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PubMed2004

Three 5H-indeno[1,2-c]pyridazin-5-one derivatives, potent type-B monoamine oxidase inhibitors.

The structures of three compounds, namely 7-methoxy-2-[3-(trifluoromethyl)phenyl]-9H-indeno[1,2-c]pyridazin-9-one, C19H11F3N2O2, (Id), 6-methoxy-2-[3-(trifluoromethyl)phenyl]-9H-indeno[1,2-c]pyridazin-9-one, C19H11F3N2O2, (IId), and 2-methyl-6-(4,4,4-trifluorobutoxy)-9H-indeno[1,2-c]pyridazin-9-one, C16H13F3N2O2, (IIf), which are potent reversible type-B monoamine oxidase (MAO-B) inhibitors, are presented and discussed. Compounds (Id) and (IId) crystallize in a nearly planar conformation. The crystal structures are stabilized by weak C-H...O hydrogen bonds. The packing is dominated by pi-pi stacking interactions between the heterocyclic central moieties of centrosymmetrically related molecules. In compound (IIf), the trifluoroethyl termination is almost perpendicular to the plane of the ring.

Crystallography, X-Ray↗
PubMed1998

Imidazo[1,5-b]pyridazine-d4T conjugates: synthesis and anti-human immunodeficiency virus evaluation.

In an attempt to combine the human immunodeficiency virus type 1 (HIV-1)-inhibitory capacity of 2',3'-dideoxy-2',3'-didehydronucleoside analogues [nucleoside reverse transcriptase (RT) inhibitors; NRTI] and non-nucleoside RT inhibitors (NNRTI), we have designed, synthesized and evaluated for their anti-HIV activity several heterodimers of the general formula [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine]. The synthesis of these heterodimers was conducted in three parts. The first part focused on the synthesis of the NRTI. The second part was devoted to the NNRTI and the NNRTI linked to appropriate spacers: [NNRTI]-NH-(CH2)n-NH2. In the third part, the condensation between the NRTI and the [NNRTI]-NH-(CH2)n-NH2 was performed. The in vitro inhibitory activities against HIV-1 of the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers were found to be comparable to that of d4T (stavudine) in HIV-infected cells. Moreover, the heterodimers were endowed with anti-HIV-2 activity and with anti-nevirapine-resistant HIV-1 activity. None of the heterodimers proved markedly cytotoxic to CEM-SS or MT-4 cells. There was not a clear trend toward antiviral potency on lengthening the methylene spacer in the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers.

Antiviral Agents↗
PubMed1990

[Studies on the synthesis of condensed pyridazine derivatives. III. Synthesis and benzodiazepine receptor binding studies of condensed triazolopyridazine derivatives].

A series of 6H-(1)benzothiopyrano[3,4-e][1,2,4]triazolo[4,3- b]pyridazines and 6,7-dihydro-(1)benzothiepino[4,5- e][1,2,4]triazolo [4,3-b]pyridazines were prepared and tested for their ability to displace [3H] diazepam from rat brain membranes. An approximately planar shape of these molecules was essential for high affinity to the benzodiazepine receptor. Among them, 11-aryl compounds in the latter series were found to have high affinity to the benzodiazepine receptor. 11-Phenyl- and 11-thienyl- 6,7-dihydro-(1)benzothiepino[4,5-e][1,2,4]triazolo[4,3- b]pyridazine (3b-5 and 3b-11 respectively) showed the potent affinity comparable to that of diazepam. The structure-activity relationships are also discussed.

Animals↗
PubMed2004

Synthesis and properties of N-methyl and N-phenyl derivatives of 1,4-dioxo-1,2,3,4-tetrahydropyrido[3,4-d]pyridazines.

2-Methoxy- and 2-ethoxy-6-methyl-3,4-pyridinedicarboximides (XI, XII) reacted with N-methylhydrazine giving 2- and 3-methyl derivatives of the appropriate 1,4-dioxo-1,2,3,4-tetrahydropyrido[3,4-d]pyridazines (XV, XIII and XVI, XIV). In both cases 3-methyl isomer (XIII, XIV) was formed in higher yield than 2-methyl derivative (XV, XVI). Reaction of the imide XII with N-phenylhydrazine gave the salts of the suitable N-phenyldihydropyrido[3,4d]pyridazines with NH2-NHC6H5 (XXI and XXII) which transformed into N-phenylaminoimide (XXIII) during the boiling in 80% CH3COOH. Imide XXIII isomerized to the appropriate 2-phenyl and 3-phenylpyrido[3,4-d]pyridazines (XXIV - main reaction product and XXV) under the influence of heating in ethanolic solution of C2H5ONa. Some of N-phenylpiperazinylhydroxyalkyl(alkyl) derivatives of compound XXIV (XXVII, XXVIII) were pharmacologically active.

Analgesics, Non-Narcotic↗
PubMed1991

[Studies on synthesis and anticonvulsant activity of 3-GABA derivatives of 6-(substituted-phenyl) pyridazines].

In recent years considerable emphasis has been placed on the hypothesis that enhancement of GABA transmission could be beneficial in some types of epilepsy. The alpha-(aryl)-4-morpholineacetonitrile obtained by the interaction of aryl aldehydes, morpholine and potassium cyanide, have been used to synthesize 3-(aroyl)-propionic acids and esters by 1,4-additions to acrylonitrile or acrylic ester. 3-(Aroyl) propionic acids reacting with hydrazine can yield 6-aryl-4,5-dihydro-3(2H) pyridazinones which are dehydrogenated by bromine (via bromination dehydrobromination) to give 6-aryl-3(2H) pyridazinones. The latter compounds were converted into 3-(N-GABA)-6-(substitutedphenyl) pyridazines and 3-(N-butyryllactamyl)-6-(substitutedphenyl) pyridazines by the chlorination (by means of phosphorus oxychloride) and then reaction with GABA. By this method seventeen 3-GABA derivatives of 6-(substituted-phenyl)pyridazines were synthesized. The anticonvulsant activity (MES) of these compounds were also tested. 3-(N-GABA)-6-(2',4'-dichloro)phenylpyridazine; potent anticonvulsant (ED50 = 21.05 mg/kg).

Animals↗
PubMedDate not supplied

[New pyridazine compounds with possible physiological action].

The methods of obtaining and the physicochemical and spectral characterization of eight new pyridazine derivatives are presented. Thus, the reaction of chlorine-hydrazino-pyridazine with pyruvic and alpha-ketoglutaric acids resulted in the corresponding hydrazones. Using the indications in the literature the tetrazolic, triazolic, pyrazolonic and phenyl-thiocarbazidic derivatives of hydrazino-pyridazine were synthetized. The structure of the new compounds was confirmed by carbon, hydrogen and nitrogen analyses and spectral ones in infrared.

Chemical Phenomena↗
PubMed1984

New 2-substituted derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one.

Several new 2-substituted derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one were synthesized. The derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one (1-4) were used as the substrates. These compounds were converted by the reactions of cyanoethylation, hydroxymethylation and aminomethylation into appropriate 2-substituted derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one (5-28). Some of these compounds (5, 9 and 16) show anticonvulsant activity, while compounds 6, 7, 11-13 and 20 possess immunosuppressive activity.

Animals↗
PubMed1982

[On analgetically, antipyretically and antiphlogistically active sulphur-containing pyridazines (author's transl)].

12 newly synthetized sulphur-containing pyridazines were tested for analgetic, antipyretic and antiphlogistic activity. Using the tail-flick and the hot-plate test as well as the writhing syndrome as screening procedures, the author stated that 9 of these compounds produced a good analgetic effect. The majority of these compounds exerted a marked antipyretic effect as evidenced by the antipyresis model. The action of these pyridazines on the acute oedema of the rat hind paw was relatively poor. Determination of the acute lethal doses and of adverse effects due to an action on the central nervous system showed that 3 of the 12 compounds under investigation are characterized by low toxicity. Furthermore, the analgetic and antiphlogistic screening methods revealed that one of these 3 compounds, 3-amino-4-mercapto-6-methylpyridazine (1), is particularly active. The beneficial properties of this substance and also those of some other derivatives justify more detailed studies concerning the pharmacological characterization of sulphur-containing pyridazines.

Animals↗
PubMed1982

[Structure-activity analysis of analgetically active sulphur-containing pyridazines (author's transl)].

The distribution coefficients in n-octanol/water and the RM values in two different solvents have been determined for 12 newly synthetized sulphur-containing pyridazines. The establishment of dose-effect curves by means of three screening methods (writhing syndrome, tail flick test and hot-plate test) permitted to estimate the analgetic activities of the substances under investigation. Regression analyses revealed a highly significant correlation between the ED50 values and the RM values of the pyridazines in butanol/glacial acetic acid/water. The greatest analgetic effect was observed with compounds, the RM values of which tended to 0. To complement this study, the LD50 values and the side-effects on the central nervous system wee considered, too. There was no correlation between the LD50 values and the distribution coefficients; however, a low-significant correlation existed between the side-effects on the central nervous system (as measured by the failure rates in the rotarod test) and the distribution coefficients. In summary, the results hitherto obtained permit to conclude that four of the twelve pyridazines excel by "favourable" analgetic activities. Considering the therapeutic quotients, further investigations, especially of one of these compounds, 3-amino-4-mercapto-6-methylpyridazine, seem justified.

Analgesics↗
PubMed1981

[Pharmacological characterization of novel pyridazines. Part 1: Physicochemical parameters, acute toxicity and action on the central nervous system (author's transl)].

The author determined the distribution coefficients (in n-octanol/water) and the RM values (thin-layer chromatographically, using two solvent systems) of 17 newly synthetized pyridazines. These determinations evidenced that the majority of these compounds are relatively polar. Altogether the acute toxicity of the compounds under investigation may be regarded as weak, because LD50 values could be determined for only 10 of the orally applied 17 pyridazines. The characteristic features of acute toxicity caused by high doses of the compounds under investigation were a stimulation of the central nervous system associated with convulsions or a depressant action on the central nervous system. The screening tests performed to date do not permit to classify the compounds under investigation into defined groups of substances action on the central nervous system. In conjunction with data from the literature, the possible mechanisms of the attack of these novel pyridazines on the central nervous system are discussed.

Animals↗
PubMed1995

Synthesis of new serotonergic 2-substituted 4,6-diaryl pyridazin-3-ones.

A series of 4,6-diaryl pyridazin-3-ones substituted in the 2-position by [4-(4-aryl piperazin-1-yl]-but-2-ynyl moieties was synthesized and evaluated for antidepressant activity. The structures of these new pyridazine derivatives were confirmed by IR, 1H-NMR spectra and by elementary analysis. At 150 mg/kg i.p., they induced little or no reduction of the duration of immobility of mice in the forced swimming test. Head twitches produced by L-5-hydroxytryptophan in mice pretreated with pargyline were significantly potentiated by most of the tested compounds. In addition, pyridazine derivatives did not antagonize reserpine-induced palpebral ptosis or enhance the toxic effects of yohimbine and were almost devoid of anticholinergic properties in mice.

5-Hydroxytryptophan↗
PubMedDate not supplied

In vitro cytostatic activity of 1,2,4-triazolo- and 1,2,3,4-tetrazolo pyridazines.

Out of a series of fourteen 1,2,4-triazolo(4,3-b)-, and 1,2,3,4-tetrazolo-(1,5-b)pyridazine derivatives, 4 compounds have been found to reveal high cytostatic activity in KB and HeLa human cancer cell lines in vitro with ED50 activity values ranging from 0.25 to 3.0 micrograms/cm3 (0.009-0.158 x 10(-4) mole/l), and according to DR and D, NCI, NIH Bethesda criterion were qualified for further in vivo screening investigation. 6-Chloro-8-(N,N-dimethylaminosulfonylmethyl)-1,2,3,4-tetrazolo+ ++-(1,5-b)- pyridazine exhibited the strongest in vitro cytostatic activity (ED50 = 0.009 x 10(-4) mole/l), comparable with the best standards, and higher in comparison with a standard cytosine arabinoside (ED50 = 0.03-0.04 x 10(-4) mole/l). The presence of chlorine atom at C-6 position in the pyridazine ring determines the cytotoxic activity of tetrazolopyridazines as the primary factor and C-8 substituents, which influence their better solubility seems to be a secondary one, as confirmed by the results of the structure-activity and solubility-activity relationship analysis. However, for the exhibition of the triazolopyridazine activities the presence of two chlorine atoms at C-6 and C-3 position was essential.

Antineoplastic Agents↗
PubMed2006

Microwave-assisted synthesis of 3,6-di(pyridin-2-yl)pyridazines: unexpected ketone and aldehyde cycloadditions.

3,6-Di(pyridin-2-yl)pyridazines are an interesting class of compounds because of their metal-coordinating ability resulting in the self-assembly into [2x2] gridlike metal complexes with copper(I) or silver(I) ions. These and other substituted pyridazines can be prepared by the inverse-electron-demand Diels-Alder reactions between acetylenes and 1,2,4,5-tetrazines. In this contribution, the effect of (superheated) microwave conditions on these generally slow cycloadditions is described. The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine could be accelerated from several days reflux in toluene or N,N-dimethylformamide to several hours in dichloromethane at 150 degrees C. In addition, the unexpected cycloaddition of the enol tautomers of various ketones and aldehydes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine is described in detail providing an alternative route for the synthesis of (substituted) pyridazines.

Journal Article↗
PubMed2006

Vibrational spectroscopy of the pyridazine cation in the ground state.

Vibrational structure of the pyridazine cation in the ground state has been revealed by a vacuum-ultraviolet mass-analyzed threshold ionization (VUV-MATI) spectroscopy. The adiabatic ionization energy is precisely measured to be 70241 +/- 6 cm(-1) (8.7088 +/- 0.0007 eV). The origin is very weakly observed, while a long progression of the nu9(+) (a1) band of which the fundamental vibrational frequency is 647 cm(-1) is predominantly observed. The nu9(+) (a1) mode progression combined with one quantum of the nu3(+) (a1) band at 1698 cm(-1) is found to be even stronger. Many other weakly observed vibrational features of the pyridazine cation are identified in the vibrational energy of 0-3500 cm(-1). The structural change of pyridazine upon ionization, reflected in the vibrational spectrum obtained by the one-photon direct ionization process, is theoretically predicted by ab initio calculations. Ring distortion including contraction of the N=N bond should be responsible for strong excitations of nu3(+) and nu9(+) modes. Franck-Condon analysis is given for the comparison of the experiment and theory.

Journal Article↗
PubMed2002

Novel 3-arylamino- and 3-cycloalkylamino-5, 6-diphenyl-pyridazines active as ACAT inhibitors.

A new series of pyridazine derivatives, structurally related to the previously reported ACAT inhibitors 3-(cyclo)alkylamino-5, 6-diphenyl-pyridazines, were synthesized and tested for their inhibitory properties. Substitution of the 3-alkylamino chain with a phenylamino group maintains activity. In contrast, the presence of either substituents on the phenylamino group or aliphatic rings having more or less than six carbon atoms lowers it.

Animals↗
PubMed2004

Realization of unusual ligand binding motifs in metalated container molecules: synthesis, structures, and magnetic properties of the complexes [(LMe)Ni2(mu-L')]n+ with L'=NO3-, NO2-, N3-, N2H4, pyridazine, phthalazine, pyrazolate, and benzoate.

A series of dinickel(II) complexes with the 24-membered macrocyclic hexaazadithiophenol ligand H(2)L(Me) was prepared and examined. The doubly deprotonated form (L(Me))(2-) forms complexes of the type [(L(Me))Ni2II(mu-L')](n+) with a bioctahedral N(3)Ni(II)(mu-SR)(2)(mu-L')Ni(II)N(3) core and an overall calixarene-like structure. The bridging coordination site L' is accessible for a wide range of exogenous coligands. In this study L'=NO(3)(-), NO(2)(-), N(3)(-), N(2)H(4), pyrazolate (pz), pyridazine (pydz), phthalazine (phtz), and benzoate (OBz). Crystallographic studies reveal that each substrate binds in a distinct fashion to the [(L(Me))Ni(2)](2+) portion: NO(2)(-), N(2)H(4), pz, pydz, and phtz form mu(1,2)-bridges, whereas NO(3)(-), N(3)(-), and OBz(-) are mu(1,3)-bridging. These distinctive binding motifs and the fact that some of the coligands adopt unusual conformations is discussed in terms of complementary host-guest interactions and the size and form of the binding pocket of the [(L(Me))Ni(2)](2+) fragment. UV/Vis and electrochemical studies reveal that the solid-state structures are retained in the solution state. The relative stabilities of the complexes indicate that the [(L(Me))Ni(2)](2+) fragment binds anionic coligands preferentially over neutral ones and strong-field ligands over weak-field ligands. Secondary van der Waals interactions also contribute to the stability of the complexes. Intramolecular ferromagnetic exchange interactions are present in the nitrito-, pyridazine-, and the benzoato-bridged complexes where J=+6.7, +3.5, and +5.8 cm(-1) (H=-2 JS(1)S(2), S(1)=S(2)=1) as indicated by magnetic susceptibility data taken from 300 to 2 K. In contrast, the azido bridge in [(L(Me))Ni(2)(mu(1,3)-N(3))](+) results in an antiferromagnetic exchange interaction J=-46.7 cm(-1). An explanation for this difference is qualitatively discussed in terms of bonding differences.

Azides↗
PubMed1990

Synthesis and pharmacological evaluation of 6,8-diaryl 1,2,4-triazolo [4,3,-b] and 1,2,3,4,-tetrazolo [1,5-b] pyridazines.

A series of 6,8-diaryl-1,2,4-triazolo[4,3-b] and 1,2,3,4-tetrazolo[1,5-b]pyridazines was synthesized from suitable chloropyridazines. The compounds were screened in mice for their ability to antagonize maximal electroshock-, pentylenetetrazole- and bicuculline-induced seizures; sedative effects were evaluated by a study of the spontaneous motor activity. Some of pyridazine derivatives exhibited appreciable anticonvulsant activity. Substituting the phenyl ring in the 6-position with an halogen atom led to a substantial increase of activity. Furthermore, none of the compounds was notably active in tests predictive of anxiolytic activity.

Animals↗