KR102641463B1 - Compounds for preventing or treating virus infection disease, composition comprising the same and use thereof - Google Patents
Compounds for preventing or treating virus infection disease, composition comprising the same and use thereof Download PDFInfo
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- KR102641463B1 KR102641463B1 KR1020210108908A KR20210108908A KR102641463B1 KR 102641463 B1 KR102641463 B1 KR 102641463B1 KR 1020210108908 A KR1020210108908 A KR 1020210108908A KR 20210108908 A KR20210108908 A KR 20210108908A KR 102641463 B1 KR102641463 B1 KR 102641463B1
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/111—Aromatic compounds
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Abstract
본 발명은 바이러스 감염질환의 예방 또는 치료를 위한 화합물, 이를 포함하는 조성물 및 이의 용도에 관한 것이다.The present invention relates to compounds for preventing or treating viral infectious diseases, compositions containing them, and uses thereof.
Description
본 발명은 바이러스 감염질환의 예방 또는 치료를 위한 화합물, 이를 포함하는 조성물 및 이의 용도에 관한 것이다.The present invention relates to compounds for preventing or treating viral infectious diseases, compositions containing them, and uses thereof.
바이러스는 세균보다 작은 전염성 병원체이다. 유전물질인 RNA와 그 유전 물질을 둘러싸고 있는 단백질로 구성되며 극소수 바이러스는 DNA를 가지고 있기도 한다. 크기는 세균 여과기를 통과할 수 있을 정도로 작으며 주로 10 ~ 1000 nm 사이이다. 스스로 물질대사를 할 수 없기 때문에, 자신의 DNA나 RNA를 숙주 세포 안에 침투시킨 뒤 침투당한 세포의 소기관들을 이용하여 자신의 유전물질을 복제하고, 자기 자신과 같은 바이러스를 생산하며 번식한다.Viruses are infectious pathogens that are smaller than bacteria. It consists of RNA, the genetic material, and proteins surrounding the genetic material, and very few viruses also contain DNA. The size is small enough to pass through bacterial filters and is usually between 10 and 1000 nm. Since it cannot metabolize itself, it infiltrates its own DNA or RNA into a host cell and then uses the organelles of the infiltrated cell to replicate its genetic material and reproduce by producing viruses like itself.
이러한 바이러스가 원인이 되는 질병 중 국내에서는 특히 인플루엔자 바이러스로 인한 독감과 코로나바이러스로 인한 호흡기 증후군의 발병이 큰 문제점으로 대두되고 있다.Among diseases caused by these viruses, the outbreak of influenza caused by influenza viruses and respiratory syndrome caused by coronaviruses is emerging as a major problem in Korea.
인플루엔자 (influenza)는 흔히 '독감'이라 알려져 있고, 인플루엔자 바이러스 (influenza virus)에 의해서 발병되는 급성 호흡기 질환이다. 인플루엔자는 매년 전 세계적으로 크고 작은 유행을 일으키며, 유행이 시작되면 2-3주 내에 통상 인구의 10-20%가 감염될 정도로 전염성이 대단히 큰 질병이다.Influenza, commonly known as 'flu', is an acute respiratory disease caused by the influenza virus. Influenza causes large and small epidemics around the world every year, and is a highly contagious disease that usually infects 10-20% of the population within 2-3 weeks when the epidemic begins.
한편, COVID-19는 2019년 말 중국 후베이 지방의 수도인 우한에서 처음 확인되어 전세계로 확산되어 진행성 팬데믹을 초래한 질환으로, 사스-코로나바이러스-2에 의해 유발되는 감염성 질환이다. 바이러스는 주로 밀접접촉하는 동안, 때로는 기침, 재채기 및 대화시 발생하는 비말을 통해 사람 간에 전파된다. 세계보건기구(World Health Organization;WHO)는 국제적 공중보건 비상사태(Public Health Emergency of International Concern; PHEIC)로 COVID-19의 진행성 팬데믹(ongoing pandemic)을 선언하였으며, 2020년 5월 7일을 기준으로 3.75백만 케이스 이상이 187개국에서 보고되었고, 사망자는 263천명에 이르며, 1.24백만명이 회복되었다.Meanwhile, COVID-19 is a disease that was first identified in Wuhan, the capital of Hubei Province, China, in late 2019 and has spread worldwide, causing a progressive pandemic. It is an infectious disease caused by SARS-coronavirus-2. The virus spreads from person to person mainly during close contact and sometimes through droplets produced when coughing, sneezing and talking. The World Health Organization (WHO) declared COVID-19 an ongoing pandemic as a Public Health Emergency of International Concern (PHEIC) as of May 7, 2020. More than 3.75 million cases have been reported in 187 countries, with 263,000 deaths and 1.24 million recoveries.
한편, 현재까지 개발된 항바이러스제들은 심한 부작용을 나타내고 있으므로, 그 응용에 있어서 많은 주의가 필요하다. 특히, COVID-19의 치료제로 초기에 널리 사용되었던 렘데시비르(Remdesivir)는 효과 입증에 실패했다는 연구 결과도 게제된 바 있으며, 심각한 부작용이 있다는 사실이 보고된 바 있다(Kujawski, Stephanie et al (2020). First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. 10.1101/2020.03.09.20032896). Meanwhile, antiviral drugs developed to date have severe side effects, so great caution is required in their application. In particular, research results showed that Remdesivir, which was initially widely used as a treatment for COVID-19, failed to prove effectiveness and was reported to have serious side effects (Kujawski, Stephanie et al ( 2020). First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. 10.1101/2020.03.09.20032896).
따라서, 바이러스 감염을 예방하고 치료하기 위한, 감염 억제 효과가 뛰어나고 독성이 적은 우수한 새로운 항바이러스제의 개발의 필요성이 증가하고 있다.Therefore, there is an increasing need to develop new excellent antiviral agents with excellent infection inhibition effect and low toxicity to prevent and treat viral infections.
이러한 배경 하에, 본 발명자들은 예의 연구 노력한 끝에 본 발명의 화합물이 바이러스 예방 및 치료에 우수한 효과가 있음을 확인하여 본 발명을 완성하였다.Against this background, after extensive research efforts, the present inventors confirmed that the compound of the present invention has excellent effects in preventing and treating viruses and completed the present invention.
본 발명의 목적은, 화학식 1로 표시되는 화합물의, 바이러스 감염질환의 예방 또는 치료 용도를 제공한다.The object of the present invention is to provide a use of the compound represented by Formula 1 for preventing or treating viral infectious diseases.
본 발명의 다른 목적은 상기 화합물 또는 그의 염을 유효성분으로 포함하는, 바이러스 감염질환의 예방 또는 치료용 약학적 조성물; 바이러스 감염질환의 예방 또는 개선용 건강기능식품 조성물, 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating viral infectious diseases, comprising the above compound or a salt thereof as an active ingredient; The aim is to provide health functional food compositions and feed compositions for preventing or improving viral infectious diseases.
본 발명의 또 다른 목적은 상기 화합물 또는 그의 염을 개체에 투여하는 단계를 포함하는 바이러스 감염질환의 예방 또는 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating viral infectious diseases comprising administering the compound or a salt thereof to an individual.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered to be limited by the specific description described below.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Additionally, such equivalents are intended to be encompassed by this invention.
본 발명의 하나의 양태는, 하기 화학식 1로 표시되는 화합물의, 바이러스 감염질환의 예방 또는 치료 용도를 제공한다:One aspect of the present invention provides the use of a compound represented by the following formula (1) for preventing or treating viral infectious diseases:
[화학식 1][Formula 1]
상기 화학식 1에서, In Formula 1,
Ra, Rb, Rc, Rd, Re, Rf는 서로 독립적으로 C 또는 N이고;R a , R b , R c , R d , R e , R f are each independently C or N;
n은 0 또는 1의 값을 가지고;n has the value of 0 or 1;
R1은 H, Ac 및 Bn 중에서 선택되고; R 1 is selected from H, Ac and Bn;
R2 및 R3은 서로 독립적으로 H 또는 할로젠이거나, 서로 결합하여 벤젠고리를 형성하고; R 2 and R 3 are independently H or halogen, or are combined with each other to form a benzene ring;
R4는 H, CH3, OCH3, NO2, CN, CONH2 및 할로젠 중에서 선택되고; R 4 is selected from H, CH 3 , OCH 3 , NO 2 , CN, CONH 2 and halogen;
R'1은 H, CH3, CF3 및 할로젠 중에서 선택되고; R' 1 is selected from H, CH 3 , CF 3 and halogen;
R'2 및 R'3은 서로 독립적으로 H, CH3, CF3, OCH3, CN 및 할로젠 중에서 선택되거나, 서로 결합하여 벤젠고리를 형성하고; R' 2 and R' 3 are independently selected from H, CH 3 , CF 3 , OCH 3 , CN, and halogen, or are combined with each other to form a benzene ring;
R'4는 H, CF3 및 할로젠 중에서 선택된다.R' 4 is selected from H, CF 3 and halogen.
본 발명의 일 구현예로, 상기 화학식 1로 표시되는 화합물에서, In one embodiment of the present invention, in the compound represented by Formula 1,
Ra, Rb, Rc, Rd, Re 및 Rf는 C이고, n은 0이고,R a , R b , R c , R d , R e and R f are C, n is 0,
R1, R2 및 R3은 H이고, R4는 할로젠이고,R 1 , R 2 and R 3 are H, R 4 is halogen,
R'1은 CF3이고, R'2는 H 또는 할로젠이고, R'3은 CF3이고, R'4는 H인 것일 수 있다.R' 1 may be CF 3 , R' 2 may be H or a halogen, R' 3 may be CF 3 , and R' 4 may be H.
구체적으로는, 상기 화학식 1로 표시되는 화합물에서, Specifically, in the compound represented by Formula 1,
Ra, Rb, Rc, Rd, Re 및 Rf는 C이고, n은 0이고, R1, R2 및 R3은 H이고, R4는 Cl이고,R a , R b , R c , R d , Re and R f are C, n is 0, R 1 , R 2 and R 3 are H, R 4 is Cl,
R'1은 CF3이고, R'2는 H 또는 Br이고, R'3은 CF3이고, R'4는 H인 것일 수 있다.R' 1 may be CF 3 , R' 2 may be H or Br, R' 3 may be CF 3 , and R' 4 may be H.
본 발명의 일 구현예로, 상기 화합물은, 하기 화학식 2a 또는 2b로 표시되는 화합물일 수 있다:In one embodiment of the present invention, the compound may be a compound represented by the following formula 2a or 2b:
[화학식 2a][Formula 2a]
[화학식 2b][Formula 2b]
. .
한편 본원 명세서에서 상기 화학식 2a로 표시된 화합물은 Compound K로, 화학식 2b로 표시된 화합물은 Compound I로 지칭할 수 있다.Meanwhile, in the present specification, the compound represented by Formula 2a may be referred to as Compound K, and the compound represented by Formula 2b may be referred to as Compound I.
상기 화학식 2a로 표시된 화합물은 N-[4-Bromo-3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide로 명명되는 화합물일 수 있고, 화학식 2b로 표시된 화합물은 N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxy-benzamide로 명명되는 화합물 일 수 있다.The compound represented by Formula 2a may be a compound named N-[4-Bromo-3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, and the compound represented by Formula 2b may be N-[3 It may be a compound named ,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxy-benzamide.
본 발명에서 사용될 수 있는 화합물의 다른 예시로, 상기 화학식 1의 Ra, Rb, Rc, Rd, Re, Rf, n, R1, R2, R3, R4, R'1, R'2, R'3, R'4는 하기 표 1 내지 표 3에 기재된 것일 수 있다. As another example of a compound that can be used in the present invention, R a , R b , R c , R d , R e , R f , n, R 1 , R 2 , R 3 , R 4 , R' of Formula 1 1 , R' 2 , R' 3 , and R' 4 may be listed in Tables 1 to 3 below.
다만 상기 화합물들은 본 발명에서 사용될 수 있는 화합물들의 일 예시이며, 이들 화합물의 염, 이와 유사한 구조를 갖는 화합물, 이의 유도체, 이로부터 제조될 수 있는 가능한 용매화물, 수화물 및 라세미체 등 당업자가 예상 가능한 범위의 유도체로서 본 발명에서와 동일한 항바이러스 효과를 나타내는 것이라면 제한 없이 포함될 수 있다.본 발명의 다른 하나의 양태는, 본 발명의 화학식 1로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는, 바이러스 감염질환의 예방 또는 치료용 약학적 조성물을 제공한다.However, the above compounds are examples of compounds that can be used in the present invention, and salts of these compounds, compounds with similar structures, derivatives thereof, and possible solvates, hydrates, and racemates that can be prepared therefrom can be expected by those skilled in the art. A possible range of derivatives may be included without limitation as long as they exhibit the same antiviral effect as in the present invention. Another aspect of the present invention includes the compound represented by Formula 1 of the present invention or a salt thereof as an active ingredient, A pharmaceutical composition for preventing or treating viral infectious diseases is provided.
상기 약학적 조성물은 전술한 본 발명의 화합물을 1종 이상 유효성분으로 포함하는 것일 수 있다. 구체적으로는 본 발명의 화학식 1로 표시된 화합물 중 1 이상의 화합물을 유효성분으로 포함하는 것일 수 있고, 보다 구체적으로는 화학식 2a 및/또는 화학식 2b의 화합물을 유효성분으로 포함하는 것일 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition may contain one or more of the compounds of the present invention described above as active ingredients. Specifically, it may contain one or more compounds among the compounds represented by Formula 1 of the present invention as an active ingredient, and more specifically, it may contain a compound of Formula 2a and/or Formula 2b as an active ingredient, but is limited thereto. It doesn't work.
본 발명에서, "바이러스"는 식물, 동물, 세균 등의 살아 있는 세포에 기생하고 증식하여 여러 질환을 일으키는 여과성 병원체이다. 본 발명의 바이러스는 사람 및/또는 동물에서 질병을 일으키는 병원성 바이러스일 수 있고, 이러한 바이러스의 예시로는 오소믹소비리데(Orthomyxoviridae) 속 바이러스, 피코르나비리데(Picorna viridae) 속 바이러스, 레트로비리데(Retroviridae) 속 바이러스, 헤르페스(Herpes) 속 바이러스, 필로비리데(Filoviridae) 속 바이러스, 코로나비리데(Coronaviridae) 속 바이러스, 헤파드나비리데(Hepadnaviridae) 속 바이러스, 플라비비리데(Flaviviridae) 속 바이러스, 부냐비리데(Bunyaviridae) 속 바이러스 등을 포함할 수 있다. In the present invention, a “virus” is a filterable pathogen that parasitizes and proliferates in living cells of plants, animals, bacteria, etc., causing various diseases. The virus of the present invention may be a pathogenic virus that causes disease in humans and/or animals, and examples of such viruses include Orthomyxoviridae genus viruses, Picorna viridae genus viruses, and retroviridae. Retroviridae genus virus, Herpes genus virus, Filoviridae genus virus, Coronaviridae genus virus, Hepadnaviridae genus virus, Flaviviridae genus It may include viruses, viruses of the Bunyaviridae genus, etc.
상기 바이러스는 구체적으로, 코로나바이러스(coronavirus), 인플루엔자바이러스(influenza virus), 파라인플루엔자바이러스(parainfluenza virus), 리노바이러스(rhinovirus), 아데노바이러스(adenovirus), 호흡기 합포체 바이러스(respiratory syncytial virus), 포진 바이러스(Herpesvirus, HSV), 후천성 면역결핍 증후군 바이러스(human immunodeficiency virus, HIV), 로타바이러스(rotavirus) 및 간염바이러스로 이루어진 군으로부터 선택된 하나 이상의 바이러스일 수 있으나, 이에 제한되지 않는다.The virus specifically includes coronavirus, influenza virus, parainfluenza virus, rhinovirus, adenovirus, respiratory syncytial virus, and herpes. It may be, but is not limited to, one or more viruses selected from the group consisting of Herpesvirus (HSV), human immunodeficiency virus (HIV), rotavirus, and hepatitis virus.
본 발명에서, "감염"은 병원성 미생물이 숙주가 되는 생물체의 체내에 침입하여, 발육증식한 상태를 의미한다. In the present invention, “infection” refers to a state in which pathogenic microorganisms invade the body of a host organism and grow and proliferate.
본 발명에서,"바이러스 감염질환"이란, 상기 바이러스의 감염에 의해 숙주에서 발생할 수 있는 모든 질환을 포함한다. In the present invention, “viral infectious disease” includes all diseases that can occur in the host due to infection by the virus.
구체적으로, 본 발명의 바이러스 감염질환은 코로나바이러스 또는 인플루엔자 바이러스 감염질환일 수 있다.Specifically, the viral infectious disease of the present invention may be a coronavirus or influenza virus infectious disease.
본 발명의 코로나바이러스는 알파 코로나바이러스(alphacoronavirus) 또는 베타 코로나바이러스(betacoronavirus)로 분류되는 것일 수 있으며, 구체적으로는 베타 코로나바이러스일 수 있고, 예를 들어 사람 코로나바이러스(HCoV), 사스-코로나바이러스(SARS-CoV), 메르스-코로나바이러스(MERS-CoV) 및 2019년 신종 코로나바이러스(SARS-CoV-2; 2019-nCoV) 중에서 선택되는 것일 수 있다.The coronavirus of the present invention may be classified as an alphacoronavirus or a betacoronavirus, and may specifically be a betacoronavirus, for example, human coronavirus (HCoV), SARS-coronavirus. It may be selected from (SARS-CoV), MERS-CoV (MERS-CoV), and 2019 novel coronavirus (SARS-CoV-2; 2019-nCoV).
본 발명에서, "사람 코로나바이러스(HCoV)"는 "인간 코로나바이러스" 라고도 칭해지며, 사람을 포함한 동물에 감염될 수 있는 바이러스를 의미한다. 상기 사람 코로나바이러스는 알파 코로나바이러스로 분류되는 229E, NL63 및 베타 코로나바이러스로 분류되는 OC43, HKU1, SARS-CoV, MERS-CoV 등을 모두 포함한다. In the present invention, “human coronavirus (HCoV)” is also referred to as “human coronavirus” and refers to a virus that can infect animals, including humans. The human coronaviruses include 229E and NL63, which are classified as alpha coronaviruses, and OC43, HKU1, SARS-CoV, and MERS-CoV, which are classified as beta coronaviruses.
상기 사람코로나바이러스 중 229E, OC43, NL63, HKU1은 감기를 유발하는 것으로 알려져 있다. 또한, 영아, 노인 및 화학용번 중이거나 HIV-AIDS 보균자와 같이 면역력이 약화된(immunocompromised) 개체에서 폐렴을 포함한 중증 하기도 감염을 유발할 수 있다. 한편 SARS-CoV, MERS-CoV는 중증 폐렴을 일으킬 수 있는 것으로 알려져 있다. Among the above human coronaviruses, 229E, OC43, NL63, and HKU1 are known to cause colds. Additionally, it can cause severe lower respiratory tract infections, including pneumonia, in infants, the elderly, and immunocompromised individuals such as those undergoing chemical treatment or those with HIV-AIDS. Meanwhile, SARS-CoV and MERS-CoV are known to cause severe pneumonia.
본 발명에서, "사스-코로나바이러스(SARS-CoV)"는 외피를 지닌 베타 코로나바이러스 속에 속하는 ssRNA 바이러스이고, 현재까지 알려진 RNA 바이러스 중에서 가장 큰 게놈을 갖는 바이러스이다. 사스-코로나바이러스의 게놈은 11개의 오픈 리딩 프레임 (open reading frame, ORF)을 갖고 있으며 23종에 달하는 단백질을 코딩하고 있는 것으로 알려졌다. 사스-코로나바이러스의 주요 구조 단백질은 뉴클레오캡시드 (nucleocapsid,N), 스파이크 (spike, S), 멤브레인 (membrane, M), 스몰 엔벨로프 (small envelope, E) 단백질임이 밝혀졌다. In the present invention, “SARS-CoV” is an ssRNA virus belonging to the enveloped beta coronavirus genus and is a virus with the largest genome among RNA viruses known to date. The SARS-coronavirus genome is known to have 11 open reading frames (ORFs) and encodes 23 different proteins. It was revealed that the main structural proteins of the SARS-coronavirus are nucleocapsid (N), spike (S), membrane (M), and small envelope (E) proteins.
상기 "사스-코로나바이러스"에 의한 감염질환은 "SARS(Severe Acute Respiratory Syndrome)", "중증급성호흡기증후군"으로도 칭해질 수 있다. 상기 SARS는 002년 11월 중국 남부 광둥성에서 발생, 홍콩을 거쳐 세계로 확산된 전염병으로, 갑작스런 발열, 기침 및 호흡곤란이 주 증상이며, 심한 경우 폐렴으로 진행돼 죽음에 이를 수도 있는 질환이다. 보통 잠복기는 2~7일이며, 10일이 걸릴 수도 있다.The infectious disease caused by the “SARS-coronavirus” may also be referred to as “SARS (Severe Acute Respiratory Syndrome)” or “Severe Acute Respiratory Syndrome.” The above-mentioned SARS is an infectious disease that broke out in Guangdong Province, southern China in November 2002, and spread to the world via Hong Kong. The main symptoms are sudden fever, cough, and difficulty breathing. In severe cases, it progresses to pneumonia and can lead to death. The incubation period is usually 2 to 7 days, but can take up to 10 days.
본 발명에서, "메르스-코로나바이러스(MERS-CoV)"는 인간 MERS 코로나바이러스 및 박쥐 MERS-유사 코로나바이러스를 포함하는 의미로 사용될 수 있다. "MERS 코로나바이러스"는, 2012년 9월 24일에 새롭게 발견된 베타 코로나바이러스 속에 속하는 ssRNA 바이러스로, 5′-복제효소-구조 단백질(spike-envelope-membrane-nucleocapsid)-poly(A)-3′[5′-ORF1a/b-S-E-M-N-poly(A)]의 구조를 갖는다. "박쥐 MERS-유사 코로나바이러스"란, 박쥐로부터 유래된 바이러스로, MERS 코로나바이러스와 유전자형이 상당 부분 유사하여 계통수 상에서 연관성이 높은 것으로 확인되는 바이러스를 의미한다. In the present invention, “MERS-CoV” may be used to include human MERS coronavirus and bat MERS-like coronavirus. "MERS coronavirus" is an ssRNA virus belonging to the betacoronavirus genus newly discovered on September 24, 2012, and has 5'-replicase-structural protein (spike-envelope-membrane-nucleocapsid)-poly(A)-3. It has the structure of ′[5′-ORF1a/b-S-E-M-N-poly(A)]. “Bat MERS-like coronavirus” refers to a virus originating from bats that has a significant genotype similarity to the MERS coronavirus and is therefore confirmed to be highly related on the phylogenetic tree.
상기 "메르스-코로나바이러스"에 의한 감염질환은 "MERS(Middle East Respiratory Syndrome)", "중동 호흡기증후군"으로도 칭해질 수 있다. 낙타나 박쥐 등의 동물이 바이러스의 주요 매개체로 추정되며, 낙타에서는 MERS-CoV의 항체가 있음이 알려졌으나, 낙타의 감염이 정확히 어디로부터 비롯되었는지는 확인되지 않았다.The infectious disease caused by the “MERS-Coronavirus” may also be referred to as “MERS (Middle East Respiratory Syndrome)” or “Middle East Respiratory Syndrome.” Animals such as camels and bats are presumed to be the main carriers of the virus, and it has been known that camels have antibodies to MERS-CoV, but it has not been confirmed where exactly the camel's infection originated.
*본 발명에서, "2019년 신종 코로나바이러스" 는 "SARS-CoV-2", "COVID-19", "2019-nCoV", "사스-코로나바이러스-2" 등으로도 칭해지는 바이러스이다. 국립보건원(National Institutes of Health; NIH)에 의해 공지된 바와 같이, 양성 단일가닥 RNA 바이러스(positive-sense single-stranded RNA virus)이고, 사스-코로나바이러스(SARS-CoV)의 계승자(successor)로 분류되기도 한다. SARS-CoV-2는 분류학적으로 SARS-CoV의 계통(strain)으로, 동물원성 감염증의 기원(zoonotic origins)을 가지며, 박쥐 코로나바이러스와 근접한 유전적 유사성을 갖는 것으로 간주된다. 바이러스는 주로 밀접 접촉하는 동안, 때로는 기침, 재채기 및 대화 시 발생하는 비말을 통해 사람 간에 전파된다. 증상 발현 후 처음 3일 동안 가장 전염성이 높으며, 증상이 나타나기 전이나 질환의 말기에라도 전파될 수 있다. 보편적인 증상은 발열(fever), 기침(cough), 피로(fatigue), 호흡곤란(shortness of breath) 및 후각 및 미각의 상실로 알려져 있다. 대부분의 경우 증상이 경미하나, 바이러스성 폐렴(viral pneumonia), 다중기관부전(multi-organ failure) 및 사이토카인 폭풍(cyrokine storm)으로 진행할 수 있다. 증상의 발현으로부터 발병까지의 시간은 2 내지 14일 사이일 수 있다.*In the present invention, “2019 novel coronavirus” is a virus also called “SARS-CoV-2”, “COVID-19”, “2019-nCoV”, “SARS-coronavirus-2”, etc. As known by the National Institutes of Health (NIH), it is a positive-sense single-stranded RNA virus and is classified as the successor of SARS-CoV. It can also happen. SARS-CoV-2 is taxonomically a strain of SARS-CoV, has zoonotic origins, and is considered to have close genetic similarity to bat coronaviruses. The virus spreads from person to person primarily during close contact and sometimes through droplets produced when coughing, sneezing and talking. It is most contagious during the first three days after symptoms appear, and can spread even before symptoms appear or in the later stages of the disease. Common symptoms are known to be fever, cough, fatigue, shortness of breath, and loss of smell and taste. In most cases, symptoms are mild, but can progress to viral pneumonia, multi-organ failure, and cytokine storm. The time from onset of symptoms to onset can be between 2 and 14 days.
본 발명에서 "인플루엔자 바이러스"는 오트로믹소바이러스과 (Orthomyxoviridae)에 속하는 바이러스를 말한다. 상기 인플루엔자 바이러스는 단쇄, 나선형 RNA 바이러스로, 핵산의 구성에 따라 A,B,C 형으로 구분할 수 있다. 인간에게 감염을 일으키는 형태는 주로 A형 인플루엔자 바이러스로 알려져 있다. A형 인플루엔자 바이러스는 표면 항원인 헤마글루티닌(hemagglutinin, HA)과 뉴라미니다제(neuraminidase, NA)에 의해서 아형(subtype)이 결정된다. 이러한 HA는 바이러스가 체세포에 부착하는 역할을 하며 16가지 아형(H1~H16)이 있다. NA는 바이러스가 감염된 세포로부터 방출되어 새로운 호흡기 세포로 전파되는데 중요한 역할을 하며, 이는 9가지 아형(N1~N9)이 있다.In the present invention, “influenza virus” refers to a virus belonging to the Orthomyxoviridae family. The influenza virus is a single-stranded, helical RNA virus and can be divided into types A, B, and C depending on the composition of the nucleic acid. The form that causes infection in humans is mainly known as the type A influenza virus. The subtype of type A influenza virus is determined by the surface antigens hemagglutinin (HA) and neuraminidase (NA). This HA plays a role in the attachment of viruses to body cells, and there are 16 subtypes (H1 to H16). NA plays an important role in the virus being released from infected cells and spreading to new respiratory cells, and there are nine subtypes (N1 to N9).
상기 인플루엔자 바이러스는 인플루엔자 바이러스 A, 인플루엔자 바이러스 B, 인플루엔자 바이러스 C일 수 있으며, 구체적으로는 H1N1형 인플루엔자 바이러스 A, H2N2형 인플루엔자 바이러스 A, H3N2형 인플루엔자 바이러스 A, H2N3형 인플루엔자 바이러스 A, 인플루엔자 바이러스 B일 수 있다. 또한, 상기 인플루엔자 바이러스는 독감, 감기, 인후염, 기관지염, 폐렴을 일으킬 수 있으며, 인간 외의 동물에서 조류독감, 돼지독감 또는 염소독감 등을 야기시킬 수 있다.The influenza virus may be influenza virus A, influenza virus B, or influenza virus C, and specifically, H1N1 influenza virus A, H2N2 influenza virus A, H3N2 influenza virus A, H2N3 influenza virus A, or influenza virus B. You can. Additionally, the influenza virus can cause flu, cold, sore throat, bronchitis, and pneumonia, and can cause avian flu, swine flu, or goat flu in animals other than humans.
일 구현예로, 본 발명의 바이러스 감염질환은 바이러스의 감염성이 TMPRSS2에 의존하는 질환을 포함한다. 구체적으로 본 발명의 화합물은 TMPRSS2 활성을 억제함으로써 바이러스 감염을 조기에 예방하거나 또는 바이러스 감염질환을 치료할 수 있다.In one embodiment, the viral infectious disease of the present invention includes a disease in which the infectivity of the virus depends on TMPRSS2. Specifically, the compounds of the present invention can prevent viral infections early or treat viral infectious diseases by inhibiting TMPRSS2 activity.
그러나 본 발명의 바이러스 감염질환은 전술한 바이러스에 의해 발병하는 것에 제한되지 않고, 본 발명의 화합물에 의해 예방, 치료 효과가 나타날 수 있는 것이면 제한 없이 포함한다.However, the viral infectious disease of the present invention is not limited to those caused by the above-mentioned viruses, and includes without limitation any disease for which a preventive or therapeutic effect can be achieved by the compound of the present invention.
본 발명에서 용어, "예방"이란 본 발명의 화합물 또는 이를 포함하는 조성물의 투여에 의해 바이러스 감염 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present invention, the term “prevention” refers to all actions that suppress or delay the onset of a viral infectious disease by administering the compound of the present invention or a composition containing the same.
본 발명의 용어, "치료"는 본 발명의 화합물 또는 이를 포함하는 조성물의 의 투여에 의해 바이러스 감염질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which the symptoms of an individual suspected of or suffering from a viral infectious disease are improved or beneficially changed by administration of the compound of the present invention or a composition containing the same.
본 발명의 조성물은 전술한 화합물의 염을 유효성분으로 포함할 수 있다. 상기 염은 약학적으로 허용가능한 염일 수 있다.The composition of the present invention may include salts of the above-mentioned compounds as active ingredients. The salt may be a pharmaceutically acceptable salt.
본 발명의 용어, "약학적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다. 다만 이는 일 예시로, 바이러스 감염질환의 예방 또는 치료 효과를 갖는 범위에서 당업자가 적절한 형태를 선택하여 사용할 수 있다.As used herein, the term "pharmaceutically acceptable salt" refers to a salt that can be used pharmaceutically among salts that are substances in which cations and anions are combined by electrostatic attraction, and are usually metal salts, organic bases, and It can be a salt of, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt, etc.; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylenediamine. It may be a salt with, etc.; Salts with inorganic acids may include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; Salts with organic acids may include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; Salts with basic amino acids may include salts with arginine, lysine, ornithine, etc.; Salts with acidic amino acids can be salts with aspartic acid, glutamic acid, etc. However, this is just an example, and a person skilled in the art can select and use an appropriate form within the range that has the effect of preventing or treating viral infectious diseases.
본 발명의 약학적 조성물은, 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient, or diluent. The carrier may include a non-naturally occurring carrier.
보다 구체적으로, 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 폴리카프로락톤(polycaprolactone), 폴리락틱액시드(Poly Lactic Acid), 폴리-L-락틱액시드(poly-L-lactic acid), 광물유 등을 들 수 있다.More specifically, carriers, excipients, and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, and calcium phosphate. , calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, polycaprolactone, polylactic acid. (Poly Lactic Acid), poly-L-lactic acid, mineral oil, etc.
상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주 사용액의 형태로 제형화하여 사용될 수 있으며, 담체의 형태로는 각종 부정형의 담체, 마이크로 스피어, 나노파이버 등을 포함할 수 있다.The pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. The form of the carrier may include various amorphous carriers, microspheres, nanofibers, etc.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.When formulated, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 추출물과 이의 분획물들에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the extract and its fractions with at least one excipient, such as starch, calcium carbonate, It can be prepared by mixing sucrose, lactose, gelatin, etc. Additionally, in addition to simple excipients, lubricants such as magnesium styrate and talc may also be used.
경구투여를 위한 액상 제제로는 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.Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함될 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸 올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
본 발명의 약학적 조성물에 포함된 화합물 또는 이의 약학적으로 허용 가능한 염의 함량은 특별히 제한되지 않으며, 바이러스 감염질환의 예방 또는 치료를 나타내는 범위에서 당업자가 적절한 중량%로 포함시켜 사용할 수 있다.The content of the compound or its pharmaceutically acceptable salt contained in the pharmaceutical composition of the present invention is not particularly limited, and a person skilled in the art can use it by including it in an appropriate weight percent within the range indicated for the prevention or treatment of viral infectious diseases.
본 발명의 다른 하나의 양태는, 본 발명의 화학식 1로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는, 항바이러스용 조성물을 제공한다.Another aspect of the present invention provides an antiviral composition comprising the compound represented by Formula 1 of the present invention or a salt thereof as an active ingredient.
상기 항바이러스용 조성물은 전술한 화합물을 1종 이상 유효성분으로 포함하는 것일 수 있다. 구체적으로는 본 발명의 화학식 1로 표시된 화합물 중 1 이상의 화합물을 유효성분으로 포함하는 것일 수 있고, 보다 구체적으로는 화학식 2a 및/또는 화학식 2b의 화합물을 유효성분으로 포함하는 것일 수 있으나, 이에 제한되지 않는다.The antiviral composition may contain one or more of the above-mentioned compounds as active ingredients. Specifically, it may contain one or more compounds among the compounds represented by Formula 1 of the present invention as an active ingredient, and more specifically, it may contain a compound of Formula 2a and/or Formula 2b as an active ingredient, but is limited thereto. It doesn't work.
본 발명에서 "항바이러스"는 바이러스의 증식 또는 복제를 억제하여 바이러스 감염을 감소, 억제 또는 예방하는 것을 의미하나, 이에 제한되지 않는다. 상기 바이러스에 대해서는 전술한 바와 같다.In the present invention, “antiviral” refers to reducing, suppressing, or preventing viral infection by inhibiting the proliferation or replication of the virus, but is not limited thereto. The virus is the same as described above.
본 발명의 다른 하나의 양태는, 본 발명의 화학식 1로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는, 바이러스 감염질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another aspect of the present invention provides a health functional food composition for preventing or improving viral infectious diseases, comprising the compound represented by Formula 1 of the present invention or a salt thereof as an active ingredient.
상기 건강기능식품 조성물은 전술한 본 발명의 화합물을 1종 이상 유효성분으로 포함하는 것일 수 있다. 구체적으로는 본 발명의 화학식 1로 표시된 화합물 중 1 이상의 화합물을 유효성분으로 포함하는 것일 수 있고, 보다 구체적으로는 화학식 2a 및/또는 화학식 2b의 화합물을 유효성분으로 포함하는 것일 수 있으나, 이에 제한되지 않는다.The health functional food composition may contain one or more of the compounds of the present invention described above as active ingredients. Specifically, it may contain one or more compounds among the compounds represented by Formula 1 of the present invention as an active ingredient, and more specifically, it may contain a compound of Formula 2a and/or Formula 2b as an active ingredient, but is limited thereto. It doesn't work.
본 발명의 용어, "개선"은 본 발명에 따른 건강기능식품 조성물 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" in the present invention means any action that reduces at least the degree of symptoms, for example, parameters related to the condition being treated by administration of the health functional food composition according to the present invention.
본 발명에서, "건강기능식품" 이란 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, '기능성'은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학 적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다. 한편, 건강식품은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품은 건강 보조 목적의 식품을 의미하는데, 경우에 따라, 건강기능식품, 건강식품, 건강보조식품의 용어는 혼용될 수 있다.In the present invention, “health functional food” refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and “functionality” refers to the structure and structure of the human body. It means controlling nutrients for function or obtaining useful effects for health purposes such as physiological effects. Meanwhile, health food refers to food that has a more active health maintenance or promotion effect compared to general food, and health supplement refers to food for health supplement purposes. In some cases, the terms health functional food, health food, and health supplement food are used. can be used interchangeably.
본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조 시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 구체적으로, 상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다. 또한, 상기 식품 조성물은 방부제, 살균제, 산화방지제, 착색제, 발색제, 표백제, 조미료, 감미료, 향료, 팽창제, 강화제, 유화제, 증점제, 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.The food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. Specifically, the food composition may further include a physiologically acceptable carrier. The type of carrier is not particularly limited, and any carrier commonly used in the art can be used. In addition, the food composition contains food additives such as preservatives, disinfectants, antioxidants, colorants, coloring agents, bleaches, seasonings, sweeteners, flavorings, leavening agents, strengthening agents, emulsifiers, thickening agents, coating agents, gum base agents, foam suppressants, solvents, and improvers. It can be included. The additives can be selected depending on the type of food and used in an appropriate amount.
또한, 상기 식품의 제형은 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있다. 본 발명의 식품은 코로나바이러스에 의한 감염질환의 예방 또는 개선의 효과를 증진시키기 위한 보조제로 섭취가 가능하다. 본 발명의 식품 조성물에 포함되는 화합물의 함량은 특별히 제한되지 않으며, 바이러스 감염질환의 예방 또는 개선 효과를 나타낼 수 있다면 식품 조성물에 다양한 중량%로 포함될 수 있다.Additionally, the food formulation can be manufactured without limitation as long as it is a formulation recognized as a food. The food composition of the present invention can be prepared in various dosage forms. The food of the present invention can be consumed as an adjuvant to enhance the effect of preventing or improving infectious diseases caused by coronaviruses. The content of the compound included in the food composition of the present invention is not particularly limited, and may be included in the food composition in various weight percentages as long as it can show the effect of preventing or improving viral infectious diseases.
본 발명의 다른 하나의 양태는, 본 발명의 화학식 1로 표시되는 화합물 또는 그의 염을 유효성분으로 포함하는, 바이러스 감염질환의 예방 또는 개선용 사료 조성물을 제공한다.Another aspect of the present invention provides a feed composition for preventing or improving viral infectious diseases, comprising the compound represented by Formula 1 of the present invention or a salt thereof as an active ingredient.
상기 사료 조성물은 전술한 본 발명의 화합물을 1종 이상 유효성분으로 포함하는 것일 수 있다. 구체적으로는 본 발명의 화학식 1로 표시된 화합물 중 1 이상의 화합물을 유효성분으로 포함하는 것일 수 있고, 보다 구체적으로는 화학식 2a 및/또는 화학식 2b의 화합물을 유효성분으로 포함하는 것일 수 있으나, 이에 제한되지 않는다.The feed composition may contain one or more of the compounds of the present invention described above as active ingredients. Specifically, it may contain one or more compounds among the compounds represented by Formula 1 of the present invention as an active ingredient, and more specifically, it may contain a compound of Formula 2a and/or Formula 2b as an active ingredient, but is limited thereto. It doesn't work.
본 발명의 용어, "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미한다.As used herein, the term "feed" means any natural or artificial diet, meal, etc., or a component of the meal, for or suitable for eating, ingestion, and digestion by animals.
상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant feeds such as grains, roots and fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, cucurbits or grain by-products; Examples include animal feeds such as proteins, inorganic substances, fats and oils, minerals, oils and fats, single-cell proteins, zooplanktons or foods. These may be used alone or in combination of two or more types.
본 발명의 다른 하나의 양태는, 본 발명의 화합물 또는 이의 염을 투여하는 단계를 포함하는 바이러스 감염질환의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention provides a method for preventing or treating viral infectious diseases comprising the step of administering the compound of the present invention or a salt thereof.
상기 화합물, 이의 염, 바이러스 감염질환, 예방, 치료에 대해서는 전술한 바와 같다.The compounds, their salts, viral infectious diseases, prevention, and treatment are as described above.
본 발명의 용어, "투여"는 적절한 방법으로 개체에게 본 발명의 화합물을 도입하는 것을 의미한다.As used herein, the term “administration” means introducing a compound of the present invention into an individual by an appropriate method.
상기 화합물 또는 그의 염은, 약학적 조성물 혹은 의약외품 조성물 형태일 수 있다. The compound or its salt may be in the form of a pharmaceutical composition or quasi-drug composition.
구체적으로 상기 화합물은 화학식 1로 표시된 것 중 1 이상일 수 있고, 보다 구체적으로는 화학식 2a 및/또는 화학식 2b의 화합물 일 수 있으나 이에 제한되지 않는다.Specifically, the compound may be one or more of those represented by Formula 1, and more specifically, it may be a compound of Formula 2a and/or Formula 2b, but is not limited thereto.
상기 바이러스 감염질환의 예방 또는 치료 방법은 본 발명의 화합물 또는 그의 염을, 약학적 조성물을 바이러스 감염 질환이 발병되거나 발병 의심이 있는 개체에 투여는 단계를 포함하는 것일 수 있다.The method for preventing or treating the viral infectious disease may include the step of administering the compound of the present invention or a salt thereof or a pharmaceutical composition to an individual suffering from or suspected of developing the viral infectious disease.
상기 개체는 바이러스 감염질환이 발생할 수 있는 동물은 제한 없이 포함한다. 구체적으로는, 소, 돼지, 양, 닭, 개, 인간 등을 포함하는 포유동물, 조류 등을 포함하며, 본 발명의 상기 조성물의 투여에 의해 바이러스 감염 질환이 치료되는 개체는 제한 없이 포함한다.The subject includes, without limitation, animals that can develop viral infectious diseases. Specifically, it includes mammals, birds, etc., including cattle, pigs, sheep, chickens, dogs, humans, etc., and includes without limitation individuals whose viral infectious diseases are treated by administration of the composition of the present invention.
본 발명의 화합물은, 약학적으로 유효한 양으로 투여될 수 있는데, 상기 용어, "약학적으로 유효한 양"은 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The compounds of the present invention may be administered in a pharmaceutically effective amount, wherein the term "pharmaceutically effective amount" refers to an amount sufficient to treat or prevent a disease with a reasonable benefit/risk ratio applicable to medical treatment or prevention. This means that the effective dose level is the severity of the disease, the activity of the drug, the patient's age, weight, health, gender, the patient's sensitivity to the drug, the administration time, administration route and excretion rate of the composition of the present invention used, treatment period, It can be determined according to factors including the composition of the present invention used and the drugs used in combination or concurrently with it, and other factors well known in the medical field.
본 발명의 화합물은, 단독으로 투여하거나 공지된 치료제와 병용하여 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.The compounds of the present invention can be administered alone or in combination with known therapeutic agents. It is important to consider all of the above factors and administer the amount that will achieve the maximum effect with the minimum amount without side effects.
본 발명의 화합물은, 경구, 정맥 내, 피하, 피 내, 비강 내, 복강 내, 근육 내, 경피 등 다양한 방식을 이용하여 투여할 수 있으며, 이에 따라 당업자는 투여용량을 적절하게 조절할 수 있다.The compound of the present invention can be administered using various methods such as orally, intravenously, subcutaneously, intradermally, intranasally, intraperitoneally, intramuscularly, and transdermally, and a person skilled in the art can accordingly adjust the administration dose appropriately.
본 발명의 화합물은 바이러스 감염질환의 예방 또는 치료에 유용하게 사용될 수 있다.The compounds of the present invention can be usefully used in the prevention or treatment of viral infectious diseases.
도 1은 Compound K(Compd K), Compound I(Compd I) 및 렘데시비르(Remdesivir)를 처리하여 Vero 세포에서 SARS-CoV-2에 대한 각 화합물의 용량에 따른 항 바이러스 활성을 확인한 것이다.
도 2는 인간 TMPRSS2 단백질을 발현하기 위한 벡터의 구조를 도시한 것이다.
도 3은 정제된 pro-form과 active form TMPRSS2 프로테아제의 SDS-PAGE 결과이다.
도 4 및 도 5는 Compound I 및 Compound K의 TMPRSS2 활성 억제 효과를 확인한 것이다. Figure 1 shows the antiviral activity of each compound according to the dose against SARS-CoV-2 in Vero cells treated with Compound K (Compd K), Compound I (Compd I), and Remdesivir.
Figure 2 shows the structure of a vector for expressing human TMPRSS2 protein.
Figure 3 shows SDS-PAGE results of purified pro-form and active form TMPRSS2 protease.
Figures 4 and 5 confirm the inhibitory effect of Compound I and Compound K on TMPRSS2 activity.
이하 본 발명을 실시예 및 실험예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예 및 실험예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예 및 실험예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples and experimental examples are for illustrative purposes only and the scope of the present invention is not limited to these examples and experimental examples.
실시예 1: Vero 세포에서 SARS-CoV-2에 대한 화합물의 항바이러스 활성 확인Example 1: Confirmation of antiviral activity of compounds against SARS-CoV-2 in Vero cells
하기 화학식 2a (이하 Compound K) 및 화학식 2b (이하 Compound I)의 화합물에 대해 항바이러스 활성을 확인하는 실험을 수행하였다.An experiment was performed to confirm the antiviral activity of the compounds of Formula 2a (hereinafter referred to as Compound K) and Formula 2b (hereinafter referred to as Compound I) below.
[화학식 2a][Formula 2a]
[화학식 2b][Formula 2b]
구체적으로 SARS-CoV-2 (BetaCoV / Korea / KCDC03 / 2020)는 Dulbecco의 변형된 Eagle (DMEM; HyClone, South Logan, UT, USA) 배지에서 3계대동안 Vero CCL-81 세포에서 증폭되었다. 대조군인 렘데시비르 (순도 99.84%) 는 MedChemExpress (Monmouth Junction, NJ, USA)에서 구입하여 사용하였다.Specifically, SARS-CoV-2 (BetaCoV / Korea / KCDC03 / 2020) was amplified in Vero CCL-81 cells for three passages in Dulbecco's modified Eagle (DMEM; HyClone, South Logan, UT, USA) medium. Remdesivir (purity 99.84%), a control group, was purchased and used from MedChemExpress (Monmouth Junction, NJ, USA).
항-SARS-CoV-2 활성을 측정하기 위해, Vero cell을 96-웰 플레이트에서 (웰 당 2 × 104 세포) 하룻밤동안 배양하였다. Compound K, Compound I 및 렘데시비르를 단계적으로 3배 희석하여 세포에 처리하였다. 이후 37℃의 biosafety level 3 laboratory에서, 각 실험군에 동일한 양의 SARS-CoV-2 (MOI 0.05)로 감염시켰다. To measure anti-SARS-CoV-2 activity, Vero cells were cultured overnight in 96-well plates (2 × 10 4 cells per well). Compound K, Compound I, and remdesivir were stepwise diluted 3-fold and treated with cells. Afterwards, in a biosafety level 3 laboratory at 37°C, each experimental group was infected with the same amount of SARS-CoV-2 (MOI 0.05).
이틀 후 세포를 고정하고, 냉각된 아세톤:메탄올 (1:3)로 투과화(permeabilization)하여 항-S 항체(Genetex, Irvine, CA)를 처리한 후, Alexa Fluor 488-congujated goat anti-mouse IgG (Invitrogen, Carlsbad, CA) 를 처리하여 EC50 값을 확인하였다. 세포핵은 4',6-diamidino-2-phenylindole (DAPI; Invitrogen)로 대조 염색하여 CC50 값을 계산하였다. Two days later, the cells were fixed, permeabilized with cold acetone:methanol (1:3), treated with anti-S antibody (Genetex, Irvine, CA), and then incubated with Alexa Fluor 488-congujated goat anti-mouse IgG. (Invitrogen, Carlsbad, CA) was used to confirm the EC 50 value. Cell nuclei were counterstained with 4',6-diamidino-2-phenylindole (DAPI; Invitrogen), and CC 50 values were calculated.
3개의 독립 샘플로부터 웰당 4 개 지점에서 검출된 S-유래 (녹색) 및 세포 핵 유래 (파란색) 신호의 수는 Operetta 고 함량 스크리닝 시스템 (Perkin Elmer, Waltham, MA, USA) 및 built-in Harmony 소프트웨어를 사용하여 정량화하였고, 정량화한 결과를 도 1에 표시하였다. Number of S-derived (green) and cell nucleus-derived (blue) signals detected at four spots per well from three independent samples using the Operetta high content screening system (Perkin Elmer, Waltham, MA, USA) and built-in Harmony software. It was quantified using , and the quantified results are shown in Figure 1.
실험 결과 Compound I 및 Compound K가 기존 알려진 렘데시비르에 비해서 적은 용량으로도 우수한 항바이러스 활성을 나타내는 것을 확인하였다.As a result of the experiment, it was confirmed that Compound I and Compound K showed excellent antiviral activity even at a small dose compared to the previously known remdesivir.
이를 통해, 본 발명의 화합물이 바이러스 감염질환의 예방, 개선 및 치료에 유용하게 사용될 수 있음을 알 수 있다.Through this, it can be seen that the compound of the present invention can be usefully used in the prevention, improvement, and treatment of viral infectious diseases.
실시예 2: 화합물의 TMPRSS2 억제능 확인Example 2: Confirmation of TMPRSS2 inhibitory ability of the compound
TMPRSS2는 SARS-CoV-2가 세포에 부착 및 침투하는 데 관여하여, 세포내로 유입되는 데 중요한 역할을 하는 단백질이다. 이에, Compound K, Compound I의 TMPRSS2 단백질 활성 억제 효과를 확인하였다.TMPRSS2 is a protein that plays an important role in the attachment and penetration of SARS-CoV-2 into cells. Accordingly, the inhibitory effect of Compound K and Compound I on TMPRSS2 protein activity was confirmed.
구체적으로, 하기 2종의 프라이머를 이용하여 도 2에 표시한 구조와 같이 인간 TMPRSS2 프로테아제 도메인(256번 아미노산-492번 아미노산)과 엔테로키나아제 절단 도메인(DYKDDDGDYKDDDDK)을 pET21b 벡터에 subcloning 하였다. Specifically, the human TMPRSS2 protease domain (amino acid 256 - amino acid 492) and enterokinase cleavage domain (DYKDDDGDYKDDDDK) were subcloned into the pET21b vector as shown in the structure shown in Figure 2 using the following two types of primers.
EZ fusion hTMPRSS2PD_2XFlag_EK_Nde1_Forward primerEZ fusion hTMPRSS2PD_2XFlag_EK_Nde1_Forward primer
GAAGGAGATATACATATGGATTACAAAGACGATGACGGTGACTACAAAGATGACGACGATAAGATTGTGGGCGGTGAGAGCGCGAAGGAGATATACATATGGATTACAAAGACGATGACGGTGACTACAAAGATGACGACGATAAGATTGTGGGCGGTTGAGAGCGC
hTMPRSS2PD_nostop_Xho1_Reverse primerhTMPRSS2PD_nostop_Xho1_Reverse primer
GTGGTGGTGGTGCTCGAGGCCGTCTGCCCTCATTTGTCGTGGTGTGTGGTGCTCGAGGCCGTCTGCCCTCATTTGTC
제작된 벡터를 E.coli BL21(DE3)에 형질전환하고 OD600이 0.5-0.8 이 될 때까지 배양한 후 IPTG induction (0.1 mM, , 37℃ 6 hr) 하여 단백질을 발현시켰다. 이후 Cell pellet을 수득하여 lysis buffer에 풀고 초음파 처리 후 원심분리하여 단백질을 수득하였다. The constructed vector was transformed into E. coli BL21(DE3) and cultured until the OD600 reached 0.5-0.8, and the protein was expressed by IPTG induction (0.1 mM, 37°C for 6 hr). Afterwards, the cell pellet was obtained, dissolved in lysis buffer, sonicated, and centrifuged to obtain protein.
수득한 단백질은 Ni-NTA 컬럼을 이용하여 정제하였다. 정제된 엔테로키나제 절단 부위가 표지된 형태의 TMPRSS2 프로테아제 (즉, pro-form)는 Ni-NTA 레진에 결합시키고, 엔테로키나제를 처리하여 세척, 용리 단계를 거쳐 활성 형태(active form)의 TMPRSS2 프로테아제를 수득하였다. 수득한 pro-form과 active form 프로테아제를 SDS-PAGE로 분석(Coomassie brilliant blue로 염색)하여 도 3에 나타내었다.The obtained protein was purified using a Ni-NTA column. The purified enterokinase cleavage site-labeled form of TMPRSS2 protease (i.e., pro-form) is bound to Ni-NTA resin, treated with enterokinase, washed, and eluted to produce the active form of TMPRSS2 protease. Obtained. The obtained pro-form and active form proteases were analyzed by SDS-PAGE (stained with Coomassie brilliant blue) and are shown in Figure 3.
수득한 활성 형태의 TMPRSS2 프로테아제 활성은 compound K, compound I 존재하에 fluorometry 기법으로 측정하였다.The protease activity of the obtained active form of TMPRSS2 was measured by fluorometry technique in the presence of compound K and compound I.
실험 결과, compound K, compound I 처리 시 TMPRSS2 프로테아제 활성이 억제되는 것을 확인하였다(도 4-도 5). As a result of the experiment, it was confirmed that TMPRSS2 protease activity was inhibited when treated with compound K and compound I (Figures 4-5).
이를 통해 본 발명의 화합물이 SARS-CoV-2가 세포로 유입되는 데 중요하게 관여하는 TMPRSS2 프로테아제 억제활성을 가지는 것을 확인하였는바, 본 발명의 화합물은 바이러스 증식의 초기단계를 저해할 수 있는 SARS-CoV-2 감염질환 예방 및 치료용 조성물로 유용하게 사용될 수 있다. Through this, it was confirmed that the compound of the present invention has TMPRSS2 protease inhibitory activity, which is important in the entry of SARS-CoV-2 into cells. The compound of the present invention is capable of inhibiting the initial stage of virus proliferation. It can be useful as a composition for preventing and treating CoV-2 infectious diseases.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.
Claims (10)
상기 바이러스는 사람 코로나바이러스(HCoV), 사스-코로나바이러스(SARS-CoV), 및 메르스-코로나바이러스(MERS-CoV) 중에서 선택되는 것인, 조성물:
[화학식 2a]
.
A pharmaceutical composition for preventing or treating viral infectious diseases, comprising a compound represented by the following formula (2a) or a salt thereof as an active ingredient,
The composition: wherein the virus is selected from human coronavirus (HCoV), SARS-CoV, and MERS-CoV.
[Formula 2a]
.
The pharmaceutical composition for preventing or treating viral infectious diseases according to claim 1, wherein the virus is SARS-coronavirus.
The pharmaceutical composition for preventing or treating viral infectious diseases according to claim 2, wherein the SARS-coronavirus is a 2019 novel coronavirus (SARS-CoV-2; 2019-nCoV).
The pharmaceutical composition for preventing or treating viral infectious diseases according to claim 1, wherein the compound prevents viral infection or treats viral infectious diseases by inhibiting TMPRSS2 activity.
상기 바이러스는 사람 코로나바이러스(HCoV), 사스-코로나바이러스(SARS-CoV), 및 메르스-코로나바이러스(MERS-CoV) 중에서 선택되는 것인, 조성물:
[화학식 2a]
.
An antiviral composition comprising a compound represented by the following formula (2a) or a pharmaceutically acceptable salt thereof as an active ingredient,
The composition: wherein the virus is selected from human coronavirus (HCoV), SARS-CoV, and MERS-CoV.
[Formula 2a]
.
상기 바이러스는 사람 코로나바이러스(HCoV), 사스-코로나바이러스(SARS-CoV), 및 메르스-코로나바이러스(MERS-CoV) 중에서 선택되는 것인, 조성물:
[화학식 2a]
A health functional food composition for preventing or improving viral infectious diseases, comprising a compound represented by the following formula (2a) or a pharmaceutically acceptable salt thereof as an active ingredient,
The composition: wherein the virus is selected from human coronavirus (HCoV), SARS-CoV, and MERS-CoV.
[Formula 2a]
상기 바이러스는 사람 코로나바이러스(HCoV), 사스-코로나바이러스(SARS-CoV), 및 메르스-코로나바이러스(MERS-CoV) 중에서 선택되는 것인, 조성물:
[화학식 2a]
A feed composition for preventing or improving viral infectious diseases, comprising a compound represented by the following formula (2a) or a pharmaceutically acceptable salt thereof as an active ingredient,
The composition: wherein the virus is selected from human coronavirus (HCoV), SARS-CoV, and MERS-CoV.
[Formula 2a]
상기 바이러스는 사람 코로나바이러스(HCoV), 사스-코로나바이러스(SARS-CoV), 및 메르스-코로나바이러스(MERS-CoV) 중에서 선택되는 것인, 방법:
[화학식 2a]
.
A method for preventing or treating viral infectious diseases, comprising the step of administering a compound represented by Formula 2a below or a pharmaceutically acceptable salt thereof to an entity other than a human,
The method: wherein the virus is selected from human coronavirus (HCoV), SARS-CoV, and MERS-CoV.
[Formula 2a]
.
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US20140221411A1 (en) | 2011-10-21 | 2014-08-07 | Korea Research Institute Of Bioscience And Biotechnology | 2-hydroxyarylamide derivative or pharmaceutically acceptable salt thereof, preparation method thereof, and pharmaceutical composition for preventing or treating cancer containing same as active ingredient |
Non-Patent Citations (4)
Title |
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논문1: MICROBIOL. IMMUNOL. |
논문2: BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS |
논문3: NATURE PUBLIC HEALTH EMERGENCY COLLECTION |
논문4: SCIENTIFIC REPORTS |
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