加那索酮的合成

目的:合成加那索酮.方法:以剑麻皂苷元制得的单烯醇酮醋酸酯为原料,通过6步反应合成目标化合物.结果和结论:目标物经红外光谱、核磁共振氢谱和质谱确证其化学结构,总收率达51.6%.     

脱氢氯甲睾酮的合成工艺

目的 合成脱氢氯甲睾酮并改进其工艺.方法 以甲睾酮和H2O2环氧化反应得到环氧甲睾酮,再与盐酸在丙酮溶媒中进行氯化反应,得到氯甲睾酮,最后用2,3-二氯-5,6-二氰基对苯醌在PTS催化下脱氢得到脱氢氯甲睾酮.结果 总收率30%,产物结构经熔点、质谱和核磁共振氢谱确证.结论 此合成路线操作简单可行,有利于工业化生产.     

N,N''-双(1-羟基甲基-2,3-二羟基丙基)-2,3,5,6-四碘对苯二甲酰胺的合成

目的设计并合成标题化合物。方法以1,4-丁烯二醇为原料,经过酯化、环氧化、氨解开环,再与四碘对苯二甲酰氯反应合成目标产物。结果产物经红外、核磁共振氢谱、元素分析得到确认。结论成功的合成了所设计的标题化合物,有助于新一代四碘苯类非离子型X线造影剂的研制。     

N,N＇-双（1-羟基甲基-2,3-二羟基丙基）-2,3,5,6-四碘对苯二甲酰胺的合成

目的设计并合成标题化合物。方法以1,4-丁烯二醇为原料,经过酯化、环氧化、氨解开环,再与四碘对苯二甲酰氯反应合成目标产物。结果产物经红外、核磁共振氢谱、元素分析得到确认。结论成功的合成了所设计的标题化合物,有助于新一代四碘苯类非离子型X线造影剂的研制。     

孕酮受体拮抗剂米非司酮衍生物的合成及抗早孕作用

目的寻找单一的孕酮受体拮抗剂.方法对米非司酮的C11、C13、C17-取代基进行修饰,以3,3-乙撑二氧-5(10),9(11)-雌甾二烯-17-酮为原料,经环氧化、格氏加成、加成、还原、水解等反应,设计并合成了未见文献报道的7个目标化合物,经红外、核磁共振氢谱及高分辨质谱确证其结构.并对目标化合物的活性进行了初步的体内、体外试验.结果目标化合物的抗早孕作用类似或低于米非司酮,其中,化合物9d拮抗孕酮受体能力与米非司酮相似,但抗糖皮质激素受体作用小于米非司酮.结论C11位引入较大的取代基能够保持米非司酮的抗孕酮受体活性,C17位引入极性取代基可以降低其抗糖皮质激素受体活性.     

脱氢诺龙醋酸酯的合成工艺研究

目的研究脱氢诺龙醋酸酯的合成工艺。方法以雌甾-4-烯-3,17-二酮为起始原料,经醋酸酐酯化、硼氢化钠还原、醋酸酐再酯化、N-溴代丁二酰亚胺(NBS)溴代、脱溴化氢5步反应合成脱氢诺龙醋酸酯。结果与结论目标化合物的结构经1H-NMR、IR谱等确证,总收率由文献报道的51%提高到68.1%。改进后的工艺路线反应条件温和、操作简便、收率高、成本低廉,有利于工业化生产。     

甲孕酮醋酸酯氢化转位工艺改进

甲孕酮醋酸酯(Medroxyprogesterone Acetate),化学名:17α羟基-6α-甲基孕甾-4-烯-3,20-二酮-17-醋酸酯,为强效女性黄体激素类药物,适用于先兆性与习惯性流产,月经不调,子宫功能性出血及子宫内膜异位症等。甲孕酮醋酸酯的合成,通常以17α-羟基黄体酮为原料。其关键性的一步反应为在6位上引入α-甲基。国内生产甲孕酮醋酸酯系由17α-羟基黄体酮经乙酰化、醚化后,再经Vilsmeier反应还原得6-次甲基物(Ⅰ),后者在钯炭存在下,以环己烯作供氢剂进行氢化反应,并在酸性条件下     

二氢欧山芹醇的合成研究进展

二氢欧山芹醇(columbianetin)及其衍生物属于香豆素类化合物,具有广泛的生物活性。二氢欧山芹醇是合成一些天然产物如二氢欧山芹醇当归酸酯、二氢山芹醇醋酸酯、libanorin和angelmarin的关键中间体,研究人员已提出多种二氢欧山芹醇的合成策略,如史氏环氧化反应、水催化多米诺反应等,本文概述了二氢欧山芹醇的化学合成方法。     

抗生素替加环素合成研究

目的 优化替加环素合成工艺,制备合格替加环素产品.方法以9-氨基米诺环素硫酸盐为原料,与氯乙酸酐反应得中问体9-氯乙酰氨基米诺环素,再与叔丁胺反应生成替加环素.结果 合成的目标化合物经核磁共振氢谱、质谱、红外确认结构.结论本工艺提高了中 间体收率和粗品的纯度.     

盐酸纳呋拉啡的合成工艺改进

目的 优化盐酸纳呋拉啡的合成工艺。方法 以14-羟基二氢降吗啡酮(2)为起始原料,与溴甲基环丙烷经取代反应生成纳曲酮(3),3与N-甲基苄胺在氰基硼氢化钠作用下经还原胺化反应得到6β-(N-苄基)甲氨基-17-环丙甲基-4,5α-环氧-3,14β-二羟基吗啡喃(4),4经钯炭催化氢解脱苄基得到6β-甲氨基-17-环丙甲基-4,5α-环氧-3,14β-二羟基吗啡喃(5),5与(E)-3-(3-呋喃基)丙烯酰氯经酰化反应得到纳呋拉啡(6),6与盐酸成盐制得盐酸纳呋拉啡。结果 目标产物结构经质谱、核磁共振谱以及红外光谱确证,总收率52%(以2计),纯度99.971%(HPLC法)。结论 优化后的合成工艺反应条件温和,操作简便,生产成本较低,已经过中试放大实验验证,适合工业化生产。     

Involvement of iron (ferric) reduction in the iron absorption mechanism of a trivalent iron-protein complex (iron protein succinylate)

Iron protein succinylate is a non-toxic therapeutic iron compound. We set out to characterise the structure of this compound and investigate the importance of digestion and intestinal reduction in determining absorption of the compound. The structure of the compound was investigated by variable temperature M?ssbauer spectroscopy, molecular size determinations and kinetics of iron release by chelators. Intestinal uptake was determined with radioactive compound force fed to mice. Reduction of the compound was determined by in vitro incubation with intestinal fragments. The compound was found to contain only ferric iron, present as small particles including sizes below 10 nm. The iron was released rapidly to chelators. Digestion with trypsin reduced the molecular size of the compound. Intestinal absorption of the compound was inhibited by a ferrous chelator (ferrozine), indicating that reduction to ferrous iron may be important for absorption. The native compound was a poor substrate for duodenal reduction activity, but digestion with pepsin, followed by pancreatin, released soluble iron complexes with an increased reduction rate. We conclude that iron protein succinylate is absorbed by a mechanism involving digestion to release soluble, available ferric species which may be reduced at the mucosal surface to provide ferrous iron for membrane transport into enterocytes.     

Involvement of Iron (Ferric) Reduction in the Iron Absorption Mechanism of a Trivalent Iron‐Protein Complex (Iron Protein Succinylate

Iron protein succinylate is a non‐toxic therapeutic iron compound. We set out to characterise the structure of this compound and investigate the importance of digestion and intestinal reduction in determining absorption of the compound. The structure of the compound was investigated by variable temperature Mössbauer spectroscopy, molecular size determinations and kinetics of iron release by chelators. Intestinal uptake was determined with radioactive compound force fed to mice. Reduction of the compound was determined by in vitro incubation with intestinal fragments. The compound was found to contain only ferric iron, present as small particles including sizes below 10 nm. The iron was released rapidly to chelators. Digestion with trypsin reduced the molecular size of the compound. Intestinal absorption of the compound was inhibited by a ferrous chelator (ferrozine), indicating that reduction to ferrous iron may be important for absorption. The native compound was a poor substrate for duodenal reduction activity, but digestion with pepsin, followed by pancreatin, released soluble iron complexes with an increased reduction rate. We conclude that iron protein succinylate is absorbed by a mechanism involving digestion to release soluble, available ferric species which may be reduced at the mucosal surface to provide ferrous iron for membrane transport into enterocytes.     

保健品中一种新型他达拉非相关化合物的结构鉴定

目的 鉴定保健品中发现的一种新型他达拉非化合物的结构。方法 通过高效液相色谱-二极管阵列检测器联用筛查,发现一种补肾壮阳类保健食品中添加了一种他达拉非类化合物。经过制备液相提纯后,得到目标化合物,用高效液相色谱-四级杆/飞行时间质谱获得相对分子质量和结构碎片。结合核磁共振氢谱和碳谱及相关文献数据,鉴定出该化合物的结构。结果 在保健品中发现添加了一种新型的他达拉非类化合物二乙氨基前他达拉非。结论 该化合物不在现有补肾壮阳类中成药检验标准的11种目标化合物范围内,有必要加以研究。     

Evidence for a multivalent interaction of symmetrical, N-linked, lidocaine dimers with voltage-gated Na+ channels

The interaction of symmetrical lidocaine dimers with voltage-gated Na+ channels (VGSCs) was examined using a FLIPR membrane potential assay and voltage-clamp. The dimers, in which the tertiary amines of the lidocaine moieties are linked by an alkylene chain (two to six methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rat (r) Na(v)1.2a, human (h) Na(v)1.5, and rNa(v)1.8, with potencies 10- to 100-fold higher than lidocaine (compound 1). The rank order of potency (C4 (compound 4) > C3 (compound 3) > or = C2 (compound 2) = C5 (compound 5) = C6 (compound 6) > compound 1) was similar at each VGSC. Compound 4 exhibited strong use-dependent inhibition of hNa(v)1.5 with pIC50 values < 4.5 and 6.0 for tonic and phasic block, respectively. Coincubation with local anesthetics but not tetrodotoxin attenuated compound 4-mediated inhibition of hNa(v)1.5. These data suggest that the compound 4 binding site(s) is identical, or allosterically coupled, to the local anesthetic receptor. The dissociation rate of the dimers from hNa(v)1.5 was dependent upon the linker length, with a rank order of compound 1 > compound 5 = compound 6 > compound 2 > compound 3. The observation that both the potency and dissociation rate of the dimers was dependent upon linker length is consistent with a multivalent interaction at VGSCs. hNa(v)1.5 VGSCs did not recover from inhibition by compound 4. However, "chase" with free local anesthetic site inhibitors increased the rate of dissociation of compound 4. Together, these data support the hypothesis that compound 4 simultaneously occupies two binding sites on VGSCs, both of which can be bound by known local anesthetic site inhibitors.     

Location of the sulphonylurea receptor at the cytoplasmic face of the beta-cell membrane.

1. In insulin-secreting cells the location of the sulphonylurea receptor was examined by use of a sulphonylurea derivative representing the glibenclamide molecule devoid of its cyclohexy moiety (compound III) and a benzenesulphonic acid derivative representing the glibenclamide molecule devoid of its cyclohexylurea moiety (compound IV). At pH 7.4 compound IV is only present in charged form. 2. Lipid solubility declined in the order tolbutamide > compound III > compound IV. 3. The dissociation constant (KD) for binding of compound IV to the sulphonylurea receptor in HIT-cells (pancreatic beta-cell line) was similar to the KD value for tolbutamide and fourfold higher than the KD value for compound III. 4. In mouse pancreatic beta-cells, drug concentrations inhibiting adenosine 5'-triphosphate-sensitive K+ channels (KATP-channels) half-maximally (EC50) were determined by use of the patch-clamp technique. When the drugs were applied to the extracellular side of outside-out or the intracellular side of inside-out membrane patches, the ratio of extracellular to intracellular EC50 values was 281 for compound IV, 25.5 for compound III and 1.2 for tolbutamide. 5. In mouse pancreatic beta-cells, measurement of KATP-channel activity in cell-attached patches and recording of insulin release displayed much higher EC50 values for compound IV than inside-out patch experiments. A corresponding, but less pronounced difference in EC50 values was observed for compound III, whereas the EC50 values for tolbutamide did not differ significantly. 6. It is concluded that the sulphonylurea receptor is located at the cytoplasmic face of the beta-cell plasma membrane. Receptor activation is induced by the anionic forms of sulphonylureas and their analogues.     

新型氨基二硫代甲酸酯类抗肿瘤化合物HGWJ—11c的发现

为发现新结构类型的抗肿瘤化合物,基于我们发现的氨基二硫代甲酸酯类化合物的合成新方法,利用液相组合化学技术,通过两轮共构建了74个化合物库,对从中筛选出的6个可能具有活性的化合物进行了合成及活性验证,发现结构新颖的化合物13（HGWJ-11C）具有明显抗肿瘤作用,其中的氨基二硫代甲酸骨架是产生活性的必需结构。化合物13值得作为一个苗头化合物进行深入研究。     

双苄基异喹啉类化合物Fs对钙调素拮抗作用的研究

采用钙调素（ＣａＭ）依赖性磷酸二酯酶及丹磺酰标记ＣａＭ，研究了双苄基异喹啉类化合物Ｆｓ对ＣａＭ的拮抗作用。实验结果表明，化合物Ｆｓ能抑制ＣａＭ刺激磷酸二酯酶活性，抑制作用可被过量ＣａＭ完全克服，化合物ＦＳ拮抗作用大于三氟啦嗪，为强的拮抗剂。化合物Ｆｓ在Ｃａ￣（２＋）存在下，可降低丹磺酰钙调素（ＤＮＳ－ＣａＭ）的荧光强度，滴加ＣａＭ，荧光强度逐渐回升，在ＥＧＴＡ条件下，化合物ＦＳ没有作用。实验结果显示：双苄基异喹啉化合物ＦＳ是钙调素拮抗剂，且作用强于三氟啦嗪。     

Synthesis of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydrochloride, a novel, orally active antifungal agent

The preparation, determination of isomeric configuration, and antifungal properties of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydrochloride (1) are described. In vitro, compound 1 has been shown to have activity against Candida albicans comparable with miconazole. When administered orally to animals with experimentally induced vaginal candidiasis or systemic candidiasis, compound 1 produced results approaching those produced by ketoconazole. In addition, topical administration of compound 1 to rats with vaginal candidiasis produced results comparable with those produced by similar administration of clotrimazole. Unlike ketoconazole, which is active by a mechanism that is essentially fungistatic, compound 1 shares with miconazole a mode of action that is fungicidal. However, unlike miconazole, compound 1 exhibits activity following oral administration. Compound 1 has been found to be negative in the Ames test.     

氯法拉滨的合成工艺改进

目的合成标题化合物,并进行工艺改进。方法以1-乙酰基-2,3,5三-O-苯甲酰基-β-D-呋喃核糖为起始原料,制得1-氯-2-脱氧-2-氟-3,5-二-O-苯甲酰基-α—D-阿拉伯糖（化合物6）。化合物6与2-氯腺嘌呤在四氯化锡作用下发生缩合反应生成氯法拉滨。结果总收率为8．4％,目标化合物的结构经IR、^1H—NMR、MS等方法确证。结论该合成工艺具有原料易得,操作简便,易于工业化生产等特点。     

A Simple Method for Isolation of Plumbagin from Roots of Plumbago rosea.

Abstract

Plumbagin, the major active compound and a potential biomarker characteristically found to be present in different Plumbaginales, is isolated by an austere and efficient method involving column chromatography. A literature survey suggests that the roots of Plumbago rosea. Linn. are the richest source of plumbagin. Chemically identified as a naphthoquinone, the compound is claimed to sublime at 90°C. This disposition of the compound correlates with the implication of cold maceration employed in isolation methodology for extraction of root powder with acetone. Plumbagin, being hydrophobic and insoluble in water, was precipitated out by addition of water to the acetone extract. The filtered residue was taken in chloroform, and the concentrated chloroform extract, when subjected to column chromatography, yielded plumbagin (1.65%), elution being carried out with n-hexane:ethyl acetate (92:8). The identity of the compound was confirmed by melting point data, UV, IR, and mass spectral data reported in the literature. The purity of the compound was further analyzed by subjecting the compound to HPTLC studies.