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    Taxane derivatives having a pyridyl substituted C13 side chain, their preparation and their use as anti-tumor agents
    74.
    发明授权
    Taxane derivatives having a pyridyl substituted C13 side chain, their preparation and their use as anti-tumor agents 失效

    公开(公告)号：US6162920A

    公开(公告)日：2000-12-19

    申请号：US117506

    申请日：1998-07-30

    申请人： Ulrich Klar ,  Gunter Neef ,  Hermann Graf

    发明人： Ulrich Klar ,  Gunter Neef ,  Hermann Graf

    IPC分类号： C07D305/14 ,  A61K31/337 ,  A61K31/4427 ,  A61K31/445 ,  A61P35/00 ,  C07D405/12 ,  A61K31/44 ,  C07D405/04

    CPC分类号： C07D405/12

    摘要： The invention relates to pharmacologically active compounds that have the ability to influence the polymerisation and depolymerisation of tubulin.A range of natural mitosis toxins are used as anti-tumor agents or are in the process of being clinically tested. There are various classes of such mitosis toxins that either demonstrate their cytotoxic action by inhibiting the polymerisation of microtubules in the spindle system (for example, Vinca alkaloids, colchicine) or achieve their cytotoxic action by a GTP-independent increase in the polymerisation of the tubulin and by preventing the depolymerisation of microtubules (for example, taxol, taxoters).Owing to their physico-chemical properties, hitherto not understood, and as a result of the characteristics of neoplastic cells, mitosis toxins have a certain selectivity for tumor cells, but there still remains a not inconsiderable cytotoxicity towards non-transformed cells. The search for more selective compounds that are easier to manufacture and--like the taxane class of substances--are able to inhibit the depolymerisation of microtubules, had, surprisingly, led to the discovery of borneol esters, as described in P 4416374.6 and 19513040.5. Structural modifications in that class of compounds have revealed a considerable potential for optimisation in respect of the action on microtubules. Outstanding results have been obtained, inter alia, by formal esterification of those broneols with an acid of the Sk-H type. By synthesising the taxol derivatives described herein, in which the isoserine chain of the taxol has been replaced by Sk, the intention was to study whether it is also possible in that class of substances to achieve an improved stabilisation of microtubules, compared with taxol.

    Borenol derivatives, process for their production and their pharmaceutical use
    76.
    发明授权
    Borenol derivatives, process for their production and their pharmaceutical use 失效
    Borenol衍生物，其生产过程及其药物用途

    公开(公告)号：US5792792A

    公开(公告)日：1998-08-11

    申请号：US732449

    申请日：1997-01-03

    申请人： Ulrich Klar ,  Hermann Graf ,  Gunter Neef ,  Siegfried Blechert

    发明人： Ulrich Klar ,  Hermann Graf ,  Gunter Neef ,  Siegfried Blechert

    IPC分类号： C07D303/31 ,  C07C271/22 ,  C07C309/63 ,  C07D303/14 ,  C07D303/16 ,  C07F9/38 ,  A61K31/335 ,  C07D303/10

    CPC分类号： C07C271/22 ,  C07D303/14 ,  C07D303/16 ,  C07C2103/86

    摘要： The invention relates to borneol derivatives of general formula I ##STR1## in which R.sup.1 means C(O)--CH(OR.sup.6)--CH(NHR.sup.7)--R.sup.8, R.sup.2 means hydrogen, --OH, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --OC(O)R.sup.9a, --OSO.sub.2 R.sup.9a, --OP(O)(OH).sub.2, NHR.sup.9a, NR.sup.9a R.sup.9b, R.sup.3 means hydrogen, --OH, C.sub.1 -C.sub.10 alkoxy, --OC(O)R.sup.9b, --OSO.sub.2 R.sup.9b, --OP(O)(OH).sub.2, or R.sup.2, R.sup.3 together mean an oxygen atom, R.sup.4 means hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.n --OR.sup.11a, R.sup.5 means hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.p --OR.sup.11b, or R.sup.4, R.sup.5 together mean an oxygen atom, a=CHR.sup.10 group, n means 0 to 8, p means 1 to 8, R.sup.7 means --C(O)R.sup.12, --SO.sub.2 R.sup.12, --C(O)OR.sup.12, --C(O)NHR.sup.9d, --C(O)NR.sup.9d R.sup.9e, ##STR2## R.sup.8 means aryl, R.sup.9a-e, R.sup.12 are the same or different and mean C.sub.1 -C.sub.10 alkyl, C.sub.4 -C.sub.8 cycloalkyl, aryl, C.sub.7 -C.sub.16 aralkyl, R.sup.10 means hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.s --OR.sup.14, s means 1 to 8, R.sup.6, R.sup.11a,b, R.sup.14 are the same or different and mean hydrogen, C.sub.1 -C.sub.10 alkyl, aryl, C.sub.7 -C.sub.16 aralkyl, --SO.sub.2 R.sup.9c, --P(O)(OH).sub.2, R.sup.13, R.sup.15a,b are the same or different and mean hydrogen, C.sub.1 -C.sub.10 alkyl, aryl, C.sub.7 -C.sub.16 aralkyl, X.sup.1, X.sup.2 are the same or different and mean X, X can be hydrogen, halogen, --OH, --NO.sub.2, --N.sub.3, --CN, --NR.sup.15a R.sup.15b, --NHSO.sub.2 R.sup.15a, --CO.sub.2 R.sup.15, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 acyloxy, C.sub.1 -C.sub.10 acyl, and, if R.sup.15 means hydrogen, their salts with physiologically compatible bases, as well as the .alpha.-, .beta.-or .gamma.-cyclodextrin clathrates, as well as the compounds of formula I that are encapsulated with liposomes.

    摘要翻译： PCT No.PCT / EP95 / 01341 Sec。 371日期1997年1月3日 102（e）日期1997年1月3日PCT提交1995年4月13日PCT公布。 WO95 / 30650 PCT出版物 日本公开号为1995年11月16日本发明涉及通式I的冰片衍生物，其中R1表示C（O）-CH（OR6）-CH（NHR7）-R8，R2表示氢，-OH，C1-C10 烷基，C1-C10烷氧基，-OC（O）R9a，-OSO2R9a，-OP（O）（OH）2，NHR9a，NR9aR9b，R3表示氢，-OH，C1-C10烷氧基，-OC（O）R9b， -OSO2R9b，-OP（O）（OH）2或R2，R3一起表示氧原子，R4表示氢，C1-C10烷基， - （CH2）n-OR11a，R5表示氢，C1-C10烷基， （CH2）p-OR11b或R4，R5一起表示氧原子，a = CHR10基，n表示0至8，p表示1至8，R7表示-C（O）R12，-SO2R12，-C（O ）OR 12，-C（O）NHR 9 d，-C（O）NR 9 d R 9e，R 8表示芳基，R 9a-基，R12相同或不同，表示C1-C10烷基，C4-C8环烷基，芳基，C7- C16芳烷基，R10表示氢，C1-C10烷基， - （CH2）s-OR14，s表示1至8，R6，R11a，b，R14相同或不同，表示氢，C1-C10烷基，芳基，C7 -C 16芳烷基，-SO 2 R 9c，-P（O）（OH）2，R 13，R 15a，b相同或不同，表示氢，C 1 -C 10烷基，芳基，C 7 -C 16芳烷基， X1，X2相同或不同，表示X，X可以是氢，卤素，-OH，-NO 2，-N3，-CN，-NR15aR15b，-NHSO2R15a，-CO2R15，C1-C10烷基，C1-C10烷氧基， C1-C10酰氧基，C1-C10酰基，如果R15表示氢，则它们与生理上相容的碱的盐以及α，β或γ-环糊精包合物以及被包封的式I化合物 与脂质体。