Amine Fragment Research Articles

Structural differences/similarities of diastereotopic groups in three new chiral phosphoramides.

The crystal structures of two single-enantiomer amidophosphoesters with an (O)2P(O)(N) skeleton and one single-enantiomer phosphoric triamide with an (N)2P(O)(N) skeleton were studied. The compounds are diphenyl [(R)-(+)-α-4-dimethylbenzylamido]phosphate, (I), and diphenyl [(S)-(-)-α-4-dimethylbenzylamido]phosphate, (II), both C21H22NO3P, and N-(2,6-difluorobenzoyl)-N',N''-bis[(R)-(+)-α-ethylbenzyl]phosphoric triamide, C25H28F2N3O2P, (III). The asymmetric units contain two amidophosphoester molecules for (I) and (II), and one phosphoric triamide molecule for (III). In the crystal structures of (I) and (II), molecules are assembled in a similar one-dimensional chiral ribbon architecture, but with almost a mirror-image relationship with respect to each other through N-H...O(P) and C-H...O(P) hydrogen bonds along [010]. In the crystal structure of (III), the chiral tape architecture along [100] is mediated by N-H...O(P) and N-H...O(C) hydrogen bonds, and the tapes are connected into slabs by C-H...O interactions (along the ab plane). The differences/similarities of the two diastereotopic phenoxy groups in (I)/(II) and the two chiral amine fragments in (III) were studied on the grounds of geometry, conformation and contribution to the crystal packing, as well as 1H and 13C signals in a solution NMR study.

Thermal destruction of <i>d</i> -mannose condensation products using <i>p</i> -aminoacetanilide in solvent-free systems

Thermal destruction of D-mannose condensation products using p-aminoacetanilide in solvent-free systems, such as paraffinic oil and a KBr-matrix, was studied by the methods of electronic and vibrational spectroscopy. The thermal destruction of mannosylamine in a KBr matrix is accompanied by intense coloration. At the same time, the bands in the IR spectra characterizing the functionalization of aminoacetanilide retain their position and intensity, which indicates the absence of transformation of the amine fragment. The appearance of the 1645, 1680, 1690 cm -1 bands of enone O=C-C=C- fragments is noted, along with the 1750 and 1780 cm -1 bands attributed to the stretching C=O vibrations of esters and lactones likely formed as a result of transformation of the primary mannosylamine degradation products. The thermal destruction of a mannosylamine suspension in paraffinic oil shows a lower transformation of the mannosyla-mine structure in comparison with experimental processes in a KBr matrix. The spectra depict the bands of С = O vibrations in different structural environments, as well as the signal shift of 1280 cm -1 into the low- frequency region characterizing the elimination of arylamine. The reflection spectra of the alcohol solutions of destruction products demonstrate the presence of only the 1750 cm -1 band; the 1780 cm -1 band does not appear probably due to the instability of lactones in solutions, which causes their recyclization. An analysis of vibrational spectra showed the absence of bands characteristic of melanoidin N-heterocycles due to the predominant formation of acyclic conjugated systems and carboxylic acid derivatives in the studied solvent-free systems. In the electronic spectra of the alcohol solutions of destruction products in both systems, maxima of about 260 nm were recorded. These maxima correspond to the absorption of oxyenone chromophores and the continuous absorption region in the visible part of the spectrum, caused by the formation of extended chromophores, i.e. condensation products of the intermediates of mannosylamine decomposition. The obtained results can be useful both when selecting conditions for the Maillard reaction with a given functionalization and when developing methods for the synthesis of antioxidant agents for protecting polymers and oils.

CLUSTER COMPLEXES OF RHENIUM WITH CARBONYL AND AMINE CONTAINING LIGANDS

Methods for the synthesis of rhenium cluster complexes based on carbonyl and amine containing organic bifunctional ligands have been developed. The structure of the obtained cluster combinations were determined on the basis of IR spectroscopy data, methods of thermogravimetry and elemental analysis. Samples of ligands I and II were obtained by condensation of cyclopentane and cyclohexane carboxylic acids chloroanhydrides with ethylene, followed by the replacement of the chlorine atom by amine groups. To obtain cluster complexes of rhenium with the synthesized ligands, an ultradisperse solution of rhenium in distilled water was prepared in advance. To this end, the rhenium trichloride salt (ReCl3) was dissolved in water and the calculated amount of sodium borohydride in a nitrogen atmosphere was added in portions to the resulting solution with vigorous stirring. Rapidly arising black dispersed nanoparticles of metallic rhenium were not deposited. When organic ligands I and II are added, the corresponding cluster compounds III and IV are formed, which gradually over 30 minutes. precipitated from aqueous solution. The resulting black-brown precipitates were washed with distilled water and dried in a nitrogen atmosphere at a temperature of 35-40 °C. The melting points of the synthesized compounds are determined, which are components for cluster III-195 °С and cluster IV- 212 °С (with decomposition). In the IR spectra of cluster compounds, intense absorption bands were found, which characterize the presence of both a ketone carbonyl group (1718 sm–1, 1720 sm–1) and an amine fragment (2727 sm–1, 2720 sm–1 and 2613 sm–1, 2609 sm–1). The absorption bands of ketone groups in cluster compounds are shifted toward higher frequencies compared to the initial ligands. A similar picture is observed when comparing IR vibrations of C – N bonds in the initial ligands and the corresponding cluster compounds. The results of elemental analysis confirm the structure of cluster compounds and are in complete agreement with the notion that the reduction of rhenium salts with metal hydrides in an aqueous solution forms cluster compounds. Apparently, in this case, the most stable rhenium clusters with a tetrahedral structure are formed. Thermogravimetric analysis made it possible to establish the presence of a peak at a temperature of 318 °С with a mass number of 744.8 c.u. corresponding to the cluster combination of four rhenium atoms. At each stage of decomposition, the experimental mass loss agrees well with the calculated values.

Synthesis, structure, and photoluminescent and electroluminescent properties of zinc(II) complexes with bidentate azomethine ligands

New Zn(II) complexes of bidentate Schiff base ligands were synthesized and characterized by 1H NMR, IR spectroscopy, and elemental analysis. The single‐crystal X‐ray diffraction study revealed that all compounds can be represented as mononuclear zinc(II) complexes with two bidentate organic ligands coordinated to the central metal atom by two oxygen and two nitrogen atoms. The photophysical properties of the complexes were investigated by UV–vis and photoluminescence spectroscopy in dimethyl sulfoxide (DMSO) solutions. It was found that the positions of maxima of the long‐wavelength absorption bands and photoluminescence depend strongly on the substituent in the aldehyde and amine fragments. The nature of the bands of electronic absorption spectra in DMSO solutions was interpreted using the results of quantum chemical calculations in the time‐dependent density functional theory (TD‐DFT) approximation. The light emission performance of the complexes in organic light‐emitting diodes was investigated. The electroluminescence (EL) spectra maxima of all three complexes are located in the visible range from 470 to 550 nm. The absence of additional spectral maxima or shoulders in the EL bands means that neither exciplex nor excimer states form, and the observed EL bands are due to the intrinsic radiation of the zinc(II) complexes. EQEs were measured for these three complexes. The maximum value, close to 3%, was obtained in the case of a structure with a maximal brightness of 8000 cd m−2 at 17 V.

Influence of oligomeric unsaturated polyketone on the vulcanization of elastomeric compositions in the presence of sulfenamide C

Effect of the oligomeric unsaturated polyketone (UPK) additive on the rheological properties, vulcanization, and structural characteristics of elastomeric compositions based on butadiene and nitrile-butadiene rubbers containing N-cyclohexyl-2-benzothiazolylsulfenamide (sulfenamide C) as vulcanizing accelerator is investigated. It was demonstrated using IR and NMR spectroscopy that sulfenamide C reacts with polyketone. A mechanism for such interaction, which includes the sequential addition of benzothiazyl sulfide and amine fragments to the oligomeric chain, was proposed.

Exploring 1-adamantanamine as an alternative amine moiety for metabolically labile azepane ring in newly synthesized benzo[d]thiazol-2(3H)one σ receptor ligands.

In this work we report the structure-activity relationships, binding properties, and metabolic stability studies of a series of benzo[d]thiazol-2(3H)one as sigma receptors (σRs) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (SN56), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound 12 had low nanomolar affinity for the σ1R (K i = 7.2 nM) and moderate preference (61-fold) over the σ2R. In vitro metabolic stability studies showed a slight improvement of the metabolic stability for 7-12, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of 12 suggested that the N-methyl group of the adamantyl moiety is a major site of metabolism.

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments.

Four crystal structures of 2-amino-N-(dimethylphenoxyethyl)propan-1-ol derivatives, characterized by X-ray diffraction analysis, are reported. The free base (R,S)-2-amino-N-[2-(2,3-dimethylphenoxy)ethyl]propan-1-ol, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C13H22NO2+·Cl-, 2c, crystallizes in the space group P21, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2-picolinic acid, namely, (R,S)-N-[2-(2,3-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2+·C6H4NO2-, 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2+·C6H4NO2-, 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P-1, while salt 2p crystallizes in the space group P41212. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen-bonded chains, while the structures of the 2-picolinate salts have hydrogen-bonded rings as the major features. In both salts with 2-picolinic acid, the specific R12(5) hydrogen-bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.

Strategies to Mitigate the Bioactivation of Aryl Amines.

The bioactivation of xenobiotics to yield reactive metabolites can lead to tolerability and toxicity concerns within a drug discovery program. Development of strategies for mitigating the metabolic liability of commonly encountered toxicophores, such as anilines, relies on an understanding of the relative tendency of these functionalities to undergo bioactivation. In this report, we present the first systematic study of the structure-activity relationships of the bioactivation of aryl amine fragments (molecular weight < 250 Da) using a glutathione (GSH) trapping assay in the presence of human liver microsomes and the reduced form of nicotinamide adenine dinucleotide phosphate. This study demonstrates that conversion of anilines to nitrogen-containing heteroarylamines results in a lower abundance of GSH conjugates in the order phenyl > pyrimidine ≈ pyridine > pyridazine. Introduction of electron-withdrawing functionality on the aromatic ring had a less pronounced effect on the extent of GSH conjugation. Examination of more drug-like compounds sourced from in-house drug discovery programs revealed similar trends in bioactivation between matched pairs containing (hetero)aryl amines. This study provides medicinal chemists with insights and qualitative guidance for the minimization of risks related to aryl amine metabolism.

SYNTHESIS AND REACTIONS OF CHROMAN-2-OLS AND THEIR BENZO ANALOGS WITH N-NUCLEOPHILES

By the action of acetic acid on 2-morpholinochromanes, a series of chroman-2-ols were obtained in which the hydroxyl group is easily substituted by a primary or secondary amine or benzyl carbamate fragments. In the case of hydrazines and hydrazides of carboxylic acids, the corresponding hydrazones are isolated.

Synthesis of Fused Oxepane HIV Integrase Inhibitor MK-1376

Controlling the absolute and relative stereochemistry of a seven-membered oxepane in the formation of HIV integrase inhibitor MK-1376 was accomplished through a strategy involving the use of asymmetric allylation and stereoconvergent, substrate-directed installation of an amine fragment. Surprising reactivity was demonstrated during the asymmetric allylation in which the allyl-pyrimidone product was formed reversibly. The stereoconvergent amine addition was accomplished through an elimination/addition sequence involving a quinone methide reactive intermediate, and nucleophilic trapping of the reactive quinone methide intermediate with methylamine. This novel approach delivered MK-1376, offering 100-fold greater productivity and 50-fold less waste than the initial synthetic chemistry route.

Synthesis and catalytic activity of cationic dinuclear palladium (II) complexes supported by thioether ligands containing two di-(2-picolyl) amine arms

The design, synthesis and characterization of a series of dithioether ligands featuring two di-(2-picolyl)amine arms (2a–2d) and their corresponding cationic dinuclear palladium (II) complexes (3a–d) are reported. Crystal structures of ligand 2b and complexes 3b and 3d were determined by X-ray diffraction studies. The molecular structures of 3b and 3d display each of the two di-(2-picolyl)amine fragments coordinated to one palladium(II) atom in a (κ3-N,N,N) tridentate fashion and with the cationic metal centers displaying square-planar geometries. Weak interactions between the metal centers and the thioether fragments are observed. All bimetallic complexes 3a–d were tested as catalytic precursors in the Suzuki couplings of different o- or p-substituted iodo- or bromoaryls with boronic acids. The overall catalytic results indicate that complex 3b is the best precursor of the series demonstrating even more efficient performance compared to commercial palladium sources such as Pd(OAc)2 and the Nájera Catalysts.

Synthesis and reactions of chroman-2-ols and their benzo analogs with N-nucleophiles

By the action of acetic acid on 2-morpholinochromanes, a series of chroman-2-ols were obtained in which the hydroxyl group is easily substituted by a primary or secondary amine or benzyl carbamate fragments. In the case of hydrazines and hydrazides of carboxylic acids, the corresponding hydrazones are isolated.

Fragment-oriented synthesis: β-elaboration of cyclic amine fragments using enecarbamates as platform intermediates.

A strategy for the β-sp3 functionalisation of cyclic amines is described. Regioselective conversion of protected amines to enecarbamates is achieved through electrochemical oxidation; these intermediates can be derivatised by functionalised alkyl halides under photoredox catalysis. The potential of the methods is highlighted by direct growth of a DCP2B-binding fragment.

Synthesis, Antitumor Activity, and Docking Analysis of New Pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-8-amines.

Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3′,2′:4,5](furo)thieno[3,2-d]pyrimidines as well as of two new heterocyclic systems: furo[2–e]imidazo[1,2-c]pyrimidine and furo[2,3-e]pyrimido[1,2-c]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3′,2′:4,5]thieno(furo)[3,2-d]pyrimidines with various amines, the relevant pyrido[3′,2′:4,5]thieno(furo)[3,2-d]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2-c]pyrimidine and pyrimido[1,2-c]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure–activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds.

Thermal properties and flame retardancy of an intumescent flame-retarded epoxy system containing phosphaphenanthrene, triazine-trione and piperidine

A phosphaphenanthrene/piperidine-containing phenolic derivative (PHTD) was synthesized through the one-pot reaction between triacetonediamine, p-hydroxybenzaldehyde and 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide. The intumescent reactive flame-retardant epoxy thermosets (P-0.25, P-0.5, P-0.75 and P-1.0) were composed of diglycidyl ether of bisphenol-A, 1,3,5-triglycidyl isocyanurate (TGIC), 4,4′-diamino-diphenyl sulfone (DDS) and PHTD. Due to the incorporation of PHTD and TGIC, the flame retardancy of EP samples was remarkably improved. For instance, the LOI value and UL94 rating for P-0.75 sample with only 0.75 mass% phosphorus reached 36.6% and V-0. The average of heat release rate, peak of heat release rate and total heat release for P-1.0 system were decreased by 35.6%, 52.5% and 36.4% compared with those for EP/DDS system. During combustion, plenty of PO radicals, hindered amine and isocyanate fragments were generated by the pyrolysis of PHTD and TGIC in gaseous phase, which suppressed the combustion reaction and diluted the fuels. In condensed phase, the pyrolytic products of phosphaphenanthrene and triazine-trione groups jointly promoted the formation of a compact and intumescent char layer to isolate heat and oxygen. The remarkable improvement of flame retardancy of EP thermoset was ascribed to the flame-retardant effects of PHTD and TGIC in gaseous and condensed phases.

Synthesis of Aminomethoxy Derivatives of 1-(Butylsulfanyl)alkanes

Three-component Mannich-type condensation of equimolar amounts of 1-(butylsulfanyl)alkan-2-ols, formaldehyde, and secondary aliphatic and heterocyclic amines at 45–50°C (3–4 h) afforded 65–82% of previously unknown aminomethoxy derivatives which were characterized by elemental analyses and IR, 1H and 13C NMR, and mass spectra. Some of the synthesized compounds were tested for antimicrobial activity against gram negative, gram positive, and spore-bearing bacteria and yeast-like fungi; they showed a higher activity than commonly used antibacterial agents. Compounds containing cyclic amine fragments were more active than those obtained from aliphatic amines. The tested compounds were recommended for use as antimicrobial agents.

Синтез арилсалициламидов, обладающих антигельминтной активностью

Salicylamides (N-aryl-substituted hydroxybenzamides): well-known organic compounds with diverse biological activity, which were originally investigated as antimicrobial and antifungal substances. Salicylamides have also been used as anthelmintic or molluscicidal agents in human and veterinary medicine. The most famous is 5,2'-dichloro-4'-nitrosalicylamide (niclosamide, yomezan – Germany), resynthesized in the USSR under the name of fenasal, which is effective in treating diphyllobothriasis and hymenolepidosis and has molluscicidal properties. The works of domestic and foreign scientists F.S. Mikhaylitsyn, H. Vanden Bosshe, L.M. Scheibel, P. Andreus, G. Bonse, and others are devoted to the synthesis of salicylamides, their biological activity. I. Arkhipov, R. Gonnert, studied the anthelmintic activity of salicylamides. E. Schraufstatter, H. Mrozik et al. In the works of various authors the “structure-activity linkage” of the synthesized amides is shown. It has been established that the presence of an amide or thioamide bond, substituted amides, is important for anthelmintic activity. The presence of a hydroxyl group in the 2nd position of the aromatic ring of the salicylamide acid fragment is the main condition for the manifestation of activity with respect to tape helminths and trematodes. The best profile of the biological activity of salicylamides was obtained by introducing chlorine into various positions of acid and amine fragments. Acylation of the hydroxyl group in salicylamides leads to a decrease in their toxicity.

Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease.

5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.

Synthesis and Biological Activity of 4‐Cycloaminopolyfluorosalicylic Acids

AbstractA series of novel 4‐cycloamino‐substituted polyfluorosalicylic acids, their esters and amides have been synthesized by the reactions of alkyl polyfluorosalicylates with morpholine, N‐methylpiperazine, pyrrolidine and proline. It was observed that esters of polyfluorosalicylic acids under prolonged heating with amines could undergo one pot nucleophilic substitution of fluorine and intramolecular acidic hydrolysis owing to catalysis by the neighboring hydroxyl group. According to ADME calculations, the synthesized compounds are suitable for drug‐design. 4‐(N‐Methylpiperazinyl)‐substituted polylfluorosalicylic acids were found to have good analgesic activity while 4‐morphonyl‐containing analogs revealed moderate anti‐inflammatory action. In addition, the presence of amine fragment in polyfluorosalicylates reduced acute toxicity comparing to non‐substituted polyfluorosalicylic acids. The molecular docking of the most active compounds was carried out into the tyrosine site of cyclooxygenase‐1.

Cooperative Mn(i)-complex catalyzed transfer hydrogenation of ketones and imines.

The synthesis and reactivity of Mn(i) complexes bearing bifunctional ligands comprising both the amine N-H and benzimidazole fragments are reported. Among the various ligands, the N-((1H-benzimidazol-2-yl)methyl)aniline ligand containing Mn(i) complex presented higher reactivity in the transfer hydrogenation (TH) of ketones in 2-propanol. Experimentally, it was established that both the benzimidazole and amine N-H proton played a vital role in the enhancement of the catalytic activity. Utilizing this system a wide range of aldehydes and ketones were reduced efficiently. Notably, the TH of several imines, as well as chemoselective reduction of unsaturated ketones, was achieved in the presence of this catalyst. DFT calculations were carried out to understand the plausible reaction mechanism which disclosed that the transfer hydrogenation reaction followed a concerted outer-sphere mechanism.