TW202313598A - 苯基尿素衍生物 - Google Patents
苯基尿素衍生物 Download PDFInfo
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- TW202313598A TW202313598A TW111119648A TW111119648A TW202313598A TW 202313598 A TW202313598 A TW 202313598A TW 111119648 A TW111119648 A TW 111119648A TW 111119648 A TW111119648 A TW 111119648A TW 202313598 A TW202313598 A TW 202313598A
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- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
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- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical class [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
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- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Abstract
本發明係關於一種含有具有尿素骨架之新穎之化合物或其等之製藥學上所容許之鹽作為有效成分之針對與食慾激素受體、尤其是與食慾激素2型受體相關之疾病之治療藥或預防藥。具體而言,本發明係關於一種猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群等疾病之治療藥或預防藥。
Description
本發明係關於一種含有具有尿素骨架之新穎之化合物或該等之製藥學上所容許之鹽作為有效成分之針對與食慾激素受體、尤其是與食慾激素2型受體相關之疾病之治療藥或預防藥。具體而言,本發明係關於一種猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群等疾病之治療藥或預防藥。
食慾激素係分佈於外側下丘腦及其周邊區域之於特定神經細胞中特異性地產生之神經肽。食慾激素係主要存在於腦內之G蛋白偶聯受體即食慾激素受體之內源性配體,且與食慾激素受體結合。關於食慾激素受體,已知有1型與2型這2種亞型(非專利文獻1)。
據報告,食慾激素神經細胞變性之基因轉殖小鼠中所產生之猝睡症樣症狀係藉由腦室內投予食慾激素肽而進行改善(非專利文獻2),又,亦報告了猝睡症樣症狀係由食慾激素之前驅蛋白即食慾激素前驅物之剔除(knockout,KO)所引起(非專利文獻3),進而明確了猝睡症患者之腦脊髓液中食慾激素濃度明顯降低(非專利文獻4),表明猝睡症係由食慾激素缺乏所引起。
又,據報告,於遺傳性猝睡症之狗中,食慾激素2型受體變異(非專利文獻5),這表明食慾激素2型受體與睡眠覺醒相關,進而明確了於食慾激素2型受體KO小鼠中,亦引起猝睡症樣症狀(非專利文獻6),這表明食慾激素2型受體刺激與覺醒維持作用密切相關。根據此種背景,食慾激素2型受體激動劑可作為對於以猝睡症為首之呈睡眠過度症狀之疾病的有希望之治療藥而受到期待。
近年來,報告有具有食慾激素2型受體激動作用之化合物(專利文獻1)。
[先前技術文獻]
[專利文獻]
[專利文獻1]國際公開第2017/135306號
[非專利文獻]
[非專利文獻1]Cell、第92卷、573-585頁、1998年(Cell, Vol.92, 573-585, 1998)
[非專利文獻2]Proceedings of the National Academy of Sciences of the United States of America、第101卷、4649-4654頁、2004年(Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004)
[非專利文獻3]Cell、第98卷、437-451頁、1999年(Cell, Vol.98, 437-451, 1999)
[非專利文獻4]THE LANCET、第355卷、39-40頁、2000年(THE LANCET, Vol.355, 39-40, 2000)
[非專利文獻5]Cell、第98卷、365-376頁、1999年(Cell, Vol.98, 365-376, 1999)
[非專利文獻6]Neuron、第38卷、715-730頁、2003年(Neuron, Vol.38, 715-730, 2003)
[非專利文獻7]Brain、第130卷、1577-1585頁、2007年(Brain, Vol.130, 1577-1585, 2007)
[非專利文獻8]Neuroscience Letters、第569卷、68-73頁、2014年(Neuroscience Letters, Vol.569, 68-73, 2014)
[發明所欲解決之問題]
本發明之課題在於提供一種針對與食慾激素2型受體相關之疾病、具體而言為針對猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群等疾病之治療藥或預防藥。
[解決問題之技術手段]
本發明人等進行了銳意研究,結果發現,下述式(1)所表示之化合物或其製藥學上所容許之鹽(以下有時亦稱為「本發明之化合物」)對於與食慾激素2型受體相關之疾病,具體而言對於猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群等疾病具有治療及預防效果,從而完成本發明。
即,本發明如下所述。
[項1]
一種化合物或其製藥學上所容許之鹽,該化合物係由式(1)表示:
[化1]
[式中,
R
1表示可經取代之C
6-10芳香族碳環基、可經取代之5~10員之芳香族雜環基、可經取代之C
3-6飽和碳環基、可經取代之4~10員之飽和雜環基、或氰基;
L
1及L
2各自獨立地表示單鍵、亞甲基(該亞甲基可經1個以上之相同或不同之C
1-6烷基取代)、-NR
6-、-C(=O)-、-OC(=O)-、-SO-、-SO
2-、-S-、或氧原子;
R
2表示氫原子、羥基、鹵素原子、氰基、可經取代之C
1-6烷基、可經取代之C
1-6烷氧基、C(=O)NR
3R
4或C(=O)O-R
5;
R
3、R
4、R
5、R
6各自獨立地表示氫原子或可經取代之C
1-6烷基;
環E表示可經取代之5~10員之芳香族雜環基或可經取代之4~10員之飽和雜環基;
環G表示可經取代之C
6-10芳香族碳環基、可經取代之5~10員之芳香族雜環基、可經取代之C
3-6飽和碳環基、或可經取代之4~10員之飽和雜環基;
A表示氧原子或硫原子]。
[項2]
如項1之化合物或其製藥學上所容許之鹽,其中R
2~R
6中之「可經取代之C
1-6烷基」中之可進行取代之取代基分別獨立地為1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷氧基、或C
3-7環烷基,「可經取代之C
1-6烷氧基」中之可進行取代之取代基分別獨立地為1個或2個以上之相同或不同之鹵素原子、羥基、或C
3-7環烷基,
R
1之C
6-10芳香族碳環基、5~10員之芳香族雜環基、C
3-6飽和碳環基、及4~10員之飽和雜環基中之可進行取代之取代基分別獨立地為選自由如下取代基所組成之群中之1種以上之取代基:鹵素原子、羥基、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基或C
3-7環烷基取代)、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷氧基或C
3-7環烷基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基或C
3-7環烷基取代)、C
1-6烷基胺基(該烷基胺基中之烷基可經鹵素原子、羥基或C
3-7環烷基取代)、C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基或C
3-7環烷基取代)、氰基、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
3-7環烷基取代)及5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基或C
3-7環烷基取代),
環E及環G之C
6-10芳香族碳環基、5~10員之芳香族雜環基、C
3-6飽和碳環基、及4~10員之飽和雜環基中之可進行取代之取代基分別獨立地為選自由如下取代基所組成之群中之1種以上之取代基:鹵素原子、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷氧基或C
3-7環烷基取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基或C
3-7環烷基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
3-7環烷基取代)、C
1-6烷基胺基(該烷基胺基中之烷基可經鹵素原子、羥基或C
3-7環烷基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基或C
3-7環烷基取代)、及C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-4烷氧基或C
3-7環烷基取代);或者於取代基存在複數個之情形時,可其中2個經由C
1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構。
[項3]
如項1或2所記載之化合物或其製藥學上所容許之鹽,其中該化合物係由式(2)表示:
[化2]
[式中,
R
2表示羥基、鹵素原子、氰基、可經取代之C
1-4烷基、可經取代之C
1-4烷氧基、C(=O)NR
3R
4或C(=O)OR
5;
R
1、L
1、L
2、R
3、R
4、R
5、環E、環G、及A為與項1相同之定義]。
[項4]
如項1至3中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
1為氰基或選自下述式(1a-1)至(1a-6)中之任一者:
[化3]
[式中,
X
1~X
6各自獨立地表示氮原子或CR
a4;
Q
1及Q
2表示氧原子、-NR
a5-或硫原子;
Q
3表示CH或氮原子;
R
a1~R
a5各自獨立地(於CR
a4存在複數個之情形時,各R
a4亦各自獨立地)表示氫原子、鹵素原子、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-4烷氧基或C
3-7環烷基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、可經1個或2個以上之相同或不同之鹵素原子取代之C
1-6烷基、或C
1-6烷氧基取代)、氰基、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代)、C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)或5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)]。
[項5]
如項1至4中任一項所記載之化合物或其製藥學上所容許之鹽,其中環G為選自下述式(1b-1)至(1b-7)中之任一者:
[化4]
[式中,
W
1及W
2各自獨立地表示NR
b7、氧原子或CR
b8R
b9;
W
3、W
4、W
5及W
6各自獨立地表示氮原子或CR
b10;
R
b1~R
b10各自獨立地表示氫原子、鹵素原子、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-4烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)或C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代),只要化學上可能,則R
b2及R
b3可鍵結於同一碳原子上;
此處,R
b2及R
b3可經由C
1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構;
n、m及p各自獨立地表示1或2之整數]。
[項6A]
如項1至5中任一項所記載之化合物或其製藥學上所容許之鹽,其中環E為選自下述式(1c-1)至(1c-4)中之任一者:
[化5]
[式中,
R
c1、R
c2、R
c3及R
c4各自獨立地表示氫原子、鹵素原子、氰基、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、或C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代),只要化學上可能,則R
c1及R
c2可鍵結於同一碳原子上;
此處,R
c1及R
c2可經由C
1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構]。
[項6]
如項1至5中任一項所記載之化合物或其製藥學上所容許之鹽,其中環E為選自下述式(1c-1)至(1c-3)中之任一者:
[化6]
[式中,
R
c1、R
c2及R
c3各自獨立地表示氫原子、鹵素原子、氰基、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、或C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代),只要化學上可能,則R
c1及R
c2可鍵結於同一碳原子上;
此處,R
c1及R
c2可經由C
1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構]。
[項7A]
如項1至6A及項6中任一項所記載之化合物或其製藥學上所容許之鹽,其中環E為選自下述式(1c-11)至(1c-41)中之任一者:
[化7]
[式中,R
c4各自獨立地表示鹵素原子、氰基、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、或C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)]。
[項7]
如項1至6A及項6中任一項所記載之化合物或其製藥學上所容許之鹽,其中環E為選自下述式(1c-11)至(1c-31)中之任一者:
[化8]
[式中,R
c4各自獨立地表示鹵素原子、氰基、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、或C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)]。
[項8]
如項1至6A、項6、項7A及項7中任一項所記載之化合物或其製藥學上所容許之鹽,該化合物係以式(3)表示:
[化9]
[式中,
R
2表示可經鹵素原子取代之C
1-6烷氧基;
R
1、A、L
1及環G表示與如項1所記載之定義相同之內容]。
[項9]
如項1至6A、項6、項7A、項7及項8中任一項所記載之化合物或其製藥學上所容許之鹽,其中L
1為單鍵、-CH
2-、或氧原子之任一者。
[項10]
如項1至6A、項6、項7A及項7至9中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
1為選自下述式(1a-1)至(1a-3)中之任一者:
[化10]
[式中,
X
1~X
5各自獨立地表示氮原子或CR
a4;
Q
1及Q
2各自獨立地表示氧原子或硫原子;
R
a1表示氫原子、鹵素原子、氰基、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代)或C
1-4烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代);
R
a4(於CR
a4存在複數個之情形時,各R
a4各自獨立地)表示氫原子、鹵素原子、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷氧基或C
3-7環烷基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代)、C
3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、C
1-6烷氧基取代)或5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)]。
[項11]
如項1至6A、項6、項7A及項7至10中任一項所記載之化合物或其製藥學上所容許之鹽,其中環G為選自下述式(1b-1)至(1b-3)中之任一者:
[化11]
[式中,R
b1~R
b3各自獨立地表示氫原子、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)或C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)]。
[項12]
如項1至6A、項6、項7A及項7至11中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
2為F、Cl、Br之任一鹵素原子,且A為氧原子。
[項13]
如項1至6A、項6、項7A及項7至12中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
1係由以下之式(1a-1)表示:
[化12]
[式中,R
a1表示氫原子、鹵素原子、氰基、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代)或C
1-4烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代)]。
[項14]
如項1至6A、項6、項7A及項7至12中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
1表示以下之式(1a-2):
[化13]
[式中,
X
1~X
3各自獨立地表示氮原子或CR
a4;
Q
1表示氧原子或硫原子;
R
a4表示與項10相同之定義];
L
1為單鍵。
[項15]
如項1至6A、項6、項7A及項7至12中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
1為選自下述式(1a-21)至(1a-25)中之任一者:
[化14]
[式中,R
a4表示含義與項10所記載之內容相同之內容];
L
1為單鍵。
[項16]
如項15所記載之化合物或其製藥學上所容許之鹽,其中R
a4(於CR
a4存在複數個之情形時,各R
a4各自獨立地)為C
6-10芳香族碳環基(該C
6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)、C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷氧基或C
3-7環烷基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)、或5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)。
[項17]
如項1至6A、項6、項7A及項7至12中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
1表示以下之式(1a-3):
[化15]
[式中,X
4及X
5為與項10相同之定義];
L
1為單鍵。
[項19]
如項17或18中任一項所記載之化合物或其製藥學上所容許之鹽,其中R
a4(於CR
a4存在複數個之情形時,各R
a4各自獨立地)為C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷氧基或C
3-7環烷基取代)、C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C
1-6烷基、或C
1-6烷氧基取代)、C
1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C
1-6烷氧基取代)。
[項21]
如項1至6A、項6、項7A及項7至19中任一項所記載之化合物或其製藥學上所容許之鹽,其中環G係以下述式(1b-1)表示:
[化18]
[式中,R
b1為以C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、或C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)表示]。
[項22]
如項1至6A、項6、項7A及項7至19中任一項所記載之化合物或其製藥學上所容許之鹽,其中環G係以下述式(1b-3)表示:
[化19]
[式中,R
b3為以C
1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C
1-6烷氧基取代)、5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)、或C
3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C
1-6烷基、或C
1-6烷氧基取代)表示]。
[項23]
如項1所記載之化合物或其製藥學上所容許之鹽,其中該化合物選自以下之化合物:
實施例20:N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例22:N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)哌啶-1-甲醯胺
實施例44:4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例45:4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例53:4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例54:4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例55:4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例61:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例67:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例77:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺。
[項24]
如項1所記載之化合物或其製藥學上所容許之鹽,其中該化合物選自以下之化合物:
實施例87:4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例89:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基哌啶-1-甲醯胺
實施例101:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,3-噻唑-2-基)-4-甲基哌啶-1-甲醯胺
實施例115:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1S,2S)
-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺
實施例116:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1R,2R)
-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺
實施例117:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1S,2R)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺
實施例118:N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺
實施例130:N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例144:N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例147:N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺。
[項25]
一種醫藥組合物,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項26]
一種與食慾激素2型受體相關之疾病之治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項27]
一種治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽,且其係猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、伴隨路易體癡呆之睡眠過度、伴隨白天睡眠過度之睡眠過度症候群(例如克萊恩-萊文症候群、伴隨睡眠過度之重度抑鬱症、路易體癡呆、帕金森氏症、進行性核上麻痹、普威二氏症候群、莫比烏斯症候群、低換氣症候群、尼曼-匹克二氏病C型、腦挫傷、腦梗塞、腦腫瘤、肌肉萎縮症、多發性硬化症、急性播散性腦脊髓炎、格-巴二氏症候群、Rasmussen氏腦炎、韋尼克氏腦炎、邊緣葉腦炎、橋本腦病)、昏睡、意識喪失、肥胖(例如惡性肥胖細胞、外源性肥胖、胰島功能亢進性肥胖、原生質增生性肥胖、垂體性肥胖、原生質低減性肥胖、甲狀腺功能減退性肥胖症、下視丘性肥胖、症狀性肥胖症、兒童肥胖、上半身肥胖、飲食性肥胖症、性功能衰退性肥胖、全身性肥大細胞增生病、單純性肥胖、中心性肥胖)、胰島素抵抗症候群、阿茲海默症、昏睡等意識障礙、由麻醉導致之副作用或併發症、睡眠紊亂、睡眠問題、失眠症、間歇性睡眠、夜間肌陣攣、快速眼動(REM)睡眠中斷、時差反應、時差反應症候群、輪班工作人員之睡眠障礙、睡眠異常、夜驚症、抑鬱症、重度抑鬱症、夢遊症、夜尿症、睡眠障礙、阿茲海默症性日落症、與晝夜節律相關之疾病、肌肉纖維疼痛、因睡眠品質降低而產生之狀態、過食、強迫性飲食障礙、肥胖相關疾病、高血壓、糖尿病、血漿胰島素濃度及胰島素抵抗性之上升、高脂蛋白血症、高脂血症、子宮內膜癌、乳癌、前列腺癌、結腸癌、癌、變形性關節病、阻塞性睡眠呼吸中止、膽石症、膽石、心臟病、心臟跳動節奏不規律、心律不整、心肌梗塞、充血性心臟衰竭、心臟衰竭、冠心病、心血管障礙、猝死、多囊性卵巢病、顱咽管瘤、普威二氏症候群、肥胖性生殖器退化症候群、生長激素缺乏者、正常基因突變矮小、特納氏症候群、罹患急性淋巴細胞性白血病之兒童、X症候群、生殖系統激素異常、受孕能力減退、不孕、男性之性腺功能減退、女性之男性型多毛症等性及生殖功能障礙、與孕婦肥胖相關之胎兒之缺陷、肥胖相關胃食道逆流病等胃腸動力之疾病、肥胖低換氣症候群(匹克威克症候群)、呼吸困難等呼吸性疾病、脈管系統全身性炎症等炎症、動脈硬化、高膽固醇血症、高尿酸血症、下背部痛、膽囊疾病、痛風、腎癌、降低左心室肥大風險等肥胖繼發後果之風險、偏頭痛、頭痛、神經性疼痛、帕金森氏症、精神病、精神分裂症、顏面潮紅、盜汗、性器/泌尿系統之疾病、與性功能或受孕能力相關之疾病、低落性情感疾病、躁鬱症、I型躁鬱症、II型躁鬱症、循環情感性精神障礙、急性壓力症、廣場恐懼症、廣泛性焦慮症、強迫症、驚恐發作、驚恐障礙、創傷後壓力症、分離焦慮障礙、社交恐懼症、焦慮障礙、心臟繞道術及移植後之腦性缺損症等急性神經學及精神醫學障礙、腦中風、缺血性腦中風、腦缺血、脊髓外傷、頭部外傷、圍產期缺氧症、心臟驟停、低血糖神經損傷、亨廷頓氏舞蹈症、肌萎縮性側索硬化症、多發性硬化症、眼損傷、網膜病、認知障礙、肌肉攣縮、顫動、癲癇、與肌肉痙攣相關之障礙、妄想、健忘障礙、年齡相關性認知衰退、分裂情感性精神障礙、妄想性障礙、藥物依賴症、運動異常症、慢性疲勞症候群、疲勞、藥物誘導性帕金森症候群、妥瑞症候群、舞蹈症、肌陣攣、抽動、抖腿症候群、肌肉緊張不足、運動障礙、注意力不足過動症(ADHD)、行為障礙、尿失禁、戒斷症狀、三叉神經痛、聽力損失、耳鳴、神經損傷、網膜病、黃斑變性症、嘔吐、腦浮腫、疼痛、骨痛、關節痛、牙痛、猝倒症、或創傷性腦損傷之治療藥。
[項28]
一種治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽,且其係猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療藥。
[項29]
一種猝睡症之治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項30]
一種特發性睡眠過度之治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項31]
一種伴隨帕金森氏症之睡眠過度之治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項32]
一種伴隨路易體癡呆之睡眠過度之治療藥,其含有如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項33]
一種猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療方法,其包括對需要治療之患者投予治療上有效量之如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽。
[項34]
一種如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽之用途,其係用以製造猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療劑。
[項35]
一種醫藥組合物,其包含如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽,其係用於猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療中之使用。
[項36]
如項1至6A、項6、項7A及項7至24中任一項所記載之化合物或其製藥學上所容許之鹽,其係用於猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療及/或預防。
以下,進一步對本發明進行詳細說明。於本說明書中,亦存在將「取代基」之定義中之碳數記載為例如「C
1-6」等之情形。具體而言,「C
1-6烷基」之記法係與碳數1至6之烷基之含義相同。又,於本說明書中,關於未特別明示「可經取代」或「經取代」之用語之取代基,意指「未經取代」之取代基。例如,「C
1-6烷基」意指「未經取代之C
1-6烷基」。
又,於本說明書中之取代基之說明中,亦存在省略用語「基」之情形。再者,於以「可經取代」進行定義之情形時,存在取代基時之取代基數只要能夠取代即可,並無特別限制,為1個或複數個。即,表示可經該基中之可經取代之碳原子、或碳原子及氮原子上之可取代數之取代基所取代。又,除特別指示之情形以外,各基之說明亦適用於該基為其他基之一部分或取代基之情形。
關於取代基之鍵結位置,於本說明書中無特別明示之情形時,為化學上所能鍵結之任意位置。又,於本說明書中之結構式中,楔形之實線及虛線表示絕對構型,粗線之實線及虛線表示相對構型。
作為「鹵素」,例如可例舉:氟、氯、溴、碘等。較佳為氟或氯。
「C
1-4烷基」意指碳數為1~4個之直鏈狀或支鏈狀之飽和烴基,「C
1-6烷基」意指碳數為1~6個之直鏈狀或支鏈狀之飽和烴基。作為「C
1-4烷基」之具體例,可例舉:甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基,作為「C
1-6烷基」之具體例,除上述以外,還可例舉:戊基、異戊基、新戊基、1-乙基丙基、己基、以及該等之結構異構物。作為該「C
1-6烷基」或「C
1-4烷基」,較佳為甲基、乙基、丙基、異丙基,更佳為甲基及異丙基。
「C
1-6伸烷基」意指具有碳原子數1~6個且直鏈狀或支鏈狀之二價飽和烴基。作為「C
1-6伸烷基」,較佳可例舉「C
1-4伸烷基」,更佳可例舉「C
1-3伸烷基」。作為「C
1-3伸烷基」之具體例,例如可例舉:亞甲基、伸乙基、伸丙基、三亞甲基等。作為「C
1-4伸烷基」之具體例,例如除了上述作為「C
1-3伸烷基」之具體例所例舉者以外,還可例舉:伸丁基、1,1-二甲基伸乙基、1,2-二甲基伸乙基、1-甲基三亞甲基、2-甲基三亞甲基等。作為「C
1-6伸烷基」之具體例,例如除了上述作為「C
1-4伸烷基」之具體例所例舉者以外,還可例舉:伸戊基、1,1-二甲基三亞甲基、1,2-二甲基三亞甲基、1-甲基伸丁基、2-甲基伸丁基、1-甲基伸戊基、2-甲基伸戊基、3-甲基伸戊基、伸己基等。
「C
3-7環烷基」意指具有碳數3~7個之環狀非芳香族性烴基(飽和烴基及部分不飽和烴基)。較佳為「C
3-6環烷基」。「C
3-7環烷基」亦包括經橋接者。作為「C
3-7環烷基」之具體例,可例舉:環丙基、環丁基、環戊基、環己基、環戊烯基、環己烯基、環庚基等。
上述「C
3-7環烷基」亦包含二環式基,該二環式基係「C
3-7環烷基」與苯環或者含有選自氮、硫或氧中之1個、或者相同或不同之2個以上(例如2~4個)雜原子的5員或6員環(例如下述所說明之「5或6員之單環式芳香族雜環」、及下述所說明之「4~10員之飽和雜環」中之5或6員環)縮環而成者。
「C
1-4烷氧基」意指經上述「C
1-4烷基」取代之氧基,「C
1-6烷氧基」意指經上述「C
1-6烷基」取代之氧基。作為「C
1-4烷氧基」之具體例,可例舉: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、第三丁氧基等,作為「C
1-6烷氧基」之具體例,例如除了上述作為「C
1-4烷氧基」之具體例所例舉者以外,還可例舉:戊氧基、己氧基等。作為「C
1-4烷氧基」,較佳可例舉:甲氧基、乙氧基、異丙氧基。
「C
3-7環烷氧基」意指經上述「C
3-7環烷基」取代之氧基。較佳為「C
3-6環烷氧基」。作為「C
3-7環烷氧基」之具體例,可例舉:環丙氧基、環丁氧基、環戊氧基、環己氧基等。較佳為環己氧基。
「C
6-10芳香族碳環基」為具有碳數6~10個之芳香族烴基,亦稱為「C
6-10芳基」。更佳為苯基。作為「C
6-10芳香族碳環基」之具體例,例如可例舉:苯基、1-萘基或2-萘基等。
上述「C
6-10芳香族碳環基」亦包含「苯基」與含有選自氮、硫或氧中之1個、或者相同或不同之2個以上(例如2~4個)雜原子的5或6員環(例如下述所說明之「5或6員之單環式芳香族雜環」、下述所說明之「4~10員之飽和雜環」中之5或6員環)、或5~7員之環烷基環(例如環戊烷、環己烷或環庚烷)縮環而成之基。
「5~10員之芳香族雜環基」意指單環式或多環式之5~10員之芳香族雜環基,該5~10員之芳香族雜環基中,作為構成環之原子,除了碳以外,還含有選自氮、硫或氧中之1個、或者相同或不同之2個以上(例如2~4個)雜原子,較佳為「5或6員之單環式芳香族雜環基」。「5或6員之單環式芳香族雜環基」意指「5~10員之芳香族雜環基」中單環式之5或6員之芳香族雜環基。
作為上述「5~10員之芳香族雜環基」中之多環式芳香族雜環基,具體而言,可例舉:相同或不同之兩個單環式芳香族雜環縮環而成者、或單環式芳香族雜環與芳香族環(例如苯等)或非芳香族環(例如環己烷等)縮環而成者。
作為「5~10員之芳香族雜環基」之具體例,可例舉:吡唑基、咪唑基、吡啶基、嘧啶基、吡𠯤基、嗒𠯤基。於另一實施形態中,較佳可例舉:苯并呋喃基(鍵結位置在雜芳基(呋喃)環上)、吡啶基、嘧啶基、吡𠯤基、嗒𠯤基。
「C
3-6飽和碳環」意指碳原子數3至6之單環式之飽和或部分不飽和之烴環。作為「C
3-6飽和碳環」之具體例,例如可例舉:環丙烷、環丁烷、環戊烷、環己烷、環丙烯、環丁烯、環戊烯、環己烯、環己二烯等。較佳可例舉:環丙烷或環丁烷。
「4~10員之飽和雜環」意指包含4~10個原子之單環式或二環式之飽和雜環,該飽和雜環中,作為構成環之原子,除了碳以外,還包含選自由氧原子、氮原子及硫原子所組成之群中之相同或不同之1或2個以上(例如2~4個、較佳為2~3個、更佳為2個)雜原子,上述「4~10員之飽和雜環」包括具有部分不飽和鍵者、具有經部分橋接之結構者及經部分螺環化者。較佳為5員或6員之飽和雜環。二環式之飽和雜環亦包括單環式之飽和雜環與苯或單環式之5至6員之芳香族雜環縮環而成者。又,為了構成該飽和雜環,亦可包含1或2個羰基、硫羰基、亞磺醯基或磺醯基,例如內醯胺、硫內醯胺、內酯、硫內酯、環狀醯亞胺、環狀胺基甲酸酯、環狀硫代胺基甲酸酯等環狀基亦包含於該飽和雜環中。此處,4~10員之數(環之大小)及構成環之雜原子之數不包括羰基、亞磺醯基及磺醯基之氧原子及硫羰基之硫原子。作為「4~10員之飽和雜環」,較佳可例舉單環式或二環式之「4~8員之飽和雜環」,更佳可例舉單環式之「4~6員之飽和雜環」,進而較佳可例舉單環式之「5或6員之飽和雜環」。作為「4~10員之飽和雜環」之具體例,可例舉:哌𠯤、氧雜環丁烷、吖丁啶、吡咯啶、吡唑啶、咪唑啶、哌啶、嗎啉、高哌啶、氧雜環丁烷、硫代嗎啉、二側氧基硫代嗎啉、六亞甲基亞胺、㗁唑啶、噻唑啶、咪唑啶、側氧基咪唑啶、二側氧基咪唑啶、側氧基㗁唑啶、二側氧基㗁唑啶、二側氧基噻唑啶、四氫呋喃、四氫哌喃、四氫吡啶等。較佳為吡咯啶、哌啶、哌𠯤、嗎啉。作為二環式之飽和雜環之具體例,可例舉:吲哚啉、異吲哚啉、二氫嘌呤、二氫噻唑并嘧啶、二氫苯并二㗁烷、二氫吲唑、二氫吡咯并吡啶、四氫喹啉、十氫喹啉、四氫異喹啉、十氫異喹啉、四氫㖠啶、四氫吡啶并氮呯等。
「4~10員之飽和雜環基」意指上述「4~10員之飽和雜環」成為一價基之取代基,「4~6員之飽和雜環基」意指上述「4~10員之飽和雜環」中「4~6員之飽和雜環」成為一價基之取代基。較佳可例舉:氮雜環丁基、吡咯啶基、哌啶基、哌嗪基、嗎啉基、氧雜環丁基、四氫呋喃基、四氫吡喃基等。
本發明之化合物中亦包括各種水合物、溶劑合物及多晶型。
又,本發明之化合物可經同位素(例如D、
3H、
11C、
13C、
14C、
13N、
15N、
15O、
35S、
18F、
125I等)取代,該等化合物亦包括於本發明之化合物中。
於本發明中,「製藥學上所容許之鹽」意指容許藥學上使用之酸加成鹽及鹼加成鹽。作為「製藥學上所容許之鹽」,例如可例舉:乙酸鹽、丙酸鹽、丁酸鹽、甲酸鹽、三氟乙酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、檸檬酸鹽、硬脂酸鹽、琥珀酸鹽、乙基琥珀酸鹽、丙二酸鹽、乳糖酸鹽、葡萄糖酸鹽、葡庚糖酸鹽、苯甲酸鹽、甲磺酸鹽、苯磺酸、對甲苯磺酸鹽(tosilate)、月桂基硫酸鹽、蘋果酸鹽、抗壞血酸鹽、苦杏仁酸鹽、葡萄糖二酸鹽、羥萘甲酸鹽、雙羥萘酸鹽、肉桂酸鹽、己二酸鹽、半胱胺酸鹽、N-乙醯半胱胺酸鹽、鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽、氫碘酸鹽、菸鹼酸鹽、草酸鹽、苦味酸鹽、硫氰酸鹽、十一酸鹽、丙烯酸聚合物鹽、羧基乙烯基聚合物等酸加成鹽;鋰鹽、鈉鹽、鉀鹽、鈣鹽等無機鹼加成鹽;嗎啉、哌啶等有機鹼加成鹽;與天冬胺酸、麩胺酸等胺基酸之加成鹽等,但並不限定於該等。
本發明之化合物可藉由經口投予或非經口投予,直接或使用合適之劑型製成製劑、醫藥或醫藥組合物並投予。作為該等劑型之具體例,例如可例舉:錠劑、膠囊劑、散劑、顆粒劑、液劑、懸浮劑、注射劑、貼附劑、敷劑等,但並不限定於該等。又,該等製劑可使用作為通常之醫藥品添加物所使用之添加劑,藉由公知之方法進行製造。
作為該等添加劑,可根據目的使用賦形劑、崩解劑、結合劑、塑化劑、潤滑劑、包衣劑、溶解劑、增溶劑、增黏劑、分散劑、穩定劑、甜味劑、香料等。作為該等添加劑之具體例,例如可例舉:乳糖、甘露醇、結晶纖維素、低取代羥丙纖維素、玉米澱粉、部分α化澱粉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、羥丙纖維素、羥丙基甲基纖維素、聚乙烯醇、硬脂酸鎂、硬脂醯反丁烯二酸鈉、聚乙二醇、丙二醇、氧化鈦、滑石等,但並不限定於該等。
本發明之化合物之投予量係根據投予對象動物、投予路徑、疾病、患者之年齡、體重及症狀而適當選擇。例如於經口投予之情形時,對於成人而言,每天之下限為0.01 mg,每天之上限為10000 mg,1天投予1次或1天分數次來投予該量。
本發明之化合物係對於食慾激素2型受體具有激動活性之化合物。因此,可成為對於與食慾激素受體相關之疾病有用之預防或治療劑。作為該等疾病之具體例,可例舉:猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、伴隨路易體癡呆之睡眠過度、伴隨白天睡眠過度之睡眠過度症候群(例如克萊恩-萊文症候群、伴隨睡眠過度之重度抑鬱症、路易體癡呆、帕金森氏症、進行性核上麻痹、普威二氏症候群、莫比烏斯症候群、低換氣症候群、尼曼-匹克二氏病C型、腦挫傷、腦梗塞、腦腫瘤、肌肉萎縮症、多發性硬化症、急性播散性腦脊髓炎、格-巴二氏症候群、Rasmussen氏腦炎、韋尼克氏腦炎、邊緣葉腦炎、橋本腦病)、昏睡、意識喪失、肥胖(例如惡性肥胖細胞、外源性肥胖、胰島功能亢進性肥胖、原生質增生性肥胖、垂體性肥胖、原生質低減性肥胖、甲狀腺功能減退性肥胖症、下視丘性肥胖、症狀性肥胖症、兒童肥胖、上半身肥胖、飲食性肥胖症、性功能衰退性肥胖、全身性肥大細胞增生病、單純性肥胖、中心性肥胖)、胰島素抵抗症候群、阿茲海默症、昏睡等意識障礙、由麻醉導致之副作用或併發症、睡眠紊亂、睡眠問題、失眠症、間歇性睡眠、夜間肌陣攣、快速眼動(REM)睡眠中斷、時差反應、時差反應症候群、輪班工作人員之睡眠障礙、睡眠異常、夜驚症、抑鬱症、重度抑鬱症、夢遊症、夜尿症、睡眠障礙、阿茲海默症性日落症、與晝夜節律相關之疾病、肌肉纖維疼痛、因睡眠品質降低而產生之狀態、過食、強迫性飲食障礙、肥胖相關疾病、高血壓、糖尿病、血漿胰島素濃度及胰島素抵抗性之上升、高脂蛋白血症、高脂血症、子宮內膜癌、乳癌、前列腺癌、結腸癌、癌、變形性關節病、阻塞性睡眠呼吸中止、膽石症、膽石、心臟病、心臟跳動節奏不規律、心律不整、心肌梗塞、充血性心臟衰竭、心臟衰竭、冠心病、心血管障礙、猝死、多囊性卵巢病、顱咽管瘤、普威二氏症候群、肥胖性生殖器退化症候群、生長激素缺乏者、正常基因突變矮小、特納氏症候群、罹患急性淋巴細胞性白血病之兒童、X症候群、生殖系統激素異常、受孕能力減退、不孕、男性之性腺功能減退、女性之男性型多毛症等性及生殖功能障礙、與孕婦肥胖相關之胎兒之缺陷、肥胖相關胃食道逆流病等胃腸動力之疾病、肥胖低換氣症候群(匹克威克症候群)、呼吸困難等呼吸性疾病、脈管系統全身性炎症等炎症、動脈硬化、高膽固醇血症、高尿酸血症、下背部痛、膽囊疾病、痛風、腎癌、降低左心室肥大風險等肥胖繼發後果之風險、偏頭痛、頭痛、神經性疼痛、帕金森氏症、精神病、精神分裂症、顏面潮紅、盜汗、性器/泌尿系統之疾病、與性功能或受孕能力相關之疾病、低落性情感疾病、躁鬱症、I型躁鬱症、II型躁鬱症、循環情感性精神障礙、急性壓力症、廣場恐懼症、廣泛性焦慮症、強迫症、驚恐發作、驚恐障礙、創傷後壓力症、分離焦慮障礙、社交恐懼症、焦慮障礙、心臟繞道術及移植後之腦性缺損症等急性神經學及精神醫學障礙、腦中風、缺血性腦中風、腦缺血、脊髓外傷、頭部外傷、圍產期缺氧症、心臟驟停、低血糖神經損傷、亨廷頓氏舞蹈症、肌萎縮性側索硬化症、多發性硬化症、眼損傷、網膜病、認知障礙、肌肉攣縮、顫動、癲癇、與肌肉痙攣相關之障礙、妄想、健忘障礙、年齡相關性認知衰退、分裂情感性精神障礙、妄想性障礙、藥物依賴症、運動異常症、慢性疲勞症候群、疲勞、藥物誘導性帕金森症候群、妥瑞症候群、舞蹈症、肌陣攣、抽動、抖腿症候群、肌肉緊張不足、運動障礙、注意力不足過動症(ADHD)、行為障礙、尿失禁、戒斷症狀、三叉神經痛、聽力損失、耳鳴、神經損傷、網膜病、黃斑變性症、嘔吐、腦浮腫、疼痛、骨痛、關節痛、牙痛、猝倒症、創傷性腦損傷。較佳可例舉:猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、伴隨路易體癡呆之睡眠過度。
於本發明中,「預防」係對疾病未發病之健康人投予本發明之化合物之行為,目的在於例如防止疾病之發病。「治療」係對由醫生診斷疾病發病之人(患者)投予本發明之化合物之行為,目的在於例如減輕疾病或症狀或恢復為疾病發病前之狀態。又,即便投予之目的在於防止疾病或症狀之惡化,只要被投予者為患者,則亦為治療行為。
以下舉例對本發明中之式(1)所表示之化合物之製造法進行說明,但本發明當然不限定於此。
製造法本發明化合物亦可藉由下述所示之製造法、及組合公知之合成方法而成之方法來進行合成。
反應式中之化合物亦包括分別形成鹽之情形,作為該鹽,例如可例舉與上述「製藥學上所容許之鹽」相同者。再者,該等反應僅為例示,亦可基於熟知有機合成化學者之知識,適當藉由其他方法製造本發明化合物。
於下述所說明之各製造法中,即便於未具體地明示使用保護基之情形時,於存在需要保護之官能基之情形時,亦存在藉由如下方式獲得目標物之情況,即,視需要保護該官能基,於反應結束後或進行一系列反應後進行去保護。
作為保護基,例如可使用文獻(T. W. Greene and P. G. M. Wuts, ''Protective Groups in Organic Synthesis'', 3rd Ed., John Wiley and Sons, inc., New York (1999))等中所記載之通常之保護基,進一步具體而言,作為胺基之保護基,例如可例舉:第三丁氧基羰基、苄氧基羰基、對甲苯磺醯基、鄰硝基苯磺醯基、四氫吡喃基等,又,作為羥基之保護,例如可例舉:三烷基矽烷基、乙醯基、苄基、四氫吡喃基、甲氧基甲基等,作為醛基之保護基,例如可例舉:二烷基縮醛、環狀烷基縮醛等,作為羧基之保護基,例如可例舉:第三丁酯、原酸酯、醯胺等。
保護基之導入及脫離可藉由有機合成化學中常用之方法(例如T. W. Greene and P. G. M. Wuts, ''Protective Groups in Organic Synthesis'', 3rd Ed., John Wiley and Sons, inc., New York (1999)中所記載之方法等)或依據其之方法進行。
步驟(1):
化合物(1')可藉由在合適之惰性溶劑中,於通常使用之尿素鍵形成條件下使化合物(s-1)及化合物(s-2)進行反應而製造。本反應之條件例如可例舉使用三光氣、氯甲酸4-硝基苯酯或硫光氣之條件。作為本反應中所使用之鹼,可例舉:三乙胺或二異丙基乙基胺等。作為溶劑,可例舉:氯仿、二氯甲烷等鹵化碳;二乙醚、THF(tetrahydrofuran,四氫呋喃)、1,4-二㗁烷等醚系溶劑;苯、甲苯、二甲苯等芳香族烴系溶劑;乙酸乙酯、乙酸甲酯等酯系溶劑。反應時間通常為約1小時至24小時,反應溫度為-20℃至溶劑之沸點。
製造法 2 :式(1)所表示之化合物或其製藥學上所容許之鹽中式(s-5)所表示之化合物例如亦可藉由下述製法來製造。
[化21]
(式中,R
1、R
2、L
1、L
2、及A與項1之含義相同,R
b1與項5之含義相同,X為胺基之保護基。化合物(s-3)係製造法1之環G為經保護之含氮環之情形,可與製造法1之步驟(1)同樣地合成)
步驟(2):
化合物(s-4)可藉由在合適之惰性溶劑中,於通常使用之去保護基化條件下使化合物(s-3)進行反應而製造。關於本反應之條件,例如於X為Boc基之情形時,可藉由使用酸進行去保護。例如作為酸,可例舉:鹽酸、硫酸、氫溴酸、三氟乙酸等。作為溶劑,可例舉:二氯甲烷、氯仿等鹵化烴系溶劑;二乙醚、二異丙醚、四氫呋喃、1,4-二㗁烷等醚系溶劑;乙酸乙酯、乙酸甲酯等酯系溶劑。反應時間通常為約1小時至24小時,反應溫度為-20℃至溶劑之沸點。於X為Cbz基或Bn基之情形時,例如可藉由在氫化條件下進行接觸還原來進行去保護。作為觸媒,可使用鈀-碳等非均相觸媒。氫化條件下意指氫氣環境下、或甲酸、甲酸銨等之存在下。作為溶劑,可例舉:甲醇、乙醇、THF、乙酸乙酯等。反應時間為30分鐘至24小時,反應溫度為0℃至溶劑之沸點。
步驟(3):
化合物(s-5)可藉由在合適之惰性溶劑中,於通常使用之還原性胺基化條件下使化合物(s-4)進行反應而製造。本反應之條件可例舉例如使用三乙醯氧基硼氫化鈉、氰基硼氫化鈉、硼氫化鈉等之條件。作為本反應中所使用之酸,可例舉乙酸等。作為溶劑,可例舉:氯仿、二氯甲烷等鹵化碳;二乙醚、THF、1,4-二㗁烷等醚系溶劑;乙酸乙酯、乙酸甲酯等酯系溶劑。反應時間通常為約1小時至24小時,反應溫度為-20℃至溶劑之沸點。
[實施例]
以下,藉由參考例、實施例及試驗例,進一步具體地說明本發明,但本發明當然不限定於該等。再者,於以下之參考例及實施例中所示出之化合物名未必為依據IUPAC命名法者。
於本說明書中,存在使用以下縮寫之情況。
CDCl
3:氘代氯仿
DMSO-d
6:氘代二甲基亞碸
Rt:滯留時間
min:分鐘
HATU:O-(7-氮雜-1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽
THF:四氫呋喃
TFA:三氟乙酸
DMF:N,N-二甲基甲醯胺
Boc:第三丁氧基羰基
Ns:2-硝基苯磺醯基
Tf:三氟甲磺醯基
Abs:絕對組態(Absolute Configuration);關於附註有以四邊形包圍之Abs之縮寫的化合物之化學結構,表示將楔型鍵記為絕對組態。但,未附註該縮寫之化合物之化學結構未必意指並非絕對組態,可依據本說明書中關於對象化合物之記載、上下文及業者之常識來判斷。
Rac:外消旋混合物(Racemic compound);表示因等量存在2種鏡像異構物(對映異構物)而不表現旋光性之狀態之化合物。
參考例及實施例中之管柱層析法及胺基層析法係使用山善股份有限公司製造之矽膠管柱及胺基管柱。使用TLC(Thin-layer chromatography,薄層層析法)進行純化時之TLC(矽膠板)使用Silica gel 60F254(Merck),TLC(NH矽膠板)使用TLC板NH(FujiSilysia)。
參考例及實施例中使用以下反應裝置。參考例及實施例所記載之物理化學資料係由以下機器獲得。
微波反應裝置:Biotage AB Initiator
1H-NMR:JEOL JNM-AL400;JEOL JNM-ECS400;Brucker AVANCE 400 Spectrometer
作為NMR(nuclear magnetic resonance,核磁共振)所使用之符號,s意指單峰,d意指二重峰,dd意指雙二重峰,ddd意指雙雙二重峰,dddd意指雙雙雙二重峰,t意指三重峰,td意指三二重峰,q意指四重峰,m意指多重峰,br意指寬的單峰或多重峰,及J意指耦合常數。
實施例及參考例之各化合物之LC/MS(Liquid chromatography/mass spectrometry,液相層析/質譜法)資料係由以下任一機器獲得。
方法 A檢測機器:ACQUITY(註冊商標)SQ deteceter(Waters公司)
HPLC:ACQUITY UPLC(註冊商標)SYSTEM
管柱:Waters ACQUITY UPLC(註冊商標) BEH C18(1.7 μm,2.1 mm×30 mm)
方法 B檢測機器:島津 LCMS-2020
管柱:Phenomenex Kinetex(C18,1.7 μm,2.1 mm×50 mm)
方法 C檢測機器:ACQUITY(註冊商標)SQ deteceter(Waters公司)
HPLC:ACQUITY UPLC(註冊商標)SYSTEM
管柱:Waters ACQUITY UPLC(註冊商標)BEH C18(1.7 μm,2.1 mm×30 mm)
方法 D檢測機器:島津 LCMS-2020
管柱:Waters ACQUITY UPLC(註冊商標) C18(1.8 μm,2.1 mm×50 mm)
高速液相層析質譜儀;LC/MS之測定條件如以下所述,以[M+H]
+表示所觀察到之質譜分析之值[MS(m/z)],以Rt(min)表示滯留時間。再者,於各實測值中,以A~D之任一者對測定所使用之測定條件進行備註。
方法 A溶劑:A液;0.06%甲酸/H
2O、B液;0.06%甲酸/乙腈
梯度條件:0.0-1.3分鐘(線性梯度自B 2%洗脫至B 96%)
流速:0.8 mL/分鐘;檢測UV:220 nm及254 nm;溫度:40℃
以下,只要無特別說明,則LC-MS資料表示以方法A測得者。
方法 B溶劑:A液;0.05%TFA/H
2O、B液;乙腈
梯度條件:0.0-1.7分鐘(線性梯度自B 10%洗脫至B 99%)
流速:0.5 mL/分鐘;檢測UV:220 nm;溫度:40℃
方法 C溶劑:A液;0.05%甲酸/H
2O、B液;乙腈
梯度條件:0.0-1.3分鐘(線性梯度自B 10%洗脫至B 95%)1.3-1.5分鐘(B 10%)
流速:0.8 mL/分鐘;檢測UV:220 nm及254 nm;溫度:40℃
方法 D溶劑:A液;0.1%甲酸/H
2O、B液;0.1%甲酸/乙腈
梯度條件:0.01-4.0分鐘(線性梯度自B 5%洗脫至B 99%)4.0分-5.0分鐘(B 95%)
流速:0.5 mL/分鐘;檢測UV:220 nm;溫度:25℃
以下,於無記載之情形時,設為以方法A進行分析所獲得者。
參考例 1 :4-(2-{[4-(4-甲基苯基)哌啶-1-羰基]胺基}苯基)哌𠯤-1-羧酸第三丁酯
[化22]
步驟(i):
於0℃下向化合物1(0.100 g)、二異丙基乙基胺(0.047 g)、氯仿(1.8 mL)之混合物中添加氯甲酸4-硝基苯酯(0.073 g),並於該溫度下攪拌1小時。於0℃下向反應混合液中添加4-(4-甲基苯基)哌啶(0.070 g),於室溫下攪拌1小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物2(0.152 g)。
LCMS: [M+H]
+/Rt(min): 479/1.27
步驟(i):
將化合物3(1.41 g)、碳酸鉀(5.52 g)、異丙基哌𠯤(1.28 g)、THF(25 mL)之混合物於50℃攪拌1小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,將殘渣直接用於下一反應。
步驟(ii):
將化合物4之混合物、10%鈀碳(1.06 g)及甲醇(25 mL)之混合物於氫氣環境下在室溫下攪拌1小時。將反應混合液進行矽藻土過濾,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:氯仿/甲醇)將殘渣純化,而獲得標題化合物5(1.50 g)。
LCMS: [M+H]
+/Rt(min): 220/0.35
步驟(i):
使用化合物6(0.159 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物7之混合物。
步驟(ii):
使用化合物7之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物8(0.144 g)。
LCMS: [M+H]
+/Rt(min): 238/0.39
步驟(i):
使用化合物9(0.020 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物10之混合物。
步驟(ii):
使用化合物10之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物11(0.019 g)。
LCMS: [M+H]
+/Rt(min): 250/0.60
步驟(i):
使用化合物12(0.159 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物13之混合物。
步驟(ii):
使用化合物13之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物14(0.190 g)。
LCMS: [M+H]
+/Rt(min): 238/1.16(方法B)
步驟(i):
使用化合物15(0.477 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物16之混合物。
步驟(ii):
使用化合物16之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物17(0.443 g)。
LCMS: [M+H]
+/Rt(min): 238/0.46
步驟(i):
使用化合物18(0.310 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物19之混合物。
步驟(ii):
使用化合物19之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物20(0.410 g)。
LCMS: [M+H]
+/Rt(min): 234/0.61
步驟(i):
使用化合物21(0.209 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物22之混合物。
步驟(ii):
使用化合物22之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物23(0.220 g)。
LCMS: [M+H]
+/Rt(min): 288/1.50(方法B)
步驟(i):
使用化合物24(4.00 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物25之混合物。
步驟(ii):
於90℃下向化合物25之混合物、還原鐵(3.82 g)及甲醇(57 mL)之混合物中添加4 N氯化銨水溶液(28.5 mL),並於該溫度下攪拌2小時。放置冷卻至室溫後,將反應混合液進行矽藻土過濾,於減壓下進行濃縮後,溶解於乙酸乙酯中,利用水及飽和食鹽水進行洗淨。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:氯仿/甲醇)將殘渣純化,而獲得標題化合物26(4.10 g)。
LCMS: [M+H]
+/Rt(min): 254/1.33(方法B)
參考例 10 :2-氯-6-(4-環丙基哌𠯤-1-基)苯胺
[化31]
使用環丙基哌𠯤代替參考例9中之步驟(i)之異丙基哌𠯤,依據上述參考例9所記載之方法,合成化合物27。
LCMS: [M+H]
+/Rt(min): 252/0.60
步驟(i):
使用化合物28(1.50 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物29之混合物。
步驟(ii):
使用化合物29之混合物,依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物30(1.64 g)。
LCMS: [M+H]
+/Rt(min): 298,300/0.58
步驟(i):
使用化合物31(0.212 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物32之混合物。
步驟(ii):
使用化合物32之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物33(0.201 g)。
LCMS: [M+H]
+/Rt(min): 291/1.07(方法B)
步驟(i):
將化合物34(1.00 g)、疊氮化鈉(0.533 g)、水(10 mL)及乙醇(20 mL)之混合物於室溫下攪拌4小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,將殘渣直接用於下一反應。
步驟(ii):
將化合物35之粗產物、硼氫化鈉(0.127 g)及甲醇之混合物於0℃攪拌1小時。於反應混合液中添加飽和氯化銨水溶液,利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物36(0.488 g)。
步驟(iii):
將化合物36(0.289 g)、1-溴-3-甲基-2-丁酮(0.641 g)、碳酸銫(1.176 g)及DMF(3 mL)之混合物於室溫下攪拌5小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物37(0.402 g)。
LCMS: [M+H]
+/Rt(min): 293/1.05
步驟(iv):
將化合物37(0.82 g)、三苯基膦(0.184 g)及THF(2 mL)之混合物於室溫下攪拌10小時。將反應混合液於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物38(0.058 g)。
LCMS: [M+H]
+/Rt(min): 249/0.54
步驟(v):
將化合物38(0.059 g)、三乙醯氧基硼氫化鈉(0.100 g)及二氯甲烷(2 mL)之混合物於室溫下攪拌3小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物39(0.049 g)。
LCMS: [M+H]
+/Rt(min): 251/0.63
步驟(vi):
將化合物39(0.038 g)、二碳酸二第三丁酯(0.040 g)、N,N-二甲基-4-胺基吡啶(0.001 g)及乙腈(2 mL)之混合物於室溫下攪拌2小時。於反應混合液中添加水,並利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,將所獲得之殘渣直接用於下一反應。
LCMS: [M+H]
+/Rt(min): 325/1.24
步驟(vii):
使用化合物40之混合物,依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物41(0.036 g)。
LCMS: [M+H]
+/Rt(min): 321/1.13
步驟(i):
使用化合物42(0.282 g),依據與參考例2之步驟(i)同樣之方法,以粗產物之形式獲得標題化合物43。
步驟(ii):
將化合物43之粗產物、三氟乙酸(1.80 g)、及氯仿(1.0 mL)之混合物於室溫下攪拌1小時。將反應混合液於減壓下進行濃縮後,藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)進行純化,而獲得標題化合物44(0.370 g)。
LCMS: [M+H]
+/Rt(min): 222/1.29(方法B)
步驟(iii):
將化合物44(0.221 g)、三乙醯氧基硼氫化鈉(0.635 g)、乙酸(0.060 g)、丙酮(0.058 g)及THF(5 mL)之混合物於室溫下攪拌3小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,將所獲得之殘渣直接用於下一反應。
步驟(iv):
使用化合物45之粗產物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物46(0.170 g)。
LCMS: [M+H]
+/Rt(min): 234/0.48(方法B)
步驟(i):
使用化合物47(0.221 g),依據與參考例14之步驟(iii)同樣之方法,獲得標題化合物48之粗產物。
步驟(ii):
使用化合物48之粗產物,依據與參考例14之步驟(ii)同樣之方法,獲得標題化合物49(0.098 g)。
LCMS: [M+H]
+/Rt(min): 143/0.30
步驟(iii):
使用化合物49(0.071 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物50之粗產物。
步驟(iv):
使用化合物50之粗產物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物51(0.060 g)。
LCMS: [M+H]
+/Rt(min): 234/0.54
步驟(i):
使用化合物52(0.150 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物53之混合物。
LCMS: [M+H]
+/Rt(min): 308/0.55
步驟(ii):
使用化合物53之混合物,依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物54(0.132 g)。
LCMS: [M+H]
+/Rt(min): 278/0.58
步驟(i):
使用化合物55(1.06 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物56(2.40 g)。
LCMS: [M+H]
+/Rt(min): 322/1.08
步驟(ii):
使用化合物56(2.40 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物57(1.77 g)。
LCMS: [M+H]
+/Rt(min): 292/0.96
步驟(iii):
使用化合物57(0.095 g),依據與參考例1之步驟(i)同樣之方法,獲得標題化合物58(0.153 g)。
LCMS: [M+H]
+/Rt(min): 493/1.12
參考例 18 :4-(2-{[4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-羰基]胺基}苯基)-1,4-二氮雜環庚烷-1-羧酸第三丁酯
[化39]
步驟(i):
使用化合物57(0.104 g),依據與參考例1之步驟(i)同樣之方法,獲得標題化合物59(0.154 g)。
步驟(i):
使用化合物24(0.300 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物60之粗產物。
步驟(ii):
使用化合物60之粗產物,依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物61(0.315 g)。
LCMS: [M+H]
+/Rt(min): 268/0.56
步驟(i):
將化合物62(5.00 g)、N-Boc-1,2,5,6-四氫吡啶-4-硼酸頻那醇酯(7.60 g)、Pd(dppf)Cl
2CH
2Cl
2(2.02 g)、碳酸鈉(5.25 g)、水(25 mL)及1,4-二㗁烷(50 mL)之混合物於110℃攪拌16小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物63(7.51 g)。
LCMS: [M+H]
+/Rt(min): 305/4.24(方法D)
步驟(ii):
將化合物63(7.51 g)、4 N鹽酸二㗁烷溶液(31 mL)及甲醇(150 mL)之混合物於室溫下攪拌1小時。將反應混合液於減壓下進行濃縮後,獲得標題化合物64(5.13 g)。
LCMS: [M+H]
+/Rt(min): 205/2.15(方法D)
步驟(iii):
將化合物64(2.50 g)、三乙醯氧基硼氫化鈉(6.60 g)、丙酮(0.058 g)及二氯甲烷(75 mL)之混合物於室溫下攪拌12小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:氯仿/甲醇)將所獲得之殘渣純化,而獲得標題化合物65(1.60 g)。
LCMS: [M+H]
+/Rt(min): 247/2.17(方法D)
步驟(iv):
使用化合物65(1.60 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物66(0.675 g)。
LCMS: [M+H]
+/Rt(min): 219/1.85(方法D)
步驟(i):
使用化合物28(0.220 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物67(0.234 g)。
LCMS: [M+H]
+/Rt(min): 323/2.12(方法B)
步驟(ii):
將化合物67(0.230 g)、三氟乙酸(1.80 g)、及氯仿(1.0 mL)之混合物於室溫下攪拌1小時。將反應混合液於減壓下進行濃縮後,獲得標題化合物68之粗產物。
步驟(iii):
將化合物68之粗產物、三乙醯氧基硼氫化鈉(0.454 g)、乙酸(0.064 g)、丙酮(0.166 g)及THF(3 mL)之混合物於室溫下攪拌3小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物69(0.150 g)。
LCMS: [M+H]
+/Rt(min): 265/0.60(方法B)
步驟(iv):
使用化合物69(0.100 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物70(0.050 g)。
LCMS: [M+H]
+/Rt(min): 237/0.53(方法B)
參考例 22 :2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯胺
[化43]
步驟(i):
使用化合物69(0.100 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物71(0.077 g)
LCMS: [M+H]
+/Rt(min): 235/0.55(方法B)
步驟(i):
將化合物72(0.654 g)、碘乙烷(0.702 g)、碳酸鉀(1.66 g)及THF(10 mL)之混合物於50℃攪拌2小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物73(0.621 g)。
步驟(ii):
使用化合物73(0.500 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物74(0.558 g)。
LCMS: [M+H]
+/Rt(min): 349/2.24(方法B)
步驟(iii):
使用化合物74(0.300 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物75之粗產物。
步驟(iv):
於0℃下向化合物75之粗產物、二異丙基乙基胺(0.278 g)、氯仿(4 mL)之混合物中添加三光氣(0.064 g),並於該溫度下攪拌1小時。於0℃下向反應混合液中添加4-(4-甲基苯基)哌啶(0.084 g),於室溫下攪拌1小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物76(0.180 g)。
LCMS: [M+H]
+/Rt(min): 522/2.35(方法B)
步驟(i):
使用化合物72(0.654 g),依據與參考例23之步驟(i)同樣之方法,獲得標題化合物77(0.522 g)。
步驟(ii):
使用化合物77(0.520 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物78(0.611 g)。
LCMS: [M+H]
+/Rt(min): 363/2.30(方法B)
步驟(iii):
使用化合物78(0.300 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物79之粗產物。
步驟(iv):
使用化合物79之粗產物,依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物80(0.299 g)。
LCMS: [M+H]
+/Rt(min): 536/2.40(方法B)
步驟(i):
使用化合物81(0.709 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物82(0.502 g)。
LCMS: [M+H]
+/Rt(min): 339/2.26(方法B)
步驟(ii):
使用化合物82(0.100 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物83(0.070 g)。
LCMS: [M+H]
+/Rt(min): 309/2.22(方法B)
步驟(iii):
使用化合物83(0.070 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物84(0.082 g)。
LCMS: [M+H]
+/Rt(min): 511/2.27(方法B)
參考例 26 ~ 29使用各對應之原料化合物代替參考例25中之步驟(iii)之4-(4-甲基苯基)哌啶,依據上述參考例25所記載之方法,合成下述表所示之參考例26~29之化合物。
[表1]
參考例 | 化學結構式 | 機器分析資料 |
26 | LCMS: [M+H] +/Rt(min): 542/0.98 | |
27 | LCMS: [M+H] +/Rt(min): 542/1.68(方法B) | |
28 | LCMS: [M+H] +/Rt(min): 525/2.30(方法B) | |
29 | LCMS: [M+H] +/Rt(min): 459/0.94(方法C) |
參考例26:
4-(3-氯-2-{[4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-羰基]胺基}苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯
參考例27:
4-(3-氯-2-{[4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-羰基]胺基}苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯
參考例28:
4-(3-氯-2-{[4-甲基-4-(4-甲基苯基)哌啶-1-羰基]胺基}苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯
參考例29:
4-{3-氯-2-[(4-氰基-4-甲基哌啶-1-羰基)胺基]苯基}-3,6-二氫吡啶-1(2H)-羧酸第三丁酯
步驟(i):
使用化合物67(0.900 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物89(0.750 g)。
LCMS: [M+H]
+/Rt(min): 293/2.10(方法B)
步驟(ii):
使用化合物89(0.100 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物90(0.130 g)。
LCMS: [M+H]
+/Rt(min): 494/2.27(方法B)
步驟(i):
使用化合物67(0.100 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物91之粗產物。
步驟(ii):
使用化合物91之粗產物,依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物92(0.120 g)。
LCMS: [M+H]
+/Rt(min): 496/1.22
步驟(i):
使用化合物93(3.00 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物94(3.78 g)。
步驟(ii):
使用化合物94(3.78 g),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物95(2.80 g)。
LCMS: [M+H]
+/Rt(min): 235/2.31(方法D)
步驟(iii):
使用化合物95(2.80 g),依據與參考例20之步驟(iii)同樣之方法,獲得標題化合物96(2.80 g)。
LCMS: [M+H]
+/Rt(min): 277/2.42(方法D)
步驟(iv):
使用化合物96(2.00 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物97(1.45 g)。
LCMS: [M+H]
+/Rt(min): 249/3.57(方法C)
參考例 33 :2-甲氧基-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯胺
[化50]
步驟(i):
使用化合物96(0.350 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物98(0.237 g)。
LCMS: [M+H]
+/Rt(min): 247/5.02(方法D)
步驟(i):
使用化合物28(0.100 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物99(0.113 g)。
1H-NMR (CDCl
3) δ: 1.49 (9H, s), 4.20-4.34 (2H, m), 4.35-4.50 (2H, m), 5.90-6.04 (1H, m), 7.08-7.17 (1H, m), 7.17-7.25 (1H, m), 7.42-7.51 (1H, m).
步驟(ii):
使用化合物99(0.111 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物100(0.065 g)。
LCMS: [M+H]
+/Rt(min): 279/0.99(方法B)
步驟(iii):
使用化合物100(0.030 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物101(0.030 g)。
LCMS: [M+H]
+/Rt(min): 480/2.21(shi) (方法C)
步驟(i):
使用化合物28(0.100 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物102(0.056 g)。
1H-NMR (CDCl
3) δ: 2.34-2.42 (2H, m), 3.86-3.92 (2H, m), 4.21-4.27 (2H, m), 5.79-5.86 (1H, m), 7.07-7.13 (1H, m), 7.13-7.21 (1H, m), 7.40-7.50 (1H, m).
步驟(ii):
使用化合物102(0.054 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物103(0.032 g)。
LCMS: [M+H]
+/Rt(min): 194/0.70(方法C)
參考例 36 :2-(1-環丙基-1H-吡唑-4-基)-6-氟苯胺
[化53]
步驟(i):
使用化合物104(0.100 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物105(0.007 g)。
LCMS: [M+H]
+/Rt(min): 218/0.72(方法C)
步驟(i):
使用化合物28(0.165 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物106(0.110 g)。
LCMS: [M+H]
+/Rt(min): 261/0.98
步驟(ii):
使用化合物106(0.110 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物107(0.084 g)。
LCMS: [M+H]
+/Rt(min): 231/0.64
步驟(i):
將化合物108(0.157 g)、4-羥基哌啶-1-羧酸第三丁酯(0.201 g)、二羧酸二異丙酯(0.242 g)、三苯基膦(0.524 g)及THF(10 mL)之混合物於室溫下攪拌1小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物109(0.233 g)。
LCMS: [M+H]
+/Rt(min): 341/2.17(方法B)
步驟(ii):
使用化合物109(0.100 g),依據與參考例21之步驟(ii)同樣之方法,獲得標題化合物110之粗產物。
步驟(iii):
使用化合物110之粗產物,依據與參考例20之步驟(iii)同樣之方法,獲得標題化合物111(0.060 g)。
步驟(iv):
使用化合物111(0.060 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物112(0.030 g)。
參考例 39 :Rac-2-氯-6-{[1-(丙烷-2-基)吡咯啶-3-基]氧基}苯胺
使用各對應之原料化合物代替參考例38中之步驟(i)之化合物108及4-羥基哌啶-1-羧酸第三丁酯,依據上述參考例38所記載之方法,合成下述化合物。
[表2]
參考例 | 化學結構式 | 機器分析資料 |
39 | LCMS: [M+H] +/Rt(min): 255/0.57 (方法C) |
步驟(i):
將3-羥基吖丁啶-1-羧酸第三丁酯(1.30 g)、氫化鈉(0.41 g)、THF(21 mL)之混合物於0℃下攪拌30分鐘後,添加化合物24,並於室溫下攪拌3小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物114(2.06 g)。
LCMS: [M+H]
+/Rt(min): 329/1.11
步驟(ii):
使用化合物114(1.00 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物115(0.77 g)。
LCMS: [M+H]
+/Rt(min): 299/1.06
步驟(iii):
使用化合物115(0.060 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物116(0.110 g)。
LCMS: [M+H]
+/Rt(min): 533/1.08
步驟(i):
使用化合物117(0.181 g)及異丙基哌𠯤(0.128 g),依據與參考例20之步驟(iii)同樣之方法,獲得標題化合物118(0.231 g)。
步驟(ii):
使用化合物118(0.230 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物119(0.140 g)。
步驟(i):
使用化合物28(0.220 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物120(0.231 g)。
步驟(ii):
使用化合物120(0.230 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物121(0.165 g)。
步驟(i):
使用化合物81(0.709 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物122(0.502 g)。
LCMS: [M+H]
+/Rt(min): 339/2.26(方法B)
步驟(ii):
使用化合物122(0.10 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物123(0.039 g)。
LCMS: [M+H]
+/Rt(min): 311/2.21(方法B)
步驟(iii):
使用化合物123(0.070 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物124(0.084 g)。
LCMS: [M+H]
+/Rt(min): 545/1.12(方法C)
參考例 44 ~ 45使用各對應之原料化合物代替參考例43中之步驟(iii)之4-(4-甲基苯基)哌啶,依據上述參考例43所記載之方法,合成下述化合物。
[表3]
參考例 | 化學結構式 | 機器分析資料 |
44 | LCMS: [M+H] +/Rt(min): 527/2.06(方法B) | |
45 | LCMS: [M+H] +/Rt(min): 512/2.30(方法B) |
參考例44:
4-(3-氯-2-{[4-甲基-4-(4-甲基苯基)哌啶-1-羰基]胺基}苯基)哌啶-1-羧酸第三丁酯
參考例45:
4-(3-氯-2-{[4-(4-甲基苯基)哌啶-1-羰基]胺基}苯基)哌啶-1-羧酸第三丁酯
步驟(i):
使用化合物28(0.178 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物127(0.198 g)。
LCMS: [M+H]
+/Rt(min): 261/0.98
步驟(ii):
使用化合物127(0.184 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物128(0.148 g)。
LCMS: [M+H]
+/Rt(min): 231/0.64
步驟(i):
使用化合物81(0.247 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物129(0.147 g)。
LCMS: [M+H]
+/Rt(min): 277/1.07
步驟(ii):
使用化合物129(0.142 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物130(0.130 g)。
LCMS: [M+H]
+/Rt(min): 247/0.75
步驟(i):
使用化合物28(0.143 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物131(0.104 g)。
LCMS: [M+H]
+/Rt(min): 233/0.80
步驟(ii):
使用化合物131(0.091 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物132(0.072 g)。
LCMS: [M+H]
+/Rt(min): 203/0.53
參考例 49 :2-氟-6-[6-(三氟甲基)吡啶-3-基]苯胺
[化63]
步驟(i):
使用化合物104(0.248 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物133(0.054 g)。
LCMS: [M+H]
+/Rt(min): 257/0.90(方法C)
步驟(i):
使用化合物28(0.100 g)及對應之硼酸,依據與參考例20之步驟(i)同樣之方法,獲得標題化合物134(0.038 g)。
LCMS: [M+H]
+/Rt(min): 262/0.90(方法C)
步驟(ii):
使用化合物134(0.036 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物135(0.004 g)。
1H-NMR (CDCl
3) δ: 1.41 (6H, d, J = 6.8 Hz), 3.22-3.37 (1H, m), 3.79 (2H, br), 6.72-6.84 (1H, m), 6.84-6.94 (1H, m), 7.00-7.12 (1H, m), 8.81 (2H, s).
步驟(i):
使用化合物12(0.324 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物136(0.530 g)。
LCMS: [M+H]
+/Rt(min): 338/1.08
步驟(ii):
使用化合物136(0.530 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物137(0.385 g)。
LCMS: [M+H]
+/Rt(min): 308/1.01
步驟(iii):
使用化合物137(0.044 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物138(0.080 g)。
LCMS: [M+H]
+/Rt(min): 509/1.15
參考例 52 :(1S,4S)-5-(2-{[4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-羰基]胺基}-3-氟苯基)-2,5-二氮雜雙環[2.2.1]庚烷-2-羧酸第三丁酯
[化66]
步驟(i):
使用化合物137(0.124 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物139(0.189 g)。
LCMS: [M+H]
+/Rt(min): 541/1.01
步驟(i):
使用化合物12(0.252 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物140(0.410 g)。
LCMS: [M+H]
+/Rt(min): 338/1.08
步驟(ii):
使用化合物140(0.404 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物141(0.224 g)。
LCMS: [M+H]
+/Rt(min): 308/1.01
步驟(iii):
使用化合物141(0.037 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物142(0.080 g)。
LCMS: [M+H]
+/Rt(min): 509/1.15
參考例 54 :(1R,4R)-5-(2-{[4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-羰基]胺基}-3-氟苯基)-2,5-二氮雜雙環[2.2.1]庚烷-2-羧酸第三丁酯
[化68]
步驟(i):
使用化合物141(0.055 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物143(0.088 g)。
LCMS: [M+H]
+/Rt(min): 541/1.01
步驟(i):
使用化合物12(0.382 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物144(0.575 g)。
步驟(ii):
使用化合物144(0.563 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物145(0.451 g)。
LCMS: [M+H]
+/Rt(min): 322/1.11
步驟(iii):
使用化合物145(0.111 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物146(0.161 g)。
LCMS: [M+H]
+/Rt(min): 523/1.23
參考例 56 :3-(2-{[4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-羰基]胺基}-3-氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸第三丁酯
[化70]
步驟(i):
使用化合物145(0.107 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物147(0.189 g)。
LCMS: [M+H]
+/Rt(min): 556/1.12
步驟(i):
使用化合物12(0.204 g),依據與參考例2之步驟(i)同樣之方法,獲得標題化合物148(0.338 g)。
LCMS: [M+H]
+/Rt(min): 386/1.15
步驟(ii):
使用化合物148(0.307 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物149(0.220 g)。
LCMS: [M+H]
+/Rt(min): 356/1.10
步驟(iii):
使用化合物149(0.073 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物150(0.080 g)。
LCMS: [M+H]
+/Rt(min): 557/1.20
步驟(i):
將化合物151(3.03 g)、二氧化錳(11.56 g)及氯仿(160 mL)之混合物於加熱回流下攪拌12小時。放置冷卻後進行矽藻土過濾,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物152(2.59 g)。
LCMS: [M+H]
+/Rt(min): 186/0.81
步驟(ii):
於0℃下向甲基三苯基膦醯溴(3.25 g)與THF(21 mL)之混合物中添加正丁基鋰己烷溶液(1.57 M、5.35 mL),並於該溫度下攪拌1小時。於該混合物中滴加化合物152(1.30 g)之THF(7 mL)溶液,於室溫下攪拌3小時。於反應混合液中添加飽和氯化銨水溶液,利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物153(0.756 g)。
步驟(iii):
將化合物153(0.333 g)、間氯過苯甲酸(0.542 g)及二氯甲烷(9 mL)之混合物於室溫下攪拌4小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:氯仿/甲醇)將所獲得之殘渣純化,而獲得標題化合物154(0.141 g)。
步驟(iv):
將化合物154(0.141 g)、疊氮化鈉(0.046 g)及乙腈(3 mL)之混合物於40℃攪拌3小時。進而添加水(1 mL),於加熱回流下攪拌10小時。將反應混合液於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物155(0.084 g)。
步驟(v):
將化合物155(0.100 g)、1-溴-3-甲基丁烷-2-酮(0.086 g)、碳酸銫(0.226 g)及乙腈(3.5 mL)之混合物於室溫下攪拌2小時。將反應混合液於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物156(0.100 g)。
LCMS: [M+H]
+/Rt(min): 327/1.10
步驟(vi):
將化合物156(0.100 g)、三苯基膦(0.097 g)及THF(6 mL)之混合物於室溫下攪拌4小時。於反應混合液中添加三乙醯氧基硼氫化鈉(0.098 g),於室溫下攪拌16小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,將所獲得之殘渣直接用於下一反應。
LCMS: [M+H]
+/Rt(min): 285/0.69, 285/0.74(方法C)
步驟(vii):
將化合物157之粗產物、Boc
2O(0.067 g)及THF(6 mL)之混合物於室溫下攪拌16小時。依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物之混合物(0.55 g)。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物158(0.031 g)及標題化合物159(0.018)。
步驟(vii):
使用化合物158(0.031 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物160(0.029 g)。
LCMS: [M+H]
+/Rt(min): 355/1.29
參考例 59 :Rac-(2R,5R)-2-(2-胺基-3-氯苯基)-5-(丙烷-2-基)嗎啉-4-羧酸第三丁酯
[化73]
步驟(i):
使用化合物159(0.018 g),依據與參考例9之步驟(ii)同樣之方法,獲得標題化合物161(0.011 g)。
LCMS: [M+H]
+/Rt(min): 355/1.29
步驟(i):
將化合物162(1.42 g)、對甲苯基溴化鎂(1 M、8.52 mL)及THF(20 mL)之混合物於室溫下攪拌14小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物163(1.62 g)。
LCMS: [M+H]
+/Rt(min): 326/1.01
步驟(ii):
將化合物163(0.742 g)、對甲苯磺酸一水合物(0.217 g)及甲苯之混合物於50℃攪拌1小時。於反應混合液中添加飽和碳酸氫鈉水溶液,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物164(0.561 g)。
LCMS: [M+H]
+/Rt(min): 308/2.23(方法B)
步驟(iii):
於0℃向二乙基鋅(1 M、2.12 mL)、二碘甲烷(0.566 g)及二氯甲烷(2 mL)之混合物中滴加化合物164(0.130 g)之二氯甲烷溶液(0.8 mL),於室溫下攪拌14小時。於反應混合液中添加水,並利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,將所獲得之殘渣溶解於THF(2.8 mL)及水(2.8 mL)中。添加N-甲基嗎啉N-氧化物(0.114 g)及氧化鋨(VIII),於室溫下攪拌12小時。於反應混合液中添加THF(3 mL)及飽和硫代硫酸鈉水溶液,於0℃攪拌30分鐘。利用乙酸乙酯進行萃取,利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物165(0.018 g)。
LCMS: [M+H]
+/Rt(min): 322/2.27(方法B)
步驟(iv):
使用化合物165(0.017 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物166(0.010 g)。
LCMS: [M+H]
+/Rt(min): 188/1.37(方法B)
步驟(i):
使用化合物167(0.095 g),依據與參考例20之步驟(i)同樣之方法,獲得標題化合物168(0.100 g)。
LCMS: [M+H]
+/Rt(min): 292/2.26(方法B)
步驟(ii):
使用化合物168(0.100 g),依據與參考例2之步驟(ii)同樣之方法,獲得標題化合物169之粗產物。
步驟(iii):
使用化合物169之粗產物,依據與參考例14之步驟(ii)同樣之方法,獲得標題化合物170(0.050 g)。
LCMS: [M+H]
+/Rt(min): 194/0.58
步驟(i):
於化合物171(50.0 g)之乙醇(446 mL)溶液中添加50%羥基胺水溶液(132 mL),於70℃攪拌8小時。冷卻為室溫後,於反應混合物中添加水(892 mL),於室溫下攪拌30分鐘。濾取所獲得之白色結晶後,於室溫下再次於水(344 mL)中懸浮攪拌30分鐘。濾取所獲得之白色固體並加以乾燥,藉此獲得標題化合物172(52.3 g)。
LCMS: [M+H]
+/Rt(min): 258/0.52(方法C)
步驟(ii):
於冰浴下向化合物172(52.3 g)、環丙烷羧酸(18.4 g)、HATU(85 g)及THF(406 mL)之混合物中緩慢滴加三乙胺(142 mL),於室溫下攪拌12小時。於反應混合液中添加乙酸乙酯(406 mL),利用水(406 mL)、飽和食鹽水(406 mL)洗淨。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物173(59.1 g)。
LCMS: [M+H]
+/Rt(min): 326/0.77(方法C)
步驟(iii):
將化合物173(59.1 g)、DBU(54.2 mL)及甲苯(727 mL)之混合物於加熱回流下攪拌1小時。冷卻為室溫後,利用水(727 mL)洗淨,其後,於減壓下將有機層濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物174(54.5 g)。
LCMS: [M+H]
+/Rt(min): 308/1.11(方法C)
驟(iv):
使用化合物174(54.5 g),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物175(35.3 g)。
LCMS: [M+H]
+/Rt(min): 208/0.30(方法C)
參考例 63 ~ 87使用各對應之原料化合物代替參考例62中之步驟(i)之化合物171及步驟(ii)之環丙烷羧酸,依據上述參考例62所記載之方法,合成下述表所示之參考例63~87之化合物。
[表4]
參考例 | 化學結構式 | 機器分析資料 | |
63 | LCMS: [M+H] +/Rt(min): 182/0.20(方法C) | ||
64 | LCMS: [M+H] +/Rt(min): 196/0.32(方法C) | ||
65 | LCMS: [M+H] +/Rt(min): 210/0.37(方法C) | ||
66 | LCMS: [M+H] +/Rt(min): 222/0.42(方法C) | ||
67 | LCMS: [M+H] +/Rt(min): 236/0.53(方法C) | ||
68 | LCMS: [M+H] +/Rt(min): 236/0.45(方法C) | ||
69 | LCMS: [M+H] +/Rt(min): 250/0.43(方法C) | ||
70 | LCMS: [M+H] +/Rt(min): 258/0.24(方法C) | ||
71 | LCMS: [M+H] +/Rt(min): 222/0.42(方法C) | ||
72 | LCMS: [M+H] +/Rt(min): 222/0.48(方法C) | ||
73 | LCMS: [M+H] +/Rt(min): 212/0.28(方法C) | ||
74 | LCMS: [M+H] +/Rt(min): 200/0.23(方法C) | ||
75 | LCMS: [M+H] +/Rt(min): 222/0.57(方法C) | ||
76 | LCMS: [M+H] +/Rt(min): 222/0.54(方法C) | ||
77 | LCMS: [M+H] +/Rt(min): 236/0.65(方法C) | ||
78 | LCMS: [M+H] +/Rt(min): 276/0.64(方法C) | ||
79 | LCMS: [M+H] +/Rt(min): 238/0.49(方法C) | ||
80 | LCMS: [M+H] +/Rt(min): 226/0.37(方法C) | ||
81 | LCMS: [M+H] +/Rt(min): 244/0.50(方法C) | ||
82 | LCMS: [M+H] +/Rt(min): 226/0.32(方法C) | ||
83 | LCMS: [M+H] +/Rt(min): 226/0.36(方法C) | ||
84 | LCMS: [M+H] +/Rt(min): 226/0.29(方法C) | ||
85 | LCMS: [M+H] +/Rt(min): 226/0.31(方法C) | ||
86 | LCMS: [M+H] +/Rt(min): 222/0.44(方法C) | ||
87 | LCMS: [M+H] +/Rt(min): 222/0.45(方法C) | ||
參考例63:
4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)哌啶鹽酸鹽
參考例64:
4-(5-乙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶鹽酸鹽
參考例65:
4-甲基-4-[5-(丙烷-2-基)-1,2,4-㗁二唑-3-基]哌啶鹽酸鹽
參考例66:
4-(5-環丁基-1,2,4-㗁二唑-3-基)-4-甲基哌啶鹽酸鹽
參考例67:
4-(5-環戊基-1,2,4-㗁二唑-3-基)-4-甲基哌啶鹽酸鹽
參考例68:
4-甲基-4-[5-(三氟甲基)-1,2,4-㗁二唑-3-基]哌啶鹽酸鹽
參考例69:
4-甲基-4-[5-(2,2,2-三氟乙基)-1,2,4-㗁二唑-3-基]哌啶鹽酸鹽
參考例70:
4-[5-(3,3-二氟環丁基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶鹽酸鹽
參考例71:
4-甲基-4-[5-(1-甲基環丙基)-1,2,4-㗁二唑-3-基]哌啶鹽酸鹽
參考例72:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基哌啶鹽酸鹽
參考例73:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-氟哌啶鹽酸鹽
參考例74:
4-(5-乙基-1,2,4-㗁二唑-3-基)-4-氟哌啶鹽酸鹽
參考例75:
rac-4-甲基-4-{5-[(1R,2S)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶鹽酸鹽
參考例76:
4-[5-(環丙基甲基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶鹽酸鹽
參考例77:
4-[5-(2,2-二甲基環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶鹽酸鹽
參考例78:
4-甲基-4-{5-[1-(三氟甲基)環丙基]-1,2,4-㗁二唑-3-基}哌啶鹽酸鹽
參考例79:
4-[5-(1-甲氧基環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶鹽酸鹽
參考例80:
4-[5-(1-氟環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶鹽酸鹽
參考例81:
4-[5-(2,2-二氟環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶鹽酸鹽
參考例82:
rac-4-{5-[(1S,2S)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶鹽酸鹽
參考例83:
rac-4-{5-[(1R,2S)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶鹽酸鹽
參考例84:
4-{5-[(1S,2S)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶鹽酸鹽
參考例85:
4-{5-[(1R,2R)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶鹽酸鹽
參考例86:
4-{5-[(1R,2S)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶鹽酸鹽
參考例87:
4-{5-[(1S,2R)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶鹽酸鹽
步驟(i):
於化合物201(0.100 g)之甲苯(0.01 mL)溶液中添加CDI(Carbonyldiimidazole,羰基二咪唑)(0.070 g),於室溫下攪拌3小時。於反應混合液中添加N'-羥基環丙甲脒鹽酸鹽(0.059 mg),於加熱回流下攪拌2小時。藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將反應混合液進行純化,而獲得標題化合物202(0.123 g)。
LCMS: [M+H]
+/Rt(min): 320/1.01(方法C)
步驟(ii):
使用化合物202(0.121 g),依據與參考例14之步驟(ii)同樣之方法,獲得標題化合物203(0.091 g)。
LCMS: [M+H]
+/Rt(min): 220/0.30(方法C)
步驟(i):
於化合物204(900 mg)、乙酸鈉(650 mg)、及甲醇(5 mL)之混合物中添加羥基胺鹽酸鹽(550 mg),於室溫下攪拌24小時。將反應溶液冷卻為0℃,添加水,利用氯仿進行萃取,利用無水硫酸鈉將有機層加以乾燥後,於減壓下進行濃縮,而獲得標題化合物205(1.23 g)。
步驟(ii):
於化合物205(416 mg)與DMF(4 mL)之混合物中添加N-氯丁二醯亞胺(252 mg),並攪拌3小時。將反應溶液冷卻為0℃,添加水(6 mL),將所析出之固體加以過濾、乾燥,而獲得標題化合物206(326 mg)。
步驟(iii):
於乙炔基環丙烷(117 mg)與甲苯(5 mL)之混合物中添加化合物206(326 mg)及碳酸氫鈉(198 mg),於室溫下進行攪拌。確認原料消失後,於反應混合液中添加水,利用乙酸乙酯進行萃取,利用無水硫酸鈉將有機層加以乾燥後,於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)進行純化,而獲得標題化合物207(348 mg)。
LCMS: [M+H]
+/Rt(min): 307/1.13
步驟(iv):
使用化合物207(337 mg),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物208(307 mg)。
LCMS: [M+H]
+/Rt(min): 207/0.49
參考例 90 ~ 91使用各對應之原料化合物代替參考例89中之步驟(iii)之乙炔基環丙烷,依據上述參考例89所記載之方法,合成下述表所示之參考例90~91之化合物。
[表5]
參考例 | 化學結構式 | 機器分析資料 |
90 | LCMS: [M+H] +/Rt(min): 209/0.53 | |
91 | LCMS: [M+H] +/Rt(min): 181/0.44 |
參考例90:
4-甲基-4-[5-(丙烷-2-基)-1,2-㗁唑-3-基]哌啶
參考例91:
4-甲基-4-(5-甲基-1,2-㗁唑-3-基)哌啶
步驟(i):
於冰浴冷卻下向化合物211(1.46 g)之THF溶液(30 mL)中添加氯甲酸異丁酯(819 mg)及二異丙基乙基胺(3.88 g),並攪拌1小時。其後,於冰浴冷卻下添加2-胺基苯酚(655 mg),於70℃加熱攪拌6小時。藉由胺基矽膠管柱層析法(溶出液:乙酸乙酯/己烷)將反應液直接進行純化,而獲得標題化合物212(710 mg)。
LCMS: [M+H]
+/Rt(min): 335/2.28(方法B)
步驟(ii):
將化合物212(204 mg)與乙酸(1.10 mL)之混合物於90℃加熱攪拌2小時,於減壓下進行濃縮。將所獲得之殘渣溶解於氯仿(2 mL)中,添加三氟甲磺酸(2.1 mL),於室溫下攪拌1小時。將反應液於減壓下進行濃縮,添加乙酸乙酯及碳酸氫鈉水溶液,利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由胺基矽膠管柱層析法(溶出液:乙酸乙酯/己烷)將殘渣純化,而獲得標題化合物213(99 mg)。
LCMS: [M+H]
+/Rt(min): 217/1.36(方法B)
步驟(i):
將化合物207(500 mg)與N-氯丁二醯亞胺(240 mg)之DMF溶液(3.3 mL)於室溫下攪拌3天。於反應溶液中添加水,利用二乙醚進行萃取。利用水洗淨有機層後,利用硫酸鈉加以乾燥,於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物214(434 mg)。
步驟(ii):
使用化合物214(200 mg),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物215(120.1 mg)。
LCMS: [M+H]
+/Rt(min): 241/0.65
參考例 94 :4-(4-氯-5-甲基-1,2-㗁唑-3-基)-4-甲基哌啶鹽酸鹽
[化81]
使用參考例91之化合物210代替參考例93中之步驟(i)之化合物207,依據上述參考例93所記載之方法,合成化合物216。
LCMS: [M+H]
+/Rt(min): 215/0.51
步驟(i):
於-78℃向化合物217(700 mg)與THF(14 mL)之混合液中添加二異丙基醯胺鋰(2 M、5.18 mL),於該溫度下攪拌2小時。其後,於反應混合液中添加溴環戊烷(1.23 mL)及碘化鉀(478 mg),升溫至室溫並進行整夜攪拌後,添加水,利用乙酸乙酯進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:乙酸乙酯/己烷)將殘渣純化,而獲得標題化合物218(468 mg)。
LCMS: [M+H]
+/Rt(min): 312/1.26
步驟(ii):
於冰浴冷卻下向氫化鋁鋰(104 mg)與THF(3 mL)之混合物中添加化合物218(371 mg)與THF(6 mL)之混合物,並攪拌4小時。確認原料消失後,於0℃依序向反應混合液中添加水(0.104 mL)、15%氫氧化鈉水溶液(0.104 ml)、及水(0.312 mL)並攪拌。將反應液過濾,將濾液於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:乙酸乙酯/己烷)將殘渣純化,而獲得標題化合物219(320 mg)。
LCMS: [M+H]
+/Rt(min): 284/1.06
步驟(iii):
於化合物219(314 mg)、三乙胺(0.309 mL)、及THF(5 mL)之混合液中添加甲磺醯氯(0.104 mL),於室溫下進行攪拌。確認原料消失後,於反應混合液中添加水,並利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:乙酸乙酯/己烷)將殘渣純化,而獲得標題化合物220(290 mg)。
LCMS: [M+H]
+/Rt(min): 362/1.15
步驟(iv):
於化合物220(278 mg)與THF(3 mL)之混合物中添加三乙基硼氫化鋰(0.99 M、1.55 mL),於室溫下進行攪拌。其後將反應液加熱為70℃,確認原料消失後冷卻為0℃,並添加氯化銨水溶液。利用氯仿進行萃取,利用無水硫酸鈉將有機層加以乾燥後,於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)進行純化,而獲得標題化合物221(100 mg)。
LCMS: [M+H]
+/Rt(min): 268/1.42
步驟(v):
使用化合物221(90 mg),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物222(58.5 mg)。
LCMS: [M+H]
+/Rt(min): 168/0.62
步驟(i):
於冷卻為-78℃之化合物223(1.00 g)之THF(10 mL)溶液中滴加LHMDS(lithium hexamethyldisilazide,雙(三甲基矽烷)胺基鋰)之甲苯溶液(1 M、4.35 mL),並攪拌1小時。添加三甲基氯矽烷(0.495 g),升溫為0℃後,攪拌30分鐘。再次冷卻為-78℃後,添加溴(0.662 g),逐漸升溫為室溫。將反應混合物注入10%次氯酸鈉水溶液(7.5 mL)及飽和氯化銨水溶液(7.5 mL)之混合溶液中,利用乙酸乙酯進行萃取。將所獲得之有機層於減壓下蒸餾去除,藉此獲得標題化合物224(1.16 g)。
LCMS: [M+H]
+/Rt(min): 321/0.94
步驟(ii):
將化合物224(0.10 g)與乙醯胺(0.020 g)之混合物於130℃攪拌3小時。藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將反應混合液進行純化,而獲得標題化合物225(0.007 g)。
LCMS: [M+H]
+/Rt(min): 281/0.97
步驟(iii):
使用化合物225(0.007 g),依據與參考例14之步驟(ii)同樣之方法,獲得標題化合物226(0.005 g)。
LCMS: [M+H]
+/Rt(min): 181/0.22
步驟(i):
使用化合物224(0.10 g),依據與參考例96之步驟(ii)同樣之方法,獲得標題化合物227(0.012 g)。
LCMS: [M+H]
+/Rt(min): 309/1.18
步驟(ii):
使用化合物227(0.011 g),依據與參考例14之步驟(ii)同樣之方法,獲得標題化合物228(0.009 g)。
LCMS: [M+H]
+/Rt(min): 209/0.38
步驟(i):
於化合物211(399 mg)、環丙烷甲二醯肼鹽酸鹽(269 mg)、及DMF(5 mL)之混合物中添加HATU(686 mg)及二異丙基乙基胺(1.15 mL),於室溫下攪拌3小時。於反應液中添加水,利用乙酸乙酯進行萃取。利用無水硫酸鈉將有機層加以乾燥後,於減壓下進行濃縮。藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物229(520 mg)。
LCMS: [M+H]
+/Rt(min): 326/0.74
步驟(ii):
於化合物229(255 mg)與甲苯(6 mL)之混合物中添加勞森試劑(349 mg),於回流條件下加熱攪拌1小時。將反應液冷卻為0℃後,添加碳酸氫鈉水溶液,利用乙酸乙酯進行萃取。利用無水硫酸鈉將有機層加以乾燥後,於減壓下進行濃縮,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)進行純化,其後藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)進行純化,而獲得標題化合物230(102 mg)。
LCMS: [M+H]
+/Rt(min): 324/1.08
步驟(iii):
使用化合物230(92 mg),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物231(78 mg)。
LCMS: [M+H]
+/Rt(min): 224/0.45
步驟(i):
使用化合物211(718 mg)及2-胺基-1-環丙基乙烷-1-酮鹽酸鹽(400 mg),依據與參考例98之步驟(i)同樣之方法,獲得標題化合物232(796 mg)。
LCMS: [M+H]
+/Rt(min): 325/0.83
步驟(ii):
於化合物232(127 mg)、吡啶(0.063 mL)、及甲苯(3 mL)之混合物中添加勞森試劑(205 mg),於回流條件下加熱攪拌14小時。將反應液冷卻為室溫後,添加碳酸氫鈉水溶液,利用乙酸乙酯進行萃取。利用無水硫酸鈉將有機層加以乾燥後,於減壓下進行濃縮,藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)進行純化,而獲得標題化合物233(76.3 mg)。
LCMS: [M+H]
+/Rt(min): 323/1.43
步驟(iii):
使用化合物233(77 mg),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物234(66.5 mg)。
LCMS: [M+H]
+/Rt(min): 223/0.67
步驟(i):
將化合物224(531.6 mg)與環丙烷硫代碳醯胺(168 mg)之甲醇溶液(6 mL)於加熱回流下攪拌2個半小時。將所獲得之混合物放置冷卻至室溫後,添加飽和碳酸氫鈉水溶液,利用氯仿進行萃取。利用硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物235(119 mg)。
步驟(ii):
使用化合物235(119 mg),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物236(136.8 mg)。
LCMS: [M+H]
+/Rt(min): 223/0.57
參考例 101 :4-甲基-1-({2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}胺甲醯基)哌啶-4-羧酸乙酯
[化88]
步驟(i):
使用化合物5(0.237 g),依據與參考例1之步驟(i)同樣之方法,獲得標題化合物237(0.357 g)。
LCMS: [M+H]
+/Rt(min): 417/1.61(方法B)
參考例 102 :4-氟-1-({2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}胺甲醯基)哌啶-4-羧酸乙酯
[化89]
步驟(i):
使用化合物5(0.179 g),依據與參考例1之步驟(i)同樣之方法,獲得標題化合物238(0.040 g)。
LCMS: [M+H]
+/Rt(min): 421/1.57(方法B)
參考例 103(3aR,5s,6aS)-5-氰基六氫環戊[c]吡咯-2(1H)-羧酸第三丁酯(化合物A-2)及(3aR,5r,6aS)-5-氰基六氫環戊[c]吡咯-2(1H)-羧酸第三丁酯(化合物A-3)
[化90]
於0℃向化合物A-1(331 mg)之1,2-二甲氧基乙烷(6.7 mL)/乙醇(0.67 mL)液中添加對甲苯磺醯基甲胩(373 mg)與第三丁醇鉀(396 mg),於40℃攪拌4小時。冷卻為室溫後,將反應液進行過濾,將濾液於減壓下進行濃縮後,藉由矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物A-2(80 mg)及A-3(59.4 mg)。
化合物A-2:LCMS: [M+H]
+/Rt(min): 237/0.89
化合物A-3:LCMS: [M+H]
+/Rt(min): 237/0.88
參考例 104 ~ 105使用參考例103之化合物A-2或A-3代替參考例62中之步驟(i)之化合物171,依據上述參考例62所記載之方法,合成下述表所示之參考例104~105之化合物。
[表6]
參考例 | 化學結構式 | 機器分析資料 |
104 | LCMS: [M+H] +/Rt(min): 220/0.39 | |
105 | LCMS: [M+H] +/Rt(min): 220/0.48 |
參考例104:
(3aR,5s,6aS)-5-(5-環丙基-1,2,4-㗁二唑-3-基)八氫環戊[c]吡咯
參考例105:
(3aR,5r,6aS)-5-(5-環丙基-1,2,4-㗁二唑-3-基)八氫環戊[c]吡咯
實施例 1 :N-[2-(4-乙基哌𠯤-1-基)苯基]-4-(4-甲氧基苯基)哌啶-1-甲醯胺
[化91]
使用化合物239(0.025 g)及化合物240(0.021 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物(0.031 g)。
1H-NMR (CDCl
3) δ: 1.14 (3H, t, J = 7.2 Hz), 1.59-1.76 (3H, m), 1.94 (2H, d, J = 12.4 Hz), 2.48-2.75 (6H, m), 2.95-3.05 (6H, m), 3.80 (3H, s), 4.28 (2H, d, J = 13.2 Hz), 6.87 (2H, d, J = 7.2 Hz), 6.96 (1H, dt, J = 7.6, 5.6 Hz), 7.12-7.18 (4H, m), 8.22 (1H, dd, J = 8.4, 1.6 Hz), 8.26 (1H, s).
實施例2:
4-(1,3-苯并㗁唑-2-基)-N-[2-(4-乙基哌𠯤-1-基)苯基]哌啶-1-甲醯胺
實施例3:
4-(3,5-二甲氧基苯基)-N-[2-(4-乙基哌𠯤-1-基)苯基]哌啶-1-甲醯胺
實施例4:
N-[2-(4-乙基哌𠯤-1-基)苯基]-4-甲基-4-苯基哌啶-1-甲醯胺鹽酸鹽
實施例5:
4-甲基-4-苯基-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例6:
4-氰基-4-苯基-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例7:
4-苯基-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例8:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例9:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例10:
N-{4-氟-2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例11:
N-{3-氟-2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例12:
4-甲基-4-(3-苯基-1,2,4-㗁二唑-5-基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}
哌啶-1-甲醯胺
實施例13:
4-甲基-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[3-(吡啶-3-基)-1,2,4-㗁二唑-5-基]哌啶-1-甲醯胺
實施例14:
6-(4-甲基苯基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-3-氮雜雙環[4.1.0]庚烷-3-甲醯胺
實施例15:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[4-(三氟甲基)苯基]哌啶-1-甲醯胺
實施例16:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[4-(三氟甲氧基)苯基]哌啶-1-甲醯胺
實施例17:
4-(4-甲基苯基)-N-{2-甲基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例18:
4-(2-氟-4-甲基苯基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例19:
4-甲基-4-[5-(丙烷-2-基)-1,2,4-㗁二唑-3-基]-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例20:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例21:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例22:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)哌啶-1-甲醯胺
實施例23:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)哌啶-1-甲醯胺
實施例24:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(三氟甲基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例25:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(三氟甲基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例26:
Rac-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-3-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例27:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-苯氧基哌啶-1-甲醯胺
實施例28:
Rac-4-(4-甲基苯基)-N-{2-[3-甲基-4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例29:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(3-甲基苯基)哌啶-1-甲醯胺
實施例30:
Rac-4-(4-甲基苯基)-N-{2-[2-甲基-4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例31:
4-(4-甲基苯基)-N-{2-[1-(丙烷-2-基)哌啶-4-基]苯基}哌啶-1-甲醯胺鹽酸鹽
實施例32:
3-(3-環丙基-1,2,4-㗁二唑-5-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-8-氮雜雙環[3.2.1]辛烷-8-甲醯胺
實施例33:
N-{2-(二甲基胺甲醯基)-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例34:
4-(4-甲基苯基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]-6-(三氟甲基)苯基}哌啶-1-甲醯胺
實施例35:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例36:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(吡啶-2-基)哌啶-1-甲醯胺
實施例37:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(2-甲基苯基)哌啶-1-甲醯胺
實施例38:
2-{[4-(4-甲基苯基)哌啶-1-羰基]胺基}-3-[4-(丙烷-2-基)哌𠯤-1-基]苯甲酸甲酯
實施例39:
N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例40:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[4-(丙烷-2-基)苯基]哌啶-1-甲醯胺
實施例41:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-3-(4-甲基苯基)-8-氮雜雙環[3.2.1]辛烷-8-甲醯胺
實施例42:
N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例43:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例44:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例45:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例46:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-甲基吡啶-2-基)哌啶-1-甲醯胺
實施例47:
N-{2-甲氧基-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例48:
N-{2-甲氧基-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例49:
4-(1,3-苯并㗁唑-2-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例50:
4-(1,3-苯并㗁唑-2-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例51:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}哌啶-1-甲醯胺
實施例52:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例53:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例54:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例55:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例56:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-[2-(3,6-二氫-2H-哌喃-4-基)-6-氟苯基]-4-甲基哌啶-1-甲醯胺
實施例57:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-硫代碳醯胺
實施例58:
N-[2-(1-環丙基-1H-吡唑-4-基)-6-氟苯基]-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例59:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[6-(丙烷-2-基)吡啶-3-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例60:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[6-(丙烷-2-基)吡啶-3-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例61:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例62:
N-(2-氟-6-{[1-(丙烷-2-基)哌啶-4-基]氧基}苯基)-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例63:
N-(2-甲氧基-6-{[4-(丙烷-2-基)哌𠯤-1-基]甲基}苯基)-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例64:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-硫代碳醯胺
實施例65:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-[3-氟-4'-(丙烷-2-基)[1,1'-聯苯]-2-基]-4-甲基哌啶-1-甲醯胺
實施例66:
4-(1,3-苯并㗁唑-2-基)-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例67:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例68:
4-(5-環丙基-1,2-㗁唑-3-基)-N-[2-氟-6-(6-甲基吡啶-3-基)苯基]-4-甲基哌啶-1-甲醯胺
實施例69:
N-{2-氯-6-[6-(丙烷-2-基)吡啶-3-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例70:
4-(5-環丙基-1,2-㗁唑-3-基)-N-[2-氟-6-(5-甲基吡啶-3-基)苯基]-4-甲基哌啶-1-甲醯胺
實施例71:
4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[6-(三氟甲基)吡啶-3-基]苯基}-4-甲基哌啶-1-甲醯胺鹽酸鹽
實施例72:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[2-(丙烷-2-基)嘧啶-5-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例73:
4-(5-環戊基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例74:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環戊基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例75:
4-[5-(3,3-二氟環丁基)-1,2,4-㗁二唑-3-基]-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例76:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[5-(3,3-二氟環丁基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶-1-甲醯胺
實施例77:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例78:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丁基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例79:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(1-甲基環丙基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例80:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(1-甲基環丙基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例81:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)哌啶-1-甲醯胺
實施例82:
4-(5-乙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例83:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-乙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例84:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2-㗁唑-3-基)哌啶-1-甲醯胺
實施例85:
N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2-㗁唑-3-基)哌啶-1-甲醯胺
實施例86:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(三氟甲基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例87:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例88:
N-{2-溴-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例89:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基哌啶-1-甲醯胺
實施例90:
4-(4-氯-5-甲基-1,2-㗁唑-3-基)-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例91:
4-環戊基-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例92:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(2-甲基-1,3-㗁唑-5-基)哌啶-1-甲醯胺
實施例93:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[2-(丙烷-2-基)-1,3-㗁唑-5-基]哌啶-1-甲醯胺
實施例94:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-氟哌啶-1-甲醯胺
實施例95:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-乙基-1,2,4-㗁二唑-3-基)-4-氟哌啶-1-甲醯胺
實施例96:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(2-環丙基-1,3-噻唑-4-基)-4-甲基哌啶-1-甲醯胺
實施例97:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-1,2,4,5-四氫-3H-3-苯并氮呯-3-甲醯胺
實施例98:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-甲基嘧啶-2-基)哌啶-1-甲醯胺
實施例99:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)-1,4-二氮雜環庚烷-1-甲醯胺
實施例100:
N-[2-(4-第三丁基哌𠯤-1-基)-6-氯苯基]-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例101:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,3-噻唑-2-基)-4-甲基哌啶-1-甲醯胺
實施例102:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,3,4-噻二唑-2-基)-4-甲基哌啶-1-甲醯胺
實施例103:
4-(4-氯-5-環丙基-1,2-㗁唑-3-基)-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例104:
Rac-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺
實施例105:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[5-(環丙基甲基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶-1-甲醯胺
實施例106:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[5-(2,2-二甲基環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶-1-甲醯胺
實施例107:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[1-(三氟甲基)環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺
實施例108:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[5-(1-甲氧基環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶-1-甲醯胺
實施例109:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[5-(1-氟環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶-1-甲醯胺
實施例110:
Rac-N-(2-氯-6-{[1-(丙烷-2-基)吡咯啶-3-基]氧基}苯基)-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例111:
Rac-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1S,2S)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺
實施例112:
Rac-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1S,2R)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺
實施例113:
N-[2-氯-6-(4-環丙基哌𠯤-1-基)苯基]-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例114:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-[5-(2,2-二氟環丙基)-1,2,4-㗁二唑-3-基]-4-甲基哌啶-1-甲醯胺
實施例115:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1S,2S)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺
實施例116:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1R,2R)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺
實施例117:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1S,2R)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺
實施例118:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺
實施例119:
N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(2,2,2-三氟乙基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺
實施例120:
4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
步驟(i):
使用化合物2(0.152 g),依據與參考例20之步驟(ii)同樣之方法,獲得標題化合物242之粗產物。
LCMS: [M+H]
+/Rt(min): 208/0.30
步驟(ii):
使用化合物242之粗產物,依據與參考例20之步驟(iii)同樣之方法,獲得標題化合物243(0.202 g)。
1H-NMR (CDCl
3) δ: 1.21 (6H, d, J = 6.1 Hz), 1.62-1.71 (2H, m), 1.84 (2H, m), 2.26 (3H, s), 2.55-2.69 (6H, m), 2.85 (4H, m), 2.95 (2H, m), 4.22 (2H, m), 6.88 (1H, m), 7.03-7.11 (6H, m), 8.14 (1H, m), 8.25 (1H, brs)
實施例122:
N-[2-(4-乙基哌𠯤-1-基)苯基]-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例123:
4-(4-甲基苯基)-N-[2-(4-甲基哌𠯤-1-基)苯基]哌啶-1-甲醯胺
實施例124:
4-(4-甲基苯基)-N-{2-[4-(氧雜環戊烷-3-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例125:
N-{2-[4-(2-甲氧基乙基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例126:
N-{2-[4-(1-甲氧基丙烷-2-基)哌𠯤-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例127:
N-{2-乙氧基-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例128:
N-{2-[1-(丁烷-2-基)哌啶-4-基]-6-乙氧基苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例129:
4-(4-甲基苯基)-N-{2-[(丙烷-2-基)氧基]-6-[1-(丙烷-2-基)哌啶-4-基]苯基}哌啶-1-甲醯胺
實施例130:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例131:
N-[2-氯-6-(1-環丁基-1,2,3,6-四氫吡啶-4-基)苯基]-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例132:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例133:
N-{2-氯-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例134:
N-{2-氟-6-[1-(1-氟丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例135:
N-{2-[1-(1,1-二氟丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]-6-氟苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例136:
N-{2-[1-(1,3-二氟丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]-6-氟苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例137:
N-{2-氟-6-[1-(1-氟丙烷-2-基)哌啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例138:
N-{2-[1-(1,1-二氟丙烷-2-基)哌啶-4-基]-6-氟苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例139:
N-{2-氟-6-[1-(丙烷-2-基)-2,5-二氫-1H-吡咯-3-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例140:
N-[2-氟-6-(1-甲基-2,5-二氫-1H-吡咯-3-基)苯基]-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例141:
N-{2-氯-6-[1-(1-氟丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例142:
N-{2-氯-6-[1-(1-氟丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例143:
N-{2-氯-6-[1-(1-氟丙烷-2-基)哌啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例144:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例145:
N-{2-氯-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例146:
N-{2-氯-6-[1-(氧雜環丁烷-3-基)哌啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例147:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例148:
N-{2-氯-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例149:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-[(1S,4S)-5-乙基-2,5-二氮雜雙環[2.2.1]庚烷-2-基]-6-氟苯基}-4-甲基哌啶-1-甲醯胺
實施例150:
N-{2-氟-6-[(1S,4S)-5-(丙烷-2-基)-2,5-二氮雜雙環[2.2.1]庚烷-2-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例151:
N-{2-氟-6-[(1R,4R)-5-(丙烷-2-基)-2,5-二氮雜雙環[2.2.1]庚烷-2-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例152:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[(1R,4R)-5-(丙烷-2-基)-2,5-二氮雜雙環[2.2.1]庚烷-2-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例153:
N-[2-(4-乙基-1,4-二氮雜環庚烷-1-基)苯基]-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例154:
N-{2-氟-6-[8-(丙烷-2-基)-3,8-二氮雜雙環[3.2.1]辛烷-3-基]苯基}-4-(4-甲基苯基)哌啶-1-甲醯胺
實施例155:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[8-(丙烷-2-基)-3,8-二氮雜雙環[3.2.1]辛烷-3-基]苯基}-4-甲基哌啶-1-甲醯胺
實施例156:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-[2-(4-乙基-1,4-二氮雜環庚烷-1-基)苯基]-4-甲基哌啶-1-甲醯胺
實施例157:
4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基-N-[2-(4-丙基-1,4-二氮雜環庚烷-1-基)苯基]哌啶-1-甲醯胺
實施例158:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-氰基-4-甲基哌啶-1-甲醯胺
實施例159:
N-[2-氯-6-(1-環丁基-1,2,3,6-四氫吡啶-4-基)苯基]-4-氰基-4-甲基哌啶-1-甲醯胺
實施例160:
N-(2-氯-6-{[1-(丙烷-2-基)吖丁啶-3-基]氧基}苯基)-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
步驟(i):
將化合物150(0.079 g)、氫氧化鈀(0.020 g)及乙醇(2 mL)之混合物於室溫下在氫氣環境下攪拌3小時。利用矽藻土將反應混合液過濾,將濾液於減壓下進行濃縮後,將殘渣直接用於下一反應。
步驟(ii):
使用化合物244之粗產物,依據與參考例20之步驟(iii)同樣之方法,獲得標題化合物245(0.066 g)。
1H-NMR (CDCl
3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.61 (3H, s), 1.74 (2H, ddd, J = 25.4, 13.1, 4.0 Hz), 1.83-1.96 (6H, m), 2.33 (3H, s), 2.55 (2H, d, J = 9.8 Hz), 2.62-2.76 (4H, m), 3.03 (2H, ddd, J = 13.1, 13.1, 2.2 Hz), 3.60-3.65 (2H, m), 4.29-4.37 (2H, m), 6.17 (1H, s), 6.66 (1H, d, J = 8.3 Hz), 6.77 (1H, dd, J = 8.6, 8.3 Hz), 6.94-7.01 (1H, m), 7.11 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz).
步驟(i):
將(Z)-N'-羥基乙醯亞胺醯胺(0.0125 g)、氫化鈉(0.0134 g)及THF(1 mL)之混合物於加熱回流下攪拌2小時。放置冷卻為室溫後,添加參考例101之化合物237(0.035 g),於加熱回流下攪拌5小時。放置冷卻至室溫後,於0℃下向反應混合液中添加水,利用氯仿進行萃取。利用無水硫酸鈉乾燥有機層,於減壓下進行濃縮後,藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將殘渣純化,而獲得標題化合物246(0.005 g)。
LCMS: [M+H]
+/Rt(min): 427/0.70
實施例 163 ~ 164 :使用對應之市售化合物或參考例所記載之化合物,藉由與實施例162同樣之方法,製造下述表所示之實施例163~164之化合物。
[表9]
實施例 | 結構式 | 原料 |
光譜資料 | ||
163 | 參考例101 | |
1H-NMR (CDCl 3) δ: 1.38 (8H, d, J = 6.8 Hz), 1.86-1.85 (3H, m), 2.10 (3H, s), 2.40 (2H, m), 3.13-3.08 (2H, m), 3.30-3.29 (3H, m), 3.59-3.47 (6H, m), 3.96-3.95 (4H, m), 4.39-4.37 (2H, m), 7.25-7.22 (1H, m), 7.39-7.35 (1H, m), 7.48 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 8.0 Hz), 8.54 (1H, brs) | ||
164 | 參考例102 | |
LCMS:[M+H]+/Rt=431/1.52 min (方法B) |
實施例163:
4-甲基-4-[3-(丙烷-2-基)-1,2,4-㗁二唑-5-基]-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺鹽酸鹽
實施例164:
4-氟-4-(3-甲基-1,2,4-㗁二唑-5-基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
實施例 165 :4-甲基-4-(5-甲基-1,3,4-㗁二唑-2-基)-N-{2-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺
[化95]
於參考例101之化合物237(0.056 g)、THF(0.5 mL)、MeOH(0.5 mL)及水(0.5 mL)之混合物中添加氫氧化鈉(0.027 g),於60℃攪拌1小時。利用10%鹽酸水溶液進行中和,並利用氯仿/甲醇(4:1)溶液進行萃取。將溶劑於減壓下進行濃縮,將所獲得之殘渣溶解於DMF(0.5 mL)中,添加二異丙基乙基胺(0.059 mL)、乙醯肼(0.020 g)及HATU(0.128 g),於室溫下攪拌14小時。於反應液中添加飽和碳酸氫鈉水溶液,利用氯仿進行萃取。將溶劑於減壓下進行濃縮,將所獲得之殘渣溶解於乙腈(0.5 mL)中,添加三苯基膦(0.071 g)、三乙胺(0.057 mL)及四氯化碳(0.052 mL),於加熱回流下攪拌7小時。放置冷卻後於減壓下進行濃縮,藉由胺基矽膠管柱層析法(溶出液:己烷/乙酸乙酯)將所獲得之殘渣純化,而獲得標題化合物247(0.010 g)。
LCMS: [M+H]
+/Rt(min): 427/1.43
步驟(i):
使用化合物41(0.036 g),依據與參考例23之步驟(iv)同樣之方法,獲得標題化合物248(0.045 g)。
LCMS: [M+H]
+/Rt(min): 522/1.25
步驟(ii):
使用化合物248(0.042 g),依據與參考例14之步驟(ii)同樣之方法,獲得標題化合物249(0.031 g)。
1H-NMR (CDCl
3) δ: 0.92 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.51-1.62 (1H, m), 1.66-1.77 (2H, m), 1.86-1.94 (2H, m), 2.33 (3H, s), 2.53-2.60 (1H, m), 2.67-2.76 (1H, m), 2.95-3.04 (2H, m), 3.07 (1H, dd, J = 12.5, 2.7 Hz), 3.16 (1H, dd, J = 11.3, 11.3 Hz), 3.48 (1H, dd, J = 10.4, 10.4 Hz), 4.09 (1H, dd, J = 11.3, 2.7 Hz), 4.21-4.32 (2H, m), 4.53 (1H, dd, J = 10.4, 3.0 Hz), 6.95 (1H, dd, J = 7.3, 7.3 Hz), 7.06 (1H, d, J = 7.3 Hz), 7.11 (4H, d, J = 8.5 Hz), 7.14 (4H, d, J = 8.5 Hz), 7.27 (1H, dd, J = 7.3, 7.3 Hz), 8.10 (1H, d, J = 8.5 Hz), 8.71 (1H, s).
實施例 167 ~ 168 :使用對應之市售化合物或參考例所記載之化合物,藉由與實施例166同樣之方法,製造下述表所示之實施例167~168之化合物。
[表10]
實施例 | 結構式 | 原料 |
光譜資料 | ||
167 | 參考例58 | |
1H-NMR (CDCl 3) δ: (mixture of rotamers) 0.93 (3H, d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.35 (3H, s), 1.50-1.80 (5H, m), 2.12-2.25 (2H, m), 2.25-2.35 (2H, m), 2.47-2.56 (1H, m), 2.88 (1H, dd, J = 12.4, 10.4 Hz), 2.94-3.05 (2H, m), 3.12-3.30 (2H, m), 3.34-3.46 (2H, m) 3.80-3.92 (2H, m), 4.05 (1H, dd, J = 11.2, 3.2 Hz), 4.53 (1H, dd, J = 10.4, 2.4 Hz), 6.89 (1H, br s), 7.13 (1H, t, J = 8.0 Hz), 7.21-7.29 (1H, m), 7.36 (1H, dd, J = 8.0, 1.6 Hz). | ||
168 | 參考例59 | |
1H-NMR (CDCl 3) δ: (mixture of rotamers) 0.90-1.06 (6H, m), 1.35 (3H, s), 1.51-1.63 (1H, m) 1.62-1.81 (4H, m), 2.12-2.24 (2H, m), 2.24-2.35 (2H, m), 2.35-2.59 (1H, m), 2.87 (0.6H, dd, J = 12.0, 10.8 Hz), 2.90-3.97 (8.8H, m) 4.05 (0.6H, dd, J = 11.2, 3.2 Hz), 4.50-4.68 (1H, m), 4.97-5.03 (0.3H, m), 6.80-6.96 (0.7H, br s), 7.10-7.19 (1H, m), 7.22-7.29 (1H, m), 7.36 (0.7H, dd, J = 8.0, 1.2 Hz), 7.43 (0.3H, dd, J = 8.0, 1.2 Hz). |
實施例167:
Rac-N-{2-氯-6-[(2R,5S)-5-(丙烷-2-基)嗎啉-2-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例168:
Rac-N-{2-氯-6-[(2R,5R)-5-(丙烷-2-基)嗎啉-2-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺
實施例 169 ~ 170 :使用對應之參考例所記載之化合物,藉由與實施例1同樣之方法,製造下述表所示之實施例169~170之化合物。
[表11]
實施例 | 結構式 | 原料 | |
光譜資料 | |||
169 | 參考例9 | 參考例104 | |
1H-NMR (CDCl 3) δ: 7.16 (1H, dd, J= 7.9, 1.2 Hz), 7.07 (1H, dd, J= 7.9, 7.9 Hz), 6.97 (1H, dd, J= 7.9, 1.2 Hz), 6.28 (1H, s), 3.81-3.75 (2H, m), 3.51-3.39 (3H, m), 3.04-2.96 (2H, m), 2.95-2.87 (4H, m), 2.75-2.59 (5H, m), 2.27-2.12 (3H, m), 2.05-1.96 (2H, m), 1.24-1.18 (4H, m), 1.07 (6H, d, J= 6.7 Hz). | |||
170 | 參考例9 | 參考例105 | |
1H-NMR (CDCl 3) δ: 7.16 (1H, dd, J= 7.9, 1.2 Hz), 7.06 (1H, dd, J= 7.9, 7.9 Hz), 6.96 (1H, dd, J= 7.9, 1.2 Hz), 6.26 (1H, s), 3.74-3.68 (2H, m), 3.53 (2H, dd, J= 10.7, 3.4 Hz), 3.35-3.24 (1H, m), 2.95-2.82 (6H, m), 2.75-2.58 (5H, m), 2.43-2.35 (2H, m), 2.20-2.12 (1H, m), 1.88-1.78 (2H, m), 1.23-1.17 (4H, m), 1.07 (6H, d, J= 6.1 Hz). |
實施例169:
(3aR,5s,6aS)-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-5-(5-環丙基-1,2,4-㗁二唑-3-基)六氫環戊[c]吡咯-2(1H)-甲醯胺
實施例170:
(3aR,5r,6aS)-N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-5-(5-環丙基-1,2,4-㗁二唑-3-基)六氫環戊[c]吡咯-2(1H)-甲醯胺
試驗例 1 :食慾激素 2 型受體促效劑活性之測定使人類食慾激素2型受體及水母蛋白於CHO細胞中瞬時表現,以藉由配體刺激流入細胞內之鈣量作為指標來評價激動性。瞬時表現之細胞係以2,000 cells/孔接種至384孔培養板中,並培養16~22小時。將培養板恢復至室溫後,添加腔腸素hcp(最終濃度:1 μM),於室溫下靜置2小時後,添加食慾激素A或受驗化合物,利用FDSS7000(Hamamatsu Photonics公司製造)測定細胞之發光量。再者,食慾激素A及受驗化合物係溶解於DMSO中(最終濃度0.1%),並經緩衝液(Hanks、20 mM HEPES(4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid,4-(2-羥乙基)-1-哌嗪乙磺酸)、0.1%BSA(Bovine Serum Albumin,牛血清白蛋白))稀釋。又,受驗化合物之食慾激素2型受體激動性係將食慾激素A(100 pM)處理時之發光值設為100%,以其相對值之形式算出。
試驗結果:
針對實施例1~168中所獲得之化合物,測定食慾激素2型受體激動性,結果觀察到,本發明化合物對於食慾激素2型受體表現出激動作用。以將食慾激素A(100 pM)處理時之發光值設為100%之情形時之相對值之形式,將實施例1~168中所獲得之化合物之10 μM時之食慾激素2型受體激動性示於下述表中。
[表12]
實施例 | 激動性(%) | 實施例 | 激動性(%) | 實施例 | 激動性(%) |
1 | 77 | 57 | 171 | 113 | 157 |
2 | 35 | 58 | 71 | 114 | 155 |
3 | 27 | 59 | 158 | 115 | 159 |
4 | 125 | 60 | 102 | 116 | 136 |
5 | 156 | 61 | 156 | 117 | 158 |
6 | 151 | 62 | 75 | 118 | 149 |
7 | 154 | 63 | 26 | 119 | 154 |
8 | 145 | 64 | 140 | 120 | 125 |
9 | 132 | 65 | 93 | 121 | 130 |
10 | 34 | 66 | 129 | 122 | 122 |
11 | 142 | 67 | 154 | 123 | 105 |
12 | 123 | 68 | 68 | 124 | 27 |
13 | 99 | 69 | 129 | 125 | 141 |
14 | 126 | 70 | 45 | 126 | 139 |
15 | 101 | 71 | 88 | 127 | 145 |
16 | 82 | 72 | 144 | 128 | 136 |
17 | 133 | 73 | 141 | 129 | 138 |
18 | 128 | 74 | 145 | 130 | 142 |
19 | 133 | 75 | 131 | 131 | 150 |
20 | 111 | 76 | 148 | 132 | 171 |
21 | 156 | 77 | 158 | 133 | 156 |
22 | 97 | 78 | 170 | 134 | 135 |
23 | 92 | 79 | 156 | 135 | 103 |
24 | 127 | 80 | 157 | 136 | 105 |
25 | 136 | 81 | 145 | 137 | 126 |
26 | 63 | 82 | 156 | 138 | 44 |
27 | 129 | 83 | 146 | 139 | 121 |
28 | 104 | 84 | 110 | 140 | 75 |
29 | 77 | 85 | 145 | 141 | 121 |
30 | 36 | 86 | 138 | 142 | 130 |
31 | 164 | 87 | 142 | 143 | 109 |
32 | 30 | 88 | 161 | 144 | 143 |
33 | 150 | 89 | 152 | 145 | 148 |
34 | 161 | 90 | 164 | 146 | 104 |
35 | 163 | 91 | 195 | 147 | 167 |
36 | 123 | 92 | 196 | 148 | 176 |
37 | 47 | 93 | 203 | 149 | 146 |
38 | 119 | 94 | 179 | 150 | 116 |
39 | 106 | 95 | 178 | 151 | 97 |
40 | 122 | 96 | 160 | 152 | 136 |
41 | 47 | 97 | 69 | 153 | 54 |
42 | 128 | 98 | 165 | 154 | 40 |
43 | 135 | 99 | 75 | 155 | 55 |
44 | 143 | 100 | 160 | 156 | 38 |
45 | 127 | 101 | 157 | 157 | 94 |
46 | 49 | 102 | 160 | 158 | 133 |
47 | 165 | 103 | 178 | 159 | 150 |
48 | 146 | 104 | 180 | 160 | 141 |
49 | 196 | 105 | 165 | 161 | 90 |
50 | 187 | 106 | 185 | 162 | 100 |
51 | 151 | 107 | 163 | 163 | 110 |
52 | 155 | 108 | 157 | 164 | 128 |
53 | 140 | 109 | 161 | 165 | 96 |
54 | 140 | 110 | 148 | 166 | 72 |
55 | 154 | 111 | 146 | 167 | 183 |
56 | 44 | 112 | 151 | 168 | 184 |
試驗例 2 :食慾激素 2 型受體促效劑活性之測定使人類食慾激素2型受體及水母蛋白於CHO細胞中瞬時表現,以藉由配體刺激流入細胞內之鈣量作為指標來評價激動性。瞬時表現之細胞係以2,000 cells/孔接種至384孔培養板中,並培養16~22小時。將培養板恢復至室溫後,添加腔腸素hcp(最終濃度:1 μM),於室溫下靜置2小時後,添加食慾激素A(PEPTIDE INSTITUTE股份有限公司,Lot.671009)或受驗化合物,利用FDSS7000(Hamamatsu Photonics公司製造)測定細胞之發光量。再者,食慾激素A及受驗化合物係溶解於DMSO中(最終濃度0.1%),並經緩衝液(Hanks、20 mM HEPES、0.1%BSA)稀釋。又,受驗化合物之食慾激素2型受體激動性係將食慾激素A(100 pM)處理時之發光值設為100%,以其相對值之形式算出。
試驗結果:
針對實施例169~170中所獲得之化合物,測定食慾激素2型受體激動性,結果觀察到,本發明化合物對於食慾激素2型受體表現出激動作用。關於實施例169~170中所獲得之化合物之10 μM時之食慾激素2型受體激動性,將以食慾激素A(100 pM)處理時之發光值作為100%之情形時之相對值示於下述表中。
[表13]
[產業上之可利用性]
實施例 | 激動性(%) |
169 | 444 |
170 | 357 |
本發明之化合物對於食慾激素受體表現出較強之激動活性,作為猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、伴隨路易體癡呆之睡眠過度等之治療藥或預防藥較為有用。
Claims (35)
- 一種化合物或其製藥學上所容許之鹽,該化合物係以式(1)表示: [化1] [式中, R 1表示可經取代之C 6-10芳香族碳環基、可經取代之5~10員之芳香族雜環基、可經取代之C 3-6飽和碳環基、可經取代之4~10員之飽和雜環基、或氰基; L 1及L 2各自獨立地表示單鍵、亞甲基(該亞甲基可經1個以上之相同或不同之C 1-6烷基取代)、-NR 6-、-C(=O)-、-OC(=O)-、-SO-、-SO 2-、-S-、或氧原子; R 2表示氫原子、羥基、鹵素原子、氰基、可經取代之C 1-6烷基、可經取代之C 1-6烷氧基、C(=O)NR 3R 4或C(=O)O-R 5; R 3、R 4、R 5、R 6各自獨立地表示氫原子或可經取代之C 1-6烷基; 環E表示可經取代之5~10員之芳香族雜環基或可經取代之4~10員之飽和雜環基; 環G表示可經取代之C 6-10芳香族碳環基、可經取代之5~10員之芳香族雜環基、可經取代之C 3-6飽和碳環基、或可經取代之4~10員之飽和雜環基; A表示氧原子或硫原子]。
- 如請求項1之化合物或其製藥學上所容許之鹽,其中R 2~R 6中之「可經取代之C 1-6烷基」中之可進行取代之取代基分別獨立地為1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷氧基、或C 3-7環烷基,「可經取代之C 1-6烷氧基」中之可進行取代之取代基分別獨立地為1個或2個以上之相同或不同之鹵素原子、羥基、或C 3-7環烷基, R 1之C 6-10芳香族碳環基、5~10員之芳香族雜環基、C 3-6飽和碳環基、及4~10員之飽和雜環基中之可進行取代之取代基分別獨立地為選自由如下取代基所組成之群中之1種以上之取代基:鹵素原子、羥基、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基或C 3-7環烷基取代)、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷氧基或C 3-7環烷基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基或C 3-7環烷基取代)、C 1-6烷基胺基(該烷基胺基中之烷基可經鹵素原子、羥基或C 3-7環烷基取代)、C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基或C 3-7環烷基取代)、氰基、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 3-7環烷基取代)及5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基或C 3-7環烷基取代), 環E及環G之C 6-10芳香族碳環基、5~10員之芳香族雜環基、C 3-6飽和碳環基、及4~10員之飽和雜環基中之可進行取代之取代基分別獨立地為選自由如下取代基所組成之群中之1種以上之取代基:鹵素原子、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷氧基或C 3-7環烷基取代)、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基或C 3-7環烷基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 3-7環烷基取代)、C 1-6烷基胺基(該烷基胺基中之烷基可經鹵素原子、羥基或C 3-7環烷基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基或C 3-7環烷基取代)、及C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-4烷氧基或C 3-7環烷基取代);或者於取代基存在複數個之情形時,可其中2個經由C 1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構。
- 如請求項1至3中任一項之化合物或其製藥學上所容許之鹽,其中R 1為氰基或選自下述式(1a-1)至(1a-6)中之任一者: [化3] [式中, X 1~X 6各自獨立地表示氮原子或CR a4; Q 1及Q 2表示氧原子、-NR a5-或硫原子; Q 3表示CH或氮原子; R a1~R a5各自獨立地(於CR a4存在複數個之情形時,各R a4亦各自獨立地)表示氫原子、鹵素原子、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-4烷氧基或C 3-7環烷基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、可經1個或2個以上之相同或不同之鹵素原子取代之C 1-6烷基、或C 1-6烷氧基取代)、氰基、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 1-6烷氧基取代)、C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)或5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)]。
- 如請求項1至4中任一項之化合物或其製藥學上所容許之鹽,其中環G為選自下述式(1b-1)至(1b-7)中之任一者: [化4] [式中, W 1及W 2各自獨立地表示NR b7、氧原子或CR b8R b9; W 3、W 4、W 5及W 6各自獨立地表示氮原子或CR b10; R b1~R b10各自獨立地表示氫原子、鹵素原子、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C 1-4烷氧基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)或C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代),只要化學上可能,則R b2及R b3可鍵結於同一碳原子上; 此處,R b2及R b3可經由C 1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構; n、m及p各自獨立地表示1或2之整數]。
- 如請求項1至5中任一項之化合物或其製藥學上所容許之鹽,其中環E為選自下述式(1c-1)至(1c-4)中之任一者: [化5] [式中, R c1、R c2、R c3及R c4各自獨立地表示氫原子、鹵素原子、氰基、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C 1-6烷氧基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、或C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代),只要化學上可能,則R c1及R c2可鍵結於同一碳原子上; 此處,R c1及R c2可經由C 1-6伸烷基鍵結而形成縮合環、螺環、或橋接環中化學上可能之任意之二環式結構]。
- 如請求項1至6中任一項之化合物或其製藥學上所容許之鹽,其中環E為選自下述式(1c-11)至(1c-41)中之任一者: [化6] [式中,R c4各自獨立地表示鹵素原子、氰基、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C 1-6烷氧基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、或C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)]。
- 如請求項1至8中任一項之化合物或其製藥學上所容許之鹽,其中L 1為單鍵、-CH 2-、或氧原子之任一者。
- 如請求項1至9中任一項之化合物或其製藥學上所容許之鹽,其中R 1為選自下述式(1a-1)至(1a-3)中之任一者: [化8] [式中, X 1~X 5各自獨立地表示氮原子或CR a4; Q 1及Q 2各自獨立地表示氧原子、或硫原子; R a1表示氫原子、鹵素原子、氰基、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 1-6烷氧基取代)或C 1-4烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 1-6烷氧基取代); R a4(於CR a4存在複數個之情形時,各R a4各自獨立地)表示氫原子、鹵素原子、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷氧基或C 3-7環烷基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 1-6烷氧基取代)、C 3-7環烷氧基(該環烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、C 1-6烷氧基取代)或5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)]。
- 如請求項1至10中任一項之化合物或其製藥學上所容許之鹽,其中環G為選自下述(1b-1)至(1b-3)中之任一者: [化9] [式中,R b1~R b3各自獨立地表示氫原子、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、或C 1-6烷氧基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子取代)、5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)、C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)或C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、C 1-6烷基、或C 1-6烷氧基取代)]。
- 如請求項1至11中任一項之化合物或其製藥學上所容許之鹽,其中R 2為F、Cl、Br之任一鹵素原子,且A為氧原子。
- 如請求項15之化合物或其製藥學上所容許之鹽,其中R a4(於CR a4存在複數個之情形時,各R a4各自獨立地)為C 6-10芳香族碳環基(該C 6-10芳香族碳環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)、C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷氧基或C 3-7環烷基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)、或5~10員之芳香族雜環基(該芳香族雜環基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)。
- 如請求項17或18中任一項之化合物或其製藥學上所容許之鹽,其中R a4(於CR a4存在複數個之情形時,各R a4各自獨立地)為C 1-6烷基(該烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷氧基或C 3-7環烷基取代)、C 3-7環烷基(該環烷基可經1個或2個以上之相同或不同之鹵素原子、羥基、C 1-6烷基、或C 1-6烷氧基取代)、C 1-6烷氧基(該烷氧基可經1個或2個以上之相同或不同之鹵素原子、羥基、或C 1-6烷氧基取代)。
- 如請求項1之化合物或其製藥學上所容許之鹽,其中該化合物係選自以下之化合物: N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-㗁二唑-3-基]哌啶-1-甲醯胺 N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-㗁二唑-3-基)哌啶-1-甲醯胺 4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺 4-(5-環丙基-1,2,4-㗁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺 4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺 4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基哌啶-1-甲醯胺 4-(5-環丙基-1,2-㗁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺。
- 如請求項1之化合物或其製藥學上所容許之鹽,其中該化合物係選自以下之化合物: 4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基-N-{2-氟-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-乙基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-(5-環丙基-1,3-噻唑-2-基)-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1S,2S)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-{5-[(1R,2R)-2-氟環丙基]-1,2,4-㗁二唑-3-基}-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1S,2R)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺 N-{2-氯-6-[4-(丙烷-2-基)哌𠯤-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基環丙基]-1,2,4-㗁二唑-3-基}哌啶-1-甲醯胺 N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2,4-㗁二唑-3-基)-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-(5-環丙基-1,2-㗁唑-3-基)-4-甲基哌啶-1-甲醯胺 N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氫吡啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲醯胺。
- 一種醫藥組合物,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽。
- 一種與食慾激素2型受體相關之疾病之治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽。
- 一種治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽,且其係猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、伴隨路易體癡呆之睡眠過度、伴隨白天睡眠過度之睡眠過度症候群(例如克萊恩-萊文症候群、伴隨睡眠過度之重度抑鬱症、路易體癡呆、帕金森氏症、進行性核上麻痹、普威二氏症候群、莫比烏斯症候群、低換氣症候群、尼曼-匹克二氏病C型、腦挫傷、腦梗塞、腦腫瘤、肌肉萎縮症、多發性硬化症、急性播散性腦脊髓炎、格-巴二氏症候群、Rasmussen氏腦炎、韋尼克氏腦炎、邊緣葉腦炎、橋本腦病)、昏睡、意識喪失、肥胖(例如惡性肥胖細胞、外源性肥胖、胰島功能亢進性肥胖、原生質增生性肥胖、垂體性肥胖、原生質低減性肥胖、甲狀腺功能減退性肥胖症、下視丘性肥胖、症狀性肥胖症、兒童肥胖、上半身肥胖、飲食性肥胖症、性功能衰退性肥胖、全身性肥大細胞增生病、單純性肥胖、中心性肥胖)、胰島素抵抗症候群、阿茲海默症、昏睡等意識障礙、由麻醉導致之副作用或併發症、睡眠紊亂、睡眠問題、失眠症、間歇性睡眠、夜間肌陣攣、快速眼動(REM)睡眠中斷、時差反應、時差反應症候群、輪班工作人員之睡眠障礙、睡眠異常、夜驚症、抑鬱症、重度抑鬱症、夢遊症、夜尿症、睡眠障礙、阿茲海默症性日落症、與晝夜節律相關之疾病、肌肉纖維疼痛、因睡眠品質降低而產生之狀態、過食、強迫性飲食障礙、肥胖相關疾病、高血壓、糖尿病、血漿胰島素濃度及胰島素抵抗性之上升、高脂蛋白血症、高脂血症、子宮內膜癌、乳癌、前列腺癌、結腸癌、癌、變形性關節病、阻塞性睡眠呼吸中止、膽石症、膽石、心臟病、心臟跳動節奏不規律、心律不整、心肌梗塞、充血性心臟衰竭、心臟衰竭、冠心病、心血管障礙、猝死、多囊性卵巢病、顱咽管瘤、普威二氏症候群、肥胖性生殖器退化症候群、生長激素缺乏者、正常基因突變矮小、特納氏症候群、罹患急性淋巴細胞性白血病之兒童、X症候群、生殖系統激素異常、受孕能力減退、不孕、男性之性腺功能減退、女性之男性型多毛症等性及生殖功能障礙、與孕婦肥胖相關之胎兒之缺陷、肥胖相關胃食道逆流病等胃腸動力之疾病、肥胖低換氣症候群(匹克威克症候群)、呼吸困難等呼吸性疾病、脈管系統全身性炎症等炎症、動脈硬化、高膽固醇血症、高尿酸血症、下背部痛、膽囊疾病、痛風、腎癌、降低左心室肥大風險等肥胖繼發後果之風險、偏頭痛、頭痛、神經性疼痛、帕金森氏症、精神病、精神分裂症、顏面潮紅、盜汗、性器/泌尿系統之疾病、與性功能或受孕能力相關之疾病、低落性情感疾病、躁鬱症、I型躁鬱症、II型躁鬱症、循環情感性精神障礙、急性壓力症、廣場恐懼症、廣泛性焦慮症、強迫症、驚恐發作、驚恐障礙、創傷後壓力症、分離焦慮障礙、社交恐懼症、焦慮障礙、心臟繞道術及移植後之腦性缺損症等急性神經學及精神醫學障礙、腦中風、缺血性腦中風、腦缺血、脊髓外傷、頭部外傷、圍產期缺氧症、心臟驟停、低血糖神經損傷、亨廷頓氏舞蹈症、肌萎縮性側索硬化症、多發性硬化症、眼損傷、網膜病、認知障礙、肌肉攣縮、顫動、癲癇、與肌肉痙攣相關之障礙、妄想、健忘障礙、年齡相關性認知衰退、分裂情感性精神障礙、妄想性障礙、藥物依賴症、運動異常症、慢性疲勞症候群、疲勞、藥物誘導性帕金森症候群、妥瑞症候群、舞蹈症、肌陣攣、抽動、抖腿症候群、肌肉緊張不足、運動障礙、注意力不足過動症(ADHD)、行為障礙、尿失禁、戒斷症狀、三叉神經痛、聽力損失、耳鳴、神經損傷、網膜病、黃斑變性症、嘔吐、腦浮腫、疼痛、骨痛、關節痛、牙痛、猝倒症、或創傷性腦損傷之治療藥。
- 一種治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽,且其係猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療藥。
- 一種猝睡症之治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽。
- 一種特發性睡眠過度之治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽。
- 一種伴隨帕金森氏症之睡眠過度之治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽、。
- 一種伴隨路易體癡呆之睡眠過度之治療藥,其含有如請求項1至24中任一項之化合物或其製藥學上所容許之鹽。
- 一種猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療方法,其包括對需要治療之患者投予治療上有效量之如請求項1至24中任一項之化合物或其製藥學上所容許之鹽。
- 一種如請求項1至24中任一項之化合物或其製藥學上所容許之鹽之用途,其係用以製造猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療劑。
- 一種醫藥組合物,其包含如請求項1至24中任一項之化合物或其製藥學上所容許之鹽,其係用於猝睡症、特發性睡眠過度、睡眠過度、睡眠呼吸中止症候群、伴隨猝睡症樣症狀之猝睡症症候群、伴隨帕金森氏症之睡眠過度、或伴隨路易體癡呆之睡眠過度之治療。
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BR9917038A (pt) * | 1998-12-18 | 2002-04-02 | Du Pont Pharm Co | Composto, composição farmacêutica, método de modulação da atividade receptora de quimocinas, método de tratamento ou prevenção de doenças inflamatórias, método de tratamento ou prevenção de asma e método de tratamento ou prevenção de disfunções inflamatórias |
WO2000035877A1 (en) * | 1998-12-18 | 2000-06-22 | Du Pont Pharmaceuticals Company | Heterocyclic piperidines as modulators of chemokine receptor activity |
PT1330451E (pt) * | 2000-10-27 | 2008-03-13 | Ortho Mcneil Pharm Inc | Benzimidazol-2-onas substituídas como antagonistas do receptor da vasopressina e moduladores do neuropéptido y |
WO2006007864A1 (en) * | 2004-07-17 | 2006-01-26 | Max Planck Geselllschaft Zur Förderung Der Wissenschaft | Treating neurodegenerative conditions |
WO2006127550A1 (en) * | 2005-05-23 | 2006-11-30 | Merck & Co., Inc. | Proline bis-amide orexin receptor antagonists |
US20080070892A1 (en) * | 2006-09-15 | 2008-03-20 | Harris Joel M | Treating pain, diabetes, and disorders of lipid metabolism |
JP2010155827A (ja) * | 2008-12-04 | 2010-07-15 | Takeda Chem Ind Ltd | スピロ環化合物 |
LT3411358T (lt) | 2016-02-04 | 2022-04-25 | Takeda Pharmaceutical Company Limited | Pakeistas piperidino junginys ir jo naudojimas |
US20210161907A1 (en) * | 2018-04-13 | 2021-06-03 | Regents Of The University Of Minnesota | Use of small molecule fak activators to promote mucosal healing |
EP4232016A4 (en) * | 2020-10-26 | 2024-04-17 | Univ Of North Dakota | USE OF SMALL MOLECULE FAK ACTIVATORS TO PROMOTE MUCOSAL HEALING |
-
2022
- 2022-05-26 AU AU2022282786A patent/AU2022282786A1/en active Pending
- 2022-05-26 CN CN202280037665.2A patent/CN117561238A/zh active Pending
- 2022-05-26 JP JP2023524226A patent/JPWO2022250108A1/ja active Pending
- 2022-05-26 TW TW111119648A patent/TW202313598A/zh unknown
- 2022-05-26 CA CA3219888A patent/CA3219888A1/en active Pending
- 2022-05-26 BR BR112023024311A patent/BR112023024311A2/pt unknown
- 2022-05-26 EP EP22811378.3A patent/EP4353309A1/en active Pending
- 2022-05-26 IL IL308659A patent/IL308659A/en unknown
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BR112023024311A2 (pt) | 2024-02-06 |
CA3219888A1 (en) | 2022-12-01 |
JPWO2022250108A1 (zh) | 2022-12-01 |
EP4353309A1 (en) | 2024-04-17 |
IL308659A (en) | 2024-01-01 |
WO2022250108A1 (ja) | 2022-12-01 |
AU2022282786A1 (en) | 2023-12-07 |
CN117561238A (zh) | 2024-02-13 |
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