CN105294450A - 具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用 - Google Patents
具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用 Download PDFInfo
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- CN105294450A CN105294450A CN201410235747.5A CN201410235747A CN105294450A CN 105294450 A CN105294450 A CN 105294450A CN 201410235747 A CN201410235747 A CN 201410235747A CN 105294450 A CN105294450 A CN 105294450A
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Abstract
本发明涉及一种具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用。所述化合物具有通式(Ι)的结构:
Description
技术领域
本发明属于医药技术领域,涉及一种具有神经保护作用的金刚烷胺衍生物,其合成方法、制药用途和用于预防或治疗疾病方面的应用。
背景技术
金刚烷胺及其衍生物有多种生物活性,在医药领域中有着广泛的应用。金刚乙胺(1-氨基乙基金刚烷,Rimantadine)是目前临床上广泛应用的预防和治疗流感的药物。金刚烷胺则广泛用于流感和帕金森病(Parkinson’sDisease,PD)的治疗(Schwabetal.,J.Am.Med.Assoc.1969,208:1168)。美金刚(1,3-二甲基金刚烷胺,Memantine)是目前美国FDA批准的唯一用于治疗中度至重度阿尔兹海默症(Alzheimer’sDisease,AD)的NMDA受体拮抗剂。NMDA受体是中枢神经系统内一类重要的兴奋性氨基酸离子型谷氨酸受体的一个亚型,是学习和记忆过程中一类重要的受体。NMDA受体通路被打开后能非选择性的允许一些阳离子,如Ca2+、K+和Na+等进入细胞,这些离子特别是钙离子的进入能引起一系列的生化反应,最终导致神经毒性,引起神经元凋亡。美金刚是NMDA受体开放通道的一种非竞争性拮抗剂,它能与离子通道内的结合位点结合,阻断离子内流,起到神经保护作用。美金刚对NMDA受体的结合是可逆的,并且具有适中的解离速率,既能保证其发挥药理作用,又能确保其不会在通道内累积,影响正常的生理功能(Liptonetal.,Journalofneurochemistry.2006,97:1611-1626)。同时美金刚对NMDA受体的拮抗作用有很强的电压依赖性,只有在神经元去极化时才能与受体结合,因而能阻断病理条件下神经元持续去极化时NMDA受体的活化,却不阻断正常生理条件下NMDA受体活化(Wenketal.,CNSdrugreviews.2003,9(3):275-308;McKeage.,Drugs&aging.2010,27(2):177-179)。这种保护机制对其他的中枢神经系统疾病如脑中风、PD、ALS等的治疗也有重要意义,因而,它对这些疾病的治疗也有良好的前景。
一氧化氮(NO)在体内也具有多种生物活性,它起着信号分子的作用。一氧化氮分子能穿透细胞壁进入平滑肌细胞,使其松弛,扩张血管,降低血压。同时也能进入血小板细胞,降低其活性,从而抑制其凝集和向血管内皮的粘附,预防血栓形成,防止动脉粥样硬化。NO是一种自由基气体,带有一个未配对电子,体内极不稳定,非常容易与自由基反应,从而能降低自由基数量。而自由基的累积能够引起核酸断裂、酶钝化、多聚糖解聚、脂质过氧化最终导致神经元死亡(Yanetal.FreeRadic.Biol.Med.2013,62:90-101)。NO与各种自由基都具有较强的反应能力,能有效的降低自由基数量,但其在体内的合成需要一氧化氮合酶(NOS)的参与。正常情况下,NOS的活性都比较低,需要硝基类分子或者皂苷类物质激活。在小分子药物上引入NO释放基团,能够增加体内NO含量,具有显著的疗效,如硝酸甘油。
由于AD发病机制复杂,目前,临床上对AD的治疗方法有限,只有四个乙酰胆碱酯酶抑制剂和一个NMDA受体抑制剂。这些针对单一靶点作用的药物分子,只能缓解AD某一方面的临床症状而不能根本上治愈疾病,阻断神经退化进程。
发明内容
本发明的目的是提供一种具有多重作用靶点的,具有神经保护作用的金刚烷胺硝酸酯化合物。该类化合物通过基于药效团的药物设计理论,将多个具有明确作用靶点的药效团整合到同一分子中,使其同时具有NMDA抑制活性,释放NO,抑制钙离子内流,清除自由基,起到神经保护作用。该类化合物具有多重作用机制,能提高其药效,减少联合用药所产生的毒副作用。
本发明的目的还在于提供所述具有神经保护作用的金刚烷胺硝酸酯化合物的制备方法。
本发明的目的还在于提供所述具有神经保护作用的金刚烷胺硝酸酯化合物在制药中的应用。
本发明中的提供的化合物具有通式(I)的结构:
其中:
R1,R2,R3相同或不相同,分别为氢,直链或支链烷基,取代或未取代的芳基,芳杂基,硝酸酯基,且R1,R2,R3中至少包含有硝酸酯基。
通式(I)进一步优选的化合物具有通式(II)的结构:
其中:
R1,R2相同或不相同,分别为氢,直链或支链烷基,取代或未取代的芳基,芳杂基;
Z1为连接所述R3硝酸酯基的直链或带有分支的碳链,其中Z1上可以取代有杂原子、烷基、芳基或芳杂基,并且Z1包含的碳原子数为1-6,1-5,2-5或2-4。
通式(II)的化合物,优选地,其中R1和R2的至少之一为氢。
通式(II)的化合物,优选地,其中R2为氢,R1为直链或支链烷基,并且Z1包含的碳原子数与R1上的碳原子数之和不少于3,优选地不少于4,例如为4-6。
通式(I)的化合物,进一步优选地,其中R1和R3为硝酸酯基,亦即所述化合物具有通式(III)的结构:
其中:
R2为氢,直链或支链烷基,取代或未取代的芳基,芳杂基;
Z1和Z2,相同或者不相同,分别为连接R1和R3上各自的所述硝酸酯基的直链或带有分支的碳链,其中Z1和Z2上各自可以取代有杂原子、烷基、芳基或芳杂基,并且Z1和Z2各自包含的碳原子数为1-6,1-5,2-5或2-4。
通式(III)的化合物,优选地,为具有如下之一的结构:
通式(I)的化合物,进一步优选地,其中R1,R2和R3为硝酸酯基,亦即所述化合物具有通式(IV)的结构:
其中:
Z1,Z2和Z3,相同或者不相同,分别为连接R1,R2和R3上各自的所述硝酸酯基的直链或带有分支的碳链,其中Z1,Z2和Z3上各自可以取代有杂原子、烷基、芳基或芳杂基,并且Z1,Z2和Z3各自包含的碳原子数为1-6,1-5,2-5或2-4。
根据通式(I)的一些优化的具体化合物包括但不限于以下的化合物:
本发明还提供了一种制备所述金刚烷胺硝酸酯化合物的合成方法。所述合成包括:以溴基、烷基或烷基羧酸基团取代的或未取代的金刚烷为原料,首先经Ritter反应引入氨基,然后通过发烟硝酸与所述金刚烷环上的羟基酯化作用在具有取代的侧链上生成硝酸酯。
本发明提供的化合物对细胞尤其是神经细胞具有较好的保护作用,可以用于制备具有细胞保护作用的药物。所述药物可包含提供给患者服用的有效治疗剂量的具有前述结构式(I)的化合物或其药学上可接受的盐。
本发明提供了一种具有多重作用机制,包括抑制NMDA受体,释放NO,抑制细胞内钙离子升高,清除自由基,对细胞尤其是神经细胞具有较好的保护作用。所述化合物可以用于制备具有细胞保护作用的药物,用于预防或治疗与细胞内钙离子升高,自由基过量产生或者NMDA受体过度激活等引起的相关疾病,例如老年痴呆、帕金森、脑中风、亨廷顿舞蹈症、肌肉萎缩性侧索硬化症、重症肌无力、青光眼等疾病。用于预防或治疗上述疾病的方法包括给患者服用本发明所述化合物制备的药物,其中包括有效治疗剂量的具有前述通式(I)至(V)的化合物或其药学可接受的盐或相应的药物复合物。
以下定义用以阐明和界定该发明中所用到的各种术语的含义以及范围。
本文所用的术语“烷基”是指未被取代的或被取代的直链、支链或环形的多至10个碳原子的烷基碳链。直链烷基包括如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基等饱和烷基,也包括含有烯键、炔键、羰基、氰基等取代基的不饱和烷基。支链烷基包括如异丙基、仲丁基、异丁基、叔丁基、新戊基。环状烷基(“环烷基”)包括如环丙基、环丁基、环戊基和环己基。烷基可被一个或多个疏水取代基取代。上述取代基的非限定性例子包括N(CH3)2、F、Cl、Br、I、OCH3、CO2CH3、CN、芳基和杂芳基。术语“烷基”也指未取代或取代的直链、支链或环状的含有多至10个碳原子的在链上含有至少一个杂原子(例如氮、氧或硫)的烷基。上述直链烷基包括,例如,CH2CH2OCH3、CH2CH2N(CH3)2和CH2CH2SCH3。支链基团包括,例如,CH2CH(OCH3)CH3、CH2CH(N(CH3)2)CH3和CH2CH(OCH3)CH3。上述环状基团包括,例如六元环CH(CH2CH2)2O、CH(CH2CH2)2NCH3和CH(CH2CH2)2S及相应的五元环等。
本文所用的术语“芳基”是指未被取代的或取代的芳香化合物、碳环基团和杂芳基。芳基或者是单环或者是多环稠合化合物。芳基可以被一个或多个取代基取代,取代基的非限制性的例子包括N(CH3)2、F、Cl、Br、I、OCH3、CO2CH3、CN、芳基和杂芳基。
杂芳基涉及到取代的或非取代的单环或多环的基团,环内至少包括一个杂原子,如氮、氧以及硫。举例来说,典型的杂环基团包括一个或多个氮原子譬如四唑基、吡咯基、吡啶基(如4-吡啶基,3-吡啶基,2-吡啶基等)、哒嗪基、吲哚基、喹啉基(如2-喹啉基,3-喹啉基等)、咪唑基、异喹啉基,吡唑基、吡嗪基、嘧啶基、吡啶酮基或哒嗪基;典型的含一个氧原子的杂环基团包括2-呋喃基,3-呋喃基或苯并呋喃基;典型的硫杂原子基团包括噻吩基、苯并噻吩基;典型的混合杂原子基团包括呋吖基、噁唑基、异噁唑基、噻唑基和吩噻噁基。杂环基团能被一个或多个取代基取代。这些取代基包括O-烷基、NH-烷基、N(烷基)2、NHC(O)-烷基、F、Cl、Br、I、OH、OCF3、CO2-烷基、CN以及芳基和多芳基。
本文使用的术语“药学上可接受的”指的是在化合物如盐或赋形剂中不具有不能接受的毒性。药学上可接受的盐包括无机阴离子,例如氯离子、溴离子、碘离子、硫酸根、亚硫酸根、硝酸根、亚硝酸根、磷酸根、磷酸氢根等。有机阴离子包括乙酸根、丙酸根、肉桂酸根、苯甲磺酸根、柠檬酸根、乳酸根、葡萄糖酸根等。药学上可接受的赋形剂在后文有描述,参见E.W.Martin,inRemington’sPharmaceuticalSciencesMackPublishingCompany(1995),Philadelphia,PA,19thed。
本发明中涉及的新化合物包括前述结构式(I)至(VIII)。新化合物在金刚烷胺结构上至少再含有胺基,酯基和硝酸酯基团中的1种取代基团,因此,这些化合物具有多重作用机制,能够抑制单胺氧化酶、胆碱酯酶,释放NO,释放H2S,清除自由基,且对细胞尤其是神经细胞具有较好的保护作用,可以用于制备预防或治疗具有细胞保护作用的药物,用于与单胺氧化酶,胆碱酯酶或自由基等相关疾病的治疗,通常是指用于与神经退行性有关的疾病,以及与自由基相关的疾病等,这些疾病包括但不限于与单胺氧化酶相关的疾病如帕金森症,阿尔茨海默症,痴呆症,高血压,腹泻,抑郁症,哮喘,过敏;还包括与胆碱酯酶有关的疾病如阿尔茨海默症,帕金森症,亨廷顿舞蹈症,肌肉萎缩性侧索硬化症,重症肌无力,青光眼,老年痴呆症,甲状腺功能亢进、高血压、支气管哮喘、IV型高脂蛋白血症、肾功能衰竭;还包括与NO相关或者与氧化应激损伤或自由基相关的疾病如脑中风、脑创伤、癫痫、帕金森症、亨廷顿氏病、肌萎缩性侧索硬化、阿尔茨海默症、缺氧缺血脑损伤、脑溢血,痴呆症、缺血性心脏病,血管栓塞,动脉粥样硬化,高胆固醇血症,肺气肿,白内障,糖尿病,急性胰腺炎,酒精引起的肝脏疾病,肾脏伤害,癌症;也可用于预防、治疗与H2S相关的疾病,包括心脑血管疾病,炎症,动脉粥样硬化,糖尿病,阿尔茨海默症,帕金森症,肥胖症,癌症,脑中风,外伤性脑损伤;还可以用于预防和治疗神经退行性疾病如脑缺血,帕金森氏症,阿尔茨海默症,肌肉萎缩性侧索硬化症,共济失调毛细血管扩张症,牛海绵状脑病,克雅二氏病,小脑萎缩症,多发性硬化症,原发性侧索硬化,脊髓性肌萎缩症。
本发明涉及具有酯基(包括取代或未取代的氨基甲酸酯基),胺基,硝酸酯基及其衍生物,可以一种药学可接受的盐或药物复合物的形式对病人给药。某个复合物需与适当载体或赋形剂混合形成药物组合物从而保证达到有效治疗剂。“有效治疗剂量”是指该种类化物及其衍生物达到治疗效果所必须的剂量。
该类多重作用机制的化合物及其衍生物可以制成多种剂型,包括固体剂型,半固体剂型,液体制剂和气雾剂(Remington’sPharmaceuticalSciences,MackPublishingCompany(1995),Philadelphia,PA,19thed)。这几类剂型中的具体剂型包括片剂、丸剂、糖锭剂、颗粒剂、凝胶剂、膏剂、溶液剂、栓剂、注射剂、吸入剂以及喷雾剂。这些剂型既能用于局部或全身给药又能用于速释或缓续给药,此类药物的给药方式有很多种,除了上述方式,还有口腔给药、面颊给药、直肠给药、腹膜给药、腹膜内给药、皮表给药、皮下给药和气管内给药等。
该类多重作用机制的化合物及其衍生物注射给药时,可以用水溶性或脂溶性的溶剂将此类化合物配制成溶液剂,悬浊剂和乳剂。脂溶性溶剂具体包括植物油及类似油类,合成脂肪酸甘油酯,高级脂肪酸酯以及丙二醇酯(proyleneglycol)。这类化合物更易溶于Hank’s溶液,Ringer’s溶液或者生理盐水。
该类多重作用机制的化合物及其衍生物口服给药时,可以采用常用技术将其与药学可接受的赋形剂制成复合物。这些赋形剂可以将这些化合物制成多种可以被病人剂型,如片剂、丸剂、混悬剂、凝胶剂等。口服制剂的配制有多种方法,如先把化合物和固体赋形剂混匀,充分研磨混合物,添加适当的辅料,加工处理成颗粒。可以用于制成口服剂型的辅料包括:糖类如乳糖、蔗糖、甘露醇或山梨醇;纤维素类如玉米淀粉、小麦淀粉、马铃薯淀粉、明胶、西黄薯胶、甲基纤维素、羟甲基纤维素(hydroxyproylmethyl-cellulose)、羧甲基纤维素纳、聚乙烯吡咯酮等。
本发明涉及具有多重作用机制的化合物及其衍生物也可以制成喷雾剂,此种剂型是通过一个加压器和一个喷雾器或者一个干粉吸入装置而实现的。可以用作喷射器里合适的喷射剂如二氯二氟甲烷、氟三氯甲烷、二氯四氟乙烷、二氧化碳和二甲醚等。气雾剂给药的剂量可以通过喷射器的阀门来调节。
本发明涉及的各种剂型都关系到该类多重作用机制的化合物及其衍生物的有效治疗剂量。该类化合物的有效治疗剂量取决于接受治疗的病人。在决定适宜的剂量时,病人的体重、病情、服药方式以及处方医师的主观判断因素都要纳入考虑。该类多重作用机制的化合物及其衍生物的治疗有效量应该由有能力和丰富经验的处方医师决定。
尽管该类多重作用机制的化合物及其衍生物的有效治疗剂量会根据患者情况发生变化,但是通常适当的给药剂量范围是10mg-10g。
本发明与现有技术相比,具有如下优点:本发明提供了一种全新结构的物质,同时具有多重作用机制,能够抑制NMDA受体、抑制钙离子内流,清除自由基,且对细胞尤其是神经细胞具有较好的保护作用,可以用于制备预防或治疗具有细胞保护作用的药物,通常是指用于如老年痴呆、帕金森、脑中风等等与神经退行性有关的疾病,以及与自由基相关的疾病包括心脏疾病、糖尿病等。
附图说明
图1描述化合物NM-002的合成。
图2描述化合物NM-004的合成。
图3描述化合物NM-005的合成。
图4描述化合物NM-008的合成。
图5描述化合物NM-009的合成。
图6描述化合物NM-011的合成。
图7描述化合物NM-012的合成。
图8描述化合物NM-008对永久性脑缺血模型大鼠脑梗死的保护作用。图中*表示与对照组相比有显著差异。
具体实施方式
实施例1、化合物NM-002a的合成
将化合物AD-003e1.48g(5mmol)溶于30mL干燥除水的二氯甲烷中,冰水浴冷却。加入乙酸酐与发烟硝酸的混合液(乙酸酐:发烟硝酸体积比等于3:2)3mL。维持冰水浴,反应10-15分钟。将反应液倒入30mL1N的碳酸氢钠溶液中,分离二氯甲烷后,水层用二氯甲烷(20mL×3)萃取。合并二氯甲烷,30mL水洗涤,无水硫酸钠干燥,过滤,减压蒸馏二氯甲烷后得到无色油状粗品。硅胶柱分离(石油醚:二氯甲烷=10:1)收得无色油状物NM-002a1.07g(62.9%)。ESI-MS:m/z340.2([M]+).1H-NMR(DMSO-d6,ppm):0.83(s,3H),1.15-1.24(m,2H),1.26-1.47(m,14H),1.56-1.80(m,5H),2.06-2.14(m,1H),4.22(s,2H),6.51(s,1H)。
实施例2、化合物NM-002的合成
向化合物NM-002a680mg(2mmol)中加入氯化氢饱和的乙醚溶液5mL,室温下反应,点板监测。反应结束时,有白色固体析出。过滤,无水乙醚洗涤白色固体,即可得到NM-002纯品390mg(70.7%)。ESI-MS:m/z341.0([M+H]+).1H-NMR(DMSO-d6,ppm):0.88(s,3H),1.19-1.29(m,2H),1.30-1.38(m,2H),1.38-1.52(m,4H),1.54-1.64(m,2H),1.66-1.73(m,2H),2.18-2.24(m,1H),4.29(s,2H),8.11(s,3H)。
实施例3、化合物NM-004a的合成
取50mL圆底烧瓶置于冰水浴中冷却,向圆底烧瓶中加入浓硫酸20mL,正己烷2mL和化合物NM-003a970mg(4mmol)。维持冰水浴,缓慢滴加甲酸(1.8mL)。滴完后继续冰水浴反应3小时。将反应液倒入到100mL冰水中,析出固体。静置,抽滤后得到浅黄色固体。固体干燥后溶于乙酸乙酯中,氢氧化钠水溶液碱化至pH到9-10左右,分离水层。有机层用氢氧化钠水溶液萃取(30mL×3),合并水溶液,稀盐酸溶液酸化水层至pH为3左右。抽滤,干燥,得到纯净的化合物NM-004a640mg(77%)。ESI-MS:m/z207([M-H]-).1H-NMR(DMSO-d6,ppm):0.76(t,3H,J=7.5Hz),1.11(q,2H,J=7.5Hz),1.31-1.44(m,4H),1.47(s,2H),1.51-1.64(m,2H),1.66-1.81(m,4H),2.01(m,2H),11.99(s,1H)。
实施例4、化合物NM-004b的合成
向50mL圆底烧瓶中加入化合物NM-004a624mg(3mmol),冰浴冷却。加入浓硝酸0.55mL,搅拌均匀。向混合物中滴加浓硫酸3.5mL,冰浴反应1小时。之后滴加乙腈2.5mL(4.8mmol),继续冰浴反应1小时。将反应液倒入到20mL冰水中,剧烈搅拌30分钟,静置过夜。析出白色固体,抽滤,固体用适量水洗涤,烘干,收得化合物NM-004b(580g,73%),无需纯化,可以直接投下一步反应。ESI-MS:m/z266([M+H]+).1H-NMR(DMSO-d6,ppm):0.74(t,3H,J=7.5Hz),1.15(q,2H,J=7.5Hz),1.26-1.35(m,2H),1.36-1.47(m,2H),1.52-1.70(m,4H),1.72-1.86(m,5H),1.88-1.98(m,2H),2.13(m,1H),7.43(s,1H)。
实施例5、化合物NM-004c的合成
取化合物NM-004b878mg(3.3mmol)溶于10mL干燥四氢呋喃,冰水浴冷却。依次向混合液中加入三乙胺0.5mL和氯甲酸乙酯0.5mL,冰水浴30分钟后撤去冰浴,室温下反应4小时。过滤,适量四氢呋喃洗涤滤饼,收集滤液。向滤液中加入硼氢化钠1.5g,滴液漏斗缓慢滴加1mL水,1小时内滴完。滴完后室温下继续反应1小时。TLC监测,反应完成后,向反应体系中加水30mL,减压旋干四氢呋喃。水层用乙酸乙酯萃取(20mL×4),合并乙酸乙酯,25mL0.5N盐酸、饱和氯化钠水溶液和水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到油状粗品。硅胶柱分离(石油醚:乙酸乙酯=1:1),最后收得白色固体NM-004c348mg(42%)。ESI-MS:m/z252.2([M+H]+).1H-NMR(DMSO-d6,ppm):0.76(t,3H,J=7.5Hz),1.03-1.20(m,4H),1.28(m,4H),1.58(m,4H),1.75(m,5H),2.09(s,1H),3.02(d,2H,J=5.5Hz),4.38(t,1H,J=5.5Hz),7.33(s,1H)。
实施例6、化合物NM-004d的合成
向250mL圆底烧瓶中加入化合物NM-004c1.26g(5mmol),固体氢氧化钠3g,二乙二醇20mL,170℃回流15小时。冷却至室温,将反应液倒入40g碎冰中,搅拌均匀后,混合液用乙酸乙酯萃取(20mL×4)。合并乙酸乙酯层,30mL水和30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥。蒸干溶剂后得到淡黄色的油状物粗品。将粗品溶于50mL干燥的乙酸乙酯中,搅拌条件下通入干燥的HCl,有大量白色固体析出。抽滤,固体用适量干燥乙酸乙酯洗涤,干燥,收得白色固体NM-004d850mg(69.4%)。ESI-MS:m/z210.3([M+H]+).1H-NMR(DMSO-d6,ppm):0.74(t,3H,J=7.6Hz),1.15(q,2H,J=7.6Hz),1.26-1.35(m,2H),1.36-1.47(m,2H),1.53-1.68(m,4H),1.74-1.85(m,3H),1.88-1.96(m,2H),2.13(m,1H),7.43(s,3H)。
实施例7、化合物NM-004e的合成
取化合物NM-004d2.45g,(10mmol)溶于20mL水中,氢氧化钠溶液碱化至pH为10左右,乙酸乙酯萃取(30mL×4)。合并乙酸乙酯,30mL水洗涤,无水硫酸钠干燥。减压蒸去溶剂得到无色油状的游离胺1.57g(7.5mmol)。无需纯化,直接溶于50mL重蒸干燥的四氢呋喃,依次加入三乙胺1.56g(15.6mmol),Boc酸酐2.55g(11.7mmol)和DMAP10mg,室温下反应5小时,TLC监测反应。反应结束后,向反应液中加入饱和氯化铵溶液30mL淬灭反应。减压蒸干溶剂后,乙酸乙酯萃取(50mL×4)。合并乙酸乙酯,用30mL0.1N盐酸和30mL饱和氯化钠水溶液洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。粗品经硅胶柱分离(石油醚:乙酸乙酯=1:1),收得白色固体NM-004e1.58g(68%)。ESI-MS:m/z310.3([M+H]+).1H-NMR(DMSO-d6,ppm):0.75(t,3H,J=7.5Hz),1.03-1.19(m,4H),1.24(m,4H),1.36(s,9H),1.44–1.58(m,4H),1.52-1.73(m,2H),2.08(s,1H),3.02(d,2H,J=5.5Hz),4.38(t,1H,J=5.5Hz),6.36(s,1H)。
实施例8、化合物NM-004f的合成
将化合物NM-004e620mg(2mmol)溶于10mL干燥除水的二氯甲烷中,冰水浴冷却。加入乙酸酐与发烟硝酸的混合液(乙酸酐与发烟硝酸体积比等于3:2)2mL。冰水浴反应10-15分钟。将反应液倒入10mL1N的碳酸氢钠溶液中,分离二氯甲烷后,水层用二氯甲烷(10mL×3)萃取,合并二氯甲烷,用10mL水洗涤。无水硫酸钠干燥,过滤,减压蒸馏二氯甲烷后得到无色油状粗品。硅胶柱分离(石油醚:二氯甲烷=10:1)收得无色油状物NM-004f505mg(73.4%)。ESI-MS:m/z377.2([M+Na]+).1H-NMR(DMSO-d6,ppm):0.76(t,3H,J=7.5Hz),1.08-1.23(m,4H),1.26-1.49(m,14H),1.56-1.82(m,5H),2.12(m,1H),4.23(s,2H),6.50(s,1H)。
实施例9、化合物NM-004的合成
向化合物NM-004f710mg(2mmol)中加入氯化氢饱和的乙醚溶液5mL,室温下反应。反应结束时,有白色固体析出。过滤,无水乙醚洗涤白色固体,即可得到NM-004纯品。干燥后,收得NM-004380mg(65.5%)。ESI-MS:m/z255.1([M+H]+).1H-NMR(DMSO-d6,ppm):0.78(t,3H,J=7.5Hz),1.15-1.28(m,4H),1.30-1.39(m,2H),1.40-1.55(m,4H),1.57-1.67(m,2H),1.71(s,2H),2.23(m,1H),4.30(s,2H),8.21(s,3H)。
实施例10、化合物NM-005a的合成
取化合物NM-003a3.66g(15.0mmol)溶于45mL干燥甲苯,依次加入AIBN0.122g(0.74mol),n-Bu3SnH4.95g(16.7mmol),丙烯酸乙酯3.10g(31.0mmol),氮气保护下110℃回流3小时,TLC监测反应。反应完全后,冷却,将反应液倒入105mL0.2M氨水,搅拌1小时,乙酸乙酯萃取(100mL×4),合并有机相,无水硫酸钠干燥。过滤,减压除去溶剂,得到无色透明液体,硅胶柱分离(石油醚:乙酸乙酯=6:1),得到无色透明液体NM-005a(2.50g,62.8%)。1H-NMR(DMSO-d6,ppm):0.72(t,3H,J=7.5Hz),1.10(m,4H),1.17(t,3H,J=7.8Hz),1.32(m,10H),1.53(s,2H),1.97(s,2H),2.21(t,2H,J=8.1Hz),4.02(q,1H,J=7.2Hz)。
实施例11、化合物NM-005b的合成
向化合物NM-005a2.50g(9.5mmol)中加入60mL甲醇,5mL水,搅拌溶解后加入氢氧化钾3.2g(57mmol),室温反应12小时,TLC监测反应。反应完全后减压除去溶剂,加水30mL,乙酸乙酯20mL萃取除去有机杂质。水层用浓盐酸调节PH至1-2,此时有大量白色固体析出,减压抽滤,滤饼用少量水洗涤,干燥,得到白色固体NM-005b1.60g(71.6%)。ESI-MS:m/z237.1([M+H]+).1H-NMR(DMSO-d6,ppm):0.75(t,3H,J=7.5Hz),1.10(m,4H),1.32(m,10H),1.54(s,2H),1.97(s,2H),2.14(t,2H,J=8.1Hz),11.98(s,1H)。
实施例12、化合物NM-005c的合成
取化合物NM-005b1.6g(6.8mmol)置于50mL圆底烧瓶中,冰浴冷却。加入浓硝酸1.1mL,搅拌均匀。向混合物中缓慢滴加浓硫酸6.8mL,滴完之后,冰浴反应1小时。缓慢滴加乙腈5mL,继续冰浴1小时。将反应液倒入到30mL冰水中,剧烈搅拌30分钟,乙酸乙酯萃取(50mL×5),合并有机相,无水硫酸钠干燥。过滤,减压除去溶剂,得到无色粘稠液体,硅胶柱层析分离(洗脱剂为乙酸乙酯),得到无色透明粘稠半固体NM-005c1.60g(80.6%)。1H-NMR(DMSO-d6,ppm):0.75(t,3H,J=7.5Hz),1.11(m,4H),1.28(m,6H),1.54(m,4H),1.73(m,5H),2.08(s,1H),2.16(m,2H),3.16(s,1H),1.77(m,1H),4.38(m,2H),4.40(s,1H)。
实施例13、化合物NM-005d的合成
将化合物NM-005c2.8g(9.5mmol)溶于10mL干燥四氢呋喃,冰浴冷却。依次加入三乙胺1.5mL和氯甲酸乙酯1.5mL(15.8mmol),冰水浴30分钟后撤去冰浴,室温下继续反应4小时后过滤,洗涤滤饼用四氢呋喃,收集滤液。向滤液中加入2.7g硼氢化钠(0.07mol),缓慢滴加1.8mL水,滴完后室温下继续反应2小时。向反应体系中加水50mL,减压除去四氢呋喃。水层用乙酸乙酯萃取(50mL×5),合并有机相,饱和氯化钠水溶液洗涤,无水硫酸钠干燥。过滤,减压除去溶剂后得到油状粗品。硅胶柱分离(甲醇:乙酸乙酯=1:6),得到无色透明粘稠状半固体NM-005d1.7g(63.75%)。ESI-MS:m/z280.1([M+H]+)。1H-NMR(DMSO-d6,ppm):0.75(t,3H,J=7.5Hz),1.11(m,4H),1.36(m,6H),1.54(m,4H),1.73(m,5H),2.08(s,1H),2.18(m,2H),3.57(m,2H)。
实施例14、化合物NM-005e的合成
向100mL圆底烧瓶中依次加入化合物NM-005d1.7g(6.1mmol),氢氧化钠5.5g(0.14mol),二乙二醇35mL。混合液175℃回流反应16h。冷却至室温,将反应液倒入50g碎冰中,搅拌均匀后,乙酸乙酯与甲基叔丁基醚的混合溶剂萃取(V乙酸乙酯:V甲基叔丁基醚=4:1,50mL×6)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥。过滤,减压除去溶剂得到棕色液体1.1g。无需纯化,直接加入重蒸干燥的二氯甲烷(50mL),依次加入三乙胺2.5mL,Boc酸酐1.1g(5mmol),室温下搅拌5小时,TLC监测反应。待反应结束后,反应液用饱和氯化钠溶液洗涤数次,有机相用无水硫酸钠干燥。过滤,减压除去溶剂后得到棕色油状物。硅胶柱层析分离(石油醚:乙酸乙酯=1:5),收得无色液体NM-005e0.48g(23.38%)。1H-NMR(CDCl3-d,ppm):0.80(t,3H,J=7.5Hz),1.14(m,2H),1.20(m,4H),1.33(m,6H),1.43(s,9H),1.51(m,2H),1.61(m,2H),1.72(m,1H),1.78(m,2H),2.17(m,1H),3.61(m,2H,J=6.3Hz),4.43(s,1H)。
实施例15、化合物NM-005f的合成
取化合物NM-005e380mg(1.1mmol)溶于8mL干燥的二氯甲烷,冰浴冷却。加入1.2mL乙酸酐与发烟硝酸的混合液(V乙酸酐:V发烟硝酸=3:2,)。反应10-15分钟,TLC监测反应。反应完全后,将反应液倒入40mL1N的碳酸氢钠溶液中,二氯甲烷继续萃取(20mL×3),合并二氯甲烷,饱和氯化钠溶液洗涤,无水硫酸钠干燥。过滤,减压除去溶剂,得到无色油状物。硅胶柱分离(石油醚:乙酸乙酯=20:1),收得无色油状物NM-005f230mg(53.41%)。1H-NMR(CDCl3-d,ppm):0.76(t,3H,J=7.5Hz),1.10(m,2H),1.23(m,6H),1.33(m,2H),1.40(s,9H),1.51(m,2H),1.68(m,4H),1.68(m,4H),1.77(m,1H),4.38(m,2H),4.40(s,1H)。
实施例16、化合物NM-005的合成
化合物NM-005f110mg(0.29mmol)置于25mL的圆底烧瓶中,加入氯化氢饱和的乙醚溶液10mL,室温下反应30-45分钟,TLC监测反应。反应结束后,减压除去溶剂,得到无色油状物,再加入无水乙醚20mL,减压除去溶剂,重复多次,直至固体析出。抽滤,滤饼用少量无水乙醚洗涤,干燥,得到白色固体NM-005(32mg,39.4%)。ESI-MS:m/z283.1([M+H]+).1H-NMR(DMSO-d6,ppm):0.77(t,3H,J=7.5Hz),1.18(m,6H),1.30(m,4H),1.46(m,4H),1.60(m,2H),1.67(m,2H),2.18(m,1H),4.49(t,2H,J=6.6Hz),8.18(s,3H)。
实施例17、化合物NM-008a的合成
取原料1,3-金刚烷二醇8.4g(50mmol)加入到250mL装有冷凝装置的两颈圆底烧瓶中,冰水浴冷却。加入浓硫酸56mL,搅拌均匀后,缓慢滴加无水甲酸5mL,滴完后维持冰水浴反应2小时后,室温下反应10小时。将淡黄色粘稠透明的反应液缓慢倒入到200g冰水中,此时有大量白色固体析出。抽滤,滤饼水洗后干燥,即可得到化合物NM-008a8.9g(79.5%)。ESI-MS:m/z223.2([M-H]-).1H-NMR(DMSO-d6,ppm):1.56-1.88(m,12H),2.06(s,2H),12.12(s,2H)。
实施例18、化合物NM-008b的合成
将化合物NM-008a2.24g(10mmol)溶于100mL重蒸除水的四氢呋喃,冰水浴冷却。依次向混合液中加入三乙胺3.0mL和氯甲酸乙酯3.0mL,冰水浴30分钟后撤去冰浴,室温下继续反应4小时。过滤,适量四氢呋喃洗涤滤饼,收集滤液。向滤液中加入硼氢化钠6g,滴液漏斗缓慢滴加3mL水,1小时内滴完。滴完后室温下继续反应1小时。TLC监测,反应完成后,向反应体系中加水50mL,减压旋干四氢呋喃。水层用乙酸乙酯萃取(40mL×4),合并乙酸乙酯层,分别用50mL0.5N盐酸、饱和氯化钠水溶液和水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到白色固体粗品。白色固体用乙酸乙酯洗涤,最后收得白色固体NM-008b1.08g(55%)。ESI-MS:m/z274.2([M+2K]2+).1H-NMR(DMSO-d6,ppm):1.14(s,2H),1.26-1.47(m,8H),1.54(s,2H),1.99(m,2H),2.99(d,4H,J=5.5Hz),4.30(t,1H,J=5.5Hz)。
实施例19、化合物NM-008c的合成
取化合物NM-008b白色固体784mg(4mmol)加入到25mL圆底烧瓶中,加入乙酸酐5mL,搅拌均匀。向悬浮液中加入2-3滴(催化量)高氯酸,室温下反应3小时。将反应液倒入到20g冰水中,乙酸乙酯萃取(20mL×3)。合并乙酸乙酯,用30mL1N的碳酸氢钠溶液和30mL水洗涤。无水硫酸钠干燥。减压蒸干溶剂后,得到无色油状物粗品。硅胶柱分离(石油醚:乙酸乙酯=10:1),最后收到无色油状NM-008c1.0g(90%)。ESI-MS:m/z298.3([M+H2O]+).1H-NMR(DMSO-d6,ppm):1.284(s,2H),1.36-1.52(m,8H),1.59(s,2H),2.02(s,8H),3.66(s,4H)。
实施例20、化合物NM-008d的合成
向25mL圆底烧瓶中加入化合物NM-008c840mg(3mmol),冰浴冷却。加入浓硝酸0.55mL,搅拌均匀。向混合物中缓慢滴加浓硫酸3.5mL,滴完之后,冰浴反应1小时。缓慢滴加乙腈(2.5mL,4.8mmol),继续冰浴反应1小时。将反应液倒入到20mL冰水中,水层用乙酸乙酯(20mL×4)萃取。合并乙酸乙酯,30mL1N的碳酸氢钠溶液和30mL水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=1:3),收得油状化合物NM-008d425mg(42%)。ESI-MS:m/z360.3([M+Na]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例21、化合物NM-008e的合成
取化合物NM-008d670mg(2mmol)加入到25mL圆底烧瓶中,加入18%HCl10mL,回流48小时。减压蒸干水后,干燥,得到白色固体。固体用乙酸乙酯洗涤后干燥可得到NM-008e296mg(60%)。ESI-MS:m/z21.3([M+H]+).1H-NMR(DMSO-d6,ppm):。
实施例22、化合物NM-008f的合成
取化合物NM-008e500mg(2mmol)加入到25mL圆底烧瓶中,加入DMF5mL。依次加入三乙胺(800mg,8mmol),Boc酸酐(650mg,3mmol)和DMAP(2mg),室温下搅拌5小时,TLC监测反应。待反应结束后,向反应液中加入饱和氯化铵溶液20mL淬灭反应。减压蒸干溶剂后,水层用乙酸乙酯萃取(10mL×4)。合并乙酸乙酯层,用10mL0.1N盐酸和10mL饱和氯化钠水溶液洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。粗品经硅胶柱分离(石油醚:乙酸乙酯=1:1),收得白色固体NM-008f404mg(65%)。ESI-MS:m/z312.3([M+H]+).1H-NMR(DMSO-d6,ppm):1.07(m,2H),1.20-1.29(m,4H),1.39(s,9H),1.43–1.59(m,4H),1.62-1.72(m,2H),2.08(m,1H),3.02(d,4H,J=5.5Hz),4.38(t,2H,J=5.5Hz),6.39(s,1H)。
实施例23、化合物NM-008g的合成
取化合物NM-008f624mg(2mmol)溶于10mL干燥除水的二氯甲烷中,冰水浴冷却。加入乙酸酐与发烟硝酸的混合液然(乙酸酐:发烟硝酸体积比等于3:2)2mL。维持冰水浴,反应10-15分钟。将反应液倒入10mL1N的碳酸氢钠溶液中,分离二氯甲烷后,水层用二氯甲烷(10mL×3)萃取,合并二氯甲烷液体,用10mL水洗涤,无水硫酸钠干燥。过滤,减压蒸馏二氯甲烷后得到无色油状粗品。硅胶柱分离(石油醚:二氯甲烷=10:1)收得无色油状物NM-008g600mg(75%)。ESI-MS:m/z419.3([M+H]+).1H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H)。
实施例24、化合物NM-008的合成
向化合物NM-008g401mg(1mmol)中加入氯化氢饱和的乙醚溶液5mL,室温下反应,点板监测。反应结束时,有白色固体析出。过滤,无水乙醚洗涤白色固体,即可得到NM-008纯品。干燥后,收得NM-008380mg(65.5%)。ESI-MS:m/z255.1([M+H]+).1H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H)。
实施例25、化合物NM-009a的合成
取化合物1,3-金刚烷二乙酸2.52g(10mmol)加入到100mL重蒸除水的四氢呋喃中,冰水浴冷却。依次向混悬液中加入三乙胺(3.0mL)和氯甲酸乙酯(3.0mL),冰水浴30分钟后撤去冰浴,室温下继续反应4小时。过滤,适量四氢呋喃洗涤滤饼,收集滤液。向滤液中加入硼氢化钠6g,滴液漏斗缓慢滴加3mL水,1小时内滴完。滴完后室温下继续反应1小时。TLC监测,反应完成后,向反应体系中加水50mL,减压旋干四氢呋喃。水层用乙酸乙酯萃取(40mL×4),合并乙酸乙酯,分别用50mL0.5N盐酸、饱和氯化钠水溶液和水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到白色固体粗品。白色固体用乙酸乙酯洗涤,最后收得白色固体NM-009a1.43g(63.8%)。ESI-MS:m/z247.2([M+Na]+).1H-NMR(DMSO-d6,ppm):1.21-1.26(m,6H),1.33-1.45(m,4H),1.54(m,2H),1.93(m,2H),3.40-3.47(m,4H),4.20(t,2H,J=5.5Hz)。
实施例26、化合物NM-009b的合成
向25mL圆底烧瓶中加入化合物NM-009a白色固体1.12g(5mmol),乙酸酐5mL,搅拌均匀。向悬浮液中加入2-3滴(催化量)高氯酸,室温下反应3小时。将反应液倒入到20g冰水中,乙酸乙酯萃取(20mL×3)。合并乙酸乙酯,用30mL1N的碳酸氢钠溶液和30mL水洗涤。无水硫酸钠干燥。减压蒸干溶剂后,得到无色油状物粗品。硅胶柱分离(石油醚:乙酸乙酯=10:1),最后收到无色油状NM-009b1.43g(92.9%)。ESI-MS:m/z309.3([M+H2O]+).1H-NMR(DMSO-d6,ppm):1.25(s,2H),1.35-1.47(m,12H),1.55(s,2H),1.98(s,8H),4.04(t,4H)。
实施例27、化合物NM-009c的合成
取化合物NM-009b616mg(2mmol)置于25mL圆底烧瓶中,冰浴冷却。加入浓硝酸0.4mL,搅拌均匀。向混合物中缓慢滴加浓硫酸2.5mL,冰浴反应1小时。之后缓慢滴加乙腈2mL(4.8mmol),继续冰浴反应1小时。将反应液倒入到20mL冰水中,水层用乙酸乙酯(20mL×4)萃取。合并乙酸乙酯,30mL1N的碳酸氢钠溶液和30mL水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=1:3),收得油状化合物NM-009c423mg(57.9%)。ESI-MS:m/z366.3([M+H]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例28、化合物NM-009d的合成
依次将化合物NM-009c1g(2.7mmol),固体氢氧化钠1.5g,二乙二醇30mL加入100mL圆底烧瓶中,170℃反应15小时。冷却至室温后,加水20mL,乙酸乙酯(20mL×3)萃取除去杂质后,减压蒸去水分,剩余溶液中加四氢呋喃30mL,Boc酸酐1.18g(5.4mmol),三乙胺540mg(5.4mmol),DMAP10mg,室温下反应5小时。TLC点板监测。反应完全后,向反应液中加入饱和氯化铵溶液20mL,乙酸乙酯萃取(30mL×4),合并乙酸乙酯层,依次用30mL水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到浅黄色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=2:1),收得油状化合物NM-009d700mg(75.4%)。ESI-MS:m/z340.4([M+H]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例29、化合物NM-009e的合成
取化合物NM-009d680mg(2mmol)溶于10mL干燥除水的二氯甲烷中,冰水浴冷却。加入乙酸酐与发烟硝酸的混合液然(乙酸酐:发烟硝酸体积比等于3:2)2mL。维持冰水浴,反应10-15分钟。将反应液倒入10mL1N的碳酸氢钠溶液中,分离二氯甲烷后,水层用二氯甲烷(10mL×3)萃取,合并二氯甲烷液体,用10mL水洗涤,无水硫酸钠干燥。过滤,减压蒸馏二氯甲烷后得到无色油状粗品。硅胶柱分离(石油醚:二氯甲烷=10:1)收得无色油状物NM-008g620mg(72.3%)。ESI-MS:m/z452.1([M+Na]+).1H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H)。
实施例30、化合物NM-009的合成
向化合物NM-008g401mg(1mmol)中加入氯化氢饱和的乙醚溶液5mL,室温下反应,点板监测。反应结束时,有白色固体析出。过滤,无水乙醚洗涤白色固体,即可得到NM-008纯品。干燥后,收得NM-008380mg(65.5%)。ESI-MS:m/z255.1([M+H]+).1H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H)。
实施例31、化合物NM-011a的合成
将化合物1,3-二溴金刚烷3g(10mmol)溶于30mL甲苯,依次加入AIBN250mg(1.5mmol),三正丁基氢锡7g(24mmol),丙烯酸乙酯3g(30mmol),氮气保护下110℃回流3小时。将反应液冷却至室温后,倒入30mL0.2M氨水中,充分搅拌均匀后,分离有机层,水层用乙酸乙酯萃取(20mL×4),合并有机层层,30mL水和30mL饱和氯化钠溶液洗涤。无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=10:1),收得无色油状液体化合物NM-011a2g(46.6%)。ESI-MS:m/z337.4([M+H]+).1H-NMR(DMSO-d6,ppm):1.11(s,2H),1.15-1.19(m,6H),1.28-1.39(m,12H),1.53(s,2H),1.97(s,2H),2.19-2.24(m,2H),4.03(q,4H,J=7.1Hz)。
实施例32、化合物NM-011b的合成
取化合物NM-011a2.2g(6mmol)置于50mL圆底烧瓶中,冰浴冷却。加入浓硝酸1.2mL,搅拌均匀。向混合物中缓慢滴加浓硫酸8.5mL,冰浴反应1小时。之后缓慢滴加乙腈5.6mL(13.4mmol),继续冰浴反应1小时。将反应液倒入到20mL冰水中,水层用乙酸乙酯(20mL×4)萃取。合并乙酸乙酯,30mL1N的碳酸氢钠溶液和30mL水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=1:3),收得油状化合物NM-011b2g(57.9%)。ESI-MS:m/z394.2([M+H]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例33、化合物NM-011c的合成
取化合物NM-011b1g(2.5mmol)溶于20mL重蒸除水四氢呋喃,加入硼氢化钠450mg。将1.33g三氯化铝溶于10mL四氢呋喃中,缓慢滴入原料中,滴完后室温下搅拌过夜。将反应液倒入50mL冰水中,充分搅拌后,乙酸乙酯萃取(30mL×4)。合并萃取液,30mL饱和氯化钠洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(乙酸乙酯:甲醇=10:1),收得无色油状NM-011c470mg(60.8%)。ESI-MS:m/z310.1([M+H]+).1H-NMR(DMSO-d6,ppm):1.05-1.09(m,6H),1.22-1.39(m,8H),1.51-1.60(m,4H),1.73(s,3H),1.76(s,2H),2.07(m,1H),3.30-3.36(m,4H),4.39(t,2H,J=5.2Hz),7.36(s,1H)。
实施例34、化合物NM-011d的合成
将化合物NM-011c440mg(1.4mmol),固体氢氧化钠750mg,二乙二醇10mL,依次加入50mL圆底烧瓶中,170℃反应15小时。冷却至室温后,加水20mL,乙酸乙酯(20mL×3)萃取除去杂质后,减压旋蒸除去水,剩余溶液中加四氢呋喃30mL,Boc酸酐560mg(2.8mmol),三乙胺280mg(2.8mmol),DMAP10mg,室温下反应5小时。TLC点板监测。反应完全后,向反应液中加入饱和氯化铵溶液20mL,乙酸乙酯萃取(30mL×4),合并乙酸乙酯层,依次用30mL水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到浅黄色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=2:1),收得油状化合物NM-011d320mg(55.9%)。ESI-MS:m/z340.4([M+H]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例35、化合物NM-011e的合成
取化合物NM-011d680mg(2mmol)溶于10mL干燥除水的二氯甲烷中,冰水浴冷却。加入乙酸酐与发烟硝酸的混合液然(乙酸酐:发烟硝酸体积比等于3:2)2mL。维持冰水浴,反应10-15分钟。将反应液倒入10mL1N的碳酸氢钠溶液中,分离二氯甲烷后,水层用二氯甲烷(10mL×3)萃取,合并二氯甲烷液体,用10mL水洗涤,无水硫酸钠干燥。过滤,减压蒸馏二氯甲烷后得到无色油状粗品。硅胶柱分离(石油醚:二氯甲烷=10:1)收得无色油状物NM-011e620mg(72.3%)。ESI-MS:m/z452.1([M+Na]+).1H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H)。
实施例36、化合物NM-011的合成
向化合物NM-011e401mg(1mmol)中加入氯化氢饱和的乙醚溶液5mL,室温下反应,点板监测。反应结束时,有白色固体析出。过滤,无水乙醚洗涤白色固体,即可得到NM-011纯品。干燥后,收得NM-011380mg(65.5%)。ESI-MS:m/z255.1([M+H]+).1H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H)。
实施例37、化合物NM-012a的合成
取化合物1,3-二溴金刚烷3g(10mmol)溶于甲苯30mL,依次加入AIBN250mg(1.5mmol),三正丁基氢锡7g(24mmol),2-甲基丙烯酸乙酯3g(30mmol),氮气保护下110℃回流3小时。将反应液冷却至室温后,倒入30mL0.2M氨水中,充分搅拌均匀后,分离有机层,水层用乙酸乙酯萃取(20mL×4),合并有机层,30mL水和30mL饱和氯化钠溶液洗涤。无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=10:1),收得无色油状液体化合物NM-012a1.6g(43.1%)。ESI-MS:m/z337.4([M+H]+).1H-NMR(DMSO-d6,ppm):0.97(s,2H),1.02-1.08(m,8H),1.15-1.20(m,7H),1.22-1.40(m,7H),1.50(s,2H),1.57-1.65(m,2H),1.93(s,2H),2.39-2.47(m,2H),3.98-4.11(m,4H)。
实施例38、化合物NM-012b的合成
取化合物NM-012a2g(5.5mmol)置于50mL圆底烧瓶中,冰浴冷却。加入浓硝酸1.1mL,搅拌均匀。向混合物中缓慢滴加浓硫酸7.7mL,冰浴反应1小时。之后缓慢滴加乙腈4.9mL(11.7mmol),继续冰浴反应1小时。将反应液倒入到20mL冰水中,水层用乙酸乙酯(20mL×4)萃取。合并乙酸乙酯,30mL1N的碳酸氢钠溶液和30mL水洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=1:3),收得油状化合物NM-011b1.6g(69.2%)。ESI-MS:m/z422.2([M+H]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例39、化合物NM-012c的合成
取化合物NM-012b2g(4.7mmol)溶解于30mL重蒸除水四氢呋喃,加入硼氢化钠900mg。将2.6g三氯化铝溶于20mL四氢呋喃中,缓慢滴入原料中,滴完后室温下搅拌过夜。将反应液倒入50mL冰水中,充分搅拌后,乙酸乙酯萃取(30mL×4)。合并萃取液,30mL饱和氯化钠洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到无色油状粗品。硅胶柱分离(乙酸乙酯:甲醇=10:1),收得无色油状NM-012c880mg(55.6%)。ESI-MS:m/z338.1([M+H]+).1H-NMR(DMSO-d6,ppm):1.05-1.09(m,6H),1.22-1.39(m,8H),1.51-1.60(m,4H),1.73(s,3H),1.76(s,2H),2.07(m,1H),3.30-3.36(m,4H),4.39(t,2H,J=5.2Hz),7.36(s,1H)。
实施例40、化合物NM-012d的合成
将化合物NM-012c670mg(2mmol),固体氢氧化钠1g,二乙二醇10mL加入50mL圆底烧瓶,170℃反应15小时。冷却至室温后,加水20mL,乙酸乙酯(20mL×3)洗涤,减压旋蒸除去水,剩余溶液中加四氢呋喃30mL,Boc酸酐900mg(4mmol),三乙胺400mg(4mmol),DMAP10mg,室温下反应5小时。TLC点板监测。反应完全后,向反应液中加入饱和氯化铵溶液20mL,乙酸乙酯萃取(30mL×4),合并乙酸乙酯层,依次用30mL水和饱和氯化钠溶液洗涤,无水硫酸钠干燥。减压蒸干溶剂后得到浅黄色油状粗品。硅胶柱分离(石油醚:乙酸乙酯=2:1),收得油状化合物NM-012d500mg(63.3%)。ESI-MS:m/z340.4([M+H]+).1H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H)。
实施例41、化合物NM-012e的合成
取化合物NM-012d680mg(2mmol)溶于10mL干燥除水的二氯甲烷中,冰水浴冷却。加入乙酸酐与发烟硝酸的混合液然(乙酸酐:发烟硝酸体积比等于3:2)2mL。维持冰水浴,反应10-15分钟。将反应液倒入10mL1N的碳酸氢钠溶液中,分离二氯甲烷后,水层用二氯甲烷(10mL×3)萃取,合并二氯甲烷液体,用10mL水洗涤,无水硫酸钠干燥。过滤,减压蒸馏二氯甲烷后得到无色油状粗品。硅胶柱分离(石油醚:二氯甲烷=10:1)收得无色油状物NM-008g620mg(72.3%)。ESI-MS:m/z508.1([M+Na]+).1H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H)。
实施例42、化合物NM-012的合成
向化合物NM-011e401mg(1mmol)中加入氯化氢饱和的乙醚溶液5mL,室温下反应,点板监测。反应结束时,有白色固体析出。过滤,无水乙醚洗涤白色固体,即可得到NM-011纯品。干燥后,收得NM-011380mg(65.5%)。ESI-MS:m/z255.1([M+H]+).1H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H)。
实施例43、化合物对大鼠原代小脑颗粒细胞的保护作用
原代分离的新生大鼠小脑颗粒细胞以1.2×105/孔接种在96孔板中,使用含10%FBS+25mMKCl+2mMGlutamine+1%双抗的BME培养基。24h后加入终浓度为10ìM的阿糖胞苷,抑制神经胶质细胞的增殖。从第4天起,每隔4天加入终浓度为5mM的葡萄糖,用以补充细胞的能量代谢及水分蒸发,放于细胞培养箱(37℃,5%CO2)中培养10天。用200ìM谷氨酸诱导原代小脑颗粒细胞兴奋性毒性损伤,分为正常对照组、谷氨酸组、不同美金刚硝酸酯化合物预处理组、美金刚预处理对照组。按实验分组加入不同浓度化合物NM-001、NM-002、NM-003、NM-004、NM-005、NM-008、NM-009、NM-011、NM-012以及美金刚预保护2h后,加入200ìM的谷氨酸诱导细胞损伤24h,然后加入MTT继续培养4h,吸走上清后每孔加入150ìLDMSO溶解,震荡混匀后使用酶标仪在570nm波长条件下测定吸光值,计算细胞存活率。细胞存活率(%)=不同处理组吸光度/正常对照组吸光度×100%。
表1、描述化合物对大鼠脑神经细胞的保护作用。
化合物 | EC50(μM) | 化合物 | EC50(μM) |
NM-001 | 24.62 | NM-009 | 5.20 |
NM-002 | 25.2 | NM-011 | 5.86 |
NM-003 | 15.36 | NM-012 | 9.30 |
NM-004 | 8.12 | YQW-036 | 31.4 |
NM-005 | 6.06 | 美金刚 | 2.72 |
NM-008 | 4.37 |
实施例44、化合物NM-008对大鼠脑缺血MCAo模型的保护作用
将体重为280-295g的SD雌性大鼠用异氟烷麻醉后,分离结扎颈总动脉近心端和颈外动脉,将线栓小从颈总动脉插入颈内动脉,线栓插入后用血流仪测定脑局部血流量变化。大鼠在造模前、栓塞后5min应用激光多普勒血流仪监测右侧大脑缺血区血流变化,以栓塞后脑血流降低到正常值60%以下为模型成功的评判标准。
大鼠造模成功后3h和6h各静脉注射给药一次(60mg/kg)。造模24h后,动物用戊巴比妥钠麻醉,断头取脑切片,TTC染色后统计脑梗死面积。与模型组相比较,NM-008显著的降低脑卒中模型脑梗死面积(P<0.05),其保护率为15.3%(图8)。
Claims (11)
1.一种具有神经保护作用的金刚烷胺硝酸酯化合物及其药学上可接受的盐,所述化合物具有通式(Ι)的结构:
其中:
R1,R2,R3相同或不相同,分别为氢,取代或未取代的烃基,取代或未取代的芳基,芳杂基,硝酸酯基,且R1,R2,R3中至少有一个包含有硝酸酯基。
2.根据权利要求1所述的化合物,其中R3为硝酸酯基,亦即所述化合物具有通式(II)的结构:
其中:
R1,R2相同或不相同,分别为氢,直链或支链烷基,取代或未取代的芳基,芳杂基;
Z1为连接所述R3硝酸酯基的直链或带有分支的碳链,其中Z1上可以取代有杂原子、烷基、芳基或芳杂基,并且Z1包含的碳原子数为1-6。
3.根据权利要求2所述的化合物,其中R2为氢,R1为直链或支链烷基,并且Z1包含的碳原子数与R1上的碳原子数之和不少于3。
4.根据权利要求1所述的化合物,其中R1和R3为硝酸酯基,亦即所述化合物具有通式(III)的结构:
其中:
R2为氢,直链或支链烷基,取代或未取代的芳基,芳杂基;
Z1和Z2,相同或者不相同,分别为连接硝酸酯基的直链或带有分支的碳链,其中Z1和Z2上各自可以取代有杂原子、烷基、芳基或芳杂基,并且Z1和Z2各自包含的碳原子数为1-6。
5.根据权利要求4所述的化合物,具有如下之一的结构。
6.根据权利要求1所述的化合物,其中R1,R2和R3为硝酸酯基,亦即所述化合物具有通式(IV)的结构:
其中:
Z1,Z2和Z3,相同或者不相同,分别为连接各自的所述硝酸酯基的直链或带有分支的碳链,其中Z1,Z2和Z3上各自可以取代有杂原子、烷基、芳基或芳杂基,并且Z1,Z2和Z3各自包含的碳原子数为1-6。
7.一种制备权利要求1-6之一所述化合物的合成方法,包括:以溴基、烷基或烷基羧酸基团取代的或者未取代的金刚烷为原料,首先经Ritter反应引入氨基,然后通过发烟硝酸与所述金刚烷环上的羟基酯化作用在具有取代的侧链上生成硝酸酯。
8.一种权利要求1-7之一所述的化合物在制备保健品或药物方面的用途,其中,所述保健品或药物用于预防或治疗的疾病为与NMDA受体、细胞内钙离子超载、NO产生和自由基超载相关的疾病或神经退行性疾病。
9.根据权利要求10所述用途,其中所述与NMDA受体相关的疾病包括:脑缺血,帕金森症,阿尔茨海默症,肌肉萎缩性侧索硬化症,共济失调毛细血管扩张症,牛海绵状脑病,克雅二氏病,顿舞蹈症,小脑萎缩症,多发性硬化症,原发性侧索硬化,脊髓性肌萎缩症,青光眼,老年性黄斑变性。
10.根据权利要求11所述的用途,其中所述与NO相关的疾病包括:脑中风、脑创伤、癫痫、帕金森症、亨廷顿舞蹈症、肌萎缩性侧索硬化、阿尔茨海默症、缺氧缺血脑损伤、脑溢血,痴呆症、缺血性心脏病,血管栓塞,动脉粥样硬化,高胆固醇血症,肺气肿,糖尿病,急性胰腺炎,酒精引起的肝脏疾病,肾脏伤害,癌症。
11.根据权利要求10所述用途,其中所述神经退行性疾病包括:脑缺血,帕金森症,阿尔茨海默症,肌肉萎缩性侧索硬化症,共济失调毛细血管扩张症,牛海绵状脑病,克雅二氏病,顿舞蹈症,小脑萎缩症,多发性硬化症,原发性侧索硬化,脊髓性肌萎缩症。
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EP4121403A4 (en) * | 2020-03-19 | 2024-04-03 | Eumentis Therapeutics Inc | NITRO-AMINOADAMANTANE COMPOUNDS FOR THE TREATMENT OF BETACORONAVIRUS INFECTIONS |
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CN106344551A (zh) * | 2016-08-22 | 2017-01-25 | 广州喜鹊医药有限公司 | 氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用 |
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CN106344551B (zh) * | 2016-08-22 | 2020-07-28 | 广州喜鹊医药有限公司 | 氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用 |
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WO2020052179A1 (zh) | 2018-09-12 | 2020-03-19 | 青岛海蓝医药有限公司 | 一种金刚烷胺类硝酸酯衍生物的制备工艺 |
CN109172560A (zh) * | 2018-10-15 | 2019-01-11 | 佛山喜鹊医药有限公司 | 氨基金刚烷硝酸酯类化合物或其药学上可接受的盐在预防和/或治疗肺部疾病中的应用 |
CN109172560B (zh) * | 2018-10-15 | 2022-08-16 | 佛山喜鹊医药有限公司 | 氨基金刚烷硝酸酯类化合物或其药学上可接受的盐在预防和/或治疗肺部疾病中的应用 |
WO2023165255A1 (zh) * | 2022-03-01 | 2023-09-07 | 广州喜鹊医药有限公司 | 氨基金刚烷单硝酸酯类化合物在制药领域中的应用 |
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EP3150574A1 (en) | 2017-04-05 |
JP2017521482A (ja) | 2017-08-03 |
AU2015267968B2 (en) | 2018-05-17 |
CA2950452C (en) | 2020-03-31 |
EP3150574A4 (en) | 2017-11-22 |
IL249242B (en) | 2020-03-31 |
ES2946987T3 (es) | 2023-07-31 |
IL249242A0 (en) | 2017-02-28 |
WO2015180485A1 (zh) | 2015-12-03 |
AU2015267968A1 (en) | 2016-12-15 |
CN105294450B (zh) | 2024-05-17 |
JP6639483B2 (ja) | 2020-02-05 |
EP3150574B1 (en) | 2023-03-15 |
CA2950452A1 (en) | 2015-12-03 |
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