CN103180312A - 用于治疗或预防因血清素、去甲肾上腺素或多巴胺的神经传导的降低所导致的紊乱的杂环化合物 - Google Patents
用于治疗或预防因血清素、去甲肾上腺素或多巴胺的神经传导的降低所导致的紊乱的杂环化合物 Download PDFInfo
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- CN103180312A CN103180312A CN2011800440909A CN201180044090A CN103180312A CN 103180312 A CN103180312 A CN 103180312A CN 2011800440909 A CN2011800440909 A CN 2011800440909A CN 201180044090 A CN201180044090 A CN 201180044090A CN 103180312 A CN103180312 A CN 103180312A
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Abstract
Description
技术领域
本发明涉及一种新的杂环化合物。
背景技术
已知有血清素、去甲肾上腺素和多巴胺三种单胺在体内作为神经递质起作用。因此,对这些单胺的再摄取具有抑制作用的药物已被广泛用作与中枢或外周神经系统相关的疾病的治疗药物。
大多数以前用于治疗抑郁症的药物会选择性地抑制去甲肾上腺素或血清素的再摄取。这类药物的例子包括丙咪嗪(第一代抗抑郁药)、马普替林(第二代抗抑郁药)、以氟西汀为代表的选择性血清素再摄取抑制剂(SSRI,第三代抗抑郁药)和以文拉法辛(venlafaxine)为代表的血清素和/或去甲肾上腺素再摄取抑制剂(SNRI,第四代抗抑郁药)(S.三浦,日本临床精神药理学杂志,2000,3:311-318(S.Miura,Janpanese Journal of ClinicalPsychopharmacology,2000,3:311-318))。
然而,所有这些药物都需要为期3周或更长的时间以发挥其治疗效果,此外,对约30%的抑郁症患者无法发挥足够的治疗效果(菲尔什科尔尼克,欧洲药理学杂志,1999,375:31-40(Phil Skolnick,European Journal of Pharmacology,1999,375:31-40))。
发明内容
本发明的一个目的是提供一种药物,其与本领域中已知的抗抑郁药相比,具有广泛的治疗频谱且能够在短期内发挥足够的治疗效果。
本发明人进行了深入的研究以达到上述目的,结果发现,在所需药物的生产中可以使用由下面所示通式(1)所表示的杂环化合物。本发明即依据这些发现而完成。
本发明提供了根据以下所示的1~15项中的任意一项的杂环化合物或其盐,包含所述化合物的药物组合物或所述化合物的用途,用于治疗或预防疾病的方法或用于制备所述化合物的方法。
第1项,一种由通式(1)表示的杂环化合物或其盐:
其中,m、l和n分别代表1或2的整数;X表示-O-或-CH2-;
R1代表氢、低级烷基、羟基-低级烷基、保护基团或三-低级烷基甲硅烷氧基-低级烷基;
R2和R3是相同的或不同的,且各自独立地表示氢或低级烷基;或者R2和R3结合形成环C3-C8烷基;以及
R4表示芳香族基团或杂环基团,其中,
所述芳香族基团或杂环基团可以具有一个或多个任意的取代基。
第2项,根据第1项所述的由通式(1)表示的杂环化合物或其盐,其中,
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(3)苯并噻吩基,
(4)萘基,
(5)苯并呋喃基,
(6)喹啉基,
(7)异喹啉基,
(8)吡啶基,
(9)噻吩基,
(10)二氢苯并噁嗪基,
(11)二氢苯并二噁英基,
(12)二氢喹啉基,
(13)苯并二氢吡喃基,
(14)喹喔啉基,
(15)二氢茚基,
(16)二氢苯并呋喃基,
(17)苯并间二氧杂环戊烯基(benzodioxolyl group),
(18)吲唑基,
(19)苯并噻唑基,
(20)二氢吲哚基,
(21)噻吩并吡啶基,
(22)四氢苯并氮杂卓基(tetrahydrobenzazepinyl group),
(23)四氢苯并二氮杂卓基(tetrahydrobenzodiazepinyl group),
(24)二氢苯并二氧杂环庚烯基(dihydrobenzodioxepinyl group),
(25)芴基,
(26)哒嗪基,
(27)四氢喹啉基,
(28)咔唑基,
(29)菲基,
(30)二氢苊烯基(dihydroacenaphthylenyl group),
(31)吡咯并吡啶基,
(32)蒽基,
(33)苯并二噁英基,
(34)吡咯烷基,
(35)吡唑基,
(36)噁二唑基,
(37)嘧啶基,
(38)四氢萘基,
(39)二氢喹唑啉基,
(40)苯并噁唑基,
(41)噻唑基,
(42)喹唑啉基,
(43)酞嗪基,
(44)吡嗪基,以及
(45)苯并吡喃基,其中
这些芳香族基团或杂环基团可以具有一个或多个选自以下的取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-3)低级烷酰基,
(1-4)卤素取代的低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,
(1-7)低级烷氧基,
(1-8)低级烷基硫基,
(1-9)咪唑基,
(1-10)三-低级烷基甲硅烷基,
(1-11)可具有低级烷基的噁二唑基,
(1-12)可具有氧代基团的吡咯烷基,
(1-13)可具有低级烷氧基的苯基,
(1-14)低级烷基氨基-低级烷基,
(1-15)氧代基团,
(1-16)可具有低级烷基的吡唑基,
(1-17)噻吩基,
(1-18)呋喃基(furyl group),
(1-19)可具有低级烷基的噻唑基,
(1-20)低级烷基氨基,
(1-21)可具有低级烷基的嘧啶基,
(1-22)苯基-低级烯基,
(1-23)可具有卤素原子的苯氧基,
(1-24)苯氧基-低级烷基,
(1-25)吡咯烷基-低级烷氧基,
(1-26)低级烷基氨磺酰基,
(1-27)可具有低级烷基的哒嗪基氧基,
(1-28)苯基-低级烷基,
(1-29)低级烷基氨基-低级烷氧基,
(1-30)咪唑基-低级烷基,
(1-31)苯基-低级烷氧基,
(1-32)羟基,
(1-33)低级烷氧基羰基,
(1-34)羟基-低级烷基,
(1-35)噁唑基,
(1-36)哌啶基,
(1-37)吡咯基,
(1-38)吗啉基-低级烷基,
(1-39)可具有低级烷基的哌嗪基-低级烷基,
(1-40)哌啶基-低级烷基,
(1-41)吡咯烷基-低级烷基,
(1-42)吗啉基,以及
(1-43)可具有低级烷基的哌嗪基。
第3项,根据第2项所述的由通式(1)表示的杂环化合物或其盐,其中,
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(3)苯并噻吩基,
(4)萘基,
(5)苯并呋喃基,
(6)喹啉基,
(7)异喹啉基,
(8)吡啶基,
(9)噻吩基,
(10)二氢苯并噁嗪基,
(11)二氢苯并二噁英基,
(12)二氢喹啉基,
(13)苯并二氢吡喃基,
(14)喹喔啉基,
(15)二氢茚基,
(16)二氢苯并呋喃基,
(17)苯并间二氧杂环戊烯基,
(18)吲唑基,
(19)苯并噻唑基,
(20)二氢吲哚基,
(21)噻吩并吡啶基,
(22)四氢苯并氮杂卓基,
(23)四氢苯并二氮杂卓基,
(24)二氢苯并二氧杂环庚烯基,
(25)芴基,
(26)哒嗪基,
(27)四氢喹啉基,
(28)咔唑基,
(29)菲基,
(30)二氢苊烯基,
(31)吡咯并吡啶基,
(32)蒽基,
(33)苯并二噁英基,
(34)吡咯烷基,
(35)吡唑基,
(36)噁二唑基,
(37)嘧啶基,
(38)四氢萘基,
(39)二氢喹唑啉基,
(40)苯并噁唑基,
(41)噻唑基,
(42)喹唑啉基,
(43)酞嗪基,
(44)吡嗪基,以及
(45)苯并吡喃基,其中
这些芳香族基团或杂环基团可以具有选自以下的1至4个取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-3)低级烷酰基,
(1-4)卤素取代的低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,
(1-7)低级烷氧基,
(1-8)低级烷基硫基,
(1-9)咪唑基,
(1-10)三-低级烷基甲硅烷基,
(1-11)可具有一低级烷基的噁二唑基,
(1-12)可具有一氧代基团的吡咯烷基,
(1-13)可具有一低级烷氧基的苯基,
(1-14)低级烷基氨基-低级烷基,
(1-15)氧代基团,
(1-16)可具有一低级烷基的吡唑基,
(1-17)噻吩基,
(1-18)呋喃基,
(1-19)可具有一低级烷基的噻唑基,
(1-20)低级烷基氨基,
(1-21)可具有一低级烷基的嘧啶基,
(1-22)苯基-低级烯基,
(1-23)可具有一卤素原子的苯氧基,
(1-24)苯氧基-低级烷基,
(1-25)吡咯烷基-低级烷氧基,
(1-26)低级烷基氨磺酰基,
(1-27)可具有一低级烷基的哒嗪基氧基,
(1-28)苯基-低级烷基,
(1-29)低级烷基氨基-低级烷氧基,
(1-30)咪唑基-低级烷基,
(1-31)苯基-低级烷氧基,
(1-32)羟基,
(1-33)低级烷氧基羰基,
(1-34)羟基-低级烷基,
(1-35)噁唑基,
(1-36)哌啶基,
(1-37)吡咯基,
(1-38)吗啉基-低级烷基,
(1-39)可具有一低级烷基的哌嗪基-低级烷基,
(1-40)哌啶基-低级烷基,
(1-41)吡咯烷基-低级烷基,
(1-42)吗啉基,以及
(1-43)可具有一低级烷基的哌嗪基。
第4项,根据第3项所述的由通式(1)表示的杂环化合物或其盐,其中,
m表示2;l和n分别表示整数1;X表示-CH2-;
R1表示氢、低级烷基、羟基-低级烷基、苯甲基或三-低级烷基甲硅烷氧基-低级烷基;以及
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(4)萘基,
(5)苯并呋喃基,以及
(31)吡咯并吡啶基,其中
这些芳香族基团或杂环基团可以具有选自以下的1至4个取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-3)低级烷酰基,
(1-4)卤素取代的低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,
(1-7)低级烷氧基,
(1-8)低级烷基硫基,
(1-9)咪唑基,
(1-10)三-低级烷基甲硅烷基,
(1-11)可具有一低级烷基的噁二唑基,
(1-12)可具有一氧代基团的吡咯烷基,
(1-13)可具有一低级烷氧基的苯基,
(1-14)低级烷基氨基-低级烷基,
(1-15)氧代基团,
(1-16)可具有一低级烷基的吡唑基,
(1-17)噻吩基,
(1-18)呋喃基,
(1-19)可具有一低级烷基的噻唑基,
(1-20)低级烷基氨基,
(1-21)可具有一低级烷基的嘧啶基,
(1-22)苯基-低级烯基,
(1-23)可具有一卤素原子的苯氧基,
(1-24)苯氧基-低级烷基,
(1-25)吡咯烷基-低级烷氧基,
(1-26)低级烷基氨磺酰基,
(1-27)可具有一低级烷基的哒嗪基氧基,
(1-28)苯基-低级烷基,
(1-29)低级烷基氨基-低级烷氧基,
(1-30)咪唑基-低级烷基,
(1-31)苯基-低级烷氧基,
(1-32)羟基,
(1-34)羟基-低级烷基,
(1-35)噁唑基,
(1-36)哌啶基,
(1-37)吡咯基,
(1-38)吗啉基-低级烷基,
(1-39)可具有低级烷基的哌嗪基-低级烷基,
(1-40)哌啶基-低级烷基,
(1-41)吡咯烷基-低级烷基,
(1-42)吗啉基,以及
(1-43)可具有一低级烷基的哌嗪基。
第5项,根据第4项所述的由通式(1)表示的杂环化合物或其盐,其中,
R1表示氢;
R2和R3是相同的或不同的,且各自独立地表示低级烷基;或者R2和R3结合形成环C3-C8烷基;以及
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(4)萘基,
(5)苯并呋喃基,以及
(31)吡咯并吡啶基,其中
这些芳香族基团或杂环基团可以具有选自以下的1至2个取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,以及
(1-7)低级烷氧基。
第6项,根据第5项所述的由通式(1)表示的杂环化合物或其盐,其选自以下化合物:
(4aS,8aR)-1-(4-氯苯基)-3,3-二甲基十氢喹喔啉,
2-氯-4-((4aS,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)苯基腈,
(4aS,8aR)-1-(3-氯-4-氟苯基)-3,3-二甲基十氢喹喔啉,
(4aS,8aR)-1-(7-氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉,
5-((4aR,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)-1-甲基-1H-吲哚-2-腈,
(4a’R,8a’S)-4’-(7-甲氧基苯并呋喃-4-基)八氢-1’H-螺[环丁烷-1,2’-喹喔啉],
(4aS,8aR)-1-(6,7-二氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉,
5-((4aS,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)-1H-吲哚-2-腈
(4aS,8aR)-1-(7-氯-2,3-二氢-1H-茚-4-基)-3,3-二甲基十氢喹喔啉,
6-((4aS,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)-2-萘甲腈,
(4aS,8aS)-3,3-二甲基-1-(1H-吡咯并[2,3-b]吡啶-4-基)十氢喹喔啉,以及
(4aS,8aS)-1-(4-(二氟甲氧基)-3-氟苯基)3,3-二甲基十氢喹喔啉。
第7项,一种药物组合物,其包含根据第1项所述的由通式(1)表示的杂环化合物或其盐作为活性成分,以及药学上可接受的载体。
第8项,一种用于因血清素、去甲肾上腺素或多巴胺的神经传导的降低所导致的紊乱的预防剂和/或治疗剂,其包括根据第1项所述的由通式(1)表示的杂环化合物或其盐作为活性成分。
第9项,根据第8项所述的预防剂和/或治疗剂,其中,所述紊乱选自以下:抑郁症、由适应性障碍导致的抑郁状态,由适应性障碍导致的焦虑,由各种疾病导致的焦虑,广泛性焦虑症,恐怖症,强制性障碍,惊恐性障碍,创伤后应激障碍,急性应激障碍,疑病症,分离性遗忘症,回避型人格障碍,躯体变形障碍,进食障碍,肥胖症,化学品依赖,疼痛,纤维肌痛,阿耳茨海默氏症,记忆缺失,帕金森氏症,下肢不宁综合征,内分泌紊乱,血管痉挛,小脑性共济失调,胃肠道病症,精神分裂症负综合征,月经前期综合征,压迫性尿失禁,图雷特氏精神障碍,注意缺陷多动障碍(ADHD),孤独症,阿斯佩各综合征,冲动控制障碍,拔毛狂,偷窃狂,赌博症,丛集性头痛,偏头痛,慢性发作性偏头痛,慢性疲乏综合征,性早熟射精,男性阳痿,发作性睡病,原发性嗜睡症,猝倒,睡眠呼吸暂停综合征和头痛。
第10项,根据第9项所述的预防剂和/或治疗剂,其中,所述抑郁症选自以下:严重的抑郁性障碍;I型双相障碍;II型双相障碍;混合状态;心境恶劣障碍;快速循环型;非典型抑郁症;季节性情感障碍;产后精神抑郁;轻抑郁症;复发性短时抑郁障碍;顽固性抑郁症;慢性抑郁症;双重抑郁症;酒精引起的心境障碍;混合性焦虑抑郁症;由各种躯体疾病导致的抑郁症,如库欣综合征、甲状腺功能减退症、甲状旁腺功能亢进症、阿狄森氏病、闭经-溢乳综合征、帕金森氏症、阿耳茨海默氏病、脑血管性痴呆、脑梗塞、脑出血、蛛网膜下腔出血、糖尿病、病毒感染、多发性硬化症、慢性疲乏综合征、冠状动脉疾病、疼痛、癌症等;早老性抑郁症;老年抑郁症;儿童和青少年抑郁症;由药物,如干扰素等诱导的抑郁症。
第11项,根据第9项所述的预防剂和/或治疗剂,其中,所述由各种疾病导致的焦虑选自以下:由颅脑损伤、脑感染、内耳病损、心力衰竭、心律失常、肾上腺机能亢进、甲状腺功能亢进症、哮喘和慢性阻塞性肺疾病导致的焦虑。
第12项,根据第9项所述的预防剂和/或治疗剂,其中,所述疼痛选自慢性痛、精神性疼痛、神经性疼痛、幻肢痛、疱疹后神经痛、外伤性颈痛综合征、脊髓损伤疼痛、三叉神经痛、糖尿病神经病变。
第13项,根据第1项至第6项中任意一项所述的由通式(1)表示的杂环化合物或其盐作为药物的用途。
第14项,根据第1项至第6项中任意一项所述的由通式(1)表示的杂环化合物或其盐作为血清素再摄取抑制剂和/或去甲肾上腺素再摄取抑制剂和/或多巴胺再摄取抑制剂的用途。
第15项,一种用于治疗和/或预防因血清素、去甲肾上腺素或多巴胺的神经传导的降低所导致的紊乱的方法,该方法包括向人或动物施用根据第1项至第6项中任意一项所述的由通式(1)表示的杂环化合物或其盐的步骤。
第16项,一种用于制备由通式(1)表示的杂环化合物或其盐的方法:
其中,m、l和n分别代表1或2的整数;X、R1、R2和R3如在以上第1项中所定义,该方法包括使由以下通式表示的化合物
与由以下通式所表示的化合物反应的步骤,
其中,m、l和n分别代表1或2的整数;X、R1、R2和R3如在以上第1项中所定义,其中,R4和X1定义如下。
在所述通式中的各个基团定义具体如下。
除非另有定义,否则术语“低级”是指具有1至6个(优选1至4个,更优选1至3个)碳原子的基团。
杂环基包括饱和的或不饱和的含有选自氧原子、硫原子和氮原子的至少一种杂原子的单环或多环的杂环。优选地,它包括以下的杂环:
可提及3至8元,优选5或6元包含1至4个氮原子的不饱和的杂单环,例如,吡咯基、吡咯啉基(pyrroliny)、咪唑基、吡唑基、吡啶基和其N-氧化物、嘧啶基、吡嗪基、哒嗪基、三唑基(例如,4H-1,2,4-三唑基,1H-1,2,3-三唑基,2H-1,2,3-三唑基等)、四唑基(例如,1H-四唑基,2H-四唑基等)、二氢三嗪基(例如,4,5-二氢-1,2,4-三嗪基,2,5-二氢-1,2,4-三嗪基)等。优选地,可提及咪唑基、哒嗪基、吡啶基、吡嗪基、嘧啶基、吡唑基等。
可提及3至8元,优选5或6元包含1至4个氮原子的不饱和杂单环,例如,氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、吡唑烷基、哌嗪基等。优选地,可提及吡咯烷基。
可提及7至12元包含1至5个氮原子的部分饱和或不饱和的稠合杂环基团,例如,吲哚基、二氢吲哚基(例如,2,3-二氢-1H-二氢吲哚基等)、异吲哚基、中氮茚基、苯并咪唑基、喹啉基、异喹啉基、二氢异喹啉基(例如,3,4-二氢-1H-异喹啉基等)、四氢喹啉基、四氢异喹啉基(例如,1,2,3,4-四氢-1H-异喹啉基、5,6,7,8-四氢异喹啉基等)、喹诺酮、二氢喹诺酮(如,3,4-二氢喹诺酮基等)、吲唑基、苯并三唑基、四唑并吡啶基、四唑并哒嗪基(例如,四唑并[1,5-b]哒嗪基等)、二氢三唑并哒嗪基、咪唑并吡啶基(例如,咪唑并[1,2-a]吡啶基等)、萘啶基、噌啉基、喹喔啉基、吡唑并吡啶基(例如,吡唑并[2,3-a]吡啶基等)、吡咯并吡啶基、咔唑基、二氢吲哚基、四氢苯并二氮杂卓基、四氢苯并氮杂卓基、喹唑啉基、酞嗪基等。优选可提及喹啉基、异喹啉基、喹喔啉基、吲哚基、吲唑基、吡咯并吡啶基、四氢喹啉基、咔唑基、二氢吲哚基、喹唑啉基、酞嗪基、四氢苯并二氮杂卓基或四氢苯并氮杂卓基等。
可提及3至8元,优选5或6元包含1至2个氧原子的不饱和杂单环,例如,呋喃基等。
可提及7至12元的包含1至3个氧原子的部分饱和或不饱和的稠合杂环基团,例如,苯并呋喃基、二氢苯并呋喃基(例如,2,3-二氢苯并[b]呋喃基等)、苯并二氢吡喃基、苯并二噁烷基(例如,1,4-苯并二噁烷基等)、二氢苯并噁嗪基(例如,2,3-二氢苯并-1,4-噁嗪基)、苯并间二氧杂环戊烯基(例如,苯并[1,3]二氧杂环戊烯基等)、苯并二噁英基、二氢苯并二噁英基、二氢苯并二氧杂环庚烯基等。优选可提及苯并呋喃基、苯并二噁英基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、二氢苯并二氧杂环庚烯基、二氢苯并二氧杂环庚烯基、苯并吡喃基或苯并二氢吡喃基。
可提及3至8元,优选5或6元包含1至2个氧原子和1至3个氮原子的不饱和杂单环,例如,噁唑基、异噁唑基、噁二唑基(例如,1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基等)等。优选可提及噁唑基、噁二唑基。
可提及3至8元,优选5或6元包含1至2个氧原子和1至3个氮原子的饱和杂单环,例如,吗啉基等。
可提及7至12元的包含1至2个氧原子和1至3个氮原子的部分饱和或不饱和的稠合杂环,例如,苯并噁唑基、苯并噁二唑基、苯并异噁唑基、呋喃并吡啶基(例如,呋喃并[2,3-b]吡啶基、呋喃并[3,2-c]吡啶基等),二氢苯并噁嗪基等。优选可提及苯并噁唑基,二氢苯并噁嗪基。
可提及3至8元,优选5或6元包含1至2个硫原子和1至3个氮原子的不饱和杂单环,例如,噻唑基、1,2-噻唑基、噻唑基、噻二唑基(例如,1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基、1,2,3-噻二唑基等)等。优选可提及噻唑基。
可提及3至8元,优选5或6元包含1至2个硫原子和1至3个氮原子的饱和杂单环,例如,噻唑烷基等。
可提及3至8元,优选5或6元包含1个硫原子的不饱和杂单环,例如,噻吩基等。
可提及7至12元的包含1至3个硫原子的不饱和的稠合杂环,例如,苯并噻吩基(例如,苯并[b]噻吩基等)等。
可提及7至12元的包含1至2个硫原子和1至3个氮原子的部分饱和或不饱和的稠合杂环基团,例如,苯并噻唑基、苯并噻二唑基、噻吩并吡啶基(例如,噻吩并[2,3-b]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[3,2-c]吡啶基等)、咪唑并噻唑基(例如,咪唑并[2,1-b]噻唑基等)、二氢咪唑并噻唑基(例如,2,3-二氢咪唑并[2,1-b]噻唑基等)、噻吩并吡嗪基(例如,噻吩并[2,3-b]吡嗪基等)等。优选可提及噻吩并吡啶基或苯并噻唑基。
上述杂环可以被一个或多个可选的取代基取代。
作为芳族环,其包括,例如,可提及C6-14芳基。所述芳基的优选的例子是苯基、萘基、蒽基、菲基、苊烯基、联苯基、茚基。其中,优选苯基、萘基、蒽基、菲基。所述芳基可以是部分饱和的。作为部分不饱和的芳基基团,例如为二氢茚基、芴基、二氢苊烯基,四氢萘基基团。在此,上述杂环可以被一个或多个可选的取代基取代。
作为饱和烃基,例如,其包括低级烷基、环C3-C8烷基等。
作为不饱和烃基,例如,其包括低级烯基、低级炔基、苯基等。
特征基团是通用术语,它用来指除了碳碳结合以外的直接结合到母体结构的基团(氢以外的原子或原子团),以及–C≡N和>C=X(X=O、S、Se、Te、NH、NR)。作为特征基团,其包括,例如,羧基、氨基甲酰基、氰基、羟基、氨基等。
所述可选的取代基是上述杂环、芳族环基团、饱和烃基、不饱和烃基、特征基团等。优选地,可提及上述第2项中所述的取代基(1-1)至(1-43)。
除非另有定义,低级烷基的例子可包括具有1至6个碳原子(优选1至4个碳原子)的直链或支链烷基。具体而言,其包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1-乙基丙基、异戊基、新戊基、正己基、1,2,2-三甲基丙基、3,3-二甲基丁基、2-乙基丁基、异己基和3-甲基戊基等。
除非另有定义,低级烷氧基的例子可包括具有1至6个碳原子(优选1至4个碳原子)的直链或支链烷氧基。具体而言,其包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、1-乙基丙氧基、异戊氧基、新戊氧基、正己氧基、1,2,2-三甲基丙氧基、3,3-二甲基丁氧基、2-乙基丁氧基、异己氧基和3-甲基戊氧基等。
除非另有定义,卤素原子的例子包括氟、氯、溴和碘原子。
除非另有定义,卤素取代的低级烷基的例子可包括由1至7个(更优选1至3个)卤素原子取代的上述例举的低级烷基。更具体而言,其包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、溴甲基、二溴甲基、二氯氟甲基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、2-氟乙基、2-氯乙基、3,3,3-三氟丙基、七氟丙基、2,2,3,3,3-五氟丙基、七氟异丙基、3-氯丙基、2-氯丙基、3-溴丙基、4,4,4-三氟丁基、4,4,4,3,3-五氟丁基、4-氯丁基、4-溴丁基、2-氯丁基、5,5,5-三氟戊基、5-氯戊基、6,6,6-三氟己基、6-氯己基和全氟己基等。
除非另有定义,卤素取代的低级烷氧基的例子可包括由1至7个(更优选1至3个)卤素原子取代的上述例举的低级烷氧基。更具体而言,其包括氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基、溴甲氧基、二溴甲氧基、二氯氟甲氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基、五氟乙氧基、2-氟乙氧基、2-氯乙氧基、3,3,3-三氟丙氧基、七氟丙氧基、七氟异丙氧基、3-氯丙氧基、2-氯丙氧基、3-溴丙氧基、4,4,4-三氟丁氧基、4,4,4,3,3-五氟丁氧基、4-氯丁氧基、4-溴丁氧基、2-氯丁氧基、5,5,5-三氟戊氧基、5-氯戊氧基、6,6,6-三氟己氧基、6-氯己氧基和全氟己氧基等。
除非另有定义,环C3-C8烷基的例子包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基等。
除非另有定义,低级烷酰基的例子可包括具有1至6个碳原子(优选1至4个碳原子)的直链或支链烷酰基。更具体而言,其包括甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、叔丁基羰基和己酰基等。
除非另有定义,低级烷基硫基的例子可包括由具有1至6个碳原子(优选1至4个碳原子)的直链或支链烷基取代的硫基。具体而言,其包括甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、仲丁硫基、正戊硫基、1-乙基丙硫基、异戊硫基、新戊硫基、正己硫基、1,2,2-三甲基丙硫基、3,3-二甲基丁硫基、2-乙基丁硫基、异己硫基和3-甲基戊硫基等。
除非另有定义,低级烯基的例子可包括具有1至3个双键以及2至6个碳原子(优选2至4个碳原子)的直链或支链烯基,且所述低级烯基包括反式和顺式两种形式。更具体而言,其包括乙烯基、1-丙烯基、2-丙烯基、1-甲基-1-丙烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、2-丁烯基、1-丁烯基、3-丁烯基、2-戊烯基、1-戊烯基、3-戊烯基、4-戊烯基、1,3-丁二烯基、1,3-戊二烯基、2-戊烯-4-基、2-己烯基、1-己烯基、5-己烯基、3-己烯基、4-己烯基、3,3-二甲基-1-丙烯基、2-乙基-1-丙烯基、1,3,5-己三烯基、1,3-己二烯基和1,4-己二烯基等。
除非另有定义,羟基-低级烷基的例子可包括具有1至5个、优选1至3个羟基的上述例举的低级烷基(优选地,具有1至6个碳原子(更优选1至4个碳原子)的直链或支链烷基)。更具体而言,其包括羟甲基、2-羟乙基、2-羟丙基、1-羟乙基、3-羟丙基、2,3-二羟基丙基、4-羟丁基、3,4-二羟基丁基、1,1-二甲基-2-羟乙基、5-羟基戊基、6-羟基己基、3,3-二甲基-3-羟基丙基、2-甲基-3-羟基丙基、2,3,4-三羟基丁基和全羟基己基等。
除非另有定义,低级烷基氨基的例子可包括具有1至2个上述例举的低级烷基(优选地,具有1至6个(更优选1至4个,更优选1至3个)碳原子的直链或支链烷基)的氨基。更具体而言,其包括甲基氨基、二甲基氨基、二乙基氨基和二异丙基氨基等。
除非另有定义,低级烷基氨磺酰基的例子可包括具有1至2个上述例举的低级烷基(优选地,具有1至6个(更优选1至4个,更优选1至3个)碳原子的直链或支链烷基)的氨磺酰基。更具体而言,其包括甲基氨磺酰基、乙基氨磺酰基、二甲基氨磺酰基、二乙基氨磺酰基和乙基甲基氨磺酰基等。
三-低级烷基甲硅烷基可例举有:由3个具有1至6个碳原子的直链或支链烷基所取代的甲硅烷基,如三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三甲基甲硅烷基、正丁基乙基甲基甲硅烷基、叔丁基二丙基甲硅烷基、正戊基二乙基甲硅烷基和正己基正丙基甲基甲硅烷基等。
除非另有定义,三(低级烷基)甲硅烷氧基-低级烷基可包括:三(低级烷基)甲硅烷氧基-低级烷基,其中的低级烷基部分为上述例举的任意低级烷基(优选地,具有1至6个碳原子(更优选1至4个碳原子)的直链或支链烷基)。更具体而言,其包括三甲基甲硅烷氧基甲基、1-(或2-)三甲基甲硅烷氧基乙基、1-(或2-或3-)三甲基甲硅烷氧基丙基,三乙基甲硅烷氧基甲基,1-(或2-)三乙基甲硅烷氧基乙基,1-(或2-或3-)三乙基甲硅烷氧基丙基,三异丙基甲硅烷氧基甲基,1-(或2-)三异丙基甲硅烷氧基乙基和1-(或2-或3-)三异丙基甲硅烷氧基丙基等。
除非另有定义,苯氧基-低级烷基的例子可包括具有1至3个、优选1个苯氧基的上述例举的低级烷基(优选地,具有1至6个(更优选1至4个,更优选1至3个)碳原子的直链或支链烷基)。更具体而言,其包括苯氧基甲基、1-苯氧基乙基、2-苯氧基乙基、3-苯氧基丙基、2-苯氧基丙基、4-苯氧基丁基、5-苯氧基戊基、4-苯氧基戊基、6-苯氧基己基、2-甲基-3-苯氧基丙基和1,1-二甲基-2-苯氧基乙基等。
除非另有定义,苯基-低级烷氧基的例子可包括具有1至3个、优选1个苯基的上述例举的低级烷氧基(优选地,具有1至6个(更优选1至4个,更优选1至3个)碳原子的直链或支链烷氧基)。更具体而言,其包括苯甲基氧基、2-苯基乙氧基、1-苯基乙氧基、3-苯基丙氧基、4-苯氧基丁基、5-苯基戊氧基、6-苯基己氧基、1,1-二甲基-2-苯基乙氧基和2-甲基-3-苯基丙氧基等。
除非另有定义,苯基-低级烯基的例子可包括具有1至3个、优选1个苯基的上述例举的低级烯基(优选地,具有2至6个(更优选2至4个)碳原子的直链或支链烯基)。更具体而言,其包括苯乙烯基、3-苯基-2-丙烯基(俗称肉桂基)、4-苯基-2-丁烯基、4-苯基-3-丁烯基、5-苯基-4-戊烯基、5-苯基-3-戊烯基、6-苯基-5-己烯基、6-苯基-4-己烯基、6-苯基-3-己烯基、4-苯基-1,3-丁二烯基和6-苯基-1,3,5-己三烯基等。
除非另有定义,低级烷基氨基-低级烷基的例子可以包括具有1至2个上述例举的低级烷基氨基的低级烷基。更具体而言,其包括甲氨基甲基、乙基氨基甲基、二甲基氨基甲基、1-(或2-)二甲基氨基乙基、1-(或2-或3-)二甲基氨基丙基、二异丙基氨基甲基、1-(或2-)二乙基氨基乙基和双(二甲基氨基)甲基等。
除非另有定义,低级烷基氨基-低级烷氧基的例子可以包括具有1至2个上述例举的低级烷基氨基的低级烷氧基基团。更具体而言,其包括甲氨基甲氧基、乙基氨基甲氧基、二甲基氨基甲氧基、1-(或2-)二甲基氨基乙氧基、1-(或2-或3-)二甲基氨基丙氧基、二异丙基氨基甲氧基、1-(或2-)二乙基氨基乙氧基和双(二甲基氨基)甲氧基等。
二氢苯并二噁英基的例子包括2,3-二氢苯并[b][1,4]二噁英基、3,4-二氢苯并[c][1,2]二噁英基和2,4-二氢苯并[d][1,3]二噁英基等。
除非另有定义,咪唑基-低级烷基的例子可包括具有1至3个、优选1个咪唑基的上述例举的低级烷基(优选地,具有1至6个(更优选1至4个)碳原子的直链或支链烷基)。更具体而言,其包括1-(或2-或4-或5-)咪唑基甲基、1-(或2-){1-(或2-或4-或5-)咪唑基}乙基,和1-(或2-或3-){1-(或2-或4-或5-)咪唑基}丙基等。
二氢茚基包括(1-,2-,4-,或5-)-1,2-二氢茚基等。
二氢喹啉基包括1,2-二氢喹啉基、3,4-二氢喹啉基、1,4-二氢喹啉基、4a,8a-二氢喹啉基、5,6-二氢喹啉基、7,8-二氢喹啉基和5,8-二氢喹啉基等。
芴基包括1H-芴基、2H-芴基、3H-芴基、4aH-芴基、5H-芴基、6H-芴基、7H-芴基、8H-芴基、8aH-芴基和9H-芴基等。
二氢苯并呋喃基包括2,3-二氢-(2-,3-,4-,5-,6-,或7-)苯并呋喃基等。
二氢苯并噁嗪基包括(2-,3-,4-,5-,6-,7-,或8-)3,4-二氢-2H-苯并[b][1.4]噁嗪基和(1-,2-,4-,5-,6-,7-,或8-)2,4-二氢-1H-苯并[d][1.3]噁嗪基等。
四氢苯并二氮杂卓基包括(1-,2-,3-,4-,5-,6-,7-,8-,或9-)2,3,4,5-四氢-1H-苯并[b][1.4]二氮杂卓基和(1-,2-,3-,4-,5-,6-,7-,8-,或9-)2,3,4,5-四氢-1H-苯并[e][1.4]二氮杂卓基等。
四氢苯并二氮杂卓基的例子可包括(1-,2-,3-,4-,5-,6-,7-,8-,或9-)2,3,4,5-四氢-1H-苯并[b][1.4]二氮杂卓基和(1-,2-,3-,4-,5-,6-,7-,8-,或9-)2,3,4,5-四氢-1H-苯并[e][1.4]二氮杂卓基等。
二氢苯并二氧杂环庚烯基包括3,4-二氢-2H-1,5-苯并二氧杂环庚烯基、4,5-二氢-3H-1,2-苯并二氧杂环庚烯基和3,5-二氢-2H-1,4-苯并二氧杂环庚烯基等。
除非另有定义,可具有氧代基团的吡咯烷基的例子包括具有1至2个(优选为1个)氧代基团的吡咯烷基。更具体而言,其包括(1-,2-或3-)吡咯烷基、(2-或3-)氧代-1-吡咯烷基、(3-,4-或5-)氧代-2-吡咯烷基和(2-,4-或5-)氧代-3-吡咯基等。
除非另有定义,可具有低级烷基的噁二唑基的例子可包括可具有1至2个(优选为1个)上述例举的低级烷基的噁二唑基。更具体而言,其包括5-甲基-1,3,4-噁二唑基、5-乙基-1,3,4-噁二唑基、5-丙基-1,3,4-噁二唑基、5-丁基-1,3,4-噁二唑基、5-戊基-1,3,4-噁二唑基和5-己基-1,3,4-噁二唑基等。
除非另有定义,可具有低级烷基的吡唑基的例子可包括可具有1至2个(优选为1个)上述例举的低级烷基的吡唑基。具体而言,其包括1-甲基-1H-吡唑基、1-乙基-1H-吡唑基、1-丙基-1H-吡唑基、1-异丙基-1H-吡唑基、1-丁基-1H-吡唑基、1-叔丁基-1H-吡唑基和1,3-二甲基-1H-吡唑基等。
除非另有定义,可具有低级烷基的噻唑基的例子可包括可具有1至2个(优选为1个)上述例举的低级烷基的噻唑基。具体而言,其包括2-甲基噻唑基、2-乙基噻唑基、2-丙基噻唑基、2-异丙基噻唑基、2-丁基噻唑基、2-叔丁基噻唑基和2,5-二甲基噻唑基等。
除非另有定义,可具有低级烷基的嘧啶基的例子可包括可具有1至2个(优选为1个)上述例举的低级烷基的嘧啶基。具体而言,其包括2-甲基嘧啶基、2-乙基嘧啶基、2-丙基嘧啶基、2-异丙基嘧啶基、2-丁基嘧啶基、2-叔丁基嘧啶基和2,4-二甲基嘧啶基等。
除非另有定义,可具有低级烷基的哒嗪基的例子可包括可具有1至2个(优选为1个)上述例举的低级烷基的哒嗪基。具体而言,其包括3-甲基哒嗪基、3-乙基哒嗪基、3-丙基哒嗪基、3-异丙基哒嗪基、3-丁基哒嗪基、3-叔丁基哒嗪基和3,4-二甲基哒嗪基等。
除非另有定义,可具有低级烷基的哒嗪基氧基的例子可包括由可具有1至2个(优选为1个)上述例举的低级烷基的哒嗪基所取代的氧基。更具体而言,其包括6-甲基哒嗪-3-基氧基和4-甲基哒嗪-3-基氧基等。
除非另有定义,吡咯烷基-低级烷氧基的例子可包括具有1至3个、优选1个吡咯烷基的上述例举的低级烷氧基(优选地,具有1至6个(更优选1至4个,更优选1至3个)碳原子的直链或支链烷氧基)。其具体例子包括(1-,2-或3-)吡咯烷基甲氧基、2-[(1-,2-或3-)吡咯烷基]乙氧基、1-[(1-,2-或3-)吡咯烷基]乙氧基、3-[(1-,2-或3-)吡咯烷基]丙氧基、4-[(1-,2-或3-)吡咯烷基]丁氧基、5-[(1-,2-或3-)吡咯烷基]戊氧基、6-[(1-,2-或3-)吡咯烷基]己氧基、1,1-二甲基-2-[(1-,2-或3-)吡咯烷基]乙氧基和2-甲基-3-[(1-,2-或3-)吡咯烷基]丙氧基等。
保护基团的例子包括常规使用的保护基团,如取代的或未取代的低级烷酰基[例如,甲酰基、乙酰基、丙酰基和三氟乙酰基]、邻苯二甲酰基、低级烷氧羰基[例如,叔丁氧基羰基和叔戊氧羰基]、取代的或未取代的芳烷氧羰基[例如,苄氧羰基和对硝基苄氧羰基]、9-芴基甲氧羰基、取代的或未取代的芳基磺酰基[例如,苯磺酰基和甲苯磺酰基]、硝基苯基亚磺酰基、芳烷基[例如三苯甲基和苄基],以及低级烷基甲硅烷基[例如,三异丙基甲硅烷基]。
除非另有定义,苯基-低级烷基的例子可包括具有1至3个、优选1个苯基的上述例举的低级烷基(优选地,具有1至6个(更优选1至4个)碳原子的直链或支链烷基)。具体而言,其包括苯甲基、苯乙基、3-苯基丙基,二苯甲基,三苯甲基,4-苯基丁基,5-苯基戊基和6-苯基己基等。
除非另有定义,吗啉基-低级烷基的例子可包括具有1至2个、优选1个吗啉基的上述例举的低级烷基(优选具有1至6个碳原子的直链或支链烷基)。更具体而言,其包括2-吗啉基甲基、3-吗啉基甲基、4-吗啉基甲基、2-(2-吗啉基)乙基、2-(3-吗啉基)乙基、2-(4-吗啉基)乙基)、1-(2-吗啉基)乙基、1-(3-吗啉基)乙基、1-(4-吗啉基)乙基、3-(2-吗啉基)丙基、3-(3-吗啉基)丙基、3-(4-吗啉基)丙基、4-(2-吗啉基)丁基、4-(3-吗啉基)丁基、4-(4-吗啉基)丁基、5-(2-吗啉基)戊基、5-(3-吗啉基)戊基、5-(4-吗啉基)戊基、6-(2-吗啉基)己基、6-(3-吗啉基)己基、6-(4-吗啉基)己基、3-甲基-3-(2-吗啉基)丙基、3-甲基-3-(3-吗啉基)丙基、1,1-二甲基-2-(2-吗啉基)乙基、1,1-二甲基-2-(3-吗啉基)乙基和1,1-二甲基-2-(4-吗啉基)乙基等。
除非另有定义,吡咯烷基-低级烷基的例子可包括具有1至3个(优选1个)吡咯烷基的上述例举的低级烷基。更具体而言,其包括(1-,2-或3-)吡咯烷基甲基、2-[(1-,2-或3-)吡咯烷基]乙基、1-[(1-,2-或3-)]吡咯烷基〕乙基、3-[(1-,2-或3-)]吡咯烷基]丙基、4-[(1-,2-或3-)]吡咯烷基]丁基、5-[(1-,2-或3-)]吡咯烷基]戊基、6-[(1-,2-或3-)]吡咯烷基]己基、1,1-二甲基-2-[(1-,2-或3-)]吡咯烷基]乙基、和2-甲基-3-[(1-,2-或3-)]吡咯烷基]丙基等。
除非另有定义,哌啶基-低级烷基的例子可包括具有1至2个、优选1个哌啶基的上述例举的低级烷基(优选具有1至6个碳原子的直链或支链烷基)。更具体而言,其包括(1-,2-,3-或4-)哌啶基甲基、2-[(1-,2-,3-或4-)哌啶基]乙基、1-[(1-,2-,3-或4-)哌啶基]乙基、3-[(1-,2-,3-或4-)哌啶基]丙基、4-[(1-,2-,3-或4-)哌啶基]丁基、1,1-二甲基-2-[(1-,2-,3-或4-)哌啶基〕乙基、5-[(1-,2-,3-或4-)哌啶基]戊基、6-[(1-,2-,3-或4-)哌啶基]己基、1-[(1-,2-,3-或4-)哌啶基]异丙基、和2-甲基-3-[(1-,2-,3-或4-)哌啶基]丙基等。
低级烷氧基羰基的例子可包括具有优选1至6个碳原子并具有上述例举的低级烷氧基羰基部分的直链或支链的烷氧基。具体而言,其包括甲氧羰基、乙氧羰基、正丙氧羰基、异丙氧基羰基、正丁氧基羰基、异丁氧基羰基、叔丁氧基羰基、仲丁氧基羰基、正戊氧基羰基、新戊基氧羰基、正己基氧基羰基、异己基氧基羰基、3-甲基戊氧羰基等。
除非另有定义,可具有低级烷基的哌嗪基的例子可包括可具有1至2个(优选为1个)低级烷基的哌嗪基。具体而言,其包括2-甲基哌嗪基、4-甲基哌嗪基、2-乙基哌嗪基、2-丙基哌嗪基、2-异丙基哌嗪基、2-丁基哌嗪基、2-叔丁基哌嗪基和2,4-二甲基哌嗪基等。
除非另有定义,可具有低级烷基的哌嗪基-低级烷基的例子包括可具有1至2个(优选为1个)低级烷基的上述例举的哌嗪基。具体而言,其包括1-(4-甲基哌嗪基)甲基、1-(2-甲基哌嗪基)甲基、2-(1-甲基哌嗪基)乙基、3-(1-甲基哌嗪基)丙基、4-(1-甲基哌嗪基)丁基等。
除非另有定义,可具有低级烷氧基的苯基的例子包括可具有1至2个(优选为1个)低级烷氧基的上述例举的苯基。更具体而言,其包括可提及的4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-异丙基苯基、4-丁氧基苯基、4-叔丁氧基苯基基团等。除非另有定义,作为可具有卤素原子的上述例举的苯氧基,其包括可具有1至4个(优选为1个)卤素原子的苯氧基。具体而言,其包括4-氟苯氧基、3,4-二氟苯氧基、3,4,5-三氟苯氧基,和3-氯-4,5-二氟苯氧基等。
四氢喹啉基包括,例如,1,2,3,4-四氢喹啉基、5,6,7,8-四氢喹啉基、4a,5,8,8a-四氢喹啉基、3,4,4a,8a-四氢喹啉基、4a,5,8,8a-四氢喹啉基和4a,5,6,7-四氢喹啉基等。
二氢苊烯基包括,例如,1,2-二氢苊烯基、2a1,3-二氢苊烯基,5,6-二氢苊烯基、3,7-二氢苊烯基、2a1,6-二氢苊烯基、1,2a1-二氢苊烯基和6,8a-二氢苊烯基等。更优选地可提及1,2-二氢苊烯基。
四氢萘基包括,例如,可提及1,2,3,4-四氢萘基、1,2,3,5-四氢萘基、以及5,6,7,8-四氢萘基、2,3,7,8-四氢萘基等。
二氢喹唑啉基包括,例如,可提及1,2-二氢喹唑啉基、3,4-二氢喹唑啉基、4a,5-二氢喹唑啉基、5,6-二氢喹唑啉基、6,7-二氢喹唑啉基、7,8-二氢喹唑啉基、8,8a-二氢喹唑啉基和4a,8a-二氢喹唑啉基等。
由通式(1)表示的杂环化合物可以通过不同方法制备。作为一个例子,由通式(1)表示的杂环化合物通过如下所示的反应式表示的方法制备。
反应式1
其中,R1、R2、R3、R4、X、l、m和n如上述所定义,以及X1表示离去基团。
在通式(3)中,由X1表示的离去基团可例举有卤素原子、低级烷磺酰基氧基、芳基磺酰基氧基、芳烷基磺酰基氧基、三卤甲烷磺酰基氧基、锍基(sulfonio group)和甲苯硫氧基。用于本反应的离去基团的优选的例子包括卤素原子。
由X1表示的卤素原子的例子可包括氟、氯、溴和碘原子。
由X1表示的低级烷基磺酰基氧基,具体可以举出:具有1至6个碳原子的直链或支链的烷磺酰基氧基,如甲烷磺酰氧基、乙烷磺酰氧基、正丙烷磺酰氧基、异丙烷磺酰氧基、正丁烷磺酰氧基、叔丁烷磺酰氧基、正戊烷磺酰氧基和正己烷磺酰氧基。
由X1表示的芳基磺酰氧基的例子可包括:可具有选自具有1至6个碳原子的直链或支链的烷基、具有1至6个碳原子的直链或支链的烷氧基、硝基和卤素原子的1至3个基团作为在苯环上的取代基的苯基磺酰氧基;以及萘基磺酰氧基。可具有取代基的苯基磺酰氧基,具体可以举出:苯基磺酰氧基、4-甲基苯基磺酰氧基、2-甲基苯基磺酰氧基、4-硝基苯基磺酰氧基、4-甲氧基苯基磺酰氧基、2-硝基苯基磺酰氧基和3-氯苯基磺酰氧基。萘基磺酰氧基具体可以举出:α-萘基磺酰氧基和β-萘基磺酰氧基。
由X1表示的芳烷基磺酰氧基的例子可包括:具有1至6个碳原子的直链或支链烷磺酰氧基,其可被具有选自具有1至6个碳原子的直链或支链的烷基、具有1至6个碳原子的直链或支链的烷氧基、硝基和卤素原子的1至3个基团作为在苯环上的取代基的苯基所取代;以及具有1至6个碳原子的直链或支链的烷磺酰氧基,其被萘基取代。由苯基取代的烷磺酰氧基,具体可以举出:苯甲基磺酰氧基、2-苯基乙基磺酰氧基、4-苯基丁基磺酰氧基、4-甲基苯甲基磺酰氧基、2-甲基苯甲基磺酰氧基、4-硝基苯甲基磺酰氧基、4-甲氧基苯甲基磺酰氧基和3-氯苯甲基磺酰氧基。被萘基取代的烷磺酰氧基具体可以举出:α-萘基甲基磺酰氧基和β-萘基甲基磺酰氧基。
由X1表示的全卤烷磺酰氧基具体可以举出:三氟甲烷磺酰氧基。
由X1表示的锍基的例子可具体包括二甲基锍基、二乙基锍基、二丙基锍基、二-(2-氰乙基)锍基、二-(2-硝基乙基)锍基、二-(氨基乙基)锍基、二-(2-甲基氨基乙基)锍基、二-(2-二甲基氨基乙基)锍基、二-(2-羟基乙基)锍基、二-(3-羟丙基)锍基、二-(2-甲氧基乙基)锍基、二-(2-氨基甲酰基乙基)锍基、二-(2-氨基甲酰基乙基)锍基、二-(2-羧乙基)锍基和二-(2-甲氧基羰基乙基)锍基、以及二苯基锍基基团。
由通式(2)表示的化合物和由通式(3)表示的化合物可以在钯催化剂的存在下,在存在或不存在碱性化合物并在或不在惰性溶剂中反应,从而制得化合物(1)。
所述惰性溶剂的例子可包括,例如:水;醚溶剂,如二噁烷、四氢呋喃、乙醚、1,2-二甲氧基乙烷、二乙二醇二甲醚和乙二醇二甲醚;芳族烃溶剂如苯、甲苯和二甲苯;低级醇溶剂,如甲醇、乙醇和异丙醇;酮溶剂,如丙酮和甲基乙基酮;以及极性溶剂,如N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、六甲基磷酰三胺和乙腈。这些惰性溶剂单独使用或以二种以上的其混合物来使用。
在本反应中所用的钯化合物没有特别的限制。其例子包括:四价钯催化剂,如六氯合钯(IV)酸钠四水合物和六氯合钯(IV)酸钾;二价钯催化剂,如氯化钯(II)、溴化钯(II)、乙酸钯(II)、乙酰丙酮酸钯(II)、双(苯甲腈)二氯化钯(II)、双(乙腈)二氯化钯(II)、双(三苯基膦)二氯化钯(II)、二氯四氨合钯(II)(dichlorotetraammine palladium(II))、二氯(环辛-1,5-二烯)合钯(II),以及三氟乙酸钯(II)1,1'-双(二苯基膦基)二茂铁二氯化钯(II)-二氯甲烷络合物;以及零价钯催化剂,如三(二亚苄基丙酮)二钯(0)、三(二亚苄基丙酮)二钯(0)-氯仿络合物,以及四(三苯基膦)钯(0)。这些钯化合物单独使用或以二种或以上的其混合物来使用。
在本反应中,所使用的钯催化剂的量没有特别的限制,通常取值范围为相对于1摩尔的通式(2)的化合物,0.000001至20摩尔的钯。优选地,相对于1摩尔的通式(2)的化合物,所使用的钯化合物的量为0.0001至5摩尔的钯。
本反应可在适当的配体的存在下有利地进行。例如,可使用2,2'-双(二苯基膦基)-1,1'-联萘(BINAP)、三邻甲苯基膦、双(二苯基膦基)二茂铁、三苯基膦、三-叔丁基膦、三环己基膦和9,9-二甲基-4,5-双(二苯基膦基)呫吨(XANTPHOS)作为用于钯催化剂的配体。这些配体单独使用或以二种或以上的其混合物来使用。
此外,在本发明中,叔膦可以以络合物形式预先制备并加入其中。络合物的例子可包括三叔丁基鏻四氟硼酸盐和三叔丁基鏻四苯基硼酸盐。
钯催化剂和所用的配体之间的比例没有特别限定。相对于1摩尔的钯催化剂,所用的配体的量是约0.1至100摩尔,优选约0.5至15摩尔。
可广泛使用本领域中已知的无机和有机碱作为碱性化合物。
无机碱的例子可包括:碱金属氢氧化物,如氢氧化钠、氢氧化钾、氢氧化铯和氢氧化锂;碱金属碳酸盐,如碳酸钠、碳酸钾、碳酸铯和碳酸锂;碱金属碳酸氢盐,如碳酸氢锂、碳酸氢钠和碳酸氢钾;碱金属如钠和钾;磷酸盐,如磷酸钠和磷酸钾;酰胺如氨基钠;以及碱金属氢化物,如氢化钠和氢化钾。
有机碱的例子可包括:碱金属低级醇盐,如甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾、叔丁醇钾;以及胺,如三乙胺、三丙胺、吡啶、喹啉、哌啶、咪唑、N-乙基二异丙基胺、二甲基氨基吡啶、三甲胺、二甲基苯胺、N-甲基吗啉、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)和1,4-二氮杂双环[2.2.2]辛烷(DABCO)。
这些碱性化合物单独使用或以二种或以上的其混合物来使用。在本反应中所使用的碱性化合物的更优选的例子包括碱金属碳酸盐,如碳酸钠、碳酸钾、碳酸铯和碳酸锂,以及叔丁醇钠。
相对于1摩尔的通式(2)的化合物,所使用的碱性化合物的量通常为0.5至10摩尔,优选为0.5至6摩尔。
在反应式1中使用的通式(2)的化合物和通式(3)的化合物之间的比例为:至少1摩尔,优选约1至5摩尔的在后化合物相对于1摩尔的在前化合物。
该反应可以在惰性气体如氮气或氩气的气氛中在大气压下进行,或可在增加的压力下进行。
本反应通常在室温到200℃,优选为室温到150℃的温度条件下进行,且一般在约1至30小时内完成。其也可以使用微波反应器通过在100至200℃加热5分钟至1小时而实现。
在反应完成后,反应产物可以由标准的方法处理以得到的感兴趣的化合物。
在反应式1中作为起始原料使用的通式(2)所表示的化合物是由本领域中公知的化合物制备的,例如,通过由下面所示的反应式3和4表示的方法。由通式(3)表示的化合物是本领域中公知的容易得到的化合物或通过在本领域中公知的方法容易制备的化合物。
反应式2
其中,R2、R3、R4、X、l、m和n如上述所定义;以及R1a表示保护基团。
所述保护基团的例子包括上面例举的保护基团。
由通式(1b)表示的化合物可以通过将由通式(1a)表示的化合物进行保护基团的消除反应而制备。
可以以常规使用的方法,如水解或氢解应用于保护基团的消除反应。
本反应通常在不会不利地影响反应的常规使用的溶剂中进行。所述溶剂的例子包括:水;醇溶剂,如甲醇、乙醇、异丙醇、正丁醇、三氟乙醇和乙二醇;酮溶剂,如丙酮和甲基乙基酮;醚溶剂,如四氢呋喃、二噁烷、乙醚、二甲氧基乙烷和二甘醇二甲醚;酯溶剂,如乙酸甲酯和乙酸乙酯;非质子性极性溶剂如乙腈、N,N-二甲基甲酰胺、二甲亚砜和N-甲基吡咯烷酮;卤化烃溶剂,如二氯甲烷和二氯乙烷;以及其它有机溶剂。
(ⅰ)水解:
水解优选是在碱或酸(包括路易斯酸)的存在下进行。
可广泛使用本领域中已知的无机碱和有机碱作为所述碱。无机碱的优选的例子包括碱金属(例如,钠和钾)、碱土金属(例如,镁和钙)、以及其氢化物、碳酸盐或碳酸氢盐。有机碱的优选的例子包括三烷基胺(例如,三甲胺和三乙胺)、甲基吡啶、1,5-二氮杂双环[4.3.0]壬-5-烯。
可广泛使用本领域中已知的有机酸和无机酸作为所述酸。所述有机酸的优选的例子包括:脂肪酸,如甲酸、乙酸和丙酸;以及三卤乙酸,如三氯乙酸和三氟乙酸。所述无机酸的优选的例子包括盐酸,氢溴酸,硫酸,氯化氢和溴化氢。所述路易斯酸的例子包括三氟化硼-乙醚络合物,三溴化硼,氯化铝和氯化铁。
当使用三卤乙酸或路易斯酸作为所述酸时,该反应优选在阳离子清除剂(例如,苯甲醚和苯酚)的存在下进行。
所使用的碱或酸的量没有特别的限制,只要其是足够水解所需的量即可。
反应温度通常为0至120℃,优选为室温至100℃,更优选为室温至80℃。反应时间通常为30分钟至24小时,优选为30分钟至12小时,更优选为1至8小时。
(ⅱ)氢解:
可广泛地将本领域中公知的氢解方法应用于氢解。这种氢解方法的例子包括化学还原和催化还原。
在化学还原中使用的优选的还原剂是氢化物(例如,碘化氢、硫化氢、氢化铝锂、硼氢化钠和氰基硼氢化钠)、金属(如锡、锌和铁)、或金属化合物(例如氯化铬和乙酸铬)与有机或无机酸(例如,甲酸、乙酸、丙酸、三氟乙酸、对甲苯磺酸、盐酸和氢溴酸)的组合。
在催化还原中使用的优选的催化剂是铂催化剂(如铂板、海绵铂、铂黑、胶态铂、氧化铂和铂线)、钯催化剂(如海绵钯、钯黑、氧化钯、钯-碳、钯/硫酸钡和钯/碳酸钡)、镍催化剂(如还原镍、氧化镍和阮内镍(Raney nickel))、钴催化剂(如还原钴和阮内钴(Raneycobalt))、铁催化剂(如还原铁)等。
当在化学还原中所用的这些酸在液体状态下时,它们也可以被用作溶剂。
在化学还原中所用的还原剂或在催化还原中所用的催化剂的量没有特别的限制,其可以是通常使用的量。
本发明的反应可以在惰性气体如氮气或氩气的气氛中在大气压下进行,或可在增加的压力下进行。
反应温度通常为0至120℃,优选为室温至100℃,更优选为室温至80℃。反应时间通常为30分钟至24小时,优选为30分钟至10小时,更优选为30分钟至4小时。
在反应完成后,反应产物可以由标准的方法处理以得到的感兴趣的通式(1b)的化合物。
保护基团的脱保护反应并不限定于上述的反应条件。例如,也可使用在T.W.格林,P.G.M.Wuts,“有机合成中的保护基团”(Protective Groups in Organic Synthesis),第4版,或John Wiley&Sons;纽约,1991,第309页中所述的反应用于本反应步骤。
由通式(2)表示的化合物是新化合物,其可用作用于由如上所述的通式(1)表示的化合物的中间体。
通式(2)的化合物根据,例如,如下所示的反应式3、4或5制备。
以下将描述各反应式。
反应式3
其中,R1、R2、R3、X、l、m和n如上述所定义。
由通式(2a)表示的化合物是通过使由通式(4)表示的化合物与由通式(5)表示的化合物进行环化反应以形成由通式(6)表示的化合物(步骤A),然后将其还原(步骤B)而制备的。
步骤A
由通式(4)表示的化合物和由通式(5)表示的化合物之间的反应可以在存在或不存在碱,并在或不在惰性溶剂中进行。
所述惰性溶剂的例子可包括,例如:水;醚,如二噁烷、四氢呋喃、乙醚、二乙二醇二甲醚和乙二醇二甲醚;芳族烃,如苯、甲苯和二甲苯;低级醇,如甲醇、乙醇和异丙醇;酮,如丙酮和甲基乙基酮;以及极性溶剂,如N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、六甲基磷酰三胺和乙腈。
可以广泛地使用现有技术中公知的碱性化合物。其例子可包括:碱金属氢氧化物,如氢氧化钠、氢氧化钾、氢氧化铯和氢氧化锂;碱金属碳酸盐,如碳酸钠、碳酸钾、碳酸铯和碳酸锂;碱金属,如钠和钾;其他无机碱,如氨基钠、氢化钠和氢化钾;碱金属醇化物,如甲醇钠、乙醇钠、甲醇钾和乙醇钾;以及其它的有机碱,如三乙胺、三丙胺、吡啶、喹啉、哌啶、咪唑、N-乙基二异丙基胺、二甲基氨基吡啶、三甲胺、二甲基苯胺、N-甲基吗啉、1,5-二氮杂环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)和1,4-二氮杂双环[2.2.2]辛烷(DABCO)。
这些碱性化合物单独使用或以二种或以上的其混合物来使用。
相对于通式(4)的化合物,所使用的碱性化合物的量通常为0.5至10摩尔,优选为0.5至6摩尔。
必要时,该反应可以通过添加作为反应促进剂的碱金属碘化物(例如,碘化钾和碘化钠)来进行。
在反应式中使用的通式(4)的化合物和通式(5)的化合物之间的比例通常为:至少0.5摩尔,优选约0.5至5摩尔的在后化合物相对于1摩尔的在前化合物。
本发明的反应可以在惰性气体如氮气或氩气的气氛中在大气压下进行,或可在增加的压力下进行。
该反应通常在0℃至200℃,优选为室温到150℃的温度条件下进行,且一般在约1至30小时内完成。
在步骤A中作为起始原料使用的通式(4)的化合物和通式(5)的化合物是本领域中公知的容易得到的化合物或通过在本领域中公知的方法容易制备的化合物。
步骤B
由通式(2b)表示的化合物可以通过将由通式(6)表示的化合物不在或者在惰性溶剂中进行还原反应而制备。
这种还原方法的例子包括化学还原和催化还原。
所述惰性溶剂的例子可包括:水;醚,如二噁烷、四氢呋喃、乙醚、二乙二醇甲醚和乙二醇二甲醚;芳族烃,如苯、甲苯和二甲苯;低级醇,如甲醇、乙醇和异丙醇;酮,如丙酮和甲基乙基酮;以及极性溶剂,如N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、六甲基磷酰三胺和乙腈。
在化学还原中使用的优选的还原剂是氢化物(例如,碘化氢、硫化氢、氢化铝锂、硼烷、硼氢化钠和氰基硼氢化钠)、金属(如锡、锌和铁)、或金属化合物(例如氯化铬和乙酸铬)与有机或无机酸(例如,甲酸、乙酸、丙酸、三氟乙酸、对甲苯磺酸、盐酸和氢溴酸)的组合。
在催化还原中使用的优选的催化剂是铂催化剂(如铂板、海绵铂、铂黑、胶态铂、氧化铂和铂线)、钯催化剂(如海绵钯、钯黑、氧化钯、钯-碳、钯/硫酸钡和钯/碳酸钡)、镍催化剂(如还原镍、氧化镍和阮内镍)、钴催化剂(如还原钴和阮内钴)、铁催化剂(如还原铁)等。
当在化学还原中所用的这些酸在液体状态下时,它们也可以被用作溶剂。
在化学还原中所用的还原剂或在催化还原中所用的催化剂的量没有特别的限制,其可以是通常使用的量。
本发明的反应可以在惰性气体如氮气或氩气的气氛中在大气压下进行,或可在增加的压力下进行。
反应温度通常为0至120℃,优选为室温至100℃,更优选为室温至80℃。反应时间通常为30分钟至24小时,优选为30分钟至10小时,更优选为30分钟至4小时。
在反应完成后,反应产物可以由标准的方法处理以得到的感兴趣的通式(2a)的化合物。
反应式4
其中,R1、R2、R3、X、l、m和n如上述所定义。
由通式(2b)表示的化合物是通过使由通式(4)表示的化合物与由通式(7)表示的化合物进行环化反应以形成由通式(8)表示的化合物(步骤C),然后将其还原(步骤D)而制备的。所述反应条件是与在反应式3中相同的反应条件。
反应式5
其中,R1、R2、R3、R4、l、m、n和X如上述所定义,以及Y和Z相同或不同,各自独立地表示离去基团。
在通式(9)中由Y和Z表示的离去基团的例子包括上述例举的离去基团。
步骤E
由通式(2)表示的化合物可以通过将由通式(4)表示的化合物和由通式(9)表示的化合物进行环化反应而制备。该环化反应通常在存在或不存在碱性化合物下进行。
本反应通常在不会不利地影响反应的常规使用的溶剂中进行。所述溶剂的例子包括:水;醇溶剂,如甲醇、乙醇、异丙醇、正丁醇、三氟乙醇和乙二醇;酮溶剂,如丙酮和甲基乙基酮;醚溶剂,如四氢呋喃、二噁烷、乙醚、二甲氧基乙烷和二甘醇二甲醚;酯溶剂,如乙酸甲酯和乙酸乙酯;非质子性极性溶剂如乙腈、N,N-二甲基甲酰胺、二甲亚砜和N-甲基吡咯烷酮;卤化烃溶剂,如二氯甲烷和二氯乙烷;以及其它有机溶剂。
可在该反应中使用过渡金属催化剂和配体。所述过渡金属的例子包括氯化钌、二氯三(三苯基膦)合钌、二溴三(三苯基膦)合钌、二氢化四(三苯基膦)合钌、(η4-环辛二烯)(η6-环辛三烯)合钌、二氯三羰基钌二聚物、十二羰基合三钌、(η5-五甲基环戊二烯基)氯(η4-环辛三烯)合钌、乙酸钯、氯化钯、二氯双(三苯基膦)合钯、四(三苯基膦)合钯、双(二亚苄基丙酮)合钯、氯化铑、三(三苯基膦)氯化铑、氢化羰基三(三苯基膦)合铑、氢化三(三苯基膦)合铑、二-μ-氯四羰基合二铑、羰基双(三苯基膦)氯化铱、(η5-五甲基环戊二烯基)二氯化铱二聚体、四(三苯基膦)合镍、八羰基合二钴、以及(η5-环戊二烯基)二羰基合钴。
所述配体的例子包括:以三甲基膦、三乙基膦、三正丙基膦、三异丙基膦、三正丁基膦、三叔丁基膦、三环己基膦、三苯基膦和三(邻甲苯基)膦为代表的单齿膦配体;以1,2-双(二苯基膦基)乙烷、1,3-双(二苯基膦基)丙烷、1,4-双(二苯基膦基)丁烷和1,2-(二乙基膦基)乙烷为代表的二齿膦配体;以及以亚磷酸三乙酯、亚磷酸三丁酯、亚磷酸三苯酯和三(邻甲苯基)亚磷酸酯为代表的亚磷酸酯配体。
该反应可在碱的存在下进行。可广泛使用本领域中已知的无机碱和有机碱作为所述碱。所述无机碱的例子包括碱金属(例如,钠和钾)、碱金属碳酸氢盐(例如,碳酸氢锂、碳酸氢钠和碳酸氢钾)、碱金属氢氧化物(例如,氢氧化锂、氢氧化钠、氢氧化钾和氢氧化铯)、碱金属碳酸盐(例如,碳酸锂、碳酸钠、碳酸钾和碳酸铯)、碱金属低级醇盐(例如,甲醇钠和乙醇钠)、以及碱金属氢化物(例如,氢化钠和氢化钾)。所述有机碱的例子包括三烷基胺(例如,三甲胺、三乙胺和N-乙基二异丙基胺)、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲基氨基吡啶、二甲基苯胺、N-甲基吗啉、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)。当这些碱在液体状态下时,它们也可以被用作溶剂。这些碱单独使用或以二种或以上的其混合物来使用。相对于1摩尔的通式(7)的化合物,所使用的碱的量通常为0.1至10摩尔,优选为0.1至3摩尔。
该反应也可以在氧化剂和还原剂的混合物的存在下进行。
氧化剂的例子包括二氧化锰、铬酸、四乙酸铅、氧化银、氧化铜、氢卤酸、二甲亚砜(Swern氧化)、有机过氧化物和氧气。也可使用如电极氧化的方法。
还原剂的例子包括硼氢化物试剂,如硼氢化钠,以及氢化铝试剂,如氢化铝锂。
在反应式中使用的通式(9)的化合物和通式(4)的化合物之间的通常比例为:至少1摩尔,优选约1至5摩尔的在前化合物相对于1摩尔的在后化合物。
本发明的反应可以在惰性气体如氮气或氩气的气氛中在大气压下进行,或可在增加的压力下进行。
反应温度并无特别的限制。该反应通常在冷却下,在室温下或在加热下进行。该反应优选在室温至100℃的温度条件下进行,持续30分钟至30小时,优选30分钟至5小时。
在反应完成后,反应产物可以由标准的方法处理以得到的感兴趣的通式(2)的化合物。
通式(1)的化合物的优选的盐的例子包括药学上可接受的盐,例如:金属盐,如碱金属盐(例如,钠盐和钾盐)和碱土金属盐(例如,钙盐和镁盐);铵盐;无机碱的盐,如碱金属碳酸盐(例如,碳酸锂、碳酸钾、碳酸钠和碳酸铯)、碱金属碳酸氢盐(例如,碳酸氢锂、碳酸氢钠和碳酸氢钾)、以及碱金属氢氧化物(例如,氢氧化锂、氢氧化钠、氢氧化钾和氢氧化铯);有机碱的盐,如三(低级)烷基胺(例如,三甲胺、三乙胺和N-乙基二异丙基胺)、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲基氨基吡啶、二甲基苯胺、N-(低级)烷基-吗啉(例如,N-甲基吗啉)、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)和1,4-二氮杂双环[2.2.2]辛烷(DABCO);无机酸的盐,如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐和磷酸盐;以及有机酸盐,如甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐(fumarate)、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、碳酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐和谷氨酸盐。
此外,在各个通式中还包括添加到原材料中的溶剂化物形式的化合物,或者在各个反应式中显示的感兴趣的化合物。溶剂化物的优选的例子包括水合物。
根据各反应式得到的每种感兴趣的化合物可从反应混合物中分离和纯化,例如,通过在冷却后使反应混合物通过如过滤、浓缩和萃取的分离步骤分离成粗反应产物,并将所述粗反应产物进行通过如柱层析和重结晶的常规纯化步骤。
本发明的由通式(1)表示的化合物当然还包括异构体,如几何异构体、立体异构体和光学异构体。
不同的异构体可以利用异构体之间的物理化学性质的差异通过标准方法分离。例如,外消旋化合物可以通过一般的光学拆分方法[例如,以具有一般光学活性的酸(酒石酸等)与非对映的盐进行转化,然后光学拆分的方法]转换为立体上纯的异构体。非对映混合物可以通过,例如,分步结晶或者层析法分离。光学活性的化合物也可以使用适当的光学活性的起始原料制备。
本发明还包括同位素标记的化合物,除了一个或多个原子由具有特定的原子质量或质量数的一个或多个原子取代以外,其与由通式(1)表示的化合物相同。可以并入本发明的化合物中的同位素的例子包括氢、碳、氮、氧、硫、氟和氯的同位素,如2H、3H、13C、14C、15N、18O、17O、18F和36Cl。本发明的这些含有任何同位素和/或其他原子的其他同位素的特定的同位素标记的化合物,例如,包含放射性同位素(例如,3H和14C)的化合物在用于组织中的药物和/或底物的分布的测定中是有用的。因为其易于制备和可探测性,氚(即3H)和碳-14(即14C)同位素是特别优选的。此外,可以预期的是,由较重的同位素,如重氢(即,2H)的取代可以带来特定的治疗上的优点,这可归因于改进的代谢稳定性,例如,增加的体内半衰期,或减少的所需剂量。本发明的由同位素标记的化合物,一般可通过在以下的反应式和/或实施例中公开的方法,并由容易得到的同位素标记的试剂代替未标记的试剂而制备。
以下将描述包含本发明的化合物作为活性成分的药物制剂。
药物制剂通过使本发明的化合物成为通常的药物制剂的剂型而得到,并使用通常使用的稀释剂和/或赋形剂,如填充剂、膨胀剂、粘合剂、湿润剂、崩解剂、表面活性剂和润滑剂制备。
这样的药物制剂可根据治疗目的从不同形式中选择。其典型的例子包括片剂、丸剂、粉剂、溶液、悬浮液、乳剂、颗粒剂、胶囊剂、栓剂和注射剂(溶液、悬浮液等)。
可以广泛使用在本领域中公知的用于形成片剂的载体。其例子包括:赋形剂,如乳糖、蔗糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土和结晶纤维素;粘合剂,例如水、乙醇、丙醇、单糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、虫胶、甲基纤维素、磷酸钾和聚乙烯吡咯烷酮;崩解剂,例如干淀粉、藻酸钠、琼脂粉、昆布粉、碳酸氢钠、碳酸钙、聚氧乙烯山梨糖醇酐脂肪酸酯、月桂基硫酸钠、硬脂酸单甘油酯、淀粉和乳糖;崩解抑制剂,如蔗糖、硬脂精、可可脂和氢化油;吸收促进剂,如季铵碱和月桂基硫酸钠;湿润剂,如甘油和淀粉;吸附剂,如淀粉、乳糖、高岭土、膨润土和胶体硅酸;以及润滑剂,如精制滑石、硬脂酸盐、硼酸粉末和聚乙二醇。
此外,如果需要,片剂可以由通常的涂覆材料涂覆,以制备,例如,糖包衣片剂、明胶包衣片剂、肠溶包衣片剂、薄膜包衣片剂、以及双层或多层片剂。
可以广泛使用在本领域中公知的用于形成丸剂的载体。其例子包括:赋形剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、高岭土和滑石;粘合剂,如阿拉伯树胶粉末、粉末状黄蓍胶、明胶和乙醇;以及崩解剂,如昆布糖和琼脂。
可以广泛使用在本领域中公知的用于形成栓剂的载体。其例子包括聚乙二醇、可可脂、高级醇、高级醇的酯、明胶和半合成甘油酯。
当由通式(1)表示的化合物制备为注射剂时,溶液、乳液和悬浮液优选是无菌和与血液等渗的。可以广泛使用在本领域中公知的用于形成这些溶液、乳液和悬浮液的稀释剂。其例子包括水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚氧化异硬脂醇和聚氧乙烯山梨糖醇酐脂肪酸酯。在此情况下,药物制剂可以包含足以制备等渗溶液的量的通常的食盐,葡萄糖或甘油,并可以包含通常的增溶剂、缓冲剂、安抚剂等,以及必要时还可包含,着色剂、防腐剂、香料、矫味剂、增甜剂等,和/或其他药物。
在药物制剂中所包含的本发明的化合物的量没有特别的限制,并且可以在宽范围内适当地选择。本发明的化合物通常以优选约1至70wt%的量包含在药物制剂中。
根据本发明的药物制剂的给药方法没有特别的限定。所述药物制剂通过根据不同的剂型、患者的年龄、性别和疾病状态,以及其他条件的方法给药。例如,片剂、丸剂、溶液、悬浮液、乳剂、颗粒剂和胶囊通过口服给药。此外,注射剂可以通过静脉内途径单独,或作为与通常的补液(如葡萄糖或氨基酸)的混合物给药,或者,如果需要,可通过肌内、皮内、皮下或腹膜内途径单独给药。栓剂在直肠给药。
所述药物制剂的剂量可根据用途、患者的年龄、性别和疾病状态,以及其他条件合适地选择。药物制剂通常以每kg体重约0.001至100毫克,优选约0.001至50毫克的每日剂量,每天一次或者数次给药。
剂量根据各种条件而有所不同。因此,在某些情况下,小于这个范围的剂量就足够了。而在其他情况下,则需要超过这个范围的剂量。
本发明的杂环化合物对1、2或3单胺(血清素、去甲肾上腺素和多巴胺)具有再摄取抑制作用。
与具有单胺摄取抑制活性的已知化合物相比,本发明的杂环化合物在体外或离体试验中对任何一个、任何两个或全部的3单胺具有相当强的摄取抑制活性。此外,与具有单胺摄取抑制活性的已知化合物相比,本发明的杂环化合物在脑微透析研究中对于对抗任何一个、任何两个或全部的3单胺的增加显示出相当强的活性。
与本领域中已知的抗抑郁药相比,本发明的杂环化合物的具有广泛的治疗谱。
本发明的杂环化合物即使在短期给药中也能发挥足够的治疗效果。
本发明的杂环化合物具有优良的生物利用度,对肝脏中的代谢酶的抑制活性弱,副作用少,以及具有优异的安全性。
本发明的杂环化合物可优异地传输到大脑。
本发明的杂环化合物在用于筛选抑郁症的小鼠强迫游泳试验中也发挥出强活性。此外,本发明的杂环化合物在用于筛选抑郁症的大鼠强迫游泳试验中也发挥出强活性。此外,本发明的杂环化合物在用于筛选抑郁症的利血平诱导的低体温测试中也发挥出强活性。
本发明的杂环化合物在焦虑或压力病模型小鼠和恐惧状态压力模型的埋珠行为(marble burying behavior)测试中发挥出强活性。
本发明的杂环化合物对1、2或3单胺(血清素、去甲肾上腺素和多巴胺)具有再摄取抑制作用,并且因此对于治疗与血清素、去甲肾上腺素或多巴胺的神经传导的降低相关的各种疾病均有效。
所述疾病包括抑郁症(例如:严重的抑郁性障碍;I型双相障碍;II型双相障碍;混合状态;心境恶劣障碍;快速循环型;非典型抑郁症;季节性情感障碍;产后精神抑郁;轻抑郁症;复发性短时抑郁障碍;顽固性抑郁症/慢性抑郁症;双重抑郁症;酒精引起的心境障碍;混合性焦虑抑郁症;由各种躯体疾病导致的抑郁症,如库欣综合征、甲状腺功能减退症、甲状旁腺功能亢进症、阿狄森氏病、闭经-溢乳综合征、帕金森氏症、阿耳茨海默氏病、脑血管性痴呆、脑梗塞、脑出血、蛛网膜下腔出血、糖尿病、病毒感染、多发性硬化症、慢性疲乏综合征、冠状动脉疾病、疼痛、癌症等;早老性抑郁症;老年抑郁症;儿童和青少年抑郁症;由药物,如干扰素等诱导的抑郁症);由适应性障碍导致的抑郁状态,由适应性障碍导致的焦虑,由各种疾病[例如:神经症(颅脑损伤、脑感染、内耳病损);心血管疾病(心力衰竭和心律失常);内分泌失调(肾上腺机能亢进和甲状腺功能亢进症);以及呼吸系统疾病(哮喘和慢性阻塞性肺疾病)]导致的焦虑,广泛性焦虑症,恐惧症(例如,广场恐惧症、社交恐惧、简单的恐惧症、社交恐惧症、社交焦虑症、红脸恐惧症、恐人症、恐高症、牙科手术恐惧,针头恐惧症,特定恐惧症,简单的恐惧症,动物恐惧症,幽闭恐惧症,黑夜恐惧症和恐惧性焦虑),强制性障碍,惊恐性障碍,创伤后应激障碍,急性应激综合征,疑病症,分离性遗忘症,回避型人格障碍,躯体变形障碍,进食障碍(如神经性厌食症和神经性贪食症),肥胖症,化学品依赖(例如,除了酒精,可卡因,海洛因,苯巴比妥,尼古丁和苯并二氮杂卓),疼痛(如慢性痛、精神性疼痛、神经性疼痛、幻肢痛、疱疹后神经痛、外伤性颈痛综合征、脊髓损伤(SCI)疼痛、三叉神经痛、糖尿病神经病变),纤维肌痛(FMS),阿耳茨海默氏症,记忆缺失(例如,痴呆、遗忘症和与年龄有关的认知衰退(ARCD)),帕金森氏病(例如,非运动性/精神病症状,帕金森病痴呆,神经安定药诱导的帕金森氏综合征,以及迟发性运动障碍),下肢不宁症,内分泌紊乱(例如,高催乳素血症),血管痉挛(特别是脑血管),小脑性共济失调,胃肠道病症(其中包括分泌和运动的变化),精神分裂症负综合征,月经前期综合征,压迫性尿失禁,图雷特氏精神障碍,注意缺陷多动障碍(ADHD),孤独症,阿斯佩各综合征,冲动控制障碍,拔毛狂,偷窃狂,赌博症,丛集性头痛,偏头痛,慢性发作性偏头痛,慢性疲乏综合征,性早熟射精,男性阳痿,发作性睡病,原发性嗜睡症,猝倒,睡眠呼吸暂停综合征和头痛(与血管病相关)。
实施例
以下,将参照参考实施例、实施例和药理学试验更详细地描述本发明。外消旋体和光学活性形式的化学结构,例如,如下图所示的表明。
外消旋体
相对构型
光学活性形式
绝对构型
参考实施例1
顺式-3,3-二甲基八氢环戊二烯并吡嗪-2-酮的制备
相对构型
在室温下向顺式-环戊烷-1,2-二胺(9.88g,98.6mmol)的水溶液(100ml)中加入90%的丙酮氰醇(9.79g,104mmol),并将该混合物在回流下搅拌16小时。在减压下从反应混合物中除去溶剂,然后用乙醇共沸。将所得到的残余物通过硅胶柱层析法(二氯甲烷/甲醇=1/10)纯化以得到白色粉末状的顺式-3,3-二甲基八氢环戊二烯并吡嗪-2-酮(5.00g,30%)。
1H-NMR(CDCl3)δppm:1.20(1H,brs),1.34(3H,s),1.39(3H,s),1.40-2.20(6H,m),3.50-3.70(2H,m),5.89(1H,brs).
使用适当的起始原料以与参考实施例1中相同的方式制备以下所示的参考实施例2至12的化合物。
参考实施例2
反式-3,3-二甲基八氢环戊二烯并吡嗪-2-酮
相对构型
1H-NMR(CDCl3)δppm:1.26-1.55(9H,m),1.75-2.00(4H,m),2.85-3.02(1H,m),3.05-3.20(1H,m),6.02(1H,brs).
参考实施例3
顺式-3,3-二甲基六氢呋喃并[3,4-b]吡嗪-2-酮
相对构型
1H-NMR(CDCl3)δppm:1.37(3H,s),1.40(3H,s),1.50-1.85(1H,br),3.73-4.10(6H,m),6.02-6.22(1H,br).
参考实施例4
反式-3,3-二甲基六氢呋喃并[3,4-b]吡嗪-2-酮
相对构型
1H-NMR(CDCl3)δppm:1.38-1.43(1H,br),1.44(3H,s),1.47(3H,s),3.38-3.52(1H,m),3.52-3.65(3H,m),4.00-4.14(2H,m),6.28-6.45(1H,br).
参考实施例5
(4aS,8aS)-3,3-二甲基八氢喹喔啉-2-酮
绝对构型
1H-NMR(CDCl3)δppm:1.14-1.37(6H,m),1.38(3H,s),1.42(3H,s),1.69(1H,brs),1.74-1.84(2H,m),2.57-2.65(1H,m),2.96-3.04(1H,m),5.61(1H,s)
参考实施例6
(4aR,8aR)-3,3-二甲基八氢喹喔啉-2-酮
绝对构型
1H-NMR(CDCl3)δppm:1.14-1.37(6H,m),1.38(3H,s),1.42(3H,s),1.63(1H,brs),1.73-1.83(2H,m),2.57-2.66(1H,m),2.95-3.04(1H,m),5.55(1H,s)
参考实施例7
反式-3,3-二乙基八氢喹喔啉-2-酮的制备
相对构型
1H-NMR(CDCl3)δppm:0.92(3H,t,J=7.5Hz),0.93(3H,t,J=7.3Hz),1.13-1.49(7H,m),1.60-1.99(6H,m),2.55-2.60(1H,m),2.91-3.00(1H,m),5.69(1H,brs)
参考实施例8
反式-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]-3'-酮
相对构型
1H-NMR(CDCl3)δppm:1.14-1.46(4H,m),1.70-2.17(9H,m),2.43-2.52(1H,m),2.55-2.66(1H,m),2.78-2.88(1H,m),2.97-3.06(1H,m),5.65(1H,brs)
参考实施例9
顺式-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]-3'-酮
相对构型
1H-NMR(CDCl3)δppm:1.1-1.3(1H,m),1.35-2.15(12H,m),2.5-2.6(1H,m),2.75-2.85(1H,m),3.15-3.3(2H,m),5.65(1H,br).
参考实施例10
反式-八氢-1'H-螺[环己烷-1,2'-喹喔啉]-3'-酮
相对构型
1H-NMR(CDCl3)δppm:1.18-1.88(18H,m),2.03-2.13(1H,m),2.47-2.58(1H,m),2.92-3.00(1H,m),5.59(1H,s)
参考实施例11
顺式-3,3-二甲基十氢环庚二烯并吡嗪-2-酮
相对构型
1H-NMR(CDCl3)δppm:1.12-2.00(16H,m),2.03-2.20(1H,m),3.35-3.55(2H,m),5.88(1H,brs).
参考实施例12
反式-3,3-二甲基十氢环庚二烯并吡嗪-2-酮
相对构型
1H-NMR(CDCl3)δppm:1.35(3H,s),1.39(3H,s),1.42-1.90(11H,m),2.73-2.85(1H,m),3.13-3.26(1H,m),5.51(1H,brs).
参考实施例13
顺式-4,4-二甲基八氢环戊二烯并[b][1,4]二氮杂卓-2-酮的制备
相对构型
使用Dean-Stark装置在共沸条件下将顺式-环戊烷-1,2-二胺(19.7g,197mmol)和3-甲基-2-丁烯酸(19.7g,197mmol)的甲苯(200mL)悬浮液在回流下搅拌24小时。将反应混合物冷却至室温,然后在减压下浓缩,并通过过滤收集析出的晶体。将得到的晶体用乙醚洗涤,然后干燥以得到浅褐色粉末状的顺式-4,4-二甲基八氢环戊二烯并[b][1,4]二氮杂卓-2-酮(8.60g,24%)。
1H-NMR(CDCl3)δppm:1.10-1.56(10H,m),1.65-1.80(1H,m),2.02-2.30(3H,m),2.60(1H,d,J=12.8Hz),3.18-3.37(1H,m),3.68-3.85(1H,m),5.73(1H,brs).
使用适当的起始原料以与参考实施例13中相同的方式制备以下的参考实施例14至15的化合物。
参考实施例14
(5aS,9aS)-4,4-二甲基十氢[b][1,4]二氮杂卓-2-酮
绝对构型
1H-NMR(CDCl3)δppm:1.00-1.45(11H,m),1.63-1.83(3H,m),1.83-2.00(1H,m),2.31-2.43(1H,m),2.65-2.81(2H,m),3.00-3.16(1H,m),5.54-5.90(1H,br).
参考实施例15
(5aR,9aR)-4,4-二甲基十氢[b][1,4]二氮杂卓-2-酮
绝对构型
1H-NMR(CDCl3)δppm:1.02-1.36(11H,m),1.64-1.83(3H,m),1.83-1.97(1H,m),2.37(1H,dd,J=2.4,13.9Hz),2.66-2.81(2H,m),3.01-3.15(1H,m),5.75-5.92(1H,brs).
参考实施例16
顺式-2,2-二甲基八氢-1H-环戊二烯并[b]吡嗪的制备
相对构型
在室温搅拌下向顺式-3,3-二甲基八氢环戊二烯并吡嗪-2-酮(2.00g,11.9mmol)的无水二噁烷(40ml)溶液中加入氢化铝锂(541mg,14.3mmol),将混合物在回流下逐渐加热并搅拌10分钟。将反应混合物冷却至冰的温度。然后,以小份向其中加入硫酸钠十水合物直到不再产生氢气。然后,将混合物在室温下搅拌1小时。通过硅藻土过滤不溶物,并浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(乙酸乙酯/己烷=1/10)纯化以得到浅黄色油状的顺式-2,2-二甲基八氢-1H-环戊二烯并[b]吡嗪(1.67g,91%)。
1H-NMR(CDCl3)δppm:1.04(3H,s),1.16(3H,s),1.28-2.02(8H,m),2.37(1H,d,J=12.9Hz),2.70(1H,d,J=12.9Hz),3.00-3.15(1H,m),3.15-3.32(1H,m).
使用适当的起始原料以与参考实施例16中相同的方式制备以下的参考实施例17至34的化合物。
参考实施例17
反式-2,2-二甲基八氢-1H-环戊二烯并[b]吡嗪
相对构型
1H-NMR(CDCl3)δppm:1.08(3H,s),1.19-1.92(11H,m),2.15-2.30(1H,m),2.55-2.74(2H,m),2.77(1H,d,J=12.2Hz).
参考实施例18
顺式-2,2-二甲基十氢环戊二烯并[b][1,4]二氮杂卓
相对构型
1H-NMR(CDCl3)δppm:1.11(3H,s),1.14(3H,s),1.15-1.45(6H,m),1.55-1.67(1H,m),1.67-1.77(1H,m),1.97-2.12(2H,m),2.68-2.80(1H,m),2.98-3.11(2H,m),3.16-3.28(1H,m).
参考实施例19
顺式-2,2-二甲基八氢呋喃并[3,4-b]吡嗪
相对构型
1H-NMR(CDCl3)δppm:1.08(3H,s),1.18(3H,s),1.40-1.80(2H,br),2.41(1H,d,J=13.2Hz),2.69(1H,d,J=13.2Hz),3.33-3.43(1H,m),3.43-3.55(1H,m),3.63-3.72(1H,m),3.75-3.96(3H,m).
参考实施例20
反式-2,2-二甲基八氢呋喃并[3,4-b]吡嗪
相对构型
1H-NMR(CDCl3)δppm:1.13(3H,s),1.30(3H,s),1.44-1.65(2H,m),2.64-2.78(2H,m),2.83(1H,d,J=12.2Hz),3.11-3.22(1H,m),3.46(1H,dd,J=7.3,10.5Hz),3.55(1H,dd,J=7.4,10.5Hz),3.94(1H,t,J=7.1Hz),4.00(1H,t,J=7.2Hz).
参考实施例21
顺式-2,2-二甲基十氢-1H-苯并[b][1,4]二氮杂卓
相对构型
1H-NMR(CDCl3)δppm:1.08(3H,s),1.13(3H,s),1.18-1.84(12H,m),2.65-2.93(3H,m),3.14-3.22(1H,m).
参考实施例22
(5aS,9aS)-2,2-二甲基十氢-1H-苯并[b][1,4]二氮杂卓
绝对构型
1H-NMR(CDCl3)δppm:1.00-1.35(11H,m),1.50-1.85(7H,m),2.20-2.31(1H,m),2.31-2.43(1H,m),2.79-2.90(1H,m),2.90-3.04(1H,m).
参考实施例23
(5aR,9aR)-2,2-二甲基十氢-1H-苯并[b][1,4]二氮杂卓
绝对构型
1H-NMR(CDCl3)δppm:1.00-1.35(11H,m),1.50-1.85(7H,m),2.20-2.31(1H,m),2.31-2.43(1H,m),2.79-2.90(1H,m),2.90-3.04(1H,m).
参考实施例24
顺式-2,2-二甲基十氢喹喔啉
相对构型
1H-NMR(CDCl3)δppm:1.06(3H,s),1.19(3H,s),1.20-1.40(5H,m),1.53-1.60(3H,m),1.70-1.77(1H,m),1.92-2.15(1H,m),2.36(1H,d,J=12.7Hz),2.66-2.72(1H,m),2.72(1H,d,J=12.7Hz),3.16-3.28(1H,m).
参考实施例25
反式-2,2-二甲基十氢喹喔啉
相对构型
1H-NMR(CDCl3)δppm:1.05(3H,s),1.08-1.74(10H,m),1.23(3H,s),2.02-2.12(1H,m),2.40-2.50(1H,m),2.60(1H,d,J=12.1Hz),2.73(1H,d,J=12.1Hz).
参考实施例26
(4aS,8aS)-2,2-二甲基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.01-1.43(6H,m),1.05(3H,s),1.23(3H,s),1.58-1.63(1H,m),1.68-1.74(3H,m),2.03-2.19(1H,m),2.40-2.49(1H,m),2.60(1H,d,J=12.1Hz),2.73(1H,d,J=12.1Hz).
参考实施例27
(4aR,8aR)-2,2-二甲基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.05(3H,s),1.09-1.56(6H,m),1.23(3H,s),1.58-1.63(1H,m),1.66-1.75(3H,m),2.03-2.12(1H,m),2.41-2.50(1H,m),2.61(1H,d,J=12.1Hz),2.75(1H,d,J=12.1Hz).
参考实施例28
反式-2,2-二乙基十氢喹喔啉
相对构型
1H-NMR(CDCl3)δppm:0.79(3H,t,J=7.5Hz),0.81(3H,t,J=7.5Hz),0.86-1.02(1H,m),1.08-1.40(8H,m),1.47-1.60(2H,m),1.67-1.87(3H,m),2.06-2.15(1H,m),2.33-2.42(1H,m),2.57(1H,d,J=12.1Hz),2.81(1H,d,J=12.1Hz).
参考实施例29
反式-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]
相对构型
参考实施例30
顺式-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]
相对构型
参考实施例31
反式-八氢-1'H-螺[环戊烷-1,2'-喹喔啉]
相对构型
1H-NMR(CDCl3)δppm:1.10-1.97(18H,m),2.10-2.21(1H,m),2.29-2.38(1H,m),2.71(1H,d,J=12.2Hz),2.76(1H,d,J=12.2Hz).
参考实施例32
反式-八氢-1'H-螺[环己烷-1,2'-喹喔啉]
相对构型
1H-NMR(CDCl3)δppm:1.12-1.76(20H,m),2.12-2.20(1H,m),2.44-2.53(1H,m),2.55(1H,d,J=12.2Hz),2.98(1H,d,J=12.2Hz).
参考实施例33
顺式-2,2-二甲基十氢-1H-环庚二烯并[b]吡嗪
相对构型
1H-NMR(CDCl3)δppm:1.00-2.02(18H,m),2.42(1H,d,J=12.4Hz),2.58(1H,d,J=12.4Hz),2.75-2.86(1H,m),3.13-3.25(1H,m).
参考实施例34
反式-2,2-二甲基十氢-1H-环庚二烯并[b]吡嗪
相对构型
1H-NMR(CDCl3)δppm:1.05(3H,s),1.21(3H,s),1.23-1.80(12H,m),2.09-2.20(1H,m),2.46-2.60(2H,m),2.68(1H,d,J=11.8Hz).
参考实施例35
(2RS,4aSR,8aSR)-2-乙基十氢喹喔啉的制备
相对构型
在室温搅拌下向反式-环己烷-1,2-二胺(2.00g,17.5mmol)和(±)-1,2-丁二醇(1.69mL,18.4mmol)的水(20mL)溶液中加入二氯(五甲基环戊二烯基)合铱(III)二聚体(70mg,0.090mmol)和碳酸氢钠(73mg,0.87mmol)。重复脱气和用氩气置换3次,然后将混合物在回流下搅拌24小时。在减压下浓缩反应混合物。将所得到的残余物通过碱性硅胶柱层析法(二氯甲烷/甲醇)纯化以得到黄色固体状的(2R*,4aS*,8aS*)-2-乙基十氢喹喔啉(2.03g,收率:69%)。
1H-NMR(CDCl3)δppm:0.92(3H,t,J=7.5Hz),1.10-1.60(7H,m),1.64-1.83(5H,m),2.16-2.31(2H,m),2.44(1H,dd,J=11.5,10.4Hz),2.58-2.67(1H,m),3.02(1H,dd,J=11.5,2.7Hz).
参考实施例36
(4aS,8aS)-1-苄基十氢喹喔啉的制备
绝对构型
在室温搅拌下向(1S,2S)-环己烷-1,2-二胺(3.43g,30.0mmol)的甲醇(300mL)溶液中加入苯甲醛(3.05mL,30.0mmol),并将混合物在相同的温度下搅拌整夜。将反应混合物冷却至0℃。向其中加入硼氢化钠(2.27g,60.0mmol),并将该混合物在0℃下搅拌2小时。向反应混合物中加入水(30mL),并将产物用二氯甲烷(50mL)萃取两次。将有机层合并,并用硫酸镁干燥,然后在减压下蒸馏除去溶剂。将所得到的残余物通过碱性硅胶柱层析法(乙酸乙酯/己烷)纯化以得到浅黄色油状的(1S,2S)-N-苄基环己烷-1,2-二胺(CAS号207450-11-1)(2.95g,收率:48%)。
将得到的(1S,2S)-N-苄基环己烷-1,2-二胺(2.90g,14.2mmol)溶解在二氯甲烷(284nL)中。在氮气气氛中冰冷却下向该溶液中加入60%氢化钠(1.99g,49.7mmol)。5分钟后,在冰冷却和搅拌下向反应混合物中加入(2-溴乙基)二苯基锍三氟甲磺酸酯(6.92g,15.6mmol),并在室温下将混合物搅拌整夜。向反应混合物中以小份逐滴加入氯化铵的饱和水溶液,并将产物用二氯甲烷(100mL)萃取两次。将有机层合并,并用硫酸镁干燥,然后在减压下蒸馏除去溶剂。将所得到的残余物通过NH-硅胶柱层析法(乙酸乙酯/己烷)纯化以得到浅褐色固体状的(4aS,8aS)-1-苄基十氢喹喔啉(2.28g,70%)。
1H-NMR(CDCl3)δppm:1.05-1.4(4H,m),1.50(1H,br),1.6-1.9(4H,m),2.05-2.2(1H,m),2.2-2.3(1H,m),2.4-2.5(1H,m),2.65-2.75(1H,m),2.8-2.95(2H,m),3.14(1H,d,J=13.4Hz),4.11(1H,d,J=13.4Hz),7.15-7.4(5H,m).
使用适当的起始原料以与参考实施例36中相同的方式制备以下的参考实施例37至39的化合物。
参考实施例37
(4aS,8aS)-1-苄基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.05-1.4(4H,m),1.50(1H,br),1.6-1.9(4H,m),2.05-2.2(1H,m),2.2-2.3(1H,m),2.4-2.5(1H,m),2.65-2.75(1H,m),2.8-2.95(2H,m),3.13(1H,d,J=13.4Hz),4.11(1H,d,J=13.4Hz),7.15-7.4(5H,m).
参考实施例38
顺式-十氢喹喔啉-1-羧酸叔丁酯
相对构型
1H-NMR(CDCl3)δppm:1.05-1.15(1H,m),1.2-1.75(19H,m),1.75-1.85(1H,m),1.85-2.2(1H,m),3.70(1H,br),4.83(1H,br).
参考实施例39
顺式-1-苄基十氢喹喔啉
相对构型
1H-NMR(CDCl3)δppm:1.0-2.0(10H,m),2.2-2.4(1H,m),2.45-2.7(2H,m),2.75-3.1(2H,m),3.63(2H,br),7.05-7.45(5H,m).
参考实施例40
(4aR,8aS)-2,2-二甲基十氢喹喔啉的制备
绝对构型
参考实施例41
(4aS,8aR)-2,2-二甲基十氢喹喔啉
绝对构型
在室温搅拌下向顺式-2,2-二甲基十氢喹喔啉(13.7g,81.4mmol)的乙醇(140mL)溶液中加入乙醇(140毫升)中的(-)-二苯甲酰基-L-酒石酸一水合物(13.8g,36.7mmol)。在回流下将反应混合物搅拌30分钟并冷却至室温,然后通过过滤收集析出的白色晶体。将所得到的晶体用乙醇(20mL)洗涤,然后干燥以得到白色固体<1>(13.1g)。将滤液和在获得固体<1>时所得到的洗液在减压下浓缩。将所得到的残余物溶解在乙醇(100mL)中。在室温搅拌下向溶液中加入(+)-二苯甲酰基-D-酒石酸(13.1g,36.6mmol)的乙醇(130mL)溶液,并通过过滤收集析出的晶体。将所得到的晶体用乙醇(20mL)洗涤,然后干燥以得到浅褐色固体<2>(16.6g)。
将固体<1>的甲醇(130mL)/水(10mL)悬浮液在回流下搅拌30分钟。然后,将反应混合物冷却至室温,并通过过滤收集析出的晶体。将析出的晶体用甲醇(10mL)洗涤,然后干燥以得到白色固体状的(4aR,8aS)-2,2-二甲基十氢喹喔啉二苯甲酰基-L-酒石酸盐(11.4g,21.6mmol)(顺式-2.2-二甲基十氢喹喔啉的绝对构型通过该白色固体的X-射线晶体分析测定)。将该固体溶解在1N的氢氧化钠水溶液(44mL)中,并将产物用乙醚(100mL)萃取三次,并用二氯甲烷(100mL)萃取三次。将萃取的有机层合并,并用硫酸镁干燥,然后在减压下浓缩以得到白色固体状的(4aR,8aS)-2,2-二甲基十氢喹喔啉(3.44g,收率:25%)。
1H-NMR(CDCl3)δppm:1.06(3H,s),1.20(3H,s),1.2-1.4(4H,m),1.45-1.95(5H,m),1.95-2.15(1H,m),2.36(1H,d,J=12.7Hz),2.65-2.75(2H,m),3.15-3.25(1H,m).
将固体<2>的甲醇(130mL)/水(10mL)悬浮液在回流下搅拌1小时。然后,将反应混合物冷却至室温,并通过过滤收集析出的晶体。将析出的晶体用甲醇(10mL)洗涤,然后干燥以得到白色固体状的(4aS,8aR)-2,2-二甲基十氢喹喔啉二苯甲酰基-D-酒石酸盐(16.0g,30.4mmol)。将此固体溶解在1N的氢氧化钠水溶液(65mL)中,并将产物用二氯甲烷(100mL)萃取三次。将萃取的有机层合并,并用硫酸镁干燥,然后在减压下浓缩以得到浅褐色固体状的(4aS,8aR)-2,2-二甲基十氢喹喔啉(4.63g,收率:34%)。
1H-NMR(CDCl3)δppm:1.06(3H,s),1.19(3H,s),1.2-1.45(5H,m),1.45-1.65(3H,m),1.65-1.8(1H,m),1.95-2.15(1H,m),2.36(1H,d,J=12.7Hz),2.6-2.8(2H,m),3.15-3.25(1H,m).
使用适当的起始原料以与参考实施例40和41中相同的方式制备以下的参考实施例42至45的化合物。
参考实施例42
(4a'R,8a'S)-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]
绝对构型
1H-NMR(CDCl3)δppm:1.20-2.20(16H,m),2.69(1H,d,J=12.4Hz),2.72-2.82(1H,m),2.87-3.02(2H,m).
参考实施例43
(4a'S,8a'R)-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]
绝对构型
1H-NMR(CDCl3)δppm:1.20-2.20(16H,m),2.68(1H,d,J=12.5Hz),2.72-2.82(1H,m),2.87-3.02(2H,m).
参考实施例44
(4aR,8aS)-1-苄基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.0-1.25(1H,m),1.25-1.65(5H,m),1.65-2.05(3H,m),2.2-2.4(1H,m),2.45-2.7(2H,m),2.75-3.1(3H,m),3.63(2H,br),7.15-7.4(5H,m).
参考实施例45
(4aS,8aR)-1-苄基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.05-1.25(1H,m),1.25-1.65(5H,m),1.65-2.05(3H,m),2.2-2.4(1H,m),2.5-2.7(2H,m),2.75-3.1(3H,m),3.63(2H,br),7.15-7.4(5H,m).
参考实施例46
(反式-3-氧代十氢喹喔啉-1-基)乙酸乙酯的制备
相对构型
用乙醇(15ml)稀释反式-环己烷-1,2-二胺(3.00g,26.3mmol)。在冰冷却下向溶液中逐滴加入乙酸溴乙酯(6.12mL,55.2mmol),然后将混合物在室温下搅拌整夜。
向反应溶液中加入水,并搅拌该混合物。将产物用二氯甲烷萃取。将有机层用饱和盐水洗涤并用硫酸镁干燥,然后过滤。在减压下浓缩滤液。将所得到的残余物通过硅胶柱层析法(二氯甲烷/甲醇)分离并纯化以得到橙色固体颗粒状的(反式-3-氧代十氢喹喔啉-1-基)乙酸乙酯(2.35g,收率:74.4%)。
1H-NMR(CDCl3)δppm:1.13-1.41(4H,m),1.28(3H,t,J=7.1Hz),1.72-1.97(4H,m),2.59-2.67(1H,m),3.06-3.13(1H,m),3.35(1H,d,J=17.4Hz),3.48(1H,d,J=16.8Hz),3.52(1H,d,J=17.4Hz),3.60(1H,d,J=16.8Hz),4.17(2H,q,J=7.1Hz),6.79(1H,brs).
参考实施例47
2-(反式-十氢喹喔啉-1-基)乙醇的制备
相对构型
将氢化铝锂(1.00g,26.4mmol)悬浮在无水二噁烷(40ml)中。在室温搅拌下向该悬浮液中逐滴加入(反式-3-氧代十氢喹喔啉-1-基)乙酸乙酯(2.35g,9.78mmol)的无水二噁烷(10ml)溶液,然后将混合物在回流下搅拌10分钟。将反应混合物在冰上冷却,并以小份向其中加入硫酸钠十水合物直到不再产生气体。将此混合物通过硅藻土过滤并用二氯甲烷洗涤,然后将滤液在减压下浓缩以得到褐色油状的2-(反式十氢喹喔啉-1-基)乙醇(1.74g,收率:97%)。
1H-NMR(CDCl3)δppm:0.95-1.11(1H,m),1.15-1.44(3H,m),1.68-1.80(5H,m),1.85-1.94(1H,m),2.05-2.44(4H,m),2.87-2.97(3H,m),3.04-3.16(1H,m),3.46-3.54(1H,m),3.60-3.69(1H,m).
参考实施例48
反式-1-[2-(叔丁基二甲基甲硅烷氧基)乙基]十氢喹喔啉的制备
相对构型
在冰冷却和搅拌下向2-(反式十氢喹喔啉-1-基)乙醇(1.74g,9.44mmol)的二氯甲烷(40mL)溶液中加入三乙胺(4.61mL,33.0mmol),随后加入叔丁基二甲基甲硅烷基氯(4.27g,28.3mmol),并将混合物在室温下搅拌整夜。向反应混合物中加入水(100mL)以终止反应。将产物用二氯甲烷(100mL)萃取。将有机层用水洗涤两次,并用饱和盐水洗涤一次,然后用硫酸镁干燥,并在减压下浓缩。将所得到的残余物通过硅胶柱层析法(二氯甲烷/甲醇)纯化以得到浅褐色油状的反式-1-[2-(叔丁基二甲基甲硅烷氧基)乙基]十氢喹喔啉(2.00g,收率:71%)。
1H-NMR(CDCl3)δppm:0.06(6H,s),0.89(9H,s),0.98-1.36(4H,m),1.65-1.79(4H,m),1.85-1.95(1H,m),2.08-2.14(1H,m),2.24-2.39(1H,m),2.45-2.61(2H,m),2.79-3.03(4H,m),3.62-3.80(2H,m).
使用适当的起始原料以与参考实施例1中相同的方式制备以下的参考实施例50和51的化合物。
参考实施例50
(4a'S,8a'S)-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]-3'-酮
绝对构型
1H-NMR(CDCl3)δppm:0.99-1.38(4H,m),1.55-1.78(5H,m),1.78-1.94(3H,m),2.21-2.33(2H,m),2.48-2.59(1H,m),2.63(1H,brs),2.76-2.87(1H,m),7.36(1H,s).
参考实施例51
(4a'R,8a'R)-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]-3'-酮
绝对构型
1H-NMR(CDCl3)δppm:0.97-1.36(4H,m),1.55-1.77(5H,m),1.77-1.92(3H,m),2.20-2.32(2H,m),2.47-2.57(1H,m),2.63(1H,brs),2.76-2.86(1H,m),7.36(1H,s).
使用适当的起始原料以与参考实施例16中相同的方式制备以下的参考实施例52和53的化合物。
参考实施例52
(4a'S,8a'S)-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]
绝对构型
1H-NMR(CDCl3)δppm:1.05-1.90(15H,m),2.15-2.30(3H,m),2.69(1H,dd,J=1.5,12.2Hz),3.01(1H,d,J=12.2Hz).
参考实施例53
(4a'R,8a'R)-八氢-1'H-螺[环丁烷-1,2'-喹喔啉]
绝对构型
1H-NMR(CDCl3)δppm:1.05-1.91(15H,m),2.15-2.30(3H,m),2.69(1H,d,J=12.2Hz),3.01(1H,d,J=12.2Hz).
参考实施例54
(4aS,8aR)-4-苄基十氢喹喔啉-1-羧酸叔丁酯的制备
绝对构型
向(4aR,8aS)-1-苄基十氢喹喔啉(1.63g,7.08mmol)的甲醇(MeOH)(16ml)溶液中加入二叔丁基二碳酸酯(1.70g,7.79mmol),并将该混合物在室温下搅拌2小时。蒸馏除去溶剂,然后将残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到无色油状的(4aS,8aR)-4-苄基十氢喹喔啉-1-羧酸叔丁酯(2.38克,收率:定量)。
1H-NMR(CDCl3)δppm:1.26-1.66(14H,m),1.79-1.96(2H,m),2.14-2.33(2H,m),2.40-2.45(1H,m),2.66(1H,brs),2.86(1H,d,J=13.2Hz),3.03(1H,brs),3.50-4.10(2H,br),4.16(1H,d,J=13.2Hz),7.21-7.36(5H,m).
使用适当的起始原料以与参考实施例54中相同的方式制备以下的参考实施例55的化合物。
参考实施例55
(4aR,8aS)-4-苄基十氢喹喔啉-1-羧酸叔丁酯
绝对构型
1H-NMR(CDCl3)δppm:1.26-1.66(14H,m),1.79-1.96(2H,m),2.14-2.33(2H,m),2.40-2.45(1H,m),2.65(1H,brs),2.86(1H,d,J=13.2Hz),3.03(1H,brs),3.51-4.10(2H,br),4.16(1H,d,J=13.2Hz),7.21-7.36(5H,m).
参考实施例56
(4aS,8aR)十氢喹喔啉-1-羧酸叔丁酯的制备方法
绝对构型
向(4aS,8aR)-4-苄基十氢喹喔啉-1-羧酸叔丁酯(2.4g,7.26mmol)的乙醇(EtOH)(25ml)溶液中加入Pearlman催化剂(0.24g)。在室温下氢气气氛中将此悬浮液搅拌1小时。将催化剂通过硅藻土过滤,并将残余物用EtOH洗涤。然后,将滤液在减压下浓缩以得到无色油状的(4aS,8aR)-十氢喹喔啉-1-羧酸叔丁酯(1.67g,收率:96%)。
1H-NMR(CDCl3)δppm:1.16-1.53(14H,m),1.53-1.82(3H,m),1.83-2.00(1H,m),2.68-2.83(1H,m),2.85-3.10(3H,m),3.65-4.06(2H,m).
使用适当的起始原料以与参考实施例56中相同的方式制备以下的参考实施例57的化合物。
参考实施例57
(4aR,8aS)-十氢喹喔啉-1-羧酸叔丁酯
绝对构型
1H-NMR(CDCl3)δppm:1.18-1.55(14H,m),1.55-1.82(3H,m),1.85-2.00(1H,m),2.68-2.82(1H,m),2.85-3.10(3H,m),3.65-4.04(2H,m).
参考实施例58
顺式-4-(4-氯苯基)十氢喹喔啉-1-羧酸叔丁酯的制备方法
相对构型
在氮气氛中在回流下将顺式-十氢喹喔啉-1-羧酸叔丁酯(240mg,0.999mmol)、1-溴-4-氯苯(211mg,1.10mmol)、Pd(OAc)2(11.2mg,0.0499mmol),t-Bu3P.HBF4(14.5mg,0.0500mmol)和NaOt-Bu(135mg,1.40mmol)的甲苯(4ml)悬浮液搅拌5小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。通过硅藻土过滤不溶物,并用AcOEt(5ml×2)洗涤硅藻土层。然后,在减压下浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到白色固体(87mg,收率:25%)。
1H-NMR(CDCl3)δppm:1.10-1.40(4H,m),1.40-1.52(10H,m),1.63-1.71(1H,m),1.73-1.82(1H,m),2.15-2.28(1H,m),2.74(1H,dt,J=3.6,11.8Hz),2.90-2.97(1H,m),3.05-3.11(1H,m),3.27(1H,dt,J=3.4,12.6Hz),3.77-3.86(1H,m),4.01-4.10(1H,m),7.08-7.13(2H,m),7.25-7.30(2H,m).
使用适当的起始原料以与参考实施例35中相同的方式制备以下的参考实施例59至63的化合物。
参考实施例59
(4aS,8aS)-十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.12-1.58(6H,m),1.62-1.78(4H,m),2.20-2.29(2H,m),2.82-3.02(4H,m).
参考实施例60
(4aR,8aR)-十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.14-1.27(2H,m),1.27-1.57(4H,m),1.62-1.79(4H,m),2.19-2.30(2H,m),2.83-3.03(4H,m).
参考实施例61
(2R,4aS,8aS)-2-甲基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.02(3H,d,J=6.3Hz),1.11-1.51(6H,m),1.62-1.79(4H,m),2.14-2.22(1H,m),2.24-2.33(1H,m),2.44(1H,dd,J=10.2,11.7Hz),2.81-2.91(1H,m),2.94(1H,dd,J=2.9,11.7Hz).
参考实施例62
(2S,4aR,8aR)-2-甲基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:1.02(3H,d,J=6.3Hz),1.10-1.49(6H,m),1.62-1.80(4H,m),2.14-2.22(1H,m),2.24-2.33(1H,m),2.44(1H,dd,J=10.3,11.7Hz),2.80-2.91(1H,m),2.94(1H,dd,J=2.9,11.7Hz).
参考实施例63
(2R,4aS,8aS)-2-乙基十氢喹喔啉
绝对构型
1H-NMR(CDCl3)δppm:0.92(3H,t,J=7.5Hz),1.1-1.55(8H,m),1.6-1.8(4H,m),2.14-2.32(2H,m),2.39-2.5(1H,m),2.57-2.68(1H,m),3.01(1H,dd,J=2.6,11.6Hz).
实施例1
(4aR,8aS)-3,3-二甲基-1-(1-(三异丙基甲硅烷基)-1H-吲哚-6-基)十氢喹喔啉的制备
绝对构型
在氮气气氛中在回流下将(4aS,8aR)-2,2-二甲基十氢喹喔啉(337mg,2.00mmol)、6-溴-1-(三异丙基甲硅烷基)-1H-吲哚(846mg,2.40mmol)、叔丁醇钠(269mg,2.80mmol)、乙酸钯(II)(22.5mg,0.0902mmol)和三叔丁基膦四氟硼酸盐(29.1mg,0.101mmol)的甲苯(8mL)悬浮液搅拌5小时。将反应混合物冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(10mL),并搅拌该混合物,然后加入硫酸镁。通过硅藻土过滤不溶物,然后在减压下浓缩滤液。将所得到的残余物通过NH-硅胶柱层析法(正己烷:乙酸乙酯)纯化以得到无色的无定形的(4aR,8aS)-3,3-二甲基-1-(1-(三异丙基甲硅烷基)-1H-吲哚--6-基)十氢喹喔啉(0.75g,收率:85%)。
1H-NMR(CDCl3)δppm:1.1-1.2(18H,m),1.21(3H,s),1.29(3H,s),1.3-1.55(5H,m),1.55-1.8(7H,m),2.79(1H,d,J=11.6Hz),2.91(1H,d,J=11.6Hz),3.45-3.6(2H,m),6.49(1H,dd,J=0.7,3.2Hz),6.82(1H,dd,J=2.0,8.6Hz),6.93(1H,s),7.08(1H,d,J=3.2Hz),7.45(1H,d,J=8.6Hz).
实施例2
(4aR,8aS)-1-(1H-吲哚-6-基)-3,3-二甲基十氢喹喔啉的制备
绝对构型
在室温搅拌下向(4aR,8aS)-3,3-二甲基-1-(1-(三异丙基甲硅烷基)-1H-吲哚-6-基)十氢喹喔啉(0.750g,1.71mmol)的四氢呋喃(15mL)溶液中加入四正丁基氟化铵(1M,在THF中)(3.41mL,3.41mol),并将混合物在室温下搅拌1小时。在减压下从反应混合物中蒸馏除去溶剂。将所得到的残余物通过NH-硅胶柱层析法(乙酸乙酯/己烷)纯化以得到白色固体。将所得到的固体由二异丙基醚/己烷重结晶以得到(4aR,8aS)-1-(1H-吲哚-6-基)-3,3-二甲基十氢喹喔啉(305mg,收率:63%)。
1H-NMR(CDCl3)δppm:1.0-1.55(11H,m),1.55-1.85(4H,m),2.79(1H,d,J=11.6Hz),2.94(1H,d,J=11.6Hz),3.45-3.55(1H,m),3.6-3.75(1H,m),6.35-6.5(1H,m),6.79(1H,s),6.86(1H,dd,J=2.1,8.7Hz),7.03(1H,dd,J=2.7,2.7Hz),7.47(1H,d,J=8.6Hz),7.92(1H,br).
实施例3
(4aS,8aS)-1-(4-氯苯基)十氢喹喔啉的制备
绝对构型
在冰冷却和搅拌下向(4aS,8aS)-1-苄基-4-(4-氯苯基)十氢喹喔啉(0.650g,1.91mmol)的二氯甲烷(6.5mL)溶液中加入氯甲酸1-氯乙酯(229μL,2.10mmol)。混合物在室温下搅拌15小时,然后将反应混合物在减压下浓缩。将得到的残余物溶解在甲醇(6.5mL)中,并在回流下将此溶液搅拌1小时。从反应混合物中蒸馏除去溶剂。向所得到的残余物中加入丙酮(5mL),并搅拌该混合物。通过过滤收集析出的晶体。将所得到的晶体用丙酮(1mL)洗涤,然后干燥以得到白色粉末状的(4aS,8aS)-1-(4-氯苯基)十氢喹喔啉(253mg,收率:53%)。
1H-NMR(DMSO-d6)δppm:0.85-1.05(1H,m),1.1-1.4(2H,m),1.4-1.65(3H,m),1.65-1.8(1H,m),1.9-2.05(1H,m),2.8-3.0(2H,m),3.05-3.2(3H,m),3.2-3.5(1H,m),7.1-7.2(2H,m),7.35-7.45(2H,m),9.2-9.65(2H,m).
实施例4
顺式-4-(苯并[b]噻吩-5-基)-1,2,2-三甲基十氢喹喔啉盐酸盐的制备
相对构型
在室温搅拌下向顺式-1-(苯并[b]噻吩-5-基)-3,3-二甲基十氢喹喔啉(298mg,0.992mmol)的甲醇(10mL)溶液中加入37%的甲醛水溶液(0.81mL,9.9mmol)。在30分钟后,在室温下向反应溶液中加入氰基硼氢化钠(311mg,4.96mmol)和乙酸(0.30mL),并将混合物搅拌整夜。在减压下从反应混合物中蒸馏除去溶剂。然后,向其中加入碳酸氢钠的饱和水溶液(50mL),随后用乙酸乙酯(50mL)萃取两次。将有机层用水洗涤两次,并用饱和盐水洗涤一次,然后用硫酸镁干燥,并在减压下浓缩。将所得到的残余物通过硅胶柱层析法(二氯甲烷:甲醇=10:1)纯化以得到褐色油状物。在室温搅拌下向所得到的油状的乙醇溶液中加入4N盐酸/乙酸乙酯(0.6mL),并通过过滤收集析出的晶体。将所得到的晶体用乙酸乙酯洗涤,然后在减压下干燥以得到白色粉末状的顺式-4-(苯并[b]噻吩-5-基)-1,2,2-三甲基十氢喹喔啉盐酸盐(258mg,收率:74%)。
1H-NMR(CDCl3)δppm:1.17-1.34(1H,m),1.37-1.74(2H,m),1.47(3H,s),1.87-2.04(1H,m),1.90(3H,s),2.20-2.30(1H,m),2.39-2.54(1H,m),2.64-2.88(2H,m),2.75(3H,d,J=4.9Hz),3.12(1H,d,J=13.2Hz),3.69-3.74(1H,m),3.85-3.93(1H,m),3.87(1H,d,J=13.2Hz),7.01(1H,dd,J=8.8,2.3Hz),7.21-7.32(2H,m),7.44(1H,d,J=5.4Hz),7.75(1H,d,J=8.8Hz),11.20(1H,brs).
实施例5
2-(反式-4-(萘-2-基)十氢喹喔啉-1-基)乙醇二盐酸盐的制备
相对构型
在室温搅拌下向反式-1-(2-(叔丁基二甲基甲硅烷氧基)乙基)-4-(萘-2-基)十氢喹喔啉(820mg,1.93mmol)的THF(10mL)溶液中加入四正丁基氟化铵(1M,在THF中)(2.1mL,2.1mmol),并将混合物搅拌整夜。向反应混合物中加入乙酸乙酯,将所得混合物用水洗涤两次,并用饱和盐水洗涤一次,然后用硫酸镁干燥,并在减压下浓缩。将所得到的残余物通过硅胶柱层析法(二氯甲烷:甲醇=10:1)纯化以得到无色的无定形固体(534mg)。将所得到的固体的319mg的等分试样溶解在乙醇中。在室温搅拌下向该溶液中加入4N盐酸/乙酸乙酯(1.0mL),并通过过滤收集析出的晶体。将所得到的晶体用乙酸乙酯洗涤,然后在减压下干燥以得到白色粉末状的2-(反式-4-(萘-2-基)十氢喹喔啉-1-基)乙醇二盐酸盐(365mg,收率:49%)。
1H-NMR(CDCl3)δppm:1.23-1.76(4H,m),1.86-2.08(3H,m),2.43-2.48(1H,m),3.18-3.25(1H,m),3.72-3.77(2H,m),3.93-3.98(1H,m),3.93-4.78(1H,br),4.08-4.20(2H,m),4.39-4.55(1H,m),4.57-4.78(2H,m),4.97-5.06(1H,m),7.61-7.68(3H,m),7.81-8.07(3H,m),8.17-8.69(1H,br),12.73(1H,brs),14.91(1H,brs).
实施例77
(4aS,8aR)-1-(7-氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉的制备
绝对构型
在氮气气氛中在回流下将(4aR,8aS)-2,2-二甲基十氢喹喔啉(168mg,0.998mmol)、4-溴-7-氟苯并呋喃(258mg,1.20mmol)、Pd(OAc)2(11.2mg,0.0499mmol)、t-Bu3P.HBF4(14.5mg,0.0500mmol)和NaOt-Bu(135mg,1.40mmol)的甲苯(4ml)悬浮液搅拌4小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。过滤不溶物,并用AcOEt(5ml×2)洗涤残余物。然后,在减压下浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到无色油状物(167mg)。该油状物从己烷(1mL)中结晶以得到白色粉末状的(4aS,8aR)-1-(7-氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉(107mg,收率:35%)。
1H-NMR(CDCl3)δppm:1.0-1.45(11H,m),1.6-1.8(3H,m),1.8-1.95(1H,m),2.70(1H,d,J=11.3Hz),3.04(1H,d,J=11.3Hz),3.50(1H,ddd,J=3.8,3.8,12.1Hz),3.55-3.65(1H,m),6.47(1H,dd,J=3.4,8.6Hz),6.84(1H,dd,J=2.5,2.5Hz),6.89(1H,dd,J=8.6,10.4Hz),7.60(1H,d,J=2.2Hz).
实施例106
(4aS,8aR)-1-(4-氯苯基)-3,3-二甲基十氢喹喔啉盐酸盐的制备
绝对构型
在氮气气氛中在回流下将(4aR,8aS)-2,2-二甲基十氢喹喔啉(252mg,1.50mmol)、1-溴-4-氯苯(345mg,1.80mmol)、Pd(OAc)2(16.8mg,0.0748mmol)、t-Bu3P.HBF4(21.8mg,0.0751mmol)和NaOt-Bu(202mg,2.10mmol)的甲苯(10ml)悬浮液搅拌5小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。然后,通过硅藻土过滤不溶物。在减压下浓缩滤液,并将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化。将所得到的油状物溶解于1N HCl-EtOH(3mL)中,并在减压下蒸馏除去溶剂。将析出的晶体从乙醇/丙酮重结晶以得到白色粉末状的(4aS,8aR)-1-(4-氯苯基)-3,3-二甲基十氢喹喔啉盐酸盐(262mg,收率:55%)。
1H-NMR(DMSO-d6)δppm:1.2-1.45(6H,m),1.51(3H,s),1.6-2.1(5H,m),2.93(1H,d,J=13.6Hz),3.40(1H,d,J=13.8Hz),3.65-3.85(1H,m),3.9-4.1(1H,m),6.8-7.05(2H,m),7.1-7.35(2H,m),8.14(1H,br),9.77(1H,br).
实施例112
(4aS,8aR)-1-(3-氯-4-氟苯基)-3,3-二甲基十氢喹喔啉盐酸盐的制备
绝对构型
在氮气气氛中在回流下将(4aR,8aS)-2,2-二甲基十氢喹喔啉(168mg,0.998mmol)、4-溴-2-氯-1-氟苯(251mg,1.20mmol)、Pd(OAc)2(11.2mg,0.0500mmol)、t-Bu3P.HBF4(14.5mg,0.0500mmol)和NaOt-Bu(135mg,1.40mmol)的甲苯(10ml)悬浮液搅拌5小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。然后过滤不溶物。在减压下浓缩滤液,并将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化。将所得到的油状物溶解于1NHCl-EtOH(3mL)中,并在减压下蒸馏除去乙醇。将析出的晶体从乙醇/丙酮重结晶以得到白色粉末状的(4aS,8aR)-1-(3-氯-4-氟苯基)-3,3-二甲基十氢喹喔啉盐酸盐(153mg,收率:46%)。
1H-NMR(DMSO-d6)δppm:1.15-1.45(6H,m),1.51(3H,s),1.6-1.9(4H,m),1.9-2.05(1H,m),2.94(1H,d,J=13.5Hz),3.3-3.45(1H,m),3.65-3.8(1H,m),3.95-4.1(1H,m),6.85-7.0(1H,m),7.12(1H,dd,J=3.0,6.2Hz),7.25(1H,dd,J=9.1,9.1Hz),8.13(1H,br),9.86(1H,br).
实施例150
5-((4aR,8aS)-3,3-二甲基十氢喹喔啉-1-基)-1-甲基-1H-吲哚-2-腈的制备
绝对构型
在氮气气氛中在回流下将(4aS,8aR)-2,2-二甲基十氢喹喔啉(168mg,0.998mmol)、5-溴-1-甲基-1H-吲哚-2-腈(259mg,1.10mmol)、Pd(OAc)2(11.2mg,0.0499mmol)、t-Bu3P.HBF4(14.5mg,0.0500mmol)和NaOt-Bu(135mg,1.40mmol)的甲苯(4ml)悬浮液搅拌4小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。通过硅藻土过滤不溶物,并用CH2Cl2:MeOH(3:1)(5mL×2)洗涤残余物。然后,在减压下浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到无色油状物。该油状物从己烷(1mL)中结晶以得到浅黄色粉末状的(4aS,8aR)-1-(7-氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉(148mg,收率:46%)。
1H-NMR(CDCl3)δppm:0.7-2.3(15H,m),2.7-3.2(2H,m),3.5-3.8(2H,m),3.85(3H,s),6.95-7.05(2H,m),7.15-7.3(2H,m).
实施例237
(4aS,8aS)-1-(3-氯-4-氰基苯基)-3,3-二甲基十氢喹喔啉盐酸盐的制备
绝对构型
在氮气气氛中在回流下将(4aS,8aS)-2,2-二甲基十氢喹喔啉(400mg,2.38mmol)、4-溴-2-氯苯甲腈(669mg,3.09mmol)、Pd(OAc)2(53mg,0.24mmol)、t-Bu3P.HBF4(70mg,0.24mmol)和t-BuONa(320mg,3.33mmol)的甲苯(10ml)悬浮液搅拌5小时。将反应溶液冷却。然后,通过硅藻土过滤不溶物,并浓缩滤液。将所得到的残余物通过硅胶柱层析法(CH2Cl2/MeOH)纯化以得到橙色无定形固体。将该无定形固体溶解在乙酸乙酯(5mL)中。通过过滤和减压下干燥收集由添加4N HCl/AcOEt(0.6mL)而沉积的晶体,以得到浅橙色粉末状的(4aS,8aS)-1-(3-氯-4-氰基苯基)-3,3-二甲基十氢喹喔啉(304mgm,48%)。
1H-NMR(CDCl3)δppm:1.05-1.20(1H,m),1.23-1.44(2H,m),1.54-2.10(4H,m),1.63(3H,s),1.68(3H,s),2.35-2.40(1H,m),2.89(1H,d,J=12.7Hz),3.19(2H,br),3.34(1H,d,J=12.7Hz),7.06(1H,dd,J=8.4,2.0Hz),7.20(1H,d,J=2.0Hz),7.61(1H,d,J=8.4Hz),9.62(1H,brs),9.90(1H,br)
实施例579
(4a'R,8a'S)-4'-(7-甲氧基苯并呋喃-4-基)八氢-1'H-螺[环丁烷-1,2'-喹喔啉]的制备
绝对构型
在氮气气氛中在回流下将(4a'R,8a'S)-八氢-l'H-螺[环丁烷-1,2'-喹喔啉](180mg,0.998mmol)、4-溴-7-甲氧基苯并呋喃(250mg,1.10mmol)、Pd(OAc)2(11.2mg,0.0499mmol)、t-Bu3P.HBF4(14.5mg,0.0500mmol)和NaOt-Bu(135mg,1.40mmol)的甲苯(4ml)悬浮液搅拌4小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。过滤不溶物,并用AcOEt(5mL×2)洗涤残余物。然后,在减压下浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到无色的无定形固体。该固体从己烷(1mL)中结晶以得到白色粉末状的(4a'R,8a'S)-4'-(7-甲氧基苯并呋喃-4-基)八氢-1'H-螺[环丁烷-1,2'-喹喔啉](107mg,收率:35%)。
1H-NMR(CDCl3)δppm:0.95-1.1(2H,m),1.3-1.4(1H,m),1,4-2.1(11H,m),2.25-2.4(1H,m),3.01(1H,d,J=11.0Hz),3.17(1H,d,J=11.1Hz),3.40(1H,br),3.45-3.5(1H,m),3.97(3H,s),6.58(1H,d,J=8.4Hz),6.70(1H,d,J=8.4Hz),6.80(1H,d,J=2.1Hz),7.58(1H,d,J=2.1Hz).
实施例580
(4aS,8aR)-1-(6,7-二氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉盐酸盐的制备
绝对构型
在氮气气氛中在回流下将(4aR,8aS)-2,2-二甲基十氢喹喔啉(252mg,1.50mmol)、4-溴-6,7-二氟苯并呋喃(384mg,1.65mmol)、Pd(OAc)2(16.8mg,0.0748mmol)、t-Bu3P.HBF4(21.8mg,0.0751mmol)和NaOt-Bu(202mg,2.10mmol)的甲苯(6ml)悬浮液搅拌3小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。然后,通过硅藻土过滤不溶物。在减压下浓缩滤液,并将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到浅黄色油状物(193mg)。将此油状物溶解在乙醇(2mL)中。向该溶液中加入1N HCl-EtOH(1.2mL),并搅拌该混合物。通过过滤收集沉积的晶体,并用乙酸乙酯洗涤,然后在减压下干燥以得到白色粉末状的(4aS,8aR)-1-(6,7-二氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉盐酸盐(167mg,收率:31%)。
1H-NMR(DMSO-d6)δppm:1.01-1.17(2H,m),1.34-1.44(1H,m),1.48(3H,s),1.52(3H,s),1.59-2.07(5H,m),3.00(1H,d,J=13.0Hz),3.28(1H,d,J=13.2Hz),3.75-3.9(1H,m),4.0-4.15(1H,m),6.83(1H,dd,J=5.9,13.5Hz),7.36(1H,dd,J=2.6,2.6Hz),8.0-8.2(2H,m),9.7-9.9(1H,m).
实施例581
(4aS,8aS)-1-(2-氰基-1-(三异丙基甲硅烷基)-1H-吲哚-5-基)3,3-二甲基十氢喹喔啉的制备
绝对构型
在100℃氮气气氛中将(4aS,8aS)-2,2-二甲基十氢喹喔啉(200mg,1.19mmol)、5-溴-1-(三异丙基甲硅烷基)-1H-吲哚-2-腈(493mg,1.31mmol)、Pd(OAc)2(13.3mg,0.0594mmol)、t-Bu3P.HBF4(17.2mg,0.0594mmol)和t-BuONa(137mg,1.43mmol)的甲苯(5ml)悬浮液搅拌4小时。通过硅藻土过滤不溶物,并浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(AcOEt/己烷)纯化以得到白色无定形固体状的(4aS,8aS)-1-(2-氰基-1-(三异丙基甲硅烷基)-1H-吲哚-5-基)3,3-二甲基十氢喹喔啉(430mg,78%)。
1H-NMR(CDCl3)δppm:0.75-1.38(26H,m),1.41(3H,s),1.54-1.77(4H,m),2.01(3H,quintet,J=7.5Hz),2.25-2.32(1H,m),2.65(1H,d,J=11.2Hz),2.75-2.85(2H,m),7.11(1H,dd,J=2.0,9.1Hz),7.32(1H,d,J=2.0Hz),7.33(1H,d,J=0.5Hz),7.50(1H,d,J=9.1Hz).
实施例582
(4aS,8aS)-1-(2-氰基-1H-吲哚-5-基)3,3-二甲基十氢喹喔啉的制备
绝对构型
在室温下向(4aS,8aS)-1-(2-氰基-1-(三异丙基甲硅烷基)-1H-吲哚-5-基)3,3-二甲基十氢喹喔啉(170mg,0.366mmol)的无水四氢呋喃(5mL)溶液中加入四丁基氟化铵(1M的THF溶液,0.73mL,0.73mmol),并将该反应溶液在室温下搅拌1小时。在减压下浓缩反应溶液,并将所得到的残余物通过碱性硅胶柱层析法(AcOEt/己烷=1/10→1/1)纯化。在减压下移除溶剂。将所得到的残余物从乙酸乙酯/正己烷重结晶以得到白色粉末状的(4aS,8aS)-1-(2-氰基-1H-吲哚-5-基)3,3-二甲基十氢喹喔啉(30mg,收率:27%)。
1H-NMR(DMSO-d6)δppm:0.82-1.00(4H,m),1.08-1.34(6H,m),1.42-1.67(5H,m),2.19-2.27(1H,m),2.55(1H,d,J=10.9Hz),2.59-2.69(2H,m),7.11(1H,dd,J=1.8,8.8Hz),7.26(1H,d,J=0.8Hz),7.32(1H,d,J=1.8Hz),7.36(1H,d,J=8.8Hz)12.25(1H,brs).
实施例583
(4aS,8aR)-1-(7-氯-2,3-二氢-1H-茚-4-基)-3,3-二甲基十氢喹喔啉的制备
绝对构型
向(4aR,8aS)-2,2-二甲基十氢喹喔啉(168mg,0.998mmol)、4-溴-7-氯-2,3-二氢-1H-茚(255mg,1.10mmol)和NaOt-Bu(135mg,1.40mmol)的甲苯(4ml)悬浮液中加入双(三叔丁基膦)钯(25.6mg,0.0501mmol)的甲苯(1mL)溶液,并在氮气气氛中在回流下将该混合物搅拌4小时。将反应溶液冷却至室温。然后,向其中加入水(0.5mL)和乙酸乙酯(AcOEt)(10mL),并搅拌该混合物。再向其中加入MgSO4,并搅拌该混合物。通过硅藻土过滤不溶物,并用AcOEt(5mL×2)洗涤残余物。然后,在减压下浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(Hex-AcOEt)纯化以得到白色固体(167mg)。将此固体从乙醇/水重结晶以得到白色粉末状的(4aS,8aR)-1-(7-氯-2,3-二氢-1H-茚-4-基)-3,3-二甲基十氢喹喔啉(136mg,收率:43%)。
1H-NMR(CDCl3)δppm:0.97-1.12(3H,m),1.16(3H,s),1.27(3H,s),1.31-1.44(2H,m),1.45-1.76(3H,m),1.78-1.92(1H,m),1.94-2.06(1H,m),2.12-2.23(1H,m),2.51(1H,d,J=11.2Hz),2.85-3.05(5H,m),3.1-3.2(1H,m),3.45-3.55(1H,m),6.58(1H,d,J=8.4Hz),7.03(1H,d,J=8.4Hz).
实施例584
(4aS,8aS)-1-(6-氰基萘-2-基)-3,3-二甲基十氢喹喔啉二盐酸盐的制备
绝对构型
在100℃下将(4aR,8aS)-2,2-二甲基十氢喹喔啉(200mg,1.19mmol)、6-溴-2-萘甲腈(303mg,1.31mmol)、Pd(OAc)2(13.3mg,0.0594mmol)、t-Bu3P.HBF4(17.2mg,0.0594mmol)和t-BuONa(137mg,1.43mmol)的甲苯(5mL)悬浮液搅拌4小时。通过硅藻土过滤不溶物,并浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(乙酸乙酯/己烷)纯化。在减压下移除溶剂。将所得到的残余物溶解在乙酸乙酯中。向此溶液中加入1N盐酸-乙醇,通过过滤收集析出的晶体。将所得到的晶体在减压下干燥以得到白色粉末状的(4aS,8aS)-1-(6-氰基萘-2-基)-3,3-二甲基十氢喹喔啉二盐酸盐(303mg,收率:65%)。
1H-NMR(DMSO-d6)δppm:1.10-1.50(6H,m),1.56-1.90(7H,m),2.00-2.14(1H,m),3.08-3.45(4H,m),4.68-5.32(1H,br),7.45(1H,dd,J=2.0,8.9Hz),7.64(1H,d,J=1.8Hz),7.73(1H,dd,J=1.6,8.6Hz),8.00(1H,d,J=8.6Hz),8.04(1H,d,J=8.6Hz),8.49(1H,s),9.10-9.28(1H,br),10.04-10.28(1H,br).
实施例585
(4aS,8aS)-3,3-二甲基-1-(1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-4-基)十氢喹喔啉的制备
绝对构型
在100℃氮气气氛中将(4aS,8aS)-2,2-二甲基十氢喹喔啉(200mg,1.19mmol)、4-溴-1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶(462mg,1.31mmol)、Pd(OAc)2(13.3mg,0.0594mmol)、t-Bu3P.HBF4(17.2mg,0.0594mmol)和t-BuONa(137mg,1.43mmol)的甲苯(5ml)悬浮液搅拌4小时。通过硅藻土过滤不溶物,并浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(乙酸乙酯/己烷)纯化以得到白色无定形固体状的(4aS,8aS)-3,3-二甲基-1-(1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-4-基)十氢喹喔啉(439mg,84%)。
1H-NMR(CDCl3)δppm:0.95-1.20(22H,m),1.36-1.45(3H,m),1.52(3H,s),1.65-1.92(7H,m),2.11-2.20(1H,m),2.57-2.67(2H,m),2.83-2.95(1H,m),3.26-(1H,d,J=11.7Hz),6.55(1H,d,J=3.5Hz),6.63(1H,d,J=5.3Hz),7.18(1H,d,J=3.5Hz),8.12(1H,d,J=5.3Hz).
实施例586
(4aS,8aS)-3,3-二甲基-1-(1H-吡咯并[2,3-b〕吡啶-4-基)十氢喹喔啉富马酸盐的制备
绝对构型
向(4aS,8aS)-3,3-二甲基-1-(1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-4-基)十氢喹喔啉(430mg,0.976nmol)的无水四氢呋喃(5mL)溶液中加入四丁基氟化铵(1M的THF溶液,1.95mL,1.95mmol),并将该混合物在室温下搅拌1小时。在减压下浓缩反应溶液,并将所得到的残余物通过碱性硅胶柱层析法(AcOEt/己烷=1/10→1/1)纯化以得到油状产物(370mg,1.30mmol)。将此油状物溶解在乙醇(5mL)中。向此溶液中加入富马酸(151mg)的乙醇(5mL)溶液,并在减压下除去乙醇。将所得到的固体从乙醇/乙酸乙酯重结晶以得到白色粉末状的5-((4aS,8aS)-3,3-二甲基十氢喹喔啉-1-基)-1H-吲哚-2-腈(246mg,收率:63%)。
1H-NMR(DMSO-d6)δppm:0.94-1.09(1H,m),1.20(3H,s),1.26-1.55(7H,m),1.68-1.78(1H,m),1.85-2.04(2H,m),2.81-2.93(1H,m),2.95-3.23(3H,m),6.36-6.42(1H,m),6.49(2H,s),6.71(1H,d,J=5.2Hz),7.32-7.38(1H,m),8.09(1H,d,J=5.2Hz),8.50-11.20(1H,br),11.59(1H,s).
实施例587
(4aS,8aS)-1-(4-(二氟甲氧基)-3-氟苯基)-3,3-二甲基十氢喹喔啉二盐酸盐的制备
绝对构型
在100℃下将(4aR,8aS)-2,2-二甲基十氢喹喔啉(200mg,1.19mmol)、4-溴-1-二氟甲氧基-2-氟苯(315mg,1.31mmol)、Pd(OAc)2(13.3mg,0.0594mmol)、t-Bu3P.HBF4(17.2mg,0.0594mmol)和t-BuONa(137mg,1.43mmol)的甲苯(5mL)悬浮液搅拌4小时。通过硅藻土过滤不溶物,并浓缩滤液。将所得到的残余物通过碱性硅胶柱层析法(乙酸乙酯/己烷)纯化。在减压下移除溶剂。将所得到的残余物溶解在乙酸乙酯中。向此溶液中加入1N盐酸-乙醇,通过过滤收集析出的晶体。将所得到的晶体在减压下干燥以得到白色粉末状的(4aS,8aS)-1-(4-(二氟甲氧基)-3-氟苯基)-3,3-二甲基十氢喹喔啉二盐酸盐(193mg,收率:40%)。
1H-NMR(DMSO-d6)δppm:1.01-1.39(6H,m),1.49-1.67(6H,m),1.67-1.77(1H,m),1.96-2.05(1H,m),2.81-2.95(2H,m),3.02(1H,d,J=12.5Hz),3.10-3.23(1H,m),4.30-4.80(1H,br),6.96-7.01(1H,m),7.02(0.25H,s),7.17(1H,dd,J=2.5,12.1Hz),7.20(0.5H,s),7.33(1H,t,J=8.9Hz),7.39(0.25H,s),9.04-9.21(1H,m),9.70-9.85(1H,m).
使用对应的适当的起始原料以与实施例中相同的方式制备以下表格中所示的实施例6至76、78至105、107至111、113至149、151至236、238至578、588至1656的化合物。在这些表中,例如,所制备的化合物具有物理性质,如结晶形式、m.p.(熔点)、盐、1H-NMR和MS(质谱)。
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药理研究1
使用大鼠脑突触体对试验化合物的血清素(5-HT)摄取抑制活性的测量
将雄性Wistar大鼠断头,去除并解剖其大脑以去除额皮质。将分离的额皮质放置在20倍重量的0.32摩尔浓度(M)的蔗糖溶液中,并以波特匀浆器(potter homogenizer)匀浆。将匀浆在4℃下以1000g离心10分钟,并将上清液在4℃下进一步以20000g离心20分钟。将颗粒在孵育缓冲液(20mM HEPES缓冲液(pH7.4),包含10mM葡萄糖、145mM氯化钠、4.5mM氯化钾、1.2mM氯化镁和1.5mM氯化钙)中悬浮。该悬浮液用作粗突触体部分。
使用96孔圆底板的各孔,以及共200μl体积的包含优降宁(最终浓度:10μM)和抗坏血酸(最终浓度:0.2mg/ml)的溶液进行摄取反应。
具体而言,溶剂、未标记的5-HT和连续稀释的试验化合物分别加入到孔中,且突触体部分以最终体积的1/10的量加入到各孔中,并在37℃下预孵育10分钟。然后,在37℃下向其中加入用氚标记的5-HT溶液(最终浓度:8nM)以引发摄取反应。10分钟后,通过96孔的玻璃纤维过滤板以吸滤终止摄取反应。此外,过滤器以冷生理盐水洗涤,然后充分干燥。向其中加入MicroScint-O(PerkinElmer有限公司),并在过滤器上测量残余放射性。
通过仅添加溶剂而得到的摄取值被定义为100%,且通过添加未标记的5-HT(最终浓度:10μM)而得到的摄取值(非特异性摄取值)被定义为0%。从试验化合物的浓度和该处的抑制活性计算50%抑制浓度。其结果呈现于表60。
[表60]
药理研究2
使用大鼠脑突触体对试验化合物的去甲肾上腺素(NE)摄取抑制活性的测量
将雄性Wistar大鼠断头,去除并解剖其大脑以去除海马。将分离的海马放置在20倍重量的0.32摩尔浓度(M)的蔗糖溶液中,并以波特匀浆器匀浆。将匀浆在4℃下以1000g离心10分钟,并将上清液在4℃下进一步以20000g离心20分钟。将颗粒在孵育缓冲液(20mM HEPES缓冲液(pH7.4),包含10mM葡萄糖、145mM氯化钠、4.5mM氯化钾、1.2mM氯化镁和1.5mM氯化钙)中悬浮。该悬浮液用作粗突触体部分。
使用96孔圆底板的各孔,以及共200μl体积的包含优降宁(最终浓度:10μM)和抗坏血酸(最终浓度:0.2mg/ml)的溶液进行摄取反应。
具体而言,溶剂、未标记的NE和连续稀释的试验化合物分别加入到孔中,且突触体部分以最终体积的1/10的量加入到各孔中,并在37℃下预孵育10分钟。然后,在37℃下向其中加入用氚标记的NE溶液(最终浓度:12nM)以引发摄取反应。十分钟后,通过96孔的玻璃纤维过滤板以吸滤终止摄取反应。此外,过滤器以冷生理盐水洗涤,然后充分干燥。向其中加入MicroScint-O(PerkinElmer有限公司),并在过滤器上测量残余放射性。
通过仅添加溶剂而得到的摄取值被定义为100%,且通过添加未标记的NE(最终浓度:10μM)而得到的摄取值(非特异性摄取值)被定义为0%。从试验化合物的浓度和该处的抑制活性计算50%抑制浓度。其结果呈现于表61。
[表61]
药理研究3
使用大鼠脑突触体对试验化合物的多巴胺(DA)摄取抑制活性的测量
将雄性Wistar大鼠断头,去除并解剖其大脑以去除纹状体。将分离的纹状体放置在20倍重量的0.32摩尔浓度(M)的蔗糖溶液中,并以波特匀浆器匀浆。将匀浆在4℃下以1000g离心10分钟,并将上清液在4℃下进一步以20000g离心20分钟。将颗粒在孵育缓冲液(20mM HEPES缓冲液(pH7.4),包含10mM葡萄糖、145mM氯化钠、4.5mM氯化钾、1.2mM氯化镁和1.5mM氯化钙)中悬浮。该悬浮液用作粗突触体部分。
使用96孔圆底板的各孔,以及共200μl体积的包含优降宁(最终浓度:10μM)和抗坏血酸(最终浓度:0.2mg/ml)的溶液进行摄取反应。
具体而言,溶剂、未标记的DA和连续稀释的试验化合物分别加入到孔中,且突触体部分以最终体积的1/10的量加入到各孔中,并在37℃下预孵育10分钟。然后,在37℃下向其中加入用氚标记的DA溶液(最终浓度:2nM)以引发摄取反应。十分钟后,通过96孔的玻璃纤维过滤板以吸滤终止摄取反应。此外,过滤器以冷生理盐水洗涤,然后充分干燥。向其中加入MicroScint-O(PerkinElmer有限公司),并在过滤器上测量残余放射性。
通过仅添加溶剂而得到的摄取值被定义为100%,且通过添加未标记的DA(最终浓度:10μM)而得到的摄取值(非特异性摄取值)被定义为0%。从试验化合物的浓度和该处的抑制活性计算50%抑制浓度。其结果呈现于表62。
[表62]
药理研究4
强迫游泳试验
根据Porsolt等人的方法(Porsolt,R.D.等,小鼠中的绝望行为学:抗抑郁药的初步筛选测试(Behavioural despair in mice:A primary screening test for antidepressants),Arch.int.Pharmacodyn.Ther.,229,327-336页,1977)进行此试验。
试验化合物悬浮在5%的阿拉伯胶/盐水(w/v)中,并将该悬浮液口服给予雄性ICR小鼠(CLEA日本公司(JCL),5至6周龄)。一小时后,将小鼠放在具有9.5厘米水深和21至25℃水温的水箱中,此后立即使其尝试游泳6分钟。然后,在最后4分钟测量小鼠不动的时间(不动时间)。在不动时间的测量和分析中使用由Melquest有限公司生产的SCANETMV-20AQ系统。
在此实验中,用试验化合物处理的动物表现出减少的不动时间。这表明该试验化合物作为抗抑郁药是有用的。
Claims (16)
1.一种由通式(1)表示的杂环化合物或其盐:
其中,m、l和n分别代表1或2的整数;X表示-O-或-CH2-;
R1代表氢、低级烷基、羟基-低级烷基、保护基团或三-低级烷基甲硅烷氧基-低级烷基;
R2和R3是相同的或不同的,且各自独立地表示氢或低级烷基;或者R2和R3结合形成环C3-C8烷基;以及
R4表示芳香族基团或杂环基团,其中,
所述芳香族基团或杂环基团可以具有一个或多个任意的取代基。
2.根据权利要求1所述的由通式(1)表示的杂环化合物或其盐,其中,
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(3)苯并噻吩基,
(4)萘基,
(5)苯并呋喃基,
(6)喹啉基,
(7)异喹啉基,
(8)吡啶基,
(9)噻吩基,
(10)二氢苯并噁嗪基,
(11)二氢苯并二噁英基,
(12)二氢喹啉基,
(13)苯并二氢吡喃基,
(14)喹喔啉基,
(15)二氢茚基,
(16)二氢苯并呋喃基,
(17)苯并间二氧杂环戊烯基,
(18)吲唑基,
(19)苯并噻唑基,
(20)二氢吲哚基,
(21)噻吩并吡啶基,
(22)四氢苯并氮杂卓基,
(23)四氢苯并二氮杂卓基,
(24)二氢苯并二氧杂环庚烯基,
(25)芴基,
(26)哒嗪基,
(27)四氢喹啉基,
(28)咔唑基,
(29)菲基,
(30)二氢苊烯基,
(31)吡咯并吡啶基,
(32)蒽基,
(33)苯并二噁英基,
(34)吡咯烷基,
(35)吡唑基,
(36)噁二唑基,
(37)嘧啶基,
(38)四氢萘基,
(39)二氢喹唑啉基,
(40)苯并噁唑基,
(41)噻唑基,
(42)喹唑啉基,
(43)酞嗪基,
(44)吡嗪基,以及
(45)苯并吡喃基,其中
这些芳香族基团或杂环基团可以具有一个或多个选自以下的取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-3)低级烷酰基,
(1-4)卤素取代的低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,
(1-7)低级烷氧基,
(1-8)低级烷基硫基,
(1-9)咪唑基,
(1-10)三-低级烷基甲硅烷基,
(1-11)可具有低级烷基的噁二唑基,
(1-12)可具有氧代基团的吡咯烷基,
(1-13)可具有低级烷氧基的苯基,
(1-14)低级烷基氨基-低级烷基,
(1-15)氧代基团,
(1-16)可具有低级烷基的吡唑基,
(1-17)噻吩基,
(1-18)呋喃基,
(1-19)可具有低级烷基的噻唑基,
(1-20)低级烷基氨基,
(1-21)可具有低级烷基的嘧啶基,
(1-22)苯基-低级烯基,
(1-23)可具有卤素原子的苯氧基,
(1-24)苯氧基-低级烷基,
(1-25)吡咯烷基-低级烷氧基,
(1-26)低级烷基氨磺酰基,
(1-27)可具有低级烷基的哒嗪基氧基,
(1-28)苯基-低级烷基,
(1-29)低级烷基氨基-低级烷氧基,
(1-30)咪唑基-低级烷基,
(1-31)苯基-低级烷氧基,
(1-32)羟基,
(1-33)低级烷氧基羰基,
(1-34)羟基-低级烷基,
(1-35)噁唑基,
(1-36)哌啶基,
(1-37)吡咯基,
(1-38)吗啉基-低级烷基,
(1-39)可具有低级烷基的哌嗪基-低级烷基,
(1-40)哌啶基-低级烷基,
(1-41)吡咯烷基-低级烷基,
(1-42)吗啉基,以及
(1-43)可具有低级烷基的哌嗪基。
3.根据权利要求2所述的由通式(1)表示的杂环化合物或其盐,其中,
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(3)苯并噻吩基,
(4)萘基,
(5)苯并呋喃基,
(6)喹啉基,
(7)异喹啉基,
(8)吡啶基,
(9)噻吩基,
(10)二氢苯并噁嗪基,
(11)二氢苯并二噁英基,
(12)二氢喹啉基,
(13)苯并二氢吡喃基,
(14)喹喔啉基,
(15)二氢茚基,
(16)二氢苯并呋喃基,
(17)苯并间二氧杂环戊烯基,
(18)吲唑基,
(19)苯并噻唑基,
(20)二氢吲哚基,
(21)噻吩并吡啶基,
(22)四氢苯并氮杂卓基,
(23)四氢苯并二氮杂卓基,
(24)二氢苯并二氧杂环庚烯基,
(25)芴基,
(26)哒嗪基,
(27)四氢喹啉基,
(28)咔唑基,
(29)菲基,
(30)二氢苊烯基,
(31)吡咯并吡啶基,
(32)蒽基,
(33)苯并二噁英基,
(34)吡咯烷基,
(35)吡唑基,
(36)噁二唑基,
(37)嘧啶基,
(38)四氢萘基,
(39)二氢喹唑啉基,
(40)苯并噁唑基,
(41)噻唑基,
(42)喹唑啉基,
(43)酞嗪基,
(44)吡嗪基,以及
(45)苯并吡喃基,其中
这些芳香族基团或杂环基团可以具有选自以下的1至4个取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-3)低级烷酰基,
(1-4)卤素取代的低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,
(1-7)低级烷氧基,
(1-8)低级烷基硫基,
(1-9)咪唑基,
(1-10)三-低级烷基甲硅烷基,
(1-11)可具有一低级烷基的噁二唑基,
(1-12)可具有一氧代基团的吡咯烷基,
(1-13)可具有一低级烷氧基的苯基,
(1-14)低级烷基氨基-低级烷基,
(1-15)氧代基团,
(1-16)可具有一低级烷基的吡唑基,
(1-17)噻吩基,
(1-18)呋喃基,
(1-19)可具有一低级烷基的噻唑基,
(1-20)低级烷基氨基,
(1-21)可具有一低级烷基的嘧啶基,
(1-22)苯基-低级烯基,
(1-23)可具有一卤素原子的苯氧基,
(1-24)苯氧基-低级烷基,
(1-25)吡咯烷基-低级烷氧基,
(1-26)低级烷基氨磺酰基,
(1-27)可具有一低级烷基的哒嗪基氧基,
(1-28)苯基-低级烷基,
(1-29)低级烷基氨基-低级烷氧基,
(1-30)咪唑基-低级烷基,
(1-31)苯基-低级烷氧基,
(1-32)羟基,
(1-33)低级烷氧基羰基,
(1-34)羟基-低级烷基,
(1-35)噁唑基,
(1-36)哌啶基,
(1-37)吡咯基,
(1-38)吗啉基-低级烷基,
(1-39)可具有一低级烷基的哌嗪基-低级烷基,
(1-40)哌啶基-低级烷基,
(1-41)吡咯烷基-低级烷基,
(1-42)吗啉基,以及
(1-43)可具有一低级烷基的哌嗪基。
4.根据权利要求3所述的由通式(1)表示的杂环化合物或其盐,其中,
m表示2;l和n分别表示整数1;X表示-CH2-;
R1表示氢、低级烷基、羟基-低级烷基、苯甲基或三-低级烷基甲硅烷氧基-低级烷基;以及
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(4)萘基,
(5)苯并呋喃基,以及
(31)吡咯并吡啶基,其中
这些芳香族基团或杂环基团可以具有选自以下的1至4个取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-3)低级烷酰基,
(1-4)卤素取代的低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,
(1-7)低级烷氧基,
(1-8)低级烷基硫基,
(1-9)咪唑基,
(1-10)三-低级烷基甲硅烷基,
(1-11)可具有一低级烷基的噁二唑基,
(1-12)可具有一氧代基团的吡咯烷基,
(1-13)可具有一低级烷氧基的苯基,
(1-14)低级烷基氨基-低级烷基,
(1-15)氧代基团,
(1-16)可具有一低级烷基的吡唑基,
(1-17)噻吩基,
(1-18)呋喃基,
(1-19)可具有一低级烷基的噻唑基,
(1-20)低级烷基氨基,
(1-21)可具有一低级烷基的嘧啶基,
(1-22)苯基-低级烯基,
(1-23)可具有一卤素原子的苯氧基,
(1-24)苯氧基-低级烷基,
(1-25)吡咯烷基-低级烷氧基,
(1-26)低级烷基氨磺酰基,
(1-27)可具有一低级烷基的哒嗪基氧基,
(1-28)苯基-低级烷基,
(1-29)低级烷基氨基-低级烷氧基,
(1-30)咪唑基-低级烷基,
(1-31)苯基-低级烷氧基,
(1-32)羟基,
(1-34)羟基-低级烷基,
(1-35)噁唑基,
(1-36)哌啶基,
(1-37)吡咯基,
(1-38)吗啉基-低级烷基,
(1-39)可具有低级烷基的哌嗪基-低级烷基,
(1-40)哌啶基-低级烷基,
(1-41)吡咯烷基-低级烷基,
(1-42)吗啉基,以及
(1-43)可具有一低级烷基的哌嗪基。
5.根据权利要求4所述的由通式(1)表示的杂环化合物或其盐,其中,
R1表示氢;
R2和R3是相同的或不同的,且各自独立地表示低级烷基;或者R2和R3结合形成环C3-C8烷基;以及
R4表示以下的任意基团:
(1)苯基,
(2)吲哚基,
(4)萘基,
(5)苯并呋喃基,以及
(31)吡咯并吡啶基,其中
这些芳香族基团或杂环基团可以具有选自以下的1至2个取代基:
(1-1)卤素原子,
(1-2)低级烷基,
(1-5)卤素取代的低级烷氧基,
(1-6)氰基,以及
(1-7)低级烷氧基。
6.根据权利要求5所述的由通式(1)表示的杂环化合物或其盐,其选自以下化合物:
(4aS,8aR)-1-(4-氯苯基)-3,3-二甲基十氢喹喔啉,
2-氯-4-((4aS,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)苯甲腈,
(4aS,8aR)-1-(3-氯-4-氟苯基)-3,3-二甲基十氢喹喔啉,
(4aS,8aR)-1-(7-氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉,
5-((4aR,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)-1-甲基-1H-吲哚-2-腈,
(4a’R,8a’S)-4’-(7-甲氧基苯并呋喃-4-基)八氢-1’H-螺[环丁烷-1,2’-喹喔啉],
(4aS,8aR)-1-(6,7-二氟苯并呋喃-4-基)-3,3-二甲基十氢喹喔啉,
5-((4aS,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)-1H-吲哚-2-腈
(4aS,8aR)-1-(7-氯-2,3-二氢-1H-茚-4-基)-3,3-二甲基十氢喹喔啉,
6-((4aS,8aS)-3,3-二甲基八氢喹喔啉-1(2H)-基)-2-萘甲腈,
(4aS,8aS)-3,3-二甲基-1-(1H-吡咯并[2,3-b]吡啶-4-基)十氢喹喔啉,以及
(4aS,8aS)-1-(4-(二氟甲氧基)-3-氟苯基)3,3-二甲基十氢喹喔啉。
7.一种药物组合物,其包含根据权利要求1所述的由通式(1)表示的杂环化合物或其盐作为活性成分,以及药学上可接受的载体。
8.一种用于因血清素、去甲肾上腺素或多巴胺的神经传导的降低所导致的紊乱的预防剂和/或治疗剂,其包含根据权利要求1所述的由通式(1)表示的杂环化合物或其盐作为活性成分。
9.根据权利要求8所述的预防剂和/或治疗剂,其中,所述紊乱选自以下:抑郁症,由适应性障碍导致的抑郁状态,由适应性障碍导致的焦虑,由各种疾病导致的焦虑,广泛性焦虑症,恐怖症,强制性障碍,惊恐性障碍,创伤后应激障碍,急性应激障碍,疑病症,分离性遗忘症,回避型人格障碍,躯体变形障碍,进食障碍,肥胖症,化学品依赖,疼痛,纤维肌痛,阿耳茨海默氏症,记忆缺失,帕金森氏症,下肢不宁综合征,内分泌紊乱,血管痉挛,小脑性共济失调,胃肠道病症,精神分裂症负综合征,月经前期综合征,压迫性尿失禁,图雷特氏精神障碍,注意缺陷多动障碍(ADHD),孤独症,阿斯佩各综合征,冲动控制障碍,拔毛狂,偷窃狂,赌博症,丛集性头痛,偏头痛,慢性发作性偏头痛,慢性疲乏综合征,性早熟射精,男性阳痿,发作性睡病,原发性嗜睡症,猝倒,睡眠呼吸暂停综合征和头痛。
10.根据权利要求9所述的预防剂和/或治疗剂,其中,所述抑郁症选自以下:严重的抑郁性障碍;I型双相障碍;II型双相障碍;混合状态;心境恶劣障碍;快速循环型;非典型抑郁症;季节性情感障碍;产后精神抑郁;轻抑郁症;复发性短时抑郁障碍;顽固性抑郁症;慢性抑郁症;双重抑郁症;酒精引起的心境障碍;混合性焦虑抑郁症;由各种躯体疾病导致的抑郁症,如库欣综合征、甲状腺功能减退症、甲状旁腺功能亢进症、阿狄森氏病、闭经-溢乳综合征、帕金森氏症、阿耳茨海默氏病、脑血管性痴呆、脑梗塞、脑出血、蛛网膜下腔出血、糖尿病、病毒感染、多发性硬化症、慢性疲乏综合征、冠状动脉疾病、疼痛、癌症等;早老性抑郁症;老年抑郁症;儿童和青少年抑郁症;由药物如干扰素等诱导的抑郁症。
11.根据权利要求9所述的预防剂和/或治疗剂,其中,所述由各种疾病导致的焦虑选自以下:由颅脑损伤、脑感染、内耳病损、心力衰竭、心律失常、肾上腺机能亢进、甲状腺功能亢进症、哮喘和慢性阻塞性肺疾病导致的焦虑。
12.根据权利要求9所述的预防剂和/或治疗剂,其中,所述疼痛选自以下:慢性痛、精神性疼痛、神经性疼痛、幻肢痛、疱疹后神经痛、外伤性颈痛综合征、脊髓损伤疼痛、三叉神经痛、糖尿病神经病变。
13.根据权利要求1至6中任意一项所述的由通式(1)表示的杂环化合物或其盐作为药物的用途。
14.根据权利要求1至6中任意一项所述的由通式(1)表示的杂环化合物或其盐作为血清素再摄取抑制剂和/或去甲肾上腺素再摄取抑制剂和/或多巴胺再摄取抑制剂的用途。
15.一种用于治疗和/或预防因血清素、去甲肾上腺素或多巴胺的神经传导的降低所导致的紊乱的方法,该方法包括向人或动物施用根据权利要求1至6中任意一项所述的由通式(1)表示的杂环化合物或其盐的步骤。
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JP6326043B2 (ja) | 2012-05-09 | 2018-05-16 | バイエル・クロップサイエンス・アクチェンゲゼルシャフト | 5−ハロゲノピラゾールインダニルカルボキサミド類 |
EP2958920A1 (en) | 2013-02-20 | 2015-12-30 | Bayer Pharma Aktiengesellschaft | Substituted-imidazo[1,2-b]pyridazines as mknk1 inhibitors |
CA3079478A1 (en) * | 2017-10-19 | 2019-04-25 | Js Innopharm (Shanghai) Ltd. | Heterocyclic compounds, compositions comprising heterocyclic compound, and methods of use thereof |
CN117616013A (zh) * | 2021-07-13 | 2024-02-27 | 大塚制药株式会社 | 氢化喹喔啉 |
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