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CN86107767A - 新有机硒化合物 - Google Patents

新有机硒化合物 Download PDF

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Publication number
CN86107767A
CN86107767A CN198686107767A CN86107767A CN86107767A CN 86107767 A CN86107767 A CN 86107767A CN 198686107767 A CN198686107767 A CN 198686107767A CN 86107767 A CN86107767 A CN 86107767A CN 86107767 A CN86107767 A CN 86107767A
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Inventor
浴本久雄
铃木政信
伊泽孝夫
高桥克俊
中谷得二
藤井�
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Nippon Kayaku Co Ltd
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Nippon Kayaku Co Ltd
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Publication of CN86107767A publication Critical patent/CN86107767A/zh
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    • C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明揭示了用式I表示的抗肿瘤及抗诱变活性新硒化合物的制备过程。该过程包括将通式(II)化合物与通式F化合物相反应，当所得化合物为通式I化合物，其中M是0(零)时，如果需要，再进一步与通式Y化合物反应。通式I、II化合物的取代基定义同说明书。通式F和通式Y化合物的定义亦与说明书中定义相同。

Description

本发明涉及具有抗肿瘤活性的新有机硒化合物。
已报导，某些类型的硒化合物具有抗肿瘤或抗癌活性（例如见日本专利公报（公开）号，20271/84和EP-95663A）。
然而尚未发现实际有用的可作为抗肿瘤或癌的硒化合物。
本发明涉及的通式（Ⅰ）表示的新硒化合物
Se（O）a（R）b（X）c（A）m（Y）n    （Ⅰ）其中R，X，A和Y分别表示下面详述的基团，a表示0或1，b表示0、1，b表示0、1或2，（1）当a是0，b也是0时，c是4，n是1或2，m是0，（2）当a是1，b是0时，c是2，n是1或2，m是0或1，（3）当b是1或2时，c，n和m都是0;
（ⅰ）当b是2，R代表（Ⅰ）囟原子取代的直链C4-10烷氧基团;（2）囟原子和苯基取代的低级烷氧基团或（3）囟原子取代的环烷氧基，（ⅱ）当b是1，R表示下式基团：
Figure 86107767_IMG14
（其中R0表示C2-6烷基）;
X表示囟原子;
A表示咖啡因、茶碱、N-苄基茶碱、N-苄基可可碱、2，2′-联喹啉、1，6-萘啶、1，10-菲绕啉或下式表示的化合物：
（其中R1和R2可相同或不同并分别表示氢原子、羟基、低级烷基、囟原子、苯基、氰基、低级烷氧羰基、苯氧羰基、氨基（该基上可连接低级烷基、低级烷氨羰基、低级囟烷氨基羰基或低级烷氧羰基）、苯甲酰基、低级烷氧基、氨甲酰基或烯丙氧基羰基;R3表示C1-10烷基或苄基;R4和R5各自表示氢原子、囟原子或烷基或R4和R5可联合表示
Figure 86107767_IMG16
;R6表示低级烷氧基、苯基或苯氧基;R7表示氢原子、低级烷基或下式表示的基团 （其中R9表示氨基或低级烷氧基）;R10表示氢原子或硝基;B和D之一表示氮原子，另一则表示
Figure 86107767_IMG18
）;
Y表示H2O或以式R8-OH表示的醇[其中R8表示苄基或烷基（该基可被低级烷氧基取代）];
其中当X是氯原子并且m是0时，R1和R10表示除氢原子以外的原子或基团。
上述通式（Ⅰ）中囟原子可以是氟、氯、溴或碘，但优选氯、溴和氟。低级烷基可以是，例如，C1-5烷基如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基等，至于烷基则为C1-10烷基，可提及者如甲基、乙基、丙基、异丙基、丁基仲丁基、叔丁基、戊基，己基、辛基和癸基、低级烷氧基选自：C1-5烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基。低级烷氨基可以是，例如，C1-4单或双烷氨基。环烷氧基可以选自C4-8环烷氧基。在低级烷氧羰基中的低级烷氧基可以是C1-5烷氧基。在囟烷氨基羰基和低级囟烷基中的囟原子可以是，氟、溴、氯或碘。低级烷基是C1-5低级烷基。
在通式（Ⅰ）表示的化合物中，当a是1，b是1或2，c，m和n是0，即当SeO（R）1、或SeO（R）2时囟原子取代的C4-10烷氧基可以是，例如2-氯丁氧基、2-溴丁氧基、2-氯戊氧基、2-溴戊氧基、2-氯己氧基、2-溴己氧基、2-氯庚氧基、2-溴庚氧基、2-氯辛氧基、2-溴辛氧基、2-氯壬氧基、2-溴壬氧基、2-氯癸氧基、2-溴癸氧基、2-氯-1-甲基乙氧基、2-氯-1-甲基丙氧基、2-氯-2-甲基丙氧基、2-氯-1，1-二甲基丙氧基、2-氯-1，2-二甲基丙氧基、2-氯-1，1-2-三甲基丙氧基、2-氯-1-甲基丁氧基、2-氯-2-甲基丁氧基、2-氯-3-甲基丁氧基、2-氯-1，1-二甲基丁氧基、2-氯-1，2-二甲基丁氧基、2-氯-1，2，3-三甲基丁氧基、2-氯-1，1，2，3-四甲基丁氧基、2-氯-1，1，2，3，3-五甲基丁氧基、2-溴-1-丁基丁氧基等。
囟原子和苯基取代的低级烷氧基可以是，例如，C2-4烷氧基如2-氯-1-苯乙氧基、2-氯-2-苯乙氧基、2-氯-1-苯丙氧基、2-氯-2-苯-丙氧基、2-氯-3-苯丙氧基和2-溴-2-苯丁氧基。
囟代环烷氧基的例子是C4-8环烷氧基如2-氯环丁氧基、2-氯环戊氧基、2-氯环己氧基、2-氯环辛氧基和3-氯降冰片-2-基氧基。用R0表示的C2-6烷基包括乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基等。
通式（Ⅰ）表示的化合物中，当b是0时即当Se（O）a（X）x（A）m（Y）n′或Se（O）a（X）4（A）m（Y）n′时，以式
Figure 86107767_IMG19
表示的化合物包括吡啶、甲基吡啶、二甲基吡啶、乙基吡啶、异丙基吡啶、叔丁基吡啶、苯基吡啶、氟吡啶、氯吡啶、溴吡啶、二氯吡啶、氰基吡啶、吡啶羧酸乙酯、烟酸甲酯、烟酸乙酯、异烟酸甲酯、异烟酸乙酯、异烟酸苯酯、4-苯甲酰基吡啶、4-氨基吡啶、4-二甲基氨基吡啶、2-N-甲基氨基吡啶、吡啶-3-甲酰草氨甲酯、2-羟基吡啶、4-羟基吡啶、4-甲氧基吡啶、烯丙基烟酸盐、N-甲基-N′-（3-吡啶基）-脲、N（2-氯）乙基-N′-（3-吡啶基）-脲和6-氨基烟酰胺。
以下式
Figure 86107767_IMG20
表示的化合物的例子包括：
N-甲基咪唑、N-乙基咪唑、N-己基咪唑、N-癸基咪唑、N-苄基咪唑、1，2-二甲咪唑、1-甲基-5-溴咪唑、N-甲基苯并咪唑、N-苄基苯并咪唑、1-苄基吡唑等。
通式 化合物的例子是：三苯基氧膦、磷酸三苯酯、磷酸三甲酯、磷酸三乙酯等。
通式
Figure 86107767_IMG22
化合物的例子是：异喹啉、1-羟基异喹啉、5-羟基异喹啉、5-硝基喹啉、6-硝基喹啉、8-硝基喹啉、5-硝基异喹啉等。
通式
Figure 86107767_IMG23
化合物的例子是：2，2′-联吡啶、2，2′-二-异烟酸甲酯、2，2′-二-异烟酸乙酯、2，2′-二-4-甲基吡啶等。用Y表示的醇的例子是：甲醇、乙醇、丙醇、辛醇、苄醇、茴香醇。
至于A和n的配合情况，在A是2，2′-联吡啶衍生物、2，2′-双喹啉或1，10-二氮杂菲时，n是1，在其余情况下n是1或2。
本发明化合物的典型例子列入下述表Ⅰ中
表1-1 SeO（R）1或2
化合物    符号
3-1    SOC1    P    亚硒酸双-（2-氯-1-甲基丙基）酯
3-2    SOC2    P    亚硒酸双-（2-氯-1-甲基丙基）酯
3-3    SOCB    亚硒酸双-（2-氯-1-甲基丙基）酯
3-4    SOCO    亚硒酸双-（2-氯-1-甲基丙基）酯
3-5    SOPE    亚硒酸双-（2-氯乙氧苯基）酯
3-6    SOCH    亚硒酸双-（2-氯环己基）酯
3-7    SOCN    亚硒酸双-（3-氯降冰片-2-基）酯
3-8    SOEEC    亚硒酸1，2-丁二醇酯
3-9    SOEPC    亚硒酸2，2-二乙基-1，3-丙二醇酯
表1-2 SeO（X）2（A）m（Y）n
化合物    符号
号
1-1    SBPy    硒溴氧化物-吡啶（1∶2）络合物.
1-2    SC2    Pc    硒氯氧化物-2-甲基吡啶（1∶2）络合物.
3-3    SC3    Pc    硒氯氧化物-3-甲基吡啶（1∶3）络合物.
1-4    SC4    Pc    硒氯氧化物-4-甲基吡啶（1∶2）络合物.
1-5    SC35    Lt    硒氯氧化物-3，5-二甲基吡啶（1∶2）络合物.
1-6    SC4    Et    硒氯氧化物-4-乙基吡啶（1∶2）络合物.
1-7    SC4    Ip    硒氯氧化物-4-异丙基吡啶（1∶2）络合物.
1-8    SC4    Bt    硒氯氧化物-4-叔-丁基吡啶（1∶2）络合物.
1-9    SC2    Ph    硒氯氧化物-2-苯基吡啶（1∶2）络合物.
1-10    SC3    Ph    硒氯氧化物-3-苯基吡啶（1∶2）络合物.
1-11    SC4    Ph    硒氯氧化物-4-苯基吡啶（1∶2）络合物.
1-12    SC3    Fl    硒氯氧化物-3-氟吡啶（1∶2）络合物.
1-13    SC3    Cl    硒氯氧化物-3-氯吡啶（1∶2）络合物.
1-14    SC3    Br    硒氯氧化物-3-溴吡啶（1∶2）络合物.
1-15    SC35    Dc    硒氯氧化物-3，5-二氯吡啶（1∶2）络合物.
1-16    SC3    Cy    硒氯氧化物-3-氰基吡啶（1∶2）络合物.
1-17    SC4    Cy    硒氯氧化物-4-氰基吡啶（1∶2）络合物.
1-18    SCPE    硒氯氧化物吡啶羧酸乙酯（1∶2）络合物.
1-19    SCNM    硒氯氧化物烟酸酯（1∶2）络合物.
1-20    SCNE    硒氯氧化物烟酸乙酯（1∶2）络合物.
1-21    SCIE    硒氯氧化物-异烟酸乙酯（1∶2）络合物.
1-22    SCM    Im    硒氯氧化物-N-甲基咪唑（1∶2）络合物.
1-23    SCE    Im    硒氯氧化物-N-乙基咪唑（1∶2）络合物.
1-24    SCH    Im    硒氯氧化物-N-乙基咪唑（1∶2）络合物.
1-25    SCT    Im    硒氯氧化物-N-癸基咪唑（1∶2）络合物.
1-26    SCB    Im    硒氯氧化物-N-苄基咪唑（1∶2）络合物.
1-27    SCD    Im    硒氯氧化物-1，2-二甲咪唑（1∶2）络合物.
表1-2续
化合物    符号
号
1-28    SCRIm    硒氯氧化物-1-甲基-5-溴咪唑（1∶2）络合物
1-29    SCMBi    硒氯氧化物-N-甲基苯并咪唑（1∶2）络合物
1-30    SCBBi    硒氯氧化物-N-苄基苯并咪唑（1∶2）络合物
1-31    SCCf    硒氯氧化物-咖啡因（1∶2）络合物
1-32    SBCf    硒溴氧化物-咖啡因（1∶2）络合物
1-33    SCBTf    硒氯氧化物-N-苄基萘碱（1∶2）络合物
1-34    SCBTb    硒氯氧化物-N-苄基可可碱（1∶2）络合物
1-35    SCBPr    硒氯氧化物-1-苄基吡唑（1∶2）络合物
1-36    SCPP    硒氯氧化物-三苯基膦氧（1∶2）络合物
1-37    SCPOP    硒氯氧化物-磷酸三苯酯（1∶2）络合物
1-38    SCMOP    硒氯氧化物-磷酸三乙酯（1∶2）络合物
1-39    SCEOP    硒氯氧化物-磷酸三甲酯（1∶2）络合物
1-40    SC1MBi    硒氯氧化物-N-甲基苯并咪唑（1∶2）络合物
1-41    SCDP    硒氯氧化物-2，2′-联吡啶（1∶1）络合物
1-42    SBDp    硒溴氧化物-2，2′-联吡啶（1∶1）络合物
1-43    SCBPc    硒氯氧化物-2，2′-二-4-吡咯啉（1∶1）络合物
1-44    SCBQn    硒氯氧化物-2，2′-双喹啉（1∶1）络合物
1-45    SCPn    硒氯氧化物-1，10-二氮杂菲（1∶1）络合物
1-46    SCPy（M）    硒氯氧化物-吡啶（1∶1）络合物单甲醇合物
1-47    SCPy（E）    硒氯氧化物-吡啶（1∶2）络合物单乙醇合物
1-48    SCPy（A）    硒氯氧化物-吡啶（1∶2）络合物单茴香醇合物
1-49    SCPy（O）    硒氯氧化物-吡啶（1∶2）络合物单辛醇合物
1-50    SCPy（B）    硒氯氧化物-吡啶（1∶2）络合物单苄醇合物
1-51    SCIM    硒氯氧化物-异烟酸甲酯（1∶2）络合物
1-52    SCIP    硒氯氧化物-异烟酸苯酯（1∶2）络合物
3-10    SC4    Bz    硒氯氧化物-4-苄基吡啶（1∶2）络合物
3-11    SC4    AP.aq    硒氯氧化物-4-氨基吡啶（1∶2）络合物单水合
物
3-12    SC4    MAp    硒氯氧化物-4-二甲基氨基吡啶（1∶2）络合物
3-13    SC2    Hy    硒氯氧化物-2-羟基吡啶（1∶2）络合物
3-14    SC4    Hy.aq    硒氯氧化物-4-羟基吡啶（1∶2）络合物单水
合物
3-15    SC4    Mo    硒氯氧化物-4-甲氧基吡啶（1∶2）络合物
3-18    SCIA    硒氯氧化物-异烟酸烯丙酯（1∶2）络合物
3-19    SC16NP    硒氯氧化物-1，6-萘啶（1∶2）络合物
3-20    SC5    NQ    硒氯氧化物-5-硝基喹啉（1∶2）络合物
3-21    SC6    NQ    硒氯氧化物-6-硝基喹啉（1∶2）络合物
3-22    SC8    NQ    硒氯氧化物-8-硝基喹啉（1∶2）络合物
3-23    SC5    NI    硒氯氧化物-5-硝基异喹啉（1∶2）络合物
3-24    SCTf    硒氯氧化物-茶碱（1∶2）络合物
3-25    SCBIM    硒氯氧化物-2，2′-双-（异烟酸甲酯）（1∶1）络
合物
3-26    SCBIE    硒氯氧化物-2，2′-双-（异烟酸乙酯（1∶1）络
合物
3-28    SC2    AP.aq    硒氯氧化物-2-氨基吡啶（1∶2）络合物单水
合物
3-29    SC25AAm    硒氯氧化物-6-氨基烟酰胺（1∶2）络合物
3-30    SC25HN    硒氯氧化物-2-羟基-5-硝基吡啶（1∶2）络
合物
3-31    SC4    HQ    硒氯氧化物-4-羟基喹啉（1∶2）络合物
3-32    SC8    HQ    硒氯氧化物-8-羟基喹啉（1∶2）络合物
3-33    SC4    BI    硒氯氧化物-4-溴异喹啉（1∶2）络合
4-1    SC3    CUa.aq    硒氯氧化物-3-（2-氯乙基氨基羰基氨基）吡啶
（1∶2）络合物单水合物
4-2    SC2    MAP.aq    硒氯氧化物-2-（N-甲基氨基）吡啶（1∶2）络
合物单水合物。
表1-3    SeX（A）m
化合物
号    符号
2-1    B4    SPy    四溴硒-吡啶（1∶2）络合物
2-2    C4    S3    Pc    四氯硒-3-甲基吡啶（1∶2）络合物
2-3    C4    S35    Lt    四氯硒-3，5-二甲基吡啶（1∶2）络合物
2-4    C4    S3    Ph    四氯硒-3-苯基吡啶（1∶2）络合物
2-5    C4    S4    Ph    四氯硒-4-苯基吡啶（1∶2）络合物
2-6    C4    S3    Fl    四氯硒-3-氟吡啶（1∶2）络合物
2-7    C4    S3    Cy    四氯硒-3-氰基吡啶（1∶2）络合物
2-8    C4    S4    Cy    四氯硒-4-氰基吡啶（1∶2）络合物
2-9    C4    SNM    四氯硒-烟酸甲基酯（1∶2）络合物
2-10    C4    SIq    四氯硒-异喹啉（1∶2）络合物
2-11    C4    SMI    四氯硒-N-甲基咪唑（1∶2）络合物
2-12    C4    SCf    四氯硒-咖啡因（1∶2）络合物
2-13    C4    SDp    四氯硒-2，2′-联吡啶（1∶2）络合物
2-14    C4    SDp    四溴硒-2，2′-联吡啶（1∶2）络合物
在这些化合物中较好的是：1-7、1-10、1-17、1-28、1-30、1-41、1-44、1-46、1-47、2-1、2-4、2-5、2-6、2-7、2-9、3-2、3-6、3-9、3-14、3-18、3-21和3-23。最好的是1-41和3-14。
通式（Ⅰ）所示的本发明化合物可从以下反应获得：
Figure 86107767_IMG24
[其中X代表囟原子;a是0或1，当a是0时，c′是4以及d是0，当a是1时，c′是2，d是0或1;F表示A（A定义如上），直链1，2-环氧烷、低级烷基或苯基取代的低级1，2-环氧烷、环氧环烷或下式表示的化合物：
（其中Ro定义如上）]。
式（Ⅱ）表示的化合物包括硒囟氧化物诸如硒氯氧化物，硒溴氧化物等及其1，4-二氧六环络合物，硒四囟化物如四氯硒、四溴硒等（硒囟氧化物二氧六环（1∶1）络合物的生产过程描述于以下文献：耶鲁凡科等，有机化学杂志，31卷40006页，1961（Yarovenko    et    al.，Zh.Obshch.Khim.vol.31，P40006，1961）
式F中A表示的化合物就像上面提到的那样。直链1，2-环氧烷可以是C4-101，2-环氧烷如1，2-环氧丁烷、1，2-环氧戊烷、1，2-环氧己烷、1，2-环氧庚烷、1，2-环氧辛烷、1，2-环氧壬烷和1，2-环氧癸烷。
低级烷基取代的1，2-环氧烷是低级烷基取代的C烷基如1，2-环氧丙烷、1-甲基-1，2-环氧丙烷、1，1-二甲基-1，2-环氧丙烷、1，2-二甲基-1，2-环氧丙烷、1，1，2-三甲基-1，2-环氧丙烷、1-甲基-1，2-环氧丁烷、2-甲基-1，2-环氧丁烷、3-甲基-1，2-环氧丁烷、1，1-二甲基-1，2-环氧丁烷、1，2-二甲基-1，2-环氧丁烷、1，2，3-三甲基-1，2-环氧丁烷、1，1，2，3-四甲基-1，2-环氧丁烷、1，1，2，3，3-戊甲基-1，2-环氧丁烷和1-丁基-1，2-环氧丁烷。
苯基取代的低级1，2-环氧烷是C2-41，2-环氧烷类如1-苯基-1，2-环氧乙烷、2-苯基-1，2-环氧乙烷、1-苯基-1，2-烷氧丙烷、2-苯基-1，2-环氧丙烷、3-苯基-1，2-环氧丙烷和2-苯基-1，2-环氧丁烷。
环氧环烷的例子是C4-81，2-环氧环烷如1，2-环氧环丁烷、1，2-环氧环戊烷、1，2-环氧环己烷、1，2-环氧环辛烷以及2，3-环氧降冰片烷。
Figure 86107767_IMG26
表示的化合物的例子是1，2-丁二醇、1，2-戊二醇、1，2-己二醇。和1，2-辛二醇。
式 表示的化合物的例子是2，2-二乙基-1，3-丙二醇、2，2-丙基-1，3-丙二醇、2，2-二异丙基-1，3-丙二醇、2，2-二丁基-1，3-丙二醇和2，2-二戊基-1，3-丙二醇。
为了制备本发明化合物可将F表示的化合物与式（Ⅱ）表示的化合物相反应，如果必要，反应产物可进一步与水或醇反应。
特别是，通式Ⅰ表示的本发明化合物可用以通式Ⅱ表示的化合物与式F表示的化合物在沸点为150℃或低于此的溶剂中反应制得，最好是110℃或低于此温度，如二氧六环、己烷、氯仿、乙醚、二氯甲烷、四氢呋喃等反应较佳温度是0至100℃，更佳是10到40℃，反应周期是30分钟至5天，更好是1至3天。
本反应中若使用含水溶剂则所得式（Ⅰ）化合物中m是1，Y是H2O，若使用无水含醇溶剂则所得式（Ⅰ）化合物中Y是醇，当使用无水非醇溶剂时所得式（Ⅰ）化合物中m是0。
还有，式（Ⅰ）化合物中a是1，b是1或2，c，m和n是0，即下式化合物SeO（R）1或SeO（R）2可按下法制得：
（1）b＝2
将硒囟氧化物-1，4-二氧六环（1∶1）络合物或硒囟氧化物与1，2-环氧烷或1，2-环氧环烷（该烷可被烷基或苯基取代）（它们在上述所示式中相当于R）在无水溶剂中反应，然后除去溶剂。上面提到的溶剂在此均可用。反应在-20至150℃温度范围内进行，较好在0°至100℃，更好在10至40℃。反应周期在30分钟至24小时内较好在1至8小时内。
1，2-环氧烷或1，2-环氧环烷（该烷可被烷基或苯基取代），（它们在上述所示中相当于R）的数量必须恰好二倍于起始原料硒囟氧化物-1，4-二氧六环（1∶1）络合物或硒囟氧物。
（2）b＝1
将硒囟氧化物或硒囟氧化物-1，4-二氧六环（1∶1）络合物与在上述式中相当于R的二醇在无水溶剂中反应。如反应在有机酸金属盐诱导下，较好是脂族羧酸或含氧羧酸金属盐如草酸、柠檬酸、乙酸、丙酸等的钠、钾或银盐等存在下则反应平稳。反应结束后除去溶剂。在使用有机羧酸金属盐类的情况下则溶剂在滤除金属盐沉淀后除去。
上面提到的溶剂可用于本反应。反应温度是-20至150℃，较好是0至100℃，更好是10至40℃，反应时间是0.5至5天，较好是1至3天。
有机羧酸及二醇在反应中的量，前者较好是约二倍于起始物硒化合物的量，后者约与硒化合物的量相等。
式（Ⅰ）化合物中当b和m是0，即下式Se（O）a（X）2或4A1或2化合物可从下法制得。
将硒四囟化物，硒囟氧化物或硒囟氧化物-1，4-二氧六环（1∶1）络合物与式（Ⅰ）中以A表示的化合物在无水溶剂中反应，然后除去溶剂。
前述溶剂可用于此反应。反应温度范围是-20至150℃，较好的是0至100℃，更好是10至35℃，反应时间是30至24小时，较好1至8小时。
欲得n＝2的式（Ⅰ）化合物，A的加入量是起始物硒化合物的1至10倍，较好是2至3倍;欲得n＝1的式（Ⅰ）化合物则A的用量为上述硒化合物量的0.5至5倍较好是1至2倍。
式（Ⅰ）化合物中a是1，b是0，c是2，m是1，即下式SeOX2（A）1或2Y表示的化合物可在有水溶剂或无水含醇溶剂中用上述反应制得。
（1）上式所示化合物其Y是H2O者可用上述反应为了获得m＝0之化合物制得，所用含水溶剂其含水量以0.05至15%为好，含0.5至10%更好。或用含水醇溶剂如含水量为0.5至10%的含水甲醇而以含水量1至5%为较好。此时所用含水醇的量随醇中水的含量而各异，但对反应中所用溶剂计它可以在1至20%左右。
（2）上式所示化合物其Y是醇者可按照前述反应过程（m是0）获得但要用无水溶剂，此无水溶剂是以Y表示的醇与上述溶剂相混合制得。
上式所示化合物其Y是H2O或醇者亦可用m＝0的化合物与水或无水醇反应制得，即将式Y表示的H2O或醇加到用于合成m＝0的化合物的反应溶液中或将已分离出的式（Ⅰ）m＝0的化合物溶于Y所表示的H2O或醇中溶于含水或醇的溶液中，此过程较好在10至40℃并放置10分钟至2小时，然后除去溶剂。水和醇的用量无任何限制只要不少于式（Ⅰ）m＝0化合物用量的一倍，其比例仅根据反应采用的工艺而定。
通过上述反应可得目的物为油状物、无定形粉末、脂膏状油状物或结晶，其结构用红外（IR）及核磁共振分析证实。
本发明化合物典型实例测得的性质数据列于表2中。
Figure 86107767_IMG28
Figure 86107767_IMG29
Figure 86107767_IMG30
Figure 86107767_IMG31
Figure 86107767_IMG32
Figure 86107767_IMG33
Figure 86107767_IMG34
Figure 86107767_IMG35
Figure 86107767_IMG38
Figure 86107767_IMG39
Figure 86107767_IMG40
Figure 86107767_IMG42
Figure 86107767_IMG43
Figure 86107767_IMG45
Figure 86107767_IMG46
Figure 86107767_IMG47
本发明化合物如下所述可望用作抗肿瘤制剂。各种已知方法可用于制备此类化合物的药物及其制剂。可能的给药方式有：注射、口服、直肠给药等。药物剂型有针剂、粉剂、丸剂、片剂、栓剂等。
在药剂制备时，各类在药物制备中常用的载体、佐剂如稳定剂、灭菌剂、止痛剂、乳化剂等只要它们对用作基质的硒化合物无反作用，则均可因随时需要而采用。
根据采用的药物剂及其它因素硒化合物在每一单位药剂中的含量可有较大幅度的变化，但通常硒化合物的含量比是0.01到100%，较好的是0.1到70%（重量百分比）药剂的其它组成部分是载体和佐剂。
本发明化合物每天的推荐剂量是0.01至10毫克/公斤（从基础药效试验测得），口服时较好是0.1至2毫克/公斤，注射时为0.01至5毫克/公斤较好是0.1至1毫克/公斤，栓剂时为0.01至10毫克/公斤较好是0.1至2毫克/公斤。
实验测得的本发明化合物的抗肿瘤及抗诱变活性描述于下：
试验实施例1）对埃利希氏癌（Ehrlich    carcinoma）之抗肿瘤活性。
试验方法：
将大约10细胞10.2毫升埃利希氏癌细胞接种至每个五周龄受试ICR小鼠（雄）的腹腔中，从接种日起7天内将受试药物每天一次腹膜内给药予受试组小鼠。对照组小鼠用同样方式给予生理盐水溶液。给药后对二组动物持续观察60天，存活率（T/C%，T/C×100）是从受试组小鼠（T）平均生存时间（天数）和对照组小鼠（C）平均生存时间（天数）测得，半致死量（LD50）是从首试组小鼠由于受试化合物的毒性而死亡的数中测得。
结果列于表3
Figure 86107767_IMG48
Figure 86107767_IMG49
Figure 86107767_IMG51
＊剂量（毫克/公斤/天），＊＊使用溶剂：二甲基亚砜
注1）给药4天
注2）给药2天
注3）给药3天
注4）给药5天
注5）给药6天
试验实施例2）抗诱变活性
试验方法：
抗诱变活性是按艾曼斯（Ames）法用鼠伤寒杆菌（Salmonella    typhimarium）TA-98作为受试菌株并以苯并（α）芘（B（α）P）为突变体。
将0.5毫升S-9混合物和0.1毫升TA-98混悬液加到5微克（μg）苯并（α）芘和适量本发明化合物的0.1毫升二甲基亚砜的溶液中，混合液在37℃预培养20分钟。
在予培养的混合液中再加入软琼脂2毫升，充份搅拌，将混合液均匀分布在葡糖低琼脂介质盘中，37℃培养48小时，计数变异产生的菌落。
在无苯并（α）芘及本发明化合物的介质中存在的菌落数作为对照背景值。
从下式变异抑制率来测定抗变异活性。
抑制率＝〔1-｛ (本发明化合物加入后形成的菌落-背景值)/(未加入本发明化合物时形成的菌落数-背景值) ｝〕×100
结果列于表4
表4    本发明化合物抗苯并致变异作用的抑制活性
化合物    背景值    受试化合物用量（微克/盘）
0    0.5    1    5    10    50    100    500
1～41    菌落数    33    298    238    234    209    49    119    96    16
（抑制率）    -    （0）（22.6）（24.2）（33.6）（56.2）（67.5）（76.2）（100）
本发明化合物在抗腹癌肝癌等恶性肿瘤中有高度抗肿瘤活性。亦有抗变异活性可望用作有效的抗肿瘤药剂。
本发明化合物的制备过程将用实施例具体地描述于下：
实施例1-1    1-22号化合物的合成
秤386毫克（1.52毫克分子）硒氯氧化物-1，4-二氧六环络合物，溶于4毫升无水二氯甲烷中。将4.2毫升由250毫克（3.04毫克分子）N-甲基咪唑经无水二氯甲烷稀释的溶液在室温下滴加到上述溶液中。所得浅黄色溶液放置30分钟，浓缩，减压蒸发至干得503毫克黄色微细结晶（收率100.0%）
以相应化合物代替N-甲基咪唑用上述同样方法可制得化合物号为：1-2至1-31，1-33至1-39，1-51和1-52的化合物
用硒溴氧化物-1，4-二氧六环（1∶1）络合物代替硒氯氧化物-1，4-二氧六环（1∶1）络合物并与相应的化合物反应可制得1-1以及1-32号化合物。这些化合物的性质列于表2中。
实施例1-2    1-41号化合物的合成
将419毫克（1.65毫克分子）硒氯氧化物-1，4-二氧六环（1∶1）络合物溶于2毫升无水二氯甲烷中。2毫升258毫克（1.65毫克分子）2，2′-联吡啶的无水二氯甲烷溶液在室温振摇下逐滴加入上述溶液中。滴加毕，混合液放置1小时。然后除去上清液留下微细结晶状粉末。残留物用少量无水二氯甲烷洗涤，真空干燥得508毫克微黄白色微细结晶性粉末（收率：95.6%）
1-40和1-43至1-45号化合物可用相应化合物代替2，2′-联吡啶用同样方法合成。
1-42号化合物用硒溴氧化物-二氧六环（1∶1）络合物为起始原料与2，2′-联吡啶反应制得。
这些化合物的性质列入表2中。
实施例1-3    1-47号化合物的合成
将310毫克（1.22毫克分子）硒氯氧化物-1，4-二氧六环（1∶1）络合物溶于3毫升无水二氯甲烷中，在振摇和室温下滴加1.6毫升193毫克（2.44毫克分子）无水吡啶的二氯甲烷溶液于上述溶液中，15分钟后振摇下再将1毫升118毫克（2.56毫克分子）无水乙醇的二氯甲烷溶液加入其中。滴加毕，混合液放置30分钟，减压逐渐除去溶剂，得453毫克白色湿粉（收率：100.3%）
1-46，1-48至1-50号化合物可用上述同样反应步骤以相应的醇替代乙醇制得。
这些化合物的性质列于表2中。
实施例2-1    2-13（C4    SDp）化合物的合成
秤250毫克（1.23毫克分子）四氯硒，溶于10毫升无水四氢呋喃中。对此生成的微黄色溶液在冰水冷却下逐滴将3.8毫升177毫克（1.13毫克分子）2，2′-联吡啶的无水四氢呋喃溶液滴入其中。然后混合液在冰水冷却下放置1小时，反应结束后，除上清液，留下产生的黄色结晶性粉末、残留物用少量无水四氢呋喃洗涤，真空干燥得380毫克黄色微细结晶性粉末（收率：89.1%）
实施例2-2    2-5（C4    S4    Ph）号化合物的合成
秤255毫克（1.16毫克分子）四氯硒，溶于4毫升无水四氢呋喃中形成-浅黄色溶液。向此溶液，在室温下，滴加4.6毫升358毫克（2.31毫克分子）4-苯基吡啶的无水四氢呋喃溶液。混合液室温放置2小时，反应毕，减压浓缩并蒸发至干得615毫克黄色微细结晶状粉末（收率：100.2%）
2-1至2-12号化合物按上述类似反应步骤合成。
实施例2-3    2-14（B4    SDp）号化合物的合成
秤448毫克（1.12毫克分子）四溴硒，溶于10毫升无水乙醚中，向上述溶液中在室温下滴加5毫升175毫克（1.12毫克分子）2，2′-联吡啶的无水乙醚溶液。然后此混合液室温放置2小时，反应毕，除上清液，留下生成的浅棕色粉末。用少量无水乙醚洗涤，真空干燥，得574毫克浅棕色粉末（收率：92.1%）
实施例3-1    3-6（SOCH）号化合物的合成
370毫克（1.457毫克分子）硒氯氧化物-1，4-二氧六环（1∶1）络合物溶于11毫升无水二氯甲烷中，室温并摇动下向其中滴加入将3毫升286毫克（2.91毫克分子）环己烯氧化物的无水二氯甲烷溶液。三小时后混合液减压浓缩，除尽溶剂得513毫克浅黄色稠油状亚硒双-（2-氯环己基）酯酸（SOCH）（收率：97.27%）
按同法用下述相应氧化物可合成3-1至3-7号化合物。
氧化物    所得化合物序号
2，3-环氧丁烷    3-1
2-甲基-1，2-环氧丙烷    3-2
1，2-环氧丁烷    3-3
1，2-环氧辛烷    3-4
苯乙烯氧化物    3-5
2，3-环氧降冰片烷    3-7
实施例3-2    3-8（SDEEC）号化合物的合成
3.33克（0.0131毫克分子）硒氯氧化物-1，4-二氧六环（1∶1）络合物溶于33毫升无水1，4-二氧六环中，将2.83克（0.0288克分子）无水醋酸钾加入其中，室温搅拌。24小时后加入1.125克（0.0125克分子）1，2-丁二醇，混合液继续搅拌2天。然后将混合液减压过滤，除去副产物氯化钾，溶液部分进行浓缩，然后减压蒸馏得1.657克亚硒1，2-丁二醇酯酸（SOEEC）为无色油状物沸点110.5-112.0℃（6毫米汞柱）（收率：72.5%）
实施例3-3    3-9（SOEPC）号化合物的合成
828毫克（4.99毫克分子）硒氯氧化物溶于25毫升无水乙醚向此溶液加入1.078毫克（10.98毫克分子）无水醋酸钾并在室温下搅拌。20小时后将660毫克（4.99毫克分子）2，2′-二乙基-1，3-丙二醇加入其中，反应混合液继续搅拌24小时。然后减压过滤除去副产物氯化钾。减压浓缩透明滤液，除尽溶剂得1.019毫克亚硒酸2，2-二乙基-1，3-丙二醇酯为-微黄色稠状油（收率：90.7%）
实施例3-4    3-14（SC4    Hy·aq）号化合物的合成
将1.6毫升含1.5～2%水的甲醇及16毫升二氯甲烷加到306毫克（3.22毫克分子）4-羟基吡啶中，后者溶于其中。向此溶液在振摇下6分钟内滴加4毫升409毫克（1.61毫克分子）硒氯氧化物的无水二氯甲烷溶液。2小时后将生成的透明液减压浓缩得633毫克白色微细结晶（收率：107.8%）产品用少量无水二氯甲烷洗涤数次，真空干燥得428毫克硒氯氧化物-4-羟基吡啶（1∶2）络合物单水合物为一白色微细结晶（收率：72.9%）
化合物3-11，3-28，4-1和4-2用通式Ⅰ中下述A化合物代替4-羟基吡啶按上述相同的方法制得。
起始化合物（通式（Ⅰ）中的A化合物）    所得化合物序号
4-氨基吡啶    3-11
2-氨基吡啶    3-28
N-（2-氯乙基）-N′-（3-吡啶基）脲    4-1
2-（N-甲基氨基）吡啶    4-2
实施例3-5    3-23（SC5NI）号化合物的合成
396毫克（1.56毫克分子）硒氯氧化物-1，4-二氧六环络合物溶于4毫升无水二氯甲烷中。室温下将溶有544毫克（3.12毫克分子）5-硝基异喹啉之5毫升无水二氯甲烷溶液滴入其中。所得浅黄色溶液放置60分钟左右，减压浓缩并蒸发至干得809毫克黄色微细结晶（收率：100.6%）。用上述同样手续并用式（Ⅰ）中下述A化合物代替5-硝基异喹啉可合成化合物3-10，3-12，3-13，3-15，3-18至3-22，3-24至3-26，3-29至3-33。
起始化合物（通式（Ⅰ）中A）    所得化合物序号
4-苯甲酰基吡啶    3-10
4-二甲基氨基吡啶    3-12
2-羟基吡啶    3-13
4-甲氧基吡啶    3-15
异烟酸烯丙酯    3-18
1，6-萘啶    3-19
5-硝基喹啉    3-20
6-硝基喹啉    3-21
8-硝基喹啉    3-22
茶碱    3-24
2，2′-双-（异烟酸甲酯）    3-25
2，2′-双-（异烟酸乙酯）    3-26
6-氨基异烟酰胺    3-29
2-羟基-5硝基吡啶    3-20
4-羟基喹啉    3-31
8-羟基喹啉    3-32
4-溴异喹啉    3-33

Claims (9)

1、通式(Ⅰ)表示的硒化合物的制备过程：
其中R、X、A和Y表示的基团详述如下，a表示0或1，b表示0、1或2。(1)当a是0，b也是0时，c是4，n是1或2，m是0。(2)当a是1时，b是0时，c是2，n是1或2，m是0或1。(3)当b是1或2时，c，n和m都是0；
ⅰ)当b是2，R代表(1)囟原子取代的C4-10烷氧基团；(2)囟原子和苯基取代的低级烷氧基团或(3)囟原子取代的环烷氧基，ⅱ)当b是1时，R表示下式基团：
Figure 86107767_IMG2
(其中R0是C2-6烷基)；
X表示囟原子；
A表示咖啡因、茶碱、N-苄基茶碱、N-苄基可可碱、2，2′-联喹啉、1，6-萘啶、1，10-菲绕啉或下式表示的化合物：
Figure 86107767_IMG3
(其中R1和R2可以相同或不同并表示氢原子、羟基、低级烷基、囟原子、苯基、氰基、低级烷氧羰基、苯氧羰基、氨基(此基团上可连接低级烷基、低级烷氨羰基、低级囟烷氨羰基或低级烷氧羰基)，苯甲酰基、低级烷氧基、氨甲酰基或烯丙氧基羰基；R3表示C1-10烷基或苄基；R4和R6各自表示氢原子、囟原子或烷基或R4和R5可联合表示 ；R6表示低级烷氧基、苯基或苯氧基；R7表示氢原子、低级烷基或下式表示的基团-C-R9(其中R9表示氨基或低级烷氧基)；R10表示氢原子或硝基；B和D之一表示氮原子，另一则表示
Figure 86107767_IMG5
；以及
Y表示H2O或用式R8OH表示的醇[其中R8表示苄基或烷基(该基可被低级烷氧基取代)]；
其中当X是氯原子，m是0时，R1和R10表示除氢原子以外的原子或基团。
所述过程包括将式(Ⅱ)表示的化合物
(其中X是囟原子，a是0或1，当a是0时，c′是4，d是0，当a是1时，c′是2，d是0或1)与式F表示的化合物(其中F表示A(A的定义如上)，直链1，2-环氧烷、低级烷基或苯基取代的低级1，2-环氧烷，环氧烷或下式表示的化合物
Figure 86107767_IMG7
(其中Ro定义如上)]在有机溶剂中，在式Y表示的化合物(其中Y定义如上)存在或短缺下进行反应，当所得化合物是m为0的式(Ⅰ)表示的化合物时，如果必要可进一步与以式Y表示的化合物反应(其中Y定义如上)。
2、根据权利要求1所述的过程，其中F表示A，低级烷基取代的低级1，2-环氧烷，环氧环烷，或式
Figure 86107767_IMG8
，表示的化合物，其中A表示2，2′-联吡啶，2，2′-双喹啉或下式表示的基团
Figure 86107767_IMG9
， （其中R1和R2可以相同或不同并表示氢原子羟基、低级烷基、囟原子、苯基、氰基、低级烷氧羰基或烯丙氧基羰基;R3表示低级烷基或苄基;R4表示氢原子;R5表示囟原子或R4和R5可联合表示
Figure 86107767_IMG11
;R10表示硝基;B和D之一表示氮原子，则另一表示
Figure 86107767_IMG12
。
3、根据权利要求1所述的过程，其中式（Ⅱ）化合物是一用前述式（Ⅱ）代表的化合物，其中a是1，c′是2，d是0或1，式F化合物是A〔A是2，2′-联吡啶或式 表示的基团（其中R1是氢原子，R2是羟基）〕，Y是H2O。
4、根据权利要求3所述的过程，其中A是2，2′-联吡啶或4-羟基吡啶。
5、根据权利要求4所述的过程，其中2，2-联吡啶的用量是起始硒化合物克分子数的0.5至5倍。
6、根据权利要求4所述的过程，其中4-羟基吡啶的用量是起始硒化合物克分子数的1至10倍。
7、根据权利要求1所述的过程，其中反应温度是-20至150℃。
8、根据权利要求1所述的过程，其中所用溶剂的沸点为150℃或低于此温度。
9、根据权利要求1所述的过程，其中式（Ⅱ）化合物是硒氯氧化物-1，4-二氧六环（1∶1）络合物，式F化合物是4-羟基吡啶，所述两化合物在-20至150℃在沸点为150℃或低于此温度的含水溶剂中进行反应。
CN198686107767A 1985-11-15 1986-11-15 新有机硒化合物 Pending CN86107767A (zh)

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