Methyl imidazo[1,2-b]pyridazine-2-carbamates and related compounds as potential antifilarial agents

A series of imidazo[1,2-b]pyridazines have been synthesized for antifilarial evaluation. The compounds prepared include methyl 6-benzoylimidazo[1,2-b]pyridazine-2-carbamate ( 12 ), 6-benzoyl-2-t-butylimidazo[1,2-b]pyridazine ( 13 ), methyl 6-(4-fluorobenzoyl)imidazo[1,2-b]pyridazine-2-carbamate ( 14 ), and methyl 6-(2-thienylcarbonylcarbonyl)imidazo[1,2-b]pyridazine-2-carbamate ( 15 ) which are aza analogs of the anthelmintic agents mebendazole, flubendazole and nocadazole. In addition, the preparation of a series of 2-t-butylimidazo[1,2-b]-pyridazine-6-carboxylic acid derivatives is described. Electrophilic bromination and iodination substitutions of 2-t-butyl-6-methylimidazo[1,2-b]pyridazine afforded 3-halo derivatives. Methyl 6-(4-fluorobenzoyl)pyridazine-3-carbamate was also prepared for antifilarial evaluation. None of these compounds possessed significant antifilarial activity against Brugia pahangi or Acanthocheilonema viteae infections in jirds.     

Stepwise approach to the 2,3-dihydroimidazo[1,2-a]pyridine and 5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine ring systems

The syntheses of 2,3-dihydro-8-fluoro-6-trifluoromethylimidazo[1,2-a]pyridine-3-carbonitrile ( 2 ), 8-fluoro-6-trifluoromethylimidazo[1,2-a]pyridine-3-carbonitrile ( 9 ) and 5-oxo-8-trifluoromethyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-3-carbonitrile ( 3 ) are described. These compounds are constructed in a stepwise approach starting from the properly substituted 2-halopyridines.     

New fused pyrazolopyrimidine derivatives; heterocyclic styling,synthesis, molecular docking and anticancer evaluation

Novel pyrazolopyrimidines and their fused derivatives derived from aminopyrazole moiety as pyrazoloquinazoline, chromenopyrazolopyrimidine, pyrazolopyrimidopyrimidine, pyrazolopyrimidotriazepine and benzoimidazopyrazolopyrimidine were designed, synthesized and evaluated for their anticancer activities. Twenty of the synthesized compounds were tested by the National Cancer Institute (NCI, Bethesda, USA) at a single high dose (10^-5 M). It was found that 5-amino-1H-pyrazole-4-carbonitrile derivative, pyrazolo[5,1-b]quinazoline-11-carbonitrile derivative and 1-amino-2,4-dihydro-5H-benzo[4,5]imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-one were own widely selective powerful anticancer activity towards certain cancer cell lines and this also proved through docking studies with cyclooxygenase-2 (COX-2) enzyme.     

Purines,pyrimidines, and related fused systems. 19. Use of S N H methodology for the synthesis of a new heterocyclic system,pyrrolo[3",2":3,4]pyrimido[4,5-c]pyridazine

Sonogashira cross-coupling of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with terminal alkynes afforded the corresponding 3-(alkyn-1-yl) derivatives. Oxidative amination of the latter compounds with primary alkylamines was accompanied by heterocyclization to give 6,8-dimethylpyrrolo[3",2":3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones.     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

The synthesis of pyrimido[4,5-c]pyridazines and pyrimido[5,4-c]pyridazines

The Hofmann reaction on 6-methylpyridazine-3,4-dicarboxamide (1) gave a mixture of 3-methylpyrimido[4,5-c]pyridazine-5,7-dione (2), 3-methylpyrimido[5,4-c]pyridazine-6,8-dione (3) and an acid (4) of unknown structure. The Hofmann reaction on pyridazine-3,4-dicarboxamide (9) gave a mixture of pyrimido[4,5-c]pyridazine-5,7-dione ( 10 ) and an acid ( 11 ) of unknown structure. The reaction of 3-amino-6-methylpyridazine-4-carboxamide ( 18 ) with ethyl orthoformate gave 3-methylpyrimido[4,5-c]pyridazin-5-one ( 21 ). 4-Aminopyridazine-3-carboxamide ( 36 ) upon fusion with urea gave pyrimido[5,4-c]pyridazine-6,8-dione ( 37 ) while with ethyl orthoformate 36 gave pyrimido[5,4-c]pyridazin-8-one ( 38 ). Pyrimido[5,4-c]-pyridazine-8-thione ( 39 ) was obtained by the action of phosphorus pentasulfide on 38. 4-Amino-3-cyanopyridazine ( 16 ) when treated with formamide produced 8-aminopyrimido[5,4-c]-pyridazine ( 41 ). The synthesis of 4-aminopyridazine-3-carboxamide ( 36 ) and 4-amino-3-cyanopyridazine ( 16 ), both key intermediates in the synthesis of the novel pyrimido[5,4-c]pyridazine ring system was accomplished by the Reissert reaction of 4-aminopyridazine-2-oxides and subsequent conversion of the nitrile to the amide.     

Synthesen mit Nitrilen. 34. Mitteilung. Phenylhydrazone des Dicyanmethylenindandions: Photolyse von 2-Dicyanmethylen-1,3-indandion-monophenylhydrazon in Methylenchlorid

Photolysis of 2-dicyanomethylene-1, 3-indandione-monophenylhydrazone 1 during several days yielded 3-(N-chlorimino)-5-oxo-2-phenyl-2.3-dihydro-5H-indeno[1.2-c]pyridazine-4-carbonitrile 2 . Isomerization to 3-imino-5-oxo-2-phenyl-2.3-dihydro-5H-indeno[1.2-c]pyridazine-4-carbonitrile 4 was also observed. Radical formation from the first triplet state leads to chlorine abstraction from the solvent and to formation of 2 . The same reaction occurs from the first triplet state of 4 .     

Purines, pyrimidines, and related fused systems. 21. Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione

Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with primary alkylamines and potassium amide in liquid ammonia gives rise to the corresponding 4-amino derivatives as the major products. The reactions with acyclic secondary amines are accompanied by annelation of the pyrrole moiety to the starting heterosystem to form 1-R-3-R"-6,8-dimethylpyrrolo[2",3";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones. The reaction with piperidine as the aminating agent occurs exclusively as aminodehalogenation. The Sonogashira cross-coupling of 4-amino-3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with terminal alkynes affords 1-R-2-R"-6,8-dimethylpyrrolo[3",2";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones.     

Synthesis of nitrogen-containing heterocycles. 8. Preparation and ring-opening of spiro[cycloalkane-[1′,2′,4′]triazolo[1′,5′-c]pyrimidine] derivatives

Diaminomethylene- and aminomethylthiomethylenehydrazones [2] of cyclic ketones 1–8 readily reacted with ethoxymethylenemalononitrile to give spiro[cycloalkane-1,2′-[1,2′,4′]triazolo[1,5′-c]pyrimidine-8′-carbonitrile] derivatives 12–19 through the electrocyclic reaction of the initially formed condensation products 26 in moderate to high yields. The spiro[cyclopentanetriazolopyrimidine] derivatives underwent ring-opening at the cycloalkane moiety upon heating in solution to give 2-alkyl-5-substituted-[1,2,4]triazolo[1,5-c]pyrimidine-8′-carbonitriles 20–23 . When an alkyl substituent was introduced into the cyclopentane ring, cleavage of the spiro compounds occurred preferentially at the cyclopentane moiety between the spiro carbon and the more branched one. In contrast, the cyclohexane ring, especially of spiro-5-amino-triazolopyrimidines 17 and 18 strongly resisted to ring-opening under similar conditions, but those of 5-methylthiotriazolopyrimidines 14 gave up to 17 percent of cleavage after prolonged heating in hot ethanol. 2-t-Butyl-5-methylthio-2,3-dihydro[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile 25 [R³ = C(CH₃)₃] was highly susceptible to the cleavage even at room temperature and produced the corresponding 2-unsubstituted triazolopyrimidine 24 with loss of the t-butyl group.     

Polycyclic N-Heterocyclic Compounds,Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and Evaluation of Their Antiplatelet Aggregation Activity

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2′,3′:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Synthesis of novel imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines

Several 1 1-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines have been used as starting material to prepare a number of derivatives of 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and 10H-pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines. The imidazole nucleus was built by reaction of amidines with ethyl bromopyruvate or aminoacetaldehyde dimethylacetal. Several derivatives of imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine have been prepared by formylation of the pyrrole ring followed by formation of thioamides. Condensation of 11-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines with diethyl ethoxymethylenemalonate afforded intermediate diesters which were transformed into the corresponding 10H-pyrimido[1,2-a]pyrrolo[2,1-c]-benzodiazepines.     

Purines, Pyrimidines, and Condensed Systems Based on them. 18. Reaction of 6,8-Dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)dione N(2)-oxide with Alkylamines

Heating 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione N₍₂₎-oxide (2) with piperidine or morpholine gave a moderate yield of 3-piperidino- and 3-morpholino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones (3a,b). Reaction of N-oxide (2) with ammonia and alkylamines in the presence of an oxidant led to formation of the 3-amino derivatives of 2 and the corresponding desoxy products 3. The latter were also obtained by an independent method by heating 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with alkylamines in butanol.     

A Convenient Synthesis of 1-Amino-4-methyl-4H-3-thia-4,5a,10-triazacyclopenta[a]fluoren-5-ones and Some New 2,3-Dihydro-1,3,4-thiadiazoles

1-amino-4-methyl-4H-3-thia-4,5a,10-triazacyclopenta-[a]fluoren-5-one and 6-methyl-6H-,9H-thia-4b,6,9,11,12-pentaazaindeno[1,2-a]-fluorene-5,8-dione derivatives were prepared from 2-methyl-1-oxo-3-thioxo-2,4,9b-trihydropyrimidino[1,6-a] benzimidazole-4-carbonitrile. Also, 2,3-dihydro-1,3,4-thidazoles were synthesized via a reaction of hydrazonoyl chlorides with 3-(methylamino)-2-substituted 3-thioxopropanenitrile. Structures of newly synthesized compounds were elucidated on the basis of elemental analyses, spectral data, and alternative methods synthesis whenever possible.     

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).     

Pyrrolopyridazines. II. Synthesis of the novel pyrrolo[3,2-c]pyridazine ring system

The first derivatives of the pyrrolo[3,2-c]pyridazine ring system, ethyl pyrrolo[3,2-c]pyridazine-6-carboxylate 2-oxide (5) and ethyl 3-chloro-6-methylpyrrolo[3,2-c]pyridazine-7-glyoxalate 1-oxide ( 12 ), were obtained in good yields from the cyclization of 4-ethoxymethyl-eneamino-3-methylpyridazine 1-oxide (3) and 3-chloro-5-(α-ethoxyethylideneamino)-6-methylpyridazine 1-oxide (14, R ? Cl, R₁ ? OMe), respectively, with diethyl oxalate and potassium ethoxide in ether.     

Pyrimidine derivatives. VII. Nucleophilic reactions of 5-bromo-1-(bromoalkyl)-6-bromomethyl-2,4(1H,3H)-pyrimidinediones

The reactions of 1-(bromoalkyl)-5-bromo-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1) with several nucleophiles were examined as follows: by reaction with sodium methoxide, 6-(bismethoxy)methyl-5-debrominated derivatives 2, 3 , and 4 were prepared; the corresponding di-substituted compounds (side chains in 1-and 6-positions) 5, 6, 7 , and 9 were obtained by treatment with silver nitrate, silver acetate, potassium thiocyanate, and potassium thioacetate; the reaction with thioacetamide and iso-butylamine gave bicyclic compounds [1,4]thiazino[4,3-c]- 11 , pyrazino[1,2-c]- 12 , and [1,4]diazepino[1,2-c]pyrimidinedione 13 , respectively; pyrrolidine, morpholine, and sodium azide afforded the corresponding 6-substituted compounds 14, 15 , and 16 .     

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.     

Synthesis of 1,4-dihydro-4-oxopyrrolo[1,2-b]pyridazine-3-carboxylic acids and 1,4-dihydro-4-oxoimidazo[1,5-b]pyridazine-3-carboxylic acids as potential antibacterial agents

To check the antibacterial potential of two families of aza analogues of the quinolones, 1,4-dihydro-4-oxopyrrolo[1,2-b]pyridazine-3-carboxylic acids and 1,4-dihydro-4-oxoimidazo[1,5-b]pyridazine-3-carboxylic acids, we have prepared a few derivatives in theses families using N-aminopyrrole and N-aminoimidazole derivatives as starting building blocks and the classical pathways of the quinolone series. The compounds showed no interesting antibacterial activity.     

Conversion of 4-amino-1H-1,5-benzodiazepine-3-carbonitrile to pyrazolo[3,4-d]pyrimidines,pyrimido[1,6-a]benzimidazole,and pyrazolo[3′,4′:4,5]pyrimido[1,6-a]benzimidazoles

The reactions of multifunctional compounds 2a, b, c, 3a, b and 4a, b which were readily obtained from 4-amino-1H-1,5-benzodiazepine-3-carbonitrile 1 with orthoesters are described, and derivatives of pyrazolo-[3,4-d]pyrimidines 5 , pyrimido[1,6-a]benzimidazole 9 , and pyrazolo[3′,4′:4,5]pyrimido[1,6-a]benzimidazole 10 are synthesized.     

On The Chemistry of Cinnoline IV [1]. Synthesis and Reactions of (4-Aminocinnolin-3-yl)-aryl-methanones

Summary.  The synthesis of a series of disubstituted (4-aminocinnolin-3-yl)-aryl-methanones from aryl-hydrazonomalononitrile in a one-step procedure is described. Cyclocondensation of (4-amino-6,8-dimethyl-cinnolin-3-yl)-phenyl-methanone with malononitrile, diethylmalonate, and dimethylacetamide-dimethylacetal gave the corresponding pyrido[3,2-c]cinnoline derivatives. Treatment of (4-amino-6,8-dimethyl-cinnolin-3-yl)-phenyl-methanone with triethyl-orthoacetate under reflux readily afforded the corresponding imidoester which underwent cyclization to a pyrido[3,2-c]cinnoline derivative. This starting compound could also be annelated to the corresponding 1,2-dihydro-4-aryl-2-oxo-pyrido[3,2-c]cinnoline derivatives via the (4-acetamidocinnolin-3-yl)-aryl-methanones. Chemical and spectroscopic evidences for the structures of the new compounds are presented. The effect of three of the compounds against sixty cancer types was tested. Received November 27, 2000. Accepted December 4, 2000