KR960041174A - Irreversible HIV Protease Inhibitor with Anti-Aids (AIDS) Effect, Method of Preparation and Composition Comprising the Same - Google Patents

Irreversible HIV Protease Inhibitor with Anti-Aids (AIDS) Effect, Method of Preparation and Composition Comprising the Same Download PDF

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Publication number
KR960041174A
KR960041174A KR1019950013368A KR19950013368A KR960041174A KR 960041174 A KR960041174 A KR 960041174A KR 1019950013368 A KR1019950013368 A KR 1019950013368A KR 19950013368 A KR19950013368 A KR 19950013368A KR 960041174 A KR960041174 A KR 960041174A
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South Korea
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compound
formula
phenyl
amino
valinyl
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KR1019950013368A
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Korean (ko)
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KR0161138B1 (en
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윤흥식
손영찬
박지효
정원희
최낙현
문광률
최호일
김성천
김충렬
이태규
권영도
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성재갑
주식회사 Lg 화학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/46—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by amide or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

본 발명은 HIV 프로테아제의 억제제로서 유용한 신규 화합물 및 그의 제조방법 및 이를 포함하는 조성물에 관한 것으로서, 하기의 일반식(Ⅰ)의 시스-에폭사이드 구조를 갖는 화합물 및 그의 약학적으로 허용되는 염, 수화물 또는 용매화물은, HIV 프로테아제의 비가역적 억제제로서 억제 효과는 높은 반면 그 세포독성은 낮기 때문에, 에이즈 또는 HIV감염의 치료 또는 예방용 제제로서 유용하게 사용될 수 있다.The present invention relates to a novel compound useful as an inhibitor of HIV protease, a method for preparing the same, and a composition comprising the same, the compound having a cis-epoxide structure of the following general formula (I) and a pharmaceutically acceptable salt and hydrate thereof Alternatively, solvates can be usefully used as agents for the treatment or prevention of HIV or HIV infection because of their high inhibitory effect and low cytotoxicity as irreversible inhibitors of HIV proteases.

상기 식에서, R1, R2및 R3는 명세서중에서 정의한 바와 같다.In the above formula, R 1 , R 2 and R 3 are as defined in the specification.

Description

항 에이즈(AIDS)효과를 갖는 비가역적 HIV 프로테아제 억제제, 이의 제조방법 및 이를 포함하는 조성물Irreversible HIV Protease Inhibitor with Anti-Aids (AIDS) Effect, Method of Preparation and Composition Comprising the Same

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (6)

하기 일반식(Ⅰ)의 시스-에폭사이드 구조를 갖는 화합물 또는 그의 약제학적으로 허용되는 염, 수화물 또는 용매화물;A compound having a cis-epoxide structure of the general formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof; 상기 식에서, R1은 탄소수 1 내지 8의 직쇄, 측쇄 또는 사이클릭 알킬 라디칼; 탄소수 1 내지 8의 직쇄, 측쇄 또는 사이클릭 알콕시; 아릴로 치환된 저급 알콕시; 또는 헤테로사이클이고, R2및 R3는 서로 독립적으로 저급알킬, 방향족 라디칼로 치환된 저급 알킬, 탄소수 3 내지 8의 사이클릭 알킬, 사이클릭 알킬 라티칼로 치환된 저급 알킬 또는 방향족 라디칼이다.Wherein R 1 is a straight, branched or cyclic alkyl radical having 1 to 8 carbon atoms; Straight, branched or cyclic alkoxy of 1 to 8 carbon atoms; Lower alkoxy substituted with aryl; Or heterocycle, and R 2 and R 3 are independently of each other lower alkyl, lower alkyl substituted with aromatic radicals, cyclic alkyl having 3 to 8 carbon atoms, lower alkyl substituted with cyclic alkyl radicals or aromatic radicals. 제1항에 있어서, R1이 3-티오펜이고, R2가 이소프로필이며, R3가 벤질인 화합물.The compound of claim 1, wherein R 1 is 3-thiophene, R 2 is isopropyl, and R 3 is benzyl. 제1항에 있어서, 〔(5S)-〔〔(N-메톡시아세틸)-β-메탄설포닐-L-발리닐〕아미노〕-(4R,3S)-에폭시-6-페닐-1-헥사노일〕-〔(2S)-〔1-페닐-3-메틸〕부틸〕아미드;〔(5S)-〔〔(N-이소프로피옥시아세틸)-β-메탄설포닐-L-발리닐〕아미노〕-(4R,3S)-에폭시-6-페닐-1-헥사노일〕-〔(2S)-〔1-페닐-3-메틸〕부틸〕아미드;〔(5S)-〔〔(N-이소발레로일)-β-메탄설포닐-L-발리닐〕아미노〕-(4R,3S)-에폭시-6-페닐-1-헥사노일〕-〔(2S)-〔1-페닐-3-메틸〕부틸〕아미드;〔(5S)-〔〔(N-3-티오펜아세틸-β-메탄설포닐-L-발리닐〕아미노〕-(4R,3S)-에폭시-6-페닐-1-헥사노일〕-〔(2S)-〔1-페닐-3-메틸〕부틸〕아미드;〔(5S)-〔〔(N-3-푸란아세틸)-β-메탄설포닐-L-발리닐〕아미노〕-(4R,3S)-에폭시-6-페닐-1-헥사노일〕-〔(2S)-〔1-페닐-3-메틸〕부틸〕아미드 및 이들이 약학적으로 허용되는 염, 수화물 및 용매화물 중에서 선택된 화합물.The compound according to claim 1, wherein ((5S)-[[(N-methoxyacetyl) -β-methanesulfonyl-L-valinyl] amino]-(4R, 3S) -epoxy-6-phenyl-1-hexa Noyl]-[(2S)-[1-phenyl-3-methyl] butyl] amide; [(5S)-[[(N-isopropoxyoxyacetyl)-[beta] -methanesulfonyl-L-valinyl] amino] -(4R, 3S) -epoxy-6-phenyl-1-hexanoyl]-[(2S)-[1-phenyl-3-methyl] butyl] amide; [(5S)-[[(N-isovalero Il) -β-methanesulfonyl-L-valinyl] amino]-(4R, 3S) -epoxy-6-phenyl-1-hexanoyl]-[(2S)-[1-phenyl-3-methyl] butyl ] Amide; [(5S)-[[(N-3-thiophenacetyl-β-methanesulfonyl-L-valinyl] amino]-(4R, 3S) -epoxy-6-phenyl-1-hexanoyl] -[(2S)-[1-phenyl-3-methyl] butyl] amide; [(5S)-[[(N-3-furanacetyl) -β-methanesulfonyl-L-valinyl] amino]-( 4R, 3S) -epoxy-6-phenyl-1-hexanoyl]-[(2S)-[1-phenyl-3-methyl] butyl] amide and their pharmaceutically acceptable salts, hydrates and solvates A compound selected from the. 일반식(Ⅱ)의 화합물을 일반식(Ⅲ)의 화합물과 커플링 반응시킨 후 산화시켜 일반식(Ⅳ)의 화합물을 얻고; 일반식(Ⅳ)의 화합물을 탈보호시킨 후 일반식(Ⅴ)의 화합물을 커플링시키고 산화시켜 일반식(Ⅵ)의 화합물을 얻고; 일반식(Ⅵ)의 화합물을 탈보호시킨 후 R1-CH2COOH를 커플링시키는 것을 특징으로 하는 일반식(Ⅰ)의 화합물의 제조방법.Coupling the compound of formula (II) with the compound of formula (III) and then oxidizing to obtain a compound of formula (IV); Deprotecting the compound of formula (IV) followed by coupling and oxidizing the compound of formula (V) to obtain a compound of formula (VI); A process for preparing a compound of formula (I) characterized by coupling R 1 -CH 2 COOH after deprotecting the compound of formula (VI). 상기에서, R1, R2및 R3는 제1항에서 정의한 바와 같고, ⓟ는 아미노기 보호그룹이다.In the above, R 1 , R 2 and R 3 are as defined in claim 1, ⓟ is an amino group protecting group. 제4항에 있어서, 일반식(Ⅶ)의 화합물을 비티그 반응시켜 일반식(Ⅷ)의 화합물을 수득한 다음, 이를 산촉매 존재하에 t-부탄올중에서 용매의 환류온도로 가열하는 것에 의해 상기 일반식(Ⅱ)의 화합물을 제조하는 단계를 더욱 포함하는 것을 특징으로 하는 방법.The compound of formula (IV) according to claim 4, wherein the compound of formula (IV) is subjected to a BIG reaction to obtain a compound of formula (IV), which is then heated to the reflux temperature of the solvent in t-butanol in the presence of an acid catalyst. Further comprising preparing the compound of (II). 상기에서, X는 할로겐 원자이고, ⓟ는 아미노기 보호그룹이다.In the above, X is a halogen atom, ⓟ is an amino group protecting group. 제1항 내지 제3항 중 어느 한 항의 화합물 또는 그의 약학적으로 허용되는 염, 수화물 또는 용매화합물을 유효성분으로 포함하는, 후천성 면역결핍증 또는 인간 면역결핍 바이러스(HIV)감염의 예방 또는 치료에 유용한 조성물.Useful for the prevention or treatment of acquired immunodeficiency or human immunodeficiency virus (HIV) infection, comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient. Composition. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
KR1019950013368A 1995-05-26 1995-05-26 Irreversible hiv protease inhibitors with anti-aids effect, process for the preparation thereof and compositions containing the same KR0161138B1 (en)

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KR1019950013368A KR0161138B1 (en) 1995-05-26 1995-05-26 Irreversible hiv protease inhibitors with anti-aids effect, process for the preparation thereof and compositions containing the same

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