氧化去除皮质甾醇类二羟基丙酮侧链方法的改进

氧化去除皮质激素类(Ⅰ)侧链而生成17-酮基雄甾类(Ⅱ),可用于确定化合物Ⅰ的结构和制取化合物Ⅱ。但已知的转化方法Ⅱ的收率(与原化合物Ⅰ的结构有关)一般不超过50%。本文指出,增加活性二氧化锰用量,缩短反应时间,可排除副反应,获得较好效果。方法是在氯仿中,Ⅰ与二氧化锰之比为1:20,于沸腾下反应3～4小时,氧化结束,滤去二氧化锰,得到的溶液几乎为纯化合物Ⅱ,收率为55～77%。     

3′(5α-3β,17β-双羟基-雄甾烷-17α)-丙酸内酯(Ⅴ)的微生物转化——螺旋内酯甾(Ⅱ)的合成

3′-(5α-3β,17β-双羟基-雄甾烷-17α)-丙酸内酯(Ⅴ)经诺卡氏菌(Nocardia sp.)转化获得6个化合物(Ⅱ和Ⅵ～Ⅹ),其中螺旋内酯甾(Ⅱ)为其主要产物(～50%)。Ⅷ～Ⅹ是尚未被鉴定的羟基化合物。化合物(Ⅴ)用诺卡氏菌在氮源贫乏的培养基中转化主要生成△⁴-3-酮化合物,而在氮源丰富的培养基中转化则主要为△^1,4-3-酮的产物。     

黄褐毛忍冬化学成分的研究

从我省商品药材金银花的主要品种之一,黄褐毛忍冬(Lonicera fulvotomentosa Hsu et S.C.Cheng)的花蕾中分离到五种以常春藤皂甙元构成甙元的皂甙(Ⅰ～Ⅴ),本文报道化合物Ⅰ,Ⅱ和Ⅴ的结构测定。Ⅴ为新的三萜酸双糖链甙,命名为黄褐毛忍冬皂甙甲(fulvotomentoside A),Ⅰ和Ⅱ为已知化合物,分别被鉴定为α-常春藤皂甙(α-hederin)和无患子皂甙B(sapindoside B)。     

氯霉素,Ⅱ.α-溴代-对-硝基苯乙酮的合成

本文叙述了二种制备氯霉素的重要中間体α-溴代-对-硝基苯乙酮的方法。(一) α-苯基-β-溴代乙醇(Ⅱ)經硝化生成α-对-硝基苯基-β-溴代乙醇硝酸酯(Ⅲ),将此硝酸酯直接水解即生成相应的醇,但以先轉化成α-对-硝基苯基-β-溴代乙醇乙酸酯(Ⅳ),然后醇解成α-对硝基苯基-β-溴代乙醇(Ⅴ)收率較高,后者可用鉻酸氧化成α-溴代-对-硝基苯乙酮(Ⅳ),由最初原料苯乙烯(Ⅰ)計算全程收率分別为37.2%与40.8%。(二) β-溴代乙苯(Ⅶ)依次經硝化及氧化作用亦生成α-溴代-对-硝基苯乙酮(Ⅵ),全程收率50.8%。     

新疆藁本有效成分研究

从新疆藁本(ConiselinumvaginatumThell)的根茎中分到七个化合物,根据理化常数和光谱解析,分别鉴定为coniselin(Ⅰ),(E)-3-methoxy-4,5-methyenedioxycinnamicaldehyde(Ⅱ),(E)-3-methoxy-4,5-methylenedioxycinnamicalcohol(Ⅲ),(E)-3-methoxy-4,5-methylenedoxycinnamicacid(Ⅳ),肉豆劳动蔻酸(myristicicacid,V),阿魏酸(ferulicacid,Ⅵ)和香草醛(vanilin,Ⅶ)。其中Ⅰ为新化合物,其余均为首次从该植物中分到。经药理实验表明化合物Ⅱ～Ⅴ对四氯化碳引起的小鼠转氨酶升高有降低作用,对丙酸杆菌引起的小鼠免疫性肝损伤有保护作用。     

铁轴草二萜成分的化学研究

从铁轴草(Teurcium quadrifarium Buch-Ham)的丙酮提取部分分离出六个新—克罗烷(neoclerodane)型二萜(Ⅰ,Ⅱ,Ⅳ～Ⅶ)。其中五个为已知化合物,分别鉴定是teucvidin(Ⅰ),12-epi-teucvidin(Ⅱ),teufiin(Ⅳ),19-acetyl-tetmpinin(Ⅴ)和tcucvin(Ⅶ)。Ⅵ为新化合物,命名为teuquadrin B。     

国外合成药物及其中间体工艺简讯

3,4,5-三甲氧基苯甲醛是磺胺增效剂TMP的主要中间体。本专利报道上述化合物可用香兰醛为原料在48％氢溴酸中以溴素溴化,可得5-溴化香兰醛(Ⅰ),收率99.4％。Ⅰ在氢氧化钠水溶液中水解,以铜粉为触媒,得5-羟基香兰醛(Ⅱ),收率83.3％。Ⅱ在丙酮中在碳酸钠     

△4.9雌甾二烯—3,17双酮的合成

本文报道了合成RU-486的中间体Δ~(4,9)一雌二烯—3,17—双酮[Ⅰ]的制备。以1?—羟甲基—Δ~4—雄甾烯—3,17—双酮[Ⅷ]为起始原料,与Jones试剂反应得Δ~4—雄甾烯—3,17—双酮—10—羧酸[Ⅸ],收率为79～84%。[Ⅸ]在吡啶中用碘处理生成化合物[Ⅰ],收率为48～52%。化合物[Ⅰ]的结构经红外光谱和紫外光谱证实。     

长瓣金莲花茎叶化学成分的研究

从长瓣金莲花(Trollius macropetalus Fr.Schmidt)的干燥茎叶中分离到五个单体,经理化常数测定和光谱分析,确定化合物Ⅰ为牡荆素-2″-O-β-D-吡喃木糖甙(vitexin-2″-O-β-D-pyranxyloside),Ⅱ为荭草素-2″-O-β-D-吡喃木糖甙(orientin-2″-O-β-D-pyranxyloside),Ⅲ为牡荆甙(vitexin),Ⅳ为荭草甙(orientin)Ⅴ为3-甲氧基-4-羟基-5-(3′-甲基-2′-)西烯基甲酸(3-methoxy-4-hydroxyl-5-(3′-methyl-2′-)butylenyl benzoic acid)。其中Ⅰ和Ⅱ系首次从金莲花属植物中获得。Ⅴ为新化合物,命名为原金莲酸(proglobeflowery acid)。     

缩胺硫脲类化合物的合成及其抗癌活性研究

合成了16个新型缩胺硫脲类化合物。先由硫酸二甲酯、水合肼与二硫化碳反应,生成肼基二硫代甲酸甲酯（Ⅱ）,产率为60％。取代芳香酮、醛与Ⅱ反应,制备中间体Ⅲ,收率：51％－91％。Ⅲ与N－取代哌嗪反应制备目标代合物Ⅰ,收率：27．3％－85．7％。其结构经IR、^1H-NMR和元素分析等确证。体外抗癌活性测定表明,在适当的基代基匹配下,此类化合物有一定的抗癌活性。     

Exploitation of the unusual thermodynamic properties of human myeloperoxidase in inhibitor design

Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. It uses hydrogen peroxide and chloride to catalyze the production of hypochlorous acid (HOCl), which contributes to both bacterial killing and oxidative injury of host tissue. Thus, MPO is an interesting target for anti-inflammatory therapy. Here, based on the extraordinary and MPO-specific redox properties of its intermediates compound I and compound II, we present a rational approach in selection and design of reversible inhibitors of HOCl production mediated by MPO. In detail, indole and tryptamine derivatives were investigated for their ability to reduce compounds I and II and to affect the chlorinating activity of MPO. It is shown that these aromatic one-electron donors bound to the hydrophobic pocket at the distal heme cavity and were oxidized efficiently by compound I (k3), which has a one-electron reduction potential of 1.35 V. By contrast, compound II (E degrees ' of the compound II/ferric couple is 0.97 V) reduction (k4) was extremely slow. As a consequence compound II, which does not participate in the halogenation cycle, accumulated. The extent of chlorinating activity inhibition (IC50) was related to the k3/k4 ratio. The most efficient inhibitors were 5-fluorotryptamine and 5-chlorotryptamine with IC50 of 0.79 microM and 0.73 microM and k3/k4 ratios of 386,000 and 224,000, respectively. The reversible mechanism of inhibition is discussed with respect to the enzymology of MPO and the development of drugs against HOCl-dependent tissue damage.     

心血管系统药物异黄酮化合物的合成

在黄豆甙元化学结构的基础上,合成了一系列异黄酮衍生物。由相应的脱氧安息香与N,N-二甲基甲酰胺缩二甲醇环合而得相应的异黄酮或与醋酐醋酸钠环合而为2-甲基异黄酮,再进行Mannich反应和醚化而得目的物。初筛表明化合物Ⅰ_1～3,Ⅰ₅,Ⅱ₁,Ⅲ₂有明显耐缺氧作用。Ⅰ₁,Ⅰ₅还有显著的扩张冠脉作用。     

Oxazolidines: prodrugs for the delivery of β-aminoalcohols through human skin from aqueous solution

Ephedrine (I) is delivered through human skin, in vitro, significantly faster from aqueous solutions of 3,4-dimethyl-5-phenyl-oxazolidine (II) with pH values between 7.0 and 10.88 than from corresponding solutions of I. The difference in penetration rates was most marked at pH 7.0 where 917 μg and < 10 μg of I was delivered through 1.3 cm² of skin in 24 h from 1% w/v solutions of II and I, respectively. No detectable amounts of I were delivered through 1.3 cm² of skin in 24 h from 1% w/v solutions of I or II in propylene glycol and delivery of I was faster from 1% w/v solutions of I in liquid paraffin than from corresponding solutions of II. Compound II has a lower pK_a value than compound I (ca. 5.5 vs 9.63) and a higher partition coefficient between water and liquid paraffin (5.6 vs 1.0). Although II rapidly hydrolyzed to I plus formaldehyde (t_50% < 1 min at pH values between 6 and 8), the system rapidly came to an equilibrium which increasingly favoured compound II as the initial concentration of II or the pH value was increased. Hence, it can be concluded that compound II and possibly other oxazolidines are potentially useful prodrugs for promoting the delivery through skin of I and other β-aminoalcohols from aqueous solutions with pH values close to 7.     

中药独活活性成分香豆素及其甙的化学研究

独活为伞形科重齿毛当归(Angelica pubescens Maxim.F.biserrataShan et Yuan)的根及根茎,为常用中药,有祛风通络,活血舒筋,宜通百脉的作用。治腰膝酸痛,手脚挛痛。本研究证明独活有抑制血小板聚集抗血栓形成的作用,可能为独活善行血分,活血舒筋,宜通百脉的作用机制之一。我们将湖北资丘产独活以CH_2Cl_2,C_2H_5OH及H_2O提取,各提取部位分别按Born     

铁棒锤化学成分研究

铁棒锤(Aconitum szechenyianum Gay)又名铁牛七、黑草乌。用于消炎止痛、祛风除湿,治疗风湿性关节炎及疮痈肿毒等。与铁棒锤同名的植物有雪上一枝蒿(A.pendulumBush)、伏毛铁棒锤(A.flavum Hand-Maii),此二者成分已有报道,前者主要含乌头碱,     

儿茶氨基酮及类似物的合成

本文报道儿茶氨基酮Ⅰ_1～12及类似物Ⅱ_1～12共24个和一个尿嘧啶氨基酮Ⅲ的合成。并对上述化合物的核磁共振谱及质谱进行了讨论。药理研究表明这类化合物对5-HT和Ca^#引起的离体犬肠系膜动脉和基底动脉的收缩无明显对抗作用。某些化合物能增加在体犬股动脉血流量,显示其扩血管作用。其中以Ⅰ₁₀作用最明显,静脉注射后有轻度的降压反应,并能增加麻醉犬的冠状动脉血流量和心肌收缩力,对乌头碱及氯仿诱导的心律失常亦有保护作用。     

Enhanced delivery of mitomycin C prodrugs through the skin

The percutaneous permeation characteristics through the excised rat skin of seven lipophilic 1a-N-substituted derivatives of mitomycin C (I) were determined in relation to their physicochemical and pharmaceutical properties. Among the four derivatives of compound I [benzyl (II), benzoyl (III), benzylcarbonyl (IV) and benzoyloxycarbonylmitomycin C (V)] possessing aromatic pro-moieties with different linkage structures, compounds II and V showed higher steady-state penetration rates than I. II penetrated the skin without metabolic conversion, while V was completely converted to I. Three alkoxycarbonyl-type derivates of I [propyl (VI), pentyl (VII), and nonyloxycarbonylmitomycin C (VIII)] with different alcoholic pro-moieties were studied to elucidate the effect of the carrier moiety on their permeation. VII showed an improved permeability, but the most lipophilic prodrug, VIII, failed to enhance the delivery of I. Compounds III and VI, which had high melting points and low biphasic solubilities, only slightly permeated the skin. Permeation rates of the test compounds reached a plateau in the concentration range over their solubilities in the vehicle; the maximum rates of II, V and VII were, respectively, 6.5, 5.3 and 3.4 times larger than that of I.     

Relationships between in vivo and in vitro inhibition of acetylcholinesterase (AChE) and impairment of neuromuscular transmission in the rat phrenic-nerve diaphragm by a tertiary anticholinesterase and its quaternary analogue

The tertiary anticholinesterase agent pinacolyl S-(2-dimethylaminoethyl) methylphosphonothioate (compound I) and its quaternary analogue (compound II), were administered subcutaneously to atropinized rats. The animals were killed 30 min later and the tension of the isolated phrenic nerve-diaphragm preparation, stimulated indirectly at 100 Hz for 10 sec, was compared with that of preparations from control animals. A dose of 1.5 μmole/kg of the quaternary compound II, which has a bimolecular rate constant of inhibition twice that of the tertiary compound I, reduced the tetanic response of the diaphragm by 50 per cent; the equivalent dose of the tertiary compound I was 5.2 μmole/kg. At these dose levels, compound II inhibited 65 per cent of the diaphragm acetylcholinesterase (AChE) activity, determined on homogenates, and compound 192 per cent. When the phrenic nerve-diaphragm preparation from untreated animals was incubated for 20 min with various concentrations of compound I or II, the rate of enzyme inhibition conformed approximately to first order kinetics and equimolar concentrations of the inhibitors reduced tetanic tension to 50 per cent in the same time. There was no discontinuity in the plot of per cent AChE inhibition vs logarithm of the concentration of compound I or II but the slope was much less with the quaternary compound II. The results provide additional evidence that quaternary compounds can reach all sites with AChE activity only in vitro and that their distribution when applied in vitro is not the same as that in vivo.     

Comparison of imidazole- and 2-methyl imidazole-containing farnesyl-protein transferase inhibitors: interaction with and metabolism by rat hepatic cytochrome P450s.

Methylation at the 2-position of the imidazole ring of IBN (I), a 1, 5-substituted imidazole-containing compound, was carried out to minimize its inhibition of rat cytochrome P450 (CYP)3A activity. The resulting analog 2-MIBN (II) exhibited an inhibitory potency 70-fold weaker (K(i) = 25 microM) than that of I (K(i) = 0.3 microM) toward CYP3A, the major rat liver microsomal P450 isoform(s) for the metabolism of I and II by rat liver microsomes in the presence of NADPH. The structural modification did not switch the major metabolic pathways for I and II, but significantly decreased the affinity of II to the metabolizing enzyme(s) as reflected by the difference in their K(i) values for CYP3A. Enzyme kinetic studies also demonstrated that I had a lower apparent K(m) (0.3 microM) than than II (18 microM), but an apparent V(max) 14 times lower than II. This finding indicates that methylation at the imidazole ring reduced the affinity of the compound to CYP3A, but increased the catalytic capacity, turning I as a substrate of low K(m) value but low capacity into a compound of high K(m) but high capacity for the metabolism. Our results suggest the significance of substrate concentration in comparing the metabolic stability of compounds with different kinetic parameters. Although higher intrinsic clearance is implied for I when the substrate concentration is below or close to its K(m) value, higher metabolic rate was constantly seen with II over micromolar range. The different kinetic parameters of I and II may also explain the observation that no significant difference in pharmacokinetic behavior was seen after an i.v. administration of I and II to the rat.     

7-Bromo-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I), a new tranquillizing agent: metabolism in rats.

1. After intraperitoneal injection of rats with the new benzodiazepine (compound I), four metabolites (compounds II, III, IV and V) were found in the urine. 2. Compound II was identified as 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one by comparison of g.l.c. and mass spectral properties of the metabolite and synthetic compound. 3. Mass spectra of compound III and its acid hydrolysis products indicate that compound III contains a hydroxyl group in the C(5)-phenyl ring. 4. Compounds IV and V were identified by mass spectrometry as products of simultaneous aromatic hydroxylation and methoxylation of the diazepine I. 5. The major urinary excretion products are compounds III, IV and V. Only very small amounts of compounds I and II were detected.