KR20080020862A - Urea derivatives, process for the preparation thereof, and antiviral composition containing the same - Google Patents

Urea derivatives, process for the preparation thereof, and antiviral composition containing the same Download PDF

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KR20080020862A
KR20080020862A KR1020060084295A KR20060084295A KR20080020862A KR 20080020862 A KR20080020862 A KR 20080020862A KR 1020060084295 A KR1020060084295 A KR 1020060084295A KR 20060084295 A KR20060084295 A KR 20060084295A KR 20080020862 A KR20080020862 A KR 20080020862A
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urea
ethyl
methoxy
formula
group
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조의환
정순간
명현남
권호석
이순환
이재웅
주정호
이영희
김현태
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삼진제약주식회사
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/155Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring

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Abstract

Urea derivatives are provided to inhibit the growth of virus, especially coronavirus strongly. An antiviral composition comprising the urea derivatives is also provided to treat diseases caused by coronavirus including SARS(severe acute respiratory syndrome). The urea derivatives represented by the formula(1) or pharmaceutically acceptable salts thereof are prepared by reacting compounds represented by the formula(2) with compounds represented by the formula(3) at 0-25 deg. C, wherein R^1 is C1-C4 alkyl group, C1-C2 alkyl carbonyl group, C1-C2 alkoxy carbonyl group, C1-C2 hydroxyalkyl group or carboxyl group; R^2 is C1-C4 alkyl group; R^3 and R^4 are each independently C1-C4 alkyl group or C1-C4 alkoxy group; and n is an integer from 1 to 3. Further, the C1-C4 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or sec-butyl.

Description

우레아 유도체, 이의 제조방법 및 이를 포함하는 항바이러스제 조성물{UREA DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, AND ANTIVIRAL COMPOSITION CONTAINING THE SAME} Urea derivatives, a method for preparing the same, and an antiviral composition comprising the same {UREA DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, AND ANTIVIRAL COMPOSITION CONTAINING THE SAME}

본 발명은 특히 코로나 바이러스에 대한 항바이러스 활성을 가지는 신규한 우레아 유도체, 이의 제조방법 및 이를 포함하는 항바이러스제 조성물에 관한 것이다.The present invention relates in particular to novel urea derivatives having antiviral activity against coronaviruses, methods for their preparation and antiviral compositions comprising the same.

코로나 바이러스는 1937년 닭에서 처음 발견된 후, 개·돼지·조류 등의 동물을 거쳐 1965년에는 사람에게서도 발견되었으며, 이전까지는 사람에게는 거의 감염되지 않고 주로 개·돼지·소 등의 동물에 감염되는 병원균으로 인식되어 왔다. 또한, 사람에게 감염될 때에도 호흡기 증상을 유발하는 여러 바이러스 가운데 하나로 단순한 감기를 유발하거나, 어린이의 설사 등 장질환을 일으키는 경우가 있기는 하지만 위험성이 높지 않았다. 그러다 2003년 3월 중순 처음으로 발생해 세계적으로 100명이 넘는 사망자와 3,000여 명의 환자를 발생시킨 중증급성호흡기증후군(사스:SARS)의 원인균이 신종(변종) 코로나 바이러스인 것으로 알려지면서 주목받기 시작하였다.Corona virus was first discovered in chickens in 1937 and then in humans in 1965 through dogs, pigs, and other animals. Until now, it was rarely infected by humans, but mainly by dogs, pigs, cows, and other animals. It has been recognized as a pathogen. In addition, even when infected with humans, one of several viruses that cause respiratory symptoms may cause a simple cold, or diarrhea in children, such as diarrhea, but not high risk. Then, in mid-March 2003, the causative agent of Severe Acute Respiratory Syndrome (SARS: SARS), which occurred for the first time in the world and caused more than 100 deaths and more than 3,000 patients, began to attract attention as it was known as the new (variant) coronavirus. .

이러한 코로나 바이러스는 일부 동물의 경우에는 발열·호흡곤란·구토·설사·탈수 등을 유발해 치명적인 병원균으로 작용하기도 한다. 또한, 전염성이 강하고 다른 병원균과 결합하는 능력이 뛰어나 증상을 더욱 악화시키는 바이러스로 알려져 있다. 이런 결합 능력을 이용해 사스를 유발하는 신종 코로나 바이러스 역시 동물의 몸 속에 있던 코로나 바이러스가 변형되어 사람의 몸 속으로 들어와 질병을 일으킨 것으로 전문가들은 추정하고 있다.In some animals, these corona viruses can cause fever, dyspnea, vomiting, diarrhea, and dehydration, which can act as lethal pathogens. In addition, it is known as a virus that is highly infectious and has excellent ability to bind with other pathogens, thereby worsening symptoms. The new coronavirus, which uses this binding ability to cause SARS, also predicts that the corona virus in the animal's body has been altered into the human body causing disease, experts estimate.

사스 감염 후 2-7일의 잠복기동안, 고열, 약한 감기증세, 두통, 기침 및 호흡곤란 등의 증세를 보이며, 호흡기 상피세포에서 증식한 후, 폐에 까지 침투하여 호흡곤란증후군(respiratory distress syndrome) 및 폐렴(pneumonia)으로 진행하며, 사망하는 경우도 나타난다.During the incubation period of 2-7 days after SARS infection, symptoms of high fever, mild cold, headache, cough, and dyspnea are shown. After proliferation in respiratory epithelial cells, they penetrate into the lungs and respiratory distress syndrome. And pneumonia, and death occurs.

현재까지는 감염이 의심되는 환자와 접촉을 피하고, 개인 위생을 철저히 하는 것 이외에는 특별한 치료 및 예방법이 없는 실정이다.To date, there are no special treatments and preventive measures except avoiding contact with patients suspected of being infected and thorough personal hygiene.

아직까지 사스의 치료효과가 입증된 약제는 없다. 처음에 지역 획득성 폐렴에 효과가 있는 항생제나 리바비린(ribavirin)과 같은 광범위한 항바이러스제를 투여하기도 하였다. 이외에 스테로이드, 인터페론 베타(interferon beta), 싸이믹 펩타이드(thymic peptides), 환자의 혈청 등이 사용되기도 하였으나 치료효과는 확실하지 않으며, 현재까지 뚜렷한 예방 백신이 개발되지 않은 상황이다.There is no drug that has proven to be effective for SARS. Initially, a broad range of antiviral agents, such as antibiotics or ribavirin, were effective in treating regionally acquired pneumonia. In addition, steroids, interferon beta (interferon beta), thymic peptides (hymic peptides), and the serum of the patient has been used, but the therapeutic effect is not clear, and no clear preventive vaccines have been developed to date.

이에, 본 발명자들은 코로나 바이러스에 대해 항바이러스 활성을 갖는 물질을 개발하기 위하여 연구를 거듭하던 중, 특정 구조의 신규한 우레아 유도체가 코 로나 바이러스에 대한 강력한 항바이러스 활성을 나타내는 것을 발견하고 본 발명을 완성하였다.Accordingly, the present inventors, while continuing to develop a material having antiviral activity against the corona virus, found that a novel urea derivative of a specific structure exhibits strong antiviral activity against the corona virus and the present invention. Completed.

따라서, 본 발명의 목적은 코로나 바이러스에 대해 강력한 항바이러스 활성을 나타내는 신규한 우레아 유도체를 제공하는 것이다.Accordingly, it is an object of the present invention to provide novel urea derivatives that exhibit potent antiviral activity against coronaviruses.

본 발명의 다른 목적은 상기 우레아 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the urea derivative.

본 발명의 또 다른 목적은 상기 우레아 유도체 또는 약학적으로 허용되는 그의 염을 유효성분으로 함유하는 항바이러스제 조성물을 제공하는 것이다.Still another object of the present invention is to provide an antiviral composition containing the urea derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

상기의 목적에 따라, 본 발명은 하기 화학식 1의 우레아 유도체 및 약학적으로 허용가능한 그의 염을 제공한다:In accordance with the above object, the present invention provides a urea derivative of the formula (1) and a pharmaceutically acceptable salt thereof:

Figure 112006063514683-PAT00002
Figure 112006063514683-PAT00002

상기 식에서, Where

R1은 C1-C4 알킬기, C1-C2 알킬 카르보닐기, C1-C2 알콕시 카르보닐기, C1-C2 하이드록시알킬기 또는 카르복실기이고;R 1 is a C 1 -C 4 alkyl group, a C 1 -C 2 alkyl carbonyl group, a C 1 -C 2 alkoxy carbonyl group, a C 1 -C 2 hydroxyalkyl group or a carboxyl group;

R2는 C1-C4 알킬기이고;R 2 is a C 1 -C 4 alkyl group;

R3 및 R4는 각각 독립적으로 C1-C4 알킬기 또는 C1-C4 알콕시기이고;R 3 and R 4 are each independently a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group;

n은 1~3이다.n is 1-3.

상기 다른 목적에 따라, 본 발명은 상기 우레아 유도체의 제조방법 및 유효성분으로서 상기 우레아 유도체 또는 약학적으로 허용 가능한 그의 염을 함유하는 항바이러스제 조성물을 제공한다.According to the above another object, the present invention provides an antiviral composition containing the urea derivative or a pharmaceutically acceptable salt thereof as a method for producing the urea derivative and an active ingredient.

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

본 발명은 신규한 우레아 유도체, 이의 제조방법 및 이를 포함하는 항바이러스제 조성물에 관한 것으로서, 본 발명의 우레아 유도체는 코로나바이러스에 대하여 강력한 항바이러스 활성을 나타냄으로써 코로나바이러스를 원인으로 하는 사스 등의 질병 치료용 제제로 유용하게 사용될 수 있다.The present invention relates to a novel urea derivative, a method for preparing the same, and an antiviral composition comprising the same. The urea derivative of the present invention exhibits strong antiviral activity against coronavirus, thereby treating diseases such as SARS caused by coronavirus. It can be usefully used as a formulation.

본 발명의 우레아 유도체 중 바람직한 것은, 상기 화학식 1에서.Preferred among the urea derivatives of the present invention, in the formula (1).

C1-C4 알킬기가 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸 또는 sec-부틸이고;C 1 -C 4 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or sec-butyl;

C1-C2 알킬 카르보닐기가 메틸 또는 에틸 카르보닐이고;C 1 -C 2 alkyl carbonyl group is methyl or ethyl carbonyl;

C1-C2 알콕시 카르보닐기가 메톡시 또는 에톡시 카르보닐이고;C 1 -C 2 alkoxy carbonyl group is methoxy or ethoxy carbonyl;

C1-C2 하이드록시알킬기가 하이드록시메틸, 1-하이드록시에틸 또는 2-하이드록시에틸이다.C 1 -C 2 hydroxyalkyl group is hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl.

본 발명의 우레아 유도체는 이의 약학적으로 허용가능한 염 뿐 아니라 이로부터 제조될 수 있는 가능한 용매화물, 수화물 및 입체이성질체를 모두 포함한다.Urea derivatives of the present invention include not only pharmaceutically acceptable salts thereof, but also all possible solvates, hydrates and stereoisomers that may be prepared therefrom.

본 발명의 우레아 유도체의 약학적으로 허용가능한 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염을 예시할 수 있다. 상기 유리산으로는 유기산 또는 무기산을 사용할 수 있는데, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 아세트산, 글리콜산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파트산 등을 사용할 수 있고, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있으며, 바람직하게는 메탄설폰산, 염산 등을 사용할 수 있다.Pharmaceutically acceptable salts of the urea derivatives of the present invention can be exemplified by acid addition salts formed with pharmaceutically acceptable free acids. The free acid may be an organic acid or an inorganic acid, and an organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, Galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, and the like can be used, and preferably methanesulfonic acid, hydrochloric acid, or the like can be used. Can be.

본 발명에 따른 산 부가염은 통상의 방법, 즉, 상기 화학식 1의 우레아 유도체를 아세톤, 메탄올, 에탄올, 아세토니트릴 등과 같은 수혼화성 유기용매에 녹이고 과량의 유기산을 가하거나, 무기산의 산 수용액을 가한 후 침전시키거나 결정화시킨 후, 이 혼합물에서 용매나 과량의 산을 증발시킨 다음 건조시키거나 석출된 염을 흡인 여과시킴으로써 제조할 수 있다.Acid addition salt according to the present invention is a conventional method, that is, by dissolving the urea derivative of Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile and the like, adding an excess of an organic acid, or an acid aqueous solution of an inorganic acid After precipitation or crystallization, the mixture can be prepared by evaporating the solvent or excess acid and then drying or suction filtering the precipitated salt.

본 발명에 따른 더욱 바람직한 우레아 유도체의 예는 다음과 같고, 이에 대한 각각의 구조식을 하기 표 1에 표시하였다.Examples of more preferred urea derivatives according to the present invention are as follows, and the respective structural formulas thereof are shown in Table 1 below.

1) 1-[(3,5-다이메틸페닐아미노)메틸]-3-(2-메톡시-5,6-다이메틸피리딘-3-일)우레아1) 1-[(3,5-dimethylphenylamino) methyl] -3- (2-methoxy-5,6-dimethylpyridin-3-yl) urea

2) 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5,6-다이메틸피리딘-3-일)우레아2) 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5,6-dimethylpyridin-3-yl) urea

3) 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)우레아3) 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) urea

4) 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)우레아4) 1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) urea

5) 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-프로필피리딘-3-일)우레아5) 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-propylpyridin-3-yl) urea

6) 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-6-에틸-5-메틸옥시카르보닐피리딘-3-일)우레아6) 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-6-ethyl-5-methyloxycarbonylpyridin-3-yl) urea

7) 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아7) 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea

8) 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아8) 1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea

9) 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-[5-(1-하이드록시에틸)-2-메톡시- 6-메틸피리딘-3-일)우레아9) 1- [2- (3,5-dimethylphenylamino) ethyl] -3- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) urea

10) 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-[5-(1-하이드록시에틸)-2-메톡시-6-메틸피리딘-3-일)우레아10) 1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) urea

Figure 112006063514683-PAT00003
Figure 112006063514683-PAT00003

또한, 본 발명은 상기 화학식 1의 우레아 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing the urea derivative of Chemical Formula 1.

본 발명에 따른 상기 화학식 1로 표시되는 우레아 유도체는 적절한 용매와 염기의 존재 하에 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시킴으로써 제조할 수 있다. 화학식 2의 화합물은 공지된 방법(J. Med. Chem., 35, 3784~3791, 1993; J. Med. Chem., 35, 3792~3802, 1992; J. Med. Chem., 36, 249~255, 1992; J. Med. Chem., 36, 249~255, 1993; J. Med. Chem., 35, 3792~3793, 1993; J. Org. Chem., 58, 3176~3178, 1993)에 의해 합성할 수 있고, 화합물 3의 화합물들은 기존의 알려진 방법에 의해서 합성할 수 있다.The urea derivative represented by Formula 1 according to the present invention may be prepared by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a suitable solvent and a base. Compounds of formula (2) are known according to known methods ( J. Med. Chem. , 35 , 3784-3791, 1993; J. Med. Chem. , 35 , 3792-3380, 1992; J. Med. Chem. , 36 , 249-255, 1992; J. Med. Chem. , 36 , 249-255, 1993; J. Med. Chem. , 35 , 3792-3793, 1993; J. Org. Chem. , 58 , 3176-3178, 1993), and the compounds of compound 3 can be synthesized by known methods.

또한, 화학식 2의 화합물과 화학식 3의 화합물은 1 : 1 내지 2몰의 몰비로 반응시킬 수 있다. In addition, the compound of Formula 2 and the compound of Formula 3 may be reacted in a molar ratio of 1: 1 to 2 moles.

Figure 112006063514683-PAT00004
Figure 112006063514683-PAT00004

Figure 112006063514683-PAT00005
Figure 112006063514683-PAT00005

[화학식 1][Formula 1]

Figure 112006063514683-PAT00006
Figure 112006063514683-PAT00006

상기 식에서, R1, R2, R3, R4 및 n은 상기 화학식 1에서 정의한 바와 같다.Wherein R 1 , R 2 , R 3 , R 4 and n are as defined in Formula 1 above.

본 발명의 우레아 유도체는 통상의 유기용매 및 염기 하에서, 0 내지 25 ℃ 에서 0.5 내지 4시간 동안 반응시켜 제조하는 것이 바람직하다.The urea derivative of the present invention is preferably prepared by reaction under a conventional organic solvent and a base at 0 to 25 ° C. for 0.5 to 4 hours.

이때, 유기용매로는 다이클로로메탄, 클로로포름, 테트라하이드로퓨란 또는 다이에틸이써를 사용할 수 있으며, 염기로는 트리에틸아민, 피리딘 또는 1,8-다이아자바이사이클로[5.4.0]운데크-7-엔을 사용할 수 있다.In this case, dichloromethane, chloroform, tetrahydrofuran or diethyl ether may be used as the organic solvent, and triethylamine, pyridine or 1,8-diazabicyclo [5.4.0] undec-7 as a base. You can use yen.

본 발명의 조성물은 투여된 후 활성성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 잘 알려진 방법을 사용하여 약학 제형으로 제형화될 수 있다. 제형의 제조에 있어서, 활성성분을 담체와 함께 혼합 또는 희석하거나, 용기 형태의 담체 내에 봉입시키는 것이 바람직하다. 담체가 희석제로 사용되는 경우, 제형은 활성성분에 대한 담체, 부형제 또는 매질(medium)로 작용하는 고형, 반고형 또는 액상의 물질일 수 있으며, 예를 들면 정제, 환제, 분제, 새세이, 엘릭시르, 현탁제, 유제, 용액제, 시럽제, 에어로졸, 연질 또는 경질 젤라틴 캅셀제, 멸균 주사제, 멸균 분제 등의 형태일 수 있다. 또한, 제형은 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.The compositions of the present invention may be formulated into pharmaceutical formulations using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration. In the preparation of the formulation, it is preferable to mix or dilute the active ingredient with the carrier or to enclose it in a carrier in the form of a container. When the carrier is used as a diluent, the formulation may be a solid, semisolid or liquid substance which acts as a carrier, excipient or medium for the active ingredient, e.g. tablets, pills, powders, sachets, elixirs , Suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectables, sterile powders and the like. In addition, the formulation may further comprise fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like.

적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, Propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

본 발명의 우레아 유도체 또는 이의 약학적으로 허용가능한 염의 투여량은 처리되는 대상, 질병 또는 상태의 심각도, 투여의 속도 및 처방 의사의 판단에 따른다. 유효성분으로서 화학식 1의 화합물은 사람을 포함하는 포유동물에 대해 하 루 1 내지 200 mg/kg(체중), 바람직하게는 5 내지 50 mg/kg(체중)의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여될 수 있다. 일부의 경우에 있어서, 상기 언급된 범위보다 적은 투여량이 보다 적합할 수 있고, 해로운 부작용을 일으키지 않으면서도 보다 많은 양이 사용될 수도 있으며, 보다 많은 투여량의 경우는 하루에 걸쳐 수회의 적은 분량으로 분배될 수 있다.The dosage of the urea derivatives or pharmaceutically acceptable salts thereof of the present invention depends on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. As an active ingredient, the compound of formula 1 may be divided or divided once a day in an amount of 1 to 200 mg / kg body weight, preferably 5 to 50 mg / kg body weight, for mammals including humans. Administration can be via oral or parenteral routes. In some cases, smaller dosages may be more suitable than the above-mentioned ranges, and larger amounts may be used without causing harmful side effects, and higher dosages may be dispensed in several smaller portions throughout the day. Can be.

이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail with reference to Examples.

단, 하기 실시예들은 본 발명을 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.

본 발명에서는 핵자기 공명 스펙트럼에 의해 화합물들의 분자구조를 확인하였다.In the present invention, the molecular structure of the compounds was confirmed by nuclear magnetic resonance spectra.

<실시예 1> 1-[(3,5-다이메틸페닐아미노)메틸]-3-(2-메톡시-5,6-다이메틸피리딘-3-일)우레아Example 1 1-[(3,5-dimethylphenylamino) methyl] -3- (2-methoxy-5,6-dimethylpyridin-3-yl) urea

페닐-N-(2-메톡시-5,6-다이메틸피리딘-3-일)카바메이트(200 ㎎, 0.7 mmol)와 N-(3,5-다이메틸페닐)메탄다이아민(110 ㎎, 0.7 mmol)을 무수 테트라하이드로퓨란(10 ㎖)에 녹이고 DBU(112 ㎎, 0.7 mmol)을 가한 후 실온에서 2시간 동안 교반하였다. 반응 용액을 감압 농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(에틸아세테이트:헥산=1:1)로 분리 정제하여 95 %의 수율로 목적화합물을 얻었다.Phenyl-N- (2-methoxy-5,6-dimethylpyridin-3-yl) carbamate (200 mg, 0.7 mmol) and N- (3,5-dimethylphenyl) methanediamine (110 mg, 0.7 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), DBU (112 mg, 0.7 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound in a yield of 95%.

1H NMR(CDCl3) δ : 2.23(6H,s), 2.30(6H,s), 3.37(2H,m), 3.98(3H,s), 6.24(2H,d), 6.40(1H,s), 8.03(1H,s) 1 H NMR (CDCl 3 ) δ: 2.23 (6H, s), 2.30 (6H, s), 3.37 (2H, m), 3.98 (3H, s), 6.24 (2H, d), 6.40 (1H, s) , 8.03 (1H, s)

<실시예 2> 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5,6-다이메틸피리딘-3-일)우레아Example 2 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5,6-dimethylpyridin-3-yl) urea

페닐-N-(2-메톡시-5,6-다이메틸피리딘-3-일)카바메이트와 N1-(3,5-다이메틸페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.Phenyl-N- (2-methoxy-5,6-dimethylpyridin-3-yl) carbamate and N 1- (3,5-dimethylphenyl) ethane-1,2-diamine are the same as in Example 1 Reaction was carried out to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 2.22(9H,s), 2.32(3H,s), 3.35(4H,m), 3.91(3H,s), 6.26(2H,s), 6.38(1H,s), 8.03(1H,s) 1 H NMR (CDCl 3 ) δ: 2.22 (9H, s), 2.32 (3H, s), 3.35 (4H, m), 3.91 (3H, s), 6.26 (2H, s), 6.38 (1H, s) , 8.03 (1H, s)

<실시예 3> 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)우레아Example 3 1- [2- (3,5-Dimethylphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) urea

페닐-N-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)카바메이트와 N1-(3,5-다이메틸페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.Phenyl-N- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) carbamate and N 1- (3,5-dimethylphenyl) ethane-1,2-diamine The reaction was carried out in the same manner as in Example 1, to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 1.36(3H,t), 2.22(6H,s), 2.68(3H,s), 3.67(4H,m), 3.97(3H,s), 4.26(2H,m), 6.26(2H,s), 6.38(1H,s), 8.80(1H,s) 1 H NMR (CDCl 3 ) δ: 1.36 (3H, t), 2.22 (6H, s), 2.68 (3H, s), 3.67 (4H, m), 3.97 (3H, s), 4.26 (2H, m) , 6.26 (2H, s), 6.38 (1H, s), 8.80 (1H, s)

<실시예 4> 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)우레아Example 4 1- [2- (3,5-Dimethoxyphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) urea

페닐-N-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)카바메이트와 N1-(3,5-다이메톡시페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.Phenyl-N- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) carbamate and N 1- (3,5-dimethoxyphenyl) ethane-1,2-diamine Was reacted in the same manner as in Example 1 to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 1.36(3H,t), 2.66(3H,s), 3.67(4H,m), 3.78(6H,s), 3.99(3H,s), 4.26(2H,m), 6.14(2H,d), 6.94(1H,s), 8.80(1H,s) 1 H NMR (CDCl 3 ) δ: 1.36 (3H, t), 2.66 (3H, s), 3.67 (4H, m), 3.78 (6H, s), 3.99 (3H, s), 4.26 (2H, m) , 6.14 (2H, d), 6.94 (1H, s), 8.80 (1H, s)

<실시예 5> 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-프로필피리딘-3-일)우레아Example 5 1- [2- (3,5-Dimethylphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-propylpyridin-3-yl) urea

페닐-N-(2-메톡시-5-에틸옥시카르보닐-6-프로필피리딘-3-일)카바메이트와 N1-(3,5-다이메틸페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.N 1- (3,5-dimethylphenyl) ethane-1,2-diamine with phenyl-N- (2-methoxy-5-ethyloxycarbonyl-6-propylpyridin-3-yl) carbamate The reaction was carried out in the same manner as in Example 1, to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 0.96(3H,t), 1.14(2H,m), 1.36(2H,m), 1.39(3H,t), 2.21(6H,s), 3.67(4H,m), 3.86(3H,s), 4.24(2H,q), 6.38(2H,d), 6.78(1H,s), 8.80(1H,s) 1 H NMR (CDCl 3 ) δ: 0.96 (3H, t), 1.14 (2H, m), 1.36 (2H, m), 1.39 (3H, t), 2.21 (6H, s), 3.67 (4H, m) , 3.86 (3H, s), 4.24 (2H, q), 6.38 (2H, d), 6.78 (1H, s), 8.80 (1H, s)

<실시예 6> 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-6-에틸-5-메틸옥시카르보닐피리딘-3-일)우레아Example 6 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-6-ethyl-5-methyloxycarbonylpyridin-3-yl) urea

페닐-N-(2-메톡시-5-에틸옥시카르보닐-6-프로필피리딘-3-일)카바메이트와 N1-(3,5-다이메틸페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.N 1- (3,5-dimethylphenyl) ethane-1,2-diamine with phenyl-N- (2-methoxy-5-ethyloxycarbonyl-6-propylpyridin-3-yl) carbamate The reaction was carried out in the same manner as in Example 1, to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 1.08(3H,t), 2.16(2H,m), 2.21(6H,s), 3.67(4H,m), 3.86(3H,s), 4.10(3H,s), 6.38(2H,d), 6.80(1H,s), 8.97(1H,s) 1 H NMR (CDCl 3 ) δ: 1.08 (3H, t), 2.16 (2H, m), 2.21 (6H, s), 3.67 (4H, m), 3.86 (3H, s), 4.10 (3H, s) , 6.38 (2H, d), 6.80 (1H, s), 8.97 (1H, s)

<실시예 7> 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아Example 7 1- [2- (3,5-dimethylphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea

페닐-N-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)카바메이트와 N1-(3,5-다이메틸페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.Phenyl-N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) carbamate and N 1- (3,5-dimethylphenyl) ethane-1,2-diamine with Example 1 The reaction was carried out in the same manner to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 2.31(3H,s), 2.57(3H,s), 2.65(3H,s), 3.38(4H,m), 4.10(3H,s), 6.71(2H,d), 6.94(1H,s), 8.89(1H,s) 1 H NMR (CDCl 3 ) δ: 2.31 (3H, s), 2.57 (3H, s), 2.65 (3H, s), 3.38 (4H, m), 4.10 (3H, s), 6.71 (2H, d) , 6.94 (1H, s), 8.89 (1H, s)

<실시예 8> 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아Example 8 1- [2- (3,5-Dimethoxyphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea

페닐-N-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)카바메이트와 N1-(3,5-다이메톡시페닐)에탄-1,2-다이아민을 실시예 1과 동일한 방법으로 반응시켜 96 %의 수율로 목적화합물을 얻었다.Example of Phenyl-N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) carbamate and N 1- (3,5-dimethoxyphenyl) ethane-1,2-diamine The reaction was carried out in the same manner as in 1, to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 2.56(3H,s), 2.63(3H,s), 3.38(4H,m), 3.74(6H,s), 3.99(3H,s), 5.84(3H,s), 8.91(1H,s) 1 H NMR (CDCl 3 ) δ: 2.56 (3H, s), 2.63 (3H, s), 3.38 (4H, m), 3.74 (6H, s), 3.99 (3H, s), 5.84 (3H, s) , 8.91 (1H, s)

<실시예 9> 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-[5-(1-하이드록시에틸)-2-메톡시-6-메틸피리딘-3-일)우레아Example 9 1- [2- (3,5-dimethylphenylamino) ethyl] -3- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) urea

1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아(200 ㎎, 0.5 mmol)를 메탄올(10 ㎖)에 녹인 다음 소디움보로하이드라이드(26㎎, 0.5 mmol)를 가한 후 0 ℃에서 30분 동안 교반하였다. 반응 용액을 감압 농축하여 메탄올을 제거하고 관 크로마토그래피(에틸아세테이트:헥산=1:1)로 분리 정제하여 96%의 수율로 목적화합물을 얻었다.1- [2- (3,5-dimethylphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea (200 mg, 0.5 mmol) in methanol (10 Ml), sodium borohydride (26 mg, 0.5 mmol) was added thereto, followed by stirring at 0 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure to remove methanol, and the residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound in a yield of 96%.

1H NMR(CDCl3) δ : 1.48(3H,d), 2.42(3H,s), 3.40(4H,m), 3.99(3H,s), 5.04(1H,q), 6.01(1H,s), 6.15(2H,d), 8.46(1H,s) 1 H NMR (CDCl 3 ) δ: 1.48 (3H, d), 2.42 (3H, s), 3.40 (4H, m), 3.99 (3H, s), 5.04 (1H, q), 6.01 (1H, s) , 6.15 (2H, d), 8.46 (1H, s)

<실시예 10> 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-[5-(1-하이드록시에틸)-2-메톡시-6-메틸피리딘-3-일)우레아Example 10 1- [2- (3,5-Dimethoxyphenylamino) ethyl] -3- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl Urea

1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아를 메탄올(10 ㎖)에 녹인 다음 소디움보로하이드라이드를 가하여 96 %의 수율로 목적화합물을 얻었다.Dissolve 1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea in methanol (10 ml) and then Sodium borohydride was added to obtain the target compound in a yield of 96%.

1H NMR(CDCl3) δ : 1.48(3H,d), 2.42(3H,s), 3.39(4H,m), 3.79(6H,s), 3.99(3H,s), 5.05(1H,q), 6.71(2H,d), 6.96(1H,s), 8.46(1H,s) 1 H NMR (CDCl 3 ) δ: 1.48 (3H, d), 2.42 (3H, s), 3.39 (4H, m), 3.79 (6H, s), 3.99 (3H, s), 5.05 (1H, q) , 6.71 (2H, d), 6.96 (1H, s), 8.46 (1H, s)

본 발명에 의한 우레아 유도체에 대하여 하기와 같은 실험을 실시하고 코로나 바이러스에 대한 항바이러스 활성에 대하여 평가하였다. The following experiments were performed on the urea derivatives according to the present invention and evaluated for antiviral activity against coronavirus.

<시험예> 코로나 바이러스에 대한 항바이러스 활성Test Example Antiviral Activity against Corona Virus

본 발명의 우레아 유도체의 항바이러스 활성을 바이러스-유도성 세포병변 효과(virus-induced cytopathic effect(CPE)) 저해법을 이용하여 하기와 같이 측정하였다. The antiviral activity of the urea derivatives of the present invention was measured as follows using the virus-induced cytopathic effect (CPE) inhibition method.

96-웰 플레이트(96-well plate)에 CRFK [펠리스 카투스 고양이 신장 세포; cat(Felis catus) kidney cell] 세포를 증식시킨 다음, DME/2% FBS 배양액으로 희석된 바이러스를 각 웰(well)에 접종량이 100 CCID50(50% 세포 배양 저해량)가 되도록 100 ㎕씩 접종하고 1시간 동안 37 ℃에서 흡착시킨 후 배양액을 제거하였다.CRFK [Felice Catus Cat Kidney Cells in 96-well plate; cat ( Felis catus ) kidney cell] cells were grown, and then 100 µl of the virus diluted in DME / 2% FBS culture was added to each well so that the dose was 100 CCID 50 (50% cell culture inhibition). After adsorbing at 37 ° C. for 1 hour, the culture solution was removed.

이때, 바이러스는 고양이 코로나 바이러스[FCV(Feline coronavirus)] 및 고양이 전염성 복막염 바이러스[FIP(Feline infectious peritonitis virus)]를 사용하였다.At this time, the virus used feline corona virus [FCV (Feline coronavirus)] and feline infectious peritonitis virus [FIP (Feline infectious peritonitis virus)].

각 농도로 배양액에 희석된 시료 약물을 이중으로 각 웰에 100 ㎕씩 첨가하고 37 ℃, CO2 배양기에서 3일 배양한 다음 MTT 검색법을 이용하여 바이러스에 감염된 세포의 50%가 살아남도록 항바이러스 활성을 보인 약물의 농도를 EC50 (50% 효과 농도)으로 결정하였다. 세포 생존률(%)은 바이러스 및 시료 약물을 첨가하지 않은 대조군의 세포수를 기준으로 하기 수학식 1을 이용하여 측정하였다. 이때, 세포생존률이 100 %이면 항바이러스 활성이 100 %이고, 0 %이면 항바이러스 활성이 없는 것으로 하였다.100 μl of the sample drug diluted in the culture solution was added to each well in duplicate, and then cultured for 3 days in a CO 2 incubator at 37 ° C., and 50% of the virus-infected cells were survived by MTT detection. The concentration of drug with activity was determined as EC 50 (50% effect concentration). Cell survival rate (%) was measured using the following equation 1 based on the number of cells of the control group without the virus and sample drug. At this time, if the cell survival rate is 100%, antiviral activity is 100%, and if it is 0%, antiviral activity is assumed.

세포 생존률(%)=(A약물/바이러스-A바이러스)/(A대조-A바이러스) × 100(%)Cell survival rate (%) = (A drug / virus- A virus ) / (A control- A virus ) × 100 (%)

상기 식에서,Where

A약물/바이러스는 바이러스와 약물이 모두 처리된 웰의 세포수이고, Drug A / Virus is the number of cells in wells treated with both virus and drug,

A바이러스는 바이러스만이 처리된 웰의 세포수이고,A virus is the number of cells in wells treated with virus only,

A대조는 바이러스와 약물이 모두 처리되지 않은 웰의 세포수이다.A control is the number of cells in wells that were not treated with both virus and drug.

한편, 시료 약물 자체의 독성을 평가하기 위하여, 바이러스가 감염되지 않은 세포(mock-infected)를 상기와 동일한 방법으로 처리하여 세포독성을 측정하였다. 즉, CRFK 세포에 DME/2% FBS 배양액만을 처리하여 1시간 동안 배양한 후, 배지를 제거하고 상기와 동일한 시료 약물을 이중으로 첨가하였다. 3일 배양 후, MTT 검색법으로 시료 약물을 처리한 웰의 생존 세포 수와 시료 약물을 처리하지 않은 웰의 생존 세포수를 비교하여 감염되지 않은(mock-infected) 세포의 50%를 죽도록 독성을 나타낸 약물 농도를 CC50[50 % 세포독성 농도(cytotoxic concentration)]으로 결정하였다.On the other hand, in order to evaluate the toxicity of the sample drug itself, virus-infected cells (mock-infected) was treated in the same manner as above to measure the cytotoxicity. In other words, CRFK cells were treated with only DME / 2% FBS culture and incubated for 1 hour, and then the medium was removed and the same sample drug was added in duplicate. After 3 days of incubation, the viability of killing 50% of mock-infected cells was compared by comparing the viable cell count of the wells treated with the sample drug with the viable cell counts of the sample drug-treated wells using the MTT assay. The drug concentrations indicated were determined as CC 50 [50% cytotoxic concentration].

세포 생존률(%)은 하기 수학식 2를 이용하여 측정하였으며, 이때 세포생존률이 100 %이면 시료 약물에 세포독성이 없는 것이고, 0 %이면 세포독성이 가장 강한 것으로 하였다.Cell survival rate (%) was measured using Equation 2 below, wherein the cell survival rate was 100%, there was no cytotoxicity to the sample drug, and 0% was the strongest cytotoxicity.

세포 생존률(%)=(A약물-ABlank)/(A대조-ABlank) × 100(%)Cell viability (%) = (A drug -A Blank ) / (A control -A Blank ) × 100 (%)

상기 식에서,Where

A약물은 바이러스가 첨가되지 않은 웰(mock-infected well)에 시료 약물을 처리한 웰의 세포수이고, Drug A is the number of cells in wells treated with the sample drug in mock-infected wells,

ABlank는 배양액만 첨가된 웰의 세포수이고,A Blank is the cell number of the well to which only the culture medium was added.

A대조는 바이러스 및 시료 약물을 처리하지 않은 웰의 세포수이다.A control is the number of cells in wells that were not treated with virus and sample drug.

상기와 같이, EC50과 CC50을 구한 후, 선택도지수[selectivity index(SI, CC50/EC50)]를 산출하여 하기 표 2에 표시하였다.As described above, after obtaining the EC 50 and CC 50 , the selectivity index (selectivity index (SI, CC 50 / EC 50 )) was calculated and shown in Table 2 below.

Figure 112006063514683-PAT00007
Figure 112006063514683-PAT00007

상기 표 2에 나타난 바와 같이, 본 발명의 우레아 유도체(실시예 2, 3, 4, 6 및 7)를 유효성분으로 함유하는 약물은 리바비린에 비하여 훨씬 적은 농도로도 코로나 바이러스에 대하여 우수한 항바이러스 활성을 나타내었음을 알 수 있다.As shown in Table 2, the drug containing the urea derivatives of the present invention (Examples 2, 3, 4, 6 and 7) as an active ingredient has excellent antiviral activity against coronavirus even at a much lower concentration than ribavirin. It can be seen that.

본 발명에 의한 우레아 유도체는 코로나 바이러스에 대한 강력한 항바이러스 활성을 나타냄으로써, 본 발명의 우레아 유도체 또는 약학적으로 허용되는 그의 염을 유효성분으로 하는 항바이러스제 조성물은 사스 등 코로나 바이러스에 의해 발생되는 질병에 대하여 치료용 제제로 유용하게 사용될 수 있다.The urea derivative according to the present invention exhibits strong antiviral activity against the corona virus, so that the antiviral composition comprising the urea derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a disease caused by a corona virus such as SARS. It can be usefully used as a therapeutic agent for.

Claims (7)

하기 화학식 1로 표시되는 우레아 유도체 또는 약학적으로 허용 가능한 그의 염:A urea derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112006063514683-PAT00008
Figure 112006063514683-PAT00008
상기 식에서, Where R1은 C1-C4 알킬기, C1-C2 알킬 카르보닐기, C1-C2 알콕시 카르보닐기, C1-C2 하이드록시알킬기 또는 카르복실기이고;R 1 is a C 1 -C 4 alkyl group, a C 1 -C 2 alkyl carbonyl group, a C 1 -C 2 alkoxy carbonyl group, a C 1 -C 2 hydroxyalkyl group or a carboxyl group; R2는 C1-C4 알킬기이고;R 2 is a C 1 -C 4 alkyl group; R3 및 R4는 각각 독립적으로 C1-C4 알킬기 또는 C1-C4 알콕시기이고;R 3 and R 4 are each independently a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group; n은 1~3이다.n is 1-3.
제 1항에 있어서, The method of claim 1, C1-C4 알킬기가 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸 또는 sec-부틸이고;C 1 -C 4 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or sec-butyl; C1-C2 알킬 카르보닐기가 메틸 또는 에틸 카르보닐이고;C 1 -C 2 alkyl carbonyl group is methyl or ethyl carbonyl; C1-C2 알콕시 카르보닐기가 메톡시 또는 에톡시 카르보닐이고;C 1 -C 2 alkoxy carbonyl group is methoxy or ethoxy carbonyl; C1-C2 하이드록시알킬기가 하이드록시메틸, 1-하이드록시에틸 또는 2-하이드록시에틸인 것을 특징으로 하는,Wherein the C 1 -C 2 hydroxyalkyl group is hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl, 우레아 유도체 또는 약학적으로 허용가능한 그의 염.Urea derivatives or pharmaceutically acceptable salts thereof. 제 1항에 있어서,The method of claim 1, 하기 화합물로 구성된 군으로부터 선택된 것임을 특징으로 하는, 우레아 유도체 또는 약학적으로 허용가능한 그의 염:Urea derivatives or pharmaceutically acceptable salts thereof, characterized in that they are selected from the group consisting of: 1-[(3,5-다이메틸페닐아미노)메틸]-3-(2-메톡시-5,6-다이메틸피리딘-3-일)우레아;1-[(3,5-dimethylphenylamino) methyl] -3- (2-methoxy-5,6-dimethylpyridin-3-yl) urea; 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5,6-다이메틸피리딘-3-일)우레아;1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5,6-dimethylpyridin-3-yl) urea; 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)우레아;1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) urea; 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-메틸피리딘-3-일)우레아;1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-methylpyridin-3-yl) urea; 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-5-에틸옥시카르보닐-6-프로필피리딘-3-일)우레아;1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-5-ethyloxycarbonyl-6-propylpyridin-3-yl) urea; 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(2-메톡시-6-에틸-5-메틸옥시카르보닐피리 딘-3-일)우레아;1- [2- (3,5-dimethylphenylamino) ethyl] -3- (2-methoxy-6-ethyl-5-methyloxycarbonylpyridin-3-yl) urea; 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아;1- [2- (3,5-dimethylphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea; 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-(5-아세틸-2-메톡시-6-메틸피리딘-3-일)우레아;1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) urea; 1-[2-(3,5-다이메틸페닐아미노)에틸]-3-[5-(1-하이드록시에틸)-2-메톡시-6-메틸피리딘-3-일)우레아; 및1- [2- (3,5-dimethylphenylamino) ethyl] -3- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) urea; And 1-[2-(3,5-다이메톡시페닐아미노)에틸]-3-[5-(1-하이드록시에틸)-2-메톡시-6-메틸피리딘-3-일)우레아.1- [2- (3,5-dimethoxyphenylamino) ethyl] -3- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) urea. 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시켜 하기 화학식 1의 우레아 유도체를 얻는 것을 특징으로 하는, 하기 화학식 1의 우레아 유도체의 제조방법:A method for preparing a urea derivative of formula 1, characterized in that by reacting a compound of formula 2 with a compound of formula 3 to obtain a urea derivative of formula 1 [화학식 2][Formula 2]
Figure 112006063514683-PAT00009
Figure 112006063514683-PAT00009
[화학식 3][Formula 3]
Figure 112006063514683-PAT00010
Figure 112006063514683-PAT00010
[화학식 1][Formula 1]
Figure 112006063514683-PAT00011
Figure 112006063514683-PAT00011
상기 식에서,Where R1, R2, R3, R4 및 n은 제1항에서 정의한 바와 같다.R 1 , R 2 , R 3 , R 4 and n are as defined in claim 1.
제 4항에 있어서, The method of claim 4, wherein 유기용매 및 염기 존재 하에 0 내지 25 ℃에서 반응을 수행함을 특징으로 하는 방법.The process is characterized in that the reaction is carried out at 0 to 25 ℃ in the presence of an organic solvent and a base. 제 1항의 우레아 유도체 또는 약학적으로 허용되는 그의 염을 유효성분으로 함유하는 코로나 바이러스에 의해 발생되는 질병의 예방 또는 치료용 조성물.A composition for preventing or treating a disease caused by a corona virus containing the urea derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 제 6항에 있어서,The method of claim 6, 상기 코로나 바이러스에 의해 발생되는 질병이 사스(SARS)인 것을 특징으로 하는 조성물.The disease caused by the corona virus is SARS.
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