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At least 19 recordsLinked to original sources
PubMed1989

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↗
PubMed1991

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↗
PubMed1988

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↗
PubMed1990

Fluorinated pyrido[2,3-c]pyridazines. II. Synthesis and antibacterial activity of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pyridazine-3- carboxylic acids.

Chemical modification of pyridonecarboxylic acid antibacterials with a 1,8-naphthyridine ring, such as enoxacin and tosufloxacin, to their 2-aza derivatives was studied. A new series of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pridazine-3-carboxylic acids (25-27) was prepared by a route involving either alkylation of ethyl 6-fluoro-4(1H)-oxo-7-(p-tolylthio)pyrido[2,3-c]pyridazine-3-carbox ylate (7) or intramolecular cyclization of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-2-[2-(p-fluorophenyl)hydraz ono]acetate, (20), followed by displacement reaction with cyclic amines at C-7; the N-1 substituent in these compounds included of ethyl, 2-fluoroethyl and p-fluorophenyl groups, and the C-7 functional group comprised variously-substituted piperazines and pyrrolidines. Antibacterial activities of these compounds were markedly inferior to those of enoxacin and tosufloxacin.

4-Quinolones↗
PubMed1990

[Studies on the synthesis of condensed pyridazine derivatives. II. Synthesis and anxiolytic activities of 2-aryl-4,4a,5,6-tetrahydropyridazino[4,3-c]quinolin-3(2H)-ones, 2-aryl-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyridazin-3(4H)-ones, and related compounds].

A series of 2-aryl-4,4a,5,6-tetrahydropyridazino[4,3-c]quinolin-3(2H)- ones, 2-aryl-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyridazin-3( 4H)-ones, and related compounds were synthesized and tested for their ability to displace [3H]diazepam from rat brain membranes in vitro, and to prevent bicuculline-induced convulsions in mice in vivo. Among them, 2-(4-chlorophenyl)-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyr idazin-3(4H)- one (16b) showed remarkable activities both in vitro (Ki 48 nM) and in vivo (ED50 12.4 mg/kg, p.o.). The trans sulfoxide (19a) of 16b exhibited anxioselective pharmacological activities. Compound 19a was equipotent with diazepam in the anticonflict assay (Vogel type, rat, MED 10 mg/kg, p.o.) while exhibiting reduced muscle relaxation (rotarod test) and narcotic potentiation. The structure-activity relationships are discussed.

Animals↗
PubMed1989

[Biotransformation of pyridazines. 1. Pyridazine and 3-methylpyridazine].

Pyridazin (1) and 3-methylpyridazine (6) undergo oxidative biotransformation in an unexpected high degree. Beside the unchanged compounds, after administration of 1 two isomeric monohydroxylated products (2, 3), 4,5-dihydrodihydroxypyridazine (4) and 4,5-dihydroxypyridazine (5) and after administration of 6 one ringhydroxylated 6-derivative (7), 3-hydroxymethylpyridazine (8), one ringhydroxylated 3-hydroxymethylpyridazine derivative (9) and 4,5-dihydroxy-3-methylpyridazine (10) were suggested as urinary metabolites in rats. 2 and 7 are the main metabolites of 1 and 6, respectively.

Animals↗
PubMed1979

[Unexpected anti-inflammatory activity of rigid structures derived from 6-arylpyridazinone antihypertensive agents. II. Synthesis and activity of 5H-indeno(1,2-c)pyridazine and 5H-indeno(1,2-c)pyridazin-3-one].

The synthesis of 5H-indeno[1,2-c]pyridazine (V) and of some derivatives were reported. The compounds synthesised generally retained the antiinflammatory activity exhibited by the 4,4a-dihydro derivatives of this class, previously tested. Moreover (V) showed analgesic and antipyretic properties higher than those of acetylsalicylic acid.

Animals↗
PubMed1978

Synthesis of three metabolites of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine. A new rearrangement of 3-[1-methylethyliden)hydrazino] derivative.

The synthesis of three metabolites (I), (II), (III) , isolated from rat urine, of the hypotensive compound 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride (IV), is described. The first metabolite, 3-[bis-(2-hydroxyethyl)amino]pyridazine (I) (Scheme 1) was obtained either by reaction of 6(3)-chloro-3(6)-[bis-(2-hydroxyethyl)amino]pyridazine-N-oxide (V) with hydrazine hydrate or by catalytic hydrogenation of 3-chloro-6-[bis(2-hydrxyethyl)amino]pyridazine (VI). 3-Methyl-6-[bis-(2-hydroxyethyl)amino]-2-triazolo [4,3-b]pyridazine (II) was prepared (Scheme 2) by reaction of (IV) with acetic anhydride and subsequent hydrolysis of the resutling 6-[bis-(2-acetyloxyethyl)amino]-s-triazolo[4,3-b]pyridazine (VII). The third metabolite, 3-[bis-(2-hydroxyethyl)amino]-6-isopropyloxypyridazine (III) Scheme 3), was synthesized from 3-[(1-methylethyliden)hydrazino]-6-[bis-(2-hydroxyethyl)amino]pyridazine (VIII) which in phosphate buffer (pH 7.38) or in sodium hydrogen carbonate solution, underwent a rearrangement of new type to give (III).

Animals↗
PubMed1986

Synthesis and activity of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines in animal models of epilepsy.

A series of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines derivatives was synthesized and evaluated for anticonvulsant activity. The compounds were screened in mice for their ability to antagonize maximal electroshock- and bicuculline-induced seizures; neurotoxicity was evaluated in the rotorod test. The anticonvulsant activity of the most potent compounds in this series was also examined in kindled amygdaloid rats and in photoepileptic Papio papio baboons. Phenobarbital, diphenylhydantoin, carbamazepine, and sodium valproate were used as standard antiepileptic drugs. The structure-activity relationships in this series were examined by either varying the aryl ring in the 6-position of the pyridazine ring or by modifying the 3-amino side chain. Only the compounds with a phenyl ring in the 6-position of the pyridazine ring exhibited appreciable anticonvulsant activity. Furthermore, a 4-hydroxypiperidine side chain in the 3-position of the pyridazine ring appeared essential for anticonvulsant activity. Substituting the phenyl ring with a Cl in the 2-position led to a substantial increase of activity; disubstituting the phenyl ring with a Cl in the 2- and 4-positions yielded the most potent compounds in this series, some of which were as potent or more potent than phenobarbital. Two compounds, 6-(2-chlorophenyl)-3-(4-hydroxypiperidino)pyridazine (2) and 6-(2,4-dichlorophenyl)-3-(4-hydroxypiperidino)pyridazine (3), were selected for further studies. Clinical evaluation of these compounds is in progress.

Animals↗
PubMed1992

Synthesis, antiproliferative, and antiviral activity of certain 4-aminopyrrolo[2,3-d]pyridazine nucleosides: an entry into a novel series of adenosine analogues.

The preparation of novel heterocyclic base modified adenosine analogues, the 4-aminopyrrolo[2,3-d]pyridazine nucleosides, is described. Crucial to their successful preparation was the use of the pyrrole glycoside intermediates 3-cyano-2-formyl-1-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrrole (11) and 3-cyano-2-formyl-1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)pyrrole (17). Treatment of 11 and 17 with hydrazine dihydrochloride followed by treatment with boron trichloride provided 4-amino-1-beta-D-ribofuranosylpyrrolo[2,3-d]pyridazine (2) and 4-amino-1-beta-D-arabinofuranosylpyrrolo[2,3-d]pyridazine (3), respectively. 4-Amino-3-bromo-1-beta-D-ribofuranosylpyrrolo[2,3-d]-pyridazine (4) was prepared by a bromination of 4-amino-1-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyri daz ine (12) and subsequent removal of the benzyl groups with boron trichloride. Compounds 2-4 were evaluated for antiproliferative and antiviral activity. The tubercidin analogue (2) and its arabinosyl derivative (3) were virtually inactive in all assays. In contrast, the 3-bromo analogue 4 inhibited growth of L1210 and H. Ep. 2 cells. Compound 4 was also active against human cytomegalovirus and herpes simplex virus type 1, but the antiviral activity was not completely separated from cytotoxicity.

Adenosine↗
PubMed1979

Metabolites of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride in rat urine.

In 24 hr urine of rats orally given 150 mg/kg of 3-hydrazino-6-[bis-(2-hydroxyethyl)amino]pyridazine dihydrochloride (DL 150), no unchanged compound was detected. Three metabolites, less polar than DL 150, were isolated, their structures assigned by UV, MS, IR and 1H NMR spectroscopies, and confirmed by synthesis. They are: 3-[bis-(2-hydroxyethyl)amino]-6-isopropoxypyridazine (1); 3-[bis-(2-hydroxyethyl)amino]pyridazine (2); 3-methyl-6-[bis-(2-hydroxyethyl)amino]-s-triazolo[4,3-b]pyridazine (3). The metabolism of DL 150 in the rat follows some of the metabolic pathways reported for hydralazine.

Animals↗