Synthesis in the Pyridazine Series. I. Pyridazine and 3,6-Dichloropyridazine

Mizzoni, R. H.; Spoerri, Paul E.

doi:10.1021/ja01148a537

Cited by 72 publications

(16 citation statements)

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“…tion of a hydrazine molecule to an anhydride or to 1,4 ketoesters or ketoacids to form pyridazinones [48][49][50][51]. These linear dicarbonyls can be purchased or assembled to create diversity at R 6 and R 4 .…”

Section: Main Textmentioning

confidence: 99%

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

Wing¹,

Behanna²,

Eldik³

et al. 2006

CAR

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There is immediate potential to enhance success and innovation in drug development by pairing newly emerging approaches in medicinal chemistry and computational biology with knowledge gained from the recent era of high throughput screens and the early years of modern drug discovery when in vivo efficacy was an early "Go/No Go" project management decision. Focused, in-parallel synthetic chemistry platforms, combined with computational analyses serving as decision aids in planning, minimize the total number of compounds synthesized while maximizing the probability of creating bioavailable compounds that sample diverse chemical space. Incorporating a hierarchal strategy that emphasizes early selection of synthesized compounds based on biological or biophysical endpoints presents fewer and more relevant compounds for secondary evaluation of in vivo efficacy using animal screens with disease relevant or clinically translatable endpoints. We summarize here an interdisciplinary approach at the chemistry-biology interface that is used for the rapid discovery of novel lead compounds for neurodegenerative disorders, such as Alzheimer's disease (AD). The chemistry platform uses established chemistries amenable to in-parallel strategies to create synthetic diversifications of the privileged pyridazine chemotype that sample a restricted chemical space. The hierarchal biology platform uses primary screens for in vitro activity and selectivity with the target cell type, and rapid secondary screens for in vivo efficacy and toxicity in animal models with good phenotypic penetrance for disease relevant pathophysiological endpoints or clinically translatable surrogate endpoints. For the AD case study, novel lead compounds were developed in less than two years by a small academic group, and corporate sponsored clinical trials are planned.

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Section: Main Textmentioning

confidence: 99%

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

Wing¹,

Behanna²,

Eldik³

et al. 2006

CAR

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“…6,8,11 Reaction of maleic anhydride with hydrazine, 12 tetrazines with alkenes or alkynes, 13 1,2-azadienes with alkenes 14 or active methylene compounds 15 are the commonly employed methods for the synthesis of pyridazines.…”

Section: Figurementioning

confidence: 99%

Regioselective synthesis of pyrazole and pyridazine esters from chalcones and α-diazo-β-ketoesters

Nair

Pavashe

Katiyar

et al. 2016

Tetrahedron Letters

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“…The starting substrates IV and V were prepared by the procedures described in [7,8,15]. We found that pyridazine IV in ethanol at 78oC reacts with methylhydrazine selectively with substitution of one chlorine atom to give 3-(1-methylhydrazino)-6-chloropyridazine XIII in 55% yield.…”

Section: VIIImentioning

confidence: 99%

Nucleophilic substitution of chlorine with hydrazine and methylhydrazine in chlorinated pyridazines and pyridazones

Baranov¹,

Tsypin²,

Laskin³

2004

Russ J Appl Chem

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The reactions of methylhydrazine and hydrazine hydrate with chlorinated pyridazines and pyridazones were studied.The reactivity of hydrazine and methylhydrazine toward aliphatic and aromatic compounds has been well studied [1,2]. However, data on reactions of hydrazine and methylhydrazine with heterocycles and, in particular, with pyridazines are scarce. The interest in the chemistry of hydrazine is determined by its diverse applications in science and technology. In particular, hydrazine derivatives are widely used in medicine as physiologically active compounds exhibiting antitubercular, anticancer, radiation-protective, and other effects; in agriculture, as plant growth regulators and stimulants, as insecticides, fungicides, and hebricides; and in industry, for preparing synthetic fibers, films, and coatings [3,4].In this study we examined the reactions of hydrazine hydrate and methylhydrazine with some chlorinated pyridazines and pyridazones.In the pyridazine series, available substrates for nucleophilic substitution are 4,5-dichloro-6-pyridazone I, 1-methyl-4, 5-dichloro-6-pyridazone II, 3, 4, 5-trichloropyridazine III, 3,6-dichloropyridazine IV, and 3-methyl-6-chloropyridazine V [538]: Q 8 ? C 9 9 O N N Q R S Cl Cl Q S Cl Cl 9 Cl 6 N N 9 Cl 6 N N 9 R I, II III IV, V Q 8 ? C 9 9 O N N Q R S Cl Cl Q S Cl Cl 9 Cl 6 N N 9 Cl 6 N N 9 R I, II III IV, V where R = H (I), Me (II, V), Cl (IV).It is known that pyridazone I reacts with ammonia [9], alkylamines [10], and hydrazine [11] selectively with chlorine substitution at the 4-position of the pyridazine ring. This is due to the activating effect of the keto group on the 4-position in I [10,12]. However, it has been reported [13,14] that the reaction of I with ammonia yields a mixture of 4-amino-5-chloro-6-pyridazone VI and 5-amino-4-chloro-6-pyridazone VII.Our experiments showed that pyridazone I reacts with methylhydrazine in 2-propanol strictly specifically to give 4-(1-methylhydrazino)-5-chloro-6-pyridazone VIII in 95% yield. In methylation of VIII with dimethyl sulfate in methanol in the presence of sodium, the reaction occurs selectively at the 1-position of the pyridazine ring, giving 1-methyl-4-(1-methylhydrazino)-5-chloro-6-pyridazone IX in 37% yield.It is known [11] that the reaction of I with 95% hydrazine in methanol yields exclusively 4-hydrazino-5-chloro-6-pyridazone X. Its structure was determined by hydrogenation (Pd/C) and independent synthesis of the dechlorination products. However, under the experimental conditions, the reaction of I with 100% hydrazine hydrate in ethanol yields a mixture of pyridazone X and 5-hydrazino-4-chloro-6-pyridazone XI in 29 and 48% yields, respectively, which is confirmed by the 1 H NMR and TLC data, and also by depression of the melting point, observed on mixing X and XI.Then we performed methylation of X with dimethyl sulfate. The reaction was performed in the system 10% aqueous NaOH solution3CHCl 3 in the presence of Et 4 NI. The reaction occurs selectively at the N 1 atom of the hydrazine moiety, yielding pyridazon...

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Synthesis in the Pyridazine Series. I. Pyridazine and 3,6-Dichloropyridazine

Cited by 72 publications

References 1 publication

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

Regioselective synthesis of pyrazole and pyridazine esters from chalcones and α-diazo-β-ketoesters

Nucleophilic substitution of chlorine with hydrazine and methylhydrazine in chlorinated pyridazines and pyridazones

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