Paulo Beck

Antinociceptive effect of novel trihalomethyl-substituted pyrazoline methyl esters in formalin and hot-plate tests in mice.

The aim of the present study was to evaluate the antinociceptive potential of four novel pyrazoline methyl ester compounds on chemical and thermal models of pain in mice. The following 5-trihalomethylated-4,5-dihydro-1H-pyrazole methyl ester compounds were tested: 3-methyl-5-trifluoromethyl-(MPF3), 4-methyl-5-trifluoromethyl-(MPF4), 3-methyl-5-trichloromethyl-(MPCl3) and 4-methyl-5-trichloromethyl-(MPCl4). MPF3, MPF4, MPCl3 and MPCl4 (0.03-1.0 mmol/kg) given intraperitoneally decreased neurogenic and inflammatory phases of nociception in the formalin test. Moreover, MPF3, MPF4, MPCl3, MPCl4 (0.1-1.0 mmol/kg) and dipyrone (1.5 mmol/kg) also produced a dose-dependent antinociceptive effect in the hot-plate test. However, MPF3, MPF4, MPCl3 and MPCl4 did not impair motor coordination in the rotarod test or spontaneous locomotion in the open field test. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was reversed by the opioid receptor antagonist naloxone (2 mg/kg, i.p.), but not by the alpha(2)-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or by p-chlorophenylalanine ethyl ester (PCPA, 300 mg/kg, i.p.) treatment. In contrast to morphine (5 mg/kg, i.p.), MPF4 given daily for up to 8 days did not generate a tolerance to its antinociceptive effect. However, similar to morphine (11 mg/kg, i.p.), MPF4 reduced gastrointestinal transit in mice. Taken together these results demonstrate that these novel pyrazoline methyl esters tested may be promising prototypes of additional mild analgesics.

Effect of 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles on chronic inflammatory pain model in rats.

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for treatment of arthritis. However, their long-term use has been associated with considerable morbidity, limiting their application. Thus, there remains a need to develop new drugs for the effective and safe relief of chronic inflammatory pain. In this context, the present study was designed to evaluate the antinociceptive and antiedematogenic effects of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazole derivatives EPFCA3 and MPFCA4 after acute (1-1000 micromol/kg) and chronic (100 micromol/kg for 15 days) administration in rats submitted to a model of adjuvant-induced arthritis. We also analyzed some biochemical indicators of toxicity (alanine aminotransferase, aspartate aminotransferase, urea and creatinine levels) after prolonged administration of these compounds. We found that acute and chronic subcutaneuous administration of EPFCA3 and MPFCA4 produces an antinociceptive, but not antiedematogenic, effect on the arthritis animal model induced by complete Freunds adjuvant (CFA). No signs of toxicity were observed in the animals chronically treated with EPFCA3 or MPFCA4. Dipyrone (1-1000 micromol/kg) was used as the positive control and its effect was similar to that of the novel pyrazoles. The activity of tissue myeloperoxidase, the tissue TNF-alpha level and the serum haptoglobin level was increased by intraplantar CFA injection. However, chronic administration of EPFCA3, MPFCA4 or dipyrone was not able to alter the relation between these parameters and inflammation. Our results suggest that EPFCA3 and MPFCA4 are good candidates for the development of new drugs for pain treatment.

Antinociceptive action of 4-methyl-5-trifluoromethyl-5-hydroxy-4, 5-dihydro-1H-pyrazole methyl ester in models of inflammatory pain in mice.

AIMS The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4). MAIN METHODS The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freunds Adjuvant (CFA) and postoperative pain caused by surgical incision in mice. KEY FINDINGS MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66+/-7%, 73+/-9% and 88+/-8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53+/-9%, 83+/-7% and 84+/-7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity. SIGNIFICANCE The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.

Microwave-assisted synthesis of 5-trichloromethyl substituted 1-phenyl-1H-pyrazoles and 1,2-dimethylpyrazolium chlorides

Abstract A series of five 5-trichloromethyl-1-phenyl-1 H -pyrazoles and six 5-trichloromethyl-1,2-dimethylpyrazolium chlorides have been synthesized in 80–98% yield by environmentally benign microwave induced techniques involving the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones [Cl 3 C(O)C(R 2 )=C(R 1 )OR, where R 2 =H, Me; R 1 =H, alkyl, phenyl and R=Me, Et] with phenyl hydrazine and 1,2-dimethylhydrazine dihydrochloride, respectively, using toluene as solvent. The use of microwave and classical methods are comparable for making pyrazoles, but the formation of pyrazolium chlorides can be achieved in a significant shorter time, and in some cases better yield.

Regiospecific synthesis of polyfluorinated heterocycles

A series of 10 heterocycles was obtained from the reaction of 1,1,1-trifluoro-4,4-diethoxy-3-buten-2-one and 1,1,1,2,2-pentafluoro-4,4-diethoxy-3-penten-2-one with different dinucleofiles (hydrazine, methyl hydrazine, hydroxylamine and sodium cyanide). The pyrazoles, 4,5-dihydroisoxazoles and pyrrolidinones polyfluoroalkyl substituted were obtained in moderate to good yields under mild conditions.

Microwave assisted synthesis of 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles

Abstract A series of 13 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles have been synthesized in 78–96% yield by environmentally benign microwave induced techniques involving the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones [CCl 3 C(O)C(R 2 )=C(R 1 )OR, where R 2 =H, alkyl; R 1 =H, alkyl, aryl and R=H, alkyl] with hydroxylamine using toluene as solvent. The advantages obtained by the use of microwave irradiation in relation to a classical method were demonstrated.

5-Trifluoromethyl-1,2-dimethyl-1H-pyrazolium chlorides: synthesis and 1H, 13C, 19F and 35Cl NMR chemical shifts

Abstract The one-pot synthesis of nine novel 5-trifluoromethyl-1,2-dimethyl-1H-pyrazolium chlorides 2 from the cyclocondensation of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones 1 [CF3C(O)CH=C(R1)OR, where R1=H, Me, n-Pr, n-Hex, Ph, 4-Me-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-NO2-C6H4, and R=Me, Et] with 1-2-dimethyl hydrazine, in quantitative yields, is reported. The 1 H , 13 C , 19 F and 35 Cl NMR chemical shifts of compounds 2 also are described.

Microwave-assisted synthesis of novel 5-trichloromethyl-4,5-dihydro-1H-1-pyrazole methyl esters under solvent free conditions

Twelve novel 5-trichloromethyl-4,5-dihydro-1H-1-pyrazole ethyl esters have been synthesized in good yields (70-98%) by using environmentally benign microwave induced techniques. The compounds were synthesized from the cyclocondensation of 1,1,1-trichloro-4-alkoxy-3-alken-2-ones [CCl3C(O)C(R2)=C(R1 )OR, where R, R2 = H, alkyl; R1 = H, alkyl and aryl] with hydrazine methyl carboxylate. The advantages obtained by the using of microwave irradiation under solvent-free conditions, rather than a conventional method, were demonstrated.

One‐Pot Synthesis of Pyrazole‐5(3)‐carboxyamides

Abstract A convenient one‐pot synthesis of eight pyrazole‐5(3)‐carboxyamides from the reaction of the 5(3)‐trichloromethylpyrazoles with amines, in good yield, is reported. These reactions show that the trichloromethyl group is a convenient precursor to carboxyamide groups.

Simplified Approach to the Regiospecific Synthesis of Trichloromethylpyrazolines Using Microwave Irradiation

Abstract Twelve novel 3-alkyl[aryl]-1-carboxamides-5-trichloromethyl-5-hydroxy-4,5-dihydro-lH-pyrazole have been synthesized in good yields (72–90%) using environmentally benign microwave-induced techniques. The compounds were synthesized from the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alkyl[aryl]-2-ones [Cl3CC(O)C(R2) = C(R1)OR, where R = Me, Et; R1 = H, Me, Et, Pr, i-Pr, i-Bu, t-Bu, Ph, Ph-4-NO2, Ph-4-F, Ph-4-Cl, Ph-4-Br; and R2 = H, Me] with semicarbazide hydrochloride in the presence of pyridine and using methanol/water (3:1 v/v) as the solvent. The advantages of using microwave irradiation, rather than a conventional method, were demonstrated.