Showing papers by "Helio G. Bonacorso published in 2009"

Antinociceptive effect of a novel tosylpyrazole compound in mice.

Abstract: Pain is the most common complaint in the medical field and the identification of compounds that can effectively treat painful states without induction of side-effects remains a major challenge in biomedical research. The aim of the present study was to investigate the antinociceptive effect of a novel compound, 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (compound A) in several models of pain in mice and compare with those produced by the known trifluoromethyl-containing pyrazole compound celecoxib. Compound A or celecoxib were administrated by oral (78–780 µmol/kg), intrathecal (9–22.5 nmol/site) or intracerebroventricular (9–22.5 nmol/site) routes. Oral administration of either compound A or celecoxib abolished the mechanical allodynia, but not the oedema caused by intraplantar injection of carrageenan. Similarly, compound A reduced the overt nociception, but not the oedema, produced by bradykinin or capsaicin. However, compound A (500 µmol/kg, orally) did not alter nociception nor oedema caused by intraplantar injection of prostaglandin E2 or glutamate, whereas celecoxib reduced only the nociception induced by the former. Moreover, oral and intrathecal administration of compound A or celecoxib also reduced the nociception induced by acetic acid. However, only celecoxib reduced the acetic acid-induced nociception when it was injected by the intracerebroventricular route. Finally, neither compound A nor celecoxib was able to produce antinociceptive effect in the tail-flick test or to alter the motor performance and the body temperature. Besides, compound A or celecoxib did not induce gastric lesion. Thus, compound A seems to be an interesting prototype for the development of novel analgesic drugs.

2-methyl-7-substituted pyrazolo[1,5-a]pyrimidines: highly regioselective synthesis and bromination

Abstract: The reaction of 3-amino-5-methyl-1H-pyrazole with 1,1,1-trichloro-4-alkoxy-3-alken-2-ones [CCl3C(O)CH=C(R1)OR, where R1/R = H/Me, Me/Et, Et/Me, Pr/Et, Bu/Me, iso-Bu/Me] or β-dimethylaminovinyl ketones [R2C(O)CH=CHNMe2, where R2 = Ph, Ph-4-Me, Ph-4-F, Ph-4-Cl, Ph-4-Br, Ph-4-NO2, fur-2-yl, thien-2-yl, pyrrol-2-yl, pyrid-2-yl], in acetic acid under reflux for 16 hours, furnished highly regioselective the halomethylated pyrazolo[1,5-a]pyrimidines and aryl[heteroaryl]pyrazolo[1,5-a]pyrimidines, respectively. A protocol for the bromination reaction at the 3-position pyrazolo[1,5-a]pyrimidines also was investigated.

Antioxidant Potential of New Pyrazoline Derivatives to Prevent Oxidative Damage

Abstract: The antioxidant capacity of a series of six novel synthetic pyrazoline derivatives (i) 5-hydroxy-3-methyl-5- trifluoromethyl-4,5-dihydro-1 H -carbaldehyde-pyrazole, (ii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-acetyl-pyrazole, (iii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -carboxyamide-pyrazole, (iv) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5- dihydro-1 H -1-benzoyl-pyrazole, (v) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(2-hydroxybenzoyl)-pyrazole and (vi) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(4-methoxybenzoyl)-pyrazole was evaluated as the capacity of compounds to transfer a hydrogen atom (protection against brain lipid peroxidation and glutathione oxidation) and their capacity to transfer a single electron (ferric-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl radical scavenging (DPPH) assays). Compound 5 had the highest free radical scavenging capacity in the DPPH assay, while compound 2 had the highest FRAP value (P < 0.05). Only compounds 1, 4 and 5 protected against lipid peroxidation in rat brain homogenate. However, compound 5 was the most effective to prevent basal and iron-, sodium nitroprusside- and H 2 O 2 -stimulated lipid peroxidation (IC 50 < 15 μ M) and the only one effective to block glutathione oxidation-mediated by H 2 O 2 (at 150 μ M). Our results indicate that compound 5 has the greatest potential to prevent oxidative damage in brain homogenates.

Ionic Liquids Promoted the C-Acylation of Acetals in Solvent-free Conditions

Abstract: The synthesis of a series of fourteen 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (2,3) [CX3COC(R2)=C(R1)OMe, where X = Cl, F; R1/R2 = Me/H, Bu/H, i-Bu/H, Ph/H, Thien-2-yl/H, –(CH2)4–, –CH(CH2)4CH(CH2)2–] from the acylation reactions of acetals (1) with trichloroacetyl chloride or trifluoroacetic anhydride in the presence of equimolar amounts of pyridine and imidazolium based ionic liquid ([BMIM][BF4] or [BMIM][PF6]) is reported. The reaction time, yields and IL recyclation are also investigated and this method showed advantages over the methods described in the literature.

Convenient One-Pot Synthesis of N-Substituted 3-Trifluoroacetyl Pyrroles

Abstract: A new one-pot strategy for the synthesis of a series of new N-substituted 3-trifluoroacetyl pyrroles is presented. These compounds were obtained by the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with primary amines, which generated 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-alkylaminobut-3-en-2-one intermediates. In most cases these intermediates were not stable enough to be isolated. Thus, in the same reaction vessel they were directly submitted to oxidation with PCC (Corey's reagent) to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-alkylaminobut-3-en-2-ones, which under reflux underwent intramolecular cyclization to give the desired N-substituted 3-trifluoroacetyl pyrroles, in moderate yields. All of these pyrroles were tested against pan-susceptible Mycobacterium tuberculosis H37Rv and clinical isolates INH- and RMP-resistant strain and some of these compounds showed significant in vitro antimicrobial activity.

Synthesis of new trihalomethylated and non-symmetrical substituted 2-(1H-pyrazolyl)-5-(1H-pyrazolylcarbonyl)pyridines

Abstract: This paper describes the synthesis of a new series of 2-[3-alkyl(aryl/heteroaryl)- 5-trifluoro(chloro)methyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]-5-[3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl-1-carbonyl]pyridines by the cyclocondensation reaction of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoro(chloro)-3-alken- 2-ones [CX3C(O)CH=CR1OR, where R = Me, Et; R1 = H, Me, Ph, 4-MeOPh, 4-NO2Ph, 4,4'-Biphenyl, 1-Naphthyl, Fur-2-yl, Thien-2-yl and X = F, Cl] with 6-hydrazinonicotinic hydrazide hydrate Yields of 62 to 97% were obtained when the reactions were performed in ethanol as solvent at 78 oC for 4 hours In a subsequent step, the dehydration reactions of 2-(5-hydroxy-1H-pyrazol-1-yl)-5-(5-hydroxy-1H-pyrazol-1-yl-1-carbonyl)pyridines were carried out in pyridine/benzene in the presence of thionyl chloride and led to the isolation of a series of 2- [3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-1H-pyrazol-1-yl]-5-[3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-1H-pyrazol-1-yl-1-carbonyl]pyridines, in 64 to 86% yields

Preparation of novel trifluoroacetylketene O,N-acetals and trifluoromethyl-containing S,S-sulfoximido N-substituted heterocycles

Abstract: Two new trifluoroacetylketene O,N-acetals [CF3C(O)CH=C(OEt)(NS(O)R2), where R = CH3, Ph] derived from the reaction of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one [CF3C(O)CH=C(OEt)2] with S,S-dimethyl- and S-methyl-S-phenyl-sulfoximide [HN=S(O)R2], in the presence of triethylamine, have been obtained, in 60-72% yields, and applied in the synthesis of S,S-dimethylsulfoximido-substituted pyrazoles, isoxazoles and pyrimidines, in 55-89% yields, from the reactions of 4-ethoxy-4-(S,S-dimethylsulfoximido)-1,1,1-trifluorobut-3-en-2-one with hydrazines, hydroxylamine hydrochloride and acetylguanidine.

β-Alkoxyvinyl trifluoromethyl ketones as efficient precursors for the one-pot synthesis of bis-(4,5-dihydro-1H-pyrazol-1-yl)methanones and 1H-pyrazolyl-1-carbohydrazides

Abstract: The one-pot and regioselective synthesis of a novel series of 3-aryl(heteroaryl)-5trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazolyl-1-carbohydrazides and bis-(3-aryl-5trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)methanones from the cyclocondensation reactions of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones, where aryl substituents are H, Me, Ph, 4-OMePh, 4-ClPh, 4-BrPh, 4,4’-biphenyl and heteroaryl are 2-thienyl and 2furyl, with carbohydrazide is reported.

Ultrasound Promoted Synthesis of 2‐Imidazolines in Water: A Greener Approach Toward Monoamine Oxidase Inhibitors.

Abstract: A series of sixteen 2-substituted-2-imidazolines (where the substituent R=Ph, Me-4-Ph; MeO-4-Ph; (MeO)(2)-3,4-Ph; (MeO)(3)-3,4,5-Ph; Ph-4-O-C(O)-Ph; Cl-4-Ph; Cl-2-Ph; Cl(2)-2,4-Ph; NO(2)-4-Ph; NO(2)-3-Ph; Naphth-2-yl; Fur-2-yl; Benzofur-2-yl; Pyridin-2-yl; Quinolin-2-yl) has been synthesized from the reaction of the substituted-aldehydes and ethylenediamine by ultrasound irradiation with NBS in an aqueous medium in high yields (80-99%). The 2-imidazoline ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO) was investigated and some of them showed potent and selective MAO inhibitory activity especially for the MAO-B isoform and could become promising candidates for future development.

Synthesis of Ethyl Pyrimidine‐4‐carboxylates from Unsymmetrical Enamino Diketones and Their Application in the First Synthesis of Pyrimido[4,5‐d]pyridazin‐8(7H)‐ones

Abstract: SYNTHESIS 2008, No. 22, pp 3639–3648xx.xx.2008 Advanced online publication: 23.10.2008 DOI: 10.1055/s-0028-1083202; Art ID: M03208SS © Georg Thieme Verlag Stuttgart · New York Abstract: The reaction of unsymmetrical enamino diketones [RC(O)C(=CNMe2)C(O)CO2Et, where R = Ph, 4-MeC6H4, 4MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, 2-thienyl, benzofuran-2-yl, and CF3] with N–C–N dinucleophiles, such as benzamidine hydrochloride or 1H-pyrazole-1-carboxamidine monohydrochloride, afforded a series of ethyl 2,5-disubstituted pyrimidine-4-carboxylates in a chemoselective and highly chemoselective manner (51–86%). Reaction of these two series of pyrimidines (R = Ph, 4-MeOC6H4, 4-FC6H4, and 2-thienyl) with hydrazine monohydrate under mild conditions led to 2,5-substituted pyrimido[4,5-d]pyridazin-8(7H)-ones in high yields (81–92%).

N -Alkylation of 4-Trichloromethylpyrimidinones: Synthesis of Some New and Interesting Modified Nucleoside Analogues

Abstract: The N1-alkylation of 4-(trichloromethyl)pyrimidin-2(1H)-one, 4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin- 2(1H)-one, and 5-bromo-4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin-2(1H)-one with selected alkylating agents such as 2-chloroacetamide, diethyl 2-bromomalonate, and 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, is presented. Further reactions of 1-[5,5,5-trichloro-2-methoxy-4-oxo-penten-2-yl]4-trichloromethyl-pyrimidin-2(1H)-one with primary amines and aminoalcohols furnished a series of unexpected new acyclic nucleoside analogues.

DAST Promotes the Synthesis of New 5‐(Trifluoromethyl)‐3‐(1,1‐difluoroethan‐2‐yl)‐1H‐pyrazoles.

Abstract: This study describes, firstly, the synthesis of a new precursor, 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one ( 1 ), from the trifluoroacetylation reaction of 1,1,3,3-tetramethoxybutane, in 65% yields. Afterwards, the reaction of 1 with two hydrazines (NH 2 NHR, where R = 2-furanoyl, C 6 F 5 ) led to a new series of 4,5-dihydro-1 H -pyrazoles, containing an acetal-protected aldehyde function as substituent, in 90–97% yields. In a subsequent step, the dehydration reactions of these 4,5-dihydro-1 H -pyrazoles gave the respective aromatic 1 H -pyrazoles. Finally, we report the results of the deprotection reactions of the acetals to obtain the respective aldehyde function, as well as, the subsequent fluorination reaction using DAST, leading to new difluorinated derivatives in 55–60% yields.

Convenient One-Pot Synthesis of N-Substituted 3-Trifluoroacetyl Pyrroles.

Abstract: A new one-pot strategy for the synthesis of a series of new N-substituted 3-trifluoroacetyl pyrroles is presented. These compounds were obtained by the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with primary amines, which generated 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-alkylaminobut-3-en-2-one intermediates. In most cases these intermediates were not stable enough to be isolated. Thus, in the same reaction vessel they were directly submitted to oxidation with PCC (Corey's reagent) to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-alkylaminobut-3-en-2-ones, which under reflux underwent intramolecular cyclization to give the desired N-substituted 3-trifluoroacetyl pyrroles, in moderate yields. All of these pyrroles were tested against pan-susceptible Mycobacterium tuberculosis H37Rv and clinical isolates INH- and RMP-resistant strain and some of these compounds showed significant in vitro antimicrobial activity.

An Ionic Liquid as Reaction Medium for the Synthesis of Halo‐Containing β‐Enaminones at Room Temperature.

Abstract: A series of twenty halomethylated β-enaminones [RC(O)CH=C(R 1)NR 3 R 4, where R = CF3,CCl3, CHCl2; R 1 = H, Me, Ph; R 3 = H, Me, Bu, Et; R 4 = Me, Et, Bu, allyl, tert-amyl, CH2CH2OH, Bn, Ph] were synthesized using the ionic liquid [bmim]BF4 at room temperature. It is demonstrated that this ionic liquid is a reaction medium suitable for the amination of β-alkoxyvinyl halomethyl ketones. The advantages of this method are the absence of solvents, short reaction times, and good yields.

Highly Chemoselective Synthesis of 6‐Alkoxy‐1‐alkyl(aryl)‐3‐trifluoroacetyl‐1,4,5,6‐tetrahydropyridines and 1‐Alkyl(aryl)‐6‐amino‐3‐trifluoroacetyl‐1,4,5,6‐tetrahydropyridines.

Abstract: A simple and highly chemoselective method for the synthesis of a large series of novel 6-alkoxy-1-alkyl(aryl)-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines and 1-alkyl(aryl)-6-amino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridines, from the reaction of 6-alkoxy-3-trifluoroacetyl-4,5-dihydro-6H-pyrans with primary alkyl and arylamines, in good yields, is reported. Preliminary in vitro antimicrobial activity of the 1-alkyl(aryl)-6-amino-3-trifluoroacetyl-1,4,5,6-tetrahydropyridine series was assessed against a variety of microorganisms including yeast-like fungi, bacteria and algae, and some of these compounds exhibit significant antimicrobial activity.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Regiospecific Bromination of 2-Phenyl-3H-pyrimidin-4-ones.

Abstract: Three methods for the regiospecific bromination of 2-pnenyl-3H-pyrimidin-4-ones are presented: bromination or the 5-position of the pyrimidine ring, bromination of the 6-benzylic position and simultaneous bromination of both the 5-position of the pyrimidine ring and 6-benzylic position. Reactions were carried out using simple protocols and the brominated pyrimidines were obtained in good yields.