TWI455928B - 作為TAFIa抑制劑之巨環脲衍生物及磺醯脲衍生物 - Google Patents

作為TAFIa抑制劑之巨環脲衍生物及磺醯脲衍生物 Download PDF

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TWI455928B
TWI455928B TW98118477A TW98118477A TWI455928B TW I455928 B TWI455928 B TW I455928B TW 98118477 A TW98118477 A TW 98118477A TW 98118477 A TW98118477 A TW 98118477A TW I455928 B TWI455928 B TW I455928B
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Christopher Kallus
Mark Broenstrup
Andreas Evers
Anja Globisch
Herman Schreuder
Michael Wagner
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Claims (8)

  1. 一種式I化合物 與/或式I化合物之立體異構型與/或此等型式依任何比例形式之混合物,與/或式I化合物之生理上可耐受之鹽類,其中X為-C(O)-或-SO2 -,U為氧原子、硫原子、NH、-C(O)-NH-或-(C0 -C4 )-伸烷基-,A為氧原子、硫原子、NH、-C(O)-NH- -NH-C(O)-、-NR2-或-(C0 -C4 )-伸烷基-,V為1)-(C2 -C9 )-伸烷基-,其中伸烷基未經取代或分別獨立經-OH、NH2 或鹵素取代一次、二次或三次,2)-(C1 -C2 )-伸烷基-(C3 -C6 )-環烷基-(C1 -C2 )-伸烷基-,其中環烷基分別獨立經R15取代一次、二次或三次,或3)-(C3 -C9 )-伸烯基-,D為-(C1 -C2 )-伸烷基-,Y為1)共價鍵,2)-(C3 -C12 )-環烷基,其中環烷基分別獨立經R15取代一次、二次或三次, 3)-(C6 -C14 )-芳基,其中芳基未經取代或分別獨立經R15取代一次、二次或三次,或4)Het,其中Het意指具有4至15個環原子相接出現在1、2或3個環系中之4-至15-員雜環系,其依環之大小而定,包含1、2、3或4個選自氧、氮或硫中之相同或相異雜原子,且其中Het未經取代或分別獨立經-(C1 -C3 )-烷基、鹵素、-NH2 、-CF3 或-O-CF3 取代一次、二次或三次,R1為1)氫原子,2)-(C1 -C6 )-烷基,3)-(C1 -C6 )-烷基-OH,4)-(C0 -C4 )-烷基-(C3 -C6 )-環烷基,5)-(C1 -C10 )-烷基-O-C(O)-O-R2,6)-(CH2 )r -(C6 -C14 )-芳基,其中芳基未經取代或分別獨立經R15取代一次、二次或三次,且r為零、1、2或3之整數,或7)-(CH2 )s -Het,其中Het意指具有4至15個環原子相接出現在1、2或3個環系中之4-至15-員雜環系,其依環之大小而定,包含1、2、3或4個選自氧、氮或硫中之相同或相異雜原子,且其中Het未經取代或分別獨立經R15取代一次、二次或三次,且s為 零、1、2或3之整數,R2為1)-(C1 -C6 )-烷基,2)-(CH2 )r -(C6 -C14 )-芳基,其中芳基未經取代或分別獨立經R15取代一次、二次或三次,且r為零、1、2或3之整數,或3)-(C0 -C4 )-烷基-(C3 -C6 )-環烷基,R3為1)-(C2 -C6 )-伸烷基-NH2 ,其中伸烷基未經取代或經鹵素取代一次、二次、三次或四次,2)-(C1 -C4 )-伸烷基-O-(C1 -C4 )-伸烷基-NH2 ,3)-(C1 -C4 )-伸烷基-SO2 -(C1 -C4 )-伸烷基-NH2 ,4)-(C0 -C4 )-伸烷基-Het,其中Het如上述定義,且係經-NH2 取代及經R15取代一次、二次或三次,5)-(C0 -C4 )-伸烷基-(C3 -C8 )-環烷基-NH2 或6)-(C0 -C6 )-伸烷基-環狀胺,R6為1)氫原子,2)-(C1 -C6 )-烷基,其中烷基未經取代或分別獨立經R16取代一次、二次或三次,3)-O-(C1 -C6 )-烷基,其中烷基未經取代或分別獨立經R16取代一次、二次或三次,4)-(C0 -C4 )-伸烷基-Het,其中Het如上述定 義,其中伸烷基與Het未經取代或分別獨立經R16取代一次、二次或三次,5)-(C0 -C4 )-伸烷基-芳基,其中伸烷基與芳基未經取代或分別獨立經R16取代一次、二次或三次,或6)-(C0 -C4 )-伸烷基-(C3 -C8 )-環烷基,其中伸烷基與環烷基未經取代或分別獨立經R16取代一次、二次或三次,R7為氫原子、鹵素或-(C1 -C6 )-烷基,R8為氫原子、鹵素或-(C1 -C6 )-烷基,R9為氫原子、鹵素或-(C1 -C6 )-烷基,R15為氫原子、-(C1 -C4 )-烷基、-O-CF3 、-NH2 、-OH、-CF3 或鹵素,且R16為-O-CF3 、-NH2 、-OH、-CF3 或鹵素。
  2. 根據申請專利範圍第1項之式I化合物,其中X為-C(O)-或-SO2 -,U為氧原子、硫原子、NH、-C(O)-NH-或-(C0 -C4 )-伸烷基-,A為氧原子、硫原子、NH、-C(O)-NH-或-(C0 -C4 )-伸烷基-,V為1)-(C2 -C9 )-伸烷基-或2)-(C3 -C9 )-伸烯基-,D為-(C1 -C2 )-伸烷基-,Y為1)共價鍵, 2)-(C3 -C12 )-環烷基,其中環烷基分別獨立經R15取代一次、二次或三次,3)-(C6 -C14 )-芳基,其中芳基未經取代或分別獨立經R15取代一次、二次或三次,或4)Het,其中Het意指具有4至15個環原子相接出現在1、2或3個環系中之4-至15-員雜環系,其依環之大小而定,包含1、2、3或4個選自氧、氮或硫中之相同或相異雜原子,且其中Het未經取代或分別獨立經-(C1 -C3 )-烷基、鹵素、-NH2 、-CF3 或-O-CF3 取代一次、二次或三次,R1為1)氫原子,2)-(C1 -C6 )-烷基,3)-(C1 -C6 )-烷基-OH,4)-(C0 -C4 )-烷基-(C3 -C6 )-環烷基,5)-(C1 -C10 )-烷基-O-C(O)-O-R2,6)-(CH2 )r -(C6 -C14 )-芳基,其中芳基未經取代或分別獨立經R15取代一次、二次或三次,且r為零、1、2或3之整數,或7)-(CH2 )s -Het,其中Het意指具有4至15個環原子相接出現在1、2或3個環系中之4-至15-員雜環系,其依環之大小而定,包含1、2、3或4個選自氧、氮或硫中之相同 或相異雜原子,且其中Het未經取代或分別獨立經R15取代一次、二次或三次,且s為零、1、2或3之整數,R2為1)-(C1 -C6 )-烷基,2)-(CH2 )r -(C6 -C14 )-芳基,其中芳基未經取代或分別獨立經R15取代一次、二次或三次,且r為零、1、2或3之整數,或3)-(C0 -C4 )-烷基-(C3 -C6 )-環烷基,R3為1)-(C2 -C6 )-伸烷基-NH2 ,其中伸烷基未經取代或經鹵素取代一次、二次、三次或四次,2)-(C1 -C4 )-伸烷基-O-(C1 -C4 )-伸烷基-NH2 ,3)-(C1 -C4 )-伸烷基-SO2 -(C1 -C4 )-伸烷基-NH2 ,4)-(C0 -C4 )-伸烷基-Het,其中Het如上述定義,且係經-NH2 取代及經R15取代一次、二次或三次,5)-(C0 -C4 )-伸烷基-(C3 -C8 )-環烷基-NH2 或6)-(C0 -C6 )-伸烷基-環狀胺,R6為1)氫原子,2)-(C1 -C6 )-烷基,其中烷基未經取代或分別獨立經R16取代一次、二次或三次,3)-O-(C1 -C6 )-烷基,其中烷基未經取代或分 別獨立經R16取代一次、二次或三次,4)-(C0 -C4 )-伸烷基-Het,其中Het如上述定義,其中伸烷基與Het未經取代或分別獨立經R16取代一次、二次或三次,5)-(C0 -C4 )-伸烷基-芳基,其中伸烷基與芳基未經取代或分別獨立經R16取代一次、二次或三次,或6)-(C0 -C4 )-伸烷基-(C3 -C8 )-環烷基,其中伸烷基與環烷基未經取代或分別獨立經R16取代一次、二次或三次,R7為氫原子、鹵素或-(C1 -C6 )-烷基,R8為氫原子、鹵素或-(C1 -C6 )-烷基,R9為氫原子、鹵素或-(C1 -C6 )-烷基,R15為氫原子、-(C1 -C4 )-烷基、-O-CF3 、-NH2 、-OH、-CF3 或鹵素,且R16為-O-CF3 、-NH2 、-OH、-CF3 或鹵素。
  3. 根據申請專利範圍第1或2項之式I化合物,其中X為-C(O)-或-SO2 -,U為氧原子、硫原子、NH、-C(O)-NH-或-(C0 -C4 )-伸烷基-,A為氧原子或-(C0 -C4 )-伸烷基-,V為-(C2 -C8 )-伸烷基-或-(C3 -C6 )-伸烯基-,D為-(C1 -C2 )-伸烷基-, Y為1)共價鍵,2)-(C3 -C6 )-環烷基,其中環烷基分別獨立經R15取代一次、二次或三次,3)-(C6 -C14 )-芳基,其中芳基係選自下列:苯基、萘基、蒽基或茀基,且其中芳基未經取代或分別獨立經R15取代一次、二次或三次,或4)Het,其中Het係選自下列:吖啶基、吖呯基、氮雜環丁烷基、氮雜環丙烷基、苯并咪唑啉基、苯并咪唑基、苯并[1,3]二茂烷基、苯并呋喃基、苯并硫呋喃基、苯并噻吩基、苯并唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異唑基、苯并異噻唑基、咔唑基、4aH-咔唑基、咔啉基、喹唑啉基、喹啉基、4H-喹基、喹啉基、奎寧環基、色滿基、色烯基、噌啉基、十氫喹啉基、二苯并呋喃基、二苯并噻吩基、二氫呋喃[2,3-b]-四氫呋喃基、二氫呋喃基、二茂烷基、二烷基、2H,6H-1,5,2-二噻基、呋喃基、呋咱基、咪唑啶基、咪唑啉基、咪唑基、1H-吲唑基、吲哚啉基、吲哚基、吲哚基、3H-吲哚基、異苯并呋喃基、異色滿基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基(苯并咪唑基)、異噻唑啶基、2-異噻唑啉基、異噻 唑基、異唑基、異唑啶基、2-異唑啉基、嗎啉基、萘啶基、八氫異喹啉基、二唑基、1,2,3-二唑基、1,2,4-二唑基、1,2,5-二唑基、1,3,4-二唑基、唑啶基、唑基、唑啶基、噻茂烷基、嘧啶基、啡啶基、啡繞啉基、啡基、啡噻基、啡噻基、啡基、酞基、哌基、哌啶基、蝶啶基、嘌呤基、哌喃基、吡基、吡唑啶基、吡唑啉基、吡唑基、嗒基、吡啶并唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶并噻吩基、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯啶基、吡咯啉基、2H-吡咯基、吡咯基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、四氫吡啶基、6H-1,2,5-噻嗒基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并咪唑基、噻吩并唑基、噻吩并吡啶基、噻吩并噻唑基、硫嗎啉基、噻吩基、三基、1,2,3-三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基與呫噸基,與其中Het未經取代或分別獨立經-(C1 -C3 )-烷基、鹵素、-NH2 、-CF3 或-O-CF3 取代一次、二次或三次, R1為1)氫原子或2)-(C1 -C4 )-烷基,R3為1)-(C2 -C6 )-伸烷基-NH2 ,其中伸烷基未經取代或經鹵素取代一次、二次、三次或四次,2)-(C1 -C4 )-伸烷基-SO2 -(C1 -C4 )-伸烷基-NH2 或3)-(C0 -C4 )-伸烷基-Het,其中Het如上述定義,且係經-NH2 取代及經R15取代一次、二次或三次,R6為1)氫原子,2)-(C1 -C6 )-烷基,其中烷基未經取代或分別獨立經R16取代一次、二次或三次,3)-O-(C1 -C6 )-烷基,其中烷基未經取代或分別獨立經R16取代一次、二次或三次,4)-(C0 -C4 )-伸烷基-Het,其中Het如上述定義,其中伸烷基與Het未經取代或分別獨立經R16取代一次、二次或三次,5)-(C0 -C4 )-伸烷基-芳基,其中伸烷基與芳基未經取代或分別獨立經R16取代一次、二次或三次,或6)-(C0 -C4 )-伸烷基-(C3 -C6 )-環烷基,其中伸烷基與環烷基未經取代或分別獨立經R16取代一次、二次或三次, R7為氫原子、F或-(C1 -C4 )-烷基,R8為氫原子、F或-(C1 -C4 )-烷基,R9為氫原子、F或-(C1 -C4 )-烷基,R15為氫原子、-(C1 -C4 )-烷基、-O-CF3 、-NH2 、-OH、-CF3 或鹵素,且R16為-O-CF3 、-OH、-CF3 或F。
  4. 根據申請專利範圍第1或2項之式I化合物,其中X為-C(O)-,U為氧原子,A為氧原子或-(C0 -C4 )-伸烷基-,V為1)-(C2 -C8 )-伸烷基-,其中伸烷基未經取代或分別獨立經-OH、F或Cl取代一或二次,2)-(C1 -C2 )-伸烷基-環丙基-(C1 -C2 )-伸烷基-,其中環丙基經F取代一或二次,或3)-(C3 -C6 )-伸烯基-,D為-(C1 -C2 )-伸烷基-,Y為1)共價鍵或2)苯基,其中苯基未經取代或分別獨立經R15取代一次、二次或三次,R1為1)氫原子或2)-(C1 -C4 )-烷基,R3為1)-(C2 -C6 )-伸烷基-NH2 ,2)-(C1 -C4 )-伸烷基-SO2 -(C1 -C4 )-伸烷基 -NH2 或3)-(C0 -C4 )-伸烷基-吡啶基,其中吡啶基經-NH2 取代及經R15取代一次、二次或三次,R6為1)氫原子,2)-(C1 -C6 )-烷基,3)-CF3 ,4)-(C0 -C4 )-伸烷基-苯基或5)-(C0 -C4 )-伸烷基-(C3 -C6 )-環烷基,R7、R8與R9分別為氫原子,及R15為氫原子、-(C1 -C4 )-烷基、-CF3 或鹵素。
  5. 根據申請專利範圍第1或2項之式I化合物,其中X為-C(O)-,U為氧原子,A為氧原子或-(C0 -C4 )-伸烷基-,V為-(C2 -C8 )-伸烷基-或-(C3 -C6 )-伸烯基-,D為-(C1 -C2 )-伸烷基-,Y為1)共價鍵或2)苯基,其中苯基未經取代或分別獨立經R15取代一次、二次或三次,R1為1)氫原子或2)-(C1 -C4 )-烷基,R3為1)-(C2 -C6 )-伸烷基-NH2 ,2)-(C1 -C4 )-伸烷基-SO2 -(C1 -C4 )-伸烷基 -NH2 或3)-(C0 -C4 )-伸烷基-吡啶基,其中吡啶基經-NH2 取代或經R15取代一次、二次或三次,R6為1)氫原子,2)-(C1 -C6 )-烷基,3)-CF3 ,4)-(C0 -C4 )-伸烷基-苯基或5)-(C0 -C4 )-伸烷基-(C3 -C6 )-環烷基,R7、R8與R9分別為氫原子,與R15為氫原子、-(C1 -C4 )-烷基、-CF3 或鹵素。
  6. 根據申請專利範圍第1或2項之式I化合物,其係式I化合物(S)-6-胺基-2-[3-((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((R)-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((R)-9,9-二甲基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12R)-11-側氧基-9-苯基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸, (S)-6-胺基-2-[3-((9S,12R)-9-苯甲基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12R)-9-環己基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12R)-9-乙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12R)-9-甲基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12R)-9-第三丁基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-{3-[(9S,12R)-9-((S)-第二丁基)-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基]脲基}己酸,(S)-6-胺基-2-[3-((13S,16R)-13-異丙基-15-側氧基-2,11-二氧雜-14-氮雜雙環[16.2.2]二十二碳-1(21),18(22),19-三烯-16-基)脲基]己酸,(S)-6-胺基-2-[3-((E)-(9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),4,14(18),15-四烯-12-基)脲基]己酸, (S)-6-胺基-2-[3-((3S,6R)-3-異丙基-5-側氧基-1-氧雜-4-氮雜環十四碳-6-基)脲基]己酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((3S,6R)-3-異丙基-5-側氧基-1-氧雜-4-氮雜環十四碳-6-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((3S,6R)-3-甲基-5-側氧基-1-氧雜-4-氮雜環十四碳-6-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((3S,6R)-3-異丙基-5-側氧基-1-氧雜-4-氮雜環十四碳-6-基)脲基]丙酸乙酯,(S)-3-(6-胺基-吡啶-3-基)-2-[3-((3S,6R)-3-甲基-5-側氧基-1-氧雜-4-氮雜環十四碳-6-基)脲基]丙酸乙酯,(R)-3-(2-胺基乙磺醯基)-2-[3-((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((9S,12R)-9-環丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]丙酸,(S)-6-胺基-2-[3-((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]-6-甲基庚酸, (S)-3-(6-胺基吡啶-3-基)-2-[3-((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1-(17),14(18),15-三烯-12-基)脲基]丙酸乙酯,(S)-2-[3-((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜-雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)-脲基]-3-哌啶-3-基-丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((8S,11R)-8-異丙基-10-側氧基-6-氧雜-1,9,14-三氮雜雙環[11.2.1]十六碳-13(16),14-二烯-11-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((3R,6S)-6-異丙基-4-側氧基-8-氧雜-5-氮雜雙環[11.2.2]十七碳-1(16),13(17),14-三烯-3-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((9S,12R)-16-氟-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((3S,6R)-3-異丙基-5-側氧基-1,8-二氧雜-4-氮雜環十二碳-6-基)脲基]丙酸,(S)-3-(6-胺基吡啶-3-基)-2-[3-((3S,6R)-3-異丙基-5-側氧基-1,8-二氧雜-4-氮雜環十二碳-6-基)脲基]丙酸甲酯,(S)-6-胺基-2-[3-((3S,6R)-3-異丙基-5-側氧基-1,8-二氧雜-4-氮雜環十二碳-6-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12S)-9-異丙基-11-側氧基 -2,7-二氧雜-10-氮雜雙環-[12.2.2]十八碳-12-基)脲基]己酸,(S)-6-胺基-2-[3-((8S,11R)-8-異丙基-3,10-二側氧基-6-氧雜-2,9-重氮雙環[11.2.2]十七碳-1(16),13(17),14-三烯-11-基)脲基]己酸,(S)-3-(6-胺基-吡啶-3-基)-2-[3-((8S,11R)-8-甲基-3,10-二側氧基-6-氧雜-2,9-重氮-雙環[11.2.2]十七碳-1(16),13(17),14-三烯-11-基)-脲基]-丙酸,(S)-3-(6-胺基-吡啶-3-基)-2-[3-((3S,6R)-3-異丙基-5,9-二側氧基-1-氧雜-4,10-重氮-環十三碳-6-基)-脲基]-丙酸,(S)-6-胺基-2-[3-((9S,12R)-4,5-二羥基-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,(S)-6-胺基-2-[3-((9S,12R)-5-羥基-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)脲基]己酸,3-(6-胺基-吡啶-3-基)-2-[3-((9S,12R)-4,5-二羥基-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜-雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基)-脲基]-丙酸,(S)-6-胺基-2-[((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基胺磺醯基)胺基]己酸或 (S)-6-胺基-2-[((9S,12R)-9-異丙基-11-側氧基-2,7-二氧雜-10-氮雜雙環[12.2.2]十八碳-1(17),14(18),15-三烯-12-基胺磺醯基)胺基]己酸。
  7. 一種製備根據申請專利範圍第1至6項中一項或多項之式I化合物之方法,其包括a)由式(II)化合物 其中U、R6與R8如式(I)化合物中之定義,與式(III)胺基酸反應 其中R9、A、Y與D如式(I)化合物中之定義,產生式(IV)化合物 其再於環封合複分解反應條件下及隨後氫化所得雙鍵下,轉化成式(V)化合物 其中V為-(C2 -C9 )-伸烷基-或-(C3 -C9 )-伸烯基-,隨後脫除保護基PG,得到式(VI)化合物, 並與式(VII)化合物 其中R3與R7如式(I)化合物中之定義,PG為合適之酯保護基,R3中之氮若適當時可使用合適胺基保護基保護,使用碳醯氯或碳醯氯同等物反應,產生式(VIII)化合物 隨後脫除保護基PG與若適當時出現在R3中氮上之保護基,產生式(I)化合物,或b)由式(IX)化合物 其中U、V、R6與R8如式(I)化合物中之定義,PGa 為合適之羧基保護基,與式(X)胺基酸反應 其中R9、Y與D如式I化合物中之定義,PGb 與PGc 為合適之胺基保護基,產生式(XI)化合物 脫除保護基PGa 與PGb 後,轉化成式(XII)化合物 其利用醯胺偶合法轉化成式(V)化合物,其中A如式I化合物中之定義,隨後脫除保護基,得到式(VI)化合物,並與式(VII)化合物其中R3與R7如式I中之定義,PG為合適之酯保護基,R3中之氮若適當時可使用合適胺基保護基保護,使用碳醯氯或碳醯氯同等物反應,產生式(VIII)化合物,隨後脫除保護基PG及適當時出現在R3中氮上之保護基,產生式(I)化合物,或 c)由式(XIII)化合物 其中U、V、R6與R8如式I化合物中之定義,PGd 為合適之胺基保護基,與式(XIV)胺基酸反應 其中R9、Y與D如式I化合物中之定義,PGc 為合適之胺基保護基與PGe 為合適之羧基保護基,產生式(XV)化合物 脫除保護基PGd 與PGe 後,轉化成式(XVI)化合物 其反應產生式(V)化合物,其中A如式I化合物中之定義,隨後脫除保護基,得到式(VI)化合物,並與式(VII)化合物, 其中R3與R7如式I中之定義,PG為合適之酯保護基,R3中之氮若適當時可使用合適胺基保護基保護,使用碳醯氯或碳醯氯同等物反應,產生式(VIII)化合物,隨後脫除保護基PG及適當時出現在R3中氮上之保護基,產生式(I)化合物,或d)由式XVII化合物 其中U、V、A、Y、D、R6 、R8 與R9 如式I化合物中之定義,與式(V)化合物反應,隨後脫除保護基,得到式(VI)化合物,並與式(VII)化合物,其中R3與R7如式I中之定義,PG為合適之酯保護基,R3中之氮若適當時可使用合適胺基保護基保護,使用碳醯氯或碳醯氯同等物反應,產生式(VIII)化合物,隨後脫離保護基PG及若適當時出現在R3中氮上之保護基,產生式(I)化合物,或e)轉化式(VIIIa)化合物 其中V為-(C3 -C9 )-伸烯基-,形成式(VIIIb)化合物 其中V為-(C3 -C9 )-伸烷基-,其中伸烷基分別獨立經-OH、NH2 或鹵素取代一次、二次或三次,或為-(C1 -C2 )-伸烷基-(C3 -C6 )-環烷基-(C1 -C2 )-伸烷基-,其中環烷基分別獨立經R15取代一次、二次或三次,隨後類似製法a)轉化式(VIIIb)化合物形成式(I)化合物,或f)由式(XVIII)化合物 其中V如式(I)化合物之定義,依序與式(XIX)與(XX)化合物 使用鹼,於極性非質子性溶劑中反應,所得式(XXI)化合物 經脫除保護基PGa,隨後形成肽鏈結,轉化成式(V)化合物,後者再依製法a)反應,產生式(I)化合物,其中R6、R8、R9與A、D、U、V與Y如式(I)化合物之定義,PG為合適保護基,LG為脫離基,如:氯、溴、碘或磺酸酯,或g)由式VI化合物與式(XXII)化合物反應 其中R3與R7如式I化合物中之定義,PG為合適之保護基,產生式(XXIII)化合物 然後轉化成式(I)化合物,或h)分離製法a)、b)、c)、d)、e)、f)或g)製備之式(I)化合物,或因其化學結構產生對映異構型之合適式(I)前體,其係經由與純對映異構性之酸或鹼形成鹽、於對掌性固相上進行層析或利用對掌性純 對映異構性化合物(如:胺基酸)衍化,分離依此方式得到之非對映異構物,並脫除對掌性輔基,產生純對映異構物,或i)單離出製法a)、b)、c)、d)、e)、f)或g)製備之游離型式(I)化合物,或若含有酸或鹼基團時,轉化成生理上可耐受之鹽。
  8. 一種藥品,其包含有效量之至少一種根據申請專利範圍第1至6項中一項或多項之式I化合物,及醫藥上合適且生理上可耐受之載劑、添加劑與/或其他活性成份與賦形劑。
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