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    SELF-REPLICATING RNA MOLECULE FROM HEPATITIS C VIRUS
    1.
    发明申请
    SELF-REPLICATING RNA MOLECULE FROM HEPATITIS C VIRUS 审中-公开
    从HEPATITIS C病毒中自我更新RNA分子

    公开(公告)号：WO02052015A3

    公开(公告)日：2003-11-20

    申请号：PCT/CA0101843

    申请日：2001-12-20

    申请人： BOEHRINGER INGELHEIM CA LTD ,  KUKOLJ GEORGE ,  PAUSE ARNIM

    发明人： KUKOLJ GEORGE ,  PAUSE ARNIM

    IPC分类号： G01N33/50 ,  C07K14/18 ,  C12N5/02 ,  C12N5/10 ,  C12N7/01 ,  C12N15/09 ,  C12N15/40 ,  C12N15/51 ,  C12N15/86 ,  C12Q1/02 ,  C12Q1/68 ,  G01N33/15 ,  C12N7/04 ,  C12N15/85 ,  C12Q1/70

    CPC分类号： C07K14/005 ,  A61K2039/525 ,  C12N15/86 ,  C12N2770/24222 ,  C12N2770/24243 ,  C12N2840/206 ,  C12Q1/6897

    摘要： A unique HCV RNA molecule is provided having an enhanced efficiency of establishing cell culture replication. Novel adaptive mutations have been identified within the HCV non-structural region that improves the efficiency of establishing persistently replicating HCV RNA in cell culture. This self-replicating polynucleotide molecule contains, contrary to all previous reports, a 5'-NTR that can be either an A as an alternative to the G already disclosed and therefore provides an alternative to existing systems comprising a self-replicating HCV RNA molecule. The G-->A mutation gives rise to HCV RNA molecules that, in conjunction with mutations in the HCV non-structural region, such as the G(2042)C/R mutations, possess greater efficiency of transduction and/or replication. These RNA molecules when transfected in a cell line are useful for evaluating potential inhibitors of HCV replication.

    摘要翻译： 提供了独特的HCV RNA分子，其具有增强的建立细胞培养物复制的效率。 HCV非结构域内鉴定出新的适应性突变，提高了在细胞培养中建立持续复制的HCV RNA的效率。 这种自复制多核苷酸分子与所有先前的报道相反，包含可以是A作为已经公开的G的替代物的5'-NTR，因此提供了包含自我复制型HCV RNA分子的现有系统的替代方案。 G - > A突变产生HCV RNA分子，其结合HCV非结构区域的突变，如G（2042）C / R突变，具有更高的转导和/或复制效率。 当转染细胞系时，这些RNA分子可用于评价HCV复制的潜在抑制剂。

    DIRECT BINDING ASSAY FOR IDENTIFYING INHIBITORS OF HCV POLYMERASE
    2.
    发明申请
    DIRECT BINDING ASSAY FOR IDENTIFYING INHIBITORS OF HCV POLYMERASE 审中-公开
    用于鉴定HCV聚合酶抑制剂的直接结合测定

    公开(公告)号：WO03014377A2

    公开(公告)日：2003-02-20

    申请号：PCT/CA0201214

    申请日：2002-08-05

    申请人： BOEHRINGER INGELHEIM CA LTD ,  KUKOLJ GEORGE ,  BEAULIEU PIERRE L ,  MCKERCHER GINETTE

    发明人： KUKOLJ GEORGE ,  BEAULIEU PIERRE L ,  MCKERCHER GINETTE

    IPC分类号： G01N33/50 ,  C12N15/09 ,  C12Q1/48 ,  G01N21/76 ,  G01N21/78 ,  G01N33/15 ,  G01N33/542 ,  C12Q1/00

    CPC分类号： G01N33/542 ,  C12Q1/48 ,  G01N2333/18 ,  G01N2333/91245 ,  G01N2500/02 ,  G01N2500/04

    摘要： A method for identifying compounds binding to HCV polymerase comprising the steps of:contacting said HCV polymerase or an analog thereof with a probe formula I:wherein A is O, S, N, NR1, or CR1, wherein R1 is defined herein;----- represents either a single or a double bond;R2 is selected from: H, halogen, R21, OR21, SR21, COOR21, SO2N(R22)2, N(R22)2, CON(R22)2, NR22C(O)R22 or NR22C(O)NR22 wherein R21 and each R22 is defined herein;B is NR3 or CR3, wherein R3 is defined herein;with the proviso that, when A is not N, then one of A or B is either CR1 or CR3, K is N or CR4, wherein R4 is defined herein;L is N or CR5, wherein R5 has the same definition as R4 defined above;M is N or CR7, wherein R7 has the same definition as R4 defined above;R5 is C(Y1)Z wherein Y1 is O or S; and Z is N(R6a)R6 or OR6, wherein R6a is H or alkyl or NR61R62 wherein R61 and R62 are defined herein; and R6 is H, alkyl, cycloalkyl, alkenyl, Het, alkyl-aryl, alkyl-Het;or R6 is wherein R7 and R8 and Q are as defined herein; Y2 is O or S;R9 is H, (C1-6 alkyl), (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl, aryl, Het, (C1-6)alkyl-aryl or (C1-6)alkyl-Het, all of which optionally substituted with R90; or R9 is covalently bonded to either of R7 or R8 to form a 5- or 6-membered heterocycle;or a salt thereof; where the probe comprises a detectable label attached to any suitable position, whereby said probe binds to an HCV polymerase or an analog thereof and is capable of being displaced by an inhibitor thereof.

    摘要翻译： 用于鉴定结合HCV聚合酶的化合物的方法，包括以下步骤：使所述HCV聚合酶或其类似物与式I的探针接触：其中A是O，S，N，NR1或CR1，其中R 1在本文中定义; ---表示单键或双键; R2选自：H，卤素，R21，OR21，SR21，COOR21，SO2N（R22）2，N（R22）2，CON（R22）2，NR22C ）R 22或NR 22 C（O）NR 22，其中R 21和每个R 22如本文所定义; B是NR 3或CR 3，其中R 3在本文中定义;条件是当A不为N时，A或B中的一个为CR1或 CR 3，K是N或CR 4，其中R 4在本文中定义; L是N或CR 5，其中R5具有与上述定义的R4相同的定义; M是N或CR7，其中R7具有与上述定义的R4相同的定义; R5是 C（Y1）Z，其中Y1是O或S; 并且Z是N（R6a）R6或OR6，其中R6a是H或烷基或NR61R62，其中R61和R62在本文中定义; 并且R 6是H，烷基，环烷基，烯基，Het，烷基 - 芳基，烷基-Het;或R 6是其中R 7和R 8和Q如本文所定义; Y2是O或S; R9是H，（C1-6烷基），（C3-7）环烷基或（C1-6）烷基 - （C3-7）环烷基，芳基，Het，（C1-6）烷基 - 芳基 或（C 1-6）烷基-Het，它们全部被R 90取代; 或R 9与R 7或R 8中的任一个共价键合以形成5-或6-元杂环;或其盐; 其中所述探针包含连接到任何合适位置的可检测标记，由此所述探针结合HCV聚合酶或其类似物，并且能够被其抑制剂置换。

    HEPATITIS C INHIBITOR PEPTIDE ANALOGUES
    5.
    发明申请
    HEPATITIS C INHIBITOR PEPTIDE ANALOGUES 审中-公开
    HEPATITIS C抑制肽类似物

    公开(公告)号：WO9907734A3

    公开(公告)日：1999-05-20

    申请号：PCT/CA9800764

    申请日：1998-08-10

    申请人： BOEHRINGER INGELHEIM CA LTD ,  LLINAS BRUNET MONTSE ,  BAILEY MURRAY DOUGLAS ,  HALMOS TEDDY ,  POUPART MARC ANDRE ,  TSANTRIZOS YOULA

    发明人： LLINAS-BRUNET MONTSE ,  BAILEY MURRAY DOUGLAS ,  HALMOS TEDDY ,  POUPART MARC-ANDRE ,  TSANTRIZOS YOULA

    IPC分类号： A61K45/00 ,  A61K31/13 ,  A61K31/7056 ,  A61K38/00 ,  A61K38/21 ,  A61P31/14 ,  C07K7/06 ,  C07K14/18 ,  A61K38/04 ,  A61K38/16 ,  C07K5/093 ,  C07K5/107

    CPC分类号： C07K7/06 ,  A61K38/00 ,  C07K14/005 ,  C12N2770/24222

    摘要： Compound of formula (I) active against the Hepatitis C virus, wherein B is an acyl derivative; a is 0 or 1; R6, when present, is carboxy(lower)alkyl; b is 0 or 1; R5, when present, is C1-6 alkyl, or carboxy(lower)alkyl; Y is H or C1-6 alkyl; R4 is C1-10 alkyl; R3 is C1-10 alkyl; W is -NH-CH(R2)-C(O)-, wherein R2 is C1-6 alkyl; C6 or C10 aryl; C7-16 aralkyl; or carboxy(lower)alkyl; or W is a proline derivative; Q is a group of the formula -Z(R1)-C(O)-R13, wherein Z is CH or N; R1 is C1-6 alkyl or C1-6 alkenyl both optionally substituted with thio or halo; and R13 is an activated carbonyl substituent, or Q is a phosphonate group of the formula -CH(R1)-P(O)R15R16 wherein R15 and R16 are independently C6-20 aryloxy; and R1 is as defined above.

    摘要翻译： 对丙型肝炎病毒有活性的式（I）化合物，其中B为酰基衍生物; a是0或1; 当存在时，R 6为羧基（低级）烷基; b为0或1; 当存在时，R 5为C 1-6烷基或羧基（低级）烷基; Y是H或C 1-6烷基; R4是C1-10烷基; R3是C1-10烷基; W是-NH-CH（R 2）-C（O） - ，其中R 2是C 1-6烷基; C6或C10芳基; C7-16芳烷基; 或羧基（低级）烷基; 或W是脯氨酸衍生物; Q是式-Z（R1）-C（O）-R13的基团，其中Z是CH或N; R 1是任选被硫或卤代取代的C 1-6烷基或C 1-6链烯基; 并且R 13是活化的羰基取代基，或Q是式-CH（R 1）-P（O）R 15 R 16的膦酸酯基团，其中R 15和R 16独立地是C 6-20芳氧基; 并且R 1如上所定义。

    ASSAY FOR IDENTIFYING INHIBITORS OF HIV RT DIMERIZATION
    6.
    发明申请
    ASSAY FOR IDENTIFYING INHIBITORS OF HIV RT DIMERIZATION 审中-公开
    分析鉴定HIV逆转录酶抑制剂的抑制剂

    公开(公告)号：WO03012127A3

    公开(公告)日：2003-10-16

    申请号：PCT/CA0201162

    申请日：2002-07-26

    申请人： BOEHRINGER INGELHEIM CA LTD ,  SLUIS-CREMER NICOLAS ,  PARNIAK MICHAEL ,  PELLETIER ALEX

    发明人： SLUIS-CREMER NICOLAS ,  PARNIAK MICHAEL ,  PELLETIER ALEX

    IPC分类号： G01N33/53 ,  A61K38/00 ,  C07K2/00 ,  C07K4/00 ,  C07K5/00 ,  C07K7/00 ,  C07K14/00 ,  C07K16/00 ,  C07K17/00 ,  C12N15/09 ,  C12P19/34 ,  C12P21/06 ,  C12Q1/48 ,  C12Q1/68 ,  C12Q1/70 ,  G01N21/78 ,  G01N33/15 ,  G01N33/50

    CPC分类号： C12Q1/48 ,  G01N2333/9125 ,  G01N2500/02

    摘要： A method for measuring heterodimerization of HIV RT, which comprises the steps of:a) providing a first solution comprising p66 subunit homodimers in the presence of a dissociation agent; b) contacting the first solution with p51 RT subunits and incubating in the presence of a reassociation buffer to allow association of a complex of p66/p51 RT subunits, wherein one of the subunits comprises an affinity tag and the other of the subunits comprises a detectable label; c) contacting the incubate of step b) with an affinity medium under conditions that enable the p66/p51 complex to bind to the affinity medium; and d) determining the amount of complex formed by measuring the level of detectable label bound to the affinity medium (or by measuring the reconstituted RT polymerase activity). Steps a) to d) can be carried out in the presence or absence of a test compound followed by e) comparing the test compound sample to a control sample lacking the compound, whereby modulated p66/p51 complex formation in the test compound sample is indicative of the ability of the compound to modulate, inhibit or enhance heterodimerization.The method can be used to screen for inhibitors of HIV RT dimerization.

    摘要翻译： 用于测量HIV RT的异源二聚化的方法，其包括以下步骤：a）在解离剂存在下提供包含p66亚基同源二聚体的第一溶液; b）使第一溶液与p51RT亚基接触，并在重新结合缓冲液存在下温育以允许p66 / p51RT亚基复合物的缔合，其中一个亚基包含亲和标签并且另一个亚基包含可检测的 标签; c）在能够使p66 / p51复合物结合亲和介质的条件下，将步骤b）的孵育物与亲和介质接触; 和d）通过测量与亲和介质结合的可检测标记的水平（或通过测量重建的RT聚合酶活性）来确定形成的复合物的量。 可以在存在或不存在测试化合物的情况下进行步骤a）至d），然后e）将测试化合物样品与缺乏该化合物的对照样品进行比较，由此在测试化合物样品中调节的p66 / p51复合物形成是指示性的 该化合物调节，抑制或增强异二聚化的能力。该方法可用于筛选HIV RT二聚化的抑制剂。

    XENOGRAFT ANIMAL MODEL FOR THE INDUCTION OF PAPILLOMAS, THE PRODUCTION OF PAPILLOMAVIRUS AND THE PROPAGATION THEREOF
    9.
    发明申请
    XENOGRAFT ANIMAL MODEL FOR THE INDUCTION OF PAPILLOMAS, THE PRODUCTION OF PAPILLOMAVIRUS AND THE PROPAGATION THEREOF 审中-公开
    刺激动物动物模型，生产斑马鱼及其传播

    公开(公告)号：WO0032226B1

    公开(公告)日：2001-01-11

    申请号：PCT/CA9901153

    申请日：1999-11-30

    申请人： BOEHRINGER INGELHEIM CA LTD ,  DUAN JIANMIN

    发明人： DUAN JIANMIN

    IPC分类号： A01K67/027 ,  A61K39/12 ,  A61P31/12 ,  C12N7/02 ,  A61K49/00

    CPC分类号： A01K67/0271 ,  A01K2267/0337 ,  C12N2710/20051

    摘要： The present invention relates to an animal model for inducing, producing and propagating papillomavirus and for evaluating candidate therapeutic agents against papillomavirus. The animal model comprises an immuno-deficient animal recipient onto which is grafted excised skin from a xenogeneic donor animal that is free from apparent PV infection and is a host to a host-specific papillomavirus. The grafted skin on the recipient animal supports the propagation of its host-specific papillomavirus. The invention particularly relates to, a recipient animal being a xenograft animal, capable of being a host for propagating a host specific papillomavirus and a means for producing infectious papillomavirus suspension. The invention further relates to the use of the xenograft animal model for evaluating potential therapeutic agents against papillomavirus infection.

    摘要翻译： 本发明涉及用于诱导，产生和繁殖乳头瘤病毒的动物模型，并用于评估针对乳头瘤病毒的候选治疗剂。 动物模型包含免疫缺陷的动物接受者，其中移植切除的皮肤来自不存在明显的PV感染的异种供体动物，并且是宿主特异性乳头瘤病毒的宿主。 受体动物的嫁接皮肤支持其宿主特异性乳头瘤病毒的繁殖。 本发明特别涉及能够作为繁殖宿主特异性乳头瘤病毒的宿主的异种移植动物的受体动物和用于产生感染性乳头瘤病毒悬浮液的手段。 本发明还涉及异种移植物动物模型用于评估针对乳头瘤病毒感染的潜在治疗剂的用途。

    HSV PRIMASE INHIBITORS
    10.
    发明申请
    HSV PRIMASE INHIBITORS 审中-公开

    公开(公告)号：WO0058270A2

    公开(公告)日：2000-10-05

    申请号：PCT/CA0000324

    申请日：2000-03-23

    申请人： BOEHRINGER INGELHEIM CA LTD ,  SIMONEAU BRUNO ,  LIUZZI MICHELE ,  MENTRUP ANTON

    发明人： SIMONEAU BRUNO ,  LIUZZI MICHELE ,  MENTRUP ANTON

    IPC分类号： C07D295/18 ,  A61K31/165 ,  A61K31/167 ,  A61K31/4402 ,  A61K31/4453 ,  A61K31/52 ,  A61K31/522 ,  A61K31/535 ,  A61P31/22 ,  C07C235/00 ,  C07C235/60 ,  C07C235/62 ,  C07C235/64 ,  C07C237/30 ,  C07C237/38 ,  C07C237/40 ,  C07C237/42 ,  C07C237/44 ,  C07C247/18 ,  C07D213/30 ,  C07D213/40 ,  C07D295/192

    CPC分类号： C07D295/192 ,  A61K31/52 ,  A61K31/535 ,  C07C235/64 ,  C07C237/30 ,  C07C237/38 ,  C07C237/40 ,  C07C237/44 ,  C07C247/18 ,  C07C2601/14 ,  C07D213/30 ,  C07D213/40 ,  A61K2300/00

    摘要： The invention provides compounds of formula (1) that are active against the HSV primase enzyme: wherein R1 is hydroxy or amino; R2 is hydrogen, halo, (C1-4)alkyl or (C1-4)alkoxy; R3 is hydrogen, halo, (C1-4)alkyl, (C1-4)alkoxy, amino or azido; R4 has the same significance as R2; R5 is hydrogen or (C1-4)alkyl; and R is (C1-7)alkyl, (C3-6)cycloalkyl, {phenyl(C1-7)alkyl}, {phenyl(C1-7)alkoxy}, {{(monocyclic heterocyclo)-{(C1-7)alkoxy}}, CH(W)C(O){O-(C1-4)alkyl} wherein W is hydrogen or (C1-7)alkyl, or (A) wherein Y is hydrogen or (C1-7)alkyl, and Z is (C1-7)alkyl, (C3-6) cycloalkyl, {(C3-6)cycloalkyl}-{(C1-7)alkyl}, phenyl(C1-7)alkyl or {{(monocyclic heterocyclo)-{(C1-7)alkyl}}, or Y and Z together with the nitrogen atom to which they are attached represent, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or 1-(4-methylpiperazinyl); with the provisos that (1) when R is CH(W)C(O)-{O-(C1-4)alkyl} as defined herein, then R5 is hydrogen; and (2) at least one of R2, R3 and R4 is other than hydrogen.

    摘要翻译： 本发明提供对HSV引物酶具有活性的式（1）化合物：其中R1是羟基或氨基; R2是氢，卤素，（C1-4）烷基或（C1-4）烷氧基; R3是氢，卤素，（C1-4）烷基，（C1-4）烷氧基，氨基或叠氮基; R4与R2具有相同的意义; R5是氢或（C1-4）烷基; （C 1-7）烷基，（C 3-6）烷基}，{苯基（C 1-7）烷氧基}，{（（单环杂环） - {（C 1-7） 烷氧基}}，CH（W）C（O）{O-（C1-4）烷基}其中W是氢或（C1-7）烷基，或（A）其中Y是氢或（C1-7）烷基， 并且Z是（C 1-7）烷基，（C 3-6）环烷基，{（C 3-6）环烷基} - {（C 1-7）烷基}，苯基（C 1-7）烷基或{{（单环杂环） {（C 1-7）烷基}}或Y和Z与它们所连接的氮原子一起代表1-吡咯烷基，1-哌啶基，4-吗啉基或1-（4-甲基哌嗪基） 条件是（1）当R是本文定义的CH（W）C（O） - {O-（C 1-4）烷基}时，则R 5是氢; 和（2）R2，R3和R4中的至少一个不是氢。