Synthesis and antiproliferative evaluation of new aryl substituted pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazoles

The preparation and the cytotoxic properties of new derivatives of the planar pyrido[3′,2′:5,6]thiopyrano‐[4,3‐c]pyrazole system, carrying an arylic side group in the 1 or 2 positions, are described. The novel substituted derivatives were obtained by reaction of suitable arylhydrazines with the appropriate key intermediate 3‐hydroxymethylene‐2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐ones. Moreover the preparation was reported of the 2‐carboxamidophenyl derivatives, which was accomplished from the previously obtained pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazole nucleus, by reaction with phenylisocyanate. All the new compounds were evaluated for their antiproliferative ability, by an in vitro assay on human tumor cell lines (HL‐60 and HeLa).     

Synthesis of some pyrano[2,3‐c]pyrazoles

Synthetic methods have been developed to prepare pyrano[2,3‐c]pyrazoles with various substituents at ring positions 1, 3, and 6. The ¹H‐ and ¹³C‐NMR properties of these products and their precursors are presented and discussed. J. Heterocyclic Chem., (2011).     

Synthesis of substituted pyrimido[4,5‐b] and [5,4‐c]‐[1,8]naphthyridines

Ethyl 1‐ethyl‐7‐methyl‐4‐oxo‐1,4‐dihydro[1,8]naphthyridine‐3‐carboxylate ( 1 ), precursor of nalidixic acid, has been converted in two steps through ([1,8]naphthyridin‐3‐yl)carbonylguanidine derivatives into substituted pyrimido[4,5‐b] and [5,4‐c][1,8]naphthyridines.     

Synthesis and chemistry of N‐arylated pyrano[2,3‐c]pyrazoles

Novel N2‐arylated pyrano[2,3‐c]pyrazol‐6‐ones 2 can be prepared in a selective manner by generating the anion of 1 ( R?H ) with lithium hexamethyldisilazide in DMF and quenching with activated aryl halides. Sterically demanding groups such as phenyl as in 5 reduce reactivity significantly while electronwithdrawing substituents such as trifluoromethyl and phenyl at C4 of the pyranone ring as in 10 and 15 render the pyranone carbonyl particularly susceptible to attack by nucleophiles resulting in ring‐opening to give novel crotonyl derivatives. Proof of structure required a variety of nmr methods involving proton, carbon, and nitrogen nuclei.     

Synthesis of novel 1,4‐dihydropyrido[3′,2′:5,6]thiopyrano[4,3‐c]‐pyrazoles and 5H‐pyrido[3′,2′:5,6]thiopyrano[4,3‐d]pyrimidines as potential antiproliferative agents

The synthesis of new planar derivatives characterized by the presence of a pyridothiopyranopyrazole or pyridothiopyranopyrimidine nucleus, carrying a substituted aryl group, is reported. The novel 1,4‐dihydropyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazole derivatives were obtained by condensation of 2,3‐dihydro‐3‐hydroxymethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐ones with appropriate hydrazines. The preparation of 2‐substituted pyrido[3′,2′:5,6]thiopyrano[4,3‐d]pyrimidines was accomplished from the intermediate 2,3‐dihy‐dro‐3‐dimethylaminomethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐ones by reaction with the appropriate binucleophile amidines. The antiproliferative activity of some new products was tested by an in vitro assay on human tumour cell lines (HL‐60 and HeLa), but none of them showed any significant effects in the tests performed. Accordingly, linear flow dichroism measurements indicated their inability to form a molecular complex with DNA.     

Synthesis and Antimicrobial Activity of Some 1,3‐Disubstituted Indeno[1,2‐c]pyrazoles

Synthesis of new 3‐alkyl indeno[1,2‐c]pyrazoles, possessing 4‐substituted thiazole moiety at position‐1 derived from 2‐acyl indane‐1,3‐diones, has been described. These compounds and their precursor were screened for their antibacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli) and antifungal (Aspergillus niger, Candida albicans) activities.     

Synthesis of New Chromeno[4,3‐b]pyrazolo[4,3‐e]pyridines Derivatives with Antimicrobial Evaluation

A series of 2‐oxo‐2,5‐dihydro‐1H‐chromeno[4,3‐b]pyridine derivatives were obtained by using a one‐pot three component reaction of 2,2‐disubstituted chroman‐4‐one with aromatic aldehydes and 2‐cyanoacetamide in the presence of sodium hydroxide under solvent‐free conditions. Heating chromenopyridine derivatives with phosphoryl chloride gave the corresponding chloro derivatives. The reaction of the chloro derivatives with hydrazine hydrate afforded dihydrochromeno[4,3‐b]pyrazolo[4,3‐e]pyridines derivatives. Condensation of the dimethyl derivative compound with the aromatic aldehydes gave 8‐Arylideneamino‐6,6‐dimethyl‐10H‐chromeno[4,3‐b]pyrazolo[4,3‐e]pyridine.     

A Simple Efficient Procedure for the Synthesis of Benzopyrano[2,3‐c]pyrazoles

A one‐step procedure is proposed for synthesizing 2‐acyl benzopyrano[2,3‐c]pyrazoles and 2‐aryl benzopyrano[2,3‐c]pyrazoles. The method is based on the condensation of 2‐iminocoumarin‐3‐carbonitriles with hydrazides and hydrazines in acid as catalysts. A mechanism of reaction is proposed. All prepared compounds are identified by FTIR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis.     

A convenient synthesis of novel 7‐phosphonylbenzyl‐2‐substituted pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]‐pyrimidine derivatives

A series of pyrazolo[4,3‐e]‐1,2,4‐triazolo‐[1,5‐c]pyrimidine derivatives, bearing phosphonylbenzyl chain in position 7, were conveniently synthesized in an attempt to obtain potent and selective antagonists for the A_2A adenosine receptor or potent pesticide lead compounds. Diethyl[(5‐amino‐4‐cyano‐3‐methylsulfanyl‐pyrazol‐1‐yl)‐benzyl]phospho‐nate ( 3 ), which was prepared by the cyclization of diethyl 1‐hydrazinobenzylphosphonate ( 1 ) with 2‐[bis(methylthio)methylene]malononitrile ( 2 ), reacted with triethyl orthoformate to afford diethyl[(4‐cyano‐5‐ethoxymethyleneamino‐3‐methylsulfanyl‐pyrazol‐1‐yl)‐benzyl]phosphonate ( 4 ), which reacted with various acyl hydrazines in refluxing 2‐methoxyethanol to give the target compounds 5a–h in good yields. Their structures were confirmed by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. The crystal structure of 5e was determined by single crystal X‐ray diffraction © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:634–638, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20478     

2,5‐Disubstituted Pyrazolo[4,3‐c]cinnolin‐3‐ones

Complementary strategies to 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones are reported herein, providing late stage substituent introduction at either the 2‐ or the 5‐position. Treating a readily prepared 4‐thiocinnoline ester with substituted hydrazines afforded late stage access to the 2‐position, while late stage substituent introduction at the 5‐position was achieved via two different strategies: alkylation of 4‐hydrazonopyrazol‐3‐ones, followed by a ring‐closing intramolecular S_NAr tactic and direct reaction of 5‐(2‐fluorophenyl)‐2,4‐dihydro‐3H‐pyrazol‐3‐ones with aryl diazonium salts, followed by cyclization. The strategies described herein provide practical and general methods to prepare 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones.     

New 1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidine derivatives II

The 7‐chloro‐3‐(2‐chlorobenzyl)‐ and 7‐chloro‐3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐d]pyrimidines ( 1 and 4 ), by nucleophilic replacement with some hydrazides, gave the corresponding 7‐hydrazidoderivatives ( 2a‐e and 5a‐e ). These, by heating in Dowtherm, underwent an intramolecular cyclization to form the new tricyclic 7‐substituted‐3‐(2‐chlorobenzyl)‐ and 3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidines ( 3a‐d and 6a‐d ). The 7‐hydrazino‐3‐(2‐chlorobenzyl)‐ and 7‐hydrazino‐3‐(2‐fluorobenzyl)‐triazolo‐pyrimidines ( 9a and 9b ) were also prepared via the corresponding mercapto ( 7a and 7b ) and thiomethyl ( 8a and 8b ) derivatives.     

Syntheses of N10‐substituted 7‐Arylpyrrolo[2,1‐c]‐[1,4]benzodiazepine‐5,11‐diones

Pyrrolo[2,1‐c][1,4]benzodiazepine‐5,11‐dione and its 7‐bromo derivative were alkylated at the N10 atom applying various methods. The resulting products were subjected to Suzuki–Miyaura reactions using a catalyst system consisting of Pd(Cl)₂(PPh₃)₂ and sodium tert‐butanolate in toluene. Results of an X‐ray single crystal analysis are presented.     

Synthesis,PM3‐Semiempirical,and Biological Evaluation of Pyrazolo[4,3‐c]quinolinones

A series of α,β‐unsaturated ketones containing quinolone moieties 2 , 3 , 4 , 5 , 6 were synthesized by condensation of 7‐methoxyquinoline‐2,4(1H,3H)‐dione ( 1 ) with different aryl aldehydes. Pyrazole derivatives 8 , 9 , 10 , 11 were also synthesized via refluxing of α,β‐unsaturated ketones 2 , 3 , 4 , 5 , 6 with hydrazine derivatives. Newly synthesized compounds were characterized by elemental analyses, spectral data, and screened for their antioxidant and antitumor activities. Geometrical optimizations of the molecular structures for different synthesized compounds were studied.     

Facile Synthesis of Pyrazolo[3,4‐c]pyrazoles Bearing Coumarine Ring as Anticancer Agents

In the present study, 2‐(2‐oxo‐2H‐chromene‐3‐carbonyl)‐5‐phenyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one was prepared and reacted with various hydrazonoyl halides to give a series of 2‐(2‐oxo‐2H‐chromene‐3‐carbonyl)‐5‐phenyl‐4‐((2‐phenylhydrazono)methyl)‐2,4‐dihydro‐3H‐pyrazol‐3‐one in good yield. Cyclization of the latter hydrazone with POCl₃ yielded the respective 3‐(3‐phenyl‐ 4,6‐disubstituted‐1,6‐dihydropyrazolo[3,4‐c]pyrazole‐1‐carbonyl)‐2H‐chromen‐2‐ones. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. The newly synthesized compounds were evaluated for their antitumor activities against hepatocellular carcinoma (HepG2) cell line and the results revealed promising activities of compounds 4e , 4c , and 4d with IC₅₀ equal 0.92 ± 0.22, 1.43 ± 0.19, and 2.17 ± 0.21 μM, respectively.     

Synthesis of N4‐substituted[1,3,4]oxadiazinan‐2‐ones derived from norephedrine

[1,3,4]‐Oxadiazinan‐2‐ones bearing substitution at the N₄‐position have been synthesized from norephedrine in good yield via N‐alkylation, nitrosation, reduction and cyclization.     

Facile Synthesis of New [1,2,4]Triazolo[4,3‐b]pyridazine

A number of new [1,2,4]triazolo[4,3‐b]pyridazines were prepared by either cyclocondesation of substituted hydrazinopyridazines with orthoesters or oxidative cyclization of their hydrazone analogs in nitrobenzene as an oxidizing agent. A host of other new [1,2,4]triazolo[4,3‐b]pyridazine derivatives were synthesized by sequential treatment of the latter compounds with carbon disulfide and alkyl halides.     

Thermally Stable 3,6‐Dinitropyrazolo[4,3‐c]pyrazole‐based Energetic Materials

3,6‐Dinitropyrazolo[4,3‐c]pyrazole was prepared using an efficient modified process. With selected cations, ten nitrogen‐rich energetic salts and three metal salts were synthesized in high yield based on the 3,6‐dinitropyrazolo[4,3‐c]pyrazolate anion. These compounds were fully characterized by IR and multinuclear NMR spectroscopies, as well as elemental analyses. The structures of the neutral compounds 4 and its salt 16 were confirmed by single‐crystal X‐ray diffraction showing extensive hydrogen‐bonding interactions. The neutral pyrazole precursor and its salts are remarkably thermally stable. Based on the calculated heats of formation and measured densities, detonation pressures (22.5–35.4 GPa) and velocities (7948–9005 m s^?1) were determined, and they compare favorably with those of TNT and RDX. Their impact and friction sensitivities range from 12 to >40 J and 80 to 360 N, respectively. These properties make them competitive as insensitive and thermally stable high‐energy density materials.