Synthesis of New Imidazolidin-2,4-dione and 2-Thioxo-imidazolidin-4-ones via C-Phenylglycine Derivatives

Hydantoins and their derivatives constitute a group of pharmaceutical compounds with anticonvulsant and antiarrhythmic properties, and are also used against diabetes. N-3 and C-5 substituted imidazolidines are examples of such products. As such, we have developed a synthesis of 2,4-dione and 2-thioxo-4-one imidazolidinic derivatives by reaction of amino acids with C-phenylglycine, phenyl isocyanate and phenyl isothiocyanate. Four amino-derivatives IG(1-4) and eight imidazolidinic derivatives, IM(1-8), were obtained in yields of 70–74%. The mass, infrared, 1H and 13C-NMR spectra of representative products are discussed.


Introduction
Nowadays, there is an incessant search for biological functional compounds suitable for treating diverse illnesses. The development of more efficient and less toxic products often involves the study of new synthetic routes or structural modifications of existing molecules and medicinal drugs are often manufactured by modification or molecular variation using bioisosterism [1]. The influence of an atom or an atom group modification by bioisosters can be analyzed based on the biological activity presented by the drug, having an identical or exact antagonistic effect. The synthesis of heterocyclic 2,4-imidazolidinones or hydantoins (1) has been studied intensively for their important pharmacological properties [2]. Substances that contain these heterocyclic moieties present significant biological activities as antifungal [3], antibacterial and anti-inflammatory [4] drugs, for the treatment of hypoglycemia [5], or as plant growth inhibitors [6], among other properties. Thiohydantoins are sulfur analogs of hydantoins with one or two carbonyl groups replaced by thiocarbonyl groups. The 2thiohydantoins have been widely evaluated due to their applications as hypolipidemic, anticarcinogenic, antiviral (e.g., herpes virus, HSV, HIV and tuberculosis), antimicrobial, anti-ulcer and anti-inflammatory agents [7].
Several studies [8][9][10] have described the synthesis of amino acid compounds, their importance and applications as intermediates for the synthesis of heterocyclics [11,12]. The present study aimed to contribute with the chemical and pharmacological studies of imidazolidinic compounds, whereby imidazolidinic bioisosters obtained from amino acids were synthesized and characterized as imidazolidin-2,4-dione and 2-thioxo-imidazolidin-4-one derivatives. Among the compounds synthesized we evaluated 3-phenyl-5-(4-isopropylphenyl)-imidazolidin-2,4-dione (IM-7), and a focus of this study was to investigate the acute cardiovascular effects induced by IM-7 in rats. In addition, the effects of 5-(4-ethylphenyl)-3-phenylimidazolidin-2,4-dione (IM-3) on the Central Nervous System was investigated, and its possible involvement in antinociception was considered based on results obtained with early pharmacological screening [13].
The present study showed that treatment of mice with 5-(4-ethylphenyl)-3-phenylimidazolidin-2,4dione IM-3 in doses of 250 and 500 mg/kg, i.p caused a significant decrease in writhing numbers after administration (7.3 ± 2.3; 3.6 ± 1.7, respectively) in relation to control (22.1 ± 6.0), indicating a antinociceptive effect, however, the central depressant effect was not confirmed because this compound did not increase the response time in the Hot Plate Test in comparison with a standard drug (morphine 6 mg/kg, i.p).

General
Mass spectra were obtained using a Finnigan GCQ Mat type quadrupole-ion trap spectrometer. IR spectra were obtained by means of a Bruker IFS66 spectrometer with the samples in KBr discs. 1 H-and 13 C-NMR spectra were recorded on a Varian Unity Plus 200 MHz spectrometer operating at 200 MHz for 1 H and 50 MHz for 13 C, the sample being dissolved in DMSO-d 6 with TMS as reference. Elemental analysis was carried out using a Perkin Elmer Elemental Microanalyser. The melting points were determined using a Kofler hot-plate apparatus combined with a Carl-Zeiss microscope and are uncorrected. In the pharmacological studies with IM-7, male Wistar rats (250-300 g) were anesthetized and the abdominal aorta and inferior vena cava were cannulated for pressure recordings and administration of drugs. Rat superior mesenteric rings (1-2 mm) were suspended by cotton threads for isometric tension recordings in Tyrode´s solution, 37 ºC, gassed with 95% O 2 and 5% CO 2 , resting tension 0.75 g. For the pharmacological studies of IM-3, Male Swiss mice (25-35 g) were treated with increased doses of IM-3 (125, 250 and 500 mg/kg) in the toxicological Test, for calculus of Median Letal Dose (LD 50 ), a posteriori writhing and Hot Plate Tests were realized. The parameters utilized were writhing numbers, reaction time(s) and latency(s).

General method for the preparation of C-arylglycines
Appropriate amounts of KCN and ammonium chloride were dissolved in distilled H 2 O (100 mL). Equimolar quantities of the arylaldehyde in MeOH (100 mL), were added under vigorous stirring and the reaction continued for 120 minutes. H 2 O (250 mL) was added and the resulting mixture was then added to toluene (250 mL). The toluene phase was separated and then extracted with HCl (6N, 3 × 100 mL). The combined acid extract was refluxed for 8 hours, giving the desired product in the form of white crystals after cooling. These were filtered off, washed with CHCl 3 and air-dried.

Conclusions
Four new C-phenylglycine derivatives IG(1-4) containing different groups and obtained via Strecker synthesis were subjected to reactions with phenyl isocyanate and phenyl isothiocyanate to furnish eight imidazolidinic compounds IM (1-8), seven of which were new, and one, IM-5, whose structure was not previously elucidated. Their structures were confirmed by infrared, 1 H-and 13 C-NMR and mass spectroscopies. The pharmacological studies with IM-3 and IM-7 show that these compounds are bioactive structures. In the cardiovascular system IM-7 induced a marked hypotension and bradycardia which are probably due to decrease of the peripheral resistances. Likewise in vivo, the relaxant effect of this compound seems to involve endothelial muscarinic receptor activation and consequent NO release. The results obtained with pharmacological and behavior tests suggest that IM-3 showed peripheral antinociceptive effect considering the negative results in the Hot Plate test.