KR20070040281A - A pharmaceutical composition for prevention and treatment of hepatitis c virus - Google Patents

A pharmaceutical composition for prevention and treatment of hepatitis c virus Download PDF

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KR20070040281A
KR20070040281A KR1020060027608A KR20060027608A KR20070040281A KR 20070040281 A KR20070040281 A KR 20070040281A KR 1020060027608 A KR1020060027608 A KR 1020060027608A KR 20060027608 A KR20060027608 A KR 20060027608A KR 20070040281 A KR20070040281 A KR 20070040281A
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oxo
dihydropyridin
urea
dichlorobenzyl
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KR100798634B1 (en
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한철규
윤정혁
김남두
성백린
최성일
류기선
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주식회사 이큐스팜
성백린
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone

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Abstract

본 발명은 C형 간염 예방 및 치료용 약학적 조성물에 관한 것으로, 상세하게는 3-(6-아미노-퓨린-9-일)-프로페논 유도체 또는 [1-(벤질)-2-옥소-1,2-디하이드로-피리딘-3-일 유도체를 유효성분으로 하는 C형 간염 예방 및 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing and treating hepatitis C. Specifically, 3- (6-amino-purin-9-yl) -propenone derivative or [1- (benzyl) -2-oxo-1 It relates to a pharmaceutical composition for the prevention and treatment of hepatitis C comprising, as an active ingredient, a 2-dihydro-pyridin-3-yl derivative.

본 발명의 조성물은 HCV RNA 중합효소 활성을 효과적으로 저해함으로써, C형 간염 예방 및 치료에 유용하게 사용될 수 있다.The composition of the present invention can be effectively used for the prevention and treatment of hepatitis C by effectively inhibiting HCV RNA polymerase activity.

Description

Ｃ형 간염 예방 및 치료용 약학적 조성물{A pharmaceutical composition for prevention and treatment of Hepatitis C Virus}A pharmaceutical composition for prevention and treatment of Hepatitis C Virus

본 발명은 C형 간염 예방 및 치료용 약학적 조성물에 관한 것으로, 상세하게는 3-(6-아미노-퓨린-9-일)-프로페논 유도체 또는 [1-(벤질)-2-옥소-1,2-디하이드로-피리딘-3-일 유도체를 유효성분으로 하는 C형 간염 예방 및 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing and treating hepatitis C. Specifically, 3- (6-amino-purin-9-yl) -propenone derivative or [1- (benzyl) -2-oxo-1 It relates to a pharmaceutical composition for the prevention and treatment of hepatitis C comprising, as an active ingredient, a 2-dihydro-pyridin-3-yl derivative.

C형 간염 바이러스(Hepatitis C Virus; HCV)는 플라비바이러스(Flavivirus) 과에 속하는 막이 있는 바이러스이다. 게놈은 (+)-RNA(plus-strand RNA)로서 그 크기가 9.6kb이며 3,010개의 아미노산으로 구성된 다단백질(poly-protein)을 발현한다. 이 다단백질은 숙주 세포와 바이러스의 효소에 의해 3개의 구조 단백질과 6개의 비구조 단백질로 분리된다.Hepatitis C Virus (HCV) is a membraneed virus belonging to the Flavivirus family. The genome is (+)-RNA (plus-strand RNA), which is 9.6 kb in size and expresses a poly-protein consisting of 3,010 amino acids. This polyprotein is separated into three structural proteins and six nonstructural proteins by enzymes of the host cell and virus.

HCV 게놈의 5'과 3' 말단에는 거의 모든 유전형(genotype)의 염기 서열이 동일하게 유지된 비해독 부위가 있다. 5' 말단에서는 330~341개의 뉴클레오티드가, 그리고 3' 말단에서는 폴리 A(poly A) 뒤에 98개의 뉴클레오티드가 최근 발견되었 는데, 이곳이 바이러스의 RNA 복제나 해독에 중요한 역할을 하리라 추측된다. 바이러스 게놈의 아미노 말단은 바이러스 구조 단백질인 중심 항원 유전자(Core), E1, E2를 만들고 나머지 부위는 비구조 단백질을 만들게 된다. 중심 항원 유전자는 바이러스의 캡사이드(Capsid) 단백질, E1과 E2는 바이러스의 외피 단백질로 되어 있고 이들 단백질은 내형질쇄막(endoplasmic reticulum)에 있는 신호 펩티드 분해효소(signal peptidase)에 의해 분리된다. 비구조 단백질은 세린 단백질 분해효소 (serine protease)인 NS3과 보조인자(cofactor)인 NS4A에 의해 분리된다. NS5B는 RNA-의존적인 RNA 중합효소(RNA-dependent RNA polymerase) 기능을 갖고 있으며 바이러스 복제에 가장 중요한 효소이다.At the 5 'and 3' ends of the HCV genome, there is a non-toxic site where the base sequences of almost all genotypes remain the same. Recently, 330 to 341 nucleotides at the 5 'end and 98 nucleotides after the poly A at the 3' end have recently been found, which is thought to play an important role in viral RNA replication or translation. The amino terminus of the viral genome produces the core antigenic genes (Core), E1 and E2, which are viral structural proteins, and the rest of the viral genome produces nonstructural proteins. The central antigen gene is the virus's capsid protein, E1 and E2, which are the envelope proteins of the virus, and these proteins are separated by signal peptidase in the endoplasmic reticulum. Nonstructural proteins are separated by the serine protease NS3 and the cofactor NS4A. NS5B has RNA-dependent RNA polymerase function and is the most important enzyme for viral replication.

HCV에 의한 감염은 수혈 및 지역 특이적 전염(community-acquired)에 의해 일어나고, 신장 투석에 의해 약 70% 정도가 감염된다는 보고가 있다. HCV에 감염이 되면 약 20% 정도가 5년 내에 간경화를 수반한 급성 간염을 일으키게 되고 간암으로 전이된다. 이러한 높은 만성 감염율은 RNA 바이러스에서 보기 드문 일로서 HCV가 높은 비율의 간암을 일으키는 매개체임을 보여주고 있다. HCV의 지속적인 감염 기작에 대해서는 연구된 바가 없다. 최근에는 모든 혈액에 대해서 HCV 검사가 잘 이루어지고 있어 수혈로 인한 감염은 현저히 줄어들었지만 지역 특이적 감염은 아직 조절할 수가 없어 전 세계적으로 중요한 문제점으로 대두되고 있다.Infection with HCV is caused by transfusion and community-acquired, and about 70% have been infected by renal dialysis. About 20% of HCV infections cause acute hepatitis with cirrhosis within 5 years and spread to liver cancer. This high rate of chronic infection is rare in RNA viruses, demonstrating that HCV is a mediator of high rates of liver cancer. The mechanism of persistent infection of HCV has not been studied. In recent years, all blood has been well tested for HCV, and infection due to blood transfusion has been significantly reduced.

역학적으로 볼 때 HCV는 HBV와 달리 전 세계에 골고루 분포되어 있고 전 세계 인구의 1.5~2%가 감염된 것으로 보고되고 있다. HCV에 감염되면 만성 간염으로 진행되는 것이 특징인데 간경화 및 간암으로 전이되는 확률이 B형보다 상당히 높 다. C형은 분류학적으로도 B형과는 전혀 다른 바이러스과에 속하기 때문에 B형 백신으로는 예방이 불가능하며 알파-인터페론(α-IFN)으로 치료를 시도하고 있으나 유전형에 따라 반응이 현저히 다르고 효과가 극히 미약하다. 특히 많은 수가 감염되어 있는 유전형 1b(genotype 1b)의 경우 알파-인터페론 치료 효과가 가장 미약하다.Epidemiologically, HCV, unlike HBV, is evenly distributed throughout the world, with 1.5-2% of the world's population infected. HCV infection is characterized by progression to chronic hepatitis, which is more likely than hepatitis B to liver cirrhosis and liver cancer. Type C is a taxonomic group belonging to a completely different virus family, so it is impossible to prevent it with type B vaccine, and attempts to treat it with alpha-interferon (α-IFN). Extremely weak In particular, genotype 1b infected with a large number has the least effect of alpha-interferon treatment.

HCV는 1989년 처음으로 클로닝에 의해 RNA 게놈(genome)이 분리된 이후 많은 연구가 수행되었지만 아직까지 효과적인 치료제는 개발되지 못하고 있다. 현재 HCV 감염에 대한 치료제로, 인터페론과 항바이러스제인 리바비린(ribavirin) 병용요법이 사용되고 있지만, 치료율이 낮고 부작용이 나타나므로 그 효과가 미약한 실정이다. 따라서 아직까지 HCV에 대한 특이적인 증식 저해제로 개발된 것은 전무한 상태라 볼 수 있다.HCV has been studied for many years since the RNA genome was isolated by cloning for the first time in 1989, but no effective therapeutic agent has been developed. Currently, the combination of interferon and antiviral ribavirin (ribavirin) is used as a treatment for HCV infection, but the effect is low because of low treatment rate and side effects. Therefore, no development has been developed as a specific growth inhibitor for HCV.

이에 본 발명자들은 부작용 및 독성이 적은 새로운 C형 간염 치료제를 개발하기 위하여 HCV에 대해 우수한 항바이러스 활성을 나타내는 화합물에 대해 탐색하던중, 화학식 1로 표시되는 3-(6-아미노-퓨린-9-일)-프로페논 유도체 및 화학식 2로 표시되는 [1-(벤질)-2-옥소-1,2-디하이드로-피리딘-3-일 유도체에서 HCV 증식 억제 효과가 우수함을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors searched for a compound exhibiting excellent antiviral activity against HCV in order to develop a novel hepatitis C therapeutic agent having low side effects and toxicity, and the 3- (6-amino-purine-9- The present invention was confirmed that the HCV proliferation inhibitory effect is excellent in the 1) -propenone derivative and the [1- (benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl derivative represented by the formula (2). It was.

본 발명은 HCV 증식 억제 효과가 우수한 C형 간염 예방 및 치료용 약학적 조성물을 제공하고자 한다.The present invention is to provide a pharmaceutical composition for preventing and treating hepatitis C having excellent HCV proliferation inhibitory effect.

본 발명은 C형 간염 예방 및 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing and treating hepatitis C.

이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 하기 화학식 1로 표시되는 3-(6-아미노-퓨린-9-일)-프로페논 유도체 또는 화학식 2로 표시되는 [1-(벤질)-2-옥소-1,2-디하이드로-피리딘-3-일 유도체를 유효성분으로 하는 C형 간염 예방 및 치료용 약학적 조성물을 제공한다.The present invention is a 3- (6-amino-purin-9-yl) -propenone derivative represented by the following formula (1) or [1- (benzyl) -2-oxo-1,2-dihydro- represented by formula (2) Provided is a pharmaceutical composition for preventing and treating hepatitis C having pyridin-3-yl derivative as an active ingredient.

Figure 112006021509849-PAT00001
Figure 112006021509849-PAT00001

(상기 화학식 1에서,(In Formula 1,

R은 C1~C6인 직쇄 또는 분쇄상 알킬기, 또는 1~3개의 헤테로 원자를 포함하는 포화 또는 불포화된 5원자 또는 6원자 헤테로고리 화합물이다.)R is a C 1 to C 6 straight or crushed alkyl group, or a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 to 3 hetero atoms.)

Figure 112006021509849-PAT00002
Figure 112006021509849-PAT00002

(상기 화학식 2에서,(In Formula 2,

R1은 아닐린, 2,4-디플루오로아닐린, 2,6-디메틸아닐린, 아미노피리딘, 3,5-디클로로아닐린, 5-메틸피리딘-2-아민, 4-메틸-피페라진, 3-트리플루오로메틸아닐린, 4-아미노피리딘, 2-아미노메틸피리딘, 3-트리플루오로메틸-벤젠티올, 2-치환된-아미노페닐기, 벤젠티올, 에틸머캅토아세테이트, 2-트리플루오로메틸 아닐린 또는 3-이소프로필옥시아닐린을 나타내며,R 1 is aniline, 2,4-difluoroaniline, 2,6-dimethylaniline, aminopyridine, 3,5-dichloroaniline, 5-methylpyridin-2-amine, 4-methyl-piperazine, 3-tri Fluoromethylaniline, 4-aminopyridine, 2-aminomethylpyridine, 3-trifluoromethyl-benzenethiol, 2-substituted-aminophenyl group, benzenethiol, ethylmercaptoacetate, 2-trifluoromethyl aniline or 3-isopropyloxyaniline,

R2 및 R3는 서로 독립적이며, 수소 또는 할로겐이다.)R 2 and R 3 are independent of each other and are hydrogen or halogen.)

상기 화학식 1 또는 화학식 2의 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 화학식 1 또는 화학식 2의 화합물은 당해 기술 분야에서 통상적인 방법에 따라 약제학적으로 허용되는 산 부가염을 형성할 수 있다. 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고 유기산으로는 구연산, 초산, 젖산, 주석산 (tartaric acid), 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플루오로아세트산, 벤조산, 글루콘산, 메탄술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 또는 아스파르트산 등을 사용할 수 있다.The compound of Formula 1 or Formula 2 may be used in the form of a pharmaceutically acceptable salt, and acid addition salts formed by pharmaceutically acceptable free acid are useful as salts. Compounds of Formula 1 or Formula 2 may form pharmaceutically acceptable acid addition salts according to methods conventional in the art. Organic acids and inorganic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid can be used as the inorganic acid, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid , Oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid or aspartic acid.

본 발명의 조성물에서 유효성분인 화학식 1 또는 화학식 2의 화합물은 시판되는 시약을 사용할 수 있고, 공지의 방법으로 합성하여 사용할 수 있다.Compounds of the formula (1) or formula (2) as an active ingredient in the composition of the present invention can be used commercially available reagents, can be synthesized by a known method.

화학식 1로 표시되는 3-(6-아미노-퓨린-9-일)-프로페논 유도체는 이미 공지 된 방법(J. Heterocyc. Chem., 30, 379-380, 1993, Bull. Korean Chem. Soc., 17, 212-214, 1996, J. Chem. Soc., Perkin Trans.1, 2331-2342, 2000)으로 제조가 용이하며, 하기 반응식 1에 나타낸다. 또한 출발물질로 사용되는 화합물 3 및 화합물 4의 경우, 상업적으로 시판되는 물질로서 쉽게 구입하여 사용할 수 있다.The 3- (6-amino-purin-9-yl) -propenone derivative represented by the formula (1) is known from the methods already known ( J. Heterocyc. Chem. , 30, 379-380, 1993, Bull.Korean Chem. Soc. , 17, 212-214, 1996, J. Chem. Soc., Perkin Trans. 1 , 2331-2342, 2000), and is shown in Scheme 1 below. In addition, compounds 3 and 4 used as starting materials can be easily purchased and used as commercially available materials.

Figure 112006021509849-PAT00003
Figure 112006021509849-PAT00003

(상기 반응식 1에서, R은 화학식 1에서 정의한 바와 같다.)(In Scheme 1, R is as defined in Formula 1).

화학식 2로 표시되는 [1-(벤질)-2-옥소-1,2-디하이드로-피리딘-3-일 유도체는 이미 공지된 방법으로 제조가 용이하며, 하기 반응식 2에 나타낸다. 단계 1, 단계 2(Bioorg. Med. Chem. Lett., 1999, 9, 895-899, J. Med. Chem., 1992, 35, 3792-3798), 및 단계 3(Tetrahedron, 1998, 54, 487-496, Eur. J. Med. Chem., 1997, 32, 901-910, Bioorg. Med. Chem. Lett., 1999, 9, 815-820)은 이미 공지된 방법으로 제조가 용이하다. 또한, 상기 단계 1, 단계 2 및 단계 3에서 출발물질 및 반응물질로 사용되는 화합물 5, 화합물 6, 화합물 9는 상업적으로 시판되는 물질로서 용이하게 구입하여 사용할 수 있다.The [1- (benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl derivative represented by the formula (2) is easily prepared by a known method, and is shown in Scheme 2 below. Step 1, Step 2 ( Bioorg. Med. Chem. Lett ., 1999, 9, 895-899, J. Med. Chem ., 1992, 35, 3792-3798), and Step 3 ( Tetrahedron , 1998, 54, 487) -496, Eur. J. Med. Chem ., 1997, 32, 901-910, Bioorg. Med. Chem. Lett. , 1999, 9, 815-820 are readily prepared by known methods. In addition, Compound 5, Compound 6, Compound 9 used as starting materials and reactants in Step 1, Step 2 and Step 3 can be easily purchased and used as a commercially available material.

Figure 112006021509849-PAT00004
Figure 112006021509849-PAT00004

(상기 반응식 2에서, R1, R2 및 R3는 화학식 2에서 정의한 바와 같다.)(In Reaction Scheme 2, R 1 , R 2 and R 3 are as defined in Formula 2.)

상기 반응식 2는, 1) 3-니트로-1H-피리딘-2-온 (5)과 화합물 (6)을 염기성 수용액 조건에서 반응시키는 단계,Scheme 2, 1) reacting 3-nitro-1H-pyridin-2-one (5) and compound (6) in basic aqueous solution conditions,

2) 상기 단계 1에서 제조한 1-(3,4-디클로로벤질)-3-니트로-1H-피리딘-2-온 (7)을 수소 조건 하에서 활성 팔라듐-탄소를 이용하여 환원반응시켜 화합물 (8)을 제조하는 단계, 및2) Compound (8) was reduced by reaction of 1- (3,4-dichlorobenzyl) -3-nitro-1H-pyridin-2-one (7) prepared in Step 1 with active palladium-carbon under hydrogen conditions. ), And

3) 상기 단계 2에서 제조한 화합물 (8)과 화합물 (9)를 아세토니트릴 또는 디클로로메탄 용매 조건에서 반응시켜 화학식 2의 화합물을 제조하는 단계로 이루어진다.3) reacting compound (8) prepared in step 2 with compound (9) under acetonitrile or dichloromethane solvent conditions to prepare a compound of formula (2).

본 발명에 따른 화학식 1 및 화학식 2의 화합물은 HCV RNA 중합효소 활성을 효과적으로 저해함으로써, C형 간염 예방 및 치료에 유용하게 사용될 수 있다.Compounds of formulas (1) and (2) according to the present invention can be effectively used to prevent and treat hepatitis C by effectively inhibiting HCV RNA polymerase activity.

본 발명의 조성물은 상기 화학식 1 또는 화학식 2의 화합물에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다.The composition of the present invention may further contain at least one active ingredient exhibiting the same or similar function to the compound of Formula 1 or Formula 2.

상기 화학식 1 또는 화학식 2의 화합물은 임상 투여 시에 경구 또는 비경구로 투여가 가능하며 일반적인 의약품 제제의 형태로 사용될 수 있다. 즉, 화학식 1 또는 화학식 2의 화합물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제 및 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 화학식 1 또는 화학식 2의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스, 락토오스 및 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제가 포함된다. 비수성용제와 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤 및 젤라틴 등이 사용될 수 있다.The compound of Formula 1 or Formula 2 may be administered orally or parenterally during clinical administration and may be used in the form of a general pharmaceutical formulation. That is, the compound of Formula 1 or Formula 2 may be administered in various oral and parenteral dosage forms in actual clinical administration, and when formulated, it is commonly used as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants. Prepared using diluents or excipients. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose, or the like. , Lactose and gelatin are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol and gelatin may be used.

투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하며, 일일 투여량은 화학식 1 또는 화학식 2의 화합물이 1~10 ㎎/㎏이고, 바람직하게는 5~10 ㎎/㎏이며, 하루 1~6회 투여될 수 있다.Dosage varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, and severity of the disease, and the daily dosage is 1 ~ 2. 10 mg / kg, preferably 5-10 mg / kg, and may be administered 1 to 6 times a day.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

제조예 1Preparation Example 1 : 3-(6-아미노-퓨린-9-일)-1-퓨란-2-일-프로페논의 제조 Preparation of 3- (6-amino-purin-9-yl) -1-furan-2-yl-propenone

메탄올 100㎖에 아데닌 7.5g과 1-퓨란-2-일-프로피논 7.33g을 가한 후 20℃에서 25시간 반응시켰다. 반응 완결 후 메탄올을 감압농축하고 잔사에 다시 메탄올 15㎖를 가하여, 교반하면서 물 65㎖를 서서히 가하고 20℃에서 2시간 동안 교반 후 여과하고 물 25㎖로 세척하고 얻어진 결정을 40~50℃에서 진공 건조한 후 10.34g(수율 73%)의 목적화합물(1)을 얻었다.7.5 g of adenine and 7.33 g of 1-furan-2-yl-propynone were added to 100 ml of methanol, followed by reaction at 20 ° C. for 25 hours. After completion of the reaction, methanol was concentrated under reduced pressure, 15 ml of methanol was added to the residue, and 65 ml of water was added slowly while stirring. The mixture was stirred at 20 ° C. for 2 hours, filtered, washed with 25 ml of water, and the obtained crystal was vacuum at 40-50 ° C. After drying, 10.34 g (yield 73%) of the title compound (1) were obtained.

제조예 2Preparation Example 2 : 3-(6-아미노-퓨린-9-일)-1-페닐-프로페논의 제조 Preparation of 3- (6-amino-purin-9-yl) -1-phenyl-propenone

메탄올 100 ㎖에 아데닌 8g과 1-페닐-프로피논 8.48g을 가한 후 20℃에서 15시간 반응시켰다. 반응 완결 후 메탄올을 감압농축하고 잔사에 다시 메탄올 10㎖를 가하여, 교반하면서 물 75㎖를 서서히 가하고 20℃에서 1시간 동안 교반 후 여과하고 물 25㎖로 세척하고 얻어진 결정을 40~50℃에서 진공 건조한 후 12.8g(수율 82%)의 목적화합물(2)을 얻었다.8 g of adenine and 8.48 g of 1-phenyl-propynone were added to 100 ml of methanol, followed by reaction at 20 ° C. for 15 hours. After completion of the reaction, methanol was concentrated under reduced pressure, and 10 ml of methanol was further added to the residue, 75 ml of water was added slowly while stirring, stirred at 20 ° C. for 1 hour, filtered, washed with 25 ml of water, and the obtained crystal was vacuum at 40-50 ° C. After drying, 12.8 g (yield 82%) of the title compound (2) were obtained.

제조예 3Preparation Example 3 : S-{[3-(트리플루오로메틸)페닐]-1-(3,4-디클로로-벤질)-2-옥소-1,2-디하이드로-피리딘-3-일}-티오카바메이트의 제조 Of S-{[3- (trifluoromethyl) phenyl] -1- (3,4-dichloro-benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl} -thiocarbamate Produce

디클로로메탄 60㎖에 반응식 2에 표시한 화합물 [6], 3-아미노-1-(3,4-디클로로-벤질)-1H-피리딘-2-온 6.5g과, 트리에틸아민 4.3㎖를 가한 후, 0℃에서 S-[3-(트리플루오로메틸)페닐] 클로리도티오카보네이트 1-페닐-프로피논 8.48g을 서서히 가한 다음 0~5℃에서 2시간 동안 반응시켰다. 반응 완결 후 물 50㎖로 3회 세척하고, 유기층을 황산마그네슘으로 건조시켜서 감압 농축하고 얻어진 잔사를 아세토 니트릴 45㎖에서 2시간 동안 교반하여 얻어진 결정을 40~45℃에서 진공 건조하여 목적 화합물(3) 9.83g(수율 86%)을 얻었다.To 60 ml of dichloromethane was added 6.5 g of compound [6], 3-amino-1- (3,4-dichloro-benzyl) -1H-pyridin-2-one and 4.3 ml of triethylamine. , 8.48 g of S- [3- (trifluoromethyl) phenyl] chloridothiocarbonate 1-phenyl-propynone was slowly added at 0 ° C. and then reacted at 0˜5 ° C. for 2 hours. After the completion of the reaction, the mixture was washed three times with 50 ml of water, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the obtained residue was stirred for 2 hours at 45 ml of acetonitrile. ) 9.83 g (yield 86%) was obtained.

제조예 4Preparation Example 4 : 메틸-2-{[[[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]아미노]카르보닐]아미노}벤조에이트의 제조 Preparation of methyl-2-{[[[[1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino] carbonyl] amino} benzoate

무수 아세토니트릴 55 ㎖에 반응식 2에 표시한 화합물 [6], 3-아미노-1-(3,4-디클로로-벤질)-1H-피리딘-2-온 7.2g과, 메틸-2-이소시아네이토벤조에이트 4.79g을 0~5℃에서 서서히 가한 후, 70~75℃에서 6시간 동안 반응시켰다. 반응 완결 후 반응액을 감압농축하고 잔사에 다시 에탄올 20㎖에서 재결정 후 결정을 40~45℃에서 진공 건조하여 목적화합물(4) 10.98g(수율 92%)을 얻었다.7.2 g of compound [6], 3-amino-1- (3,4-dichloro-benzyl) -1H-pyridin-2-one represented by Scheme 2 in 55 ml of anhydrous acetonitrile, and methyl-2-isocyane 4.79 g of itobenzoate was slowly added at 0-5 ° C., and then reacted at 70-75 ° C. for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was recrystallized from 20 ml of ethanol.

제조예 8 ~ 19Preparation Example 8-19

상기 제조예 3 또는 제조예 4와 동일한 방법으로 하여 화합물 8~19를 제조하였다.In the same manner as in Preparation Example 3 or Preparation Example 4, Compounds 8 to 19 were prepared.

본 발명에 사용한 화학식 1 및 화학식 2의 화합물의 명칭과 구조는 표 1에 나타내었다.The names and structures of the compounds of Formula 1 and Formula 2 used in the present invention are shown in Table 1.

화합물compound 명칭designation 구조rescue 1One 3-(6-아미노-퓨린-9-일)-1-퓨란-2-일-프로페논3- (6-Amino-purin-9-yl) -1-furan-2-yl-propenone

Figure 112006021509849-PAT00005
Figure 112006021509849-PAT00005
22 3-(6-아미노-퓨린-9-일)-1-페닐-프로페논3- (6-Amino-purin-9-yl) -1-phenyl-propenone
Figure 112006021509849-PAT00006
Figure 112006021509849-PAT00006
 33 S-{[3-(트리플루오로메틸)페닐]-1-(3,4-디클로로-벤질)-2-옥소-1,2-디하이드로-피리딘-3-일}-티오카바메이트S-{[3- (trifluoromethyl) phenyl] -1- (3,4-dichloro-benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl} -thiocarbamate
Figure 112006021509849-PAT00007
Figure 112006021509849-PAT00007
 44 메틸-2-{[[[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]아미노]카르보닐]아미노}벤조에이트Methyl-2-{[[[1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino] carbonyl] amino} benzoate
Figure 112006021509849-PAT00008
Figure 112006021509849-PAT00008
 55 에틸[({[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]아미노}카르보닐)티오]아세테이트Ethyl [({[1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) thio] acetate
Figure 112006021509849-PAT00009
Figure 112006021509849-PAT00009
 66 S-[페닐-1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]티오카바메이트S- [phenyl-1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] thiocarbamate
Figure 112006021509849-PAT00010
Figure 112006021509849-PAT00010
 77 N-[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-[3-(트리플루오로메틸)페닐]우레아N- [1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-[3- (trifluoromethyl) phenyl] urea
Figure 112006021509849-PAT00011
Figure 112006021509849-PAT00011
 88 N-[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-[3-(이소프록폭시)페닐]우레아N- [1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-[3- (isopropoxy) phenyl] urea
Figure 112006021509849-PAT00012
Figure 112006021509849-PAT00012
 99 N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,4-디플루오로페닐)우레아N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,4-difluorophenyl) urea
Figure 112006021509849-PAT00013
Figure 112006021509849-PAT00013
 1010 N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,6-디메틸페닐)우레아N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,6-dimethylphenyl) urea
Figure 112006021509849-PAT00014
Figure 112006021509849-PAT00014
 1111 N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(3,5-디클로로페닐)우레아N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(3,5-dichlorophenyl) urea
Figure 112006021509849-PAT00015
Figure 112006021509849-PAT00015
 1212 N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(5-메틸피리딘-2일)우레아N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(5-methylpyridin-2 yl) urea
Figure 112006021509849-PAT00016
Figure 112006021509849-PAT00016
 1313 N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-4-메틸피페라진]-1-카르복스아미드N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -4-methylpiperazin] -1-carboxamide
Figure 112006021509849-PAT00017
Figure 112006021509849-PAT00017
 1414 N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(3-트리플루오로메틸페닐)우레아N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(3-trifluoromethylphenyl) urea
Figure 112006021509849-PAT00018
Figure 112006021509849-PAT00018
 1515 N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(페닐)우레아N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(phenyl) urea
Figure 112006021509849-PAT00019
Figure 112006021509849-PAT00019
 1616 N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,6-디메틸페닐)우레아N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,6-dimethylphenyl) urea
Figure 112006021509849-PAT00020
Figure 112006021509849-PAT00020
 1717 N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,4-디플루오로페닐)우레아N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,4-difluorophenyl) urea
Figure 112006021509849-PAT00021
Figure 112006021509849-PAT00021
 1818 N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(피리딘-2일-메틸)우레아N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(pyridin-2yl-methyl) urea
Figure 112006021509849-PAT00022
Figure 112006021509849-PAT00022
 1919 N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(피리딘-4일)우레아N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(pyridin-4yl) urea
Figure 112006021509849-PAT00023
Figure 112006021509849-PAT00023

실시예Example : 화학식 1 또는 화학식 2의 화합물의 HCV NS5B 중합효소에 대한 생체외(in vitro) 활성 저해 효과 Inhibitory Effect of Compounds of Formula 1 or Formulation 2 on HCV NS5B Polymerase

본 발명의 화학식 1 또는 화학식 2의 유도체들의 HCV RNA 의존형 RNA 중합효소의 전사 활성을 저해하는 효과를 알아보기 위하여, 하기와 같은 생체외(in vitro) 실험을 실시하였다.In order to determine the effect of inhibiting the transcriptional activity of HCV RNA-dependent RNA polymerase of the derivatives of Formula 1 or Formula 2 of the present invention, the following in vitro experiment was performed.

HCV RNA 의존형 RNA 중합효소의 RNA를 주형으로 하여 RNA를 합성하는 활성도와 이의 저해도를 측정하기 위해 다음과 같은 순서로 실험을 실시하였다. 총 반응 용량은 20㎕로서 이 반응용액에는 20mM 트리스-염산(pH=6.85), 10mM KCl, 1mM DTT, 10mM MgCl2, 리팜피신(rifampicin) 4㎍, RNase 저해제 20U 등을 포함하고 있으며, RNA 주형으로 210ng의 Poly rA/oligo dT(Amersham Pharmacia Biotech), 반응기질로서 10uM UTP와 2 Ci α-[32P] UTP(NEN Life Science), 및 62.7ng(약 1p㏖)의 C형 말단 21개의 아미노산이 제거된 HCV RNA 의존형 RNA 중합효소를 첨가하였다. 위의 용액을 30℃에서 2시간 동안 반응시킨 다음 80% 포름아미드, 100mM EDTA, 0.05% SDS, 0.025% 브로모페놀(Bromophenol) 블루(Blue) 및 0.025% 자일렌 시아놀(xylene cyanol) FF이 들어있는 RNA loading 용액을 같은 용량으로 섞어준 후 100℃에서 2분간 열을 가하여 반응을 종결시켰다. 이렇게 종결된 반응물을 7M 우레아(Urea)가 들어있는 5% PAGE 겔 상에서 반응결과물과 반응기질을 분리하였다. 위의 방법으로 분리된 반응결과물을 Phosphor imager BAS2500(Fuji Photo Film)을 이용하여 정량하였다.In order to measure the activity of synthesizing RNA and its inhibition using RNA of HCV RNA-dependent RNA polymerase as a template, experiments were carried out in the following order. The total reaction volume was 20 μl. The reaction solution contained 20 mM Tris-HCl (pH = 6.85), 10 mM KCl, 1 mM DTT, 10 mM MgCl 2 , 4 μg rifampicin, 20 U RNase inhibitor, etc. 210 ng Poly rA / oligo dT (Amersham Pharmacia Biotech), 10 uM UTP and 2 Ci α- [ 32 P] UTP (NEN Life Science) as a reductant, and 62.7 ng (about 1 mmol) of C-type 21 amino acids Removed HCV RNA dependent RNA polymerase was added. The solution was allowed to react at 30 ° C. for 2 hours, followed by 80% formamide, 100 mM EDTA, 0.05% SDS, 0.025% Bromophenol Blue and 0.025% xylene cyanol FF. After the RNA loading solution was mixed at the same volume, the reaction was terminated by applying heat at 100 ° C. for 2 minutes. The reaction was terminated and the reaction product and the reaction mixture were separated on a 5% PAGE gel containing 7M urea (Urea). The reaction product separated by the above method was quantified using Phosphor imager BAS2500 (Fuji Photo Film).

결과는 표 2에 나타내었다.The results are shown in Table 2.

화합물compound HCV RNA 중합효소의 활성 저해율(%)% Inhibition of HCV RNA polymerase activity 50㎍/㎖50 µg / ml 25㎍/㎖25 µg / ml 10㎍/㎖10 µg / ml 1㎍/㎖1 µg / ml 1One

Figure 112006021509849-PAT00024
Figure 112006021509849-PAT00024
9090 6363 5555 2020 22
Figure 112006021509849-PAT00025
Figure 112006021509849-PAT00025
 8888 5555 4747 2525 33
Figure 112006021509849-PAT00026
Figure 112006021509849-PAT00026
 9292 6767 4040 1717 44
Figure 112006021509849-PAT00027
Figure 112006021509849-PAT00027
 8383 5151 4343 2222 55
Figure 112006021509849-PAT00028
Figure 112006021509849-PAT00028
 6767 4141 3030 1212 66
Figure 112006021509849-PAT00029
Figure 112006021509849-PAT00029
 7575 4646 2828 1010 77
Figure 112006021509849-PAT00030
Figure 112006021509849-PAT00030
 6969 5252 3434 2323 88
Figure 112006021509849-PAT00031
Figure 112006021509849-PAT00031
 7373 4848 3838 2525 99
Figure 112006021509849-PAT00032
Figure 112006021509849-PAT00032
 6565 4040 2424 1212 1010
Figure 112006021509849-PAT00033
Figure 112006021509849-PAT00033
 6262 4343 3434 2323 1111
Figure 112006021509849-PAT00034
Figure 112006021509849-PAT00034
 7272 3737 2323 55 1212
Figure 112006021509849-PAT00035
Figure 112006021509849-PAT00035
 7676 5454 3636 1818 1313
Figure 112006021509849-PAT00036
Figure 112006021509849-PAT00036
 7878 3434 1515 77 1414
Figure 112006021509849-PAT00037
Figure 112006021509849-PAT00037
 8181 6363 2525 1212 1515
Figure 112006021509849-PAT00038
Figure 112006021509849-PAT00038
 7171 6767 4545 2222 1616
Figure 112006021509849-PAT00039
Figure 112006021509849-PAT00039
 7979 5656 2828 1111 1717
Figure 112006021509849-PAT00040
Figure 112006021509849-PAT00040
 6666 4545 3232 99 1818
Figure 112006021509849-PAT00041
Figure 112006021509849-PAT00041
 8282 6767 2323 1818 1919
Figure 112006021509849-PAT00042
Figure 112006021509849-PAT00042
 6363 3535 1717 66

표 1에 나타난 바와 같이, 화학식 1 및 화학식 2의 화합물은 HCV RNA 중합효소 활성을 저해함을 알 수 있으며, 농도에 비례하는 것을 알 수 있다.As shown in Table 1, it can be seen that the compounds of Formula 1 and Formula 2 inhibit HCV RNA polymerase activity, which is proportional to the concentration.

따라서, 본 발명의 화학식 1 및 화학식 2의 화합물은 C형 간염 예방 및 치료에 유용하게 사용될 수 있다.Therefore, the compounds of Formula 1 and Formula 2 of the present invention can be usefully used for the prevention and treatment of hepatitis C.

하기에 본 발명의 조성물을 위한 제제예를 예시한다.Examples of preparations for the compositions of the present invention are illustrated below.

제제예 1Formulation Example 1 : 약학적 제제의 제조 : Preparation of Pharmaceutical Formulations

1. 산제의 제조1. Preparation of powder

화학식 1(또는 화학식 2)의 화합물 2g2 g of compound of Formula 1 (or Formula 2)

유당 1g1g lactose

상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in airtight cloth to prepare a powder.

2. 정제의 제조2. Preparation of Tablets

화학식 1(또는 화학식 2)의 화합물 100㎎100 mg of compound of Formula 1 (or Formula 2)

옥수수전분 100㎎Corn Starch 100mg

유 당 100㎎Lactose 100mg

스테아린산 마그네슘 2㎎2 mg magnesium stearate

상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. 캡슐제의 제조3. Preparation of Capsule

화학식 1(또는 화학식 2)의 화합물 100㎎100 mg of compound of Formula 1 (or Formula 2)

옥수수전분 100㎎Corn Starch 100mg

유 당 100㎎Lactose 100mg

스테아린산 마그네슘 2㎎2 mg magnesium stearate

상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

본 발명의 조성물은 HCV RNA 중합효소 활성을 효과적으로 저해함으로써, C형 간염 예방 및 치료에 유용하게 사용될 수 있다.The composition of the present invention can be effectively used for the prevention and treatment of hepatitis C by effectively inhibiting HCV RNA polymerase activity.

Claims (4)

하기 화학식 1로 표시되는 [1-(벤질)-2-옥소-1,2-디하이드로-피리딘-3-일 유도체를 유효성분으로 하는 C형 간염 예방 및 치료용 약학적 조성물.A pharmaceutical composition for hepatitis C prevention and treatment comprising [1- (benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl derivative represented by Formula 1 as an active ingredient. <화학식 1><Formula 1>
Figure 112006021509849-PAT00043
Figure 112006021509849-PAT00043
 (상기 화학식 1에서,(In Formula 1, R1은 트리할로메틸, 할로겐, C1~C3 알콕시, C1~C3 알콕시카르보닐 및 C1~C3 알킬기로 이루어진 군으로부터 하나 이상 선택되는 것으로 치환된 또는 비치환된 아닐린; 트리할로메틸기로 3-치환된 또는 비치환된 벤젠 티올; C1~C3 알킬기로 5-치환된 또는 비치환된 아미노피리딘; 2-아미노메틸피리딘; C1~C3 알킬기로 4-치환된 피페라진; 및 C1~C3 알킬메르캅토아세테이트로 이루어진 군으로부터 선택되고,R 1 is aniline substituted or unsubstituted with one or more selected from the group consisting of trihalomethyl, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl and C 1 -C 3 alkyl group; Benzene thiols 3-substituted or unsubstituted with a trihalomethyl group; Aminopyridine 5-substituted or unsubstituted with a C 1 to C 3 alkyl group; 2-aminomethylpyridine; Piperazine 4-substituted with a C 1 to C 3 alkyl group; And C 1 -C 3 alkylmercaptoacetate, R2 및 R3는 서로 독립적이며, 수소 또는 할로겐이다.)R 2 and R 3 are independent of each other and are hydrogen or halogen.) 제 1항에 있어서, 상기 R1은 아닐린, 2,4-디플루오로아닐린, 2,6-디메틸아닐 린, 아미노피리딘, 3,5-디클로로아닐린, 5-메틸피리딘-2-아민, 4-메틸-피페라진, 3-트리플루오로메틸아닐린, 4-아미노피리딘, 2-아미노메틸피리딘, 3-트리플루오로메틸-벤젠티올, 벤젠티올, 에틸머캅토아세테이트, 2-메톡시카르보닐아닐린 또는 3-이소프로필옥시아닐린을 나타내며, 상기 R2 및 R3는 서로 독립적이며, 수소 또는 할로겐인 것을 특징으로 하는 C형 간염 예방 및 치료용 약학적 조성물.The compound of claim 1, wherein R 1 is aniline, 2,4-difluoroaniline, 2,6-dimethylaniline, aminopyridine, 3,5-dichloroaniline, 5-methylpyridin-2-amine, 4- Methyl-piperazine, 3-trifluoromethylaniline, 4-aminopyridine, 2-aminomethylpyridine, 3-trifluoromethyl-benzenethiol, benzenethiol, ethylmercaptoacetate, 2-methoxycarbonylaniline or Represents 3-isopropyloxyaniline, wherein R 2 and R 3 are independent of each other, hepatitis C preventive and therapeutic pharmaceutical composition, characterized in that hydrogen or halogen. 제 1항에 있어서, 상기 화학식 1의 화합물이According to claim 1, wherein the compound of Formula 1 S-{[3-(트리플루오로메틸)페닐]-1-(3,4-디클로로-벤질)-2-옥소-1,2-디하이드로-피리딘-3-일}-티오카메이트;S-{[3- (trifluoromethyl) phenyl] -1- (3,4-dichloro-benzyl) -2-oxo-1,2-dihydro-pyridin-3-yl} -thiocarmate; 메틸-2-{[[[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]아미노]카르보닐]아미노}벤조에이트;Methyl-2-{[[[1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino] carbonyl] amino} benzoate; 에틸[({[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]아미노}카르보닐)티오]아세테이트;Ethyl [({[1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) thio] acetate; S-[페닐-1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]티오카바메이트;S- [phenyl-1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] thiocarbamate; N-[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-[3-(트리플로오로메틸)페닐]우레아;N- [1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-[3- (trifluoromethyl) phenyl] urea; N-[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-[3-(이소프 로폭시)페닐]우레아;N- [1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-[3- (isopropoxy) phenyl] urea; N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,4-디플루오로페닐)우레아;N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,4-difluorophenyl) urea; N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]--(2,6-디메틸페닐)우레아;N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl]-(2,6-dimethylphenyl) urea; N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(3,5-디클로로페닐)우레아;N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(3,5-dichlorophenyl) urea; N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(5-메틸피리딘-2-일)우레아;N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(5-methylpyridin-2-yl) urea; N-[1-(4-클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-4-메틸피페라진]-1-카르복스아미드;N- [1- (4-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -4-methylpiperazin] -1-carboxamide; N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(3-트리플루오로메틸페닐)우레아;N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(3-trifluoromethylphenyl) urea; N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(페닐)우레아;N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(phenyl) urea; N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,6-디메틸페닐)우레아;N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,6-dimethylphenyl) urea; N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(2,4-디플루오로페닐)우레아;N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(2,4-difluorophenyl) urea; N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(피리딘-2- 일-메틸)우레아 또는N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(pyridin-2- yl-methyl) urea or N-[1-(2,6-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]-N'-(피리딘-4-일)우레아인 것을 특징으로 하는 C형 간염 예방 및 치료용 약학적 조성물.Hepatitis C characterized by N- [1- (2,6-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] -N '-(pyridin-4-yl) urea Prophylactic and therapeutic pharmaceutical compositions. 제 1항에 있어서, 상기 화학식 1의 화합물이 S-{[3-(트리플루오로메틸)페닐]-1-(3,4-디클로로-벤질)-2-옥소-1,2-디하이드로-피리딘-3-일}-티오카바메이트 또는 메틸-2-{[[[1-(3,4-디클로로벤질)-2-옥소-1,2-디하이드로피리딘-3-일]아미노]카르보닐]아미노}벤조에이트인 것을 특징으로 하는 C형 간염 예방 및 치료용 약학적 조성물.The compound of claim 1, wherein the compound of Formula 1 is S-{[3- (trifluoromethyl) phenyl] -1- (3,4-dichloro-benzyl) -2-oxo-1,2-dihydro- Pyridin-3-yl} -thiocarbamate or methyl-2-{[[[[1- (3,4-dichlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino] carbonyl ] Amino} benzoate, hepatitis C preventive and therapeutic pharmaceutical composition.
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