TWI455912B - ３，５，ｎ－三羥烷醯胺及其之衍生物、其之製造方法與用途 - Google Patents

３，５，ｎ－三羥烷醯胺及其之衍生物、其之製造方法與用途 Download PDF

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TWI455912B
TWI455912B TW102126066A TW102126066A TWI455912B TW I455912 B TWI455912 B TW I455912B TW 102126066 A TW102126066 A TW 102126066A TW 102126066 A TW102126066 A TW 102126066A TW I455912 B TWI455912 B TW I455912B
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Jung Hsin Lin
Jim Min Fang
Ching Chow Chen
Ting Rong Chern
Jhih Bin Chen
Tzu Tang Wei
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Univ Nat Taiwan
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Claims (24)

  1. 一種式(I)化合物或其藥學上可接受的鹽類： 其中：n是0或1；代表一單鍵或一雙鍵；X，Y，Z和U分別是碳原子或氮原子；R1，R2，R3，R4，R5，和R6係分別選自於由無、氫原子、C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-20炔基、、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基(-NC=O)、胺基、羥基、C1-6烷氧基、醯氧基、矽氧基、醯胺基、胺甲醯基(-NCO2)、和磺醯胺基所組成的物質群中；且R3可非必要地與R2或R4相連以形成碳環或雜環。
  2. 如請求項1所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種具有式(III)結構之5,氮-二羥基烷醯胺衍生物或其藥學上可接受的鹽類： ；其中：R1係選自由C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-2炔基、、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基、胺基、羥基、C1-6烷氧基、醯氧基、矽氧基、醯胺基、胺甲醯基、及磺醯胺基所組成的物質群中；R7係選自由氫原子、醯基、C1-6烷基、C2-20烯基、C2-20炔基和C6-14芳香基C1-6烷基所組成的物質群中；且R8係選自於氫原子、甲基和羥基所組成的物質群中。
  3. 如請求項2所述之化合物或其藥學上可接受的鹽類，其中該化合物係任一選自於如下物質群之化合物或其藥學上可接受的鹽類； 其中：R1係選自於C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-2炔基、、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基(-N(C=O)-)、胺基、羥基、C1-6烷氧基、醯氧基、矽氧基、醯胺基、胺甲醯基、及磺醯胺基所組成的物質群中。
  4. 如請求項3所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種3,5,氮-三羥基烷醯胺衍生物，係選自於如下所組成的物質群中： 或其藥學上可接受的鹽類。
  5. 如請求項3所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種3-氧-(對-甲氧基苯甲基)衍生物，係選自於如下所組成的物質群中： 或其藥學上可接受的鹽類。
  6. 如請求項1所述之化合物或其藥學上可接受的鹽類，其中該化合物是任一具有式(V)、(VII)，或(VIII)結構之化合物或其藥學上可接受的鹽類： 其中，R1係選自於C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-2炔基、、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基、胺基、羥基、C1-6烷氧基、醯氧基、矽氧基、醯胺基、胺甲醯基、及磺醯胺基所組成的物質群中。
  7. 如請求項6所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種3,5,氮-三羥基-6-烯醯胺衍生物，係選自於如下所組成的物質群中： 或其藥學上可接受的鹽類。
  8. 如請求項6所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種對-甲氧基苯甲基衍生物，係選自於如下所組成的物質群中： 或其藥學上可接受的鹽類。
  9. 一種式(IV)之化合物： 或其藥學上可接受的鹽類；其中，R1係選自於C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-2炔基、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基、胺基、羥基、C1-6烷氧基所組成的物質群中。
  10. 如請求項9所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種具有如下化學式之3-氧-(對-甲氧基苯基)衍生物或其藥學上可接受的鹽類：
  11. 如請求項1所述之化合物或其藥學上可接受的鹽類，其為具有式(VI)結構之化合物或其藥學上可接受的鹽類： 其中：R1係選自於由C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-2炔基、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基、胺基、羥基、C1-6烷氧基、醯氧基、矽氧基、醯胺基、胺甲醯基、及磺醯胺基所組成的物質群中。
  12. 如請求項11所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種具有如下化學式之3,5,氮-三羥基-6-烯醯胺衍生物或其藥學上可接受的鹽類：
  13. 如請求項11所述之化合物或其藥學上可接受的鹽類，其中該化合物是一種具有如下化學式之對-甲氧基苯甲基衍生物或其藥學上可接受的鹽類：
  14. 一種用以治療與組蛋白去乙醯酶和/或3-羥基3-甲基戊二基輔酶A還原酶相關疾病之藥學組合物，包含如請求項1至13任一項所述之化合物或其藥學上可接受的鹽類；以及其藥學上可接受之輔劑。
  15. 一種用以治療癌症、高膽固醇血症、急性或慢性發炎疾病、自體免疫疾病、過敏性疾病、病原感染、神經退化疾病或一與氧化壓力相關疾病或抑制耐藥性癌細胞的藥學組合物，包含如請求項1至13任一項所述之化合物或其藥學上可接受的鹽類；以及其藥學上可接受之輔劑。
  16. 一種用以製造式(I)化合物的方法，包含：讓式(II)化合物，或其鹽類與羥胺或其鹽類互相接觸： 其中：n是0或1；U、X、Y、和Z分別選自於由碳及氮原子所組成的物質群中；代表一單鍵或一雙鍵；R1、R2、R3、R4、R5和R6係分別選自於由C1-6烷基、C2-20烯基、C2-20炔基、C1-6氟烷基、C1-6氯烷基、C1-6溴烷基、C1-6碘烷基、C1-6全氟烷基、C6-14芳香基、C6-14雜芳基、C3-10環烷基、C3-10環烯基、C6-14芳香基C1-6烷基、C6-14芳香基C2-20烯基、C6-14芳香基C2-2炔基、、C6-14雜芳基C1-6烷基、C6-14雜芳基C2-20烯基、C6-14雜芳基C2-20炔基、C3-10雜環基、醯基、胺基羰基、胺基、羥基、C1-6烷氧基、醯氧基、矽氧基、醯胺基、胺甲醯基、及磺醯胺基所組成的物質群中；且R3是非必要地與R2或R4連接，以形成碳環或雜環。
  17. 如請求項16所述之方法，其中該羥胺是在溶液中或是透過讓羥胺之一鹽類與一種鹼彼此接觸而於原位生成。
  18. 如請求項17所述之方法，其中該鹽類係選自於由鹽酸鹽、硝酸鹽、磷酸鹽、和硫酸鹽類所組成的物質群中。
  19. 如請求項17所述之方法，其中該鹼係由選自於羥根、碳酸根、碳酸氫根、甲氧根、乙氧根、異丙氧根、及三級丁氧根所組成的物質群中之陰離子與其相應之陽離子所組成，該陽離子係選自於由鋰、鈉、鉀、銫、鈣和鋇所組成的物質群中。
  20. 請求項16所述之方法，其中使用一路易斯酸做為反應的促進劑，其中該路易斯酸是由一選自於鋰、鎂、鈣、鋅、鋁、硼、銦、鈧、鐿、鈰、矽、錫、鈦、鋯、釩、鐵、和鈷之鹽類所組成的陽離子與其相應之陰離子所組成，該陰離子係選自於由氟、氯、溴、碘、羥根、甲氧根、乙氧根、異丙氧根、三級丁氧根、醋酸根、草酸根、乙醯丙酮根、硝酸根、磷酸根、硫酸根、硫酸氫根、和磺酸根所組成的物質群中。
  21. 如請求項16所述之方法，其中該接觸步驟是在烴、醚、氯化、或酒精性溶劑或其之混合物中實施。
  22. 如請求項21所述之方法，其中該烴溶劑是一種非環狀、環狀、或芳香性溶劑，可選自於由正己烷、環己烷、苯、甲苯、和二甲苯所組成的物質群中。
  23. 如請求項21所述之方法，其中該醚溶劑是一種非環狀或環狀溶劑，係選自於由二乙醚、甲基-三級丁基醚、二甲氧乙烷、四氫呋喃和1,4-二氧陸圜所組成的物質群中。
  24. 如請求項17-23中任一項所述之方法，其中：X是碳原子；和Y，Z和U可分別為碳或氮原子；前題是當Y是碳原子時，Z和U皆是氮原子且連接C6和C7的化學鍵是一個雙鍵。
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