申请人:Geron Corporation
公开号:US05760062A1
公开(公告)日:1998-06-02
Methods and compositions for treating cancer and other diseases in which inhibition of telomerase activity can ameliorate disease symptoms or prevent or treat the disease relate to compounds that are derivatives of pyrido\x9bb!thiophenes, pyrido\x9bb!furans, pyridine ethers or pyridine thioethers. Such compounds are characterized by the following structure: ##STR1## X.sub.3 is oxygen or sulfur; and the double dashed lines between X.sub.4 and X.sub.5 indicate an optional double bond, which, when present, forms a fused, bicyclic pyrido\x9bb!furan or pyrido\x9bb!thiophene ring system, depending upon whether X.sub.3 is oxygen or sulfur, respectively. When the double bond is not present, the compound is a monocyclic pyridine ether or thioether, again depending upon whether X.sub.3 is oxygen or sulfur. X.sub.4 is --CH.sub.2 R.sub.21 or --CR.sub.21 --, where R.sub.21 is selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, heteroaralkylcarbonyl, aralkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylarninocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl and arylsulfonyl; and X.sub.5 is hydrogen, alkyl, hydroxyl, alkoxyl, aryloxyl, halogen, cyano, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonyl, arylsulfonyl or --CR.sub.22 -- where R.sub.22 is selected from the group consisting of hydrogen, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, hydroxyl, halogen, cyano, carboxyl, alkoxycarbonyl and aryloxycarbonyl. When X.sub.4 is --CR.sub.21 --, X.sub.5 is --CR.sub.22 --, and X.sub.4 and X.sub.5 are joined by the above-mentioned double bond, to form thereby a fused, bicyclic pyrido\x9bb!thiophene (X.sub.3 is sulfur) or pyrido\x9bb!furan (X.sub.3 is oxygen) ring system. When X.sub.4 is --CH.sub.2 R.sub.21, X.sub.5 is not --CR.sub.22 --, thereby forming a pyridine ether (X.sub.3 is oxygen) or thioether (X.sub.3 is sulfur). R.sub.18 and R.sub.19 are selected independently from the group consisting of hydrogen, halogen, hydroxy, aryloxy, alkoxy, lower alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl. R.sub.20 is selected from the group consisting of alkoxymethyl, dialkoxymethyl, arylalkylaminomethyl, arylaminomethyl, alkylaminomethyl, aminomethyl, diarylaminomethyl, dialkylaminomethyl, hydroximinyl, iminyl, aldehyde, alkylcarbonyl, arylcarbonyl, alkyliminyl, aryliminyl, aralkyliminyl, alkoximinyl, aryloximinyl, heterocycleimninyl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkene, --HC.dbd.NNHR.sub.23 where R.sub.23 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl, and --C(X.sub.6)NHR.sub.24 where X.sub.6 is oxygen or sulfur and R.sub.24 is selected from the group consisting of hydrogen, aryl, arylsulfonyl, aralkyl, heterocycle and heterocyclealkyl.
用于治疗癌症和其他疾病的方法和组合物,其中抑制端粒酶活性可以改善疾病症状或预防或治疗疾病,涉及到的化合物是吡啶并[1,4]噻吩衍生物、吡啶并[1,4]呋喃衍生物、吡啶醚或吡啶硫醚。这些化合物的特征结构如下: ##STR1## X.sub.3为氧或硫;X.sub.4和X.sub.5之间的双虚线表示可选的双键,当存在时,形成一个融合的、双环的吡啶并[1,4]呋喃或吡啶并[1,4]噻吩环系统,具体取决于X.sub.3是氧还是硫。当双键不存在时,化合物为单环的吡啶醚或硫醚,同样取决于X.sub.3是氧还是硫。X.sub.4为--CH.sub.2 R.sub.21或--CR.sub.21 --,其中R.sub.21选自以下组:芳基、杂环芳基、芳基烷基、杂环芳基烷基、烷基羰基、芳基羰基、杂基烷基羰基、杂环芳基烷基羰基、芳基烷基羰基、氨基羰基、烷基氨基羰基、芳基氨基羰基、二烷基氨基羰基、二芳基氨基羰基、芳基烷基氨基羰基、羧基、烷氧基羰基、芳氧基羰基、磺酰基、烷基磺酰基和芳基磺酰基;X.sub.5为氢、烷基、羟基、烷氧基、芳氧基、卤素、氰基、氨基、烷基氨基、芳基氨基、二烷基氨基、二芳基氨基、芳基烷基氨基、氨基羰基、烷基氨基羰基、芳基氨基羰基、二烷基氨基羰基、二芳基氨基羰基、芳基烷基氨基羰基、羧基、烷氧基羰基、芳氧基羰基、磺酰基、烷基磺酰基、芳基磺酰基或--CR.sub.22 --,其中R.sub.22选自以下组:氢、氨基、烷基氨基、芳基氨基、二烷基氨基、二芳基氨基、芳基烷基氨基、氨基羰基、烷基氨基羰基、芳基氨基羰基、二烷基氨基羰基、二芳基氨基羰基、芳基烷基氨基羰基、羟基、卤素、氰基、羧基、烷氧基羰基和芳氧基羰基。当X.sub.4为--CR.sub.21 --,X.sub.5为--CR.sub.22 --,并且X.sub.4和X.sub.5由上述双键连接在一起时,形成一个融合的、双环的吡啶并[1,4]噻吩(X.sub.3为硫)或吡啶并[1,4]呋喃(X.sub.3为氧)环系统。当X.sub.4为--CH.sub.2 R.sub.21时,X.sub.5不是--CR.sub.22 --,从而形成吡啶醚(X.sub.3为氧)或硫醚(X.sub.3为硫)。R.sub.18和R.sub.19独立地选自以下组:氢、卤素、羟基、芳基氧基、烷氧基、较低烷基、芳基、杂环芳基、芳基烷基和杂环芳基烷基。R.sub.20选自以下组:烷氧甲基、二烷氧基甲基、芳基烷基氨甲基、芳基氨甲基、烷基氨甲基、氨基甲基、二芳基氨甲基、二烷基氨甲基、羟亚胺基、亚胺基、醛、烷基羰基、芳基羰基、烷基亚胺基、芳基亚胺基、芳基烷基亚胺基、烷氧基羰基、芳氧基羰基、杂环亚胺基、烷氧基羰基、芳氧基羰基、羧基、烯烃、--HC.dbd.NNHR.sub.23,其中R.sub.23选自以下组:氢、烷基、芳基、芳基烷基、杂环、杂环烷基和--C(X.sub.6)NHR.sub.24,其中X.sub.6为氧或硫,R.sub.24选自以下组:氢、芳基、芳基磺酰基、芳基烷基、杂环和杂环烷基。