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    HIV PRODRUGS CLEAVABLE BY CD26
    2.
    发明公开
    HIV PRODRUGS CLEAVABLE BY CD26 有权
    BY CD26 FISSILE HIV前体药物

    公开(公告)号：EP1624897A2

    公开(公告)日：2006-02-15

    申请号：EP04741542.7

    申请日：2004-05-10

    申请人： Tibotec Pharmaceuticals Ltd.

    发明人： DE KOCK, Herman Augustinus ,  WIGERINCK, Piet Tom Bert Paul ,  BALZARINI, Jan

    IPC分类号： A61K47/48 ,  C07D473/00 ,  C07H15/252

    CPC分类号： C07D493/04 ,  A61K38/00 ,  A61K47/64 ,  C07H15/252 ,  C07K5/06052 ,  C07K5/06113 ,  C07K5/0808 ,  C07K5/1008 ,  C07K5/101 ,  C07K5/1019 ,  C07K5/1021 ,  C07K7/06 ,  C07K9/003

    摘要： The present invention provides new prodrugs which are conjugates of a therapeutic compound and a peptide wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present prodrugs have the formula (I), the stereoisomeric forms and salts thereof, wherein n is I to 5; Y is proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine; X is selected from any amino acid in the D- or L-configuration; X and Y in each repeat of [Y-X] are chosen independently from one another and independently from other repeats; Z is a direct bond or a bivalent straight or branched saturated hydrocarbon group having from 1 to 4 carbon atoms; R1 is an aryl, heteroaryl, aryloxy, heteroaryloxy, aryloxyC1-4alkyl, heterocycloalkyloxy, heterocycloalkylC1-4akloxy, heteroaryloxyC1-4alkyl, heteroarylC1-4alkyloxy; R2 is arylC1-4alkyl; R3 is C1-10alkyl, C2-6alkenyl or C3-7cycloalkyIC1-4alkyl; R4 is hydrogen or C1-4alkyl. The present invention furthermore provides the use of said prodrugs as medicines as well as a method of producing said prodrugs.

    MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
    4.
    发明公开
    MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS 有权
    丙型肝炎病毒的大环内酯类抑制剂

    公开(公告)号：EP1919899A1

    公开(公告)日：2008-05-14

    申请号：EP06778070.0

    申请日：2006-07-28

    申请人： Tibotec Pharmaceuticals Ltd. ,  MEDIVIR AB

    发明人： DE KOCK, Herman Augustinus ,  SIMMEN, Kenneth Alan ,  JÖNSSON, Carl Erik Daniel ,  AYESA ALVAREZ, Susana ,  CLASSON, Björn Olof ,  NILSSON, Karl Magnus ,  ROSENQUIST, Åsa Annica Kristina ,  SAMUELSSON, Bengt Bertil ,  WALLBERG, Hans Kristian

    IPC分类号： C07D401/12 ,  C07D403/12 ,  C07D413/12 ,  A61K31/538 ,  A61P31/14

    CPC分类号： C07D403/12 ,  C07D401/12 ,  C07D413/12 ,  C07D487/04

    摘要： Inhibitors of HCV replication of formula (I) and the N-oxides, salts, or stereoisomers thereof, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is -OR6, -NH-SO2R7; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, or C3-7cycloalkyl; n is 3, 4, 5, or 6; R4 and R5 taken together with the nitrogen atom to which they are attached form a bicyclic ring system selected from formula (II) wherein said ring system may optionally be substituted with 1-3 substituents; R6 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R7 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl or naphthyl, each of which may be optionally substituted with 1-3 substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from N, O or S, and being optionally substituted with 1-3 substituents pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

    摘要翻译： 式（I）的HCV复制抑制剂及其N-氧化物，盐或立体异构体，其中每个虚线表示任选的双键; X是N，CH，其中X带有一个双键，它是C; R1是-OR6，-NH-SO2R7; R2是氢，并且其中X是C或CH，R2也可以是C1-6烷基; R3是氢，C1-6烷基，C1-6烷氧基C1-6烷基或C3-7环烷基; n是3,4,5或6; R 4和R 5与它们所连接的氮原子一起形成选自式（II）的双环系统，其中所述环系统可以任选地被1-3个取代基取代; R6是氢; 芳基; HET; 任选被C 1-6烷基取代的C 3-7环烷基; 或任选被C 3-7环烷基，芳基或用Het取代的C 1-6烷基; R7是芳基; HET; 任选被C 1-6烷基取代的C 3-7环烷基; 或任选被C 3-7环烷基，芳基或用Het取代的C 1-6烷基; 芳基是苯基或萘基，它们中的每一个可以任选被1-3个取代基取代; Het是含有1至4个各自独立地选自N，O或S的杂原子的5或6元饱和，部分不饱和或完全不饱和的杂环，并且任选地被1-3个取代基药物组合物取代，所述药物组合物含有化合物（I） 制备化合物（I）。 还提供了式（I）的HCV抑制剂与利托那韦的生物可用组合。

    HIV PRODRUGS CLEAVABLE BY CD26
    6.
    发明授权
    HIV PRODRUGS CLEAVABLE BY CD26 有权
    可通过CD26切割的HIV前药

    公开(公告)号：EP1624897B1

    公开(公告)日：2007-10-10

    申请号：EP04741542.7

    申请日：2004-05-10

    申请人： Tibotec Pharmaceuticals Ltd.

    发明人： DE KOCK, Herman Augustinus ,  WIGERINCK, Piet Tom Bert Paul ,  BALZARINI, Jan

    IPC分类号： A61K47/48 ,  C07D473/00 ,  C07H15/252

    CPC分类号： C07D493/04 ,  A61K38/00 ,  A61K47/64 ,  C07H15/252 ,  C07K5/06052 ,  C07K5/06113 ,  C07K5/0808 ,  C07K5/1008 ,  C07K5/101 ,  C07K5/1019 ,  C07K5/1021 ,  C07K7/06 ,  C07K9/003

    摘要： The present invention provides new prodrugs which are conjugates of a therapeutic compound and a peptide wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present prodrugs have the formula (I), the stereoisomeric forms and salts thereof, wherein n is I to 5; Y is proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine; X is selected from any amino acid in the D- or L-configuration; X and Y in each repeat of [Y-X] are chosen independently from one another and independently from other repeats; Z is a direct bond or a bivalent straight or branched saturated hydrocarbon group having from 1 to 4 carbon atoms; R1 is an aryl, heteroaryl, aryloxy, heteroaryloxy, aryloxyC1-4alkyl, heterocycloalkyloxy, heterocycloalkylC1-4akloxy, heteroaryloxyC1-4alkyl, heteroarylC1-4alkyloxy; R2 is arylC1-4alkyl; R3 is C1-10alkyl, C2-6alkenyl or C3-7cycloalkyIC1-4alkyl; R4 is hydrogen or C1-4alkyl. The present invention furthermore provides the use of said prodrugs as medicines as well as a method of producing said prodrugs.

    摘要翻译： 本发明提供了作为治疗性化合物和肽的缀合物的新型前体药物，其中缀合物可被二肽基肽酶，更优选CD26（也称为DPPIV（二肽基氨基二肽酶IV））裂解。 本发明的前体药物具有式（I），其立体异构形式和盐，其中n为1至5; Y是脯氨酸，丙氨酸，羟脯氨酸，二羟脯氨酸，噻唑烷羧酸（硫代脯氨酸），脱氢脯氨酸，哌可酸（L-高脯氨酸），氮杂环丁烷羧酸，氮丙啶羧酸，甘氨酸，丝氨酸，缬氨酸，亮氨酸，异亮氨酸和苏氨酸; X选自D-或L-构型中的任何氨基酸; [Y-X]的每个重复中的X和Y彼此独立地选择并独立于其他重复; Z是直接键或具有1至4个碳原子的二价直链或支链饱和烃基; R 1为芳基，杂芳基，芳氧基，杂芳氧基，芳氧基C 1-4烷基，杂环烷氧基，杂环烷基C 1-4烷氧基，杂芳氧基C 1-4烷基，杂芳基C 1-4烷氧基; R2是芳基C1-4烷基; R3是C1-10烷基，C2-6链烯基或C3-7环烷基C1-4烷基; R4是氢或C1-4烷基。 本发明还提供所述前药作为药物的用途以及生产所述前药的方法。