TW201514203A - 胜肽化合物 - Google Patents
胜肽化合物 Download PDFInfo
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- TW201514203A TW201514203A TW103118374A TW103118374A TW201514203A TW 201514203 A TW201514203 A TW 201514203A TW 103118374 A TW103118374 A TW 103118374A TW 103118374 A TW103118374 A TW 103118374A TW 201514203 A TW201514203 A TW 201514203A
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Abstract
本發明提供一種具有活化GLP-1受體及GIP受體作用之新穎胜肽化合物,及該胜肽化合物作為藥物之用途。特別是提供含有式(I)所示之部分序列之胜肽或其鹽及包括該胜肽或其鹽之藥物:P1-Tyr-Aib-Glu-Gly-Thr-α MePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29 (I)其中,各符號係如本文中所定義。
Description
本發明關於具有活化GLP-1受體及GIP受體作用之新穎胜肽化合物,及該胜肽化合物作為藥物之用途。
類升糖素胜肽-1(GLP-1)及葡萄糖依賴性促胰島素多肽(GIP)兩者皆為被稱為腸泌素(incretin)之胜肽。GLP-1及GIP分別分泌自小腸之L細胞及K細胞。
GLP-1係經GLP-1受體而作用且以具有葡萄糖依賴性促胰島素作用及抑制食慾作用而聞名。反之,GIP以具有經GIP受體之葡萄糖依賴性促胰島素作用而聞名,其對於食慾之影響尚未明瞭。
已有報導共同投予GLP-1受體促效劑利拉魯肽(liraglutide)及GIP受體促效劑N-Ac-GIP較單獨投予利拉魯肽係更為促進改善葡萄糖耐受性之作用及降低體重之作用(非專利文獻1)。亦有報導GLP-1受體/GIP受體共促效劑胜肽較單獨之GLP-1受體促效劑顯示更強之降血糖作用及降低體重作用(專利文獻1)。
亦嘗試基於天然升糖素、IP、或GLP-1之
結構,研究具有GLP-1受體/GIP受體共促效劑或升糖素/GLP-1受體/GIP受體三促效劑活性的胜肽及研發該等胜肽作為抗肥胖症藥或糖尿病之治療藥(專利文獻1至8)。惟,並無文獻揭露本發明之胜肽化合物。
[專利文獻1]W02010/011439
[專利文獻2]WO2010/148089
[專利文獻3]WO2011/119657
[專利文獻4]W02012/088379
[專利文獻5]W02012/167744
[專利文獻6]WO2013/164483
[專利文獻7]WO2013/192129
[專利文獻8]WO2013/192130
[非專利文獻1] Clinical Science 121, 107-117(2011)
本發明著眼於提供一種新穎胜肽化合物,其具有高度的GLP-1受體/GIP受體共促效劑活性,且適用於作為預防或治療肥胖症等之藥劑。
本發明者們對具有良好的GLP-1受體/GIP受體共促效劑活性,且適用於作為預防或治療肥胖症等之藥劑之新穎胜肽化合物進行密集研究,因此發現含有下式(I)所示之部分序列之胜肽化合物等具有良好的GLP-1受體/GIP受體共促效劑活性,從而完成本發明。
據此,本發明係關於下述者:[1]一種胜肽或其鹽,其包括式(I)所示之部分序列:P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29(SEQ ID NO:1)其中,P1係下式所示之基:-RA1、-CO-RA1、-CO-ORA1、-CO-CORA1、-SO-RA1、-SO2-RA1、-SO2-ORA1、-CO-NRA2RA3、-SO2-NRA2RA3、或-C(=NRA1)-NRA2RA3,其中RA1、RA2及RA3各自獨立為氫原子、視需要經取代之烴基、或視需要經取代之雜環基;
A11為Aib或Ala;A12為Ala、Ile、Lys、Phe或Pya(4);A13為Aib、Cha、Leu、αMePhe或αMeTyr;A16為Lys或Ser;A17為Gln或Ile;A20為Ala或Ser;以及A29為Gln或Gly(後文有時簡稱為化合物(I));[2]上述[1]之胜肽或其鹽,其中,P1為氫原子;[3]上述[1]之胜肽或其鹽,其中,A11為Aib;[4]上述[1]之胜肽或其鹽,其中,A12為Ile;[5]上述[1]之胜肽或其鹽,其中,A13為Aib;[6]上述[1]之胜肽或其鹽,其中,A16為Lys;[7]上述[1]之胜肽或其鹽,其中,A17為Gln;[8]上述[1]之胜肽或其鹽,其中,A20為Ala;[9]上述[1]之胜肽或其鹽,其中,A29為Gly;[10]上述[1]之胜肽或其鹽,其於A29之C端側具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所示之胺基酸序列;[11]上述[1]之胜肽或其鹽,其中,P1為氫原子;A11為Aib;A12為Ile;A13為Aib;
A16為Lys;A17為Gln;A20為Ala;A29為Gly;且該胜肽於A29之C端側具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所示之胺基酸序列;[12]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其鹽;[13]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其鹽;[14]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2或其鹽;[15]H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2或其鹽;[16]一種藥物,其包括上述[1]之胜肽或其鹽;
[17]上述[16]之藥物,其係GLP-1受體及GIP受體之活化劑;[18]上述[16]之藥物,其係預防或治療肥胖症或糖尿病之藥劑;[19]一種用於預防或治療哺乳類之肥胖症或糖尿病之方法,其包括將有效量之上述[1]之胜肽或其鹽投予至哺乳類;[20]一種活化哺乳類之GLP-1受體及GIP受體之方法,其包括將有效量之上述[1]之胜肽或其鹽投予至哺乳類;[21]一種上述[1]之胜肽或其鹽之用途,其係用於製造預防或治療肥胖症或糖尿病之藥劑;[22]上述[1]之胜肽或其鹽,其係用於預防或治療肥胖症或糖尿病。
化合物(I)具有良好的GLP-1受體/GIP受體共促效劑活性,且於體內顯示顯著的抑制食慾及降低體重效果。此外,由於化合物(I)之低升糖素受體促效劑活性,其降血糖作用的風險低,且亦適用於治療與糖尿病等有關之肥胖症。再者,化合物(I)之溶解度優異,且亦具有易於將該化合物調配為藥物之優點。
本說明書中所用之各取代基之定義詳述如下。除非另有界定,否則各取代基係如下述定義。
於本說明書中,「鹵素原子」之例包括氟、氯、溴及
碘。
於本說明書中,「C1-6烷基」之例包括甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、1-乙基丙基、己基、異己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基及2-乙基丁基。
於本說明書中,「視需要經鹵化之C1-6烷基」之例包括視需要具有1至7個,較佳為1至5個鹵素原子之C1-6烷基。其具體例包括甲基、氯甲基、二氟甲基、三氯甲基、三氟甲基、乙基、2-溴乙基、2,2,2-三氟乙基、四氟乙基、五氟乙基、丙基、2,2-二氟丙基、3,3,3-三氟丙基、異丙基、丁基、4,4,4-三氟丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、5,5,5-三氟戊基、己基及6,6,6-三氟己基。
於本說明書中,「C2-6烯基」之例包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、-丁烯基、3-甲基-2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、4-甲基-3-戊烯基、1-己烯基、3-己烯基及5-己烯基。
於本說明書中,「C2-6炔基」之例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基及4-甲基-2-戊炔基。
於本說明書中,「C3-10環烷基」之例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、雙環[2.2.1]庚基、雙環[2.2.2]辛基、雙環[3.2.1]辛基及金剛烷基。
於本說明書中,「視需要經鹵化之C3-10環烷基」之例包括視需要具有1至7個,較佳為1至5個鹵素原子之C3-10環烷基。其具體例包括環丙基、2,2-二氟環丙基、2,3-二氟環丙基、環丁基、二氟環丁基、環戊基、環己基、環庚基及環辛基。
於本說明書中,「C3-10環烯基」之例包括環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基及環辛烯基。
於本說明書中,「C6-14芳基」之例包括苯基、1-萘基、2-萘基、1-蒽基、2-蒽基及9-蒽基。
於本說明書中,「C7-16芳烷基」之例包括苯甲基、苯乙基、萘基甲基及苯基丙基。
於本說明書中,「C1-6烷氧基」之例包括甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊基氧基及己基氧基。
於本說明書中,「視需要經鹵化之C1-6烷氧基」之例包括視需要具有1至7個,較佳為1至5個鹵素原子之C1-6烷氧基。其具體例包括甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、2,2,2-三氟乙氧基、丙氧基、異丙氧基、丁氧基、4,4,4-三氟丁氧基、異丁氧基、第二丁氧基、戊基氧基及己基氧基。
本說明書中,「C3-10環烷基氧基」之例包括環丙基氧基、環丁基氧基、環戊基氧基、環己基氧基、環庚基氧基及環辛基氧基。
於本說明書中,「C1-6烷基硫基」之例包括甲基硫基、乙基硫基、丙基硫基、異丙基硫基、丁基硫基、第二丁基硫基、第三丁基硫基、戊基硫基及己基硫基。
於本說明書中,「視需要經鹵化之C1-6烷基硫基」之例包括視需要具有1至7個,較佳為1至5個鹵素原子之C1-6烷基硫基。其具體例包括甲基硫基、二氟甲基硫基、三氟甲基硫基、乙基硫基、丙基硫基、異丙基硫基、丁基硫基、4,4,4-三氟丁基硫基、戊基硫基及己基硫基。
於本說明書中,「C1-6烷基羰基」之例包括乙醯基、丙醯基、丁醯基、2-甲基丙醯基、戊醯基、3-甲基丁醯基、2-甲基丁醯基、2,2-二甲基丙醯基、己醯基及庚醯基。
於本說明書中,「視需要經鹵化之C1-6烷基羰基」之例包括視需要具有1至7個,較佳為1至5個鹵素原子之C1-6烷基羰基。其具體例包括乙醯基、氯乙醯基、三氟乙醯基、三氯乙醯基、丙醯基、丁醯基、戊醯基及己醯基。
於本說明書中,「C1-6烷氧基羰基」之例包括甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙氧基羰基、丁氧基羰基、異丁氧基羰基、第二丁氧基羰基、第三丁氧
基羰基、戊基氧基羰基及己基氧基羰基。
於本說明書中,「C6-14芳基羰基」之例包括苯甲醯基、1-萘甲醯基及2-萘甲醯基。
於本說明書中,「C7-16芳烷基羰基」之例包括苯基乙醯基及苯基丙醯基。
於本說明書中,「5至14員芳香族雜環基羰基」之例包括菸鹼醯基、異菸鹼醯基、噻吩甲醯基及呋喃甲醯基。
本說明書中,「3至14員非芳香族雜環基羰基」之例包括嗎啉基羰基、哌啶基羰基及吡咯啶基羰基。
於本說明書中,「單或二C1-6烷基胺甲醯基」之例包括甲基胺甲醯基、乙基胺甲醯基、二甲基胺甲醯基、二乙基胺甲醯基及N-乙基-N-甲基胺甲醯基。
於本說明書中,「單或二C7-16芳烷基胺甲醯基」之例包括苯甲基胺甲醯基及苯乙基胺甲醯基。
於本說明書中,「C1-6烷基磺醯基」之例包括甲基磺醯基、乙基磺醯基、丙基磺醯基、異丙基磺醯基、丁基磺醯基、第二丁基磺醯基及第三丁基磺醯基。
於本說明書中,「視需要經鹵化之C1-6烷基磺醯基」之例包括視需要具有1至7個,較佳為1至5個鹵素原子之C1-6烷基磺醯基。其具體例包括甲基磺醯基、二氟甲基磺醯基、三氟甲基磺醯基、乙基磺醯基、丙基磺醯基、異丙基磺醯基、丁基磺醯基、4,4,4-三氟丁基磺醯基、戊基磺醯基及己基磺醯基。
於本說明書中,「C6-14芳基磺醯基」之例包括苯基磺醯基、1-萘基磺醯基及2-萘基磺醯基。
於本說明書中,「取代基」之例包括鹵素原子、氰基、硝基、視需要經取代之烴基、視需要經取代之雜環基、醯基、視需要經取代之胺基、視需要經取代之胺甲醯基、視需要經取代之胺硫甲醯基、視需要經取代之胺磺醯基、視需要經取代之羥基、視需要經取代之巰基(sulfanyl,SH)、及視需要經取代之矽基。
於本說明書中,「烴基」(包含「視需要經取代之烴基」的「烴基」)之例包括C1-6烷基、C2-6烯基、C2-6炔基、C3-10環烷基、C3-10環烯基、C6-14芳基及C7-16芳烷基。
於本說明書中,「視需要經取代之烴基」之例包括視需要具有一個或多個選自下列取代基群A的取代基之烴基。
(1)鹵素原子,(2)硝基,(3)氰基,(4)側氧基,(5)羥基,(6)視需要經鹵化之C1-6烷氧基,(7)C6-14芳基氧基(例如,苯氧基、萘氧基),(8)C7-16芳烷基氧基(例如,苯甲基氧基),
(9)5至14員芳香族雜環基氧基(例如,吡啶基氧基),(10)3至14員非芳香族雜環基氧基(例如,嗎啉基氧基、哌啶基氧基),(11)C1-6烷基羰基氧基(例如,乙醯氧基、丙醯基氧基),(12)C6-14芳基羰基氧基(例如,苯甲醯基氧基、1-萘甲醯基氧基、2-萘甲醯基氧基),(13)C1-6烷氧基羰基氧基(例如,甲氧基羰基氧基、乙氧基羰基氧基、丙氧基羰基氧基、丁氧基羰基氧基),(14)單或二C1-6烷基胺甲醯基氧基(例如,甲基胺甲醯基氧基、乙基胺甲醯基氧基、二甲基胺甲醯基氧基、二乙基胺甲醯基氧基),(15)C6-14芳基胺甲醯基氧基(例如,苯基胺甲醯基氧基、萘基胺甲醯基氧基),(16)5至14員芳香族雜環基羰基氧基(例如,菸鹼醯基氧基),(17)3至14員非芳香族雜環基羰基氧基(例如,嗎啉基羰基氧基、哌啶基羰基氧基),(18)視需要經鹵化之C1-6烷基磺醯基氧基(例如,甲基磺醯基氧基、三氟甲基磺醯基氧基),(19)視需要經C1-6烷基取代之C6-14芳基磺醯基氧基(例如,苯基磺醯基氧基、甲苯磺醯基氧基),(20)視需要經鹵化之C1-6烷基硫基,(21)5至14員芳香族雜環基,(22)3至14員非芳香族雜環基,(23)甲醯基,
(24)羧基,(25)視需要經鹵化之C1-6烷基羰基,(26)C6-14芳基羰基,(27)5至14員芳香族雜環基羰基,(28)3至14員非芳香族雜環基羰基,(29)C1-6烷氧基羰基,(30)C6-14芳基氧基-羰基(例如,苯基氧基羰基、1-萘基氧基羰基、2-萘基氧基羰基),(31)C7-16芳烷基氧基羰基(例如,苯甲基氧基羰基、苯乙基氧基羰基),(32)胺甲醯基,(33)胺硫甲醯基,(34)單或二C1-6烷基胺甲醯基,(35)C6-14芳基胺甲醯基(例如,苯基胺甲醯基),(36)5至14員芳香族雜環基胺甲醯基(例如,吡啶基胺甲醯基、噻吩基胺甲醯基),(37)3至14員非芳香族雜環基胺甲醯基(例如,嗎啉基胺甲醯基、哌啶基胺甲醯基),(38)視需要經鹵化之C1-6烷基磺醯基,(39)C6-14芳基磺醯基,(40)5至14員芳香族雜環基磺醯基(例如,吡啶基磺醯基、噻吩基磺醯基),(41)視需要經鹵化之C1-6烷基亞磺醯基,(42)C6-14芳基亞磺醯基(例如,苯基亞磺醯基、1-萘基亞磺
醯基、2-萘基亞磺醯基),(43)5至14員芳香族雜環基亞磺醯基(例如,吡啶基亞磺醯基、噻吩基亞磺醯基),(44)胺基,(45)單或二C1-6烷基胺基(例如,甲基胺基、乙基胺基、丙基胺基、異丙基胺基、丁基胺基、二甲基胺基、二乙基胺基、二丙基胺基、二丁基胺基、N-乙基-N-甲基胺基),(46)單或二C6-14芳基胺基(例如,苯基胺基),(47)5至14員芳香族雜環基胺基(例如,吡啶基胺基),(48)C7-16芳烷基胺基(例如,苯甲基胺基),(49)甲醯基胺基,(50)C1-6烷基羰基胺基(例如,乙醯基胺基、丙醯基胺基、丁醯基胺基),(51)(C1-6烷基)(C1-6烷基羰基)胺基(例如,N-乙醯基-N-甲基胺基),(52)C6-14芳基羰基胺基(例如,苯基羰基胺基、萘基羰基胺基),(53)C1-6烷氧基羰基胺基(例如,甲氧基羰基胺基、乙氧基羰基胺基、丙氧基羰基胺基、丁氧基羰基胺基、第三丁氧基羰基胺基),(54)C7-16芳烷基氧基羰基胺基(例如,苯甲基氧基羰基胺基),(55)C1-6烷基磺醯基胺基(例如,甲基磺醯基胺基、乙基磺醯基胺基),(56)視需要經C1-6烷基取代之C6-14芳基磺醯基胺基(例如,
苯基磺醯基胺基、甲苯磺醯基胺基),(57)視需要經鹵化之C1-6烷基,(58)C2-6烯基,(59)C2-6炔基,(60)C3-10環烷基,(61)C3-10環烯基,以及(62)C6-14芳基。
「視需要經取代之烴基」中之上述取代基數為例如,1至5個,較佳為1至3個。當取代基數為2以上時,該等取代基可各自相同或不同。
於本說明書中,「雜環基」(包含「視需要經取代之雜環基」之「雜環基」)之例包括(i)芳香族雜環基、(ii)非芳香族雜環基及(iii)7至10員橋聯雜環基,除了碳原子之外,其各自含有1至4個選自氮原子、硫原子及氧原子之雜原子作為構成環之原子。
於本說明書中,「芳香族雜環基」(包含「5至14員芳香族雜環基」)之例包括5至14員(較佳為5至10員)之芳香族雜環基,除了碳原子之外,其含有1至4個選自氮原子、硫原子及氧原子之雜原子作為構成環之原子。
「芳香族雜環基」之較佳例包括5或6員單環芳香族雜環基如噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、異噻唑基、唑基、異唑基、吡啶基、吡基、嘧啶基、嗒基、1,2,4-二唑基、1,3,4-二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、
三基等;及8至14員稠合多環(較佳為雙環或三環)芳香族雜環基如苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并唑基、苯并異唑基、苯并噻唑基、苯并異噻唑基、苯并三唑基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、唑并吡啶基、噻唑并吡啶基、咪唑并吡基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、唑并嘧啶基、噻唑并嘧啶基、吡唑并三基、萘并[2,3-b]噻吩基、啡噻基、吲哚基、異吲哚基、1H-吲唑基、嘌呤基、異喹啉基、喹啉基、呔基(phthalazinyl)、萘啶基(naphthyridinyl)、喹啉基、喹唑啉基、噌啉基、咔唑基、β-咔啉基、啡啶基、吖啶基、啡基、啡噻基、啡基等。
於本說明書中,「非芳香族雜環基」(包含「3至14員非芳香族雜環基」)之例包括3至14員(較佳為4至10員)非芳香族雜環基,除了碳原子之外,其含有1至4個選自氮原子、硫原子及氧原子之雜原子作為構成環之原子。
「非芳香族雜環基」之較佳例包括3至8員單環非芳香族雜環基如氮雜環丙烷基(aziridinyl)、環氧乙烷基(oxiranyl)、噻喃基(thiiranyl)、氮呾基(azetidinyl)、氧呾基(oxetanyl)、硫呾基(thietanyl)、四氫噻吩基、四氫呋喃基、吡咯啉基、吡咯啶基、咪唑啉基,咪唑啶基、唑啉基、唑啶基、吡唑啉基、吡唑啶基、噻唑啉基、噻唑啶
基、四氫異噻唑基、四氫唑基、四氫異唑基、哌啶基、哌基、四氫吡啶基、二氫吡啶基、二氫噻喃基、四氫嘧啶基、四氫嗒基、二氫吡喃基、四氫吡喃基、四氫噻喃基、嗎啉基、硫代嗎啉基、氮雜環庚烷基(azepanyl)、二氮雜環庚烷基、氮雜環庚三烯基(azepinyl)、氧雜環庚烷基(oxepanyl)、氮雜環辛烷基(azocanyl)、二氮雜環辛烷基等;及9至14員稠合多環(較佳為雙環或三環)非芳香族雜環基如二氫苯并呋喃基、二氫苯并咪唑基、二氫苯并唑基、二氫苯并噻唑基、二氫苯并異噻唑基、二氫萘并[2,3-b]噻吩基、四氫異喹啉基、四氫喹啉基、4H-喹基(quinolizinyl)、吲哚啉基、異吲哚啉基、四氫噻吩[2,3-c]吡啶基、四氫苯并氮雜環庚三烯基、四氫喹啉基、四氫啡啶基、六氫啡噻基、六氫啡基、四氫呔基、四氫萘啶基、四氫喹唑啉基、四氫噌啉基、四氫咔唑基、四氫-β-咔啉基、四氫吖啶基、四氫啡基、四氫噻吨基(tetrahydrothioxanthenyl)、八氫異喹啉基等。
於本說明書中,「7至10員橋聯雜環基」之較佳例包括奎寧環基(quinuclidinyl)及7-氮雜雙環[2.2.1]庚基。
於本說明書中,「含氮雜環基」之例包括含有至少一個氮原子作為構成環之原子之「雜環基」。
於本說明書中,「視需要經取代之雜環基」之例包括視需要具有選自上述取代基群A之一個或多個取
代基之雜環基。
「視需要經取代之雜環基」之取代基數為例如,1至3個。當取代基數為2以上時,該等取代基可各自相同或不同。
本說明書中,「醯基」之例包括甲醯基、羧基、胺甲醯基、胺硫甲醯基、亞磺酸基(sulfino)、磺酸基、胺磺醯基及膦醯基,其各自視需要具有「1或2個選自C1-6烷基、C2-6烯基、C3-10環烷基、C3-10環烯基、C6-14芳基、C7-16芳烷基、5至14員芳香族雜環基及3至14員非芳香族雜環基之取代基,且該等取代基各自視需要具有1至3個選自鹵素原子、視需要經鹵化之C1-6烷氧基、羥基、硝基、氰基、胺基及胺甲醯基之取代基」。
「醯基」之例亦包含烴-磺醯基、雜環基磺醯基、烴-亞磺醯基及雜環基亞磺醯基。
本文中,烴-磺醯基意指與烴基鍵結之磺醯基,雜環基磺醯基意指與雜環基鍵結之磺醯基,烴-亞磺醯基意指與烴基鍵結之亞磺醯基及雜環基亞磺醯基意指與雜環基鍵結之亞磺醯基。
「醯基」之較佳例包括甲醯基、羧基、C1-6烷基羰基、C2-6烯基-羰基(例如,巴豆醯基(crotonoyl))、C3-10環烷基-羰基(例如,環丁烷羰基、環戊烷羰基、環己烷羰基、環庚烷羰基)、C3-10環烯基-羰基(例如,2-環己烯羰基)、C6-14芳基羰基、C7-16芳烷基羰基、5至14員芳香族雜環基羰基、3至14員非芳香族雜環基羰基、C1-6烷氧基羰基、
C6-14芳基氧基-羰基(例如,苯基氧基羰基,萘基氧基羰基)、C7-16芳烷基氧基羰基(例如,苯甲基氧基羰基,苯乙基氧基羰基)、胺甲醯基、單或二C1-6烷基胺甲醯基、單或二C2-6烯基-胺甲醯基(例如,二烯丙基胺甲醯基)、單或二C3-10環烷基-胺甲醯基(例如,環丙基胺甲醯基)、單或二C6-14芳基胺甲醯基(例如,苯基胺甲醯基)、單或二C7-16芳烷基胺甲醯基、5至14員芳香族雜環基胺甲醯基(例如,吡啶基胺甲醯基)、胺硫甲醯基、單或二C1-6烷基胺硫甲醯基(例如,甲基胺硫甲醯基、N-乙基-N-甲基胺硫甲醯基)、單或二C2-6烯基-胺硫甲醯基(例如,二烯丙基胺硫甲醯基)、單或二C3-10環烷基-胺硫甲醯基(例如,環丙基胺硫甲醯基、環己基胺硫甲醯基)、單或二C6-14芳基胺硫甲醯基(例如,苯基胺硫甲醯基)、單或二C7-16芳烷基胺硫甲醯基(例如,苯甲基胺硫甲醯基、苯乙基胺硫甲醯基)、5至14員芳香族雜環基胺硫甲醯基(例如,吡啶基胺硫甲醯基)、亞磺醯基、C1-6烷基亞磺醯基(例如,甲基亞磺醯基、乙基亞磺醯基)、磺醯基、C1-6烷基磺醯基、C6-14芳基磺醯基、膦醯基及單或二C1-6烷基膦醯基(例如,二甲基膦醯基、二乙基膦醯基、二異丙基膦醯基、二丁基膦醯基)。
於本說明書中,「視需要經取代之胺基」之例包括視需要具有「1或2個選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基、C7-16芳烷基、C1-6烷基羰基、C6-14芳基羰基、C7-16芳烷基羰基、5至14員芳香族雜環基羰基、3至14員非芳香族雜環基羰基、C1-6烷氧基羰基、5至14員
芳香族雜環基、胺甲醯基、單或二C1-6烷基胺甲醯基、單或二C7-16芳烷基胺甲醯基、C1-6烷基磺醯基及C6-14芳基磺醯基,該等取代基各自視需要具有1至3個選自取代基群A之取代基」之胺基。
視需要經取代之胺基之較佳例包括胺基、單或二(視需要經鹵化之C1-6烷基)胺基(例如,甲基胺基、三氟甲基胺基、二甲基胺基、乙基胺基、二乙基胺基、丙基胺基、二丁基胺基)、單或二C2-6烯基胺基(例如,二烯丙基胺基)、單或二C3-10環烷基胺基(例如,環丙基胺基、環己基胺基)、單或二C6-14芳基胺基(例如,苯基胺基)、單或二C7-16芳烷基胺基(例如,苯甲基胺基、二苯甲基胺基)、單或二(視需要經鹵化之C1-6烷基)-羰基胺基(例如,乙醯基胺基、丙醯基胺基)、單或二C6-14芳基羰基胺基(例如,苯甲醯基胺基)、單或二C7-16芳烷基羰基胺基(例如,苯甲基羰基胺基)、單或二5至14員芳香族雜環基羰基胺基(例如,菸鹼醯基胺基、異菸鹼醯基胺基)、單或二3至14員非芳香族雜環基羰基胺基(例如,哌啶基羰基胺基)、單或二C1-6烷氧基羰基胺基(例如,第三丁氧基羰基胺基)、5至14員芳香族雜環基胺基(例如,吡啶基胺基)、胺甲醯基胺基、(單或二C1-6烷基胺甲醯基)胺基(例如,甲基胺甲醯基胺基)、(單或二C7-16芳烷基胺甲醯基)胺基(例如,苯甲基胺甲醯基胺基)、C1-6烷基磺醯基胺基(例如,甲基磺醯基胺基、乙基磺醯基胺基)、C6-14芳基磺醯基胺基(例如,苯基磺醯基胺基)、(C1-6烷基)(C1-6烷基羰基)胺基(例如,N-乙醯基-N-甲基胺基)
及(C1-6烷基)(C6-14芳基羰基)胺基(例如,N-苯甲醯基-N-甲基胺基)。
於本說明書中,「視需要經取代之胺甲醯基」之例包括視需要具有「1或2個選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基、C7-16芳烷基、C1-6烷基羰基、C6-14芳基羰基、C7-16芳烷基羰基、5至14員芳香族雜環基羰基、3至14員非芳香族雜環基羰基、C1-6烷氧基羰基、5至14員芳香族雜環基、胺甲醯基、單或二C1-6烷基胺甲醯基及單或二C7-16芳烷基胺甲醯基之取代基,該等取代基各自視需要具有1至3個選自取代基群A之取代基」之胺甲醯基。
視需要經取代之胺甲醯基之較佳例包括胺甲醯基、單或二C1-6烷基胺甲醯基、單或二C2-6烯基-胺甲醯基(例如,二烯丙基胺甲醯基)、單或二C3-10環烷基-胺甲醯基(例如,環丙基胺甲醯基、環己基胺甲醯基)、單或二C6-14芳基胺甲醯基(例如,苯基胺甲醯基)、單或二C7-16芳烷基胺甲醯基、單或二C1-6烷基羰基-胺甲醯基(例如,乙醯基胺甲醯基、丙醯基胺甲醯基)、單或二C6-14芳基羰基-胺甲醯基(例如,苯甲醯基胺甲醯基)及5至14員芳香族雜環基胺甲醯基(例如,吡啶基胺甲醯基)。
於本說明書中,「視需要經取代之胺硫甲醯基」之例包括視需要具有「1或2個選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基、C7-16芳烷基、C1-6烷基羰基、C6-14芳基羰基、C7-16芳烷基羰基、5至14員芳香族雜環基羰基、3至14員非芳香族雜環基羰基、C1-6烷氧基羰基、5
至14員芳香族雜環基、胺甲醯基、單或二C1-6烷基胺甲醯基及單或二C7-16芳烷基胺甲醯基之取代基,該等取代基各自視需要具有1至3個選自取代基群A之取代基」之胺硫甲醯基。
視需要經取代之胺硫甲醯基之較佳例包括胺硫甲醯基、單或二C1-6烷基胺硫甲醯基(例如,甲基胺硫甲醯基、乙基胺硫甲醯基、二甲基胺硫甲醯基、二乙基胺硫甲醯基、N-乙基-N-甲基胺硫甲醯基)、單或二C2-6烯基-胺硫甲醯基(例如,二烯丙基胺硫甲醯基)、單或二C3-10環烷基-胺硫甲醯基(例如,環丙基胺硫甲醯基、環己基胺硫甲醯基)、單或二C6-14芳基胺硫甲醯基(例如,苯基胺硫甲醯基)、單或二C7-16芳烷基胺硫甲醯基(例如,苯甲基胺硫甲醯基、苯乙基胺硫甲醯基)、單或二C1-6烷基羰基-胺硫甲醯基(例如,乙醯基胺硫甲醯基、丙醯基胺硫甲醯基)、單或二C6-14芳基羰基-胺硫甲醯基(例如,苯甲醯基胺硫甲醯基)及5至14員芳香族雜環基胺硫甲醯基(例如,吡啶基胺硫甲醯基)。
於本說明書中,「視需要經取代之胺磺醯基」之例包括視需要具有「1或2個選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基、C7-16芳烷基、C1-6烷基羰基、C6-14芳基羰基、C7-16芳烷基羰基、5至14員芳香族雜環基羰基、3至14員非芳香族雜環基羰基、C1-6烷氧基羰基、5至14員芳香族雜環基、胺甲醯基、單或二C1-6烷基胺甲醯基及單或二C7-16芳烷基胺甲醯基之取代基,該等取代基各自視
需要具有1至3個選自取代基群A之取代基」之胺磺醯基。
視需要經取代之胺磺醯基之較佳例包括胺磺醯基、單或二C1-6烷基胺磺醯基(例如,甲基胺磺醯基、乙基胺磺醯基、二甲基胺磺醯基、二乙基胺磺醯基、N-乙基-N-甲基胺磺醯基)、單或二C2-6烯基-胺磺醯基(例如,二烯丙基胺磺醯基)、單或二C3-10環烷基-胺磺醯基(例如,環丙基胺磺醯基、環己基胺磺醯基)、單或二C6-14芳基胺磺醯基(例如,苯基胺磺醯基)、單或二C7-16芳烷基胺磺醯基(例如,苯甲基胺磺醯基、苯乙基胺磺醯基)、單或二C1-6烷基羰基-胺磺醯基(例如,乙醯基胺磺醯基、丙醯基胺磺醯基)、單或二C6-14芳基羰基-胺磺醯基(例如,苯甲醯基胺磺醯基)及5至14員芳香族雜環基胺磺醯基(例如,吡啶基胺磺醯基)。
於本說明書中,「視需要經取代之羥基」之例包括視需要具有「選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基、C7-16芳烷基、C1-6烷基羰基、C6-14芳基羰基、C7-16芳烷基羰基、5至14員芳香族雜環基羰基、3至14員非芳香族雜環基羰基、C1-6烷氧基羰基、5至14員芳香族雜環基、胺甲醯基、單或二C1-6烷基胺甲醯基、單或二C7-16芳烷基胺甲醯基、C1-6烷基磺醯基及C6-14芳基磺醯基之取代基,該等取代基各自視需要具有1至3個選自取代基群A之取代基」之羥基。
視需要經取代之羥基之較佳例包括羥基、C1-6烷氧基、C2-6烯基氧基(例如,烯丙基氧基、2-丁烯基氧
基、2-戊烯基氧基、3-己烯基氧基)、C3-10環烷基氧基(例如,環己基氧基)、C6-14芳基氧基(例如,苯氧基、萘基氧基)、C7-16芳烷基氧基(例如,苯甲基氧基、苯乙基氧基)、C1-6烷基羰基氧基(例如,乙醯基氧基、丙醯基氧基、丁醯基氧基、異丁醯基氧基、三甲基乙醯基氧基)、C6-14芳基羰基氧基(例如,苯甲醯基氧基)、C7-16芳烷基羰基氧基(例如,苯甲基羰基氧基)、5至14員芳香族雜環基羰基氧基(例如,菸鹼醯基氧基)、3至14員非芳香族雜環基羰基氧基(例如,哌啶基羰基氧基)、C1-6烷氧基羰基氧基(例如,第三丁氧基羰基氧基)、5至14員芳香族雜環基氧基(例如,吡啶基氧基)、胺甲醯基氧基、C1-6烷基胺甲醯基氧基(例如,甲基胺甲醯基氧基)、C7-16芳烷基胺甲醯基氧基(例如,苯甲基胺甲醯基氧基)、C1-6烷基磺醯基氧基(例如,甲基磺醯基氧基、乙基磺醯基氧基)及C6-14芳基磺醯基氧基(例如,苯基磺醯基氧基)。
本說明書中,「視需要經取代之巰基」之例包括視需要具有「選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基、C7-16芳烷基、C1-6烷基羰基、C6-14芳基羰基及5至14員芳香族雜環基之取代基,該等取代基各自視需要具有1至3個選自取代基群A之取代基」之巰基及鹵化巰基。
視需要經取代之巰基之較佳例包括巰基(-SH)、C1-6烷基硫基、C2-6烯基硫基(例如,烯丙基硫基、2-丁烯基硫基、2-戊烯基硫基、3-己烯基硫基)、C3-10環烷基硫基(例如,環己基硫基)、C6-14芳基硫基(例如,苯基硫
基、萘基硫基)、C7-16芳烷基硫基(例如,苯甲基硫基、苯乙基硫基)、C1-6烷基羰基硫基(例如,乙醯基硫基、丙醯基硫基、丁醯基硫基、異丁醯基硫基、三甲基乙醯基硫基)、C6-14芳基羰基硫基(例如,苯甲醯基硫基)、5至14員芳香族雜環基硫基(例如,吡啶基硫基)及鹵化硫基(例如,五氟硫基)。
於本說明書中,「視需要經取代之矽基」之例包括視需要具有「1至3個選自C1-6烷基、C2-6烯基、C3-10環烷基、C6-14芳基及C7-16芳烷基之取代基,該等取代基各自視需要具有1至3個選自取代基群A之取代基」之矽基。
視需要經取代之矽基之較佳例包括三C1-6烷基矽基(例如,三甲基矽基、第三丁基(二甲基)矽基)。
式(I)之各符號之定義係詳述如下。
P1係下式所示之基:-RA1、-CO-RA1、-CO-ORA1、-CO-CORA1、-SO-RA1、-SO2-RA1、-SO2-ORA1、-CO-NRA2RA3、-SO2-NRA2RA3、或-C(=NRA1)-NRA2RA3其中RA1、RA2及RA各自獨立為氫原子、視需要經取代之烴
基、或視需要經取代之雜環基。
P1較佳為氫原子。
A11為Aib或Ala。
A11較佳為Aib。
A12為Ala、Ile、Lys、Phe或Pya(4)。
A12較佳為Ile。
於另一態樣中,A12較佳為Lys。
A13為Aib、Cha、Leu、αMePhe或αMeTyr。
A13較佳為Aib。
A16為Lys或Ser。
A16較佳為Lys。
A17為Gln或Ile。
A17較佳為Gln。
A20為Ala或Ser。
A20較佳為Ala。
A29為Gln或Gly。
A29較佳為Gly。
化合物(I)於式(I)所示之部分序列中之A29之C端側(C端序列)可具有額外的胜肽序列。
本文中,該C端序列之長度並無特別限制,較佳為1至11個胺基酸殘基,更佳為6至11個胺基酸殘基。
C端序列之例可包含:(i)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(SEQ ID NO:2)所示之胺基酸序列,(ii)衍生自上述(i)序列之胺基酸序列,其係經缺失、取代(較佳為保守性取代)、或加成1至11個,較佳為1至5個胺基酸者,及(iii)包括至少1個(連續的)胺基酸殘基,較佳為6個連續的胺基酸殘基之部分序列,該等殘基來自上述(i)或(ii)之序列的N端側。
特別是使用下述者作為C端序列:(1)Gly-,(2)Gly-Pro-,(3)Gly-Pro-Ser-,(4)Gly-Pro-Ser-Ser-(SEQ ID NO:3),(5)Gly-Pro-Ser-Ser-Gly-(SEQ ID NO:4),(6)Gly-Pro-Ser-Ser-Gly-Ala-(SEQ ID NO:5),(7)Gly-Pro-Ser-Ser-Gly-Ala-Pro-(SEQ ID NO:6),(8)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-(SEQ ID NO:7),(9)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-(SEQ ID NO:8),
(10)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-(SEQ ID NO: 9),(11)Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-(SEQ ID NO:2),或其類似物。
C端序列較佳為Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-或Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-。
C端序列特佳為Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-。
具有上述C端序列之化合物(I)具有良好溶解度。
具有上述C端序列之化合物(I)於體內亦具有高度的GLP-1受體及GIP受體活化作用。
化合物(I)之較佳例包括下列胜肽或其鹽。
化合物(I),其中,P1為氫原子;A11為Aib;A12為Ile;A13為Aib;A16為Lys;A17為Gln;A20為Ala;
A29為Gly;且該胜肽於A29之C端側具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所示之胺基酸序列。
可根據本身習知之胜肽合成方法製造化合物(I)。胜肽合成方法可為例如,固相合成製程及液相合成製程之任一者。亦即,根據所欲序列,藉由重複縮合可構成化合物(I)之部分胜肽及胺基酸及剩餘部份(其可由二個以上之胺基酸構成),即可製造目標胜肽。當具有所欲序列之產物具有一保護基,可藉由消除保護基製造目標胜肽。習知之縮合方法及消除保護基之方法之例包括下列(1)至(5)所述者:(1) M. Bodanszky and M.A. Ondetti: Peptide Synthesis, Interscience Publishers, New York(1966); (2) Schroeder及Luebke: The Peptide, Academic Press, New York(1965); (3) Nobuo Izumiya, et al.: Peptide Gosei-no-Kiso to Jikken(Basics and experiments of peptide synthesis), published by Maruzen Co.(1975); (4) Haruaki Yajima and Shunpei Sakakibara: Seikagaku Jikken Koza(Biochemical Experiment) 1, Tanpakushitsu no Kagaku(Chemistry of Proteins) IV, 205(1977); (5) Haruaki Yajima, ed.: Zoku Iyakuhin no Kaihatsu(A sequel to Development of Pharmaceuticals), Vol. 14, Peptide
Synthesis, published by Hirokawa Shoten。
反應後,可使用傳統純化方法如溶劑萃取、蒸餾、管柱層析法、液相層析法、再結晶等、該等方法之組合以純化及單離化合物(I)。當藉由上述方法所得之胜肽為游離態時,其可藉由習知方法轉變為適當的鹽;反之,當所得胜肽為鹽類形態時,該鹽可藉由習知方法轉變為游離態或其它鹽類。
起始化合物亦可為鹽。此鹽之例包括下述所例示之化合物(I)之鹽類。
可使用適用於胜肽合成之多種活化劑,以縮合經保護之胺基酸或胜肽,該活化劑特佳為參鏻鹽、四甲基脲(uronium)鹽、碳二亞胺等。參鏻鹽之例包括六氟磷酸苯并三唑-1-基氧基參(吡咯)鏻(PyBOP)、六氟磷酸溴化參(吡咯)鏻(PyBroP)、六氟磷酸7-氮雜苯并三唑-1-基氧基參(吡咯)鏻(PyAOP),四甲基脲鹽之例包括六氟磷酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲(HBTU)、六氟磷酸2-(7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基脲(HATU)、四氟硼酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲(TBTU)、四氟硼酸2-(5-降莰烷-2,3-二羧醯亞胺)-1,1,3,3-四甲基脲(TNTU)、四氟硼酸O-(N-琥珀醯亞胺基)-1,1,3,3-四甲基脲(TSTU),及碳二亞胺之例包括DCC、N,N’-二異丙基碳二亞胺(DIPCDI)、N-乙基-N’-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽(EDCI.HCl)等。使用此等者用以縮合,較佳為添加消旋化抑制劑(例如,HONB、HOBt、HOAt、HOOBt等)。適用
於縮合反應之溶劑可適當選自習知的適用於胜肽縮合反應之溶劑。例如,可使用醯胺類如無水或含水之N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮等,鹵化烴類如二氯甲烷、氯仿等,醇類如三氟乙醇、酚等,亞碸類如二甲基亞碸等,三級胺如吡啶等,醚類如二烷、四氫呋喃等,腈類如乙腈、丙腈等,酯類如乙酸甲酯、乙酸乙酯等,該等者之適當混合物等。反應溫度適當選自習知適用於胜肽結合反應之範圍,且通常係選自約-20℃至50℃之範圍。通常使用1.5至6倍過量之經活化之胺基酸衍生物。在合成期,當寧海準反應(ninhydrin reaction)試驗顯示縮合反應不充分,則不消除保護基而重複進行縮合反應即可充分進行縮合。若重複該反應後仍未充分進行縮合反應,可以乙酸酐、乙醯基咪唑或其類似物以醯化來反應之胺基酸,從而避免後續反應被影響。
起始胺基酸之胺基用保護基之例包括Z、Boc、第三戊基氧基羰基、異茨基氧基羰基、4-甲氧基苯甲基氧基羰基、Cl-Z、Br-Z、金剛烷基氧基羰基、三氟乙醯基、酞醯基、甲醯基、2-硝基苯基硫基(2-nitrophenylsulphenyl)、二苯基膦基亞硫醯基、Fmoc、三苯甲基等.
除了上述C1-6烷基、C3-10環烷基、C7-14芳烷基之外,起始胺基酸之羧基-保護基之例包括烯丙基、2-金剛烷基、4-硝基苯甲基、4-甲氧基苯甲基、4-氯苯甲基、苯甲醯基(phenacyl)及苯甲基氧基羰基醯肼、第三丁氧基羰基醯肼、三苯甲基醯肼等。
絲胺酸或蘇胺酸之羥基可經保護,例如,藉由酯化或醚化。適用於酯化之基之例包括低級(C2-4)烷醯基(alkanoyl)如乙醯基等、芳醯基如苯甲醯基等等、及衍生自有機酸之基等。此外,適用於醚化之基之例包括苯甲基、四氫哌喃基、第三丁基(But)、三苯甲基(Trt)等。
酪胺酸之酚系羥基所用保護基之例包括Bzl、2,6-二氯苯甲基、2-硝基苯甲基、Br-Z、第三丁基等。
組胺酸之咪唑所用保護基之例包括Tos、4-甲氧基-2,3,6-三甲基苯磺醯基(Mtr)、DNP、Bom、Bum、Boc、Trt、Fmoc等。
精胺酸之胍基所用保護基之例包括Tos、Z、4-甲氧基-2,3,6-三甲基苯磺醯基(Mtr)、對-甲氧基苯磺醯基(MBS)、2,2,5,7,8-五甲基烷-6-磺醯基(Pmc)、均三甲苯-2-磺醯基(Mts)、2,2,4,6,7-五甲基二氫苯并呋喃-5-磺醯基(Pbf)、Boc、Z、NO2等。
離胺酸之側鏈胺基所用保護基之例包括Z、Cl-Z、三氟乙醯基、Boc、Fmoc、Trt、Mtr、4,4-二甲基-2,6-二側氧基環己亞基(Dde)等。
色胺酸之吲哚基所用保護基之例包括甲醯基(For)、Z、Boc、Mts、Mtr等。
天冬醯胺酸及麩醯胺酸所用保護基之例包括Trt、呫噸基(xanthyl,Xan)、4,4’-二甲氧基二苯甲基(Mbh)、,4,6-三甲氧基苯甲基(Tmob)等.
起始材料之經活化之羧基之例包括相應酸
酐、疊氮化物、活性酯[與醇(例如,五氯酚、2,4,5-三氯酚、2,4-二硝基酚、氰基甲醇、對硝基酚、HONB、N-羥基琥珀醯亞胺、1-羥基苯并三唑(HOBt)、1-羥基-7-氮雜苯并三唑(HOAt))所成之酯]等。起始材料之經活化之胺基之例包括相應磷醯胺。
用於移除(消除)保護基之方法之例包括在催化劑(如鈀黑或鈀碳)存在下,於氫氣流中進行催化還原反應;使用無水氫氟酸、甲磺酸、三氟甲磺酸、三氟乙酸酯、溴化三甲基矽烷(TMSBr)、三氟甲磺酸三甲基矽基酯、四氟硼酸、參(三氟)硼酸、三溴化硼、或其混合溶液之酸處理;使用二異丙基乙胺、三乙胺、哌啶、哌或其類似物之鹼處理;及於氨水中以鈉還原等。藉由上述酸處理之消除反應通常於-20℃至40℃的溫度進行;藉由添加陽離子清除劑(如苯甲醚、酚、苯基甲基硫醚、間甲酚及對甲酚)、二甲基硫、1,4-丁二硫醇、1,2-乙二硫醇等而有效地進行酸處理。又,組胺酸之咪唑所用之保護基2,4-二硝基苯基係經硫酚處理而移除;色胺酸之吲哚所用之保護基甲醯基係藉由去保護而移除,該去保護係於1,2-乙二硫醇、1,4-丁二硫醇、或其類似物存在下經酸處理而進行,以及以經稀釋之氫氧化鈉、稀釋之氨水、或其類似物之鹼處理而進行。
不該涉及起始物質及保護基之反應之官能基的保護、保護基之消除、涉及反應之官能基的活化等可適當選自習知之保護基及習知手段。
於製備胜肽之醯胺之方法中,其使用醯胺
合成用之樹脂藉由固相合成而形成,或者,羧基端胺基酸之α-羧基經醯化,且胜肽鏈朝胺基側延長至所欲之鏈長,之後製備僅移除胜肽鏈之N端α-胺基用之保護基的胜肽及僅移除胜肽鏈之C端羧基用之保護基的胜肽,並於上述混合溶劑中將此二胜肽縮合。關於該縮合反應之詳情,係以與上述相同方法實施。待藉由縮合所得之經保護胜肽純化後,可藉由上述方法移除所有保護基以產生所欲之多肽粗產物。可使用多種公眾習知之純化手段純化此胜肽粗產物,並乾造冷凍其主要部份而製備所欲胜肽之醯胺。
當化合物(I)以組態異構物如鏡像異構物、非鏡像異構物等,構型異構物或其類似物存在時,該等者亦包含於化合物(I)中且各自可經本身習知之手段或必要時可以上述分離及純化方法單離。此外,當化合物(I)為消旋物之型態時,其可藉由傳統之光學解離分離成S及R型。
當化合物(I)包含立體異構物時,單獨的異構物或各異構物之混合物皆包含於化合物(I)中。
可根據本身習知之方法並使用聚乙二醇化學修飾化合物(I)。例如,可藉由將聚乙二醇與化合物(I)之Cys殘基、Asp殘基、Glu殘基、Lys殘基等接合(conjugately binding)而生產經化學修飾之化合物(I)。
經聚乙二醇(PEG)修飾之化合物(I)產生具有下列功效之治療上及診斷上重要之胜肽,例如,促進生物活性、延長血液循環時間、降低免疫性、增加溶解度、及增加代謝耐受性之功效。
PEG之分子量並未特別限制,通常為約1K至約1000K道耳吞(Dalton)。較佳為約10K至約100K道耳吞,更佳為約20K至約60K道耳吞。
可使用本領域中廣為人知之方法作為以PEG修飾化合物(I)之方法,例如,可使用下述方法。
(1)使具有活性酯之PEG化試劑(例如,SUNBRIGHT MEGC-30TS(商標名))與化合物(I)之胺基鍵結。
(2)使具有醛之PEG化試劑(例如,SUNBRIGHT ME-300AL(商標名),日本油脂股份有限公司)與化合物(I)之胺基鍵結。
(3)使二價交聯試劑(例如,GMBS(Dojindo化學研究所)、EMCS(Dojindo化學研究所)、KMUS(Dojindo化學研究所)、SMCC(Pierce))與化合物(I)鍵結,接著使具有巰基之PEG化試劑(例如,SUNBRIGHT ME-300-SH(商標名),日本油脂股份有限公司)與其鍵結。
(4)經SH導入劑(例如,D-半胱胺酸殘基、L-半胱胺酸殘基、Traut試劑)而將巰基導入化合物(I),並使該巰基與具有馬來醯亞胺之PEG化試劑(例如,SUNBRIGHT ME-300MA(商標名),日本油脂股份有限公司)反應。
(5)經SH導入劑(例如,D-半胱胺酸殘基、L-半胱胺酸殘基、Traut試劑)而將巰基導入化合物(I),並使該巰基與具有碘乙醯胺基之PEG化試劑(例如,SUNBRIGHT ME-300IA(商標名),日本油脂股份有限公司)反應。
(6)以ω-胺基羧酸或α-胺基酸作為連接子(linker)並導入至化合物(I)之N端胺基,並使衍生自此連接子之胺基與具有
活性酯之PEG化試劑(例如,SUNBRIGHT MEGC-30TS(商標名),日本油脂股份有限公司)反應。
(7)以ω-胺基羧酸或或α-胺基酸作為連接子(linker)並導入至化合物(I)之N端胺基,並使衍生自此連接子之胺基與具有醛基之PEG化試劑(例如,SUNBRIGHT ME-300AL(商標名),日本油脂股份有限公司)反應。
此外,化合物(I)可為溶劑合物(例如,水合物)或非溶劑合物(例如,非水合物)。
化合物(I)可經同位素(例如,3H、14C、35S、125I)或其類似物標記。
再者,化合物(I)可為氘轉換型態,其中1H係轉換為2H(D)。
經同位素標記或取代之化合物(I)可用作為,例如,用於正子發射斷層攝影術(Positron Emission Tomography,PET)之追蹤劑(PET tracer),且適用於醫學診斷等領域。
就本文所述之胜肽而言,根據傳統的胜肽標誌,左末端為N端(胺基端)及右末端為C端(羧基端)。胜肽之C端可為任何醯胺(-CONH2)、羧基(-COOH)、羧酸根(-COO-)、烷基醯胺(-CONHRa)、及酯(-COORa)。特佳為醯胺(-CONH2)。
化合物(I)可為鹽型態。此鹽之例包括金屬鹽類、銨鹽類、有機鹼之鹽類、無機酸之鹽類、有機酸之鹽類、鹼性或酸性胺基酸之鹽類等。
金屬鹽之較佳例包括鹼金屬鹽類如鈉鹽、鉀鹽等;鹼土金屬鹽類如鈣鹽、鎂鹽、鋇鹽等;鋁鹽等。
與有機鹼形成之鹽之較佳例包括:與三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、環己胺、二環己胺、N,N-二苯甲基乙二胺等形成之鹽類。
與無機酸形成之鹽類之較佳例包括:與鹽酸、氫溴酸、硝酸、硫酸、磷酸等形成之鹽類。
與有機酸形成之鹽類之較佳例包括:與甲酸、乙酸、三氟乙酸、酞酸、富馬酸、草酸、酒石酸、馬來酸、檸檬酸、琥珀酸、蘋果酸、甲磺酸、苯磺酸、對甲苯磺酸形成之鹽類。
與鹼性胺基酸形成之鹽類之較佳例包括:與精胺酸、離胺酸、鳥胺酸等形成之鹽類。與酸性胺基酸形成之鹽類之較佳例包括:與天冬胺酸、麩胺酸等形成之鹽類。
上述鹽類中,較佳為醫藥上可接受之鹽。例如:當化合物具有酸性官能基時,較佳為無機鹽類,如:鹼金屬鹽類(例如:鈉鹽、鉀鹽等),鹼土金屬鹽類(例如:鈣鹽、鎂鹽、鋇鹽等)等,銨鹽等,及當化合物具有鹼性官能基時,較佳為與無機酸形成之鹽類,如:鹽酸、氫溴酸、硝酸、硫酸、磷酸等,或與有機酸形成之鹽類,如:乙酸、酞酸、富馬酸、草酸、酒石酸、馬來酸、檸檬酸、琥珀酸、甲磺酸、苯磺酸、對甲苯磺酸等。
化合物(I)可呈前藥型式。
前藥係指一種可於活體內生理條件下,受到酵素、胃酸等反應轉化成化合物(I)之化合物,亦即可依據酵素之氧化、還原、水解等反應轉化成化合物(I)之化合物;及可經胃酸等水解轉化成化合物(I)之化合物。
化合物(I)之前藥實例包括化合物(I)中之胺基經醯基化、烷基化或磷酸化之化合物(例如:化合物(I)中之胺基經二十碳烷醯基化、丙胺醯基化、戊基胺基羰基化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲氧基羰基化、四氫呋喃基化、吡咯啶基甲基化、特戊醯基氧甲基化與第三丁基化等之化合物);由化合物(I)中之羥基經醯基化、烷基化、磷酸化或硼酸化之化合物(例如:由化合物(I)中之羥基經乙醯基化、棕櫚醯基化、丙醯基化、特戊醯基化、琥珀醯基化、富馬醯基化、丙胺醯基化或二甲基胺基甲基羰基化之化合物);由化合物(I)中之羧基經過酯化或醯胺化之化合物(例如:化合物(I)中之羧基經過C1-6烷基酯化、苯基酯化、羧基甲酯化、二甲基胺基甲酯化、特戊醯基氧甲酯化、乙氧基羰基氧乙酯化、酞基酯化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲酯化、環己基氧羰基乙酯化或甲基醯胺化之化合物)等。其中較佳係使用化合物(I)中之羧基經過C1-6烷基(如:甲基、乙基、第三丁基,或類似物)酯化之化合物。此等化合物均可由化合物(I)依本身已知之方法製得。
化合物(I)之前藥亦可為可於如”IYAKUHIN
no KAIHATSU(藥品發展),Vol.7,Design of Molecules,p.163-198,出版社HIROKAWA SHOTEN(1990)”中說明之彼等生理條件下轉化成化合物(I)之化合物。
本說明書中,前藥可呈鹽型。此等鹽之實例包括彼等化合物(I)例舉之鹽類。
化合物(I)可呈結晶。具有單一結晶型或數種結晶型之混合物之結晶亦包括在化合物(I)內。可由化合物(I)依本身已知之結晶法進行結晶,得到晶體。
此外,化合物(I)可為醫藥上可接受之共晶體或共晶體鹽。此時,該共晶體及共晶體鹽係指由兩種或更多種分別具有不同物理性質(例如:結構、熔點、熔解熱、吸濕性、溶解度、安定性等)且在室溫下呈固體之特定物質組成之結晶物質。該共晶體及共晶體鹽可採用本身已知之共結晶法製得。
化合物(I)之結晶具有優異之物化性質(例如:熔點,溶解度、安定性)與生物性質(例如:藥物動力學(吸收性、分佈性、代謝性、排泄性)、效力表現),因此極適用為醫藥。
化合物(I)與其前藥(下文中有時候簡稱為本發明化合物)對GLP-1受體與GIP受體具有活化作用。
本發明化合物特定言之,對活體內GLP-1受體與GIP受體具有高度活化作用。
GLP-1與GIP為腸部激素,稱為腸泌素(incretin),具有促進胰臟分泌胰島素之作用。由於腸泌素
與葡萄糖代謝作用關係密切,因此對GLP-1受體與GIP受體具有活化作用之化合物即適用於預防或治療葡萄糖代謝相關病變之症狀,包括肥胖。
因此,本發明化合物具有壓抑攝食作用、抑制體重上升作用等。
此外,本發明化合物具有優異之溶解性。本發明化合物於水中之溶解度為1mg/mL或更高,更佳為10mg/mL或更高。
本發明化合物可使用作為GLP-1受體與GIP受體之活化劑(GLP-1受體/GIP受體共促效劑)。
本發明中,GLP-1受體與GIP受體之活化劑(GLP-1受體/GIP受體共促效劑)意指同時具有GLP-1受體-活化作用(GLP-1受體促效作用)與GIP受體-活化作用(GIP受體促效作用)之製劑。明確言之。GLP-1受體與GIP受體之活化劑(GLP-1受體/GIP受體共促效劑)意指其中對抗GLP-1受體之EC50與對抗GIP受體之EC50為1:20至20:1,較佳為1:5至5:1。
本發明化合物具有低度之升糖素受體-活化作用(升糖素受體促效劑),因此造成之降血糖作用低。本發明化合物針對升糖素受體之EC50相較於本發明化合物針對GLP-1受體或GIP受體之EC50,為1/1000或更低,較佳為1/10000或更低。
本發明化合物具有低毒性(例如:急性毒性、慢性毒性、遺傳毒性、生殖毒性、心臟毒性、致癌性),副
作用少,可安全投與哺乳動物(例如:人類、牛、馬、狗、貓、猴、小鼠、大鼠),作為預防或治療下述各種不同疾病等之藥劑。
本發明化合物基於上述對GLP-1受體與GIP受體之活化作用,而可作為治療或預防各種不同疾病(包括肥胖症)之藥劑使用。本發明化合物可作為藥劑使用,供預防或治療例如:症狀性肥胖、單純肥胖、與肥胖相關之病症或疾病、攝食異常、糖尿病(例如:1型糖尿病、2型糖尿病、妊娠糖尿病、肥胖糖尿病)、高血脂症(例如:高血三酸甘油酯、高血膽固醇、高血LDL-膽固醇、低血HDL膽固醇、餐後高血脂症)、高血壓、心臟衰竭、糖尿病併發症[例如:神經病變、腎病變、視網膜病變、糖尿病性心臟病變、白內障、大血管形成作用病變、骨質減少症、滲透過快糖尿病性昏迷、感染性疾病(例如:呼吸道感染、尿道感染、胃腸道感染、皮膚軟組織感染、下肢感染)、糖尿病性壞疽、口乾症、聽覺遲鈍、腦血管病變、周邊血管循環病變]、代謝症候群(出現選自下列3項或更多項之疾病狀態:高血三酸甘油酯(TG)、低血HDL膽固醇(HDL-C)、高血壓、腹部肥胖與葡萄糖耐量異常)、肌少症等。
症狀性肥胖實例包括內分泌型肥胖(例如:庫興氏症候群(Cushing syndrome)、甲狀腺機能不足、胰島素瘤、肥胖2型糖尿病、假性副甲狀腺機能不足、性腺機能不足)、中央型肥胖(例如:下視丘型肥胖、額葉症候群、克萊-李文症候群(Kleine-Levin syndrome))、遺傳型肥胖(例
如:普瑞德威利症候群(Prader-Willi syndrome)、性幼稚-色素性視網膜炎-多指(趾)畸形症候群(Laurence-Moon-Biedl syndrome))、藥物誘發型肥胖(例如:類固醇、吩噻(phenothiazine)、胰島素、磺醯脲(SU)劑、β-阻斷劑誘發之肥胖)等。
與肥胖有關之病症或疾病實例包括葡萄糖耐量病變、糖尿病(特定言之2型(type 2)糖尿病、肥胖型糖尿病)、脂肪代謝異常(與上述高血脂症為同義字)、高血壓、心臟衰竭、高血尿酸性痛風、脂肪肝(包括非酒精性脂肪肝炎)、冠心病(心肌梗塞、狹心症)、腦梗塞(腦栓塞、暫時性腦缺血發作)、骨/關節疾病(膝蓋骨關節炎、髖骨關節炎、變形性脊椎炎、腰痛)、睡眠呼吸暫停症候群/匹克威克症候群(Pickwick syndrome)、月經異常(月經週期異常、月經流量與週期異常、閉經、月經症狀異常)、代謝症候群等。
糖尿病之診斷標準可參見日本糖尿病學會(The Japan Diabetes Society)於1999年所報告之最新診斷標準。
依據此報告,糖尿病係指一種符合下列任一項之病症:空腹血中葡萄糖濃度(靜脈血漿中葡萄糖濃度)為126mg/dl或以上,75克口服葡萄糖耐量試驗(75g OGTT)之2小時數值(靜脈血漿中葡萄糖濃度)為200mg/dl或以上,及隨機血中葡萄糖濃度(靜脈血漿中葡萄糖濃度)為200mg/dl或以上。此外,未符合上述糖尿病症狀,但不處於
“空腹血中葡萄糖濃度(靜脈血漿中葡萄糖濃度)低於110mg/dl或75克口服葡萄糖耐量試驗(75g OGTT)之2小時數值(靜脈血漿中葡萄糖濃度)低於140mg/dl”(正常型)之狀態者稱為“邊緣型”。
此外,美國糖尿病學會(ADA)於1997年及世界衛生組織(WHO)於1998年之糖尿病診斷標準中提出新的診斷標準。
依據此等報告,糖尿病係指一種符合下列症狀之病症:空腹血中葡萄糖濃度(靜脈血漿中葡萄糖濃度)為126mg/dl或以上,或75克口服葡萄糖耐量試驗之2小時數值(靜脈血漿中葡萄糖濃度)為200mg/dl或以上。
依據上述報告,葡萄糖耐量異常係指一種符合下列症狀之病症:空腹血中葡萄糖濃度(靜脈血漿中葡萄糖濃度)低於126mg/dl,及75克口服葡萄糖耐量試驗之2小時數值(靜脈血漿中葡萄糖濃度)為140mg/dl或以上,但低於200mg/dl。依據ADA之報告,出現空腹血中葡萄糖濃度(靜脈血漿中葡萄糖濃度)為110mg/dl或以上,但低於126mg/dl之症狀稱為IFG(空腹葡萄糖異常)。另一方面,依據WHO之報告,IFG(空腹葡萄糖異常)症狀中,在75克口服葡萄糖耐量試驗中出現2小時數值(靜脈血漿中葡萄糖濃度)低於140mg/dl之症狀稱為IFG(空腹血糖異常)。
本發明化合物亦可使用作為預防或治療依據上述新的診斷標準所判斷之糖尿病、邊緣型糖尿病、葡萄糖耐量異常、IFG(空腹葡萄糖異常)與IFG(空腹血糖異
常)。此外,本發明化合物可防止邊緣型、葡萄糖耐量異常、IFG(空腹葡萄糖異常)或IFG(空腹血糖異常)。此外,本發明化合物可防止邊緣型、葡萄糖耐量異常、IFG(空腹葡萄糖異常)或IFG(空腹血糖異常)發展成糖尿病。
本發明化合物具有抑制體重增加之作用,因此可作為哺乳動物之體重增加抑制劑。可接受施用本發明化合物之哺乳動物可為任何希望避免體重增加之哺乳動物。該哺乳動物可為遺傳上有增加體重風險之哺乳動物,或可為受到生活型態影響而罹患如糖尿病,高血壓與/或高血脂症等疾病之哺乳動物。體重增加可能歸因於過量攝取食物或飲食不均衡,或體重增加可能源於併用之藥物(例如:具有類似PPARγ促效劑作用之胰島素敏化劑,如:曲格列酮(troglitazone)、羅格列酮(rosiglitazone)、英格列酮(englitazone)、希格列酮(ciglitazone)、皮利酮(pioglitazone)等)。或者,體重增加可能為達成肥胖之前之體重增加,或可能為肥胖患者之體重增加。此外,對肥胖之定義為日本人體質量指數(BMI:體重(kg)÷[身高(m)]2)為25或以上(依據日本肥胖研究學會(Japan Society for the Study of Obesity)標準),及西方人之BMI為30或以上(依據WHO之標準)。
本發明化合物亦適用於預防或治療代謝症候群。相較於罹患單一生活型態相關性疾病之患者,心血管疾病顯著高度發生在代謝症候群患者中。因此,代謝症候群之治療或預防對心血管疾病非常重要。
代謝症候群之診斷標準已由WHO於1999年及由
NCEP於2001公佈。依據WHO之診斷標準,患者之必要條件為罹患高血胰島素症或葡萄糖耐量異常,及以下兩項或更多項:內臟肥胖、血脂異常(高TG或低HDL)與高血壓,即診斷為罹患代謝症候群(世界衛生組織:糖尿病之定義,診斷與分類及其併發症。第一冊:糖尿病之診斷與分類(World Health Organization:Definition,Diagnosis and Classification of Diabetes Mellitus and Its Complications).Part I:Diagnosis and Classification of Diabetes Mellitus),日內瓦世界衛生組織,1999年(World Health Organization,Geneva,1999)]。依據美國之國家膽固醇教育計畫成人治療組第三小組(Adult Treatment Panel III of the National Cholesterol Education Program)之診斷標準(缺血性心臟病指南),罹患以下三項或更多項之個體即診斷為罹患代謝症候群:內臟肥胖、高血三酸甘油酯症、低血HDL-膽固醇症、高血壓與葡萄糖耐量異常(國家膽固醇教育計畫:國家膽固醇教育計畫(NCEP)對成人高血膽固醇之檢測、分析與治療專業小組之第三報告之執行概要(成人治療組第三小組)National Cholesterol Education Program:Executive Summary of the Third Report of National Cholesterol Education Program(NCEP)Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults(Adults Treatment Panel III))。The Journal of the American Medical Association,Vol.285,2486-2497,2001)。
本發明化合物亦可作為預防或治療例如以下
疾病之藥劑使用:骨質疏鬆症、惡病質(例如:癌性惡病質、結核性惡病質、糖尿病性惡病質、血液疾病相關惡病質、內分泌疾病相關惡病質、感染性疾病相關惡病質或因後天免疫缺乏症候群引起之惡病質)、脂肪肝、多囊性卵巢症候群、腎臟疾病(例如:慢性腎衰竭、糖尿病性腎病變、血管球性腎炎、血管球硬化、腎病變症候群、高血壓腎硬化、末期腎臟病)、肌肉營養不良、心肌梗塞、狹心症、腦血管病變(例如:腦梗塞、中風)、阿茲海默症、帕金森氏症、焦慮症、失智症、胰島素阻抗性症候群、X症候群、血中胰島素過高症、血中胰島素過高所誘發之感覺異常、急性或慢性下痢、炎症(例如:慢性類風濕關節炎、變形性脊椎炎、骨關節炎、腰痛、痛風、手術後或創傷後發炎、腫脹、神經痛、咽喉炎、膀胱炎、肝炎(包括非酒精性脂肪肝炎)、肺炎、胰炎、腸炎、發炎性腸部疾病(包括發炎性大疾病)、潰瘍性結腸炎、胃黏膜傷害(包括因阿斯匹靈引起之胃黏膜傷害)、小腸黏膜傷害、吸收不良、睪丸功能障礙、內臟肥胖症候群與肌少症。
此外,本發明化合物亦可作為預防或治療各種不同癌症之藥劑使用(特定言之,乳癌(例如:侵入性導管乳癌、非侵入性導管乳癌、炎性乳癌等)、攝護腺癌(例如:激素依賴性攝護腺癌、非激素依賴性攝護腺癌等)、胰臟癌(例如:胰導管癌等)、胃癌(例如:乳頭狀腺癌瘤、黏蛋白腺癌瘤、腺鱗狀癌等)、肺癌(例如:非小細胞肺癌、小細胞肺癌、惡性間皮瘤等)、結腸癌(例如:胃腸基底瘤
等)、直腸癌(例如:胃腸基底瘤等)、結腸直腸癌(例如:家族性結腸直腸癌、遺傳性非息肉結腸直腸癌、胃腸基底瘤等)、小腸癌(例如:非霍奇金氏淋巴瘤(non-Hodgkin’s lymphoma)、胃腸基底瘤等)、食道癌、十二指腸癌、舌癌、咽癌(例如:鼻咽癌、咽喉癌、下咽癌等)、唾液腺癌、腦瘤(例如:松果體星細胞瘤、毛囊性星細胞瘤、擴散性星細胞瘤、退行性星細胞瘤等)、神經鞘瘤、肝癌(例如:原生肝癌、肝外膽導管癌等)、腎臟癌(例如:腎細胞癌、腎盂與輸尿管移行性細胞癌等)、膽管癌、子宮內膜癌、子宮頸癌、卵巢癌症(例如:上皮卵巢癌、外生殖腺胚細胞腫瘤、卵巢胚細胞腫瘤、卵巢低惡性潛在腫瘤等)、膀胱癌、尿道癌、皮膚癌(例如:眼內(眼睛)黑色素瘤、梅克爾細胞癌(Merkel cell carcinoma)等)、血管瘤、惡性淋巴瘤、惡性黑色素瘤、甲狀腺癌(例如:髓狀甲狀腺癌等)、副甲狀腺癌、鼻腔癌、竇癌、骨腫瘤(例如:骨肉瘤、伊文氏腫瘤(Ewing tumor)、子宮肉瘤、軟組織肉瘤等)、血管纖維瘤、視網膜肉瘤、陰莖癌、睪丸腫瘤、兒童實體癌(例如:威爾姆氏腫瘤(Wilms’ tumor)、兒童腎腫瘤等)、卡波西肉瘤(Kaposi’s sarcoma)、AIDS引起之卡波西肉瘤、上頜竇腫瘤、纖維組織細胞瘤、子宮肌瘤、橫紋肌肉瘤、白血病(例如:急性骨髓性白血病、急性淋巴性白血病等)等)。
本發明化合物亦可用於二次預防或抑制上述各種不同疾病之發展(例如:心血管事件,如:心肌梗塞等)。此外,本發明化合物亦適用為攝食壓抑劑與體重增加
抑制劑。本發明化合物亦可組合採用膳食療法(例如:糖尿病之膳食療法),與運動療法。
包含本發明化合物之醫藥顯示低毒性,且可依據製造醫藥製劑時常用之本身已知方法(例如:日本藥典(Japanese Pharmacopoeia)說明之方法),由本發明化合物單獨使用或混合醫藥上可接受之載劑而製得,並可呈醫藥製劑,例如:錠劑(包括糖衣錠、膜衣錠、舌下錠、口中崩解錠)、粉劑、粒劑,膠囊(包括軟膠囊、微膠囊)、液體、糖錠、糖漿、乳液、懸浮液、注射劑(例如:皮下注射劑、靜脈內注射劑、肌內注射劑、腹膜內注射劑等)、外用藥劑(例如:穿鼻式製劑、皮膚製劑、油膏)、栓劑(例如:直腸栓劑、陰道栓劑)、丸劑、鼻用藥劑、肺用製劑(吸入劑)、輸液等安全地經口或非經腸式投藥(例如:局部、經直腸、經靜脈內投藥)。
此等製劑可為控制釋放製劑,如:快速釋放性製劑、持續釋放性製劑等(例如:持續釋放性微膠囊)。
醫藥製劑中之本發明化合物含量佔總製劑約0.01-約100重量%。
上述醫藥上可接受之載劑實例為常用為製備原料之各種不同有機或無機載劑材料,例如:用於固態製劑之賦形劑、潤滑劑、結合劑及崩解劑;或用於液態製劑之溶劑、溶解劑、懸浮劑、等滲劑、緩衝劑、及舒緩劑等。此外,若需要時,亦可適當使用適量之一般添加劑,如:防腐劑、抗氧化劑、著色劑、甜味劑、吸附劑、濕化劑等。
賦形劑實例包括:乳糖、蔗糖、D-甘露糖醇、澱粉、玉米澱粉、結晶纖維素、輕質無水矽酸等。
潤滑劑實例包括硬脂酸鎂、硬脂酸鈣、滑石、膠體矽石等。
結合劑實例包括結晶纖維素、蔗糖、D-甘露糖醇、糊精、羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯吡咯啶酮、澱粉、蔗糖、明膠、甲基纖維素、羧甲基纖維素鈉等。
崩解劑實例包括:澱粉、羧甲基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、L-羥基丙基纖維素等。
溶劑實例包括注射用水、醇類、丙二醇、聚乙二醇、芝麻油、玉米油、橄欖油等。
溶解劑實例包括聚乙二醇、丙二醇、D-甘露糖醇、苯甲酸苯甲基酯、乙醇、參胺基甲烷、膽固醇、三乙醇胺、碳酸鈉、檸檬酸鈉等。
懸浮劑實例包括:界面活性劑,如:硬脂基三乙醇胺、月桂基硫酸鈉、月桂基胺基丙酸、卵磷脂、氯芐烷銨、氯化芐乙氧銨、單硬脂酸甘油酯等;親水性聚合物,如:聚乙烯基醇、聚乙烯基吡咯啶酮、羧甲基纖維素鈉、甲基纖維素、羥基甲基纖維素、羥基乙基纖維素、羥基丙基纖維素等;等等。
等滲劑實例包括:葡萄糖、D-山梨糖醇、氯化鈉、甘油、D-甘露糖醇等。
緩衝劑實例包括:緩衝液,如:磷酸鹽、乙
酸鹽、碳酸鹽、檸檬酸鹽等。
舒緩劑實例包括苯甲基醇等。
防腐劑實例包括對羥基苯甲酸酯、氯丁醇、苯甲基醇、苯乙基醇、去氫乙酸、山梨酸等。
抗氧化劑實例包括:亞硫酸鹽、抗壞血酸、α-生育酚等。
著色劑實例包括:水溶性食用焦油色素(例如:食用色素,如:食用色素紅色2號與3號、食用色素黃色4號與5號、食用色素藍色1號與2號等)、水不溶性色澱色素(例如:上述水溶性食用焦油色素之鋁鹽)、天然色素(例如:β-胡蘿蔔素、葉綠素、紅色氧化鐵)等。
甜味劑實例包括:糖精鈉、甘草酸二鉀鹽、阿斯巴甜、甜菊精等。
吸附劑實例包括多孔澱粉、矽酸鈣(商標名稱:Florite RE)、偏矽酸鎂鋁(商標名稱:Neusilin)與輕質無水矽酸(商標名稱:Sylysia)。
濕化劑實例包括丙二醇單硬脂酸酯、山梨糖醇酐單油酸酯、二乙二醇單月桂酸酯與聚氧乙烯月桂基醚。
製備口服製劑期間,可能為了遮蔽味道、腸溶性質或持久性之目的而需要包覆包衣。
用於包覆之包衣基質實例包括:糖衣基質、水性膜衣基質、腸溶性膜衣基質與持續釋放性膜衣基質。
可使用蔗糖作為糖衣基質。此外,可以組合使用選自下列之一或多種物質:滑石、沉澱碳酸鈣、明膠、
阿拉伯膠、普魯蘭多糖(pullulan)、巴西棕櫚蠟等。
水性膜衣基質實例包括纖維素聚合物、羥丙基纖維素、羥丙基甲基纖維素、羥乙基纖維素、甲基羥乙基纖維素等;合成性聚合物,如:聚乙烯縮醛二乙基胺基乙酸酯、甲基丙烯酸胺基烷基酯共聚物E[Eudragit E(商標名稱)]、聚乙烯吡咯啶酮等;多醣類,如:普魯蘭多糖等。
腸溶性膜衣基質實例包括纖維素聚合物,如:羥丙基甲基纖維素酞酸酯、羥丙基甲基纖維素乙酸酯琥珀酸酯、羧甲基乙基纖維素、纖維素乙酸酯酞酸酯等;丙烯酸聚合物,如:甲基丙烯酸共聚物L[Eudragit L(商標名稱)]、甲基丙烯酸共聚物LD[Eudragit L-30D55(商標名稱)]、甲基丙烯酸共聚物S[Eudragit S(商標名稱)]等;天然產物,如:蟲膠等。
持續釋放性膜衣基質實例包括纖維素聚合物,如:乙基纖維素等;與丙烯酸聚合物,如:甲基丙烯酸胺基烷基酯共聚物RS[Eudragit RS(商標名稱)]、丙烯酸乙酯-甲基丙烯酸甲酯共聚物懸浮液[Eudragit NE(商標名稱)]等。
上述包衣基質可在依適當比例混合其中兩種或更多種以後才使用。該包衣可以使用例如:遮光劑,如:氧化鈦、紅色氧化鐵等。
本發明化合物之劑量係隨投藥對象、症狀、投藥方法等適當決定。例如:當本發明化合物經口投與肥胖或糖尿病患者(體重60kg)時,本發明化合物之日劑量為
約0.1至100mg,較佳約1.0至50mg,更佳約1.0至20mg。當本發明化合物依非經腸式投與肥胖或糖尿病患者(體重60kg)時,本發明化合物之日劑量為約0.01至30mg,較佳為約0.1至20mg,更佳為約0.5至10mg。此等用量可在一天內分成約1至數小份投藥。
本發明化合物可以例如:每天(一天一次、一天兩次、一天三次、一天四次、一天五次、一天六次)、每2天、每3天、每4天、每5天、每6天、每週、每週2次、每隔一週、每3週、每個月、每2個月、每3個月、每4個月、每5個月或每6個月投藥。
本發明化合物可組合使用其他不會負面影響本發明化合物之藥物,以供例如:促進本發明化合物之效用(治療肥胖、糖尿病等之效用)、降低本發明化合物之劑量等。
可與本發明化合物組合使用之藥物(下文中簡稱併用藥物)實例包括:抗肥胖劑、糖尿病醫療劑、糖尿病併發症醫療劑、高血脂症醫療劑、抗高血壓劑、利尿劑、化療劑、免疫醫療劑、消炎劑、抗血栓劑、骨質疏鬆症醫療劑、維生素、抗失智症藥物、勃起功能障礙藥物、頻尿或尿失禁之醫療劑、排尿困難之醫療劑等。併用藥物之明確實例包括彼等下文說明者。
抗肥胖劑實例包括單胺吸收抑制劑(例如:吩特明(phentermine)、希特胺(sibutramine)、麻辛得(mazindol)、弗歐辛(fluoxetine)、特弗辛(tesofensine))、血
清素2C受體促效劑(例如:樂卡色林(lorcaserin))、血清素6受體擷抗劑、組織胺H3受體調控劑、GABA調控劑(例如:妥泰(topiramate))、神經肽Y擷抗劑(例如:韋利貝特(velneperit))、類大麻酚受體擷抗劑(例如:利莫納班(rimonabant)、塔拉那班(taranabant))、生長素釋質擷抗劑、生長素釋質受體擷抗劑、生長素釋質醯化酵素抑制劑、類鴉片受體擷抗劑(例如:GSK-1521498)、食慾素受體擷抗劑、黑皮質素4受體促效劑、11β-羥基類固醇去氫酶抑制劑(例如:AZD-4017)、胰脂酶抑制劑(例如:羅氏鮮(orlistat)、新利司他(cetilistat))、β3促效劑(例如:N-5984)、二醯基甘油醯基轉移酶1(DGAT1)抑制劑、乙醯基-CoA羧化酶(ACC)抑制劑、硬脂醯基-CoA脫飽和酶抑制劑、微粒體三酸甘油酯轉移蛋白質抑制劑(例如:R-256918)、鈉-葡萄糖共轉運體抑制劑(例如:JNJ-28431754、利莫格列(remogliflozin))、NF κ抑制劑(例如:HE-3286)、PPAR促效劑(例如:GFT-505、DRF-11605)、磷酸酪胺酸磷酸酶抑制劑(例如:釩酸鈉、曲度奎明(Trodusquemin))、GPR119促效劑(例如:PSN-821、MBX-2982、APD597)、葡糖激酶活化劑(例如:AZD-1656)、瘦體素、瘦體素衍生物(例如:美曲普汀(metreleptin))、CNTF(睫狀神經營養因子)、BDNF(腦部衍生之神經營養因子)、膽囊收縮素促效劑、澱粉狀蛋白質製劑(例如:普利肽(pramlintide)、AC-2307)、神經肽Y促效劑(例如:PYY3-36、PYY3-36之衍生物、奧尼匹肽(obinepitide)、TM-30339、TM-30335)、調酸素製劑:
FGF21製劑(例如:自牛或豬之胰臟中萃取之動物FGF21製劑;採用大腸桿菌(EscherichiColi)或酵母經過遺傳工程合成之人類FGF21製劑;FGF21之片段或衍生物)、食慾抑制劑(例如:P-57)等。
此時,糖尿病之醫療劑實例可述及:胰島素製劑(例如:自牛或豬之胰臟中萃取之動物胰島素製劑;採用大腸桿菌(EscherichiColi)或酵母基因合成之人類胰島素製劑;鋅胰島素;魚精蛋白鋅胰島素;胰島素之片段或衍生物(例如:INS-1)、口服胰島素製劑)、胰島素敏化劑(例如:皮利酮(pioglitazone)或其鹽(較佳為鹽酸鹽)、羅格列酮(rosiglitazone)或其鹽(較佳為馬來酸鹽)、美塔利索(Metaglidasen)、AMG-131、巴格列酮(Balaglitazone)、MBX-2044、利弗塔松(Rivoglitazone)、阿格列紮(Aleglitazar)、奇格列紮(Chiglitazar)、樂利塔松(Lobeglitazone)、PLX-204、PN-2034、GFT-505、THR-0921、說明於WO2007/013694、WO2007/018314、WO2008/093639或WO2008/099794之化合物)、α-糖苷酶抑制劑(例如:弗格布斯(voglibose)、阿卡布斯(acarbose)、米格利特(miglitol)、恩格利特(emiglitate))、雙胍類(例如:二甲雙胍(metformin)、丁雙胍(buformin)或其鹽類(例如:鹽酸鹽、富馬酸鹽、琥珀酸鹽))、促胰島素分泌劑(例如:磺醯脲類(例如:特本醯胺(tolbutamide)、格本醯胺(glibenclamide)、格賽(gliclazide)、氯丙醯胺(chlorpropamide)、特賽醯胺(tolazamide)、乙醯己醯胺(acetohexamide)、糖普醯胺
(glyclopyramide)、格皮理得(glimepiride)、格比賽得(glipizide)、格佈唑(glybuzole))、拉普格林奈(repaglinide)、納格奈(nateglide)、米格奈(mitiglinide)或其鈣鹽水合物)、二肽基肽酶IV抑制劑(例如:阿格列汀(Alogliptin)或其鹽類(較佳係苯甲酸鹽)、維格利平(Vildagliptin)、西塔利平(Sitagliptin)、賽格利平(Saxagliptin)、BI1356、GRC8200、MP-513、PF-00734200、PHX1149、SK-0403、ALS2-0426、TA-6666、TS-021、KRP-104、曲格列汀(Trelagliptin)或其鹽(較佳係琥珀酸鹽))、β3促效劑(例如:N-5984)、GPR40促效劑(例如:法格利芬(Fasiglifam)或其水合物、說明於WO2004/041266、WO2004/106276、WO2005/063729、WO2005/063725、WO2005/087710、WO2005/095338、WO2007/013689或WO2008/001931之化合物)、SGLT2(鈉-葡萄糖共運輸體2)抑制劑(例如:達格列(Depagliflozin)、AVE2268、TS-033、YM543、TA-7284、利莫格列(Remogliflozin)、ASP1941)、SGLT1抑制劑、11β-羥基類固醇去氫酶抑制劑(例如:BVT-3498、INCB-13739)、脂聯素或其促效劑、IKK抑制劑(例如:AS-2868)、改善瘦體素抗性之藥物、生長抑素受體促效劑、葡萄糖激酶活化劑(例如:吡格列汀(Piragliatin)、AZD1656、AZD6370、TTP-355、說明於WO006/112549、WO007/028135、WO008/047821、WO008/050821、WO008/136428或WO008/156757之化合物)、GPR119促效劑(例如:PSN821、MBX-2982、APD597)、FGF21、FGF類似物、ACC2抑制劑等。
糖尿病併發症之醫療劑可述及:醛糖還原酶抑制劑(例如:特洛抑制劑(tolrestat)、依帕抑制劑(epalrestat)、索普抑制劑(zopolrestat)、菲達抑制劑(fidarestat)、CT-112、阮利斯特(ranirestat)(AS-3201)、利多司他(lidorestat))、趨神經因子與其促進藥劑(例如:NGF、NT-3、BDNF、說明於WO01/14372之神經營養素製造/分泌促進劑(例如:4-(4-氯苯基)-2-(2-甲基-1-咪唑基)-5-[3-(2-甲基苯氧基)丙基]唑)、說明於WO2004/039365之化合物)、PKC抑制劑(例如:洛新斯靈(ruboxistaurin)甲磺酸鹽)、AGE抑制劑(例如:ALT946、N-苯醯甲基噻唑鎓溴化物(ALT766)、EXO-226、吡哚靈(Pyridorin)、吡哆胺(pyridoxamine))、GABA受體促效劑(例如:加巴噴汀(gabapentin)、普瑞巴林(pregabalin))、血清素與正腎上腺素再吸收抑制劑(例如:度洛西汀(duloxetine))、鈉通道抑制劑(例如:拉克醯胺(lacosamide))、活性氧清除劑(例如:硫辛酸)、腦血管鬆弛劑(例如:特普瑞(tiapride)、美樂汀(mexiletine))、生長抑素受體促效劑(例如:BIM23190)、細胞凋亡訊號調節激酶-1(ASK-1)抑制劑等。
高血脂症醫療劑可述及:HMG-CoA還原酶抑制劑(例如:普瓦抑制素(pravastatin)、辛瓦抑制素(simvastatin)、洛瓦抑制素(lovastatin)、亞特瓦抑制素(atorvastatin)、弗瓦抑制素(fluvastatin)、斯瓦抑制素(rosuvastatin)、皮特抑制素(pitavastatin)或其鹽類(例如:鈉鹽、鈣鹽))、鯊烯合成酶抑制劑(例如:說明於WO97/10224
之化合物,例如:N-[[(3R,5S)-1-(3-乙醯氧基-2,2-二甲基丙基)-7-氯-5-(2,3-二甲氧基苯基)-2-側氧基-1,2,3,5-四氫-4,1-苯并吖呯-3-基]乙醯基]哌啶-4-乙酸)、纖維酸酯(fibrate)化合物(例如:苯纖維酸酯(bezafibrate)、克洛纖維酸酯(clofibrate)、辛弗纖維酸酯(simfibrate)、克諾纖維酸酯(clinofibrate))、陰離子交換樹脂(例如:消膽胺等)、普羅布考(probucol)、菸酸藥物(例如:尼克莫(nicomol)、尼賽特洛(niceritrol)、尼斯本(niaspan))、二十五碳酸乙酯、植物固醇(例如:大豆固醇、γ-穀維素)、膽固醇吸收抑制劑(例如:益適純(zechia))、CETP抑制劑(例如:達塞曲匹(dalcetrapib)、安塞達匹(anacetrapib))、ω-3脂肪酸製劑(例如:ω-3-脂肪酸乙酯90(ω-3-酸乙酯90)等。
抗高血壓劑實例包括:血管收縮素轉化酵素抑制劑(例如:卡特利(captopril)、安拉普(enalapril)、狄拉普(delapril)等)、血管收縮素II擷抗劑(例如:博脈舒(candesartan cilexetil)、甘達斯丹(candesartan)、咯斯丹(losartan)、咯斯丹鉀、抑普斯丹(eprosartan)、法斯丹(valsartan)、特美斯丹(telmisartan)、抑斯丹(irbesartan)、塔索斯丹(tasosartan)、奧美沙坦(olmesartan)、奧美沙坦酯(olmesartan medoxomil)、艾利沙坦(azilsartan)、艾利沙坦酯(azilsartan medoxomil)等)、鈣擷抗劑(例如:曼得平(manidipine)、吩得平(nifedipine)、默得平(amlodipine)、抑得平(efonidipine)、尼克得平(nicardipine)、西尼地平(cilnidipine)等)、β阻斷劑(例如:美托洛爾(metoprolol)、壓
平樂(atenolol)、心得安(propranolol)、卡菲蒂樂(carvedilol)、心得樂(pindolol)等)、可樂定(clonidine)等。
利尿劑實例可述及:黃嘌呤素衍生物(例如:可可鹼水楊酸鈉、可可鹼水楊酸鈣等)、噻類製劑(例如:乙噻(ethia zide)、環戊噻(cyclopenthiazide)、三氯甲基噻(trichloromethyazide)、氫氯噻(hydrochlorothiazide)、氫氟噻(hydroflumethiazide)、苯甲基氫氯噻、戊氟噻(penflutizide)、聚噻(polythiazide)、甲基氯噻(methyclothiazide)等)、抗醛固酮製劑(例如:螺旋內酯固醇(spironolactone)、胺苯蝶啶(triamterene)等)、碳酸脫水酶抑制劑(例如:乙醯唑醯胺(acetazolamide)等)、氯苯磺醯胺製劑(例如:氯塔酮(chlortalidone)、美弗賽(mefruside)、印達醯胺(indapamide)等)、唑噻醯胺(azosemide)、異色普(isosorbide)、伊塔酸(ethacrynic acid)、普丹奈(piretanide)、布丹奈(bumetanide)、弗色胺(furosemide)等
化療劑實例包括烷化劑(例如:環磷醯胺、抑弗醯胺(ifosfamide))、抗代謝劑(例如:胺甲蝶呤、5-氟尿嘧啶)、抗癌抗生素(例如:絲裂黴素(mitomycin)、亞德理亞黴素(adriamycin))、植物衍生之抗癌劑(例如:長春新鹼(vincristine)、長春地辛(vindesine)、紫杉醇)、順鉑(cisplatin)、卡鉑(carboplatin)、依托泊苷(etoposide)等。其中,以5-氟尿嘧啶衍生物之弗特隆(Furtulon)與新弗特隆(Neofurtulon)等較佳。
免疫醫療劑實例包括:微生物或細菌性成分
(例如:胞壁醯基二肽衍生物、比班尼(Picibanil))、具有加強免疫活性之多醣(例如:香菇多醣、西佐糖(sizofiran)、雲芝多醣(Krestin))、利用遺傳工程技術得到之細胞素(例如:干擾素、間白素(IL))、群落刺激因子(例如:粒細胞群落刺激因子、促紅血球生成素)等。其中較佳為間白素,如:IL-1、IL-2、IL-12等。
消炎藥實例包括:非類固醇消炎藥,如:阿斯匹靈、乙醯胺酚、吲哚美辛(indomethacin)與其類似物。
抗血栓劑可述及例如:肝素(例如:肝素鈉、肝素鈣、依諾肝素(enoxaparin)鈉、達普林(dalteparin)鈉)、丙酮苄羥香豆素(warfarin)(例如:丙酮苄羥香豆素鉀)、抗凝血酶藥物(例如:亞拉格本(aragatroban)、達比加群(dabigatran))、FXa抑制劑(例如:利伐沙班(rivaroxaban))、阿哌沙班(apixaban)、依杜沙班(edoxaban)、YM150、說明於WO02/06234、WO2004/048363、WO2005/030740、WO2005/058823或WO2005/113504之化合物)、溶血栓劑(例如:尿激酶、組織型纖維蛋白溶酶原激活劑(tisokinase)、阿替普酶(alteplase)、奈普激酶(nateplase)、蒙普激酶(monteplase)、本米激酶(pamiteplase))、血小板凝集抑制劑(例如:狄克啶(ticlopidine)鹽酸鹽、氯吡格雷(clopidogrel)、普拉格雷(prasugrel)、E5555、SHC530348、西咯唑(cilostazol)、二十五碳酸乙酯、布拉斯特鈉(beraprost sodium)、沙普格(sarpogrelate)鹽酸鹽)等。
骨質疏鬆症之醫療劑實例包括:α-骨化二
醇(alfacalcidol)、骨化二醇(calcitriol)、抑特寧(elcatonin)、鮭魚降鈣素(calcitonin salmon)、雌三醇、抑普黃酮(ipriflavone)、帕米酸二鈉(pamidronate disodium)、亞忍卓酸(alendronate)鈉水合物、英康卓忍酸(incadronate)二鈉、利塞膦酸(risedronate)二鈉等。
維生素實例包括:維生素B1、維生素B12與其類似物。
抗失智症藥物實例包括:他克林(tacrine)、丹普齊(donepezil)、理法斯明(rivastigmine)、加蘭他敏(galanthamine)等。
勃起功能障礙藥物實例包括:阿朴嗎啡(apomorphine)、希丹菲(sildenafil)檸檬酸鹽等。
頻尿或尿失禁之醫療藥物實例包括:黃酮派酯(flavoxate)鹽酸鹽、羥丁寧(oxybutynin)鹽酸鹽、普咯菲林(propiverine)鹽酸鹽等。
排尿困難之醫療劑實例包括:乙醯基膽鹼酯酶抑制劑(例如:狄斯明(distigmine))等。
此外,在動物模式或臨床上已確定具有改善惡病質作用之藥物,亦即:環氧化酶抑制劑(例如:吲哚美辛(indomethacin))、黃體酮衍生物(例如:甲地孕酮(megesterol)乙酸鹽)、葡萄糖類固醇(例如:地塞美松(dexamethasone))、甲氧氯普胺(metoclopramide)藥物、四氫類大麻酚藥物、改善脂肪代謝之藥劑(例如:二十五碳烯酸)、生長激素、IGF-1或針對誘發惡病質因子(如:TNF-α、
LIF、IL-6、恩康抑制素(Oncostatin M))之抗體,或其類似物,亦可與本發明化合物組合使用。
或者,本發明化合物可組合使用糖化抑制劑(例如:ALT-711)、促進神經再生之藥物(例如:Y-128、VX853、普賽肽(prosaptide))、抗抑鬱劑(例如:去甲基丙咪(desipramine)、阿米替林(amitriptyline)、丙咪(imipramine))、抗癲癇藥(例如:拉莫三(lamotrigine)、參利帕(Trileptal)、克帕(Keppra)、佐能安(Zonegran)、普瑞巴林(Pregabalin)、赫考賽(Harkoseride)、卡馬西平(carbamazepine))、抗心律不整藥物(例如:美西律(mexiletine))、乙醯膽鹼受體配體(例如:ABT-594)、內皮肽受體擷抗劑(例如:ABT-627)、單胺吸收抑制劑(例如:曲馬朵(tramadol))、麻醉性止痛劑(例如:嗎啡)、GABA受體促效(例如:加巴噴汀(gabapentin)、加巴噴汀之MR製劑)、α2受體促效(例如:可樂定(clonidine))、局部止痛劑(例如:辣椒素(capsaicin))、抗焦慮藥物(例如:苯并氮呯(benzothiazepine))、磷酸二酯酶抑制劑(例如:希丹菲(sildenafil))、多巴胺受體促效劑(例如:阿朴嗎啡(apomorphine))、咪達唑侖(midazolam)、酮康唑(ketoconazole)或其類似物。
本發明化合物及併用藥物之投藥時間沒有特別限制,且其等可同時投藥或依序投藥給個體。
此投藥模式實例包括下列:(1)由本發明化合物及併用藥物同時製成單一製劑後
投藥,(2)由本發明化合物及併用藥物分開製造之兩種製劑依相同投藥途徑同時投藥,(3)由本發明化合物及併用藥物分開製造之兩種製劑依相同投藥途徑依序投藥,(4)由本發明化合物及併用藥物分開製造之兩種製劑依不同投藥途徑同時投藥,(5)由本發明化合物及併用藥物分開製造之兩種製劑依不同投藥途徑依序投藥(例如:先投與本發明化合物後再投與併用藥物,或依相反順序投藥),及其類似方式。
併用藥物之劑量可依據臨床狀態之使用劑量適當決定。本發明化合物與併用藥物之混合比例可依據投藥對象、症狀、投藥方法、目標疾病、組合等決定。當投藥對象為例如:人類時,該併用藥物相對於每一份本發明化合物重量比之用量為0.01-100份重量比。
組合本發明化合物與併用藥物時,可達成:(1)本發明化合物或併用藥物之劑量可比單獨投與本發明化合物或併用藥物時降低,(2)可依據患者之症狀(中度症狀、嚴重症狀等),選擇可與本發明化合物組合使用之藥物,(3)藉由選擇具有與本發明化合物不同之作用及機轉之併用藥物,可以延長治療期;(4)藉由選擇具有與本發明化合物不同之作用及機轉之併用藥物,可以設計持續之治療效果;及(5)藉由組合使用本發明化合物與併用藥物等,可達到增效性效果。
本說明書所使用之縮寫之定義如下(表1-1與表1-2)。如本文所說明用於如:α-MePhe等術語中之連字符號可以省略,且省略結果仍代表相同定義。
本說明書中,若鹼基、胺基酸等以其代碼表示時,其係依據IUPAC-IUB生化命名學會(IUPAC-IUB Commission on Biochemical Nomenclature)之慣用代碼或相關技藝上之常用代碼表示,其實例如下。若胺基酸具有光學異構物時,除非另有說明,否則係以L-型表示(例如:”Ala”為L-型Ala)。此外,”D-”意指D-型(例如:”D-Ala”為D-型Ala),及”DL-”意指D-型與L-型之消旋物(例如:”DL-Ala”為Ala之DL消旋物)。
TFA:三氟乙酸
Gly或G:甘胺酸
Ala或A:丙胺酸
Val或V:纈胺酸
Leu或L:白胺酸
Ile或I:異白胺酸
Ser或S:絲胺酸
Thr或T:蘇胺酸
Cys或C:半胱胺酸
Met或M:甲硫胺酸
Glu或E:麩胺酸
Asp或D:天冬胺酸
Lys或K:離胺酸
Arg或R:精胺酸
His或H:組胺酸
Phe或F:苯基丙胺酸
Tyr或Y:酪胺酸
Trp或W:色胺酸
Pro或P:脯胺酸
Asn或N:天冬醯胺
Gln或Q:麩醯胺
pGlu:焦麩胺酸
α-MeTyr:α-甲基酪胺酸
本發明於下文中藉由下列參考例、實例、試驗例與調配例詳細說明,但並未構成限制。此外,本發明可在不偏離本發明範圍內進行修飾。
下列實例中之術語“室溫”係指一般約10℃至約35℃之範圍。產率之“%”為莫耳/莫耳%,層析法所使用溶劑係以體積%表示,其他“%”則為重量%。
THF:四氫呋喃
DMF:N,N-二甲基甲醯胺
WSC:1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽
HOBt:1-羥基苯并三唑單水合物
參考例1
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(SEQ ID NO:10)之合成
取Sieber醯胺樹脂(0.69meq/g,362mg)加至反應管中,然後安裝至肽合成儀中。依據Fmoc/DCC/HOBt製程依序縮合胺基酸。在最後步驟中,脫除N-末端Fmoc基團。縮合結束後,使用MeOH洗滌樹脂,及減壓乾燥。結果得到1025mg(0.244meq/g)所需之受保護之肽樹脂。
參考例2
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)- Sieber醯胺樹脂(SEQ ID NO:11)之合成
取Sieber醯胺樹脂(0.69meq/g,362mg)加至反應管中,然後安裝至肽合成儀中。依據Fmoc/DCC/HOBt製程依序縮合胺基酸。在最後步驟中,脫除N-末端Fmoc基團。縮合結束後,使用MeOH洗滌樹脂,及減壓乾燥。結果得到1331mg(0.188meq/g)所需之受保護之肽樹脂。
參考例3
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro
-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(SEQ ID NO:12)之合成
取Sieber醯胺樹脂(0.61meq/g,410mg)加至反應管中,然後安裝至肽合成儀中。依據Fmoc/DCC/HOBt製程依序縮合胺基酸。進行雙重偶聯,以便引進18-位置與20-位置之Ala與19-位置之Gln(Trt)。在最後步驟中,脫除N-末端Fmoc基團。縮合結束後,使用MeOH洗滌樹脂,及減壓乾燥。結果得到1110mg(0.225meq/g)所需之受保護之肽樹脂。
實例1
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:13)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.244meq/g,41.0mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M OxymaPure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗(Kaiser test)中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再
次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生83mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在83mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生22.5mg之白色粉末。
質譜(M+H)+ 4267.4(計算值:4267.2)
HPLC溶離時間:7.1min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例2
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:14)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.244meq/g,41.0mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合
-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生84.5mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在84.5mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生21.5mg之白色粉末。
質譜(M+H)+ 4281.5(計算值:4281.2)
HPLC溶離時間:7.2min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例3
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:15)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.244meq/g,41.0mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ser(tBu)-OH(38.3mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、
Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生73.3mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在73.3mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生17.1mg之白色粉末。
質譜(M+H)+ 4283.6(計算值:4283.2)
HPLC溶離時間:7.1min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6
mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例4
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:16)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.244meq/g,41.0mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ser(tBu)-OH(38.3mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、
Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生63mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在63mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:64/36-54/46線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生14.7mg之白色粉末。
質譜(M+H)+ 4297.8(計算值:4297.2)
HPLC溶離時間:7.2min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例5
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:17)之合成
秤取參考例2製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂(0.188meq/g,53.2mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然
後減壓乾燥,產生97mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂。
在97mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:63/37-53/47線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生25.2mg之白色粉末。
質譜(M+H)+ 4139.2(計算值:4139.1)
HPLC溶離時間:7.3min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例6
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:18)之合成
秤取參考例2製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂(0.188meq/g,53.2mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生78.1mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-S
er(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂。
在78.1mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:63/37-53/47線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生18.4mg之白色粉末。
質譜(M+H)+ 4152.9(計算值:4153.1)
HPLC溶離時間:7.4min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例7
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:19)之合成
秤取參考例2製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂(0.188meq/g,53.2mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ser(tBu)-OH(38.3mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL,0.1mmol)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Ala、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生87mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys
(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂。
在87mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生17mg之白色粉末。
質譜(M+H)+ 4154.8(計算值:4155.1)
HPLC溶離時間:7.3min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例8
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe-Val-Lys-Trp-Le
u-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:20)之合成
秤取參考例2製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂(0.188meq/g,53.2mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ser(tBu)-OH(38.3mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生76.8mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂。
在76.8mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:63/37-53/47線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生16.6mg之白色粉末。
質譜(M+H)+ 4169.2(計算值:4169.1)
HPLC溶離時間:7.4min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例9
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:21)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、Aib、Lys(Boc)、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生72.4mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在72.4mg所得樹脂中添加1mL TFA:間甲
酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:67/33-57/43線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生13.9mg之白色粉末。
質譜(M+H)+ 4295.8(計算值:4296.2)
HPLC溶離時間:6.9min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例10
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ala-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:22)之合成
秤取參考例3製備之
H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、Aib、Ala、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生86.1mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ala-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在86.1mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應
溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:66/34-56/44線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生16.2mg之白色粉末。
質譜(M+H)+ 4238.6(計算值:4239.2)
HPLC溶離時間:7.1min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例11
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Phe-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:23)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro
-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、Aib、Phe、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生76.4mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Phe-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在76.4mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾
去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生4.7mg之白色粉末。
質譜(M+H)+ 4315.1(計算值:4315.2)
HPLC溶離時間:7.2min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例12
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Pya(4)-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:24)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,
依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、Aib、Pya(4)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)**、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:在縮合期間添加17.4μL DIPEA;**:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生78.4mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Pya(4)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在78.4mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾
去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:67/33-57/43線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生15.2mg之白色粉末。
質譜(M+H)+ 4316.2(計算值:4316.2)
HPLC溶離時間:6.9min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例13
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-αMePhe-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:25)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,
依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、αMePhe、Ile、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生69.1mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-αMePhe-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在69.1mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x
20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:64/36-54/46線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生14.4mg之白色粉末。
質譜(M+H)+ 4356.9(計算值:4357.3)
HPLC溶離時間:7.4min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例14
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Cha-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:26)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之
DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、Cha、Ile、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生71.5mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Cha-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在71.5mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:63/37-53/47
線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生16mg之白色粉末。
質譜(M+H)+ 4348.7(計算值:4349.3)
HPLC溶離時間:7.5min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例15
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-αMePhe-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:27)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使
用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、αMePhe、Lys(Boc)、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生77.9mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-αMePhe-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在77.9mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,
並冷凍乾燥,產生13.4mg之白色粉末。
質譜(M+H)+ 4371.7(計算值:4372.3)
HPLC溶離時間:7.1min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例16
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Cha-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:28)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添
加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、Cha、Lys(Boc)、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生75.1mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Cha-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在75.1mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生14.7mg之白色粉末。
質譜(M+H)+ 4364.7(計算值:4364.3)
HPLC溶離時間:7.1min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例17
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-αMeTyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:29)之合成
秤取參考例3製備之H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.225meq/g,44.4mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶
液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Lys(Boc)、Asp(OtBu)、Leu、αMeTyr、Ile、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生56.2mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-αMeTyr-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在56.2mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:65/35-55/45線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生1.4mg之白色粉末。
質譜(M+H)+ 4373.8(計算值:4373.2)
HPLC溶離時間:7.2min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例18
Ac-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:30)之合成
秤取類似參考例1之方法製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.253meq/g,39.5mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,
然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。隨後使用哌啶處理,脫除N-末端Fmoc基團,然後依序添加DMF(200μL),DIPEA(17.4μL)與Ac2O(9.4μL)至樹脂中,並將混合物振盪90分鐘。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,使用MeOH洗滌樹脂,及減壓乾燥,產生43mg之Ac-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在43mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:62/38-52/48線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,
產生7.8mg之白色粉末。
質譜(M+H)+ 4323.4(計算值:4323.2)
HPLC溶離時間:7.5min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例19
苯甲醯基-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:31)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.253meq/g,39.5mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6
次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。隨後,使用哌啶處理,脫除N-末端Fmoc基團,然後依序添加苯甲酸(12.2mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,混合物振盪一夜。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,使用MeOH洗滌樹脂,然後減壓乾燥,產生54.8mg之苯甲醯基-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在54.8mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾
去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:60/40-50/50線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生10.1mg之白色粉末。
質譜(M+H)+ 4385.2(計算值:4385.2)
HPLC溶離時間:7.7min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例20
4PyCO-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:32)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.253meq/g,39.5mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加
Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。隨後,使用哌啶處理,脫除N-末端Fmoc基團,然後依序添加4-吡啶羧酸(12.3mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,混合物振盪一夜。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,使用MeOH洗滌樹脂,然後減壓乾燥,產生62.9mg之4PyCO-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在62.9mg所得樹脂中添加1mL TFA:間甲
酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:62/38-52/48線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生13.3mg之白色粉末。
質譜(M+H)+ 4386.2(計算值:4386.2)
HPLC溶離時間:7.3min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例21
cPrCO-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:33)之合成
秤取參考例1製備之
H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.253meq/g,39.5mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。隨後,使用哌啶處理,脫除N-末端Fmoc基團,然後依序添加環丙烷羧酸(8.6mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,混合物振盪一夜。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,使用MeOH洗滌樹脂,然後減壓乾燥,產生61.8mg之cPrCO-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(
Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在61.8mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:61/39-51/49線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生11.7mg之白色粉末。
質譜(M+H)+ 4349.2(計算值:4349.2)
HPLC溶離時間:7.6min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例22
脒基
-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:34)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.253meq/g,39.5mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。隨後,使用哌啶處理,脫除N-末端Fmoc基團,然後依序添加DMF(200μL)、N,N’-雙(第三丁氧羰基)-1H-吡唑并-1-甲脒(31mg)與DIPEA(17.4μL)至樹脂中,混合物振盪一夜。濾除反應溶液,然後依序添加DMF(200μL)、N,N’-
雙(第三丁氧羰基)-1H-吡唑并-1-甲脒(31mg)與DIPEA(17.4μL)至樹脂中,混合物再度振盪一夜。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,使用MeOH洗滌樹脂,然後減壓乾燥,產生54.7mg之BocNHC(=NBoc)-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在54.7mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:62/38-52/48線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生10.7mg之白色粉末。
質譜(M+H)+ 4323.2(計算值:4323.2)
HPLC溶離時間:7.3min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例23
H-NMeTyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:35)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.253meq/g,39.5mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Aib、Ile*、Aib、
Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與NMeTyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生66.2mg之H-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在66.2mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:63/37-53/47線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生9mg之白色粉末。
質譜(M+H)+ 4295.1(計算值:4295.2)
HPLC溶離時間:7.2min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例24
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:36)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.244meq/g,41.0mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Ala-OH(31.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Tyr(tBu)、Lys(Boc)*、
Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生66.8mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在66.8mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:66/34-56/44線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生16.1mg之白色粉末。
質譜(M+H)+ 4374.6(計算值:4374.2)
HPLC溶離時間:6.9min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6
mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例25
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO:37)之合成
秤取參考例1製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂(0.244meq/g,41.0mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Tyr(tBu)、Lys(Boc)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、
Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗滌樹脂,然後減壓乾燥,產生55.0mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Gln(Trt)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber醯胺樹脂。
在55.0mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:66/34-56/44線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生13.7mg之白色粉末。
質譜(M+H)+ 4431.5(計算值:4431.3)
HPLC溶離時間:6.9min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
實例26
H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:38)之合成
秤取參考例2製備之H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂(0.188meq/g,53.2mg)加至反應管中,使用DMF膨脹。過濾去除DMF後,依序添加Fmoc-Gln(Trt)-OH(61.1mg)、0.5M Oxymapure之DMF溶液(200μL)與二異丙基碳二亞胺(15.9μL)至樹脂中,然後將混合物振盪1.5小時。濾除反應溶液,然後使用DMF洗滌樹脂6次。於凱薩試驗中證實陰性反應後,添加20%哌啶之DMF溶液,並將混合物振盪1分鐘。濾除溶液,再次添加20%哌啶之DMF溶液,並將混合物振盪20分鐘。濾除溶液,然後使用DMF洗滌樹脂10次。重覆此Fmoc胺基酸縮合-Fmoc脫除保護基循環,以便依序縮合Gln(Trt)、Ala、Gln(Trt)、Lys(Boc)、Asp(OtBu)、Leu、Tyr(tBu)、Lys(Boc)*、Aib、Tyr(tBu)、Asp(OtBu)、Ser(tBu)、Thr(tBu)、αMePhe、Thr(tBu)*、Gly、Glu(OtBu)、Aib與Tyr(tBu)(*:反應一夜)。使用MeOH洗
滌樹脂,然後減壓乾燥,產生95.4mg之H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Gln(Trt)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber醯胺樹脂。
在95.4mg所得樹脂中添加1mL TFA:間甲酚:硫代苯甲醚:乙二硫醇:H2O:三異丙基矽烷(80:5:5:5:2.5:2.5),攪拌混合物1.5小時。添加乙醚至反應溶液中,得到沉澱物,採用離心後排除上清液之操作法重覆洗滌沉澱物3次。使用50%乙酸水溶液萃取殘質,過濾去除樹脂,然後使用Daisopak SP-100-5-ODS-P管柱(250 x 20mm I.D.)進行製備性HPLC[溶液A:0.1%TFA-水,溶液B:含0.1%TFA之乙腈,流速8mL/min,A/B:61/39-51/49線性濃度梯度溶離(60min)]。收集含目標產物之溶離份,並冷凍乾燥,產生20.0mg之白色粉末。
質譜(M+H)+ 4303.0(計算值:4303.2)
HPLC溶離時間:7.1min
溶離條件:
管柱:Merck Chromolith Performance RP-18e(100×4.6mm I.D.)
溶離劑:使用溶液A:0.1%TFA-水,溶液B:含0.1%TFA
之乙腈,A/B:95/5-35/65線性濃度梯度溶離(10min)
流速:3.0mL/min
試驗例1
使用細胞內上升之cAMP濃度作為對抗人類GIPR、人類GLP-1R與人類升糖素R之促效劑活性指標之評估
(1)人類GIPR基因之表現質體之構築
取具有與GenBank登錄編號U39231之序列相同序列之人類GIPR基因選殖至pMSRα-neo載體中,製備hGIPR/pMSRα-neo。
(2)報導子質體-表現細胞之構築
將具有上游cAMP效應序列之螢光素酶報導子基因導入至CHO-K1細胞中,以構築CRE-LUC/CHO-K1細胞。
(3)報導子質體之構築
將四套cAMP效應序列複本與Zeocin抗性基因導入至pGL3(R2.2)-基礎載體(Promega)中,以構築Cre-luc(Zeo)報導子質體。
(4)引進人類GIPR基因至CRE-LUC/CHO-K1細胞中並得到表現細胞
將(1)項所得之質體hGIPR/pMSRα-neo導入至(2)項所得之CRE-LUC/CHO-K1細胞中,得到轉化體。然後添加GIP,從所得之轉化體中選拔經誘導而表現螢光素酶之細
胞株,亦即hGIPR/CRE-LUC/CHO-K1細胞。
(5)人類GLP-1R基因之表現質體之構築
將具有與GenBank登錄編號NM_002062之序列相同序列之人類GLP-1R基因選殖至pIRESneo3載體中,製備hGLP-1/pIRESneo3。
(6)引進人類GLP-1R基因與報導子質體至CHO-K1細胞中並得到表現細胞
將(3)項所得之Cre-luc(Zeo)與(5)項所得之質體hGLP-1/pIRESneo3導入至CHO-K1細胞中,得到轉化體。然後添加GLP-1,從所得之轉化體中選拔經誘導而表現螢光素酶之細胞株,亦即hGLP-1R/CRE-luc/CHO-K1細胞。
(7)人類升糖素R基因之表現質體之構築
將具有與GenBank登錄編號NM_000160之序列相同序之人類升糖素R基因選殖至pMSRα-neo載體中,製備hGlucagonR/pMSRα-neo。
(8)將人類升糖素R基因導入至CRE-LUC/CHO-K1細胞中並得到表現細胞
將(7)項所得之質體hGlucagonR/pMSRα-neo導入至(2)項所得之CRE-LUC/CHO-K1細胞中,得到轉化體。然後添加升糖素,從所得之轉化體中選拔經誘導而表現螢光素酶
之細胞株,亦即hGlucagonR/CRE-LUC/CHO-K1細胞。
(9)報導子分析
取hGIPR/CRE-LUC/CHO-K1細胞依25μL/孔(5×104個細胞/孔)之細胞密度接種至384-孔白色分析板(Corning)中,於包含10%胎牛血清、100U/mL青黴素與100μg/mL鏈黴素之Ham F12培養基中,於CO2培養箱中,於37℃下培養。添加包含試驗化合物之培養基(濃度為5μL/孔)至細胞中,所得細胞於CO2培養箱中,於37℃下培養4小時,終濃度為1μM。添加PicaGene LT7.5(Toyo Ink Co.,Ltd.),濃度為30μL/孔,混合物在遮光下振盪。30分鐘後,使用讀板機Envision(PerkinElmer)測定螢光素酶活性。以10nM GIP存在下之螢光素酶活性定義為100%,而以添加DMSO替代試驗化合物時測定之螢光素酶活性定義為0%。計算細胞內上升之cAMP濃度,作為GIPR促效劑活性之指數。其結果示於表2。
依上述相同方式,使用hGLP-1R/CRE-luc/CHO-K1細胞測定GLP-1R促效劑活性。以10nM GLP-1存在下之螢光素酶活性定義為100%,而以添加DMSO替代試驗化合物時測定之螢光素酶活性定義為0%。計算細胞內上升之cAMP濃度,作為GLP-1R促效劑活性之指數。其結果示於表2。
依上述相同方式,使用hGlucagonR/CRE-LUC/CHO-K1細胞測定升糖素R促效劑
活性。以10nM升糖素存在下之螢光素酶活性定義為100%,而以添加DMSO替代試驗化合物時測定之螢光素酶活性定義為0%。計算細胞內上升之cAMP濃度,作為升糖素促效劑活性之指數。其結果示於表2。
如表2所示,本發明化合物對GLP-1受體及GIP受體具有優異之活化作用。此外,本發明化合物具有低的升糖素受體-活化作用。
試驗例2
2天連續皮下投藥試驗
採用下述方法檢測試驗化合物之壓抑攝食活性。
取試驗化合物溶於溶劑(50%DMSO)中,使其依10nmol/kg/天持續釋放,填裝該溶液至Alzet幫浦(DURECT Corporation,機型:1003D)中。將已填裝該欲投藥之溶液之幫浦浸入生理食鹽水中啟動後,即可使用。採用下列方法包埋該幫浦。取每一隻8-9週大之雄性C57BL/6J小鼠
(20-26℃,可以自由攝食與飲水;12-小時照光-12-小時黑暗循環)麻醉;切開上背部皮膚,在皮下埋入上述幫浦;然後縫合切口。秤體重後,將此小鼠送回飼養籠(單獨圈養),以先秤重過之食物餵養;開始投藥2天後測定食物攝取量。由開始投藥當天給與之食物重量扣除剩餘食物重量,計算食物攝取量。當以僅接受溶劑投藥之對照組之食物攝取量定為0%壓抑率時,即可依據開始投藥後2天所累積之食物攝取量來分析各試驗化合物之壓抑攝食活性。試驗化合物之食物攝取量壓抑率(%)之定義為(對照組之食物攝取量-試驗化合物投藥組之食物攝取量)/對照組之食物攝取量×100。
如表3所示,本發明化合物具有優異之壓抑食物攝取作用。
試驗例3
以DIO小鼠進行2週連續皮下投藥試驗
採用下述方法檢測試驗化合物之抗肥胖活性。
以膳食誘發肥胖(DIO)之小鼠之準備方法為使用高脂肪膳食(D12451:Research Diets,Inc.)餵養雄性C57BL/6J小鼠。取試驗化合物溶於溶劑(50%DMSO)中,使其依1
nmol/kg/天持續釋放,填裝該溶液至Alzet幫浦(DURECT Corporation,機型:1002)中。將已填裝該欲投藥之溶液之幫浦浸入生理食鹽水中啟動後,即可使用。採用下列方法包埋該幫浦。取每一隻35-37週大之雄性DIO-C57BL/6J小鼠(20-26℃,可以自由攝食與飲水;12-小時照光-12-小時黑暗循環)麻醉;切開上背部皮膚,在皮下埋入上述幫浦;然後縫合切口。秤體重後,將此小鼠送回飼養籠(單獨圈養),以先秤重過之食物餵養;開始投藥後每1至3天測量體重。依據開始投藥後2週之體重下降率計算各試驗化合物之抗肥胖活性,其中以僅接受溶劑投藥之對照組之體重下降率定為0%。
如表4所示,本發明化合物具有優異之抗肥胖活性。
試驗例4
溶解度試驗
採用下列方法檢測試驗化合物之溶解度。
準確秤取約2mg之試驗化合物。於25℃下添加不同pH之溶劑(10μL、20μL或40μL)(Britton-Robinson緩衝劑(pH3、5、7、9))至各試驗化合物中,目視觀察溶解度。
如表5所示,所有試驗化合物在各pH下均顯示良好溶解度。
調配例1
(1)實例1化合物10.0mg
(2)乳糖70.0mg
(3)玉米澱粉50.0mg
(4)可溶性澱粉7.0mg
(5)硬脂酸鎂3.0mg
取實例1化合物(10.0mg)與硬脂酸鎂(3.0mg)使用可溶性澱粉水溶液(0.07mL)(7.0mg可溶性澱粉)造粒,乾燥,與乳糖(70.0mg)及玉米澱粉(50.0mg)混合。混合物壓縮,
產生錠劑。
調配例2
(1)實例1化合物5.0mg
(2)氯化鈉20.0mg
(3)蒸餾水加至總量2mL
取實例1化合物(5.0mg)與氯化鈉(20.0mg)溶於蒸餾水中,加水至總量2.0mL。溶液過濾,在無菌條件下填裝至2mL安瓿中。安瓿經過殺菌與密封,得到注射用溶液。
本發明化合物具有優異之GLP-1受體/GIP受體共促效劑活性,適用為預防或治療與GLP-1受體/GIP受體有關之各種不同疾病,例如:肥胖。
本文所擷用之所有公開文獻、專利案與專利申請案之揭示內容已以引用之方式完整併入本文中。
SEQ ID NO:1:人造序列(合成胜肽(式(I)))
SEQ ID NO:2:人造序列(合成胜肽(C端序列))
SEQ ID NO:3:人造序列(合成胜肽(C端序列))
SEQ ID NO:4:人造序列(合成胜肽(C端序列))
SEQ ID NO:5:人造序列(合成胜肽(C端序列))
SEQ ID NO:6:人造序列(合成胜肽(C端序列))
SEQ ID NO:7:人造序列(合成胜肽(C端序列))
SEQ ID NO:8:人造序列(合成胜肽(C端序列))
SEQ ID NO:9:人造序列(合成胜肽(C端序列))
SEQ ID NO:10:人造序列(合成胜肽(參考例1))
SEQ ID NO:11:人造序列(合成胜肽(參考例2))
SEQ ID NO:12:人造序列(合成胜肽(參考例3))
SEQ ID NO:13:人造序列(合成胜肽(實例1))
SEQ ID NO:14:人造序列(合成胜肽(實例2))
SEQ ID NO:15:人造序列(合成胜肽(實例3))
SEQ ID NO:16:人造序列(合成胜肽(實例4))
SEQ ID NO:17:人造序列(合成胜肽(實例5))
SEQ ID NO:18:人造序列(合成胜肽(實例6))
SEQ ID NO:19:人造序列(合成胜肽(實例7))
SEQ ID NO:20:人造序列(合成胜肽(實例8))
SEQ ID NO:21:人造序列(合成胜肽(實例9))
SEQ ID NO:22:人造序列(合成胜肽(實例10))
SEQ ID NO:23:人造序列(合成胜肽(實例11))
SEQ ID NO:24:人造序列(合成胜肽(實例12))
SEQ ID NO:25:人造序列(合成胜肽(實例13))
SEQ ID NO:26:人造序列(合成胜肽(實例14))
SEQ ID NO:27:人造序列(合成胜肽(實例15))
SEQ ID NO:28:人造序列(合成胜肽(實例16))
SEQ ID NO:29:人造序列(合成胜肽(實例17))
SEQ ID NO:30:人造序列(合成胜肽(實例18))
SEQ ID NO:31:人造序列(合成胜肽(實例19))
SEQ ID NO:32:人造序列(合成胜肽(實例20))
SEQ ID NO:33:人造序列(合成胜肽(實例21))
SEQ ID NO:34:人造序列(合成胜肽(實例22))
SEQ ID NO:35:人造序列(合成胜肽(實例23))
SEQ ID NO:36:人造序列(合成胜肽(實例24))
SEQ ID NO:37:人造序列(合成胜肽(實例25))
SEQ ID NO:38:人造序列(合成胜肽(實例26))
<110> 武田藥品股份有限公司
<120> 胜肽化合物
<130> PT38-5002TW
<150> JP2013-111893
<151> 2013-05-28
<160> 38
<170> PatentIn version 3.5
<210> 1
<211> 29
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(式(I))
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib或Ala
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa代表Ala、Ile、Lys、Phe或Pya(4)
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib、Cha、Leu、α-MePhe、或α-MeTyr
<220>
<221> misc_feature
<222> (16)..(16)
<223> Xaa代表Lys或Ser
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa代表Gln或Ile
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa代表Ala或Ser
<220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa代表Gln或Gly
<220>
<221> NON_TER
<222> (29)..(29)
<400> 1
<210> 2
<211> 11
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 2
<210> 3
<211> 4
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 3
<210> 4
<211> 5
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 4
<210> 5
<211> 6
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 5
<210> 6
<211> 7
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 6
<210> 7
<211> 8
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 7
<210> 8
<211> 9
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 8
<210> 9
<211> 10
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(C端序列)
<220>
<221> NON_TER
<222> (1)..(1)
<400> 9
<210> 10
<211> 20
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(參考例1)
<220>
<221> MOD_RES
<222> (1)..(1)
<223> OtBu保護基
<220>
<221> MOD_RES
<222> (4,5,8,20)..(4,5,8,20)
<223> Boc保護基
<220>
<221> MOD_RES
<222> (12,13,19)..(12,13,19)
<223> tBu保護基
<400> 10
<210> 11
<211> 19
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(參考例2)
<220>
<221> MOD_RES
<222> (1)..(1)
<223> OtBu保護基
<220>
<221> MOD_RES
<222> (4,5,8)..(4,5,8)
<223> Boc保護基
<220>
<221> MOD_RES
<222> (12,13,19)..(12,13,19)
<223> tBu保護基
<400> 11
<210> 12
<211> 23
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(參考例3)
<220>
<221> MOD_RES
<222> (2)..(2)
<223> Trt保護基
<220>
<221> MOD_RES
<222> (4)..(4)
<223> OtBu保護基
<220>
<221> MOD_RES
<222> (7,8,11,23)..(7,8,11,23)
<223> Boc保護基
<220>
<221> MOD_RES
<222> (15,16,22)..(15,16,22)
<223> tBu保護基
<400> 12
<210> 13
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例1)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 13
<210> 14
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例2)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 14
<210> 15
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例2)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 15
<210> 16
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例4)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 16
<210> 17
<211> 39
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例5)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (39)..(39)
<223> C端醯胺化
<400> 17
<210> 18
<211> 39
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例6)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (39)..(39)
<223> C端醯胺化
<400> 18
<210> 19
<211> 39
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例7)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (39)..(39)
<223> C端醯胺化
<400> 19
<210> 20
<211> 39
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例8)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (39)..(39)
<223> C端醯胺化
<400> 20
<210> 21
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例9)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 21
<210> 22
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例10)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 22
<210> 23
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例11)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 23
<210> 24
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例12)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa代表Pya(4)
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 24
<210> 25
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例13)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (13)..(13)
<223> α-甲基化
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 25
<210> 26
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例14)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Cha
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 26
<210> 27
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例15)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (13)..(13)
<223> α-甲基化
<220>
<221> MOD_RES
<222> (40)..(40)
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<222> (6)..(6)
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<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Cha
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<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
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<220>
<221> MOD_RES
<222> (13)..(13)
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<220>
<221> MOD_RES
<222> (40)..(40)
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<400> 29
<210> 30
<211> 40
<212> PRT
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<220>
<223> 合成胜肽(實例18)
<220>
<221> MOD_RES
<222> (1)..(1)
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<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
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<400> 30
<210> 31
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例19)
<220>
<221> MOD_RES
<222> (1)..(1)
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<220>
<221> misc_feature
<222> (2)..(2)
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<221> MOD_RES
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<220>
<221> misc_feature
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<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 31
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<211> 40
<212> PRT
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<220>
<223> 合成胜肽(實例20)
<220>
<221> MOD_RES
<222> (1)..(1)
<223> N端(4-PyCO(4-吡啶羰基))
<220>
<221> MOD_RES
<222> (1)..(1)
<223> N端(4-PyCO(4-吡啶羰基))
<220>
<221> misc_feature
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<221> MOD_RES
<222> (6)..(6)
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<221> misc_feature
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<221> misc_feature
<222> (13)..(13)
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<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 32
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<212> PRT
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<222> (1)..(1)
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<221> misc_feature
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<221> MOD_RES
<222> (1)..(1)
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<221> misc_feature
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<221> MOD_RES
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<220>
<221> misc_feature
<222> (11)..(11)
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<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 34
<210> 35
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例23)
<220>
<221> MOD_RES
<222> (1)..(1)
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<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (40)..(40)
<223> C端醯胺化
<400> 35
<210> 36
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例24)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<400> 36
<210> 37
<211> 40
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例25)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
<223> α-甲基化
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa代表Aib
<400> 37
<210> 38
<211> 39
<212> PRT
<213> 人造序列
<220>
<223> 合成胜肽(實例26)
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa代表Aib
<220>
<221> MOD_RES
<222> (6)..(6)
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Claims (22)
- 一種胜肽或其鹽,係包括式(I)所示之部分序列者:P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29其中,P1係下式所示之基:-RA1、-CO-RA1、-CO-ORA1、-CO-CORA1、-SO-RA1、-SO2-RA1、-SO2-ORA1、-CO-NRA2RA3、-SO2-NRA2RA3、或-C(=NRA1)-NRA2RA3,其中RA1、RA2及RA3各自獨立為氫原子、視需要經取代之烴基、或視需要經取代之雜環基;A11為Aib或Ala;A12為Ala、Ile、Lys、Phe或Pya(4);A13為Aib、Cha、Leu、αMePhe或αMeTyr;A16為Lys或Ser;A17為Gln或Ile; A20為Ala或Ser;以及A29為Gln或Gly。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,P1為氫原子。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A11為Aib。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A12為Ile。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A13為Aib。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A16為Lys。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A17為Gln。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A20為Ala。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,A29為Gly。
- 如申請專利範圍第1項所述之胜肽或其鹽,其於A29之C端側具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所示之胺基酸序列。
- 如申請專利範圍第1項所述之胜肽或其鹽,其中,P1為氫原子; A11為Aib;A12為Ile;A13為Aib;A16為Lys;A17為Gln;A20為Ala;A29為Gly;且該胜肽於A29之C端側具有Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-所示之胺基酸序列。
- 一種胜肽或其鹽,該胜肽為下式所示者H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2。
- 一種胜肽或其鹽,該胜肽為下式所示者H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2。
- 一種胜肽或其鹽,該胜肽為下式所示者H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-S er-Lys-NH2。
- 一種胜肽或其鹽,該胜肽為下式所示者H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2。
- 一種藥物,其包括申請專利範圍第1項所述之胜肽或其鹽。
- 如申請專利範圍第16項所述之藥物,其係GLP-1受體及GIP受體之活化劑。
- 如申請專利範圍第16項所述之藥物,其係預防或治療肥胖症或糖尿病之藥劑。
- 一種用於預防或治療哺乳類之肥胖症或糖尿病之方法,其包括將有效量之申請專利範圍第1項所述之胜肽或其鹽投予至哺乳類。
- 一種活化哺乳類之GLP-1受體及GIP受體之方法,其包括將有效量之申請專利範圍第1項所述之胜肽或其鹽投予至哺乳類。
- 一種申請專利範圍第1項所述之胜肽或其鹽之用途,其係用於製造預防或治療肥胖症或糖尿病之藥劑。
- 如申請專利範圍第1項所述之胜肽或其鹽,其係用於預防或治療肥胖症或糖尿病。
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