Figure 112020100818857-pat00154

<화학식 5>
Figure 112020100818857-pat00155

<화학식 6>
Figure 112020100818857-pat00156

<화학식 7>
Figure 112020100818857-pat00157

<화학식 8>
Figure 112020100818857-pat00158

<화학식 9>
Figure 112020100818857-pat00159

<화학식 10>
Figure 112020100818857-pat00160

<화학식 11>
Figure 112020100818857-pat00161

<화학식 12>
Figure 112020100818857-pat00162

<화학식 13>
Figure 112020100818857-pat00163

<화학식 14>
Figure 112020100818857-pat00164

<화학식 15>
Figure 112020100818857-pat00165
A method for inhibiting NLRP3 inflammasome activity, comprising treating an animal other than a human with a compound represented by any one of the following Chemical Formulas 1 to 15, a pharmaceutically acceptable salt thereof, or a combination thereof.
<Formula 1>
Figure 112020100818857-pat00151

<Formula 2>
Figure 112020100818857-pat00152

<Formula 3>
Figure 112020100818857-pat00153

<Formula 4>
Figure 112020100818857-pat00154

<Formula 5>
Figure 112020100818857-pat00155

<Formula 6>
Figure 112020100818857-pat00156

<Formula 7>
Figure 112020100818857-pat00157

<Formula 8>
Figure 112020100818857-pat00158

<Formula 9>
Figure 112020100818857-pat00159

<Formula 10>
Figure 112020100818857-pat00160

<Formula 11>
Figure 112020100818857-pat00161

<Formula 12>
Figure 112020100818857-pat00162

<Formula 13>
Figure 112020100818857-pat00163

<Formula 14>
Figure 112020100818857-pat00164

<Formula 15>
Figure 112020100818857-pat00165
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