Pyridine Amine Research Articles

Synthesis and evaluation of an 18F-labeled pyrimidine-pyridine amine for targeting CXCR4 receptors in gliomas

IntroductionChemokine receptor-4 (CXCR4, fusin, CD184) is expressed on several tissues involved in immune regulation and is upregulated in many diseases including malignant gliomas. A radiolabeled small molecule that readily crosses the blood–brain barrier can aid in identifying CXCR4-expressing gliomas and monitoring CXCR4-targeted therapy. In the current work, we have synthesized and evaluated an [18F]-labeled small molecule based on a pyrimidine–pyridine amine for its ability to target CXCR4. ExperimentalThe nonradioactive standards and the nitro precursor used in this study were prepared using established methods. An HPLC method was developed to separate the nitro-precursor from the nonradioactive standard and radioactive product. The nitro-precursor was radiolabeled with 18F under inert, anhydrous conditions using the [18F]-kryptofix 2.2.2 complex to form the desired N-(4-(((6-[18F]fluoropyridin-2-yl)amino)methyl)benzyl)pyrimidin-2-amine ([18F]-3). The purified radiolabeled compound was used in serum stability, partition coefficient, cellular uptake, and in vivo cancer targeting studies. Results[18F]-3 was synthesized in 4–10% decay-corrected yield (to start of synthesis). [18F]-3 (tR ≈ 27 min) was separated from the precursor (tR ≈ 30 min) using a pentafluorophenyl column with an isocratic solvent system. [18F]-3 displayed acceptable serum stability over 2 h. The amount of [18F]-3 bound to the plasma proteins was determined to be > 97%. The partition coefficient (LogD7.4) is 1.4 ± 0.5. Competitive in vitro inhibition indicated 3 does not inhibit uptake of 67Ga-pentixafor. Cell culture media incubation and ex vivo urine analysis indicate rapid metabolism of [18F]-3 into hydrophilic metabolites. Thus, in vitro uptake of [18F]-3 in CXCR4 overexpressing U87 cells (U87 CXCR4) and U87 WT indicated no specific binding. In vivo studies in mice bearing U87 CXCR4 and U87 WT tumors on the left and right shoulders were carried out using [18F]-3 and 68Ga-pentixafor on consecutive days. The CXCR4 positive tumor was clearly visualized in the PET study using 68Ga-pentixafor, but not with [18F]-3. ConclusionsWe have successfully synthesized both a radiolabeled analog to previously reported CXCR4-targeting molecules and a nitro precursor. Our in vitro and in vivo studies indicate that [18F]-3 is rapidly metabolized and, therefore, does not target CXCR4-expressing tumors. Optimization of the structure to improve the in vivo (and in vitro) stability, binding, and solubility could lead to an appropriate CXCR4-targeted radiodiagnositic molecule.

ONNO]-type oxovanadium(V) complexes containing amine pyridine bis(phenolate) ligands: synthesis, characterization and catalytic behavior for ethylene (co)polymerization

A series of oxovanadium(V) complexes bearing dianionic [ONNO] chelate ligands 2-[bis(3-R1-5-R2-2 -hydroxybenzyl) aminomethyl]pyridine (2a: R1=tBu, R2=H; 2b: R1=CF3, R2=H; 2c: R1=OCH3, R2=H; 2d: R1=R2=tBu) and 2-[bis(3-R1-5-R2-2 -hydroxybenzyl) aminoethyl]pyridine (2e: R1=R2=tBu) have been synthesized by reacting VO(OnPr)3 with 1.0 equiv. of the ligands in CH2Cl2. All these complexes were characterized by 1H, 13C, 51V NMR spectra and elemental analysis. X-ray structural analysis for 2d revealed a six-coordinate distorted octahedral geometry around the vanadium center in the solid state. It was observed that these complexes existed as a mixture of two isomers, and the main isomer had the oxo moiety in trans configuration to the tripodal nitrogen atom. In the presence of Et2AlCl and CCl3COOEt, these complexes displayed high catalytic activities for ethylene polymerization even at elevated reaction temperature, depending on ligand structures. The resultant polymers possessed high molecular weights and unimodal molecular weight distributions, indicative of a single active site nature. In addition, copolymerizations of ethylene and norbornene using precatalysts 2a–e were also investigated, and the observed catalytic activity was nearly comparable with that for ethylene homopolymerization. When the concentration of comonomer in the feed amounted to 3.0mol/L, a NBE incorporation up to 41.5% could be achieved. Other reaction parameters that influenced the polymerization behavior, such as reaction temperature and Al/V (molar ratio), are also examined in detail.

ONN]-type amine pyridine(s) phenolate-based oxovanadium(V) catalysts for ethylene homo- and copolymerization.

A series of oxovanadium(V) complexes containing amine pyridine(s) phenolate ligands [ONN] (2a-f) have been synthesized in high yields (68-83%) by reacting VO(O(n)Pr)3 with 1.0 equiv. of the ligands in CH2Cl2. These complexes were characterized by (1)H, (13)C and (51)V NMR spectroscopy and elemental analysis. X-ray structural analysis for 2a, 2c and 2d revealed that these complexes adopt a six-coordinate distorted octahedral geometry around the vanadium center in the solid state. Upon treatment with Et2AlCl and CCl3COOEt, these complexes displayed high catalytic activities for ethylene polymerization even at elevated reaction temperatures, depending on ligand structures. The resulting polymers possessed high molecular weight and unimodal molecular weight distributions, indicative of the formation of a single catalytically active species during the polymerization catalysis. Excitingly, these vanadium(V) complexes could efficiently promote ethylene/norbornene copolymerization. The observed catalytic activity for the copolymerization was higher than that for ethylene homopolymerization. Moreover, the molecular weights of the resulting copolymers increased upon increasing the norbornene feed. These results indicated that introducing a suitable amount of norbornene into the system not only could accelerate the polymerization rate but also could restrain chain transfer reactions to some extent.

Synthesis of well-defined amphiphilic branched polyethylene-graft-poly (N-isopropylacrylamide) copolymers by coordination copolymerization in tandem with RAFT polymerization and their self-assembled vesicles

A tandem synthetic strategy combining the metal catalyzed copolymerization of ethylene with trimethylsilyl-protected 10-undecen-1-ol and RAFT polymerization was successfully used to prepare well-defined branched polyethylene-graft-poly(N-isopropylacrylamide) copolymers (BPE-g-PNIPAM). The branched PEs containing multiple hydroxyls (BPE–(OH)n) were firstly synthesized by the copolymerization of ethylene with trimethylsilyl-protected 10-undecen-1-ol using a pyridine–amine nickel catalyst in a controlled fashion (Mw/Mn ∼ 1.2). Macro-chain transfer agents (macro-CTAs) for a subsequent polymerization of N-isopropylacrylamide were quantitatively obtained by an esterification reaction of BPE–(OH)n with S-1-dodecyl-S′-(α,α′-dimethyl-α′′-acetate) trithiocarbonate. Chain extensions by a RAFT polymerization were successfully achieved to afford BPE-g-PNIPAM graft copolymers with narrow polydispersities of ∼1.2. Investigations of the self-assembly behavior of the obtained BPE-g-PNIPAM graft copolymers in water by means of TEM, AFM and laser light scattering confirm that the amphiphilic graft copolymers form supramolecular vesicles with average diameters of 170–190 nm in aqueous solution. Dynamic light scattering (DLS) measurements demonstrate that the polymer vesicles are thermo-sensitive and show a distinctive two-stage response from 20 to 32 °C.

Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles, Pyridazines, and Their Fused Derivatives

Phenacylmalononitriles 8a, 8b react with hydrazines under dry conditions to afford the pyrazole derivatives 9a, 9b, 9c, 9d and in refluxing dioxane to afford the pyrazolo[3,4‐c]pyridazine derivatives 11a, 11b, 11c, 11d and the pyridazine‐6‐imine derivatives 12a, 12b, 12c, 12d. Compounds 12a, 12b were transformed into their oxo analogs 13a, 13b upon reflux in ethanolic HCl, whereas 12c, 12d were transformed into the furan derivatives 14a, 14b under the same reaction conditions (reflux in ethanolic HCl). Compounds 8a, 8b could be transformed directly into the benzoyl‐pyrazole derivatives 16a, 16b, 16c, 16d upon coupling with diazotized aromatic amines in pyridine. The structures of the new compounds were substantiated by elemental analyses and spectral data as well as x‐ray crystallographic analysis. Plausible mechanisms for the unexpected transformations are suggested.

ChemInform Abstract: Highly Enantioselective Biginelli Reaction Catalyzed by a Simple Chiral Primary Amine Catalyst: Asymmetric Synthesis of Dihydropyrimidines.

AbstractThe present asymmetric Biginelli reaction is promoted by the chiral bifunctional primary amine—pyridine catalyst CDP in combination with hydrochloric acid.

Confinement of a bioinspired nonheme Fe(ii) complex in 2D hexagonal mesoporous silica with metal site isolation

A mixed amine pyridine polydentate Fe(II) complex was covalently tethered in hexagonal mesoporous silica of the MCM-41 type. Metal site isolation was generated using adsorbed tetramethylammonium cations acting as a patterned silanol protecting mask and trimethylsilylazane as a capping agent. Then, the amine/pyridine ligand bearing a tethering triethoxysilane group was either grafted to such a pretreated silica surface prior to or after complexation to Fe(II). These two synthetic routes, denoted as two-step and one-step, respectively, were also applied to fumed silica for comparison, except that the silanol groups were capped after tethering the metal unit. The coordination of the targeted complex was monitored using UV-visible spectrophotometry and, according to XPS, the best control was achieved inside the channels of the mesoporous silica for the two-step route. For the solid prepared according to the one-step route, tethering of the complex occurred mainly at the entrance of the channel.

Mechanism Based Design of Amine Fluorogenic Derivatization Reagents: Proof of Concept, Physical–Chemical Characterization and Initial Analytical Derivatization Protocols

Herein, are described initial efforts in the design of a fluorogenic reagent applicable for the derivatization of primary and secondary amines. The initial reagent, 3-isothiocyanato-2-chloropyridine was based on physical–organic reactivity considerations to redirect the initial product of reaction between an amine and the isothiocyanate functional group, long established as a robust first step in Edman sequencing of peptides. The proposed chemistry results in the formation of a class of bicyclic fluorescent heterocycle (N,N-di-substituted [5,4-b] pyridine amines) bearing the amine analyte as substituents. Reported are the results regarding reaction kinetics in various relevant media, the ionization constants for a number of derivatives, and the associate UV and fluorescence spectral properties. These data and properties are utilized in the development of a derivatization protocol that is used in the establishment of calibration plots for several substances, with detection limits in the picomole mass range using liquid chromatography with fluorescence detection.

Combinatorial synthesis of chemical building blocks 1. Azomethines

128 Azomethines were synthesized through condensation of carbonyl compounds with various amines in pyridine in the presence of Me(3)SiCl as promoter and water scavenger in 58-98% yield. Et(3)N was added to reaction mixtures before precipitating the product with H(2)O to prevent acid catalyzed hydrolysis of the C=N bond. The scope and limitation of the method are discussed. High yields and simple setup/workup procedure make this method suitable for the combinatorial synthesis of azomethines, which are suitable as starting materials for high throughput synthesis of various combinatorial libraries. The azomethines synthesized were used as starting materials in a one-pot combinatorial synthesis of amines and amides.

Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst: asymmetric synthesis of dihydropyrimidines

Several chiral primary amines were introduced as organocatalysts for the asymmetric Biginelli reaction. The reaction was performed by using a combined catalyst consisting of a chiral bifunctional primary amine–pyridine 5j and hydrochloric acid in a mixed solvent of 1,4-dioxane/CHCl3 (8/2, v/v) at room temperature. The corresponding dihydropyrimidines were obtained in moderate to high yields with up to >99% ee under mild conditions.

Substituent Effects of Pyridine-amine Nickel Catalyst Precursors on Ethylene Polymerization

A series of pyridine-amine nickel complexes with various substituents were synthesized and used to evaluate substituent effects of catalyst precursors on the reactivity of ethylene polymerization. Substituent effects, including the steric effect of the pyridine moiety, steric effect of the bridge carbon, and steric and electronic effects of the amine moiety, were investigated systematically. Introduction of bulky aryls onto the pyridine moiety on amine pyridine nickel leads to a significant decrease in the activity and molecular weight of polyethylene, whereas an increase in bulk of substituents on the bridge carbon causes an increase in the polymerization activity and molecular weight of polyethylene. For the amine moiety, increasing the steric hindrance results in decreasing activity and affords a higher molecular weight polyethylene with a narrower polydispersity, and introduction of an electron-donating group on the amine moiety leads to formation of a high molecular weight polyethylene with enhanced ...

Synthesis of Azo-Dispersed Dyes Derived From 2-(2-Cyanoacetamido)-4,5,6,7-Tetrahydrobenzo-[b]Thiophene-3-Carboxamid

Coupling of 2-(2-cyanoacetylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (3) or 2-[2-(5-oxo-3-phenylthiazolidin-2-ylidene)]2-cyanoacetamido-4,5,7-tetrahydrobenzo[b]thiophene-3-carboximide (6) with various diazotized aryl amines in pyridine gave the corresponding aryl hydrazonopropionitrile derivatives. Some of the synthesized dyes were applied to polyester fabrics as dispersed dyes in which their colour measurements and fastness properties were evaluated.

1-Aryl substituted-3-(2' -chlorophenyl)-5-(3''-phenyl-4" -oxo-(3" H)-quinazolin-2" -mercaptoacetyl)formazans as insecticidal agents

Synthesis of some novel formazans have been carried out by the reaction of 2-mercapto-2-(methylamido-2'-chloro-N-benzylidene)-3-phenyl-4-oxo-(3H)-quinazoline with diazotised solution of aromatic amines in pyridine and screened for their insecticidal activity against Tribolium confusum.

Synthesis and antibacterial activity of azodispersed dyes incorporating a phthalazinedione moiety for dyeing polyester fabrics

Springer-Verlag 2009 Abstract 3-(1,4-Dioxo-3,4,4a,5,10,10a-hexahydro-1H- 5,10-benzenobenzo(g)phthalazin-2-yl)-3-oxopropionitrile and 3-(1,4-dioxo-3,4,4a,5,10,10a-hexahydro-1H-5,10-ben- zenobenzo(g)phthalazin-2-yl)-3-oxo-2-(5-oxo-3-phenylthia zolidin-2-ylidene)propionitrile were coupled with various diazotized aryl amines in pyridine to give the corre- sponding aryl hydrazonopropionitriles. Some of the dyes produced were applied to polyester as disperse dyes, and their antibacterial, color, and fastness properties were evaluated.

Synthesis of substituted amino‐cycloalkyl[b]thieno‐[3,2‐e]pyridines

Abstractmagnified imageAn efficient two respectively three steps procedure for the synthesis of cycloalkyl[b]thieno[3,2‐e]‐pyridine amines was developed and in general good to very good yields were obtained.

Synthesis of N‐benzoylamino‐1,2,3,6‐tetrahydropyridine derivatives as potential anti‐inflammatory agents

Abstractmagnified imageN‐Benzoylamino‐1,2,3,6‐tetrahydropyridines 9a‐q were synthesized from 4‐substituted pyridines in four steps. Amination of pyridines was carried out to prepare intermediate N‐aminopyridinium mesylates using mesytelenesulfonyl hydroxmate (MSH) as aminating agent. N‐aminopyridinium mestylates reacted with appropriately substituted acyl chlorides to form N‐ylides as stable crystalline solids. Partial reduction of N‐ylides with mild reducing agent afforded N‐benzoylamino‐1,2,3,6‐tetrahydropyridines in fair to good yields.

Simultaneous stereoselective 4-amination with cyclic secondary amines and 2-O-deacetylation of peracetylated sialic acid derivatives

Treatment of methyl 5-acetamido-2,4,7,8,9-penta- O-acetyl-3,5-dideoxy-β- l- glycero- d- galacto-2-nonulopyranosidonate ( 1) with cyclic secondary amines in pyridine at room temperature for 24 h afforded unusual products ( 2a– g). Related experiments were carried out to explain the formation of 4-amination and 2-O-deacetylation of peracetylated sialic acid derivatives ( 2a– g). This reaction may provide a new strategy for the preparation of Zanamivir analogues as neuraminidase inhibitors for anti-H5N1 subtype of avian influenza virus (AIV).

Anthracene‐Coupled Pyridine Amines: A New “Off‐On” Switch for Molecular Recognition Studies on Dicarboxylic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Stability studies of ionised and non-ionised 3,4-diaminopyridine: Hypothesis of degradation pathways and chemical structure of degradation products

3,4-Diaminopyridine is used to treat some symptoms met in Lambert–Eaton myasthenia syndrome. It was shown efficient to reduce a form of variable muscle weakness and fatigability typical of the disease and correlated to a block of acetylcholine release. In France, 3,4-diaminopyridine is nowadays given to patients under capsules form and the status of hospital preparation. Whatever the diluant used in the formulation, the stability period could not exceed 12 months. Preliminary studies were made on a salt form in order to test the influence of various stress factors and determine if there is interaction between them. From this study, the most influent stress condition, presence of hydrogen peroxide, was selected and a comparative study was performed to compare the stability of molecular and salt species. Solutions of each species were exposed to 5 or 15% of hydrogen peroxide and analyzed at 8, 24, 72 and 216 h of degradation by HPLC-UV. Fractions of detected impurities were purified and collected by semi-preparative HPLC-UV and analyzed by HPLC-UV–ESI–MS and IR spectroscopy in order to determine their structure hypotheses. Theses experiments demonstrate that the salt species were more stable under oxidative stress condition than molecular species. The two main degradation products were collected and identified as 4-amino, 3-nitropyridine and 3,4-diaminopyridine-N-oxide when the molecular form was degraded whereas only 4-amino, 3-nitropyridine was found in less quantity in the salt solutions. Nitrogen pyridine and pyridine amine could not easily be oxidized by hydrogen peroxide in salt comparatively to molecular species due to the lone pair of electron engaged in a bound with hydrogen in the first case and by resonance change of the pyridine in the second case. This modification of structure promoted different pathways of degradation for the salt form which are more dependent of energy. Owing to the better stability of the salt species, a new pharmaceutical form containing it was developed to assess its stability under ICH standard conditions allowing an industrial manufacture of this drug.

Anthracene-coupled Pyridine Amines: A New “Off–On” Switch for Molecular Recognition Studies on Dicarboxylic Acids

Abstract The fluorescent photoinduced electron-transfer (PET) chemosensor 1, which can function as “off–on” fluorescence switch for dicarboxylic acids has been designed and synthesized for the first time. The carboxylic acid binding takes place through charge neutral pyridine amine receptor sites and the sensor is found to be selective for glutaric acid. The binding has been examined by fluorescence, UV–vis, and NMR spectroscopic methods.