Condensed pyridines

Литвинов, В. П.; Sharanin, Yu. A.; Rodinovskaya, L. A.; Shestopalov, A. M.; Mortikov, V. Yu.; Promonenkov, V. K.

doi:10.1007/bf00960275

Cited by 7 publications

(15 citation statements)

References 2 publications

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“…This method for the preparation of pyridothienopyrimidine deriva tives was included in the synthetic arsenal from the early 1970s. 39 In recent years, this method has been used to prepare a series of polyfused azines with general formu las 94 and 104 (Scheme 32). 65,92a,95…”

Section: Pyridothienopyrimidinesmentioning

confidence: 99%

Thienopyridines: synthesis, properties, and biological activity

2005

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Section: Pyridothienopyrimidinesmentioning

confidence: 99%

Thienopyridines: synthesis, properties, and biological activity

2005

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“…To produce the 20-member amine library, intermediate 8 was reacted with various alkyl chlorides to generate analogues 9 a–p. The ether library was synthesized in a similar fashion by reacting ethylacetoacetate (i0) with 2-cyanothioacetamide (5) to provide the core pyridine 11,[17] which was then cyclized with compound 7 to give the key intermediate 12. Finally, alkylation of 12 with various alkyl chlorides gave analogues 13 a–s, which are similar, yet distinct from related M 4 PAMs disclosed by Eli Lilly.…”

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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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“…[1] Subsequent studies of this reactions [2,3] led to the development of a synthetic method that yields pyridine-2(1H)-thiones (1) by directly reacting arylidenecyanothioacetamides (4) and ketones (5) in the presence of an organic base. [4,5] Consequently, this method gained a widespread use in the synthesis of the corresponding 5,6-polymethylenepyridinethiones. [3,[6][7][8][9][10][11][12][13] The reaction proceeds through the intermediate 1,4-dihydropyridine, which was assumed to be oxidized by the molecular oxygen in air.…”

Section: Introductionmentioning

confidence: 99%

“…[3,[6][7][8][9][10][11][12][13] The reaction proceeds through the intermediate 1,4-dihydropyridine, which was assumed to be oxidized by the molecular oxygen in air. [5] A derivative of this method was also applied with various cycloalkanones [4,6,[14][15][16] and in the recyclization of 2,6-diamino-3,5-dicyanothiopyranes in the presence of cycloalkanones. [17,18] It is important to highlight that the yields of the final products in these reactions vary substantially from 30% to 75% even under similar reaction conditions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and domino reactions of polymethylene‐3‐cyanopyridine‐2(1Н)‐thiones

Шестопалов

Rodinovskaya

Zubarev

et al. 2019

Journal of Heterocyclic Chem

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A new and facile three-component method was developed for the synthesis of polymethylene-3-cyanopyridine-2(1Н)-thiones by the domino Knoevenagel ! Michael ! heterocyclization ! dehydrogenation reaction from cycloalkanones, cyanothioacetamide, and polymethoxy-substituted benzaldehydes. The final dehydrogenation step was found to involve arylidenecyanothioacetamide. The resulting pyridinethiones and 4-chloroacetoacetic ester were introduced into the domino S N 2 ! Thorpe-Ziegler ! Guareschi-Thorpe reaction to synthesize tetracyclic dipyridothiophenes. Starting from these compounds, 8,9polymethylenepyranothienodipyridines were also synthesized by the domino Knoevenagel ! Michael ! hetero-Thorpe-Ziegler reaction. Furthermore, a method for the synthesis of thienodipyridine annulated to the steroid skeleton is proposed.

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Condensed pyridines

Cited by 7 publications

References 2 publications

Thienopyridines: synthesis, properties, and biological activity

Thienopyridines: synthesis, properties, and biological activity

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

Synthesis and domino reactions of polymethylene‐3‐cyanopyridine‐2(1Н)‐thiones

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Condensed pyridines

Cited by 7 publications

References 2 publications

Thienopyridines: synthesis, properties, and biological activity

Thienopyridines: synthesis, properties, and biological activity

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

Synthesis and domino reactions of polymethylene‐3‐cyanopyridine‐2(1Н)‐thiones

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