Showing papers on "Piperidine published in 2018"
TL;DR: Low-potential, mediated electrolysis process is compatible with a wide range of heterocyclic and oxidatively sensitive substituents on the piperidine ring and enables synthesis of unnatural amino acids.
Abstract: Secondary piperidines are ideal pharmaceutical building blocks owing to the prevalence of piperidines in commercial drugs. Here, we report an electrochemical method for cyanation of the heterocycle adjacent to nitrogen without requiring protection or substitution of the N-H bond. The reaction utilizes ABNO (9-azabicyclononane N-oxyl) as a catalytic mediator. Electrochemical oxidation of ABNO generates the corresponding oxoammonium species, which promotes dehydrogenation of the 2° piperidine to the cyclic imine, followed by addition of cyanide. The low-potential, mediated electrolysis process is compatible with a wide range of heterocyclic and oxidatively sensitive substituents on the piperidine ring and enables synthesis of unnatural amino acids.
98 citations
TL;DR: The development of an unprecedented route to bridged sila- N-heterocycles via B(C6F5)3-catalyzed cascade silylation of N-aryl piperidines with hydrosilanes is described.
Abstract: Described herein is the development of an unprecedented route to bridged sila-N-heterocycles via B(C6F5)3-catalyzed cascade silylation of N-aryl piperidines with hydrosilanes. Mechanistic studies indicated that an outer-sphere ionic path is operative to involve three sequential catalytic steps having N-silyl piperidinium borohydride as a resting species: (i) dehydrogenation of the piperidine ring, (ii) β-selective hydrosilylation of a resultant enamine intermediate, and (iii) intramolecular dehydrogenative sp2 C–H silylation.
85 citations
TL;DR: The radical-mediated azidoheteroarylation of unactivated olefins has been accomplished for the first time based on the strategy of intramolecular distal heteroaryl migration.
Abstract: The radical-mediated azidoheteroarylation of unactivated olefins has been accomplished for the first time based on the strategy of intramolecular distal heteroaryl migration. A variety of synthetically useful heteroaryl-substituted alkyl azides are readily furnished under mild reaction conditions. The utility of the protocol is manifested by readily converting the products to piperidine, β-pipecolic acid, and triazole derivatives.
43 citations
TL;DR: The obtained compounds were easily transformed into the bi- and tricyclic analogues of piperidine, morpholine, piperazine, and GABA, which are advanced building blocks for drug discovery.
Abstract: A one-step synthesis of functionalized 3-azabicyclo[3.2.0]heptanes by [2+2]-photochemical intermolecular cycloaddition of N-benzylmaleimide to alkenes was elaborated. The obtained compounds were easily transformed into the bi- and tricyclic analogues of piperidine, morpholine, piperazine, and GABA, which are advanced building blocks for drug discovery.
35 citations
TL;DR: Two Mannich-type additions to nitrones are described, one using β-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of β-N-hydroxy-aminoketones.
Abstract: Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich-type additions to nitrones, one using β-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of β-N-hydroxy-aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (-)-lobeline and (-)-sedinone.
28 citations
TL;DR: In this article, the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab was reported.
27 citations
01 Jan 2018
TL;DR: A review of strategies for the construction of piperidines which have appeared in the literature since 2003 through mid-2017 can be found in this article, where the authors give a general overview of decoration or modification of previously generated pyridines.
Abstract: The present review focuses on strategies for the construction of piperidines which have appeared in the literature since 2003 through mid-2017. In a preceding chapter ( 2017AHC191 ), we summarized synthetic methods involving the construction of the piperidine ring from essentially acyclic starting materials in an intra- or intermolecular manner. The present chapter aims at giving a general overview of decoration or modification of previously generated pyridines or piperidines. The hydrogenation of preformed pyridine or pyridinium rings and introduction of substituents into fully saturated piperidines as well as ring expansion of pyrrolidines to piperidines are the most prevalent methods.
23 citations
TL;DR: The 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands, and the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure model in mice.
23 citations
TL;DR: The following review provides an insight on the application of piperine as an effective bioenhancer and the superiority of a bioenhanced drug formulation over the one without aBioenhancer.
Abstract: Bioenhancers can be defined as chemical entities, which when mixed with drugs promote and augment their bioavailability without showing any synergistic effect with the drug. The factors like toxicity, cost, poor bioavailability and long term administration of drugs give rise to the need of bioenhancers which help overcome most of these problems. Piper species produce a pungent alkaloid named Piperine or 1-peperoyl piperidine. Piperine increases permeability at the site of absorption by modulating lipid environment and membrane dynamics. Piperine has a molecular structure that is suitable for enzyme inhibition. It augments the bioavailability of several drugs like carbamazepine, curcumin, ciprofloxacin, ampicillin, metronidazole, oxytetracycline and many others by inhibiting various metabolizing enzymes. Thus piperine, being an efficacious inhibitor of drug metabolism is a powerful enhancer of absorption. The following review explores the mechanism, metabolism inhibition, influence of structural changes on activity, and drugs bioenhanced by piperine. It provides an insight on the application of piperine as an effective bioenhancer and the superiority of a bioenhanced drug formulation over the one without a bioenhancer. This concept which is found to be beneficial, has its roots in Ayurveda-the traditional Indian system of medicine and has been applied to various drugs. It presents a fine instance of the advantage of amalgamating a traditional system with contemporary medicine.
22 citations
TL;DR: Fifteen new piperidine derivatives, pyracyclumines A-J (1-10), including five pairs of enantiomers, (+)-1/(-)-1 to (+)-5/(--)-5, together with three known compounds, were isolated from the roots of Anacyclus pyrethrum and tested for their inhibitory effects on menin-mixed lineage leukemia 1 protein-protein interaction.
Abstract: Fifteen new piperidine derivatives, pyracyclumines A–J (1–10), including five pairs of enantiomers, (+)-1/(−)-1 to (+)-5/(−)-5, together with three known compounds, agrocybenine (11), 4,6,6-trimethyl-5,6-dihydro-2(1H)-pyridone (12), and 3,5,5-trimethyl-1,5-dihydro-2H-pyrrol-2-one (13), were isolated from the roots of Anacyclus pyrethrum. Pyracyclumines A, B, and H (1, 2, and 8) possess a novel 6/5/6/6 dimeric piperidine skeleton, a unique 6/5/6 dimeric piperidine skeleton, and a 1,4,6-triazaindan skeleton, respectively. Pyracyclumine C (3) is based on a rare cyclopentane–piperidine framework. The structures of the isolated compounds were established by analysis of their NMR and HRESIMS data. The racemic pyracyclumines A–E (1–5) were further separated by chiral HPLC to give the enantiomers (+)-1/(−)-1 to (+)-5/(−)-5, for which the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. The plausible biogenetic pathways of these piperidine alkaloids were propo...
22 citations
14 Sep 2018
TL;DR: This study synthesized a recently reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin -3-yl]benzonitrile, which bears a 4-piperidine ring, a4-methylphenyl group, and a 4 -cyanophenyl group on a pyridine ring to facilitate the rational design of more-potent reversible LSD1 inhibitors.
Abstract: Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors of LSD1 are expected to be useful for the treatment of several cancers. Reversible inhibitors of LSD1 with submicromolar inhibitory potency have recently been reported, but their exact binding modes are poorly understood. In this study, we synthesized a recently reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile, which bears a 4-piperidinylmethoxy group, a 4-methylphenyl group, and a 4-cyanophenyl group on a pyridine ring, and determined the crystal structure of LSD1 in complex with this inhibitor at 2.96 A. We observed strong electron density for the compound, showing that its cyano group forms a hydrogen bond with Lys661, which is a critical residue in the lysine demethylation reaction located deep in the catalytic center of LSD1. The piperidine ring interacts with the side chains of Asp555 and Asn540 in two conformations, and the 4-methylphenyl group is bound in a hydrophobic pocket in the catalytic center. Our elucidation of the binding mode of this compound can be expected to facilitate the rational design of more-potent reversible LSD1 inhibitors.
01 May 2018
TL;DR: In this paper, the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab was described.
Abstract: We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab Some of them were found to have good in vitro activity (MIC
TL;DR: In this paper, the reaction of hexachlorocyclotriphosphazene, N3P3Cl6, with tyramine pod and (2) substituted spiro-cyclotrisazene (3).
TL;DR: Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene‐derived fragments, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells.
Abstract: Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene-derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1-adamantyl and the monoterpene-derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti-TB activity is pointed out by a QSAR study. The most promising compound is the (+)-isopinocampheylamine-derived amide which is characterized with selectivity index of 1387.8.
TL;DR: This work has uncovered proline-catalyzed anti-selectivity for the synthesis of 1,2-amino alcohols in α-amination of aldehyde and one-pot indium-mediated Barbier type allylation of α-hydrazino aldehydes to accomplish the total synthesis of clavaminols, sphinganine and spisulosine with reduced number of steps and with high overall yields.
Abstract: The direct α-amination of carbonyl compounds using organocatalysts represents a powerful and atom-economical tool for asymmetric C–N bond formation. We describe a complete account of α-functionalization of carbonyl compounds, through iterative sequential α-aminoxylation/amination using electrophilic O and N sources, as well as sequential α-amination/HWE reaction for enantio- and diastereoselective synthesis of both syn- and anti-1,3-aminoalcohols and 1,3-diamines. Additionally this protocol is further extended for the easy construction of alkaloids such as indolizidine, pyrrolizidine, and quinolizidine fused-ring systems just by tuning the chain length of the aldehyde used as a starting material. This methodology provides further scope to extrapolate it for a variety of naturally occurring hydroxylated monocyclic and fused bicyclic pyrrolidine and piperidine based alkaloids such as lentiginosine, epi-lentiginosine, dihydroxypyrrolizidine, (+)-deoxoprosophylline and (–)-deoxoprosopinine alkaloids. Furthermore, we have also uncovered proline-catalyzed anti-selectivity for the synthesis of 1,2-amino alcohols in α-amination of aldehyde and one-pot indium-mediated Barbier type allylation of α-hydrazino aldehydes to accomplish the total synthesis of clavaminols, sphinganine and spisulosine with reduced number of steps and with high overall yields. 1 Introduction 2 Application in the Total Synthesis of Alkaloids 3 Conclusion
TL;DR: In this article, a simple and convenient protocol for the synthesis of N-amino-3-cyano-2-pyridone derivatives by a one-pot reaction of cyanoacetohydrazide, activated nitrile substrates (malononitrile, ethyl cyano-acetate, cyanoamide) and aromatic aldehydes in the presence of piperidine in water or a mixture of water and ethanol was developed.
Abstract: A simple and convenient protocol has been developed for the synthesis of N-amino-3-cyano-2-pyridone derivatives by a one-pot reaction of cyanoacetohydrazide, activated nitrile substrates (malononitrile, ethyl cyanoacetate, cyanoacetamide) and aromatic aldehydes in the presence of piperidine in water or a mixture of water and ethanol The sequence of cascade reactions includes Knoevenagel condensation, Michael addition, intramolecular cyclization, imine-enamine tautomerization and oxidative aromatization The main advantages of this procedure are availability of starting compounds, simple procedure, mild conditions, easy purification of products and the use of water or water/ethanol as green solvents
TL;DR: Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield and found to be most active in 80% ethanol-induced ulcer experimental animal model, which will result in a new class of orally active molecule for anti-ulcer activity.
Abstract: Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield. All the compounds were confirmed by elemental analysis and spectral data. Anti-ulcer activity of novel dihydropyrimidinone-piperidine hybrids (1-18) was evaluated. Among them, four compounds (3, 8, 11 and 15) were found to be most active in 80% ethanol-induced ulcer experimental animal model. All the potent compounds were further evaluated for anti-ulcer activity by different in vivo anti-ulcer models to study the effect of compounds on anti-secretory and cytoprotective activities. All the active compounds inhibited the formation of gastric ulcers and increased the formation of gastric mucin secretion. Compound 15 was found to be the most potent compound of the series as anti-ulcer agent. Additional experimental studies on lead compound 15 will result in a new class of orally active molecule for anti-ulcer activity.
TL;DR: The utility of this convenient one-pot process is demonstrated by the asymmetric synthesis of (-)-sedacryptine 3 by the Mannich process involving N,O-acetal (2S,3R)-6 and ketones in excellent yield with high diastereoselectivity.
Abstract: An efficient diastereoselective approach to access the 3-hydroxy-2,6-disubstituted piperidine scaffold 1 has been developed through the Mannich process involving N,O-acetal (2S,3R)-6 and ketones in excellent yield with high diastereoselectivity (dr > 99 : 1). In addition, the utility of this convenient one-pot process is demonstrated by the asymmetric synthesis of (−)-sedacryptine 3.
30 May 2018
TL;DR: The diffusion spectroscopy experiments and relaxation time calculations of compound 6 in the presence of COX-2 assisted in identifying the site-specific interactions of 6 with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure–activity relationship studies.
Abstract: A library of hybrid molecules was procured by the combination of triazine-indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound 6 having an IC50 value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E2 in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B2 in the calcium ionophore-treated (COX-1-activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound 6 is selective for COX-2. The association constant (Ka) of compound 6 with COX-2 was found to be of the order of 0.48 × 106 M-1. The diffusion spectroscopy experiments and relaxation time (T1) calculations of compound 6 in the presence of COX-2 assisted in identifying the site-specific interactions of 6 with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure-activity relationship studies. With maximum tolerable dose >2000 mg kg-1, compound 6 made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice.
TL;DR: An asymmetric synthesis of (-)-cytisine has been achieved and the absolute stereochemistry was established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded with an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone pair.
Abstract: An asymmetric synthesis of (-)-cytisine has been achieved. The piperidine C-ring was formed using a stereodivergent intramolecular 6- endo aza-Michael addition. The B-ring was established by intramolecular pyridine N-alkylation. The absolute stereochemistry was established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded with an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone pair.
TL;DR: Two new pyrrolidine derivative and two new piperidine derivatives were isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 together with two known alkaloids, which possessed an unprecedented 7-oxa-1-azabicyclo[3.2.1]octane skeleton with four chiral centers.
TL;DR: In this paper, the tetradentate mode of coordination of the ligand L and its complexes 1-3 was characterized on the basis of physico-chemical and spectral (FT-IR, Mass, 1H, 13C, DEPT and 77Se NMR) studies.
TL;DR: Collision-induced dissociation experiments revealed that neutral elimination of water or acetic acid is the major fragmentation pathway, which agrees with the stereochemistry proposed for (-)-cassine and (-)-spectaline and the semisynthetic derivatives of piperidine alkaloids and derivatives.
Abstract: Rationale Piperidine alkaloids from Senna spectabilis constitute a rare class of natural products with several biological activities. However, the absence of chromophores makes their structural elucidation by conventional methods a great challenge. In this context, mass spectrometry emerges as a powerful tool for metabolomics studies. Methods The piperidine alkaloids (-)-cassine and (-)-spectaline and the semisynthetic derivatives (-)-3-O-acetylcassine and (-)-3-O-acetylspectaline were investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the positive mode and electron ionization mass spectrometry (EI-MS). ESI fragmentation studies were performed with a quadrupole time-of-flight instrument; N2 was used as collision gas. The acetylcholinesterase inhibitory activity of the investigated compounds was evaluated by bioautography and microplate screening assays. Results ESI-MS/MS and EI-MS provided valuable and complementary information about the structure of the piperidine compounds. Collision-induced dissociation experiments (MS/MS) revealed that neutral elimination of water or acetic acid is the major fragmentation pathway, which agrees with the stereochemistry proposed for (-)-cassine and (-)-spectaline and the semisynthetic derivatives (-)-3-O-acetylcassine and (-)-3-O-acetylspectaline. Conclusions The ESI-MS/MS and EI-MS studies allowed us to propose fragmentation mechanisms for piperidine alkaloids and derivatives. Therefore, mass spectrometry is an important tool for characterizing the structure of these compounds and for supporting further metabolomics studies.
Patent•
30 Apr 2018
TL;DR: In this paper, a compound of formula 1 or a pharmaceutically acceptable salt thereof that is useful as a JAK inhibitor is described. But the method of using the compound to treat diseases amenable to JAK inhibitors is not described.
Abstract: The invention provides a compound of formula 1
or a pharmaceutically-acceptable salt thereof, that is useful as a JAK inhibitor. The invention also provides crystalline forms of the compound, pharmaceutical compositions comprising the compound, methods of using the compound to treat diseases amenable to a JAK inhibitor, and processes and intermediates useful for preparing the compound.
TL;DR: The studied compound is characterized by good thermal stability and was docked to the novel X-ray structure of the human dopamine D2 receptor in the inactive state and established the main contact between its protonatable nitrogen atom and Asp (3.32) of the receptor.
Abstract: Compound D2AAK1_3 was designed as a modification of the lead structure D2AAK1 (an in vivo active multi-target compound with nanomolar affinity to a number of aminergic GPCRs) and synthesized in the reaction of 5-ethoxyindole and 1-benzyl-4-piperidone This compound has an affinity to the human dopamine D₂ receptor with Ki of 151 nM The aim of these studies was the structural and thermal characterization of the compound D2AAK1_3 In particular; X-ray studies; molecular docking and molecular dynamics as well as thermal analysis were performed The studied compound crystallizes in orthorhombic system; in chiral space group P2₁2₁2₁ The compound has a non-planar conformation The studied compound was docked to the novel X-ray structure of the human dopamine D₂ receptor in the inactive state (PDB ID: 6CM4) and established the main contact between its protonatable nitrogen atom and Asp (332) of the receptor The obtained binding pose was stable in molecular dynamics simulations Thermal stability of the compound was investigated using the TG-DSC technique in the air atmosphere, while TG-FTIR analyses in air and nitrogen atmospheres were also performed The studied compound is characterized by good thermal stability The main volatile products of combustion are the following gases: CO₂; H₂O toluene and CO while in the case of pyrolysis process in the FTIR spectra; the characteristic bands of NH₃; piperidine and indole are additionally observed
TL;DR: A review of the antioxidant profile of piperidine containing compounds has been focused in this article, where the compounds were classified into naturally occurring piperidines, unsaturated piperidsines, N-substituted piperidisines, piperamides, Piperanols and hydrazides.
Abstract: Piperidine is a saturated heterocyclic ring, considered as a privileged scaffold in view of its role in wide range of biological activities. Piperidine is good candidate molecule for obtaining potent antioxidant agents. The planar nature of this heterocyclic nucleus allows the introduction of substituent groups at different positions on the ring. In the present review, the antioxidant profile of piperidine containing compounds has been focused. The compounds were classified into naturally occurring piperidines, unsaturated piperidines, N-substituted piperidines, piperamides, piperanols, piperidine oximes, and hydrazides.