CN1284057A - 金刚烷衍生物 - Google Patents
金刚烷衍生物 Download PDFInfo
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- CN1284057A CN1284057A CN98813491A CN98813491A CN1284057A CN 1284057 A CN1284057 A CN 1284057A CN 98813491 A CN98813491 A CN 98813491A CN 98813491 A CN98813491 A CN 98813491A CN 1284057 A CN1284057 A CN 1284057A
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Abstract
本发明提供了金刚烷衍生物,它们的制备方法,包含它们的药物组合物,制备这类药物组合物的方法,以及它们在治疗中的应用。通式(Ⅰ)化合物中,x代表1或2;A代表基团CH2或氧原子;B代表氢或卤原子;R代表苯基,吡啶基,吲哚基,嘧啶基或噻吩基基团,它们各自可任选地被一个或多个取代基取代。
Description
本发明涉及金刚烷衍生物、它们的制备方法、包含它们的药物组合物、制备这类药物组合物的方法、以及它们在治疗中的应用。
金刚烷衍生物是本领域中已知的。例如由WO95/04720可得知用作胃泌素和缩胆囊素受体配体的金刚烷衍生物,从化学文摘(Chem.Abs.)(1977),Vol.86,No.13(86:89560d)可得知用作止痛剂的金刚烷衍生物,以及自US-A-3464998可得知用作抗生素的金刚烷衍生物。
P2X7受体(早先称作P2Z受体)是一种配体门控离子通道,存在于多类大多都参与炎症/免疫过程的细胞上,特别是巨噬细胞、肥大细胞和淋巴细胞(T和B)。P2X7受体被胞外核苷酸(特别是三磷酸腺苷)激活后能导致白细胞介素-1β(IL-1β)释放和巨细胞形成(巨噬细胞/小神经胶质细胞)、脱粒(肥大细胞)以及L-选择蛋白脱落(淋巴细胞)。P2X7受体还位于抗原呈递细胞(APC)、角质化细胞、唾液腺泡细胞(腮腺细胞)和肝细胞上。
人们期望制备出能有效地作为P2X7受体拮抗剂而用于治疗炎症、免疫或心血管疾病的化合物,就这些疾病的病因学而言P2X7受体在其中起一定作用。
本发明提供了下述通式化合物或其可药用的盐和溶剂化物:其中x代表1或2;A代表基团CH2或氧原子;B代表氢或卤原子(如氟,溴,碘,尤其是氯);R代表苯基、吡啶基、吲哚基、吲唑基、嘧啶基或苯硫基基团,它们各自可任选地被一个或多个独立选自如下的取代基取代:卤原子或氨基、氰基、羧基、羟基、硝基、C1-C6-烷基、卤代-C1-C6-烷基、-N(R1)-C(=O)-R2、-C(O)NR3R4、-NR5R6、C3-C8-环烷基、3-至8-元杂环基、C3-C8-环烷氧基、C1-C6-烷基羰基、C1-C6-烷氧基羰基、C1-C6-烷基亚硫酰基或C1-C6-烷基磺酰基基团,或任选被一个或多个独立选自下述取代基取代的C1-C6-烷氧基、C1-C6-烷基氨基、苯氧基、苄基、C1-C6-烷硫基或苯硫基基团:卤原子或氨基、氰基、羧基、羟基、硝基、1-吡咯烷基、1-哌啶基、C1-C6-烷基、C1-C6-烷氧基、(二)C1-C6-烷基氨基、卤代-C1-C6-烷基、C1-C6-烷氧基羰基或下述基团之一:R1代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R2代表C1-C6-烷基或C3-C8环烷基;R3和R4各自独立地代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R5代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R6代表C3-C8-环烷基,另外,当R5不为氢原子时还代表C1-C6-烷基;R7代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R8代表C1-C6-烷基或C3-C8-环烷基;R9代表氢原子或羟基;以及R10代表氢原子或苯基或咪唑基基团;条件是当A代表基团CH2和B代表氢原子时,R不能代表未取代的吡啶基,以及当R代表取代的苯基、吲哚基或吲唑基时,其邻位上存在的取代基不包括酰氨基,羧基,(二)C1-C6-烷基氨基或C1-C6-烷氧基羰基。
本说明书中,除非另有说明,烷基取代基或取代基基团中的烷基部分可以是直链或支链的。而且,二烷基氨基、二环烷基氨基、二烷基酰氨基或二环烷基酰氨基取代基中的(环)烷基部分可以相同或不同。3-至8-元杂环基应理解为是指含有单个选自氮、氧或硫杂原子的脂族杂环系统。术语“邻位上”是指R的苯基、吲哚基或吲唑基环上与酰胺连接基在R上的连接位置相邻的环位置,例如如下式所示,其中星号表示“邻位”:
优选R代表苯基、吡啶基、吲哚基、吲唑基、嘧啶基或苯硫基基团,它们各自可任选地被一个、两个、三个或四个独立选自如下的取代基所取代:卤原子(如氟,氯,溴或碘)或氨基、氰基、羧基、羟基、硝基、C1-C6-烷基(如甲基,乙基,丙基,丁基,戊基或己基)、卤代-C1-C6-烷基(如三氟甲基)、-N(R1)-C(=O)-R2、-C(O)NR3R4、-NR5R6、C3-C8-环烷基(如环丙基,环丁基,环戊基或环己基)、3-至8-元杂环基(如氮丙啶基,吡咯烷基,哌啶基)、C3-C8-环烷氧基(如环丙基氧基,环丁基氧基,环戊基氧基或环己基氧基)、C1-C6-烷基羰基(如甲基-、乙基-、丙基-、丁基-、戊基-或己基羰基)、C1-C6-烷氧基羰基(如甲氧基-、乙氧基-、丙氧基-、丁氧基-、戊氧基-或己氧基羰基)、C1-C6-烷基亚硫酰基(如甲基-、乙基-、丙基-、丁基-、戊基-或己基亚硫酰基),或C1-C6-烷基磺酰基(如甲基-、乙基-、丙基-、丁基-、戊基-或己基磺酰基)基团,或任选被一个、两个、三个或四个独立选自下述取代基取代的C1-C6-烷氧基(如甲氧基,乙氧基,丙氧基,丁氧基,戊氧基或己氧基)、C1-C6-烷基氨基(如甲基-、乙基-、丙基-、丁基-、戊基-或己基氨基)、苯氧基、苄基、C1-C6-烷硫基(如甲基-、乙基-、丙基-、丁基-、戊基-或己基硫基)或苯硫基基团:卤原子(如氟,氯,溴或碘)或氨基,氰基,羧基,羟基,硝基,1-吡咯烷基,1-哌啶基,C1-C6-烷基(如甲基,乙基,丙基,丁基,戊基或己基),C1-C6-烷氧基(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(如二甲氨基或二乙基氨基),卤代-C1-C6-烷基(如三氟甲基),C1-C6-烷氧基羰基(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)或下述基团之一:
更优选R代表苯基、吡啶基或吲哚基,它们各自可任选地被一个或两个独立选自如下的取代基取代:氟、氯、溴或碘原子或氨基、羟基、硝基、氮丙啶基、吡咯烷基、C1-C4-烷基(特别是甲基)、三氟甲基、-NR5R6、C1-C4-烷基亚硫酰基(特别是甲基亚硫酰基)或C1-C4-烷基磺酰基(特别是甲磺酰基)基团,或被-个或两个独立选自下述取代基任选取代的C1-C4-烷氧基(尤其是C1-C2-烷氧基)、C1-C4-烷基氨基(尤其是C1-C2-烷基氨基)、苄基、C1-C4-烷硫基(尤其是C1-C2-烷硫基)或苯硫基基团:卤原子(尤其是氯原子)或氨基,氰基,羧基,羟基,1-吡咯烷基,1-哌啶基,甲基,甲氧基,二甲氨基,C1-C4-烷氧基羰基(尤其是叔丁氧羰基)或下述基团之一:
R1优选代表氢原子或C1-C4-烷基(如甲基、乙基、丙基或丁基)或C3-C6-环烷基(如环戊基或环己基)。
优选R2代表C1-C4-烷基(如甲基、乙基、丙基或丁基)或C3-C6-环烷基(如环戊基或环己基)。
优选R3和R4各自独立地代表氢原子或C1-C4-烷基(如甲基、乙基、丙基或丁基)或C3-C6-环烷基(如环戊基或环己基)基团。
优选R5代表代表氢原子或C1-C4-烷基(如甲基、乙基、丙基或丁基,尤其是甲基)或C3-C6-环烷基(如环戊基或环己基)基团,以及R6代表C3-C6-环烷基(如环戊基或环己基),另外当R5不为氢原子时还代表C1-C4-烷基(如甲基、乙基、丙基或丁基,尤其是甲基)。
优选R7代表氢原子或C1-C4-烷基(如甲基、乙基、丙基或丁基)或C3-C6-环烷基(如环戊基或环己基),尤其是甲基。
优选R8代表C1-C4-烷基(如甲基、乙基、丙基或丁基)或C3-C6-环烷基(如环戊基或环己基),尤其是甲基。
本发明的优选化合物包括:2,4-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,3,5-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,6-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-甲氧基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-甲基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-溴-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-碘-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-硝基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,6-二甲氧基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(三氟甲基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,6-二氟-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(三氟甲基)-6-氟-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-氨基-6-氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-氯-4-硝基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(2-氰基苯硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(4-甲基苯硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺,2-(甲硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(甲硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺,3-氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,3-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,5-二甲基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(苯甲基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(2-(N,N-二甲基氨基)乙氧基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,盐酸盐,2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基乙酸1,1-二甲基乙酯,2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基乙酸,2-(甲基亚砜)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺,N-(三环[3.3.1.13,7]癸-1-甲基)-5-吲哚甲酰胺,2-氨基-6-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2-(2-甲基磺酰基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-(2-氨基乙硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,三氟乙酸盐,2-(2-(N,N-二甲基氨基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(2-(吡咯烷-1-基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(甲氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(二甲氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,盐酸盐,2-(吡咯烷-1-基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(2,5-二甲氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-氯-5-甲硫基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-(2-(N,N-二甲基氨基)乙硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-(4-甲氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-氯-3-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-溴-5-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-(2,5-二羟基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,3-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]吡啶基-2-硫代乙酸,(2-氯-6-甲基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,3-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]吡啶基-2-(4-苯硫基)氧基乙酸,2-(4-(3-N,N-二甲基氨基)丙氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,(2-甲硫基-6-甲基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基丁酸,2-氯-5-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-3-硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3-氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,5-氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-3-(N,N-二甲基氨基)乙基氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(N,N-二甲基氨基)乙基氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(N,N-二甲基氨基)乙硫基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,富马酸盐,2-氯-3-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(N,N-二甲基氨基)乙氧基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2,5-二氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-甲基氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,5-氮丙啶-1-基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-甲基-3,5-二硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二氨基-2-甲基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二甲氧基-2-甲基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二甲氧基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,5-(N-(2-羟基-2-苯基乙基)-2-氨基乙基)氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(2-(哌啶-1-基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,盐酸盐,5-(N-(2-羟基乙基)-2-氨基乙基)氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,二盐酸盐,2-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2,3-二氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,5-氨基-2-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2,5-二甲基-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2-氯-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-3-(N-(2-[咪唑-4-基]乙基)-2-氨基乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2,5-二甲基-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二甲氧基-2-甲基-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,和2-氯-5-碘-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺。
其中x,A和B如式(Ⅰ)中定义,与通式(Ⅲ)化合物反应:
其中R的定义同式(Ⅰ),且L为离去基团,如卤原子(例如氯)。咪唑基或脲;并且任选地形成其可药用的盐或溶剂化物。
所述方法可以很方便地在溶剂(如二氯甲烷、四氢呋喃、二氧六环或二甲基甲酰胺)中且任选地有碱(如三乙胺或二异丙基乙胺)存在下进行。该方法适宜在0-100℃的温度范围下操作,优选温度为10-80℃,尤其是室温(20℃)。
式(Ⅱ)和(Ⅲ)化合物是已知化合物,或者可用本领域已知的类似方法制得。
本领域技术人员不难理解,在本发明方法中,中间体化合物中的某些官能团如羟基或氨基可能需要用保护基加以保护。这样,制备式(Ⅰ)化合物的最终阶段可能涉及除去一个或多个保护基的步骤。
有关官能团的保护和脱保护的介绍参见《有机化学中的保护基》[J.W.F.McOmie编辑,Plenum Press(1973)]和《有机合成中的保护基》[第二版,T.W.Greene和P.G.M.Wuts,Wiley-Interscience(1991)]。
上述式(Ⅰ)化合物可转化为可药用的盐或其溶剂化物,优选酸加成盐如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对-甲苯磺酸盐,或者为碱金属盐,如钠盐或钾盐。
一些式(Ⅰ)化合物能够以立体异构体形式存在。因此,应当理解,本发明包括式(Ⅰ)化合物的所有几何和光学异构体及其包括外消旋体在内的混合物。它们的互变异构体及其混合物也构成了本发明的一个方面。
本发明化合物的优越之处在于它们具有药理活性。由此说明它们可作为药物用于治疗或预防下述疾病:类风湿性关节炎,骨关节炎,牛皮癣,变应性皮炎,哮喘,气道过度反应,败血症性休克,肾小球性肾炎,过敏性肠病,节段性回肠炎,溃疡性结膜炎,动脉粥样硬化,恶性细胞的生长与转移,成肌细胞性白血病,糖尿病,Alzheimer病,脑膜炎,骨质疏松症,烧伤,心肌缺血,中风和静脉曲张。
因此,本发明提供了供治疗用的上述式(Ⅰ)化合物,或其可药用的盐和溶剂化物。
另一方面,本发明提供了上述式(Ⅰ)化合物或其可药用的盐和溶剂化物在制备治疗用的药物中的应用。
本发明进一步提供了产生免疫抑制的方法(例如在治疗类风湿性关节炎,过敏性肠病,动脉粥样硬化或牛皮癣的过程中),该方法包括对患者施用治疗有效量的上述式(Ⅰ)化合物,或其可药用的盐或溶剂化物。
对于上述治疗应用,给药剂量当然随所用化合物、给药方式、所期望的治疗效果以及所治病症而变化。
式(Ⅰ)化合物及其可药用的盐和溶剂化物可以以其原有形式使用,但通常以药物组合物形式使用,其中式(Ⅰ)化合物/盐/溶剂化物(活性成分)与可药用的辅助剂、稀释剂或载体相结合。依据给药方式,药物组合物优选包含0.05-99%w(重量百分数),更优选0.10-70%w活性成分,和1-99.95%w(更优选30-99.90%w)可药用的辅助剂、稀释剂或载体,所有重量百分数均以组合物总重量为基础。
为此,本发明还提供了药物组合物,其中包括上述式(Ⅰ)化合物,或其可药用的盐或溶剂化物以及可药用的辅助剂、稀释剂或载体。
本发明进一步提供了制备本发明药物组合物的方法,它包括将上述式(Ⅰ)化合物,或其可药用的盐或溶剂化物与可药用的辅助剂、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、七氟烷烃气雾剂以及干粉制剂形式局部施用(如施于肺脏和/或气道或施于皮肤);或全身性施用,如通过片剂、胶囊剂、糖浆剂、粉剂或颗粒剂形式口服给药,或者通过溶液或悬浮液形式非肠道给药,或通过皮下给药或者以栓剂形式直肠给药或者透皮给药。
参照下列说明性实施例将进一步了解本发明。各例中的术语MS、NMR和DMSO分别表示质谱、核磁共振和二甲亚砜。
实施例12,4-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
向1-金刚烷甲胺(0.1ml)的二氯甲烷(5ml)溶液内加入三乙胺(0.16ml)和2,4-二氯苯甲酰氯(0.118g)。搅拌所得反应混合物2小时,然后用乙醚稀释。随后分离有机相,依次用稀盐酸、碳酸氢钠溶液和盐水洗涤。有机相用硫酸钠(Na2SO4)干燥,减压浓缩后得到白色固体形式标题化合物(0.17g)。熔点:180-182℃MS(APCI+ve)338/340/342(M+H)+ 1H NMR(DMSO-d6)δ8.57(1H,t),7.67(1H,d),7.48(1H,dd),7.42(1H,d),2.93(2H,d),1.94(3H,s),1.66(3H,d),1.60(3H,d),1.51(6H,d)
实施例23,5-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,由1-金刚烷甲胺(0.1ml)和3,5-二氯苯甲酰氯(0.118g)进行制备,得到白色固体形式标题化合物(0.18g)。熔点:197-198℃MS(APCI+ve)338/340/342(M+H)+ 1H NMR(DMSO-d6)δ8.51(1H,t),7.87(2H,d),7.81(1H,dd),2.98(2H,d),1.93(3H,s),1.65(3H,d),1.60(3H,d),1.49(6H,d)
按照实施例1的方法,由1-金刚烷甲胺(0.1ml)和2-氯苯甲酰氯(0.099g)进行制备,得到白色固体形式标题化合物(0.16g)。熔点:148-152℃MS(APCI+ve)304/306(M+H)+ 1H NMR(DMSO-d6)δ8.33(1H,t),7.48(1H,d),7.45-7.37(3H,m),2.93(2H,d),1.94(3H,s),1.66(3H,d),1.60(3H,d),1.52(6H,d)
实施例42,6-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2,6-二氯苯甲酰氯(0.118g)进行制备,得到白色固体形式标题化合物(0.18g)。熔点:246-247℃MS(APCI+ve)338/340/342(M+H)+ 1H NMR(DMSO-d6)δ8.54(1H,t),7.49(2H,dd),7.41(1H,dt),2.93(2H,d),1.94(3H,s),1.67(3H,d),1.59(3H,d),1.54(6H,d)
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-甲氧基苯甲酰氯(0.087g)进行制备,得到树胶状标题化合物(0.16g)。MS(APCI+ve)300(M+H)+ 1H NMR(DMSO-d6)δ8.01(1H,t),7.70(1H,dd),7.46(1H,dt),7.14(1H,dd),7.03(1H,dt),3.90(3H,s),3.00(2H,d),1.95(3H,s),1.67(3H,d),1.61(3H,d),1.51(6H,d)
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-甲基苯甲酰氯(0.078g)进行制备,得到白色固体形式标题化合物(0.13g)。熔点:150-152℃MS(APCI+ve)284(M+H)+ 1H NMR(DMSO-d6)δ8.12(1H,t),7.31(2H,m),7.23(2H,m),2.94(2H,d),2.33(3H,s),1.94(3H,s),1.66(3H,d),1.61(3H,d),1.50(6H,d)
实施例72-溴-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-溴苯甲酰氯(0.111g)进行制备,得到白色固体形式标题化合物(0.17g)。熔点:157-159℃MS(APCI+ve)348/350(M+H)+ 1H NMR(DMSO-d6)δ8.31(1H,t),7.64(1H,dd),7.45-7.31(3H,m),2.92(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.53(6H,d)实施例82-碘-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-碘苯甲酰氯(0.134g)进行制备,得到白色固体形式标题化合物(0.18g)。熔点:194-195℃MS(APCI+ve)396(M+H)+ 1H NMR(DMSO-d6)δ8.25(1H,t),7.86(1H,dd),7.43(1H,dt),7.29(1H,dd),7.15(1H,dt),2.92(2H,d),1.94(3H,s),1.65(6H,m),1.55(6H,d)
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-硝基苯甲酰氯(0.094g)进行制备,得到浅黄色固体形式标题化合物(0.13g)。熔点:>250℃MS(APCI+ve)315(M+H)+ 1H NMR(DMSO-d6)δ8.54(1H,t),8.02(1H,dd),7.78(1H,dt),7.67(1H,dt),7.59(1H,dd),2.93(2H,d),1.94(3H,s),1.67(3H,d),1.62(3H,d),1.52(6H,d)
实施例102,6-二甲氧基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2,6-二甲氧基苯甲酰氯(0.102g)进行制备,得到白色固体形式标题化合物(0.13g)。熔点:185-186℃MS(APCI+ve)330(M+H)+.1H NMR(DMSO-d6)δ7.90(1H,t),7.26(1H,t),6.65(2H,d),3.72(6H,s),2.84(2H,d),1.93(3H,s),1.66(3H,d),1.60(3H,d),1.50(6H,d)
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-(三氟甲基)苯甲酰氯(0.090g)进行制备,得到白色固体形式标题化合物(0.13g)。熔点:165-167℃MS(APCI+ve)338(M+H)+ 1H NMR(DMSO-d6)δ8.36(1H,t),7.76(1H,d),7.72(1H,t),7.63(1H,t),7.51(1H,d),2.93(2H,d),1.94(3H,s),1.67(3H,d),1.61(3H,d),1.51(6H,d)
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2,6-二氟苯甲酰氯(0.090g)进行制备,得到白色固体形式标题化合物(0.14g)。熔点:162-163℃MS(APCI+ve)306(M+H)+ 1H NMR(DMSO-d6)δ8.58(1H,t),7.50(1H,m),7.14(2H,m),2.95(2H,d),1.94(3H,s),1.67(3H,d),1.59(3H,d),1.50(6H,d)
按照实施例1的方法,使用1-金刚烷甲胺(0.1ml)和2-(三氟甲基)-6-氟苯甲酰氯(0.115g)进行制备,得到白色固体形式标题化合物(0.18g)。熔点:151-153℃MS(APCI+ve)356(M+H)+ 1H NMR(DMSO-d6)δ8.57(1H,t),7.68-7.59(3H,m),2.95(2H,d),1.94(3H,s),1.66(3H,d),1.59(3H,d),1.50(6H,d)
向2-氨基-6-氯苯甲酸(0.087g)的N,N-二甲基甲酰胺(1.5ml)溶液中加入羰基二咪唑(0.082g).搅拌所得反应混合物2.5小时,然后加入1-金刚烷甲胺(0.1ml)。继续搅拌过夜。次日将反应混合物分配到乙酸乙酯和水之内,并分离有机层,用水及盐水洗涤,然后以硫酸钠(Na2SO4)干燥。随后减压浓缩有机层,所得残留物通过硅胶色谱纯化(以3-10%甲醇/二氯甲烷洗脱),得到白色固体形式标题化合物(0.072g)。熔点:182-183℃MS(APCI+ve)319/321(M+H)+ 1H NMR(DMSO-d6)δ8.31(1H,t),7.02(1H,t),6.63(1H,d),6.59(1H,d),5.12(2H,s),2.93(2H,d),1.93(3H,s),1.65(3H,d),1.60(3H,d),1.53(6H,d)
实施例152-氯-4-硝基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例14的方法,使用1-金刚烷甲胺(0.1ml)和2-氯-4-硝基苯甲酸(0.102g)进行制备,得到黄色固体形式标题化合物(0.10g)。熔点:154-155℃MS(APCI+ve)348/350(M+H)+ 1H NMR(DMSO-d6)δ8.59(1H,t),8.34(1H,d),8.23(1H,d),7.69(1H,d),2.96(2H,d),1.95(3H,s),1.67(3H,d),1.61(3H,d),1.53(6H,d)
按照实施例14的方法,由1-金刚烷甲胺(0.1ml)和2-(氰基苯硫基)苯甲酸(0.144g)进行制备,得到白色泡沫状标题化合物(0.19g)。熔点:62-65℃MS(APCI+ve)403(M+H)+ 1H NMR(DMSO-d6)δ8.34(1H,t),7.89(1H d),7.81(1H,d),7.55(1H,m),7.44(3H,m),7.25(1H,d),7.18(1H,m),2.92(2H,d),1.88(3H,s),1.62(3H,d),1.54(3H,d),1.41(6H,d)
实施例172-(4-甲基苯硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺
按照实施例14的方法,由1-金刚烷甲胺(0.1ml)和2-(4-甲基苯硫基)吡啶-3-羧酸(0.138g)进行制备,得到白色固体形式标题化合物(0.21g)。熔点:166-169℃MS(APCI+ve)393(M+H)+ 1H NMR(DMSO-d6)δ8.46(1H,t),8.31(1H d),7.77(1H,d),7.34(2H,d),7.20(3H,m),2.97(2H,d),2.33(3H,s),1.95(3H,s),1.67(3H,d),1.61(3H,d),1.55(6H,d)
实施例182-(甲硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例14的方法,由1-金刚烷甲胺(0.1ml)和2-甲硫基苯甲酸(0.095g)进行制备,得到白色蜡状固体形式标题化合物(0.15g)。熔点:171-172℃MS(APCI+ve)316(M+H)+ 1H NMR(DMSO-d6)δ8.16(1H,t),7.4-7.3(3H,m),7.18(1H,dt),2.91(2H,d),2.40(3H,s),1.94(3H,s),1.67(3H,d),1.60(3H,d),1.52(6H,d)
实施例192-(甲硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺
按照实施例14的方法,使用1-金刚烷甲胺(0.1ml)和2-甲硫基吡啶-3-羧酸(0.095g)进行制备,得到白色固体形式标题化合物(0.10g)。熔点:118-120℃MS(APCI+ve)317(M+H)+ 1H NMR(DMSO-d6)δ8.51(1H,dd),8.34(1H,t),7.72(1H,dd),7.17(1H,m),2.93(2H,d),2.44(3H,s),1.94(3H,s),1.67(3H,d),1.61(3H,d),1.52(6H,d)
按照实施例1的方法,由1-金刚烷甲胺(0.1ml)和3-氯苯甲酰氯(0.090g)进行制备,得到白色固体形式标题化合物(0.10g)。熔点:125-126℃MS(APCI+ve)304/306(M+H)+ 1H NMR(DMSO-d6)δ8.41(1H,t),7.89(1H,t),7.81(1H,dt),7.59(1H,ddd),7.50(1H,t),2.98(2H,d),1.93(3H,s),1.65(3H,d),1.60(3H,d),1.49(6H,d)
实施例212,3-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,由1-金刚烷甲胺(0.1ml)和2,3-二氯苯甲酰氯(0.104g)进行制备,得到白色固体形式标题化合物(0.10g)。熔点:175-176℃MS(APCI+ve)338/340/342(M+H)+ 1H NMR(DMSO-d6)δ8.42(1H,t),7.68(2H,dd),7.41(1H,t),7.36(1H,ddd),2.93(2H,d),1.94(3H,s),1.67(3H,d),1.60(3H,d),1.52(6H,d)
实施例222,5-二甲基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
向2,5-二甲基苯甲酸(0.12g)的二氯甲烷(2ml)溶液内加入4-二甲氨基吡啶和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的混合液(2ml,0.41M二氯甲烷溶液)。搅拌反应混合物0.5小时,然后加入1-金刚烷甲胺(2ml,0.45M二氯甲烷溶液)。室温下继续搅拌过夜。次日用稀盐酸、水和盐水洗涤反应混合物,硫酸钠(Na2SO4)干燥,减压浓缩后余下一黄色固体物,进一步用乙醚研制,得到白色固体形式标题化合物(0.12g)。熔点:153-154℃MS(APCI+ve)298(M+H)+ 1H NMR(DMSO-d6)δ8.07(1H,t),7.13(3H,m),2.92(2H,d),2.28(6H,s),1.82(3H,s),1.63(6H,dd),1.50(6H,d)
按照实施例22的方法,使用1-金刚烷甲胺(0.15g)和2-苯甲基苯甲酸(0.17g)进行制备,得到灰白色固体形式标题化合物(0.15g)。熔点:156-157℃MS(APCI+ve)360(M+H)+ 1H NMR(DMSO-d6)δ8.20(1H,t),7.36-7.11(9H,m),4.10(2H,s),2.93(2H,d),1.89(3H,s),1.60(6H,dd),1.46(6H,d)实施例242-(2-(N,N-二甲基氨基)乙氧基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺盐酸盐a)2-羟基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
向1-金刚烷甲胺(0.2 ml)的二氯甲烷(4ml)溶液内加入三乙胺(0.32ml)和2-乙酰氧基苯甲酰氯(0.224g)。室温搅拌反应混合物1.5小时,然后用甲醇稀释。加入碳酸钾(0.50g),并在室温下搅拌所得悬浮液2小时,尔后分配到乙醚和稀盐酸内。分离有机相,盐水洗涤,然后以硫酸钠(Na2SO4)干燥。减压浓缩有机相,得到黄色固体,用异己烷研制,从而获得白色固体形式小标题化合物(0.27g)。MS(APCI+ve)286(M+H)+ 1H NMR(DMSO-d6)δ12.52(1H,s),8.64(1H,t),7.89(1H,dd),7.39(1H,dt),6.91(2H,m),3.03(2H,d),1.94(3H,s),1.66(3H,d),1.60(3H,d),1.50(6H,d)b)2-(2-(N,N-二甲基氨基)乙氧基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺盐酸盐
向如上面步骤a)所述制备的2-羟基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺(0.09g)在乙腈(5ml)的溶液内加入碳酸铯(0.257g),搅拌反应混合物10分钟。加入2-二甲氨基乙基氯盐酸盐(0.055g),并加热回流所得悬浮液1.5小时。反应混合物然后冷却至室温,加乙醚稀释并用水提取。用硫酸钠(Na2SO4)干燥后进行减压浓缩,所得残留物随后通过硅胶色谱纯化,以4%甲醇/二氯甲烷洗脱。减压浓缩含产物馏份,并将所得残留物溶于乙醚。逐滴加入氯化氢(1ml,1M乙醚溶液),用乙醚研制所形成的固体物,然后在真空下干燥,得到白色固体形式标题化合物(0.098g)。熔点:181-183℃MS(PCI+ve)357(M+H)+(游离碱)1H NMR(DMSO-d6)δ10.63(1H,s),8.18(1H,t),7.51(1H,dd), 7.46 (1H, dt),7.19(1H,d),7.08(1H,t),4.47(2H,t),3.48(2H,d),2.97(2H,d),2.84 (6H,s),1.95(3H,s),1.67(3H,d),1.61(3H,d),1.41(6H,d)
实施例252-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基乙酸1,1-二甲基乙基酯
按照实施例24b)的方法,由2-羟基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺(0.10g)和溴乙酸叔丁酯(0.085g)进行制备,得到白色固体形式标题化合物(0.11g)。熔点:101-103℃MS(APCI+ve)400(M+H)+ 1H NMR(DMSO-d6)δ8.33(1H,t),7.86(1H,dd),7.45(1H,dd),7.13(1H d),7.08(1H,dt),4.88(2H,s),3.06(2H,d),1.92(3H,s),1.65(3H,d),1.60(3H,d),1.51(6H,d),1.44(9H,s)
实施例262-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基乙酸
向如上实施例25所述制备的酯(0.085g)在二氯甲烷(0.75ml)的溶液中加入三氟乙酸(1.5ml)。室温搅拌反应混合物3天,然后减压浓缩余下一残留物。随后将此残留物与甲苯一起共蒸发,并将所得的米色固体物用乙醚研制,从而得到白色固体形式标题化合物(0.04g)。熔点:186-187℃MS(APCI+ve)342(M+H)+ 1H NMR(DMSO-d6)δ8.52(1H,t),7.88(1H,dd),7.46(1H,dd),7.14(1Hd),7.08(1H,dt),4.89(2H,s),3.05(2H,d),1.93(3H,s),1.65(3H,d),1.59(3H,d),1.51(6H,d)
向如上实施例19所述制备的酰胺(1.00g)在80%含水甲醇(20ml)中的冰冷溶液内分批加入过一硫酸钾(4.00g)。搅拌2小时后,将反应混合物倒入饱和的偏亚硫酸钠溶液内,并用乙酸乙酯提取。合并的有机提取液依次用偏亚硫酸钠溶液和盐水洗涤,硫酸镁(MgSO4)干燥,最后减压浓缩,得到白色固体形式标题化合物(1.00g)。熔点:214℃MS(APCI+ve)333(M+H)+ 1H NMR(DMSO-d6)δ8.84(1H,dd),8.68(1H,t),8.06(1H,dd),7.65(1H,dd),2.95(1H,m),2.78(3H,s),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
按照实施例14的方法,由1-金刚烷甲胺(0.10ml)和吲哚-5-羧酸(0.09g)进行制备,得到白色固体形式标题化合物(0.09g)。熔点:206-207℃.MS(APCI+ve)309(M+H)+ 1H NMR(DMSO-d6)δ11.28(1H,s),8.13(1H,d),8.09(1H,t),7.62(1H,dd),7.42(1H,t),7.40(1H,d),6.52(1H,m),3.00(2H,d),1.93(3H,s),1.65(3H,d),1.60(3H,d),1.51(6H,d)
实施例292-氨基-6-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺
按照实施例14的方法,由1-金刚烷乙胺盐酸盐(CN 26482-53-1)(0.105g)和2-氨基-6-氯苯甲酸(0.132g)进行制备。经超临界流体色谱(洗脱剂:CO2/乙醇)纯化后,得到白色固体形式标题化合物(0.046g),其中混杂有0.35mol当量咪唑。熔点:132-134℃.MS(APCI+ve)333/335(M+H)+ 1H NMR(DMSO-d6)δ8.26(1H,t),7.01(1H,t),6.72(1H,dd),6.67(1H,dd),5.14(2H,s),3.23(2H,m),1.93(3H,s),1.70-1.59(6H,m),1.51(6H,d),1.31(2H,m).
实施例302-(2-甲基磺酰基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺
向如实施例19所述制备的酰胺(1.00g)在80%含水甲醇(20ml)中的冰冷溶液内分批加入过一硫酸钾(6.00g)。搅拌24小时后,将反应混合物倒入饱和的偏亚硫酸钠溶液内,用乙酸乙酯提取。合并的有机提取液依次用偏亚硫酸钠溶液和盐水洗涤,硫酸镁(MgSO4)干燥,最后减压浓缩,得到白色固体形式标题化合物(1.00g)。熔点:190℃.MS(APCI+ve)349(M+H)+ 1H NMR(DMSO-d6)δ8.84(1H,dd),8.57(1H,t),8.06(1H,dd),7.65(1H,dd),2.95(2H,m),2.78(3H,s),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
实施例312-(2-氨基乙硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,三氟乙酸盐
向实施例30的砜(0.1g)在乙腈(3ml)中的溶液内加入三乙胺(0.04ml)和N-(2-巯基乙基)氨基甲酸叔丁酯(0.054g)。搅拌并加热回流反应混合物24小时。冷却反应混合物,并过滤收集所形成的固体。然后将此固体溶于二氯甲烷(5ml),用三氟乙酸(1.0ml)处理所得溶液。室温搅拌2小时后,减压蒸发反应混合物,残留物用异己烷研制,从而得到白色固体形式标题化合物(0.023g)。熔点:184℃。MS(APCI+ve)346(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.52(1H,dd),8.39(1H,t),7.89(2H,bs),7.83(1H,dd),7.25(1H,dd),3.30(2H,t),3.09(2H,t),2.94(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
向实施例30所得砜(0.1g)的乙腈(3ml)溶液内加入三乙胺(0.04ml)和N,N-二甲基乙二胺(0.030g)。在密封管内于80℃加热搅拌反应混合物48小时。冷却反应混合物,加乙酸乙酯稀释,盐水洗涤并用MgSO4干燥。加入氯化氢/乙醚溶液(1.0ml,1.0M),然后减压蒸发溶剂。残留物用乙腈重结晶,得到白色固体形式标题化合物(0.025g)。熔点:258-260℃MS(APCI+ve)357(M+H)+(游离碱)1H NMR(DMSO)-d6)δ10.1(1H,bs),8.60(1H,bs),8.20(1H,bd),8.15(1H,dd),6.84(1H,t),3.90(2H,bm),3.30(2H,bm),2.95(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
向实施例30所得砜(0.1g)的二甲基甲酰胺(3ml)溶液内加入三乙胺(0.04ml)和N-(2-氨基乙基)吡咯烷(0.050g)。在密封管内于80℃加热搅拌反应混合物24小时,然后冷却至室温,加乙酸乙酯稀释,盐水洗涤并用MgSO4干燥。减压蒸发溶剂,残留物用硅胶色谱纯化,以1-3%甲醇/二氯甲烷洗脱。合并含产物馏份,用氯化氢/乙醚溶液(1.0ml,1.0M)处理,尔后减压蒸发溶剂,得到白色固体形式标题化合物(0.010g)。熔点:266-268℃MS(APCI+ve)383(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.60(1H,bs),8.20(2H,m),6.80(1H,t),3.90(2H,bm),3.40(6H,m),2.95(2H,d),1.94(7H,m),1.66(3H,d),1.62(3H,d),1.51(6H,d)
按照实施例33的方法,使用实施例30所得的砜(0.1g)和甲胺(0.2ml,2.0M四氢呋喃溶液)进行制备,得到白色固体形式标题化合物(0.010g)。熔点:160-162℃MS(APCI+ve)300(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.80(1H,t),8.40(1H,d),8.10(1H,dd),6.90(1H,t),3.05(3H,s),2.98(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
按照实施例33的方法,使用实施例30所得的砜(0.1g)和二甲胺(0.2ml,2.0M四氢呋喃溶液)进行制备,得到白色固体形式标题化合物(0.025g)。熔点:204-205℃MS(APCI+ve)314(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.56(1H,t),8.10(1H,dd),7.90(1H,d),6.95(1H,t),3.05(6H,s),2.98(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
按照实施例33的方法,使用实施例30所得的砜(0.1g)和吡咯烷(0.1ml)进行制备,得到白色固体形式标题化合物(0.009g)。熔点:157-158℃MS (APCI+ve)340(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.56(1H,t),8.05(1H,dd),7.88(1H,d),6.90(1H,t),3.65(4H,bs),2.98(2H,d),1.98(7H,bs),1.66(3H,d),1.62(3H,d),1.51(6H,d)
实施例372-(2,5-二甲氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺
按照实施例14的方法,由1-金刚烷甲胺(0.77g)和2-(2,5-二甲氧基苯硫基)吡啶-3-羧酸(1.36g)进行制备,得到白色固体形式标题化合物(1.20g)。熔点:135-136℃1H NMR(DMSO-d6)δ8.45(1H,t),8.30(1H,dd),7.80(1H,dd),7.20(1H,dd),6.95(3H,m),3.69(3H,s),3.62(3H,s),2.98(2H,d),1.98(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
向2-氯-5-甲硫基苯甲酸(0.2g)和1-羟基苯并三唑(0.13g)在二氯甲烷(10ml)中的溶液内加入1-金刚烷甲胺(0.17ml)。搅拌混合物5分钟,然后加入1,3-二环己基碳二亚胺(0.2g)。继续搅拌过夜。过滤所形成的沉淀物,并减压浓缩滤液。将残留物分配到二氯甲烷和水之间,分离有机层,依次用稀盐酸、碳酸氢钠水溶液和盐水洗涤,然后用硫酸镁(MgSO4)干燥。减压浓缩有机层,残留物用硅胶色谱纯化(以20%乙酸乙酯/异己烷洗脱),得到白色固体形式标题化合物(0.31g)。熔点:126-127℃MS(APCI+ve)350(M+H)+ 1H NMR(CDCl3)δ7.55(1H,s),7.30(1H,d),7.22(1H,dd),6.25(2H,bs),3.18(2H,d),2.49(3H,s),2.01(3H,bs),1.74(3H,d),1.65(3H,d),1,58(6H,d)
实施例392-(2-(N,N-二甲基氨基)乙硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺a)2,2′-二硫代双[N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺]
按照实施例14的方法,由1-金刚烷甲胺(0.23g),4-二甲氨基吡啶(0.006g)和2,2′-二硫代水杨酸(0.2g)进行制备,得到灰白色固体形式小标题化合物(0.12g)。b)2-(2-(N,N-二甲基氨基)乙硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
在氮气氛及搅拌下,向步骤a)产物(0.12g)的乙醇(4.6ml)溶液中分批加入硼氢化钠(0.037g)。搅拌反应混合物0.5h,然后减压蒸发溶剂,残留物用水稀释。所得水溶液用乙酸酸化至pH6,然后用二氯甲烷提取产物。水洗有机提取液,并用硫酸镁(MgSO4)干燥。减压浓缩有机相,得到一油状物(0.11g)。
向上述油在二甲基甲酰胺(5ml)的溶液中加入2-二甲氨基乙基氯盐酸盐(0.063g)和碳酸铯(0.3g)。室温搅拌所得悬浮液过夜。反应混合物用乙酸乙酯稀释并用水洗涤。以硫酸镁(MgSO4)干燥有机提取液,减压浓缩后得到一胶状物,进而用硅胶色谱纯化(以乙酸乙酯和0.1-1%氢氧化铵洗脱),得到一胶状物。向该胶状物的二氯甲烷溶液中滴加氯化氢(2ml,1M乙醚溶液)。减压除去溶剂,残留物用乙酸乙酯和乙醚研制,得到白色固体形式标题化合物(0.03g)。熔点:193-195℃MS(APCI+ve)373/374(M+H)+(游离碱)1H NMR(CDCl3)δ7.62(1H,d),7.42(3H,m),6.13(1H,bs),3.39(2H,m),3.17(4H,m),2.78(6H,s),2.02(3H,bs),1.68(12H,m).
向实施例30所得砜(1.0g)的乙腈(30ml)溶液内加入三乙胺(0.40ml)和4-甲氧基苯硫酚(0.402g)。搅拌下加热回流反应混合物24小时,然后减压浓缩。残留物用硅胶色谱纯化,以乙醚洗脱。合并含产物馏份,减压蒸发后余下白色固体形式标题化合物(0.50g)。熔点:130-131℃1H NMR(DMSO-d6)δ8.45(1H,t),8.31(1H,dd),7.76(1H,dd),7.40(2H,m),7.20(1H,dd),7.0(2H,m),3.30(2H,t),3.09(2H,t),2.94(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
室温下搅拌2-氯-3-氟苯甲酸(0.098g)和羰基二咪唑(0.091g)在N,N-二甲基甲酰胺(3.0ml)中的溶液2.5小时。然后加入1-金刚烷甲胺(0.1ml),继续搅拌过夜。反应混合物分配到乙酸乙酯和2N盐酸内,分离有机层,用10%氢氧化钠水溶液、水和盐水洗涤,然后以硫酸钠(Na2SO4)干燥。随后减压浓缩有机层,得到白色固体形式标题化合物(0.138g)。熔点:149-151℃.MS(APCI+ve)322/324(M+H)+.1H NMR(DMSO-d6)δ8.42(1H,t),7.50-7.40(2H,m),7.29-7.24(1H,m),2.94(2H,d),1.94(3H,s),1.64(6H,dd),1.53(6H,m)
按照实施例41的方法,由1-金刚烷甲胺(0.1ml)和2-溴-5-氟苯甲酸(0.123g)进行制备,得到白色固体形式标题化合物(0.140g)。熔点:143-144℃MS(APCI+ve)322/324(M+H)+ 1H NMR(DMSO-d6)δ8.40(1H,t),7.56-7.52(1H,dd),7.34-7.27(2H,m),2.93(2H,d),1.94(3H,s),1.63(6H,dd),1.52(6H,m)
实施例432-氯-5-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
按照实施例41的方法,由1-金刚烷甲胺(0.1ml)和2-氯-5-氟苯甲酸(0.098g)进行制备,得到白色固体形式标题化合物(0.165g)。熔点:176-177℃MS(APCI+ve)366/367(M+H)+ 1H NMR(DMSO-d6)δ8.37(1H,t),7.71-7.65(1H,dd),7.28-7.20(2H,m),2.92(2H,d),1.94(3H,s),1.64(6H,dd),1.53(6H,d)
-78℃下,向实施例37所得二甲氧基化合物(1.0g)的二氯甲烷(20ml)溶液中加入三溴化硼(5.5ml,1M二氯甲烷溶液)。搅拌反应混合物24小时,温热至室温。加入甲醇(5ml),然后减压除去溶剂,并将残留物通过硅胶色谱纯化(以二氯甲烷、乙酸乙酯、乙酸(4∶1∶0.1)洗脱)。合并含产物馏份,减压除去溶剂后得到白色固体形式标题化合物(0.40g)。熔点:108-110℃MS(APCI+ve)411(M+H)+ 1H NMR(DMSO-d6)δ8.95(1H,s),8.83(1H,s),8.44(1H,t),8.32(1H,d),7.75(1H,dd),7.20(1H,dd),6.75(3H,m),2.94(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
实施例453-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]吡啶基-2-硫代乙酸
向实施例30所得砜(0.1g)的乙腈(3ml)溶液内加入三乙胺(0.04ml)和巯基乙酸甲酯(0.050g)。搅拌下加热回流反应混合物24小时,然后冷却至室温,减压蒸发溶剂。残留物溶于乙醇(2ml),用2M氢氧化钠处理。室温下搅拌反应混合物24小时,用2M盐酸酸化,接着用乙酸乙酯提取。干燥(MgSO4)提取液,尔后减压蒸发。所得产物通过硅胶色谱纯化,以0-3%甲醇/二氯甲烷洗脱。合并含产物馏份,减压蒸发后得到白色固体形式标题化合物(0.008g)。熔点:147-150℃MS(APCI+ve)361(M+H)+ 1H NMR(DMSO-d6)δ8.53(1H,t),8.45(1H,dd),7.89(2H,bs),7.20(1H,dd),3.80(2H,s),2.94(2H,d),1.94(3H,s),1.66(3H,d),1.62(3H,d),1.51(6H,d)
实施例46(2-氯-6-甲基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺
按照实施例14的方法,由1-金刚烷甲胺(0.20g)和2-氯-6-甲基-3-吡啶羧酸(0.208g)进行制备,得到白色固体形式标题化合物(0.24g)。熔点:192-193℃MS(APCI+ve)320/322(M+H)+ 1H NMR(DMSO-d6)δ8.39(1H,t),7.75(1H,d),7.31(1H,d),2.96(2H,d),2.45(3H,s),1.95(3H,s),1.67(3H,d),1.61(3H,d),1.53(6H,d)
-78℃下,向实施例40所得甲氧基化合物(0.56g)的二氯甲烷(10ml)溶液中加入三溴化硼(1.5ml,1M二氯甲烷溶液)。搅拌反应混合物24小时,温热至室温。加入甲醇(5ml),将反应混合物倒入饱和氯化钠溶液内,然后提取到乙酸乙酯内。有机层用MgSO4干燥,然后减压除去溶剂,留下-白色固体物。进而将该白色固体物溶于二甲基甲酰胺(10ml),用溴乙酸乙酯(0.1ml)和碳酸钾(0.050g)处理。室温下搅拌混合物24小时,用氯化钠饱和溶液稀释,继之以乙酸乙酯提取。有机相进一步用氯化钠饱和溶液洗涤,MgSO4干燥,减压除去溶剂后余下一白色固体物。将此残留物溶于二氧六环(10ml),用2M氢氧化钠(5ml)溶液处理,在室温下搅拌24小时后再用2M盐酸酸化,过滤得到的白色固体物通过硅胶色谱纯化,用25%甲醇/二氯甲烷洗脱。合并含产物馏份,减压除去溶剂后得到白色固体形式标题化合物(0.045g)。熔点:185-186℃MS(APCI+ve)453(M+H)+ 1H NMR(DMSO-d6)δ8.47(1H,t),8.25(1H,dd),7.75(1H,dd),7.35(2H,d),7.18(1h,m),6.80(2H,d),4.15(2H,s),3.0(2H,d),2.0(3H,s),1.67(3H,d),1.61(3H,d),1.53(6H,d)
-78℃下,向实施例40所得甲氧基化合物(0.56g)的二氯甲烷(10ml)溶液中加入三溴化硼(1.5ml,1M二氯甲烷溶液)。搅拌反应混合物24小时,温热至室温。加入甲醇(5ml),将反应混合物倒入饱和氯化钠溶液内,然后用乙酸乙酯提取。有机层用MgSO4干燥,然后减压浓缩留下一白色固体物。取部分该固体物(0.10g)溶于二甲基甲酰胺(5ml),用碳酸钾(0.072g)和N,N-二甲基-3-氯丙胺盐酸盐(0.045g)处理,并在室温下搅拌24小时。反应混合物用氯化钠饱和溶液稀释,继之以乙酸乙酯提取。有机相进一步用氯化钠饱和溶液洗涤,MgSO4干燥后加入氯化氢的乙醚溶液(4ml,2.0M)。减压除去溶剂后余下一胶状物,进而用乙腈重结晶,得到白色固体形式标题化合物(0.018g)。熔点:177-178℃1H NMR(DMSO-d6)δ10.43(1H,bs),8.46(1H,t),8.30(1H,dd),7.78(1H,dd),7.4(2H,d),7.2(1H,dd),7.0(2H,d),4.09(2H,t),3.20(2H,m),3.0(2H,d),2.8(6H,2s),2.2(2H,m),1.95(3H,s),1.6(12H,m).
实施例49(2-甲硫基-6-甲基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,
向实施例46所得氯-吡啶(0.10g)的乙腈(3ml)溶液内加入甲硫醇钠(0.1g)。搅拌反应混合物,并在密封管内于80℃加热24小时。冷却反应混合物,加乙酸乙酯稀释,用饱和氯化钠溶液洗涤后以MgSO4干燥。减压蒸发溶剂,残留物用乙醚研制后得到浅黄色固体标题化合物(0.028g)。熔点:160-161℃MS(APCI+ve)331(M+H)+ 1H NMR(DMSO-d6)δ8.22(1H,t),7.64(1H,d),7.02(1H,d),2.91(2H,d),2.51(3H,s),2.40(3H,s),1.93(3H,s),1.65(3H,d),1.60(3H,d),1.53(6H,d)
实施例502-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基丁酸a)2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基丁酸甲酯
将实施例24步骤a)的2-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(0.061g)和碳酸铯(0.069g)在乙腈(3ml)中的悬浮液于40℃加热至均相。加入4-溴丁酸甲酯(0.032ml),并加热回流所得混合物0.5小时。冷却反应混合物至室温,倒入水中,用乙酸乙酯(x3)提取。合并的有机提取液用水及氯化钠饱和水溶液洗涤,经硫酸钠(Na2SO4)干燥后减压浓缩,从而得到无色油状小标题化合物。MS(APCI+ve)386(M+H)+b)2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基丁酸
将步骤a)所得的2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基丁酸甲酯和氢氧化锂一水合物(0.027g)在3∶1甲醇/水中的悬浮液室温搅拌过夜。所形成的均相溶液用2N盐酸酸化,并用乙醚(x3)提取。合并乙醚层,用氯化钠饱和水溶液洗涤。硫酸钠(Na2SO4)干燥后减压浓缩,得到不透明胶状物,进而用乙醚和异己烷研制,由此得到无色固体形式标题化合物(0.030g)。熔点:109-113℃MS(APCI+ve)372(M+H)+ 1H NMR(DMSO-d6)δ7.99(1H,t),7.74(1H,d),7.44(1H,t),7.13(1H,d),7.02(1H,t),4.13(2H,t),3.02(2H,d),2.42(2H,t),2.02(2H,m),1.94(3H,s),1.64(6H,dd),1.51(6H,m),未观测到羧酸质子。实施例512-氯-5-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
按照实施例14的方法,由2-氯-5-羟基苯甲酸(0.3g)和1-金刚烷甲胺(0.31ml)进行制备,得到白色固体形式标题化合物(0.15g)。熔点:263-264℃MS(APCI+ve)320(M+H)+ 1H NMR(DMSO-d6)δ9.85(1H,s),8.25(1H,t),7.24(1H,d),6.76-6.82(2H,m),2.90(2H,d),1.93(3H,s),1.67(3H,d),1.57(3H,d),1.51(6H,s)
实施例522-氯-3-硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
按照实施例14的方法,由1-金刚烷甲胺(1.0g)和2-氯-3-硝基苯甲酸(1.22g)进行制备,得到黄色固体形式标题化合物(1.7g)。熔点:185℃MS(APCl+ve)348/350(M+H)+ 1H NMR(CDCl3)δ7.83(1H,d),7.74(1H,d),7.48(1H,t),6.0(1H,bs),3.18(2H,d),2.0(3H,bs),1.8(12H,m)
实施例532-氯-5-硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
按照实施例14的方法,由1-金刚烷甲胺(1.0g)和2-氯-5-硝基苯甲酸(1.22g)进行制备,得到黄色固体形式标题化合物(1.7g)。熔点:178℃MS(APCI+ve)348/350(M+H)+ 1H NMR(CDCl3)δ8.53(1H,d),8.2(1H,dd),7.6(1H,d),6.2(1H,bs),3.2(2H,d),2.0(3H,bs),1.8(12H,m)
实施例543-氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺将实施例52的硝基化合物(0.50g)和氯化铵(0.5g)溶于50%乙醇水溶液.加入铁粉(0.5g),回流下搅拌混合物3小时,然后冷却,并滤除固体物。滤液用10%氢氧化钠溶液处理,并将产物提取到乙酸乙酯内。有机溶液用盐水洗涤,经硫酸钠(Na2SO4)干燥后浓缩,所得残留物进一步用硅胶色谱纯化,从而得到白色粉末状标题化合物(0.45g)。熔点:154℃MS(APCI+ve)319/21(M+H)+ 1H NMR(CDCl3)7.12(1H,t),6.91(1H,dd),6.79(1H,dd),5.92(1H,bs),4.19(2H,bs),3.15( 2H,d),2.0(3H,s),1.8(12H,m)
按照实施例54的方法由实施例53的硝基化合物(0.50g)进行制备,从而得到白色固体形式标题化合物(0.4g)。熔点:214℃MS(APCI+ve)319/21(M+H)+1H NMR(DMSO-d6)δ8.14(1H,t),7.03(1H,dd),6.56(2H,m),5.36(2H,s),2.89(2H,d),1.95(3H,s),1.7(12H,m)
将实施例54的氯基化合物(0.10g)、碳酸钾(0.087g)和N-(2-氯乙基)二甲胺盐酸盐的混合物在138℃加热搅拌72小时。将残留物溶于水,产物用乙酸乙酯提取。盐水洗涤有机提取液,硫酸钠(NasSO4)干燥并浓缩,所得油状物用超临界流体色谱纯化,使用CO2/甲醇/0.1%二乙胺洗脱,得到一油状物。加入过量氯化氢乙醚溶液产生一固体物,经乙醚/乙醇/二氯甲烷混合物研制后,得到无色粉末物(0.04g)。熔点:221℃MS(APCI+ve)390/392(M+H)+ 1H NMR(DMSO-d6)δ10.08(1H,bs),8.2(1H,t),7.2(1H,t),6.85(1H,d),6.62(1H,d),5.8(1H,t),3.6(2H,m),3.2(2H,m),2.9(2H,d),2.8(6H,bs),1.9(3H,s),1.7(12H,m).
按照实施例56的方法由实施例55的氨基化合物(0.10g)进行制备,从而得到无色固体形式标题化合物(0.035g)。熔点:215℃MS(APCI+ve)390/92(M+H)+ 1H NMR(DMSO-d6)δ10.05(1H,bs),8.18(1H,t),7.18(1H,d),6.7(1H,m),6,66(1H,m),6.2(1H,bs),3.4(2H,t),3.2(2H,t),2.9(2H,d),2.8(6H,bs),1.9(3H,s),1.7(12H,m).
实施例582-氯-5-(N,N-二甲基氨基)乙硫基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,富马酸盐a)2-氯-5-甲基亚硫酰基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
将实施例38的酰胺(0.2g)在氯仿(5ml)中的溶液用70%间-氯过苯甲酸(0.14g)处理。搅拌反应混合物2天。加入氢氧化钙(0.09g),进一步搅拌0.5小时,然后过滤。减压浓缩滤液得到白色固体小标题产物(0.23g)。b)2-氯-5-(N,N-二甲基氨基)乙硫基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,富马酸盐
向步骤a)的亚砜(0.22g)在二氯甲烷(1ml)的溶液中加入三氟乙酸酐(1.1ml),并加热回流反应混合物2小时。冷却反应混合物至室温,减压蒸发溶剂。将所得残留物在三乙胺/甲醇(10l,1∶1)中的溶液用2-二甲氨基乙基氯盐酸盐(0.086g)处理,室温搅拌反应混合物过夜。减压除去溶剂后,残留物用硅胶色谱纯化(以10-20%甲醇/乙酸乙酯洗脱),得到胶状产物。向此胶状物在二氯甲烷(10ml)的溶液中加入富马酸(0.0045g)。减压除去溶剂后余下标题化合物,为一粘性胶状物(0.023g)。MS(APCI+ve)407/409(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.35(1H,m),7.39(2H,m),7.28(1H,d),6.60(1.5H,s),3.13(2H,t),2.93(2H,d),2.57(2H,t),2.23(6H,s),1.95(3H,bs),1.63(6H,q),1.52(6H,d).
按照实施例38的方法,采用2-氯-3-羟基苯甲酸(0.39g)、1-羟基苯并三唑(0.31g)、1-金刚烷甲胺(0.4ml)和1,3-二环己基碳二亚胺(0.47g)进行制备,从而得到白色固体形式标题化合物(0.29g)。熔点:234-235℃MS(APCI+ve)320(M+H)+ 1H NMR(DMSO-d6)δ8.20(1H,t),7.15(1H,m),6.95(1H,d),6.89(1H,d),2.91(2H,d),1.95(3H,bs),1.64(6H,q),1.52(6H,d)
实施例602-氯-5-(N,N-二甲基氨基)乙氧基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
向实施例51的2-氯-5-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(0.05g)在乙腈(5ml)中的溶液内加入碳酸钾(0.065g)和2-二甲氨基乙基氯盐酸盐(0.037g)。搅拌下加热回流反应混合物48小时。然后减压蒸发反应混合物,残留物溶于乙酸乙酯,并用盐水洗涤。用硫酸钠(Na2SO4)干燥,接着减压浓缩,所得残留物随后用超临界色谱纯化,以CO2/甲醇/0.1%二乙胺洗脱.减压浓缩含产物馏份,并将所得残留物溶于乙醚,逐滴加入氯化氢(1ml,1M乙醚溶液),用乙醚研制所产生的固体物,然后在真空下干燥,余下白色固体标题化合物(0.020g)。熔点:144-147℃MS(APCI+ve)391(M+H)+(游离碱)1H NMR(DMSO-d6)δ10.33(1H,s),8.33(1H,t),7.44-6.99(3H,m),4.38(2H,t),3.50(2H,d),2.90(2H,m),2.81(6H,d),1.95(3H,s),1.66(3H,d),1.59(3H,d),1.50(6H,d)
实施例612,5-二氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
按照实施例22的方法,用2,5-二氯苯甲酸(0.319g)、1-金刚烷甲胺(0.25g)、4-二甲氨基吡啶(0.204g)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.321g)在二氯甲烷(30ml)中进行制备。粗产物用硅胶色谱纯化,以二氯甲烷洗脱,从而得到白色固体形式标题化合物(0.43g)。熔点:161-162℃MS(APCI+ve)338/340(+H)+ 1H NMR(CDCl3)δ7.68(1H,d);7.36-7.30(2H,m);6.23(1H,s);3.17(2H,d);2.01(3H,s);1.76-1.60(6H,m);1.58(6H,s).
将实施例55的氨基酰胺(0.12g)溶于原甲酸三乙酯(1.07ml),120℃加热3小时。真空蒸馏除去原甲酸三乙酯。残留物溶于乙醇(5ml)。在氮气氛下冷却此溶液至0℃,加入硼氢化钠(O.104g),90℃回流混合物3小时。减压除去乙醇,向残留物中加水(20ml),产物提取到乙酸乙酯内(3x50ml),硫酸镁干燥并减压浓缩。粗产物用硅胶色谱纯化,以二氯甲烷:乙酸乙酯(1∶1)洗脱,得到白色固体标题化合物(0.04g)。熔点:163-164℃MS(APCI+ve)333/335(M+H)+ 1H NMR(CDCl3)δ7.17(1H,d);6.96(1H,d);6.57(1H,dd);6.35(1H,s);3.84(1H,s);3.16(2H,d);3.83(3H,d);2.0(3H,s);1.75-1,62(6H,m);1.6(6H,d).
将氯乙醛(50%水溶液)(0.705ml)加到实施例55的氨基酰胺(1.5g)在甲醇(15ml)中的溶液内。10分钟后加入氢氯酸(0.77ml,50%甲醇溶液)。再加入固体氰基硼氢化钠(0.317g),并在室温下搅拌混合物2天。减压除去溶剂,将残留物溶于二氯甲烷(50ml),用碳酸氢钠水溶液(3x50ml)洗涤。有机提取液用硫酸镁干燥,过滤并减压浓缩。粗产物通过硅胶色谱纯化,使用已烷∶乙醚(1∶1)洗脱,得到黄色固体形式标题化合物(1.13g)。熔点:144-145℃1H NMR(CDCl3)δ7.19(1H,d);7.0(1H,d);6.62(1H,dd);6.37(1H,s);4.18(1H,t);3.70(2H,t);3.54-3.44(2H,m);3.16(2H,d);2.0(3H,s);1.71-1.62(6H,m);1.6(6H,d).
混合2-氯-5-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(0.15g)、碳酸铯(0.192g)和乙腈(3ml),并在密封管内于100℃加热24小时。将冷却后的反应混合物倒入水(50ml)中,产物用乙酸乙酯提取,硫酸镁干燥,过滤和减压浓缩。粗产物通过NPHPLC纯化,使用0-5%乙醇/二氯甲烷洗脱,得到白色固体标题化合物(0.023g)。熔点:154-155℃MS(APCI+ve)345/347(M+H)+ 1H NMR(CDCl3)δ8.26(1H,t);7.30(1H,d);7.02(1H,dd);6.95(1H,d);2.91(2H,d);2.08(4H,s);1.94(3H,s);1.70-1.57(6H,m);1.51(6H,s).
实施例65
亚硫酰氯(30ml)加到3,5-二硝基-邻甲基苯甲酸(6.0g)中,于回流温度下加热反应物18小时。减压浓缩除去过量的亚硫酰氯,将残留物溶于二氯甲烷(15ml)。然后于0℃将这一溶液加到1-金刚烷甲胺(2.89g)在二氯甲烷(20ml)和三乙胺(5ml)中的溶液内。10分钟后减压浓缩反应混合物,残留物用硅胶色谱纯化,以二氯甲烷∶乙酸乙酯(9∶1)洗脱,得到一固体物,进一步以二氯甲烷为洗脱剂通过硅胶柱色谱纯化,从而得到6.34g固体物。取部分该固体物在沸腾乙酸乙酯中用木炭处理,过滤并浓缩,以除去有色杂质。用乙醚洗涤产物,从而得到无色固体形式标题化合物熔点:171-172℃MS(APCI+ve)374(M+H)+ 1H NMR(CDCl3)δ8.71(1H.,),8.39(1H,d),5.9-5.8(1H,m),3.21(2H,d),2.67(3H,s),2.04(3H,s),1.8-1.7(3H,m),1.7-1.6(3H,m),1.6-1.55(6H,m).
在钯/碳(10%,0.5g)存在下氢化2-甲基-3,5-二硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(实施例65)(2.66g)的乙酸乙酯(200ml)溶液72小时。然后通过celite过滤反应混合物,残留物用乙酸乙酯洗涤。合并滤液和洗涤液,减压浓缩后得到一固体物(0.8g)。用硅胶柱色谱纯化此固体物,使用二氯甲烷∶甲醇(9∶1)洗脱。所得产物进一步按下所述纯化:在沸腾乙醇中用木炭处理,然后过滤并浓缩除去有色杂质,得到标题化合物,为近无色固体(0.58g)。熔点:220℃(分解)MS(APCI+ve)314(M+H)+ 1H NMR(DMSO-d6)δ7.78(1H,t),5.93(1H,d),5.83(1H,d),4.62(4H,bs),2.86(2H,d),1.93(3H,s),1.86(3H,s),1.7-1.6(3H,m),1.6-1.5(3H,m),1.48(6H,d).
实施例673,5-二甲氧基-2-甲基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺a)3,5-二甲氧基-2-甲基苯甲酸
将固体3,5-二甲氧基-2-甲基苯甲酸甲酯(5.83g,J.C.S.PerkinⅠ,1973,2853)溶于甲醇(80ml)。加入氢氧化钠水溶液(10%,80ml),室温搅拌所得溶液1小时。然后减压浓缩反应物至大约其原始体积的一半,加入盐酸水溶液(200ml)。所形成的白色沉淀物用乙酸乙酯(2x250ml)提取。用无水硫酸镁干燥合并的提取液,过滤并减压浓缩,得到无色固体小标题化合物(5.41g)。1H NMR(CDCl3)δ7.10(1H,d),6.64(1H,d),3.84(6H,s),2.45(3H,s).b)3,5-二甲氧基-2-甲基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
加热回流3,5-二甲氧基苯甲酸(0.15g,a部分)和亚硫酰氯(2ml)的混合物2分钟,然后冷却至室温。减压浓缩除去过量的亚硫酰氯,残留物溶于二氯甲烷(1ml)。将此溶液加到1-金刚烷甲胺(0.188g)在二氯甲烷(5ml)和三乙胺(1ml)中的溶液内,并搅拌所形成的反应混合物过夜。将反应物分配到二氯甲烷(100ml)和盐酸水溶液(1M,50ml)之间。有机相用碳酸氢钠饱和水溶液(50ml)洗涤,无水硫酸镁干燥,过滤并减压浓缩,得到一无色固体物(0.14g).将此固体在Dynamax柱上进行HPLC纯化,以异己烷∶乙酸乙酯(4∶1)为洗脱剂,得到无色固体标题化合物(0.110g)。熔点:173-175℃.MS(APCI+ve)344(M+H)+ 1H NMR(DMSO-d6)δ8.06(1H,t),6.57(1H,d),6.41(1H,d),3.78(3H,s),3.75(3H,s),2.91(2H,d),2.05(3H,s),1.94(3H,s)1.75-1.5(6H,m),1.49(6H,d).
加热回流3,5-二甲氧基苯甲酸(0.526g)和亚硫酰氯(5ml)的混合物2分钟,然后冷却至室温。减压浓缩除去过量的亚硫酰氯,残留物溶于二氯甲烷(5ml)。将此溶液加到1-金刚烷甲胺(0.336g)在二氨甲烷(10ml)和三乙胺(2ml)中的0℃溶液内,并搅拌所形成的反应混合物4天。加二氯甲烷(100ml)稀释反应物,依次用盐酸水溶液(2M,50ml)和碳酸氢钠饱和水溶液(50ml)洗涤。有机相用无水硫酸镁干燥,过滤并减压浓缩。以二氯甲烷∶乙酸乙酯(19∶1)为洗脱剂将残留物通过硅胶柱色谱纯化,从而得到无色固体标题化合物(0.600g)。熔点:130-133℃.MS(APCI+ve)330(M+H)+ 1H NMR(DMSO-d6)δ8.24(1H,t),7.01(2H,d),6.30(1H,t),3.78(6H,s),2.97(2H,d),1.91(3H,s),1.7-1.5(6H,m),1.48(6H,d)
实施例695-(N-(2-羟基-2-苯基乙基)-2-氨基乙基)氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
将实施例63所得的2-氯-5-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)苯甲酰胺(0.1g)、2-氨基-1-苯基乙醇(0.539g)和三乙胺(0.5ml)溶于四氢呋喃(3ml),并在密封管内于80℃加热60小时。减压浓缩反应混合物,将残留物悬浮在碳酸氢钠水溶液(30ml)内,产物用乙酸乙酯(3x30ml)提取,硫酸镁干燥,过滤并减压浓缩。以0-25%乙醇/二氯甲烷为洗脱剂进行NPHPLC纯化,得到白色固体标题化合物(0.044g).熔点:63-64℃MS(APCI+ve)482/484(M+H)+ 1H NMR(CDCl3)δ7.34(4H,d);7.30-7.25(1H,m);7.13(1H,d);6.94(1H,d);7.56(1H,dd);6.39(1H,t);4.73(1H,dd);4.30(1H,s);3.19-3.14(4H,m);2.93-2.83(3H,m);2.80-2.75(1H,m);2.0(3H,s);1.76-1,62(6H,m);1.57(6H,m).
按照实施例69的方法,由2-氯-5-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(0.1g)、哌啶(1ml)、三乙胺(0.5ml)和四氢呋喃(3ml)制备。以在二氯甲烷中的5%甲醇和1%三乙胺为洗脱剂进行硅胶色谱纯化,得到2-氯-5-(2-(哌啶-1-基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺玻璃体。通过用过量醚合氢氯酸(2M)处理,转化为盐酸盐,从而得到黄色固体形式标题化合物(0.062g)。熔点:142-143℃(分解)MS(APCI+ve)430/432(M+H)+(游离碱)1H NMR(DMSO-d6)δ8.18(1H,t);7.17(1H,d);6.68(1H,dd);6.62(1H,d);3.48-3.45(4H,m);3.16(2H,s);2.90(4H,d);2.50(4H,s);1.95(3H,s);1.80(3H,s);1.75-1.55(6H,m);1.52(6H,s).
实施例715-(N-(2-羟基乙基)-2-氨基乙基)氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,二盐酸盐
按照实施例69的方法,由2-氯-5-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(0.1g)、乙醇胺(0.24g)、三乙胺(0.5ml)和四氢呋喃(3ml)进行制备。以溶在二氯甲烷中的10%甲醇和1%三乙胺为洗脱剂进行快速柱色谱纯化,得到2-氯-5-(2-哌啶-1-基)乙氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺玻璃体。通过用过量氢氯酸乙醚溶液(2M)处理将其转化为盐酸盐,从而得到膏状固体标题化合物(0.056g)。熔点:143℃(分解)1H NMR(DMSO-d6)δ8.94(1H,s);8.19(1H,t);7.17(1H,dd);6.67(1H,dd);6.11(1H,d);3.68(2H,t);3.43-3.37(2H,m);3.08-3.03(4H,m);2.90(2H,d);1.94(3H,s);1.69-1.61(6H,m),1.52(6H,d).
实施例722-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺
按照实施例1的方法,由1-金刚烷乙胺盐酸盐(0.055g)和2-氯苯甲酰氯(0.033ml)进行制备,得到白色固体形式标题化合物(0.074g)。熔点:125-127℃MS(APCI+ve)318/320(M+H)+ 1H NMR(DMSO-d6)δ8.31(1H,t),7.49-7.33(4H,m),3.22(2H,m),1.93(3H,s),1.70-1.60(6H,m),1.51(6H,d),1.31(2H,m).
按照实施例1的方法,由1-金刚烷乙胺盐酸盐(0.102g)和2,3-二氯苯甲酰氯(0.102g)进行制备,得到白色固体形式标题化合物(0.090g)。熔点:158-159℃MS(APCI+ve)352/354(M+H)+ 1H NMR(DMSO-d6)δ8.42(1H,t),7.68(1H,dd),7.40(1H,t),7.34(1H,dd),3.22(2H,m),1.93(3H,s),1.64(6H,m),1.51(6H,d),1.31(2H,m).
实施例745-氨基-2-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺
按照实施例14的方法,由1-金刚烷乙胺盐酸盐(0.105g)和5-氨基-2-氯苯甲酸(0.132g)进行制备,并以CO2/乙醇洗脱剂进行超临界流体色谱纯化,得到白色泡沫状标题化合物(0.094g)。熔点:147-149℃MS(APCI+ve)333/335(M+H)+ 1H NMR(DMSO-d6)δ8.13(1H,t),7.03(1H,d),6.56-6.52(2H,m),5.36(2H,s),3.19(2H,m),1.93(3H,s),1.66-1.59(6H,m),1.50(6H,d),1.28(2H,m).
实施例752,5-二甲基-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺
按照实施例14的方法,由1-金刚烷乙胺盐酸盐(0.131g)和2,5-二甲基苯甲酸(0.099g)进行制备,得到白色固体标题化合物(0.163g)。熔点:153℃MS(APCI+ve)312(M+H)+.1H NMR(DMSO-d6)δ8.07(1H,t),7.10(3H,m),3.21(2H,m),2.26(3H,s),2.25(3H,s),1.93(3H,s),1.67(3H,d),1.62(3H,d),1.51(6H,d),1.25(2H,m).
实施例762-氯-N-(3-氯-三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺
按照实施例1的方法,由3-氯-三环[3.3.1.13,7]癸烷-1-甲胺盐酸盐(0.061g)和2-氯苯甲酰氯(0.032ml)进行制备,得到白色固体标题化合物(0.093g)。熔点:153℃MS(APCI+ve)338/340/342(M+H)+ 1H NMR(DMSO-d6)δ8.43(1H,t),7.51-7.36(4H,m),3.02(2H,d),2.17(2H,s),2.03(4H,dt),1.97(2H,s),1.64-1.36(6H,m).
实施例772-氯-3-(N-(2-[咪唑-4-基]乙基)-2-氨基乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺a)2-氯-3-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
按照实施例63的方法,由实施例54所得的3-氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺(0.7g)、50%氯乙醛水溶液(0.353ml)、氰基硼氢化钠(0.159g)、50%氢氯酸的甲醇溶液(0.385ml)和甲醇(10ml)进行制备,经快速柱色谱纯化(以3∶1异己烷∶乙酸乙酯为洗脱剂),得到白色固体形式小标题化合物(0.777g)。熔点:179-1802(分解)MS(APCI+ve)381/383(M+H)+ 1H NMR(CDCl3)δ7.18(1H,t);6.89(1H,dd);6.70(1H,dd);5.88(1H,bs);4.88(1H,t);3.75-3.70(2H,m);3.61-3.55(2H,m);3.15(2H,d);2.02(2H,bs);1.71-1.62(5H,m);1.58(5H,d);1.55(2H,s).b)2-氯-3-(N-(2-[咪唑-4-基]乙基)-2-氨基乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
混合步骤a)的氨基乙基氯(0.15g)、组胺(0.437g)、三乙胺(0.5ml)和四氢呋喃,并在密封管内于80℃加热60小时。减压除去溶剂,向残留物中加入碳酸氢钠水溶液(30ml),进而用乙酸乙酯(3x30ml)提取。合并的有机提取液用无水硫酸镁干燥并减压浓缩。粗产物用反相HPLC纯化,以85%-l5%的0.1%三氟乙酸/甲醇洗脱,得到白色泡沫状标题化合物(0.07g)。熔点:86-87℃MS(APCI+ve)456/458(M+H)+ 1H NMR(CDCl3)δ7.61(1H,s);7.17(1H,t);6.79-6.72(2H,m);6.31(1H,s);6.02(1H,t);4.76(1H,t);3.45-3.30(2H,m);3.17(2H,d);2.95-2.85(4H,m);2.75(2H,t);2.02(3H,s);1.80-1.60(6H,m);1.58(6H,d).
实施例782,5-二甲基-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
向2,5-二甲基苯甲酸(0.073g)在二氯甲烷(5ml)的悬浮液中加入草酰氯(0.5ml),加热回流所形成的反应混合物1小时。减压浓缩反应混合物,并将残留物溶于二氯甲烷(5ml)。向此溶液中加入3-氯-三环[3.3.1.13,7]癸烷-1-甲胺盐酸盐(0.113g)和三乙胺(0.30ml),室温搅拌反应混合物3小时,然后加乙醚稀释,依次用稀盐酸和碳酸氢钠溶液及盐水洗涤。有机相随后用硫酸钠(Na2SO4)干燥,并减压浓缩。再进一步通过HPLC纯化,使用0-5%乙醇/二氯甲烷洗脱,从而得到白色固体标题化合物(0.068g)。熔点:155℃MS(APCI+ve)332/334/336(M+H)+ 1H NMR(DMSO-d6)δ8.18(1H,t),7.10(3H,s),3.01(2H,d),2.29(3H,s),2.28(3H,s),2.17(2H,s),2.03(4H,m),1.90(2H,s),1.64-1.41(6H,m).
将实施例67a)所得的3,5-二甲氧基-2-甲基苯甲酸(0.15g)和亚硫酰氯(2ml)的混合物加热回流2分钟,然后冷却至室温并减压浓缩。将残留物溶于二氯甲烷(1ml),加到1-金刚烷甲胺(0.104g)在二氯甲烷(5ml)和三乙胺(1ml)中的溶液内,并搅拌所形成的反应混合物2天。将反应物分配到二氯甲烷(100ml)和盐酸水溶液(0.5M,50ml)之间。有机相用碳酸氢钠饱和水溶液(50ml)洗涤,无水硫酸镁干燥,过滤并减压浓缩。残留物在Dynamax上进行HPLC纯化,以异己烷∶乙酸乙酯(4∶1)洗脱,从而得到无色固体形式标题化合物(0.090g)。熔点:173-175℃MS(APCI+ve)378(M+H)+ 1H NMR(DMSO-d6)δ8.17(1H,t),6.58(1H,d),6.43(1H,d),3.79(3H,s),3.76(3H,s),3.00(2H,d),2.16(2H,s),2.1-1.95(4H,m),2.05(3H,s),1.89(2H,s)1.7-1.5(6H,m).
实施例802-氯-5-碘-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺
-5℃下,向实施例55所得氨基酰胺(200mg)在75%含水四氢呋喃1/3(10ml)的溶液内顺序加入硫酸(0.2ml)和亚硝酸钠(0.042g)/水(1ml)溶液。搅拌所形成的反应混合物40分钟,然后加入碘化钾(0.136g)。90℃加热反应混合物1小时,尔后冷却至室温,加水稀释并用乙酸乙酯提取。分离有机层,用硫酸镁干燥。减压浓缩过滤后的溶液,并将粗产物通过硅胶纯化,以己烷/乙酸乙酯为洗脱剂,从而得到白色固体形式标题化合物(0.23g)。熔点:161.4-161.5℃.MS(APCI+ve)430(M+H)+;1H NMR(CDCl3)δ7.99(1H,d),7.66(1H,dd),7.13(1H,d),6.18(1H,bs),3.16(2H,d),2.01(3H,bs),1.73(3H,d),1.65(3H,d),1.57(6H,bs).实施例81药理研究
已知某些化合物如苯甲酰基苯甲酰基腺苷三磷酸(bbATP)是P2X7受体的激动剂,它们能造成质膜内成孔(Drug Development Research(1996),37(3),p.126)。因此,当受体在溴化乙啶(一种荧光DNA探针)存在下用bbATP激活时,能够观测到胞内DNA结合溴化乙啶的荧光增强。这种荧光增强可用作P2X7受体活化的量度,并因此用于定量表示化合物对P2X7受体的效应。
按此方式测试实施例1-80的各标题化合物在P2X7受体上的拮抗活性。例如,试验在96孔平底微量滴定板内进行,各孔加入由200μl含10-4M溴化乙啶的THP-1细胞悬液(2.5x106细胞/ml)、25μl含10- 5M bbATP的高钾缓冲液、和25μl含3x10-5M受试化合物的高钾缓冲液组成的250μl溶液。滴定板用塑料板覆盖,37℃温育1小时。然后将滴定板在Perkin-Elmer荧光板读数器上读数,激发波长520nm,发射波长595nm,狭缝宽度:Ex15nm,Em20nm。为了比较,分别在试验中使用bbATP(一种P2X7受体激动剂)和吡哆醛5-磷酸(一种P2X7受体拮抗剂)作为对照物。根据所得读数,计算每一受试化合物的IC50值,该值为降低50%bbATP激动活性所需的受试化合物的负对数浓度。实施例1-80的每一化合物都证明具有拮抗活性,其PI50值>4.50。
Claims (12)
1.通式(Ⅰ)化合物或其可药用盐或溶剂化物:其中x代表1或2;A代表基团CH2或氧原子;B代表氢或卤原子;R代表苯基、吡啶基、吲哚基、吲唑基、嘧啶基或苯硫基基团,它们各自可任选地被一个或多个独立选自如下的取代基取代:卤原子或氨基、氰基、羧基、羟基、硝基、C1-C6-烷基、卤代-C1-C6-烷基、-N(R1)-C(=O)-R2、-C(O)NR3R4、-NR5R6、C3-C8-环烷基、3-至8-元杂环基、C3-C8-环烷氧基、C1-C6-烷基羰基、C1-C6-烷氧基羰基、C1-C6-烷基亚硫酰基或C1-C6-烷基磺酰基基团,或任选被一个或多个独立选自卤原子或氨基、氰基、羧基、羟基、硝基、1-吡咯烷基、1-哌啶基、C1-C6-烷基、C1-C6-烷氧基、(二)C1-C6-烷基氨基、卤代-C1-C6-烷基、C1-C6-烷氧基羰基或下述基团之一:的取代基取代的C1-C6-烷氧基、C1-C6-烷基氨基、苯氧基、苄基、C1-C6-烷硫基或苯硫基基团;R1代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R2代表C1-C6-烷基或C3-C8环烷基;R3和R4各自独立地代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R5代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R6代表C3-C8-环烷基,另外,当R5不为氢原子时还代表C1-C6-烷基;R7代表氢原子或C1-C6-烷基或C3-C8-环烷基基团;R8代表C1-C6-烷基或C3-C8-环烷基;R9代表氢原子或羟基;以及R10代表氢原子或苯基或咪唑基基团;条件是当A代表基团CH2和B代表氢原子时,R不能代表未取代的吡啶基,以及当R代表取代的苯基、吲哚基或吲唑基时,其邻位上存在的取代基不包括酰氨基,羧基,(二)C1-C6-烷基氨基或C1-C6-烷氧基羰基。
2.根据权利要求1的化合物,其中R代表苯基、吡啶基或吲哚基,它们各自可任选地被一个或两个独立选自如下的取代基取代:氟、氯、溴或碘原子或氨基、羟基、硝基、氮丙啶基、吡咯烷基、C1-C4-烷基、三氟甲基、-NR5R6、C1-C4-烷基亚硫酰基或C1-C4-烷基磺酰基基团,或被一个或两个独立选自下述取代基任选取代的C1-C4-烷氧基、C1-C4-烷基氨基、苄基、C1-C4-烷硫基或苯硫基基团:卤原子或氨基,氰基,羧基,羟基,1-吡咯烷基,1-哌啶基,甲基,甲氧基,二甲氨基,C1-C4-烷氧基羰基或下述基团之一:
3.根据权利要求1或2的化合物,其中R5代表氢原子或C1-C4-烷基。
4.根据权利要求1-3中任一项的化合物,其中当R5不为氢原子时,R6代表C1-C4-烷基。
5.权利要求1所述的式(Ⅰ)化合物,或其可药用的盐或溶剂化物,它为:2,4-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,3,5-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,6-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-甲氧基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-甲基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-溴-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-碘-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-硝基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,6-二甲氧基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(三氟甲基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,6-二氟-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(三氟甲基)-6-氟-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-氨基-6-氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-氯-4-硝基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(2-氰基苯硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(4-甲基苯硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺,2-(甲硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(甲硫基)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺,3-氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,3-二氯-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2,5-二甲基-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(苯甲基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,2-(2-(N,N-二甲基氨基)乙氧基)-N-(三环[3.3.1.13,7]癸-1-甲基)-苯甲酰胺,盐酸盐,2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基乙酸1,1-二甲基乙酯,2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基乙酸,2-(甲基亚砜)-N-(三环[3.3.1.13,7]癸-1-甲基)-3-吡啶甲酰胺,N-(三环[3.3.1.13,7]癸-1-甲基)-5-吲哚甲酰胺,2-氨基-6-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2-(2-甲基磺酰基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-(2-氨基乙硫基)-N-(三环[3.3.113,7]癸-1-基甲基)-3-吡啶甲酰胺,三氟乙酸盐,2-(2-(N,N-二甲基氨基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(2-(吡咯烷-1-基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(甲氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(二甲氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,盐酸盐,2-(吡咯烷-1-基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,2-(2,5-二甲氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-氯-5-甲硫基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-(2-(N,N-二甲基氨基)乙硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-(4-甲氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-氯-3-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-溴-5-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-氟-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-(2,5-二羟基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,3-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]吡啶基-2-硫基乙酸,(2-氯-6-甲基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,3-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]吡啶基-2-(4-苯硫基)氧基乙酸,2-(4-(3-N,N-二甲基氨基)丙氧基苯硫基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,二盐酸盐,(2-甲硫基-6-甲基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-3-吡啶甲酰胺,2-[[(三环[3.3.1.13,7]癸-1-基甲基)氨基]羰基]苯基-1-氧基丁酸,2-氯-5-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-3-硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3-氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,5-氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-3-(N,N-二甲基氨基)乙基氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(N,N-二甲基氨基)乙基氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(N,N-二甲基氨基)乙硫基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,富马酸盐,2-氯-3-羟基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(N,N-二甲基氨基)乙氧基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2,5-二氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-甲基氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-5-(2-氯乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,5-氮丙啶-1-基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-甲基-3,5-二硝基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二氨基-2-甲基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二甲氧基-2-甲基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二甲氧基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,5-(N-(2-羟基-2-苯基乙基)-2-氨基乙基)氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-6-(2-(哌啶-1-基)乙基氨基)-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,盐酸盐,5-(N-(2-羟基乙基)-2-氨基乙基)氨基-2-氯-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,二盐酸盐,2-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2,3-二氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,5-氨基-2-氯-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2,5-二甲基-N-(2-[三环[3.3.1.13,7]癸-1-基]乙基)-苯甲酰胺,2-氯-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2-氯-3-(N-(2-[咪唑-4-基]乙基)-2-氨基乙基)氨基-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,2,5-二甲基-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,3,5-二甲氧基-2-甲基-N-(3-氯-三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺,或2-氯-5-碘-N-(三环[3.3.1.13,7]癸-1-基甲基)-苯甲酰胺。
7.药物组合物,它包含权利要求1-5中任一项所述的式(Ⅰ)化合物,或其可药用的盐或溶剂化物以及可药用的辅助剂、稀释剂或载体。
8.权利要求7所述的药物组合物的制备方法,该方法包括将权利要求1-5中任一项所述的式(Ⅰ)化合物,或其可药用的盐或溶剂化物与可药用的辅助剂、稀释剂或载体混合。
9.治疗用的权利要求1-5中任一项所述的式(Ⅰ)化合物,或其可药用的盐或溶剂化物。
10.用于治疗类风湿性关节炎的权利要求1-5中任一项所述的式(Ⅰ)化合物,或其可药用的盐或溶剂化物。
11.权利要求1-5中任一项所述的式(Ⅰ)化合物或其可药用的盐或溶剂化物在制备治疗用的药物中的应用。
12.产生免疫抑制的方法,该方法包括对患者施用治疗有效量的权利要求1-5中任一项所述的式(Ⅰ)化合物,或其可药用的盐或溶剂化物。
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US3464998A (en) | 1968-03-04 | 1969-09-02 | Searle & Co | Adamantyl esters and amides of pyridinecarboxylic acids |
US3732305A (en) * | 1970-03-03 | 1973-05-08 | Us Army | S-substituted thiosulfuric acid derivatives and preparation thereof |
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CA2015473C (en) * | 1989-04-28 | 1998-04-14 | Iwao Kinoshita | Triphenylmethane derivatives |
CA2091194A1 (en) * | 1992-04-08 | 1993-10-09 | Richard D. Connell | 2-oxo-ethyl derivatives as immunosuppressants |
ATE197146T1 (de) | 1993-08-10 | 2000-11-15 | Black James Foundation | Gastrin-und cck-rezeptorligande |
GB9409150D0 (en) | 1994-05-09 | 1994-06-29 | Black James Foundation | Cck and gastrin receptor ligands |
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1997
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1998
- 1998-12-01 JP JP2000524258A patent/JP2001525392A/ja active Pending
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- 1998-12-01 CN CN98813491A patent/CN1284057A/zh active Pending
- 1998-12-01 PL PL98340906A patent/PL340906A1/xx unknown
- 1998-12-01 TR TR2000/01605T patent/TR200001605T2/xx unknown
- 1998-12-01 RU RU2000117574/04A patent/RU2214997C2/ru not_active IP Right Cessation
- 1998-12-01 ID IDW20001019A patent/ID28003A/id unknown
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- 1998-12-01 KR KR1020007006132A patent/KR20010032814A/ko not_active Application Discontinuation
- 1998-12-01 US US09/230,478 patent/US6201024B1/en not_active Expired - Lifetime
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- 1998-12-01 DK DK98962751T patent/DK1036059T3/da active
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KR20010032814A (ko) | 2001-04-25 |
US6201024B1 (en) | 2001-03-13 |
SE9704544D0 (sv) | 1997-12-05 |
EE200000378A (et) | 2001-12-17 |
HUP0004434A2 (hu) | 2001-05-28 |
US20010003121A1 (en) | 2001-06-07 |
US6258838B1 (en) | 2001-07-10 |
JP2001525392A (ja) | 2001-12-11 |
RU2214997C2 (ru) | 2003-10-27 |
PL340906A1 (en) | 2001-03-12 |
IL136369A0 (en) | 2001-06-14 |
US6303659B2 (en) | 2001-10-16 |
DK1036059T3 (da) | 2002-12-02 |
CA2312420A1 (en) | 1999-06-17 |
PT1036059E (pt) | 2003-02-28 |
NO20002786L (no) | 2000-07-31 |
NO20002786D0 (no) | 2000-05-31 |
BR9813390A (pt) | 2000-10-03 |
DE69808130D1 (de) | 2002-10-24 |
AU744280B2 (en) | 2002-02-21 |
TR200001605T2 (tr) | 2000-10-23 |
EP1036059A1 (en) | 2000-09-20 |
DE69808130T2 (de) | 2003-05-28 |
WO1999029661A1 (en) | 1999-06-17 |
EP1036059B1 (en) | 2002-09-18 |
ES2184352T3 (es) | 2003-04-01 |
HUP0004434A3 (en) | 2002-12-28 |
ID28003A (id) | 2001-05-03 |
ATE224360T1 (de) | 2002-10-15 |
AU1791399A (en) | 1999-06-28 |
SK8432000A3 (en) | 2000-12-11 |
NZ504447A (en) | 2002-04-26 |
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