KR100368891B1 - Novel antiviral 2,4-pyrimidinedione derivatives - Google Patents

Novel antiviral 2,4-pyrimidinedione derivatives Download PDF

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KR100368891B1
KR100368891B1 KR10-2000-0010614A KR20000010614A KR100368891B1 KR 100368891 B1 KR100368891 B1 KR 100368891B1 KR 20000010614 A KR20000010614 A KR 20000010614A KR 100368891 B1 KR100368891 B1 KR 100368891B1
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group
pyridin
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KR20010006730A (en
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손종찬
신선실
김신걸
이종교
김해수
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한국화학연구원
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    • H—ELECTRICITY
    • H02—GENERATION; CONVERSION OR DISTRIBUTION OF ELECTRIC POWER
    • H02K—DYNAMO-ELECTRIC MACHINES
    • H02K7/00—Arrangements for handling mechanical energy structurally associated with dynamo-electric machines, e.g. structural association with mechanical driving motors or auxiliary dynamo-electric machines
    • H02K7/06—Means for converting reciprocating motion into rotary motion or vice versa
    • H02K7/061—Means for converting reciprocating motion into rotary motion or vice versa using rotary unbalanced masses
    • H02K7/063—Means for converting reciprocating motion into rotary motion or vice versa using rotary unbalanced masses integrally combined with motor parts, e.g. motors with eccentric rotors
    • H—ELECTRICITY
    • H02—GENERATION; CONVERSION OR DISTRIBUTION OF ELECTRIC POWER
    • H02K—DYNAMO-ELECTRIC MACHINES
    • H02K23/00—DC commutator motors or generators having mechanical commutator; Universal AC/DC commutator motors
    • H02K23/54—Disc armature motors or generators
    • H—ELECTRICITY
    • H02—GENERATION; CONVERSION OR DISTRIBUTION OF ELECTRIC POWER
    • H02K—DYNAMO-ELECTRIC MACHINES
    • H02K33/00—Motors with reciprocating, oscillating or vibrating magnet, armature or coil system
    • H02K33/16—Motors with reciprocating, oscillating or vibrating magnet, armature or coil system with polarised armatures moving in alternate directions by reversal or energisation of a single coil system

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  • Power Engineering (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

본 발명은 하기 일반식 (I)의 2,4-피리미딘디온 유도체 및 그의 약제학적으로 허용되는 염 및 이를 활성 성분으로 함유하는 항바이러스제 조성물에 관한 것으로, 일반식 (I)의 화합물은 바이러스, 특히 야생형 및 내성 HIV-1에 대한 선택도 및 생리활성도가 우수하고 독성이 낮아서 후천성 면역결핍증(AIDS) 치료제로 유용하다.The present invention relates to a 2,4-pyrimidinedione derivative of formula (I) and a pharmaceutically acceptable salt thereof and an antiviral composition containing the same as an active ingredient, wherein the compound of formula (I) is a virus, In particular, it is useful as a treatment for acquired immunodeficiency syndrome (AIDS) because of its excellent selectivity and physiological activity and low toxicity against wild type and resistant HIV-1.

(상기식에서, A, R1, R2, R3, R4및 Z는 명세서 중에서 정의한 바와 같다.)(Wherein A, R 1 , R 2 , R 3 , R 4 and Z are as defined in the specification).

Description

신규한 항바이러스성 2,4-피리미딘디온 유도체{NOVEL ANTIVIRAL 2,4-PYRIMIDINEDIONE DERIVATIVES}Novel antiviral 2,4-pyrimidinedione derivatives {NOVEL ANTIVIRAL 2,4-PYRIMIDINEDIONE DERIVATIVES}

본 발명은 항바이러스제, 특히 후천성 면역결핍증(acquired immunodeficiency syndrome : AIDS) 치료제로 유용한 신규한 2,4-피리미딘디온 유도체 및 그의 약제학적으로 허용되는 염, 이의 제조방법 및 이를 활성 성분으로 함유하는 약학 조성물에 관한 것이다.The present invention relates to novel 2,4-pyrimidinedione derivatives and pharmaceutically acceptable salts thereof, which are useful as antiviral agents, in particular for the treatment of acquired immunodeficiency syndrome (AIDS), and methods for their preparation and pharmaceuticals containing them as active ingredients. It relates to a composition.

현재, AIDS 치료용으로 사용되고 있는 화학요법제로는 AZT (지도부딘(Zidovudine): 3'-아지도-3'-데옥시티미딘), DDC (잘시타빈(Zalcitabine) : 2',3'-디데옥시시티딘), DDI (디다노신(Didanosine) : 2', 3'-디데옥시이노신), D4T (스타부딘(Stavudine) : 3'-데옥시-2',3'-디데하이드로티미딘), 3TC(라미부딘(Lamivudine), 지아젠(Ziagen), 네비라핀(Nevirapine), 수스티바(Sustiva), 델라비르딘(Delavirdine), 인디나비르(Indinavir), 리토나비르(Ritonavir), 비라셉트(Viracept), 사퀴나비르(Saquinavir) 및 아제네라제(Agenerase)가 있으며, 이들은 바이러스의 복제를 방해하는 작용을 하는 것으로알려져 있다. 그러나, 이들 약물을 장기간 복용할 경우 약물대사 물질의 독성으로 인한 부작용이 있을 뿐만 아니라 바이러스의 약물에 대한 내성이 발현되는 것도 문제점으로 지적되고 있다.Currently, chemotherapeutic agents used to treat AIDS include AZT (Zidovudine: 3'-azido-3'-deoxythymidine), DDC (Zalcitabine: 2 ', 3'-dideoxy Cytidine), DDI (Didanosine: 2 ', 3'-dideoxyinosine), D4T (Stavudine: 3'-deoxy-2', 3'-didehydrothymidine), 3TC (Lamivudine, Ziagen, Nevirapine, Sustiiva, Delavirdine, Indinavir, Ritonavir, Viracept ), Saquinavir and Agenerase, which have been shown to interfere with the replication of the virus, but the long-term effects of these drugs have the side effects of toxic drug metabolism. In addition, the expression of resistance to the drug of the virus has been pointed out as a problem.

따라서, 이러한 문제점을 극소화시킨 화학요법제를 개발하고자 많은 연구가 진행되고 있다. 최근 발표된 관련 분야의 연구논문들에 의하면, 2,4-피리미딘디온 계열의 화합물이 인체 면역결핍 바이러스(human immunodeficiency virus : HIV)에 뛰어난 생리활성도를 가지며 독성이 적은 것으로 보고되고 있다(참고문헌 :J. Med. Chem., 35, 4713, 1992;J. Med. Chem., 35, 337, 1992;J. Med. Chem., 34, 1508, 1991;J. Med. Chem., 34, 1394, 1991;J. Med. Chem., 34, 349, 1991;Molecular Pharm., 39, 805, 1991;Tet. Lett., 35, 4531, 1994;J. Med. Chem., 38, 2860, 1995;Nucleosides and Nucleotides, 14, 575, 1995;J. Med. Chem., 39, 2427, 1996;J. Med. Chem., 42, 4500, 1999; EP 0,449,726 A1; EP 0,420,763 A2; USP 5,112,835; USP 5,278,167; USP 5,318,972; USP 5,461,060; WO 95/18109 A1; USP 5,747,500; 및 USP 5,922,727).Therefore, much research is being conducted to develop a chemotherapeutic agent that minimizes these problems. According to recently published research papers, 2,4-pyrimidinedione-based compounds are reported to have excellent physiological activity and low toxicity against human immunodeficiency virus (HIV). J. Med. Chem., 35 , 4713, 1992; J. Med.Chem ., 35 , 337, 1992; J. Med.Chem., 34 , 1508, 1991; J. Med.Chem., 34 , 1394 , 1991; J. Med. Chem., 34 , 349, 1991; Molecular Pharm., 39 , 805, 1991; Tet. Lett., 35 , 4531, 1994; J. Med. Chem., 38 , 2860, 1995; Nucleosides and Nucleotides, 14 , 575, 1995; J. Med. Chem., 39 , 2427, 1996; J. Med. Chem., 42 , 4500, 1999; EP 0,449,726 A1; EP 0,420,763 A2; USP 5,112,835; USP 5,278,167; USP 5,318,972; USP 5,461,060; WO 95/18109 A1; USP 5,747,500; and USP 5,922,727).

본 발명자들은 기존에 개발된 2,4-피리미딘디온 유도체들보다 야생형(wild type) 및 내성(mutant) HIV-1에 대한 생리활성도가 더 강력하면서도 독성이 적은 화합물을 개발하기 위해 거듭 연구한 결과, 신규한 2,4-피리미딘디온 유도체들이 야생형 및 내성 HIV-1에 대하여 강력한 생리활성도와 낮은 독성을 나타냄을 발견하여 본 발명을 완성하게 되었다.The present inventors have repeatedly studied to develop compounds having stronger physiological activity against wild type and mutant HIV-1 and less toxic than previously developed 2,4-pyrimidinedione derivatives. The present invention has been completed by discovering that the novel 2,4-pyrimidinedione derivatives exhibit strong physiological activity and low toxicity against wild type and resistant HIV-1.

본 발명의 목적은 야생형 및 내성을 가진 HIV-1에 대한 선택성 및 생리 활성도가 우수하면서도 독성이 낮은 2,4-피리미딘디온 유도체 및 그의 약제학적으로 허용되는 염, 이의 제조방법 및 이를 포함하는 약제학적 조성물을 제공하는 것이다.An object of the present invention is a 2,4-pyrimidinedione derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a drug containing the same, having low selectivity and physiological activity and low toxicity against wild type and resistant HIV-1. To provide a pharmaceutical composition.

상기 목적에 따라, 본 발명에서는 하기 일반식 (I)의 2,4-피리미딘디온 유도체 또는 이의 약제학적으로 허용되는 염을 제공한다;According to the above object, the present invention provides a 2,4-pyrimidinedione derivative of the general formula (I) or a pharmaceutically acceptable salt thereof;

화학식 1Formula 1

상기식에서,In the above formula,

R1은 C6-C10아릴기 또는 C3-C10헤테로아릴기; 할로겐원자, C1-C6의 알킬기, 하나 이상의 할로겐원자로 치환된 C1-C6의 알킬기, C3-C6의 시클로알킬기, 시아노기, 니트로기, 히드록시기, 티오히드록시기, 아지도기, C1-C6의 알콕시기, 옥시미노기, C1-C3의 알킬옥시미노기, O가 C1-C6의 알킬기로 치환된 옥시미노기, C1-C6의 알킬카르보닐기, C3-C6시클로알킬카르보닐기, 히드록시메틸기, 아지도메틸기, C1-C6의 알콕시메틸기,C1-C6의 아실옥시메틸기, 카바모일옥시메틸기, 아미노메틸기, N-(C1-C3의 알킬)아미노메틸기, N,N-디(C1-C3의 알킬)아미노메틸기, 카르복시기, C1-C6의 알콕시카르보닐기, 아지리딘기, 아미노기, 히드록시에틸아미노기, 시클로프로필아미노기, C1-C6의 알킬아미노기, 디(C1-C6의 알킬)아미노기, 트리플루오로아세트아미도기, C1-C6의 아실아미도기, 카바모일기, 히드록시에틸카바모일기, 시클로프로필카바모일기, C1-C6의 알킬카바모일기, 디(C1-C6의 알킬)카바모일기, 아미노카바모일, 디메틸아미노카바모일, 히드라지노기, 1,1-디메틸히드라지노기, 이미다졸릴기, 트리아졸릴기 또는 테트라졸릴기로 치환된 C6-C10아릴기 또는 C3-C10헤테로아릴기; 테트라히드로피리딜기 또는 피페리딜기; C1-C6의 알킬기 또는 C1-C6의 알콕시카르보닐기로 치환된 테트라히드로피리딜기 또는 피페리딜기; 테트라히드로피라닐기; 또는 테트라히드로푸릴기를 나타내고;R 1 is a C 6 -C 10 aryl group or a C 3 -C 10 heteroaryl group; A halogen atom, C 1 -C 6 alkyl group, one or more halogen atoms, alkyl groups of the substituted C 1 -C 6, cycloalkyl group of C 3 -C 6, a cyano group, a nitro group, a hydroxy group, thio hydroxy, azido, C 1 alkoxy group -C 6, oxy-diamino group, an alkyl group of C 1 -C 3 alkyloxy diamino group, O is an oxy diamino group, C 1 -C 6 substituted with an alkyl group of C 1 -C 6, C 3 - C 6 cycloalkylcarbonyl group, hydroxymethyl group, azidomethyl group, C 1 -C 6 alkoxymethyl group, C 1 -C 6 acyloxymethyl group, carbamoyloxymethyl group, aminomethyl group, N- (C 1 -C 3 of alkyl) amino group, N, N- di (C 1 -C 3 in alkyl) amino group, a carboxy group, C 1 -C 6 alkoxy group, a ahjiri dingi, an amino group, a hydroxyethyl group, a cyclopropyl group, a C 1 - C 6 alkylamino group, di (C 1 -C 6 alkyl) amino group, trifluoroacetamido group, C 1 -C 6 acylamido group, carbamoyl Group, hydroxyethyl carbamoyl group, cyclopropyl carbamoyl group, C 1 -C 6 alkyl carbamoyl group, di (C 1 -C 6 alkyl) carbamoyl group, aminocarbamoyl, dimethylaminocarbamoyl, hydra C 6 -C 10 aryl group or C 3 -C 10 heteroaryl group substituted with a zino group, 1,1-dimethylhydrazino group, imidazolyl group, triazolyl group or tetrazolyl group; Tetrahydropyridyl group or piperidyl group; The group-tetrahydropyridyl substituted with an alkoxycarbonyl group of C 1 -C 6 alkyl group or a C 1 -C 6 or a piperidyl group; Tetrahydropyranyl group; Or a tetrahydrofuryl group;

R2는 수소원자, 할로겐원자, 니트로기, 시아노기, C1-C3의 알콕시카보닐기, C1-C3의 알킬아미노기, 디(C1-C3의 알킬)아미노기, C1-C3의 알킬카바모일기, 디(C1-C3의 알킬)카바모일기, C1-C6의 알킬기, C3-C6의 시클로알킬기 또는 벤질기를 나타내며;R 2 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, C 1 -C 3 of the alkoxycarbonyl group, C 1 -C 3 alkyl group, a di (C 1 -C 3 alkyl) amino, C 1 -C of 3-alkyl carbamoyl, di (C 1 -C 3 alkyl) carbamoyl, C 1 -C 6 alkyl, C 3 -C 6 a represents a cycloalkyl group or a benzyl;

R3및 R4는 각각 독립적으로 수소원자, 할로겐원자, 히드록시기, 시아노기, 니트로기, 아미노기, 아세트아미도기, 트리플루오로아세트아미도기, 아지도기, C1-C3의 알킬기, 하나 이상의 할로겐원자로 치환된 C1-C3의 알킬기, C1-C3의 알콕시카르보닐기, 카바모일기, C1-C3의 알킬카바모일기, 디(C1-C3의 알킬)카바모일기 또는 C1-C3의 알콕시기를 나타내며;R 3 and R 4 are each independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, an amino group, an acetamido group, a trifluoroacetamido group, an azido group, an alkyl group of C 1 -C 3 , one or more halogens atoms substituted by C 1 -C 3 alkyl, C 1 -C 3 alkoxy group, a carbamoyl group, an alkyl carbamoyl group of C 1 -C 3, di (C 1 -C 3 in alkyl) carbamoyl or C An alkoxy group of 1 -C 3 ;

A는 O 또는 S를 나타내고;A represents O or S;

Z는 O, S, C=O, NH 또는 CH2를 나타낸다.Z represents O, S, C═O, NH or CH 2 .

상기 다른 목적에 따라, 본 발명에서는 염기 존재하에 하기 일반식 (II)의 화합물을 하기 일반식 (III)의 화합물과 커플링반응시키는 단계를 포함하는 상기 일반식 (I)의 화합물의 제조방법을 제공한다;According to another object, the present invention provides a method for preparing a compound of formula (I) comprising the step of coupling a compound of formula (II) to a compound of formula (III) to provide;

R1-CH2-Y (III)R 1 -CH 2 -Y (III)

상기식에서,In the above formula,

R1, R2, R3, R4및 A는 상기 정의한 바와 같고;R 1 , R 2 , R 3 , R 4 and A are as defined above;

Z'는 상기 정의된 Z와 동일하나, 단 A가 산소원자인 경우 아세트아미도기일 수 있으며;Z 'is the same as Z defined above, provided that A can be an acetamido group when A is an oxygen atom;

Y는 적합한 이탈기, 예를 들면 할로겐원자, 메탄술포닐기, 톨루엔술포닐기 또는 트리플루오로메탄술포닐기이다.Y is a suitable leaving group, for example a halogen atom, a methanesulfonyl group, a toluenesulfonyl group or a trifluoromethanesulfonyl group.

상기 또다른 목적에 따라, 본 발명에서는 일반식 (I)의 화합물 또는 그의 약제학적으로 허용되는 염 및 약제학적으로 허용되는 담체를 포함하는 항바이러스제 조성물을 제공한다.According to this another object, the present invention provides an antiviral composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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

본원 발명에 따른 상기 일반식 (I)의 화합물 중에서, R1이 페닐기, 피리딜기 또는 N-옥소피리딜기이거나 상기 일반식 (I)에 열거된 하나 이상의 치환기로 치환된 페닐기, 피리딜기 또는 N-옥소피리딜기인 화합물이 바람직하다.Among the compounds of the general formula (I) according to the present invention, R 1 is a phenyl group, pyridyl group or N-oxopyridyl group or a phenyl group, pyridyl group or N- substituted with one or more substituents listed in the general formula (I). Preference is given to compounds which are oxopyridyl groups.

본 발명에 따른 일반식 (I)의 화합물은 하기 반응식 1에 도시된 바와 같이 하기 일반식 (II)의 화합물을 하기 일반식 (III)의 화합물과 반응시켜 제조할 수 있다.The compound of formula (I) according to the present invention can be prepared by reacting a compound of formula (II) with a compound of formula (III) as shown in Scheme 1 below.

상기식에서, R1, R2, R3, R4, A, Z, Z' 및 Y는 상기 정의한 바와 같다.Wherein R 1 , R 2 , R 3 , R 4 , A, Z, Z 'and Y are as defined above.

상기 반응은 상기 일반식 (II)의 화합물을 아세토니트릴, 헥사메틸포스포아미드(HMPA), 디메틸설폭시드(DMSO), 디메틸포름아미드(DMF)와 같은 극성용매중에서수소화리튬, 수소화나트륨, 수소화칼륨, 탄산나트륨, 탄산칼륨과 같은 강염기의 존재하에 -10℃ 내지 100℃에서, 상기 일반식 (II)의 화합물과 상기 일반식 (III)의 화합물을 1: 0.8 내지 1: 1.2의 몰비로 1 내지 24 시간동안 반응시킴으로써 수행될 수 있다.The reaction is carried out by the compound of formula (II) in a polar solvent such as acetonitrile, hexamethylphosphoramide (HMPA), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), lithium hydride, sodium hydride, potassium hydride , At -10 ° C to 100 ° C in the presence of a strong base such as sodium carbonate and potassium carbonate, the compound of formula (II) and the compound of formula (III) in a molar ratio of 1: 0.8 to 1: 1.2, 1 to 24 It can be carried out by reacting for a time.

상기 일반식 (II)의 화합물 일부는 USP 제5,747,500호에 기재된 방법에 따라 제조할 수 있으며, 다르게는, 특별한 경우에 하기 반응식 2에 설명된 방법으로 제조할 수 있다.Some of the compounds of formula (II) may be prepared according to the methods described in US Pat. No. 5,747,500, or alternatively, in special cases, may be prepared by the methods described in Scheme 2 below.

상기식에서,In the above formula,

R2, R3및 R4는 상기 정의한 바와 같다.R 2 , R 3 and R 4 are as defined above.

상기 반응식 2의 방법 (i)에 따르면, 공지된 방법(Ber., 52B, 869 (1919)) 및J. Med. Chem., 7, 808 (1964) 참조)으로 합성할 수 있는 일반식 (IV)의 화합물을 질소분위기하에서 디메틸포름아미드와 같은 극성용매 중에서 수소화나트륨과 같은 강염기 존재하에 아릴포름아미드 유도체와 반응시켜 일반식 (V)의 화합물을 제조한 후(단계 (a)), 이를 메탄올에서 소디움메톡시드와 반응시켜 일반식 (VI)의 화합물을 제조하고(단계 (b)), 이를 아세틸브로미드와 반응시켜 일반식(II-a)의 화합물을 제조할 수 있다(단계 (c)).According to method (i) of Scheme 2, known methods (Ber., 52B, 869 (1919)) and J. Med. (Compound Chem ., 7, 808 (1964)) is reacted with an arylformamide derivative in the presence of a strong base such as sodium hydride in a polar solvent such as dimethylformamide under a nitrogen atmosphere. After preparing a compound of formula (V) (step (a)), it is reacted with sodium methoxide in methanol to prepare a compound of formula (VI) (step (b)), which is reacted with acetylbromide Compounds of formula (II-a) may be prepared (step (c)).

또한, 상기 반응식 2의 방법 (ii)에 따르면, 일반식 (IV)의 화합물을 디메틸포름아미드와 같은 극성용매 중에서 수소화나트륨과 같은 강염기 존재하에 아릴아세토니트릴 유도체와 반응시켜 일반식 (VII)의 화합물을 제조한 후(단계 (d)), 이를 메탄올에서 소디움메톡시드와 반응시켜 일반식(VIII)의 화합물을 제조하고(단계 (e)), 이를 산소 존재하에 디메틸포름아미드와 같은 극성용매 중에서 수소화나트륨과 같은 염기와 반응시켜 일반식 (IX)의 화합물을 제조하고(단계 (f)), 이를 염산과 같은 산과 반응시켜 일반식 (II-b)의 화합물을 제조할 수 있다(단계 (g)).In addition, according to the method (ii) of Scheme 2, the compound of formula (IV) is reacted with an arylacetonitrile derivative in the presence of a strong base such as sodium hydride in a polar solvent such as dimethylformamide. After preparing (step (d)), it is reacted with sodium methoxide in methanol to prepare a compound of formula (VIII) (step (e)), which is hydrogenated in a polar solvent such as dimethylformamide in the presence of oxygen. The compound of formula (IX) may be prepared by reaction with a base such as sodium (step (f)), which may be reacted with an acid such as hydrochloric acid to prepare a compound of formula (II-b) (step (g)). ).

상기 일반식 (II-a) 및 (II-b)의 화합물 각각은 추가의 반응을 거쳐 다양한 치환기를 함유하는 일반식 (II)의 화합물 중의 하나로 전환될 수 있다.Each of the compounds of the general formulas (II-a) and (II-b) can be converted to one of the compounds of the general formula (II) containing various substituents via further reactions.

이와 관련하여, 본 발명에 따르면, 하기 일반식 (II)의 화합물이 제공된다;In this regard, according to the present invention there is provided a compound of the general formula (II) below;

화학식 2Formula 2

상기식에서,In the above formula,

R'2는 에틸기 또는 이소프로필기이고;R ' 2 is an ethyl group or isopropyl group;

R'3은 니트로기, 아미노기, 아세트아미도기, 트리플루오로아세트아미도기 또는 C1-C3알콕시카르보닐기이고;R ' 3 is a nitro group, amino group, acetamido group, trifluoroacetamido group or C 1 -C 3 alkoxycarbonyl group;

R'4는 메틸기 또는 할로겐원자이고;R ' 4 is a methyl group or a halogen atom;

Z'는 C=O, NH 또는 아세트아미도기이다.Z 'is a C═O, NH or acetamido group.

또한, 상기 일반식 (III)의 화합물은 알려진 방법(ComprehensiveHeterocyclic Chemistry, vol. 2)으로 합성하거나 시약용으로 시판되는 것들을 사용할 수 있다.In addition, the compounds of the general formula (III) may be synthesized by known methods (Comprehensive Heterocyclic Chemistry, vol. 2) or commercially available for reagents.

전술한 바와 같은 방법에 따라 제조할 수 있는 본 발명의 일반식 (I)의 화합물의 예를 하기 표 1에 나타내었으며, 이들에 국한되는 것은 아니다.Examples of compounds of the general formula (I) of the present invention which can be prepared according to the methods as described above are shown in Table 1 below, but are not limited thereto.

본 발명의 일반식 (I)의 화합물의 약제학적으로 허용되는 염으로는 이의 알칼리 또는 알칼리토금속염, 예를 들면 나트륨염, 칼륨염, 마그네슘염 및 칼슘염이 포함된다.Pharmaceutically acceptable salts of the compounds of general formula (I) of the invention include their alkali or alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts and calcium salts.

본 발명의 일반식 (I)의 화합물 또는 이의 약제학적으로 허용되는 염은 항바이러스제, 특히 항 HIV-1제로 유용하다. 더욱이, 본 발명의 일반식 (I)의 화합물 또는 이의 약제학적으로 허용되는 염은 야생형 HIV-1 뿐 아니라 내성 HIV-1에 대해서도 효과를 나타낸다.Compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof are useful as antiviral agents, in particular anti-HIV-1 agents. Moreover, the compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof have effects on wild type HIV-1 as well as resistant HIV-1.

따라서, 본 발명에서는 또한 유효량의 일반식 (I)의 화합물 또는 이의 약제학적으로 허용되는 염과 약제학적으로 허용되는 담체를 포함하는 항바이러스제 조성물을 제공한다.Accordingly, the present invention also provides an antiviral composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

본 발명의 약학 조성물은 경구 또는 주사 투여 형태로 제형화할 수 있다.The pharmaceutical compositions of the invention may be formulated in oral or injection dosage forms.

경구 투여용 제형으로는 예를 들면 정제, 캅셀제 등이 있는데, 이들 제형은 활성성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및 글리신), 활탁제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및 폴리에틸렌 글리콜)와 같은 첨가제를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및 폴리비닐피롤리돈과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물, 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 주사용 제형으로는 등장성 수용액 또는 현탁액이 바람직하다.Formulations for oral administration include, for example, tablets, capsules, etc. These formulations may contain, in addition to the active ingredient, diluents (e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), and suspending agents (e.g. Silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycols). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, optionally starch, agar, alginic acid or its sodium salt Disintegrating or boiling mixtures, such as absorbents, colorants, flavors and sweeteners. Injectable formulations are preferably aqueous isotonic solutions or suspensions.

상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있다.The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts for regulating osmotic pressure and / or buffers and other therapeutically useful substances.

상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있으며 활성 성분을 약 0.1 내지 75%, 바람직하게는 약 1 내지 50%의 범위에서 함유할 수 있다. 약 50 내지 70kg의 포유동물에 대한 단위제형은 약 10 내지 200mg의 활성성분을 함유한다.The formulations may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of about 0.1 to 75%, preferably about 1 to 50%. The unit dosage form for about 50-70 kg mammals contains about 10-200 mg of active ingredient.

이하 하기 제조예 및 실시예에 의거하여 본 발명을 보다 상세히 설명한다.단, 이들 제조예 및 실시예는 본 발명을 설명하기 위한 것일 뿐, 본 발명이 이들 만으로 제한되는 것으로 간주되어서는 안된다. 실시예에서, 온도는 섭씨(℃)이며, 달리 언급되어 있지 않는 한 모든 증발과정은 감압하, 바람직하게는 약 15 내지 100 mmHg하에 수행하였다.Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. However, these Preparation Examples and Examples are only for illustrating the present invention, and the present invention should not be considered to be limited to these. In the examples, the temperature is in degrees Celsius (° C.) and all evaporation processes are carried out under reduced pressure, preferably about 15 to 100 mmHg, unless otherwise stated.

제조예Production Example

융점 및 NMR 데이터와 함께 하기 표 2에 보여지는 구조식 (A) 내지 (U), (II-a-1), (II-a-2) 및 (II-b-1)의 일반식 (II)의 화합물이 본 발명의 일반식 (I)의 각각의 화합물을 제조하는데 사용되었다.General formula (II) of structural formulas (A) to (U), (II-a-1), (II-a-2) and (II-b-1) shown in Table 2 below with melting point and NMR data Was used to prepare each compound of formula (I) of the present invention.

제조예 1 내지 21Preparation Examples 1 to 21

특정 구조식 (A) 내지 (U)를 갖는 각각의 화합물을 미국 특허 제5,747,500호에 기술된 방법에 따라 제조하였다.Each compound having the specific structural formulas (A)-(U) was prepared according to the method described in US Pat. No. 5,747,500.

제조예 22 : 6-(3,5-디메틸페닐아세트아미도)-5-이소프로필-2,4-피리미딘디온(화합물 II-a-1)의 합성Preparation Example 22 Synthesis of 6- (3,5-Dimethylphenylacetamido) -5-isopropyl-2,4-pyrimidinedione (Compound II-a-1)

단계 1) 2,4-디클로로-6-(3,5-디메틸페닐포르밀아미도)-5-이소프로필피리미딘의 합성Step 1) Synthesis of 2,4-dichloro-6- (3,5-dimethylphenylformylamido) -5-isopropylpyrimidine

DMF 80ml에 3,5-디메틸포름아닐린 8.94g(60mmol)을 녹이고 질소분위기하에얼음중탕으로 냉각시키고, 60% 수소화나트륨 2.88g(72mmol)을 조금씩 가하고 10분간 교반하였다. 이어서, 5-이소프로필-2,4,6-트리클로로피리미딘 16.2g(72mmol)을 가한다음 상온에서 24시간 교반하였다. 다음에, 에테르를 가하고 물로 씻어주고 무수황산마그네슘으로 건조시키고 여과하여 감압농축한 다음에 얻은 잔류물을 컬럼크로마토그래피(용출액, 에테르:헥산(1:15))로 분리하여 3.3g(수율 17%)의 표제화합물을 흰색 고체형태로 얻었다.8.94 g (60 mmol) of 3,5-dimethylformaniline was dissolved in 80 ml of DMF, cooled in an ice bath under nitrogen atmosphere, and 2.88 g (72 mmol) of 60% sodium hydride was added thereto, followed by stirring for 10 minutes. Subsequently, 16.2 g (72 mmol) of 5-isopropyl-2,4,6-trichloropyrimidine was added, followed by stirring at room temperature for 24 hours. Then, ether was added, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the residue was separated by column chromatography (eluent, ether: hexane (1:15)) and 3.3 g (yield 17%). ) Was obtained in the form of a white solid.

융점 : 151 내지 153 ℃Melting Point: 151-153 ℃

1H-NMR(200MHz, CDCl3) δ 1.12-1.24(6H, m), 2.30(6H, s), 3.22(1H, m), 6.72(2H, s), 6.96(1H, s), 8.70(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.12-1.24 (6H, m), 2.30 (6H, s), 3.22 (1H, m), 6.72 (2H, s), 6.96 (1H, s), 8.70 ( 1H, s)

m/z(EI) 338(M+).m / z (EI) 338 (M + ).

단계 2) 2,4-디메톡시-6-(3,5-디메틸페닐아미노)-5-이소프로필피리미딘의 합성Step 2) Synthesis of 2,4-dimethoxy-6- (3,5-dimethylphenylamino) -5-isopropylpyrimidine

메탄올 40ml에 나트륨 1.02g(44.4mmol)을 가하여 소디움메톡시드를 만들고 상기 단계 1)에서 얻은 화합물 3g(8.88mmol)을 가한 다음 4시간동안 교반하면서 환류시켰다. 이어서, 반응물을 상온으로 냉각시키고 과량의 염화암모늄을 가하여 중화시킨다음 감압농축하여 얻은 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(1:15))로 분리하여 2.6g(수율 97%)의 표제화합물을 흰색 고체형태로 얻었다.1.02 g (44.4 mmol) of sodium was added to 40 ml of methanol to make sodium methoxide, and 3 g (8.88 mmol) of the compound obtained in step 1) was added thereto, followed by reflux with stirring for 4 hours. The reaction was then cooled to room temperature, neutralized by addition of excess ammonium chloride, and the residue obtained by concentration under reduced pressure was separated by column chromatography (eluent, ethyl acetate: hexane (1:15)) to give 2.6 g (yield 97%). The title compound was obtained in the form of a white solid.

융점 : 126 내지 127 ℃Melting Point: 126-127 ℃

1H-NMR(200MHz, CDCl3) δ 1.31(6H, d, J=7.1Hz), 2.31(6H, s), 3.12(1H, m), 3.92(3H, s), 3.93(3H, s), 6.44(1H, s), 6.70(1H, s), 7.21(2H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.31 (6H, d, J = 7.1 Hz), 2.31 (6H, s), 3.12 (1H, m), 3.92 (3H, s), 3.93 (3H, s) , 6.44 (1H, s), 6.70 (1H, s), 7.21 (2H, s)

m/z(EI) 301(M+).m / z (EI) 301 (M + ).

단계 3) 6-(3,5-디메틸페닐아세트아미도)-5-이소프로필-2,4-피리미딘디온의 합성Step 3) Synthesis of 6- (3,5-dimethylphenylacetamido) -5-isopropyl-2,4-pyrimidinedione

상기 단계 2)에서 얻은 화합물 2.6g(8.6mmol)을 아세틸브로미드 30ml에 녹이고 19시간동안 교반하면서 환류시켰다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피 (용출액, 에틸아세테이트:헥산(2:1))로 분리하여 2.6g(수율 96%)의 표제화합물을 흰색 고체형태로 얻었다.2.6 g (8.6 mmol) of the compound obtained in step 2) was dissolved in 30 ml of acetylbromide and refluxed with stirring for 19 hours. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: hexane (2: 1)) to give 2.6 g (yield 96%) of the title compound as a white solid.

제조예 23 : 6-(3,5-디메틸페닐아세트아미도)-5-에틸-2,4-피리미딘디온(화합물 (II-a-2))의 합성Preparation Example 23 Synthesis of 6- (3,5-Dimethylphenylacetamido) -5-ethyl-2,4-pyrimidinedione (Compound (II-a-2))

5-에틸-2,4,6-트리클로로피리미딘을 상기 제조예 22와 같은 방법으로 반응시켜 표제화합물을 흰색 고체형태로 얻었다.5-ethyl-2,4,6-trichloropyrimidine was reacted in the same manner as in Preparation Example 22 to obtain the title compound as a white solid.

제조예 24 : 5-이소프로필-6-(3-메틸-5-니트로벤조일)-2,4-피리미딘디온(화합물 (II-b-1))의 합성Preparation Example 24 Synthesis of 5-isopropyl-6- (3-methyl-5-nitrobenzoyl) -2,4-pyrimidinedione (Compound (II-b-1))

단계 1) 6-(α-시아노-3-메틸-5-니트로벤질)-2,4-디클로로-5-이소프로필피리미딘의 합성Step 1) Synthesis of 6- (α-cyano-3-methyl-5-nitrobenzyl) -2,4-dichloro-5-isopropylpyrimidine

3-메틸-5-니트로페닐아세토니트릴 2.64g(15mmol)과 5-이소프로필-2,4,6-트리클로로피리미딘 4.05g(18mmol)을 DMF 30ml에 녹이고 질소분위기하에 얼음중탕으로 냉각시킨 다음 60% 수소화나트륨 1.15g(30mmol)을 조금씩 가한 다음 2시간동안 교반하였다. 이어서, 반응물을 상온에서 16시간 더 교반한 다음 염화암모늄 수용액을 가하여 중화시켰다. 다음에, 에테르를 가하고 물로 씻어주고 무수황산마그네슘으로 건조시키고 여과한 후 감압농축하여 얻은 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(1:4))로 분리하여 3.99g(수율73%)의 표제화합물을 흰색 고체형태로 얻었다.2.64 g (15 mmol) of 3-methyl-5-nitrophenylacetonitrile and 4.05 g (18 mmol) of 5-isopropyl-2,4,6-trichloropyrimidine are dissolved in 30 ml of DMF and cooled in an ice bath under nitrogen atmosphere. 1.15 g (30 mmol) of 60% sodium hydride was added little by little, followed by stirring for 2 hours. The reaction was then stirred for another 16 hours at room temperature and then neutralized by addition of aqueous ammonium chloride solution. Then, ether was added, washed with water, dried over anhydrous magnesium sulfate, filtered and the residue obtained by concentration under reduced pressure was separated by column chromatography (eluate, ethyl acetate: hexane (1: 4)) and 3.99 g (yield 73%). ) Was obtained in the form of a white solid.

융점 : 124 내지 125 ℃Melting Point: 124 to 125 ℃

1H-NMR(200MHz, CDCl3) δ 1.23(3H, d, J=7.2Hz), 1.38(3H, d, J=7.2Hz), 2.51(3H, s), 3.34(1H, m), 5.60(1H, s), 7.57(1H, s), 7.99(1H, s), 8.07(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.23 (3H, d, J = 7.2 Hz), 1.38 (3H, d, J = 7.2 Hz), 2.51 (3H, s), 3.34 (1H, m), 5.60 (1H, s), 7.57 (1H, s), 7.99 (1H, s), 8.07 (1H, s)

m/z(EI) 365(M+).m / z (EI) 365 (M + ).

단계 2) 6-(α-시아노-3-메틸-5-니트로벤질)-2,4-디메톡시-5-이소프로필피리미딘의 합성Step 2) Synthesis of 6- (α-cyano-3-methyl-5-nitrobenzyl) -2,4-dimethoxy-5-isopropylpyrimidine

상기 단계 1)에서 얻은 화합물 3.65g(10mmol)을 무수메탄올 60ml에 녹이고 소디움메톡시드 3.24g(60mmol)을 가한 다음 질소분위기하에 24시간 환류시켰다. 이어서, 과량의 염화암모늄을 가하여 중화시키고 감압농축한 다음 잔류물을 컬럼크로마토그래피(용출액, 에테르:헥산(1:3))로 분리하여 1.8g(수율50%)의 표제화합물을 옅은 노란색의 고체형태로 얻었다.3.65 g (10 mmol) of the compound obtained in step 1) was dissolved in 60 ml of anhydrous methanol, 3.24 g (60 mmol) of sodium methoxide was added thereto, and the mixture was refluxed under a nitrogen atmosphere for 24 hours. Subsequently, the resultant was neutralized with excess ammonium chloride, concentrated under reduced pressure, and the residue was separated by column chromatography (eluent, ether: hexane (1: 3)) to give 1.8 g (50% yield) of the title compound as a pale yellow solid. Obtained in form.

융점 : 134 내지 135 ℃Melting Point: 134-135 ℃

1H-NMR(200MHz, CDCl3) δ 1.15(3H, d, J=6.7Hz), 1.20(3H, d, J=6.7Hz), 2.49(3H, s), 3.05(1H, m), 4.00(3H, s), 4.01(3H, s), 5.48(1H, s), 7.62(1H, s), 8.00(2H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.15 (3H, d, J = 6.7 Hz), 1.20 (3H, d, J = 6.7 Hz), 2.49 (3H, s), 3.05 (1H, m), 4.00 (3H, s), 4.01 (3H, s), 5.48 (1H, s), 7.62 (1H, s), 8.00 (2H, s)

m/z(EI) 356(M+).m / z (EI) 356 (M + ).

단계 3) 2,4-디메톡시-5-이소프로필-6-(3-메틸-5-니트로벤조일)피리미딘의 합성Step 3) Synthesis of 2,4-dimethoxy-5-isopropyl-6- (3-methyl-5-nitrobenzoyl) pyrimidine

상기 단계 2)에서 얻은 화합물 1.7g(4.7mmol)을 DMF 20ml에 녹이고 질소분위기하에 60% 수소화나트륨 283mg(7.1mmol)을 가하였다. 이어서, 반응물을 산소 존재하에 상온에서 5시간 교반하였다. 다음에, 염화암모늄 수용액을 가하여 반응물을 중화시키고 에테르를 가한 다음 물로 씻고 무수황산마그네슘으로 건조시키고 여과하여 감압농축한 후 얻은 잔류물을 컬럼크로마토그래피(용출액, 디클로로메탄:메탄올(97:3))로 분리하여 1.03g(수율62%)의 표제화합물을 흰색 고체형태로 얻었다.1.7 g (4.7 mmol) of the compound obtained in step 2) was dissolved in 20 ml of DMF, and 283 mg (7.1 mmol) of 60% sodium hydride was added under nitrogen atmosphere. The reaction was then stirred for 5 hours at room temperature in the presence of oxygen. Then, an aqueous solution of ammonium chloride was added to neutralize the reaction, ether was added, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent, dichloromethane: methanol (97: 3)). The residue was separated to give 1.03 g (yield 62%) of the title compound as a white solid.

융점 : 111 내지 112 ℃Melting Point: 111-112 ℃

1H-NMR(200MHz, CDCl3) δ 1.21(6H, d, J=6.9Hz), 2.54(3H, s), 2.88(1H, m), 3.93(3H, s), 4.09(3H, s), 8.05(1H, s), 8.27(1H, s), 8.44(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.21 (6H, d, J = 6.9 Hz), 2.54 (3H, s), 2.88 (1H, m), 3.93 (3H, s), 4.09 (3H, s) , 8.05 (1H, s), 8.27 (1H, s), 8.44 (1H, s)

m/z(EI) 345(M+).m / z (EI) 345 (M + ).

단계 4) 5-이소프로필-6-(3-메틸-5-니트로벤조일)-2,4-피리미딘디온의 합성Step 4) Synthesis of 5-isopropyl-6- (3-methyl-5-nitrobenzoyl) -2,4-pyrimidinedione

상기 단계 3)에서 얻은 화합물 630mg(1.8mmol)을 진한 염산 6ml에 녹이고 약 4시간 교반하면서 환류시켰다. 이어서, 반응물을 상온으로 냉각시키고 생성된 침전물을 여과하여 모으고 증류수와 헥산으로 씻어준 후 감압건조시켜 560mg(수율98%)의 표제화합물을 흰색 고체형태로 얻었다.630 mg (1.8 mmol) of the compound obtained in step 3) was dissolved in 6 ml of concentrated hydrochloric acid and refluxed with stirring for about 4 hours. Subsequently, the reaction was cooled to room temperature, the resulting precipitate was collected by filtration, washed with distilled water and hexane, and dried under reduced pressure to yield 560 mg (yield 98%) of the title compound as a white solid.

실시예 1 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(피리딘-4-일메틸)-2,4-피리미딘디온(화합물 1)의 합성Example 1 Synthesis of 6- (3,5-Dimethylbenzoyl) -5-isopropyl-1- (pyridin-4-ylmethyl) -2,4-pyrimidinedione (Compound 1)

상기 제조예 1에서 얻은 화합물 (A) 286mg(1mmol)을 DMF 5ml에 녹이고 무수탄산칼륨 276mg(2mmol), 요오드화리튬 134mg(1mmol) 및 4-피콜릴클로라이드의 염산염 164mg(1mmol)을 가한 후, 상온에서 16시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트: 헥산(3:1))로 분리하여 120mg(수율 32%)의 표제화합물을 흰색 고체형태로 얻었다.286 mg (1 mmol) of Compound (A) obtained in Preparation Example 1 was dissolved in 5 ml of DMF, 276 mg (2 mmol) of anhydrous potassium carbonate, 134 mg (1 mmol) of lithium iodide, and 164 mg (1 mmol) of 4-picolyl chloride were added thereto. Stirred for 16 h. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: hexane (3: 1)) to yield 120 mg (yield 32%) of the title compound as a white solid.

융점 : 264 내지 265 ℃Melting Point: 264-265 ℃

1H NMR (200MHz, CDCl3) δ 1.12(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.30-2.40(7H, m), 4.66(1H, d, J=16.3Hz), 4.88(1H, d, J=16.3Hz), 6.98-7.36(5H, m), 8.41-8.44(2H, m), 9.91(1H, s) 1 H NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J = 6.7 Hz), 1.23 (3H, d, J = 6.7 Hz), 2.30-2.40 (7H, m), 4.66 (1H, d, J = 16.3 Hz), 4.88 (1H, d, J = 16.3 Hz), 6.98-7.36 (5H, m), 8.41-8.44 (2H, m), 9.91 (1H, s)

m/z(EI) 377(M+).m / z (EI) 377 (M < + >).

실시예 2 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(피리딘-3-일메틸)-2,4-피리미딘디온(화합물 2)의 합성Example 2 Synthesis of 6- (3,5-Dimethylbenzoyl) -5-isopropyl-1- (pyridin-3-ylmethyl) -2,4-pyrimidinedione (Compound 2)

3-피콜릴클로라이드의 염산염을 사용하여 상기 실시예 1과 같은 방법으로 반응시켜 표제화합물을 얻었다.The title compound was obtained by reacting the hydrochloride salt of 3-picolyl chloride in the same manner as in Example 1.

융점 : 179 내지 180 ℃Melting Point: 179 to 180 ℃

1H NMR (200MHz, CDCl3) δ 1.12(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz), 2.20-2.38(7H, m), 4.71(1H, d, J=16.0Hz), 4.93(1H, d, J=16.0Hz), 7.09-7.56(5H, m), 8.29-8.43(2H, m), 10.18(1H, s) 1 H NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J = 6.9 Hz), 1.22 (3H, d, J = 6.9 Hz), 2.20-2.38 (7H, m), 4.71 (1H, d, J = 16.0 Hz), 4.93 (1H, d, J = 16.0 Hz), 7.09-7.56 (5H, m), 8.29-8.43 (2H, m), 10.18 (1H, s)

m/z(EI) 377(M+).m / z (EI) 377 (M < + >).

실시예 3 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(피리딘-2-일메틸)-2,4-피리미딘디온(화합물 3)의 합성Example 3 Synthesis of 6- (3,5-Dimethylbenzoyl) -5-isopropyl-1- (pyridin-2-ylmethyl) -2,4-pyrimidinedione (Compound 3)

2-피콜릴클로라이드의 염산염을 사용하여 상기 실시예 1과 같은 방법으로 반응시켜 표제화합물을 얻었다.The title compound was obtained by reacting the hydrochloride salt of 2-picolyl chloride in the same manner as in Example 1.

융점 : 214 내지 215 ℃Melting Point: 214 to 215 ° C

1H NMR (200MHz, CDCl3) δ 1.12(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.20-2.40(7H, m), 4.77(1H, d, J=16.8Hz), 5.16(1H, d, J=16.8Hz), 7.01-7.48(6H, m), 8.36(2H, m), 9.90(1H, s) 1 H NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.9 Hz), 2.20-2.40 (7H, m), 4.77 (1H, d, J = 16.8 Hz), 5.16 (1H, d, J = 16.8 Hz), 7.01-7.48 (6H, m), 8.36 (2H, m), 9.90 (1H, s)

m/z(EI) 377(M+).m / z (EI) 377 (M < + >).

실시예 4 내지 65Examples 4 to 65

상기 실시예 1과 유사한 반응을 수행하여 실시예 4 내지 65의 2,4-피리미딘디온 유도체를 제조하였으며, 이들을 하기 표 3에 나타내었다.The reaction similar to Example 1 was carried out to prepare 2,4-pyrimidinedione derivatives of Examples 4 to 65, which are shown in Table 3 below.

실시예 66 : 6-(3,5-디메틸페닐아미노)-5-이소프로필-1-(피리딘-4-일메틸)-2,4-피리미딘디온(화합물 66)의 합성Example 66 Synthesis of 6- (3,5-Dimethylphenylamino) -5-isopropyl-1- (pyridin-4-ylmethyl) -2,4-pyrimidinedione (Compound 66)

상기 제조예 22에서 얻은 화합물 (II-a-1) 630mg(2mmol)을 DMF 10ml에 녹이고 무수탄산칼륨 552mg(4mmol), 요오드화리튬 268mg(2mmol) 및 4-피콜릴클로이드의 염산염 328mg(2mmol)을 가한 다음 상온에서 24시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트)로 분리하여 6-(3,5-디메틸페닐아세트아미도)-5-이소프로필-1-(피리딘-4-일메틸)-2,4-피리미딘디온 276mg(수율34%)을 얻었다. 이어서, 상기에서 얻은 화합물을 무수메탄올 10ml에 녹이고 소디움메톡시드 110mg(2mmol)을 가한 다음 상온에서 6시간 교반하였다. 다음에, 과량의 염화암모늄을 가하여 중화시키고 감압농축후 잔류물을 컬럼크로마토그래피(용출액, 메탄올:에테르(8:92))로 분리하여 280mg(수율88%)의 표제화합물을 흰색 고체형태로 얻었다.630 mg (2 mmol) of the compound (II-a-1) obtained in Preparation Example 22 were dissolved in 10 ml of DMF, and 552 mg (4 mmol) of anhydrous potassium carbonate, 268 mg (2 mmol) of lithium iodide, and 328 mg (2 mmol) of 4-picolyl chloride were added. Then, the mixture was stirred at room temperature for 24 hours. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate) to give 6- (3,5-dimethylphenylacetamido) -5-isopropyl-1- (pyridin-4-ylmethyl 276 mg (yield 34%) of 2,4-pyrimidinedione was obtained. Subsequently, the compound obtained above was dissolved in 10 ml of anhydrous methanol, 110 mg (2 mmol) of sodium methoxide was added thereto, followed by stirring at room temperature for 6 hours. Then, an excess of ammonium chloride was added to neutralize and the residue was concentrated under reduced pressure, and the residue was separated by column chromatography (eluent, methanol: ether (8:92)) to obtain 280 mg (yield 88%) of the title compound as a white solid. .

융점 : 272 내지 273℃Melting Point: 272 ~ 273 ℃

1H-NMR(200MHz, CDCl3/CD3OD) δ 1.20(6H, d, J=6.9Hz), 2.24(6H, s), 2.90(1H, m), 4.90(2H, s), 6.27(2H, s), 6.61(1H, s), 7.04-7.06(2H, m), 8.42-8.45(2H, m) 1 H-NMR (200 MHz, CDCl 3 / CD 3 OD) δ 1.20 (6H, d, J = 6.9 Hz), 2.24 (6H, s), 2.90 (1H, m), 4.90 (2H, s), 6.27 ( 2H, s), 6.61 (1H, s), 7.04-7.06 (2H, m), 8.42-8.45 (2H, m)

m/z(EI) 364(M+).m / z (EI) 364 (M + ).

실시예 67 : 6-(3,5-디메틸페닐아미노)-5-에틸-1-(피리딘-4-일메틸)-2,4-피리미딘디온(화합물 67)의 합성Example 67 Synthesis of 6- (3,5-Dimethylphenylamino) -5-ethyl-1- (pyridin-4-ylmethyl) -2,4-pyrimidinedione (Compound 67)

상기 제조예 23에서 얻은 화합물 (II-a-2)을 사용하여 상기 실시예 66과 같은 방법으로 반응시켜 표제화합물을 흰색 고체형태로 얻었다.The title compound was obtained in the form of a white solid by using the compound (II-a-2) obtained in Preparation Example 23 in the same manner as in Example 66.

융점 : 250 내지 251℃Melting Point: 250 ~ 251 ℃

1H-NMR(200MHz, CDCl3/CD3OD) δ 0.99(3H, t, J=7.5Hz), 2.24(6H, s), 2.37(2H, q, J=7.5Hz), 4.91(2H, s), 6.31(2H, s), 6.62(1H, s), 7.04-7.07(2H, m), 8.40-8.43(2H, m) 1 H-NMR (200 MHz, CDCl 3 / CD 3 OD) δ 0.99 (3H, t, J = 7.5 Hz), 2.24 (6H, s), 2.37 (2H, q, J = 7.5 Hz), 4.91 (2H, s), 6.31 (2H, s), 6.62 (1H, s), 7.04-7.07 (2H, m), 8.40-8.43 (2H, m)

m/z(EI) 350(M+).m / z (EI) 350 (M + ).

실시예 68 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(N-옥소피리딘-4-일메틸)-2,4-피리미딘디온(화합물 68)의 합성Example 68 Synthesis of 6- (3,5-Dimethylbenzoyl) -5-isopropyl-1- (N-oxopyridin-4-ylmethyl) -2,4-pyrimidinedione (Compound 68)

상기 실시예 1에서 얻은 화합물 2.26g(6mmol)을 디클로로메탄 120ml에 녹이고 메타클로로퍼벤조산 2.72g(9mmol)을 가한 다음 상온에서 6시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 클로로포름:메탄올(93:7))로 분리하여 2g(수율84%)의 표제화합물을 흰색 고체형태로 얻었다.2.26 g (6 mmol) of the compound obtained in Example 1 was dissolved in 120 ml of dichloromethane, and 2.72 g (9 mmol) of metachloroperbenzoic acid was added thereto, followed by stirring at room temperature for 6 hours. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, chloroform: methanol (93: 7)) to give 2 g (yield 84%) of the title compound as a white solid.

융점 : 254 내지 255℃Melting Point: 254 ~ 255 ℃

1H-NMR(200MHz, CDCl3) δ 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.25-2.36(7H, m), 4.69(2H, s), 7.05-7.41(5H, m), 8.05-8.09(2H, m), 9.52(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J = 6.7 Hz), 1.22 (3H, d, J = 6.7 Hz), 2.25-2.36 (7H, m), 4.69 (2H, s) , 7.05-7.41 (5H, m), 8.05-8.09 (2H, m), 9.52 (1H, s)

m/z(EI) 393(M+).m / z (EI) 393 (M + ).

실시예 69 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(N-옥소-2-메틸피리딘-4-일메틸)-2,4-피리미딘디온(화합물 69)의 합성Example 69 of 6- (3,5-dimethylbenzoyl) -5-isopropyl-1- (N-oxo-2-methylpyridin-4-ylmethyl) -2,4-pyrimidinedione (compound 69) synthesis

상기 실시예 45에서 얻은 화합물 834mg(2.13mmol)을 디클로로메탄 40ml에 녹이고 메타클로로퍼벤조산 969mg(3.2mmol)을 가한 다음 상온에서 5시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:메탄올(7:1))로 분리하여 860mg(수율 99%)의 표제화합물을 흰색 고체형태로 얻었다.834 mg (2.13 mmol) of the compound obtained in Example 45 was dissolved in 40 ml of dichloromethane, 969 mg (3.2 mmol) of metachloroperbenzoic acid was added thereto, followed by stirring at room temperature for 5 hours. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: methanol (7: 1)) to give 860 mg (yield 99%) of the title compound as a white solid.

융점 : 223 내지 224 ℃Melting Point: 223 to 224 ℃

1H-NMR(200MHz, CDCl3) δ 1.13(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.25-2.40(10H, m), 4.56(1H, d, J=16.0Hz), 4.85(1H, d, J=16.0Hz), 6.93(1H, m), 7.31(1H, s), 7.37(2H, s), 8.10(1H, m), 10.08(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.13 (3H, d, J = 6.7 Hz), 1.23 (3H, d, J = 6.7 Hz), 2.25-2.40 (10H, m), 4.56 (1H, d, J = 16.0 Hz), 4.85 (1H, d, J = 16.0 Hz), 6.93 (1H, m), 7.31 (1H, s), 7.37 (2H, s), 8.10 (1H, m), 10.08 (1H, s)

m/z(EI) 407(M+).m / z (EI) 407 (M + ).

실시예 70 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(N-옥소-2,6-디메틸피리딘-4-일메틸)-2,4-피리미딘디온(화합물 70)의 합성Example 70 6- (3,5-dimethylbenzoyl) -5-isopropyl-1- (N-oxo-2,6-dimethylpyridin-4-ylmethyl) -2,4-pyrimidinedione (Compound 70 ) Synthesis

상기 실시예 55에서 얻은 화합물 840mg(2mmol)을 디클로로메탄 40ml에 녹이고 메타클로로퍼벤조산 942mg(3mmol)을 가한 다음 상온에서 21시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 디클로로메탄:메탄올(15:1))로 분리하여 800mg(수율95%)의 표제화합물을 흰색 고체형태로 얻었다.840 mg (2 mmol) of the compound obtained in Example 55 was dissolved in 40 ml of dichloromethane, and 942 mg (3 mmol) of metachloroperbenzoic acid was added thereto, followed by stirring at room temperature for 21 hours. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, dichloromethane: methanol (15: 1)) to yield 800 mg (95% yield) of the title compound as a white solid.

융점 : 241 내지 242 ℃Melting Point: 241 to 242 ° C

1H-NMR(200MHz, CDCl3) δ 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.30-2.34(13H, m), 4.41(1H, d, J=16.0Hz), 4.98(1H, d, J=16.0Hz), 6.80(2H, s),7.27(1H, s), 7.34(2H, s), 9.21(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J = 6.7 Hz), 1.22 (3H, d, J = 6.7 Hz), 2.30-2.34 (13H, m), 4.41 (1H, d, J = 16.0 Hz), 4.98 (1H, d, J = 16.0 Hz), 6.80 (2H, s), 7.27 (1H, s), 7.34 (2H, s), 9.21 (1H, s)

m/z(EI) 421(M+).m / z (EI) 421 (M + ).

실시예 71 : 6-(3-클로로-5-메틸벤조일)-5-이소프로필-1-(N-옥소-2,6-디메틸피리딘-4-일메틸)-2,4-피리미딘디온(화합물 71)의 합성Example 71 6- (3-chloro-5-methylbenzoyl) -5-isopropyl-1- (N-oxo-2,6-dimethylpyridin-4-ylmethyl) -2,4-pyrimidinedione ( Synthesis of Compound 71)

상기 실시예 59에서 얻은 화합물 860mg(2mmol)을 디클로로메탄 40ml에 녹이고 메타클로로퍼벤조산 942mg(3mmol)을 가한 다음 상온에서 20시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:메탄올(10:1))로 분리하여 870mg(수율98%)의 표제화합물을 흰색 고체형태로 얻었다.860 mg (2 mmol) of the compound obtained in Example 59 was dissolved in 40 ml of dichloromethane, 942 mg (3 mmol) of metachloroperbenzoic acid was added thereto, followed by stirring at room temperature for 20 hours. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: methanol (10: 1)) to give 870 mg (yield 98%) of the title compound as a white solid.

융점 : 225 내지 226 ℃Melting Point: 225 to 226 ℃

1H-NMR(200MHz, CDCl3) δ 1.13(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz), 2.22-2.36(10H, m), 4.39(1H, d, J=16.0Hz), 5.04(1H, d, J=16.0Hz), 6.80(2H, s), 7.33-7.54(3H, m), 9.14(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.13 (3H, d, J = 6.9 Hz), 1.22 (3H, d, J = 6.9 Hz), 2.22-2.36 (10H, m), 4.39 (1H, d, J = 16.0 Hz), 5.04 (1H, d, J = 16.0 Hz), 6.80 (2H, s), 7.33-7.54 (3H, m), 9.14 (1H, s)

m/z(EI) 441(M+).m / z (EI) 441 (M + ).

실시예 72 : 1-(2-아세톡시메틸피리딘-4-일메틸)-6-(3,5-디메틸벤조일)-5-이소프로필-2,4-피리미딘디온(화합물 72)의 합성Example 72 Synthesis of 1- (2-acetoxymethylpyridin-4-ylmethyl) -6- (3,5-dimethylbenzoyl) -5-isopropyl-2,4-pyrimidinedione (Compound 72)

상기 실시예 69에서 얻은 화합물 800mg(1.96mmol)울 무수초산 10ml에 가하고 120-140℃의 oil bath에서 4시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(2:1))로 분리하여 150mg(수율 17%)의 표제화합물을 흰색의 시럽형태로 얻었다.800 mg (1.96 mmol) of the compound obtained in Example 69 was added to 10 ml of acetic anhydride and stirred for 4 hours in an oil bath at 120-140 ° C. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: hexane (2: 1)) to give 150 mg (yield 17%) of the title compound in the form of a white syrup.

1H-NMR(200MHz, CDCl3) δ 1.14(3H, d, J=6.7Hz), 1.28(3H, d, J=6.7Hz), 2.16(3H, s), 2.22-2.40(7H, m), 4.68(1H, d, J=16.2Hz), 4.88(1H, d, J=16.2Hz), 5.08(2H, s), 7.00-7.02(2H, m), 7.26(1H, s), 7.36(2H, s), 8.44(1H, m) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.14 (3H, d, J = 6.7 Hz), 1.28 (3H, d, J = 6.7 Hz), 2.16 (3H, s), 2.22-2.40 (7H, m) , 4.68 (1H, d, J = 16.2 Hz), 4.88 (1H, d, J = 16.2 Hz), 5.08 (2H, s), 7.00-7.02 (2H, m), 7.26 (1H, s), 7.36 ( 2H, s), 8.44 (1H, m)

m/z(EI) 449(M+).m / z (EI) 449 (M + ).

실시예 73 : 1-(2-아세톡시메틸-6-메틸피리딘-4-일메틸)-6-(3,5-디메틸벤조일) -5-이소프로필-2,4-피리미딘디온(화합물 73)의 합성Example 73 1- (2-acetoxymethyl-6-methylpyridin-4-ylmethyl) -6- (3,5-dimethylbenzoyl) -5-isopropyl-2,4-pyrimidinedione (compound 73 ) Synthesis

상기 실시예 70에서 얻은 화합물 300mg(0.71mmol)을 무수초산 3ml에 가하고 120-130℃의 oil bath에서 2시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(1:1))로 분리하여 110mg(수율33%)의 표제화합물을 포움 형태로 얻었다.300 mg (0.71 mmol) of the compound obtained in Example 70 was added to 3 ml of acetic anhydride and stirred for 2 hours in an oil bath at 120-130 ° C. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: hexane (1: 1)) to give 110 mg (yield 33%) of the title compound in the form of a foam.

1H-NMR(200MHz, CDCl3) δ1.13(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.10-2.41(10H, m), 4.53(1H, d, J=16.0Hz), 4.96(1H, d, J=16.0Hz), 5.00(2H, s), 6.78-6.81(2H, m), 7.24(1H, s), 7.34(2H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ1.13 (3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.9 Hz), 2.10-2.41 (10H, m), 4.53 (1H, d , J = 16.0 Hz), 4.96 (1H, d, J = 16.0 Hz), 5.00 (2H, s), 6.78-6.81 (2H, m), 7.24 (1H, s), 7.34 (2H, s)

m/z(EI) 463(M+).m / z (EI) 463 (M + ).

실시예 74 : 1-(2-아세톡시메틸-6-메틸피리딘-4-일메틸)-6-(3-클로로-5-메틸벤조일)-5-이소프로필-2,4-피리미딘디온(화합물 74)의 합성Example 74 1- (2-acetoxymethyl-6-methylpyridin-4-ylmethyl) -6- (3-chloro-5-methylbenzoyl) -5-isopropyl-2,4-pyrimidinedione ( Synthesis of Compound 74)

상기 실시예 71에서 얻은 화합물 700mg(1.58mmol)을 무수초산 10ml에 가하고 120-130℃의 oil bath에서 5시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(2:1))로 분리하여 115mg(수율15%)의 표제화합물을 흰색의 포움 형태로 얻었다.700 mg (1.58 mmol) of the compound obtained in Example 71 was added to 10 ml of acetic anhydride and stirred for 5 hours in an oil bath at 120-130 ° C. The reaction was then concentrated under reduced pressure and the residue was separated by column chromatography (eluent, ethyl acetate: hexane (2: 1)) to yield 115 mg (15% yield) of the title compound as a white foam.

1H-NMR(200MHz, CDCl3) δ 1.14(3H, d, J=6.9Hz), 1.24(3H, d, J=6.9Hz), 2.16(3H, s), 2.20-2.32(4H, m), 2.42(3H, s), 4.48(1H, d, J=16.3Hz), 5.00(2H, s), 5.06(1H, d, J=16.3Hz), 6.76(2H, d, J=5.9Hz), 7.32(1H, s), 7.39(1H, s), 7.52(1H, s), 9.46(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.14 (3H, d, J = 6.9 Hz), 1.24 (3H, d, J = 6.9 Hz), 2.16 (3H, s), 2.20-2.32 (4H, m) , 2.42 (3H, s), 4.48 (1H, d, J = 16.3 Hz), 5.00 (2H, s), 5.06 (1H, d, J = 16.3 Hz), 6.76 (2H, d, J = 5.9 Hz) , 7.32 (1H, s), 7.39 (1H, s), 7.52 (1H, s), 9.46 (1H, s)

m/z(EI) 483(M+).m / z (EI) 483 (M + ).

실시예 75 : 6-(3,5-디메틸벤조일)-1-(2-히드록시메틸피리딘-4-일메틸)-5-이소프로필-2,4-피리미딘디온(화합물 75)의 합성Example 75 Synthesis of 6- (3,5-Dimethylbenzoyl) -1- (2-hydroxymethylpyridin-4-ylmethyl) -5-isopropyl-2,4-pyrimidinedione (Compound 75)

상기 실시예 72에서 얻은 화합물 100mg(0.22mmol)을 메탄올 5ml에 녹이고 암모니아수 0.5ml를 가한 다음 상온에서 6시간 교반하였다. 이어서, 반응물을 감압농축하고 잔류물을 메탄올-클로로포름에서 재결정하여 70mg(수율 77%)의 표제화합물을 흰색 고체형태로 얻었다.100 mg (0.22 mmol) of the compound obtained in Example 72 was dissolved in 5 ml of methanol, 0.5 ml of ammonia water was added, and the mixture was stirred at room temperature for 6 hours. The reaction was then concentrated under reduced pressure and the residue was recrystallized in methanol-chloroform to give 70 mg (yield 77%) of the title compound as a white solid.

융점 : 256 내지 257 ℃Melting Point: 256 to 257 ℃

1H-NMR(200MHz, DMSO-d6) δ 1.05(3H, d, J=6.8Hz), 1.11(3H, d, J=6.8Hz), 2.15(1H, m), 2.28(6H, s), 4.44(2H, d, J=5.5Hz), 4.59(1H, d, J=16.7Hz), 4.70(1H, d, J=16.7Hz), 5.35(1H, t, J=5.5Hz), 6.90(1H, m), 7.15(1H, s), 7.32(1H, s), 7.55(2H, s), 8.25(1H, m), 11.66(1H, s) 1 H-NMR (200 MHz, DMSO-d 6 ) δ 1.05 (3H, d, J = 6.8 Hz), 1.11 (3H, d, J = 6.8 Hz), 2.15 (1H, m), 2.28 (6H, s) , 4.44 (2H, d, J = 5.5 Hz), 4.59 (1H, d, J = 16.7 Hz), 4.70 (1H, d, J = 16.7 Hz), 5.35 (1H, t, J = 5.5 Hz), 6.90 (1H, m), 7.15 (1H, s), 7.32 (1H, s), 7.55 (2H, s), 8.25 (1H, m), 11.66 (1H, s)

m/z(EI) 407 (M+).m / z (EI) 407 (M + ).

실시예 76 : 6-(3,5-디메틸벤조일)-1-(2-히드록시메틸-6-메틸피리딘-4-일메틸)-5-이소프로필-2,4-피리미딘디온(화합물 76)의 합성Example 76 6- (3,5-dimethylbenzoyl) -1- (2-hydroxymethyl-6-methylpyridin-4-ylmethyl) -5-isopropyl-2,4-pyrimidinedione (Compound 76 ) Synthesis

상기 실시예 73에서 얻은 화합물 150mg(0.32mmol)을 메탄올 5ml에 녹이고 암모니아수 0.5ml를 가한 다음 상온에서 5시간 교반하였다. 다음에 반응물을 감압농축하고 잔류물을 메탄올-클로로포름에서 재결정하여 100mg(수율 74%)의 표제화합물을 흰색 고체형태로 얻었다.150 mg (0.32 mmol) of the compound obtained in Example 73 was dissolved in 5 ml of methanol, 0.5 ml of ammonia water was added, and the mixture was stirred at room temperature for 5 hours. The reaction was then concentrated under reduced pressure and the residue was recrystallized in methanol-chloroform to give 100 mg (yield 74%) of the title compound as a white solid.

융점 : 234 내지 236 ℃Melting Point: 234 ~ 236 ℃

1H-NMR(200MHz, DMSO-d6) δ 1.05(3H, d, J=6.7Hz), 1.11(3H, d, J=6.7Hz), 2.15(1H, m), 2.26(9H, s), 4.37(2H, J=5.3Hz), 4.51(1H, d, J=17.1Hz), 4.72(1H,d, J=17.1Hz), 5.29(1H, t, J=5.3Hz), 6.72(1H, s), 6.93(1H, s), 7.30(1H, s), 7.51(2H, s), 11.64(1H, s) 1 H-NMR (200 MHz, DMSO-d 6 ) δ 1.05 (3H, d, J = 6.7 Hz), 1.11 (3H, d, J = 6.7 Hz), 2.15 (1H, m), 2.26 (9H, s) , 4.37 (2H, J = 5.3 Hz), 4.51 (1H, d, J = 17.1 Hz), 4.72 (1H, d, J = 17.1 Hz), 5.29 (1H, t, J = 5.3 Hz), 6.72 (1H , s), 6.93 (1H, s), 7.30 (1H, s), 7.51 (2H, s), 11.64 (1H, s)

m/z(EI) 421 (M+).m / z (EI) 421 (M + ).

실시예 77 : 6-(3-클로로-5-메틸벤조일)-1-(2-히드록시메틸-6-메틸피리딘-4-일메틸)-5-이소프로필-2,4-피리미딘디온(화합물 77)의 합성Example 77 6- (3-Chloro-5-methylbenzoyl) -1- (2-hydroxymethyl-6-methylpyridin-4-ylmethyl) -5-isopropyl-2,4-pyrimidinedione ( Synthesis of Compound 77)

상기 실시예 74에서 얻은 화합물 100mg(0.21mmol)을 메탄올 5ml에 녹이고 암모니아수 0.5ml를 가한 다음 상온에서 6시간 교반하였다. 다음에 반응물을 감압농축하고 잔류물을 메탄올-클로로포름에서 재결정하여 78mg(수율 85%)의 표제화합물을 흰색 고체형태로 얻었다.100 mg (0.21 mmol) of the compound obtained in Example 74 was dissolved in 5 ml of methanol, 0.5 ml of ammonia water was added, and the mixture was stirred at room temperature for 6 hours. The reaction was then concentrated under reduced pressure and the residue was recrystallized from methanol-chloroform to give 78 mg (yield 85%) of the title compound as a white solid.

융점 : 238 내지 240 ℃Melting Point: 238-240 ℃

1H-NMR(200MHz, DMSO-d6) δ 1.05(3H, d, J=6.8Hz), 1.10(3H, d, J=6.8Hz), 2.11(1H, m), 2.27(3H, s), 2.49(3H, s), 4.37(2H, d, J=5.7Hz), 4.47(1H, d, J=17.1Hz), 4.82(1H, d, J=17.1Hz), 5.27(1H, t, J=5.7Hz), 6.75(1H, s), 6.93(1H, s), 7.56(1H, s), 7.66(1H, s), 7.74(1H, s), 11.63(1H, s) 1 H-NMR (200 MHz, DMSO-d 6 ) δ 1.05 (3H, d, J = 6.8 Hz), 1.10 (3H, d, J = 6.8 Hz), 2.11 (1H, m), 2.27 (3H, s) , 2.49 (3H, s), 4.37 (2H, d, J = 5.7 Hz), 4.47 (1H, d, J = 17.1 Hz), 4.82 (1H, d, J = 17.1 Hz), 5.27 (1H, t, J = 5.7 Hz), 6.75 (1H, s), 6.93 (1H, s), 7.56 (1H, s), 7.66 (1H, s), 7.74 (1H, s), 11.63 (1H, s)

m/z(EI) 441 (M+).m / z (EI) 441 (M + ).

실시예 78 : 6-(3,5-디메틸벤조일)-5-이소프로필-1-(2-메톡시카르보닐피리딘-4-일메틸)-2,4-피리미딘디온(화합물 78)의 합성Example 78 Synthesis of 6- (3,5-Dimethylbenzoyl) -5-isopropyl-1- (2-methoxycarbonylpyridin-4-ylmethyl) -2,4-pyrimidinedione (Compound 78)

상기 실시예 62에서 얻은 화합물 100mg(0.25mmol)을 메탄올 5ml에 녹이고 무수탄산칼륨 138mg(1mmol)과 증류수 0.5ml를 가한 다음 상온에서 18시간 교반하였다. 이어서, 반응물을 빙초산으로 중화시키고 감압농축한 다음 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(4:1))로 분리하여 74mg(수율 68%)의 표제화합물을 흰색 고체형태로 얻었다.100 mg (0.25 mmol) of the compound obtained in Example 62 was dissolved in 5 ml of methanol, 138 mg (1 mmol) of anhydrous potassium carbonate and 0.5 ml of distilled water were added, followed by stirring at room temperature for 18 hours. The reaction was then neutralized with glacial acetic acid, concentrated under reduced pressure, and the residue was separated by column chromatography (eluent, ethyl acetate: hexane (4: 1)) to yield 74 mg (yield 68%) of the title compound as a white solid.

융점 : 138 내지 140 ℃Melting Point: 138-140 ℃

1H-NMR(200MHz, CDCl3) δ 1.14(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.28-2.38(7H, m), 3.98(3H, s), 4.68(1H, d, J=16.0Hz), 5.00(1H, d, J=16.0Hz), 7.21-7.33(4H, m), 7.73(1H, s), 8.54(1H, m), 9.45(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.14 (3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.9 Hz), 2.28-2.38 (7H, m), 3.98 (3H, s) , 4.68 (1H, d, J = 16.0 Hz), 5.00 (1H, d, J = 16.0 Hz), 7.21-7.33 (4H, m), 7.73 (1H, s), 8.54 (1H, m), 9.45 ( 1H, s)

m/z(EI) 435 (M+).m / z (EI) 435 (M + ).

실시예 79 : 1-(2-카바모일피리딘-4-일메틸)-6-(3,5-디메틸벤조일)-5-이소프로필-2,4-피리미딘디온(화합물 79)의 합성Example 79 Synthesis of 1- (2-carbamoylpyridin-4-ylmethyl) -6- (3,5-dimethylbenzoyl) -5-isopropyl-2,4-pyrimidinedione (Compound 79)

상기 실시예 62에서 얻은 화합물 60mg(0.15mmol)에 진한 황산(1ml)을 가하고 80℃의 oil bath에서 10분간 교반하였다. 이어서, 반응물을 상온으로 냉각시킨다음 10ml의 증류수에 가하였다. 다음에, 생성된 침전물을 여과하여 모으고 증류수와 헥산으로 씻어준 후 감압건조시켜 38mg(수율61%)의 표제화합물을 흰색 고체형태로 얻었다.Concentrated sulfuric acid (1 ml) was added to 60 mg (0.15 mmol) of the compound obtained in Example 62, and stirred for 10 minutes in an oil bath at 80 ° C. The reaction was then cooled to room temperature and added to 10 ml of distilled water. Next, the resulting precipitate was collected by filtration, washed with distilled water and hexane, and dried under reduced pressure to obtain 38 mg (yield 61%) of the title compound as a white solid.

융점 : 295 내지 296 ℃Melting Point: 295-296 ° C

1H-NMR(500MHz, DMSO-d6) δ 1.03(3H, d, J=6.9Hz), 1.10(3H, d, J=6.9Hz), 2.14(1H, m), 2.25(6H, s), 4.67(1H, d, J=17.6Hz), 4.75((1H, d, J=17.6Hz), 7.26(1H, dd, J=5.0Hz, J=1.7Hz), 7.29(1H, s), 7.53(2H, s), 7.63(1H, d, J=2.5Hz), 7.69(1H, s), 8.04(1H, d, J=2.1Hz), 8.40(1H, d, J=5.0Hz), 11.71(1H, s) 1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.03 (3H, d, J = 6.9 Hz), 1.10 (3H, d, J = 6.9 Hz), 2.14 (1H, m), 2.25 (6H, s) , 4.67 (1H, d, J = 17.6 Hz), 4.75 (1H, d, J = 17.6 Hz), 7.26 (1H, dd, J = 5.0 Hz, J = 1.7 Hz), 7.29 (1H, s), 7.53 (2H, s), 7.63 (1H, d, J = 2.5 Hz), 7.69 (1H, s), 8.04 (1H, d, J = 2.1 Hz), 8.40 (1H, d, J = 5.0 Hz), 11.71 (1 H, s)

m/z(EI) 420 (M+).m / z (EI) 420 (M + ).

실시예 80 : 1-(2-카바모일피리딘-4-일메틸)-6-(3-클로로-5-메틸벤조일)-5-이소프로필-2,4-피리미딘디온(화합물 80)의 합성Example 80 Synthesis of 1- (2-carbamoylpyridin-4-ylmethyl) -6- (3-chloro-5-methylbenzoyl) -5-isopropyl-2,4-pyrimidinedione (Compound 80)

상기 실시예 63에서 얻은 화합물 90mg(0.21mmol)에 진한 황산(1ml)을 가하고 80℃의 oil bath에서 10분간 교반하였다. 이어서, 반응물을 상온으로 냉각시킨다음 10ml의 증류수에 가하였다. 다음에, 생성된 침전물을 여과하여 모으고 증류수와 헥산으로 씻어준 후 감압건조시켜 87mg(수율 92%)의 표제화합물을 흰색 고체형태로 얻었다.Concentrated sulfuric acid (1 ml) was added to 90 mg (0.21 mmol) of the compound obtained in Example 63, followed by stirring for 10 minutes in an oil bath at 80 ° C. The reaction was then cooled to room temperature and added to 10 ml of distilled water. Then, the resulting precipitate was collected by filtration, washed with distilled water and hexane and dried under reduced pressure to give 87 mg (yield 92%) of the title compound as a white solid.

융점 : 284 내지 285 ℃Melting Point: 284-285 ° C

1H-NMR(500MHz, DMSO-d6) δ 1.03(3H, d, J=6.8Hz), 1.10(3H, d, J=6.8Hz),2.12(1H, m), 2.29(3H, s), 4.68(1H, d, J=17.3Hz), 4.76(1H, d, J=17.3Hz), 7.29(1H, dd, J=5.0Hz, J=1.7Hz), 7.58(1H, s), 7.63(1H, d, J=2.5Hz), 7.71(1H, s), 7.74(1H, s), 7.80(1H, s), 8.04(1H, d, J=2.5Hz), 8.41(1H, d, J=5.0Hz), 11.72(1H, s) 1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.03 (3H, d, J = 6.8 Hz), 1.10 (3H, d, J = 6.8 Hz), 2.12 (1H, m), 2.29 (3H, s) , 4.68 (1H, d, J = 17.3 Hz), 4.76 (1H, d, J = 17.3 Hz), 7.29 (1H, dd, J = 5.0 Hz, J = 1.7 Hz), 7.58 (1H, s), 7.63 (1H, d, J = 2.5 Hz), 7.71 (1H, s), 7.74 (1H, s), 7.80 (1H, s), 8.04 (1H, d, J = 2.5 Hz), 8.41 (1H, d, J = 5.0 Hz), 11.72 (1H, s)

m/z(EI) 440 (M+).m / z (EI) 440 (M + ).

실시예 81 : 1-(4-아미노벤질)-6-(3,5-디메틸벤조일)-5-이소프로필-2,4-피리미딘디온(화합물 81)의 합성Example 81 Synthesis of 1- (4-aminobenzyl) -6- (3,5-dimethylbenzoyl) -5-isopropyl-2,4-pyrimidinedione (Compound 81)

상기 실시예 38에서 얻은 화합물 50mg(0.12mmol)을 무수메탄올 5ml에 녹이고 PtO2(10mg)를 가한 다음 수소분위기하의 상온에서 4시간 교반하였다. 이어서, 반응물을 celite pad를 통하여 여과하고 감압농축하여 얻은 잔류물을 컬럼크로마토그래피(용출액, 에틸아세테이트:헥산(1:1))로 분리하여 32mg(수율 70%)의 표제화합물을 노란색의 고체형태로 얻었다.50 mg (0.12 mmol) of the compound obtained in Example 38 was dissolved in 5 ml of anhydrous methanol, PtO 2 (10 mg) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. Subsequently, the reaction product was filtered through a celite pad and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, ethyl acetate: hexane (1: 1)) to give 32 mg (yield 70%) of the title compound as a yellow solid. Got it.

융점 : 173 내지 175 ℃Melting Point: 173 ~ 175 ℃

1H-NMR(200MHz, CDCl3) δ 1.07(3H, d, J=6.9Hz), 1.20(3H, d, J=6.9Hz), 2.20-2.40(7H, m), 3.57(2H, s), 4.46(1H, d, J=15.2Hz), 5.00(1H, d, J=15.2Hz), 6.35(2H, d, J=8.3Hz), 6.81(2H, d, J=8.3Hz), 7.21(1H, s), 7.26(2H, s), 8.86(1H, s) 1 H-NMR (200 MHz, CDCl 3 ) δ 1.07 (3H, d, J = 6.9 Hz), 1.20 (3H, d, J = 6.9 Hz), 2.20-2.40 (7H, m), 3.57 (2H, s) , 4.46 (1H, d, J = 15.2 Hz), 5.00 (1H, d, J = 15.2 Hz), 6.35 (2H, d, J = 8.3 Hz), 6.81 (2H, d, J = 8.3 Hz), 7.21 (1H, s), 7.26 (2H, s), 8.86 (1H, s)

m/z(EI) 391 (M+).m / z (EI) 391 (M + ).

항바이러스 활성 및 세포독성 시험Antiviral Activity and Cytotoxicity Test

본 발명의 화합물의 효과를 알아보기 위해 공지된 방법(J. Med. Chem., 34, 349(1991))에 따라 다음과 같이 시험관내 HIV-1 억제 효과시험을 실시하였다. 숙주 세포로서 MT-4 세포를 사용하여 본 발명의 화합물이 바이러스에 감염된 MT-4 세포의 세포독성을 저해하는 정도를 조사하였다.In order to determine the effect of the compound of the present invention was carried out in vitro HIV-1 inhibitory effect test according to a known method ( J. Med. Chem., 34 , 349 (1991)). MT-4 cells were used as host cells to investigate the extent to which the compounds of the present invention inhibit the cytotoxicity of virus-infected MT-4 cells.

먼저, 배양 배지에 MT-4 세포를 1× 104세포/㎖의 농도로 분산시킨 다음, 500 TCID50(세포의 50%가 감염되는 농도)/웰이 되도록 HIV-1을 접종하였다. 접종 즉시 본 발명의 화합물의 시료가 들어있는 편편한 미세역가판에 세포분산액을 100㎕씩 옮기고 약 4일 내지 5일간 37 ℃에서 배양한 후, MTT 방법을 이용하여 항바이러스 활성을 판정하였다. 동시에, mock-감염된 숙주 세포의 생존성을 MTT 방법으로 측정함으로써 세포독성도 판정하였다. 참고 화합물로는 MKC-442(6-벤질-1-에톡시메틸-5-이소프로필우라실)를 사용하였다. 시험결과를 하기 표 4에 요약하였다.First, MT-4 cells were dispersed in the culture medium at a concentration of 1 × 10 4 cells / ml, and then inoculated with HIV-1 to 500 TCID 50 (a concentration at which 50% of cells are infected) / well. Immediately after inoculation, 100 μl of the cell dispersion was transferred to a flat microtiter plate containing a sample of the compound of the present invention, and cultured at 37 ° C. for about 4 days to 5 days, and then the antiviral activity was determined using the MTT method. At the same time, cytotoxicity was also determined by measuring the viability of mock-infected host cells by MTT method. MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil) was used as a reference compound. The test results are summarized in Table 4 below.

실시예 번호(화합물)Example Number (Compound) CD50(㎍/㎖)* CD 50 (μg / mL) * ED50(㎍/㎖)** ED 50 (μg / ml) ** S.I. (CD50/ED50)*** SI (CD 50 / ED 50 ) *** 1One 22.622.6 0.00260.0026 8,6008,600 22 27.227.2 0.00360.0036 7,5787,578 33 26.126.1 0.00550.0055 4,7884,788 44 64.064.0 0.00270.0027 23,94023,940 55 18.718.7 0.0120.012 1,5531,553 66 28.228.2 0.01270.0127 2,2152,215 77 22.722.7 0.00340.0034 6,5976,597 88 28.1628.16 0.0080.008 3,4513,451 99 40.540.5 0.01190.0119 3,4013,401 1010 51.751.7 0.01010.0101 5,1335,133 1111 47.447.4 0.01780.0178 2,6582,658 1212 38.938.9 0.05420.0542 716716 1313 42.342.3 0.01240.0124 3,4143,414 1414 29.8129.81 0.0490.049 612612 1515 49.8749.87 0.0530.053 943943 1616 50.650.6 0.06010.0601 841841 1717 74.374.3 0.1120.112 663663 1818 93.293.2 0.11890.1189 784784 1919 11.2811.28 0.0030.003 3,3943,394 2020 32.932.9 0.0120.012 2,7582,758 2121 55.0755.07 0.00230.0023 23,50123,501 2222 92.892.8 0.0020.002 48,30548,305 MKC-442MKC-442 27.727.7 0.0050.005 5,5445,544 *CD50: MT-4 세포에 대한 50% 세포손상 농도**ED50: HIV-1의 증식을 50% 억제하는 농도***S.I. : 선택도 = (CD50/ED50) * CD 50 : 50% cell damage concentration on MT-4 cells ** ED 50 : 50% inhibition of HIV-1 proliferation *** SI: Selectivity = (CD 50 / ED 50 )

실시예 번호(화합물)Example Number (Compound) CD50(㎍/㎖)* CD 50 (μg / mL) * ED50(㎍/㎖)** ED 50 (μg / ml) ** S.I. (CD50/ED50)*** SI (CD 50 / ED 50 ) *** 2323 52.152.1 0.0030.003 15,24515,245 2424 15.815.8 0.0100.010 1,6281,628 2525 100100 0.0180.018 5,5575,557 2626 6.56.5 0.0030.003 2,1122,112 2727 8.58.5 0.0020.002 5,7475,747 2828 12.512.5 0.0040.004 3,5163,516 2929 44.944.9 1.8671.867 2424 3030 52.352.3 1.9351.935 2727 3131 11.711.7 1.81.8 66 3232 40.440.4 0.0030.003 12,03912,039 3333 57.157.1 0.0110.011 5,0735,073 3434 37.437.4 0.0140.014 2,6632,663 3535 100100 0.06060.0606 1,6501,650 3636 8.018.01 0.0040.004 2,1702,170 3737 5.785.78 0.0030.003 2,0662,066 3838 5.655.65 0.0050.005 1,1721,172 3939 7.467.46 0.0030.003 2,6542,654 4040 7.977.97 0.03480.0348 229229 4141 4.634.63 0.0090.009 497497 4242 2.142.14 0.0020.002 921921 4343 7.167.16 0.00350.0035 2,0572,057 4444 8.178.17 1.801.80 55 MKC-442MKC-442 27.727.7 0.0050.005 5,5445,544 *CD50: MT-4 세포에 대한 50% 세포손상 농도**ED50: HIV-1의 증식을 50% 억제하는 농도***S.I. : 선택도 = (CD50/ED50) * CD 50 : 50% cell damage concentration on MT-4 cells ** ED 50 : 50% inhibition of HIV-1 proliferation *** SI: Selectivity = (CD 50 / ED 50 )

실시예 번호(화합물)Example Number (Compound) CD50(㎍/㎖)* CD 50 (μg / mL) * ED50(㎍/㎖)** ED 50 (μg / ml) ** S.I. (CD50/ED50)*** SI (CD 50 / ED 50 ) *** 4545 100100 0.00980.0098 10,17010,170 4646 22.922.9 0.00240.0024 9,6919,691 4747 93.7593.75 0.00270.0027 35,13335,133 4848 12.0712.07 0.00300.0030 4,0214,021 4949 64.3964.39 0.00760.0076 8,4408,440 5050 47.6847.68 0.00290.0029 16,35116,351 5151 17.117.1 0.00100.0010 17,81217,812 5252 14.314.3 0.00100.0010 14,68414,684 5353 37.837.8 0.00310.0031 12,11012,110 5454 8.78.7 0.00170.0017 4,9924,992 5555 9.99.9 0.00100.0010 10,27410,274 5656 87.287.2 0.00440.0044 19,64819,648 5757 9.469.46 0.00280.0028 3,4113,411 5858 36.0336.03 0.00250.0025 14,30014,300 5959 8.688.68 0.00210.0021 4,1264,126 6060 17.517.5 0.00260.0026 6,7396,739 6161 37.537.5 0.01510.0151 2,4752,475 6262 9.159.15 0.00160.0016 5,8585,858 6363 8.558.55 0.00290.0029 2,9662,966 6464 4646 0.00960.0096 4,8014,801 6565 44.0844.08 0.00750.0075 5,9165,916 6666 100100 0.080.08 1,2871,287 MKC-442MKC-442 27.727.7 0.0050.005 5,5445,544 *CD50: MT-4 세포에 대한 50% 세포손상 농도**ED50: HIV-1의 증식을 50% 억제하는 농도***S.I. : 선택도 = (CD50/ED50) * CD 50 : 50% cell damage concentration on MT-4 cells ** ED 50 : 50% inhibition of HIV-1 proliferation *** SI: Selectivity = (CD 50 / ED 50 )

실시예 번호(화합물)Example Number (Compound) CD50(㎍/㎖)* CD 50 (μg / mL) * ED50(㎍/㎖)** ED 50 (μg / ml) ** S.I. (CD50/ED50)*** SI (CD 50 / ED 50 ) *** 6767 54.554.5 0.420.42 130130 6868 56.956.9 0.01450.0145 3,9283,928 6969 48.2548.25 0.01250.0125 3,8533,853 7070 25.8425.84 0.00550.0055 4,7124,712 7171 25.4425.44 0.00820.0082 3,0923,092 7272 38.4938.49 0.00880.0088 4,3654,365 7373 39.6539.65 0.00670.0067 5,9035,903 7474 28.8128.81 0.01340.0134 2,1522,152 7575 42.0642.06 0.00310.0031 13,44413,444 7676 38.3938.39 0.00840.0084 4,5614,561 7777 23.5123.51 0.01150.0115 2,0522,052 7878 40.7940.79 0.00750.0075 5,4145,414 7979 100100 0.00910.0091 10,94210,942 8080 27.8327.83 0.01110.0111 2,5072,507 8181 9.639.63 0.0150.015 648648 MKC-442MKC-442 27.727.7 0.0050.005 5,5445,544 *CD50: MT-4 세포에 대한 50% 세포손상 농도**ED50: HIV-1의 증식을 50% 억제하는 농도***S.I. : 선택도 = (CD50/ED50) * CD 50 : 50% cell damage concentration on MT-4 cells ** ED 50 : 50% inhibition of HIV-1 proliferation *** SI: Selectivity = (CD 50 / ED 50 )

내성 HIV-1에 대한 항바이러스 활성Antiviral activity against resistant HIV-1

항-HIV-1 비뉴클레오시드, 예를 들면 네비라핀에 대해 높은 내성을 갖는 대표적인 내성 HIV-1인 Y181C에 대한 본 발명 화합물의 항바이러스 활성을 MTT 방법에 의해 측정하였다. 참고 화합물로는 MKC-442를 인용하였다. 대표적인 시험결과를 하기 표 5에 요약하였다.The antiviral activity of the compounds of the invention against Y181C, a representative resistant HIV-1 with high resistance to anti-HIV-1 nonnucleosides such as nevirapine, was determined by the MTT method. MKC-442 was cited as a reference compound. Representative test results are summarized in Table 5 below.

화합물compound EC50(μM)* EC 50 (μM) * 1One 0.005 - 0.0140.005-0.014 44 0.010 - 0.0410.010-0.041 MKC-442MKC-442 13.4** 13.4 ** *EC50: 내성 HIV-1의 증식을 50% 억제하는 농도**참고문헌 :J. Med. Chem., 42, 4500(1999) * EC 50 : Concentration that inhibits proliferation of resistant HIV-1 by 50% ** Reference: J. Med. Chem., 42 , 4500 (1999)

상기 결과로부터, 본 발명의 화합물은 세포독성은 낮으면서 야생형 HIV-1 및 내성 HIV-1 억제효과는 우수함을 알 수 있다.From the above results, it can be seen that the compound of the present invention has a low cytotoxicity and an excellent inhibitory effect on wild type HIV-1 and resistant HIV-1.

이상에서 살펴본 바와같이, 본 발명의 신규한 2,4-피리미딘디온 유도체들은 야생형 HIV-1 및 내성 HIV-1 에 대한 생리 활성도가 높고 독성이 낮아서 후천성 면역결핍증(AIDS) 치료제로 유용하다.As described above, the novel 2,4-pyrimidinedione derivatives of the present invention have high physiological activity and low toxicity against wild type HIV-1 and resistant HIV-1, and thus are useful as a treatment for acquired immunodeficiency syndrome (AIDS).

Claims (7)

하기 일반식 (I)의 화합물 또는 이의 약제학적으로 허용되는 염:A compound of formula (I) or a pharmaceutically acceptable salt thereof: 화학식 1Formula 1 상기식에서,In the above formula, R1은 피리딜기 또는 그 유도체를 나타내고;R 1 represents a pyridyl group or a derivative thereof; R2는 C1-C6의 알킬기를 나타내며;R 2 represents an alkyl group of C 1 -C 6 ; R3및 R4는 각각 독립적으로 수소원자, 할로겐원자, 시아노기, 니트로기, 하나이상의 할로겐원자로 치환되거나 치환되지 않은 C1-C3의 알킬기 또는 C1-C3의 알콕시기를 나타내며;R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an alkyl group of C 1 -C 3 which is unsubstituted or substituted with one or more halogen atoms, or an alkoxy group of C 1 -C 3 ; A는 O 또는 S를 나타내고;A represents O or S; Z는 O, S, C=O, NH 또는 CH2를 나타낸다.Z represents O, S, C═O, NH or CH 2 . 제 1 항에 있어서,The method of claim 1, R1이 피리딘-2-일기, 피리딘-3-일기, 피리딘-4-일기, N-옥소-피리딘-2-일기, N-옥소-피리딘-3-일기 또는 N-옥소-피리딘-4-일기; 할로겐원자, C1-C3의 알킬기, 시클로프로필기, 시아노기, 니트로기, 히드록시기, 티오히드록시기, 아지도기, 메톡시기, 옥시미노기, C1-C3의 아실옥시메틸기, 히드록시메틸기, 아지도메틸기, 아미노메틸기, 트리플로로메틸기, 카르복시기, 메톡시카르보닐기, 아미노기, 히드록시에틸아미노기, 시클로프로필아미노기, C1-C3의 알킬아미노기, 디(C1-C3의 알킬)아미노기, 트리플루오로아세트아미도기, C1-C3의 아실아미도기, 카바모일기, 히드록시에틸카바모일기, 시클로프로필카바모일기, C1-C3의 알킬카바모일기, 히드라지노기 또는 1,1-디메틸히드라지노기로 각각 독립적으로 한 개 또는 두 개 치환된 피리딘-2-일기, 피리딘-3-일기 또는 피리딘-4-일기를 나타내고;R 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxo-pyridin-2-yl, N-oxo-pyridin-3-yl or N-oxo-pyridin-4-yl ; Halogen atom, C 1 -C 3 alkyl group, cyclopropyl group, cyano group, nitro group, hydroxy group, thiohydroxy group, azido group, methoxy group, oxymino group, C 1 -C 3 acyloxymethyl group, hydroxymethyl group, Azidomethyl group, aminomethyl group, trifluoromethyl group, carboxyl group, methoxycarbonyl group, amino group, hydroxyethylamino group, cyclopropylamino group, C 1 -C 3 alkylamino group, di (C 1 -C 3 alkyl) amino group, Trifluoroacetamido group, C 1 -C 3 acyl amido group, carbamoyl group, hydroxyethyl carbamoyl group, cyclopropyl carbamoyl group, C 1 -C 3 alkyl carbamoyl group, hydrazino group or 1 Each independently represents one or two substituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl groups; R2는 이소프로필기 또는 에틸기를 나타내며;R 2 represents an isopropyl group or an ethyl group; R3및 R4는 각각 독립적으로 수소원자, 할로겐원자, 시아노기, 니트로기, 메틸기, 플로로메틸기, 트리플로로메틸기 또는 메톡시기를 나타내며;R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a methyl group, a phlolomethyl group, a trifluoromethyl group, or a methoxy group; A는 O 또는 S를 나타내고;A represents O or S; Z는 O, S, C=O, NH 또는 CH2를 나타낸다.Z represents O, S, C═O, NH or CH 2 . 제 1 항에 있어서,The method of claim 1, R1이 피리딘-2-일기, 피리딘-3-일기, 피리딘-4-일기, 피리미딘-4-일기, N-옥소-피리딘-2-일기, N-옥소-피리딘-3-일기 또는 N-옥소-피리딘-4-일기; 할로겐원자, C1-C3의 알킬기, 시아노기, 니트로기, 메톡시기, 아세톡시메틸기, 히드록시메틸기, 트리플로로메틸기, 카르복시기, 메톡시카르보닐기 또는 카바모일기로 각각 독립적으로 한 개 또는 두 개 치환된 피리딘-2-일기, 피리딘-3-일기 또는 피리딘-4-일기를 나타내고;R 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, N-oxo-pyridin-2-yl, N-oxo-pyridin-3-yl or N- Oxo-pyridin-4-yl group; One or two halogen atoms, C 1 -C 3 alkyl groups, cyano groups, nitro groups, methoxy groups, acetoxymethyl groups, hydroxymethyl groups, trifluoromethyl groups, carboxyl groups, methoxycarbonyl groups or carbamoyl groups each independently A dog substituted pyridin-2-yl group, a pyridin-3-yl group or a pyridin-4-yl group; R2는 이소프로필기 또는 에틸기를 나타내며;R 2 represents an isopropyl group or an ethyl group; R3및 R4는 각각 독립적으로 수소원자, 할로겐원자, 시아노기, 니트로기, 메틸기, 플로로메틸기, 트리플로로메틸기 또는 메톡시기를 나타내며;R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a methyl group, a phlolomethyl group, a trifluoromethyl group, or a methoxy group; A는 O를 나타내고;A represents O; Z는 O, S, C=O, NH 또는 CH2를 나타낸다.Z represents O, S, C═O, NH or CH 2 . 삭제delete 염기 존재하에 하기 일반식 (II)의 화합물을 하기 일반식 (III)의 화합물과 커플링반응시키는 단계를 포함하는 제 1 항에 따른 일반식 (I)의 화합물의 제조방법:A process for preparing a compound of formula (I) according to claim 1 comprising coupling a compound of formula (II) to a compound of formula (III) in the presence of a base: 화학식 2Formula 2 화학식 3Formula 3 R1-CH2-Y (III)R 1 -CH 2 -Y (III) 상기식에서,In the above formula, R1, R2, R3, R4및 A는 제 1 항에서 정의한 바와 같고;R 1 , R 2 , R 3 , R 4 and A are as defined in claim 1; Z'는 제 1 항에 정의된 Z와 동일하나, 단 A가 산소원자인 경우 아세트아미도기일 수 있으며;Z 'is the same as Z as defined in claim 1, provided that A may be an acetamido group when A is an oxygen atom; Y는 할로겐원자, 메탄술포닐기, 톨루엔술포닐기 또는 트리플루오로메탄술포닐기이다.Y is a halogen atom, a methanesulfonyl group, a toluenesulfonyl group or a trifluoromethanesulfonyl group. 하기 일반식 (II)의 화합물;Compounds of the following general formula (II); 화학식 2Formula 2 상기식에서,In the above formula, R'2는 에틸기 또는 이소프로필기이고;R ' 2 is an ethyl group or isopropyl group; R'3은 니트로기, 트리플로로메틸기 또는 시아노기이고;R ' 3 is a nitro group, a trichloromethyl group or a cyano group; R'4는 메틸기이고;R ' 4 is a methyl group; Z"는 C=O, NH 또는 아세트아미도기이다.Z ″ is a C═O, NH or acetamido group. 활성성분으로서 항바이러스 효과량의 제 1 항에 따른 일반식 (I)의 화합물 또는 이의 약제학적으로 허용되는 염, 및 약제학적으로 허용되는 담체를 포함하는 항바이러스제 조성물.An antiviral composition comprising as an active ingredient an effective amount of an antiviral compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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