Synthesis of some novel pyrimidine , thiophene , coumarin , pyridine and pyrrole derivatives and their biological evaluation as analgesic , antipyretic and anti-inflammatory agents

*Correspondence: K. A. El-Sharkawy. Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University. P.O. Box 114, Jazan 45142, Saudi Arabia. Phone: 00201010698361, 0966559686517 / Fax: 00238371543. E-mail: karamsyn@yahoo.com Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents


General procedures
The melting points of the synthesized compounds were determined in open capillaries and are uncorrected.Elemental analyses were performed on a Yanaco CHNS Corder elemental analyzer (Japan).IR spectra were measured using KBr discs on a Pye Unicam SP-1000 spectrophotometer. 1 H NMR and 13 C NMR spectra were measured on a Varian EM 390-200 MHz instrument Page 2 / 13 with CD 3 SOCD 3 as the solvent using TMS as an internal standard material, the chemical shifts were expressed as δ ppm.Mass spectra were recorded on Kratos (75 eV) MS equipment (Germany).

Analgesic activity
Analgesic activity was introduced by the tail flick method (Fadeyi et al., 2004;Vogel, 2002).Healthy albino mice weighing 20.0 g to 30.0 g were divided into different groups with six animals in each group.The control group received a 0.5% w/v carboxymethylcellulose (CMC) solution and the treated groups were given a 132 µmol/kg orally dose of compounds 3, 7, 9a ,b, 11, 13a ,b, 15, 17a,  b, 19, 21a, b, 23a, b and 25a, b, c.The reaction times were noted at 2 h and 4 h intervals after drug administration.The percentage analgesic activity was calculated by the following formula:-Percentage analgesic activity = T 2 -T 1 /T 1 ×100 where:-T 1 is the normal reaction time; T 2 is the reaction time after treatment.

Antipyretic activity
Healthy Wistar rats were given s.c.10mL/kg of a 20% aqueous suspension of sterilized brewer's yeast powder (Fadeyi et al., 2004;Vogel, 2002) weighting between 150 g and 200 g.Eighteen hours later, the animals showing an increase in rectal temperature greater than 0.5 ºC were selected.The control group received a 0.5% w/v carboxymethylcellulose solution and the treated groups received a of 132 µmol/kg dose of compounds 3, 7, 9a, b, 11, 13a, b, 15, 17a, b, 19, 21a, b, 23a, b and 25a, b, c.Rectal temperatures were noted using digital thermometer 30 minute before (pretreated) and at 1 h, 2 h and 4 h after administration of the dose.

Anti-inflammatory activity
The anti-inflammatory activity was examined using a hind paw edema method on albino rats of either six (Fadeyi et al., 2004;Vogel, 2002).A freshly prepared of carrageenan solution (0.1mL, 1%w/v) was injected into the sub-plantar surface of the right hind limb of each animal.The control group received a 0.5% w/v CMC solution and the treated groups were orally given a 132 µmol/kg dose of compounds 3, 7, 9a ,b, 11, 13a ,b, 15, 17a, b, 19, 21a, b, 23a, b and 25a, b, c 30 minute before carrageenan.The volume of each paw was measured with a plethysmometer at 2 h and 4 h intervals after carrageenan injection.The percentage inhibition of edema was calculated by the following formula: Percentage inhibition of edema: V C -V T /V C ×100 where: V C is the paw volume of control animal; V T is the paw volume of treated animals (standard /test compound).

RESULTS AND DISCUSSION
This study was a continuation of our efforts aimed at the synthesis of new heterocyclic compounds with significant biological potential (El-Sharkawy et al., 2012;Mohareb, El-Sharkawy, Sherif, 2008).The goals of this work were to study the possibility of using compounds 2 and 3 in heterocyclic synthesis to produce the pyridopyrimidine derivative 7; thiophene derivatives 9a,b; coumarin derivative 11; pyrimidine derivatives 13,15,17a,b,21a,b; pyridine derivative 19; pyrazole derivatives 23a,b and iminopyrimidine derivatives 25a,b,c, as well as biologically evaluate these compounds for analgesic, antipyretic and anti-inflammatory activities.The reaction of β-amino-α, γ-dicyanocrotono-nitrile (1) with 5-ureidohydantion (2) using triethylamine as catalyst produced compound 3.The latter product underwent cyclization in the presence of piperidine.Four isomeric structures were considered, including 4,5,6 and 7.The 1 HNMR spectral data showed that the final product contained three singlets at δ = 4.78, 4.93, 5.27 ppm and two singlets at δ = 8.73, 9.95 ppm which represented the presence of 3NH 2 and 2NH groups, respectively; thus, the structures of compounds 4,5 and 6 were ruled out, as those latter structures only containing 2NH 2 groups.Additionally, structure 6 contained an OH group which it was absent in the analytical and spectral data.In contrast, compound 7 was produced by another pathway, through the reaction of β-amino-α, γ-dicyanocrotononitrile (1) with 5-ureidohydantion (2) in the presence of sodium ethoxide directly.Compound 3 reacted with either cyclopentanone (8a) or cyclohexanone (8b) in the presence of elemental sulfur and trimethylamine afforded compounds 9a,b respectively.The structures of compounds 9a,b were verified by elemental analysis and spectral data.In compound 9a, the 1 HNMR spectrum indicated the presence of a multiplet at δ = 2.07-2.18ppm which could be assigned to the 3CH 2 groups; three singlets at δ = 4.54, 4.65, 5.81 ppm, which indicate the presence of 3NH 2 groups; a singlet at δ = 5.98 ppm, which indicate the presence of 1H of an imidazolidindione ring and three singlets at δ = 8.52, 8.77, 9.12 ppm corresponding to 3NH groups.Coumarin derivative 11 was formed via the reaction of compound 3 with salicylaldehyde (10) and the structure of the compound was confirmed.The 1 HNMR spectrum indicated the presence of two singlets at δ = 4.76, 5.25 ppm, which indicate the presence of 2NH 2 groups; a singlet at δ = 5.53 ppm, which indicates the presence of an 1H of imidazolidindione ring; a singlet at δ = 6.73 ppm, which indicate the presence of a coumarin 1H; a multiplet at δ = 7.51-7.66ppm corresponding to 4H of benzene ring; and three singlets at δ = 8.88, 9.28, 9.55 ppm, which indicate the presence of 3NH groups.Compound 3 was also reacted with aryldiazonium salts 12a,b to afford arylhydrazono derivatives 13a,b respectively.The elucidation of the structure for these compounds was then confirmed.The 1 HNMR spectrum for compound 13a showed the presence of two singlets at δ = 4.54, 5.17 ppm, which indicate the presence of 2NH 2 groups; a singlet at δ = 5.61 ppm, which indicates the presence of 1H of an imidazolidindione ring; a multiplet at δ = 7.31-7.62ppm corresponding to 5H of benzene ring; and four singlets at δ = 8.76, 9.13, 9.38, 959 ppm which indicate the presence of 4NH groups.
The last reaction of compound 3, was performed with ω-bromo-4-methoxyacetophenone ( 14   detected the presence of a singlet at δ = 3.27 ppm, which indicates the presence of 3H from a CH 3 group; four singlets at δ = 4. 38, 4.59, 4.95, 5.23 ppm, which indicate the presence of 4NH 2 groups; a singlet at δ = 5.63 ppm, which indicates the presence of 1H of imidazolidindione ring; a multiplet at δ = 6.95-7.28ppm corresponding to 4H of benzene ring and 1H of pyrrole ring and three singlets at δ = 8.51, 8.77, 9.38 ppm, which indicate the presence of 3NH groups.Finally 5-ureidohydantion (2) was reacted with compounds 24a,b,c to produce iminopyrimidine derivatives 25a,b,c, respectively and the structure of these compounds were confirmed by analytical and spectral data.
), and the 4-methoxyphenylbutenyl derivative 15 was afforded.The elucidation of this structure was based on analytical and spectral data.Compound 15 was reacted with either potassium cyanide (16a) or potassium thiocyanate (16b) to form either the 4-methoxyphenylbutenyl cyanide derivative 17a or 4-methoxyphenylbutenyl thiocyanide derivative 17b, respectively.The structures of compounds 17a,b were verified by analytical and spectral data.Compound 17a underwent a cyclization in presence of sodium ethoxide to afford pyridine derivative 19 via formation of intermediate 18.The structure of compound 19 was then confirmed.The 1 HNMR spectrum of compound 19 detected the presence of singlet at δ = 3.68 ppm, which indicates the presence of 3H of CH 3 group; three singlets at δ = 4.38, 4.93 5.33 ppm, which indicate the presence of 3NH 2 groups; a singlet at δ = 5.77 ppm, which indicates the presence of 1H of imidazolidindione ring; a singlet at δ = 7.14 ppm which indicates the presence of 1H of pyridine ring; a doublet of doublets at δ = 7.28-7.49ppm corresponding to 4H of benzene ring and two singlets at δ = 8.41, 8.82 ppm, which indicate the presence of 2NH groups.Compound 15 was reacted with either hydrazine hydrate (20a) or phenyl hydrazine (20b) to produce hydrazono derivatives 21a,b, respectively.The structures of these compounds were confirmed by analytical and spectral data.The latter products underwent a cyclization to form pyrrole derivatives 23a,b through the intermediate formation of 22a,b, respectively.The structures of compounds 23a,b were confirmed using analytical and spectral data.The 1 HNMR spectrum of compound 23a

TABLE I -
Analgesic activities of the synthesized compounds drug.Based on the results from (TablesI and II), it is clear that compounds 11 and 19 showed promising actions as analgesic and antipyretic agents.

TABLE II -
Antipyretic activities of the synthesized compounds

TABLE III -
Anti-inflammatory activities of the synthesized compounds