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    Analogs of 2',3'-dideoxy-3'-fluorothymidine 5'-monophosphate (FLTMP) for treatment human immunodeficiency virus (HIV), their application and pharmaceutically acceptable form of drug
    4.
    发明公开
    Analogs of 2',3'-dideoxy-3'-fluorothymidine 5'-monophosphate (FLTMP) for treatment human immunodeficiency virus (HIV), their application and pharmaceutically acceptable form of drug 有权
    在所造成的人HIV-1毒株感染的治疗中使用的2”，3'-二脱氧-3'-氟-5'-一磷酸类似物（FLTMP）

    公开(公告)号：EP2402357A1

    公开(公告)日：2012-01-04

    申请号：EP10172852.5

    申请日：2010-08-15

    申请人： Instytut Biochemii I Biofizyki Pan

    发明人： MIAZGA, Agnieszka ,  ZIEMKOWSKI, Przemyslaw ,  KULIKOWSKI, Tadeusz ,  HAMY, Francois ,  LOUVEL, Severine ,  KLIMKAIT, Thomas

    IPC分类号： C07H19/073 ,  C07H19/10 ,  A61K31/7068 ,  A61P31/18

    CPC分类号： C07H19/10 ,  C07H19/073

    摘要： Analogs of 3'-fluorothymidine 5'-monophosphate (FLTMP), preferably intended 2',3'-dideoxy-3'-fluoro-β-D- erythro -pentofuranoside of thymine 5'-monophosphate (FLTMP): 3'-fluoro-2-thiothymidine 5'-monophosphate intended 2',3'-dideoxy-3'-fluoro-β-D- erythro -pentofuranoside of 2-thiothymine 5'-monophosphate; 3'-fluoro-4-thiothymidine 5'-monophosphate is intended 2',3'-dideoxy-3'-fluoro-β-D- erythro -pentofuranoside of 4-thiothymine 5'-monophosphate (4-SFLTMP).
    This invention includes also medical use of analogues of 3'-fluorothymidine 5'-monophosphate (FLTMP), according to the invention, Formula 1 , for therapy of infections caused by the human immunodeficiency virus (HIV-1) wild type strain and strains showing resistance and multidrug resistance.
    The inventors unexpectedly discovered that proposed new FLTMP analogs with thiosubstituent at 2 or 4 position of FLT pyrimidine ring and monophosphate group at 5'-0-of 2,3-dideoxyribose exert very potent inhibitory activity against drug and multidrug resistant HIV-1 strains, as well as show high selectivity and good solubility in water.
    This invention also includes pharmaceutical acceptable form of drug, which according to the invention, contain known acceptable media and auxiliary substances, containing, as an active compounds analogues of general Formula 1 , in which X , Y and R have the above-mentioned importance, especially the relationship being dilithium salt of 2-SFLTMP and 4-SFLTMP.

    摘要翻译： 3'-氟：-3'-氟-5'-单磷酸（FLTMP），优选拟2”，3'-二脱氧-3'-氟 - D-赤-pentofuranoside²的胸腺嘧啶5'-单磷酸（FLTMP）的类似物 -2-硫代胸苷-5'-单磷酸拟2”，3'-二脱氧-3'-氟 - D-赤-pentofuranoside²-的2-硫胸腺嘧啶5'-一磷酸; 3'-氟-4-硫代胸苷-5'-单磷酸的目的是2”，3'-二脱氧-3'-氟 - D-赤-pentofuranoside²4-硫代胸腺嘧啶5'-单磷酸（4- SFLTMP）的。 本发明包括这样的医疗用途-3'-氟-5'-单磷酸（FLTMP），雅鼎本发明，式1中，类似物的用于由人免疫缺陷病毒（HIV-1）野生型菌株和菌株表示引起感染的治疗 性和耐多药耐药性。 意外地发现本发明人没有在5'-O-中的FLT嘧啶环和单磷酸基团的2或4位提出了具有硫代取代基的新FLTMP类似物2,3-二脱氧核糖发挥非常有效的抑制活性对药物及多药耐药性HIV-1毒株， 以及显示高选择性和良好的水溶性。 所以本发明包括药物的药学上可接受的形式，其雅丁本发明，含有的已知可接受的介质和​​辅助物质，含有作为通式1的活性化合物的类似物，其中X，Y和R 1具有上述意义的， 爱特别的关系为2-SFLTMP和4- SFLTMP的二锂盐。

    2',3'-Didehydro-3'-deoxy-4'-ethynylothymidine derivatives for treatment infections caused by human immunodeficiency virus (HIV) multidrug resistant strains, method of their synthesis and pharmaceutically acceptable forms of drugs
    5.
    发明公开
    2',3'-Didehydro-3'-deoxy-4'-ethynylothymidine derivatives for treatment infections caused by human immunodeficiency virus (HIV) multidrug resistant strains, method of their synthesis and pharmaceutically acceptable forms of drugs 审中-公开
    2”，3'-二脱氢-3'-脱氧-4'- ethynylthymidinderivate造成的多药人免疫缺陷病毒的抗性株（HIV）感染的治疗中，它们的合成和药学上可接受的药物形式的方法

    公开(公告)号：EP2402358A2

    公开(公告)日：2012-01-04

    申请号：EP10172853.3

    申请日：2010-08-15

    申请人： Instytut Biochemii I Biofizyki Pan

    发明人： ZIEMKOWSKI, Przemys?aw ,  MIAZGA, Agnieszka ,  KULIKOWSKI, Tadeusz ,  LOUVEL, Severine ,  KLIMKAIT, Thomas ,  VIDAL, Vincent

    IPC分类号： C07H19/073 ,  A61K31/7068 ,  A61P31/18

    CPC分类号： C07H19/06

    摘要： 4'-Ethynylostavudine derivatives according to the invention substituted at 4'-ethynylostavudine 5'-O-position with 12-tetradodecanoyl, 12-bromododecanoyl, 12-methoxydodecanoyl, 12-ethylothiododecanoyl, or 12-azidododecanoyl group (represented by the symbols WA37, WA38, WA40, WA42, WA39 ) in deClPhR™ cells exert very high antiviral activity against the wild type HIV-1 strain, as well as against its drug and multidrug resistant strains, without any citotoxicty at the therapeutic concentrations (CC 50 >200 µM).
    These compounds, because of their very low toxicity may be applied at all phases of AIDS, even at the final phase when the T4 lymphocytes level in patients drops down below 200/µL of peripheral blood.
    The 2',3'- didehydro-3'-deoxy-4'-ethynylothymidine derivatives, according to the invention, are synthesized by the transformation of the known compound 4'-ethynylostavudine ( WA32, wherein R represents hydrogen).

    摘要翻译： 4'- Ethynylostavudine衍生物gemäß在与12-tetradodecanoyl 4'- ethynylostavudine 5'-O-位置发明substituiertem，12 bromododecanoyl，12 methoxydodecanoyl，12 ethylothiododecanoyl，或12 azidododecanoyl组（由符号所表示WA37， WA38，WA40，WA42，WA39）在deClPhR“¢细胞在治疗浓度发挥非常高的抗病毒活性对野生型HIV-1毒株，以及针对它的药物和多药耐药性菌株，没有任何citotoxicty（CC50> 200 UM）。 由于其非常低的毒性的这些化合物中，可以在AIDS的所有阶段施加，即使在最后阶段当T4淋巴细胞患者水平下降到低于外周血200 /微升。 2”，3'-二脱氢-3'-脱氧-4'- ethynylothymidine衍生物，gemäß本发明，由公知的化合物4'- ethynylostavudine（WA32，worinřdarstellt氢）的转化合成。

    Modified 2',3'-dideoxynucleosides for treatment infections caused by human immunodeficiency virus (HIV) multidrug resistant strains, method of their synthesis and the pharmaceutical agent containing these nucleosides
    6.
    发明公开
    Modified 2',3'-dideoxynucleosides for treatment infections caused by human immunodeficiency virus (HIV) multidrug resistant strains, method of their synthesis and the pharmaceutical agent containing these nucleosides 审中-公开
    方法那些包含修改2”，3'-二脱氧核苷造成的耐人类免疫缺陷病毒的多种药物株（HIV）感染的治疗中的合成和药物，这些核苷

    公开(公告)号：EP2402356A2

    公开(公告)日：2012-01-04

    申请号：EP10172854.1

    申请日：2010-08-15

    申请人： Instytut Biochemii I Biofizyki Pan

    发明人： ZIEMKOWSKI, Przemyslaw ,  MIAZGA, Agnieszka ,  KULIKOWSKI, Tadeusz ,  KLIMKAIT, Thomas ,  LOUVEL, Severine ,  HAMY, Francois ,  Lipniacki, Andrzej ,  PIASEK, Andrzej

    IPC分类号： C07H19/06 ,  A61K31/7052 ,  A61P31/18

    CPC分类号： A61K31/7068 ,  C07H19/06

    摘要： 2',3'-Dideoxy-3'-fluoro-4-thiothymidine (4-SFLT) derivatives according to the invention substituted at 5'-O position of 4-SFLT with 12-tetradodecanoyl, 12-bromododecanoyl, 12-metoxydodecanoyl, 12-ethylothiododecanoyl, 11-ethylothioundecanoyl or 12-azidodocanoyl group (represented by the symbols WA18, WA19, WA21,WA22,WA23 and WA20 in the deCIPhR™ cell system exert high antiviral activity against wild type HIV-1 strain, as well as against its drug and multidrug resistant strains, and moreover very low citotoxicity (CC 50 > 200 µM) and very high selectivity.
    The compounds, because of lack of toxicity may be applied at all AIDS phases i.e. also them the T4 lymphocytes level in patients drops down below 200/ µL of peripheral blood.
    2',3'-Dideoxy-3'-fluoro-4-thiothymidine derivatives according to the invention are synthesized by the transformation of the known compound 2',3'-dideoxy-3'-fluoro-4-thiothymidine (4-SFLT).

    摘要翻译： 2”，3'-二脱氧-3'-氟-4-硫代胸苷（4- SFLT）衍生物gemäß在4- SFLT具有12 tetradodecanoyl，12 bromododecanoyl，12 metoxydodecanoyl的5'-O-位置发明substituiertem， 12 ethylothiododecanoyl，11-ethylothioundecanoyl或12 azidodocanoyl组（用符号WA18，WA19，WA21，WA22，WA23和WA20在deCIPhR“¢电池系统发挥高的抗病毒活性对野生型HIV-1株，以及代表 针对它的药物和多重耐药的菌株，更超过非常低citotoxicity（CC50> 200微米）和非常高的选择性，由于缺乏毒性的化合物，也可以在所有艾滋病阶段应用即，使得它们的T4淋巴细胞患者滴水平 向下下面的外周血200 /微升。2“ 3'-二脱氧-3'-氟-4-硫代胸苷衍生物gemäß本发明，通过已知的化合物2' 的转化合成，3'-二脱氧-3” 氟-4-硫代胸苷（4- SFLT）。