Tricyclic heteroaromatic systems. 1,2,3,4-tetrahydropyrazolo[4,3-c][l]benzazepin-1-ones as potential antitumor agents

The synthesis of 1,2,3,4-tetrahydropyrazolo[4,3-c][1]benzazepin-1-ones 1 and that of its 10-methyl derivative 2 is reported. The preparation of the latter from 3-(2-aminobenzyl)3-pyrazolin-5-one and triethyl ortho-formate gave as the main product a derivative of the new tricyclic ring system, pyrazolo[1,5-c][1,3]benzo-diazepine. The structures of the new compounds synthesized were assigned by means of a ¹³C nmr study.     

Reactivity of pyrazolo[4,3-c][1,2,5]oxadiazin-3(5H)-ones toward C-nucleophiles: Synthesis of pyrazolo[3,4-b]pyrazines

The reaction of pyrazolo[4,3-c][1,2,5]oxadiazin-3(5H)-ones 1 with carbanions prepared in situ from compounds containing an activated methylene group afforded pyrazolo[3,4-b]pyrazines 4–13 in good yields. The possible reaction mechanism is proposed and discussed.     

The synthesis of medium-sized cyclic lactams by the intramolecular friedel-crafts cyclization of isocyanates. Formation of novel pyrazolo[3,4-c]benzolactams

A series of 4-ω-phenylalkyl substituted-1H-pyrazol-5-amines has been synthesized from the corresponding α-acetylphenylalkanenitriles and methylhydrazine. They were converted into the corresponding 5-isocyanates and cyclized under Friedel-Crafts conditions to medium-sized cyclic lactams. The reaction was shown to give the 7-, 8-, 9-, and 10-membered lactams but failed to yield the 11-membered lactam. Rings synthesized were: pyrazolo[3,4-c][2]benzazepin-2(1H)-one; 10H-pyrazolo[3,4-c][2]benzazocin-10-one; pyrazolo[3,4-c][2]benzazonin-11(1H)-one; 12H-pyrazolo[3,4-c][2]benzazocin-12-one.     

Synthesis of derivatives of pyrazolo[1,5-a]pyrrolo[1,2-c][1,3,6]-benzotriazocine,a new class of compounds with potential CNS activity

The synthesis of derivatives of pyrazolo[1,5-a]pyrrolo[1,2-c][1,3,6]benzotriazocine was obtained by the reaction of arylaldehydes with some 1-(2-aminophenyl)-5-(pyrrol-1-yl)pyrazoles, as hydrochlorides. Characterization of this new class of compounds was effected with ir, pmr and ¹³C nmr spectral data.     

Pyrazoles as building blocks in heterocyclic synthesis: Synthesis of pyrazolo [3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo [3,4-d][1,2,3]triazine and pyrolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several new pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo[3,4-d][1,2,3]triazine and pyrolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives were prepared by the reaction of the corresponding 5-amino-pyrazole-4-carbonitrile derivative with different organic reagents under different reaction conditions. Using IR, ¹H NMR, and mass spectra we have characterized all new compounds.     

Preparation and regiochemical assignments of new pyrazolo[3,4-c] [2,1]benzodiazepines

The preparation of new pyrazolo[3,4-c][2,1]benzothiazepines substituted at the nitrogen atoms of the pyrazole moiety is described. It was carried out by reaction of the 4,9-dihydro-9-methyl-4,10,10-trioxo-1(2)H-pyrazolo[3,4-c][2,1]benzothiazepine ( 1 ) with several alkylating agents under both classical and phase-transfer catalysis (PTC) conditions. Assignments of the N-alkyl regioisomers obtained were performed by study of their ¹H nmr spectra and NOE experiments.     

Synthesis,reactions, and antimicrobial activity of some novel pyrazolo[3,4-d]pyrimidine,pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine,and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c]pyrimidine derivatives

Treatment of N-phenyl-substituted benzenecarbo-hydrazonoyl chlorides 1a - d with malononitrile in sodium ethoxide solution gave 5-amino-4-cyanopyrazole derivatives 2 - 5 . Compounds 2 - 5 were converted to formidate derivatives 6 - 9 upon treatment with TEOF in acetic anhydride. The reaction of the latter products 6 - 9 with hydrazine hydrate gave imino-amino derivatives 10 - 13 , which was converted to hydrazino derivatives 14 - 17 by refluxing with hydrazine hydrate. Hydrazino as well as imino-amino derivatives undergo condensation, cyclization, and cycloaddition reactions to give pyrazolo[3,4-d]pyrimidine 18 - 21 , pyrazolo[4,3-e][1,2,4]triazolo-[3,4-c]pyrimidine 22 - 27 , and pyrazolo[3′,4′:4,5]pyrimido[1,6-b][1,2,4]triazine 42 - 44 derivatives. Antimicrobial studies are performed using two Gram-positive bacteria and two Gram-negative bacteria. Data indicated that compounds 5 , 28D , 29B , and 31D are exploring elevated antibacterial effects against all strains tested. Compound 28D is the most promising antibacterial agent against the delicate bacterial strain Bacillus subtilis and Pseudomonas aeruginosa with high effectiveness (low minimum inhibitory concentration [MIC] value) 40 and 60 μg/mL, respectively.     

Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol.     

Synthesis and alkylation of pyrazolo[3,4-c]isoquinolines and hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridines

The condensation of 1-acyl-2-(morpholin-4-yl)cycloalkenes with 3-amino-1-phenyl-1H-pyrazol-5(4H)-ones gave the corresponding 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoline and 3,6,7,8,9,10-hexahydrocyclohepta[ d]pyrazolo[3,4-b]pyridine derivatives. Alkylation of 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]-isoquinolines with alkyl halides occurred at the nitrogen atom in the 3-position. The structure of 7-methyl-2,5-diphenyl-2,3,6,7,8,9-hexahydro-1H-pyrazolo[3,4-c]isoquinolin-1-one was proved by X-ray analysis.     

Reactions with heterocyclic diazonium salts: New routes for the synthesis of pyrazolo[1,5-c]-1,2,4-triazoles and pyrazolo[1,5-c]-as-triazines

3-Phenylpyrazole-5-(liazonium chloride ( 1 ) couples with α-chloro derivatives of acetylacetone, ethyl acetoacetate and aceto-o-anisidine to yield the corresponding pyrazole-5-yl hydrazonyl chloride derivatives 2a-c . Compounds 2a,b were cyclised to yield either the pyrazolo[1,5-c]-1,2,4-triazole derivatives 3a,b or the pyrazolo[1,5-c]-as-triazines 4a,b depending on the applied reaction conditions. Compound 2c cyclised only into 3c under different cyclization conditions. The pyrazolo[1,5-c]-as-triazine derivatives 4c-e could be prepared via condensation of 2a with potassium cyanide. Compound 2d reacted with aromatic thioles and with sodium benzene-sulphonate to yield the pyrazolo[1,5-c]-as-triazine derivatives 6a-d . Compound 1 reacted with activated double bond systems to yield pyrazolo[1,5-c]-as-triazines 8a,b and 9 .     

A comparison of electron impact mass spectrometry of isomeric pyranocoumarins (pyrano[3,2-c][1]benzopyran-5-ones) and pyranochromones (pyrano[2,3-b][1]benzopyran-5-ones)

The mass spectrometric behaviour of two pairs of isomeric 2,2-dimethylpyrano[3,2-c][1]benzopyran-5-ones (pyranocoumarins) and 2,2-dimethylpyrano[2,3-b][1]benzopyran-5-ones (pyranochromones) and four pairs of isomeric 2-hydroxymethyl-2-methylpyrano[3,2-c][1]benzopyran-5-ones (pyranocoumarins) and 2-hydroxymethyl-2-methylpyrano[2,3-b][1] benzopyran-5-ones (pyranochromones) has been studied in detail with the aid of exact mass measurements, linked scans, collisionally activated decompositions and deuterium labelling experiments. The presence in both series of compounds of the same ions derived by structural interconversion of both molecular ions is emphasized, and structural information on the ions [C₇H₅O₂]⁺ (m/z 121), highly characteristic for these classes of compounds, as for 4-hydroxycoumarins, is reported.     

Synthesis of pyrazolo[4,3-<Emphasis Type="Italic">e</Emphasis>][1,2,4]triazolo[4,3-<Emphasis Type="Italic">c</Emphasis>]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol. Correspondence: Abolghasem Davoodnia, Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran.     

Facile synthesis and antifungal activity of 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

The reactions of the pyrazole-5-diazonium salt 3 with malononitrile and ethyl cyanoacetate gave 4-amino-3-cyano-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazine 7 and 4-amino-3,8-bisethoxycarbonylpyrazolo[5,1-c]-[1,2,4]triazine 8 , whose reactions with p-chloroaniline hydrochloride afforded 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)amidinopyrazolo[5,1-c][1,2,4]triazine 9 and 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)car-bamoylpyrazolo[5,1-c][1,2,4]triazine 10 , respectively. The reactions of 7 and 8 with o-phenylenediamine di-hydrochloride provided 9-ethoxycarbonyl-13H-spiro[benzimidazole-2′(3′H),6(5H)-pyrazolo[1,5′:3,4][1,2,4]tri-azino[5,6-b][1,5]benzodiazepine] hydrochloride 11a and 9-ethoxycarbonyl-6-oxo-13H-5,6-dihydropyrazolo-[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepine 12 , respectively. The antifungal activity of the above compounds was described.     

Ring transformation of 1,5-benzoxazepines into spirobenzoxazoles. Synthesis of pyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines and spiro[benzoxazole-2′(3′H),4(1H)-pyrazolo[5,1-c][1,2,4]triazines]

The reactions of the 3-substituted 4-amino-8-ethoxycarbonyl[5,1-c][1,2,4]triazines 1 and 2 with o-amino-phenol hydrochloride gave the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5 and 8 . The alkylation of 5 with methyl iodide and isopropyl iodide afforded the 6-alkoxylpyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines 6a and 6b , respectively. Refluxing of 5, 6a, 6b and 8 in hydrochloric acid/acetic acid resulted in ring transformation to produce the spiro[benzoxazole-2′(3′H),4(1H)pyrazolo[5,1-c][1,2,4]-triazines] 7a, 7b and 9 . The screening data of the above compounds was described.     

A new method for the synthesis of novel 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

Novel 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines 7,8 were synthesized by the reactions of malononitrile and ethyl cyanoacetate with the pyrazole-5-diazonium salt 3 . Moreover, compounds 7,8 were converted into the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines 9, 10 .     

Synthesis of pyrazolo[4,5-d]- and pyrazolo[4,5-c][1]benzazepine derivatives. IV

Following our reports on synthetic tricyclic analogues of antitumor anthramycin the synthesis of some isomers pyrazolo[4,5-d]- and pyrazolo[4,5-c][1]benzazepine derivatives is reported.     

A new method for the synthesis of novel 6-quinoxalinylpyrazolo[5,1-c][1,2,4]triazines

The reaction of the quinoxaline 1 with 4-ethoxycarbonyl-1H-pyrazole-5-diazonium chloride 7 at room temperature gave 3-[α-(4-ethoxycarbonyl-1H-pyrazol-5-ylhydrazono)methoxycarbonylmethyl]-2-oxo-1,2-dihydroquinoxaline 8. The pmr spectrum of 8 in deuteriodimethylsulfoxide supported the presence of two tautomers 8-I and 8-II. Refluxing of 8 in N,N-dimethylformamide or acetic acid resulted in cyclization to afford 8-ethoxycarbonyl-4-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine 9. Compound 9 was also obtained directly by the reaction of 1 with 7 under reflux in better yield. The reaction of 9 with hydrazine hydrate provided the hydrazinium salt 10 , while the reactions of 9 with triethyl and trimethyl orthoformates in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene produced 8-ethoxycarbonyl-4-ethoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11a and 8-ethoxycarbonyl-4-methoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11b , respectively. The chlorination of 11a with phosphoryl chloride gave 3-(3-chloroquinoxalin-2-yl)-8-ethoxycarbonyl-4-ethoxylpyrazolo[5,1-c]-[1,2,4]triazine 12 , whose reaction with morpholine afforded 8-ethoxycarbonyl-4-ethoxyl-3-[3-(morpholin-4-yl)-quinoxalin-2-yl]pyrazolo[5,1-c][1,2,4]triazine 13.     

Synthesis of 8-alkylthio- and 8-selanyl-3-tert-butylpyrazolo[5,1-c][1,2,4]triazines

Abstract

Interaction of 8-lithio-3-tert-butyl-4-oxopyrazolo[5,1-c][1,2,4]triazin-1-ide with elemental sulfur or selenium in THF with further in situ alkylation at –97?°C followed by warming to room temperature furnished a series of 3-tert-butyl-8-X-pyrazolo[5,1-c][1,2,4]triazin-4(6H)-ones (X?=?n-BuS, n-BuSe, MeSe, PhCH₂S) in good yields. 8,8'-Diselanediylbis(3-tert-butylpyrazolo[5,1-c][1,2,4]triazin-4(1H)-one) was also isolated as a by-product in these reactions. One-pot interaction of the n-BuSe substituted derivative with diborane/boron trifluoride led to reduction of the 1,2,4-triazine core and partial elimination of the alkylselanyl moiety. The structures of the synthesized products were established on the basis of IR, ¹H, 13C, 2D HMBC ¹H–⁷⁷Se NMR and high resolution mass spectra, as well as X-ray single crystal diffraction analyses. Two of the prepared compounds were also tested for antimicrobial and antifungal activities.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Synthesis and selected properties of N-substituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

The reactions of methyl α-(2-formyl-1H-pyrrol-1-yl)carboxylates with N-substituted aliphatic 1,2-, 1,3-, and 1,4-diamines afford new pyrrole-containing heterocyclic systems: 1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-ones, 1,3,4,11b-tetrahydro-2H-pyrrolo[2′,1′:3,4]pyrazino[1,2-a]pyrimidin-6(7H)-ones, and 1,2,3,4,5,12b-hexahydro-pyrrolo[2′,1′:3,4]pyrazino[1,2-a][1,3]diazepin-7(8H)-ones. The reduction of these compounds with different reagents was studied.