KR100197791B1 - Novel antiviral 6-substituted pyrimidinedione homo-carbocyclic nucleocide derivative and its preparation - Google Patents

Novel antiviral 6-substituted pyrimidinedione homo-carbocyclic nucleocide derivative and its preparation Download PDF

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KR100197791B1
KR100197791B1 KR1019960047458A KR19960047458A KR100197791B1 KR 100197791 B1 KR100197791 B1 KR 100197791B1 KR 1019960047458 A KR1019960047458 A KR 1019960047458A KR 19960047458 A KR19960047458 A KR 19960047458A KR 100197791 B1 KR100197791 B1 KR 100197791B1
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group
compound
pyrimidinedione
methyl
cyclopent
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KR1019960047458A
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KR970061875A (en
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조의환
정순간
김중영
권호석
이순환
이재웅
주정호
김병철
강동욱
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최승주
삼진제약주식회사
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Priority to BRPI9604907A priority Critical patent/BRPI9604907B8/en
Priority to RU97118134A priority patent/RU2138487C1/en
Priority to AU12124/97A priority patent/AU710490B2/en
Priority to JP9530013A priority patent/JP3049095B2/en
Priority to US08/945,121 priority patent/US5922727A/en
Priority to DE69628750T priority patent/DE69628750T2/en
Priority to CA002217026A priority patent/CA2217026C/en
Priority to CN96193400A priority patent/CN1092647C/en
Priority to EP96943370A priority patent/EP0827498B1/en
Priority to PCT/KR1996/000265 priority patent/WO1997030979A1/en
Priority to AT96943370T priority patent/ATE243202T1/en
Priority to IDP970469A priority patent/ID15963A/en
Priority to TW086102026A priority patent/TW494098B/en
Priority to ARP970100732A priority patent/AR005975A1/en
Publication of KR970061875A publication Critical patent/KR970061875A/en
Priority to MX9708110A priority patent/MX9708110A/en
Publication of KR100197791B1 publication Critical patent/KR100197791B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 항바이러스제, 특히 후천성 면역결핍증(AIDS) 치료제로 유용한 다음 일반 구조식(I)로 나타내어지는 바의, 6위치에 치환된 피리미딘디온 호모 카보사이클릭 뉴클레오시드 유도체, 그의 약제학적으로 허용 가능한 염 및 그 제조 방법 및 그것을 활성성분으로 함유하는 약학 조성물에 관한 것이다.The present invention relates to pyrimidinedione homocarbocyclic nucleoside derivatives substituted at the 6 position as represented by the following general structural formula (I) useful as an antiviral agent, particularly for the treatment of acquired immunodeficiency syndrome (AIDS) And a pharmaceutical composition containing it as an active ingredient.

일반 구조식(I)General formula (I)

(Sub)cycloalk(en)yl는그리고이다.(Sub) cycloalk (en) yl is And to be.

상기 일반 구조식(I)에서 R1, R2, R3는 수소원자, 할로겐 원자, C1-C10의 알킬기, C1-C10의 티오 알킬기, C3-C8의 치환 또는 비치환 사이클릭 알킬기, 불포화 알킬기, 치환된 알킬, 아릴 히드록시기, C1-C10의 알킬 아민기, 니트로기, C1-C4의 저급에스테르기, C1-C4의 저급알콕시기, C1-C4의 저급싸이오 알콕시기, R4,R5는 각각 수소원자, 히드록시, 메틸, 보호된 히드록시 메틸기이며, Z는 산소원자, 황원자, 탄소원자 또는 카르보닐기를 나타내며, X는 산소원자, 황원자이고, 그리고 n은 0-3의 정수이다.In the above general formula (I), R 1 , R 2 and R 3 are each a hydrogen atom, a halogen atom, a C 1 -C 10 alkyl group, a C 1 -C 10 thioalkyl group, a C 3 -C 8 substituted or unsubstituted cyclic alkyl group, lower alkoxy of unsaturated alkyl, substituted alkyl, aryl, hydroxy, C 1 -C 10 alkyl amine group, a nitro group, a lower ester of a C 1 -C 4, C 1 -C 4 group, C 1 -C lower thio alkoxy group of 4, R 4, R 5 are each a hydrogen atom, hydroxy, methyl, protected hydroxy and hydroxy-methyl group, Z represents an oxygen atom, a sulfur atom, a carbon atom or a carbonyl group, X is an oxygen atom, a sulfur atom And n is an integer of 0-3.

Description

[발명의 명칭][Title of the Invention]

신규 항바이러스성 6위치에 치환된 피리미딘디온 호모 카보사이클릭 뉴클레오시드 유도체 및 그의 제조 방법Pyrimidinedione homocarbocyclic nucleoside derivatives substituted at the novel antiviral 6-position and methods for producing the same

[발명의 상세한 설명]DETAILED DESCRIPTION OF THE INVENTION [

본 발명은 항바이러스제, 특히 후천성 면역결핍증(AIDS) 치료제로 유용한 6위치에 치환된 피리미딘디온 호모 카보사이클릭 뉴클레오시드 유도체 및 그의 약제학적으로 허용 가능한 염에 관한 것이다. 본 발명은 또한 그러한 화합물을 제조하는 방법 및 그러한 화합물을 활성성분으로 함유하는 약학 조성물에 관한 것이다.The present invention relates to a pyrimidinedione homocarbocyclic nucleoside derivative substituted at the 6-position useful as an antiviral agent, particularly for the treatment of acquired immunodeficiency syndrome (AIDS), and a pharmaceutically acceptable salt thereof. The invention also relates to a process for preparing such compounds and to pharmaceutical compositions containing such compounds as active ingredients.

현재, 후천성면역결핍증(AIDS) 치료용으로 사용되고 있는 화학요법제로는 AZT, DDC, DDI 및 D4T가 있다. 이러한 화학요법제들은 바이러스 복제를 방해하는 작용기전을 가는 것으로 알려져 있고, 약물 독성 및 약물에 대한 내성의 발현이 지적되고 있다. 따라서 상기 문제점을 해결하기 위한 화학요법제를 개발하고자 많은 연구가 진행되고 있다. 후천성 면역결핍증을 치료하기 위한 항바이러스제 중 피리미딘 6위치에 치환된 뉴클레오시드 화합물 연구가 매우 활발히 진행되고 있으나, N-1 위치에 호모 카보사이클릭 부분을 치환한 유도체들에 대하여 아직까지 연구된 바가 없다. 따라서 본 발명자는 이들 화합물을 합성하여 약효실험을 진행시킨 결과 HIV(Human immunodeficiency virus)에 강한 억제효과 또는 항바이러스 작용을 가졌고, 독성이 적다는 사실을 발견하게 되었다.Currently, AZT, DDC, DDI and D4T are the chemotherapeutic agents that have been used for the treatment of AIDS. These chemotherapeutic agents are known to have a mechanism of action that interferes with viral replication, and the manifestation of drug toxicity and resistance to drugs is pointed out. Therefore, much research has been conducted to develop a chemotherapeutic agent to solve the above problems. Studies on nucleoside compounds substituted at the pyrimidine 6 position in antiviral drugs for treating AIDS have been actively conducted, but studies have been made on derivatives of homocarbocyclic moieties substituted at the N-1 position There is no bar. Therefore, the inventors of the present invention synthesized these compounds and found that they have a strong inhibitory effect or antiviral action on HIV (human immunodeficiency virus) and are less toxic as a result of the pharmacological test.

본 발명은 HIV에 대한 강한 생리활성도를 갖는 6위치에 치환된 피리미딘디온 호모 카보사이클릭 뉴클레오시드 유도체 및 그의 약제학적으로 허용되는 염을 제공하는데 있다.The present invention provides a pyrimidinedione homocarbocyclic nucleoside derivative substituted at the 6-position having a strong physiological activity against HIV and a pharmaceutically acceptable salt thereof.

일반 구조식(I)General formula (I)

(Sub)cycloalk(en)yl는그리고이다.(Sub) cycloalk (en) yl is And to be.

상기 일반 구조식(I)에서 R1, R2, R3는 수소원자, 할로겐 원자, C1-C10의 알킬기, C1-C10의 티오 알킬기, C3-C8의 치환 또는 비치환 사이클릭 알킬기, 불포화 알킬기, 치환된 알킬, 아릴 히드록시기, C1-C10의 알킬 아민기, 니트로기, C1-C4의 저급에스테르기, C1-C4의 저급알콕시기, C1-C4의 저급싸이오 알콕시기, R4,R5는 각각 수소원자, 히드록시, 메틸, 보호된 히드록시 메틸기이며, Z는 산소원자, 황원자, 탄소원자, 또는 카르보닐기를 나타내며, X는 산소원자, 황원자이고, 그리고 n은 1-3의 정수이다.In the above general formula (I), R 1 , R 2 and R 3 are each a hydrogen atom, a halogen atom, a C 1 -C 10 alkyl group, a C 1 -C 10 thioalkyl group, a C 3 -C 8 substituted or unsubstituted cyclic alkyl group, lower alkoxy of unsaturated alkyl, substituted alkyl, aryl, hydroxy, C 1 -C 10 alkyl amine group, a nitro group, a lower ester of a C 1 -C 4, C 1 -C 4 group, C 1 -C lower thio alkoxy group of 4, R4, R 5 are each a hydrogen atom, hydroxy, methyl, protected hydroxy and hydroxy-methyl group, Z represents an oxygen atom, a sulfur atom, a carbon atom, or a carbonyl group, X is an oxygen atom, a sulfur atom And n is an integer of 1-3.

C1-C10의 알킬기란 메틸, 에틸, 프로필, 부틸, 이소부틸, t-부틸, 펜틸, 이소펜틸, 헥실, 헵틸, 옥틸, 2-메틸-펜틸 등과 같은 직쇄 또는 분지상의 알킬기를 의미한다.The C 1 -C 10 alkyl group means a straight or branched alkyl group such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, .

C1-C10의 티오알킬기란 메틸티오, 에틸티오, 프로필티오, 부틸티오, 이소부틸티오, t-부틸티오, 펜틸티오, 이소텐틸티오, 헥실티오, 헵틸티오, 옥틸티오, 2-메틸-펜틸티오등과 같은 직쇄 또는 분지상의 티오알킬기를 의미한다.The C 1 -C 10 thioalkyl group is preferably a methylthio group such as methylthio, ethylthio, propylthio, butylthio, isobutylthio, t-butylthio, pentylthio, isotentylthio, hexylthio, heptylthio, Pentylthio, and the like.

C3-C8의 치환 또는 비치환 사이클릭 알킬기란 사이클릭 프로필, 사이클릭 부틸, 사이클릭 펜틸, 메틸사이클릭 프로필, 메틸사이클릭 부틸, 메틸 사이클릭 펜틸 등을 의미한다.The C 3 -C 8 substituted or unsubstituted cyclic alkyl group means cyclic propyl, cyclic butyl, cyclic pentyl, methyl cyclopropyl, methyl cyclic butyl, methyl cyclopentyl and the like.

C1-C4의 저급 에스테르기란 카르복실기가 저급알킬기에 의하여 에스테르화된 기를 의미한다.The lower ester group of C 1 -C 4 means a group in which the carboxyl group is esterified by a lower alkyl group.

C1-C10의 알콕시기란 메톡시, 에톡시, 프로필옥시, 부틸옥시, 이소부틸옥시, t-부틸옥시기등을 말한다.The C 1 -C 10 alkoxy group refers to methoxy, ethoxy, propyloxy, butyloxy, isobutyloxy, t-butyloxy, and the like.

C1-C10의 티오알콕시기란 티오메톡시, 티오에톡시, 티오프로폭시, 티오이소프로폭시, 티오부톡시, 티오이소부톡시, 티오 t-부톡시기등을 말한다.The C 1 -C 10 thioalkoxy group refers to thiomethoxy, thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy, thioisobutoxy, thio-butoxy groups and the like.

C1-C10의 알킬 아민기란 메틸아민, 에틸아민, 프로필아민, 부틸아민, 펜틸아민, 이소프로필아민, t-부틸아민 등을 말한다.Group refers to an alkyl amine of the C 1 -C 10 refers to such as methylamine, ethylamine, propylamine, butylamine, pentylamine, isopropylamine, t- butylamine.

본 발명자들은 항바이러스 활성을 가지는 화합물에 관하여 오랜동안 연구하여 왔다. 그 결과 본 발명자들은 일반 구조식(I)의 화합물, 그 산부가염들이 탁월한 항바이러스 효과를 가지며, 독성이 극히 적은 놀라운 사실을 발견하여 본 발명을 완성하였다.The present inventors have been studying compounds having antiviral activity for a long time. As a result, the present inventors have found the surprising fact that the compounds of general formula (I), the acid addition salts thereof, have an excellent antiviral effect and extremely low toxicity, and have completed the present invention.

따라서 본 발명의 목적은 탁월한 항바이러스 효과를 가지며 독성이 적은 일반 구조식(I)의 화합물 및 그 산부가염을 제공하는 것이다.It is therefore an object of the present invention to provide a compound of general formula (I) having an excellent antiviral effect and low toxicity and an acid addition salt thereof.

본 발명의 다른 목적은 일반 구조식(I)의 화합물 및 그 산부가염을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a compound of general formula (I) and a process for preparing the acid addition salt thereof.

본 발명의 화합물들은 약학적으로 허용되는 부형제등과 혼합하여 약학적으로 통상으로 사용되는 약학적 제제의 제조방밥에 다라서 약학적 제제를 제조하여 여러종류의 바이러스 예방과 치료에 사용될 수 있다. 그러므로 본 발명의 또 다른 목적은 일반 구조식(I)의 화합물을 유효성분으로 함유하는 약학적 제제를 제공하는 것이다.The compounds of the present invention can be used in the prevention and treatment of various kinds of viruses by preparing pharmaceutical preparations in addition to pharmaceutical preparations commonly used in pharmaceutical preparations mixed with pharmaceutically acceptable excipients and the like. Therefore, another object of the present invention is to provide a pharmaceutical preparation containing the compound of general formula (I) as an active ingredient.

본 발명의 화합물(I)과 반응하여 산부가염을 형성할 수 있는 산은 약학적으로 허용될 수 있는 무기 또는 유기산이며, 염산, 브롬산, 황산, 인산, 질산 등과 같은 무기산; 포름산, 초산, 삼불화초산, 프로피온산, 석신산, 시트르산, 말레인산, 말론산과 같은 유기산; 세린, 시스테린, 시스틴, 아스파라긴산, 글루타민산, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산; 설폰산, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산이 사용될 수 있다.The acid which can be reacted with the compound (I) of the present invention to form an acid addition salt is a pharmaceutically acceptable inorganic or organic acid, and includes inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; Organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, citric acid, maleic acid and malonic acid; Amino acids such as serine, cysteine, cystine, aspartic acid, glutamic acid, lysine, arginine, tyrosine, proline and the like; Sulfonic acids such as sulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like can be used.

본 발명에서 일반 구조식(I)의 화합물을 유효성분으로 함유하는 약학적 제제의 제조에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습용제, 유화제, 등장화제, 흡착제, 봉해제, 산화방지제, 방부제, 활택제, 충진제, 방향제 등이 사용될 수 있으며, 예를들면, 락토스, 엑스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 트라가칸트 고무, 메틸 셀룰로오스, 소디움카르복실메틸셀룰로오스, 아가, 알지닌산, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼륨, 오렌지엣센스, 딸기엣센스, 바닐라 향 등을 들 수 있다.In the present invention, excipients, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, releasing agents, releasing agents, It is possible to use an antioxidant, an antiseptic, a lubricant, a filler, a fragrance and the like, for example, lactose, exstrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, , Methylcellulose, sodium carboxymethylcellulose, agar, arginic acid, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla flavor and the like.

본 발명의 일반 구조식(I)의 화합물 상용량은 환자의 나이, 성별, 질병의 정도 등에 따라서 달라질 수 있으나, 일일 1mg 내지 5000mg을 일회 내지 수회 투여할 수 있다.The amount of the compound of the general formula (I) of the present invention may vary depending on the patient's age, sex, disease severity, etc., and may be administered once to several times per day from 1 mg to 5000 mg.

상기 반응식에서, (Sub)cycloalk(en)yl, R1, R2, R3, X, Z, n 등은 전술한 바와 같으며, Lie은 할로겐 원자, 알킬설포닐, 아릴설포닐 같은 이탈기이다.In the above reaction formula, (Sub) cycloalk (en) yl, R 1 , R 2 , R 3 , X, Z, n and the like are as described above. Lie is a leaving group such as a halogen atom, an alkylsulfonyl, to be.

일반 구조식(a)의 화합물을 염기하에서 일반 구조식(b)의 화합물과 반응시켜 일반 구조식(I)의 화합물을 제조한다.Compounds of general formula (I) are prepared by reacting a compound of general formula (a) with a compound of general formula (b) under base.

사용된 염기로는 탄산수소나트륨, 탄산나트륨, 탄산칼륨, 수소화나트륨, 수소화 칼륨, 세슘카보네이트 등을 사용하고, 통상의 유기용매는 디메틸 포름이미드를 사용함이 바람직하다. 이 반응은 10℃-100℃에서 5 내지 48시간 반응시킨다.As the base used, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, cesium carbonate and the like are preferably used, and dimethylformamide is preferably used as an ordinary organic solvent. This reaction is carried out at 10 ° C to 100 ° C for 5 to 48 hours.

R4, R5와 n은 전술한 바와 같으며, m은 0 내지 2의 정수이다. 환원제는 소디움보로하이드라이드, 리튬, 알루미늄 하이드라이드이고, 히드록시 활성화는 할로겐화, 설포닐화등이다. 설포닐화는 메탄설포닐 등의 알킬설포닐과 벤젠설포닐, 톨릴설포닐, 파라니트로 벤젠설포닐 등의 아릴설포닐으로 구성된다. 화합물(c)를 환원제와 반응하여 화합물(d)을 얻고, 활성기를 도입하여 화합물(b-1)을 효과적으로 제조한다.R 4 , R 5 and n are as defined above, and m is an integer of 0 to 2. The reducing agent is sodium borohydride, lithium, aluminum hydride, and hydroxy activation is halogenated, sulfonylated, and the like. The sulfonylation is composed of alkylsulfonyl such as methanesulfonyl and arylsulfonyl such as benzenesulfonyl, tolylsulfonyl, para-nitrobenzenesulfonyl and the like. Compound (c) is reacted with a reducing agent to obtain compound (d), and an active group is introduced to effectively produce compound (b-1).

일반 구조식(I)에서 사용된 6-치환된 피리미딘디온 등의 공지의 화합물들은 WO 93/02044, WO 95/18109 등에 기술되어 있거나 또는 이와 유사한 방법으로 제조하여 사용될 수 있다.Known compounds such as the 6-substituted pyrimidinedione used in the general formula (I) can be prepared by using the methods described in WO 93/02044, WO 95/18109, or the like or by a similar method.

[실시예][Example]

[실시예 1][Example 1]

[1-[(시클로펜트-3-엔-1일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온][1- (cyclopent-3-en-1-yl) methyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione]

[1-a)(시클로펜트-3-엔-1일)메틸 톨루엔 설포네이트][1-a) (Cyclopent-3-en-1-yl) methyltoluenesulfonate]

(시클로펜트-3-엔-1-일)메탄올(1.96그램, 20밀리몰)을 피리딘 30밀리리터에 녹인 후 파라톨루엔 설포닐클로라이드(3.81그램, 20밀리몰)를 가하고 실온에서 2시간동안 교반하였다. 피리딘을 감압농축하여 제거하고, 이염화메탄으로 추출하여 1노르말 염산으로 씻어낸 후 건조, 여과하여, 농축한 다음 관크로마토그래피로 분리정제하여 상기 화합물 4.20그램을 얻었다.(1.96 grams, 20 millimoles) was dissolved in 30 milliliters of pyridine. Paratoluenesulfonyl chloride (3.81 grams, 20 millimoles) was added thereto, followed by stirring at room temperature for 2 hours. The pyridine was removed by concentration under reduced pressure, extracted with dichloromethane, washed with 1N hydrochloric acid, dried, filtered, concentrated, and purified by column chromatography to obtain 4.20 grams of the compound.

수율 : 83.2%Yield: 83.2%

H NMR(CDCl) : δ 2.13(2H,m), 2.42(3H,s), 2.49(2H,m), 3.82(2H,d), 5.67(2H,s), 7.40(2H,d), 7.65(2H,d). (2H, m), 2.42 (3H, s), 2.49 (2H, m), 3.82 (2H, d).

[1-b) 1 - [(시클로펜트-3-엔-1일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온[1-b) 1 - [(cyclopent-3-en-1-yl) methyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione

5-에틸-6-페닐티오-2,4-피리미딘디온(0.10그램, 0.40밀리몰)과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트(0.12그램, 0.40밀리몰)를 디메틸포름아마이드 10밀리리터에 녹인 후 탄산수소 나트륨(41밀리그램, 0.48밀리몰)을 가한 후 90℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거한 다음 관크로마토그래피로 분리정제하여 흰색의 고체로 상기화합물 65밀리그램을 얻었다.(0.10 grams, 0.40 mmol) and (cyclopent-3-en-1-yl) methyltoluenesulfonate (0.12 grams, 0.40 mmol) were added to a solution of 5-ethyl- 6-phenylthio-2,4-pyrimidinedione (41 mg, 0.48 mmol) was added thereto, followed by stirring at 90 占 폚 for 16 hours. The dimethylformamide was removed by distillation under reduced pressure and then purified by column chromatography to obtain 65 mg of the compound as a white solid.

수율 : 49.1%Yield: 49.1%

융점 : 112-113℃Melting point: 112-113 DEG C

H NMR(CDCl) : δ 1.13(3H,t), 2.10(2H,m), 2.38(2Hm), 2.70(2H,q), 3.97(2H,d,J=7.65Hz), 6.67(2H,s), 7.14-7.53(5H,m), 8.51(1H,s). (2H, s), 3.97 (2H, d, J = 7.65Hz), 6.67 (2H, s) ), 7.14-7.53 (5H, m), 8.51 (1H, s).

[실시예 2][Example 2]

[1 - [(시클로펜트-3-엔-1일)메틸]-5-에틸-6-(3,5-디메틸페닐티오)-2,4 피리미딘디온][1- (cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5- dimethylphenylthio) -2,4-pyrimidinedione]

5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기 화합물 58밀리그램을 얻었다.Ethyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and (cyclopent-3-en-1-yl) methyltoluenesulfonate were reacted in the same manner as in Example 1 58 milligrams of the compound was obtained.

수율 : 45.2%Yield: 45.2%

융점 : 128-130℃Melting point: 128-130 DEG C

H NMR(CDCl) : δ 1.03(3H,t), 2.10(2H,m), 2.28(6H,s), 2.37(2H,m), 2.68(2H,q), 2.83(1H,m), 3.99(2H,d,J=7.65Hz), 5.68(2H,s), 6.73(2H,s), 6.88(1H,s), 8.98(1H,s). (2H, m), 2.68 (2H, q), 2.83 (1H, m), 3.99 (2H, (2H, d, J = 7.65 Hz), 5.68 (2H, s), 6.73 (2H, s), 6.88 (1H, s), 8.98 (1H, s).

Mass : m/e 356(M ), 219(100)Mass: m / e 356 (M ), 219 (100)

[실시예 3][Example 3]

[1-[(시클로펜트-3-엔-1일)메틸]-5-이소프로필-6-페닐티오-2,4 피리미딘디온][1- (cyclopent-3-en-1-yl) methyl] -5-isopropyl-6-phenylthio-2,4-pyrimidinedione]

5-이소프로필-6-페닐티오-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기 화합물 75밀리그램을 얻었다.5-isopropyl-6-phenylthio-2,4-pyrimidinedione and (cyclopent-3-en-1-yl) methyltoluenesulfonate were reacted in the same manner as in Example 1 to give 75 mg of the compound .

수율 : 57.6%Yield: 57.6%

융점 : 131-134℃Melting point: 131-134 DEG C

H NMR(CDCl) : δ 1.21(6H,d,J=6.95Hz), 2.10(2H,m), 2.39(2H,m), 2.80(1H,m), 4.06(2H,d,J=7.65Hz), 5.68(2H,s), 7.14-7.35(5H,m), 9.14(1H,s). (2H, d, J = 7.65Hz), 2.39 (2H, m), 2.80 ), 5.68 (2H, s), 7.14-7.35 (5H, m), 9.14 (1H, s).

Mass : m/e 342(M ), 233(100)Mass: m / e 342 (M ), 233 (100)

[실시예 4][Example 4]

[1 - [(시클로펜트-3-엔-1일)메틸]-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - [(cyclopent-3-en-1-yl) methyl] -5-isopropyl-6- (3,5-dimethylphenylthio)

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기 화합물 80밀리그램을 얻었다.(Cyclopent-3-en-1-yl) methyltoluenesulfonate was reacted with 5-isopropyl-6- (3,5-dimethylphenylthio) To obtain 80 mg of the compound.

수율 : 62.8%Yield: 62.8%

융점 : 139-141℃Melting point: 139-141 DEG C

H NMR(CDCl) : δ 1.20(6H,d,J=6.95Hz), 2.10(2H,m), 2.28(6H,s), 2.39(2H,m), 2.77(1H,m), 3.51(1H,m), 4.05(2H,d,J=7.65Hz), 5.68(2H,s), 6.74(2H,s), 6.88(1H,s), 8.34(1H,s) (2H, m), 2.39 (2H, m), 2.77 (1H, m), 3.51 (1H, (2H, s), 6.74 (2H, s), 6.88 (1H, s), 8.34

Mass : m/e 370(M ), 233(100)Mass: m / e 370 (M ), 233 (100)

[실시예 5][Example 5]

[1 - [(시클로펜트-3-엔-1일)메틸]-5-에틸-6-페닐티오-2,4 피리미딘디온][1 - [(cyclopent-3-en-1-yl) methyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione]

[5-a) (시클로펜트-3-엔-1-일)메틸 톨루엔 설포네이트][5-a) (Cyclopent-3-en-1-yl) methyltoluenesulfonate]

(시클로펜트-3-엔-1-일)메탄올(1.96그램, 20밀리몰)을 피리딘 30밀리리터에 녹인 후 파라돌루엔 설포닐클로라이드(3.81그램, 20밀리몰)를 가하고 실온에서 2시간동안 교반하였다. 피리딘을 감압농축하여 제거하고, 이염화탄소로 추출하여 1노르말 염산으로 씻어낸 후 건조, 여과하여 농축한 다음 관크로마토그래피로 분리 정제하여 4.52그램을 얻었다.(1.96 grams, 20 millimoles) was dissolved in 30 milliliters of pyridine. Parradolenesulfonyl chloride (3.81 grams, 20 millimoles) was added thereto and stirred at room temperature for 2 hours. The pyridine was removed by concentrating under reduced pressure, extracted with dichloromethane, washed with 1N hydrochloric acid, dried, filtered, concentrated and purified by column chromatography to obtain 4.52 grams.

수율 : 89.6%Yield: 89.6%

H NMR(CDCl) : δ 1.84(2H,m), 2.23(4H,m), 2.49(3H,s), 4.21(2H,s), 5.27(1H,s), 7.40(2H,d), 7.65(2H,d). (2H, s), 7.40 (2H, d), 7.65 (2H, s), 7.21 (2H, (2H, d).

[5-b) 1 -[(시클로펜트-3-엔-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온][5-b] 1 - [(cyclopent-3-en-1-yl) methyl] -5- ethyl-6-phenylthio-2,4-pyrimidinedione]

5-에틸-6-페닐티오-2,4-피리미딘디온(0.10그램, 0.40밀리몰)과 (시클로펜트-3-엔-1-일))메틸 톨루엔설포네이트(0.12그램, 0.40밀리몰)를 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(41밀리그램, 0.48밀리몰)를 가한 후 90℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거한 다음 관 크로마토그래피로 분리정제하여 흰색의 고체로 상기화합물 45밀리그램을 얻었다.(0.10 grams, 0.40 mmol) and (cyclopent-3-en-1-yl)) methyltoluenesulfonate (0.12 grams, 0.40 mmol) were added to a solution of dimethyl Sodium formate (41 mg, 0.48 mmol) was added thereto, followed by stirring at 90 째 C for 16 hours. The dimethylformamide was removed by distillation under reduced pressure, and then separated and purified by column chromatography to obtain 45 mg of the compound as a white solid.

수율 : 34.2%Yield: 34.2%

융점 : 181-183℃Melting point: 181-183 DEG C

H NMR(CDCl) : δ 1.01(3H,t), 184(2H,m), 2.23(4H,m), 2.69(2H,q), 4.66(2H,s), 5.26(1H,s), 7.15-7.34(5H,m), 8.94(1H,s). (2H, s), 5.26 (1H, s), 7.15 (2H, m), 2.27 -7.34 (5 H, m), 8.94 (1 H, s).

[실시예 6][Example 6]

[1 - [(4-히드록시메틸시클로펜트-1-엘-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온][1 - [(4-hydroxymethylcyclopent-1-yl-1-yl) methyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione]

[6-a) (4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드][6-a] (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide]

(4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 알콜(0.85그램, 3.5밀리몰)을 이염화메탄에 녹이고, 얼음용기에서 사브롬화 탄소(1.39그램, 4.2밀리몰)와 트리페닐포스핀(1.37그램, 5.2밀리몰)을 차례로 가하고 30분간 교반하였다. 얼음용기를 제거하고 실온에서 16시간동안 교반하였다. 이염화메탄으로 추출하여 무수 황산 나트륨으로 건조, 여과하여 감압농축한 다음 관 크로마토그래피로 분리정제하여 상기 화합물 0.53그램을 얻었다.(0.85 grams, 3.5 millimoles) was dissolved in dichloromethane and carbon tetrabromide (1.39 grams, 4.2 millimoles) was added in an ice bath to a solution of 4- And triphenylphosphine (1.37 g, 5.2 mmol) were added in this order, followed by stirring for 30 minutes. The ice bath was removed and stirred at room temperature for 16 hours. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 0.53 g of the compound.

수율 : 49.7%Yield: 49.7%

H NMR(CDCl) : δ 0.05(6H,s), 0.90(9H,s), 2.18(2H,m), 2.50(3H,m), 3.5(2H,d,J=6.75Hz), 4.05(2H,s), 5.71(1H,s). (2H, m), 3.50 (2H, d, J = 6.75 Hz), 4.05 (2H, , < / RTI > s), 5.71 (1H, s).

[6-b) 1 - [(4-디드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온][6-b] 1 - [(4-dideoxymethylcyclopent-1-en-1-yl) methyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione]

5-에틸-6-페닐티오-2,4-피리미딘디온(0.16그램, 0.66밀리몰)과 (4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드(0.20그램, 0.66밀리몰)을 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(66밀리그램, 0.79밀리몰)를 가한다음 50℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거하고 관 크로마토그래피로 분리정제하여 1-[(4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온을 합성하고, 이를 테트라히드로퓨란 10밀리리터에 녹인다음 노르말테트라부틸암모늄플로리드를 가하여 실온에서 1시간동안 교반하였다. 테트라히드로퓨란을 감압증류하여 제거하고 남은 여액을 관 크로마토그래피로 분리정제하여 상기 화합물 35밀리그램을 얻었다.(0.16 grams, 0.66 mmol) and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methyl bromide (0.20 grams , 0.66 mmol) was dissolved in 10 ml of dimethylformamide, sodium hydrogencarbonate (66 mg, 0.79 mmol) was added, and the mixture was stirred at 50 캜 for 16 hours. Dimethylformamide was removed by distillation under reduced pressure, and the residue was purified by column chromatography to obtain 1 - [(4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methyl] Thio-2,4-pyrimidinedione was synthesized and dissolved in 10 milliliters of tetrahydrofuran, and then normal tetrabutylammonium fluoride was added thereto, followed by stirring at room temperature for 1 hour. The tetrahydrofuran was removed by distillation under reduced pressure, and the remaining filtrate was separated and purified by column chromatography to obtain 35 mg of the compound.

수율 : 14.8%Yield: 14.8%

융점 : 161-163℃Melting point: 161-163 DEG C

H NMR(CDCl) : δ 1.01(3H,t), 2.03(2H,m), 2.38(2H,,), 2.50(1H,m), 2.68(2H,q), 3.50(2H,d,J=6.65Hz), 5.23(1H,s), 7.15-7.35(5H,m), 8.62((1H,s) . (2H, m), 2.50 (1H, m), 2.68 (2H, q), 3.50 (2H, d, J = 6.65 Hz), 5.23 (1H, s), 7.15-7.35 (5H, m), 8.62 (1H, s).

[실시예 7][Example 7]

[1-[(4-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - [(4-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylphenylthio)

5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 (4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 6과 동일한 방법으로 반응하여 상기화합물 48밀리그램을 얻었다.(4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was reacted with 5-ethyl-6- (3,5-dimethylphenylthio) The reaction was carried out in the same manner as in 6 to give 48 mg of the compound.

수율 : 24.1%Yield: 24.1%

융점 : 57-60℃Melting point: 57-60 DEG C

H NMR(CDCl) : δ 1.02(3H,t), 2.04(2H,m), 2.28(6H,s), 2.39(2H,m), 2.51(1H,m), 2.68(2H,q), 3.51(2H,d,J=9.70Hz), 4.63(2H,q), 5.23(1H,s), 6.75 (2H,s), 6.87(1H,s), 9.38(1H,s). (2H, m), 2.68 (2H, q), 3.51 (2H, m), 2.51 (2H, d, J = 9.70 Hz), 4.63 (2H, q), 5.23 (1H, s), 6.75 (2H, s), 6.87 (1H, s), 9.38

Mass : m/e 386(M ), 276(100)Mass: m / e 386 (M ), 276 (100)

[실시예 8][Example 8]

[1 - [(4-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-이소프로필-6-페닐티오-2,4-피리미딘디온][1 - [(4-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-isopropyl-6-phenylthio-2,4-pyrimidinedione]

5-이소프로필-6-페닐티오-2,4-피리미딘디온과 (4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 6과 동일한 방법으로 반응하여 상기화합물 67밀리그램을 얻었다.(4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was reacted with 5-isopropyl-6-phenylthio- To obtain 67 mg of the compound.

수율 : 29.5%Yield: 29.5%

융점 : 166-168℃Melting point: 166-168 DEG C

H NMR(CDCl) : δ 1.18(3H,d), 1.19(3H,d), 2.05(2H,m), 2.41(2H,m), 2.50(1H,m), 3.49(1H,m), 3.52(2H,d), 4.70(2H,q), 5.24(1H,s), 7.16-7.34(5H,m), 8.63(1H,s). (2H, m), 2.50 (1H, m), 3.49 (1H, m), 3.52 (2H, d), 4.70 (2H, q), 5.24 (1H, s), 7.16-7.34 (5H, m), 8.63 (1H, s).

[실시예 9][Example 9]

[1-[(4-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - [(4-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 (4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 6과 동일한 방법으로 반응하여 상기화합물 73밀리그램을 얻었다.(4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was carried out in the same manner as in Reference Example 1, except that 5-isopropyl-6- (3,5-dimethylphenylthio) The reaction was carried out in the same manner as in Example 6 to obtain 73 mg of the compound.

수율 : 33.1%Yield: 33.1%

융점 : 147-148℃Melting point: 147-148 DEG C

H NMR(CDCl) : δ 1.20(3H,d), 1.21(3H,d), 2.05(2H,d), 2.28(6H,s), 2.40(2H,d), 2.50(1H,m), 3.48(1H,m), 3.52(2H,d,J=6.85Hz), 4.70(2H,q), 5.24(1H,s), 6.75(2H,s), 6.87(1H,s), 9.06(1H,s). (2H, d), 2.50 (1H, m), 3.48 (3H, d), 2.50 (1H, m), 3.52 (2H, d, J = 6.85 Hz), 4.70 (2H, q), 5.24 (1H, s), 6.75 s).

Mass : m/e 400(M+), 263(100)Mass: m / e 400 (M < + >), 263 (100)

[실시예 10][Example 10]

[1-[(5-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온][1 - [(5-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione]

[10-a) (5 -t-부틸디메틸실릴옥시메틸스클로펜트-1-엔-1-일)메틸 브로마이드][10-a] (5-t-butyldimethylsilyloxymethylsclopent-1-en-1-yl) methylbromide]

(5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 알콜(5.2그램, 21.4밀리몰)을 이염화메탄에 녹이고, 얼음용기에서 사브롬화 탄소(8.5그램, 25.7밀리몰0와 트리페닐포스핀(8.4그램, 32.2밀리몰)을 차례로 가하고 30분간 교반하였다. 얼음용기를 제거하고, 실온에서 16시간동안 교반하였다. 이염화메탄으로 추출하여 무수 황산 나트륨으로 건조, 여과하여 감압농축한 다음 관 크로마토그래피로 분리정제하여 상기화합물 3,08그램을 얻었다.(5.2 grams, 21.4 millimoles) was dissolved in dichloromethane, and carbon tetrabromide (8.5 grams, 25.7 millimoles 0 < RTI ID = 0.0 > (8.4 grams, 32.2 mmol), and the mixture was stirred for 30 minutes. The ice bath was removed, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure Followed by separation and purification by tube chromatography to obtain 3,08 grams of the compound.

수율 : 47.2%Yield: 47.2%

H NMR(CDCl) : δ 0.05(6H,s), 0.90(9H,s), 1.71(2H,m), 2.05(2H,m), 2.30(2H,m), 3.62(2H,dd,J=5.80Hz), 4.15(2H,s), 5.71(1H,s) (2H, m), 2.62 (2H, m), 3.62 (2H, dd, J = 5.80 Hz), 4.15 (2H, s), 5.71 (1H, s)

[10-b) 1 - [(5-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온][10-b] 1 - [(5-hydroxymethylcyclopent-1-en-1-yl) methyl] -5- ethyl-6-phenylthio-2,4-pyrimidinedione]

5-에틸-6-페닐티오-2,4-피리미딘디온(0.16그램, 0.66밀리몰)과 (5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드(0.20그램, 0.66밀리몰)을 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(66밀리그램, 0.79밀리몰)를 가한다음 50℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거하고 관 크로마토그래피로 분리정제하여 1-[(5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-페닐티오-2,4-피리미딘디온을 합성하고, 이를 테트라히드로퓨란 10밀리리터에 녹인다음 노르말테트라부틸암모늄플로리드를 가하고, 실온에서 1시간동안 교반하였다. 테트라히드로퓨란을 감압증류하여 제거하고 남은 여액을 관 크로마토그래피로 분리정제하여 상기화합물 43밀리그램을 얻었다.(0.16 grams, 0.66 mmol) and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methyl bromide (0.20 grams , 0.66 mmol) was dissolved in 10 ml of dimethylformamide, sodium hydrogencarbonate (66 mg, 0.79 mmol) was added, and the mixture was stirred at 50 캜 for 16 hours. Dimethylformamide was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain 1 - [(5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methyl] Thio-2,4-pyrimidinedione was synthesized, dissolved in 10 milliliters of tetrahydrofuran, added with normal tetrabutylammonium fluoride, and stirred at room temperature for 1 hour. The tetrahydrofuran was removed by distillation under reduced pressure, and the remaining filtrate was separated and purified by column chromatography to obtain 43 mg of the compound.

수율 : 18.2%Yield: 18.2%

융점 : 155-156℃Melting point: 155-156 DEG C

H NMR(CDCl) : δ 1.04(3H,t), 1.81-1.90(4H,m), 2.72(3H,m), 3.56-3.74(2H,dd,J=4.35Hz), 4.70(2H,dd,J=16.9Hz), 5.32(1H,s), 7.17-7.36(5H,m) 9.90(1H,s). Dd, J = 4.35 Hz), 4.70 (2H, dd, < RTI ID = 0.0 > J = 16.9 Hz), 5.32 (1H, s), 7.17-7.36 (5H, m) 9.90 (1H, s).

[실시예 11][Example 11]

[1-[(5-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - [(5-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylphenylthio)

5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 (5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 10과 동일한 방법으로 반응하여 상기화합물 51밀리그램을 얻었다.(5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was reacted with 5-ethyl-6- (3,5-dimethylphenylthio) The reaction was carried out in the same manner as in Example 10 to obtain 51 mg of the compound.

수율 : 22.7%Yield: 22.7%

융점 : 59-60℃Melting point: 59-60 DEG C

H NMR(CDCl) : δ 1.05(3H,t), 1.83-2.27(4H,m), 2.28(6H,s), 2.73 (3H,m), 3.57-3.74(2H,dd,J=4.30Hz), 4.60(2H,dd,J=17.0Hz), 5.31(1H,s), 6.77(2H,s), 6.88(1H,s), 9.39(1H,s). (3H, t), 1.83-2.27 (4H, m), 2.28 (6H, s), 2.73 (3H, m), 3.57-3.74 (2H, dd, J = 4.30Hz) , 4.60 (2H, dd, J = 17.0 Hz), 5.31 (1H, s), 6.77 (2H, s), 6.88 (1H, s), 9.39 (1H, s).

[실시예 12][Example 12]

[1-[(5-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-이소프로필-6-페닐티오-2,4-피리미딘디온[1 - [(5-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-isopropyl-6-phenylthio-2,4-pyrimidinedione

5-이소프로필-6-페닐티오-2,4-피리미딘디온과 (5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 10과 동일한 방법으로 반응하여 상기화합물 68밀리그램을 얻었다.(5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was reacted with 5-isopropyl-6-phenylthio- To obtain 68 mg of the compound.

수율 : 29.9%Yield: 29.9%

융점 : 66-68℃Melting point: 66-68 DEG C

H NMR(CDCl) : δ 1.21(3H,d,J=7.0Hz), 1.24(3H,d,J=7.0Hz), 1.81-2.34(4H,m), 2.73(1H,m), 3.51(1H,m), 3.57-3.74(2H,dd,J=4.45Hz), 4.66(2H,dd, J=17.0Hz), 5.33(1H,s), 7.17-7.36(5H,m), 8.95(1H,s). (1H, m), 3.51 (1H, d, J = 7.0Hz), 1.24 (3H, (2H, d, J = 17.0Hz), 5.33 (1H, s), 7.17-7.36 (5H, m), 8.95 s).

[실시예 13][Example 13]

[1-[(5-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - [(5-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 (5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 10과 동일한 방법으로 반응하여 상기화합물 83밀리그램을 얻었다.(5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was carried out in the same manner as in Example 1, except that 5-isopropyl-6- (3,5-dimethylphenylthio) The reaction was conducted in the same manner as in Example 10 to obtain 83 mg of the compound.

수율 : 37.6%Yield: 37.6%

융점 : 81-82℃Melting point: 81-82 DEG C

H NMR(CDCl) : δ 1.22(3H,d,J=6.9Hz), 1.25(3H,d,J=6.9Hz), 1.82-2.25(4H,m), 2.28(6H,s), 2.74(1H,m), 3.53(1H,m), 3.55-3.77(2H,dd,J=4.25Hz), 4.70(2H,dd,J=17.0Hz), 5.32(1H,s), 6.78(2H,s), 6.88(1H,s), 8.41(1H,s). (3H, d, J = 6.9 Hz), 1.82 (3H, d, J = 6.9 Hz), 1.82-2.25 (4H, m), 2.28 (2H, s), 3.53 (1H, m), 3.55-3.77 (2H, dd, J = 4.25Hz), 4.70 (2H, dd, J = 17.0Hz), 5.32 , 6.88 (1 H, s), 8.41 (1 H, s).

[실시예 14][Example 14]

[1-[(시클로펜트-3-엔-1-일)메틸]-5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1- (cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5- dimethylphenoxy) -2,4-pyrimidinedione]

5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기화합물 68밀리그램을 얻었다.Ethyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione and (cyclopent-3-en-1-yl) methyltoluenesulfonate were reacted in the same manner as in Example 1 68 milligrams of the compound was obtained.

수율 : 49.9%Yield: 49.9%

융점 : 179-180℃Melting point: 179-180 DEG C

H NMR(CDCl) : δ 1.02(3H,t,J=7.5Hz), 2.02-2.05(2H,m), 2.32(6H,s), 2.34(2H,m), 2.68(3H,m), 3.66(2H,d,J=7.5Hz), 5.67(2H,s), 6.50(2H,s), 6.77 (1H,s), 8.92(1H,s). (2H, m), 2.68 (3H, m), 3.66 (2H, m) (2H, d, J = 7.5 Hz), 5.67 (2H, s), 6.50 (2H, s), 6.77 (1H, s), 8.92 (1H, s).

Mass : m/e 340(M+), 219(100)Mass: m / e 340 (M +), 219 (100)

[실시예 15][Example 15]

[1-[(시클로펜트-3-엔-1-일)메틸]-5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온]Yl] methyl] -5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione [

5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기화합물 73밀리그램을 얻었다.(Cyclopent-3-en-1-yl) methyltoluenesulfonate was reacted with 5-isopropyl-6- (3,5-dimethylphenoxy) To obtain 73 mg of the compound.

수율 : 51.5%Yield: 51.5%

융점 : 183-184℃Melting point: 183-184 DEG C

H NMR(CDCl) : δ 1.14(3H,s), 1.15(3H,s), 2.05(2H,dd,J=5.2, 9.0Hz), 2.31(6H,s), 2.28(2H,dd,J=8.5, 6.0Hz), 2.73-2.83(2H,m), 3.65(2H,d,J=7.5Hz) , 5.67(2H,s), 6.50(2H,s), 6.77(1H,s), 8.96(1H,s). (2H, s), 2.05 (2H, dd, J = 5.2, 9.0 Hz), 2.31 (6H, s), 2.28 (2H, s), 6.77 (1H, s), 8.96 (2H, d, J = 1H, s).

[실시예 16][Example 16]

[1-[(시클로펜트-3-엔-1-일)메틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1- (cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5- dimethylbenzoyl) -2,4-pyrimidinedione]

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기화합물 84밀리그램을 얻었다.Yl) methyltoluenesulfonate was reacted with 5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione and (cyclopent-3- 84 milligrams of the compound were obtained.

수율 : 59.6%Yield: 59.6%

융점 : 209-210℃Melting point: 209-210 DEG C

H NMR(CDCl) : δ 0.98(3H,t,J=7.5Hz), 2.02(2H,m), 2.26-2.37(2H,m), 2.41(6H,s), 2.68-2.73(3H,m), 3.82(2H,d,J=7.5Hz), 5.58-5.60(2H,m), 7.34((1H,s), 7.50(2H,s), 8.82(1H,s). (3H, m), 2.26-2.37 (2H, m), 2.41 (6H, s), 2.68-2.73 (3H, m) , 3.82 (2H, d, J = 7.5 Hz), 5.58-5.60 (2H, m), 7.34 (1H, s), 7.50 (2H, s), 8.82 (1H, s).

Mass : m/e 352(M ), 219(100)Mass: m / e 352 (M ), 219 (100)

[실시예 17][Example 17]

[1-[(시클로펜트-3-엔-1-일)메틸]-5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온]Yl] methyl] -5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione [

5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 (시클로펜트-3-엔-1-일)메틸 톨루엔설포네이트를 실시예 1과 동일한 방법으로 반응하여 상기화합물 81밀리그램을 얻었다.(Cyclopent-3-en-1-yl) methyltoluenesulfonate was reacted in the same manner as in Example 1 to give 5-isopropyl-6- (3,5-dimethylbenzoyl) 81 milligrams of the compound was obtained.

수율 : 55.2%Yield: 55.2%

융점 : 196-197℃Melting point: 196-197 DEG C

H NMR(CDCl) : δ 1.12(3H,d,J=7.0Hz), 1.23(3H,d,J=7.0Hz), 2.01-2.03(2H,m), 2.26-2.34(3H,m), 2.40(6H,s), 2.58-2.62(1H,m), 3.18(1H,dd,J= 7.5, 6.5Hz), 3.84(1H,dd,J=7.5, 6.5Hz), 5.56(1H,m), 5.60(1H,m), 7.34(1H,s), 7.51(2H,s), 8.77(1H,s). (3H, d, J = 7.0 Hz), 1.23 (3H, d, J = 7.0 Hz), 2.01-2.03 (2H, m), 2.26-2.34 (1H, s), 2.58-2.62 (1H, m), 3.18 (1H, dd, J = 7.5, 6.5Hz), 3.84 (1H, dd, J = 7.5, 6.5Hz) 5.60 (1H, m), 7.34 (1H, s), 7.51 (2H, s), 8.77 (1H, s).

[실시예 18][Example 18]

[1-[(4-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1 - [(4-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylphenoxy)

5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 (4-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 6과 동일한 방법으로 반응하여 상기화합물 52밀리그램을 얻었다.(4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) methylbromide was reacted with 5-ethyl-6- (3,5-dimethylphenoxy) The reaction was carried out in the same manner as in 6 to give 52 mg of the compound.

수율 : 21.3%Yield: 21.3%

H NMR(CDCl) : δ 0.95(3H,t,J=7.5Hz), 2.05(2H,m), 2.21(2H,q,J= 10.0Hz), 2.30(6H,s), 2.38-2.43(2H,m), 2.50-2.55(1H,m), 3.49(2H,d,J=5.0Hz ), 4.37(2H,s), 5.35(1H,s), 6.52(2H,s), 6.77(1H,s), 8.99(1H,s). (2H, m, J = 10.0 Hz), 2.30 (6H, s), 2.38-2.43 (2H, (1H, m), 2.50-2.55 (1H, m), 3.49 (2H, d, J = 5.0 Hz), 4.37 (2H, s), 5.35 s), 8.99 (1H, s).

[실시예 19][Example 19]

[1-[(5-히드록시메틸시클로펜트-1-엔-1-일)메틸]-5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1 - [(5-hydroxymethylcyclopent-1-en-1-yl) methyl] -5-ethyl-6- (3,5- dimethylphenoxy) -2,4-pyrimidinedione]

5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 (5-t-부틸디메틸실릴옥시메틸시클로펜트-1-엔-1-일)메틸 브로마이드를 실시예 10과 동일한 방법으로 반응하여 상기화합물 52밀리그램을 얻었다.Ethyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl) 10, to give 52 mg of the compound.

수율 : 21.3%Yield: 21.3%

융점 : 119-120℃Melting point: 119-120 DEG C

H NMR(CDCl) : δ 0.95(3H,t,J=7.5Hz), 1.77-1.82(1H,m), 1.98-2.04(1H,m), 2.17-2.25(2H,m), 2.30(6H,s), 3.57(1H,d,J=5.0Hz), 3.66(1H,d,J= 5.0Hz), 3.90(2H,d,J=14.0Hz), 5.50(1H,s), 6.53(2H,s), 6.78(1H,s), 8.72(1H,s) . (1H, m), 2.17-2.25 (2H, m), 2.30 (6H, m) (1H, s), 3.57 (1H, d, J = 5.0 Hz), 3.66 (1H, d, J = 5.0 Hz), 3.90 s), 6.78 (1 H, s), 8.72 (1 H, s).

[실시예 20][Example 20]

[1-[(시클로펜틸)메틸]-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1- (cyclopentyl) methyl] -5-isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione]

[20-a) (시클로펜틸)메틸 톨루엔 설포네이트][20-a] (cyclopentyl) methyltoluenesulfonate]

시클로펜탄메탄올(2.0그램, 20밀리몰)을 피리딘 30밀리리터에 녹인 후 파라톨루엔 설포닐클로라이드(3.81그램, 20밀리몰)를 가하고 실온에서 2시간동안 교반하였다. 피리딘을 감압농축하여 제거하고, 이염화탄소로 추출하여 1노르말 염산으로 씻어낸 후 건조, 여과하여 농축한 다음 관 크로마토그래피로 분리정제하여 3.80그램을 얻었다.Cyclopentane methanol (2.0 grams, 20 millimoles) was dissolved in 30 milliliters of pyridine, para-toluenesulfonyl chloride (3.81 grams, 20 millimoles) was added, and the mixture was stirred at room temperature for 2 hours. The pyridine was removed by concentration under reduced pressure, extracted with dichloromethane, washed with 1N hydrochloric acid, dried, filtered, concentrated and purified by column chromatography to obtain 3.80 grams.

수율 : 74.7%Yield: 74.7%

H NMR(CDCl) : δ 1.26-1.30(2H,m), 1.52-1.53(2H,m), 1.66(4H,m), 2.09(1H,m), 2.48(3H,s), 3.74(2H,d), 7.40(2H,d), 7.72(2H,d). (2H, m), 1.66 (4H, m), 2.09 (1H, m), 2.48 (3H, s), 3.74 d), 7.40 (2 H, d), 7.72 (2 H, d).

[20-b) 1 - [(시클로펜틸)메틸]-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][20-b] 1 - [(cyclopentyl) methyl] -5-isopropyl-6- (3,5- dimethylphenylthio) -2,4-

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온(0.10그램, 0.40밀리몰)과 (시클로펜틸)메틸 톨루엔설포네이트(0.10그램, 0.40밀리몰)을 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(41밀리그램, 0.48밀리몰)를 가한 후 100℃에서 하룻밤동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거한 다음 관 크로마토그래피로 분리정제하여 흰색의 고체로 상기화합물 75밀리그램을 얻었다.(0.10 grams, 0.40 mmol) and (cyclopentyl) methyltoluenesulfonate (0.10 grams, 0.40 mmol) were added to a solution of 5-isopropyl-6- (3,5-dimethylphenylthio) Amide, sodium hydrogencarbonate (41 mg, 0.48 mmol) was added thereto, followed by stirring at 100 ° C overnight. The dimethylformamide was removed by distillation under reduced pressure and then purified by column chromatography to obtain 75 mg of the compound as a white solid.

수율 : 50.3%Yield: 50.3%

융점 : 145-146℃Melting point: 145-146 DEG C

H NMR(CDCl) : δ 1.20(3H,s), 1.22(3H,s), 1.26-1.30(2H,m), 1.52-1.53(2H,m), 1.66(4H,m), 2.28(6H,s), 2.32-2.35(1H,m), 3.48(3.54(1H,m), 4.02 (2H,d,J=7.5Hz), 6.74(2H,s), 6.87(1H,s), 9.27(1H,s). (2H, m), 1.66 (4H, m), 2.28 (6H, s), 1.26-1.30 (2H, s), 2.32-2.35 (1H, m), 3.48 (3.54 (1H, m), 4.02 , s).

Mass : m/e 372(M ), 275(100)Mass: m / e 372 (M ), 275 (100)

[실시예 21][Example 21]

[1-(시클로펜트)메틸-5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1- (Cyclopent) methyl-5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 (시클로펜트)메틸 톨루엔설포네이트를 실시예 20과 동일한 방법으로 반응하여 상기화합물 53밀리그램을 얻었다.5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione and (cyclopent) methyltoluenesulfonate were reacted in the same manner as in Example 20 to give 53 mg of the above compound.

수율 : 37.2%Yield: 37.2%

융점 : 157-158℃Melting point: 157-158 ° C

H NMR(CDCl) : δ 1.14(3H,s), 1.15(3H,s), 1.21-1.25(2H,m), 1.53-1.55(2H,m), 1.65-1.68(4H,m), 2.26-2.29(1H,m), 2.31(6H,s), 2.78-2.83(1H,m), 3.61(2H,d,J=7.5Hz), 6.51(2H,s), 6.77(1H,s), 9.04(1H,s). (2H, m), 1.65-1.68 (4H, m), 2.26-7.14 (2H, m) (2H, s), 6.77 (1H, s), 9.04 (2H, s), 2.29 (1H, s).

[실시예 22][Example 22]

[1-(시클로펜틸)메틸-5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1- (cyclopentyl) methyl-5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 (시클로펜트)메틸 톨루엔설포네이트를 실시예 20과 동일한 방법으로 반응하여 상기화합물 84밀리그램을 얻었다.5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione and (cyclopent) methyltoluenesulfonate were reacted in the same manner as in Example 20 to obtain 84 mg of the compound.

수율 : 57.0%Yield: 57.0%

융점 : 167-168℃Melting point: 167-168 DEG C

H NMR(CDCl) : δ 1.12(3H,d,J=7.0Hz), 1.15-1.19(2H,m), 1.23(3H, d,J=7.0Hz), 1.46-1.47(2H,m), 1.587(4H,m), 2.10-2.16(1H,m), 2.30-2.36(1H,m), 2.41(6H,s), 3.15(1H,dd,J=7.0, 7.5Hz), 3.84(1H,dd,J=7.0, 6.5Hz), 7.34(1H,s), 7.52(2H,s), 9.02(1H,s). (2H, m), 1.587 (2H, m), 1.23 (3H, d, J = 7.0Hz), 1.46-1.47 (1H, m), 2.10-2.16 (1H, m), 2.30-2.36 (1H, m), 2.41 (6H, s), 3.15 (1H, dd, J = 7.0, 7.5Hz) , J = 7.0, 6.5 Hz), 7.34 (1H, s), 7.52 (2H, s), 9.02 (1H, s).

Mass : m/e 368(M ), 133(100)Mass: m / e 368 (M ), 133 (100)

[실시예 23][Example 23]

[1-(시클로펜트)메틸-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1- (Cyclopent) methyl-5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 (시클로펜트)메틸 톨루엔설포네이트를 실시예 20과 동일한 방법으로 반응하여 상기화합물 80밀리그램을 얻었다.Ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione and (cyclopent) methyltoluenesulfonate were reacted in the same manner as in Example 20 to obtain 80 mg of the compound.

수율 : 56.4%Yield: 56.4%

융점 : 186-187℃Melting point: 186-187 DEG C

H NMR(CDCl) : δ 0.94(3H,d,J=7.5Hz), 1.24(3H,d,J=7.0Hz), 1.46-1.47(2H,m), 1.56-1.58(4H,m), 2.14(1H,m), 2.41(6H,s), 2.62(2H,q,J=7.0Hz), 3.18(1H,d,J=7.0Hz), 3.84(1H,d,J=7.0Hz), 7.34(1H,s), 7.52(2H,s), 8.94(1H,s). J = 7.0 Hz), 1.46-1.47 (2H, m), 1.56-1.58 (4H, m), 2.14 (3H, d, J = (1H, m, J = 7.0Hz), 7.34 (1H, d, J = (1H, s), 7.52 (2H, s), 8.94 (1H, s).

[실시예 24][Example 24]

[1-{[4-비스(히드록시메틸)시클로펜트-1-엔-1-일)메틸}-5-에틸-6-페닐티오-2,4-피리미딘디온]1-yl) methyl} -5-ethyl-6-phenylthio-2,4-pyrimidinedione [

[24-a) [4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드][24-a] [4-bis (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] methylbromide]

[4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 알콜(1.93그램, 5.0밀리몰)을 이염화메탄에 녹이고, 얼음용기에서 사브롬화 탄소(1.99그램, 6.0밀리몰)와 트리페닐포스핀(1.97그램, 7.5밀리몰)을 차례로 가하고 30분간 교반하였다. 얼음용기를 제거하고 실온에서 16시간동안 교반하였다. 이염화메탄으로 추출하여 무수 황산 나트륨으로 건조, 여과하여 감압농축한 다음 관 크로마토그래피로 분리정제하여 상기화합물 1.43그램을 얻었다.1-yl] methyl alcohol (1.93 grams, 5.0 millimoles) was dissolved in dichloromethane, and carbon tetrabromide (1.99 grams, 6.0 mmol) and triphenylphosphine (1.97 g, 7.5 mmol) were added in this order, followed by stirring for 30 minutes. The ice bath was removed and stirred at room temperature for 16 hours. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 1.43 g of the compound.

수율 : 63.5%Yield: 63.5%

H NMR(CDCl) : δ 0.05(6H,s), 0.90(9H,s), 2.09(2H,br-s), 2.15(2H,br -s), 3.64(4H,m), 4.04(2H,s), 5.21(1H,s). (2H, br-s), 3.64 (4H, m), 4.04 (2H, s), 2.09 s), 5.21 (1 H, s).

[24-b) 1-[4-비스(히드록시메틸)시클로펜트-1-엔-1-일]메틸-5-에틸-6-페닐티오-2,4-피리미딘디온][24-b] 1- [4-bis (hydroxymethyl) cyclopent-1-en-1-yl] methyl-

5-에틸-6-페닐티오-2,4-피리미딘디온(0.16그램, 0.66밀리몰)과 [4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일)메틸 브로마이드(0.30그램, 0.66밀리몰)을 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(66밀리그램, 0.79밀리몰)를 가한다음 50℃에서 하룻밤동안 교반하였다. 디메틸포름아마이드를 감압 증류하여 제거하고 관 크로마토그래피로 분리정제하여 합성하고, 이를 테트라히드로퓨란 10밀리리터에 녹인다음 노르말테트라부틸암모늄플로리드를 가하여 실온에서 1시간동안 교반하였다. 테트라히드류퓨란을 감압증류하여 제거하고 남은 여액을 관 크로마토그래피로 분리정제하여 상기화합물 45밀리그램을 얻었다.Ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 grams, 0.66 mmol) and [4-bis (t- butyldimethylsilyloxymethyl) cyclopent- (0.30 grams, 0.66 millimoles) was dissolved in 10 milliliters of dimethylformamide, sodium hydrogencarbonate (66 milligrams, 0.79 millimoles) was added, and the mixture was stirred at 50 DEG C overnight. Dimethylformamide was distilled off under reduced pressure, and the residue was purified and purified by column chromatography. The residue was dissolved in 10 milliliters of tetrahydrofuran, and then normal tetrabutylammonium fluoride was added thereto, followed by stirring at room temperature for 1 hour. The tetrahydrofuran was removed by distillation under reduced pressure, and the remaining filtrate was separated and purified by column chromatography to obtain 45 mg of the compound.

수율 : 17.6%Yield: 17.6%

융점 : 170-171℃Melting point: 170-171 DEG C

H NMR(CDCl) : δ 1.02(3H,t,J=7.5Hz), 2.09(2H,br-s), 2.15(2H,br-s), 2.68(2H,q,J=7.5Hz), 3.64(4H,t,J=7.5Hz), 4.62(2H,s), 5.20(1H,s), 7.16(2H,d,J=7.5Hz), 7.34(2H,t,J=7.5Hz), 8.40(1H,s). (2H, br, s), 2.68 (2H, q, J = 7.5 Hz), 3.64 (2H, br-s) (2H, t, J = 7.5 Hz), 8.40 (1H, s), 7.16 (1H, s).

[실시예 25][Example 25]

[1-{[4-비스(히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온]1-yl] methyl} -5-ethyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione ]

5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 [4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 24와 동일한 방법으로 반응하여 상기화합물 48밀리그램을 얻었다.Ethyl] -6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and [4-bis (t- butyldimethylsilyloxymethyl) cyclopent- Were reacted in the same manner as in Example 24 to give 48 mg of the compound.

수율 : 17.5%Yield: 17.5%

융점 : 156-157℃Melting point: 156-157 DEG C

H NMR(CDCl) : δ 1.02(3H,t,J=7.4Hz), 2.08(2H,s), 2.14(2H,s), 2.28 (6H,s), 2.68(2H,q,J=7.5Hz), 3.62(4H,t,J=11.2Hz), 4.62(2H,s), 5.21(1H,s), 6.75(1H,s), 6.88(1H,s), 9.61(1H,s). (2H, s), 2.68 (2H, q, J = 7.5 Hz), 2.08 (2H, s), 2.14 ), 3.62 (4H, t, J = 11.2Hz), 4.62 (2H, s), 5.21 (1H, s), 6.75 (1H, s), 6.88 (1H, s), 9.61

Mass : m/e 416(M ), 91(100)Mass: m / e 416 (M ), 91 (100)

[실시예 26][Example 26]

[1-{[4-비스(히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-이소프로필-6-페닐티오-2,4-피리미딘디온][1 - {[4-bis (hydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-isopropyl-6-phenylthio-2,4-pyrimidinedione]

5-이소프로필-6-페닐티오-2,4-피리미딘디온과 [4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 24와 동일한 방법으로 반응하여 상기화합물 52밀리그램을 얻었다.Synthesis of 5-isopropyl-6-phenylthio-2,4-pyrimidinedione and [4- (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] methylbromide To give 52 mg of the compound.

수율 : 19.6%Yield: 19.6%

융점 : 148-149℃Melting point: 148-149 DEG C

H NMR(CDCl) : δ 1.19(3H,s), 1.20(3H,s), 2.06(2H,s), 2.17(2H,s), 3.45-3.51(1H,m), 3.59(4H,t,J=11.0Hz), 4.69(2H,s), 5.21(1H,s), 7.16(2H,d,J =7.5Hz), 7.25(1H,t,J=7.5Hz), 7.33(2H,t,J=7.5Hz), 9.55(1H,s). (2H, s), 3.45-3.51 (1H, m), 3.59 (4H, t, 3H, s) J = 11.0 Hz), 4.69 (2H, s), 5.21 (1H, s), 7.16 (2H, d, J = 7.5 Hz), 7.25 J = 7.5 Hz), 9.55 (1H, s).

[실시예 27][Example 27]

[1-{[4-비스(히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온]1-yl] methyl} -5-isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidine Dion]

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 [4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 24와 동일한 방법으로 반응하여 상기화합물 44밀리그램을 얻었다.(4-bis (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] methyl] methyl- Bromide was reacted in the same manner as in Example 24 to give 44 mg of the compound.

수율 : 15.5%Yield: 15.5%

H NMR(CDCl) : δ 1.20(3H,s), 1.21(3H,s), 2.08(2H,s), 2.16(2H,s), 2.28(6H,s), 3.45-3.51(1H,m), 3.62(4H,s), 4.68(2H,s), 5.21(1H,s), 6.76(2H,s ), 6.87(1H,s), 6.69(1H,s). 2.16 (2H, s), 2.28 (6H, s), 3.45-3. 51 (1H, m) , 3.62 (4H, s), 4.68 (2H, s), 5.21 (1H, s), 6.76 (2H, s), 6.87 (1H, s), 6.69 (1H, s).

[실시예 28][Example 28]

[1-{[(3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-페닐티오-2,4-피리미딘디온][1 - {[(3,4-dihydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-ethyl-6-phenylthio-2,4-pyrimidinedione]

[28-a) [3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드][28-a] [3,4-Di (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] methylbromide]

[3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 알콜(3.09그램, 8.0밀리몰)을 이염화메탄에 녹이고, 얼음용기에서 사브롬화 탄소(3.18그램, 9.6밀리몰)와 트리페닐포스핀(3.15그램, 12.0밀리몰)을 차례로 가하고 30분간 교반하였다. 얼음용기를 제거하고, 실온에서 16시간동안 교반하였다. 이염화메탄으로 추출하여 무수 황산 나트륨으로 건조, 여과하여 감암농축한 다음 관 크로마토그래피로 분리정제하여 상기화합물 2.43그램을 얻었다.1-en-1-yl] methyl alcohol (3.09 grams, 8.0 millimoles) was dissolved in dichloromethane, and carbon tetrabromide (3.18 g, Gram, 9.6 mmol) and triphenylphosphine (3.15 g, 12.0 mmol) were added in this order, followed by stirring for 30 minutes. The ice bath was removed and stirred at room temperature for 16 hours. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 2.43 g of the compound.

수율 : 67.4%Yield: 67.4%

H NMR(CDCl) : δ 0.05(6H,s), 0.91(9H,s), 1.85(1H,d,J=15.5Hz), 2.26(2H,m), 2.62-2.70(3H,m), 3.44(1H,t,J=9.0Hz), 3.60(2H,m), 3.78(1H, d,J=7.5Hz), 4.08(2H,s), 5.25(1H,s). (1H, s), 1.85 (1H, d, J = 15.5 Hz), 2.26 (2H, m), 2.62-2.70 (3H, m), 3.44 (1H, t, J = 9.0 Hz), 3.60 (2H, m), 3.78 (1H, d, J = 7.5 Hz), 4.08 (2H, s), 5.25

[28-b) 1-{[3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-페닐티오-2,4-피리미딘디온][28-b] 1 - {[3,4-dihydroxymethyl] cyclopent-1-en-1-yl] methyl} -5- ethyl-6-phenylthio-

5-에틸-6-페닐티오-2,4-피리미딘디온(0.16그램, 0.66밀리몰)과 [3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드(0.30그램, 0.66밀리몰)을 디메틸포름아마이드 10밀리터에 녹인 후 탄산 수소 나트륨(66밀리그램, 0.79밀리몰)를 가한다음 50℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압 증류하여 제거하고 관 크로마토그래피로 분리정제하여 1-{[3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-페닐티오-2,4-피리미딘디온을 합성하고, 이를 테트라히드로퓨란 10밀리리터에 녹인다음 노르말테트라부틸암모늄플로리드르 가하여 실온에서 1시간동안 교반하였다. 테트라히드로퓨란을 감압 증류하여 제거하고 남은 여액을 관 크로마토그래피로 분리정제하여 상기화합물 48밀리그램을 얻었다.(0.16 g, 0.66 mmol) and [3,4-di (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] Methyl bromide (0.30 grams, 0.66 mmol) was dissolved in 10 milliliters of dimethylformamide, sodium hydrogen carbonate (66 milligrams, 0.79 millimoles) was added and stirred at 50 DEG C for 16 hours. The dimethylformamide was removed by distillation under reduced pressure, and the residue was purified by column chromatography to obtain 1 - {[3,4-di (t-butyldimethylsilyloxymethyl) cyclopent-1-enyl] Ethyl-6-phenylthio-2,4-pyrimidinedione was synthesized, dissolved in 10 milliliters of tetrahydrofuran, and then added to normal tetrabutylammonium fluoride, followed by stirring at room temperature for 1 hour. The tetrahydrofuran was removed by distillation under reduced pressure, and the remaining filtrate was separated and purified by column chromatography to obtain 48 mg of the compound.

수율 : 18.7%Yield: 18.7%

H NMR(CDCl) : δ 1.03(3H,t), 1.84(1H,d,J=15.5Hz), 2.38(2H,m), 2.60(1H,br-s), 2.70(2H,q,J=7.0Hz), 3.44(1H,t,J=9.0Hz), 3.59-3.63(2H,m), 3.78(1H,d,J=7.5Hz), 4.59(2H,dd,J=4.5, 7.0Hz), 5.25(1H,s), 7.16(1H,d,J= 7.5Hz), 7.26(1H,t,J=8.5Hz), 7.34(2H,t,J=7.5Hz), 9.30(1H,s). (1H, br, s), 2.70 (2H, q, J = 9.5 Hz) J = 9.0 Hz), 3.59-3.63 (2H, m), 3.78 (1H, d, J = 7.5 Hz), 4.59 (2H, dd, J = , 5.25 (1H, s), 7.16 (1H, d, J = 7.5 Hz), 7.26 (1H, t, J = 8.5 Hz), 7.34 .

[실시예 29][Example 29]

[1-{[(3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - {[(3,4-dihydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-ethyl-6- (3,5-dimethylphenylthio) Lt; / RTI >

5-에틸-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 [3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 28과 동일한 방법으로 반응하여 상기화합물 53밀리그램을 얻었다.(3,4-di (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] Methyl bromide was reacted in the same manner as in Example 28 to give 53 mg of the above compound.

수율 : 19.3%Yield: 19.3%

융점 : 156-157℃Melting point: 156-157 DEG C

H NMR(CDCl) : δ 1.03(3H,t,J=8.5Hz), 1.86(1H,d,J=15.5Hz), 2.28 (6H,s), 2.42(2H,m), 2.60(1H,m), 2.68-2.73((2H,m), 3.44(1H,t,J=9.0Hz), 3.56-3.64(2H,m), 3.79(1H,d,J=7.5Hz), 4.59(2H,d,J=8.5Hz), 5.27(1H,s), 6.76(2H,s), 6.88(1H,s), 9.44(1H,s). (2H, m), 2.60 (1H, m, J = 8.5 Hz), 1.86 (1H, d, J = ), 2.69-2.73 (2H, m), 3.44 (1H, t, J = 9.0Hz), 3.56-3.64 , J = 8.5 Hz), 5.27 (1H, s), 6.76 (2H, s), 6.88 (1H, s), 9.44 (1H, s).

[실시예 30][Example 30]

[1-{[(3,4-비스(히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1 - {[(3,4-bis (hydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-isopropyl-6- (3,5-dimethylphenylthio) -Pyrimidinedione < / RTI >

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 [3,4-비스(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 28과 동일한 방법으로 반응하여 상기화합물 51밀리그램을 얻었다.Synthesis of 5-isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and [3,4-bis (t- butyldimethylsilyloxymethyl) cyclopent- ] Methyl bromide was reacted in the same manner as in Example 28 to give 51 mg of the above compound.

수율 : 17.9%Yield: 17.9%

융점 : 136-137℃Melting point: 136-137 DEG C

H NMR(CDCl) : δ 1.20(3H,d,J=7.0Hz), 1.25(3H,d,J=7.0Hz), 1.87(1H, d,J=15.5Hz), 2.28(6H,s), 2.40-2.44(2H,m), 2.60(1H,br-s), 2.96-3.00(1H,m), 3.44-3.53(2H,m), 3.58-3.65(1H,m), 3.80(1H,dd,J=4.0, 6.5Hz), 4.62-4.69(2H,m), 5.27(1H,s), 6.76(2H,s), 6.88(1H,s), 9.01(1H,s). D, J = 7.0 Hz), 1.87 (1H, d, J = 15.5 Hz), 2.28 (6H, s), 1.25 (3H, (2H, m), 2.80 (1H, m), 2.60 (1H, br s), 2.96-3.00 , J = 4.0, 6.5 Hz), 4.62-4.69 (2H, m), 5.27 (1H, s), 6.76 (2H, s), 6.88 (1H, s), 9.01 (1H, s).

[실시예 31][Example 31]

[1-{[(3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1 - {[(3,4-dihydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-ethyl-6- (3,5-dimethylphenoxy) Lt; / RTI >

5-에틸-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 [3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 28과 동일한 방법으로 반응하여 상기화합물 42밀리그램을 얻었다.(3,4-di (t-butyldimethylsilyloxymethyl) cyclopent-1-en-1-yl] Methyl bromide was reacted in the same manner as in Example 28 to give 42 mg of the compound.

수율 : 17.9%Yield: 17.9%

H NMR(CDCl) : δ 0.94(3H,t), 1.82(1H,d,J=15.5Hz), 2.18-2.22(2H,m), 2.31(6H,s), 2.38-2.45(2H,m), 2.76(1H,br-s), 3.42-3.49(2H,m), 3.60 (1H,m), 3.94(1H,m), 4.33(2H,dd,J=15.5, 29.5Hz), 5.43(1H,s), 6.52(2H,s), 6.78(1H,s), 9.79(1H,s). (2H, m), 2.31 (6H, s), 2.38-2.45 (2H, m) (2H, d, J = 15.5, 29.5 Hz), 5.43 (1H, m), 2.76 , s), 6.52 (2H, s), 6.78 (1H, s), 9.79 (1H, s).

[실시예 32][Example 32]

[1-{[(3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1 - {[(3,4-dihydroxymethyl) cyclopent-1-en-1-yl] methyl} -5- isopropyl-6- (3,5-dimethylphenoxy) Pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 [3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 28과 동일한 방법으로 반응하여 상기화합물 48밀리그램을 얻었다.Synthesis of 5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione and [3,4-di (t- butyldimethylsilyloxymethyl) cyclopent- ] Methylbromide was reacted in the same manner as in Example 28 to give 48 mg of the above compound.

수율 : 17.5%Yield: 17.5%

H NMR(CDCl) : δ 1.21(3H,d,J=7.0Hz), .24(3H,d,J=7.0Hz), 1.83(1H, d,J=15.5Hz), 2.31(6H,s), 2.37(2H,m), 2.57(1H, br-s), 2.74-2.79(1H,m), 3.38-3.50(2H,m), 3.60(1H,q,J=5.0Hz), 3.90(1H,dd,J=7.0Hz), 4.25(1H,d,J= 16.0Hz), 4.34(1H,d,J=16.0Hz), 5.42(1H,s), 6.51(2H,s), 6.77(1H,s), 9.33 (1H,s). D, J = 7.0 Hz), 1.83 (1H, d, J = 15.5 Hz), 2.31 (6H, s) , 2.37 (2H, m), 2.57 (1H, br-s), 2.74-2.79 (1H, m), 3.38-3.50 (d, J = 7.0 Hz), 4.25 (1H, d, J = 16.0 Hz), 4.34 (1H, d, J = 16.0 Hz), 5.42 , < / RTI > s), 9.33 (1H, s).

[실시예 33][Example 33]

[1-{[(3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1 - {[(3,4-dihydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4- Dion]

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 [3,4-디(t-부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 28과 동일한 방법으로 반응하여 상기화합물 68밀리그램을 얻었다.Methyl] cyclopent-1-en-1-yl] methyl] methyl] pyrimidin dione and [3,4-di (t- Bromide was reacted in the same manner as in Example 28 to give 68 mg of the compound.

수율 : 25.0%Yield: 25.0%

융점 : 79-80℃Melting point: 79-80 DEG C

H NMR(CDCl) : δ 0.94-0.97(3H,t,J=7.5Hz), 1.54(1H,d,J=15.5Hz), 2.03-2.04(1H,m), 2.31-2.35(5H,m), 2.39(3H,s), 2.40(3H,s), 3.27-3.33(1H,m), 3.41(1H,m), 3.50(1H,m), 3.79(1H,m), 4.31(1H,m), 4.40(1H,d), 5.34(1H,m), 7.31(1H,s), 7.49(2H,s), 9.06(1H,s). (1H, m), 2.31-2.35 (5H, m), 2.50-3.45 (3H, t, J = , 2.39 (3H, s), 2.40 (3H, s), 3.27-3.33 (1H, m), 3.41 (1H, m), 3.50 ), 4.40 (1H, d), 5.34 (1H, m), 7.31 (1H, s), 7.49 (2H, s), 9.06 (1H, s).

[실시예 34][Example 34]

[1-{[(3,4-디히드록시메틸)시클로펜트-1-엔-1-일]메틸}-5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1 - {[(3,4-dihydroxymethyl) cyclopent-1-en-1-yl] methyl} -5-isopropyl-6- (3,5-dimethylbenzoyl) Lt; / RTI >

5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 [(3,4-디티부틸디메틸실릴옥시메틸)시클로펜트-1-엔-1-일]메틸 브로마이드를 실시예 28과 동일한 방법으로 반응하여 상기화합물 74밀리그램을 얻었다.1-yl] methylbromide (prepared by reacting 5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione with [ Were reacted in the same manner as in Example 28 to give 74 mg of the compound.

수율 : 26.3%Yield: 26.3%

융점 : 81-82℃Melting point: 81-82 DEG C

H NMR(CDCl) : δ 1.20(3H,d,J=7.0Hz), 1.24(3H,d,J=7.0Hz), 1.50(1H, d,J=15.5Hz), 2.24-2.31(2H,m), 2.39(3H,s), 2.40(3H,s), 2.54(2H,m), 3.29 (1H,m), 3.40(1H,br-s), 3.49(1H,m), 3.71-3.84(1H,m), 4.27-4.39(1H,m), 5.20-5.34(1H,m), 7.33(1H,s), 7.49(2H,s), 9.39(1H,s). D, J = 7.0 Hz), 1.24 (3H, d, J = 7.0 Hz), 1.50 (1H, d, J = 15.5 Hz), 2.24-2.31 ), 2.39 (3H, s), 2.40 (3H, s), 2.54 (2H, m), 3.29 1H, m), 4.27-4.39 (1H, m), 5.20-5.34 (1H, m), 7.33 (1H, s), 7.49 (2H, s), 9.39

[실시예 35][Example 35]

[1-[2-(시클로펜트-1-엔-1-일)애틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온]Ethyl] -6- (3, 5-dimethylbenzoyl) -2, 4-pyrimidinedione < / RTI >

[35-a) 2-(시클로펜트-1-엔-1-일)에틸 톨루엔 설포네이트][35-a] 2- (Cyclopent-1-en-1-yl) ethyltoluenesulfonate]

2-(시클로펜트-1-엔-1-일)메탄올(2.24그램, 20밀리몰)을 피리딘 30밀리리터에 녹인 후 파라톨루엔 설포닐클로라이드(3.81그램, 20밀리몰)를 가하고 실온에서 2시간 동안 교반하였다. 피리딘을 감압농축하여 제거하고, 이염화메탄으로 추출하여 1노르말 연산으로 씻어낸 후 건조, 여과하여, 농축한 다음 관 크로마토그래피로 분리정제하여 상기화합물 2.80그램을 얻었다.2-Cyclopent-1-en-1-yl) methanol (2.24 grams, 20 millimoles) was dissolved in 30 milliliters of pyridine, and paratoluenesulfonyl chloride (3.81 grams, 20 millimoles) was added and stirred at room temperature for 2 hours . The pyridine was removed by concentration under reduced pressure, extracted with dichloromethane, washed with 1 N-hexane, dried, filtered, concentrated and purified by column chromatography to obtain 2.80 g of the compound.

수율 : 52.6%Yield: 52.6%

H NMR(CDCl) : δ 0.82(2H,m), 1.99-2.30(6H,m), 2.49(3H,s), 3.51 (1H,m), 4.03(1H,m), 5.22(1H,s), 7.419(2H,d), 7.74(2H,d). M), 5.22 (1H, s), 2.49 (3H, s), 3.51 (1H, m), 4.03 (1H, , 7.419 (2 H, d), 7.74 (2 H, d).

[35-b) 1-[2-(시클로펜트-1-엔-1-일)에틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][35-b] 1- [2- (Cyclopent-1-en-1-yl) ethyl]

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온(0.27그램, 1.0밀리몰)과 2-(시클로펜트-1-엔-1-일)메틸 톨루엔설포네이트(0.27그램, 1.0밀리몰)를 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(0.10밀리그램, 1.2밀리몰과 리튬이오다이드(13밀리그램, 0.1밀리몰)를 가한 후 90℃에서 하룻밤동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거한 다음 관 크로마토그래피로 분리정제하여 흰색의 고체로 상기화합물 148밀리그램을 얻었다.(0.27 g, 1.0 mmol) and 2- (cyclopent-1-en-1-yl) methyltoluenesulfonate (0.27 g, (0.1 mmol, 1.2 mmol) and lithium iodide (13 mg, 0.1 mmol) were added to the solution, and the mixture was stirred overnight at 90 ° C. Dimethylformamide was dissolved in 10 ml of dimethylformamide, The residue was separated by vacuum distillation and then purified by column chromatography to obtain 148 mg of the compound as a white solid.

수율 : 40.4%Yield: 40.4%

융점 : 212-213℃Melting point: 212-213 ° C

H NMR(CDCl) : δ 0.81(2H,dd,J=7.0, 1.5Hz), 0.97(3H,t,J=7.5Hz), 1.99-2.30(6H,m), 2.40(6H,s), 3.29(1H,m), 3.91(1H,m), 5.22(1H,s), 7.35(1H,s), 7.40(2H,s), 8.81(1H,s). (3H, t, J = 7.5 Hz), 1.99-2.30 (6H, m), 2.40 (6H, s), 3.29 (2H, d, J = 7.0, 1.5Hz) (1H, m), 3.91 (1H, m), 5.22 (1H, s), 7.35 (1H, s), 7.40 (2H, s), 8.81 (1H, s).

Mass : m/e 366(M ), 94(100)Mass: m / e 366 (M ), 94 (100)

[실시예 36][Example 36]

[1-[2-(시클로펜트-1-엔-1-일)에틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온]Ethyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

[36-a) 2-(시클로펜트-1-엔-1-일)에틸 톨루엔 설포네이트][36-a] 2- (Cyclopent-1-en-1-yl) ethyltoluenesulfonate]

2-(시클로펜트-1-엔-1-일)에틸 알콜(2.24그램, 20밀리몰)을 피리딘 30밀리리터에 녹인 후 파라돌루엔 설포닐크로라이드(3.81그램, 20밀리몰)를 가하고 실온에서 2시간동안 교반하였다. 피리딘을 감압농축하여 제거하고, 이염화탄소로 추출하여 1노르말 염산으로 씻어낸 후 건조, 여과하여 농축한 다음 관 크로마토그래피로 분리정제하여 3.24그램을 얻었다.(2.81 grams, 20 millimoles) of 2- (cyclopent-1-en-1-yl) ethyl alcohol was dissolved in 30 milliliters of pyridine, followed by addition of paradolenesulfonyl chloride (3.81 grams, 20 millimoles) Lt; / RTI > The pyridine was removed by concentration under reduced pressure, extracted with dichloromethane, washed with 1N hydrochloric acid, dried, filtered, concentrated and purified by column chromatography to obtain 3.24 g.

수율 : 60.8%Yield: 60.8%

H NMR(CDCl) : δ 1.69(2H,m), 1.85(2H,m), 2.02(2H,m), 2.25(1H,m), 3.42(1H,m), 3.94(1H,m), 5.56(2H,d), 7.41(2H,d), 7.74(2H,d). (1H, m), 5.52 (2H, m), 2.25 (1H, m), 3.42 (2H, d), 7.41 (2H, d), 7.74 (2H, d).

[36-b) 1 - [2-(시클로펜트-1-엔-1-일)에틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][36-b] 1- [2- (Cyclopent-1-en-1-yl) ethyl]

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온(0.27그램, 1.0밀리몰)과 2-(시클로펜트-3-엔-1-일)에틸 톨루엔설포네이트(0.27그램, 1.0밀리몰)를 디메틸포름아마이드 10밀리리터에 녹인 후 탄산 수소 나트륨(0.10밀리그램, 1.2밀리몰)과 리튬이오다이드(13밀리그램, 0.1밀리몰)를 가한 후 90℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거한 다음 관 크로마토그래피로 분리정제하여 흰색의 고체로 상기화합물 136밀리그램을 얻었다.(0.27 g, 1.0 mmol) and 2- (cyclopent-3-en-1-yl) ethyltoluenesulfonate (0.27 g, (0.10 mg, 1.2 mmol) and lithium iodide (13 mg, 0.1 mmol) were added to the solution, and the mixture was stirred at 90 ° C for 16 hours. The dimethylformamide was removed by distillation under reduced pressure, and then separated and purified by column chromatography to obtain 136 mg of the compound as a white solid.

수율 : 37.1%Yield: 37.1%

융점 : 190-191℃Melting point: 190-191 DEG C

H NMR(CDCl) : δ 0.97(3H,t,J=7.5Hz), 1.69(2H,m), 1.85(2H,m), 2.02(2H,m), 2.25(1H,m), 2.37(3H,m), 2.41(6H,s), 3.17(1H,m), 3.82(1H,m), 5.56(2H,d), 7.36(1H,s), 7.53(2H,s), 8.64(1H,s). (2H, m), 2.25 (1H, m), 2.37 (3H, m, 2H) (1H, m), 2.41 (6H, s), 3.17 (1H, m), 3.82 (1H, m), 5.56 s).

Mass : m/e 366(M ), 94(100)Mass: m / e 366 (M ), 94 (100)

[실시예 37][Example 37]

[1-[2-(시클로펜트-3-엔-1-일)에틸]-5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온]Yl] ethyl] -5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 2-(시클로펜트-3-엔-1-일)에틸 톨루엔설포네이트를 실시예 35와 동일한 방법으로 반응하여 상기화합물 140밀리그램을 얻었다.(Cyclopent-3-en-1-yl) ethyltoluenesulfonate and 5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione were reacted in the same manner as in Example 35 To obtain 140 milligrams of the compound.

수율 : 36.8%Yield: 36.8%

융점 : 175-176℃Melting point: 175-176 DEG C

H NMR(CDCl) : δ 1.13(3H,d,J=7.0Hz), 1.20(3H,d,J=7.0Hz), 1.70(2H, m), 1.82(2H,m), 2.03(1H,m), 2.33(3H,m), 2.41(6H,s), 3.13(1H,m), 3.80 (1H,m), 5.56(2H,dd,J=4.0, 10.0Hz), 7.36(1H,s), 7.55(2H,s), 8.45(1H,s). (2H, m), 2.03 (1H, m), 1.70 (2H, m), 1.20 (3H, d, J = ), 2.33 (3H, m), 2.41 (6H, s), 3.13 (1H, m), 3.80 (1H, m), 5.56 (2H, dd, J = 4.0,10.0Hz), 7.36 , 7.55 (2H, s), 8.45 (1H, s).

[실시예 38][Example 38]

[1-[2-(시클로펜트-3-엔-1-일)에틸]-5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온]Yl] ethyl] -5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 2-(시클로펜트-3-엔-1-일)에틸 톨루엔설포네이트를 실시예 35와 동일한 방법으로 반응하여 상기화합물 109밀리그램을 얻었다.2- (Cyclopent-3-en-1-yl) ethyltoluenesulfonate was reacted with 5-isopropyl-6- (3,5-dimethylphenoxy) To obtain 109 milligrams of the compound.

수율 : 29.6%Yield: 29.6%

융점 : 109-110℃Melting point: 109-110 DEG C

H NMR(CDCl) : δ 1.14(6H,d,J=7.0Hz), 1.70(2H,m), 1.93(2H,m), 2.15 (1H,m), 2.31(6H,s), 2.45(2H,m), 2.79(2H,m), 3.67(2H,t,J=7.5Hz), 5.62(2H,s) , 6.53(2H,s), 6.78(1H,s), 8.83(1H,s). (2H, m), 2.15 (1H, m), 2.31 (6H, s), 2.45 (2H, (m, 2H), 2.79 (2H, m), 3.67 (2H, t, J = 7.5 Hz), 5.62 (2H, s), 6.53 .

[실시예 39][Example 39]

[1-[2-(시클로펜트-3-엔-1-일)에틸]-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온]Yl] ethyl] -5-isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 2-(시클로펜트-3-엔-1-일)에틸 톨루엔설포네이트를 실시예 35와 동일한 방법으로 반응하여 상기화합물 134밀리그램을 얻었다.(Cyclopent-3-en-1-yl) ethyltoluenesulfonate and 5-isopropyl-6- (3,5-dimethylphenylthio) To obtain 134 mg of the compound.

수율 : 34.8%Yield: 34.8%

융점 : 128-129℃Melting point: 128-129 DEG C

H NMR(CDCl) : δ 1.24(5H,d,J=7.0Hz), 1.68(2H,m), 2.03(2H,m), 2.18 (1H,m), 2.29(6H,s), 2.48(2H,m), 3.53(1H,m), 4.00(2H,t,J=8.0Hz), 5.64(2H,s) , 6.77(2H,s), 6.88(1H,s), 8.95(1H,s). (2H, m), 2.18 (1H, m), 2.29 (6H, s), 2.48 (2H, (2H, s), 6.87 (2H, s), 6.88 (1H, s), 8.95 .

Mass : m/e 384(M ), 247(100)Mass: m / e 384 (M ), 247 (100)

[실시예 40][Example 40]

[1-[2-(시클로펜트-2-엔-1-일)에틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온[1- [2- (Cyclopent-2-en-1-yl) ethyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione

[40-a) 2-(시클로펜트-1-엔-1-일)에틸 브로마이드][40-a] 2- (Cyclopent-1-en-1-yl) ethylbromide]

2-(시클로펜트-3-엔-1-일)에틸 알코올(4.32그램, 38.5밀리몰)을 이염화메탄 15밀리리터에 녹인 후 사브롬화탄소(19.2그램, 57.8몰)을 가하고, 0℃에서 트리페닐 포스핀(15.2그램, 57.8밀리몰)을 조금씩 하고 2시간 동안 교반하였다. 이염화메탄을 제거하고, 에테르 200밀리리터를 가한 다음 고체를 여과 제거한 후 여액을 감압농축한다. 연속적으로 이 물질을 관 크로마토그래피를 이용하여 목적물 5.33그램을 얻었다.(4.32 grams, 38.5 millimoles) of 2- (cyclopent-3-en-1-yl) ethyl alcohol was dissolved in 15 milliliters of dichloromethane, then carbon tetrabromide (19.2 grams, 57.8 mole) Phosphine (15.2 grams, 57.8 mmol) was added portionwise and stirred for 2 hours. After removal of the dichloromethane, 200 milliliters of ether was added, the solid was filtered off, and the filtrate was concentrated under reduced pressure. This material was successively subjected to column chromatography to obtain 5.33 g of the target compound.

수율 : 82.0%Yield: 82.0%

H NMR(CDCl) : δ 1.26-2.29(6H,m), 2.80(1H,m), 3.43(2H,t), 5.72 (2H,s). 1 H NMR (CDCl 3):? 1.26-2.29 (6H, m), 2.80 (1H, m), 3.43 (2H, t), 5.72 (2H, s).

[40-b) 1 - [2-(시클로펜트-2-엔-1-일)에틸]-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온]Ethyl] -5- ethyl-6- (3, 5-dimethylbenzoyl) -2, 4-pyrimidinedione [

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온(0.27그램, 1.0밀리몰)과 2-(시클로펜트-2-엔-1-일)에틸 브로마이드(0.18그램, 1.0밀리몰)를 디메틸포름아마이드 10밀리리터에 녹인 후 탄산수소나트륨(0.10밀리그램, 1.20밀리몰)과 리튬이오다이드(13밀리그램, 0.1밀리몰)을 첨가한 후 90℃에서 16시간동안 교반하였다. 디메틸포름아마이드를 감압증류하여 제거한 후, 관 크로마토그래피로 목적물을 분리정제하여 상기화합물 112밀리그램을 얻었다.(0.17 g, 1.0 mmol) and 2- (cyclopent-2-en-1-yl) ethyl bromide (0.18 g, 1.0 mmol) was dissolved in 10 ml of dimethylformamide, and sodium hydrogencarbonate (0.10 mg, 1.20 mmol) and lithium iodide (13 mg, 0.1 mmol) were added and stirred at 90 캜 for 16 hours. The dimethylformamide was removed by distillation under reduced pressure, and the desired product was purified by column chromatography to obtain 112 mg of the compound.

수율 : 30.6%Yield: 30.6%

융점 : 183-185℃Melting point: 183-185 DEG C

H NMR(CDCl) : δ 0.97(3H,t), 1.24(1H,m), 1.49(1H,m), 1.70(2H,m), 1.90(1H,m), 2.00(1H,m), 2.24(2H,m), 2.41(6H,s), 2.49(1H,m), 3.23(1H,m), 3.81(1H,m), 5.489(1H,m), 5.66(1H,m), 7.35(1H,s), 7.52(2H,s), 8.73(1H,s). (2H, m), 1.90 (1H, m), 2.00 (1H, m), 2.24 (1H, (2H, m), 2.41 (6H, s), 2.49 (1H, m), 3.23 (1H, m), 3.81 (1H, m), 5.489 1H, s), 7.52 (2H, s), 8.73 (1H, s).

[실시예 41][Example 41]

[1-[2-(시클로펜트-2-엔-1-일)에틸]-5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온]Yl] ethyl] -5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 2-(시클로펜트-2-엔-1-일)에틸 브로마이드를 실시예 40과 동일한 방법으로 반응하여 상기화합물 123밀리그램을 얻었다.(Cyclopent-2-en-1-yl) ethyl bromide was reacted by the same method as in Example 40 to give 2- (4-fluorobenzyl) 123 mg of the compound was obtained.

수율 : 32.3%Yield: 32.3%

H NMR(CDCl) : δ 1.15(3H,d,J=6.85Hz), 1.23(3H,d,J=6.85Hz), 1.29 (1H,m), 1.42(1H,m), 1.75(2H,m), 1.92(1H,m), 2.05(1H,m), 2.29(2H,m), 2.45 (6H,s), 2.52(1H,m), 3.35(1H,m), 3.92(1H,m), 5.50(1H,m), 5.73(1H,m), 7.29(1H,s), 7.48(2H,s), 8.85(1H,s). 1.29 (1H, m), 1.42 (1H, m), 1.75 (2H, m), 1.23 (3H, d, J = 6.85Hz) ), 1.92 (1H, m), 2.05 (1H, m), 2.29 (2H, m), 2.45 (6H, s), 2.52 , 5.50 (1H, m), 5.73 (1H, m), 7.29 (1H, s), 7.48 (2H, s), 8.85 (1H, s).

[실시예 42][Example 42]

[1-[2-(시클로펜트-2-엔-1-일)에틸]-5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온]Yl] ethyl] -5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 2-(시클로펜트-2-엔-1-일)에틸 브로마이드를 실시예 40와 동일한 방법으로 반응하여 상기화합물 132밀리그램을 얻었다.2- (cyclopent-2-en-1-yl) ethyl bromide was reacted with 5-isopropyl-6- (3,5-dimethylphenoxy) To obtain 132 mg of the compound.

수율 : 35.8%Yield: 35.8%

융점 : 148-149℃Melting point: 148-149 DEG C

H NMR(CDCl) : δ 1.15(6H,d), 1.36(1H,m), 1.55(1H,m), 1.70(1H,m), 2.00(1H,m), 2.27(2H,m), 2.31(6H,s), 2.58(1H,m), 2.79(1H,m), 3.69(2H,m), 5.56(1H,dd,J=2.05Hz), 5.71(1H,dd,J=2.25Hz), 6.54(2H,s), 6.78(1H,s), 8.37(1H,s). (1H, m), 2.27 (2H, m), 2.31 (2H, m), 2.50 (2H, m), 5.56 (1H, dd, J = 2.05Hz), 5.71 (1H, dd, J = 2.25Hz) , 6.54 (2H, s), 6.78 (1H, s), 8.37 (1H, s).

[실시예 43][Example 43]

[1-[2-(시클로펜트-2-엔-1-일)에틸]-5-이소프로필-6-(3,5-디메틸페닐티,4-피리미딘디온]Ethyl] -5-isopropyl-6- (3, 5-dimethylphenylthiazole, 4-pyrimidinedione)

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 2-(시클로펜트-2-엔-1-일)에틸 브로마이드를 실시예 40과 동일한 방법으로 반응하여 상기화합물 98밀리그램을 얻었다.2- (cyclopent-2-en-1-yl) ethylbromide was reacted with 5-isopropyl-6- (3,5-dimethylphenylthio) 98 mg of the above compound was obtained.

수율 : 25.5%Yield: 25.5%

융점 : 138-140℃Melting point: 138-140 DEG C

H NMR(CDCl) : δ 1.25(6H,dd,j=1.85Hz), 1.45(1H,m), 1.57(1H,m), 1.68(2H,m), 2.01(1H,m), 2.29(6H,s), 2.35(1H,m), 2.61(1H,m), 3.53(1H,m), 4.02(2H,t), 5.59(1H,dd,J=2.0Hz), 5.72(1H,dd,J=2.25Hz), 6.77(2H,s), 6.88 (1H,s), 8.67(1H,s). (2H, m), 2.01 (1H, m), 2.29 (6H, d, J = 1.85Hz), 1.45 dd, J = 2.0 Hz), 2.72 (1H, m), 2.35 (1H, J = 2.25 Hz), 6.77 (2H, s), 6.88 (1H, s), 8.67 (1H, s).

[실시예 44][Example 44]

[1-(2-시클로펜틸)에틸-5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1- (2-cyclopentyl) ethyl-5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

[44-a) (2-시클로펜틸)에틸 톨루엔 설포네이트][44-a] (2-cyclopentyl) ethyltoluenesulfonate]

(2-시클로펜틸)에탄올(8.70그램, 76.2밀리몰)을 피리딘 250밀리리터에 녹인 후 파라톨루엔 설포닐 클로라이드(16.0그램, 83.8밀리몰)을 가하고 실온에서 6시간동안 교반하였다. 리피딘을 감압농축하에 제거하고, 에틸아세테이트로 추출하여, 1노르말 염산으로 씻어낸 후 건조, 여과하여, 관 크로마토그래피를 이용하여 상기화합물 15.7그램을 얻었다.(8.70 grams, 76.2 millimoles) was dissolved in 250 milliliters of pyridine, para-toluenesulfonyl chloride (16.0 grams, 83.8 millimoles) was added, and the mixture was stirred at room temperature for 6 hours. Lipidine was removed under reduced pressure, extracted with ethyl acetate, washed with 1N hydrochloric acid, dried and filtered to obtain 15.7 grams of the compound by column chromatography.

수율 : 73%Yield: 73%

H NMR(CDCl) : δ 0.90-1.89(1H,m), 2.45(3H,s), 4.05(2H,t), 7.27-7.88(4H,dd). 1 H NMR (CDCl 3):? 0.90-1.89 (1H, m), 2.45 (3H, s), 4.05 (2H, t), 7.27-7.88 (4H, dd).

[44-b) 1 - (2-시클로펜틸)에틸-5-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][44-b] l- (2-cyclopentyl) ethyl-5-6- (3,5- dimethylbenzoyl) -2,4-pyrimidinedione]

5-에틸-6-(3,5-디메틸벤조일)-2,4-피리미딘디온(0.27그램, 1.0밀리몰)과 (2-시클로펜틸)에틸 톨루엔 설포네이트(0.27그램, 1.0밀리몰)을 디메틸포름아마이드 10밀리리터에 녹인 후 탄산수소나트륨(0.1밀리그램, 1.2밀리몰)과 리튬이오다이드(13밀리그램, 0.1밀리몰)을 가한 후 90℃에서 하룻밤동안 교반하였다. 디메틸포름아마이드를 감압농축하여 제거한 다음 관 크로마토그래피로 상기화합물을 분리정제하여 90밀리그램을 얻었다.(0.27 grams, 1.0 mmol) and (2-cyclopentyl) ethyltoluenesulfonate (0.27 grams, 1.0 mmol) were dissolved in dimethylformamide (0.1 mg, 1.2 mmol) and lithium iodide (13 mg, 0.1 mmol) were added to the solution, followed by stirring at 90 ° C overnight. The dimethylformamide was removed by concentration under reduced pressure, and then the above compound was purified and purified by column chromatography to obtain 90 milligrams.

수율 : 24.5%Yield: 24.5%

융점 : 194-195℃Melting point: 194-195 DEG C

H NMR(CDCl) : δ 0.95(2H,m), 0.97(2H,t), 1.41-1.62(9H,m), 2.02 (1H,m), 2.28(1H,m), 2.41(6H,s), 3.18(1H,m), 3.79(1H,m), 7.35(1H,s), 7.52(2H,s), 8.64(1H,s). (2H, m), 2.41 (6H, s), 2.41 (2H, m) , 3.18 (1H, m), 3.79 (1H, m), 7.35 (1H, s), 7.52 (2H, s), 8.64 (1H, s).

[실시예 45][Example 45]

[1-(2-시클로펜틸)에틸-5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온][1- (2-cyclopentyl) ethyl-5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸벤조일)-2,4-피리미딘디온과 2-(시클로펜틸)에틸 톨루엔 설포네이트를 실시예 34와 동일한 방법으로 반응하여 상기화합물 95밀리그램을 얻었다.5-isopropyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione and 2- (cyclopentyl) ethyltoluenesulfonate were reacted in the same manner as in Example 34 to give 95 mg of the above compound .

수율 : 24.9%Yield: 24.9%

융점 : 174-176℃Melting point: 174-176 DEG C

H NMR(CDCl) : δ 0.95(2H,m), 1.15(3H,d,J=6.85Hz), 1.23(3H,d,J =6.85Hz), 1.39-1.69(9H,m), 2.32(1H,m), 2.41(6H,s), 3.15(1H,m), 3.77(1H, m), 7.36(1H,s), 7.55(2H,s), 8.90(1H,s). (3H, d, J = 6.85Hz), 1.39-1.69 (9H, m), 2.32 (1H, m), 2.41 (6H, s), 3.15 (1H, m), 3.77 (1H, m), 7.36 (1H, s), 7.55 (2H, s), 8.90 (1H, s).

[실시예 46][Example 46]

[1-(2-시클로펜틸)에틸-5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온][1- (2-cyclopentyl) ethyl-5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페녹시)-2,4-피리미딘디온과 2-(시클로펜틸)에틸 톨루엔 설포네이트를 실시예 44와 동일한 방법으로 반응하여 상기화합물 105밀리그램을 얻었다.2- (cyclopentyl) ethyltoluenesulfonate was reacted with 5-isopropyl-6- (3,5-dimethylphenoxy) -2,4-pyrimidinedione in the same manner as in Example 44 to obtain 105 mg of the compound .

수율 : 28.3%Yield: 28.3%

융점 : 136-138℃Melting point: 136-138 DEG C

H NMR(CDCl) : δ 1.04(2H,m), 1.15(6H,d), 1.46-1.71(9H,m), 2.31 (6H,s), 2.80(1H,m), 3.65(2H,t), 6.53(2H,s), 6.78(1H,s), 8.60(1H,s). (1H, m), 3.65 (2H, t), 2.65 (2H, m) , 6.53 (2H, s), 6.78 (1H, s), 8.60 (1H, s).

[실시예 47][Example 47]

[1-(2-시클로펜틸)에틸-5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온][1- (2-cyclopentyl) ethyl-5-isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione]

5-이소프로필-6-(3,5-디메틸페닐티오)-2,4-피리미딘디온과 2-(시클로펜틸)에틸 톨루엔 설포네이트를 실시예 44과 동일한 방법으로 반응하여 상기화합물 80밀리그램을 얻었다.2- (cyclopentyl) ethyltoluenesulfonate was reacted in the same manner as in Example 44 to give 80 mg of the compound as a white solid. 1H-NMR (DMSO-d6) .

수율 : 20.7%Yield: 20.7%

융점 : 95-98℃Melting point: 95-98 DEG C

H NMR(CDCl) : δ 1.11(2H,m), 1.25(6H,d), 1.47-1.78(9H,m), 2.29 (6H,s), 3.53(1H,m), 4.00(2H,t), 6.77(2H,s), 6.88(1H,s), 9.19(1H,s). (1H, m), 4.00 (2 H, m), 1.25 (6H, d), 1.47 , 6.77 (2H, s), 6.88 (1H, s), 9.19 (1H, s).

[효과시험 및 독성시험][Effect test and toxicity test]

본 발명의 화합물의 시험관내 항 HIV 억제효과 시험은 문헌에 공지된 방법에 의해 하기와 같이 수행한다[참조문헌 : J. Med. Chem., 34, 357, 1991]. 즉, 바이러스에 감염된 MT-4 세포의 세포독성을 본 발명의 약제가 어느정도 저해하는 가를 판정한다. 배양액에 MT-4세포를 2.5×10 세포/㎖의 농도로 분산시킨 후, 1000 CCID(세포의 50%가 감염됨)가 되도록 HIV를 접종시킨다. 즉시 여러가지 시료약제가 들어있는 편편한 미세역가판에 세포분산액을 100㎕씩 옮긴다. 약 4일 내지 5일동안 37℃에서 배양한 후 MTT 방법을 이용하여 약효를 판정한다. 세포 독성 시험도 병행하여, 실험적으로 감염시킨 감염된 세포의 생존성을 MTT 방법으로 측정함으로서 세포독성을 판정한다.The in vitro anti-HIV inhibitory effect test of the compounds of the present invention is carried out by the methods known in the literature as follows (see J. Med. Chem., 34, 357, 1991). That is, it is determined to what extent the drug of the present invention inhibits cytotoxicity of virus-infected MT-4 cells. MT-4 cells were added to the culture solution at 2.5 x 10 < After being dispersed at a concentration of cells / ml, HIV is inoculated so that 1000 CCID (50% of the cells are infected). Immediately transfer 100 μl of the cell dispersion onto a flat microtiter plate containing various sample agents. After incubation at 37 [deg.] C for about 4 to 5 days, the efficacy is determined using the MTT method. Cytotoxicity tests are also carried out to determine cytotoxicity by measuring the viability of experimentally infected infected cells by MTT method.

상기 시험방법에 의해 본 발명의 화합물을 시험한 결과는 다음과 같다.The test results of the compounds of the present invention were as follows.

본 발명의 21개의 화합물들은 in vitro 실험에서 대조약물인 AZT 보다 HIV억제효과 실험에서 동등하거나 최고 1,736,000배까지 월등한 항바이러스 효과가 관찰되었으며, 상대적으로 적은 독성이 발견되었다.The 21 compounds of the present invention showed superior anti-viral effects in the in vitro test, up to 1,736,000 times in the HIV inhibition test than the control drug AZT, and relatively low toxicity was found.

다음의 표에 제시된 각각의 성분은 통상의 주사제의 제조방법에 따라서 주사용 증류수에 용해시키고, 주사용 증류수로 용량을 맞춘다음 앰플 또는 바이알에 충진하고 멸균하여 주사제를 제조한다.Each of the ingredients shown in the following table is dissolved in distilled water for injection according to a conventional method for preparing an injectable solution, the dose is adjusted with distilled water for injections, and the ampoule or vial is filled and sterilized to prepare an injection.

Claims (3)

다음의 일반 구조식(I)로 표시되는 화합물 또는 그 제약학적으로 허용되는 산부가염.A compound represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof. 상기 일반 구조식(I)에서 R1, R2, R3는 수소원자, 할로겐 원자, C1-C10의 알킬기, C1-C10의 티오 알킬기, C3-C8의 치환 또는 비치환 사이클릭 알킬기, 불포화 알킬기, 치환된 알킬, 아릴 히드록시기, C1-C10의 알킬 아민기, 니트로기, C1-C4의 저급알콕시기 또는 C1-C4의 저급티오 알콕시기이고, (Sub)cycloalk(en)yl는또는이다.In the above general formula (I), R 1 , R 2 and R 3 are each a hydrogen atom, a halogen atom, a C 1 -C 10 alkyl group, a C 1 -C 10 thioalkyl group, a C 3 -C 8 substituted or unsubstituted cyclic alkyl group, an unsaturated alkyl group, a lower alkylthio of substituted alkyl, aryl, hydroxy, C 1 -C 10 alkyl amine group, a nitro group, C 1 -C 4 lower alkoxy groups or C 1 -C 4 alkoxy group, (Sub ) cycloalk (en) yl is or to be. (여기에서, R4, R5는 각각 수소원자, 히드록시, 메틸, 보호된 히드록시 메틸기이다.)이고, Z는 산소원자, 황원자, 탄소원자 또는 카르보닐기를 나타내며, X는 산소원자 또는 황원자이고, n은 0-3의 정수이다.(Wherein, R 4, R 5 is a hydroxymethyl group, each a hydrogen atom, hydroxy, methyl, protected.), And, Z represents an oxygen atom, a sulfur atom, a carbon atom or a carbonyl group, X is an oxygen atom or a sulfur atom, and , and n is an integer of 0-3. 구조식(a)의 화합물을 구조식(b)의 화합물과 반응시켜서 일반 구조식(I)의 화합물을 제조하는 방법.A process for preparing a compound of general formula (I) by reacting a compound of formula (a) with a compound of formula (b). 상기 반응식에서, (Sub)cycloalk(en)yl, R1, R2, R3, X, Z, n 등은 전술한 바와 같으며, Lie은 할로겐 원자와 알킬설포닐 또는 아릴설포닐 같은 이탈기이다.In the above reaction formula, (Sub) cycloalk (en) yl, R 1 , R 2 , R 3 , X, Z, n and the like are as described above, Lie represents a leaving group such as an alkylsulfonyl or arylsulfonyl to be. 일반 구조식(I)의 화합물을 통상의 약제학적으로 허용되는 부형제, 결합제, 붕해제, 활택제, 용제, 용해보조제, 보존제, 안정화제, 연고기제, pH조절제, 방향제에서 선택된 1종 이상의 보조제와 혼합하고, 통상의 약제학적으로 사용되는 방법으로, 통상의 약제학적으로 사용되는 제제형태로 제형화한 항바이러스 효과를 갖는 약학적 제제.The compound of general formula (I) is mixed with one or more auxiliaries selected from conventional pharmaceutically acceptable excipients, binders, disintegrants, lubricants, solvents, auxiliary agents for solubility, preservatives, stabilizers, ointment bases, And which has an antiviral effect, which is formulated in the form of a conventional pharmaceutical preparation, in a usual pharmaceutical manner. 상기 반응식에서, (Sub)cycloalk(en)yl, R1, R2, R3, X, Z, n 등은 전술한 바와 같으며, Lie은 할로겐 원자와 알킬설포닐 또는 아릴설포닐 같은 이탈기이다.In the above reaction formula, (Sub) cycloalk (en) yl, R 1 , R 2 , R 3 , X, Z, n and the like are as described above, Lie represents a leaving group such as an alkylsulfonyl or arylsulfonyl to be.
KR1019960047458A 1996-02-22 1996-10-22 Novel antiviral 6-substituted pyrimidinedione homo-carbocyclic nucleocide derivative and its preparation KR100197791B1 (en)

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RU97118134A RU2138487C1 (en) 1996-02-22 1996-12-30 New antiviral homocarbocyclic nucleoside derivatives of substituted pyrimidinediones, method of their synthesis and composition containing thereof as active components
AT96943370T ATE243202T1 (en) 1996-02-22 1996-12-30 NEW ANTIVIRAL, HOMOCARBOCLIC NUCLEOSIDE DERIVATIVES OF SUBSTITUTED PYRIMIDIDIONES, METHOD FOR THE PRODUCTION THEREOF AND COMPOSITIONS CONTAINING THEM AS THE ACTIVE INGREDIENTS
US08/945,121 US5922727A (en) 1996-02-22 1996-12-30 Antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
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CA002217026A CA2217026C (en) 1996-02-22 1996-12-30 New antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
BRPI9604907A BRPI9604907B8 (en) 1996-02-22 1996-12-30 antiviral substituted pyrimidinodione homocarbocyclic nucleoside derivatives and composition containing active ingredient antiviral substituted pyrimidinodione homocarbocyclic nucleoside derivatives.
CN96193400A CN1092647C (en) 1996-02-22 1996-12-30 New antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for preparation thereof and compositions containing the same as active ingredients
AU12124/97A AU710490B2 (en) 1996-02-22 1996-12-30 New antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
JP9530013A JP3049095B2 (en) 1996-02-22 1996-12-30 Novel antiviral substituted pyrimidinedione monocyclic carbocyclic nucleoside derivative, method for producing the same and composition containing the same as active ingredient
EP96943370A EP0827498B1 (en) 1996-02-22 1996-12-30 New antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
IDP970469A ID15963A (en) 1996-02-22 1997-02-19 NEW ACTIVIRUS OF PIRIMIDINDION HOMOCARBOSICLIC SUBSTITUTED NUCLEOSIDE SUBSTITUTIONS AND THE METHOD OF THEIR PRODUCTION AND COMPOSITION CONTAINING THE SAME MATERIAL AS ACTIVE MATERIALS
TW086102026A TW494098B (en) 1996-02-22 1997-02-20 New antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
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KR20020074683A (en) * 2001-03-21 2002-10-04 주식회사 엘지씨아이 Antiviral 2,4-pyrimidinedione derivatives and process for preparing same
KR100368891B1 (en) * 1999-03-04 2003-01-24 한국화학연구원 Novel antiviral 2,4-pyrimidinedione derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100368891B1 (en) * 1999-03-04 2003-01-24 한국화학연구원 Novel antiviral 2,4-pyrimidinedione derivatives
KR20020074683A (en) * 2001-03-21 2002-10-04 주식회사 엘지씨아이 Antiviral 2,4-pyrimidinedione derivatives and process for preparing same

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