Synthesis and binding studies of 1-arylpyrazolo[4,5-c]- and 2-arylpyrazolo[4,3-c]quinolin-4-ones. I

The syntheses of some 2-aryl-3-methyl-4,5-dihydro-2H-pyrazolo [4,3-c] quinolin-4-ones and 1-aryl-3-methyl-4,5-dihydro-1H-pyrazolo-[4,5-c] quinolin-4-ones are reported. Some of the latter have shown a high activity in displacing specific [3H]-flunitrazepam binding from bovine brain membranes.     

Synthesis and pharmacological activity of derivatives of pyrano- and pyrido-[3,2]carbazoles

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 23, No. 10, pp. 1197–1200, October, 1989.     

Synthesis and cytotoxic activity of novel benzopyrano[3,2-c]chromene-6,8-dione derivatives

4-Hydroxycoumarins constitute the structural nucleus of many natural products, drugs, and pesticides. Promising biological properties in new families of synthetic coumarins were recently reported. Therefore, efficient synthesis of new benzopyrano[3,2-c]chromene-6,8-dione was undertaken and the structures of 15 compounds were confirmed by their IR, Mass, ¹H-NMR, and C, H, N analysis. Then, the cytotoxic activities of these compounds were assessed on four different human cancer cell lines (Raji, HeLa, LS180, and MCF-7). The results showed that these compounds had weak-to-moderate antitumoral activities and their IC₅₀ ranged from 49 to more than 100 μM. Among the compounds 9,10-dihydro-7-(3-methoxyphenyl)-7H,11H-benzopyrano[3,2-c]chromene-6,8-dione [4k] demonstrated the highest activity. Furthermore, conformational analysis revealed that ortho substituents were clearly different from meta and para substituents.     

Synthesis and fungistatic activity of 3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives

A series of 5-acyl-4-amino-3-(2-dialkylaminoethyl)thieno-[2,3-c] and [3,2-d]isothiazole derivatives was synthesized. The compounds were evaluated for antifungal activity.     

7-trans-(2-Pyridylethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-ones: synthesis and pharmacological activity

A series of 7-trans-(2-pyridylethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-ones was synthesized and evaluated for their pharmacological activity. Some compounds were found to be effective in inhibiting restraint ulcers in the rat. Two of them also showed interesting antiinflammatory activity.     

5H-呋喃并[3,2-g]色烯类化合物的合成及其抗肿瘤活性

目的 设计合成5H-呋喃并[3,2-g]色烯类化合物,并测定其体外抗肿瘤活性。方法 以2’,4’-二羟基苯乙酮为原料,经缩合、催化氢化和 Fries 重排等反应合成目标化合物。采用人骨肉瘤细胞U2OS-EGFP-4A12G对目标化合物的体外抗肿瘤活性进行初步评价。结果与结论 合成了10个未见文献报道的5H-呋喃并[3,2-g]色烯类化合物,其结构经红外光谱、质谱、核磁共振氢谱确证。化合物7a、7e 和 7h 对人骨肉瘤细胞 U2OS-EGFP-4A12G 的抑制活性较强,其IC₅₀值分别为16.53、7.74、13.27 μmol·L^-1。5H-呋喃并[3,2-g]色烯类化合物是一类具有新型骨架结构的抗肿瘤化合物,值得进一步研究。     

Synthesis and pharmacological evaluation of perhydropyrrolo [3,4-c]pyridine derivatives

Several N,N'-bis-alkyl-perhydropyrrolo[3,4-c]pyridines 4 and the corresponding bis-quaternary derivatives 5 have been prepared through standard methods starting from the bicyclic dilactam 2. Compounds 4 and 5 were evaluated for their inhibitory properties against acetylcholine (ACh), 1,1-dimethylphenyl piperazinium iodide (DMPP), 5-hydroxytryptamine (5-HT) and histamine (H1), and the guinea pig isolated ileum. Pharmacological data indicated that the strongest anticholinergic activity was shown by the dibenzyl amine 4 g, which among the tested molecules presented also a rather potent effect at the ganglia level, resulting about three times more potent than hexamethonium as ganglionic blocking agent. The preliminary SAR coming from the analysis of the pharmacological results are presented and discussed.     

2-氧代-5,6,7,7a-四氢噻吩并[3,2-c]吡啶的合成

N-乙氧羰基-4-哌啶酮经Vilsmerier氯化甲酰化反应、在碳酸钾作用下与巯基乙酸乙酯环合制得6,7-二氧-4H-噻吩并[3,2-c]吡啶-2,5-二羧酸二乙酯(4),再经肼解、叠氮化、重排及脱保护反应制得2-氨基-6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸乙酯盐酸盐(8),8经重氮化、水解后再由氢氧化钾碱解、成盐,制得普拉格雷的关键中间体2-氧代-5,6,7,7a-四氢噻吩并[3,2-c]毗啶,总收率约25％.     

Synthesis and biological activity of [7-amino-s-triazole[1,5-c]pyrmididyl-5]-thioacetic acid derivatives

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 26, No. 2, pp. 30–32, February, 1992.     

1,3-Diarylpyrazolo[4,5-c]- and -[5,4-c]quinolin-4-ones. 4. Synthesis and specific inhibition of benzodiazepine receptor binding

A series of 1,3-diarylpyrazolo[4,5-c]- and -[5,4-c]quinolin-4-ones were prepared and tested for their ability to displace [3H]flunitrazepam from bovine brain membranes. While the 1,3-diarylpyrazolo[4,5-c]quinoline derivatives showed affinity for the receptor site, their [5,4-c] isomers were devoid of binding activity.     

Tricyclic Heteroaromatic Systems. Pyrazolo[3,4-c]quinolin-4-ones and Pyrazolo[3,4-c]quinoline-1,4-diones: Synthesis and Benzodiazepine Receptor Activity

Some pyrazolo[3,4-c]quinoline-4-ones 1–14 and pyrazolo[3,4-c]-quinoline-1,4-diones 15–17 were prepared and biologically evaluated for their binding at the benzodiazepine receptor (BZR) in rat cortical membranes. The moderate binding activity of 1–5,7,9–10, 13 is attributable to the lack of the optional proton acceptor at position-1, while the inactivity of the 1,4-dione derivatives 15–17 is due to the lack of the essential proton acceptor at position-3. These conclusions confirm the validity of our proposed pharmacophoric model.     

A novel synthesis and molluscicidal activity of some functionally substituted pyridine, pyrido[3,2-c]pyridazine, and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives

Ethyl benzoylacetate reacts with the malononitrile dimer to afford 4-amino-5-benzoyl-2-dicyano methyl-6-hydroxypyridine, which undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives. These azo derivatives could be cyclized into pyrido[3,2-c]pyridazine and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives upon reflux in ethanolic NaOH, presumably via their hydrazo tautomers. The molluscicidal activity of these compounds was evaluated.     

Synthesis and pharmacological activity of imidazolyn-5-ones

A new series of imidazolyn-5-one derivatives were synthesized. These compounds were screened for their analgesic, anti-inflammatory and antipyretic activities, as well as for their ulcerogenic potential, for behavioural effects and acute toxicity. Some of them showed higher analgesic activity than phenylbutazone (PBZ), but lower anti-inflammatory activity. Their ulcerogenic effect was lesser than that of the reference drug.     

The thieno[3,2-c]pyridine and furo[3,2-c]pyridine rings: new pharmacophores with potential antipsychotic activity

Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furo[3,2-c]pyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings. Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response. In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furo[3,2-c]pyridine derivatives, the interaction of these molecules with the dopamine D2 receptor was weak. Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10. Despite the similarity these molecules share in their behavioral indices of antipsychotic activity, it is likely that the thieno- and furo[3,2-c]pyridine rings employ different mechanisms to achieve this convergence of biological effects.     

Synthesis of 2-substituted derivatives of 5H-1,2,4-thiadiazolo[3,2-a] [1,3,5]triazin-5-one

The synthesis of 2-substituted derivatives of 5H-1,3,4-thiadiazolo[3,2-a] [1,3,5]triazin-5-one, obtained from 5-substituted 2-amino-1,3,4-thiadiazoles is described. The structure of the new compounds is confirmed by U.V. and I.R. spectra and partly by mass spectrometry.