Direct N1-Selective Alkylation of Hydantoins Using Potassium Bases.

Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N3 can be more easily alkylated than N1 under basic conditions. In this study, we explored methods for direct N1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (tBuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

Novel prodrugs with a spontaneous cleavable guanidine moiety.

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 13min, whereas sulfathiazole prodrug 7 had a moderate t1/2 of 40min. Prodrugs 3 and 7 appear to be suitable for use as an injectable formulation and orally administered drug, respectively.

Mechanochemical preparation of hydantoins from amino esters: application to the synthesis of the antiepileptic drug phenytoin.

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 ß-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.

Synthesis and anticonvulsant activity of new phenytoin derivatives.

Hybrids between phenytoin and thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole or 1,2,4-triazole were synthesized and tested for anticonvulsant activity. Preliminary anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. The neurotoxicity was determined applying the rotarod test. Among these compounds, 4 and 5d showed the highest protection (80%) in the scPTZ test at a dose of 100 mg/kg, whereas the compound 5b displayed promising anticonvulsant effect in the MES model.

Phenytoin-based bivalent ligands: design, synthesis and anticonvulsant activity.

Synthesis, characterization and anticonvulsant properties of new bivalent ligands derived from phenytoin were described. Initial anticonvulsant screening was performed using maximal electroshock (MES) and pentylenetetrazole (PTZ) screens in mice. The neurotoxicity for compounds that showed significant anticonvulsant activity was determined applying the rotorod test. Most of the test compounds were found to be effective in at least one seizure model in a dose of 100 mg/kg. Compound 5e exhibited marked anticonvulsant activity in both MES and PTZ screens. The computer-aided prediction of biological activity was carried out.

Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent.

Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities.

Antimicrobial activity of new synthesized [(oxadiazolyl)methyl]phenytoin derivatives.

A number of substituted phenytoin derivatives in addition to their sugar hydrazones were newly synthesized. Furthermore, the corresponding derived 1,3,4-oxadiazole and their thioglycoside as well as their acyclic analogs were prepared. The antimicrobial activity of the prepared compounds was evaluated against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Aspergillus niger and Candida albicans. The dithiohydrazone as well as oxadiazole thiole derivatives, sugar hydrazones and acyclic nucleoside analogs were the highly active compounds.

Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α1-adrenoceptor affinities.

An association between α(1)-adrenoceptor affinities, hERG K(+)-antagonistic properties and antiarrhythmic activities for a series of phenylpiperazine derivatives of hydantoin (2a-21a) was investigated. New compounds were synthesized and tested for their affinity for α(1)-adrenoceptors in radioligand binding assay using [(3)H]-prazosin as a selective radioligand. Antiarrhythmic activities in adrenaline- and barium chloride-induced arrhythmia models, an influence of the phenylpiperazine derivatives on the ECG-components and blood pressure were tested in vivo in normotensive rats. The hERG K(+)-antagonistic properties of the most potent antiarrhythmic agents were investigated in silico by the use of program QikProp. The highest α(1)-adrenoceptor affinity (K(i)=4.7 nM) and the strongest antiarrhythmic activity in adrenaline induced arrhythmia (ED(50)=0.1 mg/kg) was found for 1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride (19a). The results indicated a significant correlation between α(1)-AR affinities (pK(i)) and antiarrhythmic activity (ED(50)) in adrenaline model (R(2)=0.92, p <0.005). Influence of the examined phenylpiperazine hydantoin derivatives on hERG K(+) channel, predicted by means of in silico methods, suggested their hERG K(+)-blocking properties.

A rapid and efficient ultrasound-assisted synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins.

To obtain a rapid, efficient and mild synthesis of 5,5-diphenylhydantoin and 5,5-diphenyl-2-thiohydantoin derivatives, ultrasonic irradiation has been applied to the reaction mixtures containing substituted benzils and urea or thiourea derivatives catalyzed by KOH in DMSO/H(2)O, which allowed us to achieve products at room temperature in a good yield and short time without any side product. This convenient procedure will allow a further increase of the diversity within the hydantoin family.

Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.

Synthesis of 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones and their anticonvulsant, anti-nociceptive, and toxicity evaluation in mice.

A number of new 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones (4a-t) were synthesized and evaluated for their anticonvulsant, anti-nociceptive, hepatotoxic, and neurotoxic properties. The titled compounds (4a-t) were obtained by cyclization of N-{[6-substituted-1,3-benzothiazol-2-yl)amino]carbonothioyl}-2/4-substituted benzamides (3a-t) by refluxing in n-butanol. All the newly synthesized compounds were screened for their anticonvulsant activity in a mouse seizure model and were compared with the standard drug phenytoin. Compounds 4a, 4c, 4f, and 4l showed complete protection after time periods of 0.5 h and 4 h. Some of the selected compounds were evaluated for their neurotoxic and hepatotoxic effects, and none of these showed any sign of neurotoxicity or hepatotoxicity. Compounds 4a-t were also evaluated for their anti-nociceptive activity by a thermal stimulus technique using diclofenac as standard. Compounds 4o, 4q, and 4t displayed highly potent analgesic activity with p < 0.01.

Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives.

During the search for antiarrhythmic agents among amide derivatives of phenytoin, compound 7 {3-ethyl-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenyl-imidazolidine} was selected as it showed antiarrhythmic as well as antihypertensive activity. Treating this compound as a lead, new derivatives 8-19 were synthesised, differing in piperazine phenyl ring substitution (2-, 3-, 4-Cl, 2-CH3O) as well as in hydantoin N3 alkyl chain (ethyl, ethyl acetate or ethyl 2-propionate). The obtained compounds in form of hydrochlorides 7a-19a were examined for prophylactic antiarrhythmic and antihypertensive properties. Compounds containing ethyl 2-propionate moiety (17a, 18a) exhibited the highest antihypertensive properties. Water-soluble compounds, containing 2-methoxyphenylpiperazine group (11a, 19a), showed strong antiarrhythmic properties in adrenaline-induced arrhythmia; compound 9a {1-[3-(4-(3-chloro-phenyl)-piperazin-1-yl)- 2-hydroxy-propyl]- 3-ethyl-2,4-dioxo-5,5-diphenyl-imidazolidine hydrochloride} exhibited the highest antiarrhythmic activity in barium chloride arrhythmia model.

Lower phenytoin serum levels in persons switched from brand to generic phenytoin.

After generic phenytoin (PHT) was marketed, the authors identified eight adult patients (ages 34 to 49) whose seizures increased enough to require intervention after switching to generic PHT. The mean total PHT concentration on brand (before generic) was 17.7 +/- 5.3 mg/L, decreased to 12.5 +/- 2.7 mg/L with generic, and increased to 17.8 +/- 3.9 mg/L after brand was re-introduced. Brand and generic PHT do not yield equivalent concentrations in some patients and substitution should not be permitted without physician notification.

Anticonvulsant activity of reaction products of 5,5-diphenylhydantoin with substituted methylene bromides.

Some derivatives of 5,5-diphenylhydantoin (phenytoin) were synthesized by the alkylation of phenytoin with substituted methylene bromides. The hydantoins were evaluated for possible anticonvulsant activity in the maximal electroshock (MES)- and subcutaneous pentylenetetrazole (ScMet)-induced seizures and for neurotoxicity in the rotorod test in mice and rats.

Synthesis of water-soluble phenytoin prodrugs.

The synthesis of novel water-soluble phenytoin derivatives, bearing an ionizable group, and a preliminary study for in vitro blood hydrolysis are reported. The results show that hydrolysis of amino esters 8 is very fast, much more than that of fosphenytoin.

Enhancement of the oral bioavailability of phenytoin by N-acetylation and absorptive characteristics.

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.

[Racemates and enantiomers of basic, substituted 5-phenylhydantoins, synthesis and anti-arrhythmic action]. / Razemate und Enantiomere basisch substituierter 5-Phenylhydantoine, Synthese und antiarrhythmische Wirkung.

The racemates and the enantiomers of 5-phenylhydantoins with basic substituents in 5-position are synthesized on two different routes via the Bucherer-Bergs-reaction. Using lanthanide-shift-reagents the enantiomeric excess for the enantiomers of 3-methyl-5-morpholinomethyl-5-phenylhydantoin (3a) and 3-methyl-5-phenyl-5-(2-phthalimidoethyl)-hydantoin (6a) is found to be more than 98%. The enantiomers of 4d, 5b, 6b, 7a, and 7b, derived from 3a and 6a, possess the same optical purity. The racemates and the enantiomers of 3a, 4d and 5b were tested at atrium of rat hearts on their antiarrhythmic activity. At the right atrium (+)-3a, (+)-4d, and (+)-5b reduce the spontaneous frequence dependent on the dosis. At the left atrium the enantiomers of 3a and 4d show a negative inotropic action (+)-3a is 4.1, (+)-4d is 1.5 more active as the corresponding (-)-enantiomers. Compound (+)-4d exceeds the reference substance diphenylhydantoin by the factor 1.3.

[Rational conception, synthesis and evaluation of phenytoinergic potential anticonvulsants. A series ofretrobenzamides: N-(nitrophenyl) benzamides and N-(aminophenyl) benzamides]. / Conception rationnelle, synthèse et évaluation d'agents anticonvulsivants originaux à potentialité phénytoïnergique. La série des rétrobenzamides: les N-(nitrophényl) benzamides et les N-(aminophényl)benzamides.

Retrobenzamides [N-(nitrophenyl) benzamides and N-(aminophenyl)benzamides] were developed in the perpective of a design for phenytoinergic agents. Anticonvulsant and neurotoxic properties of these compounds were evaluated in mice and rats in two seizure models (maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentylenetetrazole [scPtz]) and in the rotorod test. Data obtained were compared with those recorded on carbamazepine and phenytoin (antiepileptic drugs widely utilized in human clinics), ameltolide (anticonvulsant compound recently developed by Eli Lilly in human clinical trials) and other compounds previously reported by our research group. Studies on retrobenzamides in mice administered by intraperitoneal route point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity in the case of the corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were less active in the MES test than in mice dosed intraperitoneally.

3-Hydroxymethylphenytoin valproic acid ester, a new prodrug combining two anticonvulsant drugs.

3-Hydroxymethylphenytoin valproic acid ester (VAL-PHT) was designed as a new prodrug combining valproic acid and phenytoin, two anticonvulsant drugs with different pharmacological profiles. The compound was hydrolyzed by rat plasma esterases in vitro but exhibited only activity in the maximal electroshock seizure test (MES test) after intraperitoneal administration to mice. The compound did not protect against pentylenetetrazole-induced seizures. It is concluded that VAL-PHT acts as a prodrug displaying the anticonvulsant profile of phenytoin.