Research on psychotropic agents. III. Antidepressant activity and neuropsychobehavioural effects of new 5H-Pyrrolo[1,2-b][1,2,5]benzotriazepine derivatives

The synthesis of 5H-pyrrolo[1,2-b][1,2,5]benzotriazepine derivatives related to imipramine and aptazepine antidepressant agents is reported. Pharmacological screening on new tricyclic derivatives showed that in some cases antidepressant effects at equimolecular dose with imipramine are associated with sedative-muscle relaxant activities and antinociception.     

New psychotropic agents. I. Synthesis and pharmacologic activity of derivatives of 5H-imidazo-[2,1-c][1,4]benzodiazepine

The synthesis of 5H-imidazo [2,1-c] [1,4] benzodiazepine derivatives is described. Hydroxymethylation of 1-(2-nitrobenzyl)imidazoles by reaction with formaldehyde in a sealed tube and subsequent oxidation of hydroxymethylimidazoles with activated manganese dioxide afforded 1-(2-nitrobenzyl)imidazole-2-carboxaldehydes. The latter compounds were treated with iron(II) sulphate to yield directly the expected tricyclic imidazobenzodiazepines by intramolecular cyclization of the intermediates aminoaldehydes. The tricyclic derivatives were subjected to pharmacological screening to evaluate the effects on the behavior of the animals and the interaction with some biogenic amines. Some of the tested compounds were comparable to chlordiazepoxide in sedative and muscle-relaxant activities. None of them showed antiserotonin, anticholinergic or adrenolytic activities.     

Non-steroidal antiinflammatory agents. VII. Synthesis and antiinflammatory activity of 5-methyl-10,11-dihydro-5H-pyrrolo [1,2-b] [1,2,5]benzotriazepine-11-acetic acid and its 10-aroyl derivatives

The synthesis of 5-methyl-10,11-dihydro-5H-pyrrolo [1,2-b] [1,2,5]benzotriazepine-11-acetic acid and its 10-aroyl derivatives is reported. Compounds were evaluated for antiinflammatory activity by the carrageenin-induced rat paw edema method. Antinociceptic activity was tested by the hot plate and Randall-Selitto tests. General neuropsychopharmacological effects were also screened. All test compounds showed antiinflammatory effect comparable to that of tolmetin.     

Researches on psychotropic agents. IV. Synthesis and neuropsychopharmacological effects of 1,3,4,14 b-tetrahydro-10-methyl-2H,10H- pyrazino[2,1-d] pyrrolo[1,2-b][1,2,5]benzotriazepine and its derivatives.

The synthesis and neuropsychopharmacological properties of new 1,3,4,14b-tetrahydro-2H,10H-pyrazino [2,1-d] pyrrolo [1,2-b] [1,2,5] benzotriazepine derivatives related to antidepressant agent aptazepine are reported. The new derivatives displayed sedative-miorelaxant activity in mice, but no significant antagonist effect on clonidine blockade of phenylquinone-induced abdominal constriction. Among test compounds 4a, 4l and 4n showed high antinociceptive effect on the hot-plate test and compound 4e protected from death and convulsion all the electroshocked animals.     

Synthesis and biological activity of certain novel derivatives of 1H-pyrrolo[1,2-c][1,3]thiazine

The reaction of 2-(beta-hydroxyethyl)-pyrrolidine with isothiocyanates gave rise to the formation of thiourea derivatives which cyclised on refluxing in hydrobromic acid to yield N-(3,4,4a,5,6,7-hexahydro-1H-pyrrolo[1,2-c][1,3]thiazin-1-ylidene)-aryl(alkyl)amines. The results of preliminary pharmacological screening are presented.     

Heterocyclic systems. IV. Synthesis and CNS activity of derivatives of 4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepine

The synthesis of derivatives of 4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepine is described. These compounds were tested for activity on type (I) and (II) benzodiazepine receptors by several screening tests on mice.     

Synthesis of potential anticancer agents. Pyrido[4,3-b][1,4]oxazines and pyrido[4,3-b][1,4]thiazines

Hydrolysis of the chloro group of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (3) with formic acid gave the corresponding 4-hydroxypyridine 4. Catalytic hydrogenation of the nitro group of 4 gave the 5-amino-4-hydroxypyridine 5, which was reacted with alpha-halo ketones in acetic acid at room temperature to give a series of 3- and 2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]oxazin-7-yl)carbamates 8. Treatment of 8 with hot concentrated hydrochloric acid regenerated the pyridine synthon 5. In the reaction of 3 with thioacetate, the product underwent hydrolysis and air-oxidation to give the corresponding disulfide 6. Simultaneous reduction of both the nitro group and disulfide linkage of 6 gave the 5-amino-4-mercaptopyridine 7, which was reacted with alpha-halo ketones either in acetic acid at room temperature or in a mixture of ethanol and water at reflux to give a series of 3-, 2,3-, and 2,2,3-substituted ethyl (5-amino-2H-pyridol[4,3-b][1,4]thiazin-7-yl)carbamates 9. The effects of these pyridooxazines and pyridothiazines upon the proliferation and the mitotic index of cultured L1210 cells and upon the survival of mice bearing P388 leukemia were determined.     

5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸的合成

目的制备5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸。方法以2-甲基-6-氯-3-硝基吡啶为原料,经Williamson合成法制得2-甲基-6-甲氧基-3-硝基吡啶,再经Reissert合成法制得终产物。结果反应总收率33%,产物结构由1H-NMR光谱确证。结论该方法简单、原料价廉易得,后处理容易,副产物较少,适于工业化生产。     

Synthesis of aminomethyl derivatives of naphtho[1,2-b]furan

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 11, pp. 29–31, November, 1990.     

Thiophene systems. 5. Thieno[3,4-b][1,5]benzoxazepines, thieno[3,4-b][1,5]benzothiazepines, and thieno[3,4-b][1,4]benzodiazepines as potential central nervous system agents

10-(Alkylamino)thieno[3,4-b][1,5]benzoxazepines (3) and 10-(alkylamino)thieno[3,4-b][1,5]benzothiazepines (4) were prepared by derivatization of the respective lactams (7 and 8) via phosphorus pentachloride and subsequent condensation with the appropriate alkylamines. 9-(Alkylamino)-4H-thieno[3,4-b][1,4]benzodiazepines (5) were prepared by titanium tetrachloride catalyzed condensation of the lactam 11 with alkylamines. 9-(Alkylamino)-4-methylthieno[3,4-b][1,4]benzodiazepines (6) were prepared by reductive alkylation of 5. The compounds were tested for potential neuroleptic activity by means of the blockade of d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the title compounds 3-6 were found to have neuroleptic activity. In addition, introduction of a 3-chloro substituent in the oxygen and sulfur systems (3p and 4c), as well as introduction of an N-alkyl in the dinitrogen system (6), was found to produce antidepressant effects. Structure-activity relationships are discussed.     

5H-哒嗪并[4,5-b]吲哚类新化合物的合成及 抗肿瘤细胞增殖活性

目的 设计并合成5H-哒嗪并[4,5-b]吲哚类化合物,评价其体外抗肿瘤细胞增殖活性。方法 以7-溴-1-氯-8-(3-氯丙氧基)-5-环丙基-5H-哒嗪并[4,5-b]吲哚为起始原料,经取代、醚化、Mannich 反应、选择性氧化共3步或4步反应合成目标化合物;以吉非替尼(gefitinib)为阳性对照药,采用 MTT 法测定了目标化合物对肿瘤细胞株 Bel-7402 和 HT-1080 的抗增殖活性。结果与结论 合成了13 个化合物,其中12 个是未见文献报道的新化合物,其结构经¹H-NMR、MS 谱确证;8个化合物显示出较好的抗肿瘤细胞增殖活性,其中,化合物4a和5a抗增殖活性突出,分别为吉非替尼的3倍和4倍。     

Synthesis and antisecretory activity of 6-substituted 5-cyanomethylimidazo[2,1-b]thiazoles and 2,6-dimethyl-5-hydroxymethylimidazo[2,1-b][1,3,4]thiadiazole

The synthesis of imidazo[2,1-b]thiazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives, related to known antiulcer agents, is reported. 5-Cyanomethyl-6-methylimidazo[2,1-b]thiazole showed significant antisecretory activity in the isolated rabbit gastric glands assay.     

Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives

A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC₁₆ = 0.7 μM) and 31 (IC₁₆ = 1.7 μM) and 33 (IC₁₆ = 1.7 μM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C₁₁-position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents.     

Pyrrolobenzodiazepine and related systems. I. Synthesis and pharmacological evaluation of new 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine derivatives

Some new 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine derivatives substituted at the 5 position have been synthesized and tested to evaluate their antidepressant and neuropsychopharmacological activities. The antinociceptic action of these compounds has been also assayed. The introduction of an ethoxycarbonyl group at the 4 position generally decreased the antidepressant effect.     

Compounds with psychotropic activity. VIII. Synthesis and sedative activity of various 9-substituted derivatives of 5-phenylpyrrolo[2,1-d][1,5] benzothiazepine and cis-4,5-dihydro-4-hydroxy-5-phenylpyrrolo[2,1-d][1,5]benzothiazepine

Syntheses of 9-chloro-, 9-trifluoromethyl- and 9-methoxy-5- phenylpyrrolo [2,1-d] [1,5] benzothiazepine [II a-c] and of cis-9-chloro- and cis-9-trifluoromethyl-4,5-dihydro-4-hydroxy-5- phenylpyrrolo [2,1-d] [1,5] benzothiazepine with the respective acetyl derivatives (III a-d), according to previously restated routes, are described. The sedative activity was tested against the anti-amphetamine activity in the rat. The 1-[5-trifluoromethyl-2-(alpha- hydroxycarbonylbenzyl ) thiophenyl + ++]-pyrrole ( NF34 ) and the pyrrolo [2,1-d] [1,5] benzothiazepine -5-carboxamide ( NF44 ) showed sedative activity similar to that of diazepam.     

Research on agents with antineoplastic activity. LXIII. Anthramycin and analogous compounds. X. Synthesis of 11-phenyl-5H-pyrrolo[2,1-c] [1,4] benzodiazepine derivatives

Reaction between arolychlorides and 1-(2-aminobenzyl)-2-cyanopyrrole afforded the corresponding aroylamides, which were transformed by intramolecular cyclization into 11-aryl-3-cyano-5H-pyrrolo[2,1-c] [1,4] benzodiazepines. Hydrolysis of cyanoderivatives furnished the corresponding amides or acids depending on the reaction conditions. Decarboxylation and reduction of some derivatives to afford 11-aryl-5H-pyrrolo[2,1-c] [1,4] benzodiazepines and 11-aryl-3-cyano-10,11-dihydro-5H-pyrrolo[2,1-c] [1,4] benzodiazepines are described.     

Synthesis and structure of novel 2,3, 5,6-tetrahydro-1H-imidazo[2,1-b][1,3,5]benzotriazepines with vasocontractile activity in rabbit aortic rings

A series of novel 2,3,5,6-tetrahydro-1H-imidazo[2,1-b][1,3,5]benzotriazepines (3a-n) and hydrochlorides (4a-b) were prepared and their structure was determined by IR and NMR spectroscopic data as well as by X-ray analysis of the hydrochloride 4a. The newly synthesized benzotriazepine 4b exhibited concentration-dependent vasocontractile activity in isolated rabbit aortic rings. Rimalkalim was found to induce a relaxation in rabbit aortic rings precontracted by 4b (3x10(-5) mol). Present results indicate that K(ATP)-dependant channels may contribute in the contractile activity of benzotriazepine 4b.