- Increased shelf-life of fosphenytoin: Solubilization of a degradant, phenytoin, through complexation with (SBE)(7m)-β-CD
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Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values -1 at pH 7.4 and pH 8.0, respectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)(7m)-β-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41-45 M-1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 °C in the presence of 0.03 or 0.06 M (SBE)(7m)-β-CD. It was projected from the solubility of phenytoin and the kinetic information that fosphenytoin shelf lives as high as nine years at 25 °C and pH 7.4 in the presence of 60 mM of (SBE)(7m)-β-CD might be possible while longer shelf lives might be possible at pH 8.
- Narisawa, Shinji,Stella, Valentino J.
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- Phenytoin prodrugs IV: Hydrolysis of various 3-(hydroxymethyl)phenytoin esters
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The aqueous chemical stability of various bioreversible derivatives or prodrugs of phenytoin, a poorly water-soluble and erratically absorbed drug after both oral and intramuscular parenteral dosing, were evaluated. This study, together with assessments of other physicochemical properties including cleavage in the presence of various animal tissues and anticonvulsant activity in mice, helped identify a number of promising candidate prodrugs. Various amino groups containing acyl esters of 3-(hydroxymethyl)phenytoin [3-(hydroxymethyl)-5,5-diphenylhydantoin] were identified as potential orally and perhaps parenterally useful prodrugs, while the disodium phosphate ester of 3-(hydroxymethyl)phenytoin appears to be ideally suited as a parenteral form of phenytoin.
- Varia,Schuller,Stella
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- Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin
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Glycine, which has weak anticonvulsant properties, has been shown to potentiate the activity of several antiepileptic drugs but not phenytoin. Recently, studies have shown that N-(benzyloxycarbonyl)glycine (Z-glycine) antagonized seizures more than glycine in addition to possessing activity in the maximal electroshock test, a convulsive model in which glycine is inactive. In the present study esters of 3-hydroxymethylphenytoin, a phenytoin prodrug, and Z-glycine as well as the homologous N-(benzyloxycarbonyl)-ω-amino acids, z-β-alanine and Z-γ-aminobutyric acid (Z-GABA), were prepared and tested for their anticonvulsant and acute neurotoxic activities. The phenytoin prodrugs were obtained by esterification of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride-mediated esterification of 3-hydroxymethylphenytoin with the respective N-benzyloxycarbonyl-protected amino acid. The Z-glycine-phenytoin ester was the most active anticonvulsant derivative. Compared with phenytoin the compound exhibited a decreased median effective dose (ED50) in the MES test and an increased median toxic dose (TD50), resulting in an significantly improved protective index expressed as the ratio between TD50 and ED50. The present data suggest that covalent binding of phenytoin to Z-glycine results in an improved pharmacological profile of the drug.
- Scriba, Gerhard K. E.,Lambert, Didier M.
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- Synthesis of a novel phenytoin derivative: Crystal structure, Hirshfeld surface analysis and DFT calculations
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Hydantoin compounds are important heterocyclic scaffolds and a class of well-known bioactive molecules with a broad spectrum of pharmacological properties. Consequently, considerable efforts have been devoted to the design and synthesis of a broad range of hydantoin derivatives. In this context, the compound 3-allyl-5,5-diphenylimidazolidine-2,4-dione, C18H16N2O2 (3ADID) was synthesized and its structure was determined by X-ray structure analysis. Further, the molecular structure was examined using Hirshfeld topology analysis and Density Functional Theory (DFT)-B3LYP calculations with the basis set 6–311++G (d,p). In the title molecule, C18H16N2O2, the imidazolidine ring is planar with the allyl substituent oriented nearly perpendicular to it. In the crystal, hydrogen bonded chains of molecules are arranged in sets of three about the 32 axes by C–H···π (ring) interactions. Hirshfeld surface map and 2D fingerprint plots were used to explore intermolecular interactions. The optimized geometry, global reactivity descriptors, and HOMO-LUMO orbitals of the molecule were computed by DFT and discussed. To evaluate the chemical reactivity and charge distribution on the molecule, molecular electrostatic potential (MEP) and atomic charges, computed by Mulliken population analysis and NBO theory were determined. The local reactivity was examined by determining the Fukui functions and dual descriptor indices. DFT calculations at the same level of theory, with the POP[dbnd]NBO keyword, were used to evaluate charge delocalization and hyperconjugative interactions through Natural Bond orbital analysis.
- Guerrab, Walid,Lgaz, Hassane,Kansiz, Sevgi,Mague, Joel T.,Dege, Necmi,Ansar,Marzouki, Riadh,Taoufik, Jamal,Ali, Ismat H.,Chung, Ill-Min,Ramli, Youssef
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- Experimental and theoretical study of bidirectional photoswitching behavior of 5,5′-diphenylhydantoin Schiff bases: Synthesis, crystal structure and kinetic approaches
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Herein, the synthesis and characterization of four novel 5,5′-diphenylhydantoin Schiff bases containing different aromatic species are presented. Their structure-property relationship was studied by X-ray, optical and electrochemical methods as well as DFT calculations in terms of their E/Z photoisomerization and enol/keto phototaumerization. The big challenge in photoinduced motion is achieving control and stability over the two isomers. Solvent-driven bidirectional photoswitching behavior was studied in nonpolar 1,4-dioxane and polar aprotic DMF. T-type photochromism in 1,4-DOX and opposite behavior in DMF as P-type switches (bistable system) were observed. The obtained results lead to a conclusion that by variation of the solvent environment a direct control over the bidirectional switching behaviour from T-type to P-type can be achieved.
- Georgiev, Anton,Georgieva, Stela,Peneva, Petia,Rusew, Rusi,Shivachev, Boris,Todorov, Petar
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p. 15081 - 15099
(2020/10/02)
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- Method for preparing phenytoin sodium
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The invention relates to the field of biological medicines, and discloses a method for preparing phenytoin sodium. The method is characterized by comprising the following steps: (1) carrying out an oxidation reaction on benzoin in a first solvent to obtain diphenyl ethanedione, wherein the first solvent is a mixed solution of an alcohol and water, and the alcohol is at least one selected from C1-C3 monohydric alcohols; (2) carrying out a rearrangement reaction on diphenyl ethanedione to obtain phenytoin; and (3) carrying out salt forming reaction on the phenytoin in water, and performing purifying to obtain the phenytoin sodium. According to the method provided by the invention, few solvent systems are introduced, acetic acid is prevented from being used, subsequent treatment is relativelysimple, and the prepared phenytoin sodium is relatively high in yield and purity and is convenient to large-scale production.
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- Method for preparing phenytoin sodium in mixed crystal form
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The invention provides a method for preparing phenytoin sodium in a mixed crystal form. The method comprises the following steps of 1) preparing phenytoin: taking a reaction kettle, adding water and diphenyl ethanedione, adjusting to be alkaline, adding urea, heating to reflux, filtering after the reaction is finished, dropwise adding concentrated hydrochloric acid, crystallizing, stirring, carrying out centrifugal filtration, washing a filter cake with water, discharging to obtain a phenytoin crude wet product, pulping, carrying out centrifugal filtration, and discharging to obtain a phenytoin wet product, and 2) preparing phenytoin sodium: taking another reaction kettle, put the phenytoin wet product in the reaction kettle, adding water, heating, dropwise adding a sodium hydroxide solution, adjusting the pH value, decolorizing, finely filtering, cooling to room temperature, stirring, crystallizing, carrying out centrifugal filtration, washing a filter cake, drying the washed solid, and discharging to obtain the mixed crystal form phenytoin sodium. According to the phenytoin sodium prepared by the preparation method, the mixed crystal proportion of the anhydrous substance and themonohydrate is consistent with the mixed crystal proportion of a reference preparation, and tablets prepared from the mixed crystal phenytoin sodium produced by the method can be consistent with the reference preparation in in-vitro dissolution and in-vivo bioequivalence.
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Paragraph 0046-0049
(2020/07/15)
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- Synthetic method of phenytoin sodium
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The invention relates to a synthetic method of phenytoin sodium, belonging to the technical field of biomedicine. The synthetic method of the phenytoin sodium comprises the following steps of oxidation reaction, condensation reaction and salt formation reaction, wherein a amidation reaction process is promoted through adding a phase transfer catalyst 4-dimethylamiopryidine in the condensation reaction; a two-phase system of n-butanol and water is adopted, so that the generation of diphenylacetylene diurea is greatly inhibited, and reaction time is obviously shortened; ethanol serves as a solvent in the salt formation reaction, after a sodium hydroxide ethanol solution reacts with phenytoin, cyclohexane with defective solvent ice is added to promote the phenytoin sodium to precipitate as white crystal, and compared with the salt formation reaction with water as a solvent, the phenytoin sodium is faster in precipitation rate and high in precipitation degree and purity.
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- Oxidation of Thioamides to Amides with Tetrachloro- and Tetrabromoglycolurils
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Tetrabromo- and tetrachloroglycolurils have been shown to act as good oxidants capable of converting thioamides to the corresponding amides. This approach offers such advantages as good yields (81–99%), short reaction times (10–25 min), simple workup procedure, and environmental safety.
- Arrous, S.,Boudebouz, I.,Parunov, I. V.
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p. 1874 - 1877
(2020/02/03)
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- Hydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains
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Proteolysis mediated by ClpXP is a crucial cellular process linked to bacterial pathogenesis. The development of specific inhibitors has largely focused on ClpP. However, this focus was challenged by a recent finding showing that conformational control by ClpX leads to a rejection of ClpP binders. Thus, we here follow up on a hit molecule from a high throughput screen performed against the whole ClpXP complex and demonstrate that stable inhibition with high potency is possible. Further investigations revealed that the small molecule binds to ClpP without affecting its activity. Likewise, the molecule does not inhibit ClpX and retains the overall oligomeric state of ClpXP upon binding. Structure activity relationship studies confirmed structural constraints in all three parts of the molecule suggesting binding into a defined stereospecific pocket. Overall, the inhibition of ClpXP without affecting the individual components represents a novel mechanism with perspectives for further optimization for in situ applications.
- Fetzer, Christian,Korotkov, Vadim S.,Sieber, Stephan A.
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supporting information
p. 7124 - 7127
(2019/08/07)
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- Magnetic magnetite nanoparticals catalyzed selective oxidation of Α-hydroxy ketones with air and one-pot synthesis of benzilic acid and phenytoin derivatives
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A clean and efficient protocol for selective oxidation of α-hydroxy ketones using magnetic magnetite nanoparticals (Fe3O4·MNPs) as catalyst with air as green oxidant has been developed. Application of Fe3O4·MNPs was also proved to be successful in one-pot synthesis of benzilic acid and phenytoin derivatives. The facile one-pot procedure enhanced the production efficiency, shortened the reaction time and minimized the chemical waste. Notably, the catalyst can be reused at least for five times without any appreciable loss of its activity.
- Li, Xiaona,Xia, Dandan,Wen, Zhiyong,Gong, Bowen,Sun, Maolin,Wu, Yue,Zhang, Jie,Sun, Jun,Wu, Yang,Bao, Kai,Zhang, Weige
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- Facile access to polymer supported zinc–salen complex: highly efficient heterogeneous catalyst for synthesizing hydantoins, thiohydantoins and Schiff bases in aqueous medium
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The synthesis of polymer supported zinc–salen complex (PS-Zn–salen) is described. The mononuclear zinc(II)–salen complex was characterized by Fourier-transform NMR spectroscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectrophotometry (FT-IR), thermogravimetric analysis, scanning electron microscopy, surface area and pore size distribution by Brunauer–Emmett–Teller. The synthesized PS-Zn–salen complex used as a recyclable heterogeneous catalyst for the efficient synthesis of hydantoins, thiohydantoins and Schiff bases in an aqueous medium. The isolated yields of hydantoins, thiohydantoins and Schiff bases achieved up to 89, 95 and 94%, respectively. In spite of conventional heterogeneous catalysts, current PS-Zn–salen complex shows thermal stability up to 280?°C. Moreover, the catalyst could be recovered easily by simple filtration and reused for next run with slightly declining its activity up to six successive runs. The FT-IR spectrum of recycle catalyst after 6th run confirmed that the catalyst was stable during the course of a reaction. The leaching of metal from the PS-Zn–salen is negligible, which was confirmed by AAS and hot filtration test.
- Balinge, Kamlesh Rudreshwar,Khiratkar, Avinash Ganesh,Muskawar, Prashant Narayan,Thenmozhi,Bhagat, Pundlik Rambhau
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p. 2075 - 2097
(2017/12/26)
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- Novel prodrugs with a spontaneous cleavable guanidine moiety
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Water-soluble prodrug strategy is a practical alternative for improving the drug bioavailability of sparingly-soluble drugs with reduced drug efficacy. Many water-soluble prodrugs of sparingly-soluble drugs, such as the phosphate ester of a drug, have been reported. Recently, we described a novel water-soluble prodrug based on O–N intramolecular acyl migration. However, these prodrug approaches require a hydroxy group in the structure of their drugs, and other prodrug approaches are often restricted by the structure of the parent drugs. To develop prodrugs with no restriction in the structure, we focused on a decomposition reaction of arginine methyl ester. This reaction proceeds at room temperature under neutral conditions, and we applied this reaction to the prodrug strategy for drugs with an amino group. We designed and synthesized novel prodrugs of representative sparingly soluble drugs phenytoin and sulfathiazole. Phenytoin and sulfathiazole were obtained as stable salt that were converted to parent drugs under physiological conditions. Phenytoin prodrug 3 showed a short half-life (t1/2) of 13?min, whereas sulfathiazole prodrug 7 had a moderate t1/2of 40?min. Prodrugs 3 and 7 appear to be suitable for use as an injectable formulation and orally administered drug, respectively.
- Hamada, Yoshio
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p. 1685 - 1689
(2016/07/29)
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- In vitro anti-HMPV activity of new synthetic phenytoin derivatives
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New derivatives of synthetic 5,5-diphenylhydantoin (phenytoin) were prepared by N-alkylation with 1,3-dibromopropane. Subsequent treatment with sodium azide led to the respective azide. Reaction of the azide with phenylacetylene and 2-hydroxy-3-butyne and oxidation of the resulting alcohol with MnO2 resulted in three triazolic compounds that were evaluated in vitro for their antiviral activity against human metapneumovirus (HMPV). 5,5-Diphenyl-3-[3-(4-phenyl-1H- 1,2,3-triazol-1-yl)propyl]imidazolidine-2,4-dione was the most active of the three compounds tested, with selectivity index of 129.87, even higher than ribavirin, the control substance. The three compounds showed activity in the early stages of viral replication presenting virucidal activity and binding to cellular receptors, preventing the adsorption of viral particles. These compounds showed higher activity in both experiments, inhibiting 98.3percent of infection as virucidal and 98.9percent when interacting with cellular receptors. Furthermore, they showed 73.8percent of activity during the penetration of HMPV particles into cells. The derivative 3-{3-[4-(1-hydroxyethyl)-1H-1,2,3-triazol- 1-yl]propyl}-5,5-diphenylimidazolidine-2,4-dione presented a mild anti-HMPV activity, with selectivity index of 2.74. 3-[3-(4-acetyl-1H-1,2,3-triazol-1-yl)propyl]-5,5-diphenylimidazolidine- 2,4-dione inhibited less than 50percent of HMPV replication.
- Mendes, Gabriella,Aspesi, Geisa H.,Arruda, Ana L. A.,Romanos, Maria T. V.,Andrade, Carlos K. Z.
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- Palladium Catalyzed C-Arylation of Amino Acid Derived Hydantoins
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Palladium(II) trifluoroacetate (5 mol %) catalyzes the C-arylation of N,N-disubstituted hydantoins by aryl iodides in good yield. The reaction proceeds through base-promoted enolization of the amino acid derived hydantoins, and the resulting 5,5-disubstituted hydantoins may be deprotected at one or both N atoms to yield biologically active structures or alternatively hydrolyzed to the parent α-aryl α-amino acids. The reaction is successful with a variety of parent amino acids and a range of electron-rich and electron-poor aryl iodides.
- Fernández-Nieto, Fernando,Mas Roselló, Josep,Lenoir, Simone,Hardy, Simon,Clayden, Jonathan
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supporting information
p. 3838 - 3841
(2015/08/18)
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- An oral redox-sensitive self-immolating prodrug strategy
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We report a novel oral prodrug approach where a solubilizing polymer conjugated to the drug is designed to be released by the action of an exogenously administered agent in the intestine. A redox-sensitive self-immolating design was implemented, and the reconversion kinetics were studied for three reducible prodrugs.
- Sun, Tao,Morger, Andrea,Castagner, Bastien,Leroux, Jean-Christophe
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supporting information
p. 5721 - 5724
(2015/03/30)
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- One-step liquid-phase heterogeneous synthesis of phenytoin using modified calcium oxide as a solid basic catalyst
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A highly efficient heterogeneous method for the synthesis of phenytoin from benzil and urea has been established by using modified CaO as a solid basic catalyst. A relatively high yield of phenytoin was obtained (60.5 %) with a urea/benzil molar ratio of 2.5 at a reaction temperature of 40 °C in the presence of commercial CaO. The yield of phenytoin was greatly enhanced to 90.8 % after treatment of commercial CaO with benzyl bromide. The results of Fourier transform infrared spectroscopy and thermogravimetry analysis implied that the modifier was chemically bonded onto the surface of CaO and almost no Ca(OH) 2 was formed during the modification process. The effects of modification and reaction conditions on the yield as well as the possible mechanism were studied thoroughly. Graphical abstract: [Figure not available: see fulltext.]
- Tang, Ying,Cheng, Qitong,Wang, Shanshan,Zhang, Jie
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p. 1501 - 1506
(2014/11/08)
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- Mechanochemical preparation of hydantoins from amino esters: Application to the synthesis of the antiepileptic drug phenytoin
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The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.
- Konnert, Laure,Reneaud, Benjamin,De Figueiredo, Renata Marcia,Campagne, Jean-Marc,Lamaty, Frdric,Martinez, Jean,Colacino, Evelina
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p. 10132 - 10142
(2015/02/19)
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- Chitosan decorated Fe3O4 nanoparticles as a magnetic catalyst in the synthesis of phenytoin derivatives
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In the present work, Fe3O4 nanoparticles were synthesized by the chemical coprecipitation process. Subsequently, the synthesized nanoparticles were modified with chitosan by a simple method and characterized by X-ray diffractometry (XRD), Fourier transform infrared spectrophotometry (FT-IR), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Then, phenytoin derivatives were catalyzed by magnetic Fe3O4-chitosan nanoparticles. Fe3O4-chitosan nanoparticles were found to be a recoverable organocatalyst for the efficient synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins from substituted benzils and urea or thiourea derivatives. The nanocatalyst could be recovered easily under a magnetic field for reuse, and considerable loss of its catalytic activity was not observed after reuse in seven consecutive runs. This journal is
- Safari, Javad,Javadian, Leila
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p. 48973 - 48979
(2014/12/11)
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- A one-pot synthesis of 5,5-disubstituted hydantoin derivatives using magnetic Fe3O4 nanoparticles as a reusable heterogeneous catalyst
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A facile and rapid method for the one-pot synthesis of 5,5-disubstituted hydantoins in the presence of magnetic Fe3O4 nanoparticles has been developed. The multicomponent reactions of carbonyl compounds (aldehydes and ketones), potassium cyanide and ammonium carbonate were carried out under solvent-free conditions to obtain various hydantoin derivatives. The magnetic catalyst could be readily separated by an external magnet from the reaction mixture. This procedure has many advantages, such as the use of a reusable magnetic catalyst, high yields, short reaction times, simplicity and very easiness with implementing the methodology.
- Safari, Javad,Javadian, Leila
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p. 1165 - 1171
(2013/12/04)
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- Microwave-promoted facile and rapid synthesis procedure for the efficient synthesis of 5,5-disubstituted hydantoins
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A fast, general, environmentally friendly, and facile method for preparation of 5, 5-disubstituted hydantoins from the reaction between ketone (or aldehyde) derivatives with KCN and ammonium carbonate under microwave irradiation is presented. The microwaves remarkably accelerated this reaction, the reaction times decreased dramatically, the reaction conditions were milder, and the yields were also greater. Also a comparative study of microwave versus classical conditions has been done. All the products were characterized by infrared, NMR, and CHN analysis, and their melting points are identical to those of the known compounds reported in the literature. This method might be useful in the future for the preparation of similar derivatives. Taylor & Francis Group, LLC.
- Safari, Javad,Gandomi-Ravandi, Soheila,Javadian, Leila
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supporting information
p. 3115 - 3120
(2014/01/06)
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- Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents
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Considering the importance of hydantoin derivatives in treatment of status epilepticus, four 5-phenylhydantoins, whose lipophilicities were estimated to be similar to that of phenytoin, were synthesized. Evaluation of their anticonvulsant activities was performed on rats by subcutaneous pentylenetetrazol seizure test and intravenous pentylenetetrazol threshold test, and spontaneous locomotor activity test was used to assess possible sedative effects. X-ray analysis of three compounds suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions responsible for their anticonvulsant activity. It was found that 5-ethyl-5-phenyl- 3-propylhydantoin exhibits the most favorable pharmacological properties among the synthesized compounds, i.e., anticonvulsant activity comparable to phenytoin with lower liability for induction of sedation in rats.
- Trisovic, Nemanja,Rogan, Jelena,Poleti, Dejan,Uscumlic, Gordana,Timic, Tamara,Divljakovic, Jovana,Savic, Miroslav M.
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p. 1451 - 1457,7
(2020/08/20)
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- Microwave-assisted synthesis of some novel and potent antibacterial and antifungal compounds with biological screening
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Hydantoins have widely been used as antiarrythmic, anticonvulsant and antitumor agents but recent research has shown a different and novel cytotoxic activity of hydantoins and its derivatives, i.e. anti HIV, antibacterial and antifungal. The following research article deals with the synthesis of hydantoins and their derivatives by Mannich reaction viz., 3-(substituted)-5,5- diphenylimidazolidine-2,4-dione and 1-(substituted)-3,5,5- triphenylimidazolidine-2,4-dione. The synthesised compounds are novel and some of the compounds showed good antibacterial and antifungal activity equivalent to the standards used. All synthetic procedures were carried out in a microwave and not by conventional methods, which led to speedy process and high yield for the same. Springer Science+Business Media, LLC 2011.
- Bapna, Mayank,Parashar, Bharat,Sharma, Vinod K.,Chouhan, Lalit S.
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experimental part
p. 1098 - 1106
(2012/08/07)
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- Design, synthesis, and anticonvulsant screening of some substituted piperazine and aniline derivatives of 5-phenyloxazolidin- 2,4-diones and 5,5-diphenylimidazolidin-2,4 diones
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Substituted piperazine and aniline derivatives of oxazolidin-2,4-diones and imidazolidin-2,4-diones were synthesized by N3 alkylation and screened for their anticonvulsant activity by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test. Among all the synthesized derivatives, compounds 4b, 6c, 6d, 10b, 11a, 11b, and 11d were found to exhibit maximum seizure protection in MES test and were devoid of any neurotoxic effects. Furthermore, the functional activity of these compounds were evaluated in vivo for 5-HT1A receptor affinity by using rectal body temperature and lower lip retraction in rats, while head twitch response in mice was performed for the determination of probable affinity toward HT2A receptor. The results of these tests demonstrated that compounds 4b, 6c, 6d, 10b, 11a, 11b, and 11d exhibited 5-HT1A (pre- and postsynaptic) agonist/ antagonist features whereas compounds 11a and 11b exhibited antagonist action for HT2A receptor. From the in vivo studies it was observed that a majority of aniline derivatives (6c, 6d, 11a, 11b, 11d) were found to be more active as compared to their bulky piperazine congeners (4b, 10b). Thus, the overall reduction in the bulkiness of the derivatives without compromising the lipophilicity is well appreciated for providing insights into the structural requirements necessary for development of new effective molecules having anticonvulsant effect.
- Dhanawat, Meenakshi,Banerjee, Anupam G.,Shrivastava, S. K.
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p. 2807 - 2822,16
(2020/07/30)
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- Synthesis, structure, and solvatochromic properties of pharmacologically active 5-substituted 5-phenylhydantoins
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A series of 5-substituted 5-phenylhydantoins was synthesized and their UV absorption spectra were recorded in the region 200-400 nm in selected solvents of different polarity. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen-bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The lipophilicities of the investigated hydantoins were estimated by calculation of their log P values. The quantitative relationship between the ratio of the contributions of specific solvent interactions and the corresponding lipophilicity parameter is discussed. The correlation equations were combined with the corresponding ED50 values and different physicochemical parameters to generate new equations that demonstrate the reasonable relationships between solute-solvent interactions and the structure-activity parameters. In order to determine a spectroscopic assignment of the absorption bands in different solvents, quantum chemical calculations were done. Springer-Verlag 2011.
- Trisovic, Nemanja,Valentic, Natasa,Erovic, Marko,Dakovic-Sekulic, Tatjana,Uscumlic, Gordana,Juranic, Ivan
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experimental part
p. 1227 - 1234
(2012/06/04)
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- Application of green chemistry principle in synthesis of phenytoin and its biogical evaluation as anticonvulsant agents
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Phenytoin (5,5'-dipenylimidazolidine-2,4-dione) is the prime example of anticonvulsant agent. According to reported procedure, it is synthesized by condensation of benzil and urea in presence of base (30% w/v NaOH) using ethanol as solvent which itself acts as CNS stimulant. Removal of solvent after synthesis is most difficult and non-assured process. In case of phenytoin transformation in polymorphism plays an important role when solvent other than water is used. About 30% extra cost is calculated if solvent other than water is used. Therefore by application of green chemistry principle phenytoin was synthesized by condensation of benzil and urea in presence of base (30 % NaOH) and water as green solvent. This compound was characterized on the basis of its spectral (IR, 1H NMR) data and evaluated for anticonvulsant activity using MES induced and PTZ induced seizure models in Swiss albino mice. Significant anticonvulsant activity was found by using 25 mg/kg and 50 mg/kg of phenytoin compared with standard phenytoin at 25 mg/kg dose.
- Kadam, Abhijit,Jangam, Sampada,Oswal, Rajesh
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experimental part
p. S47-S52
(2012/06/01)
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- Synthesis of glycoluril catalyzed by potassium hydroxide under ultrasound irradiation
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Synthesis of the glycolurils catalyzed by potassium hydroxide was carried out in 17-75% yield at 40 °C in EtOH under ultrasound irradiation. Compared to the method using stirring, the main advantage of the present procedure is milder conditions and shorter reaction time.
- Li, Ji-Tai,Liu, Xiao-Ru,Sun, Ming-Xuan
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experimental part
p. 55 - 57
(2010/11/16)
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- One step liquid phase heterogeneous synthesis of phenytoin over MgAl calcined hydrotalcites
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Heterogeneous liquid phase synthesis of phenytoin (5,5-diphenylhydantoin) was carried out over MgAl calcined hydrotalcites for the first time under environmental friendly conditions. The catalytic activity results showed very high conversion (80-95%) and selectivity (90-95%) of the desired product phenytoin over MgAl calcined hydrotalcites. The calcined hydrotalcites can be recycled without further loss in the activity and the possible mechanism of the reaction is also proposed.
- Sachdev, Divya,Dubey, Amit
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experimental part
p. 1063 - 1067
(2010/11/05)
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- Ultrasound-enhanced green synthesis of 5,5-diphenylhydantoin derivatives using symmetrical or unsymmetrical benzils
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A rapid, highly efficient and mild green synthesis of 5,5-diphenylhydantoin derivatives was achieved from the reaction of symmetrical or unsymmetrical benzil derivatives with urea in the presence of ethanolic KOH under ultrasound irradiation. This simple method affords 5,5-diphenylhydantoin derivatives at room temperature in short reaction time with high yield and purity. This study aimed to overcome the limitations and drawbacks of the reported methods such as tedious work-up, low yield and long reaction time.
- Safari, Javad,Moshtael Arani, Naimeh,Anousheh Isfahani, Ramezan
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experimental part
p. 255 - 258
(2010/10/19)
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- Synthesis of hydantoins, thiohydantoins, and glycocyamidines under solvent-free conditions
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Hydantoins, thiohydantoins, and glycocyamidines have been prepared in moderate to excellent yields at room temperature under solvent-free conditions. 3N-amino and carboamide derivatives of hydantoin (7-8) were prepared in single step by condensing benzil with semicarbazide and biuret respectively.
- Hashmi, Imran Ali,Aslam, Afshan,Ali, Syed Kashif,Ahmed, Viqar-Uddin,Ali, Firdous Imran
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experimental part
p. 2869 - 2874
(2010/11/05)
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- Preparation of hydantoins by catalytic oxidative carbonylation of α-amino amides
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(Chemical Equation Presented) Hydantoins can be synthesized from the corresponding amino amides employing oxidative catalytic carbonylation using W(CO)6 as the catalyst, I2 as the oxidant,COas the carbonyl source, andDBUas base. Secondary amides afford the hydantoins in good to excellent yields, which decrease as the steric bulk of the N-alkyl substituent increases. 2009 American Chemical Society.
- Dumbris, Seth M.,Diaz, Delmy J.,McElwee-White, Lisa
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experimental part
p. 8862 - 8865
(2010/03/02)
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- A novel synthesis of some new imidazothiazole and glycocyamidine derivatives and studies on their antimicrobial activities
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5,5-diphenyl-2-thioxoimidazolidin-4-one (1) reacted with chloroacetic acid 2a and ethyl chloroacetate 2b in an alkaline medium to afford 2-(4,5-dihydro-5-oxo-4,4-diphenyl-1H-imidazol-2 ylthio)acetic acid (3a) and ethyl 2-(4,5-dihydro-5-oxo-4,4-diphenyl-1H-imidazol-2 ylthio)acetate (3b), respectively. Compounds 3a,b were converted to 5,5-diphenylimidazolidine-2,4- dione (4) by boiling in ethanolic hydrochloric acid. When compounds 3a,b were treated with polyphosphoric acid, cyclization occurred, and 6,6- diphenylimidazo[2,1-b]thiazole 3,5(2H,6H)-dione (5) was obtained. 2-(methylthio)-1H-imidazol-5(4H)-one derivatives (a,b reacted with hydrazine hydrate to give the corresponding hydrazones 7a,b. The reaction of 6a,b with hydrazine hydrate afforded 3-amino-2-phenylimino imidazolidin-4-one derivatives 10a,b. The antimicrobial activities of compounds 1. 3a,b, 5, 7a,b, and 10a,b were studied. Copyright Taylor & Francis Group, LLC.
- Magd El-Din, Asmaa A.,Roaiah, Hanaa F.,Elsharabasy, Salwa A.,Hassan, Aisha Y.
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p. 529 - 536
(2007/10/03)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PHENYTOIN SODIUM
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The present invention relates to an improved process for the preparation of Phenytoin Sodium of formula (I) by reacting Phenytoin with aqueous solution of Sodium hydroxide in presence of aqueous Sodium chloride.
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Page/Page column 5-6
(2008/06/13)
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- Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates
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The demonstration of the essential role of fatty acid amide hydrolase (FAAH) in hydrolyzing endogenous bioactive fatty acid derivatives has launched the quest for the discovery of inhibitors for this enzyme. Along this line, a set of 58 imidazolidine-2,4-dione and 2-thioxoimidazolidin-4-one derivatives was evaluated as FAAH inhibitors. Among these compounds, 3-substituted 5,5′-diphenylimidazolidine-2,4-dione and 3-substituted 5,5′-diphenyl-2-thioxoimidazolidin-4-one derivatives were previously described as CB1 cannabinoid receptor ligands. In the present study, we synthesized several derivatives exhibiting interesting FAAH inhibitory activity and devoid of affinity for the CB1 and CB2 cannabinoid receptors. For instance, 3-heptyl-5,5′-diphenylimidazolidine- 2,4-dione (14) and 5,5′-diphenyl-3-tetradecyl-2-thioxo-imidazolidin-4-one (46) showed p/50 values of 5.12 and 5.94, respectively. In conclusion, it appears that even though several 3-substituted 5,5′-diphenyl-2-thioxoimidazolidin-4-one and 3-substituted 5,5′-diphenylimidazolidine-2,4-dione derivatives have been previously shown to behave as CB1 cannabinoid receptor ligands, appropriate substitutions of these templates can result in FAAH inhibitors devoid of affinity for the cannabinoid receptors.
- Muccioli, Giulio G.,Fazio, Nicola,Scriba, Gerhard K. E.,Poppitz, Wolfgang,Cannata, Fabio,Poupaert, Jacques H.,Wouters, Johan,Lambert, Didier M.
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p. 417 - 425
(2007/10/03)
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- One-pot synthesis of phenytoin analogs
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A series of phenytoin analogs (5,5-diphenylimidazolidine-2,4-dione or 5,5-diphenyl-hydantoin) were synthesized in 65-75% yield from the corresponding substituted benzils. The same products were also obtained directly from α-hydroxy ketones via one-pot procedure.
- Mahmoodi,Emadi
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p. 377 - 382
(2007/10/03)
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- A rapid and efficient microwave-assisted synthesis of hydantoins and thiohydantoins
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The present paper describes studies on the synthesis of the antiepileptic drug phenytoin, and of structurally related derivatives. First, the influence of the solvent has been investigated in the microwave-assisted synthesis of the drug, resulting in a yield improvement and a cleaner reaction. Second, a two-step reaction is described to synthesize selectively and in high yields phenytoin. The first step consists in microwave activation of the reaction of benzil with thiourea, the second step includes the conversion of the resulting 2-thiohydantoin to phenytoin using hydrogen peroxide. Moreover, microwave activation is a very convenient method for the synthesis of 3-alkylated phenytoin derivatives, resulting in a much more selective method than the previously reported procedure using alkylating agents.
- Muccioli, Giulio G.,Poupaert, Jacques H.,Wouters, Johan,Norberg, Bernadette,Poppitz, Wolfgang,Scriba, Gerhard K.E.,Lambert, Didier M.
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p. 1301 - 1307
(2007/10/03)
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- Synthesis of hydantocidin and C-2-thioxo-hydantocidin
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Hydantocidin, a naturally occurring strong herbicide, was synthesized in an overall yield of 35.2%, with the accompanying 1′-epi-hydantocidin in overall 9.6% yield from 2,3-O-isopropylidene-D-ribono-1,4-lactone. C-2-thioxo-hydantocidin and its spiro-epimer were also synthesized in an overall yield of 14.4% and 8.5%, respectively.
- Shiozaki, Masao
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p. 147 - 150
(2007/10/03)
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- 3-alkyl-(5,5'-diphenyl)imidazolidinediones as new cannabinoid receptor ligands
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Twenty-four 3-alkyl-(5,5'-diphenyl)imidazolidinediones were synthesized and evaluated as new cannabinoid receptor ligands. Three compounds exhibited a Ki value around 100 nM against [3H]-SR 141716A binding obtained from human CB1 transfected CHO cells membranes. The lack of change of affinity in the presence of a non hydrolyzable GTP analogue seems to indicate they are cannabinoid antagonists.
- Kanyonyo, Martial,Govaerts, Sophie J.,Hermans, Emmanuel,Poupaert, Jacques H.,Lambert, Didier M.
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p. 2233 - 2236
(2007/10/03)
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- Enhancement of the oral bioavailability of phenytoin by N-acetylation and absorptive characteristics
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To improve the absorbability of phenytoin (DPH), a prodrug, N-acetyl- DPH (EDPH), was synthesized, and the absorptive characteristics and pharmacokinetics of the prodrug were evaluated in rats. EDPH was rapidly hydrolyzed to DPH in the intestinal fluid and the mucosa (rate constant, 0.055 and 0.169 min-1, respectively). The plasma concentrations of DPH after intravenous dosing of EDPH declined in a biexponential manner, although two different elimination patterns were observed in these rats. When dosed orally (25 mg/kg, DPH equivalent), the plasma levels of DPH converted from the prodrug were significantly higher and more sustained than those after DPH alone, giving bioavailability 11.4 (rapid decay) and 9.1 times (slow decay) as high, respectively, as that after DPH alone. The concentrations of DPH distributed into the mucosa of the duodenum and jejunum 1 and 5 h after oral dosing of EDPH were significantly higher than those after DPH alone. The prodrug and DPH converted from the prodrug dissolved 2-4 fold more than DPH alone in bile salt solution and bile salt-oleic acid mixed micelles, indicating the increased solubility of the prodrug in the intestinal fluid. It is concluded from the data that such high solubility of EDPH enhanced the intestinal absorption of the prodrug, part of which would be absorbed in the amide form, and thus gave the high bioavailability.
- Ogiso, Taro,Tanino, Tadatoshi,Kawaratani, Dai,Iwaki, Masahiro,Tanabe, Genzoh,Muraoka, Osamu
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p. 1084 - 1089
(2007/10/03)
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- Superacid Activated Condensation of Parabanic Acid and Derivatives with Arenes. A New Synthesis of Phenytoin and 5,5-Diarylhydantoins
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A new synthetic route to phenytoin and 5,5-diarylhydantoins is repoted.Parabanic acid is converted to the 5,5-diarylhydantoins (65-98percent yield) from CF3SO3H and arenes.Deuterium substituted products are prepared in high yield from parabanic acid, CF3SO3D, and deuterated arenes.
- Klumpp, Douglas A.,Yeung, Ka Yeun,Prakash, G. K. Surya,Olah, George A.
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p. 918 - 920
(2007/10/03)
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- Synthesis, structure and properties of 5,5-diphenyl-2,3,5,6-tetrahydroimidazo-[2,1b]-imidazoline-3,6-dione
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Cyclization of N-[(5,5-diphenyl)-4-oxo-2-imidazolidinyl]glycine (3) yielded 5,5-diphenyl-2,3,5,6-tetrahydroimidazo[2,1-b]imidazoline-3,6-dione (6) or its acetyl derivative 5 depending on the method used. The stabilities of 5 and 6 in acidic or alkaline solutions were examined. The crystal structure of the hydrolysis products 7, 8 of 5 and 6 were solved by X-ray analysis.
- Kiec-Kononowicz,Karolak-Wojciechowska,Mrozek,Posel
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p. 517 - 521
(2007/10/02)
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- Gas/Solid Reactions with Nitrogen Dioxide
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Numerous gas/solid reactions of nitrogen dioxide with organic substrates are investigated preparatively and mechanistically.Gaseous NO2 reacts with crystalline stable free radicals (nitroxyls 1, verdazyl 6) by electron transfer.The nitrite ions formed are irreversibly oxidized by NO2 via oxygen atom transfer.Solid cation nitrates are formed quantitatively.Thione bonds of thiohydantoins 8 are transformed to carbonyl bonds with formation of sulfur and NO presumably via nitrites as intermediates.Hydantoin 13 oxygenates at its free 5-methylene group via C-H abstraction and nitrite or it undergoes N-1 nitration via N-H abstraction depending on the conditions.Both reactions proceed quantitatively. 1,3-Oxazolidin-2-one (15) gives N-nitration and N-nitrosation with the NO produced.Nonenolized crystalline barbituric acids 17 are quantitatively nitrated (C-N bond formation with radicals) at their methylene groups. 4-Hydroxybenzaldehyde (19) and vanilline (22) give quantitative aromatic nitration (C-N bond formation with arenes) without melting.All possible regioisomers are formed.Solid 9-methylanthracene (26) gives a quantitative yield of its 10-nitro derivative 27.Crystalline anthracene (28) and gaseous NO2 yield 3 primary products 29 (cis; trans) and the new dimeric product 30 as well as the stable secondary products 31 and 32.The gas/solid tetranitration of tetraphenylethylene (33) is severely hindered by the water of reaction.However, a 95percent yield of pure tetrakis(p-nitrophenyl)ethylene is obtained if the drying agent MgSO4*2H2O is admixed and the product 34 extracted.The gas/solid procedures avoid solvents and fuming nitric acid.They give pure products without necessity for recrystallization in most cases and they avoid wastes.Atomic force microscopy (AFM) measurements on prominent faces of single crystals of 1a, 11a, 28, and 33 reveal phase rebuildings with well-directed long-range molecular transport.Nanoliquids were only present on (110) of 28.The characteristic AFM features are correlated with known X-ray crystal structure data and compared with previous results.The shape of the features depends on the molecular packing in the crystal bulk and on the molecular shapes.Molecular interpretations of the AFM features are given.
- Kaupp, Gerd,Schmeyers, Jens
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p. 5494 - 5503
(2007/10/02)
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- Water dispersion containing ultrafine particles of organic compounds
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A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
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- Process for micronizing slightly-soluble drug
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A process for micronizing a slightly-soluble drug characterized by subjecting a mixture of said drug and a sugar or sugar alcohol to high-speed stirring comminution or impact comminution in order to produce a micronized drug having an average diameter of less than about 2-3 mm. Also provided is a pharmaceutical formulation which comprises the micronized drug.
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- A convenient preparation of symmetrical and unsymmetrical 1,2-diketones: Application to fluorinated phenytoin synthesis
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1,2-Diketones are efficiently produced in two steps by reaction of aldehydes with anions derived from 2-substituted dithianes followed by treatment of the resulting alcoholis with NBS in aqueous acetone; phenytoin derivatives were prepared from these diketones by a standard method involving treatment with urea and potassium hydroxide under reflux.
- Page,Graham,Park
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p. 7265 - 7274
(2007/10/02)
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- Improved anticonvulsant activity of phenytoin by a redox brain delivery system II: Stability in buffers and biological materials
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The stability of nine chemical delivery systems (CDSs) for phenytoin (DPH) was studied in aqueous buffers and in biological materials. The systems were based on a dihydropyridune ? quaternary pyridinium salt redox pair attached to 3-(hydroxymethyl)phenytoin via an ester linkage. The pyridinium derivatives released DPH in aqueous buffers and their hydrolytic reactivity was consistent with their chemical structure. Although in rat blood and plasma all pyridinium esters hydrolyzed rapidly, there was a wide range in the hydrolysis rates in rat brain homogenate. The sterically hindered 1-alkylcarboxynicotinamide was the least reactive ester (t( 1/2 ) = 98.2 min), while the trigonellylglycolate ester was the fastest to hydrolyze enzymatically (t( 1/2 ) = 2 min) in rat brain homogenate. In acidic media, the major products of all dihydropyridine esters were the corresponding water adducts, the 6-hydroxy-1,4,5,6-tetrahydropyridines. These adducts were of no significance in biological materials. After comparison of the relative stability of the corresponding pairs of dihydropyridine and pyridinium ion in brain homogenate and the absolute stability of the various dihydropyridines, two CDSs were chosen for further in vivo evaluations. The CDSs chosen were the dihydrotrigonellinate ester and its 6-methyl derivative.
- Murakami,Shek,Pop,Bodor
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p. 732 - 737
(2007/10/02)
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- Parenteral phenytoin preparations
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Useful parenteral phenytoin preparations can be made using certain complexes of phenytoin or phenytoin sodium.
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