New Methods in the Chemistry Pyridazones

Dury, Karl

doi:10.1002/anie.196502921

Cited by 45 publications

(22 citation statements)

References 27 publications

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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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“…Fractions containing 3d (R f = 0.14 CHCl 3 /diethyl ether = 9.5:0.5, v/v) were combined and evaporated under reduced pressure to give 3d in 13% yield (1.8 g). -2-ethyl-5-(3-bromopropyloxy)pyridazin-3(2H)-one (2e) and 1,oxy]-propane (3e).…”

Section: Methods Amentioning

confidence: 99%

Synthesis of alkyl or aryl pyridazinyl ethers

Chung

Kim

et al. 2005

Journal of Heterocyclic Chemistry

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This paper presents the synthesis of some alkyl or aryl pyridazinyl ethers from 2-alkyl-4-halo-5-hydroxyand 2-alkyl-4,5-dichloropyridazin-3(2H)-ones or 3,6-dichloropyridazine. Reaction of 2-alkyl-4-halo-5-hydroxypyridazin-3(2H)-ones 1 with 1,2-dibromoethane or 1,3-dibromopropane gave the corresponding monopyridazin-5-yl ethers 2 and α,ω-[di(pyridazin-5-oxy)]alkanes 3. Treatment of 4 with 4-substitutedphenol afforded 5-(4-substituted-phenoxy)-2-(4-substituted-phenoxymethyl) derivatives 5. Reaction of 2-alkyl-4,5-dichloro derivatives 7 with 1 gave the corresponding di(pyridazin-5-yl) ethers 8 in good yields. Compound 10 was reacted with catechol to give monopyridazin-3-yl ether 11 and/or di(pyridazin-3-yl) ether 12. Also we described the results for the reaction of 2-alkyl-4-chloro-5-(4-substituted-phenoxy)pyridazin-3(2H)-ones with nucleophiles. Reaction of 1 with 1,2-dibromoethane or 1,3-dibromopropane in the presence of potassium carbonate (mole ratio; 1/Br(CH 2 ) n )Br/K 2 CO 3 = 1:1:1) gave compounds 2 as the main product and 3. The results are summarized in Table 1. Whereas, treatment of 1a with 1,2-dibromoethane or 1,3-dibromopropane in the presence of potassium carbonate (mole ratio; 1/Br(CH 2 ) n )Br/K 2 CO 3 = 2:1:2) also gave 3 as the main product. The structures of 2 and 3 were established by ir, nmr and elemental analyses. The proton magnetic resonance spectra of 2 showed proton signals of CH 2 Br (δ 3.59-3.68 ppm range) and CH 2 O (δ 4.35-4.54 ppm range) involving other proton signals of the proposed structures, while the proton magnetic resonance spectra of 3 showed proton signals of two CH 2 O (δ 4.11-4.75 ppm range) involving other proton signals of the proposed structures.According to the literature [6b], the reaction of 4 with nucleophiles such as CH 3 O -and N 3 -selectively afford the corresponding 4-chloro-5-substituted-2-methoxy(or

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“…The intermediates, 1 and 2, were synthesized according to the literature 14,15 and got the accept yield. The synthetic conditions of the title compounds were investigated, such as temperature, time and base.…”

Section: Methodsmentioning

confidence: 99%