12-acyl-6,1 2-dihydro-6-phenyl-[1 ]benzofuro[2,3-c]- and -[1,5]benzothieno[2,3-c]-[1 ,5]-benzothiazepines--tetracyclic diltiazem derivatives

The reaction of the tetracycles 1 with chloroacetylchloride yields the amides 2. The structure of 2a was proven by X-ray analysis. The amides 2 exist as diastereomers in solution because of planar chirality. From the N-chloroacetyl compounds only 2a, b could be substituted with diethylamine to give 3a, b. Reduction experiments of 3a, b with DIBAH do not afford diltiazem analogues; instead, the starting compounds la, b are formed by hydrolysis.     

5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂的合成

目的探索合成5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂(Ⅰ)的高效、简洁的新方法。方法将线性合成方法和基于钯催化的芳香C-H键活化环合方法分别应用于化合物Ⅰ的合成,并比较两者的优劣。结果与结论两种方法都成功地实现了化合物Ⅰ的合成,其中,基于钯催化的芳香C-H键活化环合法简洁高效(二步、总收率71%)、绿色环保,为此类杂环化合物的一般合成方法。     

Zur Synthese von [1,2,5]-Triazepino-[3,4,5-jk]- und Pyrazino[3,2,1-jk]carbazol-Derivaten

Synthesis of [1,2,5]-Triazepino[3,4,5-jk]- and Pyrazino[3,2,1-jk]carbazole Derivatives Reaction of the enaminone 2 and p-benzoquinone (1) yields the carbazole 3 , which is used as precursor for the title compounds after methylation to 5b or acetylation to 5a . The nitrones 7a, b are formed from 5a, b and hydroxylamine. The structures of 7a, b are proved by reduction to 9 and 10 and rearrangement to 12 and 13 . The carbazole 5b reacts with hydrazine to yield the [1,2,5]-triazepinocarbazole 8a . The structure of 8a was determined by acetylation to 8b and spectroscopy.     

Synthesis and biological evaluation of substituted benzo[h]cinnolinones and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones: higher homologues of the antihypertensive and antithrombotic 5H-indeno[1,2-c]pyridazinones

Several substituted benzo[h]cinnolinones 3 and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones 4, which were designed as less rigid congeners of 5H-indeno[1,2-c]pyridazinones 2, were synthesized and tested as antihypertensive, inotropic, antithrombotic, antiinflammatory, and antiulcer agents. While the seven-membered ring derivatives displayed only antithrombotic properties, which were comparable to that of acetylsalicylic acid, most of the benzo[h]cinnolinones exhibited significant antihypertensive, inotropic, and antithrombotic properties. In this respect, the 8-amino (3b) and 8-acetylamino (3c) together with the 4,4a-dehydro analogue of 3c (11) were found to possess the most potent and long-lasting antihypertensive activity. In particular, the dextro isomer of 3c was more active than the racemic form, with lower tachycardiac effects. Unlike the lower homologues 2, none of the compounds showed significant antiinflammatory or antiulcer activity.     

[1]Benzothieno[3,2-b]thiochromone und Thiochromono[3,2-b]indole

[1]Benzothieno[3,2-b]thiochromones and Thiochromono[3,2-b]indoles The 2-(3-benzo[b]thienyl)- and 2-(3-indolyl)-benzothioic acids 2 cyclize with polyphosphoric acid (PPA) to yield the title compounds 3 , which are characterized by their sulfones and thiones.     

Synthesis and characterization of all four isomers of the muscarinic agonist 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane]

The four separated isomers of the muscarinic agonist 1, previously known as AF30, have been synthesized by a route that has allowed the absolute stereochemistry of each isomer to be assigned. With the chirality of (-)-camphanic acid known, X-ray analysis of the more crystalline intermediate diastereomeric camphanate 5A allowed the absolute stereochemistry at the quinuclidine chiral center to be determined. Each diastereomer was separately transformed into the spirodioxolane with concomitant introduction of the second chiral center. Chromatographic separation followed by a second crystal structure determination revealed the absolute stereochemistry of all four isomers of 1. Detailed biological evaluation of each isomer indicated that while the 3(R),2'(S) isomer was the most active in binding studies, it was the 3(R),2'(R) isomer that displayed the largest functional selectivity between ganglion (M-1 site) and heart (M-2 site). With the same internal chiral standard, the absolute configuration of the more active enantiomer of 3 was shown to be S, confirming earlier literature reports.     

Synthesis and oral antiallergic activity of carboxylic acids derived from imidazo[2,1-c][1,4]benzoxazines, imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles

4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.     

兰索拉唑临床联合用药研究进展

目的：总结兰索拉唑联合药物治疗消化系统疾病以及与其他药物间相互作用的现状并对相关问题进行思考,为提高兰索拉唑联合用药的安全性和有效性提供文献支撑。方法：本文对兰索拉唑联合西药治疗消化系统疾病及其相互作用机制研究进行文献检索、分析与归纳。结果：兰索拉唑主要通过抑酸作用治疗多种消化系统疾病,并可通过细胞色素P450、P-糖蛋白等多种机制影响联合用药药物的生物利用度。 结论：今后需着重研究LPZ联合用药的作用机制、药效学评价和个体化用药差异,以确保联合用药的安全性和科学性。     

Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography

The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.     

Synthesis and CNS- activity of cis-pyrano[2,3-b]-[1,4]dioxane derivatives

The alcohols 2, the amines 5, 7 and 10, the indole- and quinoline-derivatives 13 and 14, the enamines 3 and 4 and the silylenolethers 17 and 18 were prepared starting with the title compound 1. The 1-(7-phenyl-7-pyranodioxinyl)-piperidines 10-cis and 10-trans show striking CNS-activity. The transisomer is about twice as active as the cis-isomer.     

亚甲基[6,6]-富勒烯[C60]单羧酸的合成

目的：探索用溴乙酸乙酯合成亚甲基[6，6]-富勒烯[C60]单羧酸。方法：用溴乙酸乙酯制备硫叶立德，再与富勒烯[C60]制得相应的富勒烯[C60]羧酸乙酯，水解其乙酯。结果与结论：通过核磁、红外等分析方法确证所合成的中间体和目标化合物，并且这条路线经济、切实可行，适合大规模制备。     

Percutaneous Absorption of [14C]DDT and [14C]Benzo[a]pyrene from Soil

Percutaneous Absorption of [¹⁴C]DDT and [¹⁴C]Benzo[a]pyrenefrom Soil. WESTER, R. C, MAIBACH, H. I., BUCKS, D. A. W., SEDIK,L., MELENDRES, J., LIAO, C, AND DIZIO, S. (1990). Fundam. Appl.Toxicol. 15, 510–516. The objective was to determine percutaneousabsorption of DDT and benzo[a]pyrene in vitro and in vivo fromsoil into and through skin. Soil (Yolo County 65-California-57-8;26% sand, 26% clay, 48% silt) was passed through 10-, 20-, and48-mesh sieves. Soil then retained by 80-mesh was mixed with[¹⁴C]-labeled chemical at 10 ppm. Acetone solutions at 10 ppmwere prepared for comparative analysis. Human cadaver skin wasdermatomed to 500 µm and used in glass diffusion cellswith human plasma as the receptor fluid (3 ml/hr flow rate)for a 24-hr skin application time. With acetone vehicle, DDT(18.1 ± 13.4%) readily penetrated into human skin. Significantlyless DDT (1.0 ± 0.7%) penetrated into human skin fromsoil. DDT would not partition from human skin into human plasmain the receptor phase (<0.1%). With acetone vehicle, benzo[a]pyrene(23.7 ± 9.7%) readily penetrated into human skin. Significantlyless benzo[a]pyrene (1.4 ± 0.9%) penetrated into humanskin from soil. Benzo[a]pyrene would not partition from humanskin into human plasma in the receptor phase (<0.1 %). Substantivity(skin retention) was investigated by applying ¹⁴C-labeled chemicalto human skin in vitro for only 25 min. After soap and waterwash, 16.7 ± 13.2% of DDT applied in acetone remainedabsorbed to skin. With soil only 0.25 ±0.11% of DDT remainedabsorbed to skin. After soap and water wash 5.1 ±2.1%of benzo[a]pyrene applied in acetone remained absorbed to skin.With soil only 0.14 ±0.13% of benzo[a]pyrene remainedabsorbed to skin. In vivo percutaneous absorption of DDT inrhesus monkey was significantly less (p < 0.02) from soil(3.3 ± 0.5%) than from acetone solution (18.9 ±9.4%). DDT in vitro skin penetration values into human skinwere similar to in vivo absorption values in the rhesus monkey.In vivo absorption in the rhesus was not statistically differentfrom published in vivo absorption in man (10.4 ± 3.6%).In vivo percutaneous absorption of benzo[a]pyrene in rhesusmonkey was significantly less (p < 0.015) from soil (13.2± 3.4%) than from acetone solution (51.0 ± 13.2%).Thus, with in vitro and animal in vivo systems relevant to man,skin absorption of DDT and benzo[a]pyrene from soil was significantlyless than when the chemicals were applied to skin in acetoneSolvent.     

[18F]Fluoride recovery via gaseous [18F]HF

Acidification of target water with H₂SO₄ in a specially constructed glassy carbon/polyethylene apparatus allowed for recovery of up to 82% of [¹⁸F]fluoride as [¹⁸F]HF gas. The [¹⁸F]HF distillate was found to be acid‐free but moist; when passed through a solution of ^tBuPh₂SiOTf, it yielded [¹⁸F]^tBuPh₂SiF. The multivariate design of experiment showed that the key to high yield of [¹⁸F]HF was the efficient degassing of the reaction mixture.     

Study of the antidepressant activity of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives

A series of 23 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives were tested for acute toxicity and antidepressant activity in mice. Eight of the 23 compounds tested clearly antagonised the tetrabenazine effects and four of them (5, 7, 19, 23) showed activity values ranging from 40 to 75%, close to those shown by imipramine and viloxazine, the drugs chosen as reference standards. Compounds 7, 19 and 23 were also notably effective in the Porsolt test, shortening the immobility period of mice by more than 20%. The values obtained were very close to those elicited by imipramine and viloxazine. The most effective compounds in these tests were found among those bearing a primary amine or a benzoylamino group at the position 3 of the thieno[2,3-d]pyrimidine general structure (7, 19 and 23). The substitution of the thioxocarbonyl group at position 2 by a methylmercapto substituent maintained the activity (23). Compounds 7, 19 and 23 were chosen as prototypes for the design of new molecules with better antidepressant activity. These compounds did not present the adverse anticholinergic effects found in most tricyclic antidepressant drugs.     

Metabolism of the polynuclear sulfur heterocycle benzo[b]phenanthro[2,3-d]thiophene by rodent liver microsomes: evidence for multiple pathways in the bioactivation of benzo[b]phenanthro[2,3-d]thiophene

Benzo[b]phenanthro[2,3-d]thiophene (BPT), a thia analogue of dibenz[a,h]anthracene (DBA), is a carcinogenic environmental pollutant. We have examined the metabolism of BPT by rodent liver microsomes to investigate the mechanism by which BPT produces mutagenic and carcinogenic effects. Both rat and mouse liver microsomes biotransformed [G-(3)H]BPT to various metabolites including BPT 3,4-diol and BPT sulfoxide, which are significantly more mutagenic than the parent compound. Liver microsomes from both control mice and rats metabolize BPT at similar rates. Treatment of mice with P450 inducers DBA, 3-methylcholanthrene (3-MC), Aroclor 1254, and phenobarbital enhanced the rate of metabolism of BPT by 74-, 28-, 77-, and 6-fold, respectively. In comparison, the treatment of rats with DBA and 3-MC increased the rate of metabolism of BPT by 22- and 34-fold, respectively, suggesting that P450 enzymes responsible for the metabolism of BPT are enhanced to different extents in rats and mice by a similar class of compounds. In general, the liver microsomes from mice treated with DBA or 3-MC were more active than those from similarly treated rats in metabolizing BPT to its 3,4-diol, a precursor to the bay-region diol epoxide of BPT. BPT sulfone was a minor metabolite (if formed) in all cases. The liver microsomes from rats treated with DBA or 3-MC or from mice treated with PB produced a significant proportion of BPT sulfoxide (12-41%). In contrast, the liver microsomes from DBA- or 3-MC-treated mice formed BPT sulfoxide as a minor metabolite (<2%). These studies indicate that cytochrome P450 enzymes induced by PAHs (e.g., P450 1A1 and P450 1B1) and by PB (e.g., P450 2B1, 3A1, and/or 3A2) are involved in the metabolism of BPT to mutagenic BPT 3,4-diol and BPT sulfoxide, providing evidence for the first time that BPT and possibly other thia-PAHs are metabolically activated via the formation of both the dihydrodiol (and subsequently diol epoxide) and the sulfoxide.     

5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的制备

目的改进5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的合成工艺。方法以2-氯烟酸为起始原料,经亲核取代、环合和还原制得目标化合物。结果总收率68.6%,产物经熔点和1HNMR确证。结论改进后的工艺具有操作简便,对环境友好,收率高等优点。     

Fused 1,2,6-Thiadiazines Tetrahydrobenzo[b]thieno[2,3-c] [1,2,6]thiadiazine 2,2-Dioxides

Suitably substituted derivatives of tetrahydrobenzo[b]thiophene were treated with sulfamoyl chlorides to give sulfamoyl esters and nitriles. Ring closure of these compounds, under various conditions, afforded tetrahydrobenzo[b]thieno[2,3-c][1,2,6]thiadiazine 2,2-dioxides. Their herbicidal activities were tested.     

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT2A receptors (rat tail artery) and H1 receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4,5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1-antihistaminic activity in the guinea-pig ileum assay (pA2 = 7.37).