Pyridazines 79. Novel oxazolo[3',2':1,2]pyrrolo[3,4-d]pyridazines and imidazolo[1'2':1,2]pyrrolo[3,4-d]pyridazines: synthesis and biological evaluation.
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Antiviral Agents↗
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Pyridazines. IX. Proton magnetic resonance studies of pyridazine, pyrazine, and substituted pyridazines.
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Protons↗
Cytostatic activity of pyridazinee derivatives. Part III. Cytotoxic studies on some pyridazine-3,6-diones and pyridazin-6-ones using a particle counter and a proliferation inhibition test.
The cytoxicity of 10 pyridazine-3,6-dione and 11 pyridazine-6-one derivatives was studied on L-1210 cells using the proliferation inhibition (PI) test and particle counter (PC) test. Eight compounds with ED50 value below 1 microgram/ml in the PI system and with minimal effective concentration (MEC) below 0.2 mg/ml in the PC system, were qualified for further in vivo investigation. A good solubility-activity relationship depending on bromine substituents at C-4 and C-5 in the pyridazine-3, 6-dione group was observed. The activity of soluble, pyridazine-3,6-diones depended proportionally on the number of bromine substituents at C-4 and C-5 -contrary to solubility inversely proportional to the number of bromine atoms. The moderately soluble and moderately active compounds appear to have the highest efficiency. Activity of pyridazine-6-ones seems also to be related to the number of chlorine atoms substituted at those positions. The preliminary information about the cellular mechanism and quantitative differences in the action of model analogues in correlation to structure-solubility was obtained. A new cytotoxic particle counter index (CPCI) was helpful for differentiation of activity of pyridazine analogues.
Animals↗
Synthesis and biological evaluation of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b)pyridazines related to formycin prepared via ring closure of pyridazine precursors.
All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6) in the presence of DCC and subsequent thermal ring closure of the reaction product (8) provided 8-amino-7-chloro-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)- triazolo[4,3-b]pyridazine (9). Dehalogenation of 9, followed by debenzoylation, gave the formycin congener 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (5). Similar condensation of 5-amino-4-chloro-3-hydrazinopyridazine (13) with 6 and dehalogenation of the cyclized product (16), followed by debenzoylation, gave the isomeric 7-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (19). DCC-mediated coupling of 6 with 6-chloro-3-hydrazinopyridazine (12), followed by ammonolysis of the cyclized product (21) with liquid NH3, provided a convenient route to 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazine (20). The structural assignment of 5 was made by single-crystal X-ray diffraction analysis. Compounds 5, 19, 20, and certain deprotected nucleoside intermediates were evaluated against L1210, WI-L2, and CCRF-CEM tumor cell lines, as well as against DNA and RNA viruses in culture. These compounds did not exhibit any significant antitumor or antiviral activity in vitro.
Animals↗
Pyridazine derivatives. XI: Antihypertensive activity of 3-hydrazinocycloheptyl[1,2-c]pyridazine and its hydrazone derivatives.
3-Hydrazinocycloheptyl[1,2-c]pyridazine (4) and its hydrazone derivatives 3-[N1-(isopropylidene)]hydrazinocycloheptyl[1,2-c]pyridazine [correction of hydrazinocyclohexyl] (5) and 3-[N1-(isobutylidene)]hydrazinocycloheptyl[1,2-c]pyridazine (6) were prepared, and their activity against genetic, neurogenically-induced, and deoxycorticosterone acetate -NaCl-induced hypertension was found to be at least as great as that of hydralazine. The results of studying vasorelaxation of rat aorta by 4 and hydralazine suggest that both these compounds owe their antihypertensive activity to direct relaxation of vascular smooth muscle.
Animals↗
exo-2-(Pyridazin-4-yl)-7-azabicyclo[2.2.1]heptanes: syntheses and nicotinic acetylcholine receptor agonist activity of potent pyridazine analogues of (+/-)-epibatidine.
A new strategy for the straightforward synthesis of novel racemic epibatidine analogues is presented, in which the 2-chloropyridinyl moiety of epibatidine is bioisosterically replaced by differently substituted pyridazine rings. A key step of the new syntheses is the inverse type Diels-Alder reaction of the electron-rich enol ether 13 with the electron-deficient diazadiene systems of the 1,2,4, 5-tetrazines 14a-d to yield the novel pyridazine analogues of (+/-)-epibatidine 18, 19, 22, and 24. In addition preparation of the N-substituted derivatives, such as 26 and 28, is described. The structures of the novel epibatidine analogues were assigned on the basis of spectral data, that of compound 24 being additionally verified by X-ray crystallography exhibiting two racemic solid-state conformations in the crystal lattice and representing the first X-ray structure of an unprotected 7-azabicyclo[2.2.1]heptane moiety. The nAChR agonist activity of the racemic compounds 18, 19, 22, 24, and 28 was assayed in vitro by whole-cell current recordings from Xenopus oocytes expressing different recombinant nicotinic receptors from the rat. Among the compounds synthesized and tested, the pyridazine analogue 24 of (+/-)-epibatidine and its N-methyl derivative 28 were found to be the most active ones retaining much of the potency of natural epibatidine but with a substantially improved selectivity ratio between the alpha4beta2 and alpha3beta4 subtypes.
Animals↗
The synthesis and biological evaluation of 4-p-nitrobenzylthio-v-triazolo[4,5-d]pyridazine and imidazo[4,5-d]pyridazine ribosides as potential nucleoside transport inhibitors.
The synthesis of S4-substituted nucleosides possessing the imidazo- and v-triazolo[4,5-d]pyridazine ring systems was undertaken and the compounds prepared were evaluated as inhibitors of nucleoside transport into human erythrocytes. 1-(2,3,5-Tri-O-acetyl-beta-D-ribofuranosyl)-v-triazolo[4,5-d]pyridazine- 4 (5H)-thione and 1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazo[4,5-d]pyridazine-4 (5H)-thione were each synthesized by two different routes and served as precursors for the title analogues. The nitrobenzylmercaptopurine riboside (NBMPR) analogues, 4-(p-nitrobenzylthio)-1-(beta-D-ribofuranosyl)imidazo[4,5-d]pyrida zine and 4-(p-nitrobenzylthio)-1-(beta-D-ribofuranosyl)-v-triazolo[4,5-d]py ridazine, inhibited the transport of adenosine, but were approximately 4- and 28-fold less active, respectively, than NBMPR and nitrobenzylthioformycin, known potent and specific inhibitors of carrier-mediated transport.
Affinity Labels↗
3,6-Dichloro-4-[2-(4-thiamorpholino)ethanesulfanyl]pyridazine and 3,6-bis(pyrazol-1-yl)-4-[2-(4-thiamorpholino)ethanesulfanyl]pyridazine.
The trans-trans conformations adopted by the derivatized bis(bidentate) chelating N(4)-donor ligand 3,6-bis(pyrazol-1-yl)-4-[2-(4-thiamorpholino)ethanesulfanyl]pyridazine, C(16)H(19)N(7)S(2), and an intermediate in its formation, 3,6-dichloro-4-[2-(4-thiamorpholino)ethanesulfanyl]pyridazine, C(10)H(13)Cl(2)N(3)S(2), contrast with the cis-cis conformation found previously for 3,6-bis(thiophen-2-yl)pyridazine [Ackers, Blake, Hill & Hubberstey (2002). Acta Cryst. C58, o640-o641], which places all four heteroatoms on the same side of the molecule.
Journal Article↗
Studies on the synthesis of condensed pyridazine derivatives. IV. Synthesis and anxiolytic activity of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-ones and related compound.
A series of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)- ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo. Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39--42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5,6-dihydro- (37) and 2-(4'-chlorophenyl)-5,6-dihydro-10-fluoro-(1)benzothiepino[5,4-c]+ ++pyridazin- 3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of gamma-aminobutyric acid-induced chloride current (Icl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.
Animals↗
Pyridazine derivatives and related compounds, part 9. tetrazolo[1,5-b]pyridazine-8-carbohydrazide: synthesis and some reactions.
The reaction of the hydrazide of 6,7-diphenyltetrazolo[1,5-b]pyridazine-8-carboxylic acid 3 with aromatic aldehydes gave 8-arylidenecarbohydrazide derivatives. The reaction of 3 with methanesulfonyl chloride, benzenesulfonyl chloride, phenyl and benzylisothiocyanate afforded the corresponding N-substitute derivatives. The reaction of 3 with potassium ethylxanthate gave 5-(6,7-diphenyltetrazolo[1,5-b]pyridazin4-yl)-1,3,4-oxadiazole-2-thione 7. The alkylation of this product in an alkaline medium proceeds at the sulfur atom, while the aminomethylation and acylation proceed at the nitrogen atom. Compound 3 was also reacted with N-aminothiosemicarbazide to give 5-(6,7-diphenyltetrazolo[1,5-b]pyridazin-8 yl)4-amino-1,2,4-triazole-3-thione 11.
Alkylation↗
Synthesis and pharmacological study of 5-aryl-6-methyl-4,5-dihydro-pyridazin-3(2H)ones and related 5-aryl-6-methyl-pyridazin-3(2H)ones.
New 5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)ones (III) and related 5-aryl-6-methyl-pyridazin-3(2H)ones (IV) were synthesized in order to evaluate their pharmacological profile in comparison with that of the known class of antihypertensive and platelet aggregation inhibitors 5-methyl-6-aryl-4,5-dihydropyridazin 3(2H)ones (I). Though none of the tested derivatives was found to possess the antihypertensive potency of the reference compounds, some of them displayed significant antithrombotic and antiulcer properties. In particular, 5(p. acetylaminophenyl)-6-methyl-pyridazin-3-one (IV c) was found highly effective (ED50 = 1.2 mg/kg) in inhibiting indomethacin-induced ulcers.
Animals↗
Preparation of new [1,2,4]triazolo[4,3-b]pyridazines. Part 12: Studies in the field of pyridazine compounds.
6-Substituted-[1,2,4]triazolo[4,3-b]pyridazine-3-methanol, -aldehyde, -nitrile, -chloromethyl and -aminomethyl derivatives of potential antihypertensive activity were synthesized. The reduction of methyl[1,2,4]triazolo[4,3-b] pyridazine-3-carboxylate by lithium aluminium hydride and potassium borohydride was examined. The new compounds failed to exhibit hypotensive or antihypertensive effect. Compound 2a was a minor metabolite of GYKI-11679 [7].
Animals↗
Pyridazine N-oxides. II. Synthesis and in vitro antimicrobial evaluation of 3-chloro-4-carbamoyl-5-aryl-6-methyl-pyridazine N-oxides.
As a part of a research project on antimicrobial agents, various novel carbamoyl derivatives of pyridazine-N-oxides 7a-j were prepared in moderate to good yields from 3-chloro-4-ethoxycarbonyl-5-aryl-6-methyl-3-pyridazine. All compounds synthesized were ineffective against Gram+, Gram- bacteria and fungi while 7e and 7j exhibited a fairly good activity against Trichomonas vaginalis.
Animals↗
Bicyclic [b]-heteroannelated pyridazine derivatives. Part 5. Synthesis of some triazolo[4,3-b]pyridazine and pyridazino[6,1-c]triazine derivatives as potential benzodiazepine receptor ligands.
4-Substituted-tetrahydropyridazine-3,6-dione 3-hydrazones [I] reacted with strong carboxylic acids and some acyl chlorides to give the N-acylation products and/or triazolo[4,3-b]pyridazine derivatives. Derivatives of this bicyclic structure were obtained also in reactions of I with triethyl orthoformate and orthoacetate. In the reaction with phosgene, triazolo[4,3-b]pyridazine-3,6-dione, and with oxalyl chloride pyridazino[6,1-c]triazine-3,4,7-trione derivatives were obtained.
Animals↗
Bicyclic [b]-heteroannelated pyridazine derivatives. Part 6. Aromatization of some tetrahydrotriazolo[4,3-b]pyridazine derivatives with potential activity as benzodiazepine receptor ligands.
Aromatization of the pyridazine ring in 8-aryl-7,8-dihydro-3-trifluoromethyltriazolo[4,3-b]pyridazin -6(5H)-ones in the reaction with a phosphorus pentachloride-phosphorus oxychloride mixture yielded the corresponding 6-chloro compounds. Since halogenation at C-7 was accompanied by an instant 7,8-dehydrohalogenation, the reaction with bromine gave the 7,8-dehydro analogs with no change of the carbonyl function at C-6. Benzoylation yielded the O-benzoyl derivative as found by X-ray crystallography. Substitution of chlorine at C-6 for an amine or thioether function was effected in the reactions with hydrazine, amines, and thiophenols. In vitro tests revealed low affinity of the compounds for the benzodiazepine receptor.
Ligands↗
Pyridazine N-oxides. III. Synthesis and "in vitro" antimicrobial properties of N-oxide derivatives based on tricyclic indeno[2,1-c]pyridazine and benzo[f]cinnoline systems.
A number of 9H-indeno[2,1-c]pyridazine N-oxides (3a-c) and benzo[f]cinnoline N-oxides (4,5a-c) have been synthesized and tested for antimicrobial activity. All new products were inactive against Gram negative bacteria and fungi. In contrast, among the compounds synthesized, 3b, 4b and 5b showed a moderate activity against Gram positive Staphylococcus aureus and Staphylococcus epidermidis. Of the present series, the 9-nitro-benzo[f]cinnoline N-oxide 5b possessed the highest activity especially against Trichomonas vaginalis (MIC = 3.9 micrograms/ml).
Anti-Bacterial Agents↗
Pyridazine derivatives, VII. Synthesis and hypotensive activity of 3-hydrazinocycloalkyl[1,2-c]pyridazines and their derivatives.
The preparation of a series of 3-hydrazinocycloalkyl[1,2-c]pyridazines 7 and some derivatives as hydrazones 8, 9, triazoles 10 and pyrroles 11 are described together with their hypotensive activity in normotensive rats.
Animals↗
Use of 4-bromo pyridazine 3,6-dione for building 3-amino pyridazine libraries.
An efficient method for preparation of 4,6 or 5,6 disubstituted 3-aminopyridazines was easily carried out starting from easily available 4-bromo-pyridazine-3,6-dione, and using combination of both amination and Pd(0) cross-coupling reactions under microwave irradiation.
Catalysis↗