- FeCl3-DMF complex as efficient catalyst for the synthesis of 6-acyl-2(3H)-benzoxazolones and 6-acyl-2(3H)-benzothiazolones
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FeCl3-DMF complex has been tested on Friedel-Crafts reaction of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone with acid chlorides and anhydrides as acylating agents. In these conditions, the 6-acyl-2(3H)-benzoxazolones and 6-acyl-2(3H)-benzothiazolones were obtained in yields ranging from 52 to 89%. Among the various commonly catalysts; AlCl3-DMF, ZnCl2-DMF and PPA, explored in this study, the best conditions using FeCl3-DMF were found the most convenient one
- Guenadil, Faouzi
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p. 579 - 585
(2019/11/29)
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- Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies
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Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
- Bach, Anders,Pizzirani, Daniela,Realini, Natalia,Vozella, Valentina,Russo, Debora,Penna, Ilaria,Melzig, Laurin,Scarpelli, Rita,Piomelli, Daniele
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supporting information
p. 9258 - 9272
(2015/12/23)
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- BENZOXAZOLONE DERIVATIVES AS ACID CERAMIDASE INHIBITORS, AND THEIR USE AS MEDICAMENTS
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The present invention relates to benzoxazolone derivatives as acid ceramidase inhibitors, pharmaceutical compositions containing these inhibitors and methods of inhibiting acid ceramidase for the treatment of disorders in which modulation of the levels of ceramide is clinically relevant. The invention also provides benzoxazolone derivatives for use as a medicament in the treatment of cancer, inflammation, pain, inflammatory pain or pulmonary diseases.
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Page/Page column 42; 53
(2015/12/11)
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- Design and synthesis of 3-acyl-2(3H)-benzoxazolone and 3-acyl-2(3H)- benzothiazolone derivatives
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A simpler and efficient "green" method using solid sodium hydroxide in a solvent mixture of acetone/water was found to catalyze N-acylation of 2(3H)-benzoxazolones and 2(3H)-benzothiazolones for facile and rapid synthesis of N-acyl derivatives in excellent yields. This method was applied to the synthesis of a series of 132 compounds employing a variety of acyl chlorides. Graphical abstract: [Figure not available: see fulltext.]
- Guenadil, Faouzi,Aichaoui, Hocine,Kapanda, Coco N.,Lambert, Didier M.,McCurdy, Christopher R.,Poupaert, Jacques H.
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experimental part
p. 67 - 80
(2011/09/20)
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- Aromatase inhibitor compounds and uses thereof
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The invention concerns the use of a compound of formula (I) inhibitor of aromatase for the preparation of a pharmaceutical formulation intended for treatment of cancer or psoriasis. It equally relates to compounds of formula (I), notably for their use as active ingredients of a medication.
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Page/Page column 4
(2010/11/26)
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- Unsymmetrical Diarylketones from Electron-rich Heterocyclic Arenes
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AlCl3-mediated chlorocarbonylation of a first arene by oxalyl chloride followed by in situ Friedel-Crafts acylation of a second electron-rich arene expeditiously provides, in a one-pot procedure, either symmetrical or unsymmetrical benzophenones with yields ranging from 17-52%. Best results are obtained when the more activated substrate is used as the second arene. Another advantage is that the resultant benzophenone precipitates from the reaction mixture allowing facile workup.
- Poupaert, Jacques H.,Depreux, Patrick,McCurdy, Christopher R.
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p. 823 - 830
(2007/10/03)
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- Benzazole compounds and their use
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The present invention discloses a method for repelling insects, mites and ticks from warm-blooded animals with a benzazole compound.
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- On the reaction of Meldrum's acid with N- trimethylsilylanilines substituted by electron withdrawing groups
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The reaction of Meldrum's acid with silylated anilines substituted by an electron withdrawing group easily yields the corresponding N-phenyl malonamic acid, when the reaction is performed under high vacuum in dichlorobenzene.
- Roche, Sandrine,Yous, Said,Couturier, Daniel,Rigo, Benoit
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p. 1073 - 1075
(2007/10/03)
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- Friedel-crafts acylation of 2(3H)-benzoxazolone: Investigation of the role of the catalyst and microwave activation
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To study the scope and limitations of the use of complexed species of AlCl3 in Friedel-Crafts reactions, we investigated the acctylation and benzoylation of 2(3H)-benzoxazolone and 3-methyl-2(3H)-benzoxazolone varying the amide complexing agent. We replaced dimethylformamide by N-methylformamide, dimethylacetamide, pyrrolidone, N-methylpyrrolidone, tetramethylurea, and dimethylsulfoxide. However, there was no particular advantage of substituting dimethylformamide by another amide ligand. This can probably be ascribed to the fact that the complex formed between AlCl3 and the complexing agent becomes too stable. Alternatively, a route using polyphosphoric acid and microwave activation was explored. The major advantage of running the reaction in a microwave oven was that a good yield was reached in a rather short period of time.
- Liacha, Messaoud,Yous, Said,Poupaert, Jacques H.,Depreux, Patrick,Aichaoui, Hocine
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p. 1393 - 1397
(2007/10/03)
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- 'Fries like' rearrangement: A novel and efficient method for the synthesis of 6-acyl-2(3H)-benzoxazolones and 6-acyl-2(3H)-benzothiazolones
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6-Acyl-2(3H)-benzoxazolone and 6-acyl-2(3H)-benzothiazolone derivatives have particularly interesting anti-inflammatory, antiepileptic, analgesic and antiviral properties. In this study, we report an original method of acylation on the 6-position of 2(3H)-banzoxazolone and 2(3H)benzothiazolone which consists in a two-step procedure involving migration of the acyl group from the N-position to the 6-position of the hetexocycle, at 165 °C and catalyzed by AlCl3. This new procedure was found to be more efficient with regard to the consumption of AICI3 and the yield (76-90%) than other acylation methods previously described.
- Ucar, Huseyin,Van Derpoorten, Kim,Depovere, Paul,Lesieur, Daniel,Isa, Majed,Masereel, Bernard,Delarge, Jacques,Poupaert, Jacques H.
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p. 1763 - 1772
(2007/10/03)
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- Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)- benzothiazolone derivatives
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A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylene-tetrazole (scMet). Neurologic deficity was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of 1 receptors with nanomolar affinities.
- Ucar, Huseyin,Van Derpoorten, Kim,Cacciaguerra, Silvia,Spampinato, Santi,Stables, James P.,Depovere, Paul,Isa, Majed,Masereel, Bernard,Delarge, Jacques,Poupaert, Jacques H.
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p. 1138 - 1145
(2007/10/03)
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- Synthesis of 6-benzoyl-2(3H)-benzoxazolone and 6-benzoyl-2(3H)-benzothiazolone
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This paper reports and compares different methods to synthesize 6-benzoyl-2(3H)-benzoxazolone and 6-benzoyl-2(3H)-benzothiazolone by Friedel-Crafts acylation of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone.The best method found consisted of the transposition of the N-benzoyl derivative to the target compound, a process taking place at 160 deg C and catalyzed by AlCl3.In these conditions, 6-benzoyl-2(3H)-benzoxazolone and 6-benzoyl-2(3H)-benzothiazolone were obtained in 80 and 85 percent yield, respectively.
- Ucar, Huseyin,derpoorten, Kim Van,Kanyonyo, Martial,Isa, Majed,Lambert, Didier,et al.
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p. 773 - 776
(2007/10/03)
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- Synthesis and antibacterial and antifungal properties of thiazolinoethyl-2(3H)-benzoxazolone derivatives. II
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Cyano derivatives of 6-acyl-2(3H)-benzoxazolones were reacted with cysteamine HCl in ethanol to give the corresponding 6-acyl-3-thiazolinoethyl-2(3H)-benzoxazolones and their antibacterial and antifungal activities were investigated. The chemical structures were proved by means of their IR and 1H-NMR spectra and elemental analysis. Investigation of antimicrobiaI activity of the compounds was carried out by tube dilution and disc techniques using bacteria (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853 and Streptococcus faecalis ATCC 29212) and yeast-like fungi (Candida parapsilosis, C albicans, C pseudotropicalis and C stellatoidea). Inhibitory effects were observed for many compounds against S aureus and Bacillus subtilis. Compounds 13 and 15 had minimum inhibitory concentrations (MIC) of 8.4 and 4.2 μg/mL respectively. The antifungal studies against C albicans (10 and 16, MIC = 67.5 μg/mL), C parapsilosis (15, MIC = 67.5 μg/mL) and C stellaatoidea (9, MIC = 67.5 μg/mL) were more successful in comparison.
- Erol,Aytemir,Yulug
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p. 731 - 734
(2007/10/03)
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- Cyclization-Activated Prodrugs: N-(Substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates Based on Ring-Opened Derivatives of Active Benzoxazolones and Oxazolidinones as Mutual Prodrugs of Acetaminophen
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N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems.A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared.These are open drugs of the skeletal muscle relaxant chlorzoxazone.The corresponding 4-acetamidophenyl ester named chloracetamol is a mutual prodrug of chloroxazone and acetaminophen.Chlorzacetamol and two other mutual prodrugs of active bezoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropiate anilines.Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropiate amines.All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media.The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 deg C shows a change in the Broensted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa - 3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa - 16.03 for alkyl esters.This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k1) to departure of the leaving group ROH (step k2) when the leaving group ability decreases.This mechanism occurs for all the prodrugs related to model A.Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism).This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs.As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma.It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates.In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction.This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.
- Vigroux, Alain,Bergon, Michel,Zedde, Chantal
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p. 3983 - 3994
(2007/10/03)
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- 3-Substituted piperazinomethyl benzoxazolinones. Analgesic and anti-inflammatory compounds inhibiting prostaglandin E2
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Fourty-three new benzoxazolinone derivatives having a piperazinomethyl group at the third position of the ring were synthesized by using appropriate benzoxazolinones and 4-substituted piperazines via a Mannich reaction. The structures of the compounds were elucidated by spectral data and microanalyses. Analgesic activities were evaluated by a modified Koster test. All compounds, except 7, 14, 21, 32 and 41, showed analgesic activity higher than that of acetylsalicylic acid. The compounds were also screened for their anti-inflammatory activity using a carrageenan paw edema test, and those exhibiting high anti-inflammatory activity were investigated for their ability to inhibit prostaglandin E2 induced paw edema. The results of anti-inflammatory testing indicated that most of the compounds were more active than indomethacin. Ulcerogenic activities of the compounds were also studied and no gastrointestinal bleeding was observed at the 100 mg/kg dose level.
- Palaska,Unlu,Ozkanli,Pilli,Erdogan,Safak,Demirdamar,Gumusel,Duru
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p. 693 - 696
(2007/10/02)
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- Synthesis and antimicrobial activity of thiazolinomethyl-2(3H)-benzoxazolone derivatives (I)
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A number of thiazolinoalkyl-2(3H)-benzoxazolones have been synthesized by using cyano derivatives of 6-acyl-2(3H)-benzoxazolones with cysteamine HCl. Their antibacterial and antifungal activities have been evaluated. The chemical structures have been proved by means of their IR, 1H-NMR and mass spectroscopic data and by elemental analysis. The antimicrobial activity of compounds was investigated by tube dilution and disk techniques using bacteria (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853, Streptococcus faecalis RSKK 10541) and yeast-like fungi (Candida parapsilosis, C albicans, C pseudotropicalis, C stellatoidea). Inhibitory effects were observed for many compounds against C albicans, eg, compounds 3b and 3c MIC = 25 μg/ml, C pseudotropicalis, eg, compound 3b MIC = 12.5 μg/ml, and P aeruginosa and S faecalis, eg, compound 3c, MIC = 25 μg/ml.
- Erol,Aytemir,Yulug
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p. 521 - 524
(2007/10/02)
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- Analgesic and antiinflammatory activity screening of 6-acyl-3-piperidinomethyl-2(3H)-benzoxazolone derivatives
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6-Acyl-2(3H)-benzoxazolone derivatives were reacted with appropriate piperidine derivatives and formaldehyde in methanol to give the corresponding 6-acyl-3-piperidinomethyl-2(3H)-benzoxazolones. The obtained compounds were screened for their analgesic and antiinflammatory activities. Analgesic activity of these compounds was investigated by modified Koster test. Antiinflammatory activity was assayed by using carrageenan induced mouse paw edema test and arachidonic acid edema. The 15 compounds synthesized showed good analgesic activities; compounds 1, 3 and 6 moved to be active inhibitors of edema.
- Erol,Demirdamar
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p. 663 - 666
(2007/10/02)
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- A Convenient and Efficient Method for the Preparation of 6-Acyl-2(3H)-benzoxazolones
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Benzoxazolinone derivatives have been found to exhibit various pharmacological properties and 6-acyl-2(3H)-benzoxazolones are considered as key starting materials for the preparation of these compounds.Reported here are the optimal conditions for a regioselective acylation at the 6-position of the benzoxazolinone ring.A general method leading to the expected products in excellent yields consists in using a mixture of aluminum chloride-dimethylformamide as catalyst and acid anhydrides or chlorides as acylating agents.
- Aichaoui, Hocine,Lesieur, Daniel,Henichart, Jean-Pierre
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p. 171 - 175
(2007/10/02)
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- Regioselectivity in the c-acylation of 2(3H)-benzoxazolones
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Unequivocal synthetic routes towards 5- and 6-acyl-2(3H)-benzoxazolones are described. Comparison of the physicochemical properties of the compounds obtained by direct acylation under various Friedel-Crafts reaction conditions always leads to the conclusion that 6-acyl derivatives are the only isolated products. This observation contradicts previously published results.
- Aichaoui, Hocine,Poupaert, Jacques H.,Lesieur, Daniel,Henichart, Jean-Pierre
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p. 6649 - 6654
(2007/10/02)
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- ACYLATION OF 2,3-DIHYDROBENZOXAZOL-2-ONE IN A TWO STEPS METHOD INVOLVING AN ACYL MIGRATION
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A new method of acylation of 2,3-dihydrobenzoxazol-2-one 1 is proposed in a two-steps procedure involving an acyl migration.
- Cotelle, Nicole,Cotelle, Philippe,Lesieur, Daniel
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p. 3259 - 3266
(2007/10/02)
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- Acyl-7 dihydro-2,3 benzoxazin-1,4 ones-3 et proprietes normolipemiantes
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7-Acyl-2,3-dihydro-1,4-benzoxazin-3-ones and normolipemic properties.Fibrates are still among the most widely used drugs for the treatment of dyslipoproteinemia. 7-Acyl-2,3-dihydro-1,4-benzoxazin-3-ones (Fig.1B) can be considered as conformationally restrained analogues of fibrates, such as fenofibrate.These compounds have been prepared and studied for their normolipemic activity particularly on plasma cholesterol, triglyceride and high density lipoprotein (HDL) cholesterol levels.Hepatotoxicity and mutagenicity have also been evaluated.Some of them show an interesting activity, quite comparable to fenofibrate, and are devoid of hepatotoxicity. hyperlipidemia / hypocholesterolemic drugs / fibrates / 7-acyl-1,4-benzoxazin-3-ones
- Moussavi, Ziaeddine,Lesieur, Daniel,Lespagnol, Charles,Sauzieres, Jacques,Olivier, Philippe
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- Synthesis of some new Mannich bases derived from 6-acyl-3-(3,5-dimethylpiperidinomethyl)-2(3H)-benzoxazolones and their biological activities
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A number of 6-acyl-3-(3,5-dimethylpiperidinomethyl)-2(3H)-benzoxazolones have been synthesized by Mannich reaction and their antibacterial and antifungal activities have been tested. Their chemical structures have been proved by means of their IR, NMR, mass spectroscopic data and by elementary analysis. Investigation of antimicrobial activity of compounds was done by tube dilution and paper disc techniques using bacteria (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853, Staphylococcus faecalis RSKK 10541) and yeast-like fungi (Candida parapsilosis, Candida albicans, Candida pseudotropicalis, Candida stellatoidea). Among the compounds tested 6-(2-chlorobenzoyl)-3-(3,5-dimethylpiperidinomethyl)-2(3H)-benzoxazolone (Compound 2) and 6-(3-chlorobenzoyl)-3-(3,5-dimethylpiperidinomethyl)-2(3H)-benzoxazolone (Compound 3) showed the most favorable activity.
- Erol,Rosen,Erdogan,Yulug
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p. 851 - 853
(2007/10/02)
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