5-Aroyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepin-4-carboxylic acids: synthesis and analgesic and neurobehavioral activity

Reaction between 1-(2-aminomethylphenyl)-1H-pyrrole hydrochloride and methyl 2-methoxyglicolate in methanol afforded methyl 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepin-4-carboxylate. Aroylation at the 5-position and subsequent hydrolysis of the ester function led to 5-aroyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepin-4-ca rboxylic acids. The pharmacological profile of these acids has been studied with regard to analgesic, antiinflammatory and neuropsychobehavioural effects.     

Synthesis and anxiolytic activity of a series of pyrazino[1,2-a][1,4]benzodiazepine derivatives

The synthesis and biological evaluation of some derivatives of pyrazino[1,2-a][1,4]benzodiazepines for anxiolytic and antidepressant activity are presented. Significant levels of anxiolytic activity were noted for 7-(o-chlorophenyl)-9-chloro-1,2,3,4,4a,5-hexahydro-3-methylpyrazino[1,2-a];E11,4]benzodiazepine (4b).     

4H-Pyrrolo[1,2-a]thieno[3,2-f] and 4H-pyrrolo[1,2-a]thieno-[2,3-f][1,4]diazepines: Synthesis and Pharmacological Evaluation

As an extension of a previous work, in which a number of 4H-pyrrolo-[1,2-a]thieno[2,3-f][1,4]diazepines were described, a new series of derivatives of the isomeric pyrrolo[1,2-a]thieno[3,2-f]diazepines ring system has been synthesized. The products obtained, together with those reported in the previous paper, were tested for acute toxicity and CNS activity in mice.     

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 and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives

A novel series of 8-alkoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The newly synthesized compounds were screened for their anticonvulsant activities by the maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. Compound 8-pentyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine (3d) besides being one of the most active compounds had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED₅₀) of 17.5?mg/kg, and had protective index (PI) value of 6.5, which is slightly less than that of the prototype drug carbamazepine (PI?=?8.1). Its value of ED₅₀ and PI in the anti-scPTZ test were 21.2 and 5.4, respectively, the latter value (PI) of which is much greater than that of the prototype drug carbamazepine (ED₅₀?>100, PI?<0.72). Possible structure–activity relationship has been discussed.     

Synthesis and benzodiazepine receptor binding of 1H-pyrrolo[2,1-C][1,4]benzothiazines

The pyrrolo[2,1-c][1,4]benzothiazines 2a-n and the pyrrolo[2,1-c][1,4]thiazine 13 were prepared and tested for their ability to displace specific [3H]diazepam binding from rat brain membranes. Such compounds were found essentially devoid of binding affinity for the benzodiazepine receptor.     

Synthesis and antiinflammatory and analgesic activity of 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and related compounds

5-Acyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and the homologous pyridine and azepine derivatives were synthesized and assayed for antiinflammatory and analgesic activity. 5-Benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid and the corresponding p-methoxy compound 74 were selected for evaluation as analgesic agents in humans on the basis of their high potency in the mouse phenylquinone writhing assay as well as on their minimal liability to elicit gastrointestinal erosion in rats on chronic administration. Extensive quantitative structure-activity relationship (QSAR) studies of the benzoylpyrrolopyrrolecarboxylic acids have demonstrated that the analgesic (mouse writhing) and antiinflammatory (rat carrageenan paw) potencies of these compounds are satisfactorily correlated with the steric and hydrogen-bonding properties of the benzoyl substituent(s). The 4-vinylbenzoyl compound 95, which was correctly predicted to be highly active in both assays on this basis, is undergoing advanced pharmacological evaluation in animals as a potential antiinflammatory agent.     

Cholecystokinin antagonists. Synthesis and biological evaluation of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines

A series of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared by standard methodology. These compounds were tested in vitro as antagonists of the binding of [125I]cholecystokinin (CCK) to rat pancreas and guinea pig brain receptors and of the binding of [125I]gastrin to guinea pig gastric glands. All compounds proved to have greater affinity for the peripheral CCK receptor with some analogues having IC50's in the subnanomolar range. In vivo activity of selected compounds in mice is presented and the structure/activity profile of this class of benzodiazepines as CCK antagonists is discussed.     

Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives.

A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13).     

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.     

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.     

Synthesis and pharmacological evaluation of 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptane derivatives

1 alpha,2 beta(5Z),3 beta(1E,3S),4 alpha,5 alpha,6 alpha]-7-[5,6-Epoxy-3- (3-cyclohexyl-3-hydroxy-3-methyl-1-propenyl)-7-oxabicyclo[2.2.1]-hept-2- yl]-5-heptenoic acid (31) and [1 alpha,2 beta(5Z),3 beta(1E,3S),4 alpha,5 alpha,6 alpha]-7-[5,6-epoxy-3-[3-hydroxy-5-(p-hydroxyphenyl)-1- pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (37) were found to be selective TxA2 antagonists at the platelet and pulmonary thromboxane receptors. An efficient stereospecific synthesis of these compounds and a series of structural analogues is described. Compounds 31 and 37 both inhibited the bronchoconstriction induced by arachidonic acid in the anesthetized guinea pig.     

Synthesis and biological evaluation of new imidazo[1,2-a]pyridine derivatives designed as mefloquine analogues

This paper describes the synthesis and the in vitro antimalarial profile of two new imidazo[1,2-a]pyridine derivatives 4HCl and 13HCl, structurally proposed as mefloquine (1) analogues, by exploring bioisosterism and molecular simplification tools. The synthetic route employed to access the title compounds used, as starting material, the previously described ethyl 2-methylimidazo[1,2-aJpyridine-3-carboxylate derivative (5). These novel heterocyclic derivatives 4HCl and 13HCl presented modest antimalarial activity against the W-2 and D-6 clones of Plasmodium falciparum as well as inhibitors of in vitro heme polymerization compared to mefloquine.