短刺虎刺中5-羟基虎刺素-ω-乙基醚的分离和结构鉴定

The structure of 5-hydroxydamnacanthol-ω-ethyl ether, a new anthraquinone, isolated from the root of Damnacanthus subspinosus Hand-Mazz (Rubiaceae) was identified to be 3,5-dihydroxy-2-ethoxymethyl-1-methoxyanthraquinone V by means of UV, IR, NMR and MS analyses. The compound was found to be active against Hela cells in culture.     

疟原虫组织期裂殖体杀灭剂4-甲基-5-(对-氟苯氧基)伯氨喹类似物的合成

A series of. analogues of 4-methyl-5-(p-fluorophenoxy)-primaquine have been prepared for evaluating of tissue schizonticidal actiyity of Plasmodium yoelii in mice. 2-Bromo-4-acetamino-5-nitroanisole was reacted with pfluorophenol in the presence of potassium hydroxide to give 2-(p-fluorophenoxy) 4-acetamino-5-nitroanisole, which was subsequently hydrolyzed to yield corresponding amino compound. Cyclization of the amino compound with methyl vinyl ketone afforded 4-methyl-5-(p-fluorophenoxy)-6-methoxy-8-nitroquinoline. This product was reduced by iron and acetic acid to give corresponding 8-aminoquinoline. The latter was condensed with bromoalkylphthalimides to yield 4-methyl-5-(pfluorophenoxy)-6-methony-8- (1-phthalimidoalkyl) aminoquinolines (Ⅳ₁～Ⅳ₇). These compounds were heated with hydrazine hydrate to form 4-methyl-5-(p-fluorophenoxy)-6-methoxy-8-(1-aminoalkyl)aminoquinolines(Ⅳ₈～Ⅳ₁₃), and 4-methyl-5-(p-fluorophenoxy) primaquine (Ⅱ).Compound Ⅱ synthesized was radical curative at 10 mg/kg×1, while the analogues Ⅳ₉ and Ⅳ₁₀ were radical curative at 100 mg/kg×1 against P. yoelii in mice.     

Δ16-娠烯-3β-乙酰氧基-11:20-二酮的极谱测定

A simple and rapid method for the determination of △~(16)—pregnene-3β—acetoxy — 11:20 — dione has been worked out. In an aqueous 40% iso-propanol solution of 0.1N NH₄Cl, this steroid gave a double polarographic wave which could be used for its determination. The current was measured at —1.50 v. vs. S.C.E. and was proportional to the concentration in the range of 36 to 180/μg/ml. From the experimental results, the diffusion current constant I and the diffusion coefficient D have been calculated to be 1.30 and 1.15 ×10^-6 cm²/sec. respectively. This method has been applied to the analysis of a sample; the result agreed with that obtained by the spectrophotometric method.     

肿瘤的化学治疗ⅩⅩⅩⅣ.与对-双(2-氯乙基)氨基-ω-溴代苯乙酮-六甲撑四胺复合物(AT-584)有关的研究——Ⅲ.对-[双(2-氯乙基)氨甲基]-ω-溴代苯乙酮-六甲撑四胺复合物的合成

In a previous paper of this series we reported that the hexamethylenetetramine salt of p-bis-(2-chloroethyl)-amino-ω-bromoacetophenone (Ⅰ, AT-584) had pronounced inhibitory action with long-acting efficacy on the growth of several experimental tumoturs, and that the antiturnout property was due to the mustard group-and the long-acting efficacy was probably related to the quarternary structure. Since nitrogen mustards of aliphatic type usually possess more effective action than those of aromatic ones, the hexamethylenetetramine salt of p-[bis-(2-chloroethyl)-aminomethyl]-ω-bromoacetophenone (Ⅱ) was synthesized.The starting material for the synthesis of compound Ⅱ was p-[bis-(2-chloroethyl) aminomethyl]-benzoic acid hydrochloride (Ⅷ), which was prepared from ethyl p-toluate or p-tolunitrile via bromination with NBS, condensation with diethanolamine, Chlorination with thionyl chloride and hydrolysis with hydrochloric acid successively. Gompound Ⅷ was chlorinated by thionyl chloride in dry benzene to give its acid chloride (Ⅸ), which without being isolated, was treated with diazomethane to yield the corresponding diazoketone(Ⅹ). The latter, without being isolated in pure state was decomposed in dioxane by hydrobromic acid to give p-[bis (2-chloroethyl) aminomethyl]-ω-bromoacetophenone (Ⅺ). Finally, the desired product (Ⅱ) was obtained by treating Ⅺ with hexamethylenetetramine in chloroform.Preliminary pharmacological tests showed that compound Ⅱ did not possess significant inhibitory action against sarcoma 180 in mice.     

11-酮基-△9-炔诺酮的合成

We have introduced a carbonyl group at the 11-position and a double bond at the 9-position of norethisterone in order to increase its antifertility potency. The starting material for the preparation of 11-keto-Δ⁹-noret-histerone(9) was 19-hydroxy-Δ⁴-androstene-3,17-dione(1), which was converted to the title compound by partial synthesis through the sequence of reactions:(1)→(9).11-Keto-Δ⁹-norethisterone was found to possess very potent antifertility effect by preliminary screening tests.     

甘草叶中甘草宁P-3′-甲醚的分离和鉴定

Two flavonoids were isolated from the leaves of Glycyrrhiza uralensis Fisch (Licorice, Leguminosae). On the basis of physico-chemical properties and spectroscopy (UV, ¹HNMR and MS), a new compound was elucidated as 3,5,7,4′-tetrahydroxy-3′-methoxy- 6-isoprenyl flavone (gancaonin P-3′-methylether) and another known compound was identified as 8-C-prenyleriodictyol.     

对-氯苯丙炔酰胺类化合物的合成及其与肼反应产物的研究

Synthesis of p-chlorophenylpropiolylamides and itsreaction produets with hydrazine hydrate were studied. It was found that the reaction products varied with the different Substituent groups in the amidel When the substituent group was isopropyl or sec-butyl group, p-chloro-β-hydrazino-cinnamamides (Ⅱ) were obtained. Under similar reaction conditions, when the substituent, group was n-propyl, n-butyl or diethyl group, cyclization reaction occurred and the reaction product was 3-(p-chlorophenyl)-pyrazol-5-one (Ⅲ). All the compounds were tested in mice for anticonvulsant activity. Prelimary data showed that p-chlorophenyl-propiolyl-sec-butylamide (I₄) and p-chlorophenyl-propiolyl-n-propylamide (I₁) exhibited moderate anticonvulsant activity. The ED₅₀ was 54.5(34.4～86.4), and 56.1(31.6～99.6) mg/kg respectively. The compounds of p-chloro-β-hydrazino-cinnamamide (Ⅱ)and 3-(p-chlorophenyl)-pyrazol-5-one (Ⅲ) showed no significant effect on antieonvulsant activity. p-Chloro-cinnamoyl-hydrazide (Ⅳ) provided good anticonvulsant activity.     

手性毛细管气相色谱法测定人尿中美芬妥英光学异构体含量的方法学研究

A gas chromatographic method equipped with nitrogen-phosphorus detector was developed for the determination of the S-and R-enantiomers of the anticonvulsant, mephenytoin (MP) in human urine. Dichioromethane (4 ml) was added to 1 ml urine, the mixture was shaken and centrifuged. The organic phase was transferred to another tube and blown to dryness under nitrogen on water bath (37℃). The residue was dissolved in 10 μl ethylacetate and 1～2 μl was injected into the GC. Our results showed that direct enantiomeric separation of mephenytoin was obtained by using a chiral capillary column, the retention times for S-and R-mephenytoin were 25. 5 and 26. 2 min respectively, with a detection limit less than 50 ng/ml of mephenytoin. Similar linear and reproducible standard curves were obtained over the concentration range of 53.2 to 2128. 0 ng/ml (for S-MP, r=0. 9914±0. 0070, n=6; and for R-MP, r=0. 9939±0. 0070, n=6), and the mean recoveries of S-and R-MP were 95. 4% and 95. 8% respectively. The within--day relative standard deviations were less than 8. 8% for both S-and R-MP, and that of between--days were less than 14.3%. There was a good reproducibility of the urine S/R mephenytoin determined in China and in Sweden by using similar method in 107 Chinese volunteers after a single oral dose of 100 mg racemic mephenytoin (r=0. 9091, P<0. 001).     

Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder

Rationale: Search for alternatives to lithium therapy for mood disorders commenced with anticonvulsants, carbamazepine (CBZ) and valproic acid (VPA), in the late 1970s. The comparative safety and efficacy data of CBZ and VPA monotherapy in patients with bipolar disorder remain to be established. Objectives: The main objectives of the study were to assess the relative anti-manic efficacy and safety of CBZ and VPA; to study the feasibility of using either, as a first line anti-manic agent; to investigate and generate clinically relevant parameters involving therapeutic drug monitoring of the two drugs. Methods: After a 2-day screening period, suitable patients (n=30) were randomly assigned to treatment with CBZ or VPA. Both the drugs were started with an average dose of approximately 20 mg/kg body weight per day. Further increment in dose was carried out at weekly intervals, guided by clinical improvement, serum levels and treatment emergent adverse events. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. A favourable clinical response was defined a priori as a decrease of more than 50% from baseline in Young Mania Rating Scale total score. Results: Both CBZ and VPA were found to be efficacious as single first-line anti-manic agents, however VPA proved to be better. Using the intent-to-treat analysis, the VPA group showed a significant fall in YMRS total scores after week 1 while the CBZ group showed a significant fall after week 2. In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the CBZ group. Of the VPA treated patients, 73% showed a favourable clinical response while 53% of the patients on CBZ responded favourably. In the CBZ group, significantly more patients received rescue medication during the week 2 and the requirement was quantitatively more as compared to the VPA group. The steady state serum concentration (Css) of CBZ ranged from 3 to 9 μg/ml; however, it did not appear to correlate with the dose or clinical response. The Css of VPA ranged from 50 to 100 μg/ml; a linear correlation was found between the dose and serum levels of VPA as well as between weekly rise in serum levels and clinical response. Weekly dose escalations of VPA also correlated positively with corresponding rise in serum levels. Significantly more patients in the CBZ group reported adverse events, including nausea, vomiting and dizziness, than VPA. Conclusions: The findings from this study suggest that both CBZ and VPA monotherapy is feasible for treatment of acute mania; however, VPA is more efficacious in terms of its early onset of action, lesser requirement for rescue medication and better tolerability. Further work needs to be undertaken to characterise the manic patients in terms of their differential psychopharmacologic response profile. Received: 9 July 1999 / Accepted: 11 January 2000     

北马兜铃的化学成分研究——Ⅱ、马兜铃酸E的化学结构

From the root of Aristolochia contorta Bunge six chemical constituents were isolated; one of them is a new phenanthrene compound containing nitro group for which the name aristolochic acid E is suggested. By means of spectral methods combined with chemical analysis the chemical structure of aristolochic acid E was determined to be 7-methoxy-8-hydroxy-aristolochic acid. The other components were identified as allantoin, aristolochic acid A, magnoflorine, β-sitosterol and daucosterol respectively.     

Synthesis and Structure-Opioid Activity Relationships of trans-(±)-3,4-Dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides

To explore the effects of attaching a hydroxy function to the cyclohexane ring of κ-selective opioid N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamides, trans-(±)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides (1–4) and their benzoates (5–8) have been synthesized in a divergent and stereoselective manner. When compared with the parent compound U-50488, hydroxy derivatives 1–4 maintained high selectivity towards the κ-opioid receptor (μ/κ ratio = 24 to >91); while displaying significant reduction in binding affinity (K_i,κ = 75–218 nm ). The lowest κ-affinity was observed with compound 4, where the hydroxy group is attached at the 5-axial or 5-β position. Further reduction in κ-affinity was observed when the hydroxy function was benzoylated. However, the 4β, 5α, and 5β isomers (6–8) maintained varying degrees of κ-selectivity; the 4α-isomer compound 5, with its benzoate moiety situated at the 4-axial position is now a moderately potent μ-selective opioid (K_i/μ= 168 nm , μ/κ = 0.076). The results suggest the importance of lipophilicity in binding to opioid receptors and the presence of a specific lipophilic binding site on the μ-opioid receptor.     

Zur Darstellung des 2-(1′-Hydroxybenzyl)-3-phenyl-1.3-oxazolidins

On the Synthesis of 2-(1-Hydroxybenzyl)-3-phenyl-1,3-oxazolidine The synthesis of the 1,3-oxazolidine 8 did not succeed from the hydroxyaldehyde 1 . After protecting the hydroxy group of 1 by acetylation compound 8 was obtained in the usual manner. Attempts to prepare the O-acetylated aldehyde 5 from 1 mainly yielded mixtures of diastereomeric acetates of the dimer of aldehyde 1 . A simple method for the preparation of 5 from the O-acetylated cyanohydrine 4 is described.     

Heterocyclische 12-π- und 14-π-Molekülsysteme, 44. Mitt. Zum Reaktionsverhalten tetracyclischer Pseudohydroxyphenalenone

Heterocyclic Systems with 12 or 14 π Electrons, XLIV: Chemical Reactivity of Tetracyclic Hydroxypseudo-phenalenones 1,2-Dihydro-7-hydroxy-5H-cyclopenta[cd] phenalen-5-one (1) reacts with nitric acid in acetic acid to yield the hydroxy(nitro)pseudophenalenone 3 . With chlorine in acetic acid the dichloro derivative 4 , with bromine compound 5 , and with phenyldiazoniumsulfate the azodye 6 are formed. Compound 1 also reacts with 1,2-dibromoethane in the presence of potassium carbonate to yield the spiro compound 7 . The condensation of 1 with benzaldehyde in the presence of pyridine yields 8 . In an analogous way 5H-7-hydroxycyclopenta[cd]phenalene-5-one (2) was chlorinated to yield the dichloro derivative 9 . Compound 2 reacts with bromine at position 6 to yield compound 10 .     

Anticonvulsant and Neurotoxicity Evaluation of Some Novel Kojic Acids and Allomaltol Derivatives

A series of new 3‐hydroxy‐6‐hydroxymethyl/methyl‐2‐substituted 4H‐pyran‐4‐ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, ¹H‐NMR, and ESI‐MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)‐induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3‐hydroxy‐2‐[(4‐hydroxy‐4‐phenylpiperidin‐1‐yl)methyl]‐6‐methyl‐4H‐pyran‐4‐one (compound 1 ), 2‐{[4‐(4‐chlorophenyl)‐3,6‐dihydropyridin‐1(2H)‐yl]methyl}‐3‐hydroxy‐6‐methyl‐4H‐pyran‐4‐one (compound 6 ), 2‐[(4‐acetyl‐4‐phenylpiperidin‐1‐yl)methyl]‐3‐hydroxy‐6‐(hydroxymethyl)‐4H‐pyran‐4‐one (compound 11 ), and 2‐{[4‐(4‐chlorophenyl)‐3,6‐dihydropyridin‐1(2H)‐yl] methyl}‐3‐hydroxy‐6‐hydroxymethyl‐4H‐pyran‐4‐one (compound 12 ) were found to have anticonvulsant activity against MES‐induced seizures at 4 h. Also, 2‐{[4‐(4‐bromophenyl)‐4‐hydroxypiperidin‐1‐yl]methyl}‐3‐hydroxy‐6‐(hydroxymethyl)‐4H‐pyran‐4‐one (compound 8 ) was determined to be the most active compound against scMet‐induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.     

Antioxidant Potential of New Pyrazoline Derivatives to Prevent Oxidative Damage

Abstract: The antioxidant capacity of a series of six novel synthetic pyrazoline derivatives (i) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐carbaldehyde‐pyrazole, (ii) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐acetyl‐pyrazole, (iii) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐carboxyamide‐pyrazole, (iv) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐benzoyl‐pyrazole, (v) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐(2‐hydroxybenzoyl)‐pyrazole and (vi) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐(4‐methoxybenzoyl)‐pyrazole was evaluated as the capacity of compounds to transfer a hydrogen atom (protection against brain lipid peroxidation and glutathione oxidation) and their capacity to transfer a single electron [ferric‐reducing antioxidant power (FRAP) and 1,1‐diphenyl‐2‐picrylhydrazyl radical scavenging (DPPH) assays]. Compound 5 had the highest free radical scavenging capacity in the DPPH assay, while compound 2 had the highest FRAP value (P < 0.05). Only compounds 1, 4 and 5 protected against lipid peroxidation in rat brain homogenate. However, compound 5 was the most effective to prevent basal and iron‐, sodium nitroprusside‐ and H₂O₂‐stimulated lipid peroxidation (IC₅₀ < 15 µM) and the only one effective to block glutathione oxidation‐mediated by H₂O₂ (at 150 µM). Our results indicate that compound 5 has the greatest potential to prevent oxidative damage in brain homogenates.     

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。     

Synthesis and analgesic, anti-inflammatory activities of 3-(3-methoxyphenyl)-2-substituted amino-quinazolin-4(3H)-ones

A variety of novel 3-(3-methoxyphenyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(3-methoxyphenyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(3-methoxyphenyl)-quinazolin-4(3H)-one was synthesized from 3-methoxy aniline. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic behavior. Among these the compound 2-(1-methyl butylidene-hydrazino)-3-(3-methoxyphenyl)-3H-quinazolin-4-one (AS3) emerged as the most active compound for the analgesic activity, while the compound 2-(1-ethyl propylidene-hydrazino)-3-(3-methyoxyphenyl)-3H-quinazolin-4-one (AS2) showed most potent anti-inflammatory activity of the series and these compounds are moderately more potent when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid.     

Impaired ergosterol biosynthesis mediated fungicidal activity of oil based tin polymer

Candida represents an important group of opportunistic fungal pathogens which causes infections in immunocompromised patients. The increasing emergence of fungal resistance to currently available antimycotic agents, especially azoles is a major problem. A vegetable-based organotin polymer synthesised by the condensation of fatty amide diol (N, N ¹-bis 2 hydroxy ethyl castor oil fatty amide) and butyl tin chloride dihydroxide has been reported to posses antimicrobial activity. This study is an attempt to investigate the antifungal activity of this compound against several fluconazole-susceptible and resistant clinical Candida isolates and to understand its mode of action. The susceptibility tests for the polymer were carried out in terms of minimum inhibitory concentrations (MICs) and disc diffusion assays against fifty-nine Candida isolates by employing standard protocols. The ergosterol-mediated antifungal activity was analysed by the sterol quantitation method. The organotin polymer was found to be effective, to varying extent, against all the Candida isolates including the resistant ones. It showed a low MIC value, which was fungicidal in contrast to the fungistatic fluconazole and caused considerable impairment of ergosterol biosynthesis in all the strains tested. This compound may be targeting the ergosterol biosynthesis pathway and may be used as an alternative to fluconazole which develops resistance during therapy. The selectively fungicidal characteristics of the organotin polymer indicate that this compound might be a promising antifungal agent.     

Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor

Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.     

Synthesis and elastase inhibition activities of novel aryl,substituted aryl,and heteroaryl oxime ester derivatives

Fifteen novel aryl, substituted aryl and heteroaryl γ‐hydroxy‐ ( 2a–e ), γ‐methoxyimin o‐ (3a–e ), and γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters were investigated for their enzyme inhibition, and the synthesis of 10 compounds ( 3a–e , 4a–e ) is given in this study. The other five compounds ( 2a–e ) were synthesized before in another study. Compounds 3a–e and 4a–e were synthesized in this work as original compounds and characterized by ¹H and ¹³C NMR, IR, mass, and elemental analyses. Their (E/Z)‐isomerisation ratios were analyzed by ¹H and ¹³C NMR. All of them are of pure (E)‐configuration. Due to the literature survey, the elastase inhibition activity was not studied for these compounds. Elastase inhibition ability was investigated in this work for five γ‐hydroxy‐ ( 2a–e ), five γ‐methoxy‐ ( 3a–e ), and five γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters. All these 15 compounds showed elastase inhibition activity. Compound 2b was the best one and exhibited a better activity than the standard ursolic acid whereas compound 2a worked like the standard. All these compounds can be novel elastase inhibitor agents in the pharmaceutical and cosmetic industries.