1,4-苯并二氮-3-取代氨基乙酸酯类化合物的合成

本文报道了一系列1,4-苯并二氮(艹卓)-3-取代氮基乙酸酯类化合物的合成。A_3与取代氨基乙酸直接酯化制备最终产物,用DCC作缩合剂时只分离到反应的中间体;改用活性更大的1,1′-碳酰二咪唑作缩合剂,反应获得成功。合成的新化合物能溶于水。放射配体-受体抑制试验表明,这些化合物与苯并二氮革受体的亲和力较强,IC_(50)在10~(-8)～10~(-10)之间,其中A_9与苯并二氮(艹卓)受体的亲和力比氟安定高一个数量级,比安定高两个数量级。     

苯氧烷胺类化合物的合成及其抗高血压活性

前以2,6-二甲基苯氧乙叉为母体合成了一系列化合物,其中1-(2,6-二甲基苯氧基-2-(3,4-二甲氧基苯乙胺)-丙烷盐酸盐(Ⅰ)有较强而特久的降压作用。进一步研究又表明它具有阻断α-肾上腺素受体并兼有钙拮抗作用。     

3—烷氧羰基甲基硫甲基头孢菌素衍生物的合成及抗菌活性

合成了５个３－买在甲基硫甲基头孢菌素衍生物，初步药理试验表明，化合物１对革兰氏阳性球菌有较强的抑制作用，ＭＩＣ为０．１￣６．２μｇ／ｍｌ。     

3─烷氧羰基甲基硫甲基头孢菌素衍生物的合成及抗菌活性

合成了５个３－烷氧羰基甲基硫甲基头孢菌素衍生物。初步药理试验表明，化合物１对革兰氏阳性球菌有较强的抑制作用，ＭＩＣ为０．１～６．２μｇ／ｍｌ     

苯并二氢吡喃脘衍生物的合成及其初步药理活性

为进一步筛选活性更强、副作用更小的抗绝经后骨质疏松症药物，在综合考察雷洛昔芬和异丙氧基异黄酮的基础上，设计合成一系列苯并二氢吡喃脘化合物，化合物的结构均经波谱鉴定，并通过研究其对幼年小鼠子宫增5重血血碱性磷酸酶活性的影响。初步考察化合物的药理活性，结果表明，XY9902具有较弱的雌激素受体激动作用和一定的雌激素受体拮抗作用。并有助于成骨细胞增殖，对治疗骨质疏松症是有利的。     

氨基噻唑衍生物的合成与药理活性研究

目的:合成氨基噻唑类衍生物并研究其抗流感病毒活性。方法:以氨基噻唑类化合物为母核,合成一系列神经氨酸酶抑制剂,通过在体方法检测其对流感病毒的抑制活性。结果与结论:合成了6个新化合物,其中部分化合物具有一定的抗流感病毒活性。     

2-甲基-3-取代苯基吡咯并吡嗪酮类化合物的合成及抗癌活性研究

目的 寻找具有抗癌活性的新吡咯并吡嗪酮类化合物。方法 以吡咯、对氨基苯乙酮为原料,经Friedel-Crafts酰化、醇解、亲核取代、环合及醇解反应制得母体化合物2-甲基-3-对氨基苯基吡咯并[1,2-a]吡嗪-1(2H)-酮,再通过酰基化/磺酰基化和烷基化反应引入酰基和烷基即制得系列吡咯并吡嗪酮类化合物。结果 合成了8个未见文献报道的吡咯并吡嗪酮类化合物,其结构经¹H-NMR、MS和IR谱确证。结论 8个目标化合物的体外抗乳腺癌细胞、肝癌细胞和肺癌细胞的活性试验结果显示,化合物4、5 具有明显的抗癌活性。     

4-(甲基苯胺基)-3-氰基喹啉类衍生物的 合成及抗肿瘤活性

目的 设计合成4-(甲基苯胺基)-3-氰基喹啉类衍生物,并对其体外抗肿瘤活性进行初步评价。 方法 以氰乙酸乙酯为起始原料,经多步反应合成目标化合物。采用MTT法,以吉非替尼（gefitinib）为阳性对照药,以A549、HT-29和MDA-MB-231为测试细胞株对目标化合物的抗肿瘤活性进行了评价。 结果 合成了18个新化合物,经1H-NMR、MS和IR确认其结构。体外活性测试结果显示,多数化合物可在较低浓度抑制肿瘤细胞增殖,其中的Ⅶ2、Ⅶ3、Ⅶ6、Ⅶ12、Ⅶ13、Ⅶ15 和 Ⅶ16共7个化合物有显著的抗增殖活性,优于阳性对照药吉非替尼。 结论 体外活性实验表明：4-(甲基苯胺基)-3-氰基喹啉类衍生物作为新型的酪氨酸激酶抑制剂,其构效关系值得进一步研究。     

二苯并环庚酮的合成

用亚苄基酞经氢氧化钠水解制得2-苯乙酰基苯甲酸,经Pd/C催化氢化制得2-(2-苯乙基)苯甲酸,再在多聚磷酸作用下环合制得二苯并环庚酮,总收率约83％,纯度99.0％.     

5-溴甲基-2,1,3-苯并噻二唑的合成工艺改进

以4-甲基-1,2-苯二胺为原料,经环合、溴化两步反应合成目标化合物.将其中间体亚硫酰苯胺的合成改在甲苯中进行,并采用"一勺烩"法合成5-甲基-2,1,3-苯并噻二唑;5-甲基-2,1,3-苯并噻二唑的溴化改在低毒性的1,2-二氯乙烷中进行,革除了高毒性的四氯化碳.该法简化了操作过程,缩短了反应时间,提高了目标物的总收率.     

1-[8-甲氧基-4-[(2-甲基苯基)氨基]-3-喹啉基]-1-丁酮的合成

从商品原料丁酰乙酸乙酯经缩合和胺化直接得 2 -丁酰基 - 3- [(2 -甲氧基苯 )氨基 ]丙烯酸乙酯 ,再经分子内环化、氯化芳构化和胺化 ,得到 1- [8-甲氧基 - 4 - [(2 -甲基苯基 )氨基 ]- 3-喹啉基 ]- 1-丁酮 (SK& F 96 0 6 7)。总收率2 9.7%。     

3-[(2-ethoxyphenoxy)methyl]piperidine derivatives. Synthesis and antidepressant activity

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.     

Synthesis of 2-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]octanes and 2α-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-enes as Potential Muscarinic Agonists

Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [³H]QNB and [³H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10^–6 and 1.79 x 10^–5 M in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10^–4 M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.     

Studies on antitumor agents, 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluorouracil and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil.

Convenient and efficient methods were developed for preparing 1-(tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU, 3) [trade name, Futraful (Ftorafur) or FT-207], which is used clinically as an antitumor agent, and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil (Thf2-FU, 4). For the syntheses, 2,4-bis(trimethylsily)-5-fluorouracil (Me3Si-FU, 1) and 2-acetoxytetrahydrofuran (Thf-OAc, 2) were condensed in the presence of Friedel-Crafts catalysts, such as SnCl4 and BF3-Et2O in dichloromethane, or in the presence of NaI in acetonitrile to give Thf-Fu or Thf2-FU depending on the reaction conditions and workup procedure. A trace of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU, 5) was formed in these reactions. Thf2-FU was easily hydrolyzed to Thf-FU. 2-Methoxytetrahydrofuran can be used instead of Thf-OAc for preparation of Thf-FU under similar conditions. The optimal ratios of Me3Si-FU, Thf-OAc, and SnCl4 or NaI for preparation of Thf-FU and Thf2-FU were determined. In all cases, 2-2.5 equiv of Thf-OAc with respect to Me3Si-FU gave the best results. The yields of Thf-FU and more especially of Thf2-FU were greatly dependent on the relative amount of SnCl4, and 0.01-0.1 equiv of the catalyst with respect to Me3Si-FU gave the best results. Thf2-FU was found to be effective against murine solid tumors and it was less toxic than Thf-FU when given orally. The antitumor activity of 3-Thf-FU is also reported.     

(S)-5-乙酰胺甲基-3-[(3-氯-4-取代胺甲基)苯基]-2-噁唑烷酮的合成及抗菌活性

3-氯-4-甲基苯胺经氯甲酸苄酯酰化、与（R）-正丁酸缩水甘油酯环合、甲磺酰化、叠氮化、叠氮还原成胺、氨基乙酰化、苄位溴化得（固-5-乙酰胺甲基-3-[（3-氯-4-溴甲基）苯基]-2-噁唑烷酮（Ⅷ），后者与胺类化合物进行取代反应生成（D-5-乙酰胺甲基-3-[（3-氯-4-取代胺甲基）苯基]-2-噁唑烷酮。35个新化合物的结构经^1HNMR、元素分析或MS确证，并测定了它们的体外抗菌活性，发现化合物113对金葡菌和表葡菌的活性与吗啉噁酮相当。11和113对肠球菌的活性优于诺氟沙星。     

Synthesis and antidepressant profiles of phenyl-substituted 2-amino- and 2-[(alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines

A series of 4(6)- and 5-phenyl-substituted 2-amino- and 2-[(alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines were prepared and evaluated for central nervous system (CNS) effects in animal models. Several 5-phenyl-substituted compounds possessed potent antidepressant activity and all compounds in this series were devoid of significant activity in any of the other CNS (anticonvulsant, muscle relaxant, and depressant) assays. The most active compound in the in vivo screen for antidepressant activity (reversal of reserpine-induced hypothermia), 2-[(methoxycarbonyl)amino]-5-phenyl-1,4,5,6-tetrahydropyrimidine was considerably more potent than tricyclic antidepressant (TCA) standards. The 2-amino parent compound on the other hand was greater than 100-fold as effective as TCA's in in vitro inhibition of norepinephrine and dopamine uptake.     

4,6-二甲基-2-(2,2-二苯基-乙烯氧基)嘧啶的合成工艺研究

目的设计并合成安立生坦降解杂质4,6-二甲基-2-(2,2-二苯基-乙烯氧基)嘧啶。方法以3,3-二苯基-2,3-环氧丙酸甲酯为起始原料经水解、脱羧、开环、亲核取代反应定向合成目标化合物。结果合成目标化合物并经IR、1H-NMR、HRMS确证其结构;HPLC归一化法测得样品质量分数为99.5%。结论该杂质作为对照品用于安立生坦的质量研究工作。