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Alzheimer's disease (AD) is the most common form of dementia. It is associated with the impairment of memory and other cognitive functions that are mainly caused by progressive defects in cholinergic and glutamatergic signaling in the central nervous system. Inhibitors of acetylcholinesterase (AChE) and ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) receptor family are currently approved as AD therapeutics. We previously showed using a cell-based assay of NMDA receptor-mediated glutamate-induced excitotoxicity that bis-γ-carbolinium conjugates are useful NMDA receptor blockers. However, these compounds also act as subnanomolar AChE inhibitors, which may cause serious anticholinergic side effects when applied in vivo. Here, we evaluated new structures containing γ-carbolines linked to phenothiazine via a propionyl spacer. These compounds were superior to the previously characterized bis-γ-carbolinium conjugates because they blocked NMDA receptors without requiring a quaternary pyridine N-atom and inhibited AChE with moderate IC50 values of 0.54–5.3 μM. In addition, these new compounds displayed considerable selectivity for the inhibition of butyrylcholinesterase (BChE; IC50 = 0.008–0.041 μM), which may be favorable for AD treatment. Inhibitory activities towards the NMDA receptors and AChE were in the same micromolar range, which may be beneficial for equal dosing against multiple targets in AD patients.

An enantioselective total synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor has been achieved from the readily available 4-piperidone. Proline catalysed hydroxylation is the key step for the synthesis of enantiopure 1-benzyl-4-methylpiperidin-3-ol.

In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.

We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6′-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ～600 nM representing an ～17-fold improvement over the original compound identified in a small molecule screen.

A widely applicable approach was developed to synthesize ketones, esters, amides via the oxidative C?C bond cleavage of readily available alkyl aldehydes. Green and abundant molecular oxygen (O2) was used as the oxidant, and base metals (cobalt and copper) were used as the catalysts. This strategy can be extended to the one-pot synthesis of ketones from primary alcohols and α-ketoamides from aldehydes.

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the “physicochemical challenge” typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

Non-tuberculous mycobacterium (NTM) infections, such as those caused by Mycobacterium abscessus, are increasing globally. Due to their intrinsic drug resistance, M. abscessus pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against M. abscessus and Mycobacterium tuberculosis, the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against M. abscessus. Structure-activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD-88 as a new promising active analogue against M. abscessus. Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half-life of 3.2 hours.

New N-substituted-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives were synthesized employing a convenient one-pot three-component method and their structures were characterized by 1H-NMR and single crystal X-ray diffraction analysis. All the synthesized compounds were in vitro screened for antimicrobial activity against Gram-positive (Sarcina lutea) and Gram-negative bacteria (Escherichia coli). In this work, we introduced a chiral residue on the tetrahydropyridine nitrogen, the hitherto the less investigated position on this pharmacophore in order to explore the effect. The antibacterial results showed that the synthesized compounds were active only against Gram-positive bacteria and the (R)-enantiomers displayed a greater antimicrobial potency than their (S)-counterparts. The structure–activity relationship here investigated may provide some interesting clues for future development of tetrahydrothienopyridine derivatives with higher antimicrobial activity.

The invention provides a compound represented by a structural formula I and a non-toxic pharmaceutically acceptable salt and use thereof in preparation of medicine for treatment of depression. In theformula I shown in the description, R1, R2, R3 and R4 are independent H or deuterium (D) separately, and meanwhile, at least one of the R1, R2, R3 and R4 must be D.

The invention relates to a ceritinib preparing method. The method includes (1) reacting 4-bromo-2-isopropoxy-5-methylaniline and acetic anhydride to generate N-(4-bromo-2-isopropoxy-5-cresyl) acetamide, (2) reacting 4-piperidone to generate N-benzyl-4-piperidone, (3) subjecting the N-(4-bromo-2-isopropoxy-5-cresyl) acetamide and the N-benzyl-4-piperidone to a docking reaction, (4) subjecting a product of the former step to dehydroxylation and (5) generating a finally product that is ceritinib from N-(4-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-cresyl) acetamide under the existence of a catalyst. The novel ceritinib preparing method is provided. The synthesis route is low in cost, reaction conditions are mild and easy to control, and the method is suitable for large-scale industrial production.

Triphenylborane (BPh3) was found to catalyze the reduction of tertiary amides with hydrosilanes to give amines under mild condition with high chemoselectivity in the presence of ketones, esters, and imines. N,N-Dimethylacrylamide was reduced to provide the α-silyl amide. Preliminary studies indicate that the hydrosilylation catalyzed by BPh3may be mechanistically different from that catalyzed by the more electrophilic B(C6F5)3.

The invention discloses a penfluridol preparation method. The penfluridol preparation method includes the following steps of 1), subjecting succinic anhydride and fluorobenzene to Friedel-Crafts reaction prior to acid decomposition, and collecting a compound from the formula 2) as is shown in the description; 2), putting the compound in a solvent to collect a compound in formula 3) as is shown in the description in a solvent reduced through a reducing agent; 3), putting the compound into the fluorobenzene to perform the Friedel-Crafts reaction to collect a compound in the formula 4) as is shown in the description; subjecting the compound and ethyl chloroformate to action to generate a compound in formula 5) as is shown in the description; 5), subjecting the compound and a compound shown in formula (XVII) to reaction prior to hydrolyzation to collect a compound in formula 6) as is shown in the description; 6), performing reduction with the reducing agent prior to hydrolyzing a reduction product and then collecting penfluridol (I). The penfluridol preparation method is high in yield, low in cost, moderate in reaction condition, short in circuit, proper for industrial production, low in three wastes, easy to treat and suitable for industrial production.

Abstract To give further insight into the influence of the structural modifications of enones and dienones on their antiproliferative properties, 25 derivatives of enones: (E)-2-benzylidene-1-cyclohexanones, (E)-2-benzylidene-1-tetralones, (E)-2-benzylidene-1-indanone, and dienones: (E,E)-2,5- or 2,6-dibenzylidene-1-cyclanones, (E,E)-3,5-dibenzylidene-4-piperidones were synthesized using a newly developed "one-pot" synthetic method. Due to the fact that all of them have the same aryl substituents (phenyl or 4-chlorophenyl) in the arylidene moiety, it is possible to compare the relevant contribution of the single-point structural modifications (type of ring or N-substitution) on their potency on the basis of their IC 50 values. Their antiproliferative activity was evaluated against the following four human adherent cancer cell lines: HeLa, A431, A2780, and MCF7. The cytotoxicity screen has revealed that the dibenzylidene dienones in general dominate the monobenzylidene enones in this respect. The nitrogen-containing heterocyclic dienones at the same time displayed higher inhibitory properties toward these human carcinoma cell lines compared with their homocyclic dienone analogs. One of the eight newly prepared 4-piperidone derivatives, N-(γ-oxobutyl)-(E,E)-3,5-bis(p-chlorobenzylidene)-4-piperidone is as potent a cell growth inhibitor (IC 50 of 0.438-1.409 μM) as the N-methyl-(E,E)-3,5-bis(p-chlorobenzylidene)-4-piperidone (IC 50 of 0.447-1.048 μM), one of the most active among the previously described compounds in this series. Catalytic hydrogen-transfer isomerization of compounds with two exocyclic benzylidene double bonds to derivatives with endocyclic double bonds results in the complete loss of antiproliferative activity. The structural modifications and 50 % inhibitory concentration (IC 50) values resulted in correlations which can promote the design of more potent derivatives of the 4-piperidone dienones.

Four N-substituted 2,6-(E,E)-bis(ferrocenylidene)piperid-4-ones (NH 1, NMe 2, NEt 3, NCH2Ph 4) were prepared by aldol condensation between ferrocenecarbaldehyde and two equivalents of N-substituted piperid-4-ones with high yields. The N-protonated compounds were obtained by reaction with HBF4·Et2O acid. The molecular structures of compounds 2, 3, 2·HBF4 and 4·HBF4 were confirmed by X-ray diffraction analysis and three types of conformational isomers were elucidated. Two polymorph modifications were found for compound 2·HBF4. The electron transfer properties of the complexes were examined by electrochemical and spectroelectrochemical techniques. Complexes 1-4 undergo a reversible process of two-electron oxidation and partially reversible one-electron reduction. The photo- and electrochemically induced E/Z isomerisation of the complexes was monitored by UV-vis and 1H NMR spectroscopy.

The oxidation of alcohols into their corresponding carbonyl compounds is one of the most fundamental transformations in organic chemistry. In our recent report, 2-azaadamantane N-oxyl (AZADO)/copper catalysis promoted the highly chemoselective aerobic oxidation of unprotected amino alcohols into amino carbonyl compounds. Herein, we investigated the extension of the promising AZADO/copper-catalyzed aerobic oxidation of alcohols to other types of alcohol. During close optimization of the reaction conditions by using various alcohols, we found that the optimum combination of nitroxyl radical, copper salt, and solution concentration was dependent on the type of substrate. Various alcohols, including highly hindered and heteroatom-rich ones, were efficiently oxidized into their corresponding carbonyl compounds under mild conditions with lower amounts of the catalysts.

Laccase from Trametes versicolor together with TEMPO has been found to be a very efficient system to deprotect N-benzylated primary amines, differing from previously described methods since it uses oxygen as a mild oxidant in aqueous medium. Chemoselective removal of the benzyl group was achieved with excellent yields when secondary amines and alcohol moieties were also present.

The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2-azaadamantane N-oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol-selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen-containing compounds. Strong as an ox: The highly chemoselective aerobic oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has been achieved by using 2-azaadamantane N-oxyl (AZADO)/copper catalysis. This catalytic system oxidizes not only alcohols with tertiary amino groups but also those with secondary and primary amines in good to high yield at ambient temperature in air. bpy=2,2-bipyridyl, DMAP=4-(N,N-dimethylamino)pyridine.

Provided are N-[(4-hydroxypiperidin-4-yl)methyl]pyridin-2(1H)-one derivatives represented by formula I, stereoisomers, pharmaceutically acceptable salts or solvates thereof

Provided are N-[(4-hydroxypiperidin-4-yl)methyl]pyridin-2(1H)-one derivatives represented by formula I, stereoisomers, pharmaceutically acceptable salts or solvates thereof. The above compounds have the dual activities of 5-hydroxytryptamine 1A receptor ligand and selective serotonin reuptake inhibitor. The preparation methods of the above compounds, the uses of these compounds for the prevention or treatment of nervous system diseases related to 5-hydroxytryptamine system dysfunction and the pharmaceutical compositions containing these compounds are also provided.

A series of novel symmetrical trans-bis-Schiff bases (11a, 11b, 11c, 11d, 11e, 11f, 11g, 11h, 11i, 11j, 11k, 11l, 11m) were designed and prepared as novel anticancer analogues, with the trans-configuration confirmed by X-ray diffraction. Preliminary inhibitory effects of these compounds on CML K562 cell growth were investigated, and the potential analogue 11e showed an excellent anti-leukemia activity (IC50=6.35 μg/mL), which is higher than that of the clinical drug 5-fluorouracil (IC50=8.48 μg/mL). Complete assignments had been achieved for the title compounds by spectroscopic techniques, and their structure-activity relationships have been studied.

Previously, we reported potent pentapeptidic BACE1 inhibitors with the hydroxymethylcarbonyl isostere as a substrate transition-state mimic. To improve the in vitro potency, we further reported pentapeptidic inhibitors with carboxylic acid bioisosteres at the P4 and P1′ positions. In the current study, we screened new P1′ position 1-phenylcycloalkylamine analogs to find non-acidic inhibitors that possess double-digit nanomolar range IC50 values. An extensive structure-activity relationship study was performed with various amine derivatives at the P1′ position. The most potent inhibitor of this pentapeptide series, KMI-1830, possessing 1-phenylcyclopentylamine at the P 1′ position had an IC50 value of 11.6 nM against BACE1 in vitro enzymatic assay.

The present invention relates to oxadiazole compounds in all their stereoisomeric and tautomeric forms and mixtures thereof in all ratios; and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs and pharmaceutically acceptable polymorphs. The invention also relates to processes for the manufacture of the oxadiazole compounds and to pharmaceutical compositions containing them. The said compounds and their pharmaceutical compositions are useful in the treatment of cancer, particularly chronic myeloid leukemia (CML). The present invention further provides a method of treatment of cancer by administering a therapeutically effective amount of said compounds or their pharmaceutical compositions, to a mammal in need thereof.

A novel tandem-biocatalysts system consisting of a monooxygenase-containing microorganism and an alcohol dehydrogenase is developed for the concurrent oxidations of methylene groups to ketones in one pot, providing green, clean and simple access to valuable ketones with high yield, excellent selectivity and efficient cofactor recycling.

(Chemical Equation Presented) A novel zinc-catalyzed reduction of tertiary amides was developed. This system shows remarkable chemoselectivity and substrate scope tolerating ester, ether, nitro, cyano, azo, and keto substituents. Copyright

(Figure Presented) A new method for the synthesis of 5-azaindole derivatives is reported. A [3+2] dipolar cycloaddition between nitriles and a 3,4-cyclopropanopiperidine followed by SeO2 oxidation affords the target compounds in moderate to excellent yields. The divergent nature and cost effectiveness of this method makes it very suitable for combinatorial applications in the pharmaceutical industry.

The present invention relates to compositions comprising 4-Oxo-piperidine-carboxylates and derivatives thereof, for example derivatives substituted with phenyl, nitrophenyl or benzyl groups. It also teaches the medical use of these and related compounds for treatment of retroviral diseases, in particular, HIV and HTLV, proliferative diseases, in particular CML and Trypanosomiasis.

(Chemical Equation Presented) An efficient, formal [4 + 2] synthesis of synthetically valuable piperidin-4-ones from secondary amines in two steps has been achieved via a key gold catalysis without the purification of tertiary amine intermediates. This reaction is selective toward the less-substituted alkyl group and shows moderate to excellent diastereoselectivities. Its synthetic potential in alkaloid synthesis is demonstratedin a highly diastereoselective synthesis of (±)-cermizine C.

This communication describes the chemoselective metal-free reduction of tertiary amides to the corresponding amines. Hantzsch ester is used as a mild reducing agent for the reduction of trifluoromethanesulfonic anhydride activated amides providing the tertiary amines with high functional group tolerance. Copyright

Malaria, sleeping sickness, Chagas' disease, Aleppo boil, and AIDS are among the tropical diseases causing millions of infections and cases of deaths per year because only inefficient chemotherapy is available. Since the targeting of the enzymes of the polyamine pathway may provide novel therapy options, we aimed to inhibit the deoxyhypusine hydroxylase, which is an important step in the biosynthesis of the eukaryotic initiation factor 5A. In order to identify new lead compounds, piperidines were produced and biologically evaluated. The 3,5-diethyl piperidone-3,5-dicarboxylates 11 and 13 substituted with 4-nitrophenyl rings in the 2 and 6 positions were found to be active against Trypanosoma brucei brucei and Plasmodium falciparum combined with low cytotoxicity against macrophages. The corresponding monocarboxylates are only highly active against the T. brucei brucei. The piperidine oximether 53 demonstrated the highest plasmodicidal activity. Moreover, compounds 11 and 53 were also able to inhibit replication of HIV-1.

This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably.

The synthesis of a new series of 1β-methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime-pyrrolidine moiety showed the most potent antibacterial activity.

A novel series of 10-benzyl-9(10H)-acridinones and 1-benzyl-4-piperidones were synthesized and tested for their in vitro antitumor activities against CCRF-CEM cells. Assay-based antiproliferative activity study using CCRF-CEM cell lines revealed that the acridone group and the substitution pattern on the benzene unit had significant effect on cytotoxicity of this series of compounds, among which 10-(3,5-dimethoxy)benzyl-9(10H)-acridinone (3b) was found to be the most active compound with IC50 at about 0.7 μM. Compound 3b was also found to have antiproliferative activity against two other human leukemic cell lines K562 and HL60 using the MTT assay. The antitumor effect of 3b is believed to be due to the induction of apoptosis, which is further confirmed by PI (Propidium iodide) staining and Annexin V-FITC/PI staining assay using flow cytometry analysis.

New 4-anilidopiperidine analogues in which the phenethyl group of fentanyl was replaced by several aromatic ring-contained amino acids (or acids) were synthesized to study the biological effect of the substituents on μ and δ opioid receptor interactions. These analogues showed broad (47 nM-76 μM) but selective (up to 17-fold) binding affinities at the μ opioid receptor over the δ opioid receptor, as predicted from the message-address concept.

(l)-Proline-catalysed reaction of 1-alkyl/aralkylpiperidin-4-ones with (E)-4-arylbut-3-en-2-ones furnishes novel isoquinoline derivatives, with two or three rings, in good yields via tandem Robinson annulation-Michael addition(s) sequences, while the reaction of 1-arylpiperidin-4-ones with (E)-4-arylbut-3-en-2-ones affords 3-azabicyclo[3.3.1]nonan-9-ones via a tandem Michael addition-aldol reaction sequence.

The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3 h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC50ENZ = 25 nM and IC50MCP = 1 μ M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.

The invention relates to the use of piperidine derivatives encompassed from the general formula (I) for the control of pests, including arthropods and helminths, and a method for the control of pests.

As part of our investigation into the development of potent CCR3 antagonists, a series of piperidine analogues was designed and prepared. Exploration of the piperidine core examined both the basicity and the location of a nitrogen, as well as conformational variants. The bicyclo-piperidine 24c was found to be the most potent inhibitor of CCR3 with an IC50 of 0.0082 μM in the binding assay and 0.0024 μM in the chemotaxis assay.

Pharmacophore-based discovery, synthesis, and structure-activity relationship (SAR) of a series of 4-phenyl-1-arylalkyl piperidines are disclosed. These compounds have been evaluated for their ability to inhibit reuptake of dopamine (DA) into striatal nerve endings (synaptosomes). The lead compound 5 and the most potent analogue 43 were found to have significant functional antagonism.

The Dess-Martin Periodinane (DMP), [1,1,1-triacetoxy-1,1-dihydro-1,2- benziodoxol-3(1H)-one], regenerates ketones from the corresponding ketoximes rapidly at room temperature in very high yields.

Several analogs of the potent dopamine (DA) transporter ligand 4-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine.

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The compounds are N-piperidinyl and pyrrolidinyl-9-xanthenylamines which are inhibitors of gastric acid secretion.