治疗痤疮新药:益肤酰胺[N-(4-乙氧苯基)-2-羟基苯酰胺]的合成

益肤酰胺是近来由沈阳药学院与大庆市第一医院发现的一种治疗痤疮新药,疗效确切。它是复方乙酰水杨酸片灼烧后的产物,经分离和光谱鉴定证明为N-(4-乙氧苯基)-2-羟基苯酰胺,结构如(Ⅰ),合成方法已有报道。为了验证其化学结构和探讨合成方法,我们进行了化学合成。     

作用于神经系统药物的研究 1.4-甲氧基-1-甲基-3-(3-甲基-2-丁烯基)-2-喹啉酮和有关化合物的合成

为寻找具有较高中枢抑制作用的活性化合物,作者合成了4-甲氧基-1-甲基-3-(3-甲基-2-丁烯基)-2-喹啉酮类化合物Ⅶ、Ⅷ、Ⅸ和有关化合物Ⅹ、Ⅵ等。化合物Ⅶ、Ⅷ分别由相应的Ⅴ、Ⅵ经重氮甲烷或硫酸二甲酯甲基化获得。用二硼烷与Ⅴ加成,后以过氧化氢氧化制备Ⅸ.Ⅴ在酸性条件下经环化合成Ⅹ和Ⅺ。初步动物试验表明,上述化合物的中枢抑制活性与Ⅴ、Ⅵ相当或稍好,深入工作正在进行中。     

蔓性千斤拔化学成分的研究

从豆科植物蔓性千斤拔[Flemingia philippinensis(Merr.et Rolfe)Li]的根中分得六个化合物和一个烷酸的混合物(Ⅰ～Ⅶ)。经理化常数测定和光谱分析证明,化合物Ⅰ和Ⅱ为新化合物,分别命名为蔓性千斤拔素C(Ⅰ)和蔓性千斤拔素D(Ⅱ),其余为已知物,分别鉴定为5,7,3′,4′-四羟基-6,8-双异戊烯基异黄酮(Ⅲ),flemichin D(Ⅳ),n C₂₂～C₃₀烷酸(Ⅴ),β-谷甾醇(Ⅵ)和羽扇豆醇(Ⅶ)。化合物Ⅲ和Ⅳ对P₃₈₈白血病细胞具有显著的抑制作用。     

穆坪马兜铃化学成分的研究

自穆坪马兜铃(Aristolochia moupinensis Franch)根、茎中分得十三个化合物,其中化合物Ⅰ～Ⅻ经鉴定分別为马兜铃酸Ⅰ(aristolochic acid Ⅰ)(Ⅰ),尿囊素(allantoin)(Ⅱ),紫丁香酸(syringic acid)(Ⅲ),香豆酸(P-coumaric acid)(Ⅳ),马兜铃酸Ⅳ(aristolochic acid Ⅳ)(Ⅴ),β-谷甾醇(Ⅵ),木兰碱(magnoflorine)(Ⅶ),马兜铃酸Ⅳ甲醚aristolochic acid Ⅳ methyl ether(Ⅵ),棕榈酸(Ⅸ),马兜铃酸Ⅱ(aristolochic acid Ⅱ)(Ⅹ),N(Phydroxyphenethy1)P-coumaramide(Ⅺ),马兜铃酸Ⅳ甲醚甲酯(aristolochic acid Ⅳ methyl ether methyl ester)(Ⅻ),化合物ⅩⅢ为新化合物,经光谱分析和化学合成等方法证明其结构为N(P-hydroxyphenethyl)-ferulamide,命名为穆坪马兜铃酰胺(moupinamide)。 初步药理试验表明穆坪马兜铃酰胺体外有抑制血小板聚集和影响血小板内前列腺素合成的作用。     

走马芹中香豆素成分的研究

自走马芹根中分离出八种香豆素化合物(Ⅰ～Ⅷ),经鉴定为异佛手柑内酯(Ⅰ)、茴芹内酯(Ⅱ)、甲氧基欧芹素(Ⅲ)、佛手柑内酯(Ⅳ)、异茴芹内酯(Ⅴ)和牛防风素(Ⅵ)。4′-羟基-二氢欧山芹醇(Ⅶ)和香豆素化合物(Ⅷ)是新化合物,后者命名为走马芹内酯(moellendorffiline)。从走马芹叶和种子中均分离到六种香豆素化合物(Ⅰ～Ⅵ)。     

作用于神经系统药物的研究——1.4-羟基-3-(3-甲基-2-丁烯基)-2-喹诺酮类似物的合成

为了寻找作用于神经系统的活性化合物,作者通过相应的取代芳胺与2-(3-甲基-2-丁烯其)-丙二酸二乙酯的环合反应,合成了Ⅳ,Ⅴ两个系列14个4-羟基-3-(3-甲基-2-丁烯基)-2-喹诺酮类似物和5个有关化合物(Ⅵ,Ⅶ类)。初步药理筛选的结果表明,除Ⅵ类外,其它类化合物对神经系统均具有一定的镇痛,抗惊厥或中枢抑制作用。深入工作尚在进行中。     

作用于神经系统药物的研究——1.4-羟基-3-(3-甲基-2-丁烯基)-2-喹诺酮类似物的合成

为了寻找作用于神经系统的活性化合物,作者通过相应的取代芳胺与2-(3-甲基-2-丁烯其)-丙二酸二乙酯的环合反应,合成了Ⅳ,Ⅴ两个系列14个4-羟基-3-(3-甲基-2-丁烯基)-2-喹诺酮类似物和5个有关化合物(Ⅵ,Ⅶ类)。初步药理筛选的结果表明,除Ⅵ类外,其它类化合物对神经系统均具有一定的镇痛,抗惊厥或中枢抑制作用。深入工作尚在进行中。     

穆坪马兜铃化学成分的研究

自穆坪马兜铃(Aristolochia moupinensis Franch)根、茎中分得十三个化合物,其中化合物Ⅰ～Ⅻ经鉴定分別为马兜铃酸Ⅰ(aristolochic acid Ⅰ)(Ⅰ),尿囊素(allantoin)(Ⅱ),紫丁香酸(syringic acid)(Ⅲ),香豆酸(P-coumaric acid)(Ⅳ),马兜铃酸Ⅳ(aristolochic acid Ⅳ)(Ⅴ),β-谷甾醇(Ⅵ),木兰碱(magnoflorine)(Ⅶ),马兜铃酸Ⅳ甲醚aristolochic acid Ⅳmethyl ether(Ⅵ),棕榈酸(Ⅸ),马兜铃酸Ⅱ(aristolochic acid Ⅱ)(Ⅹ),N(Phydroxyphenethy1)P-coumaramide(Ⅺ),马兜铃酸Ⅳ甲醚甲酯(aristolochic acid Ⅳmethyl ether methyl ester)(Ⅻ),化合物ⅩⅢ为新化合物,经光谱分析和化学合成等方法证明其结构为N(P-hydroxyphenethyl)-ferulamide,命名为穆坪马兜铃酰胺(moupinamide)。初步药理试验表明穆坪马兜铃酰胺体外有抑制血小板聚集和影响血小板内前列腺素合成的作用。     

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。     

溪黄草甲素的结构研究

从溪黄草Rabdosia serra(Maxim.)Hara干叶、茎中共分得八个化合物,其中化合物Ⅲ～Ⅷ经鉴定分别为excisanin A(Ⅲ),kamebakaurin(Ⅳ),2α-羟基乌苏酸(Ⅴ),β-谷甾醇(Ⅵ),乌苏酸(Ⅶ)和β-谷甾醇D-葡萄糖甙(Ⅷ)。Ⅰ为新化合物,经光谱分析和衍生物制备证明其结构为1,14-二羟基,7,20,19,20-二环氧-16-贝壳杉烯-15-酮,命名为溪黄草甲素。药理实验表明化合物Ⅰ,Ⅲ和Ⅳ对Hela细胞具有显著的抑制作用。     

Analgesic and anti-inflammatory effects of some benzanilides

Analgesic and anti-inflammatory effects of N-(p-ethoxyphenyl)-2,6-dihydroxybenzamide (1), N-(p-ethoxyphenyl)-2,6-diacetoxybenzamide (2), N-(p-ethoxyphenyl)-2,5-dihydroxybenzamide (3), and N-(p-ethoxyphenyl)-2,5-diacetoxybenzamide (4) have been investigated in mice and rats. The analgesic effect of 2 on acetic acid-induced writhing was found to be stronger than that of aspirin, whereas that of 1, 3, and 4 was weaker than that of aspirin. In inflammatory studies, 1-4 showed inhibition of formaldehyde-induced paw swelling (edema). The effects of 1-3 were more potent than that of aspirin, 1 being the most potent. The potency of 4 was almost equal to that of aspirin.     

4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor kappaB activation

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the activation of NF-kappaB elicited by tumour necrosis factor-alpha (TNF-alpha) on human umbilical vein endothelial cells (HUVEC) was tested. 2. The expression of the mRNA of vascular cell adhesion molecule-1 (VCAM-1) was studied as an example of a gene the expression of which is regulated by NF-kappaB. To extend these findings to other systems, the induction of nitric oxide synthase in rat adherent peritoneal macrophages was studied. 3. Both HTB and triflusal were more potent than aspirin or salicylate as inhibitors of the nuclear translocation of NF-kappaB. The calculation of the IC50 values showed approximately 2 mM for HTB, 4 mM for aspirin and >4 mM for salicylate. 4. Comparison of the potency of these compounds on VCAM-1 mRNA expression showed complete inhibition by both triflusal and HTB at a concentration of 4 mM whereas aspirin and salicylate produced only 36-43% inhibition at the same concentration. 5. Inhibition of NF-kappaB activation was also observed in rat peritoneal macrophages stimulated via their receptors for the Fc portion of the antibody molecule with IgG/ovalbumin immune complexes. This was accompanied by a dose-dependent inhibition of nitrite production by the L-arginine pathway via iNOS. IC50 values for this effect were 1.13+/-0.12 mM (triflusal), 1.84+/-0.34 (HTB), 6.08+/-1.53 mM (aspirin) and 9.16+/-1.9 mM (salicylate). 6. These data indicate that the incorporation of a 4-trifluoromethyl group to the salicylate molecule strongly enhances its inhibitory effect on NF-kappaB activation, VCAM-1 mRNA expression and iNOS induction, irrespective of the presence of the acetyl moiety involved in the inhibition of cyclo-oxygenase.     

Effects of non-steroidal anti-inflammatory drugs on rat gastric mucosal leukotriene C4 and prostanoid release: relation to ethanol-induced injury.

1. The effects of oral and subcutaneous administration of the non-steroidal anti-inflammatory drugs sodium salicylate, aspirin and indomethacin on ex vivo gastric mucosal release of leukotriene C4 (LTC4) prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) were investigated in rats under basal conditions as well as after challenge with ethanol. 2. Basal release of PGE2, 6-oxo-PGF1 alpha and TXB2 was inhibited by oral administration of aspirin (0.6-400 mgkg-1) and indomethacin (4 or 20 mgkg-1), but not by sodium salicylate (up to 400 mgkg-1), in a dose-dependent manner. Oral administration of aspirin in the dose range 3.2-400 mgkg-1 and of indomethacin (20 mgkg-1) additionally inhibited release of LTC4, while sodium salicylate (up to 400 mgkg-1) had no effect. Indomethacin (20 mgkg-1) and aspirin (400 mgkg-1) administered subcutaneously inhibited generation of cyclo-oxygenase products of arachidonate metabolism, but did not significantly affect LTC4 synthesis. 3. Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC4 from rat gastric mucosa, while release of cyclo-oxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanol-stimulated gastric mucosal LTC4 release in a dose-dependent manner. Sodium salicylate had no effects on the release of PGE2 and TXB2, while that of 6-oxo-PGF1 alpha was slightly increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

抗心肌缺血药3-{4-[(2-羟基-3-烷氨基)丙氧基]苯基(苄基)}-取代4(3H)-喹唑酮的合成

In order to search for effective antimyocardial ischemic agents, fourteen new 3 4-[(3-alkylamino-2-hydroxy)propoxy] phenyl(benzyl)]-substituted 4(3H)-quin zolinones (Ⅱ) were synthesized. Substituted o-aminobenzoic acids used as the starting materials were allowed to react with acetic anhydride and then p-aminophenol (method A), or with N- (4- hydroxyphenyl)formamide (method B), or with thionyl chloride and then N - (4 - hydroxybenzyl) formamide (methode C) to form 3-[(4-hydroxyphenyl(benzyl)]-substituted 4(3H)-quinazolinones (Ⅲ). The intermediate Ⅲ reacted with epichiorohydrin to form the epoxides (Ⅳ). The reaction of Ⅳ with an excess of isopropylamine or tert-butylamine in boiling chloroform gave the desired products. Of all the compounds synthesized, Compounds Ⅱ_3～5 and Ⅱ₁₃ were found to increase the tolerance of mice to hypoxia. Further evaluation is in progress.     

Aspirin and sodium salicylate inhibit proliferation and induce apoptosis in rheumatoid synovial cells

Aspirin has been reported to induce apoptosis in a variety of cell lines. In this study, we examined whether aspirin and sodium salicylate inhibit cell growth and induce apoptosis in rheumatoid synovial cells. Synovial cells were obtained from patients with rheumatoid arthritis, and the cells were treated with aspirin or sodium salicylate (0.1-10 mM) for 24 h. Cell proliferation and viability were assessed by 5-bromo-2'-deoxyuridine incorporation and by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay, respectively. The apoptosis of synovial cells was identified by DNA fragmentation assay and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay. Aspirin and sodium salicylate suppressed the proliferation (IC50 (concentration causing 50% inhibition of cell proliferation): 2.1 and 1.2 mM, respectively) and reduced the viability (IC50: 2.0 and 1.4 mM, respectively) of synovial cells in a concentration-dependent manner at 0.3-10 mM. Furthermore, they induced DNA fragmentation and increased the number of TUNEL-positive synovial cells. These results suggest that aspirin and sodium salicylate can inhibit the proliferation of rheumatoid synovial cells through induction of apoptosis.     

The aspirin-ibuprofen interaction in rheumatoid arthritis.

1 This was a double-blind crossover trial of ibuprofen and soluble aspirin against each drug alone and against placebo in patients with rheumatoid arthritis. Two dosage regimes were tested. 2 A weak clinical additive effect was demonstrated between soluble aspirin and ibuprofen in patients with rheumatoid arthritis using moderate (1600 mg ibuprofen and 3.6 g aspirin daily) but not low (800 mg ibuprofen and 2.4 g aspirin daily) dosages of both drugs. 3 A significant correlation between clinical efficacy and serum ibuprofen but not salicylate level was found in the single drug periods of the trial. 4 No consistent effect of ibuprofen administration on serum salicylate levels was found. 5 Concurrent salicylate administration produced significant lowering of serum ibuprofen levels without affecting elimination half-lives of the drug.     

Gastric ulcer formation and cyclo-oxygenase inhibition in cat antrum follows parenteral administration of aspirin but not salicylate

The ulcerogenic actions of aspirin and sodium salicylate in cat gastric antrum following intravenous injection, and their effects on the synthesis of two major cyclo-oxygenase products by antral mucosa have been determined. Near-maximal rates of gastric acid secretion were stimulated by histamine, infused i.v. for 1 h prior to bolus injection of aspirin or salicylate and throughout the subsequent 4 h. The area of lesions in the cat gastric antrum were then assessed macroscopically and the generation of both 6-oxo-PGF1 alpha and PGE2 from strips of antral mucosal tissue following 1 min vortex-incubation was determined by radioimmunoassay. The plasma and mucosal-tissue levels of both aspirin and salicylate were determined using HPLC techniques. Aspirin (0.2 mmol. kg-1 i.v.) induced substantial deep antral ulceration during the 4 h histamine infusion, whereas sodium salicylate (0.2 mmol. kg-1 i.v.) caused no significant macroscopic damage. Sodium salicylate likewise caused no significant inhibition in the ex vivo generation of either 6-oxo-PGF1 alpha or PGE2, whereas aspirin induced 92 +/- 3 and 97 +/- 1% inhibition of generation of these prostanoids respectively. The levels of total salicylate in plasma and mucosal tissue were comparable following bolus i.v. injection of aspirin or sodium salicylate. These observations support the concept that cyclo-oxygenase inhibition is an important mechanism underlying deep gastric ulceration induced by aspirin, when administered parenterally in the cat.     

Synthesis and anticonvulsant evaluation of 1,2-diphenylethane derivatives, potential metabolites of denzimol

A number of new 1,2-diphenylethane derivatives were synthesized and tested for anticonvulsant activity. Their structure was designed on the basis of the potential metabolic degradation of the imidazole ring present in denzimol ( ( +/- )-N-[2-[4-(beta-phenylethyl)phenyl]-2-hydroxethyl]imidazole), a potent anticonvulsant. The compounds which inhibited the electroshock-induced seizures (MES) in mice, namely N-[4-(beta-phenylethyl)phenacyl]formamide (VII) and N-[2-[4-(beta-phenylethyl)phenyl]-2-hydroxyethyl]formamide (IX), proved active also as inhibitors of the pentylenetetrazole-induced tonic seizures. The results of the pharmacological screening were evaluated in relation to the lipophilicity of the compounds.     

Study of the mechanisms involved in the bradykinin-induced contraction of the pig iris sphincter muscle in vitro

This study was designed to investigate the mechanisms by which bradykinin induces contraction of the pig iris sphincter muscle in vitro. Addition of bradykinin, Lys-bradykinin and Met-Lys-bradykinin to the pig iris sphincter resulted in a graded contraction with a mean EC(50s) of 21, 11 and 5 nM, respectively. The bradykinin B(1) receptor agonist des-Arg(9)-bradykinin only caused a slight contraction, measured 6 h after the tissue was set up. The B(2) receptor antagonists FR 173657 ((E)-3-(6-acetamido-3-pyridyl)-N [N-2-4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylamino-carbonyl-ethyl] acrylamide) and Hoe 140 (D-Arg(0)-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin produced a graded shift to the right associated with marked inhibition of the bradykinin-induced contraction. Atropine, guanethidine or tetrodotoxin significantly reduced the bradykinin-induced contraction. Dazoxiben, an inhibitor of thromboxane A(2), and MK-571 (3-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid, a leukotriene D(4) receptor-selective antagonist, also caused inhibition of the bradykinin-mediated contraction. Cyclooxygenase-1 and -2 inhibitors, indomethacin, ibuprofen, valeryl salicylate and NS 398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide) all significantly inhibited the bradykinin-mediated contraction without affecting the carbachol-induced contraction of the pig iris sphincter. Taken together, these results indicate that the bradykinin-mediated contraction of the pig iris sphincter muscle seems to be mediated primarily by the activation of the B(2) receptor release of acetylcholine, noradrenaline and both cyclooxygenase-1 and -2 metabolites besides the release of leukotriene D(4) and tromboxane A(2) from the arachidonic acid pathway.     

沙蓬化学成分的分离与鉴定(Ⅱ)

目的对沙蓬地上部分体积分数70%乙醇提取物的水层和乙酸乙酯层萃取物的化学成分进行研究。方法采用反复硅胶柱色谱、ODS柱色谱、Sephadex LH-20柱色谱和半微量制备高效液相色谱分离纯化,根据ESI-MS、EI-MS、1H-NMR和13C-NMR谱学数据进行结构鉴定。结果从体积分数为70%乙醇提取物中分离得到9个单体化合物,分别鉴定为生物碱类化合物N-(4-(1H-pyrazol-1-yl)phenyl)acetamide(1)、N-(4-(1H-pyrazol-1-yl)-phenyl)formamide(2)、扑热息痛[p-(acetylamino)phenol,3]、N-(3-chloro-4-hydroxylphenyl)acetamide(4)、N-(2,5-dichloro-4-hydroxyphenyl)acetamide(5)和N-(2,3,5-trichloro-4-hydroxyphenyl)acetamide(6),2个异黄酮类化合物aya-menin A(7)和irisone B(8),1个酚苷类化合物水扬苷(salicin,9)。结论化合物2为新化合物,化合物1为新天然产物,化合物4～6为扑热息痛(3)的3种新光解产物,化合物7、8为首次从藜科植物中分离得到,化合物9为首次从沙蓬属植物中分离得到。