Reaction of aminoquinolines with unsaturated carboxylic acids. 2. Cyclization of N-quinolyl-β-alanines

The cyclization of N-(3-quinolyl)- and N-(6-quinolyl)--alanines was carried out to give uncondensed hexahydropyrimidine derivatives, while the cyclization of N-(5-quinolyl)- and N-(8-quinolyl)--alanines gave tetrahydrophenanthrolinone derivatives.Communication 1, see ref. [1].Kaunas Technological University, 3028 Kaunas, Lithuania, Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 653–657, May, 2000.     

NMR Spectral Assignment of Per-substituted Key-Intermediates of β-Cyclodextrin and Implications in the Structures of the Derivatives

The compounds, 6-per-O-(t-butyldimethylsilyl)--cyclodextrin(1), 2,3-per-O-benzyl-6-per-O-(t-butyldimethylsilyl)--cyclodextrin(2), 2,3-per-O-benzyl--cyclodextrin (3),2,3,6-per-O-benzyl--cyclodextrin (4),2,3,6-per-O-benzoyl--cyclodextrin (5), are used as keyintermediates in the synthesis of selectively substituted -CD derivatives. Simple and assignable ¹H and ¹³C NMR spectra (chemical shifts and coupling constants) were obtained for compounds1–4 indicating C₇ symmetry, ⁴C₁ glucose conformation and major arrangement of H6, H6' atoms at the primary side. The derivative 5, however, gave very broad peaksat room temperature. The peaks could partially be assigned at 270 K, but the broadening was still present at 220 K. This implies that there exist several conformers of similar energyand C₁ symmetry that continuously interchange, since there is not a single type of stabilizing interaction thatpredominates. We attributed this phenomenon to the presence of the carbonyl group, which probablydisfavors - stacking and induces random arrangements of the aromatic rings.     

β,β-Dinitro derivatives ofN-alkyl-N′-alkoxydiazene-N-oxides

Methods of synthesis ofN-alkyl-N-alkoxydiazene-N-oxides containing a carbonyl group in the -position of alkyl or alkoxy radicals were developed. ,-Dinitro derivatives ofN-alkyl-N-alkoxydiazene-N-oxides were synthesized for the first timevia nitration of oximes obtained from the ketones.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1534–1538, August, 1995.     

Enhanced dissolution and oral bioavailability of α-tocopheryl esters by dimethyl-β-cyclodextrin complexation

Inclusion complexation of heptakis (2,6-di-O-methyl)--cyclodextrin (DM--CyD) with -tocopheryl acetate and -tocopheryl nicotinate in aqueous solution was studied by the solubility method. The aqueous solubilities of the esters were about 10⁵ times increased by DM--CyD complexation. The phase-solubility diagram of the tocopheryl ester-DM--CyD systems showed a typicalA _p type, and the stability constants (K) of high-order complexes were estimated by analyzing the upward curvature of the diagrams. The solid complex of -tocopheryl nicotinate with DM--CyD in a molar ratio of 12 was prepared by the kneading method. The dissolution rate of the solid complex was much greater than that of the drug itself, and the rapidly dissolving form of -tocopheryl nicotinate, as an example, showed a markedly increased bioavailability (about 70-fold) after oral administration to fasted dogs.     

Catalytic Behaviour of Carbonate β-CD Entrapped in PEEK-WC Membranes

O-octyloxycarbonyl cyclodextrins were immobilised in flat sheetPEEK-WC membranes. The membranes were prepared by phase inversion methodand characterised. cyclodextrin (CD) catalytic action in thep-nitrophenylacetate (PNPA) hydrolysis to p-nitrophenol (PNP) was studied. The CD acylic carbonate derivative shows an effective catalytic action whenincorporated in PEEK-WC membranes, by showing an enzyme-like behaviour. Themembranes were tested at different temperatures and substrate concentrations and thevalue of activation energy for the reaction was estimated. It is well known that CDhave a catalytic action, but their immobilisation in a polymeric matrix enhances thereaction rate, in fact the entrapment optimises the interaction with the substrate andincreases the chemical stability of the catalyst. In addition, CD show morestability when incorporated in the membrane, because of their chemical resistanceto alkaline attack.     

The effect of inclusion inβ-cyclodextrin on the chemistry of peroxides: Reactions of radicals withβ-cyclodextrin

Studies by electron paramagnetic resonance (EPR), differential scanning calorimetry, thermogravimetric analysis, HPLC and NMR showed that radicals produced by thermolysis and photolysis of benzoyl peroxide,t-butyl peroxide and cumene hydroperoxide included in-cyclodextrin (-CD), undergo significant reaction with the-CD. The formation of-CD radicals was observed by EPR. Products formed by addition of radicals to-CD were also observed. Such host:guest radical reactions explain the reported stabilization of peroxides, found with-CD inclusion, as being primarily due to the interruption of chain reactions by trapping of the chain carriers. A small increase in activation barrier for cleavage of the included peroxide in-CD was also observed.     

Effects of cyclodextrin on hydrolysis and the Smiles rearrangement of salicylic acid esters

The effect of -cyclodextrin (-CD) on aqueous hydrolysis of methyl,p-, andm-nitrophenyl salicylates as well as on the Smiles rearrangement ofp-nitrophenyl salicylate was studied. No effect of -CD on the pH-independent rate constant of aqueous hydrolysis of methyl ester was observed, while -CD accelerated aqueous hydrolysis of nitrophenyl esters byca. 10 times. The inclusion of these esters into the cavity of -CD is accompanied by a change in the mechanism of hydrolysis: free ester in the deprotonated form undergoes hydrolysis through the mechanism of intramolecular general base catalysis, while the ester bound to cyclodextrin is hydrolyzed due to the nucleophilic attack of the deprotonated hydroxyl group of -CD at a neutral substrate molecule. The effects of cyclodextrin on the rate constant of borate-catalyzed hydrolysis were interpreted by assuming that the substrate bound to -CD undergoes borate-assisted attack at the deprotonated cyclodextrin hydroxyl group. The Smiles rearrangement, which is an intramolecular nucleophilic substitution reaction, is accelerated in the presence of -CD.Translated fromlzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2658–2665, November, 1996.     

Condensation of 1-Substituted 5-Aminopyrazoles with β-Dicarbonyl Compounds

Condensation of N-substituted 5-aminopyrazoles with -diketones occurs with the formation of pyrazolo[4,5-b]pyridines. Depending on the conditions, their reaction with -keto acids can give either 6-oxo- or 4-oxopyrazolo[4,5-b]pyridines.     

Binding of vitamin A byβ-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin

Inclusion complexation of all-trans-retinol, retinal and retinoic acid with -cyclodextrin (-CD) and heptakis(2,6-O-dimethyl)--cyclodextrin (DM--CD) were investigated by means of UV-vis spectroscopy. The association constants (K _a) obtained for vitamin A with DM--CD is greater than with -CD. On the other hand, for the same host compoundK _a values of retinol, retinal and retinoic acid are very close to each other.     

Ring opening of fluoroalkyl-containing α,β-epoxyketones by aromatic amines

Aromatic amines cause ,-epoxyketones containing a -fluoroalkyl group to undergo ring opening at the -position to give -amino--hydroxyketones.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 882–883, May, 1994.     

Improvement of Solubility and Dissolution of 19-Norprogesterone via Inclusion Complexation

In an effort to modify the solubility and dissolution rate of the contraceptive steroid, 19-norprogesterone in order to improve its bioavailability, the cyclodextrin complexation approach was chosen. In solution, the complex formation with -cyclodextrin (-CD), hydroxyethyl -cyclodextrin (HE--CD) and hydroxypropyl -cyclodextrin (HP--CD) was confirmed by using solubility, UV, IR and ¹H-NMR spectrophotometric techniques. The phase solubility diagrams were categorized as A_L-type. The complexing affinity of the CDs investigated were ranked as follows: -CD > HP--CD > HE--CD. The complexation thermodynamic parameters were obtained from the temperature dependence of the dissociation constants. In the solid state, differential scanning calorimetery (DSC) and optical microscopy methods were utilized to characterize the complexes. Dissolution studies showed that such molecularly encapsulated forms offered a marked improvement in the dissolution rate compared to the parent drug.     

Cyclization of O-benzoyl-β-piperidinopropionamidoximes to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles

The reactions of -piperidinopropionamidoxime with substituted benzoyl chlorides afforded O-benzoylation products, which underwent cyclization to form 5-phenyl-3-(-piperidino)ethyl-1,2,4-oxadiazoles upon heating in dimethylformamide in the presence of molecular sieves at 60 °C for 1—2.5 h. Heating of O-benzoyl--piperidinopropionamidoxime in dimethylformamide in the presence of K₂CO₃ at 85 °C for 4 h afforded a mixture of 5-phenyl-3-(-piperidino)ethyl-1,2,4-oxadiazole, benzoic acid, and N-(-piperidino)ethylurea.     

The effect of mechanical grinding on the formation and crystallinity changes of the inclusion complex of acetaminophen andβ-cyclodextrin

The effect of mechanical grinding on the physicochemical properties of acetaminophen in the presence of three additives,- or-cyclodextrin and microcrystalline cellulose, was studied by using TLC, powder X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry. The results indicate that the crystallinity of physical mixtures of acetaminophen and the described additives decreased with increased grinding time and formed an amorphous state when mixtures containing- or-cyclodextrin were ground with acetaminophen. We also found that the acetaminophen molecules could be included step-by-step into the cavity of-cyclodextrin molecules and formed an amorphous inclusion complex.-Cyclodextrin and microcrystalline cellulose did not form an inclusion complex with acetaminophen, but acted only to decrease the crystallinity of the ground mixtures. The mechanical grinding efficiency for acetaminophen was improved in the order of-cyclodextrin -cyclodextrin > microcrystalline cellulose.This paper is part XI of Drug Interaction in Pharmaceutical Formulations.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Release Rate of Metoprolol from Ternary Metoprolol/2-hydroxypropyl-β-cyclodextrin/Ethylcellulose Tablets

The effect of 2-hydroxypropyl--cyclodextrin (HP--CyD) on the release of a water-soluble ₁-selective adrenoreceptor antagonist, metoprolol (Met), from ternary Met/HP--CyD/ethylcellulose (EC) tablets was investigated. The release rate of Met from the ternary tablets was dependent on amounts of HP--CyD in the tablets, i.e., the rate decreased when small amounts of HP--CyD were added, while large amounts of HP--CyD accelerated the rate. The slowest rate was observed for the tablet consisted of a 30/10/60 weight ratio of Met/HP--CyD/EC. The analyses of the release rates by the Korsmeyer equation and their temperature dependence suggested that Met is released from the EC matrix containing HP--CyD according to the diffusion-controlled mechanism. The water penetration studies and the micro- and macroscopic observations suggested that the retarding effect of HP--CyD is attributable to a viscous gel formation in small pores on the surface of the tablets, where HP--CyD gels may work as a barrier for the water penetration into the tablets and the release of the drug from the tablets. The in-vitro release property of the ternary tablets was reflected in the in-vivo absorption profile in dogs. The results indicated that a combination of HP--CyD and EC is useful for the release control of water-soluble drugs such as Met.     

Improved synthesis of 6-deoxy-1,2-O-isopropylidene-β-L-talofuranose and 6-deoxy-1,2-O-isopropylidene-β-L-idofuranose

Summary The key step in the preparation of 6-deoxy-1,2-O-isopropylidene--L-talofuranose (7) and 6-deoxy-1,2-O-isopropylidene--L-idofuranose (13) is the selective exchange of the 6-O-mesyl rest of 3-O-acetyl-5,6-O-dimesyl-1,2-O-isopropylidene--D-allofuranose (4) and 3-O-acetyl-5,6-O-dimesyl-1,2-O-isopropylidene--D-glucofuranose (10) by acetate group (potassium acetate/18-crown-6).

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Ein neuartiger und präparativ nützlicher Zugang zu 6-Desoxy-1,2-O-isopropyliden--L-talofuranose und 6-Desoxy-1,2-O-isopropyliden--L-idofuranose

Zusammenfassung Schlüsselschritt bei der Herstellung von 6-Desoxy-1,2-O-isopropyliden--L-talofuranose (7) und 6-Desoxy-1,2-O-isopropyliden--L-idofuranose (13) ist der selektive Austausch der primären Mesyl-Gruppe in 3-O-Acetyl-5,6-O-dimesyl-1,2-O-isopropyliden--D-allofuranose (4) und 3-O-Acetyl-5,6-O-dimesyl-1,2-O-isopropyliden--D-glucofuranose (10) durch den Acetat-Rest in Gegenwart von Kaliumacetat/Kronen-Ether.

     

Factors affecting the formation in the solid state of the metastable complex between naphthalene and dimethyl-β-cyclodextrin

An equimolar mixture of naphthalene and amorphous heptakis-(2,6-di-O-methyl)--cyclodextrin (DMCD) was heated at 70 or 90°C in a sealed container. After heating ffor 15 min at 90°C, the mixture was crystallized to show an excimer fluorescence of naphthalene, and the fluorescence spectrum changed to a monomer emission by further prolongation of heating time, accompanied by a slight change in its powder X-ray diffractogram. It is suggested that a metastable complex showing the excimer emission of naphthalene was transformed to a stable complex showing the monomer emission. The mixing molar ratio of naphthalene to DMCD was also found to affect the transformation temperature of the complex.     

Reduction of photohemolytic activity of benoxaprofen byβ-cyclodextrin complexations

Inclusion complexations of benoxaprofen (BXP) with-cyclodextrin (-CyD) and heptakis (2,6-di-O-methyl)--CyD (DM--CyD) were studied by the solubility method and CD and¹H-NMR spectroscopy. Both -CyDs decelerated the photodecarboxylation of BXP, and suppressed the BXP-photosensitized hemolysis, where the inhibitory effect of DM--CyD was larger than that of -CyD. This order was well correlated with the magnitude of the stability constants of BXP--CyD complexes. The peroxidation of lipid components in erythrocyte ghosts induced by BXP was also suppressed particularly by DM--CyD. The protective effect of -CyDs on the BXP-induced photohemolysis seems to be due to the suppression in the photochemical reactions of BXP yielding toxic transient species, together with the inhibition in attacks of the transient species to the membrane, through inclusion complexation.     

Trans-cis Photoisomerization of 1-Methyl-4-(4′-hydroxystyryl)pyridinium in inclusion complexes ofβ-cyclodextrin and its derivatives

The effects of -cyclodextrin (-CyD), heptakis(2,6-di-O-methyl)--cyclodextrin (DMCyD) and heptakis(2,3,6-tri-O-methyl)--cyclodextrin (TMCyD) ontrans-cis photoisomerization of 1-ethyl-4-(4-hydroxystyryl)pyridinium (POH) have been studied in aqueous solutions. The ratio of [cis]/[trans] for POH in the photostationary state at pH 8.54 was remarkably reduced by the presence of CyD or DMCyD. The reduction of the [cis]/[trans] ratio in the photostationary state was explained in terms of the shift of the equilibrium of POH ₊ ^trans PO _trans + H^– toward PO _trans formation. The binding constants of CyD and DMCyD for PO _trans were 2.00- and 1.36-fold larger than those for POH ₊ ^trans , respectively. The binding constants of TMCyD for both species are much smaller than those of CyD and DMCyD. This result indicates that PO _trans , which has a betain structure, forms stable complexes with CyD and DMCyD with its hydrophobic parts inside and the charged parts outside the CyD cavities.     

Enantiomer separations with chromatographic supports based on β-cyclodextrin polymers immobilized on porous silica. Role of the polymer structure in separating ability

Summary Two -cyclodextrin (-CD)-containing polymers have been prepared either by condensation of -CD molecules with a bifunctional reagent or by grafting a -CD derivative on to a linear polymer (polyvinylimidazole). HPLC stationary phases were obtained by adsorption of the -CD polymers on to silica. The ability of these chromatographic supports to resolve racemic mixtures of organic compounds such as amino acid derivatives, phenylhydantoins, barbiturates, and hydroxycoumarin derivatives has been investigated. Results were found to depend on the chemical structure of the -CD polymers     

Binding forces in complexation ofp-alkylphenols withβ-cyclodextrin and methylatedβ-cyclodextrins

Fluorescence spectroscopy has been used to determine the binding constants (K) for inclusion complexes of six kinds ofp-Akyphenols with-cyclodextrin (-CDx), heptakis(2,6-di-O-methyl)--CDx (DMe--CDxg), and heptakis(2,3,6-tri-O-methyl)--CDx (TMe--CDx). The stability of the inclusion complex of each cyclodextrin increases with increasing alkyl chain length of thep-alkylphenol. TheK values decrease in the order of DMe--CDx,-CDx, and TMe--CDx for each guest. In complexation of 3-(p-hydroxyphenyl)-1-propanol (3) with-CDx as well as with DMe--CDx, negative enthalpy (H) and positive entropy changes (S) have been obtained, suggesting both van der Waals and hydrophobic interactions as binding forces. The inclusion of 3 by TMe--CDx, however, is an enthalpically favorable but entropically unfavorable process. The van der Waals interactions may be the main binding forces for complexing3 with TMe--CDx.