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1. 发明公开

EP0365149A2 Leukotriene antagonist prodrugs 失效
标题翻译： 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

2. 发明公开

EP0365149A3 Leukotriene antagonist prodrugs 失效
标题翻译：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。

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