Synthesis and anticonvulsant activity of 1-benzyl-4-alkylamino-1H-imidazo[4,5-c]pyridines

Four 3-deaza analogues of the potent anticonvulsant purine, BW A78U, were synthesized and tested for anticonvulsant activity. The imidazo[4,5-c]pyridines 9–12 were prepared in two steps from 4-chloro-1H-imidazo[4,5-c]pyridine ( 2 ). The compounds were potent anticonvulsant agents against maximal electroshock-induced seizures in rats with i.p. ED₅₀ ranging from 2 to 3.5 mg/kg. However, these 3-deazapurines were appreciably more toxic than BW A78U, which precluded their development as potential antiepileptic agents.     

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.     

Hydrazinolysis of 4-acyl and 4-ethoxycarbonyl-3H-imidazo[1,5-b]-pyridazine-5,7-(6H)diones: 8-Oxo-1,4,7,8-tetrahydropyridazino-[4,5-c]pyridazine, 8-oxo-7,8-dihydropyridazino[4,5-c]pyridazine and 5,8-dioxo-1,4,5,6,7,8-hexahydropyridazino[4,5-c]pyridazine derivatives

Reaction of 4-acyl-3H-imidazo[1,5-b]pyridazine-5,7-(6H)diones with hydrazine hydrate gave 3R-5R′-8-oxo-1,4,7,8-tetrahydropyridazino[4,5-c]pyridazine together with 3R-5R′-8-oxo-7,8-dihydropyridazino[4,5-c]pyridazine derivatives. Their structures were assigned by means of elemental analyses and spectroscopic data (ir, uv, nmr and ms). The conclusive structural elucidation involved the fact that 2R-4-ethoxycarbonyl-3H-imidazo[1,5-b]pyridazine-5,7-(6H)-diones treated with hydrazine hydrate afforded 3R-5,8-dioxo-1,4,5,6,7,8-hexahydropyridazino-[4,5-c]pyridazine which, upon dehydrogenation, gave products previously reported in the literature.     

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).     

7-(2-fluorobenzyl)-4-(substituted)-7-H-imidazo[4,5-d −1,2,3-triazines and −7H-pyrazolo[3,4-d]-1,2,3-triazines. Synthesis and anticonvulsant activity

The imidazo[4,5-d]-1,2,3-triazine and pyrazolo[3,4-d]-1,2,3-triazine analogues of the potent anticonvul-sant purine, BW 78U79 (9-(2-fluorobenzyl)-6-methylamino-9H-purine, 1 ), were synthesized and tested for anticonvulsant activity. The imidazo[4,5-d]-1,2,3-triazines 11–13 were prepared in four steps from 5-aminoimidazole-4-carboxamide (2) and the pyrazolo[3,4-d]-1,2,3-triazines 18–21 were synthesized starting with 5-amino-1-(2-fluorobenzyl)pyrazole-4-carbonitrile (14) . The intermediate 1,2,3-triazin-4-ones 6 and 16 were converted to the 4-substituted targets via the 4-(4-dimethylaminopyridinium) salts 10 and 17 . Imidazotriazine 11 had potent anticonvulsant activity against maximal electroshock-induced seizures, but its propensity to cause emesis precluded further development.     

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).     

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).     

Synthesis of some novel fused tetracyclic quinolonecarboxylic acids via 7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinoline and 6-methyl-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinoline

A series of fused tetracyclic quinolonecarboxylic acids was prepared for biological evaluation. These compounds were synthesized by a route involving a regiospecific functionalization of 5-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline to obtain a series of new substituted 7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolines and 6-methyl-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolines as convenient precursors of quinolones.     

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.     

Synthesis and electrochemical evaluation of substituted imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine scaffolds

Substituted 4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazoles were prepared from 5-amino-1-aryl-4-cyanoformimidoylimidazoles and cyanoacetamide, under mild experimental conditions. The pyrrolyl-imidazoles were cyclized to the corresponding 7,8-dihydroimidazo[4,5-b]pyrrolo[3,4-d]pyridines by reflux in ethanol, with catalysis by DBU. The same pyrrolyl-imidazoles were reacted with orthoesters, at room temperature and in the presence of sulfuric acid, to generate 3,7-dihydro-8H-imidazo[4,5-d]pyrrolo[3,2-f]diazepines in very good yield. Electrochemical studies of the imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine derivatives were carried out. The reduction potential of 7-ethyl-3-(4-methoxyphenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile was in the adequate range for presenting bioreduction properties.     

Synthetic studies of potential antimetabolites. XIII. Synthesis of 7-amino-3-β-d-ribofuranosyl-3H-imidazo[4,5-b] pyridine (1-deazaadenosine) and related nucleosides

7-Amino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (III, 1-deazaadenosine) was synthesized in 32% yield from the diacetyl derivative prepared from 7-aminoimidazo[4,5-b ]pyridine (1-deazaadenine) and 1,2,3,5-tetra-O-acetyl-β-D-ribose by the fusion method. A synthesis of 7-amino-4-b?-D-ribofuranosyl-4H-imidazo[4,5-b]pyridine (IV) was also achieved.     

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.     

2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline. Synthesis and electrophilic substitution reactions

2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline was synthesized by the Weidenhagen reaction of quinoline-5,6-diamine with furfural. Its alkylation with methyl iodide in the system KOH-DMSO gave two isomeric N-methyl derivatives, 2-(2-furyl)-1-methyl-1H- and 2-(2-furyl)-3-methyl-3H-imidazo[4,5-f]quinolines, the latter prevailing. 2-(2-Furyl)-3-methyl-3H-imidazo[4,5-f]quinoline was brought into electrophilic substitution reactions: bromination, nitration, formylation, acylation, sulfonation. Depending on the reaction conditions, electrophilic attack could be directed at both furan ring and quinoline fragment.     

Synthesis of 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine

We have synthesized 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine 1 in five steps from 1-(2-amino-methylphenyl) pyrrole 4 . Amidino derivatives 11-12 have also been prepared.     

Synthesis of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-imidazo[4,5-b]pyridin-2-amine. An aza analogue of enviroxime

6-[[(Hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-imidazo[4,5-b]pyridin-2-amine ( 1 ), an aza analogue of enviroxime, was synthesized in eight steps from 6-hydroxynicotinic acid ( 2 ). Acid 2 was nitrated, chlorinated with phosphorus pentachloride, and subjected to Friedel-Crafts aroylation to give 6-chloro-5-nitro-3-pyridyl phenyl ketone ( 5 ). Amination of 5 was followed by reduction of the nitro group and condensation with ethoxycarbonylisothiocyanate to give 6-benzyl-2-ethoxycarbonylamino-1H-imidazo[4,5-d]pyridine ( 8 ). The ethoxycarbonyl moiety of 8 was cleaved, N-1 was isopropylsulfonylated, and the carbonyl moiety was condensed with hydroxylamine to give 1 . Compound 1 was inactive against rhinovirus 1B and poliovirus type 1 .     

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.     

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.     

The synthesis of 3-(β-D-ribofuranosyl)imidazo[4,5-c] pyridazines

7-Chloro-3-(β- D -2,3,5-tri-O-benzoylribofuranosyl)imidazo[4,5-c] pyridazine ( 3 ), obtained from the condensation of 7-chloro-3-trimethylsilylimidazo[4,5-c] pyridazine ( 1 ) with 2,3,5-tri-O-benzoyl- D -ribofuranosyl bromide ( 2 ), served as the percursor of 7-chloro- ( 4 ), 7-amino- ( 8 ), and 7-mercapto-3-(β- D -ribofuranosyl)imidazo[4,5-c] pyridazine ( 9 ). 3-(β- D -ribofuranosyl)imidazo[4,5-c] pyridazine ( 7 ) was obtained from 3-(β- D -2,3,5-tri-O-benzoylribofuranosyl)imidazo-[4,5-c]pyridazine ( 6 ). The site of ribosidation is based upon uv spectral comparisons with model methyl compounds. The assignment of the anomeric configuration is derived from pmr spectral data.     

Synthesis of imidazo[4,5-c]pyridines with a trifluoromethyl group at C-4 and/or C-6

Thermal condensation of histamine with trifluoroacetaldehyde gives 4-(trifluoromethyl)spinacamine and subsequent dehydrogenation with selenium dioxide leads to 4-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (42%). Fluorination with sulfur tetrafluoride of L-spinacine, obtained from the condensation of L-histidine with formaldehyde, affords 6-(trifluoromethyl)spinacamine, which can be converted to 6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine with selenium dioxide (49%). Application of the sequential reactions to 4-(trifluoro-methyl)-L-spinacine gives 4,6-bis(trifluoromethyl)-1H-imidazo[4,5-c]pyridine. Dehydrogenation of the tetrahydropyridine ring also occurred during the fluorination with sulfur tetrafluoride.     

Synthesis of Some New Imidazo[4,5-B]Pyridine Derivatives Using 2-Cyanomethyl-1-Methyl-1H-Imidazo[4,5-B]Pyridine

Abstract

The reactions of 2-cyanomethyl-1-methyl-1H-imidazo[4,5-b]pyridine with isothiocyanates, nitroso compounds, acid chlorides, and thioglycolic acid were investigated. New imidazo[4,5-b]pyridine derivatives with various substituents in 2-position and derivatives of the new pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridine ring system were synthesized. The compounds obtained were tested in vitro for their tuberculostatic activity.