The synthesis of ω-dialkylaminoalkylaminopyrazino[2,3-d]-, pyrido[2,3-d]-, imidazo[4,5-c]- and imidazo[4,5-d]pyridazines

The synthesis of 5-chloro-8-(ω-dialkylaminoalkylamino)pyrazino[2,3-d]pyridazine (II) proceeded smoothly when 5,8-dichloropyrazino[2,3-d]pyridazine (I) was allowed to react with ω-dialkylaminoalkylamines. Similarly, the reaction of 5,8-dichloropyrido[2,3-d]pyridazine (IV) with ω-dialkylaminoalkylamines gave the two expected products 8-chloro-5-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (V) and 5-chloro-8-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (VI) in a 2:3 ratio. 4,7-Dichloroimidazo[4,5-d]pyridazine (XII) was found to be much less reactive towards nucleophilic substitutions and more vigorous conditions resulted in disubstituted products (XIII). 7-Chloroimidazo[4,5-c]pyridazine (XVIII) was also found to be much less reactive towards nucleophilic substitution. In both of these cases one of the imidazole nitrogen atoms was blocked by a tetrahydropyranyl group which increased the reactivities and led to the desired monosubstituted products XVII from XII and in the latter case the expected products (XIX).     

The synthesis of pyridazino[4,5-d] pyridazines,pyrazino [2,3-d] pyridazines and a pyrimido [4,5-d] pyridazine

The synthetic chemistry of the relatively unknown pyridazino [4,5-d]pyridazine ring system has been extended. 1,4-Diaminopyridazino [4,5-d]pyridazine (VIII) has been prepared by two routes, the most interesting of these being the one-step conversion of 4,5-dicyanopyridazine into VIII with hydrazine. Upon nitration VIII gave only the mononitramine (X). Attempts to prepare 1,4-dichloropyridazino [4,5-d]pyridazine gave only 4-chloro-2H-pyridazino [4,5-d]pyridazin-1-one (XII). Pyrimido [4,5-d]pyridazine-1,3-dione (XIV) was prepared from pyridazine-4,5-dicarboxamide (IV). The hydrolysis of 5,8-dichloropyrazino [2,3-d]pyridazine (XV) gave 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) and likewise the ammonolysis of XV gave 5-amino-8-chloropyrazino [2,3-d]pyridazine (XX). As expected the hydrolysis of 5,8-dibromo-pyrazino [2,3-d]pyridazine (XXI) gave 5-bromopyrazino [2,3-d]pyridazin-8-one (XXII). Attempted catalytic dechlorination of 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) gave 1,2,3,4-tetrahydropyrazino [2,3-d]pyridazin-5-one (XIX).     

Inverse-electron-demanddiels-alder reactions of condensed pyridazines VI: Ring transformations of pyrido[2,3-d]pyridazine intog-fused quinolines

Summary A series ofg-annelated quinolines was synthesized, employing pyrido[2,3-d]pyridazine as an azadiene in inverse-electron-demandDiels-Alder reactions with electron-rich dienophiles (enamines and a ketene-N,S-acetal). In cases where isomer mixtures were obtained, NOE difference spectroscopy was used for structural assignment.Dedicated with best wishes to Prof. Dr. F. Sauter on the occasion of his 65^th birthday     

Polycyclic pyridazines. II [3]. Synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azine derivatives from dimethyl pyrazolo[3,4-d]pyrid-azine-5,6-dicarboxylates as the key intermediates

The synthesis of the novel pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine ring system and some of its derivatives has been accomplished such as 4-amino-1-phenyl-5,8-dioxo-, 4-amino-5,8-dioxo-, 1-phenyl-5,8-dioxo-, 5,8-dioxo-, 5,8-dichloro-1-phenyl-, 5-ethoxy-1-phenyl- and 8-ethoxy-1-phenylpyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azines.     

The synthesis of pyrazino[2,3-d]pyridazine and some of its derivatives

Pyrazino[2,3-d]pyridazine (I) was synthesized by two different routes. 5, 8-Dihydroxy-pyrazino[2, 3-d]pyridazine (IV) was converted to 5, 8-dichloropyrazino[2, 3-d]pyridazine (V) and 5, 8-dibromopyrazino[2, 3-d]pyridazine (Va). When V was treated with various benzyl mercaptans and alkoxides the corresponding disubstituted derivatives were obtained. Compound V when allowed to react with aromatic amines gave 5, 8-bisamino-pyrazino[2,3-d]pyridazines, however, with aliphatic amines only mono substituted products were obtained substituted in the 8-position. The reaction of pyrazine-2, 3-dinitrile with hydrazine gave 5, 8-diaminopyrazino[2, 3-d]pyridazine (X).     

The synthesis of lmidazo[4,5-d] pyridazines. VI. v-Triazolo[4,5-d] pyridazines,pyrazino[ 2,3-d ] pyridazines and 7H-Imidazo [4,5-d] tetrazolo[ 1,5-b] pyridazine

Several pyridazines have been prepared as intermediates in the synthesis of monosubstituted imidazo[4,5-d]pyridazines, monosubstituted v-triazoIo[4,5-d]pyridazines and monosubstituted pyrazino [2,3d] pyridazines. The new ring system, 7H-imidazo[4,5-d]tetrazolo[l,5-b] pyridazine (XIV) has been prepared unsubstituted. Furthermore, unsubstituted imidazo[4,5-d]pyridazine (XI) has been prepared. Calculations for XI and XIV were made by approximate SCF LCAO-MO with CNSO II theory.     

Synthesis of pyrido[3,4-d] benzazepines

The synthesis of some derivatives of the novel heterocyclic ring system pyrido[3,4-d][1]benzazepine is reported. Thus, pyrido[3,4-d][1]benzazepin-7-one 6 was prepared by cyclisation of the Michael adduct 5 with ammonium ferric sulfate. Reaction of 6 with phosphorus pentasulfide gave the thiolactam 7 , which after methylation and subsequent reaction with amines furnished the amidines 10 .     

Pyrimidines. LII Synthesis of pyrido[2,3-d]pyrimidine-2,4-diones and pyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8-tetrones

Reactivities of 5-dimethylaminomethylene-6-imino-1,3-dimethyluracil hydrochloride ( 1 ) toward a variety of active methylene compounds 2 and 5 were investigated. Treatment of 1 with active methylene compounds such as malononitrile and ethyl cyanoacetate in the presence of triethylamine gave pyrido[2,3-d]pyrimidine-2,4-dione derivatives 3. Reaction of 1 with barbituric acids resulted in the formation of pyrido[2,3-d:6,5-d′]di-pyrimidine-2,4,6,8-tetrone derivatives 6.     

Synthesis and transformations of some pyrido[2,3-d]pyrimidines

A new synthetic approach for pyrido[2,3-d]pyrimidine 3-oxides and other pyrido[2,3-d]pyrimidines has been developed. This bicyclic system readily undergoes ring opening to give a variety of products, depending on the reagent and reaction conditions.

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Synthesen und Umwandlungen einiger Pyrido[2,3-d]pyrimidine

Zusammenfassung Synthesen von Pyrido[2,3-d]pyrimidin-3-oxiden und einigen anderen Pyrido[2,3-d]pyrimidinen werden beschrieben. Das bicyclische System reagiert leicht unter Ringöffnung, wobei entsprechend den Reaktionsbedingungen und Reagenzien verschiedene Produkte entstehen.

     

Condensed pyridazines. Part II. Synthesis of pyrido[2,3-C] pyridazines

The synthesis of some pyrido[2,3-c]pyridazines from 5,8-diehloro-3-methyl-2-oxo-2H-pyrano-[2,3-d]pyridazine (I) is described. Attempted oxidation of 8-amino-3-chloro-1,6-dimethyl-4,7-dioxo-1,4,7,8-tetrahydropyrido[2,3-c]pyridazine (VI) with LTA led only to the deaminated compound VII. Treatment of VI with LTA A in the presence of cyclohexene gave the nitrene adduct XI.     

Synthesis and biological evaluation of certain 4-alkylamino and 4-arylalkylamino derivatives of the imidazo[4,5-d]pyridazine and v-triazolo[4,5-d]pyridazine ring systems

Certain 4-alkylamino and 4-arylalkylamino derivatives of the imidazo- and v-triazolo[4,5-d]pyridazine ring systems were prepared and evaluated against two human colon carcinomas (DLD-1 and HCT-15) and one human lung carcinoma (LX-1), in vitro. 4-Methylthioimidazo[4,5-d]pyridazine ( 1 ) and 4-methylthio-v-triazolo-[4,5-d]pyridazine ( 9 ) served as precursors to the title compounds. Treatment of these heterocycles with the appropriate amine (ammonia, methylamine, dimethylamine, benzylamine and hydrazine) provided the desired derivatives of that ring system. 4-AIP ( 2 ) and 2-aza-4-AIP ( 10 ) served as precursors to the 4-dimethylaminomethyleneamino derivatives 6 and 14 , respectively. Likewise, the 4-hydrazino analogs ( 7 and 15 ) served as intermediates in the syntheses of benzaldehyde-p-[bis(2-chloroethyl)amino]amino[4,5-d]-pyridazin-4-yl-hydrazone ( 8 ) and benzaldehyde-p-[bis(2-chloroethyl)amino]amino-v-triazolo[4,5-d]pyridazin-4-yl-hydrazone ( 16 ), respectively.     

Preparation of reissert compounds derived from the thieno[3,2-c]pyridine,thieno[2,3-d]pyridazine and the thieno[2,3-d]pyrimidine ring systems

The use of tributyltin cyanide, trimethylsilyl cyanide and potassium cyanide in the Reissert reaction is contrasted in the furo[3,2-c]pyridine, thieno[3,2-c]pyridine, thieno[2,3-dpyridazine, and thieno[2,3-d]pyrimidine ring systems.     

Synthesis of imidazo[4,5-d]pyridazine nucleosides related to inosine

Several imidazo[4,5-d]pyridazine nucleosides which are structurally similar to inosine were synthesized. Anhydrous stannic chloride-catalyzed condensation of persilylated imidazo[4,5-d]-pyridazin-4(5H)one (1) and imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 16 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose ( 3 ) provided (after sodium methoxide deblocking) 6-β-D-ribo furanosylimidazo[4,5-d]pyridazin-4(5H)one (5) and 3,6-di-(β-D-ribofuranosyI)imidazo[4,5-d]pyridazin-4-one ( 7 ); and 1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 19 ) and 1,5 or 6-di-(β-D-ribofuranosyl)imidazo[4,5-d ]pyridazine-4,7(5H or 6H)dione ( 21 ), respeeitvely. 4,7-Diehloro-1-β-D-ribofuranosylimidazo[4,5-d]pyridazine ( 12 ) and dimethyl 1-β-D-ribofuranosylimidazole-4,5-dicarboxylate ( 26 ), both prepared from stannic chloride-catalyzed ribosylations of the corresponding heterocycles, were converted in several steps to 3-β-D-ribo-furanosy limidazo[4,5-d]pyridazin-4(5H)one ( 14 ) and nucleosidc 19 , respectively. Acid-catalyzed isopropylidenation of mesomeric betaine 7 or nuclcoside 14 provided 3-(2,3-isopropylidene-β-D-ribofuranosyl)imidazo[4,5-d]pyrizin-4(5H)one ( 31 ). 1-β-D-Ribofuranosylimidazo[4,5-d]-pyridazine ( 29 ) was obtained in several steps from nueleoside 12 . The structure of the nucleosides was established by the use of carbon-13 and proton nmr.     

New syntheses of pyrido[3,2-d]pyrimidines

New synthetic routes to pyrido[3,2-d]pyrimidines starting with 5-amino-1,3,6-trimethyluracil (I) or 1,3,6-trimethyl-5-nitrouracil (X) are described. Thus, condensation of I with arylaldehydes gave 5-arylideneamino-1,3,6-trimethyluracils (IIa-h), which upon heating with dimethylformamide dimethylacetal afforded 6-aryl-1,3-dimethylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-diones (Va-h) via 5-arylideneamino-1,3-dimethyl-6-(2-dimethylaminovinyl)uracils (IIIa-h). On the other hand, reaction of X with phenylacetaldehyde in the presence of base yielded Va and its 5-oxide (XI).     

Synthesis,design, and antimicrobial activity of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidinones based on quinoline derivatives

The pyrido[2,3-d]pyrimidine moieties are one of the most biologically widespread heterocyclic compounds as antimicrobial, antioxidant, antitubercular, antiviral and anti-inflammatory. Hence, we synthesized an efficient new series of 2-thioxo-pyrido[2,3-d]pyrimidinone, 2-hydrazinyl-(quinolin-2-yl)pyrido[2,3-d]pyrimidinone,N′-(quinolin-2-yl)-pyrido[2,3-d]pyrimidine-(formo/aceto)-hydrazide and substituted-(quinolin-2-yl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidinone derivatives. The characterization of new compounds was corresponded by using spectroscopic techniques, IR, NMR and Mass spectra. In vitro, all compounds were evaluated as antimicrobial activity compared with cefotaxime sodium and nystatin as the standard drug. This work deals with the exploration of the new heterocyclic compounds and medicinal diversity of quinoline-pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives that might pave the way for long in the discovery of therapeutic medicine for future drug design.     

A new base-induced ring transformation of pyrido[2,3-d]pyrimidines

8-Substituted 5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates ( 3 ) rearranged to 8-substituted 7,8-dihydro-5-hydroxy-7-oxopyrido[2,3-d]pyrimidine-6-carboxaldehydes ( 5 ) when treated with sodium ethoxide in an aprotic polar solvent at room temperature. The 6-cyano analogue ( 18 ) also underwent ring transformation under the same mild conditions giving 7-amino-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxaldehyde ( 21 ). However, the ring transformations of the pyrido[2,3-d]pyrimidine bearing no N₈-substituent ( 12 ), ethyl 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine- ( 14 ) and -quinoline-3-carboxylates ( 16 ) failed to occur. A mechanism is discussed.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Pyrido[2,3-d]pyrimidines,II. One step synthesis of pyrido[2,3-d]pyrimidines and pyrimido[4,5-b]quinolines from 6-amino uracils

Summary Reduction of 6-azidouracils2 with hydrogen palladium or sodium dithionite afforded the corresponding 6-aminouracils5 which could also be obtained by reaction of2 with triphenylphosphanevia phosphazenes and subsequent hydrolysis (Staudinger reaction). The use of trimethylphosphite instead of phosphanes yields with2b the expected trimethoxyphosphazene3c, whereas2a reacts to the phosphonoaminopyrimidine4. The syntheses of 5-hydroxy pyrido[2,3-d]pryimidine-2,4,7-triones6, pyrido[2,3-d]pyrimidine-2,4,5-triones8, cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-triones7a,c, and tetrahydro-pyrimido[4,5-b]quinolin-2,4,5-triones7b,d by condensation of 6-aminouracils5 with malonates, ethylaceto/benzoylacetate, ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate, respectively, are described.

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Pyrido[2,3-d]pyrimidine, 2. Mitt. Einstufige Synthese von Pyrido[2,3-d]pyrimidinen und Pyrimido[4,5-b]chinolinen aus 6-Aminouracilen

Zusammenfassung Reduktion der 6-Azidouracile2 mit Wasserstoff/Palladium oder Natriumdithionit ergibt die entsprechenden 6-Aminouracile5, die auch durch Reaktion von2 mit Triphenylphosphin und anschließende Hydrolyse erhalten werden können (Staudinger-Reaktion). Die Verwendung von Trimethylphosphit anstelle von von Trimethylphosphin ergibt mit2b das erwartete Trimethoxyphosphazin3c, während2a zum Phosphonoaminopyrimidin4 reagiert. Die Synthesen der 5-Hydroxy-pyrido[2,3-d]pyrimidin-2,4,7-trione6, der Pyrido[2,3-d]pyrimidin-2,4,5-trione8, der Cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-trione7a,c und der Tetrahydro-pyrimido[4,5-b]chinolin-2,4,5-trione7b,d durch Kondensation der 6-Aminouracile5 mit Malonat, Acetat, Ethyl-2-oxocyclopentancarboxylat und Ethylcyclohexancarboxylat werden beschrieben.

     

The synthesis of a pyrido[2,3-c]pyridazine: A cinnoline related to 6-fluoronalidixic acid

An analog of the pyrido[2,3-c]pyridazine ring system, 1-ethyl-6-fluoro-1,4-dihydro-7-methyl-4-oxopyrido-[2,3-c]pyridazine-3-carboxylic acid ( 13 ), related to both Cinoxacin ( 1 ) and nalidixic acid ( 2 ), has been synthesized. The reductive ring closure of 2-chloro-α-diazo-6-methyl-5-nitro-β-oxo-3-pyridinepropanoic acid, ethyl ester ( 7 ), proved to be the key reaction providing entry into the ring system.     

Synthesis of pyrido[2,3-d]pyrimidines from aminopyrimidinecarbaldehydes

2-Methoxy-4-amino-5-pyrimidinecarbaldehyde ( 2a ) as well as its 6-methyl 2b and 6-phenyl derivatives 2c were prepared by reduction of the corresponding aminopyrimidinecarbonitriles 1 . Catalytic hydrogenation of 1a, 1b gives 5-hydroxymethylpyrimidines 3a, 3b ; under the same conditions 1c afforded 5-aminomethylpyrimidine 4 . Condensation of 2 with carbonitriles, ketones and polyfunctional carbonyl compounds bearing the -CH₂CO- moiety afforded the pyrido[2,3-d]pyrimidines and pyrimido-[4,5-b]quinoline derivatives.