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Substituted cyclopentane neuraminidase inhibitor compounds, composition and methods of inhibiting influenza virus neuraminidase and treatment of influenza virus infection

机译：取代的环戊烷神经氨酸酶抑制剂化合物，抑制流感病毒神经氨酸酶的组合物和方法以及流感病毒感染的治疗

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B SUBSTITUTED CYCLOPENTAN NEURAMINIDASE INHIBITING COMPOUNDS, COMPOSITION AND METHODS OF INHIBITING THE NEURAMINIDASE OF THE D INFLUENCE VIRUS B AND TREATMENT OF INFECTION BY VIRUSES OF THE D INFLUENCES: U is CH, O or S; Z is -C (R ~ 2 ~) (R ~ 3 ~), -CHN (R ~ 2 ~), R (3 ~), C (R ~ 3 ~ [(CH ~ 2 ~) ~ n ~ R ~ 2 ~], CH-C (R ~ 3 ~) (R ~ 8 ~) (CH ~ 2 ~) ~ n ~ R ~ 2 ~, C [(CH ~ 2 ~) ~ n ~ R ~ 2 ~] - [CH (R ~ 3 ~) (R ~ 8 ~)], C [(R ~ 3 ~)] [CH [(CH ~ 2 ~) ~ n ~ R ~ 2 ~] (R ~ 8 ~)]; R ~ 1 ~ is H, (CH ~ 2 ~) ~ n ~ OH, (CH ~ 2 ~) ~ n ~ NH ~ 2 ~, (CH ~ 2 ~) ~ n ~ NR ~ 10 ~ R ~ 11 ~, (CH ~ 2 ~) ~ n ~ OR ~ 11 ~, (CH ~ 2 ~) ~ n ~ SR ~ 11 ~ or (CH ~ 2 ~) ~ n ~ halogen; R ~ 9 ~ is (CH ~ 2 ~) ~ n ~ CO ~ 2 ~ H, (CH ~ 2 ~) ~ n ~ SO ~ 3 ~ H, (CH ~ 2 ~) ~ n ~ PO ~ 3 ~ H ~ 2 ~, (CH ~ 2 ~) ~ n ~ NO ~ 2 ~, CH (SCH ~ 3 ~) ~ 3 ~, esters or salts thereof; or R ~ 1 ~ R ~ 9 ~ together represent R ~ 2 ~ is H, NHC (O) R ~ 5 ~ , NHC (S) R ~ 5 ~, NHSO ~ 2 ~ R ~ 5 ~, C (O) NHR ~ 5 ~, SO ~ 2 ~ NHR ~ 5 ~, CH ~ 2 ~ S (O) R ~ 5 ~ or CH ~ 2 ~ SO ~ 2 ~ R ~ 5 ~; R ~ 3 ~ and R ~ 8 ~ individually are H, (CH ~ 2 ~) ~ n ~ C (O) R ~ 10 ~, (CH ~ 2 ~) ~ n ~ CO ~ 2 ~ R ~ 10 ~, (CH ~ 2 ~) ~ m ~ OR ~ 10 ~, CH (OR ~ 10 ~) CH (R ~ 10 ~) ~ m ~, C (O) N ( OR ~ 10 ~) ~ m ~, C (O) N (OR ~ 10 ~) R ~ 10 ~, (CH ~ 2 ~) ~ n ~ N (R ~ 10 ~) ~ m ~, CH (R ~ 10 ~) ~ m ~, (CH ~ 2 ~) ~ n ~ (R ~ 10 ~) ~ m ~, CH ~ 2 ~ CH (OR ~ 10 ~) CH ~ 2 ~ OR ~ 10 ~, CH (OR ~ 10 ~) CH (OR ~ 10 ~) CH ~ 2 ~ OR ~ 10 ~, CH ~ 2 ~ OR ~ 10 ~, CH (OR ~ 10 ~) CH ~ 2 ~ NHR ~ 10 ~, CH ~ 2 ~ CH (OR ~ 10 ~) CH ~ 2 ~ NHR ~ 10 ~, CH (OR ~ 10 ~) CH (OR ~ 10 ~) CH ~ 2 ~ NHR ~ 10 ~, C (= NR ~ 10 ~) N (R ~ 10 ~) ~ m ~, NHR ~ 10 ~, NHC (= NR ~ 10 ~) NR ~ 10 ~) ~ m ~, (CH ~ 2 ~) ~ m ~ -XWY, CH ~ 2 ~ CH (XWY) CH ~ 2 ~ OR ~ 10 ~, CH (XWY) CH (OR ~ 10 ~) CH ~ 2 ~ OR ~ 10 ~, CH (XWY) CH ~ 2 ~ (OR ~ 10 ~), CH (OR ~ 10 ~) ) CH (XWY) CH ~ 2 ~ OR ~ 10 ~, CH (OR ~ 10 ~) CH ~ 2 ~ (XWY), CH ~ 2 ~ CH (XWY) CH ~ 2 ~ NHR ~ 10 ~, CH (XWY) CH (OR ~ 10 ~) CH ~ 2 ~ NHR ~ 10 ~, CH (XWY) CH ~ 2 ~ (NHR10), CH (OR ~ 10 ~) CH (XWY) CH ~ 2 ~ NHR ~ 10 ~ or CH ( NHR ~ 10 ~) CH ~ 2 ~ (XWY); provided that at least one of R ~ 2 ~, R ~ 3 ~ and R ~ 8 ~ is different from H; R ~ 4 ~ is H, (CH ~ 2 ~) ~ n ~ OH, (CH ~ 2 ~) ~ n ~ OR ~ 11 ~, (CH ~ 2 ~) ~ n ~ OC (O) R ~ 11 ~, (CH ~ 2 ~) ~ n ~ NHC (NR ~ 11 ~) NHR ~ 11 ~, (CH ~ 2 ~) ~ n ~ NR ~ 10 ~ R ~ 11 ~, (CH ~ 2 ~) ~ n ~ NH ~ 2 ~, (CH ~ 2 ~) ~ n ~ C (= NH) (NH ~ 2 ~), (CH ~ 2 ~) ~ n ~ NHC (= NR ~ 11 ~) NH ~ 2 ~, (CH ~ 2 ~) ~ n ~ NHC (= NR ~ 7 ~) NH ~ 2 ~, (CH ~ 2 ~) ~ n ~ CN, (CH ~ 2 ~) ~ n ~ N ~ 3 ~, C (= NH) NH ~ 2 ~, C (NR ~ 7 ~) NH ~ 2 ~ or C (NR ~ 11 ~) NH ~ 2 ~; R ~ 5 ~ is H, lower alkyl, cycloalkyl, alkyl substituted by halogen, aryl, substituted aryl or CF ~ 3 ~; R ~ 7 ~ is H, (CH ~ 2 ~) ~ n ~ OH, (CH ~ 2 ~) ~ n ~ CN, (CH ~ 2 ~) ~ n ~ NH ~ 2 ~ or (CH ~ 2 ~) ~ n ~ NO ~ 2 ~; R ~ 10 ~ is H, lower alkyl, lower alkylene, branched alkyl, cycloalkyl, (CH ~ 2 ~) ~ n ~ aromatic, aromatic substituted by (CH ~ 2 ~) ~ n ~ or when m is 2 both groups R ~ 10 ~ may also be interconnected to form an N-substituted heterocyclic ring or another 5- or 6-membered heterocyclic ring; R ~ 11 ~ is lower alkyl, branched alkyl, (CH ~ 2 ~) ~ m ~ aromatic, SO ~ 2 ~ R ~ 10 ~, C (O) R ~ 10 ~ or C (O) OR ~ 10 ~; R ~ 12 ~ and R ~ 13 ~ are H, (CH ~ 2 ~) ~ n ~ OH, (CH ~ 2 ~) ~ n ~ NH ~ 2 ~, (CH ~ 2 ~) ~ n ~ NR ~ 10 ~ R ~ 11 ~, (CH ~ 2 ~) ~ n ~ OR ~ 11 ~, (CH ~ 2 ~) ~ n ~ F, (CH ~ 2 ~) ~ n ~ OC (O) R ~ 11 ~, (CH ~ 2 ~) ~ n ~ NHC (O) R ~ 11 ~ or XWY; m is 1 or 2; n is 0-4; p is 0 or 1; X is O, S, CH ~ 2 ~ or NH; W is a spacer group formed from a chain of 1 to 100 atoms and optionally also comprising substituted carbon and / or nitrogen atoms and optionally including oxygen or sulfur atoms; and Y is H, OH, SH, NH ~ 2 ~, CH = O, CH = CH ~ 2 ~, CO ~ 2 ~ H, CONHNH ~ 2 ~ or a protected form of one of these terminal features; and pharmaceutically acceptable salts thereof and their methods of preparation. Compounds of the above formula are influenza virus neuraminidase inhibitors and can be used to treat patients infected with the influenza virus. Also provided are intermediate compounds represented by the formulas in which R ~ 4 ~ and R ~ 9 ~ are as defined above; and where each R ~ 14 ~ individually is H, O, (CH ~ 2 ~) ~ n ~ CO ~ 2 ~ H, (CH ~ 2 ~) ~ n ~ SO ~ 3 ~ H, (CH ~ 2 ~) ~ n ~ PO ~ 3 ~ H, (CH ~ 2 ~) ~ n ~ NO ~ 2 ~, CH (SCH ~ 3 ~) ~ 3 ~, esters or salts thereof and provided that at least one of R ~ 14 ~ either H and R ~ 3 ~ and R ~ 4 ~ are as defined above.

机译：取代的环磷酰胺神经氨酸酶抑制化合物，抑制感染病毒的神经氨酸酶的组成和方法，以及感染病毒的感染治疗：U是CH，O或S; Z是-C（R〜2〜）（R〜3〜），-CHN（R〜2〜），R（3〜），C（R〜3〜[（CH〜2〜）〜n〜R〜 2〜]，CH-C（R〜3〜）（R〜8〜）（CH〜2〜）〜n〜R〜2〜，C [（CH〜2〜）〜n〜R〜2〜]- [CH（R〜3〜）（R〜8〜）]，C [（R〜3〜）] [CH [（CH〜2〜）〜n〜R〜2〜]（R〜8〜）]; R〜1〜是H，（CH〜2〜）〜n〜OH，（CH〜2〜）〜n〜NH〜2〜，（CH〜2〜）〜n〜NR〜10〜R〜11〜，（CH〜2〜）〜n〜OR〜11〜，（CH〜2〜）〜n〜SR〜11〜或（CH〜2〜）〜n〜卤素; R〜9〜为（CH〜2〜）〜n〜CO〜2〜H，（CH〜2〜）〜n〜SO〜3〜H，（CH〜2〜）〜n〜PO〜3〜H〜2〜，（CH〜2〜）〜n 〜NO〜2〜，CH（SCH〜3〜）〜3〜，其酯或盐;或R〜1〜R〜9〜一起代表R〜2〜为H，NHC（O）R〜5〜，NHC （S）R〜5〜，NHSO〜2〜R〜5〜，C（O）NHR〜5〜，SO〜2〜NHR〜5〜，CH〜2〜S（O）R〜5〜或CH〜 2〜SO〜2〜R〜5〜; R〜3〜和R〜8〜分别为H（CH〜2〜）〜n〜C（O）R〜10〜，（CH〜2〜）〜n 〜CO〜2〜R〜10〜，（CH〜2〜）〜m〜OR〜10〜，CH（OR〜10〜）CH（R〜10〜）〜m〜，C（O）N（O R〜10〜）〜m〜，C（O）N（OR〜10〜）R〜10〜，（CH〜2〜）〜n〜N（R〜10〜）〜m〜，CH（R〜10 〜）〜m〜，（CH〜2〜）〜n〜（R〜10〜）〜m〜，CH〜2〜CH（OR〜10〜）CH〜2〜OR〜10〜，CH（OR〜10）〜）CH（OR〜10〜）CH〜2〜OR〜10〜，CH〜2〜OR〜10〜，CH（OR〜10〜）CH〜2〜NHR〜10〜，CH〜2〜CH（或〜10〜）CH〜2〜NHR〜10〜，CH（OR〜10〜）CH（OR〜10〜）CH〜2〜NHR〜10〜，C（= NR〜10〜）N（R〜10〜）〜m〜，NHR〜10〜，NHC（= NR〜10〜）NR〜10〜）〜m〜，（CH〜2〜）〜m〜-XWY，CH〜2〜CH（XWY）CH〜2 〜OR〜10〜，CH（XWY）CH（OR〜10〜）CH〜2〜OR〜10〜，CH（XWY）CH〜2〜（OR〜10〜），CH（OR〜10〜））CH （XWY）CH〜2〜OR〜10〜，CH（OR〜10〜）CH〜2〜（XWY），CH〜2〜CH（XWY）CH〜2〜NHR〜10〜，CH（XWY）CH（ OR〜10〜）CH〜2〜NHR〜10〜，CH（XWY）CH〜2〜（NHR10），CH（OR〜10〜）CH（XWY）CH〜2〜NHR〜10〜或CH（NHR〜 10〜）CH〜2〜（XWY）;假设R〜2〜，R〜3〜和R〜8〜中至少一个与H不同; R〜4〜是H，（CH〜2〜）〜n〜OH，（CH〜2〜）〜n〜OR〜11〜，（CH〜2〜）〜n〜OC（O）R〜11〜，（CH〜2〜）〜n〜NHC（NR〜11〜）NHR〜11〜，（CH〜2〜）〜n〜NR〜10〜R〜11〜，（CH〜2〜）〜n〜NH〜 2〜，（CH〜2〜）〜n〜C（= NH）（NH〜2〜），（CH〜2〜）〜n〜NHC（= NR〜11〜）NH〜2〜，（CH〜2 〜）〜n〜NHC（= NR〜7〜）NH〜2〜，（CH〜2〜）〜n〜CN，（CH〜2〜）〜n〜N〜3〜，C（= NH）NH〜 2〜，C（NR〜7〜）NH〜2〜或C（NR〜11〜）NH〜2〜; R〜5〜是H，低级烷基，环烷基，被卤素取代的烷基，芳基，取代的芳基或CF〜3〜; R〜7〜是H，（CH〜2〜）〜n〜OH，（CH〜2〜）〜n〜CN，（CH〜2〜）〜n〜NH〜2〜或（CH〜2〜）〜 n〜NO〜2〜; R〜10〜为H，低级烷基，低级亚烷基，支链烷基，环烷基，（CH〜2〜）〜n〜芳香族，被（CH〜2〜）〜n〜取代的芳香族或当m为2时两个基团R〜 10〜也可以相互连接形成N-取代的杂环或另一个5或6元杂环; R〜11〜为低级烷基，支链烷基，（CH〜2〜）〜m〜芳族，SO〜2〜R〜10〜，C（O）R〜10〜或C（O）OR〜10〜; R〜12〜和R〜13〜为H，（CH〜2〜）〜n〜OH，（CH〜2〜）〜n〜NH〜2〜，（CH〜2〜）〜n〜NR〜10〜 R〜11〜，（CH〜2〜）〜n〜OR〜11〜，（CH〜2〜）〜n〜F，（CH〜2〜）〜n〜OC（O）R〜11〜，（CH 〜2〜）〜n〜NHC（O）R〜11〜或XWY; m为1或2; n为0-4; p为0或1; X为O，S，CH〜2〜或NH; W是由1至100个原子的链形成的间隔基，其任选地还包含取代的碳和/或氮原子并且任选地包括氧或硫原子;并且Y为H，OH，SH，NH〜2〜，CH = O，CH = CH〜2〜，CO〜2〜H，CONHNH〜2〜或这些末端特征之一的保护形式;及其药学上可接受的盐及其制备方法。上式的化合物是流感病毒神经氨酸酶抑制剂，可用于治疗感染流感病毒的患者。还提供了由下式表示的中间体化合物：其中R〜4〜和R〜9〜如上所定义;其中每个R〜14〜分别为H，O（CH〜2〜）〜n〜CO〜2〜H，（CH〜2〜）〜n〜SO〜3〜H，（CH〜2〜）〜 n〜PO〜3〜H，（CH〜2〜）〜n〜NO〜2〜，CH（SCH〜3〜）〜3〜，其酯或盐，并提供R〜14〜H中的至少一个R〜3〜和R〜4〜如上定义。 展开▼

著录项

公开/公告号BR9813480A

专利类型

公开/公告日2000-10-10

原文格式PDF

申请/专利权人 BIOCRYST PHARMACEUTICALS INC;
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申请/专利号BR19989813480

发明设计人 YARLAGADDA S. BABU;POORAN CHAND;JOHN A. MONTGOMERY;
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申请日1998-12-17

分类号C07C69/74;C07C61/06;C07C61/20;C07C49/105;C07C49/297;C07C49/395;C07C49/597;C07D261/20;C07D233/54;C07D341/00;

国家 BR

入库时间 2022-08-22 01:57:08

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