Search

The 5-aryl(or methyl)-3-phenylcarbamoyl-1,3,4-oxadiazol-2(3H)-ones 2, in the presence of sodium hydride in anhydrous dimethylformamide, were transformed into 1-benzamido(or acetamido)-3,5-diphenyl-1,3,5-triazine-2,4,6-trione derivatives 7 in poor yields. However, compounds 7 were obtained in better yields when the sodium salts of 5-aryl(or methyl)-1,3,4-oxadiazol-2(3H)-ones 1 were treated with two equivalents of aryl(or ethyl)isocyanates. Acidic hydrolysis of 1-acetamido-3,5-diphenyl-1,3,5-triazine-2,4,6-trione (7i) provided the corresponding free N-amino derivative 9. Nitrous deamination of 9 gave the known 3,5-diphenyl-1,3,5-triazine-2,4,6-trione (11). This cyclic transformation is the first one to be reported providing 1,3,5-triazine-2,4,6-trione derivatives.

Reactions of ethyl 3-aryl-2-benzoylpropenoates 1 with guanidine and N-alkyl(or benzyl)guanidines have been investigated. Ethyl 2-aminodihydro-5-pyrimidinecarboxylate derivatives 3, 4 or 5, and 3,7-diethoxy-carbonyl-4,6-dihydro-2,4,6,8-tetraaryl-1H-pyrimido[1,2-a]pyrimidines 6 have been synthesized.

A series of ethyl 2-oxo-3(2H)-benzoxazoleacetate derivatives 2 have been synthesized. By reaction with ammonia, primary amines or hydrazine, these compounds 2 were transformed into 1-(2-hydroxyphenyl)-2,4-imidazolidinedione derivatives 4, 5 and 6, respectively. Some of these new hydantoins 4, treated with phosphorus oxychloride, gave 3H-2-oxoimidazo[2,1-b]benzoxazole derivatives 9. Ethyl 2-oxo-3(2H)-benzoxazolepropionate (10) was prepared by a Michael reaction of ethyl acrylate with 2-benzoxazolone (1a). With 10, no cyclic transformation was observed in the presence of ammonia or alkylamine.

We report the radiochemical synthesis of a specific MAO B inhibitor, namely 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-[11C]-2(3H)-one (2b) (in vitro IC50=4nM and selectivity over 71000 for MAO B), by cyclization of its hydrazide precursor1 with [11C]phosgene. The reaction occurred within 2 min. The product obtained after HPLC purification,2b, had a high specific activity (11.1–22.2 GBq/µmol), allowing its use in experiments as a radiotracer in vivo. Biodistribution of2b in the CNS and in the peripheral organs of the rat, and positron emission tomography (PET) studies in the living baboon brain, pretreated or not withl-deprenyl (1 mg/kg, 1 h), an irreversible MAO B-specific inhibitor, were undertaken. The results showed a good uptake of2b in all organs of the rat, with a rapid clearance from the blood (10 min). Metabolite analyses in plasma and in the diencephalon of the rat showed that2b was the only radioactive compound in brain structure whereas in plasma three other radioactive products appeared. PET experiments show that in thel-deprenyl-pretreated baboon brain, specific binding of2b represents around 70% of total radioactivity, whereas in the blood and plasma the radioactivity cleared rapidly (15 min).

Twenty new 2-(cyanoalkyl)tetrazoles (15 and 16) and twenty new 2-(hydroxyalkyl)tetrazoles (17 and 18) were synthesized and investigated in vitro for their abilities to inhibit selectively rat brain monoamine oxidase (MAO) B over MAO A. Most of them were MAO B inhibitors and those bearing a substituted 4-(arylmethoxy)phenyl group in the position 5 of the tetrazole ring had IC50 values between 8 microM for 18d and 2 nM for 16a (30 nM for lazabemide) with a selectivity toward MAO B of 37,000 for 16a. The reversibility of their inhibitory activity was demonstrated by in vitro dialysis tests. The 5-[4-(phenylmethoxy)phenyl]-2-(2-cyanoethyl)tetrazole (16a) its derivative 16h and the 5-[4-(phenylmethoxy)phenyl]-2-(2-hydroxyethyl)tetrazole (18a) and its derivative 18h were found to be potent, in vitro selective, and competitive MAO B inhibitors. Tetrazole 16a can be considered one of the most active and selective competitive MAO B inhibitors known up to now. This compound was selected for ex vivo experiments and was shown to be a strong and reversible MAO B inhibitor with a short duration of action after oral administration at 5 mg/kg. The structure-activity approach gives rise to the great importance of lipophilicity over electronic effects of the compounds in these series.

Summary The synthesis and the evaluation of the monoamine oxidase A and B inhibitory activities of 21 new substituted acylhydrazones of various aromatic aldehydes and 4-(benzyloxy)acetophenone, and four substituted semicarbazones of benzaldehyde and 4-(benzyloxy)benzaldehyde, are described. The 4-(benzyloxy)phenyl group contributing to a high lipophilicity led to the most active compounds. One of these, compound 3g (IC 50 = 3 nM, MAO A/MAO B selectivity > 33 000), was found to act as a reversible and probably tight-binding inhibitor. The studied acyclic hydrazones and semicarbazones are structurally related to other reversible and potent inhibitors, eg , heterocyclic compounds such as 1,3,4-oxadiazol-2(3 H )-one derivatives in which the hydrazono group is intracyclic. Some of these new inhibitors might find use in the symptomatic treatment of neurodegenerative processes.

Reactions of 2-chloroformylhydrazones of aromatic aldehydes or ketones (2) with various hydrazines were converted to monocarbonohydrazone derivatives (3) or (5) and/or tetrahydro-1,2,4,5-tetrazin-3(2H)-one derivatives (6), (7). By oxidation with lead dioxide, compounds (6) were transformed into stable 3,4-dihydro-3-oxo-1,2,4,5-tetrazin-1(2H)yl radical derivatives (8)

New 3-acylamino-2-oxazolidinone derivatives 3 were obtained in good yields by reaction of 5-aryl (or benzyl)-3-(2-hydroxyethyl)- 1,3,4-oxadiazol-2(3H)-ones (1) with sodium ethylate. Treatment of ethyl 5-aryl-2-oxo-1,3,4-oxadiazole-3(2H)-acetates (7) with aromatic aldehydes in the presence of sodium ethylate or sodium hydride afforded 3-acylamino-5-aryl-4-ethoxycarbonyl-2-oxazolidinone derivatives as two trans-5 and cis-6 racemics. Only RS,SR-racemates were obtained with acetophenone under the same conditions

Some 5-aryl(or benzyl)-(2-oxo-1,3,4-oxadiazole-3(2H)-acetones or acetophenones 2 were easily prepared. These compounds reacted with hydrazine derivatives to give 4,5-dihydro-1,2,4-triazin-3(2H)-one derivatives 3, 4 and 6 in good yields. With phenylhydrazine, the intermediate hydrazones 5 were obtained. Their conversion into triazinones necessitated the presence of sodium ethylate

Eighteen new 5-aryl-1,3,4-oxadiazol-2(3H)-one derivatives and sulfur analogues were prepared and evaluated in vitro for their inhibitory properties on monoamine oxidase (MAO) types A and B. The most active compounds in these series acted preferentially against MAO B with IC50 values in the range of 1.8-0.056 μM. The 5-(4-biphenylyl)-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one 23 and its oxadiazolethione analogue 33 were found to act as potent, selective and competitive MAO B inhibitors with a slight slow-binding character. Both compounds inhibited MAO A in a classical competitive manner. According to their Ki (MAO B) values of 2.6 and 4 × 10−8 M, respectively, and their Ki (MAO A)/Ki (MAO B) ratios of 270 and 500, respectively, 23 and 33 can be placed among the most active and selective competitive MAO B inhibitors known up to now. The structure-activity relationships are discussed.

Some ethyl 5-aryl(or benzyl)-2-oxo-1,3,4-oxadiazole-3(2H)-acetates were prepared and treated with ammonia, primary amines or hydrazine to give 1-amino-2,4-imidazolidinedione or 1,3-diamino-2,4-imidazolidinedione derivatives. The 1,3-bis(benzylideneamino)-,2,4-imidazolidinedione was obtained by reacting ethyl bromoacetate with the 1,5-dibenzylidenecarbonohydrazide sodium salt

New 3-acylamino-2-oxazolidinone derivatives 3 were obtained in good yields by reaction of 5-aryl (or benzyl)-3-(2-hydroxyethyl)- 1,3,4-oxadiazol-2(3H)-ones (1) with sodium ethylate. Treatment of ethyl 5-aryl-2-oxo-1,3,4-oxadiazole-3(2H)-acetates (7) with aromatic aldehydes in the presence of sodium ethylate or sodium hydride afforded 3-acylamino-5-aryl-4-ethoxycarbonyl-2-oxazolidinone derivatives as two trans-5 and cis-6 racemics. Only RS,SR-racemates were obtained with acetophenone under the same conditions

Twenty new 2-(cyanoalkyl)tetrazoles (15 and 16) and twenty new 2-(hydroxyalkyl)tetrazoles (17 and 18) were synthesized and investigated in vitro for their abilities to inhibit selectively rat brain monoamine oxidase (MAO) B over MAO A. Most of them were MAO B inhibitors and those bearing a substituted 4-(arylmethoxy)phenyl group in the position 5 of the tetrazole ring had IC50 values between 8 microM for 18d and 2 nM for 16a (30 nM for lazabemide) with a selectivity toward MAO B of 37,000 for 16a. The reversibility of their inhibitory activity was demonstrated by in vitro dialysis tests. The 5-[4-(phenylmethoxy)phenyl]-2-(2-cyanoethyl)tetrazole (16a) its derivative 16h and the 5-[4-(phenylmethoxy)phenyl]-2-(2-hydroxyethyl)tetrazole (18a) and its derivative 18h were found to be potent, in vitro selective, and competitive MAO B inhibitors. Tetrazole 16a can be considered one of the most active and selective competitive MAO B inhibitors known up to now. This compound was selected for ex vivo experiments and was shown to be a strong and reversible MAO B inhibitor with a short duration of action after oral administration at 5 mg/kg. The structure-activity approach gives rise to the great importance of lipophilicity over electronic effects of the compounds in these series.

The 5-aryl(or methyl)-3-phenylcarbamoyl-1,3,4-oxadiazol-2(3H)-ones 2, in the presence of sodium hydride in anhydrous dimethylformamide, were transformed into 1-benzamido(or acetamido)-3,5-diphenyl-1,3,5-triazine-2,4,6-trione derivatives 7 in poor yields. However, compounds 7 were obtained in better yields when the sodium salts of 5-aryl(or methyl)-1,3,4-oxadiazol-2(3H)-ones 1 were treated with two equivalents of aryl(or ethyl)isocyanates. Acidic hydrolysis of 1-acetamido-3,5-diphenyl-1,3,5-triazine-2,4,6-trione (7i) provided the corresponding free N-amino derivative 9. Nitrous deamination of 9 gave the known 3,5-diphenyl-1,3,5-triazine-2,4,6-trione (11). This cyclic transformation is the first one to be reported providing 1,3,5-triazine-2,4,6-trione derivatives.

The 3,5-disubstituted 1-amino-1,3,5-triazine-2,4,6-triones were synthesized in good yields from aromatic aldehyde or ketone ethoxycarbonylhydrazones by treatment with aryl or methyl isocyanates in boiling triethylamine followed by hydrolysis with hydrochloric acid solution.

Four 3-(3-benzylidene-2-phenylcarbazoyl)-2(3H)-benzoxazolone derivatives 3 have been synthesized from benzoxazolone derivatives 1 and benzaldehyde N-chloroformylphenylhydrazone 2. By acid hydrolysis, these compounds yielded 3-(2-phenylcarbazoyl)-2(3H)benzoxazolone derivatives 4 which were not isolated and were transformed via an intramolecular reaction into 4-(2-hydroxyphenyl)-1-phenyl-1,2,4-triazolidine-3,5-dione derivatives 5 in a good yield. Attempts to cyclize these compounds by intramolecular elimination of water into tricyclic compounds 6 with various dehydrating agents were unsuccessful.

5-Aryl(or benzyl)-3-(2-bromoethyl)-1,3,4-oxadiazol-2(3H)-ones 3 have been prepared. They were reacted with secondary alkylamines without any change of the heterocycle to give amino derivatives 6, but with primary alkylamines, cyclic transformation occurred to give 1-acylamino-3-alkylimidazolidin-2-ones 7. In the presence of sodium alcoholate, bromo compounds 3 were transformed into 2-aryl(or benzyl)-4-alkoxycarbonyl-5,6-dihydro-4H-1,3,4-oxadiazines 9.

Some 5-aryl(or benzyl)-(2-oxo-1,3,4-oxadiazole-3(2H)-acetones or acetophenones 2 were easily prepared. These compounds reacted with hydrazine derivatives to give 4,5-dihydro-1,2,4-triazin-3(2H)-one derivatives 3, 4 and 6 in good yields. With phenylhydrazine, the intermediate hydrazones 5 were obtained. Their conversion into triazinones necessitated the presence of sodium ethylate

Four 3-(3-benzylidene-2-phenylcarbazoyl)-2(3H)-benzoxazolone derivatives 3 have been synthesized from benzoxazolone derivatives 1 and benzaldehyde N-chloroformylphenylhydrazone 2. By acid hydrolysis, these compounds yielded 3-(2-phenylcarbazoyl)-2(3H)benzoxazolone derivatives 4 which were not isolated and were transformed via an intramolecular reaction into 4-(2-hydroxyphenyl)-1-phenyl-1,2,4-triazolidine-3,5-dione derivatives 5 in a good yield. Attempts to cyclize these compounds by intramolecular elimination of water into tricyclic compounds 6 with various dehydrating agents were unsuccessful.

Some ethyl 5-aryl(or benzyl)-2-oxo-1,3,4-oxadiazole-3(2H)-acetates were prepared and treated with ammonia, primary amines or hydrazine to give 1-amino-2,4-imidazolidinedione or 1,3-diamino-2,4-imidazolidinedione derivatives. The 1,3-bis(benzylideneamino)-,2,4-imidazolidinedione was obtained by reacting ethyl bromoacetate with the 1,5-dibenzylidenecarbonohydrazide sodium salt

Eleven 1-(4-substituted α-arylaminobenzylidene)thiosemicarbazides 1 and the related semicarbazones 2 were synthesized and tested in vitro for their inhibitory effects on the islets of Langerhans. Only the thiosemicarbazones 1 suppressed the insulin and glucagon secretions while the somatostatin release persisted. The 1-(α-anilino-4-methylbenzylidene)thiosemicarbazide 1f was the most potent suppressor of insulin release adn lysed the islet β cells. Zinc sulfate protected islets from the suppressive and toxic effects of 1f . These compounds 1 could be potential drugs for the treatment of insulinomas.

Eighteen new 5-aryl-1,3,4-oxadiazol-2(3H)-one derivatives and sulfur analogues were prepared and evaluated in vitro for their inhibitory properties on monoamine oxidase (MAO) types A and B. The most active compounds in these series acted preferentially against MAO B with IC50 values in the range of 1.8-0.056 μM. The 5-(4-biphenylyl)-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one 23 and its oxadiazolethione analogue 33 were found to act as potent, selective and competitive MAO B inhibitors with a slight slow-binding character. Both compounds inhibited MAO A in a classical competitive manner. According to their Ki (MAO B) values of 2.6 and 4 × 10−8 M, respectively, and their Ki (MAO A)/Ki (MAO B) ratios of 270 and 500, respectively, 23 and 33 can be placed among the most active and selective competitive MAO B inhibitors known up to now. The structure-activity relationships are discussed.

The 3,5-disubstituted 1-amino-1,3,5-triazine-2,4,6-triones were synthesized in good yields from aromatic aldehyde or ketone ethoxycarbonylhydrazones by treatment with aryl or methyl isocyanates in boiling triethylamine followed by hydrolysis with hydrochloric acid solution.

Thirty-three new 5-[4-(benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives including related analogues, designed as inhibitors of monoamine oxidase type B (MAO B), were synthesized and investigated both in vitro and ex vivo for their abilities to inhibit selectively rat brain MAO B over MAO A. Three inhibitors were found to act as reversible, highly potent, and selective MAO B inhibitors, namely the nitrile derivative 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (12a) and two closely related homologues, the corresponding oxadiazolethione 13a and the alcohol 14b. Their IC50 (MAO B) values are in the low nanomolar range of 1.4-4.6 nM and their selectivities, estimated by the ratio of IC50 values (A/B), are from 3200 to > 71,400. Compound 12a exhibited the highest activity against MAO B. Its IC50 was evaluated to be 1.4 nM with a quasitotal selectivity (> 71,400) toward this enzyme. In ex vivo studies, 12a showed a reversible and short duration of action. MAO B was markedly inhibited with the oral dose of 1 mg/kg without any alteration of MAO A, and the inhibition almost did not exceed 24 h. Its ED50 (1 h after oral administration) was evaluated to be 0.56 mg (1.7 mumol)/kg. Remarkably, MAO A was not affected at doses as high as 1500 mg/kg, po. In addition, no apparent toxicity or behavioral anomaly was observed during the treatment even at the maximum administrated dose. SAR studies emphasize the existence of three binding sites to the enzyme with a special importance of the terminal phenyl. Analysis of the inhibition kinetics indicated that 12a acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO B with a Ki value of 0.22 microM and an overall Ki* value at equilibrium of 0.7 nM.

L'action des aroylhydrazines sur le ehlorhydrate de benziminoether conduit aux aroyl-liydrazones du benzoate d'ethyle. Ces composes se cyclisent thermiquemenl ou dans l'alcool en presence de carbonate de sodium pour donner les aryl-5 phenyl-2 oxadiazoles-1,3,4 correspondants. L'action de 1′hydrazine conduit aux amino-4 aryl-5 phenyl-3 4H triazoles-1,2,4 et au diphenyl-3,6 tetrazine-1,2,4,5. Enfin, L'iodure de methylmagnesium reagit sur ces hydrazones en formant les aroylhydrazones de L'acetophenone. Les spectres IR, RMN, et UV des nouveaux composes sont etudies. The aroylhydrazones of ethyl benzoate have been prepared in fair yield by the action of aroylhydrazines on ethyl benzimidate hydrochloride. These products give rise, quantitatively, at their melting point, to 5-aryl-2-phenyl-1,3,4-oxadiazoles, and, in the presence of hydrazine hydrate, in boiling 1-propanol to 4-amino-5-aryl-3-phenyl(4H)-1,2,4-triazoles (Yields 50%). The addition of methylmagnesium iodide to these products give aroylhydrazones of acetophenone.

In order to study the ring expansion of N-aminoaziridines into N-amino-5-membered heterocycles, N-(dibenzyloxycarbonylamino)aziridines were synthesized. N, N-Dibenzyloxycarbonylhydrazine was prepared. It was then oxidized with lead tetraacetate to a new diacylaminonitrene. This nitrene was added to various olefins to give the corresponding N-protected aminoaziridines. Cleavage of the protecting groups was realized for one example.

La synthese des arnino-4 aryl-3 triazol-1,2,4 ones-5 a ete realisee par quatre methodes: a partir du carbohydrazide par reactions avec les chlorhydrates d'aryliminoethers, l'orthobenzoate d'ethyle ou le trichlorophenylmethane, et aussi a partir du N-carbethoxyhydrazone du benzoate d'ethyle et de ses derives par reaction avec l'hydrazine. Les mecanismes de ces reactions sont proposes; ils ont en commun la formation d'un intermediaire, la monocarbohydrazone du benzoate d'ethyle. Les spectres ir, uv, rmn de ces heterocycles sont discutes. The synthesis of 4-amino-3-aryl-l,2,4-triazol-5(4H)ones has been accomplished by four methods.

Les spectres de masse des aryl-2 alkyl-4 oxadiazol-1,3,4 ones-5 et de leurs isomeres aryl-2 alcoxy-5 oxadiazoles-1,3,4 ont ete etudies. La fragmentation de ces composes ne semble pas faire intervenir d'isomerisation unimoleculaire d'origine electronique. Pour chaque type d'heterocycle, les transferts d'hydrogene accompagnant la pete de la chaine alcoylee sont principalement induits par l'azote 4. The mass spectra of 2-aryl-4-alkyl-1,3,4-oxadiazole-5-ones and their 2-aryl-5-alkoxy 1,3,4-oxadiazole isomers have been studied. Unimolecular electron impact-induced isomerization does not seem to occur during the fragmentation of these compounds. For each type of heterocycle, the hydrogen transfers, during the cleavage of the alkyl chain, are mainly caused by the nitrogen in position 4.

L'oxydation des aroylhydrazones d'aldehydes aromatiques, par le bioxyde de plomb, dans l'acide aceti-que, constitue une nouvelle methode d'acces, simple et rapide, aux oxadiazoles-1,3,4 correspondants. Dans le dimethylformamide, et en presence du měme oxydant, les carbodihydrazones d'aldehydes aromatiques con-duisent aux aryl-3 arylideneamino-4 triazol-1,2,4 ones-5 correspondantes. Plusieurs mecanismes radicalaires sont proposes. Aromatic aldehyde aroylhydrazones when oxidizen with lead dioxide, in acetic acid, gave quickly the corresponding 1,2,4-oxadiazoles in good yields. Aromatic aldehyde carbodihydrazones on the other hand, gave derivatives of 4-amino-3-aryl-1m,2,4-triazol-5-ones, in dimethylformamide as solvent. To explane these results, some radical mechanisms are proposed.

Monoamine oxidase (MAO) assay specificity based on substrate specificity was investigated by substrate competition experiments. 10 μM serotonin (5-HT) and 5 μM β-phenylethylamine (PEA) were found to ensure total substrate specificity for, respectively, MAO types A and B. Twenty-five 2-aryl-4 H -1,3,4-oxadiazin-5(6 H )-one derivatives were synthesized and tested in vitro for their inhibitory effects on MAO A and B. Most of them inhibited preferentially MAO B. The 2-(4-biphenylyl)-4-(2-cyanoethyl)-4 H -1,3,4-oxadiazin-5(6 H )-one 32 was the most efficient MAO B inhibitor and acted as a competitive inhibitor on the two enzymes. Its K i values for MAO A and B were 11 and 0.15 μM, respectively. Structure-activity relationships suggest that these oxadiazinones should interact with a hydrophobic site and a nucleophilic site on MAO B for binding, while the functional group of the N-4 substituent should compete with the substrate for the active site of the enzyme.

Some 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one derivatives 6 and 9 have been synthesized in two ways. The expected thermal ring transformation into 2,5-disubstituted 1,3,4-oxadiazoles did not occur but, by acid hydrolysis of 5-aryl-3-[3-benzylidene-2-methyl(or phenyl)carbazoyl]-1,3,4-oxadiazol-2(3H)-ones 6, a new ring transformation took place and the corresponding 4-benzamido-1-methyl(or phenyl)-1,2,4-triazolidine-3,5-dione derivatives 11 were formed. The 4-amino-1-phenyl-1,2,4-triazolidine-3,5-dione (19) has been prepared and its structure was confirmed by some reactions.

Les spectres de masse d'un certain nombre d'amino-4 triazole-1,2,4 ones-5 differemment substituees en position 1 sont rapportes; ils mettent en evidence de nouveaux rearrangements et des migrations d'hydrogene. La comparaison des spectres normaux et des spectres d'energie cinetique obtenus selon la technique simili MIKE a permis de determinerla structure des ions moleculaires et des ions fragments et de decrirela formation de ces derniers. Ces resultats montrent que ľion moleculaire des amino-4 triazolones-5 non substituees en position 1 existe probablement en phase gazeuse sous deux formes tautomeres (N-1-H et OH). The mass spectra of several 4-amino-1,2,4-triazole-5-ones with different groups in position 1 have been recorded and show new skeletal rearrangements and hydrogen migrations. The comparison of the ‘normal’ and mass analysed ion kinetic energy spectra obtained by the ‘simili MIKE’ technique permits the determination of the molecular ion and fragment ion structures and also the mechanism of formation of these ions. These results show that the molecular ion of the N-1 unsubstituted 4-amino-1,2,4-triazole-5-ones exists in the gas phase in two tautomeric forms.

Thirty new 2-substituted-4-amino-5-alkyl or aryl-2,4-dihydro-1,2,4-triazol-3-ones and ten 2-substituted-5-alkyl or aryl-4-(5-nitro-2-furfurylidene)amino-2,4-dihydro-1,2,4-triazol-3-ones were synthesized and characterised by their sharp melting points, elemental analysis, ir and 1H nmr spectra. These new derivatives of 5-nitro-2-furaldehyde were screened for their antibacterial activities. Most of the compounds showed good activity against one test organism, Staphylococcus aureus. For a few compounds, C.M.I. ranged from 4 to 8 μg/ml (higher results than nitrofurantoin).

Une nouvelle synthese generale des dihydro-2,4 triazole-1,2,4 thiones-3 disubstituees en position 4 et 5 est proposee. Ces heterocycles sont obtenus par action d'amines primaires, d'arylhydrazines ou d'aroylhydrazines sur les thiosemicarbazones d'esters. Celles-ci sont preparees par action de chlorhydrates d'iminoethers sur la thiosemicarbazide dans le dimethylformamide. Les thiosemicarbazones se pretent a d'autres reactions avec les acides forts, les anhydrides et chlorures d'acides; par thermolyse, ils donnent des derives de l'amino-2 thiadiazole-1,3,4. Enfin, deux derives du [1,2,4triazolo][3,4-b]thiadiazole-1,3,4 ont ete prepares.

Treatment of various substituted semicarbazones of aromatic aldehydes with sulfur monochloride yields the corresponding substituted 2,4-dihydro-1,2,4-triazol-3-ones. With thiosemicarbazones, the products are derivatives either of the 2-amino-1,3,4 thiadiazole or of the 2,4-dihydro-1,2,4-triazole-3-thione depending on the experimental conditions.

La synthese du chloro-5 phenyl-2 oxadiazole-1,3,4 a ete mise au point. Ce produit est utilisable pour la preparation de derives ou O-alkyles ou O-aryles de l'hydroxy-5 pheenyl-2 oxadiazole-1,3,4. The 5-Chloro-2-Phenyl-1,3,4-oxadiazole has been prepared in fair yield. This product is a convenient starting material for the synthesis of O-alkylated or O-arylated derivatives of the 5-hydroxy-2-phenyl-1,3,4-oxadiazole.

Monoamine oxidase (MAO) assay specificity based on substrate specificity was investigated by substrate competition experiments. 10 μM serotonin (5-HT) and 5 μM β-phenylethylamine (PEA) were found to ensure total substrate specificity for, respectively, MAO types A and B. Twenty-five 2-aryl-4 H -1,3,4-oxadiazin-5(6 H )-one derivatives were synthesized and tested in vitro for their inhibitory effects on MAO A and B. Most of them inhibited preferentially MAO B. The 2-(4-biphenylyl)-4-(2-cyanoethyl)-4 H -1,3,4-oxadiazin-5(6 H )-one 32 was the most efficient MAO B inhibitor and acted as a competitive inhibitor on the two enzymes. Its K i values for MAO A and B were 11 and 0.15 μM, respectively. Structure-activity relationships suggest that these oxadiazinones should interact with a hydrophobic site and a nucleophilic site on MAO B for binding, while the functional group of the N-4 substituent should compete with the substrate for the active site of the enzyme.

Treatment of various substituted semicarbazones of aromatic aldehydes with sulfur monochloride yields the corresponding substituted 2,4-dihydro-1,2,4-triazol-3-ones. With thiosemicarbazones, the products are derivatives either of the 2-amino-1,3,4 thiadiazole or of the 2,4-dihydro-1,2,4-triazole-3-thione depending on the experimental conditions.

Unstable 5-aryl-2-(3-benzylidene-2-phenylcarbazoyl)-1,2,3,4-tetrazoles 8 have been prepared. By thermal ring transformation, they gave 5-aryl-2-(2-benzylidene-1-phenylhydrazino)-1,3,4-oxadiazoles 9., Hydrazinolysis of 9 afforded 5-aryl-2-(1-phenylhydrazino)-1,3,4-oxadiazoles 10. Elimination of a molecule of benzonitrile from 9 on heating converted them into 2-anilino-5-aryl-1,3,4-oxadiazoles 11.

In order to study the ring expansion of N-aminoaziridines into N-amino-5-membered heterocycles, N-(dibenzyloxycarbonylamino)aziridines were synthesized. N, N-Dibenzyloxycarbonylhydrazine was prepared. It was then oxidized with lead tetraacetate to a new diacylaminonitrene. This nitrene was added to various olefins to give the corresponding N-protected aminoaziridines. Cleavage of the protecting groups was realized for one example.