Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

The synthesis of N′-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a–c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N′-aryl methylidene acetohydrazides (4a–f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed starting from the corresponding acid hydrazides (2a, b) which was reported earlier. The treatment of 1,3,4-oxadiazole derivatives (5a, b) with hydrazine hydrate produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl derivatives (6a, b). Then, compound 6b was converted to the corresponding Schiff base (7) by the treatment with anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was carried out by the reaction of acid hydrazides (2a, b) with aryl iso(thio)cyanates either via the formation of the intermediates (9a, b) (for 10) or direct cyclization (for 8). 1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives (11a, b) were obtained by the reaction of 9a, b with 4-chlorophenacyl bromide. All newly synthesized compounds were screened for their antimicrobial activities and some of which was found to be active against the test microorganisms.     

N-hydroxymethyl metabolites of 450191-S, a 1H-1,2,4,-triazolyl benzophenone derivative, in dog plasma

In a metabolic experiment of 5-[(2-aminoacetamido)methyl]-1-[4-chloro-2-(o-chlorobenzoyl)phenyl ]-N, N-dimethyl-1H-1,2,4,-triazole-3-carboxamide hydrochloride dihydrate (450191-S) in dogs, two new metabolites 8-chloro-6-(o-chlorophenyl)-N-hydroxymethyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-A) and 8-chloro-6-(o-chlorophenyl)-N-hydroxymethyl-N-methyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-D) in plasma were found in addition to 8-chloro-6-(o-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo[1,5-a] [1,4] benzodiazepine-2-carboxamide (M-1), 8-chloro-6-(o-chlorophenyl)-N-methyl-4H-1,2,4-triazolo[1,5-a] [1,4] benzodiazepine-2-carboxamide (M-2), 8-chloro-6-(o-chlorophenyl)-4H-1,2,4-triazolo-[1,5-a] [1,4] benzodiazepine-2-carboxamide (M-3), and 8-chloro-6-(o-chlorophenyl)-4H-1,2,4-triazolo[1,5-a] [1,4] benzodiazepine-2-carboxylic acid (M-4). The structures of N-hydroxymethyl metabolites were elucidated mainly by mass spectrometry. The structures were confirmed by synthesizing the authentic compounds and comparing the mass spectra.     

10-Carbethoxymethyl-3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole and Derivatives at its 10-Position

Reaction of 3-phenyl-10H-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole ( 4 ) with ethyl chloroacetate gave 10-carbethoxymethyl-3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole ( 3 ). Condensation of 3 with hydrazine hydrate gave (3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indol-10-yl)acetylhydrazine ( 5 ). Reactions of 5 with a number of aromatic aldehydes, acetophenone, cyclohexanone and D-galactose gave the corresponding hydrazones 6 - 12 . Condensation of 5 with acetylacetone gave the pyrazole 15 . Cyclization of 5 with CS₂ gave (3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indol-10-yl)(2-thiol-1,3,4-oxadiazol-5-yl)methane ( 16 ). Reaction of 16 with ethyl chloroacetate gave the carbethoxy alkylated derivative (3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indol-10-yl)[2-(thiocarbethoxymethyl)1,3,4-oxadiazol-5-yl]methane ( 17 ).     

Tricyclic Heteroaromatic Systems. 1,2,4-Triazolo[4,3-a]quinoxalines and 1,2,4-Triazino[4,3-a]quinoxalines: Synthesis and Central Benzodiazepine Receptor Activity

Some 1,2,4-triazolo[4,3-a]quinoxalines 1–10 , and 1,2,4-triazino[4,3-a]quinoxalines 11–12 were prepared and biologically evaluated for their binding at the benzodiazepine receptor (BZR) in rat cortical membranes. The BZR affinity of 1–10 demonstrates that the presence of a proton acceptor at position-1 is important for the potency of a BZR ligand. On the other hand, the BZR inactivity of the 1,2,5-trione derivatives 11–12 shows that the right collocation of the essential L₂ lipophilic substituent is of paramount importance for receptor-ligand interaction.     

Synthesis and biological evaluation of analogues of 7-chloro-4,5-dihydro-4- oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (TQX-173) as novel selective AMPA receptor antagonists

In recent papers (Catarzi, D.; et al. J. Med. Chem. 2000, 43, 3824-3826; 2001, 44, 3157-3165) we reported chemical and biological studies on 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) bearing different nitrogen-containing heterocycles at position-8. In particular, from these studies it emerged that both the 7-chloro-4,5-dihydro-4-oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a] quinoxaline-2-carboxylic acid TQX-173 (compound B) and its corresponding ethyl ester (compound A) were the most active and selective compounds of this series. In pursuing our investigation on the structure-activity relationships of these TQX derivatives, different electron-withdrawing groups (CF(3), NO(2)) were introduced at position 7 on the TQX ring system, replacing the 7-chloro substituent of B and of other selected 8-heteroaryltriazoloquinoxaline-2-carboxylates previously described. All the newly synthesized compounds were biologically evaluated for their binding at the Gly/NMDA, AMPA, and KA high-affinity receptors. Gly/NMDA binding assays were performed to assess the selectivity of the reported compounds toward the AMPA receptor. Compounds endowed with micromolar binding affinity for the KA high-affinity binding site were also evaluated for their binding at the KA low-affinity receptor. Some selected compounds were also tested for their functional antagonist activity at the AMPA and NMDA receptor-ion channel complex. The results obtained in this study have pointed out that 4,5-dihydro-7-nitro-4-oxo-8-(3-carboxypyrrol-1-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (9b) and its corresponding ethyl ester (9a) are the most potent and selective AMPA receptor antagonists reported to date among the TQX series.     

1,2,4-Triazolo[4,3-a]quinoxaline-1,4-diones as antiallergic agents

A series of new 1,4-dihydro-1,2,4-triazolo[4,3-]quinoxaline-1,4-diones has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated rat passive cutaneous anaphylaxis (PCA). Most of this new class of antiallergic agents showed good activity in the RMC and PCA tests. The most potent compound, 2-acetyl-7-chloro-5-n-propyl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1x), with an I50 value of 0.1 microM, is 30 times more potent than disodium cromoglycate (DSCG) in the RMC assay.     

Synthesis and anticonvulsant activity evaluation of 7-alkoxy-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]thiazin-1-ones in various murine experimental seizure models

A novel series of 7-alkoxy-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]-thiazin-1-ones have been synthesized and tested for their anticonvulsant activity using the maximal electroshock (MES) method. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of the compounds tested, the most promising was 7-[(4-fluorobenzyl)oxy]-2,4-dihydro-1H-[1,2,4]-triazolo[4,3-d][1,4]-benzothiazin-1-one (6m), which showed an ED₅₀ value of 9.2 mg/kg in the MES test in mice. Furthermore, the compound exhibited a PI value of 15.4 which was superior to the standard drug carbamazepine (PI value of 6.4). As well as demonstrating the anti-MES efficacy of compound 6m, its potency against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that several different mechanisms of action might be involved in its anticonvulsant activity, including the inhibition of voltage-gated ion channels and the modulation of GABAergic activity.     

1-Substituted 4-[Chloropyrazolyl][1,2,4]triazolo[4,3-a]quinoxalines: Synthesis and Structure-Activity Relationships of a New Class of Benzodiazepine and Adenosine Receptor Ligands

Starting from 3-(3-chloro-1H-pyrazol-5-yl)-1H-quinoxalin-2-one ( 2 ) a series of substituted [1,2,4]triazolo[4,3-a]quinoxalines ( 3a-f ) was prepared via a multistep reaction sequence. Affinities of the novel derivatives 3a-f for benzodiazepine as well as for adenosine A₁- and A_2A-receptors of rat brain were determined by radioligand binding assays. 1-Methyl-4-(3-chloro-1H-pyrazol-5-yl) derivative 3a exhibited submicromolar affinity for the benzodiazepine binding site of GABA_A receptors (K_i = 340 nM) and was less potent at A₁- (K_i = 7.85 μM) and A_2A- (K_i = 1.43 μM) adenosine receptors (AR). Derivatives with larger substituents in the 1-position showed reduced binding to benzodiazepine and A_2A-AR, but increased A₁-AR affinity, the 2-thienylmethyl derivative 3f being the most potent and selective A₁-AR ligand of the present series (K_i = 200 nM).     

Synthesis and anti-inflammatory activity evaluation of novel 3-alkyl-6-(4<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazol-4-yl)-3,4-dihydro-2<Emphasis Type="Italic">H</Emphasis>-benzo[<Emphasis Type="Italic">e</Emphasis>][1,3]oxazine derivatives

To discover new compounds with anti-inflammatory activity, a series of novel 3-alkyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine derivatives were synthesized and their structures were confirmed by spectroscopic techniques. In vivo anti-inflammatory activity of the synthesized compounds was determined using the xylene-induced mouse ear edema model. 3-Heptyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydro-2H-benzo[e] [1,3]oxazine and 3-p-tolyl-6-(4H-1,2,4-triazol-4-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine demonstrated higher anti-inflammatory activity (74.04?% and 64.99?%, respectively) at 0.5?h after intraperitoneal administration than the reference drug ibuprofen (62.65?%). Further, the time of peak effect after oral administration was 4?h for both compounds. Our results identify new compounds with anti-inflammatory activity in vivo that may have improved safety/side effect profiles relative to the currently approved nonsteroidal anti-inflammatory drugs.     

Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2-pyrazolylquinoxalines

Three main classes of quinoxaline derivatives have been synthesized. The first class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3-a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a-d. The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16). The prepared compounds were tested in vitro for their antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as active as the antibiotic nystatin.     

Patent Evaluation: Trisubstituted tetrahydrofuran antifungal agents

Summary

Novelty: Novel tri-substituted tetrahydrofurans, stated to have potential utility as antifungal agents, are disclosed.

Biology: A range of in vivo rodent studies demonstrating pharmacological efficacy are presented. These include evaluation of antifungal activity using an Aspergillus pulmonary infection model. Oral treatment (100mg/kg/day) was initiated 24 hours post-infection and maintained for 4 days. A preferred test compound was found to have greater antifungal activity than itraconazole, fluconazole and saperconazole. Results are presented in figures.

Chemistry:(-)-[(5R)-cis]-4-[4-[4-[4-[[5-(2-4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl) tetrahydofuran-3-yl]methoxy]phenyl-1-piperazinyl]phenyl]-2,4-dihydro-2[(S)-(1-methylpropyl)]-3H-1,2,4,-triazol-3-one is one of thirty compounds specifically exemplified. Full preparative details using standard techniques are presented.     

Triazole antifungal agents

Patent Summary

Novel tri-substituted tetrahydrofurans are claimed to be antifungal agents. The compounds are stated to be particularly effective against Aspergillus and Candida.

Oral antifungal activity was assessed in mice. Against Aspergillus lung infection only one compound, for which data are presented, gave a survival rate of 100% (100 mg/kg).

Extensive synthetic details are provided and 42 compounds are exemplified. The most active is (-)-[(5R)-cis]-4-[4-[4-[4-[[5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)-tetrahydrofuran-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[(1S)-(1-methylpropyl)]-3H-1,2,4-triazo-1-3-one.     

1,5-Benzodiazepine tricyclic derivatives exerting anti-inflammatory effects in mice by inhibiting interleukin-6 and prostaglandinE(2)production.

The 1,4- and the 1,5-benzodiazepines (BDZ) are commonly used as anxiolytic and anticonvulsive drugs. It has been suggested that they influence, particularly through stimulation of peripheral BDZ receptors, some immune cell properties such as pro-inflammatory cytokine production. The availability of a new class of [1,2,4]triazolo[4,3-a][1,5]benzodiazepine derivatives (compounds IV), endowed with anti-inflammatory and/or analgesic properties but no anti-pentylenetetrazole activity, prompted us to investigate in more detail the anti-inflammatory properties of three selected compounds IV (N,N-dimethyl-1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benz- odiazepin-5-amine; N,N-dibutyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine; 1-methyl-N,N-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine) and one structurally related compound (1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5(6H)-one). These BDZ derivatives have lost their affinity for the central and peripheral BDZ receptors. The in vivo effect on leukocyte migration of these compounds was investigated by using the mouse air-pouch model of local inflammation. Compounds A and B, significantly inhibited the carrageenan-induced leukocyte recruitment in a dose-dependent manner starting from the dose of 50 mgkg(-1), whereas compound C was effective only at the higher dose of 100 mgkg(-1). Compound D did not exert such effects at any of the doses considered. The effect of compounds A, B and C on leukocyte recruitment was paralleled by a significant inhibition of interleukin-6 and prostaglandin E(2)production in the exudate, similarly to indomethacin, and by a partial reduction of vascular permeability. These features may be relevant for the design and development of innovative anti-inflammatory molecules among the 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine derivatives.     

Design,synthesis and biological evaluation of novel 1,2,3-triazole analogues of Imidazo-[1,2-a]-pyridine-3-carboxamide against Mycobacterium tuberculosis

Twenty-eight novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3-carboxamide were designed and synthesized based on hybridization approach. The structure of the final compounds are characterized using ¹HNMR, ¹³CNMR, LCMS and elemental analyses and are screened in vitro for anti-tubercular activity using low-oxygen recovery assay (LORA) non-replicating and using microplate alamar blue assay (MABA) against replicating M. tuberculosis. MIC was determined. From the obtained results, it was observed that, among (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)(4-((1-subtituted phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)methanones and (6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(4-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)methanones, compounds with substitution at para position with electron electron releasing groups exhibited the best activity (< 34 μg/mL). Amidst, (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)(4-(2-(4-alkyl/substituted aryl-1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)methanones and (6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(4-(2-(4- alkyl/substituted aryl -1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)methanones, compounds with long alkyl chain or cyclo propyl group were most active (< 21 μg/mL) in MABA method against the tested strain of MTB. Compound 10b emerged to be the most active compound in MABA and LORA with MIC values 13.74 and 24.63 μg/mL respectively. In-silico ADMET parameters were also predicted for the significantly active compound. Finally, molecular docking study was carried out to predict the feasible binding pattern of the most active compound at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB-4TZK) using Glide module of Schrodinger software.     

Anellierte 2-Tetrazolyl-4-pyrone

Fused 2-Tetrazolyl-4-pyrones The synthesis of the 2-(1H-tetrazol-5-yl)-4-oxo-4H-[1]benzofuro[3,2-b]pyrane, -4-oxo-4H–[1]benzothieno[3,2-b]pyrane and -4,5-dihydro-5-alkyl-4-oxopyrano[3,2-b]indoles is described.     

In vitro antiplatelet profile of FR171113, a novel non-peptide thrombin receptor antagonist

We have examined the potency of several adenosine receptor antagonists at adenosine A₁ and A_2A receptors using quantitative autoradiography and have compared the results with those of previous studies using the same radioligands in membrane preparations. The agonists [³H]cyclohexyladenosine and [³H]2-[p-(2-carbonylethyl)-phenylethylamino]-5′-N-ethylcarboxamido adenosine ([³H]CGS 21680) were used as radioligands for the two receptors. The results show that 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX) is almost 1000-fold and 8-chloro-4-cyclohexyl-amino-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a] quinoxaline (CP-68,247) about 300-fold more potent at adenosine A₁ receptors in cortex and striatum than at striatal adenosine A_2A receptors. Conversely, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine (SCH 58261) is approximately 1000-fold and 4-(2-[7-amino-2-(2-furyl) [1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol (ZM 241,385) about 400-fold more potent at adenosine A_2A than at A₁ receptors. Caffeine and its metabolites did not show any selectivity. Other studied antagonists were non-selective or showed a modest (20- to 40-fold) adenosine A_2A receptor selectivity. Thus, only a few of the antagonists show such high selectivity that it is not offset by differences in drug distribution and levels of receptor subtype expression.     

[1,2,4]Triazolo[4,3-a]quinoxaline: synthesis, antiviral, and antimicrobial activities

A series of novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives and their isosteres, pyrimido-quinoxaline, were synthesized as potential antiviral and antimicrobial agents. The new compounds were synthesized via aromatic nucleophilic substitution of 4-chloro-8-methyl[1,2,4]triazolo[4,3-a]quinoxaline-1-amine with different amines and triazole-2-thiol. Some of the synthesized compounds were subjected to antiviral and cytotoxicity screening using plaque-reduction assay. Most of the tested compounds exhibited cytotoxicity at concentration 160?μg/ml and compound 8b showed promising antiviral activity. In vitro antimicrobial screening against different pathogenic organisms using agar diffusion method demonstrated that compounds 4d, 6c, 7b, and 8a exhibit antibacterial and/or antifungal activities.     

Synthesis of 2-(4-substitutedbenzyl-[1,4]diazepan-1-yl)-n-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides as inotropic agents

In an attempt to search for more potent positive inotropic agents, a series of N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(substitutedbenzyl-[1,4]diazepan-1-yl)acetamides were synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)-[1,4]-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide (6m) was the most potent, increasing stroke volume by 8.38±0.16% (milrinone 2.45± 0.06%) at 3 x 10(-5) m. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Reaktionen an Heterocyclen mit 2-Acyl-2-propenon-Teilstruktur, 5. Mitt. 2,5-Dioxo-2H,5H-[1]benzopyrano[4,3-b]pyridine durch Cyclisierung 3-substituierter 4-Aminocumarine

Reactions on Heterocycles Containing the 2-Acyl-2-propenone Structure, V: [1]Benzopyrano[4,3-b]-pyridine-2,5(2H, 5H)-diones by Cyclization of 3-Substituted 4-Aminocoumarines The synthesis of fluorescent [1]Benzopyrano[4,3-b]pyridine-2,5(2H, 5H)-diones 9 by a Wittig reaction using 4-chloro-2-oxo-2H-chromene-3-carbaldehydes 1 and phosphorane 2 is described. Aminolysis of the acrylic acid esters 3 leads to the 4-aminocoumarines 8 , which are cyclized thermically.     

Synthesis of 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles as potential anticonvulsant agents

A series of 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test, subcutaneous pentylenetetrazole (Sc-PTZ), and rotarod tests in intraperitoneally injected mice. Among the synthesized compounds, compound 2-phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3a) could be considered the potentially most useful and safe therapeutic compound, with ED₅₀ = 29.6 mg/kg, TD₅₀ = 285 mg/kg, and PI = 9.7. Its neurotoxicity was the lowest of all the synthesized compounds and was also markedly lower than that of the reference drug carbamazepine with PI value of 6.4.