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The convenient synthesis of ten halo- and an isoxazole-containing acetylenes from the reaction of acetylenes with n -butyl lithium and subsequent reaction with an electrophile agent (ethyl trichloroacetate, ethyl dichloroacetate, trifluoroacetic anhydride, 3-methylisoxazol-5-carbonyl chloride, carbon tetrachloride and 1,1,1-trifluoro-4-ethoxy-3-buten-2-one) in moderated to good yields is reported. The application of 1,1,1-trichloro-4-phenyl-3-butyn-2-one on the synthesis of two azoles is also showed.

In this study we describe a low-cost and reliable method for inducing fever in young male rats (28-30 days of age, 75-90 g), which seems suitable for the screening of new antipyretics. The effects of temperature measuring procedure-induced stress on the basal rectal temperature and on Baker yeast-induced hyperthermia was assessed. Rectal temperature (T) was recorded every hour for 12 h (07:00-19:00 h) with a lubricated thermistor probe. The animals were injected intraperitoneally with baker yeast (0.25, 0.135, 0.05 g/kg) or the equivalent volume of saline at 7:00 h. The administration of 0.135 g/kg baker yeast induced a sustained increase in rectal temperature for 4 h. Classical (dipyrone and acetaminophen) and novel (MPCA and FPCA) antipyretics, at doses that had no effect per se, reverted baker yeast-induced fever. The method presented induces a clear-cut fever, which is reverted by antipyretics commonly used in human beings and selected novel antipyretics in small animals. The method also allows antipyretic evaluation with low amount of drugs, due to the use of small animals and to the small variability of the pyretic response, which ultimately causes a significant reduction in the number of animals necessary for antipyretic evaluation. Therefore, this study describes an animal model of fever that is not only advantageous from the economical and technical point of view, but that also bears ethical concerns.

In this study, we investigated whether spinal noradrenergic and serotonergic systems are involved in the antinociception induced by the novel pyrazolines 3-methyl- and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-1-pyrazole-1-carboxyamide (MPCA and PPCA, respectively), and the pyrazolinone dipyrone in the acetic acid writhing (stretching) test in mice. Intrathecal (i.t.) administration of methysergide (3 and 10 microg) and yohimbine (3 microg), but not of prazosin (0.3 and 1 microg) prevented the antinociceptive action of MPCA and PPCA (500 micromol/kg, s.c.). Dipyrone-induced antinociception (500 micromol/kg, s.c.) was not affected by methysergide or adrenoceptor antagonists. These results suggest that spinal 5-HT receptors and alpha2-adrenoceptors are involved in the antinociception induced by MPCA and PPCA, but not in that elicited by dipyrone.

The β-alkoxyvinyl dichloromethyl ketones 1a-d are cyclocondensed with hydroxylamine hydrochloride in pyridine to afford the 5-hydroxy-5-dichloromethyl-4,5-dihydroisoxazoles 2a-d in good yield. The cyclo-condensation of compound 1c gave, together with 2c, 3-cyano-2-hydroxy-2-dichloromethyltetrahydrofuran 5c. The dehydratation of compounds 2a,b, derived from acyclic enol ethers, with concentrated sulfuric acid at 30°, led the corresponding 5-dichloromethylisoxazoles 3a,b. The dehydratation of compounds 2c,d, derived from cyclic enol ethers, with concentrated sulfuric acid at 30°, led the bicyclic 4,5-dihydroisoxazoles 4c,d, and at 55°, a competitive rearrangement reaction gives the 3-cyano-2-hydroxy-2-dichloromethyl-2H-pyran 5d.

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.

The regiospecific synthesis of a novel series of 4-trifluoro[chloro]-2-(5-hydroxy-5-trifluoro[chloro]methyl-4,5-dihydro-1H-pyrazol-l-y1]-pyrimidines from the reactions of 4-alkoxy-1,1,1 -trifluoro[chloro]-alk-3-en-2-ones with 6-trifluoro(chloro]methyl-2-hydrazine pyrimidines is presented.

The synthesis of a novel series of eleven 6-aryl(5-methyl)-4-trifluoromethyl-2(1H)-pyrimidinones, where aryl ¼ Ph, 4-CH3Ph, 4-FPh, 4ClPh, 4-BrPh, 4-OCH3Ph and alkyl ¼ H, CH3, from the reaction of 4-aryl-4-methoxy-1,1,1-trifluoro-3-buten-2-ones with urea in the presence of hydrochloric acid, is reported. Trifluoroacetylation of acetophenone- and propiophenone-dimethylacetals derived from phenones, was employed to obtain the precursors. # 2002 Elsevier Science B.V. All rights reserved.

A convenient synthesis of fourteen 4-methyl- and 4-phenylseleno-1,1,1-trihalo-3-alken-2-ones [CX 3 C(O)CH=CR 1 SeR. where X = F, Cl; R = Me, Ph; and R 1 = H, alkyl, aryl from the reaction of the corresponding 4-methoxy-1,1,1-trihalo-3-alken-2-ones with methyl- or phenylselenols in the presence of boron trifluoride etherate is reported. The reaction of 4-methylseleno- 1,1,1-trihalo-3-alken-2-ones with bromine and ammonia lead to 3-trihalomethylisoselenazoles in good yields. The usefulness of the trichloromethyl group as a carboxyl group precursor was demonstrated by the conversion of 5-ethyl-3-trichloromethylisoselenazole to 5-ethyl-3-carboxyisoselenazole acid.

The effect of novel pyrazolines, 3-methyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamide (MPCA) and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole-1-carboxyamide (PPCA) on body temperature and endotoxin-induced fever was investigated in mice. The subcutaneous (s.c.) administration of 1.5 mmol/kg dipyrone, MPCA or PPCA and the intracerebroventricular (i.c.v.) administration of 225 nmol dipyrone reduced basal rectal temperature. Intracerebroventricular administration of 225 nmol MPCA or PPCA did not alter basal rectal temperature. The administration of 0.15 mmol/kg (s.c.) or 25 nmol (5 microl) dipyrone (i.c.v.), MPCA or PPCA had no effect on basal rectal temperature, but reversed lipopolysaccharide-induced fever. These results suggest that MPCA and PPCA cause antipyresis, which is similar to that caused by dipyrone, and may be useful antipyretic agents.

The one-pot synthesis of six 3-methylisoxazole-5-carboxamides 2 [where the N-substituents are R1 = H, Me and R2 = Ph, CH2Ph, n-Bu, C(CH3)2Et, 3-methylisoxazol-5-yl] and twelve 5-[(1H-pyrazol-1-yl)carbonyl]-3-methyl isoxazoles 3 and 4 [where the pyrazole substituents are R3 (C5/C3) = CO2Et, CF3 and R5 (C3/C5) = H, Me, Et, Ph] from the 3-methyl isoxazole-5-carboxylic acid, thionyl chloride and the corresponding amine or pyrazole is reported. In the synthesis of 5-[(1H-pyrazol-1-yl)carbonyl]-3-methylisoxazoles we obtained a mixture of 1,3- and 1,5-isomers 3 and 4 in variable ratios, i.e., the substituent R3 (CO2Et and CF3) are present in position 3 or 5 on the pyrazole ring.

The synthesis of a series of novel trifluoromethylated β-acetal- gem -diols, 4-alkoxy-4-ethoxy-1,1,1-trifluoro-butane-2,2-diols ( 4a = methoxy , 4b = ethoxy , 4c = allyloxy , 4d = ynyloxy ) and 1-(2-alkoxytetrahydro-furan-3-yl)-2,2,2-trifluoro-ethane-1,1-diols ( 6a = methoxy , 6b = ethoxy , 6c = allyloxy , 6d = ynyloxy ) from the reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one ( 1 ) and 1-(4,5-dihydro-furan-3-yl)-2,2,2-trifluoro-ethanone ( 2 ) with sodium azide in hydro-alcoholic medium, is presented. From these reactions, a small amount (ca. of 20%) of the parent trifluoromethylated β-acetal-ketones, 4-alkoxy-4-ethoxy-1,1,1-trifluoro-butan-2-ones ( 3a – d ) and 2,2,2-trifluoro-1-(2-alkoxy-tetrahydro-furan-3-yl)-ethanones ( 5a – d ) were also obtained. The synthetic potential of the trifluoromethylated β-acetal-diols was demonstrated by its application to the synthesis of 3-ethoxy-5-hydroxy-5-trifluoromethyl-pyrrolidin-2-one ( 7 ).

A convenient method to obtain a new series of 2-trichloromethyl-4-aryl-3H-1,5-benzodiazepines from the reaction of β-methoxyvinyl trichloromethyl ketones derived from acetals and o-phenylenediamine is reported.

Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is understudied, we evaluated the potential antinociceptive effect of the reversible MAO-A inhibitors moclobemide and 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in a mouse neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve. Neuropathic mice showed a decreased mechanical paw withdrawal threshold (PWT) 7days after lesion compared with the baseline PWT, characterizing the development of hyperalgesia. Moclobemide (100–300μmol/kg, s.c.) and 2-DMPI (30–300μmol/kg, s.c.) treatments were able to reverse the CCI-induced hyperalgesia, with 50% inhibitory dose (ID50) values of 39 (18–84) and 11 (4–33) μmol/kg, and maximum inhibition (Imax) values of 88±14 and 98±15%, respectively, at the 300μmol/kg dose. In addition, we observed a significant increase in the MAO-A activity in the lumbar spinal cord of CCI-submitted mice compared with sham-operated animals. Furthermore, the antihyperalgesic effects of both 2-DMPI and moclobemide were largely reversed by intrathecal injection of the 5-HT3 receptor antagonist ondansetron (10μg/site). These results suggest a possible involvement of MAO-A in the mechanisms of neuropathic pain and a potential utility of the reversible inhibitors of MAO-A in the development of new therapeutic approaches to treat it.

Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) μM and 46.67 (31.8-68.4) μM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 μmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 μmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 μmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.

The one-pot, simple and efficient three-component condensation protocol for the preparation of a series of twenty-five new 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-ones, where aryl = Ph, 4-tolyl, 4-ClPh, 4-NO2Ph and 4-CHOPh, and acyl = Ac, Bz, 4-FBz, furan-2-oyl, thien-2-oyl and naphth-1-oyl, employing 1,3-cyclohexanedione, five aryl aldehydes and for the first time, six 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trifluoroalk-3-en-2-ones, is described. Yields in 15–75% were obtained when the MCRs were performed in the presence of a catalytic amount of triethylamine (25 mol%) and in ethanol as solvent under reflux for 16 h. A representative X-ray diffraction data for 3-acetyl-4-phenyl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one is also showed.

An efficient and regioselective procedure for the synthesis of a series of alkyl(aryl/heteroaryl) substituted 3-trifluoromethyl-1 H -1-phenylpyrazoles and alkyl 3-carboxylate analogs, from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones [CX 3 C(O)CR 2 =CR 1 (OMe/OEt), where R 1 = H, Me, Ph, 2-Furyl; R 2 = H; R 1 -R 2 = -C 4 H 8 - and X = F, Cl] and 1-phenylsemicarbazide in an acidified alcoholic medium (R 3 OH/H 2 SO 4 ), where R 3 = Me, Et, Pr i was successfully applied and is described here in detail.

A regioselective synthesis of 3-trifluoromethyl-1-phenyl-1H-pyrazoles (1,3-isomers) as well as their 1,5-isomers (5-trifluoromethyl-1-phenyl-1H-pyrazoles), is described. The 1,3-isomers were obtained from the reaction of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with arylhydrazones followed by deprotective hydrolysis while the 1,5-isomer was obtained by direct cyclocondensation of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with phenylhydrazine. An unequivocal assignment of the 1,3- and 1,5-isomers of the pyrazole products is given.

The efficient synthesis of 1,2-dihydropyridine from the intramolecular cyclization reaction of N -propargylic β-enaminones [R 2 C(O)CH C(R 1 )(N(R)CH 2 C CH), where R = Pr, Bn, Ph, 4-Me-C 6 H 4 , R 1 = Me, Et, Pr, R 2 = CF 3 , CO 2 Et] using AgNO 3 as a catalyst (12 h at 25 °C) is reported. The products were obtained at good yields (70–90%). In particular, when the reaction of N -propargylic β-enaminone with R = Me was performed over a 24 h period, the intramolecular cyclization resulted in the formation of a pyrrole with 80% yield.

An efficient method to obtain 4-alkoxy-2-oxo-but-3-enoic acid ethyl esters [EtO2CC(O)C(R 2 )=C(R 1 )OR, where R = Me, Et; R 1 = Me, Ph, 4-MeC6H4, 4-BrC6H4, 4-FC6H4; R 2 = H, Me] from the acylation of enol ethers or acetals with ethyl oxalyl chloride is reported. The cyclocondensation reaction of these substrates and their trifluoromethylated analogues [CF3C(O)C(R2)=C(OR)R 1 ] with salicylic hydrazide furnished a series of ethyl 5-hydroxy-1-(2hydroxybenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylates and 5-hydroxy-5-trifluoromethyl-4,5dihydro-1H-1-(2-hydroxybenzoyl) pyrazoles, respectively. The structure of the compounds was supported by crystallographic data. Orally administrated, one of each of the series of pyrazoles (R 2 = H, R 1 = Me) showed significant analgesic effects in the writhing test in mice. The decrease in pain-related behavior obtained was close to that achieved with aspirin activity.

A new series of 4-[3-alkyl(aryl)(heteroaryl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl]-7-chloroquinolines, where [alkyl = CH3; aryl = C6H5, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3OCgH4, 4-NO2CgH4, 4-biphenyl, 1-naphthyl; heteroaryl = 2-furyl and 2-thienyl] has been regiospecifi-caly obtained from the reaction of 7-chloro-4-hydrazinoquinoline with 4-substituted-l,1,1-trifluoro-4-methoxybut-3-en-2-ones in 61 - 96 % yield. Subsequently, dehydration reaction of 4,5-dihydropyra-zolylquinolines under acid conditions furnished a new series of 4-(3-substituted-5-trifluoromethyl-1H-pyra-zol-1-yl)-7-chloroquinolines in 73 - 96 % yield.

The antinociceptive effect of six novel synthetic pyrazolines (3-ethoxymethyl-5-ethoxycarbonyl-1H-pyrazole (Pz 1) and its corresponding 1-substituted methyl (Pz 2) and phenyl (Pz 3) analogues, and 3-(1-ethoxyethyl)-5-ethoxycarbonyl-1H-pyrazole (Pz 4) and its corresponding 1-substituted methyl (Pz 5) and phenyl (Pz 6) analogues) was evaluated by the tail immersion test in adult male albino mice. The animals (N = 11-12 in each group) received vehicle (5% Tween 80, 10 ml/kg, sc) or 1.5 mmol/kg of each of the pyrazolines (Pz 1-Pz 6), sc. Fifteen, thirty and sixty minutes after drug administration, the mice were subjected to the tail immersion test. Thirty minutes after drug administration Pz 2 and Pz 3 increased tail withdrawal latency (vehicle = 3.4 +/- 0.2; Pz 2 = 5.2 +/- 0.4; Pz 3 = 5.9 +/- 0.4 s; mean +/- SEM), whereas the other pyrazolines did not present antinociceptive activity. Dose-effect curves (0.15 to 1.5 mmol/kg) were constructed for the bioactive pyrazolines. Pz 2 (1.5 mmol/kg, sc) impaired motor coordination in the rotarod and increased immobility in the open-field test. Pz 3 did not alter rotarod performance and spontaneous locomotion, but increased immobility in the open field at the dose of 1.5 mmol/kg. The involvement of opioid mechanisms in the pyrazoline-induced antinociception was investigated by pretreating the animals with naloxone (2.75 micro mol/kg, sc). Naloxone prevented Pz 3- but not Pz 2-induced antinociception. Moreover, naloxone pretreatment did not alter Pz 3-induced immobility. We conclude that Pz 3-induced antinociception involves opioid mechanisms but this is not the case for Pz 2.

The synthesis of a novel series of the intermediates N2(N3)-[1-alkyl(aryl/heteroaryl)-3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2-aminopyridines [F3CC(O)CHCR1(2NHC5H3N)] and 2,3-diaminopyridines [F3CC(O)CHCR1(2-NH2-3-NHC5H3N)], where R1 = H, Me, C6H5, 4-FC6H4, 4-CIC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4,4′-biphenyl, 1-naphthyl, 2-thienyl, 2-furyl, is reported. The corresponding series of 2-aryl(heteroaryl)-4-trifluoromethyl-3H-pyrido[2,3-b][1,4]diazepin-4-ols obtained from intramolecular cyclization reaction of the respective trifluoroacetyl enamines or from the direct cyclocondensation reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 2,3-diaminopyridine, under mild conditions, is also reported.

A new, efficient and easy route for the preparation of a series of 2-alkyl(aryl) substituted 4-oxo-4H-pyrido-[1,2-a]pyrimidines, where alkyl = CH3; aryl = C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4-NO2C6H4 in 45–80 % yield from the reaction of β-alkoxyvinyl trichloromethyl ketones with 2-aminopyridine under mild conditions, is then reported.

The synthesis of a novel series of twelve 4-(trihalomethyl)dipyrimidin-2-ylamines, from the cyclo-condensation reaction of 4-(trichloromethyl)-2-guanidinopyrimidine, with β-alkoxyvinyl trihalomethyl ketones, of general formula: X3C-C(O)-C(R2)=C(R1)-OR, where: X = F, Cl; R = Me, Et, -(CH2)2-, -(CH2)3-; R1 = H, Me; R2 = H, Me, -(CH2)2-, -(CH2)3-, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin-2-ylamines in 65-90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4-(trihalomethyl)dipyrimidin-2-ylamines was studied in detail by 1H-, 13C- and 2D-nmr spectroscopy.

A convenient method for the synthesis of a novel series of eighteen non-condensed 5,5-bicycles, specifically 2-(3- alkyl(phenyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyra- zol-1-yl)-4-phenyl-5-alkylthiazoles and -4,5,6,7-tetrahydroben- zothiazoles 3a-i from the reaction of 3-alkyl(phenyl)-5-hydroxy-5- trifluoromethyl-4,5-dihydro-1H-1-pyrazolethiocarboxyamide (1) with 2-bromoacetophenone, 2-bromopropiophenone and 2-bro- mocyclohexanone (2), is reported. The dehydration of compounds 3a-i with a mixture of concentrated sulfuric acid-acetic acid (1:10 v/v) led to the corresponding 2-(3-alky(phenyl)-5-trifluoromethyl- 1H-pyrazol-1-yl)-4-phenyl-5-alkylthiazoles and respective 4,5,6,7- tetrahydrobenzothiazoles 4a-i in good yield.

The tautomerism of three polymethylenepyrazoles bearing at position 3(5) a trifluoromethyl group has been studied by NMR in solution (1H, 13C, 15N, 19F) and in the solid state ( 13C, 15N). The conclusion is that in all cases they are 3-CF3 tautomers. DFT calculations have been carried out to compare these compounds to the analogous 3-CH3 derivatives and to assess the Mills-Nixon effect in the case of trimethylene derivatives as well as the effect of replacing a CH3 by a CF3 group on the tautomerism.

A convenient method to obtain a series of 3-alkyl-2-aryl-4-trifluoromethylbenzo[h]quinolines derivatives 3a-1, where alkyl = H, Me; aryl = Ph, 4-MeC 6 H 4 , 4-FC 6 H 4 , 4-ClC 6 H 4 , 4-BrC 6 H 4 , 4-OMeC 6 H 4 and 4-NO 2 C 6 H 4 , by intramolecular cyclization of the readily available intermediates N-(2-alkyl-1-aryl-3-oxo-4,4,4-trifluorobut-1-en-1-yl)-1-naphthylamines 2a-1 using poly-phosphoric acid, is reported. Compounds 2 are obtained from the reaction of 3-alkyl-4-aryl-1,1,1-trifluoro-4-alkoxybut-3-en-2-ones 1a-1 with 1-naphthylamine under reflux in chloroform.