Vol. 14 No. 4(56) (2016)
Published:
2016-12-16
Full Issue
Original Researches
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The synthesis, anti-inflammatory, analgesic and antimicrobial activities of ethyl 2-amino-4-alkyl-4,6-dihydropyrano[3,2c][2,1]benzothiazin-3-carboxylate 5,5-dioxides and triethylammonium 3-[(4-hydroxy-1-ethyl-2,2-dioxido-1h-2,1-benzothiazin-3-yl)alkyl]-1-
The search for new groups of anti-inflammatory and analgesic drugs is a topical issue of the current medicinal chemistry. It is caused by numerous diseases that are accompanied by pain and inflammation, as well as by imperfection of the existing drugs aimed to provide treatment of these pathological conditions. Derivatives of 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide are promising chemicals to search and develop drugs with the pharmacological properties required. This heterocyclic system is structurally close to 2H-1,2-benzothiazin-4-one 1,1-dioxide, which is the core of the famous non-steroidal anti-inflammatory drugs related to the “oxicam” group. Moreover, derivatives of 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide are also considered to be promising structures for searching effective antimicrobial substances among them. The present article is devoted to the synthesis of new derivatives of 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide, namely ethyl 2-amino-4-alkyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazin-3-carboxylate 5,5-dioxides and triethylammonium 3-[(4-hydroxy-1-ethyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)alkyl]-1-ethyl-1H-2,1-benzothiazin-5-olat 2,2-dioxides. Condensed 2-amino-4-alkyl-4H-pyran-3-carboxylates were synthesized via the three-component one-pot interaction of 1-ethyl-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide with ethyl cyanoacetate and aliphatic aldehydes. The abovementioned triethylammonium salts were obtained by the two component interaction of 1-ethyl-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide with aliphatic aldehydes in the presence of the equimolar amount of triethylamine. The study of the anti-inflammatory and analgesic activity has demonstrated high prospects of new effective drugs when searching among two classes of the compounds synthesized. The screening of the antimicrobial activity has shown that the compounds synthesized are the most active against the fungal strain of C. albicans.
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The interaction of 1-acetylamino-2,2-dichlorethenylphosphonium chlorides with monoethanolamine
This paper presents the synthesis of new derivatives of 5-amino-2R-1,3-oxazol-4-iltriphenylphosphonium saltsand (acylamino-(3-methyl-1,3-oxazolidin-2-ylidene)methyl)triphenylphosphonium salts previously unknown. It has been shown that the interaction of available 1-acylamino-2,2-dichloroethenyltriphenylphosphonium chlorides with monoethanolamine leads only to formation of 4-phosphorylated 1,3-oxazole derivatives, which contain a residue of 2-hydroxyethylamine in position 5. Under similar conditions N-metylmonoethanolamine with 1-acylamino-2,2-dichloroethenyltriphenylphosphonium chlorides forms phosphorylated 2-methylen-1,3-oxazolidine derivatives, which contain the triphenylphosphonium group in the side chain. The structure of the new 2-R-5-(2-hydroxyethylamino)-1,3-oxazol-4-yltriphenyl- phosphonium perchlorates and (acylamino(3-methyl-1,3- oxazolidin-2-ylidene)methyl) triphenylphosphonium perchlorates has been reliably proven by elemental analysis, IR-, 1H NMR-, 13C-, 31P-spectroscopy and mass-spectrometry. In particular, derivatives of 1,3-oxazole have characteristic signals of carbon nuclei in 13C NMR-spectra, which appear as doublets due to the spin-spin interaction with a phosphorus nucleus. These signals are absent in 2-methylen-1,3-oxazolidine derivatives, but for these derivatives the signals of acylamino residues are characteristic. The synthetic method proposed is convenient and preparative since the transformation takes place in mild conditions to provide the final products with medium to high yields and does not require time-consuming purification operations of the final products.
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The synthesis and reactions of diacethyl(dialkoxycarbonyl) substituted hydroxycyclohexanones / A.I.Ismiyev, A.M.Maherramov, V.A.Sukach, M.V.Vovk
The literature sources concerning the importance of diacetyl (dialkoxycarbonyl) substituted hydroxycyclohexanones as highly functionalized carbocyclic compounds, on the one hand, as well as, on the other hand, the research prospects in the field of synthetic methods development based on these compounds for obtaining various heterocyclic systems have been generalized and systematized. It has been noted that the main method of the synthesis for diacetyl (diethoxycarbonyl) cyclohexanolones is diketone condensation of acetylacetone or ethyl acetoacetate with aldehydes in the presence of catalytic amounts of piperidine. An important useful peculiarity of this approach is a variation of the initial reagents, allowing modification of the substituents in a wide range. However, the dependence of selectivity and regiodirection of the reaction on various factors makes the studies in this area quite interesting and not always predictable. The phenomenon of keto-enol tautomerism of diacetyl substituted cyclohexanolones and factors that control stability of their enol form have been discussed. It has been concluded that reactions of these multicarbonyl compounds with ambident nitrogen-containing nucleophilic reagents are efficacious for the synthesis of new biologically promising representatives of carbofused heterocycles, such as isoxazoles, pyrazoles, triazolo[3,4-b] quinazolines, thieno[2,3-c]isoquinolines and pyrazolo[3,4-c]isoquinolines. The importance of oxidation, dehydration and aromatization processes of hydroxycyclohexanones for organic synthesis has been emphasized.
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The study of the quantitative content, gastro-resistance and related impurities in pantoprazole tablets
The quality control of pantoprazole tablets of foreign manufacture has been carried out by the method of reversephase HPLC. The quantitative determination, the assessment of gastro-resistance and the content of related impurities have been conducted. The test results are summarized in five Tables, and the chromatogram of pantoprazole test solution is shown in Fig. The quantitative determination of the active substance was performed by the external standard method. It has been found that the content of the substance in the medicine is 40.2 mg (100.5%), i.e. within the normal range. The gastro-resistance study demonstrated that after treating with decimolar solution of hydrochloric acid 0.4% of pantoprazole was dissolved. Thus, the medicine complies with the manufacturer’s specifications. Determination of related impurities was performed using the method of the reference solution (with the known concentration of the impurity for identified impurities) and comparing with a dilute solution of the active substance (for unidentified impurities). The solution for the system suitability test (containing pantoprazole and impurities – sulphone and sulphide), reference solutions (with the pantoprazole concentration of 0.1% and 1.0% of the test solution, respectively) and the test solution were prepared to determine the amount of impurities. Our studies have shown that pantoprazole tablets contain 0.17% of the identified and 0.10% of the unidentified impurities (the total content of all impurities is up to 0.27%). Thus, the pantoprazole parameters tested correspond to the regulatory requirements, and this medicine is safe for consumers.
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A convenient approach to the synthesis of new 4-amino substituted derivatives pyrido[2,3-d]pyrimidin-7-one
This paper is devoted to development of a convenient approach to the synthesis of new pyrido[2,3-d]pyrimidin-7-one derivatives that contain alkylamino groups at position 4 of the heterocycle. The interaction of 4,6-dichloropyrimidine-5-carbaldehyde with (2-ethoxy-2-oxoethyl) triphenylphosphonium bromide in ethanol in the presence of triethylamine leads to formation of ethyl (2E)-3-(4,6-dichloropyrimidin-5-yl)acrylate. Heat treatment of 6-amino substituted pyrimidinylacrylate derivatives with sodium methylate leads to the intramolecular cyclization and replacement of the chlorine atom with the methoxy group forming 4-methoxypyrido[2,3-d]pyrimidin-7-ones. In order to introduce various nitrogen-containing substituents at position 4 of the heterocyclic system the aforementioned compounds were converted into 4-chloropyrido[2,3-d]pyrimidin-7-one derivatives using phosphorus oxychloride. The effective method has been developed for the synthesis of a series of amino substituted pyrido[2,3-d]pyrimidin-7-one by a direct reaction of ethyl (2E)-(4-chloro-6-aminopyrimidin-5-yl)acrylate with the secondary amines in the presence of triethylamine. Then ethyl acrylate formed was treated by heating with sodium methylate in methanol. Sulphur-containing derivatives of pyrido[2,3-d]pyrimidin-7-one were also synthesized. These derivatives were used to obtain pyrido[2,3-d]pyrimidin-7-ones containing the secondary amines at position 4 of the heterocyclic system. The structure of the compounds obtained has been proven using NMR-spectroscopy, mass-spectra and elemental analysis -
Imidazo(pyrimidine)annelated pyrido[3,2-d]pyrimidine. the synthesis and prediction of the biological activity / I.V.Dyachenko, R.I.Vaskevich, A.I.Vaskevich, M.V.Vovk
The literature references concerning the biological activity of pyrido[3,2-d]pyrimidines and condensed polycyclic systems based on them have been systematized and analyzed. The main methods of the synthesis of polyheterocycles containing the pyrido[3,2-d]pyrimidine moiety have been summarized. The synthetic potential of the electrophilic intramolecular cyclization as a convenient tool for the directed design of azolo- and azinoannelated pyrido[3,2-d]pyrimidine structures has been found. Regiochemistry of annеlation of the functional fragment of 2-allyl(cinnamyl)aminopyrido[3,2-d]pyrimidines has been studied under the action of three types of electrophilic reagents: iodine, polyphosphoric acid and arylsulphenylchlorides. The correlations have been found between the nature of substrate, electrophile, reaction conditions and the direction of intramolecular cyclization. It has been found that cyclization of 2-allyl(cinnamyl)aminopyrido[3,2-d]pyrimidines in the presence of polyphosphoric acid leads to linear forms of imidazopyridopyrimidinon, while in the conditions of iodocyclization and arylsulfenylation the tricyclic imidazoannelated pyridopyrimidines of the angular structure are mainly formed. Regioselectivity of annelation of the 2-cinnamyl moiety of aminopyrido[3,2-d]pyrimidine has been found. In particular, treatment of 2-cinnamylaminopyrido[3,2-d]pyrimidine with arylsulphenylchlorides or polyphosphoric acid results in formation of the linear tetrahydropyrido[3,2-d]pyrimidines, and iodocyclization leads to an angular isomer. The virtual screening of the compounds synthesized has shown that they may potentially exhibit a wide range of bioactivity.
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Cyclosulfenylation of 3-allylthiohydantoin
New fused derivatives – 2-(arylsulfanylmethyl)-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazol-7-onium perchlorates have been synthesized by the cyclosulfenylation reaction of 3-allylthiohydantoin in highly polar nitromethane in the presence of an equimolar amount of lithium perchlorate as “doping-additive”. Their structures have been reliably proven by spectral characteristics. In particular, annelation of the tetrahydrothiazolonium cycle is confirmed by multiplet signals of diastereotopic protons of the CH2-group in position C3 at 3.87-4.04 ppm and the CH-group in position C2 at 4.67-4.77 ppm in 1H NMR-spectra. Thethiazolonium salts obtained were converted to the corresponding free bases – 2-(arylsulfanylmethyl)-2,3-dihydroimidazo[2,1-b] [1,3]thiazole-5(6H)-ones by the interaction with the aqueous solution of sodium acetate at the room temperature. According in their 1H NMR spectra, protons of CH-group in position 2 resonates in a stronger field (0.4-0.5 ppm) compared to the original substrates. Imidazothiazolonium perchlorates are labile to HN-nucleophiles, and under the action of the excess of the secondary amine (morpholine or piperidine) there is the disclosure of an amide bond in the imidazolidine cycle. It leads to formation of thiazolidine derivatives with arylsulfanyl fragments. Preservation of the thiazolidine nucleus in the process of opening the imidazole cycle has been confirmed by spectral characteristics of the compounds obtained. -
Biologically active compounds from the rhizomes of iris hungarica
Species of Iris genus (Iridaceae) have a long history of traditional medicinal use in different countries as alternative aperient, tonic, cathartic, diuretic, gall bladder diseases, liver complaints, dropsy, purification of blood, venereal infections, fever, bilious infections and for a variety of heart diseases. The rhizomes of Iris are the rich source of the secondary metabolites, in which flavonoids predominate. The clinical studies of substances from irises gave positive results in the treatment of cancer, bacterial and viral infections. Continuing the search of new biologically active compounds from the plants of Iridaceae family for the first time three isoflavones that are new for this species – irigenin, iristectorigenin B and its glucoside iristectorin B have been isolated from the ethanolic extract of the rhizomes of Iris hungarica Waldst. et Kit., which is widespread in Ukraine. The structure of the compounds is described as 5,7,3’-trihydroxy-6,4’,5’-trimethoxyisoflavone, 5,7,4’-trihydroxy-6,3’-dimethoxyisoflavone and iristectorigenin B-7-O-β-D-glucoside, respectively. The compounds were obtained from the ethyl acetate fraction of the iris rhizomes by column chromatography on silica gel with sequential elution of the chloroform – ethanol solvent with different concentrations. The structure of the compounds has been determined by chemical and spectral methods and in comparison with the literature data.
