N-苯甲酰基金刚烷甲酰肼类化合物的合成

以金刚烷甲酸、甲醇为原料,浓硫酸为催化剂,经酯化反应合成金刚烷甲酸甲酯,再以金刚烷甲酸甲酯为原料,加入水合肼,经酰化反应合成金刚烷甲酰肼.将金刚烷甲酰肼与不同的芳香酰氯反应,合成五个N-芳甲酰基-金刚烷甲酰肼化合物.目标化合物结构经ESI-MS谱图确证.     

盐酸金刚烷胺的合成

用金刚烷与乙腈、20％发烟硫酸“一锅法”反应制得1-乙酰胺基金刚烷,再经氢氧化钠水解、与盐酸成盐制得抗病毒药盐酸金刚烷胺,总收率约82％.     

N-金刚烷-2-基-N''''-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺的合成

目的 建立简便、经济的合成N-金刚烷-2-基-N'-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(SQ109)的方法.方法 以香叶醇、2-金刚烷酮为原料通过两条路线合成SQ109.第一条路线香叶醇经Mitsunobu反应、胺解反应得到香叶胺;2-金刚烷酮经亚胺化、硼氢化钠还原、催化氢化脱苄基得2-金刚烷胺.香叶胺经氯乙酰化,与2-金刚烷胺对接,再经红铝还原得到SQ109.第二条路线香叶醇首先转化成香叶基氯(12);2-金刚烷酮与乙二胺经亚胺化、硼氢化钠还原得到的中间产物11,11与香叶基氯12对接得到SQ109.结果与结论 路线1总收率38%,路线2总收率31%.两条合成路线均使用香叶醇与2-金刚烷酮代替了价格较高的香叶胺与2-金刚烷胺,从而降低了SQ109的合成成本.第二条路线,缩短了反应步骤,具有较大应用价值.     

N-金刚烷-2-基-N′-（3,7-二甲基-辛-2,6-二烯基）-乙烷-1,2-二胺的合成

目的建立简便、经济的合成N-金刚烷-2-基-N′-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(SQ109)的方法。方法以香叶醇、2-金刚烷酮为原料通过两条路线合成SQ109。第一条路线香叶醇经Mitsunobu反应、胺解反应得到香叶胺;2-金刚烷酮经亚胺化、硼氢化钠还原、催化氢化脱苄基得2-金刚烷胺。香叶胺经氯乙酰化,与2-金刚烷胺对接,再经红铝还原得到SQ109。第二条路线香叶醇首先转化成香叶基氯(12);2-金刚烷酮与乙二胺经亚胺化、硼氢化钠还原得到的中间产物11,11与香叶基氯12对接得到SQ109。结果与结论路线1总收率38%,路线2总收率31%。两条合成路线均使用香叶醇与2-金刚烷酮代替了价格较高的香叶胺与2-金刚烷胺,从而降低了SQ109的合成成本。第二条路线,缩短了反应步骤,具有较大应用价值。     

2-(3-羟基-1-金刚烷)-2-氧代乙酸的合成

金刚烷甲酮(2)经高锰酸钾两步氧化制得糖尿病药物沙格列汀中间体2-(3-羟基-1-金刚烷)-2-氧代乙酸,总收率为74.7％:氧化条件①以溴化四丁铵为相转移催化剂,高锰酸钾与2投料摩尔比2.05∶1,反应温度50～55℃、pH12～13;②续加1.2当量的高锰酸钾,温度40～45℃,pH8～9.     

GC法测定3-氨基-1-金刚烷醇的有关物质

目的:建立GC法测定3-氨基-1-金刚烷醇(VILS-03)中有关物质金刚烷胺、1,3-金刚烷二醇、1,3,5-金刚烷三醇、1,3,5,7-金刚烷四醇的含量。方法:采用DB-1毛细管柱(50 m×0.53 mm×5μm),进样口温度300℃,柱流速2.0 mL·min^-1,进样方式用分流进样,分流比5∶1,载气为氮气,进样量为1μL;外标法计算。结果:空白溶剂均不干扰VILS-03有关物质的检测;金刚烷胺、1,3-金刚烷二醇、1,3,5-金刚烷三醇、1,3,5,7-金刚烷四醇均在一定范围内线性良好,r均>0.990;定量限分别为1.375、1.557、1.363、4.042μg·mL^-1;50%、100%、150%水平的加样回收率均良好。金刚烷胺平均加样回收率(n=3)分别为107.3%、107.3%、105.2%,RSD分别为0.67%、1.1%、2.3%。1,3-金刚烷二醇平均加样回收率(n=3)分别为93.6%、100.3%、95.6%,RSD分别为4.7%、1.6%、2.6%。1,3,5-金刚烷三醇平均加样回收率(n=3)分别为...     

赤式氨基苯基丙醇合成工艺改进

以苯丙酮为起始原料，经过羟亚氨基苯丙酮中间体和用Pt－Pd/C作催化剂加氢反应合成赤式－2－氨基－1－苯基－丙酮，并对其工艺进行了改进，降低了成本，简化了工艺，提高了收率，总收率55．5％。     

盐到金刚乙胺的合成

以金刚烷为起始原料，经溴化、乙酰化、甲酰胺加成和水解反应，制得盐酸金刚乙胺，总收率３１．５％。     

叶酸的合成

目的：以二亚胺作为中间体合成叶酸。方法：以1，1，3，3－四甲氧基丙醇和N－对氨基苯甲酰－L－谷氨酸为原料生成二亚胺，二亚胺与三氨啶硫酸盐反应生成叶酸。结果与结论：合成了叶酸，总产率可达65．5％，本工艺简单易行。     

1-[2-(N-甲基)氨基-2-(2,4-二氯苯基)乙基]-1H-1,2,4-三唑化合物的合成

目的：改进1－[2-（N－甲基）氨基－2－（2,4－二氯苯基）乙基]-1H-1,2,4-三唑的合成方法,降低成本,提高收率,方法：以2－氯－1－（2,4－二氯苯基）乙酮为原料,经三唑烷基化与甲胺反应生成酮亚胺后还原（A法）,或与N－甲基甲酰胺进行Leukart反应（B法）,结果：A和B两种方法制得目标化合物的收率分别为57．6％和63．2％。结论：A和B两种方法原料易得,反应简便,降低了成本,提高了收率。     

盐酸金刚乙胺的合成

以金刚烷为起始原料,经溴化、乙酰化、甲酰胺加成和水解反应,制得盐酸金刚乙胺,总收率31.5%。     

盐酸美金刚的合成工艺改进

目的设计一条全新的反应路线,合成阿尔茨海默病治疗药物盐酸美金刚,并对其合成工艺进行改进。方法以1,3-二甲基金刚烷为原料,在催化剂N一羟基邻苯二甲酰亚胺（NHPI）的催化下,经硝酸硝化得1-硝基-3,5-二甲基金刚烷,再在Pd—c的催化下与氢气还原得1-氨基-3,5-二甲基金刚烷,最后与干燥氯化氢反应得盐酸美金刚。对第一步反应采用四因素三水平的正交设计试验优化其反应条件。结果最佳合成工艺条件为温度70℃、时间15h、溶剂乙酸,催化剂量0．2o结论优选出的合成路线反应步骤短、操作简单、经济合理。     

Inhibitory activity of the new adamantane derivative N,N'-bis(ethylene)-P(1-adamantyl)-phosphonic diamide against Rous sarcoma virus

A new adamantane derivative N,N'-bis (ethylene)P(1-adamantyl)-phosphonis diamide, was found to inhibit Rous sarcoma virus replication in much the same manner as reported for the parent compound, 1-adamantanamine hydrochloride.     

金刚烷胺衍生物的设计、合成及其抗禽流感病毒活性

目的 设计合成金刚烷胺衍生物并对其进行抗禽流感病毒活性测试。方法 以金刚烷甲酰氯和氨基酸甲酯盐酸盐为起始原料经酰胺化、水解、成盐等反应依次得到3个系列金刚烷胺衍生物。以金刚烷胺为阳性对照,采用幼犬肾（MDCK）细胞系噬斑形成实验测定目标化合物的抗禽流感病毒活性。结果与结论 共合成了20 个未见报道的新化合物,目标化合物的结构均经¹H-NMR、IR、MS 谱确证;仅有化合物 A₅ 显示出较好的抗禽流感病毒活性。     

Substituted adamantylphthalimides: Synthesis,antiviral and antiproliferative activity

In this study, three groups of adamantylphthalimides, bearing different substituents at the phthalimide moiety, N-(4′-R²)phthalimidoadamantanes ( 1 – 7 ), 3-[N-(4′-R²)phthalimido]-1-adamantanols ( 8 – 10 ), and 3-[N-(4′-R²)phthalimido]adamantane-1-carboxylic acids ( 11 – 15 ), were synthesized and screened against tumor cells and viruses. The most potent compounds are not substituted at the adamantane and bear an OH or NH₂ substituent at the phthalimide (compounds 3 and 5 ). The antiproliferative activities of compounds 3 and 5 are in the micromolar range, much higher than the one of thalidomide. A minor antiviral activity against cytomegalovirus and varicella-zoster virus was found for compounds 3 and 5 , but these compounds lacked selectivity. The results presented are important for the rational design of the next-generation compounds with anticancer and antiviral activities.     

毛细管柱气相色谱法测定盐酸金刚烷胺有关物质

目的:建立气相色谱法测定盐酸金刚烷胺的有关物质并对有关物质进行确证。方法:采用毛细管柱,程序升温,FID检测器测定有关物质;采用MSD检测器,测得有关物质的EI质谱图,进行结构确证。结果:通过方法学验证,可以采用面积归一化法测定有关物质,检测限为2 ng;并确证了杂质A为二氨基取代金刚烷,杂质B为2-氨基金刚烷。结论:本方法准确、灵敏,可以控制盐酸金刚烷胺的质量。     

In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes

Aim:

To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations.

Methods:

A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software.

Results:

A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data.

Conclusion:

The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer''s disease.     

2-(3-羟基-1-金刚烷基)-2-乙醛酸的合成

金刚烷经相继甲酸化、酰氯化后与丙二酸二乙酯乙氧基镁反应,得到1-金刚烷甲酰基丙二酸二乙酯,再经水解脱羧、高锰酸钾氧化得到沙克列汀中间体2-(3-羟基-1-金刚烷基)-2-乙醛酸,总收率约28%。     

The effects of ladasten on dopaminergic neurotransmission and hippocampal synaptic plasticity in rats

Derivatives of adamantane, like memantine, are potentially neuroprotective drugs for the favourable care of Alzheimer's and Parkinson's diseases. A further adamantane derivate is N-(2-adamantyl)-N-(para-bromophenyl)-amine (ladasten) which is capable to modulate animal performance in different learning paradigms. To clarify if some of those behavioural alterations are mediated by modulation of catecholamine syntheses we studied the effects of single administration of ladasten (50 mg/kg, per os) on catecholamines' biosynthesis in the ventral tegmental area, nucleus accumbens, hypothalamus, striatum and hippocampus. We found that ladasten differentially regulates tyrosine hydroxylase mRNA and protein as well as dopamine and L-DOPA content. We then investigated the effects of ladasten on activity-dependent hippocampal synaptic plasticity in vitro and found that application of 10 microM ladasten transforms short-term potentiation of synaptic transmission to a long-lasting form. A transformation of short-term into long-term potentiation was also observed, when ladasten was applied 40 min after a single 100 Hz 200 ms tetanization. This reinforcement was blocked by the protein synthesis inhibitor anisomycin and could be attenuated by the D1/D5 receptor antagonist SCH23390. These results suggest that ladasten induces reinforcement of short-term potentiation via protein synthesis and dopamine dependent mechanisms.