发明公开
- 专利标题： Leukotriene antagonist prodrugs
- 专利标题（中）： Leukotrienantagonistenprodrugs。
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申请号： EP89309643.8申请日： 1989-09-21
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公开(公告)号： EP0365149A2公开(公告)日： 1990-04-25
- 发明人: Gleason, John Gerald , Newton, John Frederick , Smallheer, Joanne , Hall, Ralph Floyd , Phipps, Kathleen A.
- 申请人： SMITHKLINE BEECHAM CORPORATION
- 申请人地址： One Franklin Plaza P.O. Box 7929 Philadelphia Pennsylvania 19103 US
- 专利权人： SMITHKLINE BEECHAM CORPORATION
- 当前专利权人： SMITHKLINE BEECHAM CORPORATION
- 当前专利权人地址： One Franklin Plaza P.O. Box 7929 Philadelphia Pennsylvania 19103 US
- 代理机构： Waters, David Martin, Dr.
- 优先权： US248770 19880923
- 主分类号： C07C323/56
- IPC分类号： C07C323/56 ; C07C323/60 ; C07C323/66 ; C07C323/67 ; C07D233/84 ; C07D257/04 ; A61K31/19
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.
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.
公开/授权文献
- EP0365149A3 Leukotriene antagonist prodrugs 公开/授权日：1990-07-25
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