(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇的合成工艺研究

目的 对(2S,3R)- 1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇合成工艺进行研究.方法 以3-戊酮为起始原料,经Mannich反应、手性拆分、Grignard反应等步骤合成(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇,并对化学拆分进行工艺优化.结果 合成(2S,3R)-1...     

Novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-l-ylmethy)-2-methylisoxazolidine derivatives

The synthesis and antifungal activity of a series of novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-1-ylmethyl)-2- methylisoxazolidine derivatives are described. When tested in vitro in solid agar assays, some of the compounds demonstrated moderate to potent activity against Trichophyton rubrum and Candida albicans.     

Synthesis and pharmacological properties of some 2-(3-aminopropionyl)- and 2-(3-aminopropyl)-1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carbolines

Five derivatives of 2-(3-aminopropionyl)-1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carboline (2a-e) were obtained, which yielded, as a result of reduction with LiAlH4, five respective 2-aminopropyl-derivatives (3a-e). Pharmacological studies revealed that phenylpiperazine-derivatives 2d, 2e, 3d and 3e have sedative and analgesic properties. All compounds are devoided of neuroleptic, antidepressant, anxiolytic and antiparkinsonic activity.     

3-(3-氯丙基)-1,3,4,5-四氢-7,8-二甲氧基-2H-3-苯并氮杂 -2-酮合成工艺的改进

目的 改进3-(3-氯丙基)-1,3,4,5-四氢-7,8-二甲氧基-2H-3-苯并氮 -2-酮的合成工艺.方法 以3,4-二甲氧基苯乙酸为原料,先后经氯代、酰化、环和、取代和氢化等反应合成目标化合物.结果 与结论改进后的方法操作简单,易于纯化,试剂价廉易得,适合于工业化生产,总产率由44%提高到48%.     

2-(2-(3-(2-(7-氯-2-喹啉基)乙烯基)苯基)-3-氧代丙基)苯基丙醇的合成工艺

目的对2-(2-(3-(2-(7-氯-2-喹啉基)乙烯基)苯基-3-氧代丙基)苯基)丙醇的合成工艺进行研究。方法以间氰基苯甲醛和邻甲基苯乙酮分别作为起始原料,经过缩合、格氏反应、羟基保护、羟甲基反应、卤化反应,缩合得到最终目标产物。结果总收率为质量分数47.5%。结论该工艺原料易得,降低了制备成本、简化了反应操作条件、提高了产率,更适合工业化生产。     

7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂革-2-酮的制备

目的合成抗心绞痛的新药伊伐布雷定的关键中间体7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂--2-酮。方法以3,4-二甲氧基苯乙酸为原料,经卤化、酰化、环合、烷基化、碘取代等反应制得目标化合物。结果五步反应总收率为63.6%,产物经MS1、HNMR确证结构。结论所用工艺路线具有原料易得、操作简便、收率较高的特点,适用于该中间体的放大制备。     

Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.     

3-(2-烷氧基-5-甲基苯基)-3-苯基丙胺类化合物的合成

目的 设计合成3－（2－烷氧基－5－甲基苯基）－3－苯基丙胺类化合物，从中筛选有抗尿失禁作用而无口干等不良反应的活性化合物。方法 以肉桂酸和对甲酚为起始原料，经环合、甲基化、酰胺化、还原或再经脱甲基化得目标产物。结果 共合成10个新化合物，经IR，^1H-NMR等确证其结构。     

3-（2-甲氧基-5-甲基苯基）-3-苯丙醇的合成

对甲苯酚和肉桂酸经脱水环合、水解甲基化制得3-(2-甲氧基-5-甲基苯基)-3-苯丙酸,用硼氧化钠在三氟化硼乙醚复合物作用下以无水THF为溶剂直接还原制得托特罗定中间体3-(2-甲氧基-5-甲基苯基)-3-苯丙醇,总收率89%.     

Ringoffene Serotonin-Analoga, 2. Mitt.1) Synthese von 3-(2-Aminophenyl)-propanamin- und 1-(N-Piperidino)-3-(2-aminophenyl)-3-oxo-propan-Derivaten

Ring-Opened Analogues of Serotonine, II: Synthesis of 3-(2-Aminophenyl)propanamine and 1-(Piperidin-1-yl)-3-(2-aminophenyl)propan-3-one and Their Derivatives The synthesis of the title compounds was achieved by Mannich reaction of suitably substituted acetophenones. The preparation of 3-(2-aminophenyl)propanamine and its derivatives requires complete hydrogenation of the carbonyl group of the Mannich bases.     

Structure-activity relationship in ring-opened serotonin analogs: 3-(2-aminophenyl)-propanamine and 1-(N-piperidino)-3-(2-aminophenyl)-3-oxopropane

The complete reduction of the carbonyl group of the 5-HT agonist 3-(2-amino-5-hydroxy-phenyl)-3-oxo-propanamine results in a drastic loss of activity: as investigations on the isolated gastric fundus of the rat showed, the affinity to the D receptor of serotonin is reduced by a factor of 100 whereas the relative intrinsic activity also decreases from 0.83 to values less than 0.3. The additional suppression of the phenolic hydroxyl group causes only a relatively unimportant decrease of the affinity while the relative intrinsic activity increases again up to 0.65. These results support the postulate according to which the active conformation of serotonin shows a stretched side chain, as its logical interpretation is only possible under this assumption. Inside the 1-(N-piperidino)-3-(2-amino-phenyl)-3-oxo-propanes the derivative methoxylated at C-5 of the benzene nucleus with a pA2 value of 7.39 proved to be the most effective 5-HT antagonist the mechanism being a purely competitive one.     

Synthesis and 5-HT2A, 5-HT1A and alpha1-binding affinities of 2-[2-Hydroxy-3-(pyridin-3-yl-methyl)amino]-, 2-[2-hydroxy-3-(2-pyridin-2-yl-ethyl)amino]- and 2-[2-hydroxy-3-(4-N-methyl-piperazin-1-yl)-amino]propoxybenzaldehyde-O-(substituted) benzyl oximes

Some oxime ether-substituted aryloxypropanolamines 3-5, structurally related to the active metabolite 2 of sarpogrelate 1, were synthesized and tested for their affinities at 5-HT2A and 5-HT1A serotoninergic receptors as well as at the alpha1-adrenoceptor. The results show that the compounds possess, at least partially, the ability of the model compounds 1 and 2 to interact with the 5-HT2A-receptors; they have the same selectivity towards 5-HT2A receptors vs alpha1-adrenoceptors.     

Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone

In the previous report, we reported the results of absorption, protein binding, and pharmacokinetics of the dopamine-2 agonists (D2-agonists) 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone, N-(2'-hydroxy-5'-[N,N-di-n-propylaminoethylphenyl])methanesulfonamide, and 4-(di-n-propylaminoethyl)-2-(3H)-indolone. Both phenolic compounds, 1 and 2, were subject to more rapid metabolism than the nonphenol 3. In the present study, we investigated the metabolic basis of the differences in the pharmacokinetics of these compounds. In both rats and dogs, the principal urinary metabolite of 1 and 2 was the corresponding glucuronide. In contrast, 3 was first converted to 1 which then was converted to a glucuronide. On the basis of the urinary excretion of 1 and its glucuronide after intravenous administration of 1 and 3, approximately 78% of the dose of 3 in rats and 58% in dogs was converted to 1. The depropyl analogue of 3 was identified as a minor urinary metabolite. 4-(2-Di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone was found in the plasma of rats, dogs, and cynomolgus monkeys treated with 3. The concentration of 1 declined in parallel with that of 3 in dogs and monkeys, indicating that the true half-life of 1 is shorter than or equal to that of 3. On the basis of plasma concentrations of 1 in dogs, the apparent conversion of 3 to 1 was 9%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Darstellung,Kristallstruktur und Wirkung von 2-Methyl-3-(4-oxo-3-phenyl-thiazolidin-2-ylidenamino)-4-(3H)-chinazolinon

Quinazolinones, I: Preparation, Crystal Structure, and Activity of 2-Methyl-3-(4-oxo-3-phenylthiazolidine-2-ylidenamino)-4(3H)-quinazolinone The cyclisation of 1-(3,4-dihydro-2-methyl-4-oxo-3H-quinazoline-3-yl)-3-phenylthiourea (2) with chloroacetic acid leads to 2-methyl-3-(4-oxo-3-phenyl-thiazolidine-2-ylidenamino)-4(3H)-quinazolinone (3) and not to the isomer 4 . The crystal structure of 3 has been determined and refined until R = 0.0715. Compound 3 possesses good hypnotic and anticonvulsant activities.     

Synthesis and antimycobacterial activity of some N1-[1-[3-aryl-1-(pyridin-2-, 3-, or 4-yl)-3-oxo]propyl]-2- pyridinecarboxamidrazones

N1-[1-[3-aryl-1-(pyridin-2,3-, and 4-yl)-3-oxo[propyl]-2- pyridinecarboxamidrazone derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed interesting activity against a strain of Mycobacterium tuberculosis and a strain of Mycobacterium avium.