CN1280560A - 金刚烷衍生物 - Google Patents
金刚烷衍生物 Download PDFInfo
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- CN1280560A CN1280560A CN98811835A CN98811835A CN1280560A CN 1280560 A CN1280560 A CN 1280560A CN 98811835 A CN98811835 A CN 98811835A CN 98811835 A CN98811835 A CN 98811835A CN 1280560 A CN1280560 A CN 1280560A
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Abstract
本发明提供式(Ⅰ)所代表的金刚烷衍生物、其制备方法、含有该衍生物的药物组合物及其在治疗中的用途。所说的式(Ⅰ)中,A代表基团CH2或O原子,B代表H或卤原子,D代表基团CH2、OCH2、NHCH2或CH2CH2,R代表苯基、苯并噻唑基、吲哚基、吲唑基、嘌呤基、吡啶基、嘧啶基或噻吩基,各基团可以选择性地被一个或多个取代基取代。
Description
本发明涉及式(Ⅰ)所代表的金刚烷衍生物、其制备方法、含有它们的药物组合物及其在治疗中的用途。
金刚烷衍生物是本领域中已知的,例如从US-A-3,789,072中已知作为血清素抑制剂,从“化学文献”〔Chem.Abs.(1974),Vol.80,No.5(26871m)〕中已知作为炎症和浮肿抑制剂或止痛剂,从“化学文献”〔Chem.Abs.(1975),Vol.82,No.1(3853j)和Chem.Abs.(1977),Vol.86,No.17(120855e)〕中已知作为抗病毒药,以及从“化学文献”〔Chem.Abs.(1968),Vol.69,No.1(2562h)、Chem.Abs.(1975),Vol.82,No.3(16510v)〕和“四面体”〔Tetrahedron(1988),44,No.23,7234-7242〕中已知。
作为配体选通离子通道,P2X7受体(以前称为P2Z受体)存在于多种细胞上,主要是那些已知与发炎/免疫过程有关的细胞,特别是巨噬细胞、肥大细胞和淋巴细胞(I细胞和B细胞)。P2X7受体被细胞外核苷酸(特别是腺苷三磷酸)活化,导致白介素-1β(IL-β)释放,巨细胞(巨噬细胞/小神经视质细胞)形成、失粒(肥大细胞)和L-选择素脱落(淋巴细胞)。P2X7受体还位于含有抗原的细胞(APC)、角质细胞、唾液腺细胞(腮腺细胞)和肝细胞上。
制造作为有效P2X7受体拮抗剂、用于治疗病原学中P2X7受体引起的炎症、免疫疾病或心血管疾病的化合物将是令人欣喜的。
因此,本发明提供一种下列通式的化合物或其药学上可接受的盐或溶剂化物:其中A代表基团CH2或O原子,B代表H或卤原子(例如氟、氯、碘,特别是溴),D代表基团CH2、OCH2、NHCH2或CH2CH2;特别是CH2、OCH2或NHCH2;
R代表苯基、苯并噻唑基、吲哚基、吲唑基、嘌呤基、吡啶基、嘧啶基或噻吩基,各基团可以选择性地被一个或多个独立地选自下述的基团取代:卤原子或氰基、羧基、羟基、硝基、卤代-C1-C6烷基、-N(R1)-C(=O)-R2、-C(O)R3R4、-NR5R6、C3-C8环烷基、3-8员杂环基、C3-C8环烷氧基、C1-C6烷基羰基、苯氧基、苄基、C1-C6烷硫基、苯硫基、C1-C6烷氧羰基、C1-C6烷基亚磺酰基或C1-C6烷基磺酰基、视需要被-个或多个独立地选自下述取代基所取代的C1-C6烷基或C1-C6烷氧基:卤原子或氨基、羧基、羟基、C1-C6烷氧基、(二)C1-C6烷基氨基、C1-C6烷氧羰基、咪唑基、吗啉基、哌啶基或吡咯烷基;
R1代表H或C1-C6烷基或C3-C8环烷基;
R2代表C1-C6烷基或C3-C8环烷基;而
R3、R4、R5和R6各自独立地代表H或C1-C6烷基或C3-C8环烷基;
条件是:当A是CH2,B是H,而D是CH2时,则R不代表苯基、邻羧基苯基、甲基苯基或对苯氧基苯基,而且当A是CH2,D是CH2或CH2CH2,而R代表取代的苯基时,邻位上的取代基不包括被氨基取代的C1-C6烷氧基、(二)C1-C6烷基氨基、咪唑基、吗啉基、哌啶基或吡咯烷基。
本发明的说明书中,除非特别指明,取代基中的烷基取代基或基团可以是线形的或带支链的。而且,二烷基氨基、二环烷基氨基、二烷基酰胺基或二环烷基酰胺基取代基中的(环)烷基可以相同或不同。当D代表基团OCH2或NHCH2时,基团的取向要使得O或N直接与金刚烷基相连。应当明白,3-8员杂环基是指含有选自N、O或S单杂原子的脂族杂环系。术语“在邻位”定义为R代表的苯环上其与酰胺基团相连点相邻的位置,例如下式所示,其中*号定义“邻位”:相似地,用其与酰胺连接基的连接点的相对位置来定义R代表的苯基上的间位和对位,在上式中分别用+和#指示。
优选地,R代表苯基、苯并噻唑基、吲哚基、吲唑基、嘌呤基、吡啶基、嘧啶基或噻吩基,各基团可以视需要被1、2、3或4个独立地选自下述的基团取代:卤原子(例如氟、氯、溴或碘)或氰基、羧基、羟基、硝基、卤素-C1-C6烷基(例如三氟甲基)、-N(R1)-C(=O)-R2、-C(O)NR3R4、-NR5R6、C3-C8环烷基(例如环丙基、环丁基、环戊基或环己基)、3-8员杂环基(例如1-氮杂环丙烷基、吡咯烷基或哌啶基)、C3-C8环烷氧基(例如环丙氧基、环丁氧基、环戊氧基或环己氧基)、C1-C6烷基羰基(例如甲基-,乙基-,丙基-,丁基-,戊基-或己基羰基)、苯氧基、苄基、C1-C6烷硫基(例如甲硫基、乙硫基、丙硫基、丁硫基、戊硫基或己硫基)、苯硫基、C1-C6烷氧羰基(例如甲氧基-,乙氧基-,丙氧基-,丁氧基-,戊氧基-或已氧基-羰基)、C1-C6烷基亚磺酰基(例如甲基-,乙基-,丙基-,丁基-,戊基-或己基亚磺酰基)或C1-C6烷基磺酰基(例如甲基-,乙基-,丙基-,丁基-,戊基-或己基磺酰基)、视需要被1、2、3或4个独立地选自下述的基团取代的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)或C1-C6烷氧基(例如甲氧基、乙氧基-、丙氧基-、丁氧基-、戊氧基-或己氧基):卤原子(氟、氯、溴或碘)或氨基、羧基、羟基、C1-C6烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基)、(二)C1-C6烷基氨基(例如(二)甲基氨基或(二)乙基氨基)、C1-C6烷氧羰基(例如甲氧基-,乙氧基-,丙氧基-,丁氧基-,叔丁氧基-,戊氧基-或己氧基-羰基)、咪唑基、吗啉基、哌啶基或吡咯烷基。
更优选R代表苯基、苯并噻唑基、吲哚基、吲唑基、嘌呤基、吡啶基或噻吩基,各基团可以选择性地被1、2或3个独立地选自下述的基团取代:卤原子(特别是氯)或羟基、硝基或C1-C4烷氧基羰基(特别是甲氧基羰基)、视需要被1或2个独立地选自下述的基团取代的C1-C4-烷基(最优选C1-C2烷基)或C1-C4-烷氧基(最优选C1-C3烷氧基):卤原子(氟、氯、溴或碘)或氨基、羧基、羟基、C1-C4-烷氧基(特别优选甲氧基)、(二)C1-C4-烷基氨基(特别是甲基氨基或二甲基氨基)、C1-C4-烷氧基羰基(特别是叔丁氧基羰基)、咪唑基、吗啉基、哌啶基或吡咯烷基。
优选R1代表H或C1-C4-烷基(例如甲基、乙基、丙基或丁基)或C3-C6-环烷基(例如环戊基或环己基)。
优选R2代表C1-C4-烷基(例如甲基、乙基、丙基或丁基)或C3-C6-环烷基(例如环戊基或环己基)。
优选R3、R4、R5和R6各自独立地代表H或C1-C4-烷基(例如甲基、乙基、丙基或丁基)或C3-C6-环烷基(例如环戊基或环己基)。
本发明的优选化合物包括:
N-(2-甲基-6-苯并噻唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-(3-(氨基丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-氯苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,4,5-三甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,3-二甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-吲哚基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,3-二甲基-5-吲哚基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-[5-(3-N,N-二甲基氨基丙氧基)-2-甲基苯基]-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-吲唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(6-吲唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(1H-吲哚-4-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
4-甲基-3-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]苯氧基-乙酸盐酸盐、
N-(1-甲基-1H--吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(1-N,N-二甲基氨基)乙基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
5-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]-1H-吲哚-1-乙酸-1,1-二甲基乙基酯、
N-(3-(2-氯吡啶基))-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-(N,N-二甲基氨基)甲基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(4-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-氯-5-甲氧基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(4-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-甲氧基-2-甲基-3-硝基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-5-(1-吡咯烷甲基)苯基-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-氯-5-羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-氯-4-羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-3-(2-(1-吡咯烷基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-甲氧基甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-3-(2-(1-吗啉基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-甲基-3-(2-(1-哌啶基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-甲基-5-(1-吗啉基甲基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(3-(2-N,N-二甲基氨基乙基)吲哚基))-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
4-甲基-3-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]噻吩-2-甲酸甲酯、
N-(3-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-3-(2-(1-咪唑啉基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,4,6-三甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-(3-氨基丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N6-(三环[3.3.1.13.7]癸烷-1-乙酰基)腺嘌呤、
N-(3,5-二甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(3-(N,N-二甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-(3-溴-三环[3.3.1.13.7]癸烷)-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-2-(三环[3.3.1.13.7]癸烷-1-氨基)乙酰胺、
N-(3,5-二甲氧基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3,5-二羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3,5-二甲氧基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、
N-(3,5-双-(3-氨基丙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,4,5-三甲基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、
N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、
N-(5-(2-(N-甲基氨基)乙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(2-(N-甲基氨基)乙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺、
N-(5-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、和
N-(3,5-二羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷乙酰胺。
本发明还提供一种制备上面定义的式(Ⅰ)化合物的方法,包括使一种下列通式的化合物:其中L代表离去基团(例如卤原子如氯或咪唑基),而A、B和D如式(Ⅰ)中所定义,与通式(Ⅲ)R-NH2,其中R如式(Ⅰ)中所定义的化合物反应,并且视需要制成其药学上可接受的盐或溶剂化物。
该方法可以方便地在溶剂(例如乙腈、N,N-二甲基甲酰胺或二氯甲烷)中并且视需要在碱(例如三乙胺、4-二甲基氨基吡啶或二异丙基乙胺)的存在下进行。该方法方便地在0-100℃范围的温度,优选在10-80℃、特别优选在室温下(20℃)进行。
式(Ⅱ)和(Ⅲ)的化合物是已知化合物,可以用本领域中的类似方法制备。
本领域技术人员将会明白,在本发明的方法中,中间体中的某些官能团,例如羟基或氨基需要用保护基保护。因此,在制备式(Ⅰ)化合物的最后阶段中要将有关一个或多个保护基的去除。
在由J.W.F.McOmie编辑、Plenum Press(1973)出版的“有机化学中的保护基”及由T.W.Greene和P.G.M.Wuts编辑、Wiley-Interscience(1991)出版的“有机化学中的保护基”,第二版中描述了官能团的保护和脱保护。
可以把上述式(Ⅰ)的化合物转变为其药学上可接受的盐或溶剂化物,优选转变为其酸加成盐,例如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、反式丁烯二酸盐、顺式丁烯二酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐,或者转变为碱金属盐,例如钠盐或钾盐。
某些式(Ⅰ)的化合物能以立体异构体形式存在。应当明确,本发明包括式(Ⅰ)化合物的所有几何异构体和旋光异构体及其混合物,包括外消旋体。互变异构体及其混合物也构成本发明的一个方面。
本发明化合物的优势在于它们具有药理活性。表明它们可作为药物,用于治疗或预防类风湿性关节炎、骨关节炎、牛皮癣、过敏性皮炎、哮喘、呼吸道过敏、腐败性休克、肾小球肾炎、过敏性肠炎、节段性回肠炎、溃疡性结肠炎、动脉粥样硬化、肿瘤细胞的生长和转移、心肌缺血、成肌细胞白血病、糖尿病、早老性痴呆症、骨质疏松、烧伤、中风、静脉曲张和脑膜炎。
因此,本发明提供一种前面定义的治疗用式(Ⅰ)化合物,或其药学上可接受的盐或溶剂化物。
本发明的另一个方面是提供一种前面定义的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物在生产治疗用药物中的用途。
本发明还提供一种进行免疫抑制(例如在治疗风湿性关节炎、过敏性肠炎、动脉粥样硬化或牛皮癣中)的方法,包括给病人服用治疗有效量的前面定义的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物。
用于上述治疗时,给药剂量当然会随所用的化合物、给药方式、所要进行的治疗和疾病症状而变化。
式(Ⅰ)的化合物或其药学上可接受的盐或溶剂化物可以单独使用,但是一般以药物组合物形式给药,其中把式(Ⅰ)化合物/盐/溶剂化物(活性成分)与药学上可接受的助剂、稀释剂或载体结合使用。随给药方式不同,药物组合物将优选包含0.05%-99%w(%重量),更优选包含0.10-70%w的活性组分,和1-99.95%w,更优选包含30-99.90%w的药学上可接受的助剂、稀释剂或载体,所有的重量百分数都以总的组合物重量计。
因此,本发明还提供一种包含前面定义的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物和一种药学上可接受的助剂、稀释剂或载体的药物组合物。
本发明还提供一种制备本发明的药物组合物的方法,包括把一种前面定义的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物与一种药学上可接受的助剂、稀释剂或载体混合。
本发明的药物组合物可以以溶液、悬浮液、七氟烷烃气雾剂和干燥的粉末制剂形式局部给药(例如向肺和/或呼吸道或皮肤给药);或者全身性给药,例如以片剂、胶囊、糖浆、粉末或颗粒形式通过口服给药,或以溶液或悬浮液形式通过非肠胃方式,或通过皮下给药,或以栓剂形式通过直肠给药,或通过透皮方式给药。
通过参考下列举例说明的实施例可以进一步理解本发明,其中术语MS、NMR、CDCl3和DMSO分别表示质谱、核磁共振、氘代氯仿和二甲基亚砜。
实施例1
N-(2-甲基-6-苯并噻唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
a)1-金刚烷乙酰氯
把1-金刚烷乙酸(4.5g)的亚硫酰氯(20ml)溶液加热回流24小时,然后冷却到室温。减压下除去过量的亚硫酰氯,留下本小标题化合物的浆液(4.9g)。
b)N-(2-甲基-6-苯并噻唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
向上述a)中制备的1-金刚烷乙酰氯(0.5g)的乙腈(10ml)溶液中加入三乙胺(0.38ml)和6-氨基-2-甲基苯并噻唑(0.39g)。室温下搅拌反应混合物1小时,然后用乙酸乙酯稀释。然后有机相用稀盐酸和水稀释,通过硫酸镁(MgSO4)干燥,最后减压下浓缩,得到标题化合物的白色固体(0.12g)。
熔点:172℃MS(APCI+ve) 341(M+H)+ 1H NMR(CDCl3)δ8.45(1H,d),7.84(1H,d),7.19(2H,m),2.81(3H,s),2.13(2H,s),2.00(3H,s),1.75(12H.m)
实施例2
N-(3-(3-(氨基丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
把偶氮二甲酸二乙酯(1.0ml)加入N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.408g,实施例26)、N-(3-羟基丙基)氨基甲酸叔丁基酯(1.11g)和三苯基膦(1.74g)的四氢呋喃(5ml)溶液中。室温下搅拌过夜后,减压下浓缩反应混合物。残留物通过硅胶柱色谱纯化,用二氯甲烷:乙酸乙酯(9∶1)洗脱,然后进一步用HPLC使用WatersPrep4000的Dynamax柱纯化,用异己烷:乙酸乙酯(7∶3)洗脱,得到Mitsunobu反应产物(0.34g),把该产物溶于甲醇(10ml)中。然后向该溶液中加入盐酸溶液(通过0℃下把乙酰氯(12ml)缓慢地加入甲醇(10ml)中而得到,小心!放出大量的热),在室温下搅拌反应混合物2小时。反应混合物在饱和碳酸氢钠水溶液(100ml)和乙酸乙酯(100ml)之间分配。有机萃取液通过无水硫酸钠干燥,过滤,减压下浓缩。残留物通过硅胶色谱纯化,用二氯甲烷∶乙醇∶三乙胺(18∶2∶1)纯化,得到黄色油状物。把油状物溶于甲醇(10ml)和二氯甲烷(2ml)中,用HCl的乙醚溶液(1M,5ml)处理。2分钟后,减压下除去溶剂。残留的浆料在乙醚∶异己烷(1∶1)中搅拌过夜,过滤除去溶剂,留下标题化合物的固体(0.186g),通过倾滗然后干燥残留物把固体分离出来。MS(APCI+ve) 357(M-HCl+H)+ 1H NMR(DMSO-d6)δ9.20(1H,s),7.97(3H,bs),7.10(1H,t),6.94(1H,d),6.77(1H,d),4.05(2H,t),3.05-2.9(2H,m),2.1-2.0(7H,m),1.94(3H,s),1.75-1.55(12H,m).
实施例3
以1-金刚烷乙酰氯(0.2g)和2-氯苯胺(0.12g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.05g)。
熔点:122-124℃.MS(APCI+ve)304/306(M+H)+ 1H NMR(CDCl3)δ8.40(1H,d),7.55(1H,s),7.40(1H,dd),7.3(1H,m),7.05(1H,m),2.16(2H,s),2.00(3H,s),1.75(12H,m)
实施例4
以1-金刚烷乙酰氯(0.2g)和2,4,5-三甲基苯胺(0.13g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.042g)。
熔点:158℃。MS(APCI+ve)312(M+H)+ 1H NMR (DMSO-d6)δ9.00(1H,s),7.08(1H,s),6.94(1H,s),2.14(6H,s),2.10(3H,s),2.04(2H,s),1.98(3H,s),1.75(12H,m)
实施例5
N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
以1-金刚烷乙酰氯(0.2g)和5-甲氧基-2-甲基苯胺(0.13g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.043g)。
熔点:147℃。MS(APCI+ve)314(M+H)+ 1H NMR(DMSO-d6)9.00(1H,s),7.07(1H,d),7,04(1H,d),6.65(1H,dd),3.69(3H,s),2.13(3H,s),2.09(2H,s),1.95(3H,s),1.75(12H,m)
实施例6
以1-金刚烷乙酰氯(0.2g)和2,3-二甲基苯胺(0.11g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.034g)。
熔点:170℃。MS(APCI+ve)298(M+H)+ 1H NMR(DMSO-d6)δ9.20(1H,s),7.20-6.95(3H,m),2.23(3H,s),2.07(5H,s),1.95(3H,s),1.75(12H,m)
实施例7
以1-金刚烷乙酰氯(0.076g)和5-氨基吲哚(0.05g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.05g)。
熔点:184-185℃。MS(APCI+ve)309(M+H)+ 1H NMR(DMSO-d6)δ10.95(1H,s),9.51(1H,s),7.85(1H,s),7.28(2H,m),7.16(1H,dd),6.35(1H,t),2.04(2H,s),1.94(3H,s),1.70-1.50(12H,m)
实施例8
N-(2,3-二甲基-5-吲哚基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
向1-金刚烷乙酸(0.30g)的二氯甲烷(10ml)溶液中加入4-二甲基氨基吡啶(0.19g)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.30g)。把反应混合物搅拌0.5小时,然后加入5-氨基-2,3-二甲基吲哚(0.25g),然后室温下持续搅拌过夜。第二天,用稀盐酸、水和盐水洗涤反应混合物,通过硫酸钠(Na2SO4)干燥,最后减压下浓缩,留下残留物。通过硅胶色谱纯化残留物,用40%乙酸乙酯的异己烷溶液洗脱,得到白色固体的标题化合物(0.14g)。
熔点:234-235℃。MS(APCI+ve)337(M+H)+ 1H NMR (DMSO-d6)δ10.50(1H,s),9.46(1H,s),7.67(1H,s),7.08(2H,m),2.28(3H,s),2.03(3H,s),1.99(2H,s),1.94(3H,s),1.70-1.50(12H,m)
实施例9
在-78℃和惰性气氛下,向按照实施例5中所述的方法制备的N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(1.00g)的二氯甲烷(20ml)溶液中加入三溴化硼(4ml 1.0M的二氯甲烷溶液)。搅拌反应混合物24小时,然后温热到室温,用盐水洗涤。有机层通过硫酸镁干燥,减压下浓缩,得到残留物。向残留物(200mg)的N,N-二甲基甲酰胺(10ml)溶液中加入碳酸钾(0.185g)和N,N-二甲基-3-氯丙胺盐酸盐(0.11g),搅拌下把反应混合物加热到80℃维持4小时。冷却后,立刻用乙酸乙酯稀释反应混合物,用饱和的盐水洗涤。分离出有机相,通过硫酸镁干燥,然后通过“ISOLUTE”(商标)NH2固相萃取柱,用乙酸乙酯洗脱。蒸馏洗脱液,然后用1.0M HCl的乙醚溶液处理,最后减压下浓缩,得到白色固体的标题化合物(O.02g)。
熔点:139-140℃。MS(APCI+ve)385(M+H)+(for free base)1H NMR(DMSO-d6)δ10.38 (1H,s),9.05 (1H,s),7.08 (2H,d+s),3.95 (4H,m),3.2(2H,m),2.78(6H,2s),2.13 (3H,s),2.10(2H,s),1.95(3H,s),1.6 12H,m)
实施例10
N-(5-吲唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
以1-金刚烷乙酰氯(0.1g)和5-氨基吲唑(0.067g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.12g)。
熔点:265℃。MS(APCI+ve)310(M+H)+ 1H NMR(DMSO-d6)δ12.93(1H,s),9.73(1H,s),8.12(1H,s),7.99(1H,s),7.40 (2H,m), 2.04 2H,s),1.94(3H,s),1.70-1.50(12H,m)
实施例11
N-(6-吲唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
以1-金刚烷乙酰氯(0.2g)和6-氨基吲唑(0.13g)为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.064g)。
熔点:245℃。MS(APCI+ve)310 (M+H)+ 1H NMR(DMSO-d6)δ12.84 (1H,s),9.87(1H,s),8.16(1H,s),7.94(1H,s),7.62(1H,d),7.05 (1H,dd),2.04(2H,s),1.94(3H,s),1.70-1.50(12H,m)
实施例12
N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
在-78℃和惰性气氛下,向按照实施例5中所述的方法制备的N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(1.00g)的二氯甲烷(20ml)溶液中加入三溴化硼(4ml 1.0M的二氯甲烷溶液)。搅拌反应混合物24小时,然后温热到室温,用盐水洗涤。有机层通过硫酸镁干燥,减压下浓缩,得到残留物。用乙醚研制残留物,得到固体(0.335g)。部分产物(0.050g)通过超临界流体色谱使用Cyano柱进一步纯化,用甲醇/超临界二氧化碳梯度洗脱,得到白色固体的标题化合物(0.030g)。
熔点:255-256℃。MS(APCI+ve)300(M+H)+ 1H NMR (DMSO-d6)δ9.11 (1H,s),8.92(1H,s),6.92(1H,m),6.45(1H,dd),2.04(5H,s),1,94(3H,s),1.70-1.50(12H,m)
实施例13
N-(1H-吲哚-4-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
以1-金刚烷乙酰氯(0.074g)和4-氨基吲哚(0.059g)盐酸盐为原料,按照实施例1b)的方法制备得到白色固体的标题化合物(0.068g)。
熔点:211-213℃。MS(APCI+ve)309(M+H)+ 1H NMR (DMSO-d6)δ11.07(1H,s),9.35(1H,s),7.53(1H,d),7.27(1H,t),7.12(1H,d),6.99(1H,t),6.66(1H,s),2.19(2H,s),1.94(3H,s),1.68(6H,d),1.68-1.58(6H,m).
实施例14
4-甲基-3-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]苯氧基-乙酸盐酸盐
向按照实施例12制备的N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.20g)的溶液中加入碳酸钾(0.106g)和溴代乙酸乙酯(0.30ml),在80℃加热搅拌反应混合物24小时。冷却后,反应混合物用乙酸乙酯稀释,用饱和的盐水洗涤。分离出有机相,通过硫酸镁干燥,减压下蒸馏,留下残留物。通过硅胶色谱纯化残留物,用异己烷/乙醚(1∶1)洗脱,得到白色固体。把白色固体溶于二噁烷(20ml)中,用2M氢氧化钠溶液处理,室温下搅拌反应混合物24小时,酸化(2M盐酸),萃取到乙酸乙酯中。用盐水洗涤有机相,通过硫酸镁干燥,减压下蒸馏。用乙醚研制残留物,得到白色固体的标题化合物(0.070g)。
熔点:204-205℃。MS(APCI+ve)358(M+H)+ 1H NMR(DMSO-d6)δ12.95(1H,s),9.03(1H,s),7.05(2H,m),6.60(1H,dd),4.58(2H,s),2.12(3H,s),2.090(2H,s),1.94(3H,s),1.70-1.50(12H,m)
实施例15
N-(1-甲基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
a)1-甲基-5-硝基-1H-吲哚
向5-硝基吲哚(0.20g)的四氢呋喃(2ml)溶液中加入氢化钠(0.06g60%的油悬浮液),有气体逸出。搅拌30分钟后,向暗棕色的反应混合物中加入碘甲烷(0.086ml),把反应混合物加热到65℃维持2小时,然后冷却到室温,在二氯甲烷和水之间分配。分离出有机相,用硫代硫酸钠溶液洗涤,干燥(硫酸钠)并浓缩,得到黄色固体的小标题化合物(0.20g)
1H NMR(DMSO-d6)δ8.58(1H,d),8.04(1H,dd),7.65(1H,d),7.61(1H,d),6.75(1H,dd),3.88(3H,s).
b)N-(1-甲基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺向步骤a)中得到的1-甲基-5-硝基吲哚(0.11g)的乙醇(10ml)溶液中加入10%钯/碳(0.023g),在4巴的氢气压力下搅拌所得的悬浮液0.75小时,然后滤去催化剂,减压下浓缩。使所得的残留物与1-金刚烷乙酰氯(0.10g)按照实施例1b)的方法缩合,得到白色固体的标题化合物(0.11g)。
熔点:183-184℃。MS(APCI+ve) 323(M+H)+ 1H NMR(DMSO-d6)δ9.55 (1H,s),7.87(1H,d),7.32(1H,d),7.26(1H,d),7.23(1H,dd), 6.34 (1H,dd),3.75(3H,s),2.04(2H,s),1.94(3H,s),1.75-1.50(12H,m).
实施例16
N-(1-(N,N-二甲基氨基)乙基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
a)1-(N,N-二甲基氨基)乙基-5-硝基-1H-吲哚
按照实施例15a)的方法,从5-硝基吲哚(0.217g)和二甲基氨基乙基氯盐酸盐(0.21g)制备得到橙色/棕色固体的小标题化合物(0.24g)。1H NMR(DMSO-d6)δ8.56(1H,d),8.02(1H,dd),7.71(1H,d),7.61(1H,d),6.74(1H,dd),4.35(2H,t),2.62(2H,t),2.17(6H,s).
b)N-(1-(N,N-二甲基氨基)乙基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
按照实施例15b)的方法,从1-(N,N-二甲基氨基)乙基-5-硝基吲哚(0.23g)和1-金刚烷乙酰氯(0.21g)制备得到白色固体的标题化合物(0.22g)。
熔点:125-127℃。
MS(APCI+ve)380(M+H)+ 1H NMR(DMSO-d6)δ9.54(1H,s),7.85(1H,d),7.36(1H,d),7.32 (1H,d),7.20(1H,dd),6.33(1H,d),4,20(2H,t),2.58(2H,t),2.17(6H,s),2.04(2H,s),1.94(3H,s),1.65(12H,m).
实施例17
5-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]-1H-吲哚-1-乙酸-1,1-二甲基乙基酯
a)5-硝基-1H-吲哚-1-乙酸-1,1-二甲基乙基酯
按照实施例15a)的方法,从5-硝基吲哚(0.207g)和2-溴代乙酸-1,1-二甲基乙基酯(0.23ml)制备得到黄色油状固体的小标题化合物(0.29g)。1H NMR(DMSO-d6)δ8.58(1H,d),8.04(1H,dd),7.60(2H,m),6.77(1H,dd),3.15(2H,s),1.42(9H,s)
b)5-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]-1H-吲哚-1-乙酸-1,1-二甲基乙基酯
按照实施例15b)的方法,从5-硝基-1H-吲哚-1-乙酸-1,1-二甲基乙基酯(0.29g)和1-金刚烷乙酰氯(0.20g)制备得到白色固体的标题化合物(0.24g)。
熔点:199℃。
MS(APCI+ve)423(M+H)+ 1H NMR(DMSO-d6)δ9.56(1H,s),7.86(1H,d),7.27(1H,d),7.22(2H,m), 6.38 (1H,d),4.94(2H,s),2.04(2H,s),1.94(3H,s),1.65(12H,m),1.41(9H,s).
实施例18
N-(3-(2-氯吡啶基))-三环[3.3.1.13.7]癸烷-1-乙酰胺
按照实施例15b)的方法,从1-金刚烷乙酰氯(0.5g)和2-氯-3-氨基吡啶(0.31g)制备得到白色固体的标题化合物(0.27g)。
熔点:135-136℃。
MS(APCI+ve)305(M+H)+ 1H NMR(DMSO-d6)δ9.51(1H,s),8.22(1H,dd),8.15(1H,dd),7.4(1H,dd),2.20(2H,s),1.98(3H,s),1.60(12H,m)
实施例19
N-(3-(N,N-二甲基氨基)甲基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
向实施例7得到的吲哚酰胺(0.163g)的乙酸(0.20ml)悬浮液中加入二甲基胺的水溶液(0.065ml 40%的溶液)、甲醛水溶液(0.043ml 37%的溶液)和乙酸(0.10ml),把所得的反应混合物加热到60℃维持2小时,然后冷却到0-5℃。通过加入氨水溶液碱化反应混合物,在乙酸乙酯和水之间分配。分离出有机相,用盐水洗涤,干燥(硫酸钠)并浓缩,残留物通过氧化铝色谱纯化,用0-10%甲醇的二氯甲烷溶液洗脱,得到棕色固体的标题化合物(0.07g)。
熔点:194-213℃(分解)。MS(APCI+ve)366(M+H)+ 1H NMR(DMSO-d6)δ11.24(1H,s),9.62(1H,s),8.00(1H,s),7.46(1H,d),7.32(1H,d),7.21(1H,dd),4.12(2H,br s),2.55(6H,s),2.06(2H,s),1.94(3H,s),1.70-1.58(12H,m).
实施例20
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.0g)和4-甲氧基-2-甲基苯胺(1.29g)制备得到白色固体的标题化合物(1.37g)。
熔点:156-157℃。MS(APCI+ve)314(M+H)+ 1H NMR (DMSO-d6)δ9.01(1H,s),7.15(1H,d),6.80(1H,d),6.7(1H,dd),3.7(3H,s),2.20(3H,s),2.05(2H,s),1.95(3H,s),1.60(12H,m)
实施例21
N-(2-氯-5-甲氧基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.0g)和2-氯-5-甲氧基苯胺(1.49g)制备得到白色固体的标题化合物(0.60g)。
熔点:122-123℃。MS(APCI+ve)334(M+H)+ 1H NMR (DMSO-d6)δ9.20 (1H,s),7.36(2H,m),6.76(1H,dd),6.7(1H,dd),3.73(3H,s),2.20(2H,s),1.95(3H,s),1.60(12H,m)
实施例22
在-78℃和惰性气氛下,向从实施例20得到的N-(4-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(1.20g)的二氯甲烷(50ml)溶液中加入三溴化硼(4ml 1.0M的二氯甲烷溶液)。搅拌反应混合物24小时,然后温热到室温,用盐水洗涤。有机层通过硫酸镁干燥,减压下浓缩,得到残留物,用硅胶色谱纯化残留物,用异己烷/乙醚(1∶1)洗脱,得到白色固体的标题化合物(0.54g)。
熔点:205-206℃。MS(APCI+ve)300(M+H)+ 1H NMR(DMSO-d6)δ9.15(1H,s),8.91(1H,s),7.00 (1H,d),6.54(2H,m),2.53(3H,s),2.03(2H,s),1.94(3H,s),1.70-1.50(12H,m)
实施例23
N-(3-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.0g)和3-氨基-2-甲基苯甲醇(1.29g)制备,通过硅胶色谱纯化,用5%乙酸乙酯的二氯甲烷溶液洗脱,得到白色固体的标题化合物(0.80g)。
熔点:205-206℃。MS(APCI+ve)314(M+H)+ 1H NMR (DMSO-d6)δ9.16(1H,s),7.20-7.05(3H,m),5.07 (1H,bs),4.47(2H,s),2.09(2H,s),2.08 (3H,s),1.95(3H,s),1.60(12H,m)
实施例24
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.0g)和5-甲氧基-2-甲基-4-硝基苯胺(1.71g)制备,通过硅胶色谱纯化,用异己烷/乙醚(1∶1)洗脱,得到黄色固体的标题化合物(1.10g)。
熔点:141-142℃。MS(APCI+ve)359(M+H)+ 1H NMR(DMSO-d6)δ9.26(1H,s),7.82(1H,s),7.76(1H,s),3.86(3H,s),2.23(3H,s),2.08(2H,s),1.95(3H,s),1.60(12H,m)
实施例25
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.0g)和3-氨基-4-甲基苯甲醇(1.29g)制备,通过硅胶色谱纯化,用5%乙酸乙酯的二氯甲烷溶液洗脱,得到白色固体的标题化合物(1.10g)。
熔点:190℃。MS(APCI+ve)314(M+H)+ 1H NMR(DMSO-d6)δ8.54(1H,bs),7.46(1H,s),7.1(2H,m),4.70(1H,bs),4.54(2H,d),2.24(3H,s),2.15(2H,s),2.0(3H,s),1.70(12H,m)
实施例26
N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
按照实施例1b)的方法,从1-金刚烷乙酰氯(0.81g)和3-氨基-2-甲基苯酚(0.5g)制备得到白色固体的标题化合物(0.50g)。
熔点:211℃。MS(APCI+ve)300(M+H)+ 1H NMR (DMSO-d6)δ9.28(1H,bs),9.04(1H,bs),6.91(1H,t),6.8(1H,d),6.6(1H,d),2.05(2H,s),1.98(3H,S) 1.94 (3H,bs),1.6(12H,m)
实施例27
N-(2-甲基-5-(1-吡咯烷甲基)苯基-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
向实施例25)得到的N-(5-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(1.0g)的乙腈溶液中加入三苯基膦(0.93g)和四溴化碳(1.2g)。室温下搅拌反应混合物24小时,减压下蒸馏。通过硅胶色谱纯化残留物,用异己烷/乙醚洗脱,得到白色固体。把-部分固体(0.1g)溶于乙腈(3ml)中,用吡咯烷(0.2ml)处理。在80℃下搅拌加热反应混合物24小时。冷却后,反应混合物用乙酸乙酯稀释,用饱和盐水洗涤。分离出有机相,通过硫酸镁干燥,用HCl的乙醚溶液(1ml的1.0M溶液)处理,减压下蒸馏,留下残留物,用异己烷研制该残留物,得到浅白色固体的标题化合物(0.030g)。
熔点:214-215℃。MS(APCI+ve)367(M+H)+游离碱.1H NMR(DMSO-d6)δ9.22(1H,s),7.60(1H,s),7.27(2H,s),4.27(2H,d),3.35(2H,m),3.05(2H,m),2.21(3H,s),2.1(2H,s),2.0-1.8(7H,m),1.60(12H,m)
实施例28
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.9g)和2-氯-4-羟基苯胺(2.0g)制备,通过硅胶色谱纯化,用30%乙醚的异己烷溶液洗脱,然后在乙腈中重结晶,得到白色固体的标题化合物(0.15g).
熔点:224-225℃。MS(APCI+ve)320(M+H)+ 1H NMR(DMSO-d6)δ9.76(1H,s),9.14(1H,s),7.26(1H,d),6.83(1H,d),6.69(1H,dd),2.05(2H,s),1.95(3H,s),1.60(12H,m)
实施例29
按照实施例1b)的方法,从1-金刚烷乙酰氯(2.9g)和2-氯-4-羟基苯胺制备得到白色固体的标题化合物(0.15g)。
熔点:224-225℃。MS(APCI+ve)320(M+H)+ 1H NMR(DMSO-d6)δ9.65(1H,s),9.09(1H,s),7.23(2H,m),6.55(1H,dd),2.20(2H,s),1.95(3H,s),1.60(12H m)
实施例30
N-(2-甲基-3-(2-(1-吡咯烷基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
向实施例26得到的N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.060g)的乙腈(3ml)溶液中加入碳酸铯(0.196g)和N-(2-氯乙基)-吡咯烷盐酸盐(0.068g)。在80℃搅拌加热反应混合物24小时。冷却后,反应混合物用乙酸乙酯稀释,用水洗涤.有机相通过硫酸镁干燥,减压下蒸馏,留下残留物,通过超临界流体色谱在Cyano柱上纯化残留物,用0.1%v/v二乙胺的甲醇溶液和超临界二氧化碳进行梯度洗脱。把纯产物溶于二氯甲烷中,用1.0M HCl的乙醚溶液处理,减压下蒸馏,得到白色固体的标题化合物(0.010g)。
熔点:105-106℃。MS(APCI+ve)397(M+H)+for free base.1H NMR(DMSO-d6)δ9.22(1H,s),7.12(1H,t),6.97(1H,d),6.81(1H,d),4.30(2H,t),3.60(4H,m),3.10(2H,m),2.05(6H,s),1.95(6H,m),1.60(12H,m)
实施例31
N-(5-甲氧基甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
向实施例27中制备的苄基溴(0.10g)的甲醇(5ml)溶液中加入甲醇钠(0.020g)。在室温下搅拌反应混合物2小时,然后减压下蒸馏,留下残留物,把该残留物溶于乙酸乙酯中,用2M盐酸洗涤.有机相通过硫酸镁干燥,减压下蒸馏。用乙醚研制残留物,得到白色固体的标题化合物(0.015g).
熔点:127-128℃。MS(APCI+ve)328(M+H)+ 1H NMR(DMSO-d6)δ9.10(1H,s),7.33(1H,s),7.15(1H,d),6.99(1H,d),4.34(2H,s),2.20(3H,s),2.10(2H,s),1.95(6H,m),1.60(12H,m)
实施例32
N-(2-甲基-3-(2-(1-吗啉基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
按照实施例30的方法,从N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.060g)和N-(2-氯乙基)吗啉盐酸盐(0.075g)制备,得到白色固体的标题化合物(0.024g)。
熔点:195-197℃。MS(APCI+ve)413(M+H)+ for free base.1H NMR(DMSO-d6)δ11.36(1H,bs),9.23(1H,s),7.15(1H,t),6.99(1H,d),6.83(1H,d), 4.42(2H,t),4.10-3.0(12H,m),2.08(2H,s),2.07(3H,s),1.95 (3H,s),1.60(12H,m)
实施例33
N-(2-甲基-3-(2-(1-哌啶基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
按照实施例30的方法,从N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.060g)和N-(2-氯乙基)哌啶盐酸盐(0.074g)制备得到白色固体的标题化合物(0.036g)。
熔点:105-106℃。MS(APCI+ve)412(M+H)+游离碱1H NMR(DMSO-d6)δ10.62(1H,bs),9.24(1H,s),7.12(1H,t),6.97(1H,d),6.82(1H,d),4.42(2H,t),3.50(4H,m),3.05(2H,m),2.10(2H,s),2.05(3H,s),2.0(3H,s),1.90-1.50(18H,m)
实施例34
按照实施例27的方法,从N-(5-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺和吗啉盐酸盐(0.040ml)制备,通过超临界流体色谱在Cyano柱上纯化,用0.1%v/v二乙胺的甲醇溶液和超临界二氧化碳进行梯度洗脱,得到纯产物,把纯产物溶于二氯甲烷中,用1.0MHCl的乙醚溶液处理,减压下蒸馏,得到白色固体的标题化合物(0.085g)。
熔点:204-205℃。MS(APCI+ve)384(M+H)+游离碱.1H NMR(DMSO-d6)δ9.22(1H,s),7.60(1H,s),7.27(2H,s),4.30(2H,d),4.0(2H,m),3.8-3.6(4H,m),3.40-2.8(7H,m),2.25(3H,s),2.15(2H,s),2.0(3H,s),1.60(12H,m)
实施例35
按照实施例1b)的方法,从1-金刚烷乙酰氯(0.040g)和5-氨基-3-(2-二甲基氨基乙基)吲哚二盐酸盐(0.18g)制备,通过超临界流体色谱在Cyano柱上纯化,用0.1%v/v二乙胺的甲醇溶液和超临界二氧化碳进行梯度洗脱,得到纯产物,把纯产物溶于二氯甲烷中,用1.0M HCl的乙醚溶液处理,在减压下蒸馏,得到浅黄色固体的标题化合物(0.031g)。
熔点:145-147℃。MS(APCI+ve)380(M+H)+游离碱1H NMR(DMSO-d6)δ10.89 (1H,s),9.58(1H,s),7.95(1H,d),7.25(1H,dd),7.15(1H,d),7.12(1H,dd),3.33(2H,m),3.05(2H,m),2.85(6H,2s),2.03 (2H, s),1.95(3H,s),1.60(12H,m)
实施例36
把按照实施例1a)所述方法制备的1-金刚烷乙酰氯(0.2g)的溶液加入3-氨基-4-甲基噻吩-2-甲酸甲酯(0.16g)的吡啶(2ml)和二氯甲烷(4ml)溶液中。室温下搅拌反应混合物2天,然后用乙酸乙酯稀释。有机相用稀盐酸和水洗涤,通过硫酸镁干燥,最后减压下浓缩,得到油状物。通过硅胶色谱纯化残留物,用10%乙酸乙酯的异己烷溶液洗脱,得到白色固体的标题化合物(0.049g)。
熔点:124-124.5℃。MS(APCI+ve)348(M+H)+ 1H NMR(CDCl3)δ8.76(1H,s),7.13(1H,s),3.86(3H,s),2.23(3H,s),2.18(2H,s),2.0(3H,bs),1.70(12H,m).
实施例37
N-(3-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
把偶氮二甲酸二乙酯(0.20ml)加入N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.20g,实施例26)、甲醇(0.10ml)和三苯基膦(0.41g)的甲苯(10ml)和四氢呋喃(5ml)溶液中。室温下搅拌2小时后,再次加入三苯基膦(0.20g)和偶氮二甲酸二乙酯(0.10ml),把溶液搅拌2小时。减压下浓缩反应混合物,残留物通过硅胶色谱纯化,用二氯甲烷∶乙酸乙酯(19∶1)洗脱,得到无色固体的标题化合物(0.20g)。
熔点:173-175℃。MS(APCI+ve)314(M+H)+ 1H NMR(CDCl3)δ7.48(1H,d),7.16(1H,t),6.86(1H,bs),6.69(1H,d),3.82(3H,s),2.13(5H,s),2.00(3H,s),1.75-1.6(12H,m).
实施例38
N-(2-甲基-3-(2-(1-咪唑基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
把偶氮二甲酸二乙酯(0.060ml)加入N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.100g,实施例26)、1-(2-羟基乙基)咪唑(0.048g,J.Heterocyclic Chem.,1990,27,215)和三苯基膦(0.097g)的四氢呋喃(4ml)溶液中。室温下搅拌24小时后,再次加入三苯基膦(0.100g)和偶氮二甲酸二乙酯(0.060ml),把溶液搅拌6天。减压下浓缩反应混合物,残留物通过NPHPLC使用Gilson自动色谱仪在Novapak柱上纯化,用0-10%乙醇的二氯甲烷溶液洗脱,得到油状物,用乙醚研制该油状物,得到无色固体的标题化合物(0.041g)。
熔点:119.5-121℃。MS(APCI+ve)394(M+H)+ 1H NMR(CDCl3)δ7.60 (1H,s),7.51(1H,d),7.14(1H,t),7.08(1H,s),7.03(1H,s),6.85(1H,bs),6.61(1H,d),4.37(2H,t),4.21(2H,t),2.13(2H,s),2.09(3H,s),2.00(3H,s),1-8-1.6(12H,m).
实施例39
把亚硫酰氯(3ml)加入1-金刚烷乙酸(0.50g)中,加热回流反应混合物2分钟。通过减压下蒸馏除去过量的亚硫酰氯,把残留物溶于二氯甲烷(5ml)中。在室温下,用1分钟的时间把该溶液加入2,4,6-三甲基苯胺(0.72ml)的二氯甲烷(20ml)和三乙胺(1ml)溶液中。5分钟后,在减压下浓缩反应混合物,把残留物加到硅胶柱上。通过色谱纯化混合物,用二氯甲烷洗脱,然后用二氯甲烷∶乙酸乙酯(9∶1)洗脱,得到无色固体的标题化合物(0.469g)。
熔点:212-215℃。MS(APCI+ve)312(M+H)+ 1H NMR(DMSO-d6)δ8.97(1H,s),6.85(2H,s),2.21(3H,s),2.10(6H,s),2.06(2H,s),1.95(3H,s),1.8-1.5(12H,m).
实施例40
使用偶氮二甲酸二乙酯(1.05ml)、N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.506g,实施例12)、N-(3-羟基丙基)氨基甲酸叔丁基酯(1.15g)和三苯基膦(1.75g),按照实施例2的方法,制得黄色固体的标题化合物(0.21g)。
熔点:145℃(分解)。MS(APCI+ve)357(M-HCl+H)+ 1H NMR(DMSO-d6)δ9.05(1H,s),7.91(3H,bs),7.15-7.05(2H,m),6.66(1H,dd),3.99(2H,t),2.94(2H,t),2.13(3H,s),2.10(2H,s),2.05-1.9(5H,m),1.75-1.55(12H,m).
实施例41
把偶氮二甲酸二乙酯(0.50ml)加入N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.50g,实施例12)、N-(3-羟基丙基)-N-甲基氨基甲酸叔丁基酯(0.60g,J.Org.Chem.,1988,53(10),2229)和三苯基膦(0.88g)的四氢呋喃溶液(5ml)中。室温下搅拌溶液19小时后,再加入三苯基膦(0.90g)和偶氮二甲酸二乙酯(0.50ml)。室温下搅拌4小时后,再次加入三苯基膦(0.90g)和偶氮二甲酸二乙酯(0.50ml),把反应混合物搅拌3天。然后在减压下浓缩反应混合物,残留物通过硅胶色谱纯化,用二氯甲烷∶乙酸乙酯(9∶1)洗脱,得到的产物进一步通过色谱使用Gilson自动色谱仪在Dynamax柱上纯化,用异己烷∶乙酸乙酯(4∶1)洗脱,得到Mitsunobu反应产物(0.29g),把该产物溶于甲醇(10ml)中。然后向溶液中加入HCl溶液(通过0℃下把乙酰氯(12ml)缓慢地加入甲醇(10ml)中而产生,小心!放出大量的热),在室温下搅拌反应混合物1小时。然后在减压下浓缩反应混合物,得到黄色固体的标题化合物(0.13g)。MS(APCI+ve)371(M-HCl+H)+ 1H NMR(DMSO-d6)δ9.05(1H s),8.76(2H,bs),7.15-7,05(2H,m),6.66(1H,dd),3.99(2H,t),3.1-2.95(2H,m),2.6-2.5(3H,n),2.13(3H,s),2.10(2H,s),2.1-2.0(2H,m),1.94(3H,m),1.75-1.55(12H,m).
实施例42
N6-(三环[3.3.1.13.7]癸烷-1-乙酰基)腺嘌呤
向实施例1a)得到的1-金刚烷乙酰氯(0.226g)的二氯甲烷(5ml)溶液中加入4-硝基苯酚(0.149g),室温下搅拌反应混合物1小时,然后减压下浓缩。所得的4-硝基苯酚酯不需要进一步纯化就可使用。
向4-硝基苯酚酯(0.209g)、腺嘌呤(0.09g)的二甲基亚砜(1.4ml)悬浮液中加入三乙胺(0.19ml),把反应混合物加热到90℃维持2天,然后冷却到室温。把反应混合物倒入碳酸氢钠水溶液中,用乙酸乙酯萃取。合并后的有机萃取液用水(3次)、盐水洗涤,干燥(硫酸钠),减压下浓缩。用异己烷和乙醚研制残留物,得到浅黄色的固体产物(0.036g)。
熔点:309℃(分解)。MS(APCI+ve)312(M+H)+ 1H NMR (DMSO-d6)δ12.10(1H,s),11.06(1H,s),8.61(1H,s),8.40(1H,s),2.29(2H,s),1.92(3H,s),1.66(6H,d),1.60 (6H,m).
实施例43
N-(3,5-二甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
a)3,5-二甲氧基-2-甲基苯甲酸
向3,5-二甲氧基-2-甲基苯甲酸甲酯(5.83g,J.C.S.Perkin I,1973,2853)的甲醇(80ml)溶液中加入氢氧化钠水溶液(10%,80ml),室温下搅拌反应混合物1小时。然后减压下把反应混合物浓缩到原来体积的一半,然后加入盐酸水溶液(200ml)。用乙酸乙酯(2×250ml)萃取生成的白色沉淀。合并后的萃取液通过无水硫酸镁干燥,过滤,减压下浓缩,得到无色固体的小标题化合物(5.41g)。1H NMR(CDCl3)δ7.10(1H,d),6,64(1H,d),3.84(6H,s),2.45(3H,s).
b)N-(3,5-二甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
向3,5-二甲氧基-2-甲基苯甲酸(1.0g)的叔丁醇(30ml)溶液中加入三乙胺(0.8ml),然后加入二苯基磷酰基叠氮化物(1.2ml),回流温度下加热混合物12小时。冷却反应混合物,减压下浓缩。残留物在氢氧化钠水溶液(2M,100ml)和二氯甲烷(300ml)之间分配。有机相通过无水硫酸钠干燥,过滤,减压下浓缩,得到油状物(0.74g),把该油状物溶于甲醇(10ml)中。然后向溶液中加入HCl溶液(通过在0℃下把乙酰氯(12ml)缓慢地加入甲醇(10ml)中而产生,小心!放出大量的热),在室温下搅拌反应混合物1小时。减压下浓缩反应混合物,残留物在饱和碳酸氢钠水溶液(100ml)和二氯甲烷(100ml)之间分配。有机相通过硫酸镁干燥,过滤,减压下浓缩,得到油状物(0.5g),把该油状物溶于二氯甲烷(10ml)和三乙胺(2ml)中。向溶液中加入1-金刚烷乙酰氯(从1-金刚烷乙酸(0.50g)和亚硫酰氯产生)的二氯甲烷(5ml)溶液,室温下搅拌混合物2小时。反应混合物用二氯甲烷(100ml)稀释,溶液用盐酸水溶液(2M,50ml)洗涤,然后用饱和碳酸氢钠水溶液(50ml)洗涤。有机相通过无水硫酸镁干燥,过滤,减压下浓缩。残留物通过硅胶柱色谱纯化,用二氯甲烷洗脱,然后用二氯甲烷∶乙酸乙酯(19∶1)洗脱,得到无色固体的标题化合物(0.54g)。
熔点:201-203℃。MS(APCI+ve)344(M+H)+ 1H NMR(DMSO-d6)δ9.08(1H,s),6.61(1H,d),6.38(1H,d),3.76(3H,s),3.70(3H,t),2.07(2H,s),1.94(6H,s),1.75-1.55(12H,m).
实施例44
N-(3-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
依次把干燥的二氯甲烷(40ml)、三苯基膦(3.28g)、咪唑(1.05g)和碘(3.85g)混合。加入N-(3-羟基丙基)-N-甲基氨基甲酸叔丁基酯(1.90g,J.Org.Chem.,1988,53(10),2229)的二氯甲烷(10ml)溶液,室温下搅拌所得的反应混合物1小时。然后加入硫氢化钠(6g,溶于100ml中)的水溶液,分离出有机层。有机层通过无水硫酸镁干燥,过滤,减压下浓缩。通过硅胶柱色谱纯化残留物,用异己烷∶乙醚(7∶3)洗脱,得到N-(3-碘代丙基)-N-甲基氨基甲酸叔丁基酯(2.54g),立刻使用该产物。
向N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.453g,实施例26)的乙腈(35ml)悬浮液中加入碳酸铯(0.655g),100℃下加热混合物10分钟。冷却到室温后,加入N-(3-碘代丙基)-N-甲基氨基甲酸叔丁基酯(0.600g)的乙腈(5ml)溶液,加热回流反应混合物90分钟。减压下浓缩反应混合物,残留物在二氯甲烷(100ml)和水(100ml)之间分配。有机层通过无水硫酸镁干燥,过滤,减压下浓缩。残留物通过硅胶色谱纯化,用二氯甲烷∶乙酸乙酯(9∶1)洗脱,得到固体,把该固体溶于甲醇(10ml)中。然后向溶液中加入HCl溶液(通过在0℃下把乙酰氯(12ml)缓慢地加入甲醇(15ml)中而产生,小心!放出大量的热),在室温下搅拌反应混合物1小时。然后减压下浓缩反应混合物,得到胶状物,在乙醚∶己烷(1∶1)中刮磨该胶状物,得到浅黄色粉末状的标题化合物(0.477g)。MS(APCI+ve)371(M-HCl+H)+ 1H NMR (DMSO-d6)δ9.20(1H,s),8.82(2H,bs),7.10(1H,t),6.94(1H,d),6.78(1H,d),4.05(2H,t),3.15-3.0(2H,m),2.58(3H,t),2.15-2.0(7H,m),1.94(3H,m),1.75-1.55(12H,m).
实施例45
N-(5-(3-(N,N-二甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐
把碳酸铯(1.31g)加入N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.473g,实施例26)的乙腈(35ml)悬浮液中,80℃下加热混合物5分钟。冷却到室温后,加入固体N,N-二甲基-3-氯丙胺(0.274g),把反应混合物回流过夜。在减压下浓缩反应混合物,残留物在二氯甲烷(100ml)和水(100ml)之间分配。有机层通过无水硫酸钠干燥,过滤,减压下浓缩。残留物通过硅胶色谱纯化,用二氯甲烷∶乙醇∶三乙胺(95∶4∶1)洗脱,得到黄色胶状物。把该胶溶于甲醇(10ml)中,用过量的HCl乙醚化物(1M,5当量)处理。减压下浓缩溶液,得到胶状物,乙醚(20ml)中搅拌该胶2天,得到一固体,过滤分离出该固体(0.588g)。MS(APCI+ve)385(M-HCl+H)+ 1H NMR (DMSO-d6)δ 10.33(1H,bs),9.21(1H,s),7.10(1H,t),6.94 (1H,d),6.78(1H,d),4.04 (2H,t),3.3-3.1(2H,m),2.79(6H,d),2.2-2.1(2H,m), 2.08 (2H, s),2.05(3H,s),1.95(3H,s),1.75-1.55(12H,m).
实施例46
把亚硫酰氯(3ml)加入1-金刚烷基氧基乙酸(0.38g,CA 1966,65,2149a)中,加热回流反应混合物2分钟。通过减压下蒸馏除去过量的亚硫酰氯,把残留物溶于二氯甲烷(2.5ml)中。在室温下,用1分钟的时间把该溶液加入5-甲氧基-2-甲基苯胺(0.37g)的二氯甲烷(20ml)和三乙胺(1ml)溶液中。3天后,在减压下浓缩反应混合物,把残留物加到硅胶柱上。通过色谱纯化混合物,用二氯甲烷洗脱,然后用二氯甲烷∶乙酸乙酯(19∶1)洗脱,得到固体。把该固体溶于二氯甲烷(75ml)中,用盐酸水溶液(2M,2×30ml)洗涤溶液。有机溶液通过无水硫酸镁干燥,过滤,减压下浓缩。用乙醚∶已烷(1∶1)洗涤残留物,得到无色固体的标题化合物(0.409g)。
熔点:128-130℃。MS (APCI+ve) 330 (M+H)+ 1H NMR (DMSO-d6)δ8.81 (1H,s),7.46 (1H,d),7.12(1H,d),6.65(1H,dd),4.04(2H,s),3.71(3H,s),2.15-2.12(6H,m),1.78(6H,d),1.7-1.5(6H,m).
实施例47
向3-溴代金刚烷乙酸(CN 17768-34-2)(0.123g)的二氯甲烷(5ml)溶液中加入草酰氯(0.5ml),把所得的反应混合物加热回流2小时,然后减压下浓缩。把残留物溶于二氯甲烷(5ml)中,滴加5-甲氧基-2-甲基苯胺(0.062g)和三乙胺(0.2ml)的二氯甲烷(2ml)混合溶液,室温下搅拌反应混合物18小时,然后倒入稀盐酸中,用乙醚萃取。合并后的有机萃取液用水、15%NaOH溶液、盐水洗涤,干燥(硫酸钠),浓缩,留下固体,用乙醚研制该固体,得到白色固体的标题化合物(0.07g)。
熔点:133℃。MS(APCI+ve)392/394(M+H)+ 1H NMR (DMSO-d6)δ9.13(1H,s),7.09(1H,d),7.05(1H,d),6.66(1H,dd),3.70(3H,s),2.28-2.13(11H,m),2.18(2H,s),1.68-1.55(6H,m).
实施例48
N-(5-甲氧基-2-甲基苯基)-(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酰胺
a)(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酸乙酯
把硼氢化钠(0.093g)加入7-氧代双环[3.3.1]壬-3-亚基乙酸乙酯(0.113g,Chem.Pharm.Bull.,1979,27,824)的乙醇(2ml)溶液中,室温下搅拌反应混合物3天,用二氯甲烷(60ml)稀释,用饱和氯化铵水溶液(20ml)洗涤。有机相通过无水硫酸镁干燥,过滤,减压下浓缩。残留物通过硅胶柱色谱纯化,用二氯甲烷洗脱,然后用二氯甲烷∶乙醚(9∶1)洗脱,得到油状的小标题化合物(0.078g)。1H NMR (CDCl3)δ4.15(2H,q),4.09(1H,bs),2.37(2H,s),2.16(2H,bs),2.2-1.5(10H,m),1.27(3H,t).
b)N-(5-甲氧基-2-甲基苯基)-(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酰胺
把氢氧化钠水溶液(10%,2ml)加入(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酸乙酯(66mg)的乙醇(2ml)溶液中。室温下搅拌1小时后,减压下除取溶剂。残留物在盐酸水溶液(2M,6ml)和二氯甲烷(2×20ml)之间分配。有机萃取液通过无水硫酸镁干燥,过滤,减压下浓缩,得到(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酸。向酸中加入亚硫酰氯(3ml),加热回流反应混合物2分钟。通过减压浓缩除去过量的亚硫酰氯,然后把残留物溶于二氯甲烷(5ml)中。然后室温下用1分钟的时间把该溶液加入5-甲氧基-2-甲基苯胺(69mg)的二氯甲烷(5ml)和三乙胺(1ml)溶液中,维持20分钟。用二氯甲烷把反应混合物稀释到60ml,然后用盐酸水溶液(2M,30ml)洗涤。有机相通过无水硫酸镁干燥,过滤,减压下浓缩。残留物通过硅胶柱色谱纯化,用二氯甲烷洗脱,然后用二氯甲烷∶乙醚(19∶1)洗脱,用异己烷研制,得到无色固体(0.05g)。
熔点:108-109.5℃。MS(APCI+ve)316(M+H)+ 1H NMR(DMSO-d6)δ9.12(1H,s),7.39(1H,d),7.08 (1H,d),6.61(1H,dd),4.09(1H,bs),3.69 3H,s),2.37(2H,s),2.15-2.05(2H,m),2.13(3H, s), 1-9-1.55 (10H, m).
实施例49
a)N-(5-甲氧基-2-甲基苯基)-2-氯乙酰胺
在0-5℃下,向5-甲氧基-2-甲基苯胺(7.62g)和三乙胺(15.5ml)的二氯甲烷(150ml)溶液中滴加氯代乙酰氯(5.0ml),然后移去冰浴。搅拌所得的反应混合物45分钟,然后倒入稀HCl中,用乙酸乙酯萃取。合并后的有机萃取液用水洗涤,干燥(硫酸钠),浓缩,得到棕色固体,用乙醚研制该固体,得到灰棕色固体标题化合物(5.7g)。
熔点:89-91℃。1H NMR (DMSO-d6)δ9.58 (1H,s),7.12(1H,d),7.05(1H,d),6.71(1H,dd),4.30(2H,s),3.71(3H,s),2.13(3H,s).
b)N-(5-甲氧基-2-甲基苯基)-2-(三环[3.3.1.13.7]癸烷-1-氨基)乙酰胺
在密封的Wheaton管形瓶中,把步骤a)得到的氯代酰胺(0.092g)、金刚烷胺(0.13g)、二异丙基乙胺(0.17ml)和四氢呋喃(1.5ml)的溶液加热到100℃维持18小时。把反应混合物冷却到室温,倒入水中,用乙醚萃取。合并后的有机萃取液用盐水洗涤,干燥(硫酸钠),浓缩,残留物通过硅胶柱色谱纯化,用0-2%甲醇的二氯甲烷溶液洗脱,得到白色固体标题化合物(0.034g)。
熔点:158℃。MS(APCI+ve)329(M+H)+ 1H NMR(DMSO-d6)δ9.92(1H,s),7.76(1H,d),7.10(1H,d),6.57(1H,dd),3.69(3H,s),3.22(2H,s),2.27 (1H,br s),2.18(3H,s),2.01(3H,s),1.58(12H,s).
实施例50
按照实施例39的方法,从1-金刚烷乙酸(3.0g)和3,5-二甲氧基苯胺(3.0g)制备得到白色固体的标题化合物(4.2g)。
熔点:144-146℃。MS(APCI+ve)330(M+H)+ 1H NMR (DMSO-d6)δ9.69 (1H,S),6.86(2H,d),6.18(1H,t),3.70(6H,s),2.02(2H,s),1.93(3H,s),1.68-1.57(12H,m).
实施例51
在-78℃下,向N-(3,5-二甲氧基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(2.22g)的二氯甲烷(200ml)溶液中加入三溴化硼(60ml 1M的二氯甲烷溶液)。移去冷却浴,室温下搅拌反应混合物3天。通过加入冰(230g)来淬灭反应。剧烈搅拌30分钟后,加入乙酸乙酯(700ml),分离出有机层,干燥并浓缩。残留物通过硅胶柱色谱纯化,用5%乙醇的二氯甲烷溶液洗脱,得到白色固体(1.95g)。一部分固体从热的乙酸乙酯中重结晶,得到浅白色固体的标题化合物。
熔点:239-242℃。MS(APCI+ve)302(M+H)+ 1H NMR(DMSO-d6)δ9.42(1H,s),9.09(2H,s),6.55(2H,d),5.87(1H,t),1.99(2H,s),1.92(3H,s),1.69-1.56(12H,m).
实施例52
N-(3,5-二甲氧基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺
按照实施例46的方法,使用1-金刚烷基氧基乙酸(2.0g)和3,5-二甲氧基苯胺(1.75g)制备得到油状的标题化合物(2.5g)。MS(APCI+ve)346(M+H)+ 1H NMR (DMSO-d6)δ9.23(1H,s),6.94(2H,s),6.23(1H,s),3.98(2H,s),3.71(6H,s),2.12(3H,s),1.76(6H,d),1.59(6H,m).
实施例53
按照实施例2的方法,使用从实施例51得到的N-(3,5-二羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(0.60g)、N-(3-羟基丙基)氨基甲酸叔丁基酯(1.43g)、亚磷酸三丁基酯(2.0ml)和1,1’-(偶氮二羰基)二哌啶(2.05g)制备,得到淡黄褐色固体(0.12g)。MS(APCI+ve)416(M+H)+ 1H NMR(DMSO-d6)δ9.81(1H,s),8.00 (6H,br s),6.91(2H,d),6.22(1H,t),4.00(4H,t),2.93(4H,t),2.04-1.98(9H,m),1.69-1.56(12H,m).
实施例54
N-(2,4,5-三甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺
按照实施例46的方法,从2,4,5-三甲基苯胺(0.30g)和1-金刚烷基氧基乙酸(0.38g,CA 1966,65,2149a)制备得到无色固体的标题化合物(0.41g)。
熔点:138-140℃。MS(APCI+ve)328(M+H)+ 1H NMR(DMSO-d6)δ8.76(1H,s),7.42(1H,s),6.98(1H,s),4.00(2H,s),2.2-2.1(12H,m),1.8-1.75(6H,m),1.65-1.55(6H,m).
实施例55
N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺
把亚硫酰氯(5ml)加入1-金刚烷氧基乙酸(2.00g,CA 1966,65,2149a)中,加热回流反应混合物5分钟。通过减压下蒸馏除去过量的亚硫酰氯,把残留物溶于二氯甲烷(10ml)中。在0℃下,用5分钟的时间把该溶液加入2-甲基-5-羟基苯胺盐酸盐(1.00g,J.Chem.Soc.PerkinTrans.2,1972,539)的二氯甲烷(20ml)和三乙胺(10ml)溶液中。然后使溶液温热到室温,30分钟后,减压下浓缩反应混合物,把残留物溶于甲醇(20ml)和四氢呋喃(10ml)中,用甲醇钠的甲醇溶液(25%重量,10ml)处理。搅拌15分钟后,用甲酸(4ml)处理反应混合物,然后减压下浓缩。残留物在盐酸水溶液(2M,90ml)、乙酸乙酯(90ml)和四氢呋喃(50ml)之间分配,通过无水硫酸镁干燥,过滤,减压下浓缩,得到固体(2.62g)。通过硅胶柱色谱纯化该固体,用二氯甲烷∶乙酸乙酯(4∶1)洗脱,得到无色固体(1.39g)。
熔点:258℃(分解)。MS(APCI+ve)316(M+H)+ 1H NMR (DMSO-d6)δ9.22(1H,s),8.71(1H,s),7.37(1H,d),6.98(1H,d),6.45(1H,dd),4.02(2H,s),2.13(3H,bs),2.10(3H,s),2.15-2.12(6H,m), 1.78 (6H, d),1.7-1.5(6H,m).
实施例56
把N-(2-羟基乙基)-N-甲基氨基甲酸叔丁基酯(1.05g,Synth.Commun.,1993,23(17),2443)、N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺(1.00g,实施例12)、四氢呋喃(40ml)和三丁基膦(1.35ml)混合,在冰/水浴中冷却,然后加入1,1’-(偶氮二羰基)二哌啶(1.39g),搅拌反应混合物10分钟。室温下搅拌90分钟后,再加入N-(2-羟基乙基)-N-甲基氨基甲酸叔丁基酯(1.04g)和三丁基膦(1.35ml),将该溶液再次在冰/水浴中冷却,然后加入1,1’-(偶氮二羰基)二哌啶(1.39g),在冰/水浴中搅拌10分钟,然后在室温下搅拌过夜。用异己烷(50ml)稀释反应混合物并过滤。残留物用乙醚(100ml)洗涤,合并后的有机相减压下浓缩。残留物通过硅胶柱色谱纯化,用异己烷∶乙酸乙酯(7∶3)洗脱,再次通过硅胶柱色谱纯化,用二氯甲烷∶乙酸乙酯(9∶1)洗脱,得到偶合产物(0.57g)。把产物溶于甲醇(10ml)中。然后向溶液中加入盐酸溶液(通过在0℃下把乙酰氯(10ml)缓慢地加入甲醇(15ml)中而得到,小心!放出大量的热),室温下搅拌反应混合物2小时。反应混合物减压下浓缩,然后用乙醚(100ml)研制,得到无色固体的标题化合物(0.35g)。
熔点:193-195℃。MS(APCI+ve)357(M+H)+游离碱1H NMR (DMSO-d6)δ9,06(1H,s),8,91(2H,bs),7.19(1H,6),7.12(1H,d),6.70(1H,dd),4.17(2H,t),3.4-3.25(2H,m),2.61(3H,s),2.15(3H,s),2.11(2H,s),1.95(3H,s),1.75-1.55(12H,m).
实施例57
a)N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺
把亚硫酰氯(5ml)加入1-金刚烷氧基乙酸(2.00g,CA 1966,65,2149a)中,加热回流反应混合物5分钟。通过减压下蒸馏除去过量的亚硫酰氯,把残留物溶于二氯甲烷(10ml)中。在0℃下,用5分钟的时间把该溶液加入2-甲基-5-羟基苯胺盐酸盐(1.00g,J.Chem.Soc.PerkinTrans.2,1972,539)的二氯甲烷(20ml)和三乙胺(10ml)溶液中。然后使溶液温热到室温,30分钟后,减压下浓缩反应混合物,把残留物溶于甲醇(20ml)和四氢呋喃(10ml)中,用甲醇钠的甲醇溶液(25%重量,10ml)处理。搅拌15分钟后,用甲酸(4ml)处理反应混合物,然后减压下浓缩。残留物在盐酸水溶液(2M,90ml)、乙酸乙酯(90ml)和四氢呋喃(50ml)之间分配。分离出有机相,用饱和的氯化钠水溶液(50ml)洗涤,通过无水硫酸镁干燥,过滤,减压下浓缩。残留物通过硅胶柱色谱纯化,用二氯甲烷∶乙酸乙酯(4∶1)洗脱,得到无色固体的小标题化合物(1.39g)。
熔点:258℃(分解)。MS(APCI+ve)316(M+H)+ 1H NMR (DMSO-d6)δ9.22(1H,s),8.71(1H,s),7.37(1H,d),6.98 (1H,d),6.45(1H,dd),4.02(2H,s),2.13(3H,bs),2.10(3H,s),2.15-2.12(6H,m),1.78(6H,d),1.7-1.5(6H,m).
b)N-(5-(2-(N-甲基氨基)乙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺
按照实施例2中所述的方法,使用N-(2-羟基乙基)-N-甲基氨基甲酸叔丁基酯(1.05g,Synth.Comnun.,1993,23(17),2443)和N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺(1.00g,步骤a)制备得到无色固体的标题化合物(0.54g)。
熔点:155-158℃。MS(APCI+ve)373(M-HCl+H)+ 1H NMR (DMSO-d6)δ9.07(2H,bs),8.84(1H,s),7.57(1H,d),7.16(1H,d),6.71(1H,dd),4.20(2H,t),4.05(2H,s),3.30(2H,t),2.60(3H,t), 2.17 (3H, s),2.13(3H,s),1.78(6H, d),1.65-1.55(6H,m).
实施例58
按照实施例56中所述的方法,从N-(3-羟基丙基)-N-甲基氨基甲酸叔丁基酯(1.01g,J.Org.Chem.,1988,53(10),2229)和N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺(1.00g,实施例55)制备得到无色固体的标题化合物(0.50g)。
熔点:151-154℃(分解)。MS(APCI+ve)387(M-HCl+H)+ 1H NMR(DMSO-d6)6 8.91(2H,bs),8.82(1H,s),7.49(1H,d),7.13(1H,d),6.67(1H,dd),4.04(2H,s),4.01(2H,t),3.03(2H,五重峰),2.55(3H,t),2.15(3H,s),2.13(3H,s),2.06(2H,五重峰),1.78(6H,d),1.65-1.55(6H,m).
实施例59
N-(3,5-二羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺
在100℃下,把从实施例43得到的二甲氧基醚(2.0g)在50%氢溴酸的乙酸中的溶液加热12小时。真空浓缩溶液,残留物放入水中,用乙酸乙酯萃取。有机层通过硫酸镁干燥,过滤,真空下浓缩。纯产物通过硅胶色谱纯化,用二氯甲烷的乙酸乙酯溶液洗脱,得到白色固体的标题化合物。
熔点:270℃(分解)。MS(APCI+ve)316(M+H)+ 1H NMR(CDCl3)δ9.09(1H,s);8.91(1H,s);8.86(1H,bs);6.35(1H,d);6,11(4H,d);2.04(2H,s);1.94(3H,bs);1.87(3H,s);1.80-1.50(12H,m).
实施例60
药理分析
已知某些化合物,例如苯甲酰基苯甲酰腺苷三磷酸(bbATP)是P2X7受体的激动剂,影响原生质膜中孢子的形成(Drug DevelopmentResearch(1996),37(3),p.126)。结果,当使用bbATP在溴化3,8-二氨基-5-乙基-6-苯基菲啶鎓(荧光DNA探针)存在下把受体激活时,观察到细胞内与DNA结合的溴化3,8-二氨基-5-乙基-6-苯基菲啶鎓的荧光增强了。可以把这种荧光增强用作P2X7受体活化的量度,从而定量测定化合物对P2X7受体的影响。
按照这种方式试验了实施例1-59的每种标题化合物对P2X7受体的拮抗活性。在96-孔的平底微量滴定板中进行试验,孔中装以250μl试验溶液,该试验溶液含有200μl包含10-4M溴化3,8-二氨基-5-乙基-6-苯基菲啶鎓的THP-1细胞(2.5×106个细胞/ml)悬浮液、25μl包含10- 5bbATP的高钾缓冲液和25μl包含3×10-5M试验化合物的高钾缓冲液。用塑料板覆盖滴定板,在37℃培养1小时,然后把该板放入Perkin-Elmer荧光板读数仪中读取荧光值,其中激发波长为520nm,发射波长为595nm,狭缝宽度为:激发15nm,发射20nm。为了进行比较,试验中单独使用bbATP(一种P2X7受体激动剂)和吡哆醛-5-磷酸盐(一种P2X7受体拮抗剂)作为对照。从得到的读数中计算出每种试验化合物的pIC50值,这个值是为了把bbATP的激动活性减少50%所需要的试验化合物的浓度的负对数。实施例1-59的每种化合物都表现了拮抗活性,其pIC50值>4.50。
Claims (13)
B代表H或卤原子;
D代表基团CH2、OCH2、NHCH2或CH2CH2;
R代表苯基、苯并噻唑基、吲哚基、吲唑基、嘌呤基、吡啶基、嘧啶基或噻吩基,各基团可以视需要被一个或多个独立地选自下述的基团取代:卤原子或氰基、羧基、羟基、硝基、卤代-C1-C6烷基、-N(R1)-C(=O)-R2、-C(O)R3R4、-NR5R6、C3-C8环烷基、3-8员杂环基、C3-C8环烷氧基、C1-C6烷基羰基、苯氧基、苄基、C1-C6烷硫基、苯硫基、C1-C6烷氧羰基、C1-C6烷基亚磺酰基或C1-C6烷基磺酰基、视需要被一个或多个独立地选自下述取代基所取代的C1-C6烷基或C1-C6烷氧基:卤原子或氨基、羧基、羟基、C1-C6烷氧基、(二)C1-C6烷基氨基、C1-C6烷氧羰基、咪唑基、吗啉基、哌啶基或吡咯烷基;
R1代表H或C1-C6烷基或C3-C8环烷基;
R2代表C1-C6烷基或C3-C8环烷基;而
R3、R4、R5和R6各自独立地代表H或C1-C6烷基或C3-C8环烷基;
条件是:当A是CH2,B是H,而D是CH2时,则R不代表苯基、邻羧基苯基、甲基苯基或对苯氧基苯基,而且当A是CH2,D是CH2或CH2CH2、而R代表取代的苯基时,邻位上的取代基不包括被氨基取代的C1-C6烷氧基、(二)C1-C6烷基氨基、咪唑基、吗啉基、哌啶基或吡咯烷基。
2.权利要求1的化合物,其中A代表基团CH2。
3.权利要求1或2的化合物,其中B代表H。
4.权利要求1-3任何一项的化合物,其中D代表基团CH2、OCH2或NHCH2。
5.权利要求1-4任何一项的化合物,其中R代表苯基、苯并噻唑基、吲哚基、吲唑基、嘌呤基、吡啶基或噻吩基,各基团可以视需要被1、2或3个独立地选自下述的基团取代:卤原子或羟基、硝基或C1-C4烷氧基羰基、或者视需要被1或2个独立地选自下述基团取代的C1-C4-烷基或C1-C4-烷氧基:卤原子或氨基、羧基、羟基、C1-C4-烷氧基、(二)C1-C4-烷基氨基、C1-C4-烷氧基羰基、咪唑基、吗啉基、哌啶基或吡咯烷基。
6.权利要求1中定义的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物是:
N-(2-甲基-6-苯并噻唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-(3-(氨基丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-氯苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,4,5-三甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,3-二甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-吲哚基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,3-二甲基-5-吲哚基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-[5-(3-N,N-二甲基氨基丙氧基)-2-甲基苯基]-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-吲唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(6-吲唑基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(1H-吲哚-4-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
4-甲基-3-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]苯氧基-乙酸盐酸盐、
N-(1-甲基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(1-N,N-二甲基氨基)乙基-1H--吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
5-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]-1H-吲哚-1-乙酸-1,1-二甲基乙基酯、
N-(3-(2-氯吡啶基))-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-(N,N-二甲基氨基)甲基-1H-吲哚-5-基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(4-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-氯-5-甲氧基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(4-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-甲氧基-2-甲基-3-硝基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-羟甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-5-(1-吡咯烷甲基)苯基-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-氯-5-羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-氯-4-羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-3-(2-(1-吡咯烷基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-甲氧基甲基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-3-(2-(1-吗啉基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-甲基-3-(2-(1-哌啶基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(2-甲基-5-(1-吗啉基甲基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(3-(2-N,N-二甲基氨基乙基)吲哚基))-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
4-甲基-3-[[1-氧代-2-(三环[3.3.1.13.7]癸-1-基)乙基]氨基]噻吩-2-甲酸甲酯、
N-(3-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2-甲基-3-(2-(1-咪唑啉基)乙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,4,6-三甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(5-(3-氨基丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N6-(三环[3.3.1.13.7]癸烷-1-乙酰基)腺嘌呤、
N-(3,5-二甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(3-(N,N-二甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-甲氧基-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-(3-溴-三环[3.3.1.13.7]癸烷)-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-(2-氧杂-三环[3.3.1.13.7]癸烷)-1-乙酰胺、
N-(5-甲氧基-2-甲基苯基)-2-(三环[3.3.1.13.7]癸烷-1-氨基)乙酰胺、
N-(3,5-二甲氧基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3,5-二羟基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(3,5-二甲氧基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、
N-(3,5-双-(3-氨基丙氧基)苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、
N-(2,4,5-三甲基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、
N-(5-羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷氧基-1-乙酰胺、
N-(5-(2-(N-甲基氨基)乙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺盐酸盐、
N-(5-(2-(N-甲基氨基)乙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸氧基-1-乙酰胺、
N-(5-(3-(N-甲基氨基)丙氧基)-2-甲基苯基)-三环[3.3.1.13.7]癸烷-1-乙酰胺、或
N-(3,5-二羟基-2-甲基苯基)-三环[3.3.1.13.7]癸烷-乙酰胺。
7.一种制备权利要求1中定义的式(Ⅰ)化合物的方法,包括使下列通式中L代表离去基团,而A、B和D如式(Ⅰ)中所定义的化合物与R如式(Ⅰ)中所定义的通式(Ⅲ)R-NH2化合物反应,并且视需要制成其药学上可接受的盐或溶剂化物。
8.一种药物组合物,含有权利要求1-6中任何一项所述的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物,并与药学上可接受的助剂、稀释剂或载体相结合。
9.一种制备权利要求8中所述药物组合物的方法,包括把权利要求1-6中任何一项所定义的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物与药学上可接受的助剂、稀释剂或载体混合。
10.权利要求1-6中任何一项所述的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物于治疗中的应用。
11.权利要求1-6中任何一项所述的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物在治疗类风湿性关节炎中的应用。
12.权利要求1-6中任何一项所述的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物在生产治疗用药物中的应用。
13.进行免疫抑制的方法,包括给患者施用治疗有效量的权利要求1-6中任何一项所述式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物。
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CN100450994C (zh) * | 2002-12-23 | 2009-01-14 | 詹森药业有限公司 | 制备1-羟基-4-氨基金刚烷的方法 |
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CN103319493A (zh) * | 2012-03-19 | 2013-09-25 | 艾琪康医药科技(上海)有限公司 | 一种合成1-羟甲基-3-氢-2-氧杂金刚烷及其衍生物的方法 |
CN103319493B (zh) * | 2012-03-19 | 2016-02-10 | 艾琪康医药科技(上海)有限公司 | 一种合成1-羟甲基-3-氢-2-氧杂金刚烷及其衍生物的方法 |
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CN107207416B (zh) * | 2014-08-29 | 2020-02-07 | 株式会社爱茉莉太平洋 | 新型金刚烷衍生物化合物 |
CN109956973A (zh) * | 2017-12-25 | 2019-07-02 | 上海启甄环境科技有限公司 | 一种放射性同位素碳-14标记毒氟磷的合成方法 |
CN109956973B (zh) * | 2017-12-25 | 2020-11-03 | 上海启甄环境科技有限公司 | 一种放射性同位素碳-14标记毒氟磷的合成方法 |
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HUP0100431A2 (hu) | 2001-07-30 |
HK1028594A1 (en) | 2001-02-23 |
DE69812159T2 (de) | 2003-12-18 |
TR200001558T2 (tr) | 2000-10-23 |
KR20010032708A (ko) | 2001-04-25 |
DK1036058T3 (da) | 2003-06-30 |
US6242470B1 (en) | 2001-06-05 |
WO1999029660A1 (en) | 1999-06-17 |
PT1036058E (pt) | 2003-07-31 |
CA2312889A1 (en) | 1999-06-17 |
RU2197477C2 (ru) | 2003-01-27 |
SK8412000A3 (en) | 2000-11-07 |
EP1036058B1 (en) | 2003-03-12 |
PL340890A1 (en) | 2001-03-12 |
DE69812159D1 (de) | 2003-04-17 |
ES2195433T3 (es) | 2003-12-01 |
AU1791499A (en) | 1999-06-28 |
JP2001525391A (ja) | 2001-12-11 |
BR9813368A (pt) | 2000-10-03 |
EE200000320A (et) | 2001-08-15 |
IL136503A0 (en) | 2001-06-14 |
AU746716B2 (en) | 2002-05-02 |
NO20002785D0 (no) | 2000-05-31 |
NZ504375A (en) | 2003-08-29 |
NO20002785L (no) | 2000-08-01 |
EP1036058A1 (en) | 2000-09-20 |
ATE234274T1 (de) | 2003-03-15 |
SE9704545D0 (sv) | 1997-12-05 |
HUP0100431A3 (en) | 2002-12-28 |
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