Synthesis of 7-(1-pyrrolidinyl)-1,2,4-triazolo[4,3-b]pyridazines

The reactions of secondary amines (pyrrolidine, piperidine and morpholine) with 3,4,5-trichloropyridazine ( 4 ) was investigated. With 4 and excess amine, disubstitution occurred in good yield and selectively at positions 3 and 5. Treatment of 4 with 2 equivalents of the amine in ethanol afforded high yields of products resulting from monosubstitution at position 5. 3,4-Dichloro-5-(1-pyrrolidinyl)pyridazine ( 6a ), resulting from 4 and 2 equivalents of pyrrolidine, was converted cleanly to 4-chloro-3-hydrazino-5-(1-pyrrolidinyl)pyridazine ( 8 ) with hydrazine hydrate. Pyridazine 8 was cyclized with formic acid to give a 1:1 complex ( 9 ) of formic acid and 8-chloro-7-(1-pyrrolidinyl)-1,2,4-triazolo[4,3-b]pyridazine ( 13 ). Triazolopyridazine 13 also formed a monohydrate ( 12 ) and a monohydrochloride salt ( 14 ). Catalytic hydrogenation of 9 gave 7-(1-pyrrolidinyl)-1,2,4-triazolo[4,3-b]pyridazine ( 3 ), which was a target compound of this investigation.     

The synthesis of imidazo[4,5-c] - and v-triazolo[4,5-c] pyridazines

The parent imidazo[4,5-c]pyridazine (IV) has been prepared for the first time by three different routes. 1-Methylimidazo[4,5-c]pyridazine (XX) and 3-methylimidazo[4,5-c]pyridazine (XXVII) have been prepared by unequivocal syntheses. The constitution of the methylation product of imidazo[4,5-c]pyridazine-2-thiol (VIII) has been shown to be 2-methylthioimidazo[4,5-c]-pyridazine (IX) by the unequivocal syntheses of 1-methylimidazo[4,5-c]pyridazine-2-thiol (XXIII) and 3-methylimidazo[4,5-c]pyridazine-2-thiol (XXXIII). Likewise, the structure of the methylation product (XIII) was shown to be S-methylation by the unequivocal syntheses of 1-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXIV) and 3-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXXI), respectively. Several 7-substituted amino-v-triazolo-[4,5-c]pyridazines (XXXVIII) have been prepared from 7-chloro-v-triazolo[4,5-c]pyridazine (XXXVII).     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Synthesis of new s-triazolo[4,3-b] pyridazines

A new synthesis of s-triazolo[4,3-b]pyridazine derivatives has been achieved starting from 3,6-dichloropyridazine. The method opens the way to substitutions in the 2- or 3- positions. A tri-cycloderivative, a bis-s-triazolopyridazine, has also been synthesized.     

The synthesis of substituted pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazines

The synthesis of 1,2,4-triazolo[4,3-b]pyridazines and the unknown ring system, pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazine, has been achieved. The preparation of the new tricyclic 1,2,4-triazole was accomplished first by ring closure of the triazole ring followed by formation of the pyrazine ring. Substitution of the pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazine ring system was carried out in order to provide information of its reactivity and to provide a variety of interesting compounds for biological testing.     

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).     

1,2,3-Triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines

Some new 1,2,3-triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyridazines via the formation of the 1,2,4-triazole ring, by condensation of an appropriate monocarbon fragment with the 4-hydrazino substituent and the nitrogen atom in the 5 position of the heterocycle. Condensation of 4-phenylhydrazino substituted derivatives with formic acid gave zwitterionic compounds.     

Synthesis and anticonvulsant activity of 3H-imidazo[4,5-c]-pyridazine, 1H-imidazo[4,5-d]pyridazine and 1H-benzimidazole analogues of 9-(2-fluorobenzyl)-6-methylamino-9H-purine

The 3H-imidazo[4,5-c]pyridazine, 1H-imidazo[4,5-d]pyridazine, and 1H-benzimidazole analogues of the potent anticonvulsant purine 9-(2-fluorobenzyl)-6-methylamino-9H-purine (1, 78U79) were synthesized and tested for anticonvulsant activity. The 3H-imidazo[4,5-c]pyridazines 8 and 9 were prepared in five stages from 3,4,5-trichloropyridazine (2) . The 1H-imidazolo[4,5-d]pyridazine 15 was synthesized in four stages from 5-[(benzyloxy)methyl]-1,5-dihydro-4H-imidazo[4,5-d] pyridazin-4-one (10a) . The benz-imidazole analogues 18 and 20 were prepared from 2,6-dinitroaniline in three stages. These compounds were one-tenth or less as active as 1 in protecting rats against maximal electroshock-induced seizures.     

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.     

6-取代苄硫基-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑类化合物的合成与抑菌活性

以4-氨基-5-(3,4,5-三甲氧基苯基)-3-巯基-1,2,4-三唑为原料,环化得到6-巯基-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑再与取代苄氯反应,得到9个6-取代苄硫基-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑类衍生物3a～3i.其结构经IR,1H NMR,MS和元素分析确证.初步生物活性测试结果表明部分化合物有一定的杀菌活性.     

The synthesis of 3,5-dimethylpyrazol-1-yl-vl-v-triazolo[4,5-d]pyridazines and substituted 3,5-dimethylpyrazol-1 -ylimidazo[4,5-d]pyridazines

The synthesis of 4-(3,5-dimethylpyrazol-1-yl)-v-triazolo[4,5-d]pyridazine, 4-(3,5-dimethylpyrazol-1-yl)imid-azo[4,5-d]pyridazine and several S-substituted derivatives of 4-(3,5-dimethylpyrazol-1-yl)imidazo[4,5-d]pyrid-azine-2-thiol is reported. These syntheses were carried out to provide a variety of interesting compounds for biological screening.     

Novel synthesis modes and properties of [1,4]benzodioxinopyridazines

A simple synthesis involving fusion of catechol and derivatives with 3,4,5-trichloropyridazine has furnished 4-chloro[1,4]benzodioxino[2,3-c]pyridazines 5 for the first time. This new method complements the previously reported base promoted procedure for preparing 4-chloro[1,4]benzodioxino-[2,3-d]pyridazines 3 . Employing both methods, 4-(trifluoromethyl)catechol was converted to the four regio isomers 3b,c and 5c,d . Structure assignment of these four was aided by the remarkably consistent influence of the pyridazine 4-chlorine substituent and diazo-linkage in inducing ¹H nmr downfield shifts of their nearest neighbor phenyl ring protons. Finally, contrary to what might be expected from previously reported results, reaction of methoxide with either 3 or 5 , gave chlorine substitution with formation of methoxybenzodioxinopyridazines 6 and 7 respectively. However, these reactions both give what appears to be an unprecedented rearrangement, with conversion of [2,3-c]-pyridazine to [2,3-d]pyridazine, and vice versa.     

Synthesis of pyridazine derivatives. XXI. Tetrazolo-azido transformations in some fused azolopyridazines

6-Azidotetrazolo[1,5-b]pyridazine (III) has been prepared by two different routes and is easily transformed into the 6-amino derivative (IV). The attempted cyclization of 6-hydrazinotetrazolo[1,5-b] pyridazine (II) into the postulated tricycle has been shown to result in the formation of 6-azido-s-triazolo [4,3-b]pyridazine (VI), obtained also in a separate experiment from VII. The azido structure of VI has been confirmed from spectroscopic data and from its conversion into 6-amino-s-triazolo [4,3-b]pyridazine (VIII), obtained in another experiment from VII. Similarly, cyclization of II with cyanogen bromide resulted in the simultaneous formation of the s-triazolo ring and ring opening of the fused tetrazolo ring, giving IX. For 6-azido-2-phenylimidazo[1,2-b]pyridazine (XII) the expected azide structure proved to be correct.     

Benzofuro[2,3-d]pyridazines IV. Etude de la chloro-4 benzofuropyridazine

[1] Benzofuro[2,3-d] pyridazone was synthesized by three methods namely8: catalytic dehalogenation of the 4-chlorobenzofuro [2,3-d] pyridazone; removal of the hydrazono group of 4-hydrazinobenzofuro [2,3-d] pyridazine and desulphurization of benzofuro [2,3-d] pyridazine and desulphurization of benzofuro [2,3-d] pyridazine-4(3H) thione. The 4-substituted derivatives were obtained by nucleophilic attack of the 4-chlorobenzofuro[2,3-d] pyridazine. Tetrazolo[1,5-b]- and s-triazolo-[1,2-b] benzofuro [2,3-d] pyridazones. The structural assignment of the benzofuro[2,3-d]pyridazones was made by the Noe effect.     

Synthesis of imidazo[1,2-b]pyridazines: Fenbendazole,oxifenbendazole analogs and related derivatives

A series of imidazo[1,2-b]pyridazines has been prepared and evaluated for macrofilaricidal activity against Brugia pahangi or Acanthocheilonema viteae infections in jirds. The imidazo[1,2-b]pyridazine analogs of fen-bendazole and oxifenbendazole are reported. In addition, several 6-aminoimidazo[1,2-b]pyridazine derivatives have been prepared. None of these compounds possessed significant activity against human cytomega-lovirus (HCMV) or filarial infections.     

Nucleophilic displacements on polyhalogenated heterocyclic N-methoxy methyl sulfates

N-Methoxy methyl sulfates of 2,3,4,5- and 2,3,5,6-tetrachloropyridine, 3,4,5- and 3,4,6-trichloropyridazine, pentachloropyridine, and tetrachloropyridazine have been prepared. Their reactions with water and aqueous potassium cyanide have been investigated.     

Synthesis of pyridazine derivatives XXII. s-triazolo[4, 3-b]pyridazine 5-oxides

The synthesis of s-triazolo[4,3-b] pyridazine 5-oxides is reported. To our knowledge, they are the first example of N-oxides of heteroaromatic azoloazines with a bridgehead nitrogen. They are easily rearranged, in particular when irradiated with ultraviolet light, into 6-hydroxy-s-triazolo[4,3-b]pyridazines.     

1,2,4-Triazines. Synthesis of selected members of the s-triazolo[3,4-f]- [1,2,4] triazine and tetrazolo[1,5-f] [1,2,4] triazine ring systems

A convenient synthesis of 3-amino-6-hydrazino-5(2H)[1,2,4]triazinone 4 has been developed and a study of the reactions of 4 with aliphatic acids, orthoesters and miscellaneous active carbonyl reagents has been undertaken. When 4 was refluxed in either neat acid or orthoester in dimethylformamide, a facile ring closure reaction with the N-1 nitrogen of the 1,2,4-triazine ring occurs affording a novel series of 3-aIkyl(aryl)-8(5H)-s-triazolo[3,4-f] [1,2,4]triazinones ( 6–11 ). Ring closure with carbon disulfide and cyanogen bromide is also reported affording 6-amino-3(2H)thio-8(5H)-s-triazolo[3,4-f] [1,2,4]triazinone 12 and 3,6-diamino-8(5H)-s-triazolo-[3,4-f] [1,2,4]triazinone 14 , respectively. In addition 4 has been converted into 3-amino-6-azido-5(2H)-1,2,4-triazinone 15 which was employed in a study of azide-tetrazole equilibrium affording 6-amino-8(5H)tetrazolo[1,5-f][1,2,4]triazinone 16 . Rates for interconversion at various temperatures were measured and an activation energy for the process determined.     

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.     

Preparation of 5-substituted- and 3,5-disubstituted-s-triazolo[4,3-a]pyridines

Cyclization of N-acyl-N′-(6-chloropyrid-2-yl)hydrazines ( 2a-2e ) with phosphorus oxychloride has produced several 5-chloro-s-triazolo[4,3-a]pyridines ( 3a-3e ). Nucleophilic displacement of the chlorosubstituent of 5-chloro-s-triazolo[4,3-a]pyridine ( 3a ) availed the 5-ethoxy ( 4a ) and 5-thioethoxy ( 4b ) derivatives and di(s-triazolo[4,3-a]pyrid-5-yl)sulfide ( 8 ) while reaction of 5-ethylsulfonyl-s-triazolo[4,3-a]pyridine ( 4d ) with potassium hydroxide yielded the 5-hydroxy/5-one system ( 4c or 6 ). Further reaction of 3a with bromine to give 3-bromo-5-chloro-s-triazolo-[4,3-a]pyridine ( 3g ) has provided the corresponding 3-cyano- and 3-carboxamido-5-chloro-s-triazolo[4,3-a]pyridine derivatives ( 3h and 3i ). Treatment of 6-chloro-2-hydrazinopyridine ( 1 ) with cyanogen bromide has provided 3-amino-5-chloro-s-triazolo[4,3-a]pyridine ( 3f ) which, with bromoacetaldehyde dimethyl acetal, transformed into 7-chloroimidazo[1,2-b]-s-triazolo[4,3-a]-pyridine ( 7 ). Finally, attempts at cyclizing N-oxalyl-N′-(6-chloropyrid-2-yl)hydrazine derivatives ( 2g-2i ) with intentions of preparing various 3-acyl-5-chloro-s-triazolo[4,3-a]pyridines for entry into other 3,5-disubstituted systems were unsuccessful.