Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives

Dyląg, Tomasz; Zygmunt, Małgorzata; Maciąg, Dorota; Handzlik, Jadwiga; Bednarski, Marek; Filipek, Barbara; Kieć‐Kononowicz, Katarzyna

doi:10.1016/j.ejmech.2004.05.008

Cited by 45 publications

(33 citation statements)

References 13 publications

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“…The starting 5-cyclopropyl-5-phenyl- (1) and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins (2) were obtained from the cyclopropyl-phenyl-or cyclopropyl-4-chlorophenyl-ketones by means of the Bú´cherer-Berg reaction with modification described by Goodson et al [16]. In the next step twenty four new Mannich bases with the 5-cyclopropyl-5-phenyl-(3-10, 19-21) and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoin (11)(12)(13)(14)(15)(16)(17)(18)(22)(23)(24) as a core fragment were prepared. The aminoalkylation of the acidic proton (N 3 H) in the imidazolidine-2,4-dione ring was carried out in the presence of formaldehyde (40% solution) and variously substituted 4-aryl-(3-6, 11-14) or 4-benzyl-piperazines (7)(8)(9)(10)(15)(16)(17)(18).…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Anticonvulsant Activity of New N‐Mannich Bases Derived from 5‐Cyclopropyl‐5‐phenyl‐hydantoins

Byrtus¹,

Obniska²,

Czopek³

et al. 2010

Archiv der Pharmazie

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Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases 3-24 derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins were described here. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. Selected derivatives were also screened in the 6-Hz test. The neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in MES and/or scPTZ tests. The quantitative studies after oral administration into rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series the most active was 3-[(4-phenylpiperazin-1-yl)-methyl]-5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (3) with the ED(50) value of 5.29 mg/kg in the MES test.

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Section: Chemistrymentioning

confidence: 99%

“…2). These amines were presented in structures of many other anticonvulsant active agents [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticonvulsant Activity of New N‐Mannich Bases Derived from 5‐Cyclopropyl‐5‐phenyl‐hydantoins

Byrtus¹,

Obniska²,

Czopek³

et al. 2010

Archiv der Pharmazie

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“…Due to their diverse biological and pharmacological properties, these compounds have been used in a wide variety of applications [1]. For instance, hydantoins have been widely used as antiarrhythmic and antihypertensive [2,3], antiviral [4], antineoplastic [5], antitumoral [6] and anticonvulsant agents [7,8]. Thiohydantoins are known for their uses as hypolipidemic [9], antimutagenic [10] and anticarcinogenic agents [11].…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of racemic and enantiomeric 5-isopropyl-5-methylhydantoin

et al. 2014

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KEYWORDSCrystal structures of racemic and enantiomeric 5-isopropyl-5-methylhydantoin (IPrMH) have been determined by single crystal X-ray diffraction. Melting temperatures and solid state infrared spectra are also measured. Racemic IPrMH has a lower melting temperature than the pure enantiomer by 25 °C. The infrared spectrum of racemic IPrMH is identical with that of the pure enantiomer. Nevertheless, the racemic IPrMH doesn't crystallize as a conglomerate but as a racemic compound. The racemic and the enantiomeric crystals are very similar to each other in molecular geometries and intermolecular interactions. In the both cases, the molecules are connected via N−H···O hydrogen bonds to form R 2 2(8) rings, and these rings are linked into infinite one-dimensional tapes. In the racemic crystal, a single tape is composed of single enantiomer and itself is homochiral. Hydantoin Enantiomer Conglomerate Crystal structure Racemic compound Imidazolidine-2,4-dione

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“…The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3]. A series of paliperidone derivatives (PDs) were synthesized ( fig.…”

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confidence: 99%

Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

Sun¹,

Su²,

Cheng³

et al. 2010

Basic Clin Pharma Tox

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The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD 50 and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0,5,10,15,20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 lmol ⁄ kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia.Risperidone, 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidin]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]py rimidine-4-one, is a serotonin 5-HT 2 and dopamine D 2 receptor antagonist and widely used in the treatment of schizophrenia as an atypical antipsychotic drug. In human beings, risperidone is mainly metabolized to 9-hydroxyrisperidone by cytochrome P450 in the liver [1]. Because of its antipsychotic activity, 9-hydroxyrisperidone has been reported under the name of paliperidone for the treatment of schizophrenia. Johnson and Johnson launched paliperidone under the trade name of Invega in the end of 2006. The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3]. A series of paliperidone derivatives (PDs) were synthesized ( fig. 1) and their physical and chemical properties are listed in table 1.Among patients with schizophrenia, accelerated heart disease is a major cause of sudden death and the risk of dying from cardiovascular disease is two to three times higher than in the general population [4]. Numerous antipsychotic drugs are well-documented for their effects on the QT interval [5]. Prolongation of the QT interval by risperidone has also been reported in a clinical study [6]. In vitro electrophysiological studies showed that supra-therapeutic doses of risperidone induced the prolongation of ventricular repolarization in a dose-related and reverse use-dependent manner, which prolonged the terminal repolariza...

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Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives

Cited by 45 publications

References 13 publications

Synthesis and Anticonvulsant Activity of New N‐Mannich Bases Derived from 5‐Cyclopropyl‐5‐phenyl‐hydantoins

Synthesis and Anticonvulsant Activity of New N‐Mannich Bases Derived from 5‐Cyclopropyl‐5‐phenyl‐hydantoins

Crystal structures of racemic and enantiomeric 5-isopropyl-5-methylhydantoin

Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

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