<i>β</i>-Aminocrotononitrile in heterocyclic synthesis: Synthesis of polysubstituted pyridines as precursors to bicycles and polycycles

Abu‐Shanab, Fathi A.; Hessen, A. M.; Gaber, Hatem M.; Mousa, Sayed A. S.

doi:10.1080/17415990600755131

Cited by 7 publications

(9 citation statements)

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“…The initial synthesis of 20-member alkylamine and 20-member ether libraries, as shown in Scheme 1, began with condensation between 3-aminocrotonitrile (4) and 2-cyanothioacetamide (5) to furnish the aminopyridyl core 6. [16] This was cyclized with a-chloro-p-methoxybenzamide (7) to give the diaminothieno[2,3-b]pyridine scaffold with the p-methoxybenzamide 8. To produce the 20-member amine library, intermediate 8 was reacted with various alkyl chlorides to generate analogues 9 a–p.…”

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confidence: 99%

Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor

et al. 2009

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The five subtypes of the muscarinic acetylcholine receptor (mAChR [1][2][3][4][5] or M 1-5 ) are differentially expressed G protein-coupled receptors (GPCRs) important to a variety of physiological functions, including attention, learning and memory, pain, sleep, movement, gastrointestinal motility and cardiovascular regulation, among others. [1][2][3][4][5] Based on mounting data, M 1 and M 4 receptors are considered potential therapeutic targets for numerous CNS diseases and disorders such as Alzheimer's disease and schizophrenia. [6][7][8][9] However, due to high sequence conservation of the orthosteric binding site across subtypes, discovery of truly subtype-selective compounds has proven historically challenging. Indeed, M 2 -and M 3 -related side effects (e.g. GI disturbance, salivation, lacrimation and bradycardia) have contributed to failure in the clinical development of muscarinic agonists despite promising therapeutic efficacy. [6,7] Furthermore, deep biological insight into the specific roles of the mAChRs in both basic neurobiology and CNS pathologies has been hindered by the paucity of selective tools. The additional drug metabolism/pharmacokinetic (DMPK)-related challenges inherent to CNS drug discovery have also hampered progress in this area. Despite these hurdles, a number of novel subtype-selective and centrally penetrating muscarinic compounds, including agonists, antagonists, and potentiators, have recently emerged from functional cell-based screening approaches. [10][11][12][13][14][15] We previously reported the identification of a series of novel M 4 -selective potentiators (positive allosteric modulators or PAMs) that enhance receptor activation in response to acetylcholine (ACh) by an allosteric mechanism (Figure 1). [10,12] These compounds increase the potency of ACh at M4 but lack intrinsic agonist activity on their own. Initial optimization focused on improving the physiochemical properties of lead compound VU10010 (1), which possessed an EC 50 value of 400 nM and elicited a 47-fold leftward shift of an ACh concentration-response curve (CRC) by Ca 2+ mobilization assay in rat M 4 /G qi5 -expressing cells, but suffered from solubility issues and lack of brain penetration. [10,12] This limited effort produced two analogues, VU0152099 (2) and VU0152100 (3), which had similar potency and comparable efficacy to the parent compound i but were centrally penetrating and displayed in vivo activity in a rodent behavioral model predictive of antipsychotic efficacy.[10] These compounds were also devoid of ancillary pharmacological activity when evaluated against a large number of GPCRs, ion channels, and enzymes.[10] Despite the utility of compounds 2 and 3 for in vitro and in vivo pharmacological studies, we sought to further explore the SAR in this series with a more exhaustive optimization campaign by employing an iterative analogue library approach. The rationale for this effort stemmed in part from an initial limited lead optimization campaign, poor metabolic stability of compounds 2 and 3...

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Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor

et al. 2009

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“…Also the treatment of 6-amino-3,5-dicyano-6-methyl-N-substitutedpyridine-2(1H)-thione (261) with DMF DMA in dry dioxane afforded the corresponding amidine (262) which on boiling with ammonium acetate in (264), respectively, as shown in Scheme 37 [160].…”

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Dimethylformamide dimethyl acetal as a building block in heterocyclic synthesis

Abu‐Shanab

Sherif

Mousa

2009

Journal of Heterocyclic Chem

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“…One type of reaction, which is potentially valuable for the future purpose, is with 1,3-dicarbonyl compounds (1) to give enamines (2) [4]. (1) 2 We have reported that these enamines (2) were used as precursors in the synthesis of pentasubstituted pyridines (3)(4)(5)(6) [6,7]. The structures of these compounds have been confirmed by X-ray crystallography [6,7].…”

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“…Formamide acetals are useful reagents; [3,4] their main application has been used for functional group transformations [5], but they may also be regarded as one-carbon synthons in the construction of carbon skeletons. One type of reaction, which is potentially valuable for the future purpose, is with 1,3-dicarbonyl compounds (1) to give enamines (2) [4]. (1) 2 We have reported that these enamines (2) were used as precursors in the synthesis of pentasubstituted pyridines (3)(4)(5)(6) [6,7].…”

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Dimethylformamide dimethyl acetal in heterocyclic synthesis: Synthesis of polyfunctionally substituted pyridine derivatives as precursors to bicycles and polycycles

Abu‐Shanab

Hessen

Mousa

2007

Journal of Heterocyclic Chem

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Polysubstituted pyridines 11a,c and 12 were prepared by the reaction of benzoylacetone with dimethylformamide dimethyl acetal followed by treatment with cyanothioacetamide 9a, cyanoacetamide 9b and the anion of malononitrile dimmer 9c in dry DMF. When the reaction was carried out in ethanol as a solvent and piperidine as a base afforded 14a,b. Thienopyridines 16a,b were prepared by the reaction of pyridinethiones 11a and 14a with 2-chloro-N-p-tolyl-acetamide (15). Further reaction of thienopyridines 16a,b with either DMFDMA or nitrous acid to gave 17a,b and 18a,b respectively. The reaction of pyridine derivative 11c with hydrazine and phenylhydrazine afforded the tricyclic compounds 19a,b. J. Heterocyclic Chem., 44, 787 (2007).Formamide acetals are useful reagents; [3,4] their main application has been used for functional group transformations [5], but they may also be regarded as one-carbon synthons in the construction of carbon skeletons. One type of reaction, which is potentially valuable for the future purpose, is with 1,3-dicarbonyl compounds (1) to give enamines (2) [4].

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β-Aminocrotononitrile in heterocyclic synthesis: Synthesis of polysubstituted pyridines as precursors to bicycles and polycycles

Cited by 7 publications

References 10 publications

Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor

Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor

Dimethylformamide dimethyl acetal as a building block in heterocyclic synthesis

Dimethylformamide dimethyl acetal in heterocyclic synthesis: Synthesis of polyfunctionally substituted pyridine derivatives as precursors to bicycles and polycycles

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β-Aminocrotononitrile in heterocyclic synthesis: Synthesis of polysubstituted pyridines as precursors to bicycles and polycycles

Cited by 7 publications

References 10 publications

Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor

Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor

Dimethylformamide dimethyl acetal as a building block in heterocyclic synthesis

Dimethylformamide dimethyl acetal in heterocyclic synthesis: Synthesis of polyfunctionally substituted pyridine derivatives as precursors to bicycles and polycycles

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Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor

Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor