Pharmaceutical Chemistry Journal (v.46, #5)

Synthesis and anxiolytic activity of 2-aminoadamantane derivatives containing monoterpene fragments by I. G. Kapitsa; E. V. Suslov; G. V. Teplov; D. V. Korchagina; N. I. Komarova; K. P. Volcho; T. A. Voronina; A. I. Shevela; N. F. Salakhutdinov (263-265).
Two new amines were synthesized from 2-aminoadamantane and the available monoterpenoid aldehydes citral and (–)-myrtenal. It was established that the synthesized amines possessed anxiolytic activity.
Keywords: 2-aminoadamantane; citral; (–)-myrtenal; terpenoids; anxiolytic activity

Synthesis and antimicrobial activity of quaternary ammonium, pyridinium, and morpholinium tetrachloroferrates by E. V. Kharitonova; O. E. Zhuravlev; V. M. Chervinets; L. I. Voronchikhina; M. A. Demidova (266-268).
Quaternary ammonium, pyridinium, and morpholinium tetrachloroferrates were prepared. The structures of the salts were confirmed using IR and visible spectroscopy. The antimicrobial activity of the synthesized compounds against several strains of Gram-positive and Gram-negative microorganisms and yeast-like fungi was studied.
Keywords: tetrachloroferrates; antimicrobial activity; ionic liquids

Analgesic activity of 4-aryl-8(arylmethylene)-5,6,7,8-tetrahydrospiro[chromen-3,1'-cycloalkan]-2(4H)-ones by N. F. Kirillov; R. R. Makhmudov; A. G. Gavrilov; L. G. Mardanova (269-270).
4-Aryl-8-(arylmethylene)-5,6,7,8-tetrahydrospiro[chromen-3,1'-cyclopentan]-2(4H)-ones, 4-aryl-8-(arylme-thylene)-5,6,7,8-tetrahydrospiro[chromen-3,1'-cyclohexan]-2(4H)-ones, and 4-aryl-8-(arylmethylene)5,6,7,8-tetrahydrospiro[chromen-3,1'-cycloheptan]-2(4H)-ones were prepared via the reaction of methyl 1-bromocycloalkanecarboxylates, zinc, and 2,6-bis-(arylmethylene)cyclohexanones. The synthesized compounds exhibited analgesic activity and low toxicity.
Keywords: analgesic activity; spiro-3,4-dihydro-2H-pyran-2-ones; spirotetrahydrochromenones

Synthesis and neurotropic activity of new condensed pyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives by V. V. Dabaeva; M. R. Bagdasaryan; A. S. Noravyan; I. A. Dzhagatspanyan; I. N. Nazaryan; A. G. Akopyan (271-273).
Methods for the synthesis of derivatives of new pyrano[3",4":5',6']pyrido[3',2':4,5]thieno[3,2-d ]pyridimdine heterosystems based on 4-oxo-7,8-dihydro-2,8,8-trimethyl-10H-pyrano[3',4':5,6]pyrido[3,2:4",5"]thieno[3",2"-d]oxazine[3,1] were developed. The neurotropic activity of the synthesized compounds was investigated.
Keywords: synthesis; pyrido[3',2':4,5]thieno[3,2-d ]pyrimidine; neurotropic activity

5-HT6 Receptor antagonists. I. Screening of the library of various heterocyclic compounds containing an alkylsulfonyl moiety by A. V. Ivachtchenko; E. S. Golovina; M. G. Kadieva; O. D. Mitkin; S. E. Tkachenko; I. M. Okun (274-284).
High-throughput screening of a specific set (focused library) of heterocyclic compounds containing an alkylsulfonyl moiety (a total of 2827 compounds from 78 combinatorial libraries) was performed in order to discover highly effective 5-HT6 receptor antagonists. The screening identified several compounds that exhibited pronounced inhibiting properties for 5-HT6 receptors that enabled them to be used to develop new highly effective drugs for treating central nervous system disturbances. The structures of most antagonists corresponded to the PhM2 pharmacophore model, which confirmed its potential in the search for effective 5-HT6 receptor antagonists. It was established that the structure of the substituent introduced in the vicinity of the sulfonyl moiety in the PhM2 ligands could affect their pharmacological activity, including the ability to block serotonin-induced 5-HT6 receptor-mediated cell responses. In particular, bulky electron-donating substituents decreased the activity whereas a methylamino group increased statistically significantly the 5-HT6 antagonistic activity. Based on these findings, a new pharmacophore model for 5-HT6 antagonists, PhM3, was proposed. It was shown that compounds from the combinatorial libraries with a sulfonyl moiety separated from the heterocyclic and/or aromatic moiety by one (or more) methylenes and heterocyclic compounds containing an alkylsulfonyl moiety or endocyclic sulfonyl, (5-aryl-sulfonyl-3H-[1,2,3]triazol-4-yl)amines, and azoles substituted simultaneously by arylsulfonyl and alkylsulfonyl moieties all had low hit rates and were not promising for discovery of new 5-HT6 receptor antagonists.
Keywords: high-throughput screening; heterocyclic compounds; sulfonyl moiety; serotonin receptor antagonists; pharmacophore model of 5-HT6 receptor ligands; cAMP; cell-based assay

Development of nimodipine production technology by A. N. Balaev; V. N. Osipov; V. E. Fedorov (285-287).
The technology for production of nimodipine drug substance based on cyclocondensation of 1-methylethyl-3-aminocrotonate and 2-methoxyethyl-2-(3-nitrobenzylidene)acetoacetate in isopropyl alcohol in the presence of HCl was developed. 1-Methylethyl-3-aminocrotonate was produced by reaction at 3 – 5°C of 1-methylethylacetoacetate with NH3 dissolved in isopropyl alcohol. 2-Methoxyethyl-2(3-nitrobenzylidene)acetoacetate was synthesized by condensation of 3-nitrobenzaldehyde and 2-methoxyethylacetoacetate.
Keywords: nimodipine; manufacturing process; production

The possibility of using Nucleodex beta-PM and Chiralcel OJ-RH chiral columns for the separation of isomers of butylhydroxyanisole and isosorbide mononitrate was studied. Chromatography over the Chiralcel OJ-RH column (150 × 4.6 mm, 5 μM) using mobile phases MeOH:H2O (80:20) and CH3CN:H2O (70:30) provided the complete separation of the 3-and 2-isomers of butylhydroxyanisole. In contrast, the separation of isosorbide mononitrate isomers over chiral columns of Nucleodex beta-PM and Chiralcel OJ-RH was not as effective. The observed separations of the 2-and 5-isomers of isosorbide mononitrate were less than over C18 and C10CN columns. Only the ability in principle of using a Nucleodex beta-PM column to separate isosorbide mononitrate isomers was demonstrated.
Keywords: HPLC; chiral column; isosorbide mononitrate; butylhydroxyanisole

Adsorption capacity of hydroxyapatite for several amino acids and heavy metal ions by A. S. Berlyand; A. P. Snyakin; A. A. Prokopov (292-294).
The adsorption capacity of hydroxyapatite for several amino acids and heavy metal ions was investigated. The quantitative characteristics and laws of adsorption were determined. Possible adsorption mechanisms were discussed.
Keywords: hydroxyapatite; adsorption capacity; amino acids; heavy metal ions

Development of antivaricose gel technology by M. B. Sapozhkova; T. P. Kalmykova; S. N. Suslina (295-298).
A technological scheme for producing an antivaricose gel containing a combination of grape leaf extract and heparin has been developed based on results of an investigation of the properties of the active ingredients and excipients. The scheme can be included into technical documentation for manufacturing the proposed gel.
Keywords: varicosity; antivaricose gel; grape leaf extract; heparin

Development of a lyophilized dosage form of cifelin by E. A. Kotova; E. V. Ignat’eva; O. L. Orlova; I. I. Krasnyuk; N. A. Oborotova (299-302).
Freshly prepared liposome dispersions have a limited shelf-life, which hinders large-scale production with subsequent storage and sales to patients. This article addresses the development of a cifelin freeze-dried pegylated liposomal form. The effects of various cryoprotectors (glucose, sucrose, lactose, and mannitol) on the hydrophobic drug entrapment efficiency and its size change in the liposome membrane during storage were studied. The best results were obtained using sucrose with an optimum lipid:cryoprotector ratio of 1:1.4. Quality parameters such as vesicle size, pH value, and cifelin entrapment efficiency for the resulting freeze-dried liposomal dosage form remained unchanged during the studied storage time.
Keywords: liposomes; lyophilization; cifelin; cryoprotector; vesicle size; storage stability

Investigation of the stability and efficacy of iodine-containing drugs in solid dosage forms by O. S. Sablina; L. V. Levchuk; A. A. Tumashov; A. S. Gavrilov (303-305).
The stability and efficacy of iodine-containing caramels were investigated. In the case of a caramel containing potassium iodide, iodine losses during three months of storage at 60 °C did not exceed 7.9 %. Preclinical trials showed that use of this caramel increased the urinary iodine level to a greater extent than did reference iodine-containing tablets. Clinical trials with caramel showed a statistically significant increase in the median urinary iodine level up to 126.1 μg/L in primary school children against an initial level of 97.1 μg/L (p < 0.05).
Keywords: iodine stability; caramel; iodine deficiency

Production of rifampicin-containing microcapsules based on apple pectin complexes with β-lactoglobulin by Z. K. Mukhidinov; G. F. Kasymova; S. R. Usmanova; K. B. Murzagulova; M. E. Kim; A. V. Yanovich (306-309).
The two-stage production of microcapsules based on high- (HM) and low-methylated (LM) apple pectin complexes with milk serum β-lactoglobulin concentrate in an oil—water emulsion was developed. It was established that the ability of the pectin chains to form an effective secondary layer on the protein molecules surrounding the oil drops depended on the molecular weight and structure of the pectin. The obtained emulsions with HM- and LM-pectins and various pectin:protein ratios were capable of forming microcapsules of various sizes and different rifampicin contents. The proposed microcapsules could be used as potential drug carriers.
Keywords: microcapsules; high- and low-methylated apple pectin; preparation method

Modern approaches to investigation of new excipients for tablet drug technology by N. A. Polyakov; L. V. Zrelova; M. M. Astrokhanova; V. A. Dubinskaya (310-312).
Aquametric and thermodynamic characteristics of the new excipients lactose 80 m, agglomerated lactose (tablettose 80), and microcellulose 101 – 200 were studied. Microcellulose 101 – 200 was more hygroscopic than both lactose derivatives at all values of relative humidity. Lactose 80 m and tablettose 80 had different thermodynamic characteristics that were probably explained by differences in the technology of raw material production. Comparative analysis of trace elements in the studied excipients by atomic absorption spectroscopy (AAS) and x-ray fluorescence (XRF) methods was carried out. Both methods gave comparable results but XRF gave high reproducibility and did not require long sample preparation. The toxicological safety of the analyzed compounds was established.
Keywords: excipients; aquametric and thermodynamic characteristics; trace elements; differential scanning calorimetry; atomic absorption spectroscopy; x-ray fluorescence spectroscopy

An improved synthesis of trantinterol by H. Wen; L. Qin; L. Pan; J. Li; M. Cheng (313-315).
An efficient synthesis of 2-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-t-butylamino-ethanol (trantinterol), a selective β2-adrenoceptor agonist, has been achieved from inexpensive and commercially available starting material. The synthesis involves the conversion of aryl iodide to aldehyde catalyzed by PdCl2(dppf) as a key step.
Keywords: Trantinterol; synthesis; palladium catalyzed carbonylation

The synthesis of 4,3-dihydro, 5-phenyl,4-(1 H-indolyl)-3-(3′4′5′-substituted pyrazole/oxazole) derivatives from [(3-phenyl-4,5-dihydro-5-substituted phenyl)-1 H-pyrazole/oxazole]-1 H-indolyl and [(3-phenyl-4,5-dihydro-5-substituted phenyl-1 H-pyrazole/oxazole]-1 H-(3-substituted indolyl) is described. The structures of the synthesized compounds have been established by elemental analysis and IR, 1 H NMR, and mass spectroscopy. The synthesized compounds have been tested against reference microbial strains, and most tests showed excellent results.
Keywords: Antibacterial activity; antifungal activity; chalcone precursor; isoxazole synthesis; pyrazole synthesis

Thin-layer chromatography characteristics of β-carotene by O. V. Checheta; E. F. Safonova; A. I. Slivkin (321-323).
The optimum conditions for chromatographic determination of β-carotene were established. The potential of a theoretical approach to choosing the TLC conditions for determining β-carotene was demonstrated.
Keywords: β-carotene; thin-layer chromatography.