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1.
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. 相似文献
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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. 相似文献
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G Cignarella D Barlocco G A Pinna M Loriga M M Curzu O Tofanetti M Germini P Cazzulani E Cavalletti 《Journal of medicinal chemistry》1989,32(10):2277-2282
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. 相似文献
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[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. 相似文献
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Synthesis and characterization of all four isomers of the muscarinic agonist 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] 总被引:1,自引:0,他引:1
J Saunders G A Showell R Baker S B Freedman D Hill A McKnight N Newberry J D Salamone J Hirshfield J P Springer 《Journal of medicinal chemistry》1987,30(6):969-975
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. 相似文献
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I R Ager A C Barnes G W Danswan P W Hairsine D P Kay P D Kennewell S S Matharu P Miller P Robson D A Rowlands 《Journal of medicinal chemistry》1988,31(6):1098-1115
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. 相似文献
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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。 相似文献
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Fookes CJ Pham TQ Mattner F Greguric I Loc'h C Liu X Berghofer P Shepherd R Gregoire MC Katsifis A 《Journal of medicinal chemistry》2008,51(13):3700-3712
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. 相似文献
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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. 相似文献
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WESTER RONALD C.; MAIBACH HOWARD I.; BUCKS DANIEL A. W.; SEDIK LENA; MELENDRES JOSEPH; LIAO CHENG; DIZIO STEPHEN 《Toxicological sciences》1990,15(3):510-516
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, 510516. 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. 相似文献
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Bente Mathiessen Mikael Jensen Fedor Zhuravlev 《Journal of labelled compounds & radiopharmaceuticals》2011,54(13):816-818
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. 相似文献
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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. 相似文献
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Yuan ZX Sikka HC Munir S Kumar A Muruganandam AV Kumar S 《Chemical research in toxicology》2003,16(12):1581-1588
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. 相似文献
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M Rinaldi P Pecorari L Costantino A Provvisionato M Malagoli C Cermelli 《Il Farmaco; edizione pratica》1992,47(10):1315-1322
Some derivatives of thiazolo[3,2-c]pyrimidine, pyrimido[6,1-b][1,3]thiazine, thiazolo[2,3-i]purine, [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c][1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo[4',5':4,5]pyrimido[6,1-b][1,3]thiazine were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely, Escherichia coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, Aspergillus sp., and for antiviral activity on Herpes simplex virus, Type 1 (HSV-1), Vesicular stomatitis virus (VSV) and Coxsackievirus B5 (CoxB5). The compounds proved to be devoid of activity against viruses, mycetes and gram-negative bacteria, while some of them exhibited a modest activity against gram-positive bacterial strains. 相似文献
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Ross D. Jansen-van Vuuren Rahul Vohra 《Journal of labelled compounds & radiopharmaceuticals》2022,65(6):156-161
Baricitinib, typically applied as a treatment for rheumatoid arthritis, has recently attracted the attention of clinicians and researchers as a potential treatment for COVID-19. Naturally, there has been a need for the preparation of the isotope-labelled analogue of baricitinib to probe the pharmacokinetics of baricitinib in this new role. As such, we have developed a simple synthetic route to deuterated [2H5]baricitinib, facilitating its formation over four steps and in a 29% overall yield based on starting [2H5]ethanethiol (19% if we start with [2H5]bromoethane instead). A critical component of the overall process involves the synthesis of [2H5]ethanesulfonyl chloride, and we describe in detail the two routes that were explored to optimize this step. 相似文献