New pyrazole derivatives of potential biological activity

5-Chloro-3-methyl-1-phenyl-1 H -pyrazole-4-carboxaldehyde ( 1 ) was reacted with hydrazine hydrate and thiosemicarbazide to afford the corresponding hydrazones 2 and thiosemicarbazones 4 . The latter compounds were used to obtain the pyrazole derivatives 3, 5-7 . A series of azines 8a-e were obtained by reacting 2 with aromatic aldehydes. Potassium permanganate oxidation of 1 gave the acid 9 , which was transformed into the corresponding acid azide 11 then used to prepare diverse urea derivatives 13-18 via Curtius reaction .


Results and Discussion
5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde (1) was utilized as a starting material.This aldehyde could be obtained from the easily accessible 3-methyl-1-phenyl-1Hpyrazol-5(4H)-one under Vilsmeier-Haack reaction conditions. 18Treatment of 1 with hydrazine hydrate gave the corresponding hydrazone 2, which was allowed to react with phenyl isothiocyanate to give the thiosemicarbazone derivative 3. 19 The thiazole 5 was obtained in a two-step sequence by reacting 1 with thiosemicarbazide to afford the corresponding thiosemicarbazone 4 followed by treatment with phenacyl bromide, in a similar procedure to that reported before. 20The IR spectrum of compound 4 showed absorption bands at νmax = 3400, 3270 and 3150 cm -1 due to νNH2 and νNH.Its 1 H NMR spectrum showed a singlet at δ 11.44 ppm (NH), a singlet at δ 8.27 ppm (NH2) and a singlet at δ 8.09 ppm (CH=N), while the 1 H NMR spectrum of 5 was characterized by a singlet at δ 6.86 ppm due to the C-5 proton of the thiazole ring, and the absence of the NH2 signal shown by 4. The two-hydrogen singlet in the 1 H NMR spectrum of 2 at δ 5.48 (NH2) was replaced by two one-hydrogen singlets at δ 9.86 and 9.15 ppm in the 1 H NMR spectrum of 3 corresponding to two N-hydrogens.

Scheme 1
Two products were obtained when the thiosemicarbazone 3 was reacted with chloroacetic acid under different conditions.Thus, when the reaction was carried out in boiling ethanol in presence of sodium acetate, the corresponding thiazolidinone derivative 6 was produced, while the reaction yielded the thioxoimidazolidinone 7 when it was carried out in refluxing pyridine (Scheme 2).This is in accordance with earlier reports. 21The structure of the thiazolidinone 6 was supported by its IR spectrum which showed the characteristic band of νC=O of the thiazolidinone ring at νmax = 1720 cm -1 .Its 1 H NMR spectrum showed a singlet for two protons at δ 3.71 ppm for the CH2 group of thiazolidinone.The IR spectrum of thioxoimidazolidinone 7 showed characteristic IR bands at 1720 cm -1 (νC=O) and 1290 cm -1 (νC=S) and in the 1 H NMR spectrum there was a singlet at δ 3.96 ppm for the CH2 protons.
Reaction of the hydrazone 2 with aromatic aldehydes in ethanol under reflux gave the corresponding hydrazones 8a-e (Scheme 3).Certain pyrazolylurea derivatives have been reported as p38 MAP Kinase inhibitors. 22,23This encouraged us to synthesize a number of different unknown pyrazolylurea derivatives.The key intermediate for this objective is the 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid azide (11), which was prepared in a two-step sequence starting from the pyrazolecarboxaldehyde 1.Thus, 1 was first oxidized by KMnO4 to the corresponding acid 9 18,24 followed by a direct conversion into its acid azide 11, by treating a solution of 9 in acetone successively with TEA then with ethyl chloroformate to give the mixed anhydride 10 which was then reacted with NaN3 to give 11 (Scheme 4).The IR spectrum of compound 11 showed the two characteristic absorption bands of an acyl azide at νmax = 2150 and 1680 cm -1 .Compound 11 was reacted with several primary aromatic amines in refluxing toluene to give the corresponding disubstituted ureas 13a-d (Scheme 5).The transformation involved a Curtius rearrangement of 11 leading to the in situ formation of the isocyanate 12 which reacted subsequently with the amines giving the ureas 13a-d.

Scheme 6
Similarly, treatment of 11 with secondary amines viz piperidine, morpholine and ethyl piperazine-1-carboxylate, in boiling toluene, led to the formation of the corresponding trisubstituted ureas 14a-c, while its reaction with piperazine itself gave the corresponding bis urea derivative 15 whether one or two equivalents of the acid azide were used (Scheme 6).Also, when the above reaction was applied to other diamines such as phenylene-1,4-diamine or ethylenediamine, the bis ureas 16 and 17 were obtained whether one or two equivalents of amine were used.The symmetric disubstituted urea 18 was obtained when the acid azide 11 was heated in boiling water (Scheme 7).
The IR spectra of the ureas 13-18 showed υNH bands in the range νmax = 3300-3250 cm -1 and νC=O bands in the range νmax =1640-1635 cm -1 with the disappearance of νCON3 band (νmax = 2150 and 1680 cm -1 ) of the starting acid azide.The 1 H NMR and 13 C-NMR spectra of all the ureas are given in the Experimental Section.

Experimental Section
General.Melting points were measured on Stuart melting point apparatus (Bibby Scientific) SMP3.The IR spectra were recorded on a Shimadzu 470 IR-Spectrophotometer using KBr wafer technique.The 1 H NMR spectra were recorded on a Bruker ARX 200 spectrometer (200 MHz for 1 H and 50 MHz for 13 C) at the Faculty of Pharmacy, University of Aix Marseille, France, and on a Jeol LA 400 MHz (400 MHz for 1 H, 100 MHz for the 13 C) at Assiut university, 1 H and 13 C NMR chemical shifts (δ) were reported in parts per million (ppm) and were referenced to the solvent peak; CDCl3 (7.26 ppm for 1 H and 76.90 ppm for 13 C) and DMSO-d6 (2.50 ppm for 1 H and 39.70 ppm for 13 C).Multiplicities are represented by s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet).Coupling constants (J) are reported in Hertz (Hz).Mass spectra were obtained with a Jeol JMS-600 mass spectrometer (Assiut University).Elemental analyses were carried out using a Perkin-Elmer 240C Microanalyzer at the Microanalytical Laboratory, Faculty of Science, Assiut University, and the results were in an acceptable range (± 0.4%).