Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives.

Several new 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives 5 and 6 were synthesized and tested for their in vitro antiproliferative activity against Raji, K562, and K562-R cell lines. The pharmacological screening showed that some 2, 6, or 7-substituted quinazolinones 5 posses a significant antiproliferative activity, with a percentage growth inhibition ranging from 44.8% to 100% at 50 microM, which was higher than that showed by the unsubstituted derivative 5a previously synthesized. For the most active compounds 5d, 5f, and 5g the IC50 were recorded.     

3-(Nitrobenzylidene)-2,4(3H,5H)-furandione in the Hantzsch-pyridine synthesis 2. 6,7-Dihydrophthalide

Melting the 3-(o- and p-nitrobenzylidene)tetronic acids 2a and 2c with the enaminocarbonyl compounds 1 at 70-90 degrees C yields the hexahydro-7a-hydroxyfuro[3,4-b]-pyridines 3, while with the m-nitro compound 2b at 100 degrees C the 6,7-dihydrophthalides 4 are obtained. Dehydrogenation of the dihydro derivatives 4 with activated manganese dioxide affords the phthalides 5.     

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)     

Design and synthesis of novel 3-(4-chlorophenyl)-2-(3-substituted propyl thio) quinazolin-4-(3H)-ones as a new class of H1-antihistaminic agents

A series of novel 3-(4-chlorophenyl)-2-(3-substituted propyl) quinazolin-4-(3H)-ones have been synthesized and tested for their in vivo H1-antihistaminic activity on conscious guinea pigs. All the test compounds have protected the animals from histamine induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(3-(4-methylpiperazin-1-yl) propylthio) quinazolin-4(3H)-one (PC5) emerged as the most active compound (77.53% protection) of the series when compared to the reference standard chlorpheniramine maleate (70.09% protection). Compound PC5 shows negligible sedation (6.16%) compared to chlorpheniramine maleate (29.58%). Therefore, compound PC5 can serve as the lead molecule for further development into a new class of H1-antihistaminic agents.     

1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶的合成

目的:合成盐酸尼非卡兰中间体1,3-二甲基-6-[2-(对甲苯磺酰氧基)乙基氨基]尿嘧啶.方法:以二甲基脲和氰乙酸为原料经3步反应合成目标产物.结果:以氰乙酸计,总收率44.4%.目标产物的光谱数据与文献报道一致.结论:新的合成方法所用原料价廉易得,适合生产.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

2-(4-氯-3-甲基苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮的合成

对硝基邻甲苯胺经重氮化、氯代、还原、闭环、水解、脱羧6步反应得到2-（4-氯-3-甲基苯基）-1,2,4-三嗪-3,5（2H,4H）-二酮,总收率约40%。     

H1- and H2-receptor sensitivity to 3-(beta-aminoethyl)-1,2,4-triazole derivatives]

Histamine-like derivatives of 3-(beta-aminoethyl)-1,2,4-trizole were synthetized and subjected to a pharmacological study. The sensitivity of H1- and H2-receptors to these substances was defined by the following tests, viz. in the isolated uterus of a rat, on the isolated atrium of a guinea pig and measurements of the blood pressure nn a cat. The derivative 3-(beta-aminoethyl)-5-amino-1,2,4-triazole (IEM-813) affects predominantly H1-receptors, while 3-(aminoethyl)-5-amino-1,2,4,triazole (IEM-759) has the closest affinity for H2-receptors, The authors presume that corresponding zones of histamine recpetors differ in their lyophilic and hydrophilic properties.     

Synthesis of 2, 3-disubstituted-Quinazolin-4-(3H)-ones

The present review covers a concise account of the synthesis of bioactive 2, 3-disubstituted-quinazoline-4(3H)-ones and the recent developments in the area of versatile quinazolinones with a special emphasis on new synthetic routes and strategies.     

The oriented development of antituberculotics (Part II): halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones

Based on our previous studies, 21 new halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones were synthesized by the reaction of salicylanilides and methyl-chloroformate. All compounds were screened in vitro against three different strains of mycobacterium, and Free-Wilson method was used to establish structure-activity relationships. 6-Bromo-3-(4-butylphenyl)-1,3-benzoxazine-2,4-(3H)-dione 3b proved to be the most active compound of the series.     

Design and synthesis of 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one as antihistamine agents

A series of novel 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one was synthesized by the reaction of 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride with various amines. The starting material, (3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride was synthesized from 4-chloroaniline by a multistep synthesis. All the title compounds were tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs at the dose level of 10 mg/kg using chlorpheniramine maleate as the reference standard. The results of the biological activity indicate that the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-2-oxoethylthio)quinazolin-4(3H)-one (1) emerged as the most potent compound of the series (71.13 % protection) when compared to the reference standard chlorpheniramine maleate (70.09 % protection). Interestingly, compound A1 shows negligible sedation (12 %) compared to chlorpheniramine maleate (32 %). Therefore, compound A1 can serve as the lead molecule for further development.     

Studies of [3H]-7-(3-Butynyl)theophylline by whole-body autoradiography (author's transl)

Studies of [³H]-7-(3-Butynyl)theophylline by Whole-Body Autoradiography The synthesis of [³H]-7-(3-butynyl)-theophylline is described. Whole-body autoradiography of Wistar rats after application of the compound shows a cumulation of radioactivity in the cerebrospinal fluid, in the vitreous body of the eye and in the intervertebral discs. Histologic analysis of the kidney showed a vacuolic structure and partial destruction of the cells in convoluted tubules I and II.     

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.     

Researches on antiinflammatory agents. Studies on some new 3-(pyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-ones and -quinazolin-4(3H)-ones

Following our research on analgesic and antiinflammatory active compounds containing the pyrazole nucleus, a number of 3-(pyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-ones and quinazolin-4(3H)-ones was synthetized and tested. The results of tests for analgesic, antiexudative and antioedema activities, as well as for induction of lesion in the gastric mucosa, are reported and discussed.