Synthesis,Characterization and Anti-Breast Cancer Activity of New 4-Aminoantipyrine-Based Heterocycles

4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, ¹H- and ¹³C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human tumor breast cancer cell line MCF7, and the results showed that (Z)-4-((3-amino-5-imino-1-phenyl-1H-pyrazol-4(5H)-ylidene)methylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 5, 3-(4-bromophenyl) -1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 13, 1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-Hpyrazol- 4-yl)-3-(4-iodophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 14, 3,3′-(4,4′-sulfonylbis(4,1-phenylene))bis(1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) 16, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-hydrazono-4-oxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 17, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-phenyl-2-(2-phenylhydrazono)-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile 18, and (Z)-4-(3-amino-6-hydrazono-7-phenyl-6,7-dihydro pyrazolo[3,4-d]pyrimidin-5-yl)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 19 were the most active compounds with IC₅₀ values ranging from 30.68 to 60.72 μM compared with Doxorubicin as positive control with the IC₅₀ value 71.8 μM.     

Radikalreaktionen von N-Heterocyclen. I. Synthese und Struktur eines N,N-verknüpften Bipyrazols

Radical Reactions of N-Heterocyclic Compounds. I. Synthesis and Structure of an N,N-Linked Bipyrazole 5(3)-Amino-3(5)-(phenylamino)-pyrazole-4-carboxylic acid ethyl ester ( 1 ), which is a very good antioxidant, reacts under mild reaction conditions with dibenzoyl peroxide or with tert.-butoxy radicals under formation of a bipyrazole 4 . Evidence of the structure of 4 is given by ¹H-n.m.r., ¹³C-n.m.r., i.r. and u.v. spectroscopic measurements, respectively and especially by ¹⁵N-n.m.r. measurements of ¹⁵N labelled compounds 1 and 4 . The bispyrazole 4 reacts with Pb(IV)-acetate, the product isolated was the 5-amino-e-anilino-1-(1-anilino-2-cyano-2-ethoxycarbonylethenyl-azo)-pyrazole-4-carboxylic acid ethyl ester (7). The formation of this substance is a chemical proof of the structure of 4 .     

Silica-Supported Ionic Liquids Prompted One-Pot Four-Component Synthesis of Pyrazolopyranopyrimidines, 3-methyl-4-aryl-4,5-dihydro-1H-pyrano[2,3-c]pyrazol-6-ones,and 1,6-diamino-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitriles

Three methods have been used for synthesis of pyrazolopyranopyrimidines, 3-methyl-4-aryl-4,5-dihydro-1H-pyrano[2,3-c]pyrazol-6-ones, and 1,6-diamino-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile derivatives via four-component reactions under solvent-free conditions. Silica-bonded 5-n-propyl-octahydro-pyrimido[1,2-a]azepiniumchloride (SB-DBU⁺Cl^?), silica-bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride (SB-DABCO⁺Cl^?), and nano silica-bonded 5-n-propyl-octahydro-pyrimido[1,2-a]azepinium chloride (NSB-DBU⁺Cl^?) as silica-supported ionic liquids catalyzed these reactions. These green, heterogeneous catalysts are separated from the reactions by simple filtration. The catalysts were recovered for at least four times without significant loss of their catalytic activities.     

Strukturaufklärung von ausgewählten nitro- und sulfonsäuresubstituierten 1,2-Naphthochinon-2-diaziden

Structure Determination of Selected Nitro and Sulfonic Acid Substituted 1,2-Naphthoquinone-2-diazides Selected nitro derivatives of 1,2-naphtoquinone-2-diazide 2 and 5 have been synthesized, the position of the NO₂-group has been unambigously determined by means of ¹H and ¹³C n.m.r. spectroscopy, and the structure of these compounds has been comprehensively determined in relation to unsubstituted 1 and sulfonic acid substituted derivatives 3 , 3a , 4 and 4a . Furthermore, the spectroscopical behaviour, especially in the uv/vis region, was examined in correlation to quantum chemical calculations.     

Inter- und intramolekulare Acylwanderungen an 1(9)H-2,3-Dihydro-imidazo[1,2-a]benzimidazolen

Inter- and Intramolecular Acyl Transfer on 1(9)H-Imidazo[1,2-a]benzimidazoles The new imidazo[1,2-a]benzimidazoles ( 3 ) react with electrophiles like aroyl chlorides, isocyanates, cyanates, chloroformates and chlorothioformates to give the 9-acyl derivatives ( 4a – 1 ). At higher temperatures intermolecular acyl transfer takes place to give the l-acyl compounds ( 5a – m ). In the case of 1-carbamoyl imidazo[1,2-a]benzimidazoles ( 5 ) was observed intramolecular acyl transfer in the presence of strong bases and 1-benzimidazol-2-yl-hydantoins ( 6 ) were isolated. The structures of the prepared compounds could be inferred from their ¹H and ¹³C n.m.r., mass spectra and were corroborated by the comparison with the data of similar derivatives as well as by chemical means.     

Reactions of 2-arylhydrazones of 1,2,3-triketones with 1,2-diaminoethane. I. Synthesis and spectral characterization of 6-arylazo-2,3-dihydro-1H-1,4-diazepines and 3,10-diarylazo-4,9-dimethyl-5,8-diaza-3,9-dodecadiene-2,11-diones

Reactions of 3-arylhydrazones of 2,3,4-pentanetrione ( 1a–1e ) and 2-arylhydrazones of 1,3-diphenyl-1,2,3-propanetrione ( 1f–1l ) with 1,2-diaminoethane have been studied. It was found, that 3-arylhydrazones of 2,3,4-pentanetrione react with 1,2-diaminoethane with formation of 6-arylazo-2,3-dihydro-1,4-diazepines ( 2a–2e ) or the diarylazo derivatives of 4,9-dimethyl-5,8-diaza-3,9-dodecadiene-2,11-dione ( 3a–3e ). Analogous reactions of 2-arylhydrazones of 1,3-diphenyl-1,2,3-propanetrione yielded exclusively the derivatives of dihydrodiazepine. The structure of obtained products has been elucidated on the basis of i.r., m.s. and ¹H-n.m.r. spectra.     

Synthesis,characterization, spectral and antifungal properties of some 5-Substituted-1,3,4-oxadiazole-2-thiones and their mannich bases

A series of 5-substituted aryloxymethyl-1,3,4-oxadiazole-2-thione ( 3a–e ) and their Mannich bases 4–8 are synthesized and subjected to fungitoxic screening. The structures of these compounds are established on the basis of elemental analysis ¹H-n.m.r. and mass spectral data. The mass spectral fragmentation pathways of these compounds are discussed.     

A novel synthesis of 1,3 Thiazetidine-2-one and 1,3-Oxazine-2-one Derivatives

In the reactions of acetylthioacetanilides ( 1a–c ) and diacetylthioacetanilides ( 3a–f ) with phosgene 1,3-thiazetidine-2-one ( 2a–c ) and 1,3-oxazine-2-one ( 5a–f ) were obtained respectively. The structures of new compounds were elucidated by elemental analyses, i.r., ¹H-n.m.r., m.s., for 1d–f by ¹⁹F-n.m.r. and for 2a and 5a by ¹³C-n.m.r. spectral data.     

Heterocyclic syntheses with malonyl chloride. 15. 7-Chloro-3,4-dihydro-4,5-dioxo-3-aryl(or-alkyl)-2-thio-2H,5H-pyrano[3,4-2-e]-1,3-oxazine from aryl or alkyl isothio-cyanates and their degradation with morpholine and ethanol

Substituted aromatic isothiocyanates with malonyl chloride yield 7-chloro-3-substituted-3,4-dihydro-4,5-dioxo-2-thio-2H,5H-pyrano [3,4-e]-1,3-oxazine ( 1 ). Alkyl isothiocyanates with malonyl chloride yield a mixture of 7-chloro-3-alkyl-2-thio pyranooxazine ( 2 ) and the 2-oxo-analogue ( 3 ). The pyrano oxazine 1 react stepwise with morpholine undergoing replacement of the 7-chloro substituent yielding the 7-morpholino analogue ( 4 ), then the pyrone ring was opened producing 5-morpholino carbonyl-4-oxo-3-substituted phenyl-2-thio-1,3-oxazine-6-ylacetomorpholid ( 5 ). Finally the oxazine ring was opened yielding 2-substituted phenyl carbomyl-3-morpholino-N,N-glutaconoyldimorpholine ( 6 ). Ethanol react with compound 1 at any molar ration causing the opening of the pyrone ring and retain the oxazine ring. Mass spectra. ¹H-n.m.r., u.v. and i.r. spectroscopic data provided information about the fine structures of the products.     

Untersuchung der sensibilisierten Photolyse von 2-Diazo-1-oxo-1,2-dihydronaphthalenen in fester Schicht

Studies on the Sensitized Photolysis of 2-Diazo-1-oxo-1,2-dihydronaphthalenes in Solid Layers The photolysis of 5-substituted 2-diazo-1-oxo-1,2-dihydronaphthalenes can be sensitized by proper dyes as could be detected in various binders. Whereas the quantum yield of the direct photolysis is hardly influenced by the glass transition temperature T_g of the binder matrix the spectral sensitization is only effectiv in a rigid binder matrix (T_g > room temperature T_r). In deformable binders (T_g < T_r) and in solution, resp., the quantum yields of the spectral sensitization drastically decrease as a result of competing desactivation processes. The observed quenching of the direct and delayed dye fluorescence by o-quinone-diazides does not allow a clear determination of the spin multiplicity of the photolysis     

2-Arylamino-thiophen-3-carbonsäurederivate

2-Arylamino-thiophene-3-carboxylic Acid Derivatives The title compounds 3 are synthesized by reaction of 2-amino-thiophene-3-carboxylic acid derivatives 1 with anilines. The nucleophilic 5-position in 3 allowed the synthesis of 5-aryliden-Δ³-thiolen-2-one-imines 5 , 6 and the oxidative coupling to yield the azo compound 7 . 1-Aryl-thieno-[2,3-d]pyrimid-4-ones 9 , the thieno[2,3-b]chinolin-4-one 10 and the 4-chloro thieno[2,3-b]chinolines 10 , 11 can be obtained from 3 .     

Reactions with 2-thiazolin-5-ones. III. The behaviour of 4-Arylazo-2-alkoxy-2-thiazolin-5-ones toward amines and Grignard reagents

Treatment of 4-arylazo-2-alkoxy-2-thiazolin-5-ones 4a – f with glycine or phenylhydrazine effects their conversion into 1-aryl-5-alkoxy-1 H-1,2,4-triazole-3-carboxylic acid derivatives 5a – j , with the loss of hydrogen sulfide. On the other hand, the reaction of the 2-ethoxy ( 4a – c ) and the 2-isopropyloxy ( 4g – i ) derivatives with strong basic amines involves the loss of an alkyl mercaptan to yield the N-substituted amines 7d – j of 1-aryl-Δ²-1,2,4-triazolin-5-one-3-carboxylic acids. The 2-benzyloxy derivatives 4d – f react with the same reagents to give the N-substituted amides 2a – g of 1-aryl-Δ²-1,2,4-triazolin-5-thione-3-carboxylic acids, with the loss of benzyl alcohol. Hetero-ring opening of 4 , followed by recyclisation, occurs upon treatment with ethyl or phenyl magnesium halides to yield the triazolinethione derivatives 13 a – c .     

Allgemeine Synthesen und rationelle Strukturparameter isomerer Derivate von [3,4]-kondensierten Pyrazolen

General Syntheses and Rational Parameters for Structural Assignment of Isomeric Derivatives of [3,4]-fused Pyrazoles 4 isomeric 1- or 2-methyl-, and 1- or 2-benzyl-pyrazolo[3,4-b]pyridones, i.e. the 4-oxo-types 17a, b or 11a, b and the 6-oxo-types 16a, b or 10a, b , are synthesized unambiguously. Cyclisation of 1-substituted 3- or 5-(1-methyl-2-ethoxycarbonyl-vinylamino)-pyrazoles 9a, b or. 15a, b , which were synthesized from 1-substituted 3- or 5-amino-pyrazoles and ethyl acetoacetate yields 11a, b or 17a, b in downtherm, but 10a, b or 16a, b in presence of acidic catalysts. The acidic cyclisation is preceded by a new rearrangement of 9 or 15 into 1- substituted 3- 27 or 5-amino-4-(1-methyl-2-ethoxycarbonyl-vinyl)-pyrazoles 30 ; mechanism and concurring reactions are explained. Because of their higher electron densities at C-4 it is easier to cyclise derivatives of 5-amino-pyrazoles compared to 3-amino-pyrazoles. All isomeric 1- or 2-substituted 4(6)-chloro-6(4)-methyl-pyrazolo-[3,4-b]pyridines are formed with POCl₃ from the corresponding oxo-compounds. The position of a substituent at N-1 or N-2 of [3,4]-fused pyrazoles can be assigned using the significant ¹H-n.m.r.-parameter Δ = δ — − δ_HMPT (conc. HC—3). If solvent influences are considered, δ(C  O) is a useful ¹³C-n.m.r.-parameter to distinguish the 4-oxo-types ( 11a, b; 17a, b ) from the 6-oxo-types ( 10a, b; 16a, b ) of pyrazolo[3,4-b]pyridones. Further own and lit. dates conc. structural assignment (n.m.r., i.r., u.v.) are discussed critically.     

Über neue Pyrazolverbindungen. IV Darstellung und Cyclisierungsverhalten einiger akzeptorsubstituierter N-(Pyrazol-3-yl)-thioharnstoffe

New Pyrazol Derivatives. IV. Preparation and Cyclization of Some Acceptor-Substituted N-(Pyrazol-3-yl)-thioureas . 3-Aminopyrazol-4-carboxylic acid derivatives ( 1 , 2 ) were transformed by reaction with different isothiocyanates R²NCS to N-(pyrazol-3-yl)-N^. -substituted thioureas ( 5 , 6 ). Ethyl 3-amino-1-benzylpyrazol-4-carboxylate reacts with CSCl₂ to form ethyl 1-benzyl-3-isothiocyanatopyrazol-4-carboxylate ( 3 ) which yields with amines the corresponding N-(pyrazol-3-yl)-N^. -substituted thioureas ( 5 ). As a byproduct in the reaction with CSCl₂ N,N^. -di-(pyrazol-3-yl)-thiourea ( 4 ) is formed. With hydrazine or phenylhydrazine N-(pyrazol-3-yl)-thiosemicarbazides ( 7a , b ) are obtained. The thioureas ( 5 , 6 ) can be cyclized in basic solution to 4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin-4-on-6-thiones ( 8 ) which on alkylation form 6-alkylthio-4,5-dihydropyrazolo[3,4-d]pyrimidin-4-ones ( 9 ). Methyl-N-(pyrazol-3-yl)-N^.-benzoylisothiourea ( 10 ) reacts with ethylamine to form N-benzoyl-N^. -ethyl-N^‥-(pyrazol-3-yl)-guanidine derivative ( 11 ) which on treatment with NaH in dimethylformamide yields 6-benzoylamino-5-ethyl-4,5-dihydropyrazolo[3,4-d]pyrimidin-4-one ( 12 ). By treatment with sulfuric acid the N-(pyrazol-3-yl)-thiourea derivatives ( 5 , 6 ) form new 6-amino substituted pyrazolo[3,4-d][1,3]thiazin-4-ones ( 13 ).     

Synthesis of biologically active 4-benzyl-1(2H)-phthalazinones and 2-aryl-3(2H)-1-benzal-isoindolinones

4-Benzyl-2-1(2H) phthalazonyl derivatives of type 2, 3, 5a, b were synthesized by Mannich reaction of 4-benzylphthalazinone 1 which by the reaction with diazomethane yielded O-methylated derivative 4 . Various 1-benzal-2-substituted aryl-3(2H) isoindolinones 7a–f, 8a–e were also prepared. Its i.r., ¹H-n.m.r. and mass spectra were discussed. Some of them exhibit pronounced antimicrobial activities. A number of phthalazinones have found application in clinical medicine [1–3] due to the their pronounced antipyretic, analgesic and tuberculostatic activity and the importance of some benzylidenephthalimidines as stabilisers for halogen containing high polymers [4] and the local anesthetic activity superior to that of procaine [5], tempted us to procure some new phthalazinones and isoindolinones with biological interest.     

Synthesis and antimicrobial evaluation of some pyrazolo-thiazolyl alkoxy-1H-isoindole-1, 3(2H)-dione derivatives

1,3-Thiazolidine-2,4-dione 2 has been synthesized by the cyclisation reaction of thiourea and chloroacetic acid in the presence of ethanol. The reaction of compound 2 with substituted aromatic aldehyde afforded the corresponding derivatives of substituted 5-benzylidene-1,3-thiazolidinone-2,4-dione 3a–d, which upon reflux with ω-bromoalkoxyphthalimide gave 2-{[-5-(substituted benzylidine)-2,4-dioxo-1,3-thiazolidine-3-yl]alkoxy} -1H-isoindole-1,3(2H)-dione 4a–i. Further, compounds 4a–i were treated with phenyl hydrazine and 2,4 dinitro phenyl hydrazine in the DMF to yield the title compound 2-[5-oxo-2,3-substituted diphenyl-2H-pyrazolo[3,4-d][1,3]thiazol-6(5H)-yl)alkoxy]-1H-isoindole-1,3(2H)-dione 5a–r. Structures of newly synthesized compounds were established based on elemental analysis, IR, ¹H NMR and mass spectral data. Synthesized compounds have been assayed for their antibacterial activities against B. subtilis, K. pneumoniae, P. aeruginosa and S. aureus and antifungal activities against A. fumigatus and C. albicans.     

Allgemeine Synthese 1-substituierter Pyrazolidone-(3) durch nucleophile Grignard-Addition an carbonylstabilisierte Azomethinimine

General Synthesis of 1-Substituted Pyrazolidine-3-ones by Nucleophilic Grignard Addition at Carbonyl-stabilized Azomethinimines By means of Grignard compounds in THF the nucleophilic addition of alkyl, aralkyl or aryl groups at the C-6 atom of carbonyl-stabilized azomethinimines 1 is achieved. This new general synthesis gives high yields of 1-substituted pyrazolidine-3-ones 8 . The C-6-substitution is proved by unambiguous syntheses and by ¹H-n.m.r. C-4-Substituted azomethinimines 1 and Grignard compounds give mixtures of diastereomeric 1-substituted pyrazolidine-3-ones 8 , as indicated by their ¹H- and ¹³C-n.m.r. spectra. The Grignard addition is thus shown to proceed not stereospecifically.     

Extracts and Constituents of Rubus chingii with 1,1-Diphenyl-2-picrylhydrazyl (DPPH) Free Radical Scavenging Activity

The 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity of the fruits of Rubus chingii was studied in vitro. Ethanolic extract, ethyl acetate and n-butanol fractions from dried R. chingii fruits revealed strong DPPH free radical scavenging activity with IC(50) values of 17.9, 3.4 and 4.0 μg/mL, respectively. The ethyl acetate and n-butanol fractions were further purified by a combination of silica gel chromatography, Lobar RP-8 chromatography, and high-pressure liquid chromatography (HPLC). Nine compounds were isolated, where methyl (3-hydroxy-2-oxo-2,3-dihydroindol-3-yl)-acetate (2), vanillic acid (5), kaempferol (7), and tiliroside (9) showed stronger DPPH free radical scavenging activity than that of ascorbic acid (131.8 μM) with IC(50) values of 45.2, 34.9, 78.5, and 13.7 μM, respectively. In addition, rubusine (1) is a new compound discovered in the present study and methyl (3-hydroxy-2-oxo-2,3-dihydroindol-3-yl)-acetate (2), methyl dioxindole-3-acetate (3), and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (4) were isolated from the fruits for the first time.     

Konfigurative Zuordnung über sterisch definierte Epoxidringe. VIII. Glycidonitrile. I. Synthese von 4-Aryl-1-oxaspiro(2,5)octan-2-nitrilen und 4-Aryl-1-oxaspiro(2,5)octan-2-carbonsäureestern

Determination of Configurations by the Aid of Sterically Corresponding Epoxides. VIII. Glycidic Nitriles. I. Synthesis of 4-Aryl-1-oxaspiro(2,5)octane-2-nitriles and 4-Aryl-1-oxaspiro(2,5)octane-2-carboxylic Acid Methyl Esters The condensation of 2-aryl-cyclohexan-1-ones ( 1–5 ) with ClCH₂CN or ClCH₂CO₂CH₃ at 80°C in the presence of NaH and in dimethoxyethane yields the corresponding glycidic nitriles and the glycidic esters, respectively. The configuration and the preferred conformation of the two isomeric 1-oxaspiro-[2,5]octane derivatives ( 12 A and 12 B ) formed have been determined by ¹H-n.m.r. spectroscopy. Some earlier results from BOEKELHEIDE and SCHILLING and from SCHWARTZMAN and WOODS have been corrected.     

Reactions with 2-thiazolin 5-ones. IV. Action of amines on 4-substituted 2-alkoxy- and 2-benzylmercapto-2-thiazolin-5-ones

Whereas treatment of 2-butyloxy-, 2-pentyloxy- and 2-β-phenylethyloxy-4-arylazo-2-thiazolin-5-ones 1d–h with strong basic amines results in their rearrangement into 1-aryl- Δ²-1,2,4-triazolin-5-one-3-carboxylic acid derivatives 2 , the 2-isobutyloxy, 2-(2-octyloxy)- and the 2-cyclohexyloxy-4-arylazo-2-thiazoline-5-ones 1i–n rearrange upon treatment with the same reagents into Δ²- 1,2,4-triazoline-5-thione-3-carboxylic acid derivatives 3 . On the other hand, 1d–h,1 react with aromatic amines to give 1-aryl-2-alkoxy-1,2,4-triazole-3-carboxylic acid anilides 4a–i , via the loss of hydrogen sulphide. The phenylhydrazides 4j–l are obtained upon treatment of 1g, h,l with phenylhadrazine. Treatment of 4-arylidene-2-benzylmercapto-2-thiazolin-5-ones 6a–c with ammonia results in the formation of the thiohydantoin derivatives 7e, g . However, 6b, c react with phenylhydrazine to yield the phenylhydrazides 8b, c . The reaction of 6a–e with piperidine or morpholine involves to molecules of the reagent to yield 10a–d which are thermally cyclised to the thiazolone derivatives 11a–d .