Pyridazine Derivatives. 32: Stille-Based Approaches in the Synthesis of 5-Substituted-6-phenyl-3(2H)-pyridazinones.

Sotelo, Eddy; Coelho, Alberto; Raviña, Enrique

doi:10.1248/cpb.51.427

Cited by 37 publications

(18 citation statements)

References 20 publications

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“…If the nitrogen is not protected, the base necessary for the coupling reactions will ionize the N 2 position and result in an increase of the electron density at the halogen that will decrease the rate of palladium insertion [60,61]. With the protected halogenated precursor in hand, however, it is possible to couple the pyridazine scaffold with a variety of boronic acids, tin reagents, alkynes and alkenes, giving rise to extensive diversity at the R 4 /R 5 position using standard Suzuki, Sonogashira, Stille and Heck reactions [62][63][64][65][66][67]. These couplings result in the formation of carbon-carbon bonds and extend single, double and triple bonds from the R 4 or R 5 position to create a diverse set of compounds.…”

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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“…In recent years a substantial number of 6-aryl-3-(2H)-pyridazinones have been reported to possess antimicrobial [1,2], potent analgesic [3], anti-inflammatory [3][4][5][6][7], antifeedant [8], herbicidal [9], antihypertensive [10][11][12] and antiplatelet activities [13][14][15], anticancer effects [16] and other anticipated biological [17] and pharmacological properties [18,19]. In particular, a large number of indolylpyridazinone derivatives are well known as antimicrobial agents [1,20], intermediates for drugs and agrochemicals [21,22], antiphlogistics [23], antipyretics [24], inflammation inhibitors [25], blood platelet aggregation inhibitors, cardiovascular and antihypertensive agents [26].…”

Section: Introductionmentioning

confidence: 99%

An Efficient Synthesis and Reactions of Novel Indol-ylpyridazinone Derivatives with Expected Biological Activity

Abubshait¹

2007

Molecules

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Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl 3 for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl 3 was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene-or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, 1 H-NMR, 13 C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity.

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“…Non-acidic or weakly acidic NSAIDs were the attention of medicinal chemists as they preferentially act by inhibiting COX-2 and possessed lower incidence of gastric ulcers than acidic NSAIDs which inhibit both COX-I & COX-II enzymes like indomethacin & aspirin.The interesting pharmacological activity is displayed by pyridazine derivatives which demonstrated in recent year. The growing number of papers describes the development of several pyridazine-based drugs and pharmacological tools (5) , drugs acting on the cardiovascular system (6)(7)(8)(9) , as agrochemicals (10) and wide range of biological action (11) . Several studies indicate that (NH) group adjacent to (C=O) group in the azine system may be an essential structural requirement in the binding of 3(2H)-pyridazinones to a variety of biological receptors (12) .…”

Section: O R E E L E C T R O S T a T I C R E P L U S I O N L E S S mentioning

confidence: 99%

2- (3, 4- Dimethylphenyl - 3- [3, 4-Dichloro (or 3, 4-Dimethyl) Benzoyl])-Propanoic Acids as Precursors in the Synthesis of Some Heterocyclic Compounds

2012

Egypt. J. Chem.

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Pyridazine Derivatives. 32: Stille-Based Approaches in the Synthesis of 5-Substituted-6-phenyl-3(2H)-pyridazinones.

Abstract: A series of 6-phenyl-3(2H)-pyridazinones bearing different substituents in the 5-position of the pyridazinone ring were prepared using Stille-based approaches in the search for new platelet-aggregation inhibitors.

Cited by 37 publications

References 20 publications

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

An Efficient Synthesis and Reactions of Novel Indol-ylpyridazinone Derivatives with Expected Biological Activity

2- (3, 4- Dimethylphenyl - 3- [3, 4-Dichloro (or 3, 4-Dimethyl) Benzoyl])-Propanoic Acids as Precursors in the Synthesis of Some Heterocyclic Compounds

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