CN117561238A - 苯基脲衍生物 - Google Patents
苯基脲衍生物 Download PDFInfo
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- CN117561238A CN117561238A CN202280037665.2A CN202280037665A CN117561238A CN 117561238 A CN117561238 A CN 117561238A CN 202280037665 A CN202280037665 A CN 202280037665A CN 117561238 A CN117561238 A CN 117561238A
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- FQIWHPALNIWULM-UHFFFAOYSA-N thiomorpholine-2,3-dione Chemical compound O=C1NCCSC1=O FQIWHPALNIWULM-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
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- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
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Classifications
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Abstract
本发明涉及含有具有脲骨架的新型化合物或其制药学上可接受的盐作为有效成分的针对与食欲素受体、特别是与食欲素2型受体相关的疾病的治疗药或预防药。具体而言,涉及发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征等疾病的治疗药或预防药。
Description
技术领域
本发明涉及含有具有脲骨架的新型化合物或其制药学上可接受的盐作为有效成分的针对与食欲素(orexin)受体、特别是与食欲素2型受体相关的疾病的治疗药或预防药。具体而言,涉及发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征等疾病的治疗药或预防药。
背景技术
食欲素是分布在下丘脑外侧区和其周边区域的特定的神经细胞中特异性产生的神经肽。食欲素是主要存在于脑内的G蛋白偶联受体即食欲素受体的内源性配体,且与食欲素受体结合。关于食欲素受体,已知有1型与2型这2种亚型(非专利文献1)。
报告有使食欲素神经细胞改性的转基因小鼠中所产生的发作性睡病样症状是通过脑室内投予食欲素肽而进行改善(非专利文献2),还报告有通过食欲素的前体蛋白即食欲素前体物的敲除(KO)而引起发作性睡病样的症状(非专利文献3),进而明确了发作性睡病患者的脑脊髓液中食欲素浓度显著降低(非专利文献4),启示发作性睡病是由于食欲素的缺乏而引起的。
此外,报告有遗传性的发作性睡病的狗中食欲素2型受体的变异(非专利文献5),启示食欲素2型受体与睡眠觉醒相关,进而明确了食欲素2型受体的KO小鼠中也会引起发作性睡病样的症状(非专利文献6),也启示食欲素2型受体刺激与觉醒维持作用的密切相关。根据这种背景,食欲素2型受体激动剂期待作为对以发作性睡病为代表的呈现睡眠过度症状的疾病有希望的治疗药。
近年来,报告有具有食欲素2型受体激动作用的化合物(专利文献1)。
现有技术文献
专利文献
[专利文献1]国际公开第2017/135306号
非专利文献
[非专利文献1]Cell、第92卷、573-585页、1998年(Cell,Vol.92,573-585,1998)
[非专利文献2]Proceedings of the National Academy of Sciences of theUnited States of America、第101卷、4649-4654页、2004年(Proc.Natl.Acad.Sci.USA,Vol.101,4649-4654,2004)
[非专利文献3]Cell、第98卷、437-451页、1999年(Cell,Vol.98,437-451,1999)
[非专利文献4]THE LANCET、第355卷、39-40页、2000年(THE LANCET,Vol.355,39-40,2000)
[非专利文献5]Cell、第98卷、365-376页、1999年(Cell,Vol.98,365-376,1999)
[非专利文献6]Neuron、第38卷、715-730页、2003年(Neuron,Vol.38,715-730,2003)
[非专利文献7]Brain、第130卷、1577-1585页、2007年(Brain,Vol.130,1577-1585,2007)
[非专利文献8]Neuroscience Letters、第569卷、68-73页、2014年(NeuroscienceLetters,Vol.569,68-73,2014)
发明内容
发明要解决的课题
本发明的课题在于提供对与食欲素2型受体相关的疾病,具体而言为发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征等疾病的治疗药或预防药。
用于解决问题的手段
本发明人等进行深入研究,结果发现下述式(1)所示的化合物或其制药学上可接受的盐(以下,也有时称为"本发明的化合物"。)对与食欲素2型受体相关的疾病、具体而言为发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征等疾病具有治疗和预防效果,从而完成本发明。
即,本发明如以下所述。
[项1]
式(1)所示的化合物或其制药学上可接受的盐,
[化1]
式中,
R1表示任选被取代的C6-10芳香族碳环基、任选被取代的5~10元的芳香族杂环基、任选被取代的C3-6饱和碳环基、任选被取代的4~10元的饱和杂环基、或氰基;
L1和L2各自独立地表示单键、亚甲基(该亚甲基任选被1个以上相同或不同的C1-6烷基取代)、-NR6-、-C(=O)-、-OC(=O)-、-SO-、-SO2-、-S-、或氧原子;
R2表示氢原子、羟基、卤素原子、氰基、任选被取代的C1-6烷基、任选被取代的C1-6烷氧基、C(=O)NR3R4或C(=O)O-R5;
R3、R4、R5、R6各自独立地表示氢原子或任选被取代的C1-6烷基;
环E表示任选被取代的5~10元的芳香族杂环基或任选被取代的4~10元的饱和杂环基;
环G表示任选被取代的C6-10芳香族碳环基、任选被取代的5~10元的芳香族杂环基、任选被取代的C3-6饱和碳环基、或任选被取代的4~10元的饱和杂环基;
A表示氧原子或硫原子。
[项2]
根据项1的化合物或其制药学上可接受的盐,其中,
R2~R6中的"任选被取代的C1-6烷基"中的能取代的取代基各自独立地为1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基、或C3-7环烷基,"任选被取代的C1-6烷氧基"中的能取代的取代基各自独立地为1或2个以上的相同或不同的卤素原子、羟基、或C3-7环烷基,
R1的C6-10芳香族碳环基、5~10元的芳香族杂环基、C3-6饱和碳环基、和4~10元的饱和杂环基中的能取代的取代基各自独立地为选自卤素原子、羟基、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、C1-6烷基氨基(该烷基氨基中的烷基任选被卤素原子、羟基或C3-7环烷基取代)、C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、氰基、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C3-7环烷基取代)和5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)中的1个以上的取代基,
环E和环G的C6-10芳香族碳环基、5~10元的芳香族杂环基、C3-6饱和碳环基、和4~10元的饱和杂环基中的能取代的取代基各自独立地为选自卤素原子、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C3-7环烷基取代)、C1-6烷基氨基(该烷基氨基中的烷基任选被卤素原子、羟基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、和C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-4烷氧基或C3-7环烷基取代)中的1个以上的取代基,或者取代基为多个时,其中2个任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构。
[项3]
根据项1或2所述的化合物或其制药学上可接受的盐,其由式(2)所示:
[化2]
式中,
R2表示羟基、卤素原子、氰基、任选被取代的C1-4烷基、任选被取代的C1-4烷氧基、C(=O)NR3R4或C(=O)OR5;
R1、L1、L2、R3、R4、R5、环E、环G、和A为与项1相同的定义。
[项4]
根据项1~3中任一项所述的化合物或其制药学上可接受的盐,其中,R1为氰基或选自下述式(1a-1)至(1a-6)中的任一者,
[化3]
式中,
X1~X6各自独立地表示氮原子或CRa4;
Q1和Q2表示氧原子、-NRa5-或硫原子;
Q3表示CH或氮原子;
Ra1~Ra5各自独立地(CRa4存在多个时,各Ra4也各自独立)表示氢原子、卤素原子、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-4烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、任选被1或2个以上的相同或不同的卤素原子取代的C1-6烷基、或C1-6烷氧基取代)、氰基、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)、C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)或5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)。
[项5]
根据项1~4中任一项所述的化合物或其制药学上可接受的盐,其中,环G为选自下述式(1b-1)至(1b-7)中的任一者,
[化4]
式中,
W1和W2各自独立地表示NRb7、氧原子或CRb8Rb9;
W3、W4、W5和W6各自独立地表示氮原子或CRb10;
Rb1~Rb10各自独立地表示氢原子、卤素原子、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-4烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代),化学上可能的话,Rb2和Rb3任选与同一碳原子键合;
在此,Rb2和Rb3任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构;
n、m和p各自独立地表示1或2的整数。
[项6A]
根据项1~5中任一项所述的化合物或其制药学上可接受的盐,其中,环E为选自下述式(1c-1)至(1c-4)中的任一者,
[化5]
式中,
Rc1、Rc2、Rc3和Rc4各自独立地表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代),化学上可能的话,Rc1和Rc2任选与同一碳原子键合;
在此,Rc1和Rc2任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构。
[项6]
根据项1~5中任一项所述的化合物或其制药学上可接受的盐,其中,环E为选自下述式(1c-1)至(1c-3)中的任一者,
[化6]
[式中,
Rc1、Rc2和Rc3各自独立地表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代),化学上可能的话,Rc1和Rc2任选与同一碳原子键合;
在此,Rc1和Rc2任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构]。
[项7A]
根据项1~6A和项6中任一项所述的化合物或其制药学上可接受的盐,其中,环E为选自下述式(1c-11)至(1c-41)中的任一者,
[化7]
式中,Rc4各自独立地表示卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)。
[项7]
根据项1~6A和项6中任一项所述的化合物或其制药学上可接受的盐,其中,环E为选自下述式(1c-11)至(1c-31)中的任一者,
[化8]
式中,Rc4各自独立地表示卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)。
[项8]
根据项1~6A、项6、项7A和项7中任一项所述的化合物或其制药学上可接受的盐,其由式(3)所示,
[化9]
式中,
R2表示任选被卤素原子取代的C1-6烷氧基;
R1、A、L1和环G表示与项1所述的定义相同的内容。。
[项9]
根据项1~6A、项6、项7A、项7和项8中任一项所述的化合物或其制药学上可接受的盐,其中,L1为单键、-CH2-、或氧原子中任一者。
[项10]
根据项1~6A、项6、项7A和项7~9中任一项所述的化合物或其制药学上可接受的盐,其中,R1为选自下述式(1a-1)至(1a-3)中的任一者,
[化10]
式中,
X1~X5各自独立地表示氮原子或CRa4;
Q1和Q2各自独立地表示氧原子、或硫原子;
Ra1表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)或C1-4烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代);
Ra4(CRa4为多个时,各Ra4各自独立)表示氢原子、卤素原子、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)、C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基取代)或5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)。
[项11]
根据项1~6A、项6、项7A和项7~10中任一项所述的化合物或其制药学上可接受的盐,其中,环G为选自下述式(1b-1)至(1b-3)中任一者,
[化11]
式中,Rb1~Rb3各自独立地表示氢原子、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)或C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)。
[项12]
根据项1~6A、项6、项7A和项7~11中任一项所述的化合物或其制药学上可接受的盐,其中,R2为F、Cl、Br中任一卤素原子,且A为氧原子。
[项13]
根据项1~6A、项6、项7A和项7~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1由以下式(1a-1)所示,
[化12]
式中,Ra1表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)或C1-4烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)。
[项14]
根据项1~6A、项6、项7A和项7~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1表示以下式(1a-2),
[化13]
式中,
X1~X3各自独立地表示氮原子或CRa4;
Q1表示氧原子、或硫原子;
Ra4表示与项10相同的定义;
L1为单键。
[项15]
根据项1~6A、项6、项7A和项7~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1为选自下述式(1a-21)至(1a-25)中的任一者,
[化14]
式中,Ra4表示与项10所述的内容相同的内容;
L1为单键。
[项16]
根据项15所述的化合物或其制药学上可接受的盐,其中,Ra4(CRa4存在多个时,各Ra4各自独立)为C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、或5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)。
[项17]
根据项1~6A、项6、项7A和项7~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1表示以下的式(1a-3),
[化15]
式中,X4和X5为与项10相同的定义;
L1为单键。
[项18]
根据项17所述的化合物或其制药学上可接受的盐,其中,R1为选自下述式(1a-31)至(1a-34)中的任一者,
[化16]
式中,Ra4为与项10相同的定义。
[项19]
根据项17或18中任一项所述的化合物或其制药学上可接受的盐,其中,Ra4(CRa4存在多个时,各Ra4各自独立)为C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)。
[项20]
根据项1~6A、项6、项7A和项7~19中任一项所述的化合物或其制药学上可接受的盐,其中,环G由下述式(1b-2)所示,
[化17]
式中,Rb2为与项11相同的定义。
[项21]
根据项1~6A、项6、项7A和项7~19中任一项所述的化合物或其制药学上可接受的盐,其中,环G由下述式(1b-1)所示,
[化18]
式中,Rb1由C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)表示。
[项22]
根据项1~6A、项6、项7A和项7~19中任一项所述的化合物或其制药学上可接受的盐,其中,环G由下述式(1b-3)表示,
[化19]
式中,Rb3由C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)表示。
[项23]
根据项1所述的化合物或其制药学上可接受的盐,其选自以下化合物:
实施例20:N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例22:N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)哌啶-1-甲酰胺
实施例44:4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例45:4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例53:4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例54:4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例55:4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例61:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例67:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例77:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺。
[项24]
根据项1所述的化合物或其制药学上可接受的盐,其选自以下化合物:
实施例87:4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例89:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基哌啶-1-甲酰胺
实施例101:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,3-噻唑-2-基)-4-甲基哌啶-1-甲酰胺
实施例115:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1S,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
实施例116:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1R,2R)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
实施例117:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1S,2R)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
实施例118:N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
实施例130:N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例144:N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例147:N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺。
[项25]
药物组合物,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项26]
与食欲素2型受体相关的疾病的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项27]
发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、路易小体痴呆所伴随的睡眠过度、伴随白天的睡眠过度的睡眠过度综合征(例如,克莱恩-莱文综合征、伴随睡眠过度的重度抑郁、路易小体痴呆、帕金森病、进行性核上性麻痹、普拉德-威利综合征、莫比乌斯综合征、低通气综合征、尼曼-匹克病C型、脑挫伤、脑梗塞、脑肿瘤、肌肉萎缩、多发性硬化症、急性播散性脑脊髓炎、吉兰-巴雷综合征、拉斯穆森脑炎、韦尼克脑炎、边缘***脑炎、桥本脑症)、昏睡、意识丧失、肥胖(例如,恶性肥胖细胞、外源性肥胖、胰岛功能亢进性肥胖症、原生质增生性肥胖、垂体性肥胖、原生质减低性肥胖症、甲状腺功能减退性肥胖症、下丘脑性肥胖、症状性肥胖症、小儿肥胖、上半身肥胖、饮食性肥胖症、性功能降低性肥胖、全身性肥胖细胞症、单纯性肥胖、中心性肥胖)、胰岛素抵抗性综合征、、阿兹海默症、昏睡等意识障碍、由麻醉导致的副作用、并发症、睡眠紊乱、睡眠问题、失眠、间歇性睡眠、夜间阵挛性肌肉痉挛、REM睡眠中断、时差反应、时差反应综合征、轮班工作人员的睡眠障碍、睡眠异常、夜惊症、抑郁、重度抑郁、梦游病、遗尿症、睡眠障碍、阿尔茨海默性黄昏综合征、与昼夜节律相关的疾病、肌肉纤维痛、睡眠质量差引起的症状、暴饮暴食、强迫性饮食障碍、肥胖相关疾病、高血压、糖尿病、血浆胰岛素浓度和胰岛素抵抗性的上升、高脂蛋白血症、高脂血症、子宫内膜癌、乳腺癌、***癌、结肠癌、癌、变形性关节症、阻塞性睡眠呼吸中止、胆结石症、胆结石、心脏病、心脏异常跳动、心律不齐、心肌梗塞、充血性心力衰竭、心力衰竭、冠心病、心血管疾病、猝死、多囊卵巢疾病、颅咽管瘤、普拉德-威利综合征、弗勒赫利希综合征、生长激素缺乏者、正常变异型身材矮小、特纳综合征、儿童急性淋巴细胞性白血病、X综合征、生殖***激素异常、受孕能力降低、***、男性性腺功能降低、女性的男性型多毛症等性和生殖功能障碍、与孕妇肥胖相关的胎儿缺陷、与肥胖相关的胃食管反流等胃肠动力疾病、肥胖通气不足综合征(匹克威克综合征)、呼吸困难等呼吸***疾病、血管***的全身性炎症等炎症、动脉硬化、高胆固醇血症、高尿酸血症、腰痛、胆囊疾病、痛风、肾癌、将左心室肥大的风险等肥胖的继发后果风险、偏头痛、头痛、神经性疼痛、帕金森病、精神病、神经***症、面部潮红、盗汗、生殖器/泌尿器***疾病、与性功能或受孕能力相关的疾病、低落性情感障碍、双相情感障碍、I型双相情感障碍、II型双相情感障碍、循环性情感精神障碍、急性应激障碍、广场恐怖症、广泛性焦虑症、强迫症、惊恐发作、惊恐障碍、创伤后应激障碍、分离焦虑症、社交恐惧症、焦虑症、心脏搭桥手术和移植后的脑缺损等急性神经学的和精神医学的障碍、中风,缺血性中风,脑缺血、脊髓外伤、头部外伤、周产期缺氧、心脏骤停、低血糖性神经损伤、亨廷顿舞蹈病、肌萎缩性侧索硬化症、多发性硬化症、眼损伤、视网膜疾病、认知障碍、肌肉痉挛、震颤、癫痫、与肌肉萎缩相关的障碍、谵妄、健忘症、与年龄增长相关的认知下降、***感情性障碍、妄想症、药物依赖症、运动异常症、慢性疲劳综合征、疲劳、药物诱发性帕金森综合征、抽动秽语综合征、舞蹈病、肌震颤、抽动、抖腿综合征、肌张力障碍、运动障碍、注意缺陷多动障碍(ADHD)、行为障碍、尿失禁、戒断症状、三叉神经痛、听力损失、耳鸣、神经损伤、视网膜疾病、黄斑变性症、呕吐、脑浮肿、疼痛、骨痛、关节痛、牙痛、猝倒症、或创伤性脑损伤的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项28]
发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项29]
发作性睡病的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项30]
特发性睡眠过度的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项31]
帕金森病所伴随的睡眠过度的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项32]
路易小体痴呆所伴随的睡眠过度的治疗药,其含有项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项33]
治疗发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的方法,其包括对需要治疗的患者投予治疗上有效量的项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐。
[项34]
项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐的用途,其用于制备发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗剂。
[项35]
包含项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐的药物组合物,其用于发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗的用途。
[项36]
项1~6A、项6、项7A和项7~24中任一项所述的化合物或其制药学上可接受的盐,其用于发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗和/或预防。
具体实施方式
以下进一步详细说明本发明。本说明书中也有时将"取代基"的定义中的碳数表述为例如"C1-6"等。具体而言,"C1-6烷基"的表述与碳原子数1至6的烷基含义相同。此外,本说明书中,关于未特别指出"任选被取代"或"被取代"的用语的取代基,是指"未取代"的取代基。例如,"C1-6烷基"是指"未取代的C1-6烷基"。
此外,本说明书中的取代基的说明中,也有时省略"基"的用语。应予说明,在用"任选被取代的"进行定义时,存在取代基时的取代基数只要能被取代则没有特别限制,为1或复数。即,表示任选被该基团中的能取代的碳原子、或碳原子和氮原子上的能取代数的取代基取代。此外,除特别指示的情况,各基团的说明也适用于该基团为其他基团的一部分或取代基的情况。
取代基的键合位置在本说明书中未特别明示的情况下是化学上能键合的任意位置。此外,本说明书中的结构式中,楔形的实线和虚线表示绝对构型,粗线的实线和虚线表示相对构型。
作为"卤素",可举出例如氟、氯、溴、碘等。优选为氟或氯。
"C1-4烷基"是指碳原子数为1~4个的直链状或支链状的饱和烃基,"C1-6烷基"是指碳原子数为1~6个的直链状或支链状的饱和烃基。作为"C1-4烷基"的具体例,可举出甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,作为"C1-6烷基"的具体例,除上述外,可举出戊基、异戊基、新戊基、1-乙基丙基、己基、以及它们的的结构异构体。作为该"C1-6烷基"或"C1-4烷基",优选为甲基、乙基、丙基、异丙基,更优选为甲基和异丙基。
"C1-6亚烷基"是指具有碳原子数1~6个的直链状或支链状的2价的饱和烃基。作为"C1-6亚烷基",优选举出"C1-4亚烷基",更优选举出"C1-3亚烷基"。作为"C1-3亚烷基"的具体例,例如可举出亚甲基、亚乙基、亚丙基、三亚甲基等。作为"C1-4亚烷基"的具体例,例如,除作为前述"C1-3亚烷基"的具体例而举出的基团外,可举出亚丁基、1,1-二甲基亚乙基、1,2-二甲基亚乙基、1-甲基三亚甲基、2-甲基三亚甲基等。作为"C1-6亚烷基"的具体例,例如,除作为前述"C1-4亚烷基"的具体例而举出的基团外,可举出亚戊基、1,1-二甲基三亚甲基、1,2-二甲基三亚甲基、1-甲基亚丁基、2-甲基亚丁基、1-甲基亚戊基、2-甲基亚戊基、3-甲基亚戊基、亚己基等。
"C3-7环烷基"是指具有碳原子数3~7个的环状的非芳香族性烃基(饱和烃基和部分不饱和烃基)。优选为"C3-6环烷基"。"C3-7环烷基"也包括桥联基团。作为"C3-7环烷基"的具体例,可举出环丙基、环丁基、环戊基、环己基、环戊烯基、环己烯基、环庚基等。
前述"C3-7环烷基"也包括"C3-7环烷基"与苯环或5元或6元的含有1个或相同或不同的2个以上(例如2~4个)的选自氮、硫或氧中的杂原子的环(例如,下述说明的"5或6元的单环式芳香族杂环"、和下述说明的"4~10元的饱和杂环"中的5或6元的环)缩环而成的2环式基团。
"C1-4烷氧基"是指被前述"C1-4烷基"取代的氧基,"C1-6烷氧基"是指被前述"C1-6烷基"取代的氧基。作为"C1-4烷氧基"的具体例,可举出甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基等,作为"C1-6烷氧基"的具体例,例如,除作为前述"C1-4烷氧基"的具体例而举出的基团外,可举出戊基氧基、己基氧基等。作为"C1-4烷氧基",优选举出甲氧基、乙氧基、异丙氧基。
"C3-7环烷氧基"是指被前述"C3-7环烷基"取代的氧基。优选为"C3-6环烷氧基"。作为"C3-7环烷氧基"的具体例,可举出环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。优选为环己基氧基。
"C6-10芳香族碳环基"是指具有碳原子数6~10个的芳香族烃基,也称为"C6-10芳基"。更优选为苯基。作为"C6-10芳香族碳环基"的具体例,例如,可举出苯基、1-萘基或2-萘基等。
前述"C6-10芳香族碳环基"也包括"苯基"与含有1个或相同或不同的2个以上(例如2~4个)的选自氮、硫或氧中的杂原子的5或6元的环(例如,下述说明的"5或6元的单环式芳香族杂环"、下述说明的"4~10元的饱和杂环"中的5或6元的环)、或5~7元的环烷基环(例如环戊烷、环己烷或环庚烷)缩环而成的基团。
"5~10元的芳香族杂环基"是指除作为构成环的原子的碳外含有1个或相同或不同的2个以上(例如2~4个)的选自氮、硫或氧中的杂原子的单环式或多环式的5~10元的芳香族杂环基,优选为"5或6元的单环式芳香族杂环基"。"5或6元的单环式芳香族杂环基"是指"5~10元的芳香族杂环基"中单环式的5或6元的芳香族杂环基。
作为前述"5~10元的芳香族杂环基"中的多环式芳香族杂环基,具体而言,可举出相同或不同的两个单环式芳香族杂环缩环而成的基团、或者单环式芳香族杂环与芳香族环(例如苯等)或非芳香族环(例如环己烷等)缩环而成的基团。
作为"5~10元的芳香族杂环基"的具体例,可举出吡唑基、咪唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基。在另一实施方式中,优选举出苯并呋喃基(键合位置在杂芳基(呋喃)环上)、吡啶基、嘧啶基、吡嗪基、哒嗪基。
"C3-6饱和碳环"是指碳原子数3至6的单环式的饱和或部分不饱和的烃环。作为"C3-6饱和碳环"的具体例,例如,可举出环丙烷、环丁烷、环戊烷、环己烷、环丙烯、环丁烯、环戊烯、环己烯、环己二烯等。优选举出环丙烷或环丁烷。
"4~10元的饱和杂环"是指除作为构成环的原子的碳外包含选自氧原子、氮原子和硫原子中的相同或不同的1或2个以上(例如,2~4个、优选为2~3个、更优选为2个)的杂原子的由4~10个的原子构成的单环式或二环式的饱和杂环,包括具有部分不饱和键的环、具有部分桥联结构的环和部分螺化的环。优选为5元或6元的饱和杂环。二环式的饱和杂环也包括单环式的饱和杂环与苯或单环式的5至6元的芳香族杂环缩环而成的环。此外,为了构成该饱和杂环,可以包括1或2个羰基、硫代羰基、亚磺酰基或磺酰基,例如,内酰胺、硫代内酰胺、内酯、硫代内酯、环状的酰亚胺、环状的氨基甲酸酯、环状的硫代氨基甲酸酯等环状基也包括在该饱和杂环中。其中,羰基、亚磺酰基和磺酰基的氧原子和硫代羰基的硫原子不包括在构成4~10元的数(环的大小)和构成环的杂原子的数之中。作为"4~10元的饱和杂环",优选举出单环式或二环式的"4~8元的饱和杂环",更优选举出单环式的"4~6元的饱和杂环",进一步优选举出单环式的"5或6元的饱和杂环"。作为"4~10元的饱和杂环"的具体例,可举出哌嗪、氧杂环丁烷、氮杂环丁烷、吡咯烷、吡唑烷、咪唑烷、哌啶、吗啉、高哌啶、氧杂环丁烷、硫代吗啉、二氧代硫代吗啉、六亚甲基亚胺、噁唑烷、噻唑烷、咪唑烷、氧代咪唑烷、二氧代咪唑烷、氧代噁唑烷、二氧代噁唑烷、二氧代噻唑烷、四氢呋喃、四氢吡喃、四氢吡啶等。优选为吡咯烷、哌啶、哌嗪、吗啉。作为二环式的饱和杂环的具体例,可举出吲哚啉、异吲哚啉、二氢嘌呤、二氢噻唑并嘧啶、二氢苯并二氧杂环己烷、二氢吲唑、二氢吡咯并吡啶、四氢喹啉、十氢喹啉、四氢异喹啉、十氢异喹啉、四氢萘啶、四氢吡啶并氮杂等。
"4~10元的饱和杂环基"是指上述"4~10元的饱和杂环"成为1价基团的取代基,"4~6元的饱和杂环基"是指上述"4~10元的饱和杂环"中"4~6元的饱和杂环"成为1价基团的取代基。优选举出氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基等。
本发明的化合物中也包括各种水合物、溶剂合物和结晶多型。
此外,本发明的化合物可以被同位体元素(例如,D、3H、11C、13C、14C、13N、15N、15O、35S、18F、125I等)取代,这些化合物也包括在本发明的化合物中。
本发明中,"制药学上可接受的盐"是指允许在药学中使用的酸加成盐和碱加成盐。作为"制药学上可接受的盐",不限定于这些,例如可举出乙酸盐、丙酸盐、丁酸盐、甲酸盐、三氟乙酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、硬脂酸盐、丁二酸盐、乙基丁二酸盐、丙二酸盐、乳糖酸盐、葡糖酸盐、葡庚糖酸盐、苯甲酸盐、甲磺酸盐、苯磺酸、对甲苯磺酸盐(tosylate)、月桂基硫酸盐、苹果酸盐、抗坏血酸盐、扁桃酸盐、糖精酸盐、昔萘酸盐、双羟萘酸盐、肉桂酸盐、己二酸盐、半胱氨酸盐、N-乙酰基半胱氨酸盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、碘化氢酸盐、烟酸盐、草酸盐、苦味酸盐、硫氰酸盐、十一烷酸盐、丙烯酸聚合物盐、羧基乙烯基聚合物等酸加成盐;锂盐、钠盐、钾盐、钙盐等无机碱加成盐;吗啉、哌啶等有机碱加成盐;与天冬酰胺酸、谷氨酸等氨基酸的加成盐等。
本发明的化合物可以通过经口给药或非经口给药、直接使用或使用适当的剂型而制成制剂、医药或医药组合物从而给药。作为这些剂型的具体例,不限定于这些,例如可举出片剂、胶囊剂、散剂、颗粒剂、液剂、悬浮剂、注射剂、贴剂、敷剂等。此外,这些制剂可以使用作为通常的医药品添加物而使用的添加剂利用公知的方法制备。
作为这些添加剂,根据目的,可使用赋形剂、崩解剂、结合剂、流动化剂、润滑剂、涂布剂、溶解剂、溶解辅助剂、增粘剂、分散剂、稳定化剂、甜味剂、香料等。作为这些添加剂的具体例,不限定于这些,例如可举出乳糖、甘露醇、结晶纤维素、低取代度羟基丙基纤维素、玉米淀粉、部分α化淀粉、羧甲基纤维素钙、交联羧甲基纤维素钠、羟基丙基纤维素、羟基丙基甲基纤维素、聚乙烯醇、硬脂酸镁、富马酸硬脂基钠、聚乙二醇、丙二醇、二氧化钛、滑石等。
本发明的化合物的给药量可根据给药对象动物、给药途径、疾病、患者的年龄、体重和症状而适当选择。例如,经口给药时,对于成人,每1天,作为下限为0.01mg,作为上限为10000mg,该量可以以1天1次或分数次给药。
本发明的化合物是对食欲素2型受体具有激动活性的化合物。因此,可成为对与食欲素受体相关的疾病有用的预防或治疗剂。作为这些疾病的具体例,可举出发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、路易小体痴呆所伴随的睡眠过度、伴随白天的睡眠过度的睡眠过度综合征(例如,克莱恩-莱文综合征、伴随睡眠过度的重度抑郁、路易小体痴呆、帕金森病、进行性核上性麻痹、普拉德-威利综合征、莫比乌斯综合征、低通气综合征、尼曼-匹克病C型、脑挫伤、脑梗塞、脑肿瘤、肌肉萎缩、多发性硬化症、急性播散性脑脊髓炎、吉兰-巴雷综合征、拉斯穆森脑炎、韦尼克脑炎、边缘***脑炎、桥本脑症)、昏睡、意识丧失、肥胖(例如,恶性肥胖细胞、外源性肥胖、胰岛功能亢进性肥胖症、原生质增生性肥胖、垂体性肥胖、原生质减低性肥胖症、甲状腺功能减退性肥胖症、下丘脑性肥胖、症状性肥胖症、小儿肥胖、上半身肥胖、饮食性肥胖症、性功能降低性肥胖、全身性肥胖细胞症、单纯性肥胖、中心性肥胖)、胰岛素抵抗性综合征、、阿兹海默症、昏睡等意识障碍、由麻醉导致的副作用、并发症、睡眠紊乱、睡眠问题、失眠、间歇性睡眠、夜间阵挛性肌肉痉挛、REM睡眠中断、时差反应、时差反应综合征、轮班工作人员的睡眠障碍、睡眠异常、夜惊症、抑郁、重度抑郁、梦游病、遗尿症、睡眠障碍、阿尔茨海默性黄昏综合征、与昼夜节律相关的疾病、肌肉纤维痛、睡眠质量差引起的症状、暴饮暴食、强迫性饮食障碍、肥胖相关疾病、高血压、糖尿病、血浆胰岛素浓度和胰岛素抵抗性的上升、高脂蛋白血症、高脂血症、子宫内膜癌、乳腺癌、***癌、结肠癌、癌、变形性关节症、阻塞性睡眠呼吸中止、胆结石症、胆结石、心脏病、心脏异常跳动、心律不齐、心肌梗塞、充血性心力衰竭、心力衰竭、冠心病、心血管疾病、猝死、多囊卵巢疾病、颅咽管瘤、普拉德-威利综合征、弗勒赫利希综合征、生长激素缺乏者、正常变异型身材矮小、特纳综合征、儿童急性淋巴细胞性白血病、X综合征、生殖***激素异常、受孕能力降低、***、男性性腺功能降低、女性的男性型多毛症等性和生殖功能障碍、与孕妇肥胖相关的胎儿缺陷、与肥胖相关的胃食管反流等胃肠动力疾病、肥胖通气不足综合征(匹克威克综合征)、呼吸困难等呼吸***疾病、血管***的全身性炎症等炎症、动脉硬化、高胆固醇血症、高尿酸血症、腰痛、胆囊疾病、痛风、肾癌、将左心室肥大的风险等肥胖的继发后果风险、偏头痛、头痛、神经性疼痛、帕金森病、精神病、神经***症、面部潮红、盗汗、生殖器/泌尿器***疾病、与性功能或受孕能力相关的疾病、低落性情感障碍、双相情感障碍、I型双相情感障碍、II型双相情感障碍、循环性情感精神障碍、急性应激障碍、广场恐怖症、广泛性焦虑症、强迫症、惊恐发作、惊恐障碍、创伤后应激障碍、分离焦虑症、社交恐惧症、焦虑症、心脏搭桥手术和移植后的脑缺损等急性神经学的和精神医学的障碍、中风,缺血性中风,脑缺血、脊髓外伤、头部外伤、周产期缺氧、心脏骤停、低血糖性神经损伤、亨廷顿舞蹈病、肌萎缩性侧索硬化症、多发性硬化症、眼损伤、视网膜疾病、认知障碍、肌肉痉挛、震颤、癫痫、与肌肉萎缩相关的障碍、谵妄、健忘症、与年龄增长相关的认知下降、***感情性障碍、妄想症、药物依赖症、运动异常症、慢性疲劳综合征、疲劳、药物诱发性帕金森综合征、抽动秽语综合征、舞蹈病、肌震颤、抽动、抖腿综合征、肌张力障碍、运动障碍、注意缺陷多动障碍(ADHD)、行为障碍、尿失禁、戒断症状、三叉神经痛、听力损失、耳鸣、神经损伤、视网膜疾病、黄斑变性症、呕吐、脑浮肿、疼痛、骨痛、关节痛、牙痛、猝倒症、或创伤性脑损伤。优选为发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、路易小体痴呆所伴随的睡眠过度。
本发明中,"预防"是指对疾病未发病的健康人投予本发明的化合物的行为,例如,目的在于防止疾病的发病。"治疗"是指对由医生诊断为疾病发病的人(患者)投予本发明的化合物的行为,例如,目的在于减轻疾病、症状或恢复为疾病发病前的状态。此外,即使投予的目的是防止疾病、症状的恶化,只要被投予者为患者,则也为治疗行为。
以下,对本发明中的式(1)所示的化合物的制备方法,举例进行说明,但本发明当然不限定于此。
制备方法
本发明化合物可通过下述所示的制备方法、和与公知的合成方法组合的方法合成。
反应式中的化合物也包括形成各自盐的情况,作为该盐,例如,可举出与上述"制药学上可接受的盐"相同的盐。应予说明,这些反应仅为例示,基于熟知有机合成化学者的知识,也可适当通过其他方法制备本发明化合物。
下述所说明的各制备方法中,即使是未具体地明示保护基的使用的情况下,在存在需要保护的官能团时,也有时根据需要保护该官能团,并在反应结束后或进行一系列反应后进行去保护从而得到目标物。
作为保护基,例如,可使用文献(T.W.Greene and P.G.M.Wuts,”ProtectiveGroups in Organic Synthesis”,3rd Ed.,John Wiley and Sons,inc.,New York(1999))等中记载的通常的保护基,更具体而言,作为氨基的保护基,例如,可举出叔丁氧基羰基、苯甲基氧基羰基、对甲苯磺酰基、邻硝基苯磺酰基、四氢吡喃基等,另外,作为羟基的保护,例如,可举出三烷基甲硅烷基、乙酰基、苯甲基、四氢吡喃基、甲氧基甲基等,作为醛基的保护基,例如,可举出二烷基缩醛、环状烷基缩醛等,作为羧基的保护基,例如,可举出叔丁基酯、原酸酯、酰胺等。
保护基的导入和脱离可通过有机合成化学中常用的方法(例如,T.W.Greene andP.G.M.Wuts,”Protective Groups in Organic Synthesis”,3rd Ed.,John Wiley andSons,inc.,New York(1999)中记载的方法等)或基于其的方法进行。
制备方法1:
式(1)所示的化合物或其制药学上可接受的盐中,式(1’)所示的化合物可通过例如下述的制备方法制备。
[化20]
(式中,R1、R2、L1、L2、环G、和A与项1含义相同。)
步骤(1):
化合物(1’)可通过在适当的不活性溶剂中在通常使用的脲键形成条件下使化合物(s-1)和化合物(s-2)进行反应而制备。本反应的条件可举出例如使用了三光气、氯甲酸4-硝基苯基酯或硫代光气的条件。作为本反应中使用的碱,可举出三乙基胺或二异丙基乙基胺等。作为溶剂,可举出氯仿、二氯甲烷等卤化碳、二乙基醚、THF、1,4-二氧杂环己烷等醚系溶剂、苯、甲苯、二甲苯等芳香族烃系溶剂、乙酸乙酯、乙酸甲酯等酯系溶剂。反应时间通常为约1小时至24小时,反应温度为-20℃至溶剂的沸点。
制备方法2:
式(1)所示的化合物或其制药学上可接受的盐中,式(s-5)所示的化合物例如可通过下述制备方法来制备。
[化21]
(式中,R1、R2、L1、L2、和A与项1含义相同,Rb1与项5含义相同,X为氨基的保护基。化合物(s-3)为制备方法1的环G被保护的含氮环时,可与制备方法1的步骤(1)同样地合成。)
步骤(2):
化合物(s-4)可通过在适当的不活性溶剂中在通常使用的去保护基化条件下使化合物(s-3)进行反应而制备。关于本反应的条件,例如X为Boc基时可通过使用酸来进行去保护。例如作为酸,可举出盐酸、硫酸、氢溴酸、三氟乙酸等。作为溶剂,可举出二氯甲烷、氯仿等卤化烃系溶剂、二乙基醚、二异丙基醚、四氢呋喃、1,4-二氧杂环己烷等醚系溶剂、乙酸乙酯、乙酸甲酯等酯系溶剂。反应时间通常为约1小时至24小时,反应温度为-20℃至溶剂的沸点。X为Cbz基、Bn基时,可通过例如在加氢条件下进行接触还原而进行去保护。作为催化剂,可使用钯-碳等非均相催化剂。加氢条件下是指氢氛围下、或者甲酸、甲酸铵等存在下。作为溶剂,可举出甲醇、乙醇、THF、乙酸乙酯等。反应时间为30分钟至24小时,反应温度为0℃至溶剂的沸点。
步骤(3):
化合物(s-5)可通过在适当的不活性溶剂中在通常使用的还原性氨基化条件下使化合物(s-4)进行反应而制备。本反应的条件可举出使用例如三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠等的条件。作为本反应中使用的酸,可举出乙酸等。作为溶剂,可举出氯仿、二氯甲烷等卤化碳、二乙基醚、THF、1,4-二氧杂环己烷等醚系溶剂、乙酸乙酯、乙酸甲酯等酯系溶剂。反应时间通常为约1小时至24小时,反应温度为-20℃至溶剂的沸点。
实施例
以下通过参考例、实施例和试验例进一步具体说明本发明,本发明当然不限定于此。应予说明,以下的参考例和实施例中所示的化合物名称并不必须依据IUPAC命名法。
本说明书中,有时使用以下的缩写。
CDCl3:氘代氯仿
DMSO-d6:氘代二甲基亚砜
Rt:保留时间
min:分钟
HATU:O-(7-氮杂-1H-苯并***-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐
THF:四氢呋喃
TFA:三氟乙酸
DMF:N,N-二甲基甲酰胺
Boc:叔丁氧基羰基
Ns:2-硝基苯磺酰基
Tf:三氟甲磺酰基
Abs:绝对立体构型(Absolute Configuration);记载为以四边包围的Abs的缩写的化合物的化学结构表示将楔型键记为绝对立体构型。其中,未记载该缩写的化合物的化学结构未必是指不是绝对立体构型,要根据本说明书中的对象化合物相关的记载、上下文和本领域技术人员的常识来判断。
Rac:外消旋混合物(Racemic compound);表示因2种镜像异构体(对映异构体)等量存在而不示出旋光性的状态的化合物。
参考例和实施例中的柱色谱和氨基色谱使用山善株式会社制的硅胶柱和氨基柱。使用TLC进行纯化时的TLC(硅胶板)使用Silica gel60F254(Merck)、TLC(NH硅胶板)使用TLC板NH(FujiSilysia)。
参考例和实施例中使用以下的反应装置。参考例和实施例所记载的物理化学数据由以下的机器获得。
微波反应装置:Biotage AB Initiator
1H-NMR:JEOL JNM-AL400;JEOL JNM-ECS400;Brucker AVANCE 400Spectrometer
作为NMR中使用的符号,s是指单峰、d是指二重峰、dd是指双二重峰、ddd是指二重的双二重峰、dddd是指二重的二重的双二重峰、t是指三重峰、td是指三重峰的二重峰、q是指四重峰、m是指多重峰、br是指宽的单峰或多重峰、和J是指键合常数。
实施例和参考例的各化合物的LC/MS数据由以下任一机器获得。
方法A
检测机器:ACQUITY(注册商标)SQ deteceter(Waters公司)
HPLC:ACQUITY UPLC(注册商标)SYSTEM
柱:Waters ACQUITY UPLC(注册商标)BEH C18(1.7μm,2.1mm×30mm)
方法B
检测机器:岛津LCMS-2020
柱:Phenomenex Kinetex(C18,1.7μm,2.1mm×50mm)
方法C
检测机器:ACQUITY(注册商标)SQ deteceter(Waters公司)
HPLC:ACQUITY UPLC(注册商标)SYSTEM
柱:Waters ACQUITY UPLC(注册商标)BEH C18(1.7μm,2.1mm×30mm)
方法D
检测机器:岛津LCMS-2020
柱:Waters ACQUITY UPLC(注册商标)C18(1.8μm,2.1mm×50mm)
高效液相色谱质谱仪;LC/MS的测定条件如以下所述,观察到的质谱值[MS(m/z)]以[M+H]+表示,保留时间以Rt(min)表示。应予说明,各实测值中,测定中所用的测定条件用A~D中任一者标注。
方法A
溶剂:A液;0.06%甲酸/H2O、B液;0.06%甲酸/乙腈
梯度条件:0.0-1.3分钟(线性梯度从B 2%至B 96%)
流速:0.8mL/分钟;检测UV:220nm and 254nm;温度:40℃
以下,LC-MS数据无特别说明的话则表示通过方法A测定而得。
方法B
溶剂:A液;0.05%TFA/H2O、B液;乙腈
梯度条件:0.0-1.7分钟(线性梯度从B10%至B 99%)
流速:0.5mL/分钟;检测UV:220nm;温度:40℃
方法C
溶剂:A液;0.05%甲酸/H2O、B液;乙腈
梯度条件:0.0-1.3分钟(线性梯度从B10%B 95%)1.3-1.5分钟(B10%)
流速:0.8mL/分钟;检测UV:220nm and 254nm;温度:40℃
方法D
溶剂:A液;0.1%甲酸/H2O、B液;0.1%甲酸/乙腈
梯度条件:0.01-4.0分钟(线性梯度从B 5%至B 99%)4.0分钟-5.0分钟(B 95%)
流速:0.5mL/分钟;检测UV:220nm;温度:25℃
以下,没有记载的情况下,为通过方法A进行分析而得。
参考例1:
4-(2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)哌嗪-1-甲酸叔丁基酯
[化22]
步骤(i):
向化合物1(0.100g)、二异丙基乙基胺(0.047g)、氯仿(1.8mL)的混合物中在0℃下加入氯甲酸4-硝基苯基酯(0.073g),在该温度下搅拌1小时。向反应混合液中在0℃下加入4-(4-甲基苯基)哌啶(0.070g),在室温下搅拌1小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物2(0.152g)。
LCMS:[M+H]+/Rt(min):479/1.27
参考例2:
2-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化23]
步骤(i):
将化合物3(1.41g)、碳酸钾(5.52g)、异丙基哌嗪(1.28g)、THF(25mL)的混合物在50℃下搅拌1小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣直接用于下一反应。
步骤(ii):
将化合物4的混合物、10%钯碳(1.06g)和甲醇(25mL)的混合物在氢气氛围下在室温下搅拌1小时。将反应混合液进行硅藻土过滤,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:氯仿/甲醇)纯化,得到标题化合物5(1.50g)。
LCMS:[M+H]+/Rt(min):220/0.35
参考例3:
4-氟-2-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化24]
步骤(i):
使用化合物6(0.159g),按照与参考例2的步骤(i)同样的方法,得到标题化合物7的混合物。
步骤(ii):
使用化合物7的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物8(0.144g)。
LCMS:[M+H]+/Rt(min):238/0.39
参考例4:
2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化25]
步骤(i):
使用化合物9(0.020g),按照与参考例2的步骤(i)同样的方法,得到标题化合物10的混合物。
步骤(ii):
使用化合物10的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物11(0.019g)。
LCMS:[M+H]+/Rt(min):250/0.60
参考例5:
2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化26]
步骤(i):
使用化合物12(0.159g),按照与参考例2的步骤(i)同样的方法,得到标题化合物13的混合物。
步骤(ii):
使用化合物13的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物14(0.190g)。
LCMS:[M+H]+/Rt(min):238/1.16(方法B)
参考例6:
3-氟-2-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化27]
步骤(i):
使用化合物15(0.477g),按照与参考例2的步骤(i)同样的方法,得到标题化合物16的混合物。
步骤(ii):
使用化合物16的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物17(0.443g)。
LCMS:[M+H]+/Rt(min):238/0.46
参考例7:
2-甲基-6-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化28]
步骤(i):
使用化合物18(0.310g),按照与参考例2的步骤(i)同样的方法,得到标题化合物19的混合物。
步骤(ii):
使用化合物19的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物20(0.410g)。
LCMS:[M+H]+/Rt(min):234/0.61
参考例8:
2-[4-(丙烷-2-基)哌嗪-1-基]-6-(三氟甲基)苯胺
[化29]
步骤(i):
使用化合物21(0.209g),按照与参考例2的步骤(i)同样的方法,得到标题化合物22的混合物。
步骤(ii):
使用化合物22的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物23(0.220g)。
LCMS:[M+H]+/Rt(min):288/1.50(方法B)
参考例9:
2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化30]
步骤(i):
使用化合物24(4.00g),按照与参考例2的步骤(i)同样的方法,得到标题化合物25的混合物。
步骤(ii):
向化合物25的混合物、还原铁(3.82g)和甲醇(57mL)的混合物中在90℃下加入4N氯化铵水溶液(28.5mL),在该温度下搅拌2小时。放冷至室温后,将反应混合液进行硅藻土过滤,减压浓缩后,溶解于乙酸乙酯,用水和饱和食盐水洗涤。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:氯仿/甲醇)纯化,得到标题化合物26(4.10g)。
LCMS:[M+H]+/Rt(min):254/1.33(方法B)
参考例10:
2-氯-6-(4-环丙基哌嗪-1-基)苯胺
[化31]
代替参考例9中的步骤(i)的异丙基哌嗪,使用环丙基哌嗪,根据上述参考例9记载的方法,合成化合物27。
LCMS:[M+H]+/Rt(min):252/0.60
参考例11:
2-溴-6-[4-(丙烷-2-基)哌嗪-1-基]苯胺
[化32]
步骤(i):
使用化合物28(1.50g),按照与参考例2的步骤(i)同样的方法,得到标题化合物29的混合物。
步骤(ii):
使用化合物29的混合物,按照与参考例9的步骤(ii)同样的方法,得到标题化合物30(1.64g)。
LCMS:[M+H]+/Rt(min):298,300/0.58
参考例12:
2-氨基-N,N-二甲基-3-[4-(丙烷-2-基)哌嗪-1-基]苯甲酰胺
[化33]
步骤(i):
使用化合物31(0.212g),按照与参考例2的步骤(i)同样的方法,得到标题化合物32的混合物。
步骤(ii):
使用化合物32的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物33(0.201g)。
LCMS:[M+H]+/Rt(min):291/1.07(方法B)
参考例13:
(2R,5S)-2-(2-氨基苯基)-5-(丙烷-2-基)吗啉-4-甲酸叔丁基酯
[化34]
步骤(i):
将化合物34(1.00g)、叠氮化钠(0.533g)、水(10mL)和乙醇(20mL)的混合物在室温下搅拌4小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣直接用于下一反应。
步骤(ii):
将化合物35的粗产物、硼氢化钠(0.127g)和甲醇的混合物在0℃下搅拌1小时。向反应混合液中加入饱和氯化铵水溶液,用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物36(0.488g)。
步骤(iii):
将化合物36(0.289g)、1-溴-3-甲基-2-丁酮(0.641g)、碳酸铯(1.176g)和DMF(3mL)的混合物在室温下搅拌5小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物37(0.402g)。
LCMS:[M+H]+/Rt(min):293/1.05
步骤(iv):
将化合物37(0.82g)、三苯基膦(0.184g)和THF(2mL)的混合物在室温下搅拌10小时。将反应混合液减压浓缩并将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物38(0.058g)。
LCMS:[M+H]+/Rt(min):249/0.54
步骤(v):
将化合物38(0.059g)、三乙酰氧基硼氢化钠(0.100g)和二氯甲烷(2mL)的混合物在室温下搅拌3小时。向反应混合液中加入饱和碳酸氢钠水溶液并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物39(0.049g)。
LCMS:[M+H]+/Rt(min):251/0.63
步骤(vi):
将化合物39(0.038g)、二碳酸二叔丁基酯(0.040g)、N,N-二甲基-4-氨基吡啶(0.001g)和乙腈(2mL)的混合物在室温下搅拌2小时。向反应混合液中加入水,并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后所得将残渣直接用于下一反应。
LCMS:[M+H]+/Rt(min):325/1.24
步骤(vii):
使用化合物40的混合物,按照与参考例9的步骤(ii)同样的方法,得到标题化合物41(0.036g)。
LCMS:[M+H]+/Rt(min):321/1.13
参考例14:
Rac-2-[3-甲基-4-(丙烷-2-基)哌嗪-1-基]苯胺
[化35]
步骤(i):
使用化合物42(0.282g),按照与参考例2的步骤(i)同样的方法,以粗产物的形式得到标题化合物43。
步骤(ii):
将化合物43的粗产物、三氟乙酸(1.80g)、和氯仿(1.0mL)的混合物在室温下搅拌1小时。将反应混合液减压浓缩后,氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物44(0.370g)。
LCMS:[M+H]+/Rt(min):222/1.29(方法B)
步骤(iii):
将化合物44(0.221g)、三乙酰氧基硼氢化钠(0.635g)、乙酸(0.060g)、丙酮(0.058g)和THF(5mL)的混合物在室温下搅拌3小时。向反应混合液中加入饱和碳酸氢钠水溶液并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,所得将残渣直接用于下一反应。
步骤(iv):
使用化合物45的粗产物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物46(0.170g)。
LCMS:[M+H]+/Rt(min):234/0.48(方法B)
参考例15:
Rac-2-[2-甲基-4-(丙烷-2-基)哌嗪-1-基]苯胺
[化36]
步骤(i):
使用化合物47(0.221g),按照与参考例14的步骤(iii)同样的方法,得到标题化合物48的粗产物。
步骤(ii):
使用化合物48的粗产物,按照与参考例14的步骤(ii)同样的方法,得到标题化合物49(0.098g)。
LCMS:[M+H]+/Rt(min):143/0.30
步骤(iii):
使用化合物49(0.071g),按照与参考例2的步骤(i)同样的方法,得到标题化合物50的粗产物。
步骤(iv):
使用化合物50的粗产物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物51(0.060g)。
LCMS:[M+H]+/Rt(min):234/0.54
参考例16:
2-氨基-3-[4-(丙烷-2-基)哌嗪-1-基]苯甲酸甲酯
[化37]
步骤(i):
使用化合物52(0.150g),按照与参考例2的步骤(i)同样的方法,得到标题化合物53的混合物。
LCMS:[M+H]+/Rt(min):308/0.55
步骤(ii):
使用化合物53的混合物,按照与参考例2的步骤(ii)同样的方法,得到标题化合物54(0.132g)。
LCMS:[M+H]+/Rt(min):278/0.58
参考例17:
4-(2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-1,4-二氮杂环庚烷-1-甲酸叔丁基酯
[化38]
步骤(i):
使用化合物55(1.06g),按照与参考例2的步骤(i)同样的方法,得到标题化合物56(2.40g)。
LCMS:[M+H]+/Rt(min):322/1.08
步骤(ii):
使用化合物56(2.40g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物57(1.77g)。
LCMS:[M+H]+/Rt(min):292/0.96
步骤(iii):
使用化合物57(0.095g),按照与参考例1的步骤(i)同样的方法,得到标题化合物58(0.153g)。
LCMS:[M+H]+/Rt(min):493/1.12
参考例18:
4-(2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}苯基)-1,4-二氮杂环庚烷-1-甲酸叔丁基酯
[化39]
步骤(i):
使用化合物57(0.104g),按照与参考例1的步骤(i)同样的方法,得到标题化合物59(0.154g)。
参考例19:
2-(4-叔丁基哌嗪-1-基)-6-氯苯胺
[化40]
步骤(i):
使用化合物24(0.300g),按照与参考例2的步骤(i)同样的方法,得到标题化合物60的粗产物。
步骤(ii):
使用化合物60的粗产物,按照与参考例9的步骤(ii)同样的方法,得到标题化合物61(0.315g)。
LCMS:[M+H]+/Rt(min):268/0.56
参考例20:
2-[1-(丙烷-2-基)哌啶-4-基]苯胺
[化41]
步骤(i):
将化合物62(5.00g)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(7.60g)、Pd(dppf)Cl2CH2Cl2(2.02g)、碳酸钠(5.25g)、水(25mL)和1,4-二氧杂环己烷(50mL)的混合物在110℃下搅拌16小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物63(7.51g)。
LCMS:[M+H]+/Rt(min):305/4.24(方法D)
步骤(ii):
将化合物63(7.51g)、4N盐酸二氧杂环己烷溶液(31mL)和甲醇(150mL)的混合物在室温下搅拌1小时。将反应混合液减压浓缩后,得到标题化合物64(5.13g)。
LCMS:[M+H]+/Rt(min):205/2.15(方法D)
步骤(iii):
将化合物64(2.50g)、三乙酰氧基硼氢化钠(6.60g)、丙酮(0.058g)和二氯甲烷(75mL)的混合物在室温下搅拌12小时。向反应混合液中加入饱和碳酸氢钠水溶液并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:氯仿/甲醇)纯化,得到标题化合物65(1.60g)。
LCMS:[M+H]+/Rt(min):247/2.17(方法D)
步骤(iv):
使用化合物65(1.60g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物66(0.675g)。
LCMS:[M+H]+/Rt(min):219/1.85(方法D)
参考例21:
2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯胺
[化42]
步骤(i):
使用化合物28(0.220g),按照与参考例20的步骤(i)同样的方法,得到标题化合物67(0.234g)。
LCMS:[M+H]+/Rt(min):323/2.12(方法B)
步骤(ii):
将化合物67(0.230g)、三氟乙酸(1.80g)、和氯仿(1.0mL)的混合物在室温下搅拌1小时。将反应混合液减压浓缩后,得到标题化合物68的粗产物。
步骤(iii):
将化合物68的粗产物、三乙酰氧基硼氢化钠(0.454g)、乙酸(0.064g)、丙酮(0.166g)和THF(3mL)的混合物在室温下搅拌3小时。向反应混合液中加入饱和碳酸氢钠水溶液并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物69(0.150g)。
LCMS:[M+H]+/Rt(min):265/0.60(方法B)
步骤(iv):
使用化合物69(0.100g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物70(0.050g)。
LCMS:[M+H]+/Rt(min):237/0.53(方法B)
参考例22:
2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯胺
[化43]
步骤(i):
使用化合物69(0.100g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物71(0.077g)。
LCMS:[M+H]+/Rt(min):235/0.55(方法B)
参考例23:
4-(3-乙氧基-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)哌啶-1-甲酸叔丁基酯
[化44]
步骤(i):
将化合物72(0.654g)、碘乙烷(0.702g)、碳酸钾(1.66g)和THF(10mL)的混合物在50℃下搅拌2小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物73(0.621g)。
步骤(ii):
使用化合物73(0.500g),按照与参考例20的步骤(i)同样的方法,得到标题化合物74(0.558g)。
LCMS:[M+H]+/Rt(min):349/2.24(方法B)
步骤(iii):
使用化合物74(0.300g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物75的粗产物。
步骤(iv):
向化合物75的粗产物、二异丙基乙基胺(0.278g)、氯仿(4mL)的混合物中在0℃下加入三光气(0.064g),在该温度下搅拌1小时。向反应混合液中在0℃下加入4-(4-甲基苯基)哌啶(0.084g),在室温下搅拌1小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物76(0.180g)。
LCMS:[M+H]+/Rt(min):522/2.35(方法B)
参考例24:
4-(2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}-3-[(丙烷-2-基)氧基]苯基)哌啶-1-甲酸叔丁基酯
[化45]
步骤(i):
使用化合物72(0.654g),按照与参考例23的步骤(i)同样的方法,得到标题化合物77(0.522g)。
步骤(ii):
使用化合物77(0.520g),按照与参考例20的步骤(i)同样的方法,得到标题化合物78(0.611g)。
LCMS:[M+H]+/Rt(min):363/2.30(方法B)
步骤(iii):
使用化合物78(0.300g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物79的粗产物。
步骤(iv):
使用化合物79的粗产物,按照与参考例23的步骤(iv)同样的方法,得到标题化合物80(0.299g)。
LCMS:[M+H]+/Rt(min):536/2.40(方法B)
参考例25:
4-(3-氯-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁基酯
[化46]
步骤(i):
使用化合物81(0.709g),按照与参考例20的步骤(i)同样的方法,得到标题化合物82(0.502g)。
LCMS:[M+H]+/Rt(min):339/2.26(方法B)
步骤(ii):
使用化合物82(0.100g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物83(0.070g)。
LCMS:[M+H]+/Rt(min):309/2.22(方法B)
步骤(iii):
使用化合物83(0.070g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物84(0.082g)。
LCMS:[M+H]+/Rt(min):511/2.27(方法B)
参考例26~29
代替参考例25中的步骤(iii)的4-(4-甲基苯基)哌啶,使用各自对应的原料化合物,根据上述参考例25记载的方法,合成下述表所示的参考例26~29的化合物。
[表1]
参考例26:
4-(3-氯-2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁基酯
参考例27:
4-(3-氯-2-{[4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-羰基]氨基}苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁基酯
参考例28:
4-(3-氯-2-{[4-甲基-4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁基酯
参考例29:
4-{3-氯-2-[(4-氰基-4-甲基哌啶-1-羰基)氨基]苯基}-3,6-二氢吡啶-1(2H)-甲酸叔丁基酯
参考例30:
4-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁基酯
[化47]
步骤(i):
使用化合物67(0.900g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物89(0.750g)。
LCMS:[M+H]+/Rt(min):293/2.10(方法B)
步骤(ii):
使用化合物89(0.100g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物90(0.130g)。
LCMS:[M+H]+/Rt(min):494/2.27(方法B)
参考例31:
4-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)哌啶-1-甲酸叔丁基酯
[化48]
步骤(i):
使用化合物67(0.100g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物91的粗产物。
步骤(ii):
使用化合物91的粗产物,按照与参考例23的步骤(iv)同样的方法,得到标题化合物92(0.120g)。
LCMS:[M+H]+/Rt(min):496/1.22
参考例32:
2-甲氧基-6-[1-(丙烷-2-基)哌啶-4-基]苯胺
[化49]
步骤(i):
使用化合物93(3.00g),按照与参考例20的步骤(i)同样的方法,得到标题化合物94(3.78g)。
步骤(ii):
使用化合物94(3.78g),按照与参考例20的步骤(ii)同样的方法,得到标题化合物95(2.80g)。
LCMS:[M+H]+/Rt(min):235/2.31(方法D)
步骤(iii):
使用化合物95(2.80g),按照与参考例20的步骤(iii)同样的方法,得到标题化合物96(2.80g)。
LCMS:[M+H]+/Rt(min):277/2.42(方法D)
步骤(iv):
使用化合物96(2.00g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物97(1.45g)。
LCMS:[M+H]+/Rt(min):249/3.57(方法C)
参考例33:
2-甲氧基-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯胺
[化50]
步骤(i):
使用化合物96(0.350g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物98(0.237g)。
LCMS:[M+H]+/Rt(min):247/5.02(方法D)
参考例34:
3-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-2,5-二氢-1H-吡咯-1-甲酸叔丁基酯
[化51]
步骤(i):
使用化合物28(0.100g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物99(0.113g)。
1H-NMR(CDCl3)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).
步骤(ii):
使用化合物99(0.111g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物100(0.065g)。
LCMS:[M+H]+/Rt(min):279/0.99(方法B)
步骤(iii):
使用化合物100(0.030g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物101(0.030g)。
LCMS:[M+H]+/Rt(min):480/2.21(shi)(方法C)
参考例35:
2-(3,6-二氢-2H-吡喃-4-基)-6-氟苯胺
[化52]
步骤(i):
使用化合物28(0.100g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物102(0.056g)。
1H-NMR(CDCl3)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).
步骤(ii):
使用化合物102(0.054g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物103(0.032g)。
LCMS:[M+H]+/Rt(min):194/0.70(方法C)
参考例36:
2-(1-环丙基-1H-吡唑-4-基)-6-氟苯胺
[化53]
步骤(i):
使用化合物104(0.100g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物105(0.007g)。
LCMS:[M+H]+/Rt(min):218/0.72(方法C)
参考例37:
2-氟-6-[6-(丙烷-2-基)吡啶-3-基]苯胺
[化54]
步骤(i):
使用化合物28(0.165g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物106(0.110g)。
LCMS:[M+H]+/Rt(min):261/0.98
步骤(ii):
使用化合物106(0.110g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物107(0.084g)。
LCMS:[M+H]+/Rt(min):231/0.64
参考例38:
2-氟-6-{[1-(丙烷-2-基)哌啶-4-基]氧基}苯胺
[化55]
步骤(i):
将化合物108(0.157g)、4-羟基哌啶-1-甲酸叔丁基酯(0.201g)、二甲酸二异丙基酯(0.242g)、三苯基膦(0.524g)和THF(10mL)的混合物在室温下搅拌1小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物109(0.233g)。
LCMS:[M+H]+/Rt(min):341/2.17(方法B)
步骤(ii):
使用化合物109(0.100g),按照与参考例21的步骤(ii)同样的方法,得到标题化合物110的粗产物。
步骤(iii):
使用化合物110的粗产物,按照与参考例20的步骤(iii)同样的方法,得到标题化合物111(0.060g)。
步骤(iv):
使用化合物111(0.060g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物112(0.030g)。
参考例39:
Rac-2-氯-6-{[1-(丙烷-2-基)吡咯烷-3-基]氧基}苯胺
代替参考例38中的步骤(i)的化合物108和4-羟基哌啶-1-甲酸叔丁基酯,使用各自对应的原料化合物,根据上述参考例38记载的方法,合成下述的化合物。
[表2]
参考例40:
3-(3-氯-2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}苯氧基)氮杂环丁烷-1-甲酸叔丁基酯
[化56]
步骤(i):
将3-羟基氮杂环丁烷-1-甲酸叔丁基酯(1.30g)、氢化钠(0.41g)、THF(21mL)的混合物在0℃下搅拌30分钟后,加入化合物24,在室温下搅拌3小时。向反应混合液中加入饱和碳酸氢钠水溶液并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物114(2.06g)。
LCMS:[M+H]+/Rt(min):329/1.11
步骤(ii):
使用化合物114(1.00g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物115(0.77g)。
LCMS:[M+H]+/Rt(min):299/1.06
步骤(iii):
使用化合物115(0.060g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物116(0.110g)。
LCMS:[M+H]+/Rt(min):533/1.08
参考例41:
2-甲氧基-6-{[4-(丙烷-2-基)哌嗪-1-基]甲基}苯胺
[化57]
/>
步骤(i):
使用化合物117(0.181g)和异丙基哌嗪(0.128g),按照与参考例20的步骤(iii)同样的方法,得到标题化合物118(0.231g)。
步骤(ii):
使用化合物118(0.230g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物119(0.140g)。
参考例42:
3-氟-4’-(丙烷-2-基)[1,1’-联苯]-2-胺
[化58]
步骤(i):
使用化合物28(0.220g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物120(0.231g)。
步骤(ii):
使用化合物120(0.230g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物121(0.165g)。
参考例43:
4-(3-氯-2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}苯基)哌啶-1-甲酸叔丁基酯
[化59]
步骤(i):
使用化合物81(0.709g),按照与参考例20的步骤(i)同样的方法,得到标题化合物122(0.502g)。
LCMS:[M+H]+/Rt(min):339/2.26(方法B)
步骤(ii):
使用化合物122(0.10g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物123(0.039g)。
LCMS:[M+H]+/Rt(min):311/2.21(方法B)
步骤(iii):
使用化合物123(0.070g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物124(0.084g)。
LCMS:[M+H]+/Rt(min):545/1.12(方法C)
参考例44~45
代替参考例43中的步骤(iii)的4-(4-甲基苯基)哌啶,使用各自对应的原料化合物,根据上述参考例43记载的方法,合成下述的化合物。
[表3]
参考例44:
4-(3-氯-2-{[4-甲基-4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)哌啶-1-甲酸叔丁基酯
参考例45:
4-(3-氯-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)哌啶-1-甲酸叔丁基酯
参考例46:
2-氟-6-(6-甲基吡啶-3-基)苯胺
[化60]
步骤(i):
使用化合物28(0.178g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物127(0.198g)。
LCMS:[M+H]+/Rt(min):261/0.98
步骤(ii):
使用化合物127(0.184g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物128(0.148g)。
LCMS:[M+H]+/Rt(min):231/0.64
参考例47:
2-氯-6-[6-(丙烷-2-基)吡啶-3-基]苯胺
[化61]
步骤(i):
使用化合物81(0.247g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物129(0.147g)。
LCMS:[M+H]+/Rt(min):277/1.07
步骤(ii):
使用化合物129(0.142g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物130(0.130g)。
LCMS:[M+H]+/Rt(min):247/0.75
参考例48:
2-氟-6-(5-甲基吡啶-3-基)苯胺
[化62]
步骤(i):
使用化合物28(0.143g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物131(0.104g)。
LCMS:[M+H]+/Rt(min):233/0.80
步骤(ii):
使用化合物131(0.091g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物132(0.072g)。
LCMS:[M+H]+/Rt(min):203/0.53
参考例49:
2-氟-6-[6-(三氟甲基)吡啶-3-基]苯胺
[化63]
步骤(i):
使用化合物104(0.248g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物133(0.054g)。
LCMS:[M+H]+/Rt(min):257/0.90(方法C)
参考例50:
2-氟-6-[2-(丙烷-2-基)嘧啶-5-基]苯胺
[化64]
步骤(i):
使用化合物28(0.100g)和对应的硼酸,按照与参考例20的步骤(i)同样的方法,得到标题化合物134(0.038g)。
LCMS:[M+H]+/Rt(min):262/0.90(方法C)
步骤(ii):
使用化合物134(0.036g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物135(0.004g)。
1H-NMR(CDCl3)δ:1.41(6H,d,J=6.8Hz),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).
参考例51:
(1S,4S)-5-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁基酯
[化65]
步骤(i):
使用化合物12(0.324g),按照与参考例2的步骤(i)同样的方法,得到标题化合物136(0.530g)。
LCMS:[M+H]+/Rt(min):338/1.08
步骤(ii):
使用化合物136(0.530g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物137(0.385g)。
LCMS:[M+H]+/Rt(min):308/1.01
步骤(iii):
使用化合物137(0.044g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物138(0.080g)。
LCMS:[M+H]+/Rt(min):509/1.15
参考例52:
(1S,4S)-5-(2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}-3-氟苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁基酯
[化66]
/>
步骤(i):
使用化合物137(0.124g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物139(0.189g)。
LCMS:[M+H]+/Rt(min):541/1.01
参考例53:
(1R,4R)-5-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁基酯
[化67]
步骤(i):
使用化合物12(0.252g),按照与参考例2的步骤(i)同样的方法,得到标题化合物140(0.410g)。
LCMS:[M+H]+/Rt(min):338/1.08
步骤(ii):
使用化合物140(0.404g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物141(0.224g)。
LCMS:[M+H]+/Rt(min):308/1.01
步骤(iii):
使用化合物141(0.037g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物142(0.080g)。
LCMS:[M+H]+/Rt(min):509/1.15
参考例54:
(1R,4R)-5-(2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}-3-氟苯基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁基酯
[化68]
步骤(i):
使用化合物141(0.055g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物143(0.088g)。
LCMS:[M+H]+/Rt(min):541/1.01
参考例55:
3-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁基酯
[化69]
步骤(i):
使用化合物12(0.382g),按照与参考例2的步骤(i)同样的方法,得到标题化合物144(0.575g)。
步骤(ii):
使用化合物144(0.563g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物145(0.451g)。
LCMS:[M+H]+/Rt(min):322/1.11
步骤(iii):
使用化合物145(0.111g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物146(0.161g)。
LCMS:[M+H]+/Rt(min):523/1.23
参考例56:
3-(2-{[4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-羰基]氨基}-3-氟苯基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁基酯
[化70]
步骤(i):
使用化合物145(0.107g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物147(0.189g)。
LCMS:[M+H]+/Rt(min):556/1.12
参考例57:
8-(3-氟-2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸苯甲基酯
[化71]
步骤(i):
使用化合物12(0.204g),按照与参考例2的步骤(i)同样的方法,得到标题化合物148(0.338g)。
LCMS:[M+H]+/Rt(min):386/1.15
步骤(ii):
使用化合物148(0.307g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物149(0.220g)。
LCMS:[M+H]+/Rt(min):356/1.10
步骤(iii):
使用化合物149(0.073g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物150(0.080g)。
LCMS:[M+H]+/Rt(min):557/1.20
参考例58:
Rac-(2R,5S)-2-(2-氨基-3-氯苯基)-5-(丙烷-2-基)吗啉-4-甲酸叔丁基酯
[化72]
步骤(i):
将化合物151(3.03g)、二氧化锰(11.56g)和氯仿(160mL)的混合物在加热回流下搅拌12小时。放冷后进行硅藻土过滤,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物152(2.59g)。
LCMS:[M+H]+/Rt(min):186/0.81
步骤(ii):
向甲基三苯基膦酰溴(3.25g)和THF(21mL)的混合物中在0℃下加入正丁基锂己烷溶液(1.57M、5.35mL),在该温度下搅拌1小时。向该混合物中滴加化合物152(1.30g)的THF(7mL)溶液,在室温下搅拌3小时。向反应混合液中加入饱和氯化铵水溶液并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物153(0.756g)。
步骤(iii):
将化合物153(0.333g)、间氯过苯甲酸(0.542g)和氯化亚甲基(9mL)的混合物在室温下搅拌4小时。向反应混合液中加入饱和碳酸氢钠水溶液并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:氯仿/甲醇)纯化,得到标题化合物154(0.141g)。
步骤(iv):
将化合物154(0.141g)、叠氮化钠(0.046g)和乙腈(3mL)的混合物在40℃下搅拌3小时。进一步加入水(1mL)并在加热回流下搅拌10小时。将反应混合液减压浓缩,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物155(0.084g)。
步骤(v):
将化合物155(0.100g)、1-溴-3-甲基丁烷-2-酮(0.086g)、碳酸铯(0.226g)和乙腈(3.5mL)的混合物在室温下搅拌2小时。将反应混合液减压浓缩,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物156(0.100g)。
LCMS:[M+H]+/Rt(min):327/1.10
步骤(vi):
将化合物156(0.100g)、三苯基膦(0.097g)和THF(6mL)的混合物在室温下搅拌4小时。在反应混合液中加入三乙酰氧基硼氢化钠(0.098g),在室温下搅拌16小时。向反应混合液中加入饱和碳酸氢钠水溶液并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,所得将残渣直接用于下一反应。
LCMS:[M+H]+/Rt(min):285/0.69,285/0.74(方法C)
步骤(vii):
将化合物157的粗产物、Boc2O(0.067g)和THF(6mL)的混合物在室温下搅拌16小时。参考例2的步骤(ii)同样的方法,得到标题化合物的混合物(0.55g)。向反应混合液中加入饱和碳酸氢钠水溶液并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物158(0.031g)和标题化合物159(0.018)。
步骤(vii):
使用化合物158(0.031g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物160(0.029g)。
LCMS:[M+H]+/Rt(min):355/1.29
参考例59:
Rac-(2R,5R)-2-(2-氨基-3-氯苯基)-5-(丙烷-2-基)吗啉-4-甲酸叔丁基酯
[化73]
步骤(i):
使用化合物159(0.018g),按照与参考例9的步骤(ii)同样的方法,得到标题化合物161(0.011g)。
LCMS:[M+H]+/Rt(min):355/1.29
参考例60:
Rac-6-(4-甲基苯基)-3-氮杂双环[4.1.0]庚烷
[化74]
步骤(i):
将化合物162(1.42g)、对甲苯基溴化镁(1M、8.52mL)和THF(20mL)的混合物在室温下搅拌14小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物163(1.62g)。
LCMS:[M+H]+/Rt(min):326/1.01
步骤(ii):
将化合物163(0.742g)、对甲苯磺酸1水合物(0.217g)和甲苯的混合物在50℃下搅拌1小时。向反应混合液中加入饱和碳酸氢钠水溶液并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物164(0.561g)。
LCMS:[M+H]+/Rt(min):308/2.23(方法B)
步骤(iii):
向二乙基锌(1M、2.12mL)、二碘甲烷(0.566g)和二氯甲烷(2mL)的混合物中在0℃下滴加化合物164(0.130g)的二氯甲烷溶液(0.8mL),在室温下搅拌14小时。向反应混合液中加入水并用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣溶于THF(2.8mL)和水(2.8mL)。加入N-甲基吗啉N-氧化物(0.114g)和氧化锇(VIII),在室温下搅拌12小时。向反应混合液中加入THF(3mL)和饱和硫代硫酸钠水溶液,在0℃下搅拌30分钟。用乙酸乙酯提取,将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物165(0.018g)。
LCMS:[M+H]+/Rt(min):322/2.27(方法B)
步骤(iv):
使用化合物165(0.017g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物166(0.010g)。
LCMS:[M+H]+/Rt(min):188/1.37(方法B)
参考例61:
4-(2-氟-4-甲基苯基)哌啶
[化75]
步骤(i):
使用化合物167(0.095g),按照与参考例20的步骤(i)同样的方法,得到标题化合物168(0.100g)。
LCMS:[M+H]+/Rt(min):292/2.26(方法B)
步骤(ii):
使用化合物168(0.100g),按照与参考例2的步骤(ii)同样的方法,得到标题化合物169的粗产物。
步骤(iii):
使用化合物169的粗产物,按照与参考例14的步骤(ii)同样的方法,得到标题化合物170(0.050g)。
LCMS:[M+H]+/Rt(min):194/0.58
参考例62:
4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶盐酸盐
[化76]
步骤(i):
向化合物171(50.0g)的乙醇(446mL)溶液中加入50%羟基胺水溶液(132mL),在70℃下搅拌8小时。冷却至室温后,向反应混合物中加入水(892mL),在室温下搅拌30分钟。滤取所得白色晶体后,在室温下再次用水(344mL)悬浮搅拌30分钟。滤取并干燥所得白色固体,由此得到标题化合物172(52.3g)。
LCMS:[M+H]+/Rt(min):258/0.52(方法C)
步骤(ii):
在冰浴下向化合物172(52.3g)、环丙烷甲酸(18.4g)、HATU(85g)和THF(406mL)的混合物缓慢滴加三乙基胺(142mL),在室温下搅拌12小时。向反应混合液中加入乙酸乙酯(406mL),用水(406mL)、饱和食盐水(406mL)洗涤。将有机层用无水硫酸钠干燥,减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物173(59.1g)。
LCMS:[M+H]+/Rt(min):326/0.77(方法C)
步骤(iii):
将化合物173(59.1g)、DBU(54.2mL)和甲苯(727mL)的混合物在加热回流下搅拌1小时。冷却至室温后,用水(727mL)洗涤后,将有机层减压浓缩,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物174(54.5g)。
LCMS:[M+H]+/Rt(min):308/1.11(方法C)
步骤(iv):
使用化合物174(54.5g),按照与参考例20的步骤(ii)同样的方法,得到标题化合物175(35.3g)。
LCMS:[M+H]+/Rt(min):208/0.30(方法C)
参考例63~87
代替参考例62中的步骤(i)的化合物171和步骤(ii)的环丙烷甲酸,使用各自对应的原料化合物,上述参考例62记载的方法,合成下述表所示的参考例63~87的化合物。
[表4]
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参考例63:
4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)哌啶盐酸盐参考例64:
4-(5-乙基-1,2,4-噁二唑-3-基)-4-甲基哌啶盐酸盐参考例65:
4-甲基-4-[5-(丙烷-2-基)-1,2,4-噁二唑-3-基]哌啶盐酸盐参考例66:
4-(5-环丁基-1,2,4-噁二唑-3-基)-4-甲基哌啶盐酸盐参考例67:
4-(5-环戊基-1,2,4-噁二唑-3-基)-4-甲基哌啶盐酸盐
参考例68:
4-甲基-4-[5-(三氟甲基)-1,2,4-噁二唑-3-基]哌啶盐酸盐
参考例69:
4-甲基-4-[5-(2,2,2-三氟乙基)-1,2,4-噁二唑-3-基]哌啶盐酸盐参考例70:
4-[5-(3,3-二氟环丁基)-1,2,4-噁二唑-3-基]-4-甲基哌啶盐酸盐参考例71:
4-甲基-4-[5-(1-甲基环丙基)-1,2,4-噁二唑-3-基]哌啶盐酸盐
参考例72:
4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基哌啶盐酸盐
参考例73:
4-(5-环丙基-1,2,4-噁二唑-3-基)-4-氟哌啶盐酸盐
参考例74:
4-(5-乙基-1,2,4-噁二唑-3-基)-4-氟哌啶盐酸盐
参考例75:
rac-4-甲基-4-{5-[(1R,2S)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶盐酸盐
参考例76:
4-[5-(环丙基甲基)-1,2,4-噁二唑-3-基]-4-甲基哌啶盐酸盐
参考例77:
4-[5-(2,2-二甲基环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶盐酸盐参考例78:
4-甲基-4-{5-[1-(三氟甲基)环丙基]-1,2,4-噁二唑-3-基}哌啶盐酸盐
参考例79:
4-[5-(1-甲氧基环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶盐酸盐参考例80:
4-[5-(1-氟环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶盐酸盐
参考例81:
4-[5-(2,2-二氟环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶盐酸盐
参考例82:
rac-4-{5-[(1S,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶盐酸盐
参考例83:
rac-4-{5-[(1R,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶盐酸盐
参考例84:
4-{5-[(1S,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶盐酸盐
参考例85:
4-{5-[(1R,2R)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶盐酸盐
参考例86:
4-{5-[(1R,2S)-2-甲基环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶盐酸盐
参考例87:
4-{5-[(1S,2R)-2-甲基环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶盐酸盐
参考例88:
3-(3-环丙基-1,2,4-噁二唑-5-基)-8-氮杂双环[3.2.1]辛烷
[化77]
步骤(i):
向化合物201(0.100g)的甲苯(0.01mL)溶液中加入CDI(0.070g),在室温下搅拌3小时。向反应混合液中加入N’-羟基环丙烷甲脒盐酸盐(0.059mg),在加热回流下搅拌2小时。将反应混合液利用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物202(0.123g)。
LCMS:[M+H]+/Rt(min):320/1.01(方法C)
步骤(ii):
使用化合物202(0.121g),按照与参考例14的步骤(ii)同样的方法,得到标题化合物203(0.091g)。
LCMS:[M+H]+/Rt(min):220/0.30(方法C)
参考例89:
4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶盐酸盐
[化78]
步骤(i):
向化合物204(900mg)、乙酸钠(650mg)、和甲醇(5mL)的混合物中加入羟基胺盐酸盐(550mg),在室温下搅拌24小时。将反应溶液冷却至0℃并加入水,用氯仿提取,将有机层用无水硫酸钠干燥后,减压浓缩而得到标题化合物205(1.23g)。
步骤(ii):
向化合物205(416mg)和DMF(4mL)的混合物中加入N-氯丁二酰亚胺(252mg)搅拌3小时。将反应溶液冷却至0℃,加入水(6mL),将析出的固体过滤·干燥,得到标题化合物206(326mg)。
步骤(iii):
向乙炔基环丙烷(117mg)和甲苯(5mL)的混合物中加入化合物206(326mg)和碳酸氢钠(198mg),在室温下搅拌。确认原料消失后,向反应混合液中加入水,用乙酸乙酯提取,将有机层用无水硫酸钠干燥后,减压浓缩,用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物207(348mg)。
LCMS:[M+H]+/Rt(min):307/1.13
步骤(iv):
使用化合物207(337mg),按照与参考例20的步骤(ii)同样的方法,得到标题化合物208(307mg)。
LCMS:[M+H]+/Rt(min):207/0.49
参考例90~91
代替参考例89中的步骤(iii)的乙炔基环丙烷,使用各自对应的原料化合物,根据上述参考例89记载的方法,合成下述表所示的参考例90~91的化合物。
[表5]
参考例90:
4-甲基-4-[5-(丙烷-2-基)-1,2-噁唑-3-基]哌啶
参考例91:
4-甲基-4-(5-甲基-1,2-噁唑-3-基)哌啶
参考例92:
2-(4-甲基哌啶-4-基)-1,3-苯并噁唑
[化79]
步骤(i):
向化合物211(1.46g)的THF溶液(30mL)中在冰冷却下加入氯甲酸异丁基酯(819mg)和二异丙基乙基胺(3.88g)并搅拌1小时。然后,在冰冷却下加入2-氨基苯酚(655mg),在70℃下加热搅拌6小时。将反应液直接用氨基硅胶柱色谱(洗脱液:乙酸乙酯/己烷)纯化,得到标题化合物212(710mg)。
LCMS:[M+H]+/Rt(min):335/2.28(方法B)
步骤(ii):
将化合物212(204mg)和乙酸(1.10mL)的混合物在90℃下加热搅拌2小时,进行减压浓缩。将所得残渣溶于氯仿(2mL),加入三氟甲磺酸(2.1mL),在室温下搅拌1小时。将反应液减压浓缩,加入乙酸乙酯和碳酸氢钠水溶液,用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用氨基硅胶柱色谱(洗脱液:乙酸乙酯/己烷)纯化,得到标题化合物213(99mg)。
LCMS:[M+H]+/Rt(min):217/1.36(方法B)
参考例93:
4-(4-氯-5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶盐酸盐
[化80]
步骤(i):
将化合物207(500mg)和N-氯丁二酰亚胺(240mg)的DMF溶液(3.3mL)在室温下搅拌3天。向反应溶液中加入水,用二乙基醚提取。将有机层用水洗涤后,用硫酸钠干燥,减压浓缩,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物214(434mg)。
步骤(ii):
使用化合物214(200mg),按照与参考例20的步骤(ii)同样的方法,得到标题化合物215(120.1mg)。
LCMS:[M+H]+/Rt(min):241/0.65
参考例94:
4-(4-氯-5-甲基-1,2-噁唑-3-基)-4-甲基哌啶盐酸盐
[化81]
代替参考例93中的步骤(i)的化合物207,使用参考例91的化合物210,根据上述参考例93记载的方法,合成化合物216。
LCMS:[M+H]+/Rt(min):215/0.51
参考例95:
4-环戊基-4-甲基哌啶盐酸盐
[化82]
步骤(i):
向化合物217(700mg)和THF(14mL)的混合液中在-78℃下加入二异丙基氨基化锂(2M、5.18mL),在该温度下搅拌2小时。然后,向反应混合液中加入溴环戊烷(1.23mL)和碘化钾(478mg),升温至室温并进行整夜搅拌后,加入水,用乙酸乙酯提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:乙酸乙酯/己烷)纯化,得到标题化合物218(468mg)。
LCMS:[M+H]+/Rt(min):312/1.26
步骤(ii):
向氢化铝锂(104mg)和THF(3mL)的混合物中在冰冷却下加入化合物218(371mg)和THF(6mL)的混合物,进行4小时搅拌。确认原料消失后,向反应混合液中在0℃下依次加入水(0.104mL)、15%氢氧化钠水溶液(0.104ml)、和水(0.312mL)并搅拌。将反应液过滤,将滤液减压浓缩后,将残渣用硅胶柱色谱(洗脱液:乙酸乙酯/己烷)纯化,得到标题化合物219(320mg)。
LCMS:[M+H]+/Rt(min):284/1.06
步骤(iii):
向化合物219(314mg)、三乙基胺(0.309mL)、和THF(5mL)的混合液中加入甲磺酰氯(0.104mL),在室温下搅拌。确认原料消失后,向反应混合液中加入水,并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:乙酸乙酯/己烷)纯化,得到标题化合物220(290mg)。
LCMS:[M+H]+/Rt(min):362/1.15
步骤(iv):
向化合物220(278mg)和THF(3mL)的混合物中加入氢化三乙基硼锂(0.99M、1.55mL),在室温下搅拌。然后将反应液加热至70℃,确认原料消失后,冷却至0℃并加入氯化铵水溶液。用氯仿提取,将有机层用无水硫酸钠干燥后,减压浓缩,用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物221(100mg)。
LCMS:[M+H]+/Rt(min):268/1.42
步骤(v):
使用化合物221(90mg),按照与参考例20的步骤(ii)同样的方法,得到标题化合物222(58.5mg)。
LCMS:[M+H]+/Rt(min):168/0.62
参考例96:
4-甲基-4-(2-甲基-1,3-噁唑-5-基)哌啶
[化83]
步骤(i):
向冷却至-78℃的化合物223(1.00g)的THF(10mL)溶液中滴加LHMDS的甲苯溶液(1M、4.35mL),搅拌1小时。加入三甲基氯硅烷(0.495g),升温至0℃后,搅拌30分钟。再次冷却至-78℃后,加入溴(0.662g),缓慢升温至室温。将反应混合物注入至10%次氯酸钠水溶液(7.5mL)和饱和氯化铵水溶液(7.5mL)的混合溶液,用乙酸乙酯提取。将所得有机层减压馏去,由此得到标题化合物224(1.16g)。
LCMS:[M+H]+/Rt(min):321/0.94
步骤(ii):
将化合物224(0.10g)和乙酰胺(0.020g)的混合物在130℃下搅拌3小时。将反应混合液用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物225(0.007g)。
LCMS:[M+H]+/Rt(min):281/0.97
步骤(iii):
使用化合物225(0.007g),按照与参考例14的步骤(ii)同样的方法,得到标题化合物226(0.005g)。
LCMS:[M+H]+/Rt(min):181/0.22
参考例97:
4-甲基-4-[2-(丙烷-2-基)-1,3-噁唑-5-基]哌啶
[化84]
步骤(i):
使用化合物224(0.10g),按照与参考例96的步骤(ii)同样的方法,得到标题化合物227(0.012g)。
LCMS:[M+H]+/Rt(min):309/1.18
步骤(ii):
使用化合物227(0.011g),按照与参考例14的步骤(ii)同样的方法,得到标题化合物228(0.009g)。
LCMS:[M+H]+/Rt(min):209/0.38
参考例98:
4-(5-环丙基-1,3,4-噻二唑-2-基)-4-甲基哌啶
[化85]
步骤(i):
向化合物211(399mg)、环丙烷碳酰肼盐酸盐(269mg)、和DMF(5mL)的混合物中加入HATU(686mg)和二异丙基乙基胺(1.15mL),在室温下搅拌3小时。向反应液中加入水,用乙酸乙酯提取。将有机层用无水硫酸钠干燥后,减压浓缩。将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物229(520mg)。
LCMS:[M+H]+/Rt(min):326/0.74
步骤(ii):
向化合物229(255mg)和甲苯(6mL)的混合物中加入劳森试剂(349mg),在回流条件下加热搅拌1小时。将反应液冷却至0℃后,加入碳酸氢钠水溶液,用乙酸乙酯提取。将有机层用无水硫酸钠干燥后,减压浓缩,用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,然后用氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物230(102mg)。
LCMS:[M+H]+/Rt(min):324/1.08
步骤(iii):
使用化合物230(92mg),按照与参考例20的步骤(ii)同样的方法,得到标题化合物231(78mg)。
LCMS:[M+H]+/Rt(min):224/0.45
参考例99:
4-(5-环丙基-1,3-噻唑-2-基)-4-甲基哌啶盐酸盐
[化86]
步骤(i):
使用化合物211(718mg)和2-氨基-1-环丙基乙烷-1-酮盐酸盐(400mg),按照与参考例98的步骤(i)同样的方法,得到标题化合物232(796mg)。
LCMS:[M+H]+/Rt(min):325/0.83
步骤(ii):
向化合物232(127mg)、吡啶(0.063mL)、和甲苯(3mL)的混合物中加入劳森试剂(205mg),在回流条件下加热搅拌14小时。将反应液冷却至室温后,加入碳酸氢钠水溶液,用乙酸乙酯提取。将有机层用无水硫酸钠干燥后,减压浓缩并用氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物233(76.3mg)。
LCMS:[M+H]+/Rt(min):323/1.43
步骤(iii):
使用化合物233(77mg),按照与参考例20的步骤(ii)同样的方法,得到标题化合物234(66.5mg)。
LCMS:[M+H]+/Rt(min):223/0.67
参考例100:
4-(2-环丙基-1,3-噻唑-4-基)-4-甲基哌啶盐酸盐
[化87]
步骤(i):
将化合物224(531.6mg)和环丙烷硫代甲酰胺(168mg)的甲醇溶液(6mL)在加热回流下搅拌2.5小时。将所得混合物放冷至室温后,加入饱和碳酸氢钠水溶液,并用氯仿提取。将有机层用硫酸钠干燥,减压浓缩后,将残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物235(119mg)。
步骤(ii):
使用化合物235(119mg),按照与参考例20的步骤(ii)同样的方法,得到标题化合物236(136.8mg)。
LCMS:[M+H]+/Rt(min):223/0.57
参考例101:
4-甲基-1-({2-[4-(丙烷-2-基)哌嗪-1-基]苯基}氨基甲酰基)哌啶-4-甲酸乙基酯
[化88]
步骤(i):
使用化合物5(0.237g),按照与参考例1的步骤(i)同样的方法,得到标题化合物237(0.357g)。
LCMS:[M+H]+/Rt(min):417/1.61(方法B)
参考例102:
4-氟-1-({2-[4-(丙烷-2-基)哌嗪-1-基]苯基}氨基甲酰基)哌啶-4-甲酸乙基酯
[化89]
步骤(i):
使用化合物5(0.179g),按照与参考例1的步骤(i)同样的方法,得到标题化合物238(0.040g)。
LCMS:[M+H]+/Rt(min):421/1.57(方法B)
参考例103
(3aR,5s,6aS)-5-氰基六氢环戊[c]吡咯-2(1H)-甲酸叔丁基酯(化合物A-2)和(3aR,5r,6aS)-5-氰基六氢环戊[c]吡咯-2(1H)-甲酸叔丁基酯(化合物A-3)
[化90]
向化合物A-1(331mg)的1,2-二甲氧基乙烷(6.7mL)/乙醇(0.67mL)溶液中在0℃下加入对甲苯磺酰基甲基异腈(373mg)和叔丁醇钾(396mg),在40℃下搅拌4小时。冷却至室温后,过滤反应液,将滤液减压浓缩后,将所得残渣用硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物A-2(80mg)和A―3(59.4mg)。
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
参考例104~105
代替参考例62中的步骤(i)的化合物171,使用参考例103的化合物A-2或A-3,根据上述参考例62记载的方法,合成下述表所示的参考例104~105的化合物。
[表6]
参考例104:
(3aR,5s,6aS)-5-(5-环丙基-1,2,4-噁二唑-3-基)八氢环戊[c]吡咯
参考例105:
(3aR,5r,6aS)-5-(5-环丙基-1,2,4-噁二唑-3-基)八氢环戊[c]吡咯
实施例1:
N-[2-(4-乙基哌嗪-1-基)苯基]-4-(4-甲氧基苯基)哌啶-1-甲酰胺
[化91]
使用化合物239(0.025g)和化合物240(0.021g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物(0.031g)。
1H-NMR(CDCl3)δ:1.14(3H,t,J=7.2Hz),1.59-1.76(3H,m),1.94(2H,d,J=12.4Hz),2.48-2.75(6H,m),2.95-3.05(6H,m),3.80(3H,s),4.28(2H,d,J=13.2Hz),6.87(2H,d,J=7.2Hz),6.96(1H,dt,J=7.6,5.6Hz),7.12-7.18(4H,m),8.22(1H,dd,J=8.4,1.6Hz),8.26(1H,s).
实施例2~120:
使用对应的市售化合物或参考例所述的化合物,利用与实施例1同样的方法,制备下述表所示的实施例2~120的化合物。
[表7]
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实施例2:
4-(1,3-苯并噁唑-2-基)-N-[2-(4-乙基哌嗪-1-基)苯基]哌啶-1-甲酰胺
实施例3:
4-(3,5-二甲氧基苯基)-N-[2-(4-乙基哌嗪-1-基)苯基]哌啶-1-甲酰胺
实施例4:
N-[2-(4-乙基哌嗪-1-基)苯基]-4-甲基-4-苯基哌啶-1-甲酰胺盐酸盐
实施例5:
4-甲基-4-苯基-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例6:
4-氰基-4-苯基-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例7:
4-苯基-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例8:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例9:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例10:
N-{4-氟-2-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例11:
N-{3-氟-2-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例12:
4-甲基-4-(3-苯基-1,2,4-噁二唑-5-基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例13:
4-甲基-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[3-(吡啶-3-基)-1,2,4-噁二唑-5-基]哌啶-1-甲酰胺
实施例14:
6-(4-甲基苯基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}-3-氮杂双环[4.1.0]庚烷-3-甲酰胺
实施例15:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[4-(三氟甲基)苯基]哌啶-1-甲酰胺
实施例16:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[4-(三氟甲氧基)苯基]哌啶-1-甲酰胺
实施例17:
4-(4-甲基苯基)-N-{2-甲基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例18:
4-(2-氟-4-甲基苯基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例19:
4-甲基-4-[5-(丙烷-2-基)-1,2,4-噁二唑-3-基]-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例20:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例21:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例22:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)哌啶-1-甲酰胺
实施例23:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)哌啶-1-甲酰胺
实施例24:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(三氟甲基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例25:
N-{2-甲氧基-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(三氟甲基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例26:
Rac-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-3-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例27:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-苯氧基哌啶-1-甲酰胺
实施例28:
Rac-4-(4-甲基苯基)-N-{2-[3-甲基-4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例29:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(3-甲基苯基)哌啶-1-甲酰胺
实施例30:
Rac-4-(4-甲基苯基)-N-{2-[2-甲基-4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例31:
4-(4-甲基苯基)-N-{2-[1-(丙烷-2-基)哌啶-4-基]苯基}哌啶-1-甲酰胺盐酸盐
实施例32:
3-(3-环丙基-1,2,4-噁二唑-5-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-8-氮杂双环[3.2.1]辛烷-8-甲酰胺
实施例33:
N-{2-(二甲基氨基甲酰基)-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例34:
4-(4-甲基苯基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]-6-(三氟甲基)苯基}哌啶-1-甲酰胺
实施例35:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例36:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(吡啶-2-基)哌啶-1-甲酰胺
实施例37:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(2-甲基苯基)哌啶-1-甲酰胺
实施例38:
2-{[4-(4-甲基苯基)哌啶-1-羰基]氨基}-3-[4-(丙烷-2-基)哌嗪-1-基]苯甲酸甲酯
实施例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-甲酰胺
实施例40:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[4-(丙烷-2-基)苯基]哌啶-1-甲酰胺
实施例41:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-3-(4-甲基苯基)-8-氮杂双环[3.2.1]辛烷-8-甲酰胺
实施例42:
N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例43:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例44:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例45:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例46:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-甲基吡啶-2-基)哌啶-1-甲酰胺
实施例47:
N-{2-甲氧基-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例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-甲酰胺
实施例49:
4-(1,3-苯并噁唑-2-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例50:
4-(1,3-苯并噁唑-2-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例51:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}哌啶-1-甲酰胺
实施例52:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例53:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例54:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例55:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例56:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-[2-(3,6-二氢-2H-吡喃-4-基)-6-氟苯基]-4-甲基哌啶-1-甲酰胺
实施例57:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-硫代甲酰胺
实施例58:
N-[2-(1-环丙基-1H-吡唑-4-基)-6-氟苯基]-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例59:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[6-(丙烷-2-基)吡啶-3-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例60:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[6-(丙烷-2-基)吡啶-3-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例61:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例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-甲酰胺
实施例63:
N-(2-甲氧基-6-{[4-(丙烷-2-基)哌嗪-1-基]甲基}苯基)-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例64:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-硫代甲酰胺
实施例65:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-[3-氟-4’-(丙烷-2-基)[1,1’-联苯]-2-基]-4-甲基哌啶-1-甲酰胺
实施例66:
4-(1,3-苯并噁唑-2-基)-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例67:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例68:
4-(5-环丙基-1,2-噁唑-3-基)-N-[2-氟-6-(6-甲基吡啶-3-基)苯基]-4-甲基哌啶-1-甲酰胺
实施例69:
N-{2-氯-6-[6-(丙烷-2-基)吡啶-3-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例70:
4-(5-环丙基-1,2-噁唑-3-基)-N-[2-氟-6-(5-甲基吡啶-3-基)苯基]-4-甲基哌啶-1-甲酰胺
实施例71:
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[6-(三氟甲基)吡啶-3-基]苯基}-4-甲基哌啶-1-甲酰胺盐酸盐
实施例72:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[2-(丙烷-2-基)嘧啶-5-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例73:
4-(5-环戊基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例74:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环戊基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例75:
4-[5-(3,3-二氟环丁基)-1,2,4-噁二唑-3-基]-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例76:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[5-(3,3-二氟环丁基)-1,2,4-噁二唑-3-基]-4-甲基哌啶-1-甲酰胺
实施例77:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例78:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丁基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例79:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(1-甲基环丙基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例80:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(1-甲基环丙基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例81:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)哌啶-1-甲酰胺
实施例82:
4-(5-乙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例83:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-乙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例84:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2-噁唑-3-基)哌啶-1-甲酰胺
实施例85:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2-噁唑-3-基)哌啶-1-甲酰胺
实施例86:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(三氟甲基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例87:
4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例88:
N-{2-溴-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例89:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基哌啶-1-甲酰胺
实施例90:
4-(4-氯-5-甲基-1,2-噁唑-3-基)-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例91:
4-环戊基-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例92:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(2-甲基-1,3-噁唑-5-基)哌啶-1-甲酰胺
实施例93:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[2-(丙烷-2-基)-1,3-噁唑-5-基]哌啶-1-甲酰胺
实施例94:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-氟哌啶-1-甲酰胺
实施例95:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-乙基-1,2,4-噁二唑-3-基)-4-氟哌啶-1-甲酰胺
实施例96:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(2-环丙基-1,3-噻唑-4-基)-4-甲基哌啶-1-甲酰胺
实施例97:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-1,2,4,5-四氢-3H-3-苯甲氮杂-3-甲酰胺
实施例98:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-甲基嘧啶-2-基)哌啶-1-甲酰胺
实施例99:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)-1,4-二氮杂环庚烷-1-甲酰胺
实施例100:
N-[2-(4-叔丁基哌嗪-1-基)-6-氯苯基]-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例101:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,3-噻唑-2-基)-4-甲基哌啶-1-甲酰胺
实施例102:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,3,4-噻二唑-2-基)-4-甲基哌啶-1-甲酰胺
实施例103:
4-(4-氯-5-环丙基-1,2-噁唑-3-基)-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例104:
Rac-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
实施例105:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[5-(环丙基甲基)-1,2,4-噁二唑-3-基]-4-甲基哌啶-1-甲酰胺
实施例106:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[5-(2,2-二甲基环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶-1-甲酰胺
实施例107:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[1-(三氟甲基)环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
实施例108:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[5-(1-甲氧基环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶-1-甲酰胺
实施例109:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[5-(1-氟环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶-1-甲酰胺
实施例110:
Rac-N-(2-氯-6-{[1-(丙烷-2-基)吡咯烷-3-基]氧基}苯基)-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例111:
Rac-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1S,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
实施例112:
Rac-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1S,2R)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
实施例113:
N-[2-氯-6-(4-环丙基哌嗪-1-基)苯基]-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例114:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-[5-(2,2-二氟环丙基)-1,2,4-噁二唑-3-基]-4-甲基哌啶-1-甲酰胺
实施例115:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1S,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
实施例116:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1R,2R)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
实施例117:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1S,2R)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
实施例118:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
实施例119:
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(2,2,2-三氟乙基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
实施例120:
4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例121:
4-(4-甲基苯基)-N-[2-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺
[化92]
步骤(i):
使用化合物2(0.152g),按照与参考例20的步骤(ii)同样的方法,得到标题化合物242的粗产物。
LCMS:[M+H]+/Rt(min):208/0.30
步骤(ii):
使用化合物242的粗产物,按照与参考例20的步骤(iii)同样的方法,得到标题化合物243(0.202g)。
1H-NMR(CDCl3)δ:1.21(6H,d,J=6.1Hz),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)
实施例122~160:
使用对应的市售化合物或参考例所述的化合物,利用与实施例121同样的方法,制备下述表所示的实施例122~160的化合物。
[表8]
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实施例122:
N-[2-(4-乙基哌嗪-1-基)苯基]-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例123:
4-(4-甲基苯基)-N-[2-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺
实施例124:
4-(4-甲基苯基)-N-{2-[4-(氧杂环戊烷-3-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例125:
N-{2-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例126:
N-{2-[4-(1-甲氧基丙烷-2-基)哌嗪-1-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例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-甲酰胺
实施例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-甲酰胺
实施例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-甲酰胺
实施例130:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例131:
N-[2-氯-6-(1-环丁基-1,2,3,6-四氢吡啶-4-基)苯基]-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例132:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例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-甲酰胺
实施例134:
N-{2-氟-6-[1-(1-氟丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例135:
N-{2-[1-(1,1-二氟丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]-6-氟苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例136:
N-{2-[1-(1,3-二氟丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]-6-氟苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例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-甲酰胺
实施例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-甲酰胺
实施例139:
N-{2-氟-6-[1-(丙烷-2-基)-2,5-二氢-1H-吡咯-3-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例140:
N-[2-氟-6-(1-甲基-2,5-二氢-1H-吡咯-3-基)苯基]-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例141:
N-{2-氯-6-[1-(1-氟丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例142:
N-{2-氯-6-[1-(1-氟丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例143:
N-{2-氯-6-[1-(1-氟丙烷-2-基)哌啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例144:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例145:
N-{2-氯-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例146:
N-{2-氯-6-[1-(氧杂环丁烷-3-基)哌啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例147:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例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-甲酰胺
实施例149:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-[(1S,4S)-5-乙基-2,5-二氮杂双环[2.2.1]庚烷-2-基]-6-氟苯基}-4-甲基哌啶-1-甲酰胺
实施例150:
N-{2-氟-6-[(1S,4S)-5-(丙烷-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例151:
N-{2-氟-6-[(1R,4R)-5-(丙烷-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例152:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[(1R,4R)-5-(丙烷-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例153:
N-[2-(4-乙基-1,4-二氮杂环庚烷-1-基)苯基]-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例154:
N-{2-氟-6-[8-(丙烷-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
实施例155:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[8-(丙烷-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基]苯基}-4-甲基哌啶-1-甲酰胺
实施例156:
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-[2-(4-乙基-1,4-二氮杂环庚烷-1-基)苯基]-4-甲基哌啶-1-甲酰胺
实施例157:
4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基-N-[2-(4-丙基-1,4-二氮杂环庚烷-1-基)苯基]哌啶-1-甲酰胺
实施例158:
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-氰基-4-甲基哌啶-1-甲酰胺
实施例159:
N-[2-氯-6-(1-环丁基-1,2,3,6-四氢吡啶-4-基)苯基]-4-氰基-4-甲基哌啶-1-甲酰胺
实施例160:
N-(2-氯-6-{[1-(丙烷-2-基)氮杂环丁烷-3-基]氧基}苯基)-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例161:
N-{2-氟-6-[3-(丙烷-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基]苯基}-4-(4-甲基苯基)哌啶-1-甲酰胺
[化93]
步骤(i):
将化合物150(0.079g)、氢氧化钯(0.020g)和乙醇(2mL)的混合物在室温下在氢氛围下搅拌3小时。将反应混合液用硅藻土过滤,将滤液减压浓缩后,将残渣直接用于下一反应。
步骤(ii):
使用化合物244的粗产物,按照与参考例20的步骤(iii)同样的方法,得到标题化合物245(0.066g)。
1H-NMR(CDCl3)δ:1.02(6H,d,J=6.7Hz),1.61(3H,s),1.74(2H,ddd,J=25.4,13.1,4.0Hz),1.83-1.96(6H,m),2.33(3H,s),2.55(2H,d,J=9.8Hz),2.62-2.76(4H,m),3.03(2H,ddd,J=13.1,13.1,2.2Hz),3.60-3.65(2H,m),4.29-4.37(2H,m),6.17(1H,s),6.66(1H,d,J=8.3Hz),6.77(1H,dd,J=8.6,8.3Hz),6.94-7.01(1H,m),7.11(2H,d,J=8.6Hz),7.14(2H,d,J=8.6Hz).
实施例162:
4-甲基-4-(3-甲基-1,2,4-噁二唑-5-基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺盐酸盐
[化94]
步骤(i):
将(Z)-N’-羟基乙酰亚胺酰胺(0.0125g)、氢化钠(0.0134g)和THF(1mL)的混合物在加热回流下搅拌2小时。放冷至室温后加入参考例101的化合物237(0.035g),在加热回流下搅拌5小时。放冷至室温为止后,向反应混合液中在0℃下加入水并用氯仿提取。将有机层用无水硫酸钠干燥,减压浓缩后,将残渣用氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物246(0.005g)。
LCMS:[M+H]+/Rt(min):427/0.70
实施例163~164:
使用对应的市售化合物或参考例所述的化合物,利用与实施例162同样的方法,制备下述表所示的实施例163~164的化合物。
[表9]
实施例163:
4-甲基-4-[3-(丙烷-2-基)-1,2,4-噁二唑-5-基]-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺盐酸盐
实施例164:
4-氟-4-(3-甲基-1,2,4-噁二唑-5-基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
实施例165:
4-甲基-4-(5-甲基-1,3,4-噁二唑-2-基)-N-{2-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
[化95]
向参考例101的化合物237(0.056g)、THF(0.5mL)、MeOH(0.5mL)和水(0.5mL)的混合物中加入氢氧化钠(0.027g),在60℃下搅拌1小时。用10%盐酸水溶液中和,用氯仿/甲醇(4:1)溶液提取。将溶剂减压浓缩,将所得残渣溶于DMF(0.5mL),加入二异丙基乙基胺(0.059mL)、乙酰肼(0.020g)和HATU(0.128g),在室温下搅拌14小时。向反应液中加入饱和碳酸氢钠水溶液并用氯仿提取。将溶剂减压浓缩,并将所得残渣溶于乙腈(0.5mL),加入三苯基膦(0.071g)、三乙基胺(0.057mL)和四氯化碳(0.052mL),在加热回流下搅拌7小时。放冷后减压浓缩,将所得残渣用氨基硅胶柱色谱(洗脱液:己烷/乙酸乙酯)纯化,得到标题化合物247(0.010g)。
LCMS:[M+H]+/Rt(min):427/1.43
实施例166:
4-(4-甲基苯基)-N-{2-[(2R,5S)-5-(丙烷-2-基)吗啉-2-基]苯基}哌啶-1-甲酰胺
[化96]
步骤(i):
使用化合物41(0.036g),按照与参考例23的步骤(iv)同样的方法,得到标题化合物248(0.045g)。
LCMS:[M+H]+/Rt(min):522/1.25
步骤(ii):
使用化合物248(0.042g),按照与参考例14的步骤(ii)同样的方法,得到标题化合物249(0.031g)。
1H-NMR(CDCl3)δ:0.92(3H,d,J=7.0Hz),0.97(3H,d,J=7.0Hz),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=12.5,2.7Hz),3.16(1H,dd,J=11.3,11.3Hz),3.48(1H,dd,J=10.4,10.4Hz),4.09(1H,dd,J=11.3,2.7Hz),4.21-4.32(2H,m),4.53(1H,dd,J=10.4,3.0Hz),6.95(1H,dd,J=7.3,7.3Hz),7.06(1H,d,J=7.3Hz),7.11(4H,d,J=8.5Hz),7.14(4H,d,J=8.5Hz),7.27(1H,dd,J=7.3,7.3Hz),8.10(1H,d,J=8.5Hz),8.71(1H,s).
实施例167~168:
使用对应的市售化合物或参考例所述的化合物,利用与实施例166同样的方法,制备下述表所示的实施例167~168的化合物。
[表10]
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实施例167:
Rac-N-{2-氯-6-[(2R,5S)-5-(丙烷-2-基)吗啉-2-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例168:
Rac-N-{2-氯-6-[(2R,5R)-5-(丙烷-2-基)吗啉-2-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
实施例169~170:
使用对应的参考例所述的化合物,利用与实施例1同样的方法,制备下述表所示的实施例169~170的化合物。
[表11]
实施例169:
(3aR,5s,6aS)-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-5-(5-环丙基-1,2,4-噁二唑-3-基)六氢环戊[c]吡咯-2(1H)-甲酰胺
实施例170:
(3aR,5r,6aS)-N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-5-(5-环丙基-1,2,4-噁二唑-3-基)六氢环戊[c]吡咯-2(1H)-甲酰胺
试验例1:食欲素2型受体激动剂活性的测定
使CHO细胞一过性表达人食欲素2型受体和脱辅基水母发光蛋白(apoaequorin),将通过配体刺激而流入细胞内的钙量作为指标来评价激动性。一过性表达的细胞以2,000细胞/孔播种在384孔板上,培养16~22小时。将板恢复至室温后,加入腔肠素hcp(终浓度:1μM),在室温下静置2小时后,添加食欲素A或受试化合物,用FDSS7000(浜松ホトニクス公司制)测定细胞的发光量。应予说明,食欲素A和受试化合物溶于DMSO(终浓度0.1%),用缓冲液(Hanks、20mM HEPES、0.1%BSA)稀释。此外,以食欲素A(100pM)处置时的发光值设为100%,受试化合物的食欲素2型受体激动性以其相对值的形式算出。
试验结果:
针对实施例1~168中所得的化合物,测定食欲素2型受体激动性,结果观察到本发明化合物对食欲素2型受体表现出激动作用。以食欲素A(100pM)处置时的发光值设为100%时,将实施例1~168中所得化合物的10μM中的食欲素2型受体激动性以相对值的形式示于下表。
[表12]
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试验例2:食欲素2型受体激动剂活性的测定
使CHO细胞一过性表达人食欲素2型受体和脱辅基水母发光蛋白(apoaequorin),将通过配体刺激而流入细胞内的钙量作为指标来评价激动性。一过性表达的细胞以2,000细胞/孔播种在384孔板上,培养16~22小时。将板恢复至室温后,加入腔肠素hcp(终浓度:1μM),在室温下静置2小时后,添加食欲素A(株式会社肽研究所、Lot.671009)或受试化合物,用FDSS7000(浜松ホトニクス公司制)测定细胞的发光量。应予说明,食欲素A和受试化合物溶于DMSO(终浓度0.1%),用缓冲液(Hanks、20mM HEPES、0.1%BSA)稀释。此外,以食欲素A(100pM)处置时的发光值设为100%,受试化合物的食欲素2型受体激动性以其相对值的形式算出。
试验结果:
针对实施例169~170中所得的化合物,测定食欲素2型受体激动性,结果观察到本发明化合物对食欲素2型受体表现出激动作用。以食欲素A(100pM)处置时的发光值设为100%时,将实施例169~170中所得化合物的10μM中的食欲素2型受体激动性以相对值的形式示于下表。
[表13]
实施例 | 激动性(%) |
169 | 444 |
170 | 357 |
产业实用性
本发明的化合物对食欲素受体表现出强的激动活性,作为发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、路易小体痴呆所伴随的睡眠过度等的治疗药或预防药有用。
Claims (35)
1.式(1)所示的化合物或其制药学上可接受的盐,
[化1]
式中,
R1表示任选被取代的C6-10芳香族碳环基、任选被取代的5~10元的芳香族杂环基、任选被取代的C3-6饱和碳环基、任选被取代的4~10元的饱和杂环基、或氰基;
L1和L2各自独立地表示单键、亚甲基(该亚甲基任选被1个以上相同或不同的C1-6烷基取代)、-NR6-、-C(=O)-、-OC(=O)-、-SO-、-SO2-、-S-、或氧原子;
R2表示氢原子、羟基、卤素原子、氰基、任选被取代的C1-6烷基、任选被取代的C1-6烷氧基、C(=O)NR3R4或C(=O)O-R5;
R3、R4、R5、R6各自独立地表示氢原子或任选被取代的C1-6烷基;
环E表示任选被取代的5~10元的芳香族杂环基或任选被取代的4~10元的饱和杂环基;
环G表示任选被取代的C6-10芳香族碳环基、任选被取代的5~10元的芳香族杂环基、任选被取代的C3-6饱和碳环基、或任选被取代的4~10元的饱和杂环基;
A表示氧原子或硫原子。
2.根据权利要求1所述的化合物或其制药学上可接受的盐,其中,
R2~R6中的"任选被取代的C1-6烷基"中的能取代的取代基各自独立地为1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基、或C3-7环烷基,"任选被取代的C1-6烷氧基"中的能取代的取代基各自独立地为1或2个以上的相同或不同的卤素原子、羟基、或C3-7环烷基,
R1的C6-10芳香族碳环基、5~10元的芳香族杂环基、C3-6饱和碳环基、和4~10元的饱和杂环基中的能取代的取代基各自独立地为选自卤素原子、羟基、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、C1-6烷基氨基(该烷基氨基中的烷基任选被卤素原子、羟基或C3-7环烷基取代)、C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、氰基、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C3-7环烷基取代)和5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)中的1个以上的取代基,
环E和环G的C6-10芳香族碳环基、5~10元的芳香族杂环基、C3-6饱和碳环基、和4~10元的饱和杂环基中的能取代的取代基各自独立地为选自卤素原子、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C3-7环烷基取代)、C1-6烷基氨基(该烷基氨基中的烷基任选被卤素原子、羟基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基或C3-7环烷基取代)、和C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-4烷氧基或C3-7环烷基取代)中的1个以上的取代基,或者取代基为多个时,其中2个任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构。
3.根据权利要求1或2所述的化合物或其制药学上可接受的盐,其由式(2)所示:
[化2]
式中,
R2表示羟基、卤素原子、氰基、任选被取代的C1-4烷基、任选被取代的C1-4烷氧基、C(=O)NR3R4或C(=O)OR5;
R1、L1、L2、R3、R4、R5、环E、环G、和A为与权利要求1相同的定义。
4.根据权利要求1~3中任一项所述的化合物或其制药学上可接受的盐,其中,R1为氰基或选自下述式(1a-1)至(1a-6)中的任一者,
[化3]
式中,
X1~X6各自独立地表示氮原子或CRa4;
Q1和Q2表示氧原子、-NRa5-或硫原子;
Q3表示CH或氮原子;
Ra1~Ra5各自独立地(CRa4存在多个时,各Ra4也各自独立)表示氢原子、卤素原子、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-4烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、任选被1或2个以上的相同或不同的卤素原子取代的C1-6烷基、或C1-6烷氧基取代)、氰基、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)、C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)或5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)。
5.根据权利要求1~4中任一项所述的化合物或其制药学上可接受的盐,其中,环G为选自下述式(1b-1)至(1b-7)中的任一者,
[化4]
式中,
W1和W2各自独立地表示NRb7、氧原子或CRb8Rb9;
W3、W4、W5和W6各自独立地表示氮原子或CRb10;
Rb1~Rb10各自独立地表示氢原子、卤素原子、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-4烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代),化学上可能的话,Rb2和Rb3任选与同一碳原子键合;
在此,Rb2和Rb3任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构;
n、m和p各自独立地表示1或2的整数。
6.根据权利要求1~5中任一项所述的化合物或其制药学上可接受的盐,其中,环E为选自下述式(1c-1)至(1c-4)中的任一者,
[化5]
式中,
Rc1、Rc2、Rc3和Rc4各自独立地表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代),化学上可能的话,Rc1和Rc2任选与同一碳原子键合;
在此,Rc1和Rc2任选通过C1-6亚烷基键合而形成稠环、螺环、或桥环中的化学上可能的任意二环式结构。
7.根据权利要求1~6中任一项所述的化合物或其制药学上可接受的盐,其中,环E为选自下述式(1c-11)至(1c-41)中的任一者,
[化6]
式中,Rc4各自独立地表示卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)。
8.根据权利要求1~7中任一项所述的化合物或其制药学上可接受的盐,其由式(3)所示,
[化7]
式中,
R2表示任选被卤素原子取代的C1-6烷氧基;
R1、A、L1和环G表示与权利要求1所述的定义相同的内容。。
9.根据权利要求1~8中任一项所述的化合物或其制药学上可接受的盐,其中,L1为单键、-CH2-、或氧原子中任一者。
10.根据权利要求1~9中任一项所述的化合物或其制药学上可接受的盐,其中,R1为选自下述式(1a-1)至(1a-3)中的任一者,
[化8]
式中,
X1~X5各自独立地表示氮原子或CRa4;
Q1和Q2各自独立地表示氧原子、或硫原子;
Ra1表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)或C1-4烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代);
Ra4(CRa4为多个时,各Ra4各自独立)表示氢原子、卤素原子、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)、C3-7环烷氧基(该环烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、C1-6烷氧基取代)或5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)。
11.根据权利要求1~10中任一项所述的化合物或其制药学上可接受的盐,其中,环G为选自下述(1b-1)至(1b-3)中任一者,
[化9]
式中,Rb1~Rb3各自独立地表示氢原子、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)或C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)。
12.根据权利要求1~11中任一项所述的化合物或其制药学上可接受的盐,其中,R2为F、Cl、Br中任一卤素原子,且A为氧原子。
13.根据权利要求1~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1由以下式(1a-1)所示,
[化10]
式中,Ra1表示氢原子、卤素原子、氰基、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)或C1-4烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)。
14.根据权利要求1~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1表示以下式(1a-2),
[化11]
式中,
X1~X3各自独立地表示氮原子或CRa4;
Q1表示氧原子、或硫原子;
Ra4表示与权利要求10相同的定义;
L1为单键。
15.根据权利要求1~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1为选自下述式(1a-21)至(1a-25)中的任一者,
[化12]
式中,Ra4表示与权利要求10所述的内容相同的内容;
L1为单键。
16.根据权利要求15所述的化合物或其制药学上可接受的盐,其中,Ra4(CRa4存在多个时,各Ra4各自独立)为C6-10芳香族碳环基(该C6-10芳香族碳环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、或5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)。
17.根据权利要求1~12中任一项所述的化合物或其制药学上可接受的盐,其中,R1表示以下的式(1a-3),
[化13]
式中,X4和X5为与权利要求10相同的定义;
L1为单键。
18.根据权利要求17所述的化合物或其制药学上可接受的盐,其中,R1为选自下述式(1a-31)至(1a-34)中的任一者,
[化14]
式中,Ra4为与权利要求10相同的定义。
19.根据权利要求17或18中任一项所述的化合物或其制药学上可接受的盐,其中,Ra4(CRa4存在多个时,各Ra4各自独立)为C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷氧基或C3-7环烷基取代)、C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、羟基、C1-6烷基、或C1-6烷氧基取代)、C1-6烷氧基(该烷氧基任选被1或2个以上的相同或不同的卤素原子、羟基、或C1-6烷氧基取代)。
20.根据权利要求1~19中任一项所述的化合物或其制药学上可接受的盐,其中,环G由下述式(1b-2)所示,
[化15]
式中,Rb2为与权利要求11相同的定义。
21.根据权利要求1~19中任一项所述的化合物或其制药学上可接受的盐,其中,环G由下述式(1b-1)所示,
[化16]
式中,Rb1由C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)表示。
22.根据权利要求1~19中任一项所述的化合物或其制药学上可接受的盐,其中,环G由下述式(1b-3)表示,
[化17]
式中,Rb3由C1-6烷基(该烷基任选被1或2个以上的相同或不同的卤素原子、或C1-6烷氧基取代)、5~10元的芳香族杂环基(该芳香族杂环基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)、或C3-7环烷基(该环烷基任选被1或2个以上的相同或不同的卤素原子、C1-6烷基、或C1-6烷氧基取代)表示。
23.根据权利要求1所述的化合物或其制药学上可接受的盐,其选自以下化合物:
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-[5-(丙烷-2-基)-1,2,4-噁二唑-3-基]哌啶-1-甲酰胺
N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(5-甲基-1,2,4-噁二唑-3-基)哌啶-1-甲酰胺
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
4-(5-环丙基-1,2,4-噁二唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)哌啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基哌啶-1-甲酰胺
4-(5-环丙基-1,2-噁唑-3-基)-N-{2-氟-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺。
24.根据权利要求1所述的化合物或其制药学上可接受的盐,其选自以下化合物:
4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基-N-{2-氟-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-乙基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-(5-环丙基-1,3-噻唑-2-基)-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1S,2S)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-{5-[(1R,2R)-2-氟环丙基]-1,2,4-噁二唑-3-基}-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1S,2R)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
N-{2-氯-6-[4-(丙烷-2-基)哌嗪-1-基]苯基}-4-甲基-4-{5-[(1R,2S)-2-甲基环丙基]-1,2,4-噁二唑-3-基}哌啶-1-甲酰胺
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2,4-噁二唑-3-基)-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-(5-环丙基-1,2-噁唑-3-基)-4-甲基哌啶-1-甲酰胺
N-{2-氯-6-[1-(丙烷-2-基)-1,2,3,6-四氢吡啶-4-基]苯基}-4-甲基-4-(4-甲基苯基)哌啶-1-甲酰胺。
25.药物组合物,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
26.与食欲素2型受体相关的疾病的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
27.发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、路易小体痴呆所伴随的睡眠过度、伴随白天的睡眠过度的睡眠过度综合征(例如,克莱恩-莱文综合征、伴随睡眠过度的重度抑郁、路易小体痴呆、帕金森病、进行性核上性麻痹、普拉德-威利综合征、莫比乌斯综合征、低通气综合征、尼曼-匹克病C型、脑挫伤、脑梗塞、脑肿瘤、肌肉萎缩、多发性硬化症、急性播散性脑脊髓炎、吉兰-巴雷综合征、拉斯穆森脑炎、韦尼克脑炎、边缘***脑炎、桥本脑症)、昏睡、意识丧失、肥胖(例如,恶性肥胖细胞、外源性肥胖、胰岛功能亢进性肥胖症、原生质增生性肥胖、垂体性肥胖、原生质减低性肥胖症、甲状腺功能减退性肥胖症、下丘脑性肥胖、症状性肥胖症、小儿肥胖、上半身肥胖、饮食性肥胖症、性功能降低性肥胖、全身性肥胖细胞症、单纯性肥胖、中心性肥胖)、胰岛素抵抗性综合征、、阿兹海默症、昏睡等意识障碍、由麻醉导致的副作用、并发症、睡眠紊乱、睡眠问题、失眠、间歇性睡眠、夜间阵挛性肌肉痉挛、REM睡眠中断、时差反应、时差反应综合征、轮班工作人员的睡眠障碍、睡眠异常、夜惊症、抑郁、重度抑郁、梦游病、遗尿症、睡眠障碍、阿尔茨海默性黄昏综合征、与昼夜节律相关的疾病、肌肉纤维痛、睡眠质量差引起的症状、暴饮暴食、强迫性饮食障碍、肥胖相关疾病、高血压、糖尿病、血浆胰岛素浓度和胰岛素抵抗性的上升、高脂蛋白血症、高脂血症、子宫内膜癌、乳腺癌、***癌、结肠癌、癌、变形性关节症、阻塞性睡眠呼吸中止、胆结石症、胆结石、心脏病、心脏异常跳动、心律不齐、心肌梗塞、充血性心力衰竭、心力衰竭、冠心病、心血管疾病、猝死、多囊卵巢疾病、颅咽管瘤、普拉德-威利综合征、弗勒赫利希综合征、生长激素缺乏者、正常变异型身材矮小、特纳综合征、儿童急性淋巴细胞性白血病、X综合征、生殖***激素异常、受孕能力降低、***、男性性腺功能降低、女性的男性型多毛症等性和生殖功能障碍、与孕妇肥胖相关的胎儿缺陷、与肥胖相关的胃食管反流等胃肠动力疾病、肥胖通气不足综合征(匹克威克综合征)、呼吸困难等呼吸***疾病、血管***的全身性炎症等炎症、动脉硬化、高胆固醇血症、高尿酸血症、腰痛、胆囊疾病、痛风、肾癌、将左心室肥大的风险等肥胖的继发后果风险、偏头痛、头痛、神经性疼痛、帕金森病、精神病、神经***症、面部潮红、盗汗、生殖器/泌尿器***疾病、与性功能或受孕能力相关的疾病、低落性情感障碍、双相情感障碍、I型双相情感障碍、II型双相情感障碍、循环性情感精神障碍、急性应激障碍、广场恐怖症、广泛性焦虑症、强迫症、惊恐发作、惊恐障碍、创伤后应激障碍、分离焦虑症、社交恐惧症、焦虑症、心脏搭桥手术和移植后的脑缺损等急性神经学的和精神医学的障碍、中风,缺血性中风,脑缺血、脊髓外伤、头部外伤、周产期缺氧、心脏骤停、低血糖性神经损伤、亨廷顿舞蹈病、肌萎缩性侧索硬化症、多发性硬化症、眼损伤、视网膜疾病、认知障碍、肌肉痉挛、震颤、癫痫、与肌肉萎缩相关的障碍、谵妄、健忘症、与年龄增长相关的认知下降、***感情性障碍、妄想症、药物依赖症、运动异常症、慢性疲劳综合征、疲劳、药物诱发性帕金森综合征、抽动秽语综合征、舞蹈病、肌震颤、抽动、抖腿综合征、肌张力障碍、运动障碍、注意缺陷多动障碍(ADHD)、行为障碍、尿失禁、戒断症状、三叉神经痛、听力损失、耳鸣、神经损伤、视网膜疾病、黄斑变性症、呕吐、脑浮肿、疼痛、骨痛、关节痛、牙痛、猝倒症、或创伤性脑损伤的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
28.发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
29.发作性睡病的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
30.特发性睡眠过度的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
31.帕金森病所伴随的睡眠过度的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
32.路易小体痴呆所伴随的睡眠过度的治疗药,其含有权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
33.治疗发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的方法,其包括对需要治疗的患者投予治疗上有效量的权利要求1~24中任一项所述的化合物或其制药学上可接受的盐。
34.权利要求1~24中任一项所述的化合物或其制药学上可接受的盐的用途,其用于制备发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗剂。
35.包含权利要求1~24中任一项所述的化合物或其制药学上可接受的盐的药物组合物,其用于发作性睡病、特发性睡眠过度、睡眠过度、睡眠呼吸中止综合征、伴随发作性睡病样症状的发作性睡病综合征、帕金森病所伴随的睡眠过度、或路易小体痴呆所伴随的睡眠过度的治疗中的用途。
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