18673-04-6Relevant academic research and scientific papers
Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ1) receptor ligands with potent anti-amnesic effect
Abatematteo, Francesca S.,Mosier, Philip D.,Niso, Mauro,Brunetti, Leonardo,Berardi, Francesco,Loiodice, Fulvio,Contino, Marialessandra,Delprat, Benjamin,Maurice, Tangui,Laghezza, Antonio,Abate, Carmen
, (2021/12/14)
The sigma-1 (σ1) receptor plays a significant role in many normal physiological functions and pathological disease states, and as such represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines based on the lead compound 1-[ω-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1a) in which the degree of methylation at the carbon atoms alpha to the piperidine nitrogen was systematically varied. The affinity at σ1 and σ2 receptors and at Δ8-Δ7 sterol isomerase (SI) ranged from subnanomolar to micromolar Ki values. While the highest-affinity was displayed at the σ1, the increase of the degree of methylation in the piperidine ring progressively decreased the affinity. The subnanomolar affinity 1a and 1-[ω-(4-methoxyphenoxy)ethyl]-4-methylpiperidine (1b) displayed potent anti-amnesic effects associated with σ1 receptor agonism, in two memory tests. Automated receptor–small-molecule ligand docking provided a molecular structure-based rationale for the agonistic effects of 1a and 1b. Overall, the class of the phenoxyalkylpiperidines holds potential for the development of high affinity σ1 receptor agonists, and compound 1a, that appears as the best in class (exceeding by far the activity of the reference compound PRE-084) deserves further investigation.
New Reactive Mesogen Compound having asymmetric linkage structure and the Method for Manufacturing the Same
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Paragraph 0191-0193, (2021/10/10)
The present invention refers to non-symmetric links by a contact lens with phosgene compounds and their manufacturing method relates to novel reactive mesoporous, more specifically the form a network polymer by dry toner particles over a wide temperature range exhibits liquid crystal phase, and excellent thermal stability, with a high birefringence rate price has large screen wide view angle liquid crystal display device is characterized in the ultra thin compensation film and phase difference film the long wave length line efficient on the opening in a thin-thickness compensation film and phase difference film formed on the multi-by a contact lens with non-symmetric links phosgene compounds and their novel reactive mesoporous relates to manufacturing method. Non-symmetric links of the present invention by a contact lens with phosgene mesoporous reactive novel compound is represented by [general formula]. [General formula] [General formula] in said P 1 and P 2 independently from each other CH 2 =CH 2-, HC=C-, CH 2 = CH-CH 2-, W 1 HCOCH-, CH 2 =CW 1-COO-, CH 2 =CW 2-(O) k1-, CH 3-CH=CH-O-, HO-CW 2 W 3-, HS-CW 2 W 3-, HW 2 N-, HO-CW 2 W 3-NH-, CH 2 =CW 1-CO-NH-, CH 2 =CH-(COO) k1-Phe-(O) k2-, Phe-CH=CH-, HOOC-, NCO-, OCN-, SCN-, W 4 W 5 W 6 Si-, , Graphical object is selected from (stage, m 2 and n2 when 0 to an event that both a, P 2 the H, OH, CH 3, alkoxy groups, phenyl, bis phenyl is coupler which has no group or polymers.), W 1 the H, Cl, CN, phenyl or 1 to 5 carbon atoms alkyl, W 2 and W 3, independently one of the other are hydrogen or 1 to 5 carbon atoms alkyl, W 4, W 5, and W 6 each independently a Cl, 1 to 5 carbon atoms oxa carbonyl alkyl or alkyl, the 1, 4-Phe k1 and polyphenylene and each independently a k2 is O or 1, Sp 1 and Sp 2 by a spacer group, independently 1-25 and carbon atoms, X 1 and X 2 independently from each other-O-, -S-, -S-CO-, -CO-S-, -CO-, -COO-, -OCO-, -O-COO-, -CO-NR-, -NR-CO-, -NR-CO-NR-, -OCH 2-, -CH 2 O-, -SCH 2-, -CH 2 S-, -CF 2 O-, -OCF 2-, -CF 2 S-, -SCF 2-, -CH 2 CH 2-, -CF 2 CH 2-, -CH 2 CF 2-, -CF=CF-, -CF 2 CF 2-, -CH=N-, -N=CH-, -N=N-, -CH=CR-, -CX=CX-, -C≡C-, -CH=CH-COO-, -OCO-CH=CH-, -NH-, -N=CH-S-, -CH=N-S-, -SO 2-, -O-Si (OH) 2-O one wave which step or ROM for storing programs, n 1 and n 2 and the 0 or 1, Z 1 and Z 2 independently from each other-O-, -S-, -S-CO-, -CO-S-, -CO-, -COO-, -OCO-, -O-COO-, -CO-NR-, -NR-CO-, -NR-CO-NR-, -OCH 2-, -CH 2 O-, -SCH 2-, -CH 2 S-, -CF 2 O-, -OCF 2-, -CF 2 S-, -SCF 2-, -CH 2 CH 2-, -CF 2 CH 2-, -CH 2 CF 2-, -CF=CF-, -CF 2 CF 2-, -CH=N-, -N=CH-, -N=N-, -CH=CR-, -CX=CX-, -C≡C-, -CH=CH-COO-, -OCO-CH=CH-, -NH-, -N=CH-S-, -CH=N-S-, -SO 2-, -O-Si (OH) 2-O one wave which step or ROM for storing programs, A 1 and A 2 phenyl independently from each other, 1, 4-phenylene, 1, 4-cyclohexenylene, naphthalene and, F, Cl, CN, OH, NO 2, or carbon number 1-7 in alkyl, alkoxy, alkanoyl a single substituted or can be multi-substituted, m 1 and m 2 independently from each other 0, 1 or 2 (m 1 + m 2 2, or carbon number 1-7 in alkyl, alkoxy, alkanoyl a single substituted or can be multi-substituted, the Or And, Y 1 and Y 2 independently from each other-O-, -S-, -S-CO-, -CO-S-, -CO-, -COO-, -OCO-, -O-COO-, -CO-NR-, -NR-CO-, -NR-CO-NR-, -OCH 2-, -CH 2 O-, -SCH 2-, -CH 2 S-, -CF 2 O-, -OCF 2-, -CF 2 S-, -SCF 2-, -CH 2 CH 2-, -CF 2 CH 2-, -CH 2 CF 2-, -CF=CF-, -CF 2 CF 2-, -CH=N-, -N=CH-, -N=N-, -CH=CR-, -CX=CX-, -C≡C-, -CH=CH-COO-, -OCO-CH=CH-, -NH-, -N=CH-S-, -CH=N-S-, -SO 2-, -O-Si (OH) 2-O-, or, Y [...] film [...] , Y 1 and Y 2 each other is coupled an asymmetric unequal, (stage, Y 1 e-COO-in when Y 2 the-CH 2 CH 2-is a not, Y 1 is-OCH 2-when Y 2-COO-of which is at, Y 1 e-CH=CH-COO-in when Y 2-COO or-CH 2 CH 2-is not.) R is hydrogen or 1 to 5 carbon atoms is alkyl.
Copper(ii)-catalyzed C-O coupling of aryl bromides with aliphatic diols: Synthesis of ethers, phenols, and benzo-fused cyclic ethers
Liu, Yajun,Park, Se Kyung,Xiao, Yan,Chae, Junghyun
supporting information, p. 4747 - 4753 (2014/06/24)
A highly efficient copper-catalyzed C-O cross-coupling reaction between aryl bromides and aliphatic diols has been developed employing a cheaper, more efficient, and easily removable copper(ii) catalyst. A broad range of aryl bromides were coupled with aliphatic diols of different lengths using 5 mol% CuCl2 and 3 equivalents of K2CO3 in the absence of any other ligands or solvents to afford the corresponding hydroxyalkyl aryl ethers in good to excellent yields. In this newly developed protocol, aliphatic diols have multilateral functions as coupling reactants, ligands, and solvents. The resulting hydroxyalkyl aryl ethers were further readily converted into the corresponding phenols, presenting a valuable alternative way to phenols from aryl bromides. Furthermore, it was demonstrated that they are useful intermediates for more advanced molecules such as benzofurans and benzo-fused cyclic ethers. This journal is
Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application
Kesteleyn, Bart,Amssoms, Katie,Schepens, Wim,Hache, Geerwin,Verschueren, Wim,Van De Vreken, Wim,Rombauts, Klara,Meurs, Greet,Sterkens, Patrick,Stoops, Bart,Baert, Lieven,Austin, Nigel,Wegner, J?rg,Masungi, Chantal,Dierynck, Inge,Lundgren, Stina,J?nsson, Daniel,Parkes, Kevin,Kalayanov, Genadiy,Wallberg, Hans,Rosenquist, ?sa,Samuelsson, Bertil,Van Emelen, Kristof,Thuring, Jan Willem
, p. 310 - 317 (2013/02/25)
The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R3) at the para-position of the P1′ benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R1) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC50s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS.
Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: Optimization of in vitro activity
Peters, Jens-Uwe,Kühne, Holger,Dehmlow, Henrietta,Grether, Uwe,Conte, Aurelia,Hainzl, Dominik,Hertel, Cornelia,Kratochwil, Nicole A.,Otteneder, Michael,Narquizian, Robert,Panousis, Constantinos G.,Ricklin, Fabienne,R?ver, Stephan
scheme or table, p. 5426 - 5430 (2010/12/25)
Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.
Substituted piperazines and diazepanes
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Page/Page column 94, (2010/02/05)
A novel class of substituted piperazines and diazepanes, pharmaceutical compositions comprising them and use thereof in the treatment of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.
Synthesis of chiral 1-[ω(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at σ1, σ2, and sterol δ8-δ7 isomerase sites
Berardi, Francesco,Loiodice, Fulvio,Fracchiolla, Giuseppe,Colabufo, Nicola Antonio,Perrone, Roberto,Tortorella, Vincenzo
, p. 2117 - 2124 (2007/10/03)
Sumitomo's patented σ ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at σ1, σ2, and sterol Δ8-Δ7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective σ1 binding relative to other σ family sites. Generally high σ1-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase σ1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)1-methylethyl]piperidine ((-)-(S)-17) reached the highest σ1 affinity (Ki = 0.34 nM) and the best selectivity relative to the σ2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.
Reactions of γ-arylalkanols via aryl radical cation and alkoxyl radical intermediates. Part 3. Reactions of 3-arylprop-1-yl hydroperoxides with iron(II) in the presence of copper(II)
Goosen, Andre,Marais, Charles F.,McCleland, Cedric W.,Rinaldi, Fabrizio C.
, p. 1227 - 1236 (2007/10/02)
A strategy for comparing the 1,5- and 1,6-cyclisation reactions of 3-phenylpropan-1-oxyl radicals is described.Iron(II)-catalysed reduction of 3-(p-methylphenyl)prop-1-yl hydroperoxide and its para-chloro and para-methoxy-substituted analogues, carried out in the presence of copper(II), has been found to give in each case the appropriate para-substituted 3-phenylpropan-1-ol, 3-phenylpropanal and a low yield of a mixture of isomeric 6- and 7-substituted chromans.The alcohols are proposed to form via reduction of either the hydroperoxide or the resulting alkoxyl radical or its cyclised intermediates, and the aldehydes as a result of rearrangement of the alkoxyl radical to an α-hydroxy alkyl radical which subsequently undergoes oxidation.The 7-substituted chromans, which arise directly from 1,6-cyclisation of the alkoxyl radical, were found to dominate the 6-substituted isomers which result from rearrangement of 1,5-cyclised intermediates.This effect is attributed to inefficient interception of the 1,5-cyclised radical intermediate which permits equilibration to the thermodynamically more stable 1,6-cyclised radical isomer to occur.The effect of pH on the reactions has been investigated and although no products typical of the intermediacy of aryl radical cations were detected (even under highly acidic conditions), the formation of such intermediates cannot be excluded.Semiempirical MO calculations have been carried out (at the PM3 level of approximation) on a series of model compounds, yielding results which have clarified our understanding of the effect of substituents on the stabilities of the various intermediates arising from the cyclisation reactions of 3-phenylpropan-1-oxyl radicals.Furthermore, these calculations have supported our assumptions regarding the probability and specificity of rearrangements of the spirodienyl intermediates.
