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    • 2. 发明授权
    • Pharmaceutical compounds
    • US07132419B2
    • 2006-11-07
    • US11024759
    • 2004-12-30
    • John MiltonNigel VickerAdrian FolkesShouming WangWilliam Alexander Denny
    • John MiltonNigel VickerAdrian FolkesShouming WangWilliam Alexander Denny
    • C07D241/46A61K31/498
    • C07D403/12C07D241/46
    • A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I) wherein each of R1 to R4, which are the same or different, is selected from hydrogen, halogen, hydroxyl, C1–C6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C1–C6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO2R10, CON(R12)2, OCON(R12), SR10, SOR11, SO2R11, SO2N(R12)2, N(R12)2, NR10SO2R11, N(SO2R11)2 NR10(CH2)nCN, NR10COR11, OCOR11 or COR10; each of R5 to R7, which are the same or different, is selected from hydrogen, halogen, hydroxy, C1–C6 alkoxy, C1–C6 alkyl, SR10 and N(R12)2; Q is C1–C6 alkylene which is unsubstituted or substituted by (i) C1–C6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not α to either of the N atoms adjacent to Q in formula (I), (iii) CO2R10, or (iv) CON(R12); R8 and R9, which are the same or different, are each hydrogen or C1–C6 alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R8 and R9 is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; R10 is hydrogen, C1–C6 alkyl, C3–C6 cycloalkyl, benzyl or phenyl; R11 is C1–C6 alkyl, C3–C6 cycloalkyl, benzyl or phenyl; each R12, which are the same or different, is hydrogen, C1–C6 alkyl cycloalkyl, benzyl or phenyl, or the two R12 groups form, together with the nitrogen atom to which they are attached a 5- or 6-membered saturated N-containing heterocyclic ring which may include 1 or 2 additional heteroatoms selected from O, N and S; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of R1 to R4 is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase II and can be used to treat tumours, including tumours which express MDR.
    • 3. 发明申请
    • Pharmaceutical compounds
    • US20050143383A1
    • 2005-06-30
    • US11024759
    • 2004-12-30
    • John MiltonNigel VickerAdrian FolkesShouming WangWilliam Denny
    • John MiltonNigel VickerAdrian FolkesShouming WangWilliam Denny
    • C07D241/46C07D403/12A61K31/498C07D241/36
    • C07D403/12C07D241/46
    • A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I) wherein each of R1 to R4, which are the same or different, is selected from hydrogen, halogen, hydroxyl, C1-C6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C1-C6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO2R10, CON(R12)2, OCON(R12), SR10, SOR11, SO2R11, SO2N(R12)2, N(R2)2, NR10SO2R11, N(SO2R11)2 NR10(CH2)nCN, NR10COR11, OCOR11 or COR10; each of R5 to R7, which are the same or different, is selected from hydrogen, halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, SR10 and N(R12)2; Q is C1-C6 alkylene which is unsubstituted or substituted by (i) C1-C6 alkyl which is unsubstituted or substituted, (II) hydroxy, provided that the hydroxy group is not α to either of the N atoms adjacent to Q in formula (I), (iii) CO2R10, or (iv) CON(R12); R8 and R9, which are the same or different, are each hydrogen or C1-C6 alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R8 and R9 is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; R10 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, benzyl or phenyl; R11 is C1-C6 alkyl, C3-C6 cycloalkyl, benzyl or phenyl; each R12, which are the same or different, is hydrogen, C1-C6 alkyl cycloalkyl, benzyl or phenyl, or the two R12 groups form, together with the nitrogen atom to which they are attached a 5- or 6-membered saturated N-containing heterocyclic ring which may include 1 or 2 additional heteroatoms selected from O, N and S; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of R1 to R4 is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase II and can be used to treat tumours, including tumours which express MDR.
    • 5. 发明授权
    • Modified nucleotides
    • 修饰的核苷酸
    • US08071739B2
    • 2011-12-06
    • US12804352
    • 2010-07-20
    • John MiltonXiaolin WuMark SmithJoseph BrennanColin BarnesXiaohai LiuSilke Ruediger
    • John MiltonXiaolin WuMark SmithJoseph BrennanColin BarnesXiaohai LiuSilke Ruediger
    • C07H21/02C07H21/04C07H19/04C12Q1/68
    • C12Q1/6869C07H1/00C07H19/06C07H19/10C07H19/14C07H19/16C07H19/20C07H21/00C12Q2525/186C12Q2535/113Y02P20/55C12Q2525/197
    • The invention provides modified nucleotide or nucleoside molecule comprising a purine or pyrimidine base and a ribose or deoxyribose sugar moiety having a removable 3′-OH blocking group covalently attached thereto, such that the 3′ carbon atom has attached a group of the structure —O—Z wherein Z is any of —C(R′)2-O—R″, —C(R′)2-N(R″)2, —C(R′)2-N(H)R″, —C(R′)2-S—R″ and —C(R′)2-F, wherein each R″ is or is part of a removable protecting group; each R′ is independently a hydrogen atom, an alkyl, substituted alkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, acyl, cyano, alkoxy, aryloxy, heteroaryloxy or amido group, or a detectable label attached through a linking group; or (R′)2 represents an alkylidene group of formula ═C(R′″)2 wherein each R′″ may be the same or different and is selected from the group comprising hydrogen and halogen atoms and alkyl groups; and wherein said molecule may be reacted to yield an intermediate in which each R″ is exchanged for H or, where Z is —C(R′)2-F, the F is exchanged for OH, SH or NH2, preferably OH, which intermediate dissociates under aqueous conditions to afford a molecule with a free 3′OH; with the proviso that where Z is —C(R′)2-S—R″, both R′ groups are not H.
    • 本发明提供了修饰的核苷酸或核苷分子,其包含嘌呤或嘧啶碱基和核糖或脱氧核糖糖部分,其具有共价连接到其上的可移除的3'-OH封闭基团,使得3'碳原子连接一组结构-O -Z其中Z是-C(R')2 -O-R“,-C(R')2 -N(R”)2,-C(R')2 -N(H)R“ -C(R')2 -S-R“和-C(R')2 -F,其中每个R”为或可移除的保护基团的一部分; 每个R'独立地是氢原子,烷基,取代的烷基,芳基烷基,烯基,炔基,芳基,杂芳基,杂环,酰基,氰基,烷氧基,芳氧基,杂芳氧基或酰氨基,或通过连接基团连接的可检测标记; 或(R')2表示式≡C(R'“)2的亚烷基,其中每个R”可以相同或不同,并且选自氢和卤素原子和烷基; 并且其中所述分子可以反应以产生其中每个R“被交换为H的中间体,或其中Z是-C(R')2 -F,F被交换成OH,SH或NH 2,优选OH,其中 中间体在水性条件下解离得到具有游离3'OH的分子; 条件是其中Z是-C(R')2 -S-R“,两个R'基团不是H.