Synthese des 6,7-Dimethoxy-3-(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisochinolins

Synthesis of 6,7-Dimethoxy-3-(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline The synthesis and chemical reactivity of 6,7-dimethoxy-3(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (I) are described.     

1-(alkylamino)isochromans: hypotensives with peripheral and central activities

A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.     

Synthesis and anti-HIV activity of novel 3-substituted phenyl-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues

A series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized by the reaction of 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1-indanone with hydroxylamine hydrochloride. The title compounds were tested for their in vitro anti-HIV activity. Among the compounds, (4g) showed a promising anti-HIV activity in the in vitro testing against IIIB and ROD strains. The IC50 of both IIIB and ROD were found to be 9.05 microM and > 125 microM, respectively.     

A comparison of the antiserotonin, antihistamine, and anticholinergic activity of cyproheptadine with analogues having furan nuclei fused to the 10,11-vinylene bridge.

A series of cyproheptadine derivatives having furan nuclei fused to the 10,11-vinylene bridge has been prepared. None of the compounds retain the potent antiserotonin and antihistaminic actions of cyproheptadine. 1-methyl-4-(1-methyl-8H-dibenzo[a,e]furo[3,4-c]cyclohepten-8-ylidene)piperidine (7), 1-methyl-4-(1,3-dihydro-1-oxo-8H-[3,4:6,7]cycloheptal[1,2-c]furan-8-ylidene)piperidine (10), and its reduction product 11 retained the peripheral anticholinergic activity of cyproheptadine.     

Aufbau des Berbin-Ringsystems mit Hilfe von Lactonen 2. Mitteilung

Preparation of the Berbine Skeleton via Lactones. Part 2. Homoveratrylamine and isochromanone-(3) yield in a four stage-synthesis 2,3-dimethoxyberbine (IV). As intermediates are isolated: N-Homoveratryl-o-hydroxymethyl-phenyl-acetamide (I), 1-(2-chloromethylbenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (II) and 2,3-dimethoxyprotoberberinium chloride (III).     

Hydroxylamin-Derivate der Quadratsäure

Hydroxylamine Derivatives of Squaric Acid Reaction of 3,4-dimethoxy-3-cyclobutene-1,2-dione (1) with equimolar amounts of substituted hydroxylamines yields 3-hydroxyamino-4-methoxy-3-cyclobutene-1,2-diones 2 . On treating 3,4-dichloro-3-cyclobutene-1,2-dione with hydroxylamines deoxygenations take place.     

Furo-1,2-naphthoquinones from Crataegus pinnatifida with ICAM-1 expression inhibition activity

Two new furo-1,2-naphthoquinones, crataequinones A (1) and B (2), were isolated from the fruits of Crataegus pinnatifida. The structures of two new compounds were determined as 11,12-dimethoxy-3,4-furo-1,2-naphthoquinone (1) and 11,12-dimethoxy-5-hydroxy-3,4-furo-1,2-naphthoquinone (2) by spectroscopic analysis. The two compounds 1 and 2 showed significant inhibitory activity with IC50 values of 33 and 90 microM, respectively, against the expression of intercellular adhesion molecule-1 (ICAM-1).     

Modification of the Benzene Moiety in the Quinolone Nucleus of 4-Hydroxy-6,7-Dimethoxy-2-Oxo-N-(Pyridin-3-Ylmethyl)-1,2-Dihydroquinoline-3-Carboxamide as an Attempt to Enhance its Analgesic Activity

Pharmaceutical Chemistry Journal - A series of close analogs of 4-hydroxy-6,7-dimethoxy-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydroquinoline-3-carboxamide modified in the benzene moiety of the...     

邻卤代苄基异喹啉碘盐抗心律失常作用的研究

目的：比较1-(邻-碘苄基)-6，7-甲二氧基-2-甲基-3，4-二氢异喹啉碘盐(O-BIMMDI)与1-(邻-溴苄基)-6，7-甲二氧基-2-甲基-3，4-二氢异喹啉碘盐(O-BBMMDI)，对实验性心律失常模型的影响。方法：采用乌头碱、氯化钡和结扎左冠状动脉前降支方法制备大鼠心律失常模型，观察并比较O-BIMMDI与O-BBMMDI的保护作用。结果：O-BIMMDI和O-BBMMDI可对抗乌头碱、氯化钡所致的大鼠心律失常，延长心律失常诱发时间，缩短心律失常持续时间；对结扎左冠状动脉前降支所诱发的大鼠心律失常也有一定的对抗作用，并可减轻结扎造成的心肌缺血。O-BBMMDI抗心律失常作用优于O-BBMMDI。结论：O-BBMMDI和O-BBMMDI均可对抗大鼠心律失常模型，而O-BBMMDI抗心律失常作用优于O-BBMMDI．     

Isoquinolone and protoberberine alkaloids from Stephania rotunda

Chemical investigation of Stephania rotunda Lour. growing in Viet Nam led to the isolation and structural elucidation of three new alkaloids, 5-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (1), thaicanine 4-O-beta-D-glucoside (6), as well as (-)-thaicanine N-oxide (4-hydroxycorynoxidine) (8), along with 23 known alkaloids. These structures were determined on the basis of MS and NMR spectroscopic data.     

1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸乙酯的合成

1-环丙基-6,7-二氟-1,4-二氢-8-甲氧基-4-氧代喹啉-3-羧酸乙酯(2)经40%氢溴酸水解得到1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸(4),再在三甲基氯硅烷存在下经乙醇酯化得1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸乙酯(1),总收率为52.1%。也可用2在无水三氯化铝作用下水解直接得到1,收率66.9%。     

Inhibition of microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions by beta-lapachone and related naphthoquinones

The lipophilic o-naphthoquinones beta-lapachone, 3,4-dihydro-2-methyl-2-ethyl-2H-naphtho[1,2b]pyran-5,6-dione (CG 8-935), 3,4-dihydro-2-methyl-2-phenyl-2H-naphtho[1,2b]pyran-5,6-dione (CG 9-442), and 3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione (CG 10-248) (a) inhibited NADPH-dependent, iron-catalyzed microsomal lipid peroxidation; (b) prevented NADPH-dependent cytochrome P-450 destruction; (c) inhibited microsomal aniline 4-hydroxylase, aminopyrine N-demethylase and 7-ethoxycoumarin deethylase; (d) did not inhibit the ascorbate- and tert-butyl hydroperoxide-dependent lipid peroxidation and the cumenyl hydroperoxide-linked aniline 4-hydroxylase reaction; and (e) stimulated NADPH oxidation, superoxide anion radical generation and Fe(III)ADP reduction by NADPH-supplemented microsomes. In the presence of ascorbate, the same o-naphthoquinones stimulated oxygen uptake and semiquinone formation, as detected by ESR measurements. The p-naphthoquinones alpha-lapachone and menadione were relatively less effective than the o-naphthoquinones. These observations support the hypothesis that, in the micromolar concentration range, o-naphthoquinones inhibit microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions, by diverting reducing equivalents from NADPH to dioxygen.     

Removal of the Pyrrolidine Group by Dehydrogenation of a 4-Pyrrolidin-2-yl-tetrahydroisoquinoline

Dehydrogenation of 6,7-dimethoxy-1-methyl-4-(N-methyl-pyrrolidin-2-yl)-3,4-dihydroisoquinoline ( 9 ) by Pd/C in tetraline leads to dehydrogenated products, rearrangement, and elimination of the pyrrolidine group mainly as N-methylpyrrolidine (Scheme 3).     

Actions of two new bradycardic agents, AQ-AH 208 and UL-FS 49, on ischemic myocardial perfusion and function

The effects of continuous infusions (30 min) of two new bradycardic agents, AQ-AH 208 (3,4-dihydro-6,7-dimethoxy-2-(3-((2-(3,4 dimethoxyphenyl) ethyl)-amino methyl) propyl)-1(2H)-isochinolinon) (10 and 25 micrograms/kg/min) and UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3(3((2-(3,4-dimethoxyphenyl) ethyl) methylimino) propyl)-2H-3-benzazepin-2 on) (1.0 and 2.5 micrograms/kg/min) on ischemic myocardial perfusion and function were studied in anesthetized open chest dogs. Coronary stenosis was induced by narrowing an extracorporeal shunt between the carotid and left anterior descending coronary artery. Regional perfusion was measured by use of radioactive microspheres and regional myocardial function (% segment shortening) was assessed by sonomicrometry. AQ-AH 208 and UL-FS 49 produced dose-dependent reductions in heart rate of 13 to 55 beats/min without prominent effects on left ventricular dP/dt, aortic blood pressure, and % segment shortening of the normally perfused area. In nonischemic myocardium, AQ-AH 208 did not change transmural blood flow in spite of the bradycardia, whereas UL-FS 49 decreased flow. At the high infusion rate, ischemic subendocardial perfusion increased from 0.43 to 0.58 ml/min/g following UL-FS 49 and from 0.57 to 0.84 ml/min/g after treatment with AQ-AH 208. Consequently, endo/epi rose from 0.52 to 0.80 and 0.62 to 0.96, respectively. Atrial pacing abolished the effects of UL-FS 49 on ischemic myocardium whereas the effects of AQ-AH 208 were only partially reduced. Ischemic myocardial function deteriorated less during treatment with UL-FS 49 and was significantly improved following AQ-AH 208 as compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification and characterization of potential impurities of donepezil

Five unknown impurities ranging from 0.05 to 0.2% in donepezil were detected by a simple isocratic reversed-phase high performance liquid chromatography (HPLC). These impurities were isolated from crude sample of donepezil using isocratic reversed-phase preparative high performance liquid chromatography. Based on the spectral data (IR, NMR and MS), the structures of these impurities were characterised as 5,6-dimethoxy-2-(4-pyridylmethyl)-1-indanone (impurity I), 4-(5,6-dimethoxy-2,3-dihydro-1H-2-indenylmethyl) piperidine (impurity II), 2-(1-benzyl-4-piperdylmethyl)-5,6-dimethoxy-1-indanol (impurity III) 1-benzyl-4(5,6-dimethoxy-2,3-dihydro-1H-2-indenylmethyl) piperidine (impurity IV) and 1,1-dibenzyl-4(5,6-dimethoxy-1-oxo-2,3-dihydro-2H-2-indenylmethyl)hexahydropyridinium bromide (impurity V). The synthesis of these impurities and their formation was discussed.     

1,2-Benzothiazine 1,1-dioxide P(2)-P(3) peptide mimetic aldehyde calpain I inhibitors

A series of peptide mimetic aldehyde inhibitors of calpain I was prepared in which the P(2) and P(3) amino acids were replaced by substituted 3,4-dihydro-1,2-benzothiazine-3-carboxylate 1,1-dioxides. The effect of 2, 6, and 7-benzothiazine substituents and the P(1) amino acid was examined. Potency of these inhibitors, 15c-p, against human recombinant calpain I is particularly dependent upon the 2-substituent, with methyl and ethyl generally more potent than hydrogen, isopropyl, isobutyl, or benzyl. The more potent diastereomer of 15m possesses the (S) absolute configuration at the 3-position of the 3,4-dihydro-1,2-benzothiazine. Potency of the best inhibitors in this series (IC(50) = 5-7 nM) compares favorably with that of conventional N-benzyloxycarbonyl dipeptide aldehyde inhibitors bearing L-Leu or L-Val residues at P(2). The achiral unsaturated 1,2-benzothiazine analogues 26a-d are also potent calpain I inhibitors, while 3,4-dihydro-2,1-benzoxathiin (15a,b), 1,2,4-benzothiadiazine (32a,b), and tetrahydroisoquinolinone (36a,b) analogues are less potent.     

Fluorine-18-labeled benzamide analogues for imaging the sigma2 receptor status of solid tumors with positron emission tomography

A series of fluorine-containing benzamide analogs was synthesized and evaluated as candidate ligands for positron emission tomography (PET) imaging of the sigma-2 (sigma2) receptor status of solid tumors. Four compounds having a moderate to high affinity for sigma2 receptors and a moderate to low affinity for sigma-1 (sigma1) receptors were radiolabeled with fluorine-18 via displacement of the corresponding mesylate precursor with [18F]fluoride. Biodistribution studies in female Balb/c mice bearing EMT-6 tumor allografts demonstrated that all four F-18-labeled compounds had a high tumor uptake (2.5-3.7% ID/g) and acceptable tumor/normal tissue ratios at 1 and 2 h post-i.v. injection. An analysis of the chemistry and biodistribution data suggested that N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[18F]-fluoroethoxy)-5-methylbenzamide ([18F]3c) and N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[18F]-fluoroethoxy)-5-iodo-3-methoxybenzamide ([18F]3f) are acceptable compounds for imaging the sigma2 receptor status of solid tumors.     

AQ-AH 208, a new bradycardic agent, increases coronary collateral blood flow to ischemic myocardium

The effect of AQ-AH 208 [3,4-dihydro-6,7-dimethoxy-2-(3 - ((2-(3,4-dimethoxphenyl)ethyl)-amino- methyl)propyl)-1(2H)-isoquinolinone], a new selective bradycardic agent, on coronary collateral perfusion was investigated in anesthetized open-chest dogs following acute occlusion of the left anterior descending coronary artery. AQ-AH 208 (0.3 mg/kg i.v.), propranolol (0.3 mg/kg i.v.), and N-dimethylpropranolol (DMP; 2.5 mg/kg i.v.) were equieffective in reducing heart rate approximately 15%. AQ-AH 208 increased collateral flow to the subepicardium, midmyocardium, and subendocardium by 24, 46, and 35% (p less than 0.05), respectively, while propranolol and DMP had no effect. Atrial pacing to predrug levels in the presence of AQ-AH 208 reduced the increases in collateral flow to the different myocardial layers to 16, 25, and 30%, respectively; however, these increases were still significantly greater than control. It is concluded that part of the AQ-AH 208-induced increase in collateral perfusion is due to an increase in diastolic duration. The nature of the frequency-independent component of the effect is unknown but may be explained by a selective decrease in extravascular coronary resistance in the ischemic zone or an increase in the conductance of large epicardial coronary or collateral vessels.     

黄连化学成分的分离与鉴定

目的研究黄连(Coptis chinensis Franch.)根茎的化学成分。方法利用硅胶柱色谱、凝胶柱色谱、中低压液相色谱、高效液相色谱等色谱技术对黄连的化学成分进行分离和纯化,通过NMR等波谱数据分析确定化合物的结构。结果从黄连正丁醇层提取物中分离得到11个已知成分,分别鉴定为降氧化北美黄连次碱(noroxyhydrastineine,1)、3,4-二氢-6,7-二甲氧基异喹诺酮(6,7-dime-thoxy-3,4-dihydro-2H-isoquinolin-1-one,2)、8-氧化黄连碱(8-oxocoptisine,3)、小檗碱(berberine,4)、氧化小檗碱(oxyberberine,5)、原儿茶酸甲酯(protocatechuic acid methyl ester,6)、丹参素甲正丁酯(n-butyl3,4-dihydroxyphenyllactate,7)、反式-3,4-二甲氧基肉桂酸(E-3,4-dimethoxycinnamicacid,8)、阿魏酸正丁酯(n-butyl ferulate,9)、5-O-feruloylquinic acid butyl ester(10)、4-O-feru-loylquinic acid butyl ester(11)。结论化合物7~11为首次从黄连属植物中分离得到。     

Zur Reaktion von Quadratsäuredimethylester mit N,N-disubstituierten Hydrazin-Derivaten

The Reaction of Squaric Acid Dimethyl Ester with N,N-Disubstituted Hydrazines Reaction of 3,4-dimethoxy-3-cyclobutene-1,2-dione (2) with N,N-disubstituted hydrazines yields 3,4-bishydrazino-3-cyclobutene-1,2-diones 3 , which are converted into 3-amino-4-hydrazino-3-cyclobutene-1,2-diones 6 with N-N splitting by refluxing in ethanol.