Phthalazines. I. : N-Oxidation of 1-Phenylphthalazine and Chemical Properties of 1-Phenylphthalazine 3-Oxide

Hayashi, Eisaku; Oishi, Etsuo

doi:10.1248/yakushi1947.86.7_576

Cited by 12 publications

(5 citation statements)

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“…The crude 3-chloropyridazine was purified by recrystallization in EtOH or i -PrOH or by flash chromatography using a mixture of hexanes−EtOAc as eluant. The 3-chloropyridazines 3 are already known and were prepared according to literature procedures. ,− ,,− …”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

et al. 2001

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Starting from the 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazine 1, we performed the design, the synthesis, and the structure-activity relationships of a series of pyridazine analogues acting as AChE inhibitors. Structural modifications were achieved on four different parts of compound 1 and led to the following observations: (i) introduction of a lipophilic environment in the C-5 position of the pyridazine ring is favorable for the AChE-inhibitory activity and the AChE/BuChE selectivity; (ii) substitution and various replacements of the C-6 phenyl group are possible and led to equivalent or slightly more active derivatives; (iii) isosteric replacements or modifications of the benzylpiperidine moiety are detrimental to the activity. Among all derivatives prepared, the indenopyridazine derivative 4g was found to be the more potent inhibitor with an IC(50) of 10 nM on electric eel AChE. Compared to compound 1, this represents a 12-fold increase in potency. Moreover, 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-5-methyl-6-phenylpyridazine 4c, which showed an IC(50) of 21 nM, is 100-times more selective for human AChE (human BuChE/AChE ratio of 24) than the reference compound tacrine.

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Section: Methodsmentioning

confidence: 99%

“…The 3-chloropyridazines 3 are already known and were prepared according to literature procedures. 28,[31][32][33]36,[41][42][43] 3-Chloro-4-isopropyl-6-phenylpyridazine (3b). Yield 94%; mp 72 °C (lit.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

et al. 2001

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“…1-Chloro-4-phenyl phthal azine (20): 79%, white crystals (EtOH); mp 158 °C (lit . mp 160−161 °C); 1 H NMR (CDCl 3 ) δ 8.41 (1H, J = 8 Hz, d), 8.12−7.71 (5H, m), 7.60−7.55 (3H, m).…”

Section: Methodsmentioning

confidence: 99%

“…These compounds were then treated with N -methylpiperazine to yield the expected 3-(4‘-methylpiperazin-1-yl)pyridazines or phthalazines 10 − 13 (Table ). The starting 3(2 H )-pyridazinones 14 and 15 or 1(2 H )-phthalazinones 16 and 17 were prepared in condensing the appropriate γ-oxo carboxylic acid with hydrazine hydrate according to the literature procedures. − …”

Section: Chemistrymentioning

confidence: 99%

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5-HT₃ Antagonists Derived from Aminopyridazine-type Muscarinic M1 Agonists

et al. 1998

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A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 +/- 0.5 A between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 +/- 0.03 A of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC50 values for 5-HT3 receptor binding ([3H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([3H] pirenzepine) layed over 10,000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist-like effects on those responsible for the slowly desensitizing components.

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Phthalazines

Patel¹

1973

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Phthalazines. I. : N-Oxidation of 1-Phenylphthalazine and Chemical Properties of 1-Phenylphthalazine 3-Oxide

Cited by 12 publications

References 0 publications

Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

5-HT₃ Antagonists Derived from Aminopyridazine-type Muscarinic M1 Agonists

Phthalazines

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Phthalazines. I. : N-Oxidation of 1-Phenylphthalazine and Chemical Properties of 1-Phenylphthalazine 3-Oxide

Cited by 12 publications

References 0 publications

Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

5-HT3 Antagonists Derived from Aminopyridazine-type Muscarinic M1 Agonists

Phthalazines

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5-HT₃ Antagonists Derived from Aminopyridazine-type Muscarinic M1 Agonists