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    Leukotriene antagonist prodrugs
    13.
    发明公开
    Leukotriene antagonist prodrugs 失效
    白三烯拮抗剂前体药物

    公开(公告)号：EP0365149A3

    公开(公告)日：1990-07-25

    申请号：EP89309643.8

    申请日：1989-09-21

    申请人： SMITHKLINE BEECHAM CORPORATION

    发明人： Gleason, John Gerald ,  Newton, John Frederick ,  Smallheer, Joanne ,  Hall, Ralph Floyd ,  Phipps, Kathleen A.

    IPC分类号： C07C323/56 ,  C07C323/60 ,  C07C323/66 ,  C07C323/67 ,  C07D233/84 ,  C07D257/04 ,  A61K31/19

    CPC分类号： C07D257/04 ,  A61K31/19 ,  C07C45/298 ,  C07C45/44 ,  C07C45/56 ,  C07C45/62 ,  C07C45/673 ,  C07C45/68 ,  C07C45/71 ,  C07C47/542 ,  C07C47/546 ,  C07C47/548 ,  C07C47/55 ,  C07C47/575 ,  C07C255/33 ,  C07C323/56 ,  C07C323/60 ,  C07C323/66 ,  C07C323/67 ,  C07D233/84 ,  C07D233/90 ,  C07D303/40 ,  C07D303/48 ,  C07D307/38 ,  C07D307/54 ,  C07D309/30

    摘要： A compound represented by the following structural formula (I):
    wherein (a) R₁ is C₈ to C₁₃ alkyl, C₇ to C₁₂ alkoxy, C₇ to C₁₂ alkylthio, C₁₀ to C₁₂ 1-alkynyl, 10-undecynyloxy, 11-­dodecynyl, phenyl-C₄ to C₁₀ alkyl, phenyl-C₃ to C₉ alkoxy, phenylthio-C₃ to C₉ alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, alkoxy, methylthio or trifluoromethylthio, thienyl-C₄ to C₁₀ alkyl furyl-C₄ to C₁₀ alkyl,trifluoromethyl-C₇ to C₁₂ alkyl or cycloheyl-C₄ to C₁₀ alkyl; and
        R₂ is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, alkoxy or nitro; (b) or R₁ is hydrogen and R₂ is C₈ to C₁₃ alkyl, C₇ to C₁₂ alkoxy, C₇ to C₁₂ alkylthio, C₁₀ to C₁₂ 1-alkynyl, 10-­undecynyloxy, 11-dodecynyl, phenyl-C₄ to C₁₀ alkyl, phenyl-C₃ to C₉ alkoxy, phenylthio-C₃ to C₉ alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoro­methyl, alkoxy, methylthio or trifluoromethylthio, furyl-C₄ to C₁₀ alkyl, trifluoromethyl-C₇ to C₁₂ alkyl or cyclohexyl-C₄ to C₁₀ alkyl;
        q is 0, 1, or 2;
        Y is COR₃, CH(R₄)(CH₂) m COR₃ or CH(R₄)(CH₂) m -­tetrazol-5-yl the tetrazol-5-yl being unsubstituted or substituted with A;     R₁₆ and R₁₇ are independently hydrogen or C₁₋₄ alkyl;
        j is 0 to 6;     R₁₈ is hydrogen, alkyl, COR₃, SO₃H, SO₂NH₂, COCH₂OH or CHOHCH₂OH;
        R₃ is amino, (CH₂) n CO₂CH₂CONR₁₆R₁₇, or OR₁₄;
        R₁₄ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, alkyl substituted amino or alkylamino, - OCH₂CONR₇R₈, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl;
        R₄ is hydrogen, methyl, alkoxy, fluoro or hydroxy;
        m is 0, or 1;
        R is (CH₂) n COR₆, CH(CO₂H)CH₂COR₆, (CH₂) n CO₂CH₂CONR₁₆,R₁₇, or an imidazole of the formula     n is 0 to 6;
        R₅ is hydrogen, amino, or NHCOCH₂CH₂CH(NH₂)CO₂H;
        R₆ is amino, NH(CH₂) n CO₂H, SO₃H, SO₂NH₂, CN, tetrazol-5-yl unsubstituted or substituted with A as defined above, or OR₁₅;
        R₇ is hydrogen, alkyl or alkenyl;
        R₈ is hydrogen, alkyl, carboxyl or carboxamido, or,
    when R₇ and R₉ are hydrogen or alkyl, (CH₂) m COOR₁₅;
        R₉ is hydrogen, alkyl or (CH₂) m COOR₁₅;
        R₁₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, allayl substituted amino or alkylamino, -OCH₂CONR₇R₈, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl;
        provided that 1) when n is 0, R₅ is hydrogen, 2) R₇, R₈ and R₉ are not all hydrogen, 3) any of R₁and R₂ above are not alkylthio or phenylthioalkyl when q is 1 or 2, 4) R₃ and R₆ are not both hydroxy, 5) OR₁₄ and OR₁₅ are not simultaneously hydroxy; 6) if R₄ is hydroxy and m is 0, R₁₄ is hydrogen; or
        a pharmaceutically acceptable salt thereof.

    摘要翻译： 由下列结构式（Ⅰ）表示的化合物：其中（a）R 1是C 8 -C 13烷基，C 8 -C 12烷氧基，C 8 -C 12烷硫基，C 10 -C 12 1-炔基， 苯基-C3-C8烷氧基，苯基硫基-C3-C8烷基，其中苯基任选地被溴，氯，三氟甲基，烷氧基，甲硫基或三氟甲硫基取代，噻吩基-C4-C10烷基呋喃基-C4-C10烷基， 三氟甲基-C 8至C 12烷基或环
    己基-C 4至C 10烷基; 和R 2是氢，溴，氯，甲基，三氟甲基，羟基，烷氧基或硝基; （b）或R 1是氢和R 2是C 8 -C 13烷基，C 8 -C 12烷氧基，C 8 -C 12烷硫基，C 10 -C 12 1-炔基，10-十一碳炔氧基，11-十二炔基，苯基-C 4 -C 10烷基， 任选地被溴，氯，三氟甲基，烷氧基，甲硫基或三氟甲硫基，呋喃基-C 4至C 10烷基，三氟甲基-C 8至C 12烷基或环己基-C 4至C 10烷基取代的苯基;苯基硫基-C 3至C 8烷基; q是0,1或2; Y是COR 3，CH（R 4）（CH 2）mCOR 3或CH（R 4）（CH 2）m-四唑-5-基，四唑-5-基未被取代或被A取代; R 16和R 18独立地是氢或C 1-4烷基; j是0至6; R 17是氢，烷​​基，COR 3，SO 3 H，SO 2 NH 2，COCH 2 OH或CHOHCH 2 OH; R 3是氨基，（CH 2）n CO 2 CH 2 CONR 16 R 17或OR 14; 烷基，烷基芳基，烷基芳基烷基，烷基取代的氨基或烷基氨基，-OCH 2 CONR 8 R 9，茚满基，新戊酰氧基甲基，乙酰氧基甲基，丙酰氧基甲基，甘氨酰氧甲基，苯基甘氨酰氧甲基或噻吩基甘氨酰氧甲基; R 4是氢，甲基，烷氧基，氟或羟基; m是0或1; R是（CH 2）n COR 6，CH（CO 2 H）CH 2 COR 6，（CH 2）n CO 2 CH 2 CONR 16，R 17或式n的咪唑是0-6; R 5是氢，氨基或NHCOCH 2 CH 2 CH（NH 2）CO 2 H; R 6为氨基，NH（CH 2）n CO 2 H，SO 3 H，SO 2 NH 2，CN，未被取代或被上述定义的A取代的四唑-5-基或OR 15; R 7是氢，烷​​基或链烯基; R 7是氢，烷​​基，羧基或甲酰氨基，或当R 7和R 7是氢或烷基时，（CH 2）m COOR 15; R 8是氢，烷基或（CH 2）m COOR 15; 烷基，环烷基，芳基，芳基烷基，烷基芳基，烷基芳基烷基，烯丙基取代的氨基或烷基氨基，-OCH 2 CONR 8 R 9，茚满基，新戊酰氧基甲基，乙酰氧基甲基，丙酰氧基甲基， 条件是1）当n是0时，R 5是氢，2）R 6，R 7和R 7不全是氢，3）当q是1或2,4时，上述R 1和R 2中的任何一个都不是烷硫基或苯硫基烷基，R 3和R 6是 不是两个羟基，5）OR 14和OR 15不同时是羟基; 6）如果R 4是羟基并且m是0，R 14是氢; 或其药学上可接受的盐。

    Leukotriene antagonists
    15.
    发明公开
    Leukotriene antagonists 失效
    白三烯拮抗剂

    公开(公告)号：EP0296732A1

    公开(公告)日：1988-12-28

    申请号：EP88305188.0

    申请日：1988-06-07

    申请人： SMITHKLINE BEECHAM CORPORATION

    发明人： Frazee, James Simpson ,  Gleason, John Gerald ,  Hall, Ralph Floyd

    IPC分类号： C07C321/04 ,  C07C317/04 ,  C07C323/00 ,  A61K31/19

    CPC分类号： C07D311/24 ,  C07C323/00

    摘要： Compounds of formula:
    in which, inter alia q is 0 to 2, R, is (L) a -(CH 2 ) b -(T) c -M wherein a and ca are 0 or 1, b is 3 to 14, L and T are independently O, S or CH 2 ; and M is C 1-4 alkyl, ethynyl, CF 3 , isopropenyl, furanyl, thienyl, cyclohexyl or optionally substituted phenyl; R 2 and A are H, CF 3 , alkyl, alkoxy, halogen, OH, N0 2 , or NH 2 or R 1 and A are H and R 2 is (L) a -(CH 2 ) b -(T) c -M as above; y is COR 3 or (CHX) n (CH 2 )p-Z wherein R 3 is OH, NH 2 , aryloxy or alkoxy, n is 0 or 1, p is 0, 1 or 2; X is H, OH, alkyl, alkoxy or F, Z is COR 3 or tetrazolyl; R is (CR 5 R 6 ) d W, R 5 and R 6 are H or alkyl and W is an optionally substituted phenyl, pyridyl or pyrimidiyl group, intermediates and processes for their preparation and their use in therapy as leukotriene antagonists.

    摘要翻译： 其中a为0或2，R为（L）a-（CH 2）b - （T）c M的式（I）化合物 独立地是O，S或CH2; M为C1-4烷基，乙炔基，CF3，异丙烯基，呋喃基，噻吩基，环己基或任选取代的苯基; R2和A是H，CF3，烷基，烷氧基，卤素，OH，NO2或NH2或R1和A是H并且R2是如上的（L）a-（CH2）b-（T）c-M; y是COR 3或（CHX）n（CH 2）p -Z，其中R 3是OH，NH 2，芳氧基或烷氧基，n是0或1，p是0,1或2; X是H，OH，烷基，烷氧基或F，Z是COR 3或四唑基; R为（CR 5 R 6）d W，R 5和R 6为H或烷基，W为任选取代的苯基，吡啶基或嘧啶基，中间体及其制备方法和它们作为白三烯拮抗剂治疗的用途。

    Leukotriene antagonists
    17.
    发明公开
    Leukotriene antagonists 失效
    白三烯，Antagonisten。

    公开(公告)号：EP0375348A1

    公开(公告)日：1990-06-27

    申请号：EP89313261.3

    申请日：1989-12-19

    申请人： SMITHKLINE BEECHAM CORPORATION

    发明人： Gleason, John Gerald ,  Smallheer, Joanne Marie ,  Hall, Ralph Floyd

    IPC分类号： C07C323/22 ,  A61K31/19

    CPC分类号： C07C323/52 ,  C07C323/56

    摘要： Compounds of structure (I)
    in which, inter alia, R is (CH₂) m CO₂H, (CH₂) m CO₂R₃, (CH₂) m CONHSO₂R₃, CH₂CH(NH₂)COR₄ or a phenyl(alkyl) or tetrazoyl ring; one of R¹ and R² is C₈₋₁₃alkyl, C₇₋₁₂alkoxy, phenyl C₄₋₁₀alkyl or phenyl C₄₋₁₀alkoxy and the other is H, Br, Cl, CH₃, CF₃, CF₃, OH, NO₂ or C₁₋₄alkoxy; R³ is alkyl, aryl or substituted aryl, R⁴ is OH or gly; R⁵ is OH, C₁₋₆alkoxy or NHSO₂R₃; m is 0 to 6; Y is ( H) n (CH₂) p CONHSO₂R₃, ( H) n (CH₂) p -T,

    ( H) n (CH₂) p CO₂H

    or (CH) n (CH₂) p COR₃, where T is tetrazoyl; A is H, OH, alkyl alkoxy OAc or F, n is 0 of 1 and p is 0 or 1; processes for their preparation, compositions containing them and their use in therapy as leukotriene antagonists.

    摘要翻译： 其中特别是R为（CH 2）m CO 2 H，（CH 2）m CO 2 R 3，（CH 2）m CONHSO 2 R 3，CH 2 CH（NH 2）COR 4或苯基（烷基）或四唑基环的结构（I）的化合物 R 1和R 2之一是C 8-13烷基，C 7-12烷氧基，苯基C 4-10烷基或苯基C 4-10烷氧基，另一个是H，Br，Cl，CH 3，CF 3，CF 3，OH，NO 2或C 1 -4alkoxy; R 3是烷基，芳基或取代的芳基，R 4是OH或者Gly; R 5是OH，C 1-6烷氧基或NHSO 2 R 3; m为0〜6; Y是（@H）n（CH2）pCONHSO2R3，（@H）n（CH2）p-T，（@H）n（CH2）pCO2H或（CH）n（CH2）pCOR3，其中T是四唑基; A是H，OH，烷基烷氧基OAc或F，n是1，p是0或1; 其制备方法，含有它们的组合物及其在治疗中作为白三烯拮抗剂的用途。

    Leukotriene antagonist prodrugs
    20.
    发明公开
    Leukotriene antagonist prodrugs 失效
    Leukotrienantagonistenprodrugs。

    公开(公告)号：EP0365149A2

    公开(公告)日：1990-04-25

    申请号：EP89309643.8

    申请日：1989-09-21

    申请人： SMITHKLINE BEECHAM CORPORATION

    发明人： Gleason, John Gerald ,  Newton, John Frederick ,  Smallheer, Joanne ,  Hall, Ralph Floyd ,  Phipps, Kathleen A.

    IPC分类号： C07C323/56 ,  C07C323/60 ,  C07C323/66 ,  C07C323/67 ,  C07D233/84 ,  C07D257/04 ,  A61K31/19

    CPC分类号： C07D257/04 ,  A61K31/19 ,  C07C45/298 ,  C07C45/44 ,  C07C45/56 ,  C07C45/62 ,  C07C45/673 ,  C07C45/68 ,  C07C45/71 ,  C07C47/542 ,  C07C47/546 ,  C07C47/548 ,  C07C47/55 ,  C07C47/575 ,  C07C255/33 ,  C07C323/56 ,  C07C323/60 ,  C07C323/66 ,  C07C323/67 ,  C07D233/84 ,  C07D233/90 ,  C07D303/40 ,  C07D303/48 ,  C07D307/38 ,  C07D307/54 ,  C07D309/30

    摘要： A compound represented by the following structural formula (I):
    wherein


    (a) R₁ is C₈ to C₁₃ alkyl, C₇ to C₁₂ alkoxy, C₇ to C₁₂ alkylthio, C₁₀ to C₁₂ 1-alkynyl, 10-undecynyloxy, 11-­dodecynyl, phenyl-C₄ to C₁₀ alkyl, phenyl-C₃ to C₉ alkoxy, phenylthio-C₃ to C₉ alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, alkoxy, methylthio or trifluoromethylthio, thienyl-C₄ to C₁₀ alkyl furyl-C₄ to C₁₀ alkyl,trifluoromethyl-C₇ to C₁₂ alkyl or cycloheyl-C₄ to C₁₀ alkyl; and
        R₂ is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, alkoxy or nitro;

    (b) or R₁ is hydrogen and R₂ is C₈ to C₁₃ alkyl, C₇ to C₁₂ alkoxy, C₇ to C₁₂ alkylthio, C₁₀ to C₁₂ 1-alkynyl, 10-­undecynyloxy, 11-dodecynyl, phenyl-C₄ to C₁₀ alkyl, phenyl-C₃ to C₉ alkoxy, phenylthio-C₃ to C₉ alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoro­methyl, alkoxy, methylthio or trifluoromethylthio, furyl-C₄ to C₁₀ alkyl, trifluoromethyl-C₇ to C₁₂ alkyl or cyclohexyl-C₄ to C₁₀ alkyl;
        q is 0, 1, or 2;
        Y is COR₃, CH(R₄)(CH₂) m COR₃ or CH(R₄)(CH₂) m -­tetrazol-5-yl the tetrazol-5-yl being unsubstituted or substituted with A;     R₁₆ and R₁₇ are independently hydrogen or C₁₋₄ alkyl;
        j is 0 to 6;
        R₁₈ is hydrogen, alkyl, COR₃, SO₃H, SO₂NH₂, COCH₂OH or CHOHCH₂OH;
        R₃ is amino, (CH₂) n CO₂CH₂CONR₁₆R₁₇, or OR₁₄;
        R₁₄ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, alkyl substituted amino or alkylamino, - OCH₂CONR₇R₈, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl;
        R₄ is hydrogen, methyl, alkoxy, fluoro or hydroxy;
        m is 0, or 1;
        R is (CH₂) n COR₆, CH(CO₂H)CH₂COR₆, (CH₂) n CO₂CH₂CONR₁₆,R₁₇, or an imidazole of the formula     n is 0 to 6;
        R₅ is hydrogen, amino, or NHCOCH₂CH₂CH(NH₂)CO₂H;
        R₆ is amino, NH(CH₂) n CO₂H, SO₃H, SO₂NH₂, CN, tetrazol-5-yl unsubstituted or substituted with A as defined above, or OR₁₅;
        R₇ is hydrogen, alkyl or alkenyl;
        R₈ is hydrogen, alkyl, carboxyl or carboxamido, or,
    when R₇ and R₉ are hydrogen or alkyl, (CH₂) m COOR₁₅;
        R₉ is hydrogen, alkyl or (CH₂) m COOR₁₅;
        R₁₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, allayl substituted amino or alkylamino, -OCH₂CONR₇R₈, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl;
        provided that 1) when n is 0, R₅ is hydrogen, 2) R₇, R₈ and R₉ are not all hydrogen, 3) any of R₁and R₂ above are not alkylthio or phenylthioalkyl when q is 1 or 2, 4) R₃ and R₆ are not both hydroxy, 5) OR₁₄ and OR₁₅ are not simultaneously hydroxy; 6) if R₄ is hydroxy and m is 0, R₁₄ is hydrogen; or
        a pharmaceutically acceptable salt thereof.

    摘要翻译： 由以下结构式（I）表示的化合物：其中（a）R 1为C 8至C 13烷基，C 7至C 12烷氧基，C 7至C 12烷硫基，C 10至C 12 1-炔基，10-十一炔氧基， 苯基-C 4至C 10烷基，苯基-C 3至C 9烷氧基，苯硫基-C 3至C 9烷基，苯基任选被溴，氯，三氟甲基，烷氧基，甲硫基或三氟甲硫基取代，噻吩基-C4至C10烷基呋喃基-C4至 C10烷基，三氟甲基-C C7至C12烷基或环己基-C4至C10烷基; 并且R 2是氢，溴，氯，甲基，三氟甲基，羟基，烷氧基或硝基; （b）或R 1是氢，R 2是C 8至C 13烷基，C 7至C 12烷氧基，C 7至C 12烷硫基，C 10至C 12 1-炔基，10-十一烷氧基，11-十二炔基，苯基-C 4至C 10烷基，苯基-C 3 C 9烷氧基，苯硫基-C 3至C 9烷基，苯基任选被溴，氯，三氟甲基，烷氧基，甲硫基或三氟甲硫基取代，呋喃基-C4至C10烷基，三氟甲基-C C7至C12烷基或环己基-C4至C10烷基; q是0,1或2; Y是COR 3，CH（R 4）（CH 2）m COOR 3或CH（R 4）（CH 2）m - 四唑-5-基，未被取代或被A取代的四唑-5-基; R 16和R 17独立地是氢或C 1-4烷基; j为0〜6; R18是氢，烷基，COR3，SO3H，SO2NH2，COCH2OH或CHOHCH2OH; R3是氨基，（CH2）nCO2CH2CONR16R17或OR14; R 14是氢，烷基，环烷基，芳基，芳基烷基，烷基芳基，烷基芳基烷基，烷基取代的氨基或烷基氨基，-OCH 2 CONR 7 R 8，茚满基，新戊酰氧基甲基，乙酰氧基甲基，丙酰氧基甲基，甘氨酰氧基甲基，苯基甘氨酰氧基甲基或噻吩基乙酰氧基甲基; R4是氢，甲基，烷氧基，氟或羟基; m为0或1; R是（CH 2）n，= COR 6，CH（CO 2 H）CH 2 COR 6，（CH 2）n CO 2 CH 2 CONR 16，R 17或式CHEM n的咪唑是0-6; R5是氢，氨基或NHCOCH2CH2CH（NH2）CO2H; R6是氨基，NH（CH2）nCO2H，SO3H，SO2NH2，CN，未取代或被如上定义的A取代的四唑-5-基，或OR15; R7是氢，烷​​基或烯基; R8是氢，烷基，羧基或甲酰氨基，或者当R7和R9是氢或烷基时，（CH2）mCOOR15; R9是氢，烷基或（CH2）mCOOR15; R 15是氢，烷基，环烷基，芳基，芳基烷基，烷基芳基，烷基芳基烷基，全酰取代的氨基或烷基氨基，-OCH 2 CONR 7 R 8，茚满基，新戊酰氧基甲基，乙酰氧基甲基，丙酰氧基甲基，甘氨酰氧基甲基，苯基甘氨酰氧基甲基或噻吩基乙酰氧基甲基; 条件是1）当n为0时，R5为氢，2）R7，R8和R9不全为氢; 3）当q为1或2,4时，R 1和R 2中的任何一个不为烷硫基或苯硫基烷基，R 3和R 6为 不是羟基，5）OR14和OR15不是同时羟基; 6）如果R4是羟基，m是0，R14是氢; 或其药学上可接受的盐。 ÿ